Note: Descriptions are shown in the official language in which they were submitted.
': ~
CA 02218741 1997-10-21
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DEMANI:~ES OU ~3R~V~TS VOLUMINEIJX
I A PRES~NTE PARTIE DE CEl~E DEMANDE OU CE BREVEr
COMPREND PLUS D'UN TOME. -
CECI FST LE TOnnE ¦ DE 5
NOTE: Pour les tomes add;tionels, veuillez c~ntacler le Bureau canadien desbrevets
~2,/,~7S//
JIJ~VIBO APPLICAT~ONS/PATENTS - -
THIS SECTION OF THE APP~ICATION/PATENT ~ONTAINS MORE
THAN ONE VOLUME
THIS 5S VOLUME ~ / OF
.
NO~E: For addit~-onal vnlumes-please c~nt~ict~the Canadlan Patent (:)ff~c~ -
. . .
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CA 02218741 1997-10-21
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Nucleotide Sequence of the Haemophilus influenzae Rd
Genome, Fragments Thereof, and Uses Thereof
~, .
Part of the work pelrc,l...ed during development of this invention
utilized U.S. Gov~rnm~nt funds. The gov~,rnm~nt may have certain rights in
this invention. NIH-5ROlGM4825 1
Field of the Invention
The present invention relates to the field of mol~o~ r biology. The
present invention discloses co---posilions comprising the nucleotide sequence
of Haemophilus influenzae, fr~gmP.ntc thereof and usage in in~1nctri~1
fermPnt~tion and ph~rm~ceutir~l development.
Background of the Invention
The co~pl-~tn genome sequence from a free living cellular organism has
never been det~,rmin~i. The first mycobacterium sequence should be
completed by 1996, while E. coli and S. cerevisae are expected to be
completed before 1998. These are being done by random and/or directed
sequencing of o~/t;lld~ g cosmid clones. No one has ~lLt;.~.pled to determine
ences of the order of a ...~-,~h~, or more by a random shotgun approach.
H. influenzae is a small (a~pluAilllalely 0.4 x 1 micron) non-motile,
non-spore forming, germ-negative b~ct.q,ri~-m whose only natural host is
human. It is a resident of the upper le~ildtOly mucosa of children and adults
and causes otitis media and lr~jl.i-"l.. ,~ tract infectinn~ mostly in children. The
most serious comrli~tinn is ...~ ;c, which produces neurological sequelae
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in up to 50% of affected children. Six H. infl~uenzae s~o~y~es (a through f)
have been id~ntifi~l based on immllnnl~ir~lly distinct c~rsul~r poly~rch~ri(l~
antigens. A number of non-typeable strains are also known. Serotype b
accounts for the majority of human ~ P~P
Interest in the mrf1ir~lly~l~ L~lL aspects of H. influenzae biology has
focused particularly on those genes which dettormine virulence rh~r~cteri~tics
of the org~ni~m. A number of the genes responsible for the capsular
poly.~r~h~ri~ have been m~d and sequenced (Kroll et al., Mol. Microbiol.
5(6):1549-1560 (1991)). Several outer membrane protein (OMP) genes have
been identifi~l and sequenced (Langford et al., J. Gen. Microbiol. 138: 155-
159 (1992)). The lipoligo~rrh~r~ (LOS) component of the outer membrane
and the genes of its synthetic ~ W~y are under intensive study (Weiser et al.,
J. Bacteriol. 172:3304-3309 (1990)). While a vaccine has been available since
1984, the study of outer membrane components is motivated to some extent
by the need for improved v~r-cin~-s. Recently, the ç~t~ e gene was
~h~rz~r.trri7~1 and ses~uenced as a possible virulence-related gene (Bishni et al.,
in press) . Flllr~ tic)n of the H. influenzae genome will enh~n~ e the
un~lçrst~nflin~ of how H. inffuenzae causes invasive disease and how best to
combat infection.
H. irffluen2ae po~_ ~s a highly çfficient natural DNA tran~ro~ aLion
system which has been intensively studied in the non-encapsulated (R),
~u~y~e d strain (Kahn and Smith, J. Membrane Biology 81:89-103 (1984)).
At least 16 ~ r .. ~ion-spe~ific genes have been idPntifi~l and sequenced.
Of these, four are regulatory (RPAfiel~, J. Bacteriol. 173:5612-5618 (1991),
and C~h~n~ r, Proc. Natl. Acad. Sci. USA 89:1626-1630 (1992)), at least two
are involved in recombination piocesses (Barouki and Smith, J. Bacteriol.
163(2):629-634 (1985)), and at least seven are targeted to the membranes and
~ h,~ir space (Tomb etal., Gene 1~4:1-10 (1991), and Tomb, Proc. Natl.
Acad. Sci. USA 89:10252-10256 (1992)), where they appear to function as
structuIal colllpo~ ls or in the ~Pmhly of the DNA transport m~rhin~-.ry, H.
ir~luen~ae Rd ~ rO~ ;ol. shows a number of in~;ie~ g r~atu,~s inclll~in~
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sequence-specific DNA uptake, rapid uptake of several double-str~nded DNA
molecules per co,..~;lenl cell into a membrane col"~ ent called the
I,d"sr,.~ om~-7 linear translocation of a single strand of the donor DNA into
the cytoplasm, and synapsis and recombination of the strand with the
chromosome by a single-strand displ~emPnt m~-~h~ni~m The H. influenzae
Rd ~ r~ l ion system is the most thoroughly studied of the gram-negative
systems and distinct in a number of ways from the gram-positive systems.
The size of H. influenzae Rd genome has been determined by
pulsed-field agarose gel electrophoresis of restriction digests to be
a~ru~i",~l~ly 1.9 Mb, making its genome a~l)r~,~i"lately 40% the size of E.
coli (Lee and Smith, J. Bacteriol. 170:4402-4405 (1988)). The restriction
map of H. influenzae is circular (Lee et al., J. Bacteriol. 171:3016-3024
(1989), and Redfield and Lee, "Haemophilus influenzae Rd", pp. 2110-2112,
In O'Brien, S.J. (ed), Genetic Maps: Locus Maps of Complex Genomes,
Cold Spring Harbor Press, New York). Various genes have been mapped to
restriction fr~gm~nt~ by Southern hybri-li7~tion probing of restriction digest
DNA bands. This map will be valuable in verific~tion of the assembly of a
complete genome sequence from randomly sequenced fr~mPnt~ GenR~nk
~;ullerllly cont~in~ about 100 kb of non-rçdl-n~l~nt H. influenzae DNA
sequences. About half are from seir~ly~e b and half from Rd.
Summa y of the Invention
The present invention is based on the sequen~ ing of the Haemophilus
influen~ae Rd genome. The primary n~ oti~le sequence which was gen~r~t~l
is provided in SEQ ID NO: 1.
The present invention provides the ~~~r~l~ nucleotide sequence of the
Haemophilus influenzae Rd genome, or a lc~les~--t~tive fragment thereof, in
a form which can be readily used, analyzed, and inlel~l~led by a skilled
artisan. In one embodiment, present invention is provided as a contiguous
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string of primary sequence information collG~onding to the nucleotide
sequence depicted in SEQ ID NO: 1.
The present invention further provides nucleotide sequences which are
at least 99.9% idPn*c~l to the nucleotide sequence of SEQ ID NO:l.
The nucleotide sequence of SEQ ID NO: 1, a lc~lect~-t~tive fr~gmPnt
thereof, or a nucleotide sequence which is at.least 99.9% identic~l to the
nucleotide sequence of SEQ ID NO:l may be provided in a variety of
mediums to f~ilit~tP its use. In one applic~tinn of this emb(!AimPnt the
Se~lucllCeS of the present invention are recorded on colllyulcl readable media.
Such media in~ d~Ps, but is not limited to: m~gnetic storage media, such as
floppy discs, hard disc storage mP51inm, and m~gnPtic tape; optical storage
media such as CD-ROM; el~P~tn~l storage media such as RAM and ROM;
and hybrids of these categ(jlies such as m~gnptic/optical storage media.
The present invention further provides systems, particularly colllpuLcl-
based systems which contain the sequence information herein described stored
in a data storage means. Such systems are d~P~ignP~1 to identify commercially
illl~l kulL f~mPnt~ of the Haemophilus influenzae Rd genome.
Another embodiment of the present invention is directed to i~ol~tP~
frz~gmPnt~ of the Haemophilus in~uenzae Rd genome. The fr~gmPnt~ of the
Haemophilus influenzae Rd genome of the present invention include, but are
not limited to, fr~gmPnt~ which encode peptides, hereinafter open reading
frames (ORFs), fra~mPnt~ which modulate the c~lc~ion of an operably
linked ORF, h~lcinarL~r c~lc~ ion modlll~*ng fr~gmPnt~ (EMFs), fr~pmPnt~
which mediate the uptake of a linked DNA fr~gmPnt into a cell, hclcinarLcl
uptake mod~ *n~ fr~gmPnt~ (UMFs), and fr~gmPnt~ which can be used to
gn~)sP the ~lcs~ce of Haemophilus influenzae Rd in a c~mplP, hereinafter,
gnostic fr~gmPnt.~ (DFs).
Each of the ORF fr~gmPnt~ of the Haemophilus influenzae Rd genome
o~l in Tables l (a) and 2, and the EMF found 5 ' to the ORF, can be used
in numerous ways as polynucleotide reagents. The sequences can be used as
noStiC probes or ~ ,nostic amplific~tion primers for the presence of a
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sperific microbe in a ~mple, for the production of commercially i...po~ t
pharm~re~ltir~l agents, and to selectively control gene c;~Lples~iom
The present invention further inch~ Ps recombinant constructs
cnmri~ing one or more fr~gmPnt~ of the Haemophilus influenzae Rd genome
" S of the present invention. The recombinant constructs of the present invention
c~...l.. ;~ vectors, such as a pl~mi~l or viral vector, into which a fr~gmPnt ofthe Haemophilus influenzae Rd has been inserted.
The present invention further provides host cells cont;~ g any one of
the isolated r.~ of the Haemophilus influen2~e Rd gPnomP of the present
invention. The host cells can be a higher eukaryotic host such as a ~ n
cell, a lower eukaryotic cell such as a yeast cell, or can be a L.r~yc Lic cell
such as a b~rtp-ri~l cell.
The present invention is further directed to i~ol~tP~ proteins encoded
by the ORFs of the present invention. A variety of methodologies known in
the art can be utilized to obtain any one of the proteins of the present
invention. At the cimr~est level, the amino acid sequence can be synthPci7~1
using c~.. ~ ;ally available peptide synthP-~i7P,rs. In an ~lLf~ e method,
the protein is purified from b~rtP~ l cells which n~tllr~lly produce the protein.
Lastly, the ploL~uls of the present invention can ~ ely be purified from
cells which have been altered to express the desired protein.
The invention further provides mPtho~ of obl~ilLu~g homologs of the
r,~g...~ of the Haemophilus influenzae Rd genome of the present invention
and homologs of the proteins encoded by the ORFs of the present invention.
Sptorifir~lly, by using the nllrl~ti~lP and amino acid sellu~ es ~ r-losp~l herein
as a probe or as primers, and techniques such as PCR cloning and
colony/plaque hybritii7~ti~ n, one skilled in the art can obtain homologs.
The invention further provides antibodies which selectively bind one
of the proteins of the present invention. Such antibodies include both
monoclonal and polyclonal antibodies.
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The invention further provides hybridomas which produce the above-
described antibodies. A hybridoma is an immortalized cell line which is
capable of s~.c~ g a specific monoclonal antibody.
The present invention further provides methods of identifying test
samples derived from cells which express one of the ORF of the present
invention, or homolog thereof. Such mPth~ comprise inc~lb~ting a test
sample with one or more of the antibodies of the present invention, or one or
more of the DFs of the present invention, under con~lition~ which allow a
skilled artisan to delt;l-l--l-e if the sample conf~in~ the ORF or product
produced the.Gr ~
In another embo limPnt of the present invention, kits are provided
which contain the n~ ~ y reagents to carry out the above-described assays.
Specifically, the invention provides a cOIllp~l .~..ont~li7F~1 kit to receive,
in close confinPment, one or more cont~iners which comrri~çs: (a) a first
con~illcr compri~ing one of the antibodies, or one of the DFs of the present
invention; and ~o) one or more other c~ ".l~in~ com~i~ing one or more of the
following: wash r~gFnt~, reagents capable of ~letFecting presence of bound
antibodies or hybridiAd DFs.
Using the i~ol~tçd p-~,~eins of the present invention, the present
invention fur~er provides .. ~ll.o~l~ of ~ining and identifying agents capable
of binding to a protein encoded by one of the ORFs of the present invention.
Specifically, such agents include antibodies (described above), peptides,
I~llydldk~s, ph~rm~rP~tir~l agents and the like. Such methods comprise the
steps of:
(a) cnn~rtin~ an agent with an isnl~tF~ protein encoded by one of
the ORFs of the present invention; and
(b) del~.lllining wh~ . the agent binds to said protein.
The complete ~em~mir s~u~l~ce of H. influen~ae will be of great value
to all lab~ ., ;F-~ ~vc, hu-g with this organism and for a variety of commerciall,u.~o~s. Many r,~g.. ~ of the Haemophilus influ~nzae Rd genome will be
immP1i~trly identified by ~imil~rity searches against GPnR~nk or protein
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~t~h~PS and will be of immPAi~tP value to Haemophilus lesealcllers and for
immPAi~tP cx~ ;dl value for the production of proteins or to control gene
c~ion. A specific PY~mrl~ a n~Prn~ PHA synthase. It has been reported
that polyhy~uAyl.u~yldL~ is present in the membranes of H. influenzae Rd and
S that the amount correlates with the level of cc~ ence for tran~rolllldLion.
The PHA synthase that synthP~i7Ps this polymer has been i(lPntifieA. and
sequenced in a number of bact~P-ri~, none of which are evolutionarily close to
H. influenzae. This gene has yet to be i~ol~tPA. from H. influenzae by use of
hybrirli7~tic)n probes or PCR techniques. However, the genomic sequence of
the present invention allows the identifi~tiQn of the gene by ~tili7ing search
means described below.
Developing the mPtho~lology and technology for el~ ting the entire
genomic sequence of b~ctP-ri~l and other small genomes has and will greatly
enh~n~e the ability to analyze and understand chromosomal org~ni7~tinn In
particular, sequenced g~nn.. --s will provide the models for developing tools for
the analysis of chromnsome structure and function, inl~h--ling the ability to
identify genes within large s~ of genomic DNA, the structure, position,
and spacing of regulatory PkPmPnts, the identifi~tion of genes with potential
indllstri~l appli~tinn~ and the ability to do co~ te genomic and
molP~c~ r phylogeny.
Des~ ion of the Figures
Figure 1 - restriction map of the Haemophilus in~uenzae Rd genome.
Figure 2 - Block ~ gr~m of a colll~ul~r system 102 that can be used
to implement the colll~u~l-based systems of present invention.
Figure 3 - A col.. r~ on of eYrerimPnt~l coverage of up to
ay~rux~ ely 4000 random sequence fr~gmPnt~ assembled with
AutoAssembler (squares) as colll~c;d to Lander-Waterlllall prediction for a
2.5 Mb genome (tri~nglP-s) and a 1.6 Mb genome (circles) with a 460 bp
average sequence length and a 25 bp overlap.
--7--
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Figure 4 - Data flow and col,lpulel programs used to manage,
q~Pmhle, edit, and annotate the H. influenzae genome. Both MqrintrJsh and
Unix ~laLrulll.s are used to handle the AB 373 sequence data files (Kerlavage
et al., Proceedings of the Twenty-Sixth Annual Hawaii International
Conference on System Sciences, IEEE Colll~ulel Society Press, W~q.~hington
D.C., 585 (1993)). Factura (AB) is a Mqrintosh plO~ UI~ ~P.~ipn~l for
au~alic vector sequence removal and end l ~ g of sequence files. The
program esp runs on a M~qrintc)sh platform and parses the feature data
rYtr.qr~d from the sequence files by Factura to the Unix based H. influenzae
rrlqtinnql d-qt~qhq-ee Assembly is acco",~lished by retrieving a specific set of~qluPnr~ files and their q~ f~alules using stp, an X-windows ~r.qphirql
interface and control program which can retrieve sequences from the H.
irffluenzae ~IAI;-h~, using user-defined or standard SQL queries. The sequence
files were q~PmhlP~l using TIGR ~~~' ler, an assembly engine de~igne~i at
TIGR for rapid and qccnr~te q~sPmhly of thousands of sequence frqgmPnt~.
TIGR Editor is a grqphicql int~rfqr~ which can parse the aligned sequence
files from TIGR ~ m'~' output and display the qlignmPnt and Lqc~oci-qtrA
ele~llu~h~ l~,,s for contig editing. T~iPntifir~tir,n of putative coding regionswas ~- r~..... ~ with C ~ 3orodovsky and MrTninrh, Computers Chem.
17~J:123 (1993)), a Markov and Bayes modPl~d pr~ for pre lirting gene
lor~tin,n~, and trained on a H. influer~ae sequence data set. Peptide searches
were ~f . r~.. rd against the three reading frames of each G~n-m ~rk predicted
coding region using blaze (Brutlag et al., Computers Chem. 17:203 (1993))
run on a Maspar MP-2 massively parallel cc,n.~uLei with 4096
mi~ Results from each frame were combined into a single output
file by mblzt. Optimal protein ~ ?nm~-.nt~ were obtained using the program
praze which extends ~lipnm~.nt~ across potential fr~mPchift~ The output was
in~pPct~ using a custom graphic viewing program, gbyob, that inter~rts
directly with theH. ir~quenzae ~l~t~h~5P The ~ nn~ent.~ were further used to
identify ~e~ fr~mP~hift errors and were targeted for ~ ition~l editing.
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Figure S - A circular rc~leselltation of the H. inf~uenzae Rd
~;lllu.~losolllP illn~tr~ting the location of each predicted coding region contain-
ing a ~ ~ match as well as s~l~t~ global r~;alu.~s of the genome. Outer
pc.~el~.. The location of the unique NotI restriction site (~le~ign~t~ as
S nucleotide 1), the Rsr~ sites, and the SmaI sites. Outer concentric circle: The
location of each identifi~ coding region for which a gene identific~tion was
made. P~rh coding region location is coded as to role according to the color
code in Fig. 6. Second concentric circle: Regions of high G/C content ( >
42%, red; > 40%, blue) and high A/T content (> 66%, black; > 64%,
green). High G/C content regions are spe~ifit~lly ~o~i~tt~ with the 6
ribosomal operons and the mu-like prophage. Third co~ ;c circle:
Coverage by lambda clones (blue). Over 300 lambda clones were sequenced
from each end to c~. . ri .. . . the overall sh ucture of the genome and identify the
6 ribosomal operons. Fourth coLc~ ;c circle: The locations of the 6
ribosomal operons (green), the tRNAs (black) and the cryptic mu-like
prophage (blue). Flfth concentric circle: Simple tandem repeats. The
lc~tic-n~ of the following repeats are shown: CTGGCT, GTCT, ATT,
AATGGC, TTGA, TTGG, TTTA, TTATC, TGAC, TCGTC, AACC, TTGC,
CAAT, CCAA. The putative origin of re~lit~hr n is illustrated by the outward
pointing arrows (green) ori~in~hng near base 603,000. Two potel,Lial
It-- ...i,. .~;rm St;Llu~;llc~s are shown near the c~osi~ midpoint of the circle (red).
Figures 6(A)-6(D)- Complete map of the H. in~?uenzae Rd genome.
Predicted coding regions are shown on each sh~nd. rRNA and tRNA genes
are shown as lines and fri~nglt-s, ~espe~ ely. Genes are color-coded by role
ca~guly as described in the legend. GeneID nulllbel~ colle~ d to those in
Tables l(a), l(b) and 2. Where possible, three-letter ~ecign~tionC are also
provided.
Figure 7 - A colllp~ison of the region of the H. inf~uenzae chromo-
some cot.l~;nillg the 8 genes of the fimbrial gene cluster present in H.
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influenzae type b and the same region in H. influenzae Rd. The region is
flanked by the pepNand purE genes in both org~ni~m~. However in the non-
inf~cti-nls Rd strain the 8 genes of the fimhri~l gene cluster have been excised.
A 172 bp spacer region is located in this region in the Rd strain and continllPs to be flanked by the pepN and purE genes.
Figure 8 - H~ hobicity analysis of five predicted ch~nnPl-proteins.
The amino acid sequences of five predicted coding regions that do not display
homology with known peptide se4uences (GenR~nk release 87), each exhibit
multiple hydrophobic domains that are ch~r~rteri~tic of channel-forming
~ ;uls. The predicted coding region sequences were analyzed by the Kyte-
Doolittle algorithm (Kyte and Doolittle, J. Mol. Biol. 157:105 (1982)) (with
a range of 11 residues) using the GeneWor_s sorLw~c package
(~ntf~lligPnptirs) .
Def~7i1e~l D~sc,~lion of the Preferred Embodiments
The present invention is based on the seqmPn~ing of the Haemophilus
iry'luenzae Rd ~PnomP The ~linldL~ "~ sequence which was gen~Pr~tP~
is provided in SEQ ID NO: 1. As used herein, the "~linlaly sequence" refers
to the nucleoti-lP- sequence ~c~r~sell~ed by the IUPAC nomencl~h-re system.
The ~uen~ provided in SEQ ID NO: 1 is ~ rd relative to a unique
Not I restriction en-lom--le~e site found in the Haemophilus influenzae Rd
f~n~lm~., A skilled artisan will readily r~og.~ that this startlstop point was
chosen for conveniPm~e and does not reflect a structural si~nific~nre
The present invention provides the nucleotide sequence of SEQ ID
NO:l, or a lc~l4se .~;.li~e fragment thereof, in a form which can be readily
used, analyzed, and intt;l~rcl~d by a skilled artisan. In one embc~limPnt the
sequence is provided as a contiguous string of primary sequence in~llllation
colrcs~nding to the nucleotide sequence provided in SEQ ID NO: 1.
-10-
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As used herein, a "lc~ s~ ;ve fragment of the nucleotide sequence
~le~ict~P~d in SEQ ID NO:l" refers to any portion of SEQ ID NO:l which is not
~leselllly r~,esellt;ed within a publicly available ~l~t~h~e P-ert; -ed
r~.eselll~ e fr~gmPnt~ of the present invention are Haemophilus influenzae
open reading frames, e~ ;,;,ion mod~ ting fr~mPnt~, uptake mo~ ting
fragments, and fr~gmPnt~ which can be used to ~ nose. the presence of
Haemophilus influenzae Rd in sample. A non-limitinf~ id.ontific~tion of such
pr~r~ d .~res~ e fr~mPnts is provided in Tables l(a) and and 2.
The nucleotide sequence information provided in SEQ ID NO: 1 was
obtained by seqllencing the Haemophilus influenzae Rd genome using a
meg~h~e shotgun sequP-ncing method. Using three parameters of accuracy
CU~d in the FY~mrl-, below, the present inventors have calculated that the
sequence in SEQ ID NO:l has a ~ xi~ ." ~rcur~y of 99.98%. Thus, the
nucleotide sequence provided in SEQ ID NO:lis a highly accurate, although
not neces~rily a 100% perfect"~L~.es.~ lion of the nucleotide sequence of
the Haemophilus influenzae Rd genome.
As r~i~cll~ in detail below, using the inÇo.lll;lLion provided in SEQ
ID NO:l and in Tables l(a) and 2 together with routine cloning and
se~lut;,l- ~.Ig methods, one of ordina. y skill in the art will be able to clone and
sequence all "re~.~s~ e fr~gmPnt~" of interest inclu-1ing open reading
frames (ORFs) encoding a large variety of Haemophilus influenzae proteins.
In very rare in.ct~nces, this may reveal a nucleotide sequence error present in
the nucleotide sequence ~ rlr,sed in SEQ ID NO: 1. Thus, once the present
invention is made available (i.e., once the information in SEQ ID NO: 1 and
Tables l(a) and 2 have been made available), resolving a rare seql~en~ing error
in SEQ ID NO: 1 will be well within the skill of the art. Nucleotide sequence
editing surlw~ is publicly available. For e~ la, Applied Biosystem's (AB)
Auto~PmhlPrTM can be used as an aid during visual inspection of nucleotide
~ sequences.
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Even if all of the very rare seqllPneing errors in SEQ ID NO: 1 were
corrected, the rçsl-lting nucleotide sequence would still be at least 99.9%
i~Pntic~l to the nucleotide sequence in SEQ ID NO: 1.
The nucleotide sequences of the genomes from dirr~e,lt strains of
S Haemophilus influenzae differ slightly. However, the nucleotide sequence of
the ~ ollles of all Haemophilus influenzae strains will be at least 99.9%
denti~l to the nll-lf oti~lP sequence provided in SEQ ID NO: 1.
Thus, the present invention further provides nucleotide sequences
which are at least 99.9% i-lPnti-~l to the nucleotide sequence of SEQ ID NO: 1
in a form which can be readily used, analyzed and hl~ ed by the skilled
artisan. Methods for delelll~ g whether a nucleotide sequence is at least
99.9% idPnti~l to the nucleotide sequence of SEQ ID NO:1 are routine and
readily available to the skilled artisan. Por ~ , the well known fasta
algvlh.i~l,m OEearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444
(1988)) can be used to generate the percent identity of nucleotide sequences.
Ca , ~.er Re~ated F bo~ Jff~
The mlrl~?tirlP sequence provided in SEQ ID NO:l, a l~r~;sce~ e
fr~mPnt thereof, or a nuckoti~lp ~u~ nce at least 99.9% identic~l to SEQ ID
NO:l may be "provided" in avariety of r..P11il....~ to f~rilit~t~ use thereof. As
used herein, provided refers to a m~nllf~rt~lre, other than an isolated nucleic
acid mf'-clllP, which c~ a n~ leotidp sequence of the present invention,
i.e., the mlçl~oti~lp sequence provided in SEQ ID NO:l, a l~r~senl~ e
r.~ thereof, or a nu l~lide sequence at least 99.9% idPnti~-~l to SEQ ID
NO: 1. Such a m~nllf~tllre provides the Haemophilus influenzae Rd genome
or a subset thereof (e.g., a Haemophilus Influenzae Rd open reading frame
(ORF)) in a form which allows a skilled artisan to PY~mine the manufacture
using means not dil~;Lly applicable to ~i,...;.)i,-g the Haemophilus influenzae
Rd genome or a subset thereof as it eYists in nature or in purified form.
SUBSTrTUTE S~E~T tRULE 26')
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In one applic~tic)n of this embc~imPnt, a nucleotide sequence of the
present invention can be recorded on col"pu~r readable media. As used
herein, "co~ uLe readable media" refers to any mPAillm which can be read
and ~"CPe~d directly by a colll~llltl. Such media include, but are not limited
to: m~gnPtic storage media, such as floppy discs, hard disc storage mPAillm,
and ",~g"~l;c tape; optical storage media such as CD-ROM; electrical storage
media such as RAM and ROM; and hybrids of these categolies such as
m~gnPti~/optical storage media. A skilled artisan can readily a~l"~iale how
any of the ~ ly known COI,,~uL~, readable mPAiume can be used to create
a m~nllf~ meco,~p~ g co.~ ul~ readable ".t~ ... having recorded thereon
a nucleotide sequence of the present invention.
As uscd herein, "recorded" refers to a process for storing inr~"".aLion
on co~ uL~l readable mPAillm A skilled artisan can readily adopt any of the
presently know methods for ,~co~u~g information on colll~uL~l readable
medium to ~Pner~tP manufactures comprieing the nucleotide sequence
information of the present invention.
A variety of data storage structures are available to a skilled artisan for
creating a cûlll~-lLel readable mPAillm having recorded thereon a nucleotide
sequence of the present invention. The choice of the data storage structure
will gPnPr~lly be based on the means chosen to access the stored information.
In addition, a variety of data p,ucessor LlU~ldlllS and fc"lllaL~ can be used tostore the nu~ o.otitlP, sP~uence il~r~ 1;nn of the present invention on computerreadable mPAi~lm The sequence inform~fion can be represented in a word
pr~cPeein~ text file, Çû~ LUed in collllll~,,ially-available software such as
WordPerfect and MicroSoft Word, or l~,~,s~llPd in the form of an ASCII
file, stored in a d; I; h~. appli~ti~m, such as DB2, Sybase, Oracle, or the like.
A skilled artisan can readily adapt any number of dataprocessor structllring
formats (e.g. text file or 11~t~h~ee) in order to obtain CO~llpuL~ readable
mPAillm having recorded thereon the nucleotide sequence information of the
present invention.
SUBS 11 l UTE S~tE~T tRULE 26)
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By providing the nucleotide sequence of SEQ ID NO: 1, a
repres~-nt~five fragmPnt thereof, or a nucleotide sequence at least 99.9%
nti~l to SEQ ID NO:1 in cu.l-~uLel readable form, a skilled artisan can
l~wLinely access the s~ut;nce ulr~ I;nn for a variety of ~ul~oses. Co...~uleL
s~rLw~e is publicly available which allows a skilled artisan to access sequence
lion provided in a colll~ul~r readable m.~ m. The eY~mrles which
follow de.mon~tr~tP how sorlw;~e which imrl~-nPnt~ the BLAST (Altschul
et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et al., Comp.
Chem. 17:203-207 (1993)) search alg..l;~1....~ on a Sybase system was used to
identify open reading frames (ORFs) within the Haemophilus influenzae Rd
genomt-. which contain homology to ORFs or proteins from other orp~ni~m~
Such ORFs are protein t-n~rling r.,.g...~ within the Haemophilus infl~uenzae
Rd genome and are useful in producing commercially important proteins such
as enzymes used in fermpnt~tic)n r~t tinn~ and in the production of
commercially useful metabolites.
The present invention fur~er provides systems, particularly colll~u~
based systems, which contain the ~.~ e ;nr~ lir)n described herein. Such
systems are de-~ign~d to identify c(~ lcially illl~l~lt fr~gmP.nt.c of the
Haemop*ilus influen~e Rd genome.
As used herein, "a colll~ulel-based system" refers to the hal.lw~
means, sonw~ means, and data storage means used to analyze the nucleotide
~uence ~nr -- ~ l;nn of the present invention. The Inil).illlUIII h~udw~e means
of the co~ ult;l-based systems of the present invention compri~es a central
pl~-~ g unit (CPU), input means, output means, and data storage means.
A skilled artisan can readily a~lc;ci~le that any one of the ~;ullc;l-lly available
colllpuler-based system are suitable for use in the present invention.
As stated above, the cc,lll~uL~r-based systems of the present invention
cnmrri.~- a data storage means having stored therein a nucleotide sequence of
the present invention and the nf~ry ha(.lw~e means and software means
for :iU~J~lLing and implem~n*np a search means. As used herein, "data
storage means" refers to memory which can store nucleotide sequence
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information of the present invention, or a memory access means which can
access manufactures having recorded thereon the nucleotide sequence
information of the present invention.
As used herein, "search means" refers to one or more programs which
~ S are impl~PmPntP11 on the co~ uLe -based system to co",pale a target sequence
or target ~Llu~;~uldl motif with the sequence info.",ation stored within the data
storage means. Search means are used to identify fr~gm~nte or regions of the
Haemophilus influenzae Rd genome which match a particular target sequence
or target motif. A variety of known algo. ilh,..e are disclosed publicly and a
variety of commercially available sorLw~u~; for condl1cting search means are
and can be used in the co",~uL~-based systems of the present invention.
Examples of such software in~ des, but is not limited to, MacPattern
(EMBL), BLASTN and BLASIX (NCBIA). A skilled artisan can readily
recognize that any one of the available algo. ;II....e or implemPnting software
packages for conducting homology searches can be adapted for use in the
present co",pule.-based ~ IIS.
As used herein, a "target sequence" can be any DNA or amino acid
sequence of six or more nucleotides or two or more amino acids. A skilled
artisan can readily l~O~ that the longer a target sequence is, the less likely
a target s~u~ce will be present as a random occurrence in the d~t~h~ ee The
most pr~r~ d sequence length of a target sequence is from about 10 to 100
amino acids or from about 30 to 300 nucleotide reeitl-les However, it is well
recognized that searches for commercially i",~- l~u~ fr~gmente of the
Haemophilus infl~uenzae Rd genome, such as sequence fr~gmente involved in
gene ~A~.~ssion and protein proceeeing, may be of shorter length.
As used herein, '!a targei structurai motif, !! or !!target motif,!! refers to
any r~tion~lly SPl~ctP~i sequence or colllbi"~lion of sequences in which the
sequence(s) are chosen based on a three-~limpnei~nal configuration which is
formed upon the folding of the target motif. There are a variety of target
motifs known in the art. Protein target motifs int~lnde, but are not limited to,enzymic active sites and signal sequences. Nucleic acid target motifs include,
SUBSTTTUTE SH EET tRULE ~6)
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but are not limited to, promoter sequences, hairpin structures and inducible
c~plcs~ion elP-ment~ (protein binding sequences).
A variety of structural Çolll,at~ for the input and output means can be
used to input and output the i,.rt.. ~ n in the col"~uLcl-based systems of the
present invention. A ~lCrcll~d format for an output means ranks fr~gmPnts of
the Haemophilus influenzae Rd genome possç~ing varying degrees of
homology to the target sequence or target motif. Such ~lcsP-n~ on provides
a skilled artisan with a ranl~ng of .~luP-~I PS which contain various amounts ofthe target sequence or target motif and identifiP.s the degree of homology
cont~in~l in the i-lPntifiPA fr~gm~Pnt
A variety of co---p~ g means can be used to COlllp~hc a target
sequence or target motif with the data storage means to identify sequence
fragments of the Haemophilus influenzae Rd genome. In the present
examples, implPmPnting sorlw~c which implPmPnt the BLAST and BLAZE
~lgorithm~ (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) was used to
identify open reading frames within the Haemophilus inffuenzae Rd genome.
A skilled artisan can readily recognize that any one of the publicly available
hn~ l~y search pl~l~LIlls can be used as the search means for the co",~uLcr-
based systems of the present invention.
One ~ 1if-~l;on of this embodiment is provided in Figure 2. Figure 2
provides a block fli~gr~m of a co,,ll.u~c~ system 102 that can be used to
implement the present invention. The co",~uler system 102 incl~ldPs a
processor 106 connected to a bus 104. Also connPctell to the bus 104 are a
main memory 108 (l~cr~ ly ~ ~' ~PntPA as random access memory, RAM)
and a variety of secondary storage devices 110, such as a hard drive 112 and
a removable mP~ m storage device 114. The removable m~ m storage
device 114 may lc~ ,l, for ~ ..l,le, a floppy disk drive, a CD-ROM drive,
a m~gnPtic tape drive, etc. A removable storage mPAi~lm 116 (such as a
floppy disk, a compact disk, a m~gnPtic tape, etc.) CO~ control logic
and/or data recorded therein may be inserted into the removable mf~ lm
storage device 114. The CO~ JU~C1 system 102 in~ des a~pLu~liatc software
SU85 l l I UTE ~{EET tRULE 2~i)
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for reading the control logic and/or the data from the removable mPAillm
storage device 114 once inserted in the removable mt-Ai~lm storage device 114.
A n~ ooti~le ~lu~n~e of the present invention may be stored in a well
known manner in the main Illellluly 108, any of the secondary storage devices
110, and/or a removable storage mPAillm 116. Software for ~ ccing and
pl~c~-~.c;ng the ~enomic s~lPn~e (such as search tools, co...p~ -g tools, etc.)
reside in main memory 108 during PY~utinn
Biochemicn~ Embodimen~s
Another embodiment of the present invention is directed to i.c~ tPA
fr~gmP.ntc of the Ha~mophilus inyquenzae Rd genome. The fr~gmto.ntc of the
Haemophilus inyquenzae Rd genome of the present invention inl~.h-dç, but are
not limited to fr~gmP.nt.c which encode peptides, hereinafter open reading
frames (ORFs), fr~gm~ntc which mod~ t~ the cA~ies~ion of an operably
linked ORF, he.ci,~LrLcr cApl~;,;,ion m-xilll~ting fr~m~.ntc (EMFs), fr~m~.nt.c
is which m~ii~t.o. the uptake of a linked DNA fr~gm~nt into a cell, hclein~rLcr
uptake mod~ ting fr~gm~ntc (IJMFs), and fr~gm.q.ntc which can be used to
gnose the prcsc,lce of Haernophilus influenzae Rd in a .c~mI~Iç, hercillarLc
diagnostic fr~gm~ntc (DFs).
As used herein, an "icol~t~ nucleic acid molecule" or an "icol:~ted
f~3~m~.nt of the Haemophilus influenzae Rd genome" refers to a nucleic acid
ml~leclll~. ~ossçs~i.-g a spe~-ific nucleotide sequence which has been subjectedto purifi~fi~n means to reduce, from the composition, the number of
co..l~ullds which are norm~lly ~ d with the composition. A variety of
purific~tinn means can be used to gen~r~tçd the isolated fr~gmP.ntc of the
~-csent invention. These incl~lde, but are not limited to methods which
se~ - conctitlllontc of a solution based on charge, solubility, or size.
In one embo~lim~-nt~ Haemophilus in~uenaze Rd DNA can be
m ~.h~nic~lly sheared to produce fr~g m ~.nt.c of 15-20 kb in length. These
- f~ g m~.ntc can then be used to generate an Haemophilus influenzae Rd library
SUBSmUTE SHEET tRULE 26)
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by inserting them into labda clones as described in the Examples below.
Primers fl~nking, for eY~mip1~, an ORF provided in Table l(a) can then be
grn~ ~ using m~ ~ti~e sequence information provided in SEQ ID NO: l.
PCR cloning can then be used to isolate the ORF from the lambda DNA
library. PCR cloning is well known in the art. Thus, given the av~ hility
of SEQ ID NO:l, Table l(a) and Table 2, it would be routine to isolate any
ORF or other nucleic acid fr~ment of the present invention.
The i~ol~t~d nucleic acid mol~c~ s of the present invention include,
but are not limited to single st~n-le~l and double st~n~lYl DNA, and single
str~n-1çd RNA.
As used herein, an "open reading frame," ORF, means a series of
triplets coding for amino acids without any lel.l-il-aLion codons and is a
sequence tr~n~1~t~hle into protein. Tables la, lb and 2 identify ORFs in the
Haemophilus infl!uenzae Rd genome. In particular, Table la in-lic~tes the
lo-~tinn of ORFs within the Haemophilus influenzae genome which encode the
recited protein based on homolngy ~ ing with protein sequences from the
organism ~I?e~; in ~arç-.l~ (see the fourth column of Table l(a)).
The first column of Table l(a) provides the "GeneID" of a particular
ORF. This i..r.,....;.I;f~n is useful for two reasons. First, the complete map of
the Haemophilus influen~ae Rd genome provided in Figures 6(A)-6(D) refers
to the ORFs acculd..~g to their GeneID numbers. Second, Table l(b) uses the
GeneID ~~u~nl~l~ to in-lic~tf~ which ORFs were provided previously in a public
.l~t~h~
The second and third cnlllmn~ in Table l(a) in~ te an ORFs position
in the nucleotide sequence provided in SEQ ID NO: l. One of O~i~ skill
will reco~,.~i~e that ORFs may be oriented in o~o~ directions in the
Haemophilus in;fluenae genome. This is rçflect~ in columns 2 and 3.
The fifth column of Table l(a) inr1i~t~s the percent identity of the
protein en-~or1~1 for by an ORF to the collcs~nding protein from the orgaism
al)~uulg in ~.,11.~tir~1~ in the fourth coll-mn
SUB5T~TUTE ~i~tE~ tRuLE
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The sixth column of Table l(a) inriic~tps the percent cimil~rity of the
protein encoded for by an ORF to the co~ .di~g protein from the organism
appearing in parenthPti~le in the fourth column. The concepts of percent
identity and percent eimil~rhy of two polypeptide sequences is well understood
- S in the art. For PY~mpl~P, two polypeptides 10 amino acids in length which
differ at three amino acid poeitit~ne (e.g., at positions 1, 3 and 5) are said to
have a percent identity of 70 % . However, the same two polypeptides would
be deemed to have a percent ~imil~rity of 80% if, for eY~mple at position 5,
the amino acids moieties, although not identir~l, were "similar" (i.e.,
poseeee~d similar biorh~mic~l ch~r~rtPrietir,e).
The seventh column in Table l(a) in-lir~t~.s the lenth of the amino acid
homology match.
Table 2 provides ORFs of the Haemophilus influenzae Rd genome
which encode poly~ Lide ~uenrp~s which did not elicit a "homology match"
with a known protein sequence from another org~niem Further details
concPrning the alg~ e and criteria used for homology searches are
provided in the Examples below.
A skilled artisan can readily identify ORFs in the Haemophilus
in~uenzae Rd genome other than those listed in Tables l(a), l(b) and 2, such
as ORFs which are ovella~ping or encoded by the opposite strand of an
identifiP~ ORF in ~ iti~m to those ascc~lLi~ihlable using the col,-pu~ based
sy~Le".s of the present invention.
As used herein, an "eA~lession mod~ ting fr~gmP-nt " EMF, means a
series of l~llr~ lP molPclllPs which modlll~tPe the eAplc~ssion of an operably
linked ORF or EMF.
As used herein, a sequence is said to "modulate the ~A~ession of an
operably linked sequence" when the eA~ression of the sequence is altered by
the presence of the EMF. EMFs inclll(le, but are not limited to, promoters,
- and pl~ IlluL~l m~ ting sequences (inducible ~lPm~nte) . One class of EMFs
are fragments which induce the eA~ s~ion or an operably linked ORF in
response to a sper-ific regulatory factor or physiological event. A review of
-19-
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known EMFs from Haemophilus are ~e~rrihed by ~romb et al. Gene 104:1-10
(1991), ~h~n-1lPr, M. S., Proc. Natl. Acad. Sci. USA 89:1626-1630 (1992).
EMF se l~ellces can be i~1PntifiP~i within the Haemophilus influenzae Rd
genome by their pruAilniLy to the ORFs provided in Tables l(a), l(b) and 2.
S An inL~l~;enic sP.gmPnt, ûr a fr~gmPnt of the hlt~l~;ellic segmPnt from about
10 to 200 nucleotides in length, taken 5' from any one of the ORFs of
Tables 1{a), 1(b), or 2 will mod~ fP the ~Al,lc~ion of an operably linked 3'
ORF in a fashion similar to that found with the n~tllr~lly linked ORF
sequence. As used herein, an "h~L~l~ ellic segmPnt" refers to the fr~gment~ of
the Haemophilus gPnome which are bcLwc~ell two ORF(s) herein described.
~ltPrn~tively~ EMFs can be irlPntifi~ using known EMFs as a target sequence
or target motif in the colll~uLt;l-based systems of the present invention.
The ~,l~cll~ and activity of an EMF can be conr,lllled using an EMF
trap vector. An EMF trap vector contains a cloning site 5' to a marker
sequence. A marker sequence enc~xles an id~Pntifi~hle phenotype, such as
antibiotic rÇ~i~t~nre or a comr'~-nPnting nutrition auxotrophic factor, which
can be identifie~1 or assayed when the EMF trap vector is placed within an
~ploLliate host under approl~liaLt; cQn~liti~n~. As described above, a EMF
will m~lll~te the ~Ayl~S~ of an operably linked marker sequence. A more
~et~ile~ cll~ n of various marker sequences is provided below.
A sequence which is sn~peot~l as being a EMF is cloned in all three
reading frames in one or more restrir*on sites u~Ll~a~ll from the marker
sequence in the EMF trap vector. The vector is then transforrned into an
applupli~L~ host using known p~c~dnrP-~ and the ~lle,loLyl,e of the transformed
host in PY~minPfl under ~lu~liat~ con-litions. As described above, an EMF
will modulate the ~;AL,le~,ion of an operably linked marker sequence.
As used herein, an "uptake mo~ ting fr~pment " UMF, means a
series of nucl~Qti~ie moleclllPs which mPAi~tP the uptake of a linked DNA
f~gmPnt into a cell. UMFs can be readily i~PntifiPll using known UMFs as
a target sequence or target motif with the colll~Lel-based systems described
above.
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The ~l~se lce and activity of a UMF can be confirmed by ~tt~hing the
s..~ ~ UMF to a marker sequence. The res--lting nucleic acid molecule is
then in~ub~tpcl with an al~p~ liale host under ~ liat~ conditions and the
uptake of the marker sequence is determined. As described above, a UMF
~ 5 wiU i-lc~se the frequency of uptake of a linked marker sequence. A review
of DNA uptake in Haemophilus is provided by Goodgall, S.H., et al., J. Bact.
172:5924-5928 (1990).
As used herein, a "~ gnostic fr~gmPnt " DF, means a series of
nucleotide molecules which selectively hybridize to Haemophilus influenzae
sequences. DFs can be readily idPntifiPIl by idell~iryillg unique sequences
within the Haemophilus in~quenzae Rd genome, or by generating and testing
probes or amplific~ti~ n primers con~i~ting of the DF sequence in an
a~yl~lial~ g~ format which determines ~mplifi~ ~tion or hybrilli7~tion
selectivity.
The sç~l-up-nrp~s faUing within the scope of the present invention are not
limited to the spe~fic sequences herein described, but also include allelic and
species v~ri~ti-~n~ thereof. Allelic and species v~ri~tion~ can be routinely
de~e~l,lined by co...~ g the sequence provided in SEQ ID NO:l, a
reprçsç.~ e fragment thereof, or a nucleotide sequence at least 99.9%
idçnti-~l to SEQ ID NO: 1 with a sequence from another isolate of the same
species. Furthermore, to accommodate codon variability, the invention
in~lll(les nucleic acid m~ l~cl~lps coding for the same amino acid sequences as
do.the .spe~-ifiG ORFs disclosed herein. In other words, in the coding region
of an ORF, substitlltion of one codon for another which encodes the same
amino acid is expressly c~'~ tP~
Any s~ific sequence disclosed herein can be readily screened for errors
by reseq~-çncing a particular fr~gm~-nt such as an ORF, in both directions
(i.e., s~uPn~ both strands). Alternatively, error screening can be ~;lÇol"led
-by sequencing collc~ndil~g poly.. ~ Ps of Haemophilus influenzae origin
isolated by using part or all of the fr~gmP-nt~ in question as a probe or primer.
SUB5~11 UTE SHEET tRULE ~
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Each of the ORFs of the Haemophilus influenzae Rd genome disclosed in
Tables l(a), l(b) and 2, and the EMF found 5' to the ORF, can be used in
numerous ways as polynucleotide r~gent~ The sequences can be used as
gnosti~ probes or rli~gnnst~ mplific~tion primers to detect the presence of
a specific microbe, such as Haemophilus in~uenzae RD, in a sample. This is
especially the case with the f~mP.nt~ or ORFs of Table 2, which will be
highly selective for Haemophilus influenzae.
In ~iition, the fr~gm~-nt~ of the present invention, as broadly described,
can be used to control gene e~ c~sion through triple helix formation or
~nti~-n~e DNA or RNA, both of which methods are based on the binding of
a poly.,ucle~Lide sequence to DNA or RNA. Polynucleotides suitable for use
in these m~.thotl~ are usually 20 to 40 bases in length and are de-~ign~l to be
complem--nt~ry to a region of the gene involved in tr~n~c-rirtion (triple
helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science
241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA
itself (~ ~, - Okano, J. Neurochem. 56:560 (1991); Oligodeo~nl~cleot7~
as Antisense Inhibitors of Gene E~cpression, CRC Press, Boca Raton, FL
(1988))-
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Triple helix- formation optimally results in a shut-off of RNA tr~n~crirtion
from DNA, while ~ ~ RNA hybritli7~ti-)n blocks t~n.~l~tion of an mRNA
molecule into polypeptide. Both techniques have been demonstrated to be
effective in model systems. Information cont~in~l in the sequences of the
present invention is n~s~ry for the design of an ~ntieçnee or triple helix
oligonucleotide .
The present invention further provides recombinant constructs
a~mrrieing one or more fr~gm-onte of the Haemophilus influenzae Rd genome
of the present invention. The recombinant constructs of the present invention
c ~ p~ a vector, such as a pl~emi(l or viral vector, into which a fr~gmPnt of
the Haemophilus iny?uenzae Rd has been inserted, in a Çulvv~d or reverse
o. ;~ l;on In the case of a vector comprieing one of the ORFs of the present
invention, the vector may further c~..,l.. ;~ regulatory sequences, inrlllrling for
~-Y~mplP, a ~,lulllO~, operably linked to the ORF. For vectors comprieing the
EMFs and UMFs of the present invention, the vector may further comprise a
marker sequence or heterologous ORF operably linked to the EMF or UMF.
Large IlUlllbel:i of suitable vectors and promoters are known to those of skill
in the art and are commercially available for gent;,~ g the recombinant
constructs of the present invention. The following vectors are provided by
way of PY~mplP R~- tçri~l: pBs, ph~g~sc.;l.l, PsiX174, pRluescrirt SK, pBs
KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3,
pKK233-3, pDR540, pRlT5 (Pharmacia). Eukaryotic: pWLneo, pSV2cat,
pOG44, pXTl, pSG (str~enp) pSVK3, pBPV, pMSG, pSVL (Pharmacia).
Plulllo~l regions can be ~1~t~ from any desired gene using CAT
(chlo.~.. l.l.r-~ nl l.,~ rr~,.~) vectors or other vectors with sPl~-~t~hle m~rkPrs
Two a~ "dL~ vectors are p~-8 and pCM7. Particular named ~ t-o.ri~l
promoters include lacI, lacZ, T3, T7, gpt, lambda PR~ and trc. Eukaryotic
promoters include CMV imm~Ai~t~ early, HSV thymidine kinase, early and
- late SV40, LTRs from retrovirus, and mouse metallothionein-I. Selection of
the appr~,iate vector and promoter is well within the level of o,.linaly slcill
m the art.
SUBSmUTE ~H~ET tRULE 2'6)
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The present invention further provides host ceUs cn~ h-g any one of
the isolated fr~gmPntc of the Haemophilus inf~uen~ae Rd genome of the present
invention, wherein the fr~mPnt has been introduced into the host cell using
known transformulation methods. The host cell can be a higher eukaryotic
S host cell, such as a m~mm~ n cell, a lower eukaryotic host cell, such as a
yeast cell, or the host cell can be a pn~c~yl)~ic cell, such as a b~c tPri~l cell.
Intro~ rtion of the lcco~-~bin~t construct into the host ceU can be effected by
calcium phnsrh~tP transfection, DEAE, dextran mP~ tP~ transfection, or
el~;L.~"~ol~lion (Davis, L. et al., Basic Methods in Molecular Biology (1986)).
The host cells col.f;~;nil-g one of the fr~f~mPnt~ of the Haemophilus
inyquenzae Rd genome of the present invention, can be used in conventional
...~1-l-~. . to produce the gene product encoded by the i~ol~tP~ fr~gmPnt (in the
case of an ORF) or can be used to produce a heterologous protein under the
control of the EMF.
The present invention further provides i~l~tPd polypeptides enrod~
by the nucleic acid fr~gmPnt~ of the present invention or by ~e~enPr~t~
variants of the nucleic acid r, ~ ; of the present invention. By "degr.~
v~iant" is int~-n~ nucleotide fr~mPnt~ which differ from a nucleic acid
r.,.~ ..l of the present invention (e.g., an ORF) by nucleotide sequence but,
due to the ~1te~ n~ry of the Genetic Code, encode an idPntic~l polypeptide
sequence. Plcrt;lled nucleic acid fr~gmPnt~ of the present invention are the
ORFs depicted in Table 1(a) which encode proteins.
A variety of mPth- dologies known in the art can be utilized to obtain
any one of the i~ol~tp~1 polypeptides or plo~ehls of the present invention. At
the ~implPst level, the amino acid sequence can be sy.. ll.P-~i7~1 using
commercially available peptide synth~i7p-r~ This is particularly useful in
prodllring smaU peptides and fr~gmPnt~ of larger polypepfi-les Fr~gmt-nt~ are
useful, for Py~mple, in gPnPr~ting antibodies against the native polypeptide.
In an ~ltp-rn~tive mPth~xl, the polypeptide or protein is purified from b~rtPri~l
ceUs which naturally pl~lUCe the poly~;~tide or protein. One skilled in the art
can readily follow known m~thn~s for i~ol~ting polpeptides and proteins in
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order to obtain one of the i~ t~l polypeptides or proteins of the present
invention. These in~ d~p~ but are not limited to, immunochlvlna~o~ld~l.y,
HPLC, size-eYclll~ion cl~ alogld~lly, ion-eYch~nge cl,lo...~ gr~phy, and
immuno-affinity ci~ la~ogl~ y.
S The pOly~e~!;rlP-s and ~ teu,s of the present invention can ~ltPrn~tively
be purified from cells which have been altered to express the desired
polypeptide or protein. As used herein, a cell is said to be altered to express
a desired polypeptide or protein when the cell, through genetic manipulation,
is made to pl~luce a polypeptide or protein which it normally does not
produce or which the ceil normally produces at a lower level. One skilled in
the art can readily adapt ~r~lules for introducing and eAples~ing either
reco"lbinallt or synthetic seguences into eukaryotic or prokaryotic cells in
order to ge~ a cell which produces one of the polypeptides or proteins of
the present invention.
Any host/vector system can be used to express one or more of the
ORFs of the present invention. These inr~ e, but are not limited to,
eukaryotic hosts such as HeLa cells, Cv-l cell, COS cells, and Sfg cells, as
well as prokaryotic host such as E. coli and B. subtilis. The most pl~relled
cells are those which do not normally express the particular polypeptide or
protein or which eApl~s the polypeptide or protein at low natural level.
"Recombinant," as used herein, means that a polypeptide or protein is
derived from ,~...hi~ (e.g., microbial or ~-~....-.~li~n) ~Aples~ion systems.
"Microbial" refers to recombinant polypeptides or proteins made in b~teri~l
or fungal (e.g., yeast) eA~,es~ion systems. As a product, "recombinant
microbial" defines a polypeptide or protein e-~i~e~ lly free of native
o~nVu~ subst~n~-s and u~ i~ by associated native glycosylation.
Polypeptides or proteins eA~,es~ in most b~-t~--ri~l cultures, e.g., E. coli,
will be free of glycosylation mn~ifi~tion~; polypeptides or proteins eA~lessed
in yeast will have a glycosylation pattern diLre cnt from that eA~le~sed in
... ~ n cells.
SVBSTlTUTE S~tEET (RULE 2~)
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"Nucleotide sequence" refers to a heteropolymer of
deoxyribom~c~ tides. Generally, DNA se~ .L~ çnc~ling the polypeptides
and proteins provided by this invention are assembled from fragmPnt~ of the
Haenwp~ulus i~?flu~nz~e Rd gPnnmP and short oligonucleotide linkers, or from
S a series of oligon~lcl~.o~tides, to provide a ~7ylltheLic gene which is capable of
being t;~ ;ssed in a recomhin~nt tr~n~criptional unit compnsing regulatory
el~mPnt~ derived from a microbial or viral operon.
"Recomhin~nt ~ ssion vehicle or vector" refers to a pl~mirl or phage
or virus or vector, for ~ g a polypeptide from a DNA (RNA) sequence.
The eAples~ion vehicle can comprise a t~n~ riptional unit compri~ing an
~Pmhly of (1) a genetic e1emPnt or plPmPnt~ having a regulatory role in gene
t;A~,ession, for eY~mrle, promoters or enh~n~prs~ (2) a structural or coding
sequence which is tr~n~rihed into mRNA and tr~n~l~tP~ into protein, and
(3) a~pro~,iat~ t~ S~ Lion initizltion and l~. ---i,-~l;nn sequences. Structuralunits intendPll for use in yeast or eukaryotic t;Aples~,ion systems preferably
include a leader s~u~nce en~h1in~ PYtracP~ r secretion of tr~n~l~tP~ protein
by a host cell. Alternatively, where lccolllh~ protein is c~lessed without
a leader or transport sequence, it may include an N~ l mPthioninP
residue. This residue may or may not be subsequently cleaved from the
eA~r~ssed ieco.. l ;--~nt protein to provide a final product.
"Recombinant ~AL"~e.,sion system" means host cells which have stably
;~lr.~,l, lrl~ a l~...l)i.~i.t tr~n~rirtional unit into chromosomal DNA or carrythe recolllbillant transcriptional unit extra chromosomally. The cells can be
prokaryotic or eukaryotic. Reco,llbinant t;A~les.,ion systems as defined herein
will express heterologous polypeptides or proteins upon induction of the
regulatory el~mPnt~ linked to the DNA s~PgmPnt or synthetic gene to be
~,Aplessed.
Mature p,~ s can be ~Ap~ sed in m~mm~ n cells, yeast, b~teri~
or other cells under the control of a~prup,iaLe promoters. Cell-free tr~n~1~tionsystems can also be employed to produce such proteins using RNAs derived
from the DNA constructs of the present invention. A~r~,~,iate cloning and
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cAylèS~iOn vectors for use with prokaryatic and eukaryotic hosts are described
by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second
Edition, Cold Spring Harbor, New York (1989), the rlic~losllre of which is
hereby incolyuld~d by reference.
- 5 Gener~lly, recombinant cAyre~ion vectors will include origins of
replir~tion and select~hle Illa,kcl~ ye~ illing tran~Çullllalion of the host cell,
e.g., the ~mpicillin reci~t~nce gene of E. coli and S. cerevisiae TRP1 gene,
and a promoter derived from a highly-cAylessed gene to direct tr~n~crirtion of
a downstream structural sequence. Such promoters can be derived from
operons çnco~ing glycolytic enzymes such as 3-phosphoglycerate kinase
(PGK), a-factor, acid phn~yh~ or heat shock proteins, among others. The
heterologous structural sequence is assembled in apylvyliate phase with
tr~n~l~tinn initi~tion and tcl~l~inalion sequences, and preferably, a leader
sequence capable of directing secretion of tr~n~l~t~ protein into the
peripl~mic space or eytr~ r m~Ainm. Optionally, the heterologous
sequence can encode a fusion protein inr~ ing an N-t~llllihlal ic~entific~tiQn
peptide illly~hLillg desired çh~r~-~t~ri~ties, e.g., stabilization or simplifiedpllrifie~tiQn of eAylc:,sed lcco",binalll product.
Useful c~yle~ion vectors for b~ tPri~l use are constructed by inserting a
structural DNA sequence en~ ing a desired protein together with suitable
tr~n~l~tinn initi~tinn and l~ ;nn signals in operable reading phase with a
functional ylulllolel. The vector will comprise one or more phenotypic
selectable Ill~l~ and an origin of rep~ tinn to ensure m~int~n~nce of the
vector and to, if desirable, provide ~mplific~tion within the host. Suitable
prokaryotic hosts for transfnrm~tion include E. coli, R(7cilll/~ su~ilis,
Salmonella typ~umurium and various species within the genera Pseudomonas,
SLI~y~llly~s, and Staphylococc~-~, although others may, also be employed as
a matter of choice.
As a leylc~lll~ re but n--nlimiting ~Y~mple, useful ~ ylc;~ion vectors for
b~ t~ri~l use can comprise a s~loct~hle marker and b~ct~ri~l origin of
re.pli~tinn derived from commercially available pl~mirl~ compri~in~ genetic
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çlemPnt~ of the well known cloning vector pBR322 (ATCC 37017). Such
commercial vectors in~ de., for PY~mrle, pKK~ 3 OEh~rm~ Fine
Chemicals, Uppsala, Sweden) and GEM 1 (P-ulllega Biotec, M~ on, WI,
USA). These pBR322 "bac~l~ne" sçctic n~ are combined with an a~pro~-iaLG
promoter and the structural sequence to be ~ A~.essed.
Following L~ srul-nation of a suitable host strain and growth of the host
strain to an appi~p idl~ cell density, the sçl~ctPd promoter is derepressed by
a~ LG means (e.g., ~ G shift or f hPmic~l inductiQn) and cells are
cultured for an ~ iticm~1 period. Cells are typically harvested by
centrifugation, disrupted by physical or ~ hPmiç~l means, and the rPsu1ting
crude extract retained for further pnrific~tion
Various m~mm~ n cell culture systems can also be employed to
eA~ress recombinant protein. Fy~mrlps of n ,~",...~ n c AplG:i~ion systems
include the COS-7 lines of monkey kidney fibroblasts, described by Gl~-7m~n,
Cell 23:175 (1981), and other cell lines capable of GA~les~il-g a cc,lllpalible
vector, for PY~mI)le, the C127, 3T3, CHO, HeLa and BHK cell lines.
M~mm~ n GA~lG:~:iion vectors will comprise an origin of reI~lic~ti-n, a
suitable promoter and ~--h~n~. .., and also any ~ y ~il~osollle binding sites,
polyadenylation site, splice donor and acceptor sites, tr~n~crirtional
te.. i~ n sequences, and 5' fl~nking nontr~n~çrihed sequences. DNA
sequences derived from the SV40 viral genome, for PY~m~le, SV40 origin,
early promoter, enh~n~Pr, splice, and polyadenylation sites may be used to
provide the required nc-nt~n~rrihed genetic elements.
Recombinant polypeptides and ~roL~ins produced in b~ tPri~l culture
is usually i~ol~tP~1 by initial P.tr~çtion from cell pellets, followed by one ormore salting-out, aqueous ion eY,--h~nge or size eYcl~ n chlo...~tugr~rhy
StGps. Protein refolding steps can be used, as n~ç~ry, in completing
configuration of the mature protein. Finally, high l?e r~ lance liquid
chro...~lc)p..~ .y (HPLC) can be employed for final pllrific~tion steps.
Microbial cells employed in GA~lession of proteins can be disrupted by any
SUBSTrrUTE ~}~FET ~RULE 26~
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convenient method, in~ rling freeze-thaw cycling, sonication, mPrh~nic~l
disruption, or use of cell lysing agents.
The present invention further inc1~des i~ol~tPc~ polypeptides, proteins
and nucleic acid molP~u1Ps which are subsf~nti~11y equivalent to those herein
S described. As used herein, subst~nti~11y equivalent can refer both to nucleic
acid and amino acid sequences, for example a mutant sequence, that varies
from a reference sequence by one or more substitlltionc~ dP1Ptionc, or
z~ litionc, the net effect of which does not result in an adverse functional
~liccimi1~rity between reference and subject sequences. For pul~oses of the
plcselll invention, sequences having equivalent biological activity, and
equivalent cA~lc~ion ch~r~tericti~s are con~ pred subct~nti~lly equivalent.
For pul~oses of dc~c~mi~ g equivalence, truncation of the mature sequence
should be disregarded.
The invention further provides mPthods of obt~u~ g homologs from
lS other st~ains of Haemophilus influenz~e, of the fr~gm~ntc of the Haemophilus
influenzae Rd genome of the present invention and homologs of the proteins
~nro~Pd by the ORFs of the present invention. As used herein, a sequence or
protein of Haemophilus influen~e is defined as a homn1Og of a fr~gm~nt of the
Haemophilus influenza~ Rd genome or a protein encoded by one of the ORFs
of the present invention, if it shares cignifi~nt homology to one of the
r.~g...~ of the Haemophilus infl~uenzae Rd genome of the present invention
or a protein encoded by one of the ORFs of the present invention.
~SpPnifi-~11y, by using the sequence disclosed herein as a probe or as primers,
and techniques such as PCR cloning and colony/plaque hybril1i7~tinn, one
skilled in the art can obtain homologs.
As used herein, two nucleic acid mo1ec111Ps or proteins are said to
"share ~i~nifi~nt h- ...o1~y" if the two contain regions which process greater
than 85 % sequence (amino acid or nucleic acid) homology.
- Region specific'primers or probes derived from the nucleotide sequence
provided in SEQ ID NO:l or from a nucleotide sequence at least 99.9%
identi~1 to SEQ ID NO:l can be used to prime DNA synthesis and PCR
~mp1ifi~tion, as well as to identify colonies U)nli inil-g cloned DNA encoding
--29--
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a homolog using known m.otho le (Innis et al., PCR Protocols, Ac~ omic
Press, San Diego, CA (1990)).
When using primers derived from SEQ ID NO: 1 or from a nucleotide
sequence at least 99.9 % identi~ to SEQ ID NO: 1, one skilled in the art will
rt~COg~ that by employing high stringency con-liti~-ne (e.g., ~nnP~linp at 50-
60~C) only sequences which are greater than 75% homologous to the primer
will be ~mrlifi~l By employing lower string~n~y con-iitinne (e.g., ~nnP~lin~
at 35-37~C), sequences which are greater than 40-50% homologous to the
primer will also be ~mplifi~d
When using DNA probes derived from SEQ ID NO:l or from a
nucleotide sequence at least 99.9 % i~l~ntir~l to SEQ ID NO: 1 for
colony/plaque hybri~li7~tion, one skilled in the art will recogni_e that by
employing high stringency con-iiti~ ne (e.g., hybri~i7in~ at 50-6S~C in 5X
SSPC and 50% r~ e, and washing at 50-65~C in 0.5X SSPC),
s~u~nces having regions which are greater than 90% homologous to the probe
can be obl~ined, and that by employing lower stringency contliti~ns (e.g.,
hybri~i7in~ at 35-37~C in 5X SSPC and 40-45% ior...~...i-le, and washing at
42~C in SSPC), sequences having regions which are greater than 35-45%
homologous to the probe will be o~ ed.
Any organism can be used as the source for homologs of the present
invention so long as the organism n~t~ lly t;A~r~sses such a protein or
cc nt~ine genes ~I lI',~i~p the same. The most pr~rc;ll~d organism for i eol~ting
homologs are b~cteri~e which are closely related to Haemophilus influen~ae
Rd.
Usesfor the 1~ ns of fhe Inventwn
Each ORF provided in Table l(a) was ~eeipn~d to one of 102 biological
role ca~egolies adapted from Riley, M., Microbiology Reviews 57(4J:862
(1993)). This allows the skilled artisan to determine a use for each i~lentifi~
coding s~~ - Tables l(a) further provides an icl.ontifi~tion of the type of
polypeptide which is ~nt~4ded for by each ORF. As a result, one skilled in the
art can use the polypeptides of the present invention for commercial,
--30--
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rld~ulic and indll~triAl purposes con~i~tent with the type of putative
ntifi~ti~n of the polypeptide.
Such ~ ntifi~ Ati~ n~ permit one sl~led in the art to use the Haemophilus
influen~ae OJ~s in a manner similar to the known type of sequences for which
- 5 the idetltificAtinn is made; for example, to ferment a particular sugar source
or to produce a particular metabolite. (For a review of enzymes used within
the commercial industry, see Biochemical Engineering and Biotechnology
Handbook 2nd, eds. Macmillan Publ. Ltd., NY (1991) and Biocatalysts in
Organic Syr.ll.P.ses, ed. J. Tramper et al., Elsevier Science Publishers,
Am~le,.la,l" The NethPrlAntl~ (1985)).
1. Bwsynthetzc Enz~ymes
Open reading frames encoding proteins involved in mt~liAting the
catalytic reactions involved in intermediary and macromnle~ulAr metabolism,
the biosynthesis of small molPcllles, cellular plucesses and other functions
in~hl~es enzymes involved in the de~rAtlAtion of the intermp~liAry products of
metabolism, elLGyl"es involved in central intermPAiAry metabolism, enzymes
involved in r~i.dtion, both aerobic and anaerobic, enzymes involved in
ferm~ntAtiQn, enzymes involved in ATP proton motor force conversion,
enzymes involved in broad regulatory function, enzymes involved in amino
acid synthesis, el~yl"es involved in nucleotide synthto~i~, enzymes involved in
cofactor and vitamin synth~ , can be used for in~ triAl biosynthesis. The
vanous metabolic pathways present in Haemophilus can be iclentifi~ based on
Ahsnlllto "~ as well as by r~ g the various enzymes
i~ientifi~d in Table l(a).
I~entifi~ within the ca~goly of intermediary metabolism, a number
of the ~lu~ills en~l~ by the i~l.ontifi~i ORPs in Tables l(a) are particularly
- involved in the degrA-l~tion of intermediary metabolites as well as non-
macromc-leculAr metabolism. Some of the enzymes i~entifi~d include
amylases, glucose oxi~lA~es, and cAtAlA~e
SUBS i i I UTE S~E T tRULE 2~)
CA 02218741 1997-10-21
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Proteolytic e";cy"les are another class of commercially i"lpol~nt
enzymes. Proteolytic enzymes find use in a number of in~ stri~1 processes
inr~ linfr the ~,locess~,lg of flax and other vegetable fibers, in the extraction,
rl~rific~tion and ~le~ l;on of fruit juices, in the eYtr~tion of vegetables'
oil and in the m~.-Pr~ti--n of fruits and vegetables to give unicPlllll~r fruits. A
~et~ile~ review of the proteolytic enzymes used in the food industry is
provided by Rombouts et a~., Symbiosis 21:79 (1986) and Voragen et al. in
Biocatalyst in Agricultural Biotechnology, edited J.R. Whitaker et al.,
American Chemical Society Symposium Series 389:93 (1989)).
The metabolism of gl~lcQse~ g~ tose, fructose and xylose are
t parts of the ~lill~y metabolism of Haemophilus. Fn7ymes involved
in the degradation of these sugars can be used in inrillstri~l ferm~nt~ti~ n.
Some of the illl~?o~ sugar tran~L~ll"ing en_ymes, from a commercial
viewpoint, include sugar isc,~ s such as glucose isomP-r~P Other
IIlG~bolic en_ymes have found CO""~G1- ial use such as glucose oxidases which
produces l~P-tQ~I~lonic acid (KGA). KGA is an intermPAi~tP in the commercial
production of ascorbic acid using the R~i~h~tPin's procedure (see Krueger
etal.,Biotechnology6(A), Rhine, H.J. etal., eds., VerlagPress, WPinh~Pim,
G~.lll~ly (1984)).
Glucose o~ e (GOD) is comlllGl~ially available and has been used
in purified form as well as in an immobilized form for the deoxygenation of
beer. SeeHartmeiretal.,BiotechnologyLettersl:21 (1979). Themost
applic~tion of GOD is the in~ tri~l scale f~ n of gluconic
acid. M~rk~t for pll-c~nic acids which are used in the detergent, textile,
leather, photographic, pharm~ ti~l, food, feed and concrete industry (see
Bigelis in Gene Maruplda~ions and Fungi, Benett, J.W. et al., eds., Ac~-lemic
Press, New York (1985), p. 357). In ~ liti~n to in~ stri~l applications, GOD
has found applic~tinn~ in m.oAi~ ine for ~lu~n~ e det~...i.~i.l;o~ of glucose
in body fluids l~cen~ly in biot~hnok)gy for analyzing syrups from starch and
cellulose hydrosylates. See Owusu et al., Biochem. et Biophysica. Acta.
872:83 (1986).
SUBST~TUTE ~ E:ET tRULE 2~3
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The main sweetener used in the world today is sugar which comes from
sugar beets and sugar cane. In the field of in~ stri~l enzymes, the glucose
isol"cld~e process shows the largest exr~n~ n in the market today. Initially,
soluble enzymes were used and later immobilized enzymes were developed
S (Krueger et al., Biotechnology, The Textbook of Industrial Microbiology,
Sinauer ~ 1~1 Incc, ~ Sun~lPrl~n-l, M~rhll~ett~ (1990)). Today,
the use of glucose-produced high rlu~;~se syrups is by far the largest in-lustri~l
business using immobilized enzymes. A review of the in-1u~tri~1 use of these
enzymes is provided by Jolgensc,l, Starch 40:307 (1988).
Protein~ps~ such as ~ll~linP serine ~ e;~ P~s, are used as de~cl~;
additives and thus lcl~lcsellt one of the largest volumes of microbial el~y",es
used in the industrial sector. Re~ e of their in-i~lstri~l i"l~ol~lce, there is
a large body of published and unpublished information lCgaL-lillg the use of
these enzymes in in~ tri~ S. (See F~ tm~n et al., Acid Proteases
Structure Function and Biology, Tang, J., ed., Plenum Press, New York
(1977) and Godfrey et al., In~strial Enzymes, ~rMi11~n Pllkli~hpr~ Surrey,
UK (1983) and Hepner et al., Report Industrial Enzymes by 1990, Hel Hepner
&.A.cs~-i~les~ T~n-lon (1986)).
Another class of co.. ~-~;ally usable proteins of the present invention
are the microbial lipases i-lPntifip~l in Table 1 (see Macrae et al., Philosophical
Transactions of the Chiral Society of Lon~lon 310:227 (1985) and Poserke,
Jou~l of the American Oil C/iemist Society 61: 1758 (1984). A major use of
lipases is in the fat and oil industry for the production of neutral glycerides
using lipase catalyzed inter-estPrifir~tion of readily available triglycPri~1p~
Appli~til n of lipases include the use as a de~l~ell~ additive to f~rilit~te theremoval of fats from fabrics in the course of the washing procedures.
The use of enzymes, and in particular microbial enzymes, as catalyst
for key steps in the ~yll~hesis of complex organic molecules is gaining
- popula~ity at a great rate. One area of great interest is the ~ n of chiral
;--I~ S. P~ n of chiral intr.rmP~ t~ is of interest to a wide range
of synthetic chemi~t~ particularly ~ose sri~onticte involved with the ~l~d~ion
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of new ph~rmaçelltif~lc, agroGhP-mic~lc, fr~r~nrps and flavors. (See Davies
et al., Recent Advances in the Generation of Chiral lntermediates Using
En~ymes, CRC Press, Boca Raton, Florida (1990)). The following re~ctions
catalyzed by enzymes are of interest to organic çhPmictc hydrolysis of
carboxylic acid esters, phnsph~tP esters, amides and nitrileC, çstprific-~tinn
re~r*onc, trans-ect~p-rific~tion re~rtionc~ ~,ynLlle~is of ~mi~les, reduction ofz~lk~nc~nPs and ox~ D.n~tPs" oxidation of ~l~hc~lc to carbonyl c~,.l~unds,
cxitl~ti-)n of sulfides to slllfoxi~l~ps~ and carbon bond forming rP~ctionC such as
the aldol r~o~rtion When cnn~ Prin~ the use of an enzyme encoded by one
of the ORFs of the present invention for biotran~ru",laLion and organic
synthesis it is somPfimPs nP~P~y to con~ er the respective advantages and
disadvantages of using a microorganism as opposed to an icol~tPA enzyme.
Pros and cons of using a whole cell system on the one hand or an icol~tP~i
partially purified enzyme on the other hand, has been ~esçribe~ in detail by
Bud et al., Chemistry in Britain (1987), p. 127.
Amino tr~ncfer~cps~ enzymes involved in the biosynthesis and
metabolism of amino acids, are useful in the catalytic pr~ucfion of amino
acids. The advantages of using microbial based enzyme systems is that the
amino tr~ncfPr~cP enzymes catalyze the stereo-selective synthesis of only
l-amino acids and generally possess ~ll~ir~llllly high catalytic rates. A
description of the use of amino transferases for amino acid production is
provided by Roselle-David, Methods of Er~ymology 136:479 (1987).
Another ~l~gUly of useful ~)luk;~lS encoded by the ORFs of the present
invention include enzymes involved in nucleic acid synthPci~, repair, and
lcco~l~binaLion. A variety of c~ ;ally illll~Ull~lllt enzymes have previously
been icol~tP~l from members of Haemophilus sp. These include the Hinc II,
Hind III, and Hinf I restriction enrlnnl~r1~ces. Table l(a) iclPntifiPs a wide
array of enzymes, such as restriction enzymes, ligases, gyrases and
metnylases, which have i.. Pfli~e use in the biotPrlmolQgy industry.
2. Generation of ~r~trbo~ies
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As described here, the proteins of the present invention, as well as
hnmnlogc thereof, can be used in a variety procedures and methods known in
the art which are ~;ul~nlly applied to other proteins. The proteins of the
present invention can further be used to gp~ an antibody which selectively
binds the protein. Such antibodies can be either mono~lon~l or polyclonal
antibodies, as well fr~gm~nt.c of these antibodies, and h~ P.1 forms.
The invention further provides antibodies which selectively bind to one
of the proteins of the present invention and hybridomas which produce these
antibodies. A hybridoma is an immortalized cell line which is capable of
se;lt;Ling a c~ific mnnoclonal antibody.
In general, techniques for p~ g polyclonal and monoclonal
antibodies as well as hybridomas capable of ~lu.h~ g the desired antibody are
well known in the art (Campbell, A.M., Monoclonal Antibody Technology:
Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier
Science Publishers, Am~l~lda"" The ~h~rl~ntls (1984); St. Groth et al., J.
Irrununol. Methods 35:1-21 (1980); Kohler and Milct~in, Nature 256:495-497
(1975)), the trioma technique, the human B-cell hybridoma technique (Kozbor
et al., Immunology Tod~y 4:72 (1983); Cole et al., in Monoclonal Antibodies
and Cancer Therapy, Alan R. Liss, Inc. (1985), pp. 77-96).
Any animal (mouse, rabbit, etc.) which is known to produce antibodies
can be immlmi7Pcl with the pseudogene polypeptide. Methods for
i..",..-..;,~l;nn are well known in the art. Such mPthorls include subcutaneous
or in~e.~.;l~ l injection of the polypeptide. One skilled in the art will
recognize that the amount of the protein en~ocled by the ORF of the present
invention used for immllni7~tinn will vary based on the animal which is
i.. -.. ~i,~d, the antigenicity of the peptide and the site of injection.
The protein which is used as an immunogen may be modified or
z~iminictt-red in an adjuvant in order to increase the protein's antigenicity.
- Methods of increasing the ~ntig~nicity of a protein are well known in the art
and include, but are not limited to coupling the antigen with a heterologous
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protein (such as globulin or ,B-g~ tc s~ cP) or through the inclusion of an
adjuvant during i,.,.."..~ inn.
For monoclonal antibodies, spleen cells from the immlmi7PA ~nim~ls
are removed, fused with myeloma cells, such as SP2/0-Agl4 myeloma cells,
and allowed to become monoclonal antibody producing hybridoma cells.
Any one of a number of mPthol1c well known in the art can be used to
identify the hybridoma cell which produces an antibody with the desired
h~r~-tPrictics. These include s~ g the hybridomas with an ELISA assay,
weslelll blot analysis, or radi~ c~y (Lut~ et al., Exp. Cell Res.
1 75: 109-124 (1988)) .
Hybridomas secreting the desired antibodies are cloned and the class
and subclass is determined using procedures known in the art (Campbell,
A.M., Monoclonal Antibo~ Technology: Laboratory Techniques in
Bioc~,.~lr~ and MolecularBiology, Elsevier Science Publishers, Am~l~ul"
The NethPrl~n-1s (1984)).
Techniques dçc~rihed for the production of single chain antibodies
(IJ.S. Patent 4,946,778) can be ~ rtPA to produce single chain antibodies to
proteins of the present invention.
For polyclonal antibodies, ~nlil,~<xly c4..'~ hlg ~nhcPr~ is isolated from
the ;~ A animal and is screened for the presence of antibodies with the
desired specificity using one of the above-described procedures.
The present invention further provides the above-described antibodies
in ~etprt~hly l~hellPA form. Antibodies can be ~etP~t~hly labelled through the
use of radioisotopes, affinity labels (such as biotin, avidin, etc.), en~y,llaLic
labels (such as hl~rcPr~-lieh peroYi~l~cP-~ ~lk~linP phosphatase, etc.) fluoL~sccllt
labels (such as FITC or rh~mine, etc.), p~r~m~gnPtic atoms, etc.
Procedures for accompliching such labelling are well-known in the art, for
example see (Sternberger, L.A. et al., J. Histochem. Cytochem. 18:315
(1970); Bayer, E.A. et al., Meth. Er~:ym. 62:308 (1979); Engval, E. et al.,
Inununol. 1~.129 (1972); Goding, J.W. J. Immunol. Meth. 13:215 (1976)).
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The labeled antibodies of the present invention can be used for in vitro,
in vivo, and in situ assays to identify cells or tissues in which a fragment of the
Naemophilus influenzae Rd genome is ~Aples.,ed.
The present invention further provides the above-described antibodies
immobilized on a solid support. Examples of such solid ~u~ , include
plastics such as polycarbonate, complex carbohydrates such as agarose and
seyharose~ acrylic resins and such as polyacrylamide and latex beads.
Techniques for coupling antibodies to such solid ~711~)1ki are well known in
the art (Weir, D.M. et al., "Handbook of Experimental Immunology" 4th Ed.,
Blackwell S~ ientific Publi~tinn~7 Oxford, P.ngl~nfl, Chapter 10 (1986);
Jacoby, W.D. et al., Meth. Enzym. 34 ~c~(lemic Press, N.Y. (1974)). The
immobilized antibodies of the present invention can be used for in vitro, in
vivo, and in situ assays as well as for immlmo~ffinity p~-rifi~tinn of the
proteins of the present invention.
lS 3. D~ , r ~ Assays and Kits
The present invention further provides m.-th~s to identify the
~Al,r~ssion of one of the ORFs of the present invention, or homolog thereof,
in a test sample, using one of the DFs or antibodies of the present invention.
In detail, such methods comri~e inc~lb~ting a test sample with one or
more of the antibodies or one or more of the DFs of the present invention and
assaying for binding of the DFs or antibodies to co.nl)onents within the test
sample.
Cnn-lition~ for i~u ub~t;l~g a DF or antibody with a test sample vary.
Incubation conditions depend on the format employed in the assay, the
~le-tection methods employed, and the type and nature of the DF or antibody
used in the assay. One skilled in the art will recognize that any one of the
- co-.. -.. only available hybri-1i7~ti~ n, amplific~tion or imm~mological assay
formats can readily be adapted to employ the DFs or antibodies of the present
invention. Examples of such assays can be found in Chard, T., An
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Introduction to Radioimrnunoassay and Related Techniques, Elsevier Science
Publishers, Am~L~ld~l" The Nt;~ lAn-l~ (1986); Bullock, G.R. et al.,
Techniques in Im~nunocytochemistry, Ac~-lPmic Press, Orlando, FL Vol. 1
(1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of
Enyme Imm~oassays: L~,~ci,~ Techniques in Biochemistry and Molecular
Biology, Elsevier Science Publi~hP-~, All~sLel-lalll, The NethPrl~n-l~ (1985).
The test ~AmplPs of the present invention include cells, protein or
~.dl~e extracts of cells, or binlngi~l fluids such as sputum, blood, serum,
plasma, or urine. The test sample used in the above-described method will
vary based on the assay format, nature of the detection method and the tissues,
cells or eYtr~-t~ used as the sample to be assayed. MethfKl~ for p.el,~,ng
protein extracts or membrane extracts of cells are well known in the art and
can be readily be adapted in order to obtain a sample which is co...l)AIihlP with
the system utili7P~
In another embo limpnt of the present invention, kits are provided
which contain the n~-C~A~ reagents to carry out the assays of the present
invention.
S~-;l;CA11Y, the invention provides a ~Il~ Ali7Pd kit to receive,
in close co..l;,~ n(, one or more CO~IA;ne~:~ which comprises: (a) a first
COj~IA;I~Pr compri~ing one of the DFs or antibodies of the present invention;
and (b) one or more other c~ ;n~:. CCi---~ ;ng one or more of the following:
wash reAgPnt~, reagents capable of ~etP~ting presence of a bound DF or
antibody.
In detail, a colll~l...PntAli7Pd kit in.-ludPs any kit in which reagents
are cnntAinPA in S~.~AIAI~.CnnlA;~ j. Such COnIA;nPI~ include small glass
containers, plastic contAinPrs or strips of plastic or paper. Such contAinPr~
allows one to efficiently transfer reagents from one co~ lllent to another
colll~alLIllent such that the ~mplPs and reagents are not cross-col-l~",il-~tP11,
and the agents or soll-tion~ of each container can be added in a 4llAntilAI;~re
fashion from one colll~llllellt to another. Such cont~inPrs will include a
conlaill~r which will accept the test ~mp1P, a contAinPr which cont~in~ the
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antibodies used in the assay, cont~int~rs which contain wash reagents (such as
pl~ urr~lcd saline, Tris-buffers, etc.), and cont~inprs which contain the
reagents used to detect the bound antibody or DF.
Types of det~ti~ n reagents include l~hP~led nucleic acid probes,
S l~hPIl~ s~n~1~ry antibodies, or in the ~ltern~tive~ if the ~ ll~y antibody is
labelled, the el~llldLiC, or antibody binding reagents which are capable of
reacting with the labelled antibody. One skilled in the art will readily
recognize that the disclosed DFs and antibodies of the present invention can
be readily incc,l~uldLed into one of the established kit folllldl~ which are well
known in the art.
4 Screening Assay for Ri~ g Agents
Using the isolated proteins of the present invention, the present
invention further provides methods of obta~ing and idellLiryillg agents which
bind to a protein ~nc(KI~ by one of the ORFs of the present invention or to
one of the fr~gmPnt~ and the Haemophilus genome herein described.
In detail, said method compri.~s the steps of:
(a) conf~ ~ting an agent with an icol~t~ protein encoded by one of
the ORFs of the present invention, or an i~ol~tPA fr~gml-nt of
the Haemophilus genome; and
(b) determining whether the agent binds to said protein or said
fragm~nt
The agents screened in the above assay can be, but are not limited to,
peptides, carbohydldl~s, vitamin derivatives, or other pharm~re~ltir~l agents.
The agents can be sPl~ted and screened at random or r~tion~lly s~--lrcteA or
~le~ nrA using protein modeling techniques.
For random sclcel~ing, agents such as peptides, carbohydrates,
- pl~ r~ ;r~l agents and the like are selected at random and are assayed for
their ability to bind to the protein encoded by the ORF of the present
invention.
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~ltPrn~tively, agents may be r~ti( n~lly selected or de~ipn-P~ As used
herein, an agent is said to be "r~ti~n~lly ~PlPct~l or de~ign-F~l" when the agent
is chosen based on the configuration of the particular protein. For eY~mrle,
one skilled in the art can readily adapt curlGlllly available procedures to
S gen~ P peptides, pharm~eutic~l agents and the like capable of binding to aspecific peptide sequence in order to generate rationally de~ignF~ lLi~ide
peptides, for example see Hurby et al., Applic~ti~ n of Synthetic Peptides:
~nti~Pn~e Peptides," In Synthetic Peptides, A User's Guide, W.H. Fl~~n~
NY (1992), pp. 289-307, and K~7~k et al., Bio~7~,~lr~ 28:9230-8 (1989),
or l,hal~ eutic~l agents, or the like.
In ~lflitinn to the rolt;goillg, one class of agents of the present
invention, as broadly /1es(~ril~ed~ can be used to control gene eApres~ion
through binding to one of the ORFs or EMFs of the present invention. As
described above, such agents can be randomly screened or r~*on~lly
de~ignP~l/sel~Pct-P~ Targeting the ORF or EMF allows a skilled artisan to
design s~u~n~ specific or P1F..~n~ specific agents, m~~ ting the e~?res~ion
of either a single ORF or mlll*rlF~ ORFs which rely on the same EMF for
t;A~l~s~ion control.
One class of DNA binding agents are agents which contain base
r~ lues which hybridi_e or form a triple helix formation by binding to DNA
or RNA. Such agents can be based on the classic phosphodiester, ribonll~lpic
acid backbone, or can be a variety of sulfhydryl or polymeric derivatives
which have base ~tt~hment capacity.
Agents suitable for use in ~ese mPtho ls usually contain 20 to 40 bases
and are de~i~n-F~ to be comp'~ to a region of the gene involved in
transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979);
Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251: 1360
(1991)) or to the mRNA itself (~n*~Pn~e - Okano, J. Neurochem. 56:560
(1991); Oligodeoxym~c~eon~es as An~isense Inhibitors of Gene Expression,
CRC Press, Boca Raton, FL (1988)). Triple helix- formation optimally results
in a shut-off of RNA transcription from DNA, while ~nti~Pn~P RNA
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hyhrilli7~ti- n blocks ~ jo~ of an mRNA molecule into polypeptide. Both
techniques have been demonstrated to be effective in model systems.
Information cnnt~in~l in the sequences of the present invention is ne~e~ry
for the design of an ~nti~n~e or triple helix oligonucleotide and other DNA
S binding agents.
Agents which bind to a protein encoded by one of the ORFs of the
present invention can be used as a diagnostic agent, in the control of b~r te
infection by mod~ ting the activity of the protein encoded by the ORF.
Agents which bind to a protein encoded by one of the ORFs of the present
invention can be formlll~t~ using known techniques to gene~; a
pharm~-eutir~l co~ osilion for use in controlling Haemophilus growth and
infection.
5. Vaccine and P*a~ a~ev~n~ ,6~ n
The present invention further provides ph~rm~ uti~l agents which can
be used to ".~ the growth of Haemophilus inJquenzae, or another related
or~ni~m, in vivo or in vitro. As used herein, a "ph~...~-euti-~l agent" is
dPfinPA as a co...posilion of matter which can be formlll~t~cl using known
techniques to provide a ph~rm~ellti~l compositions. As used herein, the
"pharm~reuti~l agents of the present invention" refers the ph~rm~-euti~
agents which are derived from the ~l~ins ~n~ ~ by the ORFs of the present
invention or are agents which are irl~ntifi~l using the herein described assays.As used herein, a pharm~ceutir~l agent is said to "mocllll~t~1 the
growth of Haemophilussp., or a related or~ni~m, in vivo or in vitro," when
the agent reduces the rate of growth, rate of division, or viability of the
organism in ~lue~liun. The ph~rm~euti~l agents of the present invention can
modulate the growth of an organism in many f~hinn~, although an
- ... u3~ g of the ul~ g m~h~ni~m of action is not needed to practice
the use of the ph~rm~eutic~l agents of the present invention. Some agents
will m~ tp the growth by binding to an i---pc,ll~lt protein thus blocking the
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binlngi~1 activity of the protein, while other agents may bind to a col-lpollentof the outer surface of the organism blocking ~tt~hmPnt or rPn~lPnng the
organism more prone to act the bodies nature immlmP system. .A1lr~ rely,
the agent may be comprise a protein encoded by one of the ORFs of the
present invention and serve as a vaccine. The development and use of a
vaccine based on outer membrane cu-l~pollents, such as the LPS, are well
known in the art.
As used herein, a "related organism" is a broad term which refers to
any organism whose growth can be mo~ tecl by one of the ph~r-m~c-eut~
agents of the present invention. In genP~1, such an organism will contain a
homolog of the protein which is the target of the pharm~ceutif ~1 agent or the
protein used as a vaccine. As such, related organism do not need to be
b~cteri~1 but may be fungal or viral p~thogt~n~.
The pharm~ccl1ti~1 agents and compo~itic n~ of the present invention
may be ~-lmini~t~Pred in a convel~ient manner such as by the oral, topical,
intravenous, i~ pe~ ;lo~ r, subc 1t~npous~ ~1 or
int~-lPnm~1 routes. The ph~nm~-~euti~1 co-l.posilions are ~lmini$tPred in an
amount which is effective for treating and/or prophylaxis of the specific
intli~tinn In genP~1, they are ~ t d~d in an amount of at least about lO
~ug/kg body weight and in most cases they will be ~lmini~tpJed in an amount
not in excess of about 8 mg/Kg body weight per day. In most cases, the
dosage is from about lO ~g/kg to about l mg/kg body weight daily, taking into
account the routes of ~(lmini~tr~tic~n, sy...~l~,...s, etc.
The agents of the present invention can be used in native form or can
be m~lifiPcl to form a chP-mic~1 derivative. As used herein, a mnlP~ulP is said
to be a "chemic~1 derivative" of another mc-lPc111e when it contains additional
chPmic~1 mnietiPs not normally a part of the molp~llle. Such moieties may
improve the molecule's solubility, absorption, bic-1Ogic~1 half life, etc. The
mc ~~iPS may ~1tPrn~tively decrease the toxicity of the mo1ec1-1P, P1imin~te or
;.ll~.. l.;.l~ any ~ hle side effect of the mo1ec111e, etc. MniPtips capable of
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lg such effects are disclosed in Remington's Pharm~7c.elltic~71 Sciences
(1980).
For; , '-, a change in the imm1-n~1ngi~ h~ ~ of the fim~ti~n:~l
derivative, such as affinity for a given antibody, is measured by a co,.,pc;~ e
S type imm1mo~c~y. Changes in immlmnmodulation activity are measured by
the a~propliate assay. M~lifi~ti~ne of such protein p~ ies as redox or
thPrm~1 stability, biological half-life, hydrophobicity, susceptibility to
proteolytic ~le~r~ ti~ n or the ten~lency to aggregate with c~rriP-rc or into
mn1tim~-rs are assayed by ",~lh~ylc well known to the or~ hily skilled artisan.
The th~pe~l;c effects of the agents of the present invention may be
obtained by providing the agent to a patient by any suitable means (i.e.,
inh~1~tion, intravenously, intr~m1-~cu1~r1y, subcutaneously, enterally, or
~ellt~ldlly). It is ~lc;fell~d to ~lmini~t~3r the agent of the present inventionso as to achieve an effective con-~nt-~tion within the blood or tissue in which
the growth of the organism is to be controlled.
To achieve an effective blood conce-ntr~ti~n~ the plert;lled method is
to ~ l the agent by ;.~je~l;fu- The ~ ;on may be by continuous
infusion, or by single or mlll~iple injecti- n~.
Ir~ providing a patient with one of the agents of the present invention,
the dosage of the ~ d agent will vary depen-ling upon such factors as
the patient's age, weight, height, sex, general m.oAic~1 condition, previous
mt~ 1 history, etc. In general, it is desirable to provide the recipient with
a dosage of agent which is in the range of from about l pg/kg to lO mg/kg
(body weight of patient), although a lower or higher dosage may be admin-
istered. The th~ 11y effective dose can be lowered by using
co",bil,~iions of ine agents or tne present invention or anotner agent.
As used herein, two or more uJlllpoul-ds or agents are said to be
~rlmini~t.ored "in combination" with each other when either (l) the
- physiological effects of each colll~und, or (2) the serum concentrations of
each compound can be measured at the same time. The composition of the
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present invention can be ~lministpred concullc l~y with, prior to, or following
the Atlminietration of the other agent.
The agents of the present invention are intPn(le~d to be provided to
recipient subjects in an amount sllffiçi~ont to decrease the rate of growth (as
S dPfin~P~l above) of the target org~niem.
The A~lminiet~tinn of the agent(s) of the invention may be for either a
hyl~ctic" or ' ~ A~ ose. When provided ~rophylA~ticAlly, the
agent(s) are provided in advance of any ~y~ tOIllS in~ Ative of the or~niem~
growth. The prophylactic A-lminietrAti~n of the agent(s) serves to prevent,
Allel~llA~P, or decrease the rate of onset of any subs_quent infection. When
provided thplApculic-Ally~ the agent(s) are provided at (or shortly after) the
onset of an inf~ tion of infç~tion The th~.Al~.lic A~lminietrAtion of the
coll-~u.ld(s) serves to AI~cl~llAl~- the PAI1IO1~;~'A1 ~y--~---s of the infection and
to increase the rate of recovery.
The agents of the present invention are ~llminietPred to the mAmmAl in
a phArmAc-p~utir~lly acceptable form and in a l]le.ld~JC~ lly effective
cnn~--l-AI;- -- A composition is said to be ''yhA~lllArologically acceptable" ifits A~lminietrAti~n can be tcl---At~i by a recipient patient. Such an agent is said
to be ~minietPred in a l'th~G-Apc-ll;~Ally effective amount" if the amount
AtlminietPred is physiologically ei~nifi~Ant An agent is physiologically
eignifi-~Ant if its presence results in a ~PtectAhle change in the physiology of a
recipient patient.
The agents of the present invention can be formulated according to
known methods to ~JlC~llC pharmA~ -ti~Ally useful compositions, whereby
these mAtPriAle, or their functional derivatives, are co---bined in A.l.. ixl.. c with
a phArm~ lti~Ally acceptable carrier vehicle. Suitable vehicles and their
f~rmlllAti~n, inclusive of other human proteins, e.g., human serum albumin,
are c~P-~ih~ for ~ -, in Remington's Pha~mnrel~cn7 Sciences (16th ed.,
Osol, A., Ed., Mack, Far~ton PA (1980)). In order to form a phArm~ceutifAlly
Al c~1AhlP co~ ;nn suitable for crr~;Live A~lmini~fr~tion, such compositions
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will contain an effective amount of one or more of the agents of the present
invention, together with a s~lit~hle amount of carrier vehicle.
Additional pharm~l~ellti~-~l methods may be employed to control the
rlllr~tit~n of action. Control release ~ ns may be achieved through the
use of polymers to ~ o ~ Y or absorb one or more of the agents of the present
invention. The controlled delivery may be exercised by se~ting al)pl~liate
macrom~ lP~IIlPs (for eY~mplP polyesters, polyamino acids, polyvinyl,
pyrr~ lone, ethylenevinyl~cet~tP, methylcP~ se, carboxymethylcellulose,
or ~n~1~.ni,-P., sulfate) and the concentr~ti()n of macromolP~lps as well as themetholi~ of inc~ in order to control release. Another possible method
to control the d--r~tion of action by controlled release p~A-,Iion~ is to
incol~ldLe agents of the present invention into particles of a polymeric
m~tPri~l such as polyesters, polyamino acids, hydlogels, poly(lactic acid) or
ethylene vinylacetate copolymers. AlL~ ly, instead of incol~Ql~ing these
agents into polymeric particles, it is possible to entrap these m~teri~l~ in
micror~rsulPs ~r~p~;d, for PY~mple, by coacervation techniques or by
interf~ l polymPri7~ti( n, for eY~mrl~P, hydn.,-y",ethylcellulose or gelatine-
llli~;ç~ lP-s and poly(,,,c;Lhylln~lh~cylate) micf~a~ les, le~ecLi~ly, or in
colloidal drug delivery systems, for eY~mrle, liposo",es, albumin
micros~h~les, microem~ ion~, nanoparticles, and nanor~rs--l~s or in
macroem--l~i~.n~. Such techniques are ~i~close~l in Remington's
Pharm~lc~l~ncn~ Sciences (1980).
The invention further provides a ph~rm~rPllti~l pack or kit compri.~ing
one or more ~nl~inf.~ filled with one or more of the ingredients of the
pharm~eu*r~l composition~ of the invention. ~soci~tP~ with such
. (s) can be a notice in the form prescribed by a government~l agency
regulating the mamlfact~lre~ use or sale of pharmace~1tic~1~ or biological
U~ i, which notice reflects approval by the agency of man11fa~t11re, use or
- sale for human a-i-,.;.. ;.~l., I;~n In ~ li*on, the agents of the present invention
may be employed in conjunction with other th~ lic compounds.
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6. Shot-Gun Approach to Megabase DNA Seque~ci~g
The present invention further provides the first ~lemon~tr~tiQn
that a sequence of greater than one m~g~h~ can be sequenced using a random
shotgun approach. This procedure, described in detail in the eY~mrles that
S follow, has Pl;.. ;l-~t~d the up front cost of i~o1~ting and ordering o~/e~ ing
or contiguous subclones prior to the start of the seqllen- ing protocols.
Certain aspects of the present invention are described in greater detail
in the non-limitin~ Examples that follow.
~6-
SU85TrrUTE S~EET tRULE 26)
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E~ ~les
Expen~e~f~71 Design and Mef~
..
1. Shotgun .~equ~nri~Jg Strategy
The overall ~ e~;Y for a shotgun approach to whole genome
se~lue". ~g is outlined in Table 3. The theory of shotgun seqllPnring follows
from the Lander and W~P....~ n-l.orrn~n and Wat~l-"an, Genomics 2: 231
(1988)) applir~ti~ n of the equation for the Poisson distribution p" = mXe~n'/x!,
where x is the number of oc-;ulle"ces of an event, m is the mean mlmb~r of
oc.;ull~nces, and Px is the probability that any given base is not sequenced after
a cer~in amount of random sequence has been ge~ PA If L is the genome
length, n is the llull~b~l of clone insert ends se luei-rRcl, and w is the
seqll~nring read length, then m = nw/L, and the ~rl~bability that no clone
origin~t~s at any of the w bases pl~ce/ling a given base, i.e., the probability
that the base is not se~luc;l~ed, is pO = e~. Using the fold coverage as the unit
for m, one sees that after 1.8 Mb of sequence has been randomly gçn.or~t~,
m = 1, Lepres~ ;ng lX covesge. In this case, pO = e~' = .37, thus
a~luxim~t~ly 37% is unsequenced. For example, 5X coverage
(ap~ i",ately 9500 clones sequenced from both insert ends and an average
sequence read length of 460 bp) yields pO = e~5 = 0.0067, or 0.67%
unsequf~-nr-e~. The total gap length is Le~, and the average gap size is L/n.
SX coverage would leave about 128 gaps averaging about 100 bp in size. The
I l r;1l 1 l Ir.~ I~ iS P~nti~lly ~at of Lander and W~ IP. ~ .-, Genomics 2:231 (1988) .
Table 4 ill~ s the coverage for a 1.9 Mb genome with an average fragment
size of 460 bp.
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2. Rnn~ Libr~uy Construction
In order to approximate the random model described above during
actual seq~len~ing, a nearly ideal library of cloned genomic fr~gm~nt is
required. The following library construction procedure was developed to
achieve this.
H. influen2~e Rd KW20 DNA was pl~?aled by phenol extr~ctinn A
IlliX.LUit; (3.3 ml) c~ .;..g 600 ~g DNA, 300 mM sodium ~t~t~7 10 mM
Tris-HCl, 1 mM Na-EDTA, 30% glycerol was sQnic~t~l (Branson Model 450
Sonir~tnr) at the lowest energy setting for 1 min. at 0~ using a 3 mm probe
The DNA was ethanol precipitated and redissolved in 500 ~41 TE buffer. To
create blunt-ends, a 100 ~Ll aliquot was digested for 10 min at 30~ in 200 ,ul
BAL31 buffer with 5 units BAL31 nuclease (New F.n~l~n~ BioLabs). The
DNA was phenol-extracted, ethanol-~l~;pil~l~d, redissolved in 100 ,ILl TE
buffer, electrophoresed on a 1.0% low mPlting agarose gel, and the 1.6-2.0
kb size fr~rtion was eYr,i~ll, phenol-~Yt~ted, and redissolved in 20 ~l TE
buffer. A two-step li~fi~n p-~lur~ was used to produce a pl~mid library
with 97% insert of which >99% were single inserts. The first ligation
Illi~LUle (50 ~1) coi.l;~ ~ 2 ~g of DNA fr~gm~nt~, 2 ~g SmaI/BAP pUC18
DNA (ph~ ), and 10 units T4 ligase (GIBCO/BRL), and incub~tion was
at 14~ for 4 hr. After phenol PYtr~tion and ethanol p~ i~lion, the DNA
was dissolved in 20 ~Ll 1~ buffer and electrophoresed on a 1.0% low melting
agaro~ gel. A ladder of ethi~ m bromide-stained linear bands, ici~ntifi~d by
si_e as in~rt (i), vector (v), v+i, v+2i, v+3i, ... was vi~ 1i7~d by 360 nm
W light, and the v+i DNA was excised and recovered in 20 ~Ll TE. The v +i
DNA was blunt-ended by T4 polymerase tre~tm~o-nt for 5 min. at 37~ in a
reaction mixture (50 ~ul) conl;~ the v+i linears, 500 ~M each of the 4
dNTP's, and 9 units of T4 polymerase (New Fngl~n-l BioLabs) under
recommt--nded buffer conditions. After phenol extraction and ethanol
pl~ ;p; I;.tinn the ~e~ d v+i linears were dissolved in 20 ~1 TE. The final
ligation to produce circles was carried out in a 50 ~1 reaction cont;.in;.)g S ~1
of v+i linears and S units of T4 ligase at 14~ ov~rni~ht After 10 min. at 70~
the reaction IllixLulc was stored at -20~. 48
SU8STTTUTE S~E~ tRULE 2
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This two-stage procedure resulted in a m~lec~ rly random collection
of single-insert pl~mi~ ,ecol,lbinallL~ with minim~l cont~min~ti~n from
double-insert cl~ ( < 1 %) or free vector ( < 3 %). Since deviation from
r~n~1OmnP~ is most likely to occur during cloning, E. coli host cells dPficient
in all recombination and restriction fimetion~ (A. Greener, Strategies 3 (1):5
(1990)) were used to prevent rearrangem~-nt~, deletions, and loss of clones by
restriction. Transformed cells were plated directly on antibiotic diffusion
plates to avoid the usual broth recovery phase which allows mllltiI)lic ~tinn and
selection of the most rapidly growing cells. Plating occured as follows:
A 100 ~1 aliquot of Epicurian Coli SURE II Su~~ico.. ~ Cells
(Stratagene 200152) was thawed on ice and transferred to a chilled Falcon
2059 tube on ice. A 1.7 ~1 aliquot of 1.42 M ,B-mercaptoeth~nol was added
to the aliquot of cells to a final C~ - of 25 mM. Cells were inc~lb~tPJi
on ice for 10 min. A 1 ~1 aliquot of the final lig~tion was added to the cells
and in~lb~tP~ on ice for 30 min. The cells were heat pulsed for 30 sec. at 42~
and placed back on ice for 2 min. The ouL~ wLh period in liquid culture was
~1;",;"~ from this protocol in order to minimi7P the ~lcÇclcllLial growth of
any given L,~ulsrulll,ed cell. Instead the tran~roll~lalion were plated diiccLly on
a nutrient rich SOB plate co..l;~ i.-g a S ml bottom layer of SOB agar
(1.5% SOB agar: 20 g lly~Lunc, 5 g yeast extract, 0.5 g NaCl, 1.5% Difco
Agar/L). The S ml bottom layer is supplemP-ntP~I with 0.4 ml ampicillin
(50 mg/ml)/100 ml SOB agar. The 15 ml top layer of SOB agar is
supplemPnt~ with 1 ml X-Gal (2%), 1 ml MgCl2 (1 M), and 1 ml
MgSO4/100 ml SOB agar. The 15 ml top layer was poured just prior to
plating. Our titer was ay~ ,lllaLcly 100 colonies/10 ,ul aliquot of
tran~Çu~ ion.
All colonies were picked for tPmpl~tP p~c~aldLion regardless of si_e.
Only clones lost due to "poison" DNA or dP-ietPriQus gene products would be
deleted from the library, r~s-llting in a slight increase in gap number over that
eYpe~t~
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SUBSTErUTE SHEET tRULE 26)
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In order to evaluate the quality of the H. influenzae library, sequence
data were obtained from approximately 4000 templ~tes using the M13-21
primer. The r~ndom sequence fr~gmPntc were ~ccpmhled using the
AutoAssembler~M sor~w~e (Applied Biosy~lc,,,s division of Perkin-Elmer
(AB)) after ol,~i.. ng 1300, 1800, 2500, 3200, and 3800 sequence fr~gmP.nt.c,
and the IIUIIII~Cl of unique ~c~Pmhl~A. base pairs was detçrminpA Based on the
equations des~.nhed above, an ideal plot of the l~umbel of base pairs ~ i n i ~gto be sequenced as a function of the .~Y of sequenced fr~gmP.ntc obtained with
an average read length of 460 bp for a 2.5Xl06 and a l.9Xl06 bp genome was
detel",il,ed (Figure 3). The ~lOgl~ ion of ~ccPmhly was plotted using the
actual data ol,l~il,ed from the as_embly of up to 3800 sequence fr~gmPntc and
co"-pa.~d the data that is provided in the ideal plot (Figure 3). Figure 3
.ctr~tes that there was e~ lly no deviation of the actual assembly data
from the ideal plot, ;nriic~ting that we had cor.sL-u. ~1 close to an ideal random
library with minim~l cont~min~ti~ n from double insert çhim~r~c and free of
vector.
3. P~ DNA Seq1~e~ g
High quality double st~nded DNA p1~cmid If-"~ t~s (19,687) were
~lc~aled using a "boiling bead" method developed in collaboration with
Advanced Genetic Technology Corp. (Gaithersburg, MD) (Adams et al.,
Scien~e 252:1651 (1991); Adams et al., Nature 355:632 (1992)). Plamid
prc~ l ion was pclrol.--ed in a 96-well format for all stages of DNA
ylc~ n from b~c f~ri~l growth through final DNA pl~rific~tion TPmplz3t
col-c~ .dLion was del~ A using ~oe~hct Dye and a Millipore Cytofluor.
DNA concpntr~tions were not adjusted, but low-yielding tpm~ tec were
identifi.-A where possible and not sequenced. Templates were also plc~alcd
from two H. influenzae lambda genomic libraries. An ~mplifiPA library was
constructed in vector Lambda GEM-12 (Promega) and an nn~mrlifiPA library
was constructed in Lambda DASH II (Stratagene). In particular, for the
e
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l~n~mplifi~ lambda library, H. in,7?uenzae Rd KW20 DNA (> 100 kb) was
partially digested in a reaction IlLU~lulG (200 ~1) cnn~ in_ 50 ~g DNA, lX
Sau3AI buffer, 20 units Sau3AI for 6 min. at 23~. The digested DNA was
phenol-extracted and elecLrophoresed on a 0.5% low mPltinp agarose gel at
~ 5 2V/cm for 7 hours. I~l,.g.. ~ from 15 to 25 kb were excised and recovered
in a final volume of 6 ~1. One ~ul of f~pmPnte was used with 1 ~1 of DASHII
vector (str~t~gpnp-) in the ~G~.. Pnrled 1i~tinn re~-~tion One ~1 of the
ligation mixture was used per p~ ging reaction following the recommP-nrle~
plùtocol with the Gi_~p~rl~ II XL p~cl~ginp Extract (Stratagene, #227711).
Phage were plated d-lccLly without ~mrlific~tinn from the p~ ping ~ ulc;
(after dilution with 500 ~1 of lGcGI.. Pn~iP~1 SM buffer and chlororol--.
tre~tmPnt). Yield was about 2.5x103 pfu/,ul. The ~mrlified library was
pl~alGd ç~Pnti~lly as above except the lambda GEM-12 vector was used.
After ~;.~ , about 3.5x104 pfu were plated on the restrictive NM539 host.
The lysate was harvested in 2 ml of SM buffer and stored frozen in 7%
dimethylsulfoxide. The phage titer was approxim~tP-ly lx109 pfu/ml.
Liquid lysates (10 ml) were ~lc~d from randomly s~l~ct~P~l plaques
and ~ was ~lG~Gd on an anion-eYch~npe resin (Qiagen). Sequ~Pncinp
reactions were carried out on pl~mi~1 ~e-..~ s using the AB Catalyst
LabStation with Applied Biosy~G --s PRISM Ready Reaction Dye Primer
Cycle SequP-ncinP Kits for the M13 rol~ l (M13-21) and the M13 reverse
(M13RPl) ~lilllCl~ (Adams et al., Nature 368:474 (1994)). Dye lelll~ aLol
seque-ncing re~t-tion~ were carried out on the lambda tpmpl~tp~s on a Perkin-
Elmer 9600 Thcl.llo~;ycler using the Applied Bio~y~LG.IIs Ready Reaction Dye
Tf .. . . ; n~ , Cycle Se4uG ~cing kits. T7 and SP6 primers were used to sequence
the ends of the inserts from the Lambda GEM-12 library and T7 and T3
primers were used to s~uG,~ce the ends of the inserts from the Lambda DASH
II library. Se~uGl- ing rP~.-tinnc (28,643) were ~GlÇol,l,ed by eight individuals
using an average of ruul L~ en AB 373 DNA .S~ lPn~-r~ per day over a 3 month
period. All sequencing r~ fion~ were analyzed using the Stretch m~ifir~tic)n
of the AB 373, primarily using a 34 cm well-to-read distance. The overall
SUBS 111 UTE St{EET (RULE 2~
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sequencing success rate was 84% for M13-21 sequences, 83% for M13RPl
sequences and 65% for dye-~~ .. reactions. The average usable read
length was 485 bp for M13-21 se lue,l~es, 444 bp for M13RPl sequences, and
375 bp for dye-l~ fillal~r ~rl;,~n~ Table S s~ . ;7PS the high-throughput
S sequPnrin~ phase of the invention.
Richards et al. (Richards et al., Automated DNA sequencing and
Analysis, M.D. Adams, C. Fields, J.C. Venter, Eds. (Academic Press,
London, 1994), Chap. 28.) ~lescrihe~ the value of using sequence from both
ends of seqU~pnrinE tP-~pl~tçs to f~rilit~tP ordering of contigs in shotgun
:l~Pmhly plu; e :t~ of lambda and cosmid clones. We b~l~nr~ the desirability
of both-end sequPnr-in~ (inrlurlinE the reduced cost of lower total number of
~r.l~pl ll~s) against shorter read-lengths for s~upncinE rP~rti~ n~ ~lrulllled with
the M13RPl (reverse) primer con~ d to the M13-21 (folw~d) primer.
A~r~ ly one-half of the templates were sequenced from both ends. In
tûtal, 9,297 M13RPl sequpnr-inE re~rfion~ were done. Random reverse
sequPnrinE re~rtinn~ were done based on succ~s~ful folw~d seqnPnrinE
Some M13RPl se~u~lce~ were obtained in a semi-directed f~hi~n
M13-21 se~lu~llces pointing uutw~d at the ends of contigs were chosen for
M13RPl sequ~nrinE in an effort to speoifir~lly order contigs. The semi-
directed ~lld~gy was effective, and clone-based ordering formed an intP.~r~l
part of assembly and gap clûsure (see below).
4 Protocolfor~ D~ Cycle SDql ~7ci~g
The seqnpnrinE c~n~i~tP~1 of using eight ABI Catalyst robots and
fuulLeell AB 373 Autulll~d DNA Seq--PnrP-rs. The Catalyst robot is a
publicly available s~phistic~tpcl ~ipc;~ g and Ir~ llle control robot which
has been developed spec-ific~lly for DNA sequPncinE re~rti~)n~ The Catalyst
coll~ -s pre-aliquoted l~-..P1 ~IP-S and reaction mixes con~i~tinE of deoxy- anddideoxynucleotides, the Taq thprrnost~hle DNA polymP~ee, fluulesc~ ly-
labelled sequPnr-in~ primPrs, and reaction buffer. l~P~rti-)n mixes and
SUBSTrrUTE ~EET tRULE 2~i)
f
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L~ s were combined in the wells of an aluminum 96-well thermocycling
plate. Thirty con~ tive cycles of linear amplific~tion (e.g., one primer
synthesis) steps were pc.rollned incl~lAing dendLu,dLion, ~nn~ling of primer
and templ~te, and eYt~neinn of DNA synthP~i.c A heated lid with rubber
gaskets on the L1~ cling plate prevented evaporation without the need for
an oil overlay.
Two sequen---ing ~luLocols were used: dye-labelled primers and dye-
labelled dideoxy chain Icl---;n~ol~. The shotgun sequPn.-ing involves use of
four dye-labelled seqll~nr-ing primers, one for each of the four t~ll..in~JI
nucleotide. Each dye-primer is labelled with a dirrc~cnt fluorcscel-t dye,
pcl~ ing the four individual reactions to be combined into one lane of the
373 DNA Sequencer for electrophoresis, det~tion, and base-calling. AB
cullcllLly ~u~lies pre-mixed reaction mixes in bulk p~e~ ge~ cnn~;.i.-il-g all the
n~ .~- y non ~ "~ reagents for s~u~ Seql~enring can be done with
both plasmid and PCR-generated templates with both dye-primers and dye-
~el...il-~-tc)rs with a~ vxi...;~ y equal fidelity, although plasmid templ-t,s
generally give longer usable sequences.
Thirty-two re~ tion~ were loaded per 373 Sequencer each day, for a
total of 960 ~mrlPs Elcctrophoresis was run overnight following the
manufacture's p,~,l~ols, and the data was c~ ll~te~A. for twelve hours.
Following electrophoresis and fluorescen-~ det~ctinn, the AB 373 pclrOllllS
automatic lane traclring and base-calling. The lane-tracking was confirmed
visually. Each sequence elecl~ hcl~ -dlll (or nuo-esc~ e lane trace) was
A, visually and ~ A for quality. Trailing sequences of low quality
were removed and the se.l~ence itself was loaded via software to a Sybase
h~ (a~h,,~" A A~;ly ~0 a 8mm ~pe). T P ~Ain~ v~tor polylu-ker sequence
was removed ~11tom~tir~11y by sorLwale program. Average edited lengths of
sequences from the standard ABI 373 were around 400 bp and depended
mostly on the quality of the temr1-~t~ used for the sequçn---ing reaction. All of
the ABI 373 Sequencers were converted to Stretch Liners, which provided a
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longer ~ L~ophoresis path prior to fluoresc~nce det~ti~ n, thus increasing the
average number of usable bases to 500-600 bp.
Infonnatics
1. Data Mana~ e~tt
5A number of information m~n~gtem~.nt systems (LIMA) for a large-
scale s~ g lab have been developed (Kt;ll~v~e et al., Proceedings of the
Twenly-Sixth Annual Nawaii International C~r~f~,~, ce on System Sciences,
IEEE Co~ uL~ir Society Press, W~hing~n D.C., 585 (1993))~ The system
used to collect and assemble the s~.lu~ P data was developed using the Sybase
relational data m~n~p;em~nt system and was clP-~igne~1 to auLu,,.aLe data flow
whereever possible and to reduce user error. The cl~t~h~e stores and
cc,llclalt;s all infoll..alion collected during the entire oppr~tion from lemplale
n to final analysis of the genomP. Re~ sP the raw output of the AB
373 .Se~ue~ was based on a M~tintf-~h platform and the dat~ management
system chosen was based on a Unix platform, it was nf~.s~. ~ to design and
implP.ment a variety of multi-user, client server applic~tinn~ which allow the
raw data as well as analysis results to flow se~m~ 1y into the ~t~h~e with
a minimum of user effort. A d~;,i~Lion of the sorLw~e pl'Ogl~lllS used for
large sequence assembly and m~n~pm~.nt is provided in Figure 4.
2. ,4.. !s~mblY
An assembly engine mGR A~cPm' ler) was developed for the rapid
and accurate assembly of thousands of sequence fr~gmP.nt.~ The AB
AutoA! ~ ~- TM was mollifi~ (and named TIGR Editor) to provide a
gr:~phi<~l infPrf~l~e to the electrophelugla~,l for the purpose of editing data
~ f~ with the aligned sequence file output of TIGR A~cPmhler TIGR
Editor ...~in~;n~ synchrony belwwl~ the electropherogram files on the
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M~intrlsh ~ r... and the se lu~lce data in the H. influenzae ~1~t~h~e on the
Unix platform.
The T~GR: ~ ~im~ ..~.u~1y clusters and ~ mh1es fr~gmt-nt~
of the genome. In order to obtain the speed n~es~ry to assemble more than
104 fr~gmPnt~, the algc,~ " builds a hash table of lO bp oligonucleotide
subsequences to gent;l~ a list of potential sequence fr~gmPnt overlaps. The
number of potential ov~l~s for each fr~gm~nt determines which fr~gm~nt~
are likely to fall into repeLiLi~e e1emPntC Re~inning with a single seed
~uellce fr~gm~nt TIGR Assembler extends the current contig by ~LL~;IIIpLillg
to add the best .. ~ h;.. g fr~gm~nt based on oligonucleotide content. The
current contig and c~n~ t~ fr~gm.ont are aligned using a modified version of
the Smith-Wat~ll"an algoliLh~ (Waterman, M.S., Methods in Enzymology
l64:765 (1988)) which provides for optimal gapped ~ nmPnt~ The current
contig is ~oYten-l~ by the fragment only if strict criteria for the quality of the
match are met. The match criteria include the Illill;llllllll length of overlap, the
...;.~i..~-.... length of an u~ cl-~l end, and the minimllm ~rcel,L~ge match.
These criteria are autom~tic~11y lowered by the algorithm in regions of
minim~1 coverage and raised in regions with a possible repetitive e1~m~-nt The
number of poLe,lLial overlaps for each fr~gmPnt determines which fr~f~mPnt~
are likely to fall into re~K;LiLi~e e1em~nt~. Fr~gmPnt~ lt;plesPI.L;l-g the
bo-..-~ s of repetitive "1_",~ and ~I~"Lially ~~himPric fr~gm~nt~ are often
rejected based on partial mi~m~t~ s at the ends of ~1ignmPnt~ and ~Y~c1~ ed
from the current contig. TIGR Assembler is deeignecl to take advantage of
clone size inrol,l,a~ion coupled with sequenting from both ends of each
~ It ~ r~es the c~tl~ in~ that sequence fr~gmt-nt~ from two ends of
the same template point toward one another in the contig and are located
within a certain ranged of base pairs (definable for each clone based on the
known clone size range for a given library). Assembly of 24,304 sequence
r. ~ of H. iry~uenzae required 30 hours of CPU time using one processor
on a SPARCenter 2000 with 512 Mb of RAM. This process resulted in
a~lu,~im~tt--ly 210 contigs. Re~use of the high string~-ncy of the TIGR
SU~ST~UTE SH E~T tRULE ~)
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A~ , all contigs were searched against each other using grasta (a
modified fasta (Person and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85:2444
(1988)). In this way, ~ 1iti~n~1 overlaps were dptrctç~ which en~hl~i
co~ ion oof the data set into 140 contigs. The location of each fragment
S in the contigs and extensive inr~ ion about the con~Aon~us sequence itself were loaded into the H. influenzee r~l~tion~ t~h~P
3. Ordenng ~ bl~d Cont~gs
After ~c~Pmhly the relative positions of the 140 contigs were unknown.
The contigs were ordered by asm align. Asm align uses a number of
relationships to identify and align contigs that are ~ rPnt to each other.
Using this algc,lilh..., the 140 contigs were placed into 42 groups tota1ing 42
physical gaps (no templ~t~-- DNA for the region) and 98 sequence gaps
(tc~.mp1~t~ available for gap closure).
Ordenng Contigs Separated by Physical Gaps and Achieving Closure
Four i~ p-, ~ lt'.E;;f-S were developed to order contigs S~ f~ by
physical gaps. Oligonllr~l~tide primers were ~le~iFn~i and synth~ i7P~ from
the end of each contig group. These ~llilllCl~ were then available for use in
one or more of the st~trgies outlined below:
1. Southern analysis was done to develop a unique "fingcl~li-.L"
for a subset of 72 of the above oligonllrl~t~ o-s. This procedure was based
upon the supposition that labeled oligon~clr-oti~ies homologous to the ends of
nt contigs should hybridize to common DNA restriction fr~gmPnt~, and
thus share a similar or i~lonti-~l hybridization pattern or "fingt;lL.fin~".
Oligonucleotides were labeled using 50 pmoles of each 20 mer and 250 mCi
of [y 32P]ATP and T4 polyn~-cl~ti-lr kinase. The labeled oligonucleotides
were purified using Seph~ley G-25 ~u~lfille (Pharmacia) and 107 cpm of
each was used in a Southern hybri~1i7~tinn analysis of H. influen2ae Rd
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chromosomal DNA digested with one frequent cutters (AseI) and five less
Lle luellt cutters (Bgm, EcoRI, PstI, XbaI, and PvuII). The DNA from each
digest was fractionated on a 0.7% agarose gel and transferred to Nytran Plus
nylon membranes (Schleich~r & Schuell). Hybri~li7~tinn was carried out for
16 hours at 40~. To remove non-specific signals, each blot was sequentially
washed at room 1~ with increasingly stringent conditions up to 0. lX
SSC + 0.5~ SDS. Blots were exposed to a Phosph~rTm~ger c~ccettP,
(Molecular Dynamics) for several hours and hybri~li7~tinn p~ttPrnC were
visually co,~,~ed.
Adjacent contigs i~lentifipci in this manner were targeted for sperific
PCR reactions.
2. Peptide links were made by sea-clling each contig end using
blastx (Altschul et al., J. Mol. Biol. 215:403 (1990)) against a peptide
~l~t~h~ce, If the ends of two contigs m~trh~ the same ~l~t~h~ce sequence in
an a~ manner, then the two contigs were tentatively considered to be
rPnt to each other.
3. The two lambda libraries constructed from H. in~uenaze
genomic DNA were probed with oligomlrl~ooti~e,s clPsi~nP~ from the ends of
contig groups (~irknP.cc et al., Genomics 10:985 (1991)). The positive
plaques were then used to ~lC;~, templates and the sequence was delell,lilled
from each end of the larnbda clone insert. These sequence fr~gmPntc were
searched using grasta against a ~t~h~ce of all contigs. Two contigs that
~l the sequence from the opposite ends of the same lambda clone were
ordered. The lambda clone then provided the temrl~tP- for closure of the
se~ut;llce gap bc~lw~ll the ~ rPnt contigs. The lambda clones were esperi~lly
valuable for solving repeat structures.
4. To confirm the order of contigs found by the other approaches
and ~t~hliCh the order of non-ordered contigs, standard and long range (XL)
PCR re~rtionC were ~l~>ll"ed as follows.
Standard PCR was ~ r~ll"ed in the following manner. Each reaction
C4~ ~ a 37 ~l cocktail; 16.5 ~l H2O, 3 ~l 25 mM MgCl2, 8 ~l of a dNTP
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mix (1.25 mM each dNTP), 4.5 ~1 lOX PCR core buffer II (Perkin Elmer),
25 ng H. influenzae Rd KW20 genomic DNA. The a~lu~liate two primers
(4 ,ul, 3.2 pmole/~l) were added to each reaction. A hot start was pclr~,l"led
at 95~ for S min followed by a 75~ hold. During the hold ~mplitA-l DNA
S polymerase (Perkin Elmer) 0.3 ~Ll in 4.3 ~1 H20, 0.5 ~1 lOX PCR core buffer
II, was added to each reaction. The PCR profile was 25 cydes of 94~/45 sec.,
denAhlre; 55~/1 min., anneal; 72~/3 m~n, eYt~-n~inn. All reactions were
~clrolll,ed in a 96 well format on a Perkin Elmer GeneAmp PCR System
9600.
Long range PCR (XL PCR) was pelrolllled as follows: Each reaction
C~ P,l a 35.2 ~1 cocktail; 12.0 ~1 H2O, 2.2 ~1 25 mM Mg(OAc)2, 4 ~cl of
a dNTP mix (200 ~M final con~nh~ation), 12.0 ~1 3.3X PCR buffer, 25 ng
H. infCuenza~ Rd KW20 genomic DNA. The a~ ,plia~c two primers (5 ~Ll,
3.2 pmoles/~l) was added to each reaction. A hot start was pclrulllled at 94~
for 1 minute. rTth polym~-~, 2.0 ~1 (4 U/reaction) in 2.8 ~1 3.3X PCR
buffer II was added to each reArtion. The PCR profile was 18 cycles of
94~/15 sec., denaLulc; 62~/8 min., anneal and extend followed by 12 cycles
94~/15 sec., dellalulc; 62~/8 min. (in~ilCi3~C 15 sec./cycle), anneal and extend;
72~/10 min., final ~Yten~inn All reA~tion~ were pclr~lllled in a 96 well
format on a Perkin Elmer GeneAmp PCR System 9600.
Although a PCR reaction was pclrulll,ed for e~.liAlly every
c~---hi--Alinn of physical gap ends, techniques such as Southern fingel~ g~
tAhA~e IllA~l~hi~g, and the probing of large insert clones were particularly
valuable in orde~ing contigs A~j~cent to each other and re~ ing the number
of combi~-Ato. ;Al PCR reArtion~ n~Ary to achieve complete gap closure.
Employing these ~ AI~ to an even greater extent in future genome projects
will illl.ilC~sC the overall effici~n~,y of complete genome closure. The number
of physical gaps ordered and closed by each of these techniques is s-lmmAri7t-~1in Table 5.
Sequence ;-~ r~.. ~AI inn from the ends of 15-20 kb clones is particularly
suitable for gap closure, solving repeat structures, and providing general
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confirmation of the overall genome ~sPmhly. We were also con~PrnPA that
some fr~gmPntc of the H. influena~e genome would be non-clonable in a high
copy plasmid in E. coli. We reasoned that lytic lambda clones would provide
the DNA for these segmPntc. A~ IP1Y 100 random plaques were picked
from the ~mplifiPcl lambda library, temrl~tPs y~ d, and sequence
i.~r~,....,.l;nn o~il.ed from each end. These sequences were searched (grasta)
agaulst the contigs and linked in the d~t~h~e to their a~lopliate contig, thus
providing a scaffolding of lambda clones contributing additional support to the
accuracy of the genome assembly (Fig 5). In z~rlr1ition to confirmation of the
contig structure, the lambda clones provided closure for 23 physical gaps.
Approxim~tPly 78% of the genome is covered by larnbda clones.
T~mhl~ clones were also useful for solving repeat structures. Repeat
structures i~lPntifip~1 in the genome were small enough to be sp~nnP~I by a
single clone from the random insert library, except for the six ribosomal RNA
operons and one repeat (2 copies) which was 5,340 bp in length.
Oligo,.~c~ P- probes were rlPqignPd from the unique flanks at the beg;~
of each repeat and hybridized to the lambda lihr~rips. Positive plaques were
identifiP~l for each flank and the sequence fr~gmPnt~ from the ends of each
clone were used to cu~ ly orient the repeats within the genome.
The ability to distinguish and ~qqPmhlP the six ribosomal RNA (rRNA)
operons of H. influena2e (16S subunit-23S subunit-5S subunit) was a test of
our overall ~LId~y to ~quPn~ and assemble a complex genome which might
contain a qignifi~nt l~u-~hr~.~ of repeat regions. The high degree of sequence
qimil~rity and the length of the six operons caused the assembly process to
cluster all the underlying sequences into a few in-liqtinguishable contigs. To
delel...ine the correct pl~PmPrlt of the operons in the sequence, a pair of
unique fl~nking sequences was required for each. No unique fl~nking
sequences could be found at the left (16S rRNA) ends. This region contains
the ribosomal promoter and a~ ed to be non-clonable in the high copy
number pUC18 pl~cmi~ However, unique sequences could be idPntifiP~l at
the right (5S) ends. Oligonucleotide primers were d~P~ignPcl from these six
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fl~nking regions and used to probe the two lambda libraries. For each of the
six rRNA operons at least one positive plaque was i~ ntifi~A which completely
~l~n~ the rRNA operon and contained unique fl~nking sequence at the 16S
and 5S ends. These plaques provided the temrl~tPc for obtaining the unique
sequence for each of the six rRNA operons.
An ~ litinn~1 confirmation of the global structure of the assembled
circular genome was obtained by col..l.~. ;ng a co~ ulel gent;,dt~d restrictionmap based on the assembled sequence for the enzymes Apal, SmaI, and RsrII
with the predicted physical map of l?~Afi~l(l and Lee (Genetic Maps: locus
0 maps of complex genomes, S.J. O'Brien, Ed. Cold Spring Harbor Laboratory
Press, New York, N.Y., 1990, 2110.). The restriction fr~gm~ntc from the
sequence-derived map m~tch~d those from the physical map in size and
relative order (Figure 5).
Editing
~im~ .n~us with the final gap filling process, each contig was edited
visually by re~c~mhling o~ ll~pil.g 10 kb s~tionc of contigs using the AB
AntQA~P~blerTM and the Fast Data F~derTM ha~w~;. AntoA~seml~lerTM
provides a gr~phic~l int~rf~ce to electropher~,gl~un data for editing. The
ele.;lropll~v~ n data was used to assign the most likely base at each position.
Where a discrepancy could not be resolved or a clear ~ccipnm~nt made, the
k,---~;c base calls were left lln-~h~nged Individual sequence changes were
written to the el~L-opllerogram files and a reFli~tion protocol (crash) was
used to m~int~in the ~yl~hl~ny of sequence data between the H. inf~uenzae
~ t:lh~ce and the electropherogram files. Following e~liting, contigs were
re~cc~mhled with TIGR Assembler prior to annotation.
Potential r.~ h;r,.~; identifi~l in the course of annotating the genome
were saved as reports in the ~l~t~h~cP These reports include the coo~linales
in a contig which the ~ nm~nt ~rlWal~ (p~e) predicts to be the most likely
location of a mic.cing or ins~;l~d base and a leprese~ ion of the sequence
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zllignmf nt co..~ g the fr~m~ehift. A~hcnt fr~mf ehifts were used to
in~1ir~tf areas of the sequence which may require further editing. Fr~mPehifte
were not c~,,ccLed in cases where clear electrophelogl~l- data disagreed with
a fr~meshift. Fr~mf ~hifit editing was ~lr~ I-ed with TIGR Editor.
The rRNA and other repeat regions precluded cu. . .~ 'e assembly of the
circular genome with TIGR Acc~ml-ler. Final assembly of the genome was
accomI-liehf~A using comb_ssm which splices together contigs based on short
ov~laps.
Ac~u~~.~, of the Genome Seqr~en~e
The ~rC~ ry of the H. influena~e genome sequence is difficult to
quantitate because there is very little previously determined H. influena~e
sequence and most of these sequences are from other strains. There are,
however, three parameters of accuracy that can be applied to the data. First,
the ~-u---ber of app~cll~ r.,....~h;rl~ in predicted H. influer~e genes, based on
~ h~ imil~ritif~s, is 148. Some of these ~u~c ~L fr~mPehifts may be in the
b~ s~lllf ~ s rather than in ours, particularly coneitlçring that 49 of the
aL~ f ~l r. ,....f ~I.; rl~ are based on ...;.k-1.PS to hypothetical proteins from other
org~ni.em.~. .Se~ond, there are 188 bases in the g.onomP that remain as N
ambiguities (1/9,735 bp). Comhining these two types of "known" errors, we
can calculate a maximum sequence ~cur~ y of 99.98 % . The average
coverage is 6.5X and less than 1% of the genome is single-fold coverage.
Identifying Genes
An attempt was made to predict aU of the coding regions of the H.
irffluenzae Rd genome and identify genes, tRNAs and rRNAs, as well as other
fealu.~s of the DNA sequence (e.g., repeats, regulatory sites, replication
origin sites, nucleotide composition). A descli~lion of some of the readily
a~l,~e.lt sequence fea~ules is provided below.
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TheH. in,fluena~e Rd genome is a circular chromosome of 1,830,121
bp. The overall G/C nucleotide content is ayy~ ldL~ly 38% (A = 31 %, C
= 19%, G = 19%, T = 31%, IUB = 0.035%). The G/C content of the
genome was ~ .in?~A with several window lengths to look for global
structural r~alul~. With a window of 5,000 bp, the G/C content is relatively
even except for 7 large G/C-Ach regions and several A/T-rich regions (Fig.
5). The G/C rich regions CO11QYOI d to six rRNA operons and the location of
a cryptic mu-like prophage. Genes for several pl~,~ins with ~imil~rity to
proteins encoded by b~r-teriophage mu are located at ayyl~x~ t~ly position
1.56-1.59 Mbp of the genome. This area of the genome has a m~rkrAly
higher G/C content than average for H. influena2e (~50% G/C colllyaled to
~38% for the rest of the genome). No ~ignifi~nre has yet been asc~lL~ined
for the source or illlyc~ ce of the A/T rich regions.
The minim~l origin of replir~fion (oriC) in E. coli is a 245 bp region
defined by three copies of a LhilL~Il base pair repeat co~ ini~g a GATC core
sequence at one end and four copies of a nine base pair repeat co~ ining a
TTAT core s~uenee at the other end. The GATC sites are Ill~;Lhylation targets
and control re~lic~tion while the TTAT sites provide the binding sites for
DnaA, the first step in the l~li- ~I;oi~ process (Genes v, B. Lewin Ed. (Oxford
University Press, New York, 1994), chap. 18-19). An ayylo~ y 281 bp
sequence (602,483 - 602,764) whose limits are defined by these same core
sequences ay~al~ to define the origin of re~lir~tion in H. inflluena~7e Rd.
These coc,l~]inaL~s lie b~l sets of ril~osoll,al operons r7nF, rrnE, mzD and
m2~, rrnB, mnC. These two groups of ribosomal o~r~lls are tr~n~crihed in
opyosite directions and the pl~c~m~nt of the origin is con~i~t~nt with their
yGlaliLy for 1., ,.~-;l,lion. Tf-.. ;n~ ,- of E. coli replic~tion is marked by two
23 bp termin~tic-n sequences located -100 kb on either side of the midway
point at which the two repli~tion forks meet. Two ~enLial le ...ii.~ion
~ nr~ sha~ing a 10 bp core s~llonre with the E. coli L~l,ninaLion sequence
were id~ntifi~d in H. influeno~e at cool-lirldL~s 1,375,949-1,375,958 and
1,558,759-1,558,768. These two sets of coordinates are offset a~r~x;...~tely
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100 kb from the point 180~ opposite of the proposed origin of H. influenaze
repli~ tinn.
Six rRNA operons were i~l~ntifie(l Each rRNA operon contains three
rRNA ~ubu~ and a variahle spacer region in the order: 16S subunit - spacer
region - 23S subunit -5S subunit. The subunit lengths are 1539 bp, 2653 bp,
and 116 bp, respectively. The G/C content of the three ribosomal subunits
(50%) is higher than the genome as a whole. The G/C content of the spacer
region (38%) is coneiet~nt with the rçm~in~er of the genome. The nucleotide
sequence of the three rRNA subunits is 100% identic~l in all six ribosomal
operons. The rRNA operons can be gluuped into two classes based on the
spacer region between the 16S and 23S sequences. The shorter of the two
spacer regions is 478 bp in length (rrnB, rrnE, and rrnF) and cont~ine the gene
for tRNA Glu. The longer spacer is 723 bp in length (~7n4, rrnC, and rrnD)
and contains the genes for tRNA Ile and tRNA Ala. The two sets of spacer
regions are also 100% i~lentirzll across each group of three operons. tRNA
genes are also present at the 16S and 5S ends of two of the rRNA operons.
The genes for tRNA Arg, tRNA His, and tRNA Pro are located at the 16S end
of rrnE while the genes for tRNA Trp, and tRNA Asp are located at the 5S
end of rrnA.
The predicted coding regions of the H. ir~fluenaze genom~ were initially
defin~cl by evaluating their coding potential with the program G~n~m~rk
(Borodovsky and ~rcTninc~h, Computers Chem. 1 7(2): 123 (1993)) using codon
frequency m~tric~s derived from 122 H. influena~e coding sequences in
GenR~nk The predicted coding region sequences (plus 300 bp of fl~nking
~5 sequence) were used in ~rches against a ~l~t~h~e.o of non-rec~lln~l~nt b~ct~ri~l
proteins (NRRP) creat~d spel~-ifir~lly for the annotation. ~llnrl~ncy was
removed from NRBP at two stages. All DNA coding sequences were
extracted from (3~nR~nk (release 85), and sequences from the sarne species
- were searched against each other. Sequences having >97% eimil~rity over
regions > 100 nucleotides were combined. In addition, the sequences were
tr~n~l~ted and used in protein co...p~. i eons with all sequences in Swiss-Prot
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(release 30). Sequences belc-nging to the same species and having >98%
~imilArity over 33 amino acids were combined. N~RP is composed of 21,445
sequences eYtrA~ted from 23,751 GPnRAnk sequences and 11,183 Swiss-Prot
sequences from 1,099 dirr~ -- s~i~s.
A total of 1,749 predicted coding regions were i~1e-n*fi-P~l Searches of
the H. infilenz~e predicted coding regions were ~ ro~llled using an algorithm
that I I A ~ '~ the query DNA s~quPn/ ~ in the three plus-strand reading frames
for sear~llillg against NRBP, idPntifiPs the protein sequences that match the
query, and aligns the protein-protein mAt hPs using praze, a mn-lifiPA Smith-
Waterman (Pearson and TipmAn, Proc. Na~l. Acad. Sci. U.S.A. 85:2444
(1988)) algorithm. In cases where insertion or rlPl~*on~ in the DNA sequence
produced a frAm~chift error, the AlignmPnt algorithm started with protein
regions of Ill~ imilArity and eYtende~ the AlignmPnt to the same
tlAtAhA~P match in alternative frames using the 300 bp fl~nking region.
Regions known to contain frameswft errors were saved in the .iAt~hA~P and
evaluated for possible co,recLion. Uni~pnt*fie~ predicted coding regions and
the ~e.~ining inl~,ellic sequences were s~uclled against a dataset of all
available peptide sequences from Swiss-Prot, PIR, and GPnRAnk
TdPntific~tion of operon structures will be f~rilitAtP~1 by ~,~. ;.--Pnt~l
dt;l~ aLion of tr~n~l~ription ~."lllo~l and t~ n sites.
Each putatively identifip~1 H. influena2e gene was A~eignP~l to one of
102 biological role catc~olies adapted from Riley (Riley7 M., Microbiology
Reviews 57(4):862 (1993)). ~ignmentc were made by linking the protein
~uence of the predicted coding regions with the Swiss-Prot sequences in the
~5 Riley ~iAtAh~e Of the 1,749 predicted coding regions, 724 have no role
A~ignment. Of these, no rlAtAhA~e match was found for 384, while 340
m~trhP~1 "hypothetical proteins" in the ~l~tAhA~P Role Ac~ignmPnts were made
for 1,025 of the predicted coding regions. A compilAti~ n of all the predicted
coding regions, their unique i~1pntifiers~ a three letter gene idPntifier, percent
identity, ~lce~ imilArity, and amino acid match length are ~ sented in
Table l(a).
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An annotated complete genome map of H. influenaze Rd is ~,csell~ed
in Figures 6(A)-(D). The map places each predicted coding region on the H.
inf~uenaze chromosome, in~ tPc its direction of tr~nccription and color codes
its role ~cci~nmPnt Role ~ccignmf ntc are also lc~lcscl~Lcd in Figure 5.
S A survey of the genes and their chromosomal o~ t;l n in H.
influenaze Rd make possible a description of the metabolic pn,cesses H.
influenaze requires for survival as a free living org~nicm, the mltrhion~l
requirements for its growth in the laboratory, and the charactprictic-s which
make it unique from other or~nicmc c~ifi~lly as it relates to its
p~thOgr~ y and virulence. The genome would be l_A~ ed to have complete
complementc of certain classes of genes known to be eccenti~l for life. For
PY~mp'-, there is a one-to-one ~lle:,~on-len~e of published E. coli ribosomal
protein sequences to potential homologs in the H. influenaze ~l~t~h~ce
Likewise, as shown in Table l(a), an aminoacyl tRNA-synth~-t~ce is present
in the genome for each amino acid. Finally, the location of tRNA genes was
mapped onto the ~enom~ There are 54 i-lentifi~d tRNA genes, inclutlin~
s~ es of all 20 amino acids.
In order to survive as a free living org~nicm, H. influenaze must
~l~luce energy in the form of ATP via r~ ;nn and/or electron transport.
As a f~yllt~tive anaerobe, H. influenaze Rd is known to ferment glucose,
fructose, g~l~ctosp7 ribose, xylose and fucose (Dorocicz et al., J. Bacteriol.
175:7142 (1993)). The genes ide-ntified in Table l(a) in~ te that transport
systems are available for the uptake of these sugars via the
phosphoenolpyruvate-phosphotransferase system (PTS), and via non-PTS
,~ ---C Genes that specify the co----- ~ hc~ ~carriers Enzyme I and
Hpr (ptsl and ptsH) of the PTS system were identifie~ as well as the glucose
specific crr gene. The ptsH, ptsl, and crr genes c~ the pts operon. We
have not however identifif-ci the gene Pn-~ling membrane-bound glucose
specific ~y~-le Il. The latter enzyme is r~uilt;d for transport of glucose by
the PTS system. A complete PTS system for fructose was idP~tifie l.
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Genes ~nr~lin~ the c~....pl~ ~ . glycolytic ~.~v~ and for the production
of fprmpnt~tive end products were id~ntifipl1 Growth utili7.ing anaerobic
r~ y m~h~ni.~m~ were found by ide,~lifyi,lg genes encoding filnl~tion~l
electron t~ systems using inol~,~nic electron ~ccel~lo. ~ such as nit~t~s,
S nitrites, and dimethylsulfoxide. Genes encoding three enzymes of thetric~l,~,Aylic acid (TCA) cycle appear to be absent from the genome. Citrate
synthase, i.~;l.,.lt~ d~l~y~,ge~, and acordtase were not found by searclling
the predicted coding regions or by using the E. coli enzymes as peptide queries
against the entire genome in tr~n~l~tit~n This provides an explanation for the
very high level of ~,l."~ (lg/L) which is l~ui~ed in ~lefin~d culture media
(E~lein and L~ul~ul~l, J. Gen. Microbiol. 113:409 (1979)). (~lut~m~tt~ can be
dil~;l~d into the TCA cycle via cc"l~/t;l:,;oll to alpha-ketogh~ te by gl,.
dehydrogenase. In the absence of a complete TCA cycle, p;~ t~
~r~;,~l...~hly serves as the source of carbon for biosynthesis of amino acids
using pl~;UlS~ i which branch from the TCA cycle. Funcfic-n~l electron
transport systems are available for the prodllction of ATP using oxygen as a
t~rmin~l electron acceptor.
Previously ul~~ d ~luc~lions l~~d~ thog~onicity and virulence
can be addressed by r~ ;n;~g certain classes of genes such as adhesions and
the lipooligo~ h~ri~e biogenesis genes. Moxon and co-wc,lkrl~ (Weiser et
al., Cell 59:657 (1989)) have obtained evidence that a number of these
virulence-related genes contain tandem lPI ,. . . ~~r repeats which undergo
frequent addition and del~*c n of one or more repeat units during replie~ti(ln
such that the reading frame of the gene is changed and its r~lession thereby
altered. It is now Fo~.~ihl~., using the complete genome sequence, to locate allsuch tandem repeat tracts (Figure 5) and to begin to determine their roles in
phase v~ri~til n of such pole"li~l virulence genes.
H. in.fluenzae Rd pqss~-s a highly effit~ient natural DNA
r..i ...i~l;on system (Kahn and Smith, J. Membrane Biol. 138:155 (1984).
A unique DNA uptake sequence site, 5' AAGTGCGGT, present in mllltiple
copies in the genome, has been shown to be nP~ ~.y for effiçient DNA
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uptake. It is now possible to locate all of these sites and completely describe
their distribution with respect to genic and u~ ,ellic regions. Fifteen genes
involved in tran~ro~ ation have already been described and sequenced
1fiPl~l, R., J. Bacteriol. 173:5612 (1991); Ch~ntllpr~ M., Proc. Natl. Acad.
S Sci. U.S.A 89:1616 (1992); Barouki and Smith, J. Bacteriol. 163(2J:629
(1985); Tomb et al., Gene 104:1 (1991); Tomb, J, Proc. Natl. Acad. Sci.
U.S.A 89:10252 (1992)). Six of the genes, cornA to comF, comprise an
operon which is under positive control by a 22-bp palindromic co-ll~nce
regulatory el~mpnt (CRE) about one helix turn U~ tiealll of the promoter. The
rec-2 Lldllsr ,. ,.. ~linn gene is also controlled by this pl-omPnt It is now possible
to locate additional copies of CRE in the genome and discover potential
tran~r~,llll~Lion genes under CRE control. In addition, it may now be possible
to discover other global regulatory çlemPntc with an ease not previously
possible.
One well-described gene regulatory system in b~etPn~ is the "two-
colllponent" system composed of a sensor m~1e~ll1P that detects some sort of
environmPnt~l signal and a regulator molcculP that is phosphorylated by the
activated form of the sensor. The regulator protein is generally a tr~nccriI)tion
factor which, when activated by the sensor, turns on or off e~les~ion of a
specific set of genes (for review, see .Alhright et al., Ann. Rev. Genet. 23:311(1989); Parkinson and Kofoid, Ann. Rev. Genet. 26:71 (1992)). It has been
~-~ili...;.l~l that E. coli harbors 40 sensor-regulator pairs (Albright et al., Ann.
Rev. Genet. 23:311 (1989); Parkinson and Kofoid, Ann. Rev. Genet. 26:71
(199V). TheH. influena2e ~enomP was searched with r~>lçsç~.l;.li~e proteins
from each family of sensor and regulator proteins using tblastn and tfasta.
Four sensor and five regulator proteins were idPntifie~l with cimil~rity to
proteins from other species (Table 6). There ~ to be a corresponding
sensor for each regulator protein except Cp~R. Searches with the CpxA
protein from E. coli idPntifiP~ three of the four sensors listed in Table 6, butno ~ 1itinn~1 ci~nifie~nt m:~t~.hP.s were found. It is possible that the level of
sequence .cimil~rity is low enough to be llnrlçt~P~t~hle with tfasta. No
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representatives of the NtrC-class of regulators were found. This class of
proteins intpr~ct~ dir~;lly with the sigma-54 subunit of RNA polymPr~P
which is not present in H. iny1uenaze. ALl of the re~ t~r proteins fall into theOmpR subclass (.Alhri~ht et al., Ann. Rev. Genet. 23:311 (1989); p~rkin~on
and Kofoid, Ann. Rev. Genet. 26:71 (1992)). The phoBR and basRS genes of
H. influenaze are ~dj~ nt to one another and ~rG~.. ~hly form an operon.
The nar and arc genes are not located ~ rPnt to one another.
Some of the most ihllGlei,Li"g questions that can be answered by a
oo rl gen~mP sequence relate to what genes or pd~lW~y~ are absent. The
non-~~ gr.~ H. iny?uenaze Rd strain varies ~i~ifi~ntly from the pathogenic
serotype b strains. Many of the dirr~.e-~ces bG~een these two strains appear
in factors affecting infectivity. For PY~mpkP, the eight genes which make up
the fimbrial gene cluster (vanHam et al., Mol. Microbiol. 13:673 (1994))
involved in ~lh~inn of b~r~ i~ to host cells are now shown to be absent in the
Rd strain. The pepN and purE genes which flank the fimbrial cluster in H.
i~1uena~ type b strains are ~ rPnt to one another in the Rd strain (Fig. 7),
.gge j~;.-g that the entire fimhri~l duster was eY~i~l On a broader level, we
d which E. coli ~ s are not in H. inJquenzae by taking advantage
of a non-re~--n-l~nt set of protein coding genes from E. coli, namely the
University of W;~ fiPn~mP. Project contigs in (3Pn~nk 1,216 predicted
protein sequences from fienR~nk ~c~ ns D10483, L10328, U00006,
U00039, U14003, and U18997 (Yura et al., Nucleic Acids Research 20:3305
(1992); Rllrl~nd etal., Genomics 16:551 (1993)). The ...;n;...~... threshold form~tçhes was set so that even weak m~tehPs would be scored as positive,
thereby giving a minim~l e~ e- of the E. coli genes not present in H.
iry~uenaze. tblastn was used to search each of the E. coli proteins against the
complete genome. A~l blast scores > 100 were considered m~tl~hes.
Altogether 627 E. coli proteins m~tf.ll~ at least one region of the H.
iry~luenaze genome and 589 proteins did not. The 589 non~ .;..g proteins
were ~ ;.. ;.~ and found to contain a ~ lionate number of hypothetical
proteins from E. coli. Sixty-eight percent of the itlentifiecl E. coli proteins
-68-
SUB5TI~UTE S~tEET tRULE 2~i)
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were m~t~hP~1 by an H. influenaze sequence whereas only 38% of the
hypothetical proteins were m~tchf?ll. Proteins are annotated as hypothetical
based on a lack of ~ S with any other known protein (Yura et al., Nucleic
Acids Research 2~.3305 (1992); Rllrl~n-l et al., Genomics 16:551 (1993)). At
least two ~ùlcllLial PYpl~n~tions can be offered for the over l~,l;se~ on of
hypothetical ~lulci~ls among those without .~ hPS some of the hypothetical
proteins are not, in fact, tr~n~l~tP~ (at least in the annotated frame), or these
are E. coli-specific proteins that are unlikely to be found in any species except
those most closely relatcd to E. coli, for PY~mrle Salmonella typhimurium.
A total of 384 predicted coding regions did not display .cignific~nt
cimil~rity with a six-frame tr~n~l~tion of GPnR~nk release 87. These
nni~lPntifiP~ coding regions were colll~d to one another with fasta. Several
novel gene f~miliPs were idP-ntified. For PY~mple, two predicted coding
regions without ~t~h~ce m~tfhP.s (HI0591, HI0852) share 75% identity over
almost their entire lengths (139 and 143 amino acid residues rc~ rely).
Their .cimil~rity to each other but failure to match any protein available in the
current d~t~h~ees suggest that they could lc~lcselll a novel cellular function.
Other types of analyses can be applied to the ~mi~l~ntifiPfl coding
regions, int~ inE~ hydru~llly analysis, which in~ tPs the p~ttPrnc of
potential membrane-cp~nning domains that are often conserved bclweel~
members of lcce~lol and L-a,ls~llcl gene f~miliPs, even in the absence of
significant amino acid identity. Five ~Y~mpl~s of uni~lentifi~i predicted
coding regions that display polcll~ial tr~ncmpmbrane domains with a periodic
pattern that is ch~r~tPrictic of membrane-bound ch~nnPl proteins are shown
in Figure 8. Such in~llllaLion can be used to focus on spe~ific aspects of
cellular function that are ~rr~l~d by targeted dPl~tion or mutation of these
genes.
Interest in the mPAic~lly illl~ll~ aspects of H. infl~uenaze biology has
~ focused particularly on those genes which ~letPrminP virulence ch~r~tPrictics
of the C,l~ lll. Recently, the catalase gene was c-h~r~ teri7Pd and sequenced
- as a possible virulence-related gene (Bishai et al., J. Bacteriol. 176:2914
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SU8STTTUTE S~EET tRULE 26)
CA 02218741 1997-10-21
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(1994)). A number of the genes responsible for the capsular poly~rçh~ricle
have been mapped and sequenced (Kroll et al., Mol. Microbiol. 5(6):1549
(1991)). Several outer membrane protein genes have been i~l~ntifi~1 and
sequenced (Langford et al., J. Gen. Microbiol. 138:155 (1992)). The
lipooligosaccharide co---ponent of the outer membrane and the genes of its
synthetic ~Lhw~y are under intensive study (Weiser et al., J. Bacteriol.
l 73:3304 (1990)). While a vaccine is available, the study of outer membrane
components is motivated to some extent by the need for improved vaccines.
Data A~ fy
The H. influenaze genome seq~l~n-~ has been deposited in the Genome
Sequence D~t~R~ (GSDB) with the ~rc~ic n number L42023. The
nucleotide sequence and peptide tr~n~1~tinn of each predicted coding region
with i~l~ntifi~ start and stop codons have also been ~e~ioned by GSDB.
Production of an Antibody to a Haeml r ~. 7~s influen~ Protein
Subst~nti~lly pure protein or polypeptide is isolated from the
L~l or Lld--srol..~d cells using any one of the ,,,~1.o~iC known in the art.
The protein can also be produced in a recombinant prokaryotic eA~res~ion
system, such as E. coli, or can by ch~mic~lly synth~i7Pd ConcPntr~tic)n of
protein in the final ~ n is adjusted, for example, by con~ntr~tinn on
an Amicon filter device, to the level of a few miclu~ la,l-s/ml. Monoclonal or
polyclonal antibody to the protein can then be pr~cd as follows:
Monoclonal Antibody Production by Hybndoma Fusion
Mnno~ n~l antibody to cpilopes of any of the peptides identifiç~l and
isolated as d~-~ihed can be pl~C d from murine hybridomas according to the
cl~ic~l method of Kohler, G. and Mil~tein, C., Na~ure 256:495 (1975) or
-70-
SUBSTITUTE S~tEET tRULE 2~;)
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modifit ~tions of the methods thereof. Briefly, a mouse is le~LiLi~ely
inoculated with a few micrograms of the sPl~t~1 protein over a period of a
few weeks. The mouse is then ~-rifi-ed, and the antibody producing cells of
the spleen i~l~t~d The spleen cells are fused by means of polyethylene glycol
with mouse myeloma cells, and the excess unfused cells de~Lluyc~d by growth
of the system on selective media comrri.~ing aminopterin (HAT media). The
~"~f ~i~r"lly fused cells are diluted and aliquots of the dillltion placed in wells
of a microtiter plate where growth of the culture is continued. Antibody-
producing clones are idPntifi~l by det~tion of antibody in the Su~-~ t
fluid of the wells by i-i----l---~e~y procedures, such as ELISA, as origin~lly
described by Engvall, E., Meth. Enymol. 70:419 (1980), and modified
methods thereof. Sele~ted positive clones can be exp~n-1e~1 and their
monoclonal antibody product harvested for use. Detailed procedures for
monoclonal antibody prod~lctinn are described in Davis, L. et al. Basic
Methods in Mol~-ll~r Biology Elsevier, New York. Section 21-2 (1989).
Polyclonal An~ibody Pro~ tion by Imm~ ~'iolz
Polyclonal ~~ ulll c ~ g antibodies to heterogenous ~iL~pes of
a single protein can be prt~ed by i-------~ g suitable ~nim~l~ with the
s~d protein described above, which can be unmodified or modified to
e~h~n~ e ;.. i~g~ ity. Effective polyclonal antibody production is affected
by many factors related both to the antigen and the host species. For example,
small mc l~lll~-s tend to be less immllnogenic than other and may require the
use of carriers and adjuvant. Also, host ~nim~l~ vary in response to site of
inocul~tion~ and dose, with both inadequate or excessive doses of antigen
resulting in low titer ~nti~ Small doses (ng level) of antigen ~imini~et~red
at multiple intr~-lermal sites a~ to be most reliable. An effective
~ i.. -.. ~;,i1l;on protocol for rabbits can be found in V~itllk~iti.C, J. et al., J.
Clin. Endocrinol. Metab. 33:988-991 (1971).
-71-
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Booster injections can be given at regular intervals, and antiserum
harvested when antibody titer thereof, as dcLellllined semi~ ely~ for
e7 by double immlln-Yliffusion in agar against known con~ntr~tion~ of
the antigen, begins to fall. See, for PY~mple, Oucht~rlony, O. et al., Chap.
19 in: Handbook of Experimental Immunology, Wier, D., ed, Blackwell
(1973). Plateau c~ n of antibody is usually in the range of 0.1 to 0.2
mg/ml of serum (about 12 ~cM). Affinity of the ~nti~r~ for the antigen is
determined by prcl~ing colll~cLiLi~le binding curves, as described, for
e-~mpl~, by Fisher, D., Chap. 42 in: Manual of Clinical Immunology, second
edition, RoseandI~ n, eds., Amer. Soc. ForMicrobiology, W~hington,
D.C. (1980).
Antibody ~le~.,~;( n~ prepared accol~ g to either protocol are useful
in 4~ e immunoassays which determine con~-ntr~tions of antigen-
bearing ~lb~ P-s in biologi~l s~ --F'--; they are also used semi-~ nf;li.li~ely
l~i or qualitatively to identify the p~e3ellce of antigen in a biological sample.
Preparation of PCR Primers and Amplification of DNA
Various f~gm~nts of the Haemophilus influenzae Rd genome, such as
those disclosed in Tables l(a) and 2 can be used, in accordance with the
present invention, to ~rc~alc PCR plilllcl~ for a variety of uses. The PCR
primers are ~lcÇ~dbly at least 15 bases, and more preferably at least 18 bases
in length. When sP~ ting a primer sequence, it is ~lcrcllcd that the primer
pairs have app~ ly the same G/C ratio, so that m~lting telll~ldlules are
approxim~te-ly the same. The PCR primers and ~mplifi~l DNA of this
FY:Imr)le find Use in the FY~mples that follow.
Gene ~ on from DNA Seq~le~es Conesponding to ORFs
A fr~gmPnt of the Haemophilus infl!uen~:ae Rd genome provided in
Tables l(a) or 2 is introduccd into an c~,lc:ision vector using convention~
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te~hnolngy. (Techniques to transfer cloned sequences into GA~re~sion vectors
that direct protein tr~n~l~tion in ~ ,.."~ n, yeast, insect or b~ctPri~l
~A~1~7~10n systems are well known in the art.) Co~ nGl- ially available vectors
and eAyre~:,ion systems are available from a variety of suppliers inrl~lrling
S str~t~E~Pn~ (La Jolla, California), Plu~ega (Madison, Wisconsin), and
Invitrogen (San Diego, California). If desired, to enh~nre ~A~ ssion and
f~ilit~t~ proper protein folding, the codon conteAt and codon pairing-of the
sequence may be o~Li..-i ~ed for the particular GA~les~ion org~ni.~m, as
~Yrl~in~d by ~tfiF-l~l et al., U.S. Patent No. 5,082,767, incol~uldlGd herein
by this reference.
The following is provided as one eyenlrl~ry method to generate
polypeptide(s) from cloned ORFs of the Haemophilus genome fr~gm~nt
Since the ORF lacks a poly A sequence because of the b~rt'--ri~l origin of the
ORF, this se~lue lce can be added to the construct by, for example, splicing outthe poly A sequence from pSGS (Str~t~genP) using Bg~I and SalI restriction
endonurle~ enzymes and inccl~ld~ing it into the m~mm~ n ~A~lc;ssion
vector pXTl (str~t~genp) for use in eukaryotic t;Apl~ion systems. pXTl
contains the LTRs and a portion of the gag gene from Moloney Murine
Leukemia Virus. The position of the LTRs in the construct allow effici~nt
stable ll~.~r~;lion. The vector inr~ es the Herpes ~impleY thymidine kinase
promoter and the sPlPrt~hle neomycin gene. The Haemophilus DNA is
obtained by PCR from the b~Ctpri~l vector using oligonucleotide prim.ors
complemPnt~ry to the Haemophilus DNA and co~ g restriction
endonuclease se~luel~ces for PstI incol~la~d into the S' primer and Bgm at
the 5' end of the corresponding Haemophilus DNA 3' primer, taking care to
ensure that the Haemophilus DNA is po j;l ionP~ such that its followed with the
poly A sequence. The purified fr~gm~nt obtained from the r~s~llting PCR
reaction is ~I;gr.~l~ with PstI, blunt ended with an e~rom~cl~ -, digested with
Bgm, purified and ligated to pXTl, now colll;.i.-;..~ a poly A sequence and
digested Bgm.
SU8STTTUTE SHEET tRULE 26)
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The ligated product is transfected into mouse NIH 3T3 cells using
Lipofectin (Life Te~hnolngies, Inc., Grand Island, New York) under
conditions outlined in the product specific~tion. Positive tran~r~;l~ are
s~-lected after growing the tr~n~f~tPA cells in 600 ug/ml G418 (Sigma, St.
Louis, Missouri). The protein is preferably released into the ~ t
However if the protein has membrane binding domains, the protein may
~ddition~lly be retained within the cell or e~res~ion may be rçstficte l to the
cell sllrf~re
Since it may be n~ry to purifv and locate the tf~n~fect~i product,
svntnetic 15-mer peptides synth~i7P~l from the predicted Haemophilus DNA
sequence are injected into mice to generate antibody to the polypeptide
encoded by the Ha~mophilus DNA.
If antibody p~ lc~ is not possible, the Ha~mophilus DNA sequence
is ~rlrlitinn~lly incul~oldt~d into eukaryotic c;A~ ion vectors and t;A~ sed
as a chimPric with, for eY~mrl~-, B-globin. AnLil~ody to B-globin is used to
purify the çhim~fic. Co,lt:~nding protease cleavage sites ~ngin~fed
b~Lw~l- the B-globin gene and the Haemophilus DNA are then used to s~~
the two polypeptide ff~gmPnt~ from one another after tf~n~l~tion. One useful
~A~l~on vector for pe~ B-globin chim-ofir~ is pSG5 (Str~t~genP). This
vector encodes rabbit B-globin. Intron II of the rabbit B-globin gene f~rilit~t~s
splicing of the t;Apr~i,sed tf~n~r-fipt, and the polyadenylation signal
inc~l~uldl~d into the consL.u~;~ increases the level of ~Al~ression. These
techniques as ri~ ~ ;1~1 are well known to those skilled in the art of molecularbiology. Standafd mf~.th~l~ are published in methods texts such as Davis et al.
and many of the methods are available from the terhnir~ iSt:3nr~
e~le,~ es from Stf~t~g~ne, Life Te~hnol~ gies, Inc., or Promega.
P~ly~lide may ~ ition~lly be produced from either construct using in vitro
tr~n~l~tion systems such as In vitro Express~M Tr~n~l~ticm Kit (str~t~g~on~-).
While the present invention has been described in some detail for ~ oses
of clarity and un~ g~ one skilled in the art will appreciate that various
SU8S i l l UTE 5}~EET tRULE 26)
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~~.h~nges in form and detail can be made without departing from the true scope
of the invention.
All p~tf~.nt~, patent applications and public~ticn.c referred to above are
hereby inc~ dl~d by reference.
SUB5TITUTE SHEET (RULE 26
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0 ~ ~D
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SUBSTITUTE S}~EET (RULE 2~i~
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CA 02218741 1997-10-21
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SUBS 111 UTE S~ET (RULE 2fi3
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764
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SUB5 111 UTE SHEET tRULE 2~)
CA 02218741 1997-10-21
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76.5
SU8STITUTE S~EET (RULE 26
CA 02218741 1997-10-21
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O -- -- -- O _ -- -- -- O O O _
- m I I I I I I I I I I I I
766
SUBSTJl UTE S}~ET tRULE 26)
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
~ 0 0 ~r o ~ O tS~ 0 ~ O r~
a~ o o a~ ~ ~ 0 c~
t~ 0 0 ~ t'_ ~D ~ C'~ ~ 0 0 0 ~
-- ~ _ C'~ ~00 _ ~ 0 ~D t~ C" ¢~ 0 er
._
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S ~O ~O o S o S ~ a ~ ~ _
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Q ô ô _ llJ ~D '3 m ~~, sC Q .. ,~ Q Q ~ ~ ~D 0
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s s ~ _ C2 Q_ D ,C C~ S S -C '~ ~D t~S
, ~ ' ;' ~ = . E O '~ ~E s D = ~ =~
O C) ~ ~ D ~~ ~ ~ ~C C Q Q ~ tD ~
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0 ~ ~ ~ ~ ~ C ~ ~ ~ ~ ~ _ ~ ~ Q ~
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O _ _ _ _ _ O O _ _ _ _ _ O _ _ O O
I T I I I I I I I I I I I I I I I
76.7
SUB5~TUTE S~E~ tRULE 2
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
-- --I,~ ~D O U~ m 0 ~ O u~ _ _ 0 a~
<1~ 0 0 t~ 0 0 0 u~
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I~~ s _ ~ co ta -- s ~ -- ~) ~
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~ Q ~s~ sc ~ O_ c C E ~ ~
,c o ,c Q ~ ~ C -- -- E ~ ~ X C~ ~ o C a~ o
o s o 5 ~~ e ~ s ~ ~ ~ ~ s = E ~ ~o s
~ ,~ o _ ~ a~ o ~ ~ ~ ~ o) o o
0 ~ ~ ~ o ~ ~E ~ ~
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0 ~ ~D ~ ~ 0 a~ U~ _ 0 0 ~_ ~ tD U~ 0 0 N
~ O r~ 0 ~ r-- 0 C~J 0 D _ C~l 0 N ~~ O C C~
a~ ro C~l O ~ ~ C~l ~ ~ 'C C''l '
-- a~
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O _ ~ c~ t~ 0 u~ J V ~ 0 ~ 0
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c _ O C'.l ~ O 1' 0 0 1' 0 C" 0 C -- C~ L' C"l t~ G E c~ _
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_ I I I I I I I I I I I I I I I I I I
76.8
SU8STJ~UTE ~H~:ET tRULE ~6)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
~ J ~ o ~ o ~ ~ _ o ~ ~ ~ ~ ~ ~ ~ o ~ ~
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E _ .~
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ID c aC~ 2 tED ~ '' Q C N E 0 -- --I 0 8 ~
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c ._ ~ ~0 ~ ~c ~ E E E ' ~ -
'~ ~ ~0-- C ~ E o C ~ C C C ~
j ~ a E ~ e
C C O _ Q Q ~c _C~l a~ _C C .- _ - ~- E o c o Q
-- _ 0 )~ ~ c~ r 0 u~ D ~ 0 ~ a~ c~ c~ ~ _
U~~ ~ t -- ~~ e~ ~ ~ O ~ C~l 0 _ C~ C ~ O
~ r~ L~ C~ J O ~t _ tD '-J 0 0 0 Lt ~ 0 ~ ~
L ~ C Q ~ ~r 1~ ~ 1~ 0 0 1-- C~ ID O 0
C~l ~D ~r N ~ .Q ~ 0 el -- ~ 0 0
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~) -- ~ r_ 0 _ .n ~_ ~) L~ ~ ~~ O 0 ~ _ 0
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O O O _ _ O = _O O O O _ O O O O O O _ O O O
O~ _ _______________
I I I I I I ~ II I I I I I I I I I I I I I I '
76.9
SU~SmUTE SHEET ~RULE 2~i~
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
r~ o u~ 0 1-~ 0 o 0 ~ ;q ~ 0 c~ t~ o _ ~r ~ I~
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~ 0 0 a~ I~ O 0~ 0 o 0) 0 a) o) o
_ o c~ 0 u~ ~ o~ > CD 0 C'~ 0 ~ O 0 0 ~O ~0 W 00 u~ a~ 1~ ~ 0 c~ ~ 07 0 a~ 0 ~ tD 0 a~ a) o) o o)
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s sO e s C 3 -- s s S s s s se
v ~ 0 ~ ~ ~ ~ ~ ~ ~ ~ ~- ~ Q
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o O c c c C ~ I I
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g O E D C ~ ~ s ~ = s s tu tD _ ~ ~ ~ tD
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t~ :~J 0 tD 0 Lo tD ~ ~ ~ 0 ~ O O _ _ N ~ _ _ tD tD D tD D ~ ~
0 ~O t. _ _ 0 a~ tD tD ~-- tD tD tD tD _ Lt~ a 0 ~ 1~ r~ ~ r~ ~_
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t~ ~1 0 0 ~~ t ~ t~ 0 a~ Lo er o 0 1~ -- 0 0 ~~ -- t ~l
aD tD 0 -- ~ 7 0 tD Ln tD ~-- 0 0 ~ L~ 1~ 0 O 0 0 t_ tD Lr
C~ 0 tD 0 L~ ~ _ ~ t - ~t O O O _ c~ t~l _ ~ tD tD tP tD tD
~ tD tD -- -- ~ 0 tD tv 1~ tD tD tD tD _ Ln 0 0 ~-- 1~ 1~ r~ r-- r~
O~ _ _ _ _ _ _ _ _ _ _ . _ _
t!~ 0 ~ 0 1~ 0 ~ t!~ ~ t~ ~ Ln tD t ~ J ~ t~ tD LO ~ 0 t ~1 _
tD Lo o _ Ln _ ~_ 0 Ln 0 ~ ~ ~ ~ tD Ln tO tD O O O O O O
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-- O _ _ O O O _ O _ _ _ _ _ _ O O O _ ~ _ _ _ ~
~ I I I I I I I I I I I I I I I I I I I I I I I I
76.10
SUBSTTTUTE SHEET tRULE 26)
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
O tD ~ O ~o o ~ ~ a~
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o ~ o ~ ~ ~ ~ ~ Q _ ~ ~ ~ ~ ~ _
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Q Q X '_ ~~ ~ C ~'C E ~E ~ - Z Z Z ~ ~
c ~ ~ 3 o Q ~ ~ ~ ~ o ~ ~ ~ ~ ~ o ~
~ ~ O C ~ ~ ~ O ~L o a~ ~ ~ O
~c~ c z ~ O O O E~ m m ~ 0 3 3 Q Q Q =
~ g X ~ ~, ZQ Z. ~ E.' .~ .c ~ ~ c
0 0 0 ~ g g g ~ ~'~ ~ ~ O c .C oQ oQ oQ oQ.Q 2
C~ c~ ~ o
cn 0 c~J~ c o ~D c~J cn c~
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a) ~D 0 0 _ C~J C~l C~~ O ~ 0 ~ U7 ~ ~ cr~
-- ~ C~ l _ 0 0_ 0 _ ~ ~ ~ U~ ~ ~ C~ ~ 0
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~- '~ o r- -- _ o o 1' o 8 g '- ~ g ~r _ ~ g 0
I T T I I I ~ I I T I I I I I I I I I I
76.11
SUB5TTTUTE ~iHE~ tRULE
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
o C'~ 1~ 0 C~l C) O~ t~ 1~ ~ Cl~ O N C'~ 0 0 0 1~ r--
- 0u) t~ t~ o 1~ ~ D 0~ O 0i _ 0 ~ t~
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~~ C -C O ~ O
S o O o S S S
c = = s s E _ ~ c s ~ ~~ ~ ~
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c m ~ ~~ ' _ o ~ E 2 2 2 ~ E ~~ '
- Q a~ -- Q ~ Q C c c ~ C C a~ ~ o at ~ E
~ ~ ~ ' ~ ~ ~ ~ ' E 2 ~ 2 2 ~n c~ ~ , c
E 4 = E -- E 7' ' ~ ~ ~ o ~ ~ E
D -- = = ~ ~ -- ~o o o ._ S S S S = o E c ~ ~ =
--Q _ N O 0 ~J 0 0 _ O> ~D _ ~ a~ 0 O ID O C'~ ' 0 O N tS~
ID 0 ~-- ID _ ') O ID ~ ~ O ~ ID O N ~ D 0 ~r N
Q ~r N 0 tD D Cl) 0 (~ ~ O ~ D N ID 1~ 0 ID N _ N ~ 0
_ ID 0 a~ 0 _ 1~ N 0C'~ 0 _ _ O N O a~ _ O N 1~ 0 ~ 0
0 0 0 O CD 0 0 C'~ N_ O ~ C'~ ~ ~r 0 0 0 0 0 ~r O O
_ r-- N ~ er1~ C~.l N 0 N N N 0 _ N N ID
~- -- - - --- - -_ _
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S _ _ ~ _ O ~ N N _ C~ _ NO NO ID
_
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t~ ~ c,~ a~ c0, ~ 2 o _ _ 2 2 2 2 C ' ~ C'' c ~ ~ 0 ~ c ~ 0
__oo _ooo_ ooooo___o_ __
I I I I I I I I I I I I I I I I I I I I I I I
76.12
SUBSTITUTE SHF~ tRULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/05320
_ ID _ 0 tD O ~ O O O ~ -- O
cq _ o o oa> c~J _ ~ _ ~I c~l o o~
-- _ N O
N ~ ~ ~ _ ~ ~D O tD
s, ~ a
~ , ~ ~ ~O ~" C ~ O ~
5~ oQ,CL C ~ ~DS C~ ~ o c o ~
O O O O ~ _o s E c ~ E ~s,
E--0 ~D ._ ~ ~ ~ 00 c o o ;-s ~
0 ~c ~ ~ t~ ~0 ~ S. a~
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,~O tD C~ ~D D ~_ ~ S ~ O ~ O cv ~ _ O
,~~ 0 a~ e~ c . ~ ~ ) o ~ o ~ ~
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8 ~~ -- D -- ~ a~ ~ o .- ~D ~ ~r ~ ~ ~ ~r o ~ 10
2 a~ _ ~ ~D a~ ~~ a) a~ ~ s o r~ Ir ~ a~
~~O O D 1~ E -- ~ c~ .C o a~ J ~ u~ rD t~ lD ~D
S lD Q U')
Q a) a) a) _ ,~D ~ ~ o crl ~ _ 0
EO ~ ~ a~ ~ o _ ~ ~ ~ ~ c-~ et ~ ~ ~
a~s ~ -- D ~ ~ ~ ~ o -- ~D o ~ ~ ~ ~ ~ o ~ 11'~
.c Q O~ Q Q -- -- -- -- -- ~ -- --
CJ ~r 1~ 0 D a) O) ~D tD ~ ~D D If~ 2
D C'~
~D ~__ --__OO _____ __
I T I I I I ~ ~ I I I I I I I
76.t3
SVBS 11 i UTE S~E~T tRULE 26
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
0 C~ O ~ C~ O O N tD _ ~ 0 ~ C~ C~ ~ 0 Cl)
O 1~ lO ~ 0 C~l O O t' O 0 t~ 0 _ O CO O N U~
0 ~ ~ c~J ~ c~ o> ~ ~~ 0 0 u~
c~J ~ e~ C'J 0 ~ r- c~ ~ C'~ -- ~ -- ~ -- -- C~ 0 ~
.~
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c C ~ ~ D D ~ C ~ .C ~ I I I m -~ ~ m ~
C a3 ~ a~ ~ Y ~) 8 ~ .-- ~ ~ c~ Y C 0
~ ._ m~ ~ ~ 3~
O E ~ ~ ~ ~ ~ g I ~ D~ ~ ~ ~ m ~ ~ _
~n o C ca ~ Q o _ o ~ o ~ =
m c _ m ~ = ~ n n ~ ~ n n ~ = E 1 c
O ~ ~ er 0 ~ ~ ~ CU O r~ ~
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_ r~ _ ~ ~ C'~ ~ ~ _ U~ O ~ ~ ~ ~ CO C~ lD 0
_ ~ CD ~D 0 0 0 ~ er _ C~ _ O cn ~ C ~ a~
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n ~ c~
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c ~ _ ~ O ~ D W ~D n ._ u~ _ o
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-- _ O N 0
__O__OOOOOOOO C OOOO
_ I I I I I I I I I I I I I I I I ~I I I I
76.14
SU8STTTUTE SHEET tRULE 2b~
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/0~320
O U~ _ tD t~ O ~ ~ O ~ I~ O _ ~
1~ a:~ ~ .- _ o~ c~ ~ _ _ _ ~ r- o ~ ~ ~ u~ tD O O ~ l' O
~ u
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~ ~ ~ v _ _ _ ~ ~ _ J E Z ~c x x~ _ ~ ~ _ ~ ~ ~ Q Q C
t~t~ ~o o~ _ o o et~ 0 c~ l 1~ o) C'J ~D O C~l C'7 N C'
t~ 10 ~J C! N ~ C'J tD O 0~ ~ ~ ~D 1~ 1~ . _ r~
a~ D O C~ o _ _ ~o _ _ ~ o a~ ~ CD 10 0 ~ ~--
a~ a~ Q _ O C~ _ O 1~ O) 0 O a~ CD a~ o _ ~ cJ o~
o _ o o c~ ~ _ a~ o ~ o _ ~ o C~l ~0 a~ r~ a~
9~ ~ o a~ ~ a o~ ~ a~ a~
n _ ~ Cv u~ o o7 c I o ~ a~ _ ~ a~ --oo a~ o 1~ a~ c~ o a~ o
~ a~ D o a~ _ ~D o _ _ ~ _ -- ~ ~ o o~ D ~ a~
a~ _ _ _ _ _ _ ~ _ _ _
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trl o _ ~ a~ o a~ _ ~D o _ _ ~n _ _ ~ o~ o~ o ~ r~ u~ co
o o_oo_ooo__oo__ oooo_ooo_o
I T I I I I I I I I I I I I I I I I I I I I I I I
76.15
SUBSTT~UTE SHEET tRULE 2~i3
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
O ~ o c~ ~o a) 0 e~
0 ~ 0 ~ N ~D O 0~ 0 CD O
In N ~ 0 ~ ~ ~r N ~ ~t FJ 0 N C'~ ~ ~
~D O ~ N ~ N -- t~
c~J a) _ ~ o 0 lD _ _ ~ ~ I~ _ O --
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0 ~ ~ D O a) ~ 0 _ tD 0 In IO ~ 1-- o N
_ 0 0 0 N N C~ ~ -- t~ ~) C'~ ~ ~ ~D
a~
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_ D-- C llJ
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C [~ 'C 'C I~ ~C ~--C D m ~ ~,~ Q ~ ' tD
~ 8 c ~D _ _ D ~ C~ ~E -- 0 a~ --
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"~ "' ~~ ~~ '' ~ -- ~ E UJ ~ u,, c
c C ~ c~ C ~ 'a ~ .c ~ E
8 = 0~ s E E ~ ~ O
s s ~ ~ ~ C ~ _ O ~ ~ E E E = ~
c LO fD Ln fn f~ O r~ 0 ~ ~D fn 0 L ' ~r Q 0 t~:)
a~ cn ~ ~ ~D fn f~ Q Ln ~ ~0 _ f'~ fn ~ I 0 0 1-)
o~ ~ N fn N fD 0 ~D ~r O n 0 0 ~D L I W
Ln fn f~ fo ~ m D ~ Ln ~D fn f.'' N tlS N D
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c -- _ . _ _ _ _ _ _ 0
O
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fn o t~ _ ~, ~ n r- ~ Ln n c~l O c~ 0 -- a~ Ln
_ _ f~ fn ~ ~ ~ _ o f~ ~ a cn ~ ~ Ln ~ -
~ f~ tO _ Ln _ ~ Ln ~D ~D ~ ~ Ln 1~ N -- O ~r
2 O O O O ~ f'~ N N N N N fJ~ D --C 1~--
~ f~ N f~J f~ t~ r_ ~ ~ N f.~ N f.~J ~D Ln n
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f'~ f~ f.'~ f'~ ~D N NN C~J a7 0 _ ~ O fn Ln ~D
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I I I I I I I I I T I I I T I
76.16
SVBST~TVTE SHEET tRULE 26
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/OS320
O O ~ U~ O U~ o ~t
a~ o ~ c~ ~ o a) ~D 1~ 0 ~
c~ o _ o ~ ~ c~ O
-- t' ~ N _ 1-- -- O ~ 1~ C~ 0 0
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s 2~ C _ ~ 0 ~ _ s .~ ~ O
8 . - 8 8 . c ~ ~ ~--a
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, ~ ~ 0 ~ 0 0 Q ~ - ~ ~ ~ ~
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, -- -- -- ~ 8 8 8 O 1~ O ' ~
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V V ~ ) ~ o C UCI c -- E E c C ~ F
N N d d ~n z ~ ca tO O ~ ~ 2 ~, 2 2 2 2 ~ 2
CD ~O .0 ~ O C~l 0 r~ 0 0 C~l ~ 0 ~D 0 ~ D N
tD ~ t~ 0 1~ 0 ~ 0 u ) a) o a7 c~l o
C~J O~ C~l _ I~ U~ 0 0 C'~ _ O) 0 0 0
.D CD O ~ a~ 1~ ~ 0 0 C~
0 0 ~ ~ -- ~ CO O _ O 0 0 1'~
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.~
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0 0 o ~ C ~ ~0 0 8 ~ 0 C ~ t~ t~ O C~) ~D cr~ I~
O Cl) U~ 0 ~ ~ 0 0 0 0 _ ~
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0 C ~ ~ o ~" _ ~ o 0 1~ t
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O Q O ~ I~ O O O ~ O O O O O O O
O O _ -- O O _ _ _ O O O O O O O _
I I I I I I I I I I I I I I I I I I I
76.17
SUBS l l l UTE ~}~EEr (RULE 26
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/0~320
0 o, c~ 0 _ ~ ~ ~D x ~ 0 o ~ o~
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0 ~1~ 0 0 ~O CD 0 ~ t~ 0 ~ 0 ~-- ~ 0 0 0 0 U7
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8 8 ~ ~
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Q - .~ D ~ ~ 0 0 0 _ - - m E ~ ~ ~
a~ 0 ,~ ~Q D~ a~0 c a) ~ ~ 0 _ Q
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~ c c S ,C C C 0 ~D D D ~~ C .~
~ c 0 0 ~ 0 ~ ~ ~ ~ ~ ~ ~ 0 0 ~ ~ ~ 2 2 x
= s = s E = E E 2 2 2
E 0 E 0 E E E E ~ ~ ~ ~ ~ 2 Q C o O ~ ~ g - ~ ~
C~ In C ~ q ~ a~ o _ ~ ~ n o ~ C~ o ~ _
Ir) r C~J l~ 0 r ~ N C') C'7 ~ ~) ~ ID C~ C~l ~D 0 C~
O ~ l _ 0 N O _ 1~ ~D ~ ~ O 0 1) 0 0 ~r e~ 1~ a
~ C~J 0 0 0 0 C'J 1~ ~J C'J ~J 0 Q C'~ ~ ~) ~ ~'
-- -- 0 0 0 0 ~ 1~ ~ 0 a~ _ ~ ~ ~ cu ~ ~ r~
-- C O
c~l 0 ~ ~ a) ~ u~ er 0 07 a) 1' ~ ~ 0 0 c~l ~ 0 c~
O C~l ~ ~1 0 U~ 0 0 c~l 0 0 c _ _ ~ ~-- CD ~ I~ C~J ~ --
-- ~ O ~~ O C') 0 _ _ U~ _ O o 0 C~ ~ 0 U~ C~ 0 ~J C
~ ~ 0 ~ 0 0 ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ ~ O ~ ~ ~ E
0 a~ 0 0 1~ tO ~
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~D ~ C') C'~ C" C" 0 C~J 0 0 0 a~ 0 ~ 1~ c~J ~ a~ tD ~D 0
-- -- O O O O O O O O O _ O _ _ ~O O O _ _ _
I I I I I I I I I T I I I I I I I I I
76 18
.
SUBS 111 UTE SHFET tRULE 2fi)
CA 02218741 1997-10-21
W 096/33Z76 PCTnUS96105320
0 c~ o 0 ~ c~l o o 0 _ u7 ~ _ e~ ~ O O
_ U~ ~ ~ O C~ U) 0 ~ C'~_ ~D 0 ~ ~ ~ O
~D ~ ~ ~ ~ 0 ~ ~ 1' 0 0 ~
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,c~
., ~
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s s = s O _ --O ~ u
s 3 ~ ~ ~ o ~ _ .o _ ~ s s s
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E s ~ _ ~ ~ O xO ~ ~ ~ ~ c c ~ ~ O
s s ~ c s ~ ~ ~ EE
c ~ ~ O S ~ c ~C~ u~ ~7 ~ ~ ~ a) ID ~
~ E C~ 2 ~ ~ O 0Q ,~ ~ ~ ~ ~ ~ ~ ~ ~ ~
q) ~D 3 ~ 0 ~ O _ E ~ ~ Q
D C 0 C O O c ~D c c ~
C ~a c ~ a) o _ _ _ ' _ _ _ _ _
~ Q ~~ ~~ a~ O O~ ~U C a~ ~ ~ C C C C ~' ~ C C
s ~ o -- -- 2 Q ~ nl ~ Q ~ 0 0 0 0 0 0 0 0 0
o ~ ~ ~ 2 ~ ~~ ~ ~ ~ ~ ~
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tO ~ 1~ a~ tD ~ 1' 10 ~) 0 ~ O ~r ~ G ~
~D ~0 _N 0 C'~ C~ N ~~~ _ C3~ o C~l ~ N 0 CD ~ ~ C3~ O
~ ~ O Ln _ 0 ~ ~D c 0 0 - ~ ~ L~ ~ O ~ ~ 0 Ln
~r tD O C'~ ~ ~ 0 ~~ _ 0
-- ~" O CO 0 0 0 _ ~ O Ir~ Q O ~ C O O ~ O~ O
Ln Q N C'~ ~D _ _ Ln ~ r- C~ I_ Lo ~ L ~ LO Ln Ln ~ Ln C~
. _ _ _~ _ ~ _
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OO O __OO_ _O OOOOOOOO_
I I I I I I I I I I I I I I I I I I I
76.19
SUBSTITUTE S}~EET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS9610~320
~r _ _ 0 u~ t~ c~ 0 a~ o u~ r 0 ~D ~ O ~
~~ ~ . ~ 0 o ~ u~ ~ tD _ I~ O ~ r o C~ 0
00 U~ ~ 0 0 Cl~ ~ a~ C~i _ ~ _ c~i ~ ~ C'~ 0 ~D U') O C'~
0(O 0 0 0 O~ 1~ 0 1'- 0 a) o~ 0 0 ID ~ CD 0
- 0 1~ 0 ~ 10 C~ i N 10 . _ O O) _ 1.0 C~i N 0 t-- 10 CD
-
O ~1
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E E ' E -" ~ 2 0 ~ .' 'a E ~ ~
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_ ~ ~ ~ I ~ - ' ' ~ CO ~ ' ~ ~ ~ E .~ ~ ~ ~ Q
~ 0 r~ 1~ 0 c~ D 0 q~ _
a~ ~ ~ ~ ~ ~ ~ o
o ~ o ~ ~ ~ 0 a ~ ~ ~ _ o o
c ~ ~ ~ O ~ C~J ~ O ~ ~ _ C~J ~ t~ O C~
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.Q
O o _ a~ 0 u~ 0 0 _ -- --
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~ ~ ~ o _ ~ _ o ~ _ 0 0 ~ c~ o _ ~ ~ 0 1~ c~l _
-- O O_ OOOO_OOO_ OOO __OOOOO
~ I I I I I I I I I I I I I I I I I I I I I I
76.20
SUBSTlTUTE S}~EET tRULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/OS320
O _ u~ r~ o 0 ~ O
~ E
~-- o _ _ ~
C ~ j E c = c - ~ ~
_ o ~ ~ ~ ~ ~ s ~ ~ ~ ~
--s ~--~c c ~ ~ m c ~ ~ E --_ E
E ", D q~ C = ~D S -- a~ ~ C --
~ E ~~ g e ~ c ~ ~ ~
.' .E ~ ~ = o E ~ ~ ~ _ s ~ ~ ~ ~ ~ s
s s c c s 0 0 c _ c_ _ ~ ~ _ ~ ~ O s s E s = s
~ ~ ~ C 0 Q -- Q ~ ~ ~ ~ a~ ,- _ _ ~ 0 ~ ~ O O ta 0 0 o o
s s ~ ~ O _ o ~ r, C ,~, ~, ~, _ _ ~ ._ ~ s , I Q _ s sQ ~,
o a)u~ u~ O oq- ~ 1~ 0 o o 0 ~ a~
-- _ ~ ~~D o _ tO oo~ ~ o) c~l ~ O _ ~ ~ ~ ~ r~
O _ ~ 0~ O CD ~ )O ' C~l ~ ~ _ 0 ~
aO ~ CD 0 U~ l ~) ~ C~ CU O ~ ~ CD
tq --IU 0 _ C~ 0 ~ t n et ~I ~ O)
-- ~ ~ ~~ ~ ~ 0 ~ rs~ ~ 0 ~ ~ ~ a ~ rD o~
cc _ -- _ _ _ _
~-' ~ ~~' ~ n~ o ~ ~ a. ~ ~ u- _ r~ ~7 ~ ~ ~ ~
~ - C ~C C~l ~ C ~ ~ C ~ ~7 ~ cr ~7 _ ~ ~ 1~ IS.7 ~
_ ~ ~,7 ~ O) ~ r~ a~ ~ ~ ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ r-7
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O O o ~~C _ _ _ _ o _ _ o _ o _ _ _ _ O _ _ _
c~ I I I I I I I I I I I I I I I I I I
76.21
SUE~STrrUTE S~E~ tRULE
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
.~ o
a~ " 8 ,
a ~S - o .c S "~
s O E o C s E 5 ~ ~", o UJ s E
~ C -C o ~ ~-Cn ~C T~ . Q a~
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c 2 Q ~r~ S 2 ~ ~--~5~ ~ ~ o N o-- --~
Q ~ 0 1~ ~ C~ ID o~ Xo a~ m o O E
~ ~- ~ - ~ LL~ E c ~ ~ Q ~- ~~C __ ~
'O -~ (~ ~ Q-- Q ~ C ~~ S ~
o ~ ~ o o> ~r lo c~ CO N
~ CO ~D Q ~ _ ~-- UD es 0 ~D er r~ r- D~ cn ~i
C~ -- C~cn un o o c~ N ~t ~t _ cn ~0 0 C~
~D UD e~rn cn ~ C~ r~ C~ et r~ ~D ~D ~O 0 cn
c a~ O C~ " 0 e~ _ O C~l CU N 1'~al o C~
O er ~ C~~ er ~ _ O ~D r~ r~ CU r~O ~D N
~QC '~ Co ~
~ ~ cn ~ 0 0 ~D et ~D r~ er 0 _ L~ etO ~r ~r
._ ~ cn ~ un ~c~ UD 0 0 _ 0 r~ _tD cn
1 r~ ~~U O X cn ~D r~ C~ 0 co cn 0~n ~ r~
E ' UD r~~ o ~ cn ~D C~ er ~D r~ ~ CD~ UD cn
~~ ~) O ~ ~ 0 ~ 1~ ~ _ O C~ ~ ~ ~ O O
~ eS 0 r~ ~U es ~ _ O ~D r~ ~ r~ cn ~ tD C~
~D er 0 r~ _ UD 0 oD 0 ~D UD _ r~ UD 0
O r~ c~ C~ ~D r~ 0 UD 0 ~D ~D tD 0 0 C~
e~ CU CU C~ eS O ~-- cn UD ~D ~D _ cn un C~
O _ _ O O O O _ _ _ . O O _
I I I I I I I I I I I I T I
76.22
SUBS i 11 UTE S~EET (RULE 26)
CA 02218741 1997-10-21
W 096133276 PCTrUS96/OS320
_ ~ ~ ~ ~ ~ m o N ~ ~ ~ ~ ~ ~ m ~
- O ~ ~ O ~ ~ ~ ~ m ~ ~ m ~ ~~ ~ o
o o c~ ~ ~ O ~ o ~i
m ~ ~ ~ o m ~ ~~ ~ m
o ~ ~ ~ ~ ~ o _ O o ~ _ . o _ ~~ ~ m
o ~ ~ ~ m ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 o
m ~ Q ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ m
O ~ ~ o O
s o ~ ~ ~' s
~ = c ~ E' - ~ o s I _ = ~
S -- ~D C ~ X C ~ ~ ~
~C ~ 1 ~ ~0~ 8 ~ ~0D ~ ~ 5 0
I c = s ~ ~ ~ o C C o c ~ n ~ O C ~ m
= ~-- ~ ~ ~ D so ~ C s s E ," '' ' m 2 0 sO s
Q ~ Q Q -- -- 0 ~. 0 .-- 0 0
Q_ ~ ~ ~' ~ ~0 ~ ~ E 0C ~0 s s ~ ~ ~ C ~Q ~ ~C
~ E 3 ' 7 ~ ~ y ~ ~
Q _ -- ~ x~ _ Q c U~ ~ 0 ~ Q
D C~l lD 0~ ~ _ 0 o~ _ _ m ID tr~ O
~D c~ D O _ D ~ ~ ~ _ a) c~ O
~D ~D _ ~ D O ~ m {~ C ~ O ~ D ~ _ tD ~D
-- t~ O~ O O _ ~D ~ ~ (D o _ r- cl) ~ m ~ ~D
c~ a~ _ ~ ID ~ _ _ ~ ~ ~ ~ In ~ ~D ~ ID C i~
_ _ . _ -- o
O O a~ D a ~-- O a~ D ~D r~ O a~
C~J O) ~ ~ ~ t~ ~ ~ lo ~ o ~ _ ~ a) ~ D ~ ~ ~ 1~ O
_ ~ ~n tD 1~ _ O o 10u) -- ,C ~ ~ ~ D ~ ~t O ~ a~ o
_ ~D m _ O c~ tD tD ~ ~0 cr7 ~ _ ~ m c~ ~D D _ D
-- -- -- _ -- a~ -- z --
l O _ _ C~J lD ~ O 1~ c~l N ~ C~) ~ N 0
~ 10 C~J ~ CJ ~ ~ ~D 1' 0 m o ~~ ~ o r~
O _ _ _ O O _ O O O _ O _ $ O g O _ _ O
I I I I I I I I I I I I I I I I I I I I
76.23
SUBSTITUTE St~EET tRULE 2~i~
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/OS320
C" I' ~ ~ al ~t a~ _ ~ I~ ~ ~ ~ o~ ~ 1-~ o o N N
D O ~ ~0 ~ Cl ~ ~_ C~l N C'~ N N C) ~ C'~
~ N 1~ C'~ _ ~ ~ r_ ~ _ N C~ _ _ ~ N N C~
0 0 ~ r' N 1~ N r-- O C'~ O N CD I
O ~-- O 1~ ~ O t'~ _ CD O 0~ i N 0 O) U~
O N 1~ 1~ _ C'~ U~ C~ _ ~ N O C~ O U) cr~
'' O r~ 0 ~ N N ~D r~ O C'~ _ N 0~ O>
O t_ q- N ~ C'~ D N O (.0 ~ C'~ D 1~ C) C'~
-
O
N N c~ ~ c
c E ~ ~sO ~ ~ s c
~sl ~ 2 ~ E ~ __ _ c _ 2 2 = O v=~ o
I E 0 ~ ~ ,~ c _ o ~ a ~ ~ --~
= O c c ~ ~ 2 ~ 2 -- O ~ c o 2 2 s
c 2 s 2 E E--~ ~ ~ ~ = 2 ~ o 0 0 E E
_ ~ ' C~ Q O C ~ ~ N CO _ ~ O ~)
1~ U~ ~ ~D In LO ~ N C'~ ~ tD ~t t~ C~ 7 C~
~D O) N _ N C~ O N N U7 10 ~ ~n 1~ C~
O~
o ~ ~ t~ N O ~ ~ tD tD L~ a~
N N t_ n n ~ ~ ~ ~ -- tD ~ ~ ~ o ~D
c ~ ~D 0 ~-- n U~ N O r~ N C'~ ~ 01 ~ N _ 1
J N ~ C~ _ a~ C~ O N C~J U~ U) C'~ 10 ¢~ ~~
20~ -- _ _ _ _ _ _
~ O C~ N U~ _ C~ _ O 11') 0 O~ m CD C'~ N U~
~' o o o _ _ o o 8 _ aO' ~o o _ o ~ ~ _ ~ o ~--
¢ I I I I I I I I I I I I I I I I I I I I
76.24
SUBSTTTUTE SHEET tRULE 26
CA 02218741 1997-10-21
PCTrUS96/05320
W 096/33276
C~J 0 0 C~ N 0 0 _ C~ 0 C~l C) 0 U~ 0~ ~ ~ O a) ~ 10 C~l ~ ~ r_
O ~ O U'~ ~ 0 a~ 0 Il~ O _ t~ c~
~t ~ _ o o o) _ ~ ~ ~ O ~ ~ o~ O ~ 0 ~O
U~ ID ~ O) I~ _ _ a~ ~D C~ _ ~ 0 0 0 C'~ _ CD ~ ~ 0 0 a~
-- 0 ~ 1~ 0 ~r o ~ o ~~ o ~D O) i~ 0 -- C~J
._ (I~
s ~ . Cs,
~e__~c~S9~9 3~_a 9-o-o
~ 99 E ~ ~ a ~ ~ 9 a ~ Q g 'E ~
~ ~ a ~ 9 9 9 9 - 9 9 1 ~ ~ ~ e
1~ U~ ~ 0 0 0 C~J o C9~ 0 0 0 C~ D N O O r_ _ ~
0 ~ ' O 0 Q If ~ n O _ 1~ ~ _ C~l ~0 _ ~ C') 0 1~
O C'~ O ~ 0 ~O ~O _ 0 ~ ~ C'~ O _ ' ~ C'J C'~ C~J O ~ O
c~ o ~ o o r~ C~J o N 1~ ~ ~ O ~ 0 _ r~ o C~
L I~ ~O _ c~ 0 er C~ O _ el ~ o ~-- o N
O C~l 0 ~n ~O ~ C~l tO 0 ~n 10 ~ ~ N ~r r-- O CO 1~ CO 0 ~r
~ ~ C~l 0 -- ~0 -- ~ o t~ 0 a~ o ~ ~ w ~ r~
0 ~ 0 ~ O C~ CO ID 1~ ~ ~r 0 U~ t~ r C~ J ~ O _ ID
1~ ~O ~ 1~ ~ O ~O _ _ _ ~ 0 C~ _ _ N N 0 O ~ O 0 O O
_ ~ Ol ~ O C~J ~ O ~ Cq 0 N c~l 0 0 ~ ~ ~D ~ 0 0 0 0 LO s~~O ~ L ~ _ 0 0 ~ In 10 O ~ ~ N u~ _ N u~ D 0 1~ ~ C~
~O O C~l 0 U) ~O q N 10 0 U~ U~ ~ U7 N e~ D N ~-- 0 0 ~ ~
_ r~ ~ 0 ~ t~ _ m C~ 10 D 0 0 _ C~J _ 0 0 0 ~-- _ N
O ~ _ O O O O~ ~O N ~O r~ ~ ~ N r~ ON ~r ~~ C" ~O N C-~ ~ 0 0
I I I I I I I I I I I I I I I I I I I I I I I I I -
76.25
SUBS 111 UTE SHFET tRul E 26)
CA 02218741 1997-10-21
W 096133276 PCTAUS96/05320
o~_ ~0 o~ O_000_Oa~
~ ~ O O C~J ~D C~ ~ CD ~ _ C'~ ~D ~ C'~ ~ ~ O _
u) ~ u~ _ _ _ o ~ o ~ u~ o a~ o 0 ~o r~ c~i u~
~D ~' ~~ I~ U~ ~ 0 ~ U~ ~~ 0 ~D ~ t' U~ a) w ~ ~
~D 0 _ ~~ O C') C'~ ~ 0 0 0 c~J 0 U~ o ~7
~n r~ cr~ ~D ~ C'~ O C~ C~ O C~ ~O 0 1~ ~ 0 0 ~
._
,_
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b E ~ O ~ .c sO ~ e ' ~ .
0 8 ~ ~C~ C E _ _ CQ C --~ E ~ ~n c G
~ 0 ~ s llJ o rL ~ " a) 0 ~ E _ ~D ~L~ 0 ~
c e a ,_ ~" 0~ E, ~ _, E O e o ~ o g~ ~o ~ O O ~ E
m c~ cv) 8 ~C a~ ~C 0 0 ~ la tl~ ~ ' n~ 0 2 2
~ ~ E ~ E ~ 2 ~ 2 0 ~ = = --
0 LD ~ ~ D c~ ~ ~ ~ ~ r~ ~ O ~ -- ~ ~ C'~ ~ ID 1~ 0
D ~ 0 tl tD C~l O C~l tD r~ ~ 2
~ LD ~D c~l D ~ ' D -- ~_ _ r~ _ 1~ 0 0 ~
ID tt~ _ tD ~D ~ ~ ~ ~) t~ 0 ~ ~ _ _ -- O ~ 0 C
C~ 0 r~ID t~ ~ O D D ~ C~ l _ 0 c~ D Lr~
~ ~D _ ID LD ~D0 ~ LD ID ~ LD LD ~ c~
---- - - g
r~ ~ LD a) U' ~J l~ D O 1' ~ O _ a~ LD Q
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O ~ D ~ ~ D _
1~ ~ 0 c~ D ~u L~ ~ _ 0 n LD C'J C 'J _ O O ~ O
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rO ID _ LD 15~ ~D 0 ~ ~ D t~ LD LD C~ ~ o ~ _ z
_ _ -- -- o
LD _ ~ 0 LD r_ ID _ LD O ~ ~ LD LD O Cq ~r C'J C~J ~ 0
D q~ ~D O ~D -- 0 ~ r ~ lD ¢~ _ _ t'~ LD O
~ -- O lo oD Do o LD ID 1~ ~r ~r ~ 8 o ~ o o o _
I I I I I I I I I I I I I I I I I I I I I ~
76.26
SUBS 111 UTE St~:ET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
_ ~ o ~ ~ ~ 0 0 ~ 0 ~ o C'~ o C') ~ o U~ ~ 0 C~ o o
u) 0 u~ ~ ~ _ ~ u~ ~ 0 o ~ ~ ~-- o r~o ~ In CD
o u~ ~ O C~ l ~ 0 0 ~ U~
_ _ o a~ o ~ co ~ o _ o c~ c~J u~ u~ _ _ a7 ~ ~D CD a~ ~ C~i
_ _ --
$ $ ~
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S U,~ ~~ ~ .C C~ ~ 0 ~ S
~ __ _.--,C 0 ' Ll~ ~ C0 ,~ 'Q,_ 0 (C~
_ -- a ~ I ~ --o o D _
T T T T 3 ~ e ~ ~
C CL ~~ o ~ D D D -- Q 2 2~u a~ ~ G) a~ ~" a) c~ c 0 a~
~ E E --,c C ~C ~C ~ ~ E E E E E E E E E E E
o o O Q ~ ~ S z z z z
D O C~l ~'3 1~ r-- CD O O C~ _ N ~:r ' _ L~ 0 C'~ t~ O
~ o o ~t o ~ o ~ o ~ ~ - ~ 0 ~o ~--
_ t!~ ~ _ ~ _ _ 0 _ 0 C~l _ U') _ C'J ~-- 1~ 0 ~ ~, N ~ ~ O LO
~O ~ LO ~ et _ 't ~ O ~ ~ _ C~l ~ L~ o _ ~ L~ L~ O ~~
O 0 q- _ C~ J Lt~ I~ O LO ~-- ~ L~ ~ _ L ~ ~ o 0
a~ o c~ C3~ o C~ C~ ~ 0 o ~ 0 _ r_ ~ L~ ~t t~
C" ~t LO O 1~ ~'~ .0 ~ C~.l 0 O' L.~ C~J 0 ~ -- O 0 0 0 C~l ~ I' ~ I~ ~
O 1~ -- C~l C3~ r~ D ~ o ~~ _ n ~ D O C~l
O tD ~t r~ ~o ~ ~ ~ ~ 0 ~ L~ ID 0 ~ ~ ~ ~D O rD ~D ~ O _ Ln _
~ ~D ~ Lr~ ~ ~ LO ~ ~ ~ 0 ~ ~ D O c~l a) ~ ~ ~ ~ r~ 0 ¢~
c~ Lo 0 ~ _ ~ ~ D Ln D ~ ~ ~ D O ~ ~ 0 0 -- ~ N ~ 0 0
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_ _ _ _ ,
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D 0 C~l _ LO _ tD U~ 0 o O O ~D LO 0 LO C~l ~ ~ o _ ~ ~ l~ Ln LO
~000~O00~0_O__OOOOOOOOO_oO_OOO
I I I I I I I I I I I I I I I I I I I I ~ I T T
76.27
SU8STlTUTE S~ T (RULE 2~i~
CA 02218741 1997-10-21
W 096t33276 PCTrUS96/OS320
o~ o c~ o 1~ 0 o~ o r~ o ~ ~ c~ o ~D ~D ~ O
0 _ ~r ~D C'.l O 0 11~ O O O C'7 0~ O') C) U~ q' ~ O N ~ O C~l 0 ~ C~ O
~t) t'') 0 r~ o o> ~ ~ o ~ o c~ D 0 0 c~ l _ 0 U~ O ~)
0 C~J 0 a) ~o a) o ~ c~ _ _ o 0 c~i _ In o _ u~ tD O a~
~7 ~ a~ ~D _ O ~ ~ ~ ~ 0 a) o 0 u~ 0 _ ~ O ~D O ~
t _ 0 O~ ~ 0 0 0 C'~ ~ O ~ ~D ~0 0 C~ ~ C~ t~ ~ O O~
~D 0 1~ Ln 1~ tD 0 a) o~ a~ Ln 0 Ln ~D Ln ~ Ln In C~ ~ Ln Ln Ln c~ Ln tD _
a~ _
~ ~ E ~ Q ~ ~ ~ ~ 0 ~ ~ ~ 0 Q ~ ~ o ~ 0 0 ~ Q Q ~ -~
I I I I ~ ~ ,~ .c ,c E ' E E E E ~ Q Q ~ ~ _
0~ C) ~ (D 0 0 ~J D c~ c~ ~ C~ 0 0 _ O' ~ ~ 0 C~l 0 0 C~ D c~
~D m 0 0 _ o ~ D tD 1' ~ 0 0 0 0 o C~l C'' _ 0 ~ et C~ C~ r'
o~ _ o o~ Ln c~ ~ n c~ D Ln 01~ C~ 0 10 0 0 C'7 _ C~ 0 Ln
_ ~ L I ~J O~D ~ ~ O _ ~ C'l 0 C~ ~qLn C ~ a~ I~ Ln 0 ~ O~ O C~J
~1 O) 01 ~ ~-- O C~ c~ O C~ ~ O ~D ~D O Ln Lr~
~ Ln O ~D Ln O Ln --~ ~ 0 0 l~ 0 c~ _ L~ J Ln 0 ~ O C' ~D
1~ 0 CJ 0 Ln ~ 0 O~ '~I Ln C'~ l O ~ _ _ 0 c~
Ln ~0 ~ O _ o 0 0 ' 0 ~D lD O O ' tD _ ~ _ 0~ O ~ O ~t ~ Ln t~
~ 0 ~ ~ ~ 0 ~ ~ _ 1 o ~ o _ ~ n ~ 0 0 ~ o ~ n ~ ~ L~
o) ~ r' Ln C~ 1 Ln ~ a~ _ _ ~ ~'~ ~ ~l C') ~,~ 0 ~ ~D q c~
~- 0 ~ o o o c~ '-'.1 o~ ~ ~ ~ _ a~ o) ~J _ o c~l lD C' ~D D O
~ ~n o ~D Ln O Ln ~ ~ ~ ~ ~ ~ N ~ ~ - Ln ~ ~ n ~ ~ o
o 0 c~l 0 ~ 0 c~J ~r 1~ 0 Ln ~ 0 ~D ~ ~ -- c-~ Ln C~ 0 -- O C'~
o ~ L0n ~ a) Ln ~ C~ ~ 0 ~ ~ ~ 0~ ~ _ o O o o o o o o o~ o
I I I I I I I I I I I I I I I I I I I I I I I I I I I I
76.28
SUBST~TUTE SHEET (RULE
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/OS320
~ C~ D N 10 _ tD ~ O O ~D O C~
. _
O o o _ ,_
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a _ c ~ ~c sO sO
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O "~-- o I ~ .~ .~ E Q Q Q 2 c ~
-- ~~ C 0 ~5 Ul ,~ ~C ~----O ~C C LL ~ C
~ E ~ ~ ~ ~ ~ C ~ -- s ~ ~ _ o _ ~ ~ O
s _ ~ X --~ ~ ~ -C C _---- -- ~~ o o o o ~ s
2 2 - ~ ~ - - ~ 2 ~ ~ ~ ~ ,2 ~~ - ~o ~~ ~ -
2 ~ .~ ~ ~ ~ o c 0 ~ E E Eo E .Q ~ 2 0 ~ ~ Z ~
Q ~S ~D ~ aJ o ~17 ~ al Q ,0 0 0 0 ~ -- -- -- -- = .--
CC -- s o ~ ~ G7 ~0 o o o o c ~ ~ o~ m
o ~ Q Q Q 0 al 3 c Q Q Q Q Q ~8 Q Q Q --Q Q ~ Q
~D 2 2 2 2 2 a~ 0 n ~0 _ O O O _ ~. ~ :~ _ ~ ~ x
0 a7 _ o C!~ ~ N ~ ~7 0 0 _ _ _ 0 1~ C!) C' U7 C'~ _
_ U~7 - ~O ~ O _ ~ U~7 ~ _ C'l 0 C~ 7 N a- o ~r ~
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OOO_____O__O___O O -- __OO
I T I I I I I I I I I I I I I I I I I I I I
76.29
SUBSTITUTE SHEET (RULE 2~i~
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
_ o 0 a~ ~ ~ o r~ 0 c~ ~ ~ O C~ ~
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I I I I I I I I I ~ T 1-- I I I I I I I I I I I I
76.30
SUBS I ITUTE S~EET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
o In ~ O ~ l W ~ ~ o ~ c~ t O
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~ _ o o c~l o c~ c u~ 0 ~ ~ ~
76.31
SUBST~TUTE S~EET tRULE 2~i~
CA 02218741 1997-10-21
W 096133276 PCTrUS96/OS320
,"~ ~
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- I I I I I I I I I I I I I I I I I I I I I I I I I I
76.32
SUBSmUTE S~E~ (RULE 2~)
CA 02218741 1997-10-21
W 096t33276 PCTrUS96/0532
_ CJ C~ r O 1~ ~ N C'~ N ~ ~ C~J O C~ 0 _ O t~ O.
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I I I I T I I I I I I I I I I T I I I I I I I T I I I
76.33
SUB5TITUTE SHE~ tRULE 2~i~
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
_ ~ t~ O ~ ~ o o ~D O O C~l ~ ~ C~ O
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0 0 a~ 0 ~_ ~ 0 0 1~ ~ 0 0 0 0 a~ ~ 0 0 c~ 0 0 o> a~ 0
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' I I I I I I I I I I I I I I I I I I I I I I I I
76.34
SU B STlTUTE ~ ET tRU LE 2
CA 02218741 1997-10-21
W O 96133276 PCTrUS96/05320
~ C~ ~ 0 ~ O U~ CD O ~ ~ ~ ~ ~ ~ e~ l O C~
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T - I I I I - - - ~ ~ ~ ~ - - ~ ~ - ~ - - - ~ -
76.35
SVBSTrTUTE S~EET ~RULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
C~l CD ~O ,~D~ ~D 0 U~ o c~ 0 _ U~ O C~ O O) _
t~ o 0 cn~ ~ c~> ~ ~ ~~ r~ u~ c~ 0 c~ 0 r~ 0 _ o~
o~ 0 c~ ~--0 r~ t~ t~ 0 0 0
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0 r~ ~ ~D~D ~n ~D r~ ~ ~~ ~ tD ~ 1~ 1~ t~ ~ ~ C~l O) ~t C~J
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~ ~ 8 ~ ~ ~ ~a ~a ~a ~8 I ~ C~ ~n o
(D D ~ r-- ~D O 0 0 0 C~ .C _ a~ Q 3~ ~~ ~ _ 0 0 _ 0
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--O_O OOO_O_ O__OO OOOOOOO_
I I I I I I I I I I I I I I I I I I I I I I I
76.36
SUBST~UTE SHEET tRULE 2~i)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/0~320
0 _ 0 ~D~O O U~ O O~ ~ . ~ _ C~l ~ -- ~'
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~r N O _ ~N O ~ ~ C~ ' O
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~O ~ -- 0 0 Q 0 0 ~ a~ O
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0 ~ Ir ~ 0 _ _ ~J ~ ~ 0--Q ~D ~ Il C ~ C~ O ~ 0 0 0
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I I I I I I I I I I I I ~I I I I I I I T I I
76.37
SUBST~UTE S~t EET ~RULE
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
~ ~ _ ~ ~ o ~ ~ ~ o , ~ Q ~ o ~ ~ ~ ~ ~ _
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0 a O ~.0 0 Q ~0 ~-- Q Q c c c Q = ~ E c Q 2
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a7 a7 C~ a7 a7 a7 ~ a7 _ a7 a7 a7 ~ a7 _ c~ a7 _ O
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, u~ 2 ~ ~ N U7 C~l 0 0 0 0 ~ ~ ~ ~ U7 C~ _ C'7
_ c~ a7 ~ cu c~ r~ r~ r~ r~ c~ cu a7 a7
a7 a7 a7 cu cn a7 CD a7 a7 _ a7 UD Lr~ a7 r- cu co O o a7
cu _ cu o u7 a7 ~ ~ a7 u7 a7 cn u~ cn O u7 a7 r~ cu ~r
O O C7 _ CD O o U a7 r- ~ a7 r~ 0 0 0 a7 c~ cn u7
a7 cu _ u7 a7 a7 u~ c~ a7 a7 ~u u~ u~ ~t u7 _ - ~r
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I I I I I I I I I I I I I I I I I I I I
76 38
SUBS i I l UTE SHELT (RULE 2~1
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
~ U~ ~ o~ O~O _ er ~ 0 0 0 C~l ~r o Ln
1~ r~ ~ o r~0 o o u~
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u~ _0 _ ~ t ~ ~ 0 o
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76.39
SUB5 111 UTE ~i~EET (RULE 2~i)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
0 _ ~ o _ C~ 0 _ 0 c~ 0 _ 0 ~ c~
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I I I I I I I I I ~ I I I I I I I I I I I I T I
76.40
SU8STITUTE S~ EET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/05320
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I I I I T I I I I I I I I I I I I I I I I I
76.41
SU8STITUTE ~EET (RULE 2~i)
CA 02218741 1997-10-21
.
.W 096/33276 PCTnUS9610S320
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- I I I I I I ~ I I I I I I I I I I I I I I I I
76.42
SUBST~UTE ~tEET tRULE ;~6)
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/OS320
~ 0 _ 0 ~~ 0 ~ ~D O ~ a~ 0
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76.43
SU85mUTE 5}~EET tRULE 263
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
0 o U~ ~0 0 ~ ~D 0 ~ U~ ~D O et _ O _ e~ 0 _ 1~ O 0
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76.44
SUBS 111 VTE SHE}~T tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96105320
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76.45
SUB5 111 UTE SHE}~T ~RULE 263
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
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76.46
SU~15 1 1 1 UTE St/l E~T tRULE 2fi')
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
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76.47
SUBSTIl UTE S~}EET ~RULE 2~i~
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
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I I I I I I I I I I I I I I I I ~ I I I I I I
76.48
SUB5T~TUTE 5~EET tRULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96105320
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SUBS 111 UTE S~E~ ~RULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
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SUBSTlTUTE S~EET tRULE 2
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
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76.51
SUBS 111 UTE ~HE~T ~RULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/0~320
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SU85mUTE S~tEET tRULE 26
CA 022i8741 1997-10-21
W 096133276 PCT~US96/05320
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SU8STITUTE SHEET tRULE 2
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W 096/33276 PCTrUS96/05320
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CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
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76.55
SUBSTITUTE SHEET tRULE 2fi~
CA 02218741 1997-10-21
PCTrUS96/05320
W 096/33276
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76.56
SUBST~TUTE S~ EET tRULE 26)
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
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76.57
SUBSTITUTE S~EET ~RULE 2fi)
- - -
CA 02218741 1997-10-21
W O 96/33276 PCTrUS96/05320
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..
76.58
SUBSmUTE ~EET (RULE 26)
CA 02218741 1997-10-21
W 096/33276PCTrUS9610S320
r~ 1~ t~ ~1 0 N ~ 0 ~ ~t C~ ~ O C) 1~ C~J O tD ~ ~ ~ l 1~ 0 O) O U~
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~ ~ el~ er m ~ a~U~ a~ o _ _ u~ D m ~ ~ o e~
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_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~
~ CD U~ O C~ o _ ~ o) e~ O . ~O O
_ el~ N ~ lC~ ' C~ ~D ~ O 1~ O _ ~ C~l O 0 10 ~D 0 0~ 0 O _ C~
O O O O O _ _ _ ~ ~ ~ W ~ ~ Q 0 O~ O) O o O
et~ et et e~ et e~ e~ el~ el~ e~ e~ el~ ~ e~ e~ el~ e~ e~ el e~ ~ el el~ ~ et et ~ In 10 ~
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
--C~J ~ a~ ~ ~ ~ o a~ a~ o o----a~ et a~ al ~ LD C~ r- _ r
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o --Ln 0--L~ o a~ et ~ et O _ _ ~ a~ o ~ ¢) 0--o Ln 0 ~D 0 Ln Ln - a~ C ~
et et ~--0 O~ ~'' ~ ~ _ et Ln 0 0 N ~ ~ ~ D ~ ~ et Ln U~ _ et In ~ 0 a o
et et e~ ~ ~ t L Ln L ~o ~D CD ~ 0 0 ~ a O O O ~ ~ ~ c~ J Cc~ O
Ln o ~: Ln et ~ ~ O O a~ o o ~--Ln a~ ~ CJ f~ a~ ~ rD et c~ o CD et
a~ o ~ r- In--Ln 0 W Ln ~D ~n---- n Ln--a~ ~ a~ cn I ~--o ~J Ln Ln et
-- ~ o c~ a~ a~ ~ ro C~J ~ c ~ Ln C~ ~ Ln ~ ~ o NNC~ J a~ Ln -- et C~J a~
et et et et e~ Ln ~ ~ D 0 ~ ~ 0 ') --N~D~0C~ a7 Ln C~
NN~N~N~
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-------_-N~N~NNNNNNNNNNNNNNN~NNN
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0 ~ 0 Ln a~ ~ o ~ o r~ D Ln Ln et N00-.0 ~-- O et Ln ~ ~ 0 0 ~0 et 0 C~l
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00000000000000__._C~NNN0 C~ C~ 0 et e~ et et 0
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La ~D 0 0 r~ et _ c7 Ln r~ ~ ~ C~ et C7 0 0 C~ _ et C~ Ln et C~ _ 0 Cq O e~ 0 C~ C~
O O Ln 0 C'~ et ~ Ln C~l 0 ~l ~ 0 ~ 0 m NC~I et O et ONLn0t':l1'0lDC~JO
_ _ C~ et Ln U~ ~D 0 0 _ ~ 0 0 C~ r~ 0 _ C~ C~ r- 0 Ln Ln r~ r~ 0 0 0 0 0--
00000000000 c~00___NNNC~lNC'~ C'> 0 L') C'~ et et et Ln 0
O O O O O O O O----~ _--_----_ _ _ _--_ _ _ _ _ _ _ _ _ _ _
0 0 0 _ r~ C~ et UD 0 0 0 _ L~ UD O ~ aD r- 0 o Ln UD r~ r~ et n UD et Ln CD r- 0
C~ C~ C~ C~ ~ C~ C~ C~ C~ t et et et Ln ~ Ln Ln Ln UD UD UD ~ ~ r ~ r- 0 0 0 0 0
o o o o o o o o o o o o o o o ~ o o o o o o ~ ~ o ~ o o o o o o
- - - - - - - - - - - - - - - - - - - - - - - - - - - - -
76.59
SUB5TITUTE Sff EET tRULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
co a) c~ o) 0 a~ o cn ~ C~ 1~ cn ~ N--O--1~ 0
o u~ ~ 0 In 0 ~ ~ ~ cr) cn 0 ~ ~ 0 o cn
r~ 0 cr~ _ o a~ ~ ~ c~ 0 c~ cn o
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~ o c~ co ~ r~ ~ o 0 co co co 0 cn n cn 0 o o _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _
cn o _ C~ t~ 0 c~ co ~ cn o c~ ~ 1~ cn o ~ ~o o _ cq ~ ~D ~ cn o CD ~_ C~l
~D ~' r~ 0 co 0 0 co cn cn cn o o ~ C~ c~ N C'~
____~_____
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
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cn co u~ ~ ~ ~ n _ ~ ~ _ u~ ID cn _ ~ co m C~l 0 cn ~ ~ u~ ~t
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co cn u~ ~o ~ ;~ ~ 2 ~o ~ ~ D $ a~ D cD w ~D
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ID 1~ C~l ~ 0 cn ~ u~ r ~ 1~ 0 ~C cU ~ ~ CD ~ ~D _ 0 ~t ~ 0 _ ~ 1~ _ cO U:~
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_______________________. ________
0 0 0 0 _ cU co cn _ CU ~ 0 _ ~ ~D 0 0 0 C~ o r~ ~ 0 cU ~ ~ 0 0
c~J C~ l CU C~ ~ 1~ 1~ 1~ 0 0 0 0 0 0 0 0
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o o o o o o o o o o o _ _ _ _ ~ C~ c~ c~ r7 r7 r7 r7 r7 r7 ~r ~ u~ u~ (D LDL U7 U7 U7 U7 U7 U7 U7 Ln Lr7 U7 U~ U~ U7 U~ I u u~ u7 u7 u7 u7 L~7 U7 U7 U7 U7 u7 u7 .-~ U7 u7
~t O _ O r~ r- cu O cu 0 0 r.7 ~t a7 0 0 ~ cn c~ C~ c~ r7 0 _ U7 _ ~ c~ _ _ 0 0
cn 0 r~ co UD 0 0 r7 L~7 ~t u~ O CD ~- 0 U7 'J O U~ ~~ r~ r7 u7 ~J _ o cn c~ ~ r~ ~ u
O cu ~t CO O cn ~7 0 ~7 ~D CU ~t C~ r- cn r~ ~J L~ ~ r~ _ ~D _ u7 r7 _ r7 ~ c~ O r7 ~-
~ L~7 U7 ~D ~ ~' 0 0 0 cn o o _ r~7 ~ _ ~ L (S,7 r~ 07 (D ~-- 0 0 _ ~-- ~ ~ O O :~JO O O O O O O O O O----------CU ~ C~, cU r r7 r7 r7 r7 ~t ~ ~t u7 u7 (D ~D D
L~7 U7 L~7 L~7 L~7 U7 U7 L~7 L~7 L~7 U7 L~7 U7 U7 U7 L~7 ~7 U U7 U'~ U7 U7 L~7 U7 U7 U7 L~7 U7 U7 U7 L~7 ~7
___~--____________________________
~ U7 ~ CO CD _ C~ r7 ~ u7 (D r~ 0 _ C~ 0 0 _ r7 o ~ u7 (D 0 0 c~ CO ~ ~-- _ CU ~t
- - - _ _ C~ C~ C~ C~ C~ CU C~ CU r7 r7 r7 ~ r u7 u7 u7 u7 u7 (D (D D r- r- CO CO 0
_______~_______________.________
-
76.60
SUB5TITUTE 5~EET (RULE 26)
=
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/OS320
o
D
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t~ ~ o m ~ m ~ ~ m ~ n _ m ID C~l In m r~ ~ ~ o _ _ m e~ > ~ o
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D D tD D D D r- ~ ~ ~ ~D ~ 0 ~D m 0 m 0 0 o o _ _ _ _ _ _ --
0 ~D ID ~D ~D D ~D ~D D ~D ID ~D ID tD D ~D D tD CD ~D ~
m -n ~ .n c.J m o m ~D ~D--t--_ O m _ _ m ID N 0 0 CJ ~ In r_ cn ~D m
o n ~D ~D D O ~ ~ In _ ~ ~ _ ~_ o m m _ ~ D m o c~ In ~ In
~D ~ m ~ o m ~ m ~ ~ m m ~ n ~D ~D In C~ m _ ~ 0 0 0 e ~ c~ m o
n ~D ~ ~D m ~D o ~ m ~D ~- ~ m 0 o o o m ~ ~ _ c~l m m ~ m o o c~
~D ~D ~D D ~D ~D ~D ~ m m ~ m m 0 0 0 0 ;> ~
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- - - - - - . - - - - - - - . - - - - - - - - - - - - - - - - -
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~ ~ O O O O O ------ -- c~ ~ q ~ In In In In In LD D ~D ~D ~D
tD ID ~D ID ID ~D D ~D tD D D D tD ~D tD ~D ID ID ~D ID ~D ID ID D D D ID ~D D ~D ~D ~D
_ _
IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
mr_0c~l In ~D o ~ o D m ~ 0 m 0 In 0 ~ ~D ~D ~ C~ m ~ O ~D c~m_~t0 In
~ ~ ~ ~ _ ~ ~D ~ O ~D 0 ~ m_O~O~m-~00~D ~ ~ 0 ~ ~ O
0 ~D ~~ O N ~ O ~ N In O r~ ~D O 0 ~ O ~ _ ~ tD O In ~ C~l tD O 0 1'~ D C~J ~D
C~J ~ Ln D ~D ~D mm000oo__~ In ~D 0 0 0 0 0 0 C~ m ~ ~ ~ mm
n In 'n m ~D n In In In LD r- r- r- r- rn ~~ G r- In n In In In In In m LD n In In LD Ln
_______________.________________
m m _ ~t m _ 0 In r- In D m m0mc~oc~mr~_oc~00r~c~ D D m ~t--
0 Lr~ 0 N et e: O In 0 mc~0 D 0 ~ _ In o ~l l~7 o e~l _ o o ~ ~t o N -- ID ~J
~ m _ co o In ~ D c~Jmo~ In m 0 ~ _ ~I~J In ~D O D m~J~D _ In ~ D c~
m ff In In D ~ r-mm00ooo__r~ m D n 0 0 o o o ~J C~J m
~D O ID tD ID ~ D D D D lD r~ ~ î~ l~ r-- r- ~ ~ ~ r- l~mmm~mmm:~m~
LD L~ Ln LD LD Lt LD LD LD LD LD LD LD Ln LD LD LD LD D D LD LD LD LD Ln ~ LD LD LD n LD
____.___________________~_______
~D ~ 0 0 _ C~l ~ LD l--mo_~cq~v~ D ~ O _ CJ ~) ~ LD ID t~ CD cn oc~ LD
mma~cn 000000oo~oo~oo---------- N N C'~ C~
t ~t ID LD ~ LD ID ~ LD LD LD LD LD ID LD ID In LD LD ID LD LD LD LD
____________,___________________
IIIIIIIIIIII_II_ITIIIIIIIITIIIIr
76.61
SUBS~tTUTE S~E~ (RULE 2~i)
CA 02218741 1997-10-21
W 096/33276
PCTrUS96/05320
~_ ~ O B o tO ~ v'
~ e E~a 9 c c ~ c ~ r
e r~ E~,T5 ~ c~,O c
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C ~V C C ~C) Xo _ v~ ~ C C _ ~ ~
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76.62
SUBS i I l UTE S}~EET tRULE 2~)
CA 02218741 1997-10-21
W 096133276 PCTAUS96/05320
~ C~
C~ S
~ I~ o o o o ~ o o l-- ~n ~ ~ oo
d o to c~ o O ~ u~ ~ oo c~ ~ C~ r~
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C V
V~a n~= ~O- s~
v~ ~ ~~ el- ~ ~ ~ c~ ~ ~ c~ O O
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t~
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C C v~ c~O O O O O O O O O O O O
Z ~ O g g g g g CO ~ O g C~
E V4 _ ~~ - ~ - C ~- Cj ~
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76.63
SVBSTrrUTE S~EET tRULE 2~i)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
C~ Z ~D t~' -- C C a:~ ~
C~ C
o
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c
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g~ o~ C~ ~ ~
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76.64
SUB5T7;rUTE S~EET (RULE 26
CA 02218741 1997-10-21
W 096/33276 PCTrUS96105320
~~ ~ ~ ~~~ ~ ~~ ~ ~ ~
CC
V
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C :: 'U _ C
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76.65
SUE~STTTUTE S~EET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
~ O ~I O O O~
C ~ ~ ~ ~~ ~
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~0. ~ ~ O. 0 00 ~ C'~
O ~ O ~ O ~ O ~ O
S ~ X ~
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76.66
SUBST~TIJTE 5HEET tRULE 2h)
CA 02218741 1997-10-21
W 096~3276 PCTrUS96/05320
(1) ~.~N~T. INFORMATION:
(i) APPLICANTS: Human Genome Sciences, Inc.;
Johns Hopkins University
(ii) TITLE OF lNV~NllON: The Nucleotide Sequence o~
the Haemophilus in~luenzae Rd Genome, Fragments
Thereo~, and Uses Thereo~ ~
(iii) NUMBER OF S~U~:N~S:
(iv) CORRESPO~N~ ADDRESS:
(A) ~n~T~T.q~q~T. Sterne, Kessler, Goldstein ~ Fox, P.L.L.C.
(B) STREET: 1100 New York Avenue, N.W.
(C) CITY: ~h;ngton
(D) STATE: DC
(E) C~U~1~Y: USA
(F) ZIP: 20005-3934
(v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: 3 1/2 inch diskette
(B) COMPUTER: Dell Pentium
(C) OPERATING SYSTEM: MS DOS v6.22
(D) SOFTWARE: ASCII Text
(vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: (Not Yet Assigned)
(B) FILING DATE: (Herewith)
(C) CLASSIFICATION:
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/476,102
(B) FILING DATE: 07-JUN-1995
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/487,429
(B) FILING DATE:07-JUN-1995
-77.1-
SUBSTITUTE ~i~tE~ tRULE 2~
CA 022l874l l997-l0-2l
W 096l33276 PCTrUS96/OS320
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/426,787
(B) FILING DATE: 21-APR-1995
(2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1830121 base pairs
(B) TYPE: nucleic acid
(C) STRAN~N~SS: double
(D) TOPOLOGY: linear
(xi) S~YU~N'-'~: DESCRIPTION: SEQ ID NO:l:
GGCCGCGGTG CATCACAAAA CATCATTCCA TCTTCAACAG GTGCAGCGAA AGCAGTAGGT 60
AAAGTATTAC CTGCATTA~A CGGTAAATTA ACTGGTATGG CTTTCCGTGT TCCAACGCCA 120
AACGTATCTG TtGTTGATTT AACAGTTAAT CTTGAAAAAC CAG~ll~llA TGATGCAATC 180
AAACAAGCAA TCAAAGATGC AGCGGAAGGT AAAACGTTCA ATGGCGAATT A~AAGGCGTA 240
T~A~GT~ACA .T~A~GAT~ T~l"L~1"l"r~l~ ACTGACTTCA ACGGTTGTGC TTTAACTTCT 300
GTATTTGATG CAGACGCTGG TATCGCATTA ACTGATTCTT TCGTTAAATT GGTATCTTGG 360
TACGATAACG A~ACGGGTTA CTCAAACA~A GTATTAGACT TAGTAGCTCA TATCTACAAC 420
TACAAAGGCT AATTAAAACT TTGAAAAAAT TAACCGCTCT TCGGAGCGTT TTTTATTATC 480
TAGAATTTAA TTTACGCTCT A~AAATGAAC AAGGGATCAC TA~AAATAAT TTAAAACAAT 540
CAATATTCTT CTAGCTTTTA TTCCTATTTA AGATTATATT AGCGCACAAC TGTTCGCTCA 600
ATGAAAATCA AAAATAGGGT TAATATGAAT CTCGATCTCC AllL~ L~A TCGTATTCAA 660
CAACAAGCCA AAACTCGTAC AAATATGACC GCACTTCGCT ATA~AGAACA CGGCTTGTGG 720
CGAGATATCT CTTGGAAAAA CTTTCAAGAG CAACTCAATC AA~ull~lCG AGCATTGCTT 780
GCTCACAATA TTGACGTACA AGATA~AATC GCCATTTTTG CCCATAATAT GGAACGTTGG 840
ACAATCGTTG ACATTGCGAC CTTACA~ATT CGAGCAATCA CAGTGCCTAT TTACGCAACC 900
AATACAGCCC AGCAAGCAGA ATTTATCCTA AATCACGCCG ATGTA~AAAT ~ C'~lC 960
GGCGATCAAG AGCAATACGA TCAAACATTG GA~ATTGCTC ATCATTGTCC AAAATTACAA 1020
AaAATTGTAG CAATGAAATC CACCATTCAA TTACAACAAG ATCCTCTTTC TTGCACTTGG 1080
-77.2-
SUBSTITUTE S~tE~T tRULE 2~)
-
CA 022l874l 1997-10-21
W 096/33276 PCTAUS96/05320
GA~AGTTTTA TTAAAACAGG TTCAAACGCC CAACAAGATG AACTAACCCA ACGCTTAAAC 1140
CAAAAACAAT TATCGGATTT ATTTACGATT ATTTATACCT CAGGCACAAC GGGAGAGCCT 1200
AAAGGTGTCA TGTTAGATTA CGCTAATCTC GCTCACCAAT TAGAAACACA TGA'l'~'l"LL~'A 1260
CTTAATGTGA CAGATCAGGA TATTTCACTT 'l'~'l''L'L'L'L'l'AC CA'L'L~'L~'L~A TA'L'L'l"l"L~AA 1320
CGGGCATGGG CGGCTTATAT TCTTCATAGA GGCGCAATAC TTTGCTATTT AGAAGACACT 1380
AATCAAGTGC GGTCAGCTTT AACGGAAATT CGCCCAACTT TAATGTGCGC CGTACCACGT 1440
TTTTACGAAA AAATTTATGC TGCCGTATTG GATA~AGTTC AAAAAGCCCC AAAACTTCGC 1500
CAAATTATGT TTCATTGGGC AATTTCCGTG GGACA~AAAT ATTTTGATCT ACGTGCGAAT 15 60
AACAAAGCTA TTCCGTTCTT ATTGAAGA~A CAATTTGCTT TAGCAGATAA ATTAGTGCTC 1620
TCAAAACTTC GTCAATTATT GGGGGGACGA ATA~AAATGA TGCCTTGCGG AGGAGCAAAA 1680
TTAGAACCGG CTATTGGGCT ATTTTTCCAT GCTATTGGTA TCAACATCAA ATTAGGCTAT 1740
GGTATGACAG AAACAACTGC AACC~11L~L TGCTGGCATG ATTTCCAATT TAACCCAAAT 1800
TCAATCGGCA CACTGATGCC AAAAGCGGAA GTGA~AATTG GGGAAAATAA TGAAATCCTT 1860
GTGCGTGGCG GAATGGTGAT GA~AGGCTAT TACAAGAAGC CAGAAGAAAC GGCTCAAGCC 1920
TTCACCGAAG ATGGTTTCTT A~AAACTGGC GATGCAGGAG AATTTGACGA ACAAGGCAAT 19 80
TTATTTATTA CCGATCGTAT CA~AGAATTA ATGA~AACCT CA~ACGGCAA ATATATCGCA 2040
CCACAATATA TCGAAAGCAA AATCGGTA~A GATA~ATTTA TCGAACA~AT TGCGATCATC 2100
GCTGATGCGr A~AAATATGT ATCCGCGCTT ATTGTGCCTT GCTTTGATAG TTTGGAAGAA 2160
TACGCTAAAC AGCTCAATAT TAAATATCAT GACCGTTTAG AACTACTAAA AAATTCTGAC 2220
ATTCTGAAAA L~LL1~AGCA TCGTATTAAT GCGGTGCAAA AAGAATTGGC TCATTTCGAG 2280
CAAGTAAAAA AATTCACGTT A~LL1~L~AA GCATTCAGCA TTAAATTAGG CGA~ATTACA 2340
CCAACATTAA AATTACGTAG AAAAGTGATT TTAGAACGTT ATCGCAAGCA AATTGAAGCA 2400
ATGTATCATT CACAAGAAGC ATAGCTA~AA GGCTCTCAAT TGAGAGCCTT 'L~'L'l''L'L~'LAA 2460
TTATTCAGGA AATTTTTCTT CTAAAATCAA TGCAAGTCCA TCTTCATTAT TGGTTGCCGT 2520
AACCACATTT GCAGCTTGTT TAATTTCATT TGGCGCATTT CCCATTGCAA CACCAAGCCC 2580
CACATGTTCT AGCATATCCA GATCATTA~A ATTATCGCCA AATGCAATCA CTTCATTAGT 2640
TTGTACGCCA A~ATAATCTT CCAAAA~CG CACCGCACTT CCTTTGGTTG CA~L~l L~LG 2700
CATTACCTCT A~AAAATTAG CGTGGGAACG ACAAATACTT A~ATGTGGAA ATTTTTCCTT 2760
-77.3-
SUBS i 1 1 UTE SHEE~ ~RULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
TAAAAGAACT TCAATCTCAA TGATTTCTTC TGCTTCCCCA ATAATTTGAA TTTTATGTGG 2820
CGAACGTGTC GCTACTTCAT CAAAAGGATG AATCTCAATT TTGGTCACGC TGCGTTCATA ~880
AATCACCCAT TTA'llll~lA CATCGCGCGC ATGGCAATCA TTATTTGTAT AATAATTCAC 2940
GCCAAGCAAA GGATGTTCCG CCAAAACAGT ATTAATCTCT A~AATATCTT TTGGCTCAAT 3000
TTGTACGCTA TAAATTGGTT CGAGATTTTG GTTCAAAATA AGCGCACCAC TAAATGCAAC 3060
AAGTACATTA l"l~llL-AA G~1~111C~A ATAAGGCAAA ATACCTAAAG GAGAACGCGC 3120
CGA~ATTGGC ACAAAAGGAA TGCCATTCGC CGTTAAACGC TTAATTACCA CAACAGTTCG 3180
AGGGGAAATT GTATGTTGAG AGGTTAATAA GGTGCCATTA AAATCACTAA ATACTGCTTT 3240
ATACATCATT ACTCCGAATA AAGATTATTT CTCTGCTAGA TAAGGATCAT CAAAGCCTAA 3300
TCCTTGCATA ATTTGGGTTT CTAAACTTTC CAlll~llCC GCTTCATCGT CTTCAATATG 3360
ATCATAACCG AGTAAATGTA AGCTACCATG CACGACCATA TGCGCCCAAT GTGCCATTAA 3420
lG~lll~l~l TGTTCTGAGG CTTCTCGCTC CACGACTTGA CGACAAATAA CGAGATCCCC 3480
TAACAATGGC AACTCCACCT CATCGGGGCA TTCAAATGGA AATGA~AGCA CGTTAGTCGG 3540
GCGAl~llll CCACGATAAG TTAAATTTAA TTCATGGCTT TCGGCTTCAT CCACAATACG 3600
CACCGTCATT TCGACTTCAT TGCCCTCAGG CTGAACAGCA CCTGTTGCCC ACTGCACAAT 3660
CTG~l~ll~l~ GTTGGCAAAC CCTCTATATT ll~l~lGGCA ATTTGCAAAT CAACCAATAC 3720
ACTTCCCATT CTA~ll~lC~l AAAl~l~llll CAATTTCTAA CCGCACTTTT GCACTTATTG 3780
AATACATATA ACAAACGGTG GGCTTATGAC CA~llll~lA TGTGTAAAAA TGAGGGGAAT 3840
TATACAATAA TAAACCTACC AATCCCCTAA ATTTAGATTA CATAATTTAT GTTTACCGCT 3900
AATTTACTCT ATTTTTAACG TACAAAGAGA CAAATCACGC TATTTCCTTA ATCAACACAA 3960
AACCTCAAAT CTCTCGCTCT TGGTTGAGGT TAATTGTGAA GTCGTAGATG TCCGCTATAA 4020
ATAlllC~ll TTC~ll~CC~l AGCAAAACCA ATTAAAGTCA AATTATGTTT TTCTGCCATT 4080
GTTACTGCTA AATCCGTTGC GGCAGAAATC GTGACTAACA TTTCCACCCC GCAAGCCACT 4140
~ll~llllGCA CCATTTCATA ACTCGCTCGA CTGGAGGCTA AAATAAAACC TCTAGGTTTA 4200
CCCGATTTTG CGTGCCAACC AAGCAATTTA TCTAATGCAA CGTGGCGACC CACATCTTCG 4260
TAaATAGCTA ACATACTTCC ATATAAATCG AAAAATGCAC AAGCATGGGT AGCACCAGTT 4320
TTACATCCAA GCAATTGATT TTTTTGAAGA TCAATAAGAC AACTATCTAG CAAATTTAAA 4380
TCAAATTGAA AAGTACAGTC TAATTTCGGA AAAGTTTTAT ATACTTGATT CAAll~ll~l 4440
-774-
SUBSTmJTE ~;~EFr tRULE 2f;)
CA 022l874l l997-l0-2l
PCTrUS96/05320
W 096/33276
GTACCACA~A TACCACAACC AGTACGCCCC GTAAGATTAC GACGATGCTC TTTTAATGCC 4500
ATA~ATTTAC GGCTGGA~AG TTCAATTTGC ACTTCAATAC CATTGCA~AC TTCTACAACA 4560
TCAATACCAT AAATATCTTC TGGTTTATTG ATAATTCCCT CTGTTAGAGA AAAGCCTA~A 4620
GsAAAATCCT CTAAATTGTT TGGGGAACAC ATCATAACTG CGTGAGAAAT GCCGTTATAT 4680
ACCAAAGAAA CTGGTATCTC AACAGCCAGT ATGTCCTCTT ll-l~llGCAA AAGTGCGGTC 4740
AATTTTnCTG TAllllll~L ~lll-~lAAAA AAGTTGATAG lll~lCGAAT CCAGCACTGC 4800
ATTTATTACC AGTCCATTAG TTAAATGTAA A~A~L~l~Ll A~ATTATTTT TATATTTATG 4860
ATCTAGATCA CAATATTTGT TGAAGCTAAT GTCATTTGAT TATGGATTTA TCGTTAAAAA 4920
ATCGTTACTC TAGCCATCCA ATAAATCAAC ~lllLlACGA TGATTTATAT ACTAGAGAGT 4980
ATTATTTTAA CGAAATCAAC ATAATCTAGC TACTAAACGA ATTTTATTAC TATCTATAAT 5040
ATCTCAACAA ~ll~ll~llG AAAGGAGTGA TTATGCAGGT CTCAAGAAGA AAALl~ll~A 5100
AGATCTGTGC AGGAGGTATG GCGGGAACGT CAGCTGCAAT GTTGGGCTTT GCTCCAGCAA 5160
ACGTATTAGC TGCGCCACGC GAATATAAAT TATTACGCGC GTTTGAATCC CGTAACACCT 5220
GTACATATTG CGCTGTAAGT TGCGGTATGT TGTTATATAG CACAGGCA~A CCTTACAATT 5280
CATTAAGCAG CCATACTGGC ACAAATACTC GTTCA~AACT CTTTCATATT GAGGGTGATC 5340
CAGATCATCC AGTCAGTCGT GGTGCGCTTT GCCCGA~AGG TGCTGGCTCA CTCGATTATG 5400
TCAATAGTGA AAGCCGTTCT TTATATCCTC AATATCGTGC GCCAGGTTCT GATA~ATGGG 5460
AACGAATTTC TTGGA~AGAT GCCATTAAAC GTATTGCTCG TTTAATGA~A GATGACCGAG 5520
ATGCCAACTT TGTTGA~AAA GATTCA~ATG GA~AAACGGT TAATCGTTGG GCAACGACAG 5580
GAATTATGAC TGCATCAGCA ATGAGCAATG AAGCTGCGTT ATTAACACAA AAGTGGATTA 5640
GAATGCTCGG TATGGTGCCA GTATGTAACC AAGCGAATAC TTGACACGGA CCAACGGTAG 5700
CAAGTCTTGC TCCATCATTT GGTCGCGGTG CCATGACA~A TAACTGGGTT GATATTA~AA 5760
ATGCCAACTT AATCATCGTT CAAGGCGGTA ACCCTGCAGA AGCCCATCCT GTTGGCTTCC 5820
GTTGGGCAAT TGAAGCGAAG AAAAACGGTG CGA~AATCAT CGTTATTGAT CCGC~llll~ 5880
ACCGTACAGC AlCC~ll~CT GATCTTCATG CGCCAATTCG TTCTGGTTCT GATATTACGT 5940
TCTTAATGGG CGTGATCCGT TACCTATTGG AAACAAACCA AATTCAACAC GAATATGTTA 6000
AACACTATAC CAACGCATCA TTCTTAATTG ATGAAGGTTT CAAATTTGAA GATGGTTTAT 6060
TTGTAGGGTA TAACGAAGAA A~ACGTAACT ACGATAAATC TA~ATGGAAC TACCAATTTG 6120
-77.5-
SUBS i 11 UTE S~E~ tRULE 2~i~
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
ATGAAAATGG TCACGCTAAA CGTGATATGA CATTACAACA TCCTCGTTGT GTCATTAACA 5180
TCTTAAAAGA GCAC~LL-l~L CGTTATACCC CAGAAATGGT TGAACGTATT ACAGGCGTAA 6240
AACAAAAACT CTTCTTACAA A~L~l~l~AAG AAATTGGTAA AACCTCTGTG CCAAATAAAA 6300
CGATGACGCA TCTATATGCA TTAGGTTTTA CAGAGCATTC AATCGGTACA CAAAATATTC 6360
GCTCAATGGC GATAATCCAG TTACTTTTAG GTAATATGGG GATGCCAGGT GGCGGTATTA 6420
ACGCATTACG TGGACACTCC AATGTGCAAG GTACGACAGA TATGGGCTTA TTGCCAATGT 6480
CTTTACCAGG TTATATGCGT TTGCCAAACG ATAAAGATAC CTCTTACGAT CAATACATTA 6540
ACGCAATTAC ACCAAAAGAT ALC~LlC~AA ACCAAGTGAA CTATTATCGT CATACTTCAA 6600
AAll~lll~l TAGCATGATG AAAACTTTCT ACGGAGATAA TGCCACTAAG GAAAATGGCT 6660
GGGGATTCGA lll~llACCA AAAGCAGATC GCCTATATGA wCCAATTACT CACGTTAAAT 6720
TGATGAATGA AGGCAAATTA CACGGTTGGA TTTTACAAGG TTTTAACGTA TTAAATTCAC 6780
TACCAAATAA AAATAAAACG TTA'l~lG~lA TGAGTAAACT GAAATACTTA ~lC~ll~ATGG 6840
ATCCATTACA AACTGAATCA TCAGAGTTTT GGAGAAATTT TGGTGAGTCA AATAATGTAA 6900
ATCCTGCAGA AATTCAAACA GAAGTTTTCC GTTTACCAAC TA~ll~LLlC GCAGAAGAAG 6960
AAGGATCAAT CGTTAATTCT GGTCGCTGGA CTCAATGGCA CTGGAAAGGT TGCGATCAAC 7020
CGGGAGAAGC CTTACCTGAT GTTGATATTC TTTCTATGCT ACGCGAAGAA ATGCACGAAC 7080
TTTATAAAAA AGAGGGTGGA CAAGGAATTG AAL~llll~A AGCGATGACT TGGAATTATG 7140
CTCAACCACA CTCACCAAGT GCGGTTGAAT TAGCCAAAGA ATTAAATGGT TATGCGCTTG 7200
AAGATCTTTA TGAtCCAAAC GGTAACTTGA TGTACAAGAA AGGTCAATTA CTCAATGGAT 7260
TTGCACATTT ACGTGATGAT GGTACAACAA CATCAGGTAA CTGGTTATAT GTTGGTCAAT 7320
GGACTGAAAA AGGCAACCAA ACTGCTAATC GCGATAATTC AGATCCATCG GGTTTAGGTT 7380
GTACTATTGG CTGGGGCTTT GCATGGCCTG CAAACCGCCG CGTACTTTAT AGCCGTGCAT 7440
CATTAGATAT CAATGGTAAT CCTTGGGATA AAAACCGCCA ATTAATCAAA TGGAACGGTA 7500
AAAACTGGAA CTGGTTTGAT ATTGCTGACT ACGGTACGCA ACCACCAGGT TCTGATACTG 7560
GGCCGTTCAT TATGTCCGCA GAAGGCGTAG GACGTTTATT TGCCGTTGAT AAAATTGCAA 7620
ATGGCCCAAT GCCAGAACAC TATGAACCAG TTGAAAGCCC AATTGATACA AACCCATTTC 7680
ATCCAAATGT AGTAACCGAT CCAACTTTAC GTATCTATAA AGAAGATCGT GAATTTATTG 7740
GTTCAAATAA AGAGTATCCA TTTGTAGCA~ CAACTTATCG TTTAACCGAG CATTTCCACA 7800
-77.6-
SU8ST~TtJTE ~;HEET (RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
GCTGGACTGC ACAATCTGCA TTAAATATCA TCGCACAACC ACAACAATTT GTGGAAATTG 7860
GCGAAAAATT AGCGGCAGAA AAAGGCATCC AAAAAGGCGA TATGGTAAAA ATTACTTCTC 7920
GTCGTGGCTA TATTAAAGCG GTCGCCGTGG TTACAAAACG TCTTAAAGAT CTCGAAATTG 7980
ATGGGCGTGT CGTACACCAT ATAGGTCTTC CAATTCACTG GAATATGAAG GCATTAAATG 3040
GCAAAGGTAA CCGTGGATTC TCTACGAATA CCTTAACACC ATCTTGGGGT GAGGCAATCA 8100
CGCAAACACC AGAATACAAA ACATTCTTGG TAAATATTGA AAAAGTTGGG GAGGCATAAT 8160
ATGGCTGGAA CTGCTCAAGG CGTTCA~ACG CAAGACGTTA TTAAAATCTC CGCAACATCT 8220
GGTTTAACAC CAGCACCACA AGCGAGAGAT CATAAAGTTG AAATCGCAAA ATTAATTGAT 8280
GTTTCAACTT GTATAGGATG TAAAGCCTGT CAAGTGGGTT GTTCAGAGTG GAATGATATT 8340
CGCTCTGATA TCAATGCACA Al~l~llGGG GTTTATGACA ATCCAGTTGA TCTTGATGCA 8400
AAAGCATGGA CAGTGATGCG TTTTAACGAA GTTGAAGAAA ACGATCGTTT AGAATGGCTG 8460
ATTCGTAAAG ATGGCTGTAT GCACTGCACA GAACCTGGTT GTTTAAAGGC TTGTCCTGCA 8520
CCCGGTGCAA TCATTCAATA TGCTAACGGT ATTGTAGATT TCCAATCCGA TAAATGTATT 8580
G~l-l~l~ll ATTGTATTGC AGGCTGTCCA TTCAATATTC CACGAATGAA TCCTGAAgAC 8640
AA~lC~l~-lAT ACAAATGTAC T~-1-11~-L~-1A GA~lC~l~-lll CTGTGGGACA AGAGCCCGCT 8700
TGCGTGAAAA CCTGTCCAAC AGGTGCTATT C~l-llCGGCT CTAAAGAAGA AATGAAAATT 8760
TACGCAGAAC AACGCGTGGC AGATTTAAAA lCCC~lG~ll ATGAAAACGC AGGACTTTAC 8820
GATCCTCCAG GTGTAGGCGG TACACACGTA ATGTATGTkT TGCATCACGC AGATAAACCT 8880
GAGCTTTACA ATGGTCTTCC AAAAGATCCT CAAATTGATT TGAGTGTGAC CTTATGGAAA 8940
GATGTATTGA AACCAGTCGC TGCAGTTGCA ATGGGTGGTC TAGCTCTAGC AGAAGTTGCG 9000
CACTACTTAA CCGTTGGCCC AAATGTAGAA GAAGATGTGG AAGATCATCA TCACGAATTT 9060
GAAGAAAATA AACCATCTAA GGGGGAAAAT AATGAGTAAA ATTGAAATTA GCAACGATAC 9120
TCGCATTATC CGCCATAGAA CCCCAGCACG TATCAGTCAC TGGATGTTGG TTATTTGCTT 9180
TTTTATGACG ATGTTCACTG GTGTTGCATT L-ll~-L-lCCCT GACTTTGCTT GGCTCACAGA 9240
AATTTTGGGT ACACCACAAA TTGCGCGCGC CATTCATCCA TTCACAGGGA TTTTAATGTT 9300
CTTCGCTTTC ATCTACTTAG CGTTATTGTA CTGGGATCAC AATATTCCAG AAAAAAACGA 9360
TATTCGCTGG GCGAAAGGTG TTATTGAAGT TCTTAAAGGG AATGAACACG CGGTTGCTGA 9420
TAATGGCAAA TATAACCTTG GTCAAAAAAT G~-l~-llllGG ACATTAAACT TGGCAATGGT 9480
-77.7-
SUBS i 11 UTE S~tEET (RULE 2~i3
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/OS320
AACGTTATTA GTCACTGGCA TCATTATGTG GCGTCAATAT TTTTCACATT A~ll~l~AAT 9540
CCCAGTATTG CGAATTGCTA TTTTACTCCA CTCTGCAAGT GCTTTTATGT TATTCACTGG 9600
TATCTTAGTG CATATATATA TGGCATTTTG GGTTAAAGGA TCAATTCGCG GTAll~ll~A 9660
AGGTTGGGTA ACC~11C~L1 GGGCGA~AAA ACACCACCCA AGATGGTATC GTGAAGAAGT 9720
TTTATCAAAA CTTGAGGAAG ATTTACTCAA CGAGCAATCT GGCAAAGTAG GTA~AACCAA 9780
AGTCTTATTT AAAGGATTTG GCAAATAAGC TGAAATCCTG AAAAAGAAAA AGTGCGGTTA 9840
AAATTGACCG CACtTTTTAT TATAAAAGTG AGAGAATATG AGTATCAAAA TCTTATCTGA 9900
ATCAGAAATT AAACAAGTAG nAAATTCATA TCAAGCCCCA GCGGTTTTAT TTGCCAATCC 9960
TaAAAATCTT TACCAACGCA GAGCGAAACG TTTAAGAGAC TTAGCACA~A ATCATCCTCT 10020
ATCTGATTAT TTATTATTTG CTGCAGACAT AGTTGAAAGC CAA~lllC~A CGTTAGAAAA 10080
A~ATCCTTTA CCGCCACAAC AGCTTGAACA GTTAAATACT ATCGAGCCAC TA~ATGCCAA 10140
AACCTTTAAn AGA~ACAGTA TCTGGCGTGA ATACTTAACA GAAATTCTTG ATGAAATAAA 10200
GCCCAAAGCT AACGAGCA~A TTGCTGCAAC AATTGAATTT CTTGA~AAAG C~L~llCCGC 10260
TGAATTAGAA GAAATGGCAA ATAArCkCTT AGCACAAGAA TTTAACTTAG TCAGCAGTGA 10320
TAAAGCCGTC TTTATTTGGG CTGCACTTTC CCTTTATTGG TTACAAGCAG CTCAACAAAT 10380
TCCTCATAAT AGCCAAGTTG AAAACGCTGA A~ATTTACAT CACTGCCCTG TTTGTGGTTC 10440
TTTACCTGTG GCAAGTATGG TACAAATTGG TACATCACAA GGTTTACGCT ACTTACATTG 10500
TAATTTATGT GAAAGTGAAT GGAATTTGGT ACGCGCACAA TGCACCAATT GTAATAGTCA 10560
TGACAAACTC GAAATGTGGT CACTAAATGA AGAACTTGCG ~ll~lLC~lG CCGAAACCTG 10620
TGGTAGTTGT GAAAGTTACT TGAAAATGAT GTTCCAAGAA A~AGATCCTT ACGTAGAACC 10680
TGTAGCCGAT GATTTGGCTT CTAllll~ll AGATATTGAA ATGGAAGAAA AAGGTTTCGC 10740
CCGAAGTGGA TTAAATCCAT TTATTTTTCC TGCAGAAGAA GCATAAAAAT ATAGCCTAGA 10800
AATATCTAGG CTAATTATTT AAATCTATAG ATAACACGCC ATTACCACTG CAllll~lCG 10860
TCCACCACTG GGTTTCGGAT AATAATTTTT CCGAATATCC ACTTCATTAA AACCAATTTT lOQ20
TTCATACAAG AAACGAGCAG AGTTAGACTC TCTGACTTCT AGCCATAAGG TTTGGACACC 10980
lllllC~lll AATTGAAAGA TTAATTTTCC TAACAATAAT TTGCCAAATC CACAACCTTG 11040
ATAAGTAGGC AAAATCGCAA TATTAAACAA AGTCGCTTCA TCCAATACTG TTTGGCAAAT 11100
AGCAAAACCG ATAATCTGAT TATTCTCTAT TAATTTTA~A TTGAGATAAC GCTCCCCTTG 11160
-77.8-
SUBSTrTUTE S~E~ (RUI E 26)
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/05320
ATTA~111111 AACGTACCAA ATGACCAAGG CACCAGATGG GCTTGCTGTT CGATTTCATA 11220
CAATCGCTCG A~ATCACAGG CTTCAATTTG AGAAATAATA GACATAATTA AGGCTGCTGA 11280
A~111~11GCC ACAACGCTCG TTTGGCTTGA TGATTAGATT GA~ATTGCTG CCAACTTGGC 11340
GAGCGATA~A CCTGCTCAGC CTGCTTGCAA AATGGCA~AG TGCGGTCAAT TTGGTCGCTA 11400
1111~LGATA GTAACCAATA ACGAATAGGC TGTTTACATT CCATATGCTG GATTTGATCG 11460
TAATTCAAAC ATAAACAATT 'l"l'~'l"l"l"L'l"l'A AGATTAAGGC TTAACAGCAC ATCAGCCAAC 11520
AAAGGCGAGC TACTGATATT TTCATCGGAA ACAGTGATAA GGCGAATATT CTCTGCCACA 11580
CTAATTCCTA CTGAACCTTG CAGTACCTCG GGGCGATATA ATTCCCACTG GGA~ATGCCC 11640
A111~11~1A A~AGAAGATC GC~1~L~LLC ATAAGTGAAT TTTTAAAAAC GTTGCTTGAA 11700
A~ATAGTGTT AA'L11~LLLL ATTAATCTTT GCTA~AATGG TGCGTAATTT TAACCAATAA 11760
CCCACAGGAT TCAAAGCGTG A1LL~L~LAG AAAGCCAAGT TTTAGAACGC CATATTTCAT 11820
1L11LGATGG TA~ATCGGTA TTATTTGCTG GCGGTATTTC TGATAGTTTT CCTCA~ACAT 11880
TAGCCTCAAA ATGCTCATCA ATCCA~ATTT GGAGTTGCTA TTTTGACTAT GCAAGAACAC 11940
AAAGTGCGGT CAA'LL1L1CC GTTGAATTTC AAGGTCAAGC GGATTTAATC GTTTATTATT 12000
GGACTAAAAA CAAACAAGAA GTCAATTTCC AACTGATTCA ACTATTAGCT CAAGCATCTA 12060
TTGGTCAAGA AATATTAATT A~1LG~L~AAA ACCGTTGTGG CGTGCGTTCA GTAGaAAAAA 12120
CATTATCACC CTATGGAGAA ATAGCAAAAA TTGACTCTGC ~LC~LC~11GC GGTTTATATC 12180
ALL111~ACT CCA~AATAAA CCGCACTTTG AACTTA~AAA 1L1~LG~AGA ACCTACCAAC 12240
ATTCAACACT TGAAAACTTA ACTATATATA GTTTACCTGG GGTATTTAGT GCGGCGGAAT 12300
TAGACACAGG CACAGAACTG TTACTTTCAA CTATTGATAA TAAAATAAAA GGAAAAGTGC 12360
TTGATCTTGG CTGTGGGGCG GGGGTAATTG GCTCTATGAT A~AAAAACGC ACGCCTAACG 12420
CACA~ATTAC AATGACAGAT ATTCACGCAA TGGCATTAGA ATCAGCGCGT A~AACACTTT 12480
CTGAAAATCA ATTACAAGGC GAGGTTTACG CCAGTGATGT ~LLLL~L~AT ATAGAAGGAA 12540
AATTTGATTT GWTCATTTCT AATCCTCCAT TCCACGATGG CATTGATACC GCCTATCGAG lZ600
CAGTGACAGA ACTCATCACT CAAGCGA~AT GGCATCTCAA TCAAGGTGGA GAATTACGCA 12660
TTGTCGCCAA TTCATTTCTG CCTTATCCCG AATTACTTAG ACAACATTTC AATGATTATC 12720
AA~1L~L1GC TCAAACAGGA AAATTTA~AG TGTATTCAGT GAAAAATTAG A~ACA~AAAA 127&0
ATCCCCATCA CAATAATGGG GATTTTTATT ATGCGTATAA ATTTTACCGC ATTTTATTCA 12840
-77.9-
SUBSTmJTE S~EET (RULE 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96105320
TCCATATATC CTAAACTACG CAGCGCACGT TCATCATCAG CCCAACCAGA TTTCACTTTT 1~900
ACCCAAAGTT CAAGATGGAC Lll~llATCA AATAAACGTT CCATATCGGC TCTAGCTTCC 12960
ATACCAATAG TTTTAATTTT TTGACCGCCC GCACCAATGA CCAll-l-lll"l' CTGACCTTCA 13020
CGTTCAACGA GAATTAAGCC ATTTATTTCA TAAGTGCCAC GTTCATTTAC TTTGAATTGT 13080
TCGATTTCAA CAGTAACAGA ATAAGGCAAT TCTTCACCGG TAAAACGCAT TAALll-ll~A 13140
CGGATTATTT CCGAGGCCAT AAAACGTTGC GAACGATCTG TGACATAATC TTCTGGAAAA 13200
TGATGCACAC CTTCACGTAA AGATTGGCGT ACAATTTTCT CTAATTCATG AACATTATTA 13260
CCACGCTGTG CAGAAATTGG CACAATGTGA GCAAAGTTAA ATTTACTGCT AAGATCTGTA 13320
ATAAACGGCA ACAAATCATC TTTATTCTTG ATGTTATCTA ~Ll"l~ll~AT AGCAAGCACA 13380
ACGGGTGCTT TTGCATTACG TAGTTTGTTT AGCACCATCT CATCATCTGC ATTCCAGTGT 13440
GTACCATCTA CGACAAAAAT AATTAAATCA ACATCGCCGA TAGCACTACT TGCGGCGCGG 13500
TTCATTAAGC GGTTAATCGC CCGTTTTTCT TCAATATGAA GCCCCGGTGT ATCCACGTAG 13560
A~Lll~l-l~AT ACGCACCTTC AGTTTTAATC CCAACAATGC GGTGACGGGT A~-Lll~lGCT 13620
TTACGCGATG TAATTGAAAT 'l"L'l"l"l'~'l'C~l AAAATTTTAT TTAAGAGCGT TGATTTACCC 13680
ACATTTGGGC GACCTACGAT AGCAATA~AG CCGCAATAGG LLL-L~LC~AA Ll~lLCGGTC 13740
ATTTGATGTC CA~LL~LLLl AAAATTTGTT CTGCTGCCGC LL~lL~AGCT TTACGACGGC 13800
TAGATCCTTT TGCCACAAAA GTGCGGTCAA LLLL~LCCGC A~LlLL-ACT TTGCATTTAA 13860
CAGTGAAAAT TTGGCAATGG GCTTCCCCTT GAATATTGAC CACTTCATAA GTTGGCAATG 13920
GCAAATGTTT GCCTTGTAAA TA~LL~-L-L~LA AACGCGTTTT CGCATCTTTT TGATTATCGC 13980
~L~LLLAAT TTCTGCCAAT AA~L~Ll~AT ACCAATTTCG TATCACTTGG GTCGTCACAG 14040
CCAATCCTTG ATCCAAAGAC ATTGCACCTA TGATCGCTTC TACACAATCG GCAAGAATAG 14100
ATTCACGGCG AAAACCACCG TTCTTTAGCT CGCCAGAACC AAGCGACATA TAATCGCCTA 14160
ATTCAAATTG GCGCGCTAAA ATCGCTAAAG TGGGTTCGCG TACCA~AGTA GCACGCATAC 14220
GGCTCAGTTC LC~Ll-~ATTA CAACGTGGAA ACTGATGATA AAGTGCTTCA GCGATAGTGA 14280
AATTAAGAAT GGAATCGCCT AGGAATTCTA GGCGTTCATT ATGTTGAGTT GCCGCACTTC 14340
GATGCGTAAG TGCCTGCTTT AAGAGCGCTA TATCATTAAA ACGATAGCCG ATTTTACGCT 14400
CAAGTCGATC TAAATGATTC ATCTTATTTT ATTGCTGTAA AGAAACGCTC AAAACGGA~A 14460
CCTGTTGGCC ATTCATTCGC LL~'L'l--l"l"l'~'l- AAGCTCATCC A~ATATAAGT GGCTTTACCC 14520
-77.10-
SUBSTITUTE SHEET tRULE 26
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
ACAATATTTT TTTCAGGTAC A~AGCCCCAG A~ACGACTGT CATCGCTGTG ATCGCGATGA 14580
TCCCCCATCA CAAAATACTG CCCCTCTGGC ACAAGCCATT CTGCAGTTTG CATTCCCTCT 14640
TGTGGGA~AA ATTCAAGGTC TGAATAACGA CGATACTCAC TAATTAACAC GTTATGTGTT 14700
ACATCGCCTT TTTCAGTCAA TTCTAATTCA TTTGGAAAAG CAGGATTTGT TGGATTTTGT 14760
GTATATTCAA ACGCCTTAGT TTCGCAATCA ATTTCACAGG GTTTCCCCTC TTTACCATAT 14820
ACCACTTTTA GC~1L1111G TTCCACATCA AAAATGACGC GATCTCCGCC CTTTCCAACA 14880
ATACGCTTAA TATAATCCAC ACCAGACATA TTATCTTTTG AACTTAACGC TA~ATTTTCT 14940
GCA~AAGCCG CTC~l~llGC CCCAAGACCA GTACGAATTA ACG~ll~llG TGGTGCTTTA 15000
AACACAATCA CATCGCCACG TTGTGGTTTT TCGCCTGCAA TAAlG~l~ll TTGGA~AATC 15060
GGAl~lll~A CACCATAAGC ATATTTATTC ACAACTAAAA AATCGCCAAC GCGTAAAGTG 15120
GACTCCATTG AGCCAGAGGG AATTTGAAAC GGTTCA~ACA AAAAAGAACG AACCAAAAAT 15180
ACCACTGCAA GCACAGGAAA AAGTGAAGAC AAAAATTCTG AAGCCTCAGA AATCGGTTCA 15240
ATTTTGGCTT lll~lLC~lC ACTTAAGGTT TTACCAGAAC ~ll~ll~lGC ACGTGCCACT 15300
TGACGATGAC GTTTTGGCAG CACCACAAAA CGATGATAAC ACCATAATAC GCCAGA~AGT 15360
GCGGTCAAAA TTAGTAACAA AATACTA~AA GTATTTGGTA ACTGAAAATA ATCTA~AACT 15420
TTCCACACAC CAAAGCCGAC AGCCAATA~A ATCACAAAAA ATAAATTTGA CATAATTTTC 15480
CTTATTTATC TTTTCCTACG TGTAAAATTG CTAAAAACGC CTCTTGCGGC ACTTCTACGT 15540
TACCTA~AGA CTTCATACGT TTTTTCCCTT ~'l L l ~'LGCTT CTGTAAGAGT TTTTTCTTAC 15600
GGCTCACGTC ACCACCATAA CATTTTGCTA ATAC~lllll ACGTAATTGT TTCACCGTAG 15660
AACGAGCAAT AATATGGTTT CCAATCGCTG CTTGAATAGC GATATCAAAT TGCTGACGAG 15720
GAATTAACTC ACGCATTTTT TCAACCAATT CACGACCACG ATATTGTGAA TTATCTTTAT 157&0
GAACGATTAA AGCCAACGCA TCTACTCGTT CGCTGTTAAT CATAATATCC ACGCGAACCA 15840
TATCTGCCGC TTGGA~ACGT TTAAAACCGT AATCTAACGA AGCATAACCA CGCGATGTTG 15900
ATTTTA~ACG ATCAAAGAAA TCTAAAACCA CTTCGCCCAT TGGAATTTCA TAAGTCAGCG 15960
CAATCTGATT ACCGTGATAT ACCATATTGG TTTGCACGCC ACGTTTTTCA ACGCAAAGGG 16020
TAATAACGTT ACCTAAATAT TCTTGCGGCA CCAGCATATT ACATTCTGCG ATTGGCTCGC 16080
GAATTTCAGC AATATTATTA AGTGGAGGCA ATTTTGCAGG ACTATCCACA TAAACCACTT 16140
CACCATTGGT CATTTCAACT TCATAAATTA CAGTTGGTGC TGTGGTAATC AAATCAAGAT 16200
-77.11-
SU~5TI~UTE 5~tE~T ~RULE ~3
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96105320
CGTATTCACG CTCTAGACGC TCTTGAATGA TTTCCATATG CAGAAGTCCA AGGAAACCAC 16260
AACGGAAACC AAAACCAAGC GCGGTCGAAG TTTCTGGTTC ATAGAAAAGT GACGCATCGT 16320
TTAAACTTAA TTTACCAAGT GCATCGCGAA ACGCTTCATA ATCATCAGAA CTTACAGGGA 16380
AAAGCCCAGC ATAAACCTGT GGTTTTACTT TTTTAAAGCC TGGTAAAACC TCAGTTGCAG 16440
AATTATGTTG ATGGGTTAAG GTATCGCCCA CTGGCGCACC TAAAATATCT TTAATCGCAC 16500
AAACAACCCA ACCCACTTCG CCGCATTCTA AAACGGTAGT AT~ll~ll~L TTTGGCGTGA 16560
AAATCCCTAA ACGATCTACG TTATAAGTTT GCC~l~-lGGA CATCACTTTA ATTTTATCGC 16620
CTTTACGTAA TACCCCGTTT TTAATACGCA CTAAAGATAC CACGCCCAAA TAATTATCGA 16680
ACCAAGAATC AATAATCAAT GCTTGTAATG GCGCATTAGG ATCACCTTCT GGTGCAGGAA 16740
TTTTTGCCAC GATTTCTTCT AATACATCTT CGATACCTAC ACCC~1L11A GCTGAGCATC 16800
GAACCGCTTC CATCGCATCA ATTCCAACAA TATCTTCAAT TTCTTCAGCG ACGCGTTCAG 16860
GATCAGCAGC TGGTAAGTCG ATTTTATTTA AAATCGGTAC TACTTCTAAA TCCATTTCGA 16920
TTGCAGTATA ACAGTTTGCT AGAGTTTGGG CTTCTACCCC TTGACCAGCA TCAACTACCA 16980
ACAATGCCCC TTCACAAGCA GCAAGAGAGC GAGACACTTC ATAGGAAAAG TCCACGTGTC 17040
CTGGTGTATC GATAAAGTTT AATTGATAAG TTTCGCCATC TTTGGCTTTA TAATTTAAAG 17100
TAACACTTTG TGCTTTGATG GTAATTCCAC GCTCACGCTC AAGATCCATT GAATCTAGCA 17160
CTTGCGCTTC CATTTCACGA TCCGAAAGGC CACCACAAGT TTGAATCAAA CGGTCAGAAA 17220
GTGTCGATTT ACCGTGGTCA ATATGGGCAA TAATAGAAAA GTTGCGAATA TTCTTCATAA 17280
AAGATTGTTT TTCTCAAAAA TCATTAAATT TAACTGGCGG ATTGTACCTG AAAAGCGCGG 17340
AAATCGCTAG GGATGAAAGG GAAAAGTGCG GTCAAATTTT CAAACTTTTT AGATAAAACA 17400
AAACCCCGAA TAACTTCGGG GTTTCTTTTT TCATTCAAAC TGAAATTATA GGCTTTCAGT 17460
GAAAGTACGA GTGATCACGT CGC~ll~llG TTCTGGCGTT AAAGAGTTGA AACGTACTGC 17520
GTAACCAGAA ACACGGATAG TTAATTGTGG ATATTTATCT GGA~ A CCGCATCTTC 17580
TAACGTTTCA CGACGTAATA CGTTTACGTT TAAGTGTTGG CCACCTTCAA CTTTAACAGT 17640
TGGTGCTACG TTTACTGGTA ATTCACGGTA TTCGATTTGA CCTAATTCGC TAACTGCAAC 17700
AACTTGGTCT TCAGCGAATT CGCCTTTTGC ACATAAGCAA CGTGCTTCAT llllllCGCT 17760
GTCTAATAAC CAGAATGAAT TAAGCAAATT GTCATTTGCT GCTTGAGTAA TTTGAATACC 17820
TTTAATCATA ATAGCCTCCT AATTGGCACG AAAATAATAA TAAAACTGTA CAAATTTTAT 17880
-77.12-
SUBSTITUTE S~EET ~RULE 26)
CA 022l874l l997-l0-2l
W 096133276 PCT~US96/05320
CA~ATCATTT TAATATTTCA AATTATTTTA TATTTATTTG ATA~AGAGCA GGTTATTTTT 17940
TTAATTAATT TTTATAAATT TGATCTA~AT TAAAATTCAT TAATTTTTAA ATA~AATTTA 18000
TATCAATAAT TTAACATTAA TTTAACTTTT TATTGAATGA A1~11111~1 TTATAATGAA 18060
TAAAAACTTA TTAATAGGAT A~AATAATGA A~AACTGGAC AGACGTTATC GGAACAGrAA 18120
AAGCGCAACC TTACTTTCAA CACACACTAC AACAGGTTCA TCTTGCAAGA GCAAGCGGGA 18180
AAACGATTTA TCCCCCACAA GAAGATGTAT TTAACGCATT CAAATATACT G~L111~AGG 18240
ATGTA~AAGT GGTAATTTTA GGTCAGGATC CTTATCATGG ACCAAACCAA GCGCACGGCT 18300
TGG~1111LC AGTAAAACCT GAAGTAGCCA TTCCCCCTTC CCTATTA~AT ATATATAAAG 18360
AACTCACACA AGATATTTCG GGATTTCA~A TGCCATCA~A TGGTTATTTA GTCA~ATGGG 13420
CAGAACAAGG GGTATTGCTA CTTAACACTG TGCTTACCGT GGAACGAGGT ATGGCACATT 18480
CACACGCCAA TTTAGGTTGG GA~AGGTTTA CAGATA~AGT TATTGCAGTA CTCAATGAAC 18540
ATCGTGAAAA ACTGGTGTTT TTACTTTGGG GCAGTCACGC ACAAAAAAAA GGGCA~ATGA 18600
TTGACCGCAC TCGTCACCTT GTTTTAACGG CTCCGCATCC TTCCCCGTTG TCAGCACATC 18660
GA~'1"1"1'~'1"1' TG~'1"1'~'1'C~j'L CA'L'L'L'1"1'C~A A~ACA~ATTC ATATTTGGAA AGCCACGGAA 18720
TAAAACCGAT AGATTGGCAA ATCTA~ACCA TATATCTCTA A~AAATAACC GCACTTTAAT 18780
CTCTCAaAGT GCGGTTAAAT ATTTCAGTAT TTTAATTAGC CGTGATAACG CCCTACGCCT 18840
AATTCATCTT CTTTACGTGT GCGATTCATC A~'L'1'~'L'1'~'LG GAGATTGCGC AATACGTAAT 18900
CCCATTTCAT CTTCAGTACG CACCACTTCG CCACGTAACG AATTAGTATA AACATCAGTG 18960
ATTTTCACAT CCACA~ACTT ACCGATCATT TCTGGAGAAC CTTGGA~ATT AACAATACGA 19020
'1LC~LL1~AG TACGTCCCGT CAATTCCATA ATAL~L1L~1 TCGATGGGCC TTCAACTAAC 19080
ACGCGCTGCT CTGTGCCAAG CATACGACGG CTA~ATTGTG CCG~LL~L1G ATTAATACGC 19140
TCTTGTAGCA CATA~AGACG ~'L~'L'L'L~'L'L'1' TCATCTTCCG TGACATCATC TGGCATATCT 19200
GCTGCTGGCG TACCTGGTCG GGCTGAGTAC ACA~AACTGA AGCTCATATC A~AGTTTACT 19260
TGTGCAATCA AATTCATAGT TTGCTCAAAA TCTTCCGCCG TTTCACCAGG GA~ACCAACA 19320
ATAAAGTCAG AGCTGATTTG AATATCTGGG CGCACAGCAC GAAGTTTACG AATAATGGAT 19380
TTATATTCTA ATGCGGTATG AGCACGTTTC ATCATTGTTA ATACACGGTC AGAACCTGCT 19440
TGCACTGGAA GATGTAAGAA ACTCACTAAT TCAGGCGTAT CACGATACAC ATCAATAATA 19 500
TCATCGGTAA ATTCTATTGG ATGACTGGTT GTGAACGTAA ACGGTCAATA CCATCAATTG 19 560
-77.13-
SUB5 i 1~ UTE S~EE~ ~RULE 263
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
ATGCGACAAG ACGAAGCAAC TCAGCAAAGC TGCAAATTTG ACCATCATGC GTTGGCCCAC 19620
GATAAGCATT TACATTTTGA CCAAGTAGAT TGACCTCACG CACACCTTGT TCCGCAAGTT 19680
GCGCAATTTC AAATAGCACA TCATCTACAG GACGGCTAAC TTCTTCTCCA CGAGTATAAG 19740
GCACAACACA AAAAGTACAG TATTTATTAC AGCCTTCCAT AATGGAAACA AATGCCGTTG 19800
GGC~ll~lGC GCGAGGTTCT GGTAAGCGGT CAAATTTCTC AATTTCAGGG A~ACTTACGT 19860
CTACGACGGA A~lllllCCA CCACGAATTT GATTAATCAT TTCAGGCAAG CGATGCAAAG 19920
TTTGCGGGCC AAAAATAATA TCCACATAAG GCGCACGATG GCGAATATGT TCCCCTTCTT 19980
GAGAGGCTAC ACAGCCGCCC ACACCAATCA CTAAATTTGG ATTATTTTTC TTTAATTCTT 20040
TCCAACGCCC AAGTTGGTGG AACACTTTTT CTTGTGCTTT TTCACGAATA GAACAGGTAT 20100
TTAATAATAA TACGTCTGCT TCTTCAGGTG ~llCC~lGAG TTCTAATCCG TGGGTGCTTA 20160
ATAAAAGATC AGCCATTTTA GATGAATCAT ATTCATTCAT CTGGCAGCCC CAAGTTTTAA 20220
TATGTAATTT TTGAGTCATT TTCTACAATA TCGTTAGGTG TTATAAATAA TTAGTTAAAT 20280
AAAGCAATGG GCTATTCTAC AGCTTGCGCT AATTCTGGCT AGTGAATATT CGGTGAAAGA 20340
CACTAAACAG AATATTTTGA TAAGCTAGAA AGGCTTGTAA ATCATTAAAA AAATAAGATA 20400
TTCATAAATA TACTCAAGAT ATAATGCAGT ATGAGGTAAA TATTAGTTCA TAAAATTAAA 20460
GGAAATACTA GCTTATCGCG ATTACAACGA TGTGTATATT CAAGGTAAAC CAAAAGGATT 20520
AAGCCCTGTA GATTACAGGA CTTAATCCTT AAATTAAATA GAGCTCACTT TTTAGTGAAA 20580
GCGCAAGCAT ATATTTATAA TCAACTACTT TGTCTACTAC ACCGTCA~AA TAGCAGTTAA 20640
ATTTAAAAAA GATTAGCTTA TAACCAGCCT AAACTCATTA ATAATTTCCA CCATGCCATA 20700
CCGATAGTTA GATGGATAAT TAAACTACCA AAAGCAATGA TCGCGCCAGT AATCCACCAA 20760
GATTTTATAT CATTATAACC TGCACCGAAT GCAATTGGAC CTGGTCCGCC TCCGTAGTGA 20820
GTTACTGAAC CACCATAAGA ATTAGCAAAG ACTAAGCCTA GAGCAAGCAA TTCAGTAGGA 20880
GCGC~l~llA CATGTCCGAC TGTTGCAAAT ACGGGTACCA TTGCAGCTAC ATATGCACCG 20540
CCTGATGCGA ATAAATAACG TACAGAGACA CTTAAGGTAA GAATCACTAT TAACGCCATC 21000
ATACCATGTC CCTCAAACTG AAGTATGGTA CTTAAGGTGT TTGCTAACCA TTTGAAAAAG 21060
CCAGATTTTT CAAGCAAGCC AGACATACCG ATGATACCAC CATACCATAC TAGGGTATTC 21120
CATGCGCCTT TG~lllllAG GATATCGTCC CAGGTGACGA TACTTAATAC AATACAAAGC 21180
ACCATTACAA TGATTGCAAC AATGGTAGCA TTGATATGAA GTGAATTAGA GAAAATCCAG 21240
-77. 1 4-
SUBSTITUTE SHEET (RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
CCGAATAATG CAATTACGAA TAACACGCTG AGTGCTTTTT CACGA~AAGA CATTGGACCT 21300
AA~ L~lA AGC~llllLl CGCAATGGCT TTATTATCCA ~lLllll~AA TTCTGGTGGA 21360
GATACCCAAT AACAAATTAA CGGAATTAAG AATAAGCAGA GTAAGCCGGG TACGGATGCA 21420
GCTAAGAACC ATTTGATCCA AGTGGTTTCA A~ACCAAGAA TTGGTGCCAT TAATGA~AGA 21480
GCTAAGGCAT TAGGAGCCAT TGCGGTTAAG A~AATATAAG AGGTAGTTTT AACCACCATA 21540
TATACGTTCA TCATCA~ATA ACGCCCTGCT LlLllCGGGC llllll~lGG ATCTGAACCA 21600
AGAGCAACCA CTACGCTATT AATGATTGGA AAGATAATCC CACCTGAACG CGCGGTGTTA 21660
GAGGGCGTTG CTGGCGAGAG TA~AAGATCT AAGAACATGG TAACATAGCC TAAGCGTAGG 21720
GTTGTGCTAC CCATTGCGCC GATCATATGA TAGGCGATAC GTTTACCTAG ACCTGTGATT 21780
ACA~ATGCTG AACTCA~AGT GAATGCGGTA AAAATAAGCC Al~ll~lGCC AGATTTATAA 21840
CCATCCAACA TATTGCCGAC TTTAACCAAT l~LllCGCCC CTTCAGTATT ACCGATGATA 21900
ACGCCAGA~A CCGCAATTGC AGCCAATAAG ATAACGGGCT CGCCATAAGG TTTAAGCACA 21960
AGCCCAACGA TAGTGGCGAT ATA~ACACCA AGTAATCGCC AAGCAATCAA AGA~AGCCCA 22020
TCAGGAGCAG GTAGTAAGAA AGTGATCAAT GGGATAGCCA TTA~AATCAC CA~llll~lA 22080
TTTTTGGATA ATGCCATATT AATTACCTCT A~ATGATA~A AAGAAAATTG TTAGTGCTAA 22140
TAAATCAGCA CTACCGCCCG AACTTA~ATT ACGTTCAATG CAGGCGGTAT CA~ATTTCAT 22200
TAATGCTTGT GTCAGTGCTG TTTTATCTGT CACAAGGTGT TGATCTGTAA GCAGATCCTG 22260
TG~l~LllGC TGTATGA~AT ACAATCCCGC TAAACCACCT CGATGAACCA CGTTAGTGTC 22320
GGAGTTAATT GCCATTA~AT TCAACAACAA AATCAGTA~A CGATGTTCCC ATTCTAACTG 22380
ATGGTACTCA TCAAATTGTG GCAACAACGT TTGAATGAGA TTAAAACCAT TTTCTGCTTC 22440
GCCACGGACA CCTGTTAAGC CATATTTTTG GAATAAACGC ACTCCAGCCG TACTAGGCAA 22500
~l~ll~AGGA TAA'LlllL~A GTTCATCCGT TA~ACCTTGA GTA~ATTGTG CAACAAGTGA 22560
GCAGATTAAT TTAACATCAA AATCTACCGC ACTTTGAACC A~A~lllLll GTGCCAATAA 22620
TCGTCCAATT GCCGTACACA CTAAACCA~A AGAAAAAATA G~1C~L11~1 GG~l~lLlAC 22680
GCCATCAGTA ACTTTA~ACA TTG~LllllC TGCTAATA~A CCTA~AGGAC GAATTTCAGA 22740
GAGAATTTGA TTTTCAGACA AATGCGCGGT CATCATGCCT TTGAGAACAA ACTGCGTA~A 22800
A~AAGGTTTT A~ACTAATCG CACTTTGCTC AAAAGTATGT AGGTTCATAT ~lLl~lGCGA 22860
ACCGTTATTG ATGGCATCCA CTA~ACCAGG TTTTGGCGAT AAGCGAGCCT CTTGTATTAA 22920
-77.15-
SUE~5 1 1 1 UTE ~ EET tRULE 26)
CA 022l874l l997-l0-2l
W O 96/33276 PCT~US96/05320
TGCCAGATAA ACTTGTTCAC CAATATGTTC TGCGA~ATCA TGAl~l~l~lG CGAGAGATTG 22980
AATTTTATCT ACAATCTCAT CAATCTCGTG CTTGTGGGTT CTCGCACAGA TTTTTGCATT 23040
TTCTCCGCAC ACTAAACAAG TTCTTGGAGA AAGATCA~AA TCTGTACGAC TCAGTAGATT 23100
GCCTTTAGCA TTAAACACAT CTA~ATCCCA CA~ACGAGCA AGAGGAATAC TTTCTTCCAA 23160
TTCAATCATC AGAACTTTTA GCGTACGAGC ATCTATCGGT AATACA~AAT AGGCTTCATG 23220
CCCC~'1"1"1'~'L AGCGGACGGA TTAlll~lll TACTGCTGTG ATGTTTAACT GAGTAAAAAG 23280
TGCGGTCAGA ~ AGAG ~''l''l''l''l'~'l'AAA AACATAATCC AACAAAGCAT 'l"l''L'l''l''l"l''l'AC 23340
TCCACCCACA GCAGTTA~AG TGATGCAAAG TAAGGTTTGT CCATATTGTG TTATAAGCTG 23400
ll~ll~lAAA ATTGCACGTT CCTCTCGAGC ATTAAGCAAT GCTTCAAGTG A~AllllL~A 23460
ACC~'1'~'1'~'1'A GAGAATGTCG TAAAAAAATG CTGCA~AATT TGACCGCTCT TTTGTATAAA 23520
AATA~ATTTT CTTAACTCTT TCCATTTATA TGGTGCTGGC GAAAGCTGAA AGAGCTAATT 23580
GAGTCCCTTT CAA~l'~lllG GGCTCCTTTC CTGATAATCA TGGGAAGACA AGAGTTAATT 23640
TTGGCTATTG AAAGTAGATC GCTTGTAATG CTGATTCTAG TCTTTAACTT GATACACCGT 23700
ATCAATCACC GAACCATCAC GATAACGAAC AACAGCCACA GGTTTATTAG TAAACTCAAT 23760
ll~llllGGT TTACCAGTAA TGCTGTAAGC ACGTTCACAA A~ll~ll~AA TAGTA~ACAA 23820
TGGAATGTCT GTTTTGCTTA AAGCTTCAAT CAAATCTGGA CGTTTAGGAT TTACTGCTAC 23880
ACCATGATCG GTAACGAGAA TATCGACGTT TTCACCAGGT GTTACACAGG TAATCACGTT 23940
TTCCACCACG GTTGGAATAC GACCACGAAC TAATGGTGCC ACAATGATTG CTACTTGTGC 24000
AGAAGCTGCG GTATCACAAT GACCACCAGA TGCACCGCGA ATCACACCGT CAGAGCCAGT 24060
CAATACATTC ACGTTAAATT TAGTGTCGAT TTCTA~AGCA GA~AGAATCA CCATATCTAA 24120
ACGTTCAACA GATGCGCCTT TGGAACTGTA ATTCGCATAT TGGTTAGCGG AGACTTCAAT 24180
ATGATTTGGG TTACGGGCAA GTGATTCAGC TGCAACAGAA TCAAAGCTTT GTACATCTAA 24240
TAAllllllA ATAAGACCAG CCTCATGTAA TGCCACCATA CTTGCAGTAA TTCCGCCAAG 24300
TGCGAAATCT GCAGTGATAT TTTCACGACG CAllllll~l TCTAGAAAGC GTGTAACAGC 24360
TAATGCTGCC CCCCCAGAAC CA~lll~lAA TGAGAAGCCA TCTTTA~AAT AACCACTGGC 24420
A~AAATTACT TCTGCACATT TACGCGCAAT GAGTAATTCG CGTGGATTGG TAGTCATTCG 24480
GGTTGCACCA CCACCAATTT TTTTCGGGTC ACCGACTGCT TCAACTTGCA CGATTA~ATC 24540
TACTTGATCT TGAGCTATGC TGATTGGGTG GTGCGGGTAT TCAACAAATT C~'l'~'l'~'l'~AG 24600
77.16-
SUBS i 11 UTE ~HEET (RULE 2~)
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
CAACACAACT TTGTCAGCAT ATTCAGCATC GACACGCGCA TAGCCTAGAG AGCCGCATTT 24660
A~lllllCCA GTAAATCCAT TGGCATTACC GAAL~l~l~A CAGCAAGGCA CGCCTAAAAA 24720
AGCAACGTCA ATTTTTAATT CGCCAGATTT TACTAAGTGA ACACGTCCAC CATGAGAATG 24780
AATATTTACA GGTTCATTCA ATAAACCGCG AGAGATTTGC TCTGCAAGTT CACCGCGTAA 24840
ACCAGAAGAA TAGATTTTGG TGACCACGCC ALllll~ATA TGTTCGACAA TCGGGAAGTG 24900
GCTATCAATT AAAGATGAAG ATGCAAGGGT CAGATTTTTG AAACCCATTT CGGCAATTTT 24960
ATTCATCACC ATATTCACCA CAAAATCTCC GCCCCGAAAA GCATGATGAA ATGAAACAGT 25020
CATACCATCT TTTAAGCCAG AGCGTTTAAT CG~Ll~ll~l AGAGAGGTAC AAAGTTTGCG 25080
ATCTTTCGCT GTACGAGAAA GGGATTCAGA TTTAGGCACC GCTTGATAGA CTGAGCGATC 25140
AGCGTGATAT TTTTCAATAC ~ll~ll~l~l ~L~lL~L~ATC TTTTTATCTC CCTTTACTCT 25200
TCACGAATAC CTGATTTCGC ACGTTCTAAT ACAAGTTTTG CGCGATCAAT AATCGGTGCG 25260
TCAATCATTT TACCGTTTAA CGAAACAACA CCAGCCCCTT ~LC~LL~AGC TTCTACTGCC 25320
GCTTCAATAA TGC~LLLLGC CTGCTCCACG ~L~LLLLL~LG TCGGTGCAAA TAA~Ll~L~l 25380
AACAATTCAA TTTGGCGTGG GTTGATTAAG GATTTACCGT CAAAACCAAG ~L~LLLAATT 25440
AACGCAGCCT CTTTTAAGAA GCCTTCTTCA LL~LlCGCGT TAGAATATAC GGTATCAAAA 25500
GCCTGAATGC AGCCGCACGT GCCGCTTGTA AAATAGAACA ACGAGCAAAA AGCAGTTCAA 25560
TCCCCTCTGG TGAACGCTCG ~LLLLlAAGT TACGTACGTA ATCCTCTGCA CCCAATGCGA 25620
TACCAATTAA ACGTTTAGAA GCGAAAGCGA TTTGGTTGGC TTGAGTGATA CCTAATGGCG 25680
ATTCGATTGC GGCTAGCATT TTAGTCGAAC CTG~LL~LCG ACCGCAAGCT TTCTCAATCT 25740
CAGTAATGGC GTGATCCATA TCCAACACAT CTTGCGCGCT TTCAGTTTTT GGCATACGTA 25800
CCACATCCAC ACCCGCACGC ACTACCGAAT TCAAATCCAA TAAACCAAAT TCAGAATCTA 25860
GCGGATTAAC ACGAACTACG GTCTCAATTT CTTTATAAAG CGGATGTTGA AGTGCATGAG 25920
CGACTAATAA ACGAGCAGAA L~lllllCTT TGAGAGCAAC CGCATCTTCT AAGTCAAACA 25980
TAATGGAATC TGGTTTATAA ATAAAGCTAT TACTTAACAT GGCGGCATTT GAGCCCGGCA 26040
CAAATAACAT ACTTCTTCTT AATTTCATAG CACAGCCTCC CAGTTAATCG CTTCATCAGT 26100
TGCACGCATT GCAGCAGCTT TTACTCGAGC TTGTAACACG CAATCTAACG CCC~LL1~1~ 26160
TTCTACAATG ACTTGTGCTG CTGTAATGCC TAGTTTTGCT AATACTTCAC GAACTGTCGC 26220
TTCAATTTGT TCACCAAATT GTTTTGCTAC TGAGCTATTG ATTTCAATAT CGAGTGAGTC 26280
-77.17-
SUBS l 11 UTE S~{EET tRULE 2~i~
CA 02218741 1997-10-21
W 096/33276 PCTAUS9610~320
AAAAGGTTGA ACCCGTACTT GAACATCACT GGATTCCAGT GTCCCTGCAA CGGCTACTTT 26340
TGTTATTTTC ATAGATTTTC CTTCCGTATA TTGATGAATA AAAATGTATT TAAAAACGAC 26400
CGCACTTTTG TAAATAATTT AACGTAGTCA TAGGCACAAA CTCTGCGAGT TGAGCCCAAT 26460
llllll~AGC CAAATGCTTT CGTACTGTAG AAGCAGAAAT AATGTGGTTG CTTGCTGTTT 26520
_ TTCTAGGTAT CTCGATAACA TTTATTTTTG GTGCATTCAT TTCGGCATCC ATTAACCAAT 26580
AATGCATTTG GCGATTATAT TCGGCAGTGA CGGGACAATT TAGCTCAGTA CCAACAAAGC 26640
GA~l~l~llAT TCCCAAAGCT TGAGCAATAT GTAAACGGAA TAACTTCAGA TCAATCTCAA 26700
AATAACTTTC ATCTGTAATT AATTGATCTT TTAGGAAATA ATTTGGAAAT GTTGCACGAG 26760
AAATAATATA GTCAGAGCCA GAATGAAGAG TGATATTGGA TAAATCGAAA ATACCTTGTT 26820
GAATCATTTC AAAlC~lL~ GTGTAAGAAA ATTGCGATGC ~l~ll~ACCG ACAATAAATA 26880
AATGCAGATG ATCACATTGT TGTAATGCTT GCTCAATTAA ATAACGATGA CCTAAGGTAA 26940
ATGGATTCGC GTTCATTACA ATCGAGCCAA TTCGATTACC ATCCACACGC Al~ ~lCCC 27000
ATAATGAGCA 1l~lllll~l A~ACGCGTAG CACTATTTTC TAATAATACT ACATAAGGAT 27060
TGGCATCAGA GATGATATAA AAACCACAAG ATTTGAACAA CGTTGCATAT TCGGGTTTTG 27120
TATAAATAAA AAGGTGTGGA CGTTTTAGCG TGTAAGCTAA ATCAACCAAT TCAGTAATTA 27180
ATTGCAAGGC AACACCGCTA CCACGCAAAG ACTCATCAAT CGCAACACAT TTTATGATAT 27240
TGCCTGCTAA ACCGCCACAG ACAACGATTT ~llC~llATC ATTATAGCCA ACAACAAAAT 27300
ACTCGATTTG TTCATCTAAT TTAAGCGCAT TTTGATGTAA AAAl~l~l~A ATGAGAGAAA 27360
G TTCAGTAGAA ATTCGCTCA~ ATTGCATCGA CTCTCCAAAA AAGAAGA~AA 27420
CATAACATCA CTACCAAGTT AGTAGTATAG AGCTATTATA AGCGATGAGC AAATTACGAT 27480
ACAAGATAAG CTCATATTTT TCCCAACTTT ATAATCTAAT ATTATCTTCA CACTGCATTA 27540
TACATTGAAT AATTTATAGG CAATATTGGC GGTTATTCTG AGTTGTA~AA ATAAaCCGCA 27600
GC AAGCA~AAAG TGCGGTTTAA TTTAGCGGAA TTTTAAATTA TTTCACTAAT 27660
CCGCCACTGG CTTGTAAATC AGCGTGATAA GAAGAACGAA CAAATGGCCC ACAAGCCGCA 27720
c TGTTCA~AGC CCATTTCATT GGCTTTATCA CGGAATTCAT CAAATTCAGT TGGCGGCACA 27780
TAACGGGCAA CAGGCAAATG ATGGCGGCTA GGTTGAAGAT ATTGACCCAA CGTGAGCATA 27840
GTCACACCGT TATCACGTAA ATCTTGCATC ACTTGCAAAA TTTCCTCGTT GGTTTCGCCT 27900
AACCCAACCA TTAAACCAGA TTTGGTTGGG ATATTTGGGA ATATTTCTTT GAATTCACGC 27960
-77.18-
SUBSTtTtJTE SH E~ tRULE 2fi)
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96/05320
AATAATTTAA GTGACCATTC GTAATCCGCA CCTGGACGAA lLl~lllATA TAAGCGCGGT 28020
AC~llll~lA AATTATGGTT A~AGACATCT GGCGGATTAT CTTTTAATTT CTCTA~AGCC 28080
TGTGTAATGC GACCACGA~A ATCAGGCACT A~AATTTCAA TCTTAATGTT AGGATTAAGC 28140
TCGCGCACAG CTTTTACACA TTCAGAAAAA TGACCAGCAC CACGATCAGG CAAGTCATCA 28200
CGATCCACCG ATGTGATTAC CACATATTTA AGTTTCATAT CTTGAATCGT TTCTGCCAAT 28260
llll~LGGCT CTTCAGGATC TGGCGGTAAT GGTTTACCGT GAGCCACATC ACAGAATGGG 28320
CAACGGCGCG TACAAATTGC ACCTA~AATC ATA~AAGTGG CTGTGCCATG ATTA~AACAT 28380
lC~l~lAAAT TTGGACAAGA TG~lLC~lCA CAAACAGAAT GTAATCCGTG ACGGCGCATT 28440
CCATTTTTAA TGCTTTCAAT TTTAGCTGAA CTTGCTGGAA GTTTAATTTT CATCCATTCT 28500
G~llllllLA ATAAATCTTG ATTAGGATCG ATATTTTTtA CGGGAATAAT TGAGGTTTTT 28560
GCCGCATCGC GATATTTTAC ACCGCGTTCC ATTTTGA~AG GCGTAGACAT AGTATTTTCC 28620
TA~ATA~AAA TGCCCAAATT GGGCATTTAG TTTTTATA~A ATGTTATA~A ~ll~llATAT 28680
TATAGCCTAA AAGATTGGCG AA~l~lllAA TTAATTTTGC TGA~ACATTA TCGCAATCAG 28740
CTTTATCTTG ATTAACA~AA TCCGCTAACT GACACATTTC AAGCCCTGCA TAACCACAAG 28800
GATTAATATA ATGGA~AGGA TTAAGATCCA TATTAATATT CAATGCCAAC CCGTGAAAAG 28860
AGCAACCACG ACGAATACGT AATCCAAGAG aACAAATCTT TTTTCCATCC ACATA~ACAC 28920
CTGGCGCATC AGGCTTTGGA TAGCTTTCAA TGCCATATTC AGCCA~AGTT TTAACCACCG 28980
~ ll~AAG TGCGGTAACT AATTGACGTA CATTTA~ATT TTTATGGCGT TTAATGTCAA 29040
TAAGCACATA CATCACTTGC TGACCGGGTG CGTGATAGGT AATTTGCCCA CCACGAACCG 29100
ATTGCACCAC AGGGATTTCA CTACGTTGTA AAAGATGCTC TGGTTTACCT GCTTGCCCTT 29160
GTGTA~AAAC AGGATAATGT TGTACTAACC A~AlllC~lC TTGC~lll~A GCATTTCGAG 29220
TATCAGtA~A ATCCTGCATT TTGTGCCA~A lll~ll~ATA ATCTTGCAAT CCTAACTGAC 29280
GAACGATAAG GGAATTGnTC ATACTAAATA ACCATTTTCA CGCCTTCAAC TTTAGCCAGT 29340
TCTTTATAGA ~l~-L-ll~lAC CTGATCAAAG TTTTCAGCAA TAATATCAAT TGA~ACTGAA 29400
TTATAAGTGC CTTTACTACT GCG~llLl~l TTTGGAATAT AATCGCCTTT AATATATTTT 29460
TGCACCACTT GTATAAGATC TTGTGCTAAC C~l~ C~AT TAATTCCCGC AACTTTA~AA 29520
GTCATTTTTG CTGGA~ATTC CATTAATTCC TTGAGTTTTG CATAATCGTT TTCTATTGTC 29580
Allll~lllC CTA~AAATAA AATA~ATCAA A~AGTGCGGT CAATTTTCAA A'1'1~'1-1'1'11'A 29640
-77.19-
SUBS 11 I UTE S~EET ~RULE 2~i)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/OS320
TGAGAATAAC C~'l"l"l'~'ACAG TCAATACTAA CCAATCCCAT AGTTTACCAA AAATACCCGC 29700
TTCTCCCACA TCATTCATCA CTTGTAAATT GGCACTTGCA ATATCCTTAC CATCCAGTTG 29760
ATAAACCACT TTACCAATCA CTTGACCTTT TACTAATGGT GCTTGTAAAT TTTTATCTGC 29820
TAATTCATAA CGAGCTTTAA CCTCACTTTG TTTACCTTTA GGGATCGTAA TAAAGTGATC 23880
CATTAAAGCA CCAAGTTTTA CTGAATTTTT ATCGCCATAA TAAACCCTTT GTTCTGAAAT 29940
ll~lllACCA GCCTCTAAAG TTTTAAATGT TTCGAAATTA GCAAAACCCC ATTGTAAAAG 30000
L~ ACTT TCTACTTCAC GAC~lll~lA AGTTGGCACA CCCATTACTA CAGA~ATTAA 30060
ACGCATATTG TTTGATGTAG TCGCTGAAGC GACTAAGTTA TATCCTGCTT GGCTAGTATG 30120
CC~'1'~'L~'-1--1'C ATTCCATCAA CATTGATAGT TTTATCCCAT AATAGTCCAT TACGGTTAGC 30180
~l-'l'~'l"l'-l~ATT TTATTAAATG TAAAGTTTTT TTCGGAGTAA ATTTTATATT CTtCAGGTAA 30240
ATCACGAATA ATATGCGCAC CAATAATTGC CATATCACGC GCGGAAGAAT ATTGATTTGG 30300
AlC~l~-lAAA CCATGGGGCG TGGTGAAATT TGTATTTTTC AAACCAAATT GTTGAACATA 30360
TTTATTCATT ~l-*l~-lACAA AGTTCGGTAC ATTGCCAGAA ATATGTTCAG CTAATGCAAC 30420
AGTCGCATCA TTACCAGAAA CAACAATCAC ACCTCGATTT AAGTCTGCTA CAGATACTTG 30480
TGTATTTAAA TCTAAAAACA ~llll-lGATGA ATCAGGGAAA TTACGCCCCC ACGCACTTTC 30540
ACCAATGGTA ACCATATCGG TATTATGGAT TTTGCCTTGT TTTAATGCGA CACCAACTAC 30600
ATAACTTGTC ATCATTTTAG TCAGTGATGC TGGATATTGA CGTTGATCTG GATTAAGTGC 30660
GGTCAAAATT GCACCTGAAT TATAATCCAT CAATACATAC GTTTGAGCCG TAATTTGTGG 30720
TGGAGTTACG CCAAACTGCA TATCCTCTGC AGATACCGAA AAAGCACTAA GTGCCACA~A 30780
ACTTGATAAA AATGCGATTT l'-l ~-l--l'~'l -l ~''L TTTCAACATA ~l~-l~l-lCCT ACAATTAATT 308gO
TTTATACGTA TAAACAATTA ATGGCTTATT ATTTGCCATT ~ll''l''l~'l-AATT TA~ll~l~AC 30900
TTGTGCCATT ll-'l~'l-l-l'l-~l CATCAAAAGG CCCAATATAA ATTTCATATT TATTTCCTGA 30960
GCGATTTACT TCAGTCTGAA TATTCGCTAA CGCAAGTTGC GTAATTAATT TATTTGCTTG 31020
GCTACGAGAG GTTAATTCAA GCATTTTCAA ACAGTA~AAT TCGGTTCCTT TTAGAGCATT 31080
TATTGACTTA GAl~l~ll-AT CAAAAAGTGT GTTAGATTTT AATACTAAAC GATCGGCAGC 31140
'l-l'C~l~AGTT TTTGCTTGTT TAGCCAGTGT ll-L-l~lGGCT GCGCCTGATA AATTCCCATT 31200
TTTAGCAACG TGCAACGCCT CAATTCTTAC CTGCCCTATG CCGCGGGA~A TTAAGCCAAT 31260
~l"l~llllGCC GCAGCGTGTG A~AGATCAAT TAAACGTTTA TCACTAAAAG GCCCACGATC 31320
-77.20-
SUBST~TUTE SHEET tRULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
ATTAATACGT ACGATAACTT TACGATTGTT ATGTAAATTT GTCACTA~AG CATAAGAATT 31380
TATTGGCAAT GTTTTATGTG CTGCAGTAAA L-l~-l-lll~AG TTATA~ACAT CGCCACTTGC 31440
l~lL-llGCGC CCATCAAATT TAAGATGATA ATAACTTGCT AAACCTTCTT TAATATAAGA 31500
TTTGGCTTCA TTCCCACTTT TAGTGGTATA AGTTTGCCCT TTTACTGAAT AA~lC~l-lGG 31560
TGCAGGCATT TGAGTTGCGA TAGA~AGATT ATCCCCTCGA ATACCATACA lLlLl-lGCGT 31620
ATCAGCCTGT GCAGGA~AAG CTACGCTTAT CATA~ATAGC A~AAGTGCGG TCAAATTTAA 31680
CCCAGTTTTT AATTTCATAA AATATTAACG ~-l-lll~ATTT All~lll~-ll TAAGA~AGAA 31740
AAAATGA~AT TAGCTCCTTT TCATA~ATTG ACTTTTATGC GTATGAATAG ACATCAGTAA 31800
ACCAA~ACTT GCCATAATCG CAACATAAGA GGTACCACCA TAACTA~ATA AAGGTAATGG 31860
CACACCCACA ACAGGCAAAA TTCCGCTTAC CATTCCAATA TTCACA~ATA CATAAACA~A 31920
GA~AATTAAT ~ll~-LlGCAC CAGCAAGAAT ACGCCCA~AA GAAGTTTGAG CATTTACGGC 31980
AATCATTA~A CCTCGCACAA TAATA~ACAA GTA~ATCGCC ATTAAAATCA AAAAACCAAT 32040
CATTCCGTGC TCTTCACCCA TTACCGCA~A AATAAAATCT GTATGAGGTT CGGGCAAAAA 32100
TTCTA~TTGT GATTGAGTCC CCTGCATCCA GCCTTTTCCG CTTAATCCAC CAGAACCAAT 32160
CGCAATCTTT GATTGTA~AA TATGATAGCC AGCACCGAGA GGa~l~lllll CTGGGTCCAA 32220
TAATGTGAGA ACGCGAGTGC GTTGATAATC GTGCATTAGA TATAACCACA TGATCGGAAT 32280
A~ATCCAGCT AAGCCAATCA CTGCCGCTAA AATAAGCCAC CAGCTCATTC CTGCTAAAAA 32340
CACGACA~AT AAACCTGACG CACTGACCAA AATTGATGTG CCTA~ATCAG GCTGAATCGC 32400
CACAAGCAAT GTTGGCAGTA GAATCATTGC AATCGCTATA AAl~lll~AC TTAATTTAGG 32460
TGGAAGCGGG CGATTACCTA AATACACCGC CACCATTAAT GGCACAGCAA GTTTTACAAT 32520
TTCAGAGGGT TGA~AACGAA TAAATCCAAG ATCAAGCCAA CGCTGTGCAC CTTTACTTGT 32580
CGTACCAATA ACATCTACCA AGATCAATAA CACAAAACCA ATTA~ATA~A GATAAGGTGC 32640
GATGCGTTGG TAAAATCTTG GTGGAAATTG AGCCATTAAC AGCATAACAA TAAATCCAAG 32700
TAAGACCTGA ATAATTCGGC TATTA~ACAT C~lllCGCTG GCACCTGATG CACTATATAA 32760
CACCAGCATA CCATAAGCAG TTATTGCAAG AAGTCCGATA AACAGCCA~A AATCAATATG 32820
CA~ACGTTGC CA~ACACGCA ACCAAAAAGG GATTTTATCT TCCATTTATT TGTTCGCTCT 32880
CTTGTGACAA A'1-~1111L11 TGCTGAATAG GTACATTATA l-l-l-ll~AACT TGTGGTAAAC 32940
GCTGATTTAA ATAGTAATCC ATCACTTTAC GTGCTAAGGG TGCGGCATTA CTTGAACCAC 33000
-77.2 1 -
SUBSmUTE S~ET tRU-E 2~i~
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/0~320
CACCTGCATT TTCTAAAATC ACTGTTACAA CTAATTTAGG ATTATCATAA GGGGCGTAAG 33060
CGGTA~ACCA AGCGTGATCA TGCAATTCTT TTTTTAAGCC TGCCGTATTA TAlllll~AT 33120
~lllC~lllAA ACTA~ACACT TGTGCAGTGC CAGATTTCCC TGCAACACGA TAATTTGCAT 33180
CTGCA~AGGC TTTTCGCCCA GTTCCATTTG CAGCATTAAC AACATTGTAC ATACCGCGTT 33240
TCGCTGCCTC CCAAGCTGCC ACTTTAGGTG TATTAATATC AGGATA~AGT AACGGATCTT 33300
CATAAGGCTC TAATACTGCA CCTTCAATTG CTTTCATCAA ATGCGGTGTA TTTACTTTGC 33360
CATTATTGAC CAATATTGTC GTCGCTTTTG CTACTTGTAG TGGTGTTGCC GTCCAATAAC 33420
CTTGACCAAT CCCAACCGAA ATCGTATCGC CTTGCACCCA AGGGCGTTTA TAAC~LLlll 33480
C~ATTC TCGAGTTGGT ATATTGGCAG CC~L11~11C TTGAATTTCA ATCCCCGTTG 33540
GCATACCA~A ACCA~AATCC TTCATCCAAT TAGA~AGGCG ATCAATACCC ATATTATAAG 33600
CCACTTGATA A~AATAAGTA TCAGAGGATT CAGTAATCGC TTTATTCAAA TCCGTATCCC 33660
CGTGGCCTGT llllllCCAA TCACGAAAAC ~llLl~lGGA ATTAGGTAAT ACCCAATATC 33720
CCGGATCAAA AAlC~Ll~lG TTTGGTGTAA TCACATTTTC A~LlL~lGCG GCTACTGCAA 33780
TA~AAGGTTT GA~l~lCGAA GCGGGCGGAT ACGCACCTTG TGTCGCACGA CTATA~AGTG 33840
GACGAGCAAG ATCATTTAAT A~ACGTTTAT AATCTTCGGA GGA~ATACCA TCAACAAATA 33900
AATTATTATC ATAACTTGGT GTAGATACCA TCGCTAATAC ACTACTATCT TTCGGATCAA 33960
GCACAACTAC AGCACCTTTT AGTCCCGATA A~AGTTCAGT AATATAACGC TGTAATGCCA 34020
AATCAATGGT TAAATGAATA ~lllllCCCG CCACAGCAGG TCGGCTACGC A~AGTGCGGA 34080
TTACTTTGCC GCGATTATTA ATTTCTACTT CTTCA~AACC CGTGGTACCT TGCAGTATAT 34140
CCTCGTAATA ACGTTCAATA CCCAATTTTC CAATATCGTT CGTTCCCGCA TAATTCGCGA 34200
ATTTATCCTC lC~lll~A~A CGTTCTACAT CTTTATCATT CATTTTACCT ACATAGCCCA 34260
AAATATGCGC CAll~lllCG CCATATA~AT AATGGCGTTT GA~ATAAGGA CGTACCTCTA 34320
AGCTCGGGTA TTGGTAGCCA TTTACCGCAA AGCGTGAAAT 'l''l'~'L'l'~'L'L~'L GTTA~ATTCG 34380
GCTTTAATAA AATCGGTGTA TAACGCGTTC CGCGGCGACG TTC~LLLLlA AAATTTTCAA 34440
TATCGTTATC CGTCAATCCC ACAATATAGC GTAATTCATC TAAAGTGCGG TCTA~ATTTT 34500
CA~lLlLlLC TGGCACAATG TATA~ACCAA AAAAAGTAAG ATTTTCGGCT AATAATTTGC 34560
CGTAACGATC ATAGATTAAG CCACGTGTTG GCGGTAAAGG TAATAATTTA ATTCGGTTAC 34620
CATTAGAACG CGTTTGGTAA GTATCGA~AT TAACAATCTG TAGCTGATAA ATATTGGTGA 34680
-77.22-
SU8STITUTE ~}tEET tRULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/OS320
ATAACACGCC TGTTAAGAGC AGAATCCCCA AAAAAGCCAC TAACGTTCGG CGTGCAAAAA 34740
GGTTACGCTC CG~llllllA TCGCGGAACG ~llC~l~CGT TGGTGTATTG AAGAATTTTT 34800
TTA~ATTCAT CTGACTAAAA TAAGGATGTA TTATTCTCGA TGATAAGGAT GATTAGTGGT 34860
TAGCGACCAC GCACGATACA AACTTTCAGC CACCACGACA CGAACAAGCG GGTGAGGTAA 34920
TGTCAAGGGA GAAAGCGACC AACTTTGCTC TGCAGCAGCT TTGCATTCTG GCGAAAGCCC 34980
CTCAGGCCCA CCAATCAATA AACAAACATC GCGACCATCA TTTTTCCACG CTTCTAGTTG 35040
CTCAGCTAGC TGCGGCGTCG TCCAAGGTTT ACCAGGAATA TCTAACGTCA CGACTTTGCC 35100
TTTTCCACAG GCCGCTAACA TCGCTTTACC ll~ll~ll~l AAAATGCGTT TAATATCAGC 35160
A111111C~A CGCTTGCCTG CTGGGATTTC AATTAGTTCA AAAGGCATAT CTTTTGGGAA 35220
ACGGCGTTGA TATTCCTCAA AACCCGTTGT AACCCAAGAA GGCATTTTTG TTCCGACGGC 35280
AATTAACGTG ATTTTCACAA GTCATCCTTA TCTAAAAAGT GCGGTTATTT TTTACCGCAC 35340
TTTACTAAAA TTTACGCCCA AA~lll~l~l AATTGATACA TTTCACGGGC GTCACGTTGC 35400
ATGATATGTA CGATAGCTTG ACCAAGATCC ACCACAATCC AATCTGCAGT ATTTTTACCT 35460
TCTTCGCCAA AGGTTTCAAA ACCTGCTTTT TTACATTCTG TAATTAAATT ATCTGCCATT 35520
GCAGAAACTT GGCGACTCGA CGTCCCCGTG CAAATAATCA TATTATCCGT AATCGAGGAT 35580
TTTCCACGTA CATCAAAATG TACAATATCT GTtCCCTTTA ACCCATCTAA GGTTTCCATC 35640
AAAAATTCAA CTAACGCCAT TTTGTTCTCA CTTAGCAATA AAGGTGCGGA ATTCTATCAT 35700
TGAATACCCT CTTGCGCAAA ATCCACGCAA A~AATAAGCG CGAAATTAAC CGCGCTTTTT 35760
ATGTCTA~AT TGAAATTATT TTTACTATGC TGCCCATAAT AACACTGCCA ATAACTGTGG 35820
CGACATTATT CGCAAGAACA TCACCAATGG ATACACAGTT GCATAAGAAA GTGCTGCAGC 35880
ACCGTTATCT TCTTTAATTT CATTCGCAAA TGCTA~AGCG GGAGGwTCCG TCATTGAACC 35940
TGCAAGTAAA CCGCATATTG TGAGGTAATT AA~llllC~A TATAAGCGTG CTATAGTCCC 36000
AACAATAATC AACGGCACAA AAGTGATA~A AATACCGTAT CCCATCCATT CAAGTCCCGA 36060
ACCATTCACT AAAGTATCAA AGAAACTTCC ACCTGATTTT AAACCAACAA CCGCCAAGA~ 36120
AAGGACAATC CCAATTTCGC GCAATGCCAA GTTAGCACTT GGTGGCATAA ACCAGTAAAG 36180
TTTACCAATC GTGCCAATTC TCGCTA~AAT CAACGCAACC ACCAATGGCC CGCCAGCAAG 36240
CCCTAATTTT AACGCAACAG GGA~ACCTGG AATATAGAAT GGAATCGAAC CAACGAGTAC 36300
CCCTAAACCA ATACCGATAA ACACTGGTAA CATTTGCACT TGAAGTAATT l~l~ll~lGC 36360
-77.23-
SUB5 1 1 1 UTE 5~ET ~RULE 26
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GTTACCAATA ACTGAAATGG CCTGATTTAG TACATCACTG CGTCCAACCA TATGTAGCAC 36420
ATCGCCAAAT TGCAGTGTGG TATTTCCCGT TGGAACTAAC TCAATCCCTG CACGATTTAA 36480
ACGTGAAATT ACAACCCCAT ATTTTTGATG AATGCCTaAC GCACGGAtCT TTTTGCCTAA 36540
TAn~ ~A nTCGTTACCA CCACACGCTC GGAACGAATT TCGCCACTAT AGGCAACGGT 36600
TGGTGCATCA A~llC~l~lC CGATAATTAA ACGCAnTTTA GCAAGCGAAT TATCATCACC 36660
CACTAATTGT AAAATATCGT TGGTACGAAT CTCAGTACTT GCCTTTGGAA CAATTTCCAT 36720
ATCATCGCGT TTTAAACGTG AACATACGAC ll~ll-ATCG CTA~ATCCCG GAATTTGAAT 36780
TAACGTCAGA CCATCTAGAT TTTGGTTCGT CACTTTTAAA GAAATATTAT GTAAACTTTC 36840
TTTATCTTGG CTGCTCTCCG CATTAAAACG AGCAGCTTCA TCGTCCACTT TGACGTTAAA 36900
AAACAAGCGG ATTAACCACA TTGCAAGCAA AATACCGCAA ATCCCGAATG GATAAGCCAT 36960
TGCATAAGAC ACCCCCATAG TTACAGTGGT TTGAGGCACC CCTAATTCTG CTAAAATTTG 37020
CTGCCCTGCC CCCAACGCAG GCGTATTAGT AACAGCACCA GAATA~ATAC CTAAGGCAAT 37080
ATCCAGTGGA ACATCCGCAA TTTTATGTAC AAGAACCACG GCAATTGACC CCAGCAGAAT 37140
AATCAAAATG GCAAAGGCAT TTAGCTTTAA ACCAGATTTT CGTAAAGA~G AAAAAAAGCC 37200
AGGTCCAACC TGAATACCAA TAGTATAAAC AAATAAAATC AAACCA~ATT CTTGCACAAA 37260
ATGCAGCGTA TGCGCATCCA GTTTCAAGCC ATATTGATTA GTGAAATGGG CAACAATAAT 37320
GCCGCCAAAC AGCACGCCAC CAATGCCAAG CCCAACCCCG CGGATCTTCC AATGCCCGAT 37380
CCATAAGCCG ATTACGGCGA CGAGGGCAAG AAGACTAATC GTGATCGCAA TATCACTCAT 37440
ATTGACCCCT TAAAAATGAA ATTTAACTCC TTCGGATTAT ATCCAAGTTG LlllllGAAA 37500
ACCTTAACCA AACTCAAAAA ATGATACGTT CGTCACATTT lll~llGCGA AATTGAGCAT 37560
AGCCTCTACA ATACCGA~AA lllll~ACCC TTTTACAAAA AGTGCGGTTA llllL~ACCG 37620
CACTTTTAtC TCGGATGGAA TATTTATGGA TTACAGCCAA GAAGCTATTA ~ll~l~llAT 37680
TTGGATTTTA CAAACGCTAG CCATCACCTC AGTC~~ l AGTTTTGGCA 'l"l"l"l"l'~''L'l"l"l' 37740
GGTGCGTTTT ACCCAATGGG GAAAACAATT TTGGATGTTT GCAGGCGGTT AL~111~ACC 37800
TAAACGTAGC ATTAAACCTA TCTTATTCTT TCTGCTTATT GTTGCAATGA CATTACTTAG 37&60
CGTACGTATC AGCCTTGTAA ATTCTGAGTG GTATAAAAAT ATGTATACCT CATTGCAAGA 37920
ATTTAATGAA CATGTATTTT GGCAACAAAT GGGCTTATTC TGCGTCATCG CAGCAAGTTC 37980
GCA GCATTAGTAA GCTATTATTT AGAGCAACGT TTCGTCATCA ACTGGATTGA 38040
-77.24-
SUB5T~TUTE SHEET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
ATGGCTTAAC GAGCAGCTTG TTAATA~ATG GATGGCACAT CGCGCCTATT ACA~AACACA 38100
GTATTTATCA GA~AATCTTG ATAACCCCGA TCAACGTATT CAACAAGATG TGCAATCTTA 38160
TGTAAAAACC ACG~1-11~-1-1 TAAGCACTGG CGTCATTGAT GCGGTCACCT CGATGATCTC 38220
TTACACGATT TTGTTATGGG GATTAGCCGG TCCAATGATA GTGCTTGGTG TAGAAATTCC 38280
GCATATGATG GTATTTTTAG TGTTTGGTTA TGTCATTTTC ACAACCCTCA TCGCATTCTG 38340
GCTCGGTCGC CCATTAATCT CATTGAATTT TATTAATGAA CGCCTAAACG CAAACTATCG 38400
TTAL-1~1-1-1A ATTCGCATTA AAGAATATGC TGA~AGCATT G~1--111-1ATG CAGGCGAAAA 38460
AGTCGAAAAA AATCAGCTTT ATCAGCAGTT CAACGCCGTC ATTCACAATA TGTGGGTCAT 38520
TATATTTAGA ACACTAAAAT TTTCAGGATT TAACCTAGTC GTAAGCCAAA 111~1~11~1 38580
11-1-LC~ATTG TTAATTCAAG TTGGACGTTA CTTTGAAAAG CAAATA~AAC TAGGCGATCT 38640
AATGCAaACC TTGCAAGTAT TTGGTCAGTT ACACGCAAAT CTTTCATTCT TCCGCAGTAC 38700
TTATGATAAT TTTGCAAGCT ATAAAGCAAC GCTAGATCGT TTAACTGGGT l~-l~l-lATGC 38760
CATTGAAAAA GCAAATAATA AATCACA~AC ACAGATCCAC AATCATCCAA CAGATGTGAT 38820
TTTCAAAAAT TTAAGTATTC A~AATCCATT AGGTCATACA CTAATTAAAC ATCTAAACAT 38880
TACCTTACCG CAAGGAACAA GTTTGCTTAT TCAAGGAAAA TCTGGAGCAG GAAAAACCAC 38940
GCTTTTACGC ACCATTGCGG GGCTTTGGAG CTATGCCGAG GGGGA~ATAA ATTGCCCTAC 39000
GCACAATCAG ~1-1-11~-1-1~1 CACAAAAGCC GTATGTGCCA CAAGGAAATT TAATGTCAGC 39060
ATTAGCTTAT CCAAATAACG CTGACAATAT TTCACATACA CAAGCTGTAG AAATATTAAA 39120
TAAAGTACAA CTAGGACATT TGGCTGAACA ATTAGA~AAA GAACAAGACT GGACGCGTAT 39180
~1~-1-11-~1~11 GGCGAACAAC AGCGTTTGGC GTTTGCACGA TTAATTCTAC ACA~ACCAGC 39240
GGTGGCATTT TTAGATGAAG CCACAGCTAG TATGGATGAA GGTTTAGAAT TTTCGATGTA 39300
TCAATTGTTA CAACAAGAAC TACCACA~AC GACAATCATC AGTGTGGGAC ACCGTTCAAC 39360
CCTTAAAACC TTACATCAAC AACAGTTAAT TCTGCAAGAC A~AGGGCAAT GGCAAGTGCT 39420
ATAAAAAACG CTAAAAAACA CTGTAATCGC AACGCTTTTT TTGATACATT TAGTGCAATT 39480
~1--111~-1ATGT TTGACAAAGT CA'1-1-11-~1AC 1111-1~-1~AA ACA~AACTAA CTTTCATTTT 39540
AAACGGTATA ATTATGTTAT TTAAAAAAAT TCGTGGGTTG TTTTCAAACG AL~-1--11~-1AT 39600
TGATTTAGGC ACAGCTAATA CTTTAATTTA TGTCAAAAGA CAGGGTATTG TACTTGATGA 39660
ACC~1~-1~11 GTTGCGATTC GTCAAGATCG CGTAGGCACA TTAAAAAGCA TTGCAGCTGT 39720
-77.25-
SVBST7TUTE S~{E~T (RULE
-
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/0~320
GGGTA~AGAA GCTA~ATTAA TGTTAGGTCG TACTCCCAAA AGTATTGTAG CAATTCGTCC 39780
GATGAAAGAT GGCGTTATTG CAGACTTTTT TGTGACAGAA A~AATGTTGC AATACTTTAT 39840
CA~ACAAGTT CATAGCGGTA ATTTTATGCG TCCAAGCCCA CGTGTATTAG TATGTGTGCC 39900
AGCTGGTGCA ACACAAGTAG AACGCCGCGC AATTAAAGAA TCAGCAATCG GTGCTGGTGC 39960
ACGTGAAGTA TATTTAATTG AAGAACCAAT GGCAGCTGCA ATTGGGGCTA AATTACCCGT 40020
TTCTACTGCA GTTGGTTCTA TGGTAATTGA TATCGGTGGC GGTACGACAG AAGTGGCTGT 40080
AA~ ~-ll-A AATGGTATCG TATATTCTTC TTCCGTGCGT ATCGGTGGTG ACC~l-ll-C~A 40140
CGAGGCGATT Al-l-l~ll-ATG TTCGCCGCAC TTTTGGCTCG GTTATCGGAG AACCTACCGC 40200
CGAACGCATC AAACAAGA~A TTGGTTCTGC TTATATTCAA GAAGGTGACG AAATTAAAGA 40260
AATGGAAGTA CACGGACATA ATTTAGCCGA AGGTGCGCCA CGTTCATTTA CTTTAACATC 40320
ACGTGATGTC CTAGAAGCCA TTCAACAACC ATTAAACGGT ATTGTAGCAG CGGTTCGAAC 40380
GGCACTTGAA GAATGCCAAC CAGAACACGC AGCAGACATT TTCGAACGTG GTATGGTATT 40440
AACTGGTGGC GGTGCTTTAT TACGTAATAT TGATATTTTA ~-l'-l'-l-~'l'AAAG AATCTGGTGT 40500
CCCTGTTATC ATCGCAGAAG ATCCATTAAC ~l~-l~-L-lGCT ~lG~lG~lG GCGAAGCATT 40560
AGAAATGATC GATATGCACG GCGGCGATAT TTTTAGTGAT GA~ATTTAAT CAGAATATGA 40620
ACAAAAAGTG CGGTTAAAAA TAACCGCACT TTTCCTTTCA ~lLll-ll~AT TCAACAAGAG 40680
A~AGTTTAAT GA~ACCCATT TTCGGCA~AG CCCCTCCCCT AGGTATTCGT CTGCTTATCG 40740
CTATCTTTGC ATCTATTGCC TTAATTTTAG CTGATGGACG TAATAGCTCA ATAACGA~AG 40800
CACGTAGnnn AATGGAAACG GCAATAGGCG GTTTATATTA TCTTGCA~AT AGCCCTAGA~ 40860
GTATCTTAGA TGGCATTTCA GAAAATCTTG TTGATACCAA TAAATTACAA ATTGAAAACA 40920
AAGTACTACG CCAACAGCTT TTGGALAAAA ATGCAGATTT ACTTTTACTT GATCAACTCA 40980
AAGTCGAAAA TCAGCGATTA C~l~llllAT TA~ATTCTCC GTTAAGAACC GATGAATACA 41040
AAAAAATTGC CGAAGTTCTT ACTGCAGAAA CAGATATTTA TCGCCAACAA ATTGTTATTA 41100
ATCAAGGCAA AAAAGACGGT GCTTATGTAG GTCAGCCTGT CATTGATGAA ALAGGCGTCA 41160
TTGGACAAAT TATTTCCGTG GGCGAAAATA CTAGCCGAGT ACTGCTACTC ACAGACGTAA 41220
CACACTCAAT TCCAGTGCAA GTTCTACGCA ATGATGTTCG TGTTATTGCG AGTGGGACTG 41280
GGCATACCGA TGAACTAAGC CTCGATAACG TGCCTCGTTC CGTTGATATA GA~AAAGGCG 41340
Al~ll~lCGT AACCTCTGGG CTTGGTGGAC ~'l"l''l"l'~"l"l'~A AGGCTATCCC GTAGCTGTTG 41400
-77.26-
SUBSTITUTE SHEET ~RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/OS320
TACA~AGCGT TTCACGTGAT AGCTCTAATT ACTTTGCAAT AGTTAAAGCT A~ACCTTTAG 41460
CTTTATTAGA ACGTTTACGT TATGTACTTT TACTTTGGCC AAGTAACCTA GATATATCAA 41520
AAGTAAAATC AATATCGCCA GAAGAAGTTC GCAATCTGGT GCAAAAACGT TTAGAAAGCC 41580
AAGCTAATGA AGCAAATTAT AGAGTGAAAA A~ACACCCTT AACAGAAAAA GA~Lll~lAG 41640
A~AATGAAGA AAAAACCATT ATTGAACCAG ATATTCCAAC AGALLLL~L1 CAAAATGAAG 41700
AAGATCTTCC CATAGAACAG CAAGAAGA~A GGATAGAAGA CTAATGCAAA CACGATTTAT 41760
TTTACAATGG TTCACTATTT TAAGCTTCTT TGTTATTGCC TTTGTATTAG AACTTGCACC 41820
TTGGCCAGTT GGTTTCCA~A TGCTAAAGCC TGCGTGGCTT GTACTTGTAT TACTTTATTG 41880
GGTATTAGCT ATTCCCAATA AAGTAAGTAT AGG~1G~L~A TTTTTACTCG GATTAACTTG 41940
GGATTTAATA TTAGGCTCTA CATTAGGCGT TCACGCTCTT GTA~11L~1A CGAGCATGTA 42000
CATCATTGCC AAAAACTATT TAATTCTGCG A~ATTTATCA CTTTGGTTCC A~AGTTTATT 42060
GGTTGTACTT 'LLC~L~11~A TTATAAGATT ACTTATTTTC TTAGTTGAAT TTTCACTCCA 42120
TACTGCCTTT TTTCATTGGC AAGCCATCTT GGGCGCATTC G~1L~1G~LL TACTATGGCC 42180
GTGGGTATTT TTATTAATGC GCAAAATACG CAGA~AAGTT A~ATTACATT A~AAAAGAGA g2240
GATAACTCTC T~LLLLLLAT GATTTATGAA 1~L1L~A~AC ACCTAATTCA ATGGCTTATT 42300
GCTATCCAGT AAAGAATCAC ATTCCCAACC GATATACTCT CCCGA~AATT GTTCAGCCAA 42360
L1LLL~AAAA C~1L~1ACTT GTTCA~AAAT TTCGCTATTT TCTAATGAAA 'L'LL~LlGCTC 42420
TAATTTTACC AAGAAATAAG GTTCGTCATC TTCATTAAAC TGAATCGCTT GTGCAGAATA 42480
TTGTAATGTC GTGAAAGAAT AATCCCCTAA ACTAAGCTCA TCCATA~AAG GGAACATTTT 42540
CTG~L~LL~A TCAAAATGAA AACTATGCTC TACTAAATAG GTATCACTTA AATTACGACC 42600
TTTACTTTTT AATA~ATCAA GCAATTCTTC CGTTGCATTT AACTTAATCT CCAATGGAGA 42660
AGCGAGCAAA AAGTCA~AAT AAGTATCCCA AATTA~ATCC TTTTGCACAT TAATATCTTT 42720
AACAAAATCA A'LL1~LL~1A AAGTTTCTAC AATAAGATTT TCATGCTTAC AATAAAAATG 42780
TATTTTTATT TGAGAATTAC AAATA~AATG CCCCGCAAAA AATACATTTG GAAGTGCGGT 42840
TA~L1~L~1C AAAATTTTAA ATACACGGTT AATTAACTTA TCGTATTCAA CTTCTGAGGG 42900
TA~ACCCGTT TCATCATCAG CCTGATAATC AATAGTA~AC TGCACTATTT TATCGAGACC 42960
TTTACCGTGA TA'LL111~AA CATCTTCAAT ATTTGCGGTA AACACGGCAG GCATACCATT 43020
CACAGTAGAA CGATAATTCT GCCAATTTGC CATATCCATT TCGCTTTCCT ATTTA~ATTC 43080
-77.27-
SUBS 111 UTE S~{EET ~RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
AGCCCAAATC GGTGCGTGAT CAGACGGTTT TTCCATTGCT CGAATATCTA ATGCAATGCC 43140
CACATCGACA CAlC~ll~AG CTAATTTTTG GCTTACCAAA ATATGATCAA TTCGTAAACC 43200
TCGATTATCA TCAAAACCTT TAGAACGGTA ATCAAACCAC GAGAATTTAT CATTTGCTGT 43260
TGGGTTCAGC TTACGAAAAC 'l'~L~'l"l~l'AA TCCGTAATCA TACAAACGTT GATACCACGC 43320
C~ll~llCC GGTAAGAAAG AACATTTCCC TGTGCGTAAC CAACGTTTAC GATTTTCATC 43380
TCCGATACCA ATATCTAAAT CACTTGGGCT AATATTCATA TCGCCCATAA TTAAAATCGG 43440
ATTCGATTTG 'LC~'l'~'l''l'~'l"l' TTTCTA~ATA ~l~ll~AAGA TCTGCATAAA ATTTCTCTTT 43500
AGCTGGAAAT TTA~l~lC~l GCGCACGGCT TTCCCCCTGT GGGAAATAGC CATTAATGAC 43560
AGTCAATAAG CCAAATTCAG TTTCCAGATC AGCCATAATA ATGCGTTTTT GTGCATCTTC 43620
ATTGTCAGTT GGA~AACCAC GACGAATCAC TTTAGGTTCT TGTTTAGTCA ATAATGCCAC 43680
GCCATAATGA C~lll~l~AC CGTGATGAAA TACGTGATAA CCTAAGTTTT CTGTAATTTC 43740
ATAGGGAAAA GC~lC~l~AG CAACTTTAAT llC~l~lAAG CCAATCACAT CTGGCTGATA 43800
'l''l''l"l"l'~'AATA ATGGCTTCAA GTTGATGTGG GCGAGCACGT AACCCATTTA TATTGAAAGA 43860
AATAAATTTC Alllll~llC CTATTAAAGA GTGAAATTGG CTTTATTATA CAGAGATTTC 43920
TATTTTGATA AAAACGGCTT TGTCAGATAA ACCTGAATTT GCTCAAATAC TGTAGGCTTA 43980
ATCCAAAATT GACCTTGAGA AGGTAAACAA GTGACCGAAA TAAAATTATT TAGATAATCA 44040
AATTCCAATT GAGTAGCGTG CAAATAAGTG CGGTCAATTT ~ TTTACCATA~ 44100
AGCCCATCGC CTAAAATCGG GCTACCTAAA ~llLl~ATCG CAACACGTAA TTGATGCGTT 44160
TTCCCCGTTT GTGGTTTTAA AATAAATAAA CGTAAATTAG GCTCACAACT TACACTTTCA 44220
AAACGCGTAA TTGCGGGATT ~'l'~'l"l''L'l'~'l"l' TGGCAAAGTT TCCATGCGCC TTCTCGAGCT 44280
~ l~ATAT CCCCGATAAT CAAACCTTGT 'l"l'~'l''l"l''l''l'AG GCTTTTGGTT ACTTAATGCC 44340
AAATAAGTTT TATGAATTTT ATGTTCAGAA AAAAGTCGTG AAAATTCAGC CGCACTTTCA 44400
GCATTTAACG CCAGAnTTAA CA~ACCCGAA GTTACTTTAT CTAAGCGATG AACCAACCAT 44460
ACTTTAGGCA CATTCAGTTG TTTTGCAACA A~ll~l~llA AG~ll~llC TTCTTGATCT 44520
TTATGAACGC TA~TACCCTC AGA~ll~llG ATAATAATAA AATCGCTATG TTGATAAACA 41580
ACCTCGATTT CCATCAGATT TGCTCCTTTT TGTAAATTTT ATTTTTACCG AGAACAATAT 44640
CTTTTACCGA ACTAAGTAAT TC~l~ll~AA TATGTGACAG TTTTGGTTTT TCGTTTAATT 44700
GAAATGCTAA CGGACGACAA AGTTCCATTG CTTTCACGCC TAATCTAGCA GTGAGTAATC 44760
-77.28-
SUB5 111 UTE ~EET tRULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
CCACACCAAT TCCTTGAGCG ATACGTGTAG ATAATTTTGC TGTCACATCT TGAGAAAGCC 44820
AATCCATTCC AATATCTTGT GCCACTTCGG TTGCTCCAGC AAAAGCGATA TTGACCAATA 44880
CCATTCTTAA CAATCTAATA CGTGnAAAAT ACCCTAATTC AATCCCATAA ATTTCAGCAA 44940
TCTTATTCAT TAATCGAAGA TTGCGCCACG CAATnAAAAA CATATCCACT ACAGCAAGTG 45000
GACTAATCGC GACAATCACA GCTGATTCAG CTGCCATTTT ACTAATCAAT TTTTTAGCTT 45060
GTGCATCAAA AGAAGACAAA ACATGACGAC TGAATAAATG AGCAATTTCT TGCGCCGAAT 45120
AAGCTTCATT TAATTGGTGT TGCCATTGAA TTACCGTTGG AGAATCATTT TCCAAACCTA 45180
AAGATTTTGC AATATCTAAG CAAAGAATTT TA~-Ll-l-lllC TGCGTTATGA ACGGAAAAAA 45240
CATCACCATT TTTTACCGCA ~L-l"l~lAACC AAATCTGCTG A~L11~11~1 TGCCATTGCT 45300
CAC~-L-l-L-l-L-l TA~ACGAACT AAACGTCGCC ACTCACAAAT AAL~l~-L-l-lA ATACCCAATA 45360
AAATGATAAT CAAACTGACT AAAGCAAAAG CAAGATAAAT CCATTGATGT TTTTGATAGC 45420
TATCCCAAAT CCACTGCACG GATTGCGCAA CCGTCGCCAA GCCAAATAAA AGTGCAGTAA 45480
ATTTTAATAA A~'1-11-1-1'~'1'A AAACTGGATT TTGGTTTCAA TG~ll~-ll~A AGTTGAGCAT 45540
CAAGTAACTC TCCGTCCAAC GCTTCATCTA GCTTTGCTTC CATATTATGG AAnTCTTGCT 45600
TGGGCTGATA ~'L~'ll'~-L-LCC TCTACATTAA CTGAATGTTC A~AAATTTGT TTTTCCATTG 45660
CCTATCCCAA AAAATAACCC CACTAAATAG TGGGGTTATA AAGTCAAAAA TCAATCATTA 45720
TTCATCACTT GnAAAGATAG AAAGTAATCT TAATAAACTC AAGAATA~AT TGTAGATTGA 45780
AACATAGATG TTCACGGTTG CGCGAATGTA A'L-L-L~L'L'L~'L CCACCGTGAA TAATATTACT 45840
GGTTTCATAC A~AATGGTCA TTGTTGAGAA CACTACA~AT AATGCACTAA TTGCGACCGA 45900
TAAAGCAGGA ATTTGGAAGA AGAAACTCGC CACCATACCA AGCAATAACA CAATAAATAA 45960
TGCGAACATT GCGCTTGATA AGAATGACAT A'L~'L-L'L-LL-LC GTAGTCAATA CATAAGCGGA 46020
ACACGCAAAA AATACGATAG CAGTTCCTGC GAATGCAAGC ATAATCAAAT CTTCCATTCC 46080
ACGTGCCACA TACATATTTA AAATTGGCCC GALG~-L~LAT CCCATA~ATC CAGTGAAAGC 46140
AAAGGCCGCC AAAATACCAG CAGGGCGATC AGCTAATTTA TTGGTTAAGA A~AGTAAGCC 46200
ATAAAAACCC ACTAGTAACA CAATAATATT TGGATAAGGC AAGTTTAAGC TCATTGAAAT 46260
AAACGCAACA ACCGCTGAAA AAGCCATTGT TAATCCCAGT AAAAAATACG TGTTACGCAA 46320
CACTTTATGT GTGCTGAGTA ACGATTCTTT TTGAGCATCC ACAATAAGAC GTGATTGCAT 46380
AAAAGCTCCT TGTAAAATAA ATAAAAAGTC LL~-l~-LAAAG TAAGGGCTAG GGATAAAAAA 46440
-77.29-
SUBS 111 UTE SHE}~T (RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GTCAATGGTA TTAATGGAAT TAATTTCATC A~AATGAATA AATTATCATC ATCTAAAGTT 46500
AAATCATCAA ATTTCTATTT ACATCAATAA AATATTCATT ATACTACGCG CATCAATCAC 46560
GGAGGAATGG TCGAGTGGTT GAAGGCACCG GTCTTGAAAA CCGGCGAGGG TTTACGCCCT 46620
CCTAGGGTTC GAATCCCTAT TCCTCCGCCA TCAGAATTAA GAAATCCCTA AGTCACAAGG 46680
CTTAGGGATT TTAACTTTGT ATTACGTTAT TTGGTCAATC CATTCACTAG TGAAATAACA 46740
GTCTGAATAT CGCTATCAGA CAATTTTCCT TCTTTCACAA ATTTTACTTT TCCC~llllG 46800
TCTAACACGA TAATTGCACT ATCTTTAGAA TTTAATCCCC AAGCATTTTT TACCGCACTT 46860
TTATCATCTA ACACAACTTG GCTATGTGGA TTTTCCTGTT TGC~llllll CGCACCATTT 46920
TTTACAAACA TACCTGTACC AACAATCGCA TCATCCGCAT TAATAATAGT G~ll~lll~G 46980
TATTTTACAG GATTAAAATG GGATGCTTTT ATCACATCAA TCATCGACTG ATTTTnCTCT 47040
TTTGCAGCCG TTCTACCCGC TAAATGATGA ACAACACGCA CTTTACCCGC TAATTCCGCA 47100
GAACCCCAAG GTTGAAACAC AGTATCTTTT CCAGAAAGCA CAATTTCACC ATACTCACTC 47160
ACTTTGACCG ATGGTAAAGA ll~ll~lAAT TGCAAATTGT GTGCCCAAGT TGAACTACTA 47220
AATATCACGC CACAAACTAA GGCAAGAATT l~llLlllCA TACATTTTCC TCAAAAATTT 47280
ATCAAAAACT TTeACGCTTT G~CGAAA~AC A~l~lllllGC TATACTCGTG CGCCTATTAT 47340
ATGTAATCAA GAAGGAAAAC CCAATGGATC AAATGCCTAA TTGCCCAAAA TGTCA~AGTG 47400
AATACGTTTA CCACGATTCA ATTAATTTTG TTTGCCCTGA TTGCGGTAAT GAATGGGATA 47460
ATAATGAAAT TCAAGAATCA GATGACGATC AACTAATCGT AAAAGACAGC AATGGGAATT 47520
TGCTTGCAGA AGGCGACAAT GTACTTTTGA TTA~AGATTT AAAATTAAAA GGTTCATCAG 47580
AAGTATTGAA AAAAGGTACA AAATTCAAAA ACATCCGCTT AGTAAATGGC GATCATAATG 47640
TCGATTGCGG CAAAATCATG TTGAAATCTG A~lllll~AA A~AGGCTTAA TCGAAAAAAC 47700
GCG~l~lAAA TAGACCGCAC TTTGCACTTT AAAGAAATAA ATTTATTTAA TAATATCAAT 47760
CA~ll~l'~lG ACTAATCGTC CAATTTCATC CCAATTATTG GATTGAATCA A111L11~1C 47820
CACAAACCAA GAGCCTCCAC AAGCAACAAT ATTAGGAATA GCAAGATAAT CCCTTATGTT 47880
ATGAAGCCCT ATACCACCAG TCGGCATTAT CTGTAATTGA GCATAAGGAC CAAGCAATGC 47940
TTTAATCATT TTCACTCCGC CTGAAGCCTC TGCAGGGAAA AATTTTACCG CCGA~ATTCC 48000
CATTTCTAAT GCAATTTCAA TTGCCATAGG ATTATTCACC CCTGGTGTTA TTGGAAAATT 48060
CAAATCTTGA CATAATTTCA CAATTTTTGG ATTTAACCCA GGAGTAACCA CAAAATCTGC 48120
-77.30-
SUBSTI i UTE ~E~T (RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TCCGCTACTT TTAGCTA~AA CTA~11~11C CGCAGTTA~A ACTGTGCCCG CAGCAATTAA 48180
A~AGTCAGGT CTATTTGCAC GCAACA~ACG GATCGCATCT GCCGCTGCTT CAGAGCGA~A 48240
AGTAATCTCT GCCACAGATA AACCATTTTT AGCCAACGTA TCTGCTAGCG GCA~AATATC 48300
GTCTGCATTA TCCAACGCAA TTACAGGCAC AATTTTGAGT TCACGAAGTT TTTCAATAAT 48360
11~11~AGTT GTGTATGACA 11LL1LLAAT TTGCTCCTAT TAGACTCCAC TATACGCAGA 48420
AAAACCGCCA TCAACAGGTA A~ACCACGCC ATTGACA~AA GCAGAATAAT TTTCATCTAT 48480
TAAGAAAAGT AATGCACCGA GCAATTCTTC TGACTCACCA A~ACGTCCCA TTG~L~l~ll 48540
AGTGAGGATT TTATTTGCTC TA1~1~L1GG TTTTCCTTCA GTATCA~ATA ATA~AGCGAG 48600
~111L~ATTA CTAACTAAAA ATCCTGGTGC GATAGCATTA CAACGAATAC CAA~ L L LC~A 48660
GA~ATATACA GCAAGCCATT GAGTA~AATT ACTGATTGCA GCTTTTGCAC CAGAGTAAGC 48720
AGGAATCTTT GTGAGTGGCG TA~AGGCATT CATACTGGAA ATATTAATAA TATTTGCCCC 48780
'LL~LL1ACCA AGCATATCTT TTGCAAAAAC TTGGGTTGGT AATAATGAAC CTAAGTAATT 48840
GAGATTAAAT ACAAATTCTA TACCAGATTT ATCTA~ATCA AAGAATGTTC TTGTCGTTTC 48900
ATTTAAATCA AATTGATGGA ACTCATTATC 1~LL~LCGCT TTTGGATTAT TCCCACCAGC 48960
ACCATTAATT AAAATATCAC AAGTGCCAAA ATCGGTTTCA ATTTGATTTC TCA~LL~Ll L 49020
AATATTTTCA AGTTCTAACA CATTAGTTTT ATAGGCTTTT G~LL11C~LC CTGATTGGTT 49080
AA11LC~11L GCTACTTTGT CTGCAGCCTC GAAATTCA~A TCTAACAAGG CAATATTAGC 49140
TTTAGTATAC GCTAATTGCT TAGCGAGA~A TGAACATAAC ACTCCGCCAG CCCCCGTGAT 49200
TATAATTAGT TTA'1LL1~LA AGTTATGGTT TGCTGCAATA TTCATAGTAA ACTCCATTAA 49260
TTA~ATTCAG ATTGAAGATG AGA~ATTGCG ACTTTATCTA TAATCGCACC TTTATGTTGA 49320
ATGACGATAC CAGCAATACG ATTGCCTTGC TGACAACAAA TTTCGAGAGA TTTATTTCGT 49380
A~ATAACCGT TCAGA~ATCC AGCATTAAAA GAATCACCAG CCGAGGTTGT ATCCACTACA 43440
TTTAAAATAG GTTCAGGTAT CACTTGCCCA TATTGAGATA AATACCTATC TGAAAAAATA 49500
GCACCATTCT TACCGCACTT CACAATCACT 11L~1ATAC CAATTTTATG TAATCGCTCT 49560
AAAGTATCCC TAGATGTTTT ATCTTTCCAT AATGCTTGTT CATCATCA~A AGTCACCAAC 49620
GCTATATTGA CACTAGGCAA AAGCTGCA~A TAACAATCTT GTG~11~1LC TAATGAATCC 49680
CA~AGTTTTG GGCGATAATT ACTATCAAAA ACAATTTCTG TGC~L1LLL1 AGCTA~AGAA 49740
GATAATTGTT CAATTAAAAA AGTGCGGTCA TTTTTAGGTA AGATTGCTAA TGAAATACCA 49800
-77.31-
SU~SmUTE ~E~ tRULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/0~320
CTTAAATA~A TCACATCAAC TTGCTGAAGT TCTGCAATAA CCTTAGCA~A ATCCGGATGT 49860
TGAACCATAT AACGTGCTGC AGATTGATTA CGCCAATA~A GGAACGTGCG TTCGCCTTGA 49920
GCATCTAATT GGATTAGATA AAGACCTGGT TGGTGCTGTT CATCCTGTAA AACCCAATTT 49980
GTTTGGATGC CATCAGCTTG CCAATATTTA AGCATTTGCT TGCTTAAATT ATCGGTTCCT 50040
AATGCAGAGA CATAATGAAC TTGAATCTCT TTTGATGAAC TTACTCGACT AAGATAAGTT 50100
GCAGAATTTA AGGTATCTCC ACCATAACTT TGCCACATTT CCGCAAAGGG TTTCCCATTG 50160
AGTTCAATCA TACACTCGCC GATAAATGCT All~lllll~A TGATGTAACT TCCTAATAAA 50220
TCAAGATAAC CAATTCATTG GAACAATTAC AATTTCAGGA A~AAATACGA TCAACATCAT 50280
AATAATTGCG TACACA~ATA AGAATGGAGC AATTCCTTTG GATAATGCTC CTATCCCTAA 50340
TTTTGATATC CCTGAGCCTA CATACAAAAC TGTTCCCACA GGCGGTGTTA TTAATCCTAT 50400
AGATA~ATTA ATCACCATCA TGATTCCA~A ATACGCAATA TCAATATTAT ATGCTCTTAA 50460
CACTGGTAAT AAGACTGGAA CAAAGATTAA TACCGCAGGA ATTAAATCCA TTACACATCC 50520
AACAAGTAAT AAAAATAGCA TTATAATA~A CATTAAAATT GTCGGACTAT CAGTTAATCC 50580
TTTAATCGTT TGGACTAATT ~l~llGGAAT TTGAGCAACT GTAATCGCAA AAGCAGATAT 50640
~ATT~e~A~ GCAGCAACAA ACATTACCAT TGAl~l;l;~ll~ TTGATGGTAC CAATGAAGAC 50700
~l~llllAAT TTAGA~AATG TTAAGCCTTT ATAAGCAATA CTTACTATGC CAGCATA~AT 50760
TGCAGCAACA ACTCCCGCTT CTGTTGGAGT AAAAATCCCT CCTCTTAATC CCACAATAAT 50820
AATGATAGGT AATAATAAAG GCCAAAATGC llllllAAAA GCAACCCATC lll~lllGCC 50880
A~lll~llll ~lll~lAGAC TTGTATCATT ATTTCTATAC A~AATTTTCC AAGTAACCCA 50940
TAATCCAACG ACCATTAATA AGCCTGGTAC AGTTCCCCCC ATAAATAATT TAGTGATGGA 51000
TGCTCCAGCA GTAATACCGT AAATGATCAT AGGAATGCTT GGAGGAATAA CAACTGAAAT 51060
AATACCTGCA GCACA~ATTA AlC'~l~lGGA ACGAGCACCA TCATATTTTT TAGAAATCAT 51120
CATAGGAATT AGTATTGCAC CTAACGCGGC CGTATCCGCT ACCGCAGAAC CAGATAACCC 51180
TGCAAATATC AACCCAGAAA TGATCGCAAC ATAACCTAAA CCACCTTTAA TATGACCAAC 51240
CATACTTGTT GCAAAATTAA TGATTCGCTC AGA~ATTCCA CCATGCTTCA TTATTTCTCC 51300
AGTAAGCATA AAGAAAGGAA TAGCCATCAA AGGnAAATTA ll~llCCCA TCACAAAGTT 51360
'll~l~lAATT AATTGCGTAT CAAACATATC AAGATGATAT AGCATAATAC TCGCACTCAA 51420
CAGCATTGAT AGTGCTACAG GTACACCAAG A~ATAACAAT AAGAATAAAC TACACAAAAT 51480
-77.32-
SUBS 111 UTE S}~E~ tRULE 76
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
AATAGTAACA TTATAAGCTC CTATTTATCA GAGGATTCTT TATAGTCTTT AATCATGCTA 51540
AACATGACAA TAAAAAAGTA AGATACGGCA GATATAACAG CAGCTAAATA TAAAAAAGAT 51600
GnAGATATAC CTGTAGCTGG CAlll~llGA GTATAGGTCA AAGACATCAG TTGTAATGCA 51660
CCATAAGCTA TAAAAATCAT TGCAATCAGA ACGCATATAT TTGCAACTAT TAAGACTATT 51720
TTTCTATACT GCTCAGGCAA CGCAGGAATA ATAATATCAA CAGTAAGATG AGCTTTATCC 51780
TTGGCnACAA GTATAATCCC A~AGnAAATC ATATATACAA AACA~ATCCT AGAAAACTCT 51840
TCAGAAAATG CAATTCCAGA ATCAAAGAAG TACCTCAAGA CAGAATTA~A AAACACGAGA 51900
GAAATCATAA TAACTAATGC CAAGATAGAA AGATATTCTA ATG~LlL~lC TA~ATACTTT 51960
GCTATTTTCA TAAAACAAGC TC~''L'L~'L'1"LA TCCCCCATGA GCAATTTATA AAATTGAACA 52020
TAGGGGATCT TATTAATTAT TTAGCTTCGT TAAlLLLL~LG GACTACATCC TTAGCCCAAT 52080
CATATTTTTT ATA~AAACTA TCATA~AGCA CCTTAGATGC ATTCACCATG TCATTTTTAA 52140
ATGCTTCACT TGGTACGATA ATTTCATTTC CATGTTTAGC TAGATAATCT TTAACTTCTA 52200
A'L'L~'L~'L'L'1"L AATTGCTAAT TCCCACTCTT L~L~LL~ATA CAATTTAGCT G~LLLLL~AA 52260
A~ATAATTTG A'L~'L'L~'L'L'L'L GGAATTTTAT TCCAAGTTTT TAAGCTAATT TGTAATAATC 52320
CTGGAGAGAA AATATGGTTA CTTTGGATAA TATATTTTTG TACTTCATAT AACCCAGAGT 52380
CTTTAATTAA CATATACGGA ~L~L~L~L~L~AC CATCAATTAC ~'L'L'L'L~'l''L~'L AATGCAGTAA 52440
A~ACTTCACT GAGCGGCATG ~lLL~LGGAT TTATATTCAT TGCTTTAGCC CAATCAACAA 52500
A~AGTGAATT CAGCGGAACT CTTAAACGTA AACCTTTA~A ATCGTCA~AT lL~L~LAATT 52560
TTTTATTAGA TGA~ATAACA CGA~ATCCAT TCATACCATA GGCAAGTAAT TTAATTCCAT 52620
ACTTCTCCAT LLlLl~ACCA ATTTTATTTG CGATTGGAGA TTCCAATACT TTTTTAGCCT 52680
CTTGATTATC CTTA~ATA~A TAAGGCCATT CCCA~ACTCC AAAAATAGGA TCTACATTTT 52740
GCAATAATAA ACCTGTAATA CCTGCTTCTA TAGTGCCATT ACGTAATCCA TTTACAATTT 52800
GATCTTCACC GCCAAGTTGA TTATTAGGAT A~AGTCTAAT CTCATATTTA TGA~LLl~Lll 52860
CATTTTCAAT 'L~'L'L'L'L~'L'LA AAATATTCCT GTAATGCAAT ATGTGATGGA TGAATATCAG 52920
AATTATAATG TCCTAACTTA ATAATTGTTT TTGCAAATGC ACTGCTACTA AACAATATAC 52980
TTGAAGCAAG TAATAATTTA CCTAAGCCTT TAATTGATTT CATAACTTTC TCCTTATTGA 53040
TTA~L~LLLlL TAGAAAACTG CATTAATTTT TAAATAATTT TCTGGATGAT CAGATAAATC 53100
AGA~ATAAAA CTAGGAATTT CTTCA~ATTT GATACACTTA GTAATGATAT GAGATGCATT 53160
-77.33 -
SUB5TITUTE S~E~ (RULE 26)
CA 022l874l l997-l0-2l
W O 96/33276 PCTrUS96/OS320
AATTTTATTA GTAGCAAGCA TATCCAATGC CTCCTCAAAT TCCCCCTTGC ~ll~ll~LAGA 53220
ACCATAAATA TTCAATTCTT TA~AGGTAAT TA~ATTTGTT GGTAATGGAG 'L'l"l'~'l'~'l"l''l''L 53280
TGGCCATCCT GTTAAAGCAA TTCTTCCTGC A~AGGAGGCA TAATGCAGAG TATTTTtGAT 53340
AGA~ATATTA GCACCAGATG CCTCCATAAC AACTTCAGCC ATACGACCAC TTGTAATTTC 53400
CTTAATTCTT TTAATGTCAT CCTCCTTATG CGGATTTACA ATATGTTCAA TTCCCAAGGA 53460
TTTTGCATAC TCAAGACGTT GTTCTAATAT ATCAACTAAA ATTGGGATTG CTCCATATTG 53520
AACCGCTGCT AATGCAGCCA TTAATCCAAT TGCACCAGCT CCAATAATTA CTA~ l~llC 53580
CCCTGATTTT AAA~ll~lLC TATGTA~AGC GTGTAAAGCT ATTGTTAAAG GTTCAGCTAA 53640
AGGTAATTGA TGAATCGGTA GGTTATCTGG GACTTTAGTT A~AAGATGAG CGGGATGTCT 53700
AATTACCTCT TGCATACCTC CATCAATATG AACACCAATT ACCTTTAATG ATTCACAACA 53760
ATTGGTTCTA CCAATTGAAC AAGGATAGCA TTGACCACAA CAAACATAAG GATCAACAAT 53820
TACTCGGTCT CCAACCCTTA CCCCATCTGA CATACCAATT CCACTTTCAA TTACTCTCCC 53880
TACAATTTCA TGCCCAAGTA TTCTTGGATA AGTTACTAAT GGATTAGTTC CTCTATATGC 53940
ACCAATATCA GAACCACAAA TCCCCATTGA TTCTACCTGA ATAAGTACAT CATTATCACT 54000
~ CGGGA TAAGGCACTT CTTTAACAAC TACATTGTTT G~11111~1A AACATATTGC 54060
TTTGATTCGC TCCTTCATTT TTAGACTCCT TATATGCCAT TGACAGAATA AAATTACTTG 54120
TTATGTTTAA CTATGATATG ATTATGAAAC ATAAAAACTC TTTTTGGAAT ACCA~ATATC 54180
TA'lllll~lG AGCCATATCA CAAA~ATAAA AAATTGGAAT ACCAATTTAA GGAAAAATAT 54240
GGAAAATATA GTAAATAGAA CATATACCCG AATAGGTCAA TTGCTAAAAC AAGATATTTC 54300
TCAAGGAATT TATAGCATTG GAGACAAACT CCCTACAGAA CGAGAAATTT CTGAAAAATT 54360
TGGTGTAAGT AGAACTATTG TTAGAGAAGC AATGGTTATG TTAGAAGTAG AAAAGTTAGT 54420
AGAGGTAAAA AAAGGGTCAG GCGTTTATGT AGTAAGAACC CCCGAATCAA TACATATGGA 54480
ACATTCAGAT TTACCAGATG TAGGTCCATT TGAACTTTTA CAAGCTAGAC AACTATTAGA 54540
AAGTAGTATT GCTGAATTCG CAGCGTTACA AGCGACTAAA AAAGATATTT TAAATTTA~A 54600
ACAAATACTG AATCGAGAGA AAGAATTACT TACTCAGAAT CAAGATGACT ATAGTGCAGA 54660
CAAAGATTTT CATTTGGCAC TTGCAGA~AT TACACA~AAT GATGTGTTAG TCAAATTACA 54720
AGAACAATTG TGGCAATATC GCTTTAATAG TGCGATGTGG GCACAATTAC ATTCTCGTAT 54780
TTTACA~AAT GATTATCATC ATTTATGGAT AGAAGATCAT CAAACAATTT TATCTGCTAT 54840
-77.34-
SUBS~T~UTE S}~E~ ~RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TCAAAAGA~A AATGCTAATG AAGCTAGA~A AGCTATGTGG CAACACTTAG A~AATGTAAA 54900
AGTA~AATTA TTTGAATTAT CTGATGTAGA AGATCCACAT TTTGATGGAT ACCTATTCAA 54960
TACAAATCCA ~~ ~lAG GTATCTA~AT ACTTGTAATA ACATAGGAGT TA~AAATGGA 55020
ACAAGCATGG CGTTGGTATG GACCA~AAGA TC~1~1L1~1 TTATCTGATA TTCGTCAAGC 55080
AGGCGCAACT GGTATAGTCA CTGCACTTCA CCATATTCCT AACGGTGA~A TATGGgGTAT 55140
TGAAGAAATT AaAAAACGCA AAACTGAAAT AGAAAATGCT GGTTTAAGCT GGTCAGTAGT 55200
GGA~AGTGTA CCAGTTCATG AAGAGATTAA AACTCAGACT GGAAATTATC AAAAATGGAT 55260
TAATAACTAC AAACAAACTC TTCGCAATCT TGCTCAATGT GGAATTGACA ~l~lllGCTA 55320
CAATTTTATG CCAGTTTTAG ACTGGACTCG AACCGATCTT GCTTATGAnT TACCAGATGG 55380
TTCTAAAGCA TTGCGCTTTG ATCATATCGC TTTTGCCGCA TTTGAACTTC ATATTTTAAA 55440
AC~lC~l~AT GCAGA~AAAA CCTATAATCA AGAAGAACAA GTTGCAGCAA GAACCTATTA 55500
TGACAATATG TCAGAGCAAG ATATAGCGCA ATTAACGCGT AATATTATTG CGGGCTTACC 55560
CGGTGCAGAA GAAGGTTACA CTCTTGATGA ATTTCAAACT CAATTAGATC GCTATAAAGA 55620
TATTTCATCC GA~AAATTCC GTACGCATTT GGCTTATTTT TTA~ATGAGA TCGTACCTGT 55680
TGCCCAAGAA ATAGGAATCA AAATGGCGAT TCATCCAGAC GATCCTCCAC GCCCAATCTT 55740
AGGCTTACCA CGCATAGTTT CAACTATTGA AGATATGCAA TG~lll~lAG A~ACTCAACC 55800
ATTACCAGCA AATGGTTTTA CAATGTGTAC GGGTTCTTAT GGCGTACGTt CCGATAATGA 55860
l~lC~lAAAA ATGACTGAAC AATTCGCTGA TCGTATTTAC TTCGCTCATT TAC~ll~LAC 55920
TCAACGTGAA GGTAATCCAC TAACCTTCCA TGAGGCAGCT CATCTAGAGG GAGACGTAGA 55980
TATGTTTAAT GTAGTA~AAG CTTTATTA~A TGAAGAATAT CGTCGATTAA ATCAAGGAGA 56040
AACGCGTTTA ATCCCAATGC GCCCAGATCA TGGGCATCAA ATATTGGATG ACTTACGTAA 56100
A~AAACCAAC CCTGGCTACT CTGCTATTGG TCGGTTAAAA GGTCTAGCTG AATTTCGCGG 56160
TTTAGAGATG GCATTAAAAA AAGTGTATTT CAATAAGTAA AAGA~AAAGT GCGGTCATAA 56220
A~AACATTAT TTTTATCGAC CGCACTTCTA ATTTATTTCA TCAATCTTCT CATTCGAATA 56280
TTGATCATCT CGACCACAAC AGAGAATCCC ATTGCA~AAT AGATGTAACC TTTCGGGATG 56340
TGAATATCCA AA~lll~lGC AATTAAACTA ATTCCGACTA A~ACCAAGAA AGCTAAAGCT 56400
AGAATTTTCA ACGTTGGGTG TGTATCCACA AAATCGCCGA TTGGTTTTGC CGCAAACATC 56460
ATCACCCCCA CGGCAATCAT A~TCGCCA~A ATCATCACAG GAAGGTGGCT TGCCATACCC 56520
-77.35-
SUBSTJTUTE S~E~T tRULE 2f~i3
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96105320
ACCGCTGTAA TGACAGAATC TA~AGaA~AT ACAATATCTA GCACAGCAAT TTGAATTAAT 56580
ACGCCAAGAT AACTCACTTT ~LllLlGCTT TCAGATTCAT G~L~ll~llG ATGATTTATC 5~640
GC~L-lllAA TTTCGCCAGA A~LllllATA ATCAGGAATA AACCACCGAT TAATAAAATC 56700
AAATCACGCC CAGAAATTTC TTGATTA~AC ACAGTAAATA ACGGTGCAGT AAGTTTCATT 56760
ATCCACGCTA GtGaCATTAA AAGTAAAATT ~ll~llAGCA TTGCCA~AGC AAGCCCAAGA 56820
ATACGACCAG ACTGGCGTTG GCGTTCAGGT AAACGTCCAA CTaGGATGTT AATAAAAwTA 56880
ATATTGTCGA TTCCTA~AAC GATCTCTAAA GCCGCAAGTG TCACAAGTGA TATCCACGCT 56940
TCAGGATCTG CAATCCATTC A~ACATAATT TTTCCTATAA TTGAGTTAAA TA~ATCCGAA 57000
AATACAGATC ATAATGGCTT TATGACGAAA AGCAATCGTT ATTTATATTT GAGAAATGAT 57060
TGATTAGTCG TTTTTAAGCG TTTCAAAAAT CCTTTCAGCA AGTTTAGGGG A~ATGCCCGG 57120
TACAGAGGCT ATTTCATCTA AGGTCGCCTT TTTCACACCT TGTAAACCAC CAAGATATTT 57180
CAGTAAAGCC TGACGACGTT TAGCTCCCAC ACCTTCAATG ~LL~L~LA~AC CA~lll~l~l 57240
AAAGGCTTTT TGAC~Lllll TACGGTGTCC GCTTATTGCG TGATTATGGC TTTCATCACG 57300
GAL~l~ll~A ATCAAATGCA ATGCCA~ACT ATCATCAGGC AAATGAATTT CGCGGTCTTG 57360
TTTGCTGATG ATCAGTACTT CCTGTCCTGC TCGACGATCC ACACCTTTTG CCACGCCAAT 57420
TAAGTGCGGT CTATTTTTAT CCCATTTTAC TTGAAGATGT TGGAATACAT TCAGCGCACG 57480
ATTTAATTGC C~L1~1 1~AC CATCAATAAA AATAATATCG GGAATTTTAT ~Ll~ll~lAA 57540
ATCACGCTCA TAAC~Lll~l GCAACACTTG TTCCATCGCA GCATAATCAT CCCCGCCAGT 57600
AATGCCTTCA ATATTAAAAC GACGATAATC AGATTTTAGT GGACCTTCTT TATTAAAAAC 57660
AACACAAGAT GCTACTGTTT GATTTCCCAT CGTGTGGCTT ATATCGAAAC ATTCCATACG 57720
CTTAATTTTA GGAAGATTTA ACAGATCACA CAACGCTTGA TAACGCTCTG ACATTCGTGA 57780
AGALl~lllA AGTTGTACAT TTAAAGCCGC TTTAGCATTA ACTTGTGCGA GCTGTAAGTA 57840
TTTACTTTTA TCGC~LLL~A CG~LLl~LlG AATCGTCACT TTTCTGCCCG CTTGCTCGCT 57900
AAGAAGTTGC TCAAGCTCCG ATTTTTCAGC TAATTGACGA TCCACAATAA TGCTATTCGG 57960
GATACTTCGT CCTTGATGAC CTTGTAAATA A~ATTGCCCC ACAAAAGTTT CGGTAAGTTC 58020
CGATAAATCC GTATTGGCGG GGACTTTTGG GA~ATAACTG CGATTGCCTA GCACTTTTCC 58080
TTGACGAATA AACATCACCT GTACACAGGC TAACCC~L~L TGGTAAGCGA TAGACATAAT 58140
ATCCATATCA TCTAAACGTT CATTGGATAC AAALl~llll TCTATAACCG AACGCACAGC 58200
-77.36-
SUBS i 11 UTE SHEET ~RULE 2h~
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
CTGAATTTGA TCGCGATAAC GAGCAGCCTG TTCAAAATCT AAATTTCTGC TTGCCTGCTC 58260
CATTTTACCG ATTAAATAAT CTAACACCTG TtGATCTTTG CCTTGTAAAA ATAAGCGAGC 58320
TAATTCAACT TGCTGATTAT ATTCTTCATC GGA~ACATAT CCCTGTACAC AAGGTGCAGA 58380
ACAACGCCCA ATTTGATACT GCA~ACAAGG ACGAGAGCGG TTGGAATAAA CGGAATTTTC 58440
ACATTGGCGA ACAGGGAAAA ~Ll-LlLGCAA AAGCGATAAC GTTTCACGCA CGGCTCCCGC 58500
GTGAGGATAA GGCCCAAAAT ATTCACCTGC AAALlllllA GAACCACGAT AAGAAGTAAT 58560
TCTTTGGTGG C~Ll~lLLGG TTAATAAAAT A~ATGGATAG GATTTATCAT CACGCAATAA 58620
TACGTTATAA CGAGGCTGAT AAAGCTTGAT AAAATTATGC TCTAGCAGTA AAG~LlCC~l 58680
TTCAGATGAA GTTAGCGTGG TGTCAATATG ATGAATTGAC GCCACCAACG C~ L~ 1 ~ L 111 58740
TTTACTGCTC AGATTTTTAC GAAAATAGCT TGA~AGACGT Ll~lllAAAT CCTTTGCTTT 58800
CCCAACATAA ATAACCTGAT CTTTATCGTC ATACATAcGA TAAACACCAG GTTCGTGAGA 58860
GACATCAGTG AGGAATTTTT TAGCATCA~A CATTTTAATT CGCCGCTAAA ATTGCCCGCA 58920
~LllllCCAA ATCTTCGGCG GTATCCACCC CCACTGCAGG CA~Ll~lLLC GCAAGTTCTA 58980
CGTGAATACG TTCGCCGTTA TATAACACAC GAAGCTGCTC AA~LLLLL~L AGATTTTCAA 59040
GTTGAGTCGG TGCCCATTGC ACATATTGTT TTATGAAACC CGCACGATAT GCGTAAATGC 59100
CAATATGACG TAAGTAAGCG TCAGAAAGCT GTA~LLL~LG AACATCCTGC AAATTCATAA 59160
ACTGATCACG ATCATAAGGA ATAACCGAAC GGGAAAAATA CAGCACATAG CCATCTTTAT 59220
CTGTTAATAC TTTCACTGCA TTTGGATTAA ATAATTCCTC AGCATCGTGA ATTTTTACCG 59280
CAAGGCTTGC CATATTGACA TTAAATTTTG CTA~ATTATC TGCCACTTGT CGCACGATAA 59340
CGGGAGGAAT CAAAGGCTCA TCGCCTTGAA TATTGACAAT GATTTCATTG TCAGGAATAG 59400
CTAATTTTTC TACAACTTCT GCTAAACGTT CTGTACCAGA ATTATGATTA ACCGAAGTCA 59460
TACAGACTTC AGCACCA~AA CTTTTGGCAA CATCAGCCAC ATTTTCATTA TCGGTGGCAA 59520
TAATCACTCG GCTCGCCCCA GACTGCAGTG CTTTCTCA~A TACATGTTGA ATCATTGGCT 59580
TACCTTTAAT ATCAGCAAGA GGTTTTCCTG GCA~ACGACT TGATGCAAAA CGAGCGGGGA 59640
TAATCACGGT AAATGACATA ATTTATTCCT TALLCLLlAA TATTTCAGCT TTATCGGCAA 59700
GCAATCAAAA CAACTGGGGA TTAATCCTTT CAGCCATTTC TGTATTGCTC CACAAGTTTG 59760
TCTATTTTGG CCCAAAAGTG CGGTAAATTT TCAC~LL~LL TTTCAGCCTC AATAATCTCC 59820
GCATCCACAG GGACATACCA CCAATTATCT TTAGCAAAAG ATTGGCATTT TACGGCATCT 59880
-77.37-
SUBSTITUTE ~FET tRULE ~
CA 022l874l l997-l0-2l
W 096t33276 PCTnUS96/05320
TTTTCCGTCA TAAAGAGCGG TTGATTTTCA GCAAGTTTTT-CTAATTGAGA CGCTTCAAAA 59940
TGTTGATGAT CTTGAAATGC TTGAGTTTGC TTTAACTGAA TCCCTAACTT TTCTAACATA 60000
GTAAAAAAAC GCTGTGGATT GCCAATCCCT GCGATGGCAA CACCAGATTG AAATTCATTT 60060
AATTGGCGTT TTTCATTGGT TTTTAAATTA ATCGCGAAAT GAGGCACAAG ACGCATAACT 60120
GCATCTGAAT ACTGATTTTT TCCACCATTA GTGATCACAA AATCGACAGA TTTTAATCGA 60180
CTTGGTAATT CACGCAATGG ACCTGCTGGC AATACAAAAC CATTTCCCAA TGCGCGCTCA 60240
GCGTCCATTA CGACAATTTC TA~ATCACGT TGTAATTGAT AATGCTGCAA ACCATCATCA 60300
GAAATAATAA TATCGCACTC TGCTTGGCTT AAGAGTAATT CAATCGCTTG CTGGCGATTC 60360
GGGGAAATCA CAACTGGCGC ATTAGTACGT TTAGCGATCA ATACAGGCTC ATCGCCACCT 60420
TCAATTGGAT TTGTATTTTT AGTGACGAAT AACGGATAAG TTTTAGATTT ACTGCCGTAA 60480
CCACGAGAAA TCACACCTAC ACGCAGACCT C~lllllll~ ATTCTTCCAT AAGCCAAACA 60540
ACCACAGGCG TTTTGCCATT TCCACCCACA GACAAATTTC CCACAATTAT CACTGGTTTT 60600
GGTGCGCGAT AAGAAGACTT CAGCCCCA~A GAGAATAAGG CGCGACGAAG TTGGCTAATC 60660
AACCAAAACA ATAAAGAAAA AGGCGATAAG AGCCAAATAA GTTTGGAGTT GGAATACCAG 60720
AAGGGCATAG AAAATCCTTT CTAATAAGTG CGGATAAAAT AACGCGAGTT TTTCAACTCG 60780
CGTTTTCGAT AATCAATAAA TTAGCCAGTA AACTGCATAC TATGCAACTG TTTATAGGCA 60840
CCAllll~l~l CAAGCAATGT TTTATGGTTG CCACGCTCAC GAATTTCTCC GTGATCAATC 60900
ACAAGAATTT CATCCGCGTT TTCAATAGTA GATAATCTAT GGGCAATCAC AACAACCGTG 60960
CGAL~lll~l TTAATTCCTC TAATGCAGAT TGGATTGCTC GTTCTGATTC CGTATCTAGT 61020
GCAGATGTAG CTTCATCTAA AATTAATACT GGCGAATTAC GCAATAAAGC ACGAGCAAtC 61080
GCTAAACGCT GACGTTGCCC ACCTGATAGG CTAGTGCCAT TTTCGCCAAT TACCGTATCA 61140
AaAACTTGCG GTAATTTTTC GATAAACTCT AAAGCATAAG CCGCTTTTGC TGCAGCGATA 61200
ATTTCTTCGC GAGAATACTT Al~Ll~lGCT GCATAAGCAA TATTATTCGC AATAGTATCG 61260
TTAAATAAAT GGA~ll~LlG AGA~ACCACA GCGCAGTTTT CACGTAAATT AGATA~ACGA 61320
TAATCTTGGA TATTTACGCC ATCCAGTA~A ATTTCGCCTT GCTCAATATC GTA~AAACGT 61380
GTCACTAAAT TAGCAATGGT TGATTTGCCC GATCCAGAAC GTCCCACTAG AGCTACGGTT 61440
TTTCCAGCTG GAACGCTAAA AGA~ATATTA TTTAATGCAA GTTCATCTTT TCCTTGATAT 61500
GCAAAACTCA CATTTTTAAA TTCTAACTCG CCTTTCGCAG GTTCTGCTTT ATAAGCCCCG 61560
-77.3 8-
SUBS 111 UTE 5HEET (RULE 2~)
CA 022l874l l997-l0-2l
W 096133276 PCTAUS96/0~320
TCAl~-lLlll CTGGCTCTAA ATCTA~AATG GCA~ATAGCG TTTGACATGC TGCCATTCCA 61620
CTTTGA~ATT GTGCATTCAC CGCAGTTAAT GATTTTAACG GACGCATCAT AGCTAACATT 61680
GAAGA~AATA CCACTGTA~A TGAGCCTGCA CTCA~ATTAT CTTCTGCAAT CAATGGAGTG 61740
GTAGCTA~AT AGAGCACCGT AGCTAATGCG AGAGATGCAA TAACTTGCAC CACAGGATCA 61800
GA~ATGGAAT TTGCTGTCAC CATTTTCATG ~-lllllC~AC GCATATCATT ACTAACATGA 61860
TTA~AATGCA ~ll~llCCAC ATGTTGCCCT CCGA~AGAAA GCACAACTTT ATGACCTTTT 61920
AACATCTGTT CTGTAGCAGA CGTAAGTTCA CCCATTGAAT CTTGTAAGTT CTTACTTAAT 61980
CTACGAAAAA ~llllL~ATAC CA~ACGAATT A~AACAGCAA TGATTGGACC TATAATA~AA 62040
AGCACAATTG TTAATTCCCA ACTGGTATAA AACATCACTG CGAATAGCGA AATAATATAT 62100
G~lC~ll~lC GCACAATTGT AATCA~AGAT CCTGAAGAAG AACTTGCAAT CATTTGGGAA 62160
TCATAAGTAA TCCGAGA~AG TA~ACGCCCT GTTGAATTTT GATCA~AGAA ACTCACTGGC 62220
ATAAACATTA AATGTTTAAA CAAGCGGCGA CGCATTGTCA TGACAACTTT GCCTGATACC 62280
CACGCCAAGC AATAATTAGA AATA~AGTTG GTAATGCCGC GTA~AATAAT CATCCCAACG 62340
ACGACA~AAG CCATCATTTT CAAAAATGAA lG~lllGCCT TACCA~AACC A~lC~lC~AAC 62400
AACGGTTTTA ACAAATA~aT CAAGCCTGAG TCAGCTAATG CATTAAAAAC TAACGCGACG 62460
CCAGA~ACAA TAAGCCCCGC TTTA~AAGGT TTAATCATTG GCCACA~ACG CTTAhACGTT 62520
TGTAAGGTTG A~AAATCATT ll~l-l~lAAT TTTTGCTCTT GCATAATCGC TATCTAATAG 62580
TA~AAATTGC ACGCATTGTA C~llllATTC CTTTGATAAT CC~ATTACAC GCGCATACCA 62640
AGGGGAAAAT TTTGTGCGAG CTTGCTGGAT TTCTAATCGG TCTTGA~AAA AATTTACCCG 62700
cACTTGCCCC GA~ACAGCGG TAllLl~lAC CGCACTTTTA TAGCGATGAA GCCTTTCCAT 62760
AACCGAATAA TGAGGGAATT TCCACGGATT CCAACGCCCA CTAGA~ATAA TCGCTACATC 62P20
TGGTCTAACc TGAGAAAGCA AGTATTCACT TGTCGATGTT TTACTCCCAT GATGCCCCAC 62880
TTGCAACACA TCGATTTTGC CTA~AGTGCG GGCA~AAATT TGCTCATTTT TTGCTTCAGC 62940
ATCGCCAGTT AGCAAAACGC TAll~lllCC ATCATCGACT A~AATCACAC AAGAATGGGA 63000
ATTATCAGCT CGTGTCACAA C~ll~l~AGG AGA~AGTATT TGA~AATGCA ACCCTTGCCA 63060
ATGCCAATCA CGCCCAGCAG TACA~AAAGT GCGGTAATTT TCCCCATAGT TTTTCCGTGA 63120
AGGGGTAATC AATTCCACAT TGGGATACGC CTTTA~AATT GTCGAAGCAC CACCTGCGTG 63180
ATCGTTATCG TCGTGGCTTA A~ATCAATTT TTCCA~AACA ATC~ll~lC TTTGTA~ATA 63240
-77. 3 9-
SUBS 111 UTE S~EET (RULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCT~US96/05320
AGGCAAAATT TCCAACTCAG CCATACTTCC ACCTCGCCAA GAAGAACCCG TATCATAAAG 63300
AATCCCTTTA CCATTTTTCA CAATCAACGT AGCTAACCCC TGCCCCACAT CTAAAGTATC 63360
TACCTGCCAA GTTGGCTTGC TCAATTGTTT A~ACAACA~A ATCGTAAAAC ACAGTAAGAT 63420
AATGCCGAAA GAACATCGCA AAACGTTGAT TCGTTCATTT TTTAGCAAAG GCTTACTGAG 63480
ATTTAATGTA AAAAATTTTG CTCGTTTTAT TTGCCAGTTT GATGATGAAA TCTCGGGTTC 63540
TCGGTAAATA TTCCAAATAA TTAACATAAA AATTCCTGCA CAAAGTGCGG TTAAACCCAA 63600
TGCTAAATTA AATGAAACCG TGAGCCAATT CCCTTGAAAA ACAGA~ATTA ACCCAGTAAT 63660
LC~llCGGCT AG~Ll~lllG CTAGTTGCCA AGAAAACATT GTGCCGTTAG TAAAAACGGC 63720
AAATAAAATT AATGGCACAA GCA~AAAACT ATAAATTGGA ACCGCCATAA AATTGGCTAA 63780
AAATCCACTC AACGATAAGC CATTAAATAG AAAAAGTTGC A~AGGTGTAA AAAAGAGCAA 63840
TAACCCA~AT TGCAAATGAA ATA~ACTAAA AATCCACCGC ACTTTTGGAG A~AAAGGGCG 63900
ATTTTTCCAT TGAAAAAGTG AAAAAGGCAC ATAACGATAC CAGAGGAGCA AACACCCAAC 63960
CGCTCCACAA GAAAGCCA~A AACTGACCGA AAGCGGCATT AATGGATCGC AGAAAAGCAA 64020
GAATCCGACA ACCAACGTAA AAAACTGAAT GGGCGAATAA TGTCGCCTCA TTATTTGAAT 64080
AAATAAAACG A~AACAAGTG CTGAAATGGC ACGAAAAGTT GGCACACTAA AACCAGCCAA 64140
ATACGCATAA ATTA~AGCAA ATAAAACACC AAAAACTAAA GGAAAATAAG GATGAATAAA 64200
ACGCGTAGGA AAGAACACTT GCACAACACG CGCCAAGcAA AATCCAATTC CCATAGCCAA 64260
CCCAATATGT AAGCCAGAAA TAGCAATAAG ATGTGCGGTA LlG~LLL~Ll GGTA~ATTGA 64320
CCAAGTGGTT TTATCTAACC AAGCCCGTTC GCCAAAAGCT AAGGCAATCA ATAAACCTTG 64380
TAGAGATAAT CCTTCCGTTT G~LL~111AC TTGTTGCAAT LlLl~lGCAC GCAATGATGA 64440
AACATCCGCA ATTTTCACCG CA~LLLLL~C CGTTCCAACA GCCGTAATTC CTTTTGAAAA 64500
ATACCATTGT TGCCGATCAA ACCCACCGAA ATTTAATCGT GCAGAAAGGG AACGTAAAGA 64560
AATTTCAGCT TGCCA~ATTT CCGATAATTG AGGCACCTCT TTCGCTTTCC AATTTAAGAA 64620
AAll~lL~l TCTTGCAAAT TATTCTCCAA TGTTGCTGTG GCGATAAGCG TTTGATAATC 61680
CTGTTGGTGC AAAATTTCTT GAATCTTA~A AGTTACCACT TG~LllLGAG CGGTAATATT 64740
TTGAGCTTGT TGTGATAAAC TCAAAGCCGA ATAATGA~AA TAGCCAAGAG AGGCAACA~A 64800
AAAAGCAAGG CTAACTAAGA AATTTCTACG CAAGAAAATA AAAAGA~AAA TCA~AACAAG 64860
CGCAATAACG AGAGCAACTT GCCAAGGCAA TAGCAACGGT TGCGGTAGAA ATAACAACGT 64920
-77.40-
SUBS 111 UTE S~EET ~RULE 26)
,
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/OS320
TA~ATCCGCG ACAATTAACA AGACAACTAA AGTTATTAAG TTTAATTTCA TTTTTATAAA 64980
AGATTAATTC CAGC~L~l~l AAGCCTAGGC TAGTTTTATT TAAATATGCA AACGGTTGCT 65040
TCAAATTTTG CGATCCATAT CGTAAAAATA AALll-LL~AG GAAAATTTAC TTGCTAAAAC 65100
AAACAACTTC TGATATTTAT ACCGCCCGCA A~AATTGGGT TCCTA~AATA GCAGTCAGGA 65160
ACA~ACTAAA ATAACAAGAC AGGAAGTCGT GAAATCCACG CTTAATTCTG TATGTATTAG 65220
GAGTGAGAGA TGTCAAGAGC ATCATTGAGC TTGCTAGATT TAGCAGGCGT TAAGCCTTAT 65280
CAAATGAAAA AAGATGAAGA ATATATGAnT GAnGAGCA~A lL~LL~ATTT CAGA~AAATT 65340
CTTAATGCTT GGCACGAGCA AATCGTGGAA GAAGCTTCTC GCACCGTTGC ACATATGCAG 65400
GATGAAGTAA CCAATTTCCC CGATCCTGCA GACCGAGCAA CTCAAGAAGA GGAATTTAGT 65460
CTAGAATTAC GTAATCGAGA TCGCGAACGT AAACTAATGA AAAAAATCGA AGCAACCTTG 65520
AAGAAACTTG ATACCGATGA TTTTGGTTAC TGCGATTGTT GTGGTGAAGA AATCGGCATT 65580
CGCCGTTTAG AAGCGCGCCC AACAGCAGAT CTTTGCATTG ATTGCAAAAC TTTAGCTGAA 65640
ATCCGCGAAA AACAAGTCGC TGGTTAATTC ATTCTATTGA AAAATACAAA AGTGCGGTTA 65700
AAATTAACCG CA~LLLl"llG CATTTAAAAA TGCAGGA~AA TCCACTTGCC 'L'l"l"l"l'~'L'l''LA 65760
CAAGAAAAGA GCCAAGTCAT TTATTTCCAA CAACA~AACG GAGTAAATTA TTCTTACTTA 65820
TATCAAAAAT LL~LlLGGCA AGAAGACAAA A~AATCAAAA GAGGTTGCCA AAACAAGTGC 65880
TCATTCTAAA CGAGTTGAGC GTTCTAATAG CCAAATGCCA AAAGCGCGAG CA~AAAAATC 65940
AGAACAAACA CGTCGCTATG ATAAAAATGT GATTAAAGCG GCTCAATTTG ATALLl~lCC 66000
GCGTGATTTT AGCCGTAATG CTCTCAATGT AGTGGAAAAA CTGCAACGTC AAG~lLLL~A 66060
GGCTTATATC GTCGGTGGAT GTATCCGCGA TTTATTGCTC GGTAAAAAAC CA~AAGATTT 66120
CGATGTTGCA ACAAACGCCC GCCCTGAGCA AATCCAAAAC ATTTTCCAAC GCCAATGCCG 66180
TTTAGTGGGT CGCCGTTTCC GCTTAGCACA TATTATGTTT GGTCGAGATA TTATTGAAGT 66240
CGCCACTTTC CGTGCTAATC ACAGTGATGC TCGCAATGAA AATCAAGCGA AACAGAGCAA 66300
TGAAGGCATG TTACTGCGCG ATAATGTTTA CGGTACGATC GAACAAGATG CAGCACGCCG 66360
TGATTTTACG GTCAATGCAC TGTATTACAA TCCGCAAGAT AATACGTTAC GAGATTATTT 66420
CGAGGGCATT AAAGATCTCA AAGCAGGCAA GCTACGCTTA ATTGGCGAtC CTGTTACACG 66480
TTATCAAGAA GATCCTGTGC GCATGCTACG CTCAATTCGT TTTATGGCAA AACTTGATAT 66540
~lLC~lL~AA AAACCGAGCG AACAACCAAT TCGTGrACTT GCGCCTTTAT TA~AAAATAT 66600
-77.4 1 -
SU8ST~TUTE S~EET tRULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TCCGCCAGCT CGCTTATTTG ACGA~AGCTT AAAATTATTG CAGGCGGGAC AAGGGGTAAA 66660
AACTATCGGT TATTACGCCA ATATGGTTTA TTTGAACAAC TTTTCCCTGC ATTAAGCGCA 66720
TATTTTACAG AGAAAGAAGA TAGCTTTGCG GAACGTATGA TCGTCACTGC ACTTACTTCT 66780
ACGGATGAAC GTGTTGCGGA TA~ACTTCGT ATTAATCCTG CATTCTTATT TGCAGCATTT 66840
TTCTGGTATC CATTGCGCGA AAAAGTGGAA ATTTTAAAAA ATGAAGGTGG TTTAAATAAT 66900
CATGATGCTT ATGCTTTAGC AGGCAATGAA GTTTTAGACT TATTCTGCCG AGCTTTAGCT 66960
GCACCACGTC GTCATACTGC GGTCATTCGT GACATTTGGt TCTTACAACT GCAATTATTA 67020
AAACGTACTG GATCAGCACC AATGCGTACC ATGGAACATC CAAAATTCCG TGCAGGCTTT 67080
GATTTATTGG CTATGCGAGC AGA~ATTGAA GGTGGCGA~A CCATTGAATT AGCCAAATGG 67140
TGGCACGAAT ATCAATTCAG CAATGGTGAA CAGCGTGAAC AGTTGATACA AGAGCAACAA 67200
CGCTTACATC CTAAACCA~A GAAAAAATAC TACCGTCCAC GCC~lC~lAA AACAACGTGC 67260
TCAGCAGAAT AAGGGAAAAG ATGATTACGG CATATATTGC TCTAGGTAGC AATTTAAACA 67320
CACCAGTAGA ACAATTACAT GCTGCGCTTA AAGCGATAAG TCAGTTATCA AACACTCATT 67380
TGGTAACAAC GAG~l~llll TATAAAAGCA AACCGCTCGG CCCACAAGAT CAACCCGATT 67440
ATGTGAATGC CGTTGCAAAA ATTGAAACCG AACTTAGTCC GCTCAAGCTA TTAGATGAAT 67500
TACAGCGTAT TGAAAACGAG CAAGGTCGAG TGCGTTTACG TCGCTGGGGC GAACGCACGT 67560
TAGATTTAGA TATTTTGCTC TACGGCAATG A~ATTATTCA A~ACGAACGC TTAACAATTC 67620
CCCATTATGA TATGCATAAC CGTGAGTTTG TCATTGTGCC ~ll~lLl~AA ATCGCATCGG 67680
ATTTAGTTTT ACCAAATAGT CAAATCATAA CAGAGCTGGT CAAGCAATTT GCTGACCACA 67740
AAATGATAAA ATTAAATCCC TAGA~ATTTC ACCGCACTTT TATGAACCTC AAAAGTGCGG 67800
TAGAATCAGC CCACATTTTT CTTCATTCAT GACCCGTTAT GGA~AGTTTG ACTCAATATA 67860
TCCCTGATGA Allll~lATG CTCCGCTTCG GCAAAAAATT TGCCGAAATT CTTTTAAAAT 67920
TGCATACAGA AAAAGCAATT ATGGTTTATC TTAACGGTGA TCTTGGGGCA GGA~AAACAA 67980
CGCTAACGCG CGGAATGTTG CAAGGTATCG GTCATCAAGG TAATGTAAAA AGCCCAACTT 68040
ATACGCTGGT TGAAGAATAC AATATTGCAG GCAAAATGAT TTATCATTTT GATTTATATC 68100
GTTTAGCAGA TCCTGAAGAG CTCGAATTTA TGGGCATTAG AGATTATTTT AATACGGATA 68160
GCATCTGCTT AATTGAATGG TCTGAAAAAG GTCAAGGCAT ATTGCCAGAA GCGGATATTT 68220
TAGTGAATAT TGATTATTAC GATGATGCAC GAAATATTGA ATTAATCGCA CA~ACAAATT 68280
-77.42-
SU8ST~TtJTE SHEET (RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS9610S320
TGGGTAAAAA TATTATAAGC GCA~ ~lA ATTAACTTAT TTATGAAAAC TAAAATTTTA 68340
'lllllC~lll llll~l~AAC GTTTAGTTTC TCTATTTTTG CAGCACCTAT TACGATTGCG 68400
ATTGACCCAG GTCATGGGGG AAAAGATCCT GGTGCAATCA GCCGAAACTT AGGCATTTAT 68460
GAAA~AAATG TTACCCTTTC AATTGCA~AA GAATTAAAAG CCTTATTAGA TAAAGATCCA 68520
CATTTTCGCG GTGTATTAAC GCGTA~AAGT GATTATTATA TTTCCGTGCC AGAACGTTCA 68580
GAAATCGCAC GTAAATTTAA AGCGAATTAT CTTATTTCCA TTCATGCCGA TTCATCTAAA 68640
TCACCTGATC GTCGCGGGGC ll~l~LllGG GTATTGTCAA ACCGTCGAGC CAATGATGAA 68700
ATGGGTCAAT GGTTAGAAGA CGATGAAAAA CGCTCGGAAT TACTTGGTGG AGCGGGA~AG 68760
GTGCTTTCAC ACAATAATGA CAAATATCTT GACCAGACTG TACTTGATCT GCAATTCGGA 68820
CATAGCCAAC GTACAGGCTA l~l~llAGGC GAACATATTT TGCACCATTT TGCTAAAGTA 68880
ACAACATTAA GTCGCAGTAC GCCACAACAT GCAAGTCTGG ~l~Ll~lACG TTCGCCAGAT 68940
AllC~ll~lG TGTTGGTAGA AACTGGATTT CTTTCCAATT CAGAAGAAGA AAAAAAACTT 69000
AATTCCCAAA CTTATCGTCG CCGCATTGCT TATATGATTT ATGAAGGCTT AGTTGCATTC 69060
CATAGCGGTA AAACCAACAC TTTAGTTAAA GACAATTTAG TGCAAAACAT CA~ACAAAAC 69120
GATATAAAAA AATCAGGGAA A~ATAACCGC ACTTCAGAAC A~AATATA~A TGAAGATAAT 69180
ATTAAAGACA GTGGCATTCG CCATATTGTA A~AAAAGGAG AAAGTTTAGG TAGCTTATCA 69240
AATAAATATC ACGTA~AAGT CTCTGATATT ATTA~ATTAA ATCAATTAAA GAGAAAAACA 69300
CTTTGGCTAA ATGAAAGTAT TAAAATCCCT GATAATGTCG AGATAAAAAA TA~ATCATTA 69360
ACAATTAAAG AAAATGATTT TCATAAAAAA CA~AATAGCT TAGTA~ATAA TACCAATA~A 69420
GATTTAAAAA AAGAGAAAAA TACACAAACT AATAATCA~A AAAATATAAT TCCGCTCTAT 69480
CATA~AGTAA CAAAAAACCA AACACTTTAT GCTATTTCGA GGGAATATAA CATTCCAGTA 63540
AATATACTAT TGAGCCTAAA TCCACATTTA AAAAATGGCA AAGTTATTAC AGGACAAAAA 69600
ATAAAATTAA GAGA~AAATA AATGCCTATT A~AATTCTTT CCCCACAACT TGCTAACCAA 69660
ATTGCTGCTG GAGAAGTGGT AGAACGCCCT GCATCAGTGG TA~AAGAATT AGTGGAAAAT 69720
AGCCTTGATG CAGGTGCAAA TAAAATCCAA ATTGATATCG AAAATGGTGG GGCA~ATTTA 69780
ATCCGCATTC GTGACAATGG CTGTGGTATT CCAAAAGAAG AATTAAGCCT CGCTTTGGCA 69840
CGACATGCCA CGAGTA~AAT AGCCGATCTT GATGATCTCG AAGCGATTTT AAGTTTAGGT 69900
lllC~lGGCG AGGCATTAGC TAGTATCAGT TCCGTATCAC GCCTAACCCT TACTTCTCGT 69960
-77.43-
SUBS i I I UTE S}{E~ tRULE 2~
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96/05320
ACCGAAGAAC A~ACTGAAGC GTGGCAAGTT TATGCGCAAG ~1C~1~ATAT GGAAACCACA 7002D
ATCA~ACCCG CATCACATCC TGTCGGCACA ACAGTTGAAG TCGCCAATCT llllLl~AAc 70080
ACACCAGCCC GCCGAAAATT TTTGCGCACA GATA~AACAG AATTTTCCCA TATTGATGAA 70140
GTCATTCGTC GTATTGCTTT AACGA~ATTC AACACAGCAT TTACATTAAC GCATAATGGA 70200
AAAATTATCC GTCAATACCG TCCTGCCGAA GCAATCAATC AACAACTA~A AC~1~1CGCC 70260
GCTATTTGTG GGGATGATTT TGTCA~AAAT GCCTTACGAA TTGAGTGGAA ACACGATGAT 70320
TTACATTTAT CAGGTTGGGT GGCGACACCA AATTTTAGCC GAACTCA~AA TGATTTAAGT 70380
TATTGCTATA TTAATGGCCG AATGGTTCGA GATAAGGTAA TCAGCCATGC TATTCGACAA 70440
GCCTATGCAC AATATTTACC AACCGATGCT TATCCTGCGT '11~1~11~11 TATTGATTTA 70500
AACCCGCACG ATGTAGATGT CAATGTTCAT CCAACCA~AC ATGAAGTACG CTTTCATCAA 70560
CAACGCCTCA TTCATGATTT TATTTACGAA GGCATAAGTC ATGCGCTAAA CAATCAAGAA 70620
CAGATTAATT GGCATACAGA CCA~AGTGCG GTAGA~AATC ACGAAGA~AA TACGGTGCGT 70680
GAGCCCCAAC CGAATTACAG CATTCGTCCT AATCGTGCAA CTGCGGGGCA AAATAGCTTT 70740
GCGCCACAAT ATCATGA~AA ACCACAGCAA AATCAACCGC A~L111~1AA CACACCAATG 70800
TTTCCAAATC ATGTAAGTAC TGGTTATCGA GATTACCGTT CTGATGCACC GAGTAAAACT 70860
GAGCAACGTT TATATGCTGA ATTGTTACGC ACGTTACCGC CTACAGCGCA AAAGGATATA 70920
TCGGATACAG CACAACAAAA TATTTCAGAT ACAGCTAAAA TCATCTCAAC TGAAATAATT 70980
GA~1~1L~AT CACATCTACG AGCCCTTTCA CTTATTGA~A ATCGTGCGTT GTTATTACAA 71040
CAGAACCAAG A111~11111 GCTTTCATTG GAAAAATTAC AACGCTTGCA ATGGCAACTA 71100
GCGTTAAAAC AAATACAGAT TGAACAACAG GCTTTATTGA TTCCAATCGT GTTCCGATTA 71160
ACCGAATCAC AATTTCAAGC ATGGCAACAA TATTCAGATG ACTTCA~AAA AATTGGCTTT 71220
GAATTTATCG AAAATCAAGC ACAATTACGC TTAACCTTAA ATAAAGTGCC AAGTGCATTA 71280
CGCACACA~A ATCTACAAAA ATGCGTGATG GCAATGCTGA CTAGAGATGA A~ATTCATCA 71340
TCATTTTTAA CCGCACTTTG CGCACAATTA GAATGCA~AA CCTTTAACGC TTTAGCGGAT 71400
GCACTCAATT TATTGAGCGA GACGGAACGT TTACTCACGC A~ACAAATCG CACAGCATTC 71460
ACCCAATTAC TCA~ACCTGT TAATTGGCAG CCTTTATTAG ACGA~ATTTA AA'11~11~AT 71520
GA~ACCAACC GCAATTTTTT TAATGGGCCC AACAGCCTCA GGTAAAACAG ATTTAGCCAT 71580
TCAACTACGA AGCCAACTTC CAGTCGAAGT GATTAGTGTG GATTCAGCTC TTATTTATAA 71640
-77.44-
SUBS i i I UTE SHEET (RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTtUS96tO5320
GGGAATGGAT ATTGGCACAG CGA~ACCATC A~AAGAAGAA CTTGCCCTTG CGCCTCACCG 71700
TTTAATTGAT ATTTTAGATC CATCAGA~AG CTATTCCGCA ATGAATTTCC GCGATGATGC 71760
GCTACGCGAA ATGGCGGATA TTACCGCACA AGGCA~AATT CCGTTACTAG TGGGCGGCAC 71820
GA~1~11~1AT TACA~AGCCT TAATCGAAGG GCTTTCGCCC TTGCCTTCTG CTGATGA~AA 71880
TATTCGCGCC GAGCTTGAAC A~AAAGCAGC TCAACAAGGT TGGGCAGCAT TGCATACAGA 71940
ACTCGCCAAA ATCGATCCCA TTTCTGCCGC CCGAATTAAT CCCAGTGATT CTCAACGAAT 72000
CAATCGCGCT TTAGAAGTTT TTTACATCAC AGGA~AATCA CTCACAGAGC TGACTGAAGA 72060
AAAAGGCGAA GCCTTGCCTT ATGATTTTGT GCAATTTGCA ATTGCGCCGC AAGATCGCCA 72120
1~111-LGCAT GAACGCATCG AACAACGCTT TCATA~AATG ATTGAACTAG GCTTTCAAGC 72180
AGAAGTGGAA A~ACTTTATG CGCGTGGCGA TTTAAATATT AATCTGCCGT CAATTCGCTG 72240
TGTAGGCTAT CGTCA~ATGT GGGAATATTT GCAAGGTGAT TACGCTTACG AGGA~ATGAT 72300
LllCC~lG~l ATTTGCGCTA CGCGCCAACT TGCAAAACGC CAGCTTACTT GGCTGCGTGG 72360
TTGGA~AACA CCAATACAAT GGCTAGATAG TTTACAACCT CAACAAGCGA AAGA~ACTGT 72420
ATTACGTCAC TTAGATTCTT ATCA~AAAGG TTAGA~AAAA TGACCGCACT TTCTGCCCTC 72480
ATCGAACA~A AATTACAATC TCTTGGCACA A~1C~1~LGCC AA1~1111CC AGAACTTTCC 72540
CCAGAAAAAA TTCACGAAGC CATTCAACAA AATTCA~ATC ATCCAGAACT GC~L~lllAT 72600
CAATTAGGCT ATGCCATAGC AATGTCTGAC TTTGTGGA~A AAGTCTTGCA A~AATACCCG 72660
CACTTAGTGA AACAATGGTG GGA~AAATCC CC~1~L1--L-LG CAGATTGCAC TGCCTATATT 72720
GAACGTTTGA ATAAAGAGTT AGCCAATGTA CATGACGA~A CTG~-L~-L~1A TCA~ACATTA 72780
CGCCAATTCC GTAACATTGA AATGGCA~AA TTAAGTTTTT GTCA~AGTTT GAATCTTGCG 72840
ACAGTTGAGG A~A'1--L-L-L1~1 TCAGCTTTCA CAACTTGCAG AGAGTTTAAT TATCGCTGCC 72gOO
CGCGATTGGC TTTATCATCA AGCCTGTGCG GAGATAGGCA CACCAATGGA TGAACAAGGC 72960
AATCCGCAGC AGCTTTATAT TCTAGGAATG GGGA~ATTAG GCGGCTTTGA ACTA~ATTTT 73020
TCCTCAGATA TTGATTTAAT TTTCACTTAT CCATCACAAG GGGA~ACGTC CGTTGAGAAT 73080
ACGAATGCTC GAC~L-L~1~1 GGATAATGGA AAALLLLL-1A CACGTTTAGG GCAACGCCTT 73140
ATTTCTGCCT TAGATGAATT TACCTCTGAT G~LLLL~LAT ATCGAACCGA TATGCGCTTG 7~200
CGCCCATTTG GCGATAGTGG CGTGCTTGTT CTCAGCTTTT CAGCAATGGA ACAATATTAT 73260
CAAGATCAAG GTCGAGATTG GGAACGCTAT GCAATGATTA AAGGACGAGT ATTGGGCGCA 73320
-77.45-
SUE~5TITUTE 5~E~T (RULE 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
CAAACAAAGG ATCCCAACGT TTCAAAATTG A~AAAAATGT TACGCCCTTT TGTCTATCGC 73380
CGTTACATTG ACTTTAGTGT GATTCAATCT TTACGTGA~A TGA~AGGCAA AATTGAGCGA 73440
GAAGTACGCC GTC~lG~lll GA~AGATAAT ATTAAACTAG GTGCTGGTGG TAllC~l~AA 73500
GTCGAATTTA TCGTACAAGT TTTTCAACTC ATTCGAGGCG GGCGAGAAAT CAATCTGCAA 73560
CAACATTCAC TCTTAAAGAT CTTGCCTGAA ATTACCA~AC TAAGATTAAT TACCGAACAA 73620
CAATTCCACG ATTTACGTGA AAGTTATATT TTTTTACGCC GCGTAGAAAA CATTCTACAA 73680
GCCATTAACG ATCAACAAAC GCA~ACACTA CCAACCGATG AAATAGATCA AAllC~lllA 73740
GTCGAGGCAT GTAAAACTTT CAC~l~LllA AATGA~AATA ATCAAACCAT TGAAAAACAT 73800
TATCCAATAG A~AATTGGGA CGATTTTTAC CGCACTTTAC AACAAAAACA AGAAAAAGTG 73860
CGGGCAGTAT TTACTCAATT AATCGGTGAT GAACAAGATG A~l~llCACA AACTGATAGC 73920
CAATGGCAAG AlLlLllAGA AGCAGATTTT GAGGATATTG AACA~ACATT ATTAGAGAGT 73980
AGTGTATCGG AAAATAATAT TGATGAAGTT TTAGAAAAGC TTGCTCAATT CAAAGACGGC 74040
CTAAATCACA GAGTGATTGG TTCGCGTGGG CGTGATGTTT TGAGTCATTT GATGCCAACA 74100
GTACTTGCAC TCATTTTTGA ACAAGA~AAT TACCGCACTT TGCTTCCGCG GATTCTGAAC 74160
ATTATTGA~A A~ATTTCGAG TCGCACGACT TATTTAGAAT TATTATTGGA A~ATCCTCGC 74220
GCACTTCAGC AAGTTATTGA A~lll~LGCG CAGTCTCAAC TTATTTCAGA ACAATTGGCG 74280
CACTATCCTA TTTTATTAGA TGAATTGCTT AATACGGAAG CACTACGTCA TCCTTTGCCA 74340
TTTACCCAAT ATCCTGCAGA GTTACACCAA TATTTGCTTC GTTTACCCCC TGATGATGAA 74400
GAACAGCTTA TCGATGCTTT ACGTCAATTT AAACAAGCAA CCCTATTA~A AGTGGCAGCG 74460
GCAGATATTT TAGGTGCATT GCCAGTAATG A~AGTAAGCG ATCATTTAAC CTATCTTGCT 74520
GAAGCCATTA TTGAAGTGGT TGTGAATCTA GCTTGGA~AC AA~lllC~lC TAGATTTGGT 74580
GTACCTGAAC ATTTACAAAA TAACGA~AAA GGATTTTTAG TTAllG~llA TGGAAAACTA 74640
GGTGGTATTG AACTCGGTTA TAAATCCGAT TTAGACCTCG TA~ l~lA CGATGCCGTA 74700
GAAAGTCA~A CAACAGGTGG CAAAAAAGTG ATTGATAGCA ATCAATTTTA CCTACGCTTG 74760
GCACAAAAGA TTGTGAGTAT TTTCAGCATA AATACTTCTG CTGGCGTACT TTATGAGGCA 74820
GATATGCGCC TGCGCCCTTC TGGCGATGCI GGCTTAATTG GCTGCTCTCT TTCTGCATTT 74880
TCTCATTATC AATTGAATGA CGCTTGGACA TGGGAAAAAC AAGCACTTGT GCGCGCTCGT 74940
CCAGTATTTG GCGAATCATC TCTTAAAGCT AAATTTGAGC ATATCCGCCA ACAAGTGCTT 75000
-77.46-
SUBST~TUTE ~t~EET tRULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TCTGCATCAC GAGATATTGA ACAATTA~AA CAAGATGTTG TTGAGATGCG GA~AAAAATG 75060
TTTGCCCATT TATCTCACTC A~AACACAGT GAATTTAACC TTA~AACAGA TCGCGGTGGC 75120
ATTACAGATA TAGAATTTAT TGCTCAATAT TTAATGCTTG CCAATGCCCC GALAAAACCA 75180
CAACTAACAA AATGGTCAGA CAATGTACGT AllLlC~ATG ATATGGCAGA GGCTA~AATT 75240
ATTAGCCA~A CAGACTGCGA CACATTA~AA CAATGTTATG TCGATTTACG CAATACCATT 75300
CATCATTTAA ALll~llGGG TA~ATCTTCC GTTGTGGAAG ACAGTGAATT TGTTA~AGAG 75360
CGGTCATTTA TTCAAGCATT TTGGGATAGG TTATTTGTAT CCTA~AATAT GGCTTGTGGA 75420
C~Lll~AAAA ATAGCCTTCA TCACA~ATCT TCTTGA~ACC TCCCA~AAAC TA~ATATTCA 75480
ATCCTATTTT TAATGAACCA AATCTAACAT TTCCTGTGCA TTGGCTAGAG CTAATTCTGT 75540
AATTTCACTT CCGCCCAAGA GTCTTGCCAA CGCAGGTACA CGTTCAGCTT GTGA~AGTGC 75600
GGTCATTTTT GTTTCAGTTT TATTATCAAC AGTA~ATTTT TCCACATTAA ACTGATGATG 75660
GCCATGACAA GCAACCTGTG GCAGGTGGGT TACGCATAAT ACTTGACAAC GCTCACTTAA 75720
TTGACGTA~A AGTTTTCCGA CAACACTTGC L~lllllCCG CTAATGCCCA CGTCCACTTC 75780
ATCGA~AATT AAGGTTGGAA TAGCCGATTG ATCAGAAGTT A~AACTTGAA TGGCTA~AGA 75840
AATACGAGAA AGCTCACCAC CAGAGGCAAT TTTAGCTAAT GGCTGCGGTT GTTGTCCTAA 75900
ATTACTACGC A~AGTGA~AA TCACATTATC CGCACCATTT GCACTCACTT TATCTA~ATC 75960
CGTATTCAAC TCTACATA~A ATTCAGCGTT TTCCATTGCA A~Ll~LlllA TCGACTGTGT 76020
GACATTTTGC GCTAAGCGGG TTGCAGATTG CTGACGACTT GCTGTTAATG CTGTAGCCGT 76080
TGCTTGCATT TGTTCA~ATG ~'LC~'l"l"L'l"l'C TTGCTCAATC AACATCTCTT CACTTTCAGA 76140
AAAATCTA~A AGTGCGGTTA ATTCTGCTTT TAA'LLllllG TG~L~ll~lA CAAGATCTTC 76200
AGGTTTAACT TGATGTTTAC GAGCAAGTTG TA~AGTCTGA CTAATTCTTT GTTCGATTTC 76260
CTGTA~AAGC TGAGGATCTT GCTCGATATT ACTTGATA~A TTTTGCACTT CACTGGTTGC 76320
TTCTTGCACT TGAATCAACG CATCATTCAA CATATTTTGC ACTTCAGCAT ATTGCGGATC 76380
AAGTTCAGCT AATTCATCAA TATATTGTGT CGCACGATAA AGCA~ACTAT CGATATTTAC 76440
GGTGTCATTT TCACTTA~AA TTTGTAGGGC TGATTGGGAA AGTTGAGTTA G~L~llCGCT 76500
GCTAGATA~A CGACGTTGTT CAl~l"l~lAA TTCCA~ATAT TCATTTGGTC GAAGGTTA~A 76560
TTCATCTAAC TCATCCACTT GATACTGTAA AA~Ll~lllA CGTGCTTCAT TTTCCGCCAC 76620
'l"l"l"L'L~'L'L~A AAGGTTTTAA CTTGATTTTG AAGATTTTTC CA'L~L~'L~AT AATCTTCACG 76680
-77.47-
SUBSTITUTE ~t E~T tRULE 2
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
CATTTTCACA AGTAATTCAG GATGAGCGGC A~AATTATCA ACTAACTGAA GCTGATAGTC 76740
AllllllAAC AATAATTGAG AAGC~l~llG CCCATTAATA TGAACGAGAT ATTGAGCAAT 76800
~ llAAT TGAGAAGCGG ATACTGGTGT ACTATTAATA AAAGCCTTAG AACGTCCGTC 76860
TGCATTAATT ATGCGACGTA AAATACATTC AGTTGGATTA TCTGGATCCT GTAATTCTTG 76920
CTCACTCAAC CAGTGATAAG CAGGATTTTG CGATTCTAGT TGGA~AGTTG CACAAATTTC 76980
CGCACGCTCT TGCCCTTCAC GCACCATTGA G~lll~lACT ~lll~lCCGA AACATA~ACC 77040
TA~AGCATCA ATGGCGATAG AllllC~AGC ACCAGTTTCC CCTGTTATAA CAGACATTCC 77100
TTTCGCCAAT TCAATATCAA GCTGACGGAC AATCGCAAAA TTATTGATAG TAAGTTGAGT 77160
AAGCATAGCA AAATCCTTTA ACTGTATATT TAATATGATA TAACTGACTT AATTTACAGT 77220
A~AGGATTTT TTACAGTATT TTGTCAAATC TATTTCAATC GAAAATTTTT ACCATAATCA 77280
A~ATGATTTT AACCAACCTA ATTTGCTACT TAACACATTG TAATAATTAT AATTTTCAGA 77340
TGAAGCAATC GGAGTTTATG CTCGCTTTTT TGAATATGCA CCACATCATC TGGGGTAAAA 77400
GGTAAGGTAA TTTGACTATC ACAGCCCACT TCTAATTGAG AGGTATTATG TTCAGCA~AA 77460
CGAATCGATA TTTTACTATC CCCATCAACA ACAAGAGGGC GAGAAGTTAA TGTATGTGGA 77520
AACATTGGCA CTAATGCAAT GGCATTAAGG TTTGGTGTCA A~ATAGGTCC ACCAGCGGAA 77580
AGAGAATAAG CCGTAGAACC TGTTGGAGTA GA~ACAATTA ATCCATCAGA ACGTTGAGAA 77640
AATGCAAACT TATCATTGAT ATATACGTGA A~ATCAATCA TATGTGCAAT TTTGGCGGGA 77700
TGAATAACCG CTTCATTTAC CGCATTGCTG GTTGATACGA TTTCACTTGC TCGTTCGATT 77760
TTTGCTTCCA ATAAAAAACG TTCTTCCACA AAAAATTCGC CACGTTCTAA ACAAGCTTCA 77820
AGCTGGGAAT AGGCATTTTT CGGGTCAATA TCCGTTAAAA ATCCCA~ATT ACCACGATTA 77880
ATACCAATCA ATGGAATATC ATATTTTGCT AATACGCGAG CGCGCCCTAG CATATTGCCG 77940
TCTCCACCAA TCACAATGGC TAATTGGGCT CGGTGGCCTA ~lLl~ll~LAA CGTAGCAAGA 78000
TGTTCAAAAG GTAACTCAAG TGTTATGGCG A~11~111L1 CCACCAACAC TTGATAACCA 78060
CGTTCCATTA ACCAATGAAA TAA~LllllG TGCATTTGTA AGTTAATATC ATTGCGAGGC 78120
TTACCTACAA GAGCAATGGT TTTA~AGGAA CGATATA~AT GATTCATA~A ATGACCGCAC 78180
TTGAATTTAA CAllllC~lC ATTATATCGT TTTTTGCTAC ACTATGCCCA ATTACGATTA 78240
ATCAATTTTG TTTTACGGAG AAAAAAATGT CAGAACAAGA ACA~AAAGTT GA~ATCCCAG 78300
AAGTAGAAAA GCAAGAAGAA ~lC~ll~lGG AAGA~ACACA ACAAGCAGAG CATTCTCAAG 78360
-77.48-
SUBST~UTE S}tEET tRULE 2
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
AATTTGATCC TTTAGAAGAA GCAATTGCTC GCGTGCAAGA GCTTGAAGAG CAGCTA~AAA 78420
CTCAAATAGA AGAAGCGGCA AACA~AGAAC AGGATATTTT ACTTCGCTCT CGTGCTGA~A 78480
TTGA~AATCT TCGTCGTCGT ACTGAACAAG ACGTAGAAAA AGCACATA~A TTCGCCTTGG 78540
AAAAATTTTC AAAAGACATT TTGAATACTA TCGATAACCT AGAGCGTGCC CTTGCCACTC 78600
CAGCAAATAA AGAAGATGAA AGCGTA~AAG CCTTATTTGA CGGTGTAGAA CTAACCTTAA 78660
AAGAATTAGT TTCAACCGTT GGGC~-L-1--1-1'G GCGTGGAAGC TGTGGGAGTT GTCGGTGAAG 78720
CATTTAATCC TGATTTACAT CAAGCCATTT CAATGCAACC AGCTGAAGGC TTTGAAACCA 78780
ATCAAATTAG C~1C~LATTG CAAAAAGGCT ACACCTTA~A TGGTCGAGTC ATTCGCCCAG 78840
CGATGGTAAT GGTGGCAGCT TAATTTACAT ~L~1-L~-L~1A~A GAGCGGTCGG ~L-L-L'l' L ~GACC 78900
~-1-1-L-L'L'L~-1--1' TTTCCTGAAT AACTACATAA ACTTTACGGA TAATTTCCCT AAAATCTTCG 78960
~'LC~'L'L~'1'AG CCCAATCTAG AAGATCAACG CGCCACGGTA AATCTGATTC AGA~AAAGCT 79020
TCCTTTAATC TGTCACGAGC TAAAAAATCT A~AGGTTCCT CAGAGATAAT CGCAAGGTCA 79080
AGATCGGAAT A~LL1L1-LLGC TTTTCCCTTT ACACGAGAAC CGA~AGCCCA CACGGTATAA 79140
TCAGGTACTA AL1~1-L~LAA AATAGTTTTC ACAATCGCCA A~LL~LL~AGA TTTTATATCA 79200
AGCTGTGCAA AACTAGTCAT ATTGATTTCT CTGACGTAAT TGTTCCAATA GGA~ACTACT 79260
TTCTATTA~A AAATCATCAA TTTGTGCATA AACAGCCATG G~1-1-1-L-LC~-L GATCATAAGT 79320
ATGTGATGTA ATATTACGCA TATCACGATA AGCAACCCAT TTTGACATAT CTCCAATCAA 79380
ACCAAATCTC AATGCTTCTC GCAAAATATC CTTA~ATCCA TAAGCCCCAA TGTCATCGGT 79440
ATTAATTGCA 'L~LL~L1~AA GTTGGCGTTT CATCATTTTT A~ACTTAACT CATA~ACA~A 79500
TTCA~ATTTC TGAATTGCAC CTGCAATTAA GGTATCTTGT ACAATAGAGG GTTGCATATC 79560
A~ACCAATTT ~L~L~1~A~A TTTGTACTAC GGTTTGCTCT AACGAATA~A ATGCAGCATC 79620
TAATACATTT A~ATTTAGCT TATCAGTCAT CATTTTTACC 'L~1~LLA~AT ACTCATCTAT 79680
TTTACCATAG ACTATTTTTT CTCAAAACCT ATAACCCCAA AAGTA~ACAT TGTGATATTG 79740
ATCACAAAAT CA~AAATATT TGAGA~AAGC TCTCAACAAC TTAATTTGAT A'L'1"1''1'-L~'1'AA 79800
TAAAATCAAT CTTTAACA~A ATTATCTTAC GACA~AAAGG TCTAAAACAC TACATATTGT 79860
~L~-LL~ATTA 'L~1LL1LAGA TCTATATATA GTGCAATCCG CATTTCAAAA ACACTATATA 73920
TTGGAGCTAT ATCATGAGTA ACTTTGGGGT CATCAAGCGC GA1G~1-L~-1C GTGCGGAGTT 79980
TGAGATTCAA CGTATCATTA ATGCCATTAA AAAAGCCGCA AGTnCGGTCA ATATTTCCGA 80040
-77.49-
SUE~S 1 i i UTE S~EET (RULE 26~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TGAATTTTAT TGCCACCAAA TTGGGCAAGA AGTAGGGAAT GA~ATTTTCA CCCGTCATCA 80100
AGGCGAGATT GATATTAATC AGATTCAAAA AATCGTTGAA GATA~ATTGA TGGCAAGTCG 80160
TTATCCTGAG GTTGCTCGTG CGTATATCGA ATATCGTCAT GATCGTGATT TAGCACGAGA 80220
AAAACGTAGC CAGCTAACAA AAGA~ATTGA AGGTTTGATT GAACA~AGCA ACGTAGAATT 80280
ACTTAATGAA AACGCCAATA AAGACGCGAA AGTGATTCCA ACGCAACGAG ATTTGCTTGC 80340
TGGAATTGTG GCAAAACATT ATGCCAAGCA CAATATTCTT CCACGCGATG TGGTAGAGGC 80400
TCACGAAAAA GGTGAAATTC ATTATCACGA TTTAGATTAC GCGCCGTTCT TTCCAATGTT 80460
TAACTGTATG TTAGTTGATT TAGAAGGGAT GCTTTCTCGT GGTTTCA~AA TGGGCAATGC 80520
GGAAATCGAA CCCCCTA~AT CTATCGGCAC CGCAACGGCA GTGACAGCAC A~ATTATCGC 80580
CCAAGTTGCC AGCCATATTT ACGGTGGCAC AACCATTAAT CGTATTGATG AAGTGCTTTC 80640
CCCTTATGTG CA~ATCAGTT ACGA~AAACA CCTCA~ACAT GCCCAAGAAT GGAACGTGCC 80700
TGATGTTGAA GGTTATGCCA AAGCATTGAT TGAAAAAGAA TGTTTCGATG CCTTCCAATC 80760
CTTAGAATAT GAAGTTAATA CACTACATAC TTCA~ATGGG CAAACACCAT TTGTGACCTT 80820
LG~ G~l- TTAGGTACAA GCTGGCAATC CCGCTTAATT CAGCAAGCTA TTTTA~AAAA 80880
TCGGATTCGT GGACTTGGAA AAAATCATAA AACACCAGTA TTTCCA~AAC 'Ll'~l-l"ll'~AC 80940
CATCAAAAAA GGTTTGAACC AAAATAAAGG CGATCCGAAT TACGATATCA AACAACTCGC 81000
ATTAGAATGC GCATCAAAAC GTATGTATCC AGATATTCTC AATTACGATC AG~Ll~L~AA 81060
AGTCACGGGC L~-ll-llAAAG CCCCAATGGG ATGCCGTAGC TTTTTAGGTG CATACGAAGA 81120
A~AAGGCCAC GA~ATTCACG ATGGGCGTAA TAATCTTGGC GTGGTGAGTT TGAATTTACC 81180
GCGTATTGCG TTGGAGTCCA AAAACGAAGA AGATTTCTAC CGCACTTTAG ATGAACGTTT 81240
GGCTATTGCG AAAAAAGCAT TAATGACGCG CATTGCCCGC CTTGAGAATA CCAAAGCTCG 81300
CGTCGCTCCT ATTCTTTATA TGGAAGGTGC TTGCGGAGTG CGGTTAAAAG CGGATGA~AA 81360
TGTGGCACAA ATTTTCA~AA ATGGACGTGC CTCTATTTCA CTTGGCTATA TCGGTATTCA 81420
CGAAACCATT AATGCACTAT ATAACA~AGG ACATATTTTT GATGATGAAC AATTACGCGA 81480
AAAAGGCATT GCGATTGTTC GCCACCTTAG CGAGGCAGTG AAACGCTGGC AAAAAGAAAC 81540
AGGTTATGCC TTCAGCCTTT ACTCCACGCC AAGCGA~AAC TTATGCGACC GCTTCTGCCG 81600
TCTAGATACC A~AAAATTTG GCGTAATTGA AGGCGTCACG GATA~AGGCT ACTACACGAA 81660
CAGTTACCAC TTAGATGTAG AAAAGAAAGT GAATCCTTAC GATA~ACTAG ATTTCGA~AT 81720
-77.50-
SUB5 1 i I UTE S}~EET tRULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
GACATATCCC CCACTCGCCA GCGGCGGTTT TATTTGCTAC GGCGAATATC CCAATATTCA 81780
ACACAACTTA AAAGCATTGG AAGATGTGTG GGATTATAGC TACGATCGCG TACCTTACTA 81840
CGGCACA~AC ACACCGATTG ACGAATGTTA TGAATGTGGT TTCACCGGCG AATTTGAATG 81900
TACCAGCA~A G~L1-11~1~L GCCCGA~ATG TGGCAATCAC GACAGCACAA AA~L~l~l~l 81960
CACTCGCCGC GTCTGTGGCT ATCTAGGCAG TCCTGATGCC CGCCCATTTA ATGCGGGA~A 82020
ACAGGAAGAA GTGAAGAGAA GAGTTA~ACA CCTTTGATTA ACACGATAGC A~AAGCACGC 82080
AL-l-l-lllAAT GCGTGCTTTT TGTTTCCAAC TTTGGCATTC CTA~AAATCT CCGCTAAAAT 82140
AACCGCACTT L-L-l~-l-lATCT TCTAGGA~AG CAATATGTCA GATATTCTCA ATAACCTTAT 82200
TCAL~-Ll~ll A~ACTTGAAA A~ATTGATGA TTTAATCTTT CGTGGAGA~A GCCAAGATTT 82260
AG~LlllC~l CAAGTATTTG GTGGGCAAGT TGTGGCTCAA GCATTATCAG CGGCAATGCA 82320
GGTGGCGCCA GAAGATCGTA TTTTACATTC TTGTCATGCC TAllll~llG CTCCGGGAGA 82380
TAGCCAATAT CCGATTATTT ACGATGTAGA AACCTTGCGT GAAGGGCGTA A~LllL~lGC 82440
ATTATGCGTA A~AGCCATTC AACATA~AAA TACCATTTGT CATGTAACCG ~LL~LLLCCA 82500
AGTGCCTGAA A~AGGTTTTG AACATCA~AA TACAATGCCA AAL~LLG~lG CGCCTGAAGA 82560
CTTTACGGAT GAAAATGTGA TGCTACA~AA AGTAGCTCAA ACCTTGCCAG AACCACTCAA 82620
TGA~AAATTT GCAGCAGAGC GTCCATTTGA GGTGAGAACA A~ATATTTGA ATAACCCATT 82680
TAACGGGACA AAATTGCCAG CCGAGCAATA TTCTTGGTTT A~AACCAATG GTGA~ACGCC 82740
GCTTGATATA A~AATTCAGC AATGTTTATT AGCTTATTTT TCCGATTTTC ACTGTATTTT 82800
GACCGCACTT CATCCGCACG A~AAAGGCTT TTTACAAAAA GGAATGAAAG TGGCAACCAT 82860
TGATCACAGT ATTTGGTTCC ATCGTCCGTT TGATTTAAAT CACTGGCATT TGCACGCAAT 82520
TGA~AGCAAT AATGCCTTTG GAGGTCGTGG TTTGGCCCAA GGGCAGATTT TCTCGCAAGA 82980
TGGTCAATTA ATCGCAACAA CACAACAAGA AGGCTTGATC C~LLLlAGCG AATAAGAGAG 83040
A~AAAATGAC CGCACTTATT ACACAATTTT GGCAACAAGT TGA~ACTGCG CTGA~AACAG 83100
CA~ATCCACA AGAAAAATGT CGTTTAGTCA ATGATCTCTA CGATAATCTT CTGCcAcA~A 83160
TTCAGTTGAT TA~ATTAGAA GATTTTCCCG AAATCGTGCC GCAAGATAAT ATTGCCGCTT 83220
TTCCTGA~AA ACCGCTCTTA GTTGCACCGA AAGATGTGCC A~AACGTTCT TTTGCCACAG 83280
AAGAAGGCTA TGCTGCCACA TTACACGCTA TCGCACATAT TGAGTTTAAT GCCATTAATT 83340
TAGGCTTAGA TGCGGCTTGG CGATTCGGGC GTAATGCACA AGAAGAACTT GGCGAAGGTT 83400
-77.5 1 -
SUBSTITUTE S} IEET ~RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/05320
TAG~L-ll-l~l GAAAGATTGG CTGCGTGTCG CTCGTGAAGA AAGCACGCAT TTTTCCTTAG 83460
TCAATGAACA TTTGAAAACA TTGGGTTATC AATATGGTGA TTTTGAAGCT CATGCTGGAT 83520
TATGGGAAAT GGCGCAAGCC ACTGCTCACG ATATTTGGGA ACGAATGGCG TTAGTTCCTC 83580
GTGTATTAGA AGCAAGAGGC CTCGATGCAA CAC~L~ll~-l GCAAGAGAAA ATCGCACAAC 83640
GTAAAGATTT TGCCGCAGTG AACATTTTGG ATATTATTTT GCGCGATGAA ATTGGCCATG 83700
TGTATATCGG CAATCATTGG TATCACGCCC TTTCTAAAAA ACGGGGTTTA GATGCGATGA 83760
AA~L~l-L-L-LAC AGAGCTGTTA CACAAATATC GTATTGTAAT TTTTAAAGGT GTCATTAATA 83820
CCGATGCTCG CATTCAAGCA GGTTTCACTC AGCATGAGTT GGATTGGATT TATGAAGTGG 83880
AACAAACATT AAAATCCTAT ATTAAGAAAT GATGA~AAAA TAAAGAGACT AAGTTCGATT 83940
GAATACCGAA CTTAGTCCTT TTAATGAAAG TGATTTAACG TTTGAATTTA TTGCTTACGC 84000
CAAGTTGTCC CATTCGGCCC AL~L-l-~LAAT ACGATGCCCA TAGCTGTCAA TTCATTACGT 84060
GCTGAATCTG CGGCAGACCA ATCTTTAGCA GTGCGGGCTT CGTTGCGTTG TTTGATGAGT 84120
GCCTCAATTT TTGCCACTTC ATCATCGTTA GAACCTGCTT GTAAGAATTT CTCTGGTTCT 84180
TGTTGAAGTA ATCCTAAAAT CGCCCCCAAT TCACGCAAAC GTGCAGCAAG TCCATTAGCT 84240
TTCTCAACAT ~-L 1'~''1'~'1'1-'1"1' TAACTTATTA ATTTCACGTG CCATTTCGAA TAAAACAGAA 84300
AGTGCATTTG GCGTATTAAA ATCATCATCC ATTGCTTCAC GGAAAGTTGC AACAAAATTT 84360
TCTCCGCCAA AAGCAACCGC ACTTTGATCT GTTCCGCGTA AAGCCGTGTA TAAACGTTCC 84420
AACGCACCTT GTgCTAAATT CAA~Llll~''l' TCGCTATAAT TGAGCTGGCT ACGATAATGT 84480
GCCGTTAATA AGAAATAACG CACCGCTTCT GCATTGTAGT GGTTTAATAC ATCACGAATT 84540
GTGAAGAAAT TGCCGAGGGA TTTCGACATT LLL-L~-L-LLAT CCACCATAAT CATGCCAGAA 84600
TGGATCCAAT AATTCACATA TTGGCCGCCA TGCGCACAGC AAGATTGTGC AATTTCATTT 84660
TCGTGGTGAG GGAACATTAA ATCAGAGCCA CCACCGTGAA TATCAAAATA TTCGCCAAGC 84720
TGTTTGCAGT TCATTGCAGA ACATTCAATA TGCCAACCCG GACGACCTGC CCCCCAAGGG 84780
GAAGCCCAAC TTG~L-LC~-ll LL~lllCGAC ALlL-LC~A~A GCACGAAATC CATTGGATTT 84840
TTCTTGATTT CATTGATTTC AATACGTGCG CCAGCTTGTA ATTGCTCAAG ATCTTGACGG 84900
GATAATTTGC CGTATTCTTT GAAGCTTTCT ACATCAAACA TCACGTCCCC ATTATCCGCA 84960
ACATAAGCAT GTCCGCGTTT AATTAATTTT TCCACAATTT CAATAATTTC TGGAATATGA 85020
TGCGTCGCAC GAGGTTCAAA ATCAGGGCGT AAGACATTAA GTGCATCAAA ATCTTTATAC 85080
-77.52-
SUB5 imJTE SHEET tRULE 2
-
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
ALllC~lGCA CCATGCGATC CACTAACTGA TCGCAGGTTT ~Lll~llllC TAACGCACGT 85140
TTAATAATTT TGTCATCTAC GTCCGTTATA TTACGCACAT AAGTTA~ATC GTAACCCAAA 85200
GAACGTA~AT AACGGGCAAT CACATCA~AA CACACA~AAG TGCGTCCATG GCCGATATGG 85260
CACA~ATCAT A~ACAGTGAC GCCGCA~ACA TACATTCCCA CTTTATTTTC GTGGATAGGT 85320
TTA~AGATTT ~'l''l"l''L'l'~'l'~'l' CGTTAAGGTA TTGA~AATTT TTAGCATTTT TAAGCTCGTA 85380
AAATGA~ATA A~AACA~ACC GCACTTTTAT AGCACTTTTA CCTCGATTGT GGAATAATAC 85440
AACCCTTAAT TTTTTAGAGG GA~AACA~AA TGGTTACATT ACACACA~AC TTTGGcGACA 85500
TTA~AATTAA ATTGGATTTT GATA~AGCTC CAGTTACAGC AGAAAACTTC TTA~ATTACT 85560
GCA~AGACGG TTTTTATAAT AACACAATTT TTCATCGTGT TATTGATGGC TTTATGATTC 85620
AAGGTGGCGG TATGGA~AGC GGTATGCGCG A~AAAGCAAC TAAAGCCCCA ATCCAAAATG 85680
AAGCGAACAA TCGTTTAAGT AACA~ACGTG GAACCATTGC AATGGCTCGC ACTTCAGATC 85740
CACATTCAGC GACAGCACAA LLlLl~ATTA ACGTGGCAGA CAATGATTTC TTA~ATTATC 85800
GTTCA~AAGA AATGTTTGGT CGCGAAGTCG TTCAAGAATG GGGCTATGCA GTATTTGGCG 85860
AA~LG~ll~A AGGTATGGAT GTTGTGGATA A~ATCA~AAA AGTGA~AACA GGCAACA~AG 85Q20
GCTTTCATCA AGAL~llC~A ACTGAAGATG TAGTGATTAC ATCGGTTTCT ATTGAGTAAC 85980
A~ATGAGCAT AAAACAACAT CGCCCTA~AG TTGGAGA~AT TCTAGAATGT GATTATGGTC 86040
AATTTTCGCA TACCTGTCAC GTTGATGGAC ATATTCCACC TGA~ATGGTT A~AAAACGTT 86100
TG~LL~Ll~l TTTGAATGCT AAACTGAATG GGCTTATTTT AGTTGCACCA ATTTCATCTA 86160
A~ATTAATTT AGATGGTATA A~AAATGGCT ATCATATTGA AATAGATTCA GAATTAATAA 86220
AAGCAACAGG CTTTTATGAT AAAAGGACTC GCTGGATTAA ATCTGAATTA ATTCAATCAG 86280
TAA~LC~L~-l CC~l~-l~-lAT CATATTTATG ATA~AGGAAC TA~AATTACT CAATATTTGC 86340
CAAGGGATGT TGTAACA~AA GTTCA~AGAG CTATCATAAA AGCAATCAAT GCAAGCTCAT 86400
TACTTGACAA GTAGATAGAA TACAGTATAG ACTTCCGAGC GTAACGCCTT AGAGCGATCA 86460
TCATCGA~AG ATGAGTTTTT A~ACGCCATT GAGCGATGAA TCCCCTGATT AGCGATAATT 86520
AGGGGATTTT TTATAGAATT TAGATA~AGA TATTTATGCA ~LL~L-LC~AC ACTCACACGC 86580
ATCTTAATTA TCTCCAACAA TTTACTGGGG AACCGTTGTC ACAGCTTATT GATAATGCTA 86640
AGCAAGCCGA TGTGCAAAAA ATACTGGTTG TGGCGGTGAA AGAAGCTGAT TTTA~AACAA 86700
TCCA~AATAT GACCGCACTT TTTCCTGATA ATTTGTGCTA TGGGCTTGGG CTCCATCCTC 86760
-77.s3-
SUBSTITUTE S}~EET tRULE ~6)
CA 022l874l l997-l0-2l
W O 96/33276 PCTnUS96/05320
TTTATATTCA AGAACACGCC GAAAATGATT TGAL-L~l~Ll AGAACAAGCC TTAAAAAATC 86820
GTGATACAAA TTGCACGGCA GTGGCAGAAA TTGGTTTGGA ACGCGCGATT CCCGATTTGC 86880
TCACCGATGA ACTTTGGGCA AAACAATGTC ALl-L-l-l-llGA AAGCCAACTT TATTTGGCAA 86940
AACAATTTAA TTTACCCGTC AATATTCACA GTCGA~AAAC CCATGATCAA ATTTTTACTT 87000
TTTTAAAACG TATTCCATTA TCTAAACTTG GCGTGGTACA TG~LL-L-L-L~A GGAAGTTACG 87060
ATCAAGCAAA ACG~-Lll~Ll GATTTAGGCT ATAAAATCGG AGTTGGCGGC ACTATCACTT 87120
ATGAACGAGC CAATAAAACT CGTCAAGCAA TCGCGAAGTT GCCGCTTGAT GCCTTAGTGT 87180
TGGAAACAGA CAGCCCAGAT ATGCCTGTAT TTG~Llll-A AGGCCAACCT AATCGACCAG 87240
AACGTATTGT GGAAAGTTTT AAAGCTCTTT GCACCTTAAG AAATGAACCT GCTGAATTGA 87300
TTAAAAAACT TACATGGGAA AATGCTTGCC AGALLLLLlC TTGATCCACG TCACATTACT 87360
GAAATTATTT TGAATTAAAT ACTAGAAAAA AGAAACTGGC ATAATAATAT CCGCCTCGTA 87420
GA~AGTTTTT CTCAACACAC AATAAGGATA TATTATGTCG CAAATCTATA CTCAGGTGAG 87480
AAAGTTAGCG GAACAGTTTA TTGAGCCTTA CGCCGACGAA CTCGATCAAA AAAAGAGGCA 87540
TTTAAGGAAT TAGGTAAAGC TGGTTGGTTT TCACTTTTAA TTCCAAAAGA ATACGGCAGA 87600
ATGGGATTAA CCCTAAAAGA ACACGCTGAA ~L~L~LATGG CATTAGCTGA AAGTTCAGCC 87660
TCTGCTGGTC TCTGTTATAT GATGAGTAAC GTTGCAGTGA AL-l-~LL-lAAA TCTATTCGGC 87720
AGCTATCAAC TCAAACAAAA AA~L~-ll--LL~L GACATTGTTC A~AATAAAAC CTTTGCCGCA 87780
CTCGCCTATA GTGAATTAGG CACGGGTACT CACTTCTATT CGA~Ll--L-LlA CATCAACATG 87840
GCTTGGAATT TGGTCAAGAT TATGTAGAAA AACGCTTTGA TGTGGGTGTT GGTTTGCACG 87900
GTGATCATGT AGGCGGTGAA TTAAATTCAG CCAATGCATT CACCGAAACC Ll~l-l~AAAA 87960
TGGATTACAA CAATCCAGAA CATAAAGAAA TGATGGATTT GGAAGGATTA A~ACGTTGGA 88020
TTGCGCGCAG AAAAAGCCTT AAATTACCTT CCACCAGAGC AAATATCAAA ATTTCAGACA 88080
AAAAATTGCC CCATTAAGGG GCAATCTTAT CAAL~-ll~lA AAGTTACTTA TAGCTTTAAA 88140
CAACGATTAA ATATGTTGGT TAATGAAGTT AGCCAATTGA ~-L-L-L-l--lG~lA ATGCACCAAC 88200
TTGAGTTGCA ACAACTTGAC CATTTTTAAT CAATAATAAT GTTGGGATAC TACGAACACC 88260
AAATTGTGCT GGCGTTGCTT GGTTATCATC CACATTCATT TTCACGATTT TAACTTTACC 88320
TGCAAATTCA GGTGCAAGTT CATCTAACAC TGGTGCAATC ATTTTGCAAG GACCACACCA 88380
AGGTGCCCAA AAGTCTAATA AAATGGGGAT ATCTGAATTA ACTACAACAC TTTCAAAATC 88440
-77 . s4-
SUBSTITUTE S}~EET (RULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/OS320
TGCGTCATTA ATGTGTAATA CTTCGCTCAT 1"1--1~L111~C TTA1-1-1-1~-1G AATGGAATCC 88500
CTATATAAGG G~1-1-L1-1-11A AACTTACAAG TGCGGTGCAG AATAACACCG TTTTA~AAAA 88560
TGTA~ACTAA ~1C~-1111AAT TGCCGA~AAC TAAGACGGCA A~ACAATATT TTCACACACT 88620
TTACCCGATT TCAATTTATA AA1~111~AT A~AGTCACGT CTGCAATATT GGTTAGTGCT 88680
TCTTCGGTTA A~AACGCTTG GTGACCTGTT AGCAATACAT TATGGCAAGA AGATAAACGG 88740
CGGA~AATAT CATCTTGAAT CA~-1-1C~1~L~A GACTTATCTT CA~AGAATAA ATCACGCTCA 88800
11~1C~1AAA CATCCATACC TAACGCACCG ATTTTACGCT GTTTTAACGC ATCAATCGCA 88860
GCTTGAGTAT CAATCA~AGA ACCGCGACTC GTATTAACGA TCATCACGCC AL~lll~ATT 88920
TTTGCAAAAG CCTCGCAATT TAATA~ATGA TA~1111~1G GCGTTGCTGG GCAATGAAGC 88980
GTAATCACAT GAGATTTAGC ATA~AGTTCA TCTAATTCAA CATATTGTCC CCCCAGTTCT 89040
TCTACTACTG GA1111-L~AA AGGATCGTAC GCCAAGATAT TCATGCCA~A ACCTTTCA~A 89100
ATTCGCATCA CTGCGATCCC GATTTTTCCT GTTCCGATTA CGCCGACTGT GCGTCCGTAC 89160
ATATTGA~AC CAATTAACCC CTCAAGAGAG A~ATTCGCTT CTCGGGTACG CTGATAAGCA 89220
CGATGAATTC GACG~-11~AG AGTCATCATC A~ACCGATGG TA1~11CCGC CACCGCTTCA 89280
GGCGAATAAG CTGGAACGCG GACAACTTGG ATGCCTAATT CTTGAGCTGC TTTTAAATCA 89340
ACATTATTGA AACCGGCACA GCGCAAAGCC ACAATTTTCA CACCAAGTGC GGCTAATTTT 89400
TCTAATACTT TTCGGCTACC ATTATCATTC ACGA~AATGC ATACTACTTC GCAATGTTCT 89460
GCCA~ACGCA CAGTGCTCTC GTTCAACATA A~ATCA~AAA ATTCTA~ATC GA~ATTATAT 89520
TTCGCGTTAA TGAGCTCAAT ATA1-L-1--L~-1-~ TCATAACTTT TAGTGCTATA GATTGCAATT 89580
TTCATGGTTT GCTCCAATTA TTTTAAGTTT GCAAAAGCTT GTAATAAGTC CGCTTTAATA 83640
~L~-L-L~-1-ACAT CTTCAATACC GACTGA~AAA CGCAACAAGG TATTAGTAAT CCCACGAGCT 89700
ACACGCTCGG ATTCTGGAAT ATCCATATGA GTTTGAGTGG CAGGATAAGT AATA~AACTT 89760
TCTGTGCCGC CTAGACTTTC TGCA~AAGTA ATCAATTTGA TGGATTTTAA A~ATGTATTA 89820
ACCCAAGCTT CATCTTGCAA ACGGA~AGAC AACATCCCAC CTTTATTCGG ATAAAGCACC 89880
GATTCCACTT GTGGTTGAGC TTTTA~AAAT TCCGCAATAG CTTGTGCATT TTCTTGATGG 89940
C~-LL-L~ATAC GCAAAGAAAG G~-L~1L~ATA CCACGAATAG TCAGCCaAGA ATCA~AAGGA 90000
GA~AGCACCG CCCCTGCACC ATTTTGAATA TAAGCAATGC GATCACAAAG TTCTTGCCCT 90060
TTCGCAACAA TTAAACCAAC AAGTGCATCA TTATGCCCAG CAATATATTT AGTTCCGCTG 90120
-77.55-
SUBS 1 1 1 UTE S~E~T tRULE 2~i3
CA 022l874l l997-l0-2l
W 096/33276 ' PCTrUS9610S320
TGAATTACCA CATCCGCACC TA~ATCTAAT GGACGAGAAA GCACAGGCGT TAAAAACGTA 90180
TTATCCACGA TCAACATTAA GTTATGTTTT TTCGCAAGTT TTGCAATTTC AACCACATCA 90240
CAll~llC~A TTAAAGGATT CGATGGGGTT TCAATA~AAA TCG~lllC~l ATTTGGGTTA 90300
ATGGCAGCCT CAATTGCTGA AGCAGATGCT GTATTAACAT A~ACAGGTTT TACACTATTG 90360
TTATTTTTAT AAGAAAAATC TAATAATCGA TAAGTACCAC CATACACATC GCTAGAAACA 90420
ATCCATTCAT CTGGGGCGGT AAAAAGCGTC ATCAAAACTT GAATTGCAGC CATACCAGAA 90480
GAAAACGCAA AACCACGATC TCCATTCTCT AATTTAGCTA TC~lll~llC TAATACTGTG 90540
CGAGTTGGAT TTTTGGTACG TGTGTAATCA AATCCCGTAC TTTCACCGAT ACCACAATGA 90600
CCATAAGCCG TAGAAAGAAA AATTGGTGCA GAAACCGCGC CCGTACGCTC ATCACTGCGA 90660
TTGCCTGCTT GAGCTAATAA AGTATCGATA GCATATTGTT GTGTCATAAC ATCCTCTAAA 90720
AATAATGAAA AAATTGACCG CACTTTACGT GTTAAAAAAC GTTTAGCATT TTGGCACAAA 90780
GGA~AAAGTG ATAAAAGTAG AAATTAGA~A ATTACATA~A ATTTCATTTT TCCATCATTT 90840
~l~l~l~ATTT ATTTGAACAA AATGAACTTT TTTTAAACGG TTAGACAATT TTTTTAAATC 90900
TGTAATTGAC AGTTATCTGA ATTTCCGTAA AATGCGCACC AATAACAGCG AATGCGGGAA 90960
TAGCTCAGTT GGTAGAGCAC GACCTTGCCA AGGTCGGGGT CGCGAGTTCG AGCCTCGTTT 91020
CCCGCTCCAA TTCGTGGCGT GTTAGCA~AG CGGTTATGCA CTGGATTGCA AATCCATGTA 91080
GCTCGGTTCG ACTCCGGGAC ACGCCTCCAT AATACGCA~A TGTTAGTTGT CTATATGCCC 91140
GAGTGGTGGA ATCGGTAGAC ACAAGGGATT TAAAATCCCT CGCCTTTCGA GGCGTGCCAG 91200
TTCAAGTCTG GCTTCGGGCA CCATTTAAAC ACCAATCCAA AGATTTTAAA ATTTACTTTA 91260
AAATCATCTA ATTGGGTCGT TAGCTCAGTC GGTAGAGCAG CGGACTTTTA ATCCGTTGGT 91320
CGAAGGTTCG AATCCTTCAC GACCCACCAC TTAAAAATAA AGTAAGCACC GAAAGGTGTT 91380
TTTTTATTGC CTAAATCTGA TACTACTTTT TA~ATTACTT GCTTATTGAA A~ATAGCTAT 91440
TCTCTCCATC CAATCTAAAA TAATTAATAT ATTTTATCGC TACGTTATAC TTTCTAAATA 91500
AAATAGCACC TGAAAATCAG ATGCTATCCA AAACACAATA AAAATTTACC GCACTTTATG 91560
ACTTCAATAA GTAAGCCCGT AGTTGTGCAA AATCATTATC CATTTCATCT GA~AGCAATG 91620
GTAGCTGATT ATGTTTATCC A~l~lll-AG GTAATGGAAG CTGAATACCA AGAATACGTT 91680
CTACGGATTC TTTAAATTTC GCAGGATGCG CCGTACACAG GAAGATTCCT GTTTCACTCG 91740
CTTTAAGTTG A~l~lll~AAC ACCTGATAAG CTATCGCACC GTGAGGTTCA CATAAATAAC 91800
-77.s6-
SUBSTTTUTE SHEET tRULE 26)
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
CTTTCGACTG CATCGCTTTT AAGGTATCTT ~''1'~1''1"1'CGCT ATCACTTAGC ATCCCCGAAC 91860
CTAAATCAGT TAAATCCCAA CCA'1"1"1'C~'1"1' TAAACAATTC CTCCACTCTT GGCCAATTAT 91920
TTGGGCGACT TACATCCATT GCATTAGA~A GGGTTGCAAC TGTCGTTTTA GGATCCCAAT 91980
TACCCGATTT CAAATAACGT GGCACAGTAT CATTTGCGTT TGTTGAGGCG ACA~AGCGTT 92040
TTATTGGCAA GCCTAAGGTT TTTGCAATTA ATCCCGCAGT TAAGTTACCA AAATTACCAC 92100
TTGGCACAGA AACCACGACA TTATCACGTT '111~1-11LGG CAATTGTGCG ACAGCTTCAA 92160
AGTAATAACA AACTTGAGCT AATA~ACGGC TGATATTAAT AGAATTTGCA GAGTTAAGCC 92220
CGATAGCTTG GCGCAATTCA ACATCATCAA AGGCTTGCTT AACCAAAGCC TGACACGCAT 9 2280
CGA~ATCAGC GTTAATCGCA ACAGTACGAA TATTCCCACC TAAAGTACAG AACAGCTTTT 9 2340
CTTGCAATGG GCTGATTTTG CCTTTTGGAT A~AGGATAAC TACATTAATA '1"1"1"1'~'1'AATC 92400
CATAAAACGC ATGTGCTACA GCGGCTCCAG TATCGCCAGA CGTAGCCGTT A~AATAGTAA 92460
TTTTGCCATC GCCACGTACC GCAGCAAGTG CCTGTGCCAT A~AACGCCCA CCA~AATCTT 92520
TAAATGCTAG CGTTGGACCG TGA~ATAATT CAAGTGCATA AATATTTTCT TCCACTTTTT 9 2580
CTAACGGTGC AGGAAAAGTG AATGCATTTT TCACCATCGC ATCTAACGTT GCTTGTGGTA 92640
ACTCGCCATC AATTAATGCA CCTAGAATTT TTTGACTACG CTCAACAAGA GGCAATTCAA 92700
GTAATTCATT AATGTTATTA AGTTGAGGAA TAACTTCTGG A~AGAATAGA CCTTGATCCC 92760
GCCCAAGACC TTGACGAACA GCCTGAGA~A AAGTGACTTG L L~l L~LGGG 'L~LLL~ATAT 92820
TGTATAAATT CATATTTAAT CC~'L'L'1"L'LAA TCTGATTTCA TCTATTTAAA TTAACTTATT 92880
TAA'1''1''L~'1'~"1' TGTGCCTTCG TTATCAACTT TACATACATG CACA~AACCT TCATTATTTT 92940
GTA~ATAATG G~'L'L'1'~'1'AAA TAACTTGA~A GTTTAATTGC A~'1"1''1'~'1'AAA TCAGGGGCAA 93000
TAGAGA~AAT AGTTGGCCCT GAGCCTGA~A TAC~L~LGGC AAGTGCGCCT AA~L~lC~AG 93060
TAG~'L'L~'1''L'L TACTTCAGCA AAATTAGGTA ACAGAGATTC ACGATAAGGC TCGGCAATGA 93120
CA'1'~'L'L'L~AT CATAATCGCG GCAAGATTTT CCTGATGGGT ATGGCAAGCA TGCACAAAGC 93180
CACCTAAATG ACGACCATGG GCAATCACGT '1LL~LCGAGT ATAGCTTTTC GGTA~AATTG 9 3240
CTCGAGCTTC AGCAGTAGAA ACTTCAATTC CCGGATAGGC TAACACCCAA TACCAATTAT 93300
CA~AAAATGG CAATTTTTGA CAAATATTGC CGAGCGATTG CACCATA~AT TGCACACCGC 9 3360
CAAGATAGCA AGGTGCGACG TTATCATAAT GGATTGAACC AGAAATACGA CCTTCCAATT 93420
CTCCCATCAT TTCAAGCAAT TCCATTTTCG A~AAAGGTTC ATTATGA~AC TGATTTAATG 93480
-77.57-
SU8STITUTE 5t{~:ET tRULE 2~3
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/05320
CCACTAATGC AGCAACAATA GAACAAGCAC TAGAGCCTAA ACCAGAGCCA ATAGGCATAT 93540
llllll~GAG CGTTAAACGT AAAGGTTTAA CATTTGCTCC GCGTAATTTT AATTGCTCGC 93600
TAAATAGCAC ATAAGCTTGG TAAACAATAT llllllGCGG ~ll~l~llCGGT AATTTACGAA 93660
CAAAATAGCC CGCACTTTCT AACTCAAAAC CAGTTGAAAT AGATTCTATT TGAACCACAT 93720
CGCCTAACAA AGAACCATCA ATAGGAGAGA TCGCAGCACC TAAAGTATCG AAACCTACGC 93780
TAATATTCGC GCTAGATGCA GGGGCGTAAA TTCTTAACAT TGGGAATCCT TATTAATGTT 93840
GTAATGTTCT TA~AATATCT GCAAAGATAC CTGCCGCAGT AACTGCATTA CCTGCGCCAT 93900
AACCACGTAA TAAAAGTGGA ATCGGCTGAT AATAGCGAGT GTAAAATGCC AAGGCATTTT 93960
CACCATCTTT CACTTTATAA AGTGGATTAT TCAGATCTAC CGCAACGATG GATACTTTGC 94020
ATTTTCCTTC ACTAATTTTT CCAACATAAC GCAATACTTT GC~ll~lGCT TTAGCTGTGG 94080
CAACGCGAGT TTTAAATTCT TCATCAAGCT GAGGCAACAT TGCCATAAAC TCATCTGCAG 94140
ATTTTCCATC GGAGAAGCCT TTTGGCAATA CACCTTCAAC TTCAACATCT GAAAGTTCAA 94200
GTTCAATTCC CGCTTCACGA GCAAGAATTA ATAATTTGCG TGCTACATCT TGTCCAGAAA 94260
GATCATCTCG AGGATCTGGC TCAGTAAAGC ~~ CACG CGCAAGTGCG GTTACTTCTG 94320
AAAGAGAAAG TCCTTCTTCC AACTTACCAA AAATAAAGGA AAGCGAGCCA GATAAAATCC 94380
CTTCAAAATA TTCAAGCTCA TCACCTGCTG CAAGTAAGTT TTGGAGATTT TCAATAACTG 94440
GCAAGCCCGC ACCTACATTG GTTTCATATA AAAATTTATG CTGGCTTGCT TGGGCATTTT 94500
GGCGTAACTC ATTGTAATAA ACTAATTCTC GTGTATTCGC llllll~lll GGCGTAACCA 94560
CATGGAAACC ~Ll~llllAAC GCACGAGCAT AAAGCCCTGC TACAGATTCG GCTGAAGTAC 94620
AATCTACAAA TACTGGATTC ACCACATGAT GTAATTTAAT GAAAGAAAGC AATACATCAA 94680
AATCTGATGG CTGAGTCGCA llLl~lAAAT C~lllllCCA ATCCTCTAAA TTTAATCCAT 94740
TTTCATCAAG CAACATACGG TTGGAATTCG CAATAGCACA AACTCGAATT TCAACATTCT 94800
TCTTTGCTAG ATACTCCTTT TGACGCTTTA CCTGCTCAAT TAAll~lCCG CCTACTCCAC 94860
CAACGCCCAC TAAAAACATA TCCACGACTT TTTTATTATT GAAAAGCGCC TGATGGGTAG 94920
CCTTCACCGC TTCAATGGCT TTATTTTGCG GCACAACCGC AGAAATTGAA CGTTCGCTAG 94980
ATCCTTGTGC AATCGCCACA ATGCTAATGT TTGCCTGCGC TAATGCCGAG AAGAAACGAG 95040
CAGCAATGCC TTTCGCTTGC TTCATTCCAT CGCCCACAAC AGAAATAATG GATAAGTCTT 95100
TAATCACTTC AATTGGTTCT AATTGATGTT CATTTAATTC ATTAGCAAAC TCC~111~1A 95160
-77.s8-
SUBST~UTE SHEET tRULE ~)
-
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
GTACGGTTTT CGCTACTTCT GCAGATTTCA CAGGCACACA GA~ACTAATA CTATATTCAG 95220
ACGAAGACTG AGTAATTAaA ATAACTGA~A TGCCTGCGCC TGACATGGCT GAAAATACGC 95280
GAGATGCCAT GCCTACCATA CCTTGCATAC CAGGGCCTGA CACATTAAAC ATCGCCAaAT 95340
TGTCTAAGTT AGTGATACCT TTAACTTGCA AA~111~1~A TTTCACATTG CCATCAATAA 95400
TCGAACCTGG TGCAGAAGGA TTTCCTGTAT TTTTAATGAC ACAAGGAATA 1111~1GGCA 95460
ACAATGGCCC AATCGTACGA GGATGAATCA CTTTCGCACC GA~ATAAGAG AGTTCCATCG 95520
CTTCACGATA AGAAAGCGTT GGTAATA~AC GTGCATCAGG CACTA~ACGC GGATCGCAAG 9 5580
TATA~ACGCC GTCCACATCG GTCCAAATTT CGCATACACT TGCGCCTA~A CAAGCGGCTA 9~ 640
AACAGGCGGC AGAATAGTCT GAGCCATTAC GACCGAGCAA TACCAACTCG C~ L 1 1 1 L ~AT 9 5700
TACCCGCAGT AAAACCTGCC ATCAGCACCA CTTTATCTTT TGCGATATTT GCTGCATCAA 9 5760
CAC~1-L-1L~1- TGA1-L~LL~A ATTTCAACAG AAGATTCAAG ATAACCGCCT TTTGCCAATA 95820
A11~L-1L~AC AGGATCCACA ATATGTACGC TATAGCCACG CGCTTCA~AC CAAGCTTTCA 9 5880
TCATTGCAAT AGAAAGTTTT TCCCCACGGC AATCAATGGT CGCTTTAACT GCAL~ll~lA 95940
CTTTTCCTGC CTGACGGATT L~L1~1AATA ATCCTTTAAT TTGAACA~AT TCAGCATCAA 9 6000
TAAGTGCTTT GGTACCATTT AAGTCGAATT GATTATTTTC CGTATGTAAG CCGTTGATGA 9 6060
TGTTATAGAA AATTTCGATT G~-L-1C~-11~A AATGCGTATC GGTTGATTGA TTTAATGCTG 96120
~LL-L-1L~'AGA AAGGGCGACG AGATGGTTGG TTATTTTGGC TGGTGCAGAT A~AACACCTG 9 6180
CAGCCTGCTC TTCTAAATGA GCTTGCTCGA TCAATTTCGC CGCTTGGGAA A~ACGTTCCG 96240
GATTTGCAAG CGAAGTGCCG CCAAATTTAA GTACGCGCAT AA11G~L-L~-L CCTAGATATT 96300
~1~1-1111-AA ATTTATA~AA AAACCCGCTA TTCAGTTGAA TCGCGGGTTT TCTGTATCTT 96360
~11-1L-LQCTG CACTAACCCG CACCATTAAT CATAATAATG GTCATCATAA TGGCGGTAAT 96420
CGTGCTAATG ATTACGGATA AAGTGCGGTT A1LL1L~ATT ~L~-LLL1ATC TTGAAAAATG 96480
AATGCGTAAA GAAATACCGA AATTTCCCGA G~L-L~-L~A~A CAGA~AGTGA CAAATTTTTC 96540
AGAAATTTTC TTAGTCAATA AATTTCGTGT A~ACTAACCG CA~LLLLLLA TA~AGGAAAA 96600
CCTATGAATA TCCAGCATAA TCTCAACCTA ATTCAGCAAA A~ATTGA~AC GGCTTGTA~A 9 6660
GAAGAAAATC GCAATCAAAA TACCGTA~AA TTACTTGCCG TATCTAAGAC CA~ACCTATT 96720
TCTGCTATTC TTTCGGCTTA TCAAGCGGGA CA~ACGGCTT TTGGGGA~AA TTACGTGCAA 96780
GAGGGGGTAG AAAAGATCCA ATATTTTGAA TCGCAAGGAA TTAACCTTGA ATGGCATTTT 9 6840
-77.59-
SUBSTITUTE ~HEET (RULE 2~;)
CA 02218741 1997-10-21
W 096/33276 PCT~uS96/05320
ATCGGCCCAT TACAATCGAA TAAAACCCGT ~LC~llGCAG AACATTTTGA TTGGATGCAA 96900
ACGCTTGATC GAGCA~AAAT TGCAGATCGT TTA~ATGAAC AACGACCGAC CAACAAGGCT 96960
CCATTGAATG TATTGATTCA GATTAATATC AGCGATGAAG A~AGTA~ATC AGGTATTCAA 97020
CCTGAGGAAA TGCTAACACT AGCAAAACAC ATCGAAAATT TACCGCACTT ATGCCTACGT 97080
GGCTTAATGG CAATACCCGC ACCAACCGAC AACATCGCAG AACAAGAAAA TGCATTTAGA 97140
AAGATGTTGG AG~l~lllGA ACAACTTA~A CAAGTCTTAC CCAATCAACA AATTGATACA 97200
~lll~lATGG GAATGACGGA TGATATGCCG AGCGCAATAA AATGCGGTTC TACAATGGTA 97260
CGCATTGGCA CTGCGATTTT TGGTGCGAGA AATTATTCAA CATCACAAAA TAAATAATCA 97320
TGGAATAAGG CCCGAATTTA AAACAAGCCT TA~ ~llAA TGA~ATTTAA ATGCCAGTAC 97380
TCTCGCCACA TTTTGAGCGG TAGA~ATTAA A~LLLL~llCG C~lL~lLlGA GAATATCCGA 97440
TAAATCGCCA AGTTGGTGAA TAATAGGGAA CACCGCATCA ATACCGTGAT CAAACACCAC 97500
ATCATAATCT TCACGCAAAC ACCCTGCGAT GGCGATCACT GGCTTATTGA A~L~llllGC 97560
CGTACGTGCC ACACCAATTG GCGTTTTACC CATAATACTT TGTGCATCTA TTCGCCCTTC 97620
ACCCGTAATC ACTACATCAG CAL~llllAC ATAGTCAATT A~ATGTAACC GGTCTAACAC 97680
AATTTGTATG CCTGCTTTCA GTTGTACGCT TGGTAATAAT AGCAAGCCAC CACCCATACC 97740
ACCAGCAGCA CCTGCGCCAG CCTGATCACG AAlLL~lllA CCGCAATCGC GTTCGGCAAT 97800
TTCAGCAAAA TGCGA~AGTG CAGCATCAAG Ll~Lll~ACC ATTTCAGGCG TTGCGCCTTT 97860
TTGTGGTCCA AAAATGGCAG ATGCACCACA TTCACCACAG AGCGGATTAT TCACATCGCA 97920
CGCTACTTCA ATGTGAACTT GTTGCAAACG TGGATCTAAT TGTTGAACGT CAATCTTCAC 97980
AATATTTGCT AGCTCTGCTC CACCAAAACC GATAGGCTTA TCTTGCGAAT CTAAACATTG 98040
CATCCCTAGT GCTTGCAACA TTCCTACACC ACCATCGTTG GTTGCGCTAC CGCCAATGCC 98100
AAGAATGA~A ~L~l~lACGC CTAAATCTAA TGCCAGTTTA ATCAACTCCC CTGTGCCGTA 98160
ACTGGTGGTA AGCAAGGGAT TGCGTTTTTC AGGCGGAACA AGATGTAAAC CAGAAGCTGC 98220
TGCCATTTCG ATAATCGCGG TTTTTCCATC TCCCGATA~A CCGAAGAAAC TTTTCACTTT 98280
GTCACCCA~A GGCGCGGTGA CTTCACATTC AATGAGCTTG CCTTGCGTGG CATCCACAAG 98340
GGATTGAACT GTACCTTCGC CCCCATCTGC CATTGGCAAT TTTACATAGT CCGCATCGGG 98400
GAATACACGT TTGAAGCCTG TTTCAATGGC GGTAGCGACT TCAAGTGCGG TCAAACTTTC 98460
TTTAAAAGAA TCAGGTGCAA TCACA~ATTT CATAACAACT CCTAGAATTT AAATACGCCA 98520
-77.60-
SU8ST~TUTE S~i~ET tRULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
A~AATTAAGG TAGA~ACGAT GGTCATCATC AaACCGACCG CACTTTCATA AGGAATAAGT 9 8580
TTTA~ACGTT CTTTGATATC CATATTCACA CTACCGCCTG TGGCATGGAA GA~AGAACCA 9 8640
TGTGGCATAT GATCA~ATAC GGTCGCCCCT GCATGAATCA TTGCTGCACC AGCAAGACTG 9 8700
CTAACTCCAA GTTCTAACAA GGTACTACTG AACACATTGG ATGCCACCGC AGTACCTGCC 98760
GTGGTAGAAG CTGTCGCTAA AGACATCAAC ACCCCTGA~A TTGGTGCAAG AATGTATGAT 9 8820
GGCA~ACCTG AATGTTCCAA ACCTTGAATC AATACTTCTT TTA~ACCAGA ATTAGCAATG 9 8880
ATGCCAGCAA GCGCGCCTGT ACCAAGTAAC ATAATTGCCA CGG~'1~'L~AT TTTACTCAAT 98940
CCATTGATAG CATAACTATT TATATTGCGA AGTTTGCCCA TACA~AACGC ACCAATCA~A 99000
CCACCTAACG GCAATGCAAT TAATGGATCA ACTTTAATAT CAAACAATGG ACGAAGTGCC 99060
AATAGCAAAA TTGCCACTAA AGGTGCGACA AGTGCGGTCA GA~ATGAAGG TA~ATTTTGC 99120
GTTTCAAGCA CGATTACCTC 'LL-L~-L~AGTC ACTTTAGAAC ~L-L-1~-L-L~AT TAAGCGTTTT 99180GCTAAGAAGT AGGTGAGAAT CA~ACCA~AT AGCGCGGGAA TTATACCAGC CATCATCACG 99240
GAAGTGAGTG GCA~ATGA~A AGTATCTGCT GCCGCAATGG CATTTGGGTT TGGCGACATA 99 300
ATATTACCAG CTTTACCACC GCCAATCATG GCGAGCA~AA TTGCAGCTTT CGATA~ATCG 99360
CTGCGACGCG ATAACGCTAA AGCAATTGGT GA~ACAGTAA TCACTGCCAC ATCCACGAAC 99420
ACACCCACCG CAGTTA~AAT CATCGTCGCT AGTGCCAAGG CGAGTA~AGC TCGAGTTTCA 99480
CCCAATTTAT TAGTAATGGT TTCCGTGATG GAATTTGCTG CACCCGATTC AATCAGCACA 99540
CCGGCCAACA CACCAGCAGC TAAGATACGC ATAACCGCAG TAGTAATACC CTGTGCGCCA 99600
CCGATCATTA GGCTCACTGT TTGCGATA~A TCCGCACCAC CAATTAAGCC TCCAACCA~A 99660
GCTCCCACTA ACATACCATA AGCTGGTGAG A~'L'1-1"1-'L-L~A A~ATGAGGAA GATAGCAACG 99 720
ATTAACGCCA CCAACGCACC TATTGCTGAG A~-1~'L-L~-L~'A 'L-LL-1-L-L~-1~'L CCTATAAAAA 99780
TTA~AACCAA GGAGATTATT ~1~1-~-1--1-11'AT AGGGGA~ATG CTTTATTAGA GCAAACA~AA 99 840
AGTGCGGTTA A~AATCATCA AA~-L-1'L~'LAA AGTTATACAA CCTCAATGTT CTAACAACGT 99900
TCCGAGATAG AGCGTTAATT TATCATCTAT CTTATTGA~A AATAAGCCAG TTATTTGCTC 99960
TA1--L'L-1~-1--LC AATCGATAAC GCA~AGTATT CGGGTGAACA AATAATTTTT CCGCAGTGAG 1000 20
ATA~AGATCA CAATTTGATA A~AAATATTG TTGAAGGGTT TTATAAAGTA TCGCATTTYC 1000 80
TTCTGAGA~A nGGGGAGA~A GGGGTTTTAT CAATTCGTTC CCTTGCCAAG AATGGGATAA 100140
TCCAGCAAGT AACACAGGCA ATCGATGCTC ATCAAACACA TA~ATACCTT TGCGTGGATG 100 200
-77.61-
SUBSTITUTE ~i~tEE~ (RULE 2~;)
- =
CA 02218741 l997-l0-2l
W 096/33276 PCTrUS96/05320
A~l~Ll-l-lAAT CCATAAGAAA GCGTGCTTTG CGCACTTTGA AAAGACAAGG GAAGCTGCTC 100260
AAAAAGCGGT AGATTTAGAC AAGCGCCTAC AGCAATTTTA TAAL~-Ll~l--l TTGAATAATC 100320
TGCAGGTAAA AGC~-LlllCA TTTGAGCAGA AAGTACGGTG GAGTTTTGCC A.~GTCTTTAA 100380
GACCACAACC TGATCAAGGG ACA~AATTGC CACATCCTGT GCA~ATTCAG ACTGTTCCAA 100440
ATAATTGATC AGA~LL~l~-lA AATTATCCAG GGCTGGATTA AGTAACTTAA TCAATACAAC 100500
CACACGAGAT TTATTTAAAT CAAAAGAAAA AAATTTCGCC TG~-L~ll-C-'A L~-l~l-llCCA 100560
ATTCAAATTG CAATGTAATA ATTGTAAAAT AAALl~ll~l TTGTAACGAC GATGCCAGCT 100620
'Ll~ll~-llCG AGTAAAGCCT ~Ll~ll~CCAC AATAAGTTCT GCCGTCATTT TCACTAGTTC 100680
GGCATATTGT TTCACCTGAG TTGGCTCACC AGAAATCCCC ACCACTCCAA TATTTTTGCC 100740
TAAATAATGA ATCGGTAAAT TAATCCCTGG TTGTGCTTCA AAATTCCATT TTTGTGCCAA 100800
CGCTTGATCA ATCTCTACCA CACGATTTTC CCGCAACGCC AACACCGCTC ~L~-l~l-GCCG 100860
TTGATTCAAA CGCGTTGAAT TTCCCGACGC AATGATCACA CCGTCGTGAT CCATTACATT 100920
TACAGAGTGA TGAATGATCT TCATTGCACG TTTAACAATT TTTTTGGCAG TGTATTTGTC 100980
AAGTTGCATA TTTGTAATAA AGAAGATAAA TGAAGATAAA ATATTGAGAA AAAGAAAGTT 101040
AGTCAAATAT L~ll-l-lATCT GCAAGAAAAG ACGGGAGACT ATTCTCCCGC ACTGCGTTTT 101100
TATCGCTATA AL~ll-l-lATT CTGAACTTGA ACATATCCCA TAATTAATGC CAAAATACCT 101160
AGTGGAAAAA TGAGATCTAT TACAGAACCA TCATTTCCCC AAATCAAGAA TAGCTTTGAT 101220
GAAAATAATT AAAATCGGTA AGACAATAGG AATACTCACG ACATAGCCCG TAATGGCTAA 101280
TGCCCATTCT TC~-L 1111~1 TACCTAGAAA TTTGATAAAG CTGAACGCCA ~Lllll-l~AGC 101340
AACTGGGCAG ATTGAAGTTT CACCATGTAA AG~ll~lC'~A ATAATGCTAC TTACAAAGGA 101400
AGAAGTCGCT TTATTTGGTT TTCCTGGACG GATACA~ATT GTGGGCAGGC GAAGACAGAG 101460
ACCATCAACA AAAC~-L-l-lLC TTGTATAGTC ATTAATAAGT AATTCACTCA TTG~Lll-l--lG 101520
TGCACCATAA GTCGATTGTG GCGTTACAGC AGTAGAATCC TGAATAATTT CTGGTAAATC 101580
ACCACCAAAT ACAGCAAGTG AACTAGA~AA ATAAAACGAA TTTTAGTATC AGATTCATCA 101640
AAATATGGGA AAGTGGCGAC ATTCCATATT TGTCCACTAA CA~ATTTTGA TCACATAATT 101700
TGCGACAAAA AL~-l-l-~-L-LGA ATCTGCACAG AATGGCATTA GAGAATTA~A TATTAATTTA 101760
ACTATCGTAT AAATAAATTA ATATA~ATGA TCTGCACCCC AAAACTA~AC AAATAAGCTT 101820
r ACTCATTAAG GTGCAAATCA AAGTGCGGTT CATTTTTATA TTATTTTTGG CTACATACAG 101880
-77~62-
SUBS i 11 UTE S~ET tRULE 2~)
CA 022l874l l997-l0-2l
W 096133276 PCTAUS96/05320
CAATAAAATG TAATTTATGT TCAGGATCAT TA~AGGTTTT GAACATTCTT TTA~ATTGCT 101940
CACGATTTTC CGCTTTCATC GCATTACGGA TGATTTTTAA CGTACCGaAA ATTCCTTCAT 102000
CATA~ATCAT TC~llllGGG GA~AGTAATG TCATCTCACC AGAGA~AGTA TCAACATTTC 102060
TA~AACCACT TTCTTGGAAT ATGCCTTTCC ATCCATCTTT CGTTAATGGC GTGACAGTCA 102120
CGTTAATCGC TTTGCGCATA lllL~lAGAA TAGTTTGATG ATCATTCCCC ACCAGCATAA 102180
CATCGTGAGT AAGCAATAAA CCATTGGGTT TTAACACTCG A~AATATTCT GCAATGGCTT 102240
l-l-l-L~-l-lCGC TTCCACGGGT AACATTGTGA GCATCGCTTC ATTGATGACA ATATCAAAAC 102300
TTTCATCCTC GA~AGGCAAC TTCATCGCAT TCGCACGCTG TACATGAATT TTTTCCTGCA 102360
AGCCATTTGC TTCAATATTT GCTTGTGCTT TTGCTAACGC ATTTTCATCT AAATCAACAC 102420
CTTCAATATG ACAACCA~AT l~lllCGCCA ATCCAATTGC AGTCGTCCCC ATATTACAGG 102480
CAACCTCCAA CA~LlllllA TCTTGGCTAA AACCGCCATT AGCAATTAAC CAATCTGTCG 102540
~ l-l-l"l'ACC GCCTGGACGC A~ACGCGTTT TACCCA~ACG TGCAAGA~AA TTATGCCCTA 102600
CTTCATCTTT TGCCATTTTT Al~lC~lAGT AATTAACTTG ~llLllATAT TATAGATA~A 102660
AATGATAACT ATTAAAATGT CAGATCA~AT A~ATAnGGCG GAATAATTGT TCCGCCTTTT 102720
CCTATTATTT CTTCAATGCT lllll~AATT CAAGTAATTC ACGACGTAAC TGTTTCAATT 102780
CGCTTTCCAT TTCAGCTTGT TTATACAGTT L~ CG~l TTCTGCTTGT TGAGAGCGCA 102840
TCATCACTAC ~ ~AC AATTGCA~AA CTTCCGCAGA ATTGACCGCA ~-L-l'-l~-l~'l-LG 1 0 2900
AAACTTAATC TCTCAAGCGG TTTATTATCC ~-~T~r~AA Lll~llGGTG TGGATTTAGC 102960
GGATAGTCAA ATTACCCAAG GTAATGA~AT TATTCAATCA ATGGGCTTAA CA~ACGTTCG 103020
TTTGCTTGAA TATTTTATTT ATCAAGTTGG tTCATTTACT ATTCAATCTT TAACACAGCA 103080
TATTGAGGAA AATA~AGAAT TTGCCAATAT TACTGAAAAT GAACTGTATT CTGCGGTGCT 103140
ATCTTTAGTT ATTTTAGGTT ATGTCTATGT TTATCTTACG ACCTATCCAA TTTATTCCTT 103200
TGAAGATAAC A~AACTTACA TACCGAAAAG CTTTACTCAA TATGTAAAAA CATTGGTAGA 103260
AGGCGCAAAT CAGTATATTG GTGCTGGA~A TATGTATAAC GGCGACGTAG AAGATTTGAA 103320
TA~ACTGCAT CTTTATATAA l~l~l~A~AT GGA~AAACCG ACAACTA~AG CTGAATTGAA 103380
ATCAGCATTA CAAGGCTATT TAATTCA~AA TGAATATCAA GATATGAATA ACAATGATAA 103440
ATTGATTGAT GAAACTTATG ATTGCACTGA ~-l-l~ll-lAAT GCG~llLll~ ATGTATTAAC 103500
AAGATTAGGT ATATCCAGCC TGTA~ACCTA TAA~l~l~l~l ATG~llC~Ll TAATGTACCG 103560
-77 .63 -
SUBSTTTUTE S~EET tRULE 2~i~
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/05320
Llll~lllll CATCTAAATA TCAATTTAAA TTGAGAACTA TTTGCATTTA AATAAAATTA 103620
GGCATAGAAT AGCCACAATT CAGGCTGAAC TGAATAATTT GCACTCAACA TAAGGAGCTT 103680
TTCAATGCAA TTTAAACATT TCA~ACTTGC TACCCTTGCG GCaCACTTGC lllLL~LGCT 103740
AATAGTTTTG CTGATATTAC CGTTTATAAT GGTCAGCACA AAGAAGCCGC TACGGCTGTG 103800
GCAAAAGCCT TTGAACAGGA AACAGGCATT AAAGTTACGC TAAATAGCGG GAAAAGTGAG 103860
CAACTTGCAG GTCAATTAAA AGAAGAAGGC GATAAAACAC CAGCCGATGT TTTCTACACT 103920
GAACAAACAG CGACTTTTGC CGAL~LLL~L GAAGCAGGGC TTTTAGCACC AATTTCAGAA 103980
CAAACCATTC AACAAACCGC ACAAAAAGGC GTACCACTTG CACCGAAAAA AGACTGGATT 104040
GCATTAAGTG GCC~Ll~lCG AGTAGTGGTT TACGATCACA CTAAATTATC TGAAAAAGAT 104100
ATGGAAAAAT CAGTGCTTGA TTATGCAACA CCAAAATGGA AAGGCAAAAT CGGTTATGTA 104160
TCAACTTCTG GTGC~Ll~lL AGAGCAAGTT GTTGCGTTAA GCAAAATGAA AGGGGACAAA 104220
GTTGCGCTTA ATTGGTTAAA AGGTTTAAAA GAGAACGGAA AACTTTACGC TAAAAATAGT 104280
GTGGCATTAC AAGCG~LL~A AAATGGCGAA GTACCTgCTG CGTTAATCAA TAACTATTAT 104340
TGGTATAACC TAGCAAAAGA AAAAGGCGTG GAAAACCTAA AAAGCCGTCT TTALlll~ll 104400
CGCCACCAAG ATCCAGGTGC GTTAGTTAGC TATTCAGGTG CAGCAGTATT GAAAGCCTCT 104460
AAAAATCAAG CTGAAGCACA AAAATTCGTT GALLL~llAG CGAGTA~AAA AGGTCAAGAA 104520
GCATTAGTGG CAGCGCGTGC AGAATATCCG TTACGTGCTG ATGTGGTTTC GCCATTTAAT 104580
CTTGAACCTT ATGAAAAATT AGAAGCACCA ~LG~l~lCCG CAACAACAGC TCAAGATAAA 104640
GAACATGCGA TCAAATTAAT TGAAGAAGCT GGATTGAAAT AATCCAAATA TTGCGTGCGT 104700
GTATTTGAAA AAATTCACGC ACGCGTTTAC AALl~L~l~A CAAAATTAAC CGCTTGCGTG 104760
CGTGAACTGA AAAGTTCACA TTCCTAAAAG GATTTAACTT TGCCTCGCAG ACCGCCATTC 104820
TGGCTCACTT TACTTATCAT CTTAATCGGG CTTCCGTTAT GTTTGCCGTT TCTGTATGTC 104880
ATTTTGCGTG CGACAGAAGT GGGATTAACG CGAAGTGTTG AGCTATTGTT TCGCCCTCGA 104940
ATGGCTGAAT TATTAAGCAA TACAATGCTT TTAATGGTTT GTGTAACTAT CGGTGCTATT 105000
TCACTTGGCA C~LLlL~lGC TTTTTtACTT GAACGTTATC GCTTTTyCGG TAAAGCTTTT 105060
TTTGAAGTGG CAATGACGTT ACCCCTTTGT ATTCCCGCCT TTGTAAGTgG TTTTACTTGG 105120
nTCAGCCTCA CATTCCGCGT TGAGGTTTTT TGGGGAACAA TTGGTATTAT GACATTAAGT 105180
TCATTTCCTT TGGCTTATTT GCCCGTTTCC GCCATACTAA AAAGACTTGA TC~L1~1~11 105240
-77.64-
SUBS i 11 UTE ~HEET ~RULE ~)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96105320
GAAGAAGTAA GC~1~ CGCt TGGTAAAAGC C~1~1~LATA CCTTTTGGTA TGCTATTTCC 105300
CCGCAACTTA AACCCGCCAT TGGTAGTAGT ATCTTACTGA TTGCTTTACA TAL~LlG~lC 105360
GAATTTGGTG CAGTGTCAAT TTTAAATTAT CAAACCTTTA CCACTGCCAT TTTCCAAGAA 105420
TATGAAATGT CTTTTAACAA CAGCACTGCT GCATTATTAT CCGCCGTTTT AATGGCGATT 105480
TGTATACTTA '11~L1111GG GGAAATTTTC TTTCGTGGAA AACAAACCCT TTACCACAGT 105540
GGAAAAGGCG TTA~LC~LCC TTATCTCGTA AAAACACTTT CCTTTGGAAA ACAATGTTTA 10 5600
ACCTTCGGAT 111L~L~1AG CATATTCATT TTAAGCATTG GCGTGCCTGT GATTATGTTA 105660
ATTTACTGGC TTATTGTGGG AACTTCACTT GAAAGTGCGG GTGATTTTTC AGAATTTTTA 10 5720
TCGGCATTCA GCAATTCATT TATCATTTCA GGCTTAGGCG CATTGCTTAC CGTAATGTGC 10 5780
GCCTTGCCAT TA~LL1GGGC AG~L~11C~1 TACCGTAGTT ATTTAACGAT TTGGATCGAC 105840
CGCTTGCCAT ATCTATTACA CGCTGTGCCA GGCTTAGTCA TTGCCTTATC ATTAGTCTAT 10 5900
TTTTCCATCC ATTACGCTAA CGACCTATAT CAAACCTTTT TTGTGATTAT CATTGCCTAC 105960
TTTATGCTCT ATTTGCCAAT GGCACAAACT ACATTAAGAG C~L~LLLAGA GCAACTTTCC 1060 20
GATCAAATTG AAAAAGTCGG ACAAAGTCTT GGGCGAAACC ~111~1ATAT TTTTCGCACC 10 6080
TTGACGCTAC CAGCCATATT ACCAGGTGTG GCAGCCGCAT TTG~''L'L LG~ l 'L'L L l L'L~AAT 106140
TTAATGAAAG AGCTTACCGC GACGCTTTTG CTCACATCAA ATGATATTAA AACCTTATCC 106200
ATTGCTGTGT GGGAACATAC CAGCGATGCA CAATATGCTG CTGCCACCCC TTATGCGTTA 10 6260
ATGCTCGTtC '1LL1LLCGGG TATTCCTGTA TTTTTATTGA AAAAATATGC GTTTAAATAA 106320
AATGATA~AT AATCCGTTAT TAACCGTTAA A~ATCTCAAT AAAL1LLL1A ATGAACAACA 10 6380
AGTTCTGCAC GATATTTCAT TCAGCTTACA ACGCGGAGAA ATC~1~11L1 TACTTGGTTC 106440
TTCAGGATGT GGCAAAACTA CATTATTACG TGCCATTGCA G~LLL1~AAC AACCCTCTAA 106500
TGGCGAAATT TGGCTAAAAG AGCGGTTAAT TTTTGGCGAG AATTTTAATC TTCCAACGCA 10 6560
ACAACGTCAT CTCGGTTATG TGGTGCAAGA GGGCGTACTT TTTCCTCACT TAAATGTCTA 106620
TCGCAACATT GCTTACGGAT TAGGCAACGG CA~AGGAAAA AATAGCGAAG AAAAAACGCG 10 6680
GATTGAACAA ATAATGCAAC TAACGGGTAT TTTTGAACTG GCGGATCGCT TTCCACATCA 106740
ACTTTCAGGC GGACAACAAC AACGCGTAGC ATTGGCGCGT GCTTTAGCCC CTAATCCAGA 10 6800
ACTGATTTTA TTAGACGAGC CTTTCAGTGC CTTAGACGAG CATCTTCGCC AACAAATTCG 10 6860
CCAAGAGATG CTCCAAGCAC TTCGCCA~AG CGGTGCTTCC GCAATTTTCG TTACTCACGA 106920 t
-77.65-
SVF3STrTUTE S}{EET (RULE 2~')
CA 02218741 1997-10-21
W 096/33276 PCT~US96/05320
CCGTGATGAA TCCTTACGCT ACGCTGATAA AATCGCCATT ATTCAGCAAG GTAAAATTTT 106980
ACAAATCGAT ACACCTCGCA CCCTTTATTG GTCGCCTAAT CATCTTGAAA CAGCAAAATT 107040
TATGGGGGAA AGTATTGTTT TGCCTGCAAA TCTACTCGAT GAAAATACCG CTCAATGCCA 107100
ATTAGGCAAT ATTCCTATAA AAAATAAATC AATCTCACAA AATCAAGGTA GGATTTTGCT 107].60
TCGTCCAGAA CAATTTAGCC TGTTTAAAAC ATCAGAAAAT CCAACCGCAC TTTTTAATGG 107220
ACAAATAAAA CAAATTGAAT TTAAAGGnAA AATTACCTCC ATTCAAATTG AAATTAATGG 107280
CTACGCAATA TGGATTGAGA ACGTTATTTC TCCCGATTTA TCTATTGGCG ATAATTTGCC 107340
TGTTTATTTA CATAGAAAAG GG~~ llA CTCCTAAGAA TAAAGCCTTA TCTTCACGAT 107400
AAGGCTTATT TTTAAACAAT ATATTCGGAA AAAATTTGTT CAAGATGTGA TATTAAACAG 107460
TCTGCGCCTA AAATATTTTC CCCTTTCCAC GCCTGTGGCA AAATCTCTGG AGAAAATTGC 107520
TGGCTTGCCA ATTCAGCTAA CGGCAAATAA CTGATATGCC AAGGCTCCCG CCCCACTTTC 107580
TTATTGGACT GCATATTCAT AAAAGGCAAA GCAAAATCAA AGTGCGGTAA ATTTTCGGCA 107640
AGAAATTCAC TCAATTCAAA GAAGTAGCCG C~'l''l"l''l"l'~'AT ATTCCCAAGG CTCCAGTTGT 107700
AAAGATTGAC ~l~lGGCAA AAGATCAGGA TCAAAAATAT CCACTTCCGT TCCCCAATGA 107760
TGACGACTAG CCGCAGTAAT GCAGACCAAC GTAAAATCGC CTGACATTTT TGCCAGTCAT 107820
CTAATTGATT CAAATCTAAT GCCTTTCCTG CATCATCGTG TACTTTTCGC TCGCCCTTAA 107880
ATTTACTGTT CCAAATAAGT TGTTGGCGTT CAAAATCACG AAAACTGCTC GCAGGCTGTA 107940
AATTAAAGCC A~llllllGCC GCA~lll~ll GCAAAGCTTG AAATGCTTGC ACAGCTTGCG 108000
TTTGCAAAAA ATGATTTGAT GAATGAGTTG TGGGTAAATT GACTAAATGC TCACGGGACT 108060
TTCCTGTAAG CATTTCTGGG GTTAATTTCA TTTTAGCTAT CCAATAAATT CACTAACATT 108120
TTGTGGTAAA TTTCACCGCA CTTGCCAAGG l~lL~lACAC TGACACATTC ATTGACTTTA 108180
TGAATGGTTG AATTTAACGG GCCAAATTCC ACTACTTCTG CGCCCATCAA TGCAATAAAA 108240
CGACCGTCTG ACGTGCCGCC ACCTGTTTCA GCCTTTGGCG TTATGCCTAT GGTTTCCTCA 108300
ATAGCGGAGG TTATCGAATC TAATAATTTA CCTGGTTTTG TTAAAAAGGG TTTGCCTGAT 108360
AAATTCCATT CAATACGATA TTTCAAATTG 'l'~'l"l"l"l''l'~''l'A GCATTTCAGC CA~lllllGC 108420
TTAATGATTT CATCCGTGAC ll~L~lGCAA TAACGCAAAT TGAACTGAAT ATATAACTCA 108480
GCAGGAATTA CATTATTACT TCCCGTACCC GCGTGAATGT TAGCAATTTG TAGGCTTGTT 108540
r GGCGGGAAAA ATTCATTGCC TTTATCCCAT TGGTAAGTCG TTAATTCTTG CAAAAATAGC 108600
-77 66-
SUBS i 11 UTE S~ET tRULE ;~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GCTGCTTTAT GGATTGGGTT TTCAGCTA~A TGCGGATAGG CTACGTGTCC TTGAATACCT 10 8660
TGAATATAGA GA111C~1~L AATTGAGCCG CGGCGACCAT TTTTGACAAC AL~lC~lAAG 108720
TTTTTAGCAC TCGATGGCTC GCCAACCATA CAATAAGTAA '11111L~ATC ACGCGCCATT 10 8780
AAC~1~1~AA CCACGTGTAT AGTTCCATCT TTTGCGGTAG C~L~ll~ATC AGAGGTAATC 108840
AATAATGCAA TGGTGCCTTT ATGATTAGGA TTTGCTTTTA CGTATTCTTC TGCCGCCACA 10 8900
ATCATTGCTG CAAGGGAGCC TTTCATATCC GCCGCACCAC GCCCATA~AG CATGCCATCA 10 8960
ATAATCTCCG CAGAAAACGG CGGAGACGAC CATTGATTTT CATCGCCAGT AGGCACAACA 109020
TCCGTATGAC CTGCA~AAGC AATAACTGGC TCG~1C~L1C C~'1'~'L'L'L'1'GC CCACA~ATTC 1090 80
AAC~L~LLAT TA~AAGGCAT CCATTCAATT TGA~AACCTA A'L'L'L'L'1'~'1'AA ACGTTCGGCA 109140
ATAATTTGCT GACAGCCTTC GTCATTTGGG CTAATAGACG GGCGACGAAT TA~ATCTTGT 109200
GCCAACGA~A CCA~LLLLLC TTTCATA~AA ACTCCTAAGA A~ATAACCGC ACTTTAAGCA 109260
A~AGCAGCCT GATATTCCTT TTCATTA~AT CCAATTAATG C~LLLC~ATC TTGTA~AATA 109320
ATTGGGCGTT TAATTA~AGT TGGATTCTCA GCCAACACGG A~AGTGCGGT GGTTTTATCA 109 380
AGAGAATTTT TAACTTGCTC ATCCAAATTA CGCCAAGTTG TACTGCGTTT ATTCACTAAC 109440
ACATCCCAGC CA~ATTGAGT TTCCGCTTGG GTTA~AAAAT TTA~ATCTAA CCCATCAACA 109500
CGGTAGTCGT GAA~LLL~LG TTCGATATTG TGATCCGCCA GCCATTTCAA CG~'LLL~L'L'l 109560
ACTGTATCGC AATTTTTAAT GCCGTA~ACT GTAATCATAT TTCACCTA~A A~AGA~AAAT 109 620
CCTCAATCTA ATCAGACTGA GGATTTTAAC CCTTATGCTA CTTCATCTCA AATGAATTAA 109680
CCTAACAACT TATTGATACG TTTAATA~AC GCAGCTGGAT TTTCCA~AGA TCCGCGCTCT 109740
GCTAACATAG ~L1~LL~AAG TAATAATTCC ACCCAATCAG CAAATTCAGT TTCATCTGCA 109 800
ATATCAGCCA ~'L'L'L'1''1''L~AC TA~ATGGTGT TCTGGATTCA GTTCA~ATGT GTATTTTACT 109 860
TCTGGTACAG GTTGCCCTGC GGCTGCAAAC AATTTCGCCA TTTGGGTCGT CATTTGATCG 1099 20
TTATCCGTAG A~ACCACCGC TGGTGTATCC GTTA~ATTGT GAGTTA~ACG CACC~'L'1"L'LC 1099 80
ACACGTTCGC CAAGCAAGTT TTTCACACGC TCAATA~AAC TACCA~AGGC TTCATCTTGT 110040
'L~'L'L'L'L'L~'1G TTTCAGATTC TTTATCCGCT A~ATCGCCTA AATCCA~ATC TG~'1"L'L'L~'1'A 110100
ATA~LLL~LA A~LL~LLLACC ATCGAATTCA GTTA~ATAGC TTAACATCCA TTCATCAATG 110160
CGATCGGA~A GCAACA~AAC CTCAATGCCT TTTTTATTGA ATAATTCCAA GTGCGGGCTA 110220
~LLLLLC~CTG CAACATAACT ATCCGCTGTA ATGTAATAGA TAG~LLLLlG CCC~L~11LC 110280
-77.67-
SUBSTITUTE SHEET (RULE 2~i)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
ATACGCAAGA TGTAATCTTC TAAAGAGACA GTTTGCTCGC TACCATCATT ATGTGTCGAA 110340
GCAAAACGCA ATAACTTCGC GACAGTTTCT TTGTTAGCAA AA1~1-1~1GC AGGGCCTTCT 110400
TTTAAGACTA AACCAAACTC TTTCCAGAAT TGAAGATATT TTTCTGCATC A'L~1111GCT 110460
AA11111~1A GCATTTGTAA TGAACGCTTA GTTAATGCTT TGCGTAGTGC AGCCGTAATT 110520
TTGTTATCCT GTAAAATTTC ACGAGATACA TTTAATGGCA AGTCATTGCT ATCGATTAAA 110 580
CCACGCATAA AACGTAGATA ATTCGGTATA AATTGCTCAG CATCATCCAT AATAAATACA 110640
CGTTGAACAT AAAGTTTTAA GCCATGTTTA L~11~1C~AT TAAATAAATC CCAAGGTGCT 110700
TTAGCTGGTA CATAAAGCAA ACTAGTATAT GCTTGATTTC CCTCAACTTT GTTATGCGCC 110760
CAAGTCACAG GATCAACAAA ATCATGGCTT AA~1~111~1 AAAACGCTTT GTATTCCTCA 110820
TCAGACACAT CATTTTTAGA ACGCGTCCAA AGGGCATCAG ATTTATTGAT TTTTTCCCAT 110 880
TTTTCGCCGC A~1~111GCC TTCATCATCG TA'11~111'CG TCAGCATTTC CACTGGCAAG 110940
CCAATATGGT CAGAATATTT ACCAATAATT TCACGCAAAC GCCATTCATT TAAAAATTCT 111000
TTTTCATCTT CACGTAAATG CAAAATCACA TCTGTACCAC GGGATTTTTT CTCAATATCC 111060
GCCACAGAAT ATTCGCCTTC ACCCGCAGAT TCCCAAAGTA CGGCTTTATC CGC~l~ll~A 111120
CCAGCTGCTC TG~11111AC AGTCACTTTA TCTGCCACAA TAAAAGCAGA ATAAAAACCC 111180
ACACCAAACT GCCCAATAAG CTGGCTATTT TTTGCTTGAT CTTGACCAAG TGCGGTTAAA 111240
AA11~1111G 11C~1GATTT TGCAATCGTA CCCAAATGAT CGATGACTTG CTCACGGGTC 111300
ATGCCAATGC CGTTATCGCT AATTGTGATA GTGCCTTTAT CCGCATCAAA GCTAACACGC 111360
ACACGCAAGT CGCCATCGCC TTCATATAAA GCAGGGTTGG AAAGTGCTTT AAAGCGTAAT 111420
TTATCTGCCG CATCAGAAGC ATTAGAAATC AATTCACGTA AGAAAATTTC llL~lLAGAG 111480
TACAAAGAAT GAATCATTAA TTGGAGTAGT l~lll~ACTT CAGATTGGAA TCCGCGAGTT 111540
TCTTGATTTT GTGACATAAT 11111C~L1C ATAAAGATAA AAATTGAACG TCACAGATAT 111600
AAGAATAAAA AGAAAGATTT CAAGAGGAAT TTAAGAGGAA AAGTGCGGTA AAAAAACACA 111660
AGGAATTTAA ACCGCACTTT AAATGAAATA AAAAATTTCT TATCCCCCTT GATCGCTATA 111720
AATTTATGTA TATAATGAAT T~1~1111AG ATACTAGATA GTAATTTAAT AGTAATGAAA 111780
CTTGGCTAGT GCATTCCCCC A~1C~L11CG CACTAGCCAT 111111GGGA A'1'11"1~1'ACC 111840
ATATCCCAAC TTTTTCCAAT CAACGATCCA TTATGAATAA TCTTGAACTT GAACAACTCA 111900
TTAATCAAAA A~111~11~1 GATAAAATCA ATGACTATGC GCCCAACGGC TTACAAGTCG 111960
-77.68-
SUBSTrTUTE SHEET tRULE 2
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
AAGGTAAAAC AGAAATCAAA AAAATCATTA CTGGCGTAAC GGCGAGTCAG GCTTTAATCA 112020
ATTACGCAAT CAGCCAAAAT GCCGATGCTA TTTTAGTTCA TCATGGCTAT TTTTGGAAAA 112080
GTGAAACCCC TTGTATCCGA GGAATGAAAG GCAAGCGAAT TAAAGCCCTT TTAGTGAACG 112140
ACATTAATTT ATATGGCTAT CATTTGCCAT TAGATGTGCA CCCAGAATTA GGTAACAATG 112200
CACAATTAGC CAAACTGCTC GATATTGA~A ATTTACAACC ATTAGAA~AA GGCTCTGTGA 112260
GTATTCCTGT TTGGGGCGAA TTAAAAGAAC CGATGACAGG TAAAGACTTT GCAGAAAAAA 112320
TAGAA~AAGT GTTAAATCGA AAACCGTTAA TTTGCATTGA AAACGGACCG CACTTAATCC 112380
GAAAAATTGG CATCTGTACC GGTGGCGGAC AAGGTTATAT TGATCTTGCT GCAGAACAAG 112440
GCTGCGACGC ATTTATTACA GGGGAAGTGT CAGAACAAAC GATTCATTCT GCCC~l~AGC 112500
AAGGATTGTA 11-1-~-11~-1~-1 GCAGGTCATC ACGCAACAGA ACGCTATGGC ATCAAGGCAT 112560
TAGGCGAATG GTTGGCGAAA GAATATGGCT TTGACGTAGA ATTTA~AGAT ATAGATAATC 112620
CAGCATAAAA TACAAAAGTG CGGTAAAAAT A1-L-1-~-11111 TAACCGCACT TTTATCTTCT 112680
GAAATTATCG TTTAAACATT CCGCCTAAAC CGCCAAGACC GCCTAAGCCT CCGCCCATTA 112740
AGCCTTGCAT TCCACGCATC ATTTTAGCCA TGCCGCCTTT ACGCATTTTC TTCATCATAC 112800
GTTGCATTTC ATCGAATTGT TTAAGTAATT TATTGACATC TTGCACTTGA GTGCCAGAGC 112860
CTAATGCAAT ACGACGACGG CGAGAtCCTT TGATAATATC TGGGTTGGCA C~L1-~1-L-L-LA 112920
GGGTCATGGA GTTAATGATC GCTTCCATTT TGACA~ACAT l--L-l~l~ATCT ACTTGATTTT 112980
TAACGTGCTC AGACAAATTT TTTGCACCTG GTAATTTCTC AAGCATAGAC ATCATGCCGC 113040
CCAlll--l-lll CATTTCGATC AG~l~llCGC GGA~ATCATC TA~AGTAAAA TCATCGCCTT 113100
TCTTGAATTT CTGCGCCATT TTTTCCGCTT TTTCACGATC AACAGAACGT TCAAGATCTT 113160
CGATAAGGGA AAGCACATCG CCCATGCCCA AAATACGGGA AGCGACACGA TCAGGATGGA 113220
ATGGCTCAAG CGC~L~l~Ll TTCTCGCCCA CACCCAAGAA TTTGATTGGT TTACCTGTGA 113280
TTTGACGAAT CGATAACGCC GCACCACCGC GCGCATCACC GTCCACTTTC GTCAAAATAA 113340
CCC~-L~-lAAG AGGCAATGCT TCATTAAAGG CTTTTGCTGT ATTTGCCGCA TCTTGACCAG 113400
TCATCGCATC AACAGTGAAA AGAGTTTCGA TTGGATTTAA TGCAGCATGG ACTTGCTTGA 113460
lLlC~LCCAT CALLl~-l~LA TCAACGTGTA GGCGACCTGC CGTATCCACA ATCAACACAT 113520
CGTAGAATTT CAGTTTTGCA TCAGCAAGCG CCGATTTAGC AATATCAACG GG~L-L-LL~ll 113580
TAACATCCGA TGGAA~AAAA TCCACGCCAA CGGATTGAGC CAAGGTTTCA AGTTGCTTAA 113640
-77.69-
SUB5 111 UTE S}~E T tRULE 26
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TCGCAGCAGG GCGATATACG TCAGCAGACA CCACTAACAC 'l"l"L~'l"l'-l"l"l'A TGGCGTTCAC 113700
GCAAGAATTT TGCCAATTTA CCCACACTGG TGGTTTTACC CGCCCCTTGT AAACCCGCCA 113760
TTAAGATAAC TGCTGGTGGT TGGGTTGCGA GATTTA~ACT CTCATTCGCT TCGCCCATGG 113820
AG CTCACGCTGA ACGATTTTTA AGAATTCTTG CCCTGGCGTT AAACTTTTAT 113880
TGA~ll~LlC CCCAAGCGCG ~'l"l''l'~'l"l''l''l'A CTTTTGCGAT A~ATTCACGC ACCACAGGCA 113940
AGGCAACATC GGCTTCAAGT AATGCCATAC GCACTTCGCG TAAGGTTTCT TTAATATTAT 114000
CTTCCGTTAA ACGGCCTTTT CCTGTGATAT TACGTAAGGT TTTGGAAAGG CGATCCGATA 114060
AATTCTCAAA CATGGCTAAC AAlC~l~lll TTCTTA~AAA ATTGTGCTGA TTATACCGAA 114120
ATTTAGGCGT TTTTCATCAT TTCAAATGAA AATGACTTTT TGAGTAGGCG ATTTCATAAA 114180
GAAAGTATAG GACATAAGGA AAAAGAATGA TTATTTAGCC AATTTCAGGT ATTATTCTGC 114240
CCACTCTTAG CTATTTGAGC AGCTATTTGA TTTAGCAAAA TCAAATAACA GGTAAAAAGT 114300
GCGGTGAAAA ATGACCGCAC lllll~llGA TTAACGAACA AAAGGATTTT CCCTTGGATA 114360
GCATTCCCCT TAGTACTTTA TTTATTATTC TTATTATCTG TTTAGTGTTA TCAGCCTATT 114420
TTtCTGGTTC TGAAACTGGA TTA~l~lCCC TCAATAAATA lC~l~lLC~l TTTCTATCTG 114480
AACAAGGCAA TAAAGGCGCG AAAAAAGCGG AAAAACTGCT AGA~AAGCCA GATACCTTGT 114540
TAAGTTTTAT TCTTATTTTT AATAACCTTG TGAATATCAG CGCATCTGCA ATTGCAACAG 114600
TAATTGGTAT GCGTTTATAT GGCGATGCCG GCGTGGCGAT TGCAACGGGT TTGCTCACTT 114660
TCGTAATGCT CGTATTTTCT GAAATATTCC CCA~AACTGT GGCTGCAATG CACGCAGAAA 114720
AAGTGAGTTT TTTTTCAAGT CATATTTTAA CTTCATTGCT TAAAATCTTT TATCCGCTCG 114780
TTTGGTTAAT GAATATTTTT ACTAAATCCT TGATGCAAAT AGTAGGGTTA AAACTTGATA 114840
TGCAAAAACA AGTAATTAGT AGTGAAGAAC TGCGTAGTAT TGTATCAGAa GCGGGCGAAG 114900
CAACACCAAA TGAACAACAT CCACAAATGT TGCTGTCTAT TTTGGATATG GA~ACCGTCA 114960
CCGTTGATGA CATTATGGTT CCCCGCAACG AAATCGGCGG TATAAATATT GATGATGATT 115020
GGCGAGCCAT TATGCGCCAC TCAATCATGC TGCACATAAC CGCGTGGTGC TTTACAAAGG 115080
CAGCCTTGAT GAACAAGTGC TTGGCATTTT GCGCGTGCGT GA~GCATTCC GCTTGCTCCT 115140
TGAAA~AAAT GAATTTACCA AAGAAACCTT AATTCGTGCC GCAGATGAAG TGTATTTCAT 115200
TCCTGAAAGC ACGCCATTAA AAACGCAACT TGCAAATTTC CGTACAAATA AAGAGCGAAT 115260
TGGCTTAGTT GTAGATGAAT ACGGCGATAT TAAAGGGCTT GTGACGTTGG AAGATATTTT 115320
-77.70-
SUBSTJTUTE 5HEET ~RULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
GGAAGA~ATT GTTGGGGATT TTACCACTTC CACCGCCCCA AGCATTGACA AAGAAGTAAT 115380
TCAACAGTCT GATGGTTCAA TGATTATCGA TGGCTCCGCT AATCTACGCG ATCTCAACAA 115440
AATGTTTAAC TGGGAATTAG ATACAGAAGA TGCTCGTACT TTTAATGGTT TAATCTTAGA llS500
ACACTTAGAG GAAATACCCG ATGAAGGCAC GATTTGCGAA ATTGATGGTT TGCTAATCAC 115560
TALl~ll~AA GTGGGCGATA ATATGATA~A ACAGGCGA~A ~LC~l~AaAC TTTAATCATA 115620
AAAAACTCCA CCAAATTGAA CCGCACTTTT GACTTGGATC ATAAGTGCGG 'L'l'~'l"l''l''L'l"l"l' 115680
GCGCATTTTT TAGAAAAGAT TTTTATAATT ~lll~lAGGT ATATTTTGAT AGA~AAGA~A 115740
GATATGGAAC ACGAATATCA ACGGGCGGTG ACTCGCGTGT GCGTACA~AC GGCACTGCTC 115800
TTGTTACAAC ATGGGGCAGA AAGTACCGTG GTGGTACA~A TGGCACAGCG TTTAGGCGTA 115860
GCACTTGGCG TAGAAAGTGT AGAATGTGCG CTTACGGCAA ATGCAGTTGT GCTGACGACC 115920
TTATCAGATA ATCATTGCAT TACTACCGCA CGA~AAAATA CAGATA~AGG CATTAATATG 115980
CA~ATGGTTA CTGATGTTCA ACGCATTGTG ATTGCCGTTG AGCATCATTT GTATGAGTTA 116040
GAGATCGCAC AAAGA~AACT GGATCAATTA A~ACCGCTTA AATATAACCG ATGGTTAGTT 116100
GTATTCATGA TTGGCTTATC TTGTGCAGCA TTCGCCCATT TATCTAGTGG CGATTGGATA 116160
ATTTGCGGCA TCACAATATT TATGTTGA~A TTACTCTATG ATATGCTATT TGCTGCGATT 116220
CCAGCGGTGG GCTTTGCTTT AGTATTTAAT GTACCGCCCA AAGCCTTA~A ATATTGTGCA 116280
ATTTTAGCCG CACTTGGGCA TGTTACACGC ACATTATTAC TGCATATTAA TATGCCTATT 116340
GTATTTGCTA CAll~lllGC CaCTTGCGTG ATTGGATTTT TAGGCGTGCA TCTTTCCCAT 116400
CGTTATTTAG CCCATCCCAA AGCCTTCACC GTTGCCGCAA TTATCCCCAT GATCCCCGGT 116460
GTTCATGCTT ATAAAGCAAT GATTTCAATG GTACA~ATTC ATCATTTTGG ~Llll~l~AT 116520
GCTTTATTTG AACAGATGAT TAGCTCCTTT ATTAATACCA GTTTTATCCT AGGCGCAATA 116580
GTATTTGGAT TGGCTTTACC AGGCTTATTG TTTTATCGAC A~AAACCTGT GGTGTAACAC 116640
TA~AAACAGT GCAACA~AAA AGCCGACATT TGTCGGTTTC TACTATTCTT GTGATTTTTT 116700
CTTGAGGTAT TCATA~AGCT CATCTTTAAT CCGTAATTTT C~'1''1"L'L'L'L~A AATAACGATT 116760
TCCATTTTGT AATCAATTCA TTATTTAATG TTTGGCGCAC TTGATTATTC ACATAACGAA 116820
TGTATTCCAC A~AAAGTTGA TCCACTTCTT CACGATCA~A AGAGGATAGA ATTAATTGAT 116880
TAAGATTATT TTCTTGAGAA AACTTA~AAT GTGAGGCAAT TTGCTGAACA GTTTCATTTT 116940
CAACTTTAGC TCTCGCTTTC ACA~AATCAG ATTGATTTAA A~AAGCCATT AATTGAGCGG 117000
-77.71 -
SUBSmUTE S~EFr (RULE 2~i)
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/05320
ATGAAGTAAG AAlllll~lA AATTCATGAT ACGCAGAATC TGTCGCCTTA CGCTCAATTT 117060
TTACCATATC AACGGCATCA GCATCACCAC TAACTAAATG GGGCGTGGAT TCTAATACAA 117120
AGTGCGGTCA ATTTTnCTTT ATTTTTATAC GTTGGCTTTT AAA~lG~lll ATTTGAAGAA 117180
AGCACGCTAG AATAAGGTTG TTTTCATTTC AACGAAAAAA GTAAGGAAAT TCTATGATCG 117240
ATCCAAATTT ACTCCGTAAT AATTTAGCAG AAGTCGCAGA AAAATTAAAA GTAAAACGCA 117300
ACTTTATGCT TGATACGGAA AAACTCACCG CGTTAGAAGA TCAGCGCAAA AACTTACAAG 117360
TCACTACCGA AAACTTACAA GCGGAACGTA ATGCTCGTTC CAAAGCCATT GGTGCTGCTA 117420
AAGCGCGTGG TGAAGATATC GCACCATTAT TGGCAGA~AT GGATGATATG GGCAATCAAT 117480
TGACTGAAGC AAAAGCACAA TTAGATGCGG TACTTGCAGA AATCAATCAA ATTGCATTAA 117540
GTATTCCAAA TCTACCCGCA GACGAAGTGC CATTAGGCAA AGATGACACA GAAAATAAAG 117600
AAATCTTACG TTGGGGTACA CCGCGTACAT TTGATTTTGA AGTGAAAGAT CATATCACTT 117660
TGGGTGAAGA AGCAAATGGC TTAGATTTTG CTGCTGGGGC TAAATTAGCT GGTGCACGTT 117720
TTGCCGTAAT GAAAGGTCAA ATCGCTAAAA TGCACCGTGC ATTGGCACAA TTCATGTTAG 117780
ATCTTCATAC GGAACAACAC GGCTATTTAG AAACCTATGT GCCTTATTTA GTAAATCACG 117840
CCACACTTTA TGGAACAGGG CAATTACCAA AATTCGGGGA AGATTTATTC CATACTTTAG 117900
CCTTAGAAGG CGAACAACCT TACGCATTAA TTCCAACTGC AGAAGTGCCC GTCACTAATT 117960
TAGTGCGTGA CGTGATTATT GATGAAGCAG AATTACCAAT AAAAATGACC GCACATACGC 118020
CATGTTTCCG TTCTGAAGCA G~ll~llACG ~'l'C~'l'~ATAC TCGTGGTTTA ATTCGTATGC 118080
ACCAATTTGA TAAAGTAGAA ATGGTACAAA TCGTTGATCC AGATA~ATCA ATGGAAGCAC 118140
TTGAAGAATT AACAGGTCAT GCGGAAAAAG TATTGCAATT ATTAAATTTA CCATACCGTA 118200
AAGTTTTACT TTGCACAGGC GATATGGGCT TTG~ll~llG CAAAACTTAC GATTTAGAAG 118260
TTTGGGTGCC TGCACAAAAT ACTTATCGAG AAATLl~llC TTGCTCAAAT ATGTGGGATT 118320
TCCAAGCTCG CCGTATGCAA GCAC~ll~lA AAGCA~AAGG CGATAAGAAA ACTCGCTTAG 118380
TGCACkCATT AAATGGTTCA GGCTTAGCGG TTGGTCGTAC TTTAGTGGCT GTACTTGAAA 118440
ACTATCAAAA TGCCGATGGT TCAATTACCG TGCCAGAAGA GCTACGTCCA TATATGGGCG 118500
GATTAGACGT TATCGGAAAA TAATCCTTCT AGAAGATAAA AAAGCGTGGA TTTTAAAATT 118560
TCCACGCTTT TTTATTATCA AAGCCTTACA ATAACTGTTT TAAATTTTTT GGTATTCAAG 118620
CCAATTAGGA ACTTTATTCT ATTATAAAAT TATATCTATA ACATAGAAAA TTTATCTTTC 118680
-77.72-
SUBSmUTE ~{EET (RULE 26
CA 022l874l l997-l0-2l
W 096133276 PCTAUS96/05320
AATTGACATC AATATCCAGA ACATTACTCT A~AAAACATA TCAAAGTATC TAAATTGTTA 118740
TAATATTAGT TCACTTTACG ATTAAACAAT AGTAAGAAGC AATTTTAATA AGTTAGATAT 118800
TCCACGTATA AAACAGTATA ATTCCATCA~ TAGCTCATAA ACCAACAGGA GTATTTTATG 118860
A~ATTATATG GTTTAATTGG TGC~1~1L~A 111~11CCAC ATGTGGCATT AGAGTGGGTA 118920
AAAATACGTG AAAATGCTGA TTATGAATTT GAAC~1~L~A CTCGTGAGTT AATTA~ATCA 118980
CCTGAATTTT TATCATTGAA TCCACGCGGG GCAGTACCTG TATTAGTTGA TGGCGATTTA 119040
~-L-L~LLLCGC AGAACCAAGC GATTTTGCAC TATTTAGATG AACTTTATCC TAATTCAAAA 119100
TTATTTGGTA GCAAAACCGT ACGTGATA~A GCCAAAGCAG CTCGCTGGTT AGCATTTTTT 119160
AATTCCGATG TGCATAAATC ATTTGTGCCT CTGTTCCGTT TGCCAAACTA TGCA~AAGAT 119220
AACGAAACAC TTGCACACAC TATTCGCCAA CAAGCAGTAG AGCAAATTTT AGATCAACTT 119280
GCAGTCGCAA ATGAGCATTT AGA~AGTCAC ATTTATTTTG GAGAAAATAT TTCCGTTGCA 119340
GATGCCTATC TTTACATTAT GCTAAACTGG TGCAAAGCAG TCA~AATTGA TTTCAGCCAC 119400
TTAACACAAC TTTCGGCTTT TATGCAACGT GTTGAGACTG ATCAAGCTGT CGAAAATGTG 119460
AGAAAAAGTG AAGAACTAAA AGTATAAACA GGAAGTTTCT ACAAAAATTG CCC~1"L'L-L-1-A 119520
ACC~-L-L-L~-1A TCACGTTAAG TTTAAATTTA AGTGAGTAAT TTCGCGTCTT ACCCAACACA 119580
GCTAACCCAT TGATTCTACT ATGATTAAAC TGGTTAATCC AATGTCGCAA TGtTCTACTG 119640
TCAAGTTGAA AATGTTTACT GATGAGTGAA TAATTTTTAC CATTTTGAAT ATAAAATTCG 119700
ATGACTTGTT GTTTGAAAAG A~L~1-L~-1AT TTGGCTATAA AAAATCTGCn TCTTACAATT 119760
AATTTATATA AGTAAAAATA TCTTGCTTTT ATCATCGTTA AACTTAGAAT AAATATAAAT 119 820
AATTATCATT AAGATTTAAG GGTATATATG AATATTTTAA TTAATAAACG TA~l-~-l LLLLA 119880
TTAGTTACCC TTGTAGGTAT TCAACTAAAT GTAACCGCAA AACnAAATTC TTCTAATTCT 119940
AATAGAGAGG AGTTATTACC TATTATTGTG AACACTAATG ATGATAGTAA TAAACTACCT 120000
G~LC~LL~AG TATTAAAACA GAAAAATATC GAACAACnAC AAGCGGATAA TGCAGCAAAT 120060
TTAATTAATA TCTTGCCAGG TGTGAATATG GCTGGCGGGT TTCGCCCTGG TGGGCA~ACA 120120
TTAAATATTA ATGGAATGGG TGATGCTGAA GATGTTAGAG TGCAGTTAGA TGGGGCTACA 120180
AAAAGTTTTG AAAAATACCA ACAGGGTTCT ATTTTTATTG AGCCTGAATT ATTAAGAAGA 120240
GTAACAGTAG ACA~AGGAAA TTATTCTCCT CAATATGGTA ATGGTGGTTT TGCTGGAACA 120300
GTA~AATTTG AAACTAAGGA TGCTAGGGAT TTCTTGCAAG A~AACCAGAA AATAGGTGGT 120360
-77.73-
SUBSmUTE SHEET ~RULE 2~i3
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/05320
TTTTTAAAGT ATGGA~ATAA TAGCAATAAT AACCAAAAAA CTTATAGTAC TGCACTAGTT 120420
TTACA~AATG AACAAAAAAA TATTGATTTA TTACTATTTG ~Ll~l~lAAG AAATGCTGGC 120480
GATTATA~AA GACCCGATAA TAGCAAAATT ~LllllL~AA A~AATAATCA AAAAACCGGA 120540
TTAATAAAAT TAAATTGGCA AATTTCACCC GAGCATTTAC TCACATTATC GA~L~lLlAT 120600
GGTATTCATA AAGGCTGGGA GC~lLlCGCA GCGAAAAGAG ATATCCTACC TAAACCAAGT 120660
TTGAGTGATA TAATGCGTTA TGGTACTGAT ATAGCGTGGA AACGTA~ACT GGTTTATCGA 120720
GATCAAAAAG ATGAAAATTA CACATTAAAA TACAACTATC TACCTGA~AA TAACCCATGG 120780
ATTAACTTAT CTACTCAGTT CAGCTACAGT AAAACCACAC A~AATGATAT GCGTCCCAAA 120840
GAAGCATCTT CAGGATTAGT GGGTAGCTTA GGTAATCA~A GCTGGATAAC TTATTCAGAT 120900
CTTACTTTTG ATATAAATAA CACAAGTACT TTTAATATCA A~ACTACTGT TCATGAACTA 120960
TTATTTGGTT TGCAATGGTT AAAAAACACA AGA~ATACTT TAATGTATGA TAAAAGTA~A 121020
GTGAGA~AAG CGGATTATAA TTATGGCTAT TTCCAACCCT ATTATATGCC ATCTGGACGT 121080
CAATATACAC AGGC~LlllA TTTACAAGAT CA~ATA~AAT GGAAGAATAT AATTTTTAGC 121140
ACAGGAGTGC GTTATGACCA TATCAATAAT ATAGGGCAGA A~AATTTAGC ACTAAAATAT 121200
AATGATATCT CTGCAGGACA TGATTATAGC CAGA~AAATT ATAATGGTTG GTCTTATTAT 121260
TTAGGTTTAA ATTATGATGT A~ACCATTAT TTAAGTTTAT TTACGAATTT TAGTAAAACT 121320
TGGCGAGCAC CTGTTATTGA TGAnCAGTAT GAGACGCAAT TTAAGCAATC lL~l~lGCCT 121380
GCAACCTCTT TAAATTTAGA A~AAGA~ATG ATTAATCA~A CGAGAGTGGG TGGAATTATT 121440
ACTCTCAATC ATCTATTTCA GGAAAATGAT GCTTTTCAAT TTAGAACTAC TTATTTTTAC 121500
AATCGCGGCA AGAATGAAAT ATTTAAAACC AGAGGAGTTA ALl~l~LAGG CAATGCTGCA 121560
GATACCAATA ATAAGGTTTG TCCTA~AATC ATTGAAAATT ATCGTAATTT GCCAGGTTAT 121620
GTTATTCAAG GTGCAGAGTT AGAAGCTTAT TATCAATCTA CTTATTTATT TGGTGAGATA 121680
ACATATTCTT ATGTA~AAGG AAAACGTGAC ACCTCACCAA GA~ACCCATG GGGTAAAACC 121740
TCAACATGGA TTGCTGA~AT TCCCCCTAGA AAAGCAACTA CTGCTTTAGG TTTCAATGTT 121800
CCA~AATATT ATCTCACAGT AGGTTGGCGT GCTGAGTTTG TAAGAAGACA AGATCGATCG 121860
CCATTATCTG GTGATCCTAA AGCATCATCT TGGTCATTGC CAGCTTCAAG AGGATACAGC 121920
CTACATAACC TATTCCTTTC TTGGAGCCCT GCAAAAATTA AAGGTATGAA TGTTAAGATT 121980
ACAGTGGATA ATTTATTCAA TCGAGCATAC AACCCTTATC TAGGCGAATT GGCTTCTGGA 122040
-77.74-
SUBST~TUTE S~tEET (RULE 2~)
.
CA 02218741 1997-10-21
W 096/33276 . PCTAUS96/05320
ACAGGTAGGA ATATCAAATT TAGCCTATCT CAGA~ATTTT AGAATA~ATA GCCCGATTGA 122100
ATCTAATCGG GCTTTATCAT AACTATAATT AGATCATA~A A~AATGTAGA GATAATA~AT 122160
ATAATTnCCT ATACTAATTT TAGTATTCTT TA~AGAGCAA ATTTA~ATAA TA~ATCCA~A 122220
TAAGTACGAC ATCTTAAATT ATAGATAAAT ATCA~AATTA '1~1111ATCT TTACCCTATT 122280
ACTTTCCATA ATAGAAACTA AACTTACCTA A~AATTTAAA TATAATTTAG CATCTnGCTT 122340
AACAACAAAG TCAATACACA l'-L l ~''1"1~ lAG TTTTCCTTTC TTTCCGATTA ATATACCCCA 122400
AACTATATAG C~L~11~11C TCACTAACTT TCCTACTATA GGAATATCAT TAGCATAAGC 122460
TATGAAGAAG AAAGTTA~AA CAGAGGCATT ATGTAATATA AGTTATTTAT ATAATTTAAC 122520
ATAACTTTCC ATATAACAAC AACGCATCTT TATAACATAA TTGCAATGTA '1"1'~'1'~'1"L'1''1'A 122580
AATTTATAGC AATTACCTAA ATAGTA~AGA GTACGAATAA AGTACATATA GGCTATTAAT 122640
TACTTTAAAA AAAATTA~AA TATATTTGTA GATTTATGGA CAATTACATT TATCCTTTA~ 122700
AAGGTAGTTA ATCTAGAGAA A'1"1''1''1''1"1'ATA GCAATACAAC AAGTTTACAA GGAATTCA~A 122760
TATTTTTAAT TTTTAGAAAA AAACA~AAAC CCTAGCTTTT CAACTAGGGT '1'~'1'~'1''1"L'L'1'A 122820
TGTGATTTAG ATTTGTATCT GATAACCTGG CGGTGCCCTA CTCTCACATG GGGA~ACCCC 122880
ACACTACCAT CGGCATTACA GC~'L'L'L~'ACT TCTGAGTTCG GTATGGTCTC AGGTGGGTCC 122940
ACCGCACTAT CGCCGCCAGG ATAATTCTTT GATAACTCGT ~'1''1"L'L~'L~''L'L TTATCTCTCG 123000
'L~L~LLL1AT ~L~LC~L1AC TCA~L~LLLC CTCTTACCTT TCA~LC~LLC TTATTGGTCA 123060
CAAGCTGAAT CCGATTTTCT TTCTATTAAG L~LL~LATAT TTA~LLl l~'L 'L'L~L'l"l'AGTC 123120
TTTTACTTCT CTTTCGCTCT GCTTTTATTT GCTTCGCTTT TCA'1'~'L~'1"1'A CTTCACTTAG 123180
CTCCCAAAAA CACTTGAGCG TTGTATAGTT AAGCCTCTCG GGCAATTAGT ATTGGTTAGC 123240
TCAATGACTC ACATCACTTA CACACCCAAC CTATCTACGT CGTAGTCTAC AACAACCCTT 123300
ACTGACTTAA AGTCAGGGAT GACTCATCTC TTGGCAAGTT TCGTGCTTAG ATGCTTTCAG 123360
CACTTATCTC TTCCGCATTT AGCTACCCGG CAATGCGTCT GGCGACACA~ CCGGAACACC 123420
AGTGATGCGT CCACTCCGGT C~'L~'LC~'1'AC TAGGAGCAGC CCCAATCAAT CATCCTACGC 123480
CCACGGCAGA TAGGGACCGA ACTGTCTCAC GAC~'1''1'~'1'AA ACCCAGCTCG CGTACCACTT 123540
TAAATGGCGA ACAGCCATAC CCTTGGGACC TACTTCAGCC CCAGGATGTG ATGAGCCGAC 123600
ATCGAGGTGC CAAACACCGC CGTCGATATG AACTCTTGGG CGGTATCAGC CTGTTATCCC 123660
CGGAGTACCT TTTATCCGTT GAGCGATGGC CCTTCCATTC AGAACCACCG GATCACTATG 123720
-77.75-
SUBS i I I UTE SHEET ~RULE Z~i3
CA 02218741 1997-10-21
W 096133276 PCT/U~ 320
ACCTACTTTC GTACCTGCTC GA~-Ll~l~lG TCTCGCAGTT AAGCTTGCTT ATACCATTGC 123780
ACTAACCTCA CGATGTCCGA CCGTGATTAG CAAACCTTCG TGCTCCTCCG TTACGCTTTG 123840
GGAGGAGACC GCCCCAGTCA AACTACCCAC CAGACACTGT CCGAGACCAC GTTTCGTCAT 123900
~LlC~llAGA ACATCAAACG TTAAAGGGTG GTATTTCAAG GTCGCCTCCA CAATGACTGG 123960
,.
CGTCACTGCT TCAAAGGCTC CCACCTATCC TACACATCAA AATTCAATGT TCAGTGTCAA 124020
GCTATAGTAA AGGTTCACGG G~L~111CC~ TCTAGCCGCG GGTACACCGC ATCTTCACGG 124080
CGATTTCAAT TTCACTGAGT CTCGGGTGGA GACAGCCTGG CCATCATTAT GCCATTCGTG 124140
CAGGTCGGAA CTTACCCGAC AAGGAATTTC GCTACCTTAG GACCGTTATA GTTACGGCCG 124200
CCGTTTACTG GGGCTTCGAT CAGGTGCTTC L~lLlCGATG ACACCATCAA TTAACCTTCC 124260
AGCACCGGGC AGGCATCACA CCCTATACGT CCA~LllC~l GTTTGCAGAG TG~L~l~lll 124320
TTAATAAACA GTTGCAGCCA GCTGGTATCT TCGACCGGTT CAACCTTCAG GGGCTAGCCC 124380
TTACAATCTA CGCCGGCGCA CCTTCTCCCG AAGTTACGGT GCTATTTTGC CTAGTTCCTT 124440
CACCCGAGTT CTCTCAAGCG CCTGAGTATT CTCTACCTGA CCAC~l~*~l CG~Llll~AG 124500
TACG~lllAG TAAAGCCTTT CGCTTAGTGG CTTTTCCTGG AAGTGTGGTA TCAGTTACTT 124560
CAGCTCCGTA GAGCCTCGTC ATCATCTCTC l~l~llAAGG AAGTCCGGAT TTGCCTAAAC 124620
TTCCCACCTA CCAACTTAAA CGCACATATC CAACAGTGCG ATAACCTAAC CTACTCCGTC 124680
CCCACATCGC AGCTTTACCA AGTACAGGAA TATTAACCTG TTTCCCATCG ACTACGCTTT 124740
TCAGCCTCGC CTTAGGAGCC GACTCACCCT GCCCCGATTA ACGTTGGACA GGAACCCTTG 124800
CCGGC GAACGGGTTT TTCACCCGTT TTATCGTTAC TTATGTCAGC ATTCGCACTT 124860
GTGATACGTC CAGCCCACCT CTCGATGAAC ~Ll~llCCGC TTACACAACG CTCCCCTACC 124520
CAACAGAATA AATTCTGATG CCGCAGCTTC GGTGCTATAT TTCAGCCCCG TTACATCTTC 124980
CGCGCAGGCC GACTCGACTA GTGAGCTATT ACG~LLL~ll TAAATGATGG CTGCTTCTAA 125040
GCCAACATCC TAG~L~l~lA AGCCTTCCCA ~LlC~lLlCC CACTTAATAT AGACTTGGGG 125100
ACCTTAGCTG GCGGTCTGGG TTGTTTCCCT CTCCACGACG GACGTTAGCA CCCGCCGTGT 125160
GTCTCCTGAG TATCACTCTT TGGTATTCGT AGTTTGCATC GGGTTGGTAA GCCGGGATGG 125220
CCCCCTAGCC GAAACAGTGC TCTACCCCCA AAGGTGTCAC CTCAAGGCTC TACCTAAATA 125280
GATTTCGGGG AGAACCAGCT ATCTCCCGGT TTGATTGGCC TTTCACCCCC AGCCACAAGT 125340
CATCCGCTAA llLll~AACA TTAGTCGGTT CGGTCCTCCA GTTAGTGTTA CCCAACCTTC 125400
-77.76-
SUBSTmJTE SHEET tRULE 26)
CA 022l874l l997-l0-2l
W O 96/33276 . PCTAUS96105320
AACCTGCCCA TGGCTAGATC ACCGGGTTTC GGGTCTATAC CTTGCAACTA TTCGCCCAGT 125460
TAAGACTCGG TTTCCCTTCG GCTCCCCTAT TCGGTTAACC TCGCTACAAA ATATAAGTCG 125520
CTGACCCATT ATACA~AAGG TACGCAGTCA CAAGGTTGCC CTCGCTCCCA CTGCTTGTAC 125580
GTACAAGGTT TCAGGTTCTA TTTCACTCCC CTCACCGGGG '11~1L11CGC CTTTCCTTCA 125640
CAGTACTGGT TCACTATCGG TCAATCAGGA GTATTTAGCC TTGGAGGATG GGCCCCCCTT 125700
CTTCA~ACAG GATATCACGT GTCCCGCCCT ACTTCTCGTT AGCTTAGTAC CACAATATGG 125760
TTTTTAGATA CGGGATTATC ACC~'1'~'1"L'1'~ ATTGTGCTTC CCAACACATT CTCCTCACTA 125820
TATTGCTATC ACTTACTGGC TCTTTCGCTT TCGCTCGCCG CTACTGACGA AATCTCGGTT 125880
GA111~1111 CCTCGGGGTA CTTAGATGTT TCAGTTCTCC CGGTtTGCCT CAACAAGCTA 125940
TGAATTCACT TGTTGATAGT AGA11~11~A TCTACTGGGT TTCCCCATTC GGATATCTTG 126000
GATTA~ACGC CTCTTATCGA CTCATCCAAG ~L111CGCAG ATTAGCACGT C~L1~LLCGC 126060
CTCTGATTGC CAAGGCATCC AC~'L'1'~'1'ACG CTTAGTCACT TAACTATACA ACCTCAAATG 126120
TTTTCAATCA CTTTACGTTT TCACTTCA~A GTGCGGTCAA TTTGATGCGT ATTTTCATTC 126180
AACTAAACAC TTGATTGCTT TtGTTCAATC AAGATTTTTT TACA~AACAG ~'L'L'L'L~'L'L'L'1' 126240
TAGAGTTTCC TTTTCAGTTC TCTCTtTCAC TTTACTGTTt TGCCTACTCA GACTTTCTCT 126300
CGA~AATCTC '1''L~'1''L'11~AG ~LL~LLLCCA A'1"L'L'1"1"1'A~A GAACAGTAAG ACAATCTAAT 126360
A~AGTTATCT TTAATTGGCG TCCCCACGGG GATTCGAACC CCGGTTACCG CCGTGA~AGG 126420
GCGATGTCCT AGGCCTCTAG ACGATGGGGA CATCAATTAA AGATACTCTA 'L'L'1''1'~''1"1"1"1''1' 126480
A'L~'1"1''L'LAAC GTTTATTTTT CAACGTTGCT TTCGCTTCGT TTTTAATCTT GTCTACAACT 126540
ATCAGCCAAT ~1~L~1GAGC ACTCGCTGTC ~L~LC~L~L~LC AGTAAGGAGG TGATCCAACC 126600
GCAGGTTCCC CTACGGTTAC ~11~L1ACGA CTTCACCCCA GTCATGAATC ATACCGTGGT 126660
A~ACGCCCTC CAAAAGGTTA AGCTATCTAC TTCTGGTACA ACCCACTCCC A'l'G~l~'L~AC 126720
GGGCGGTGTG TACAAGGCCC GGGAACGTAT TCACCGCGAC ATTCTGATTC GCGATTACTA 126780
GCGATTCCGA CTTCATGGAG TCGAGTTGCA GACTCCAATC CGGACTTAGA CGTACTTTAT 126840
GAGATTCGCT CCACCTCGCA GCTTCGCTTC C~L~L~LATA CGCCATTGTA GCAC~L~L~1 126900
AGCCCTACTC GTAAGGGCCA TGATGACTTG ACGTCATCCC CACCTTCCTC CAGTTTATCA 126960
CTGGCAGTCT CCTTTGAGTT CCCGACCAAG TCGCTGGCAA CA~AGGATAA GGGTTGCGCT 127020
C~LLGC~GGA CTTAACCCAA CATTTCACAA CACGAGCTGA CGACAGCCAT GCAGCACCTG 127080
-77.77-
SUBSmUTE S~EFr tRULE 26)
-
CA 02218741 l997-l0-2l
W 096/33276 PCTrUS96/05320
TCTCTAAGTT CCCGAAGGCA CAAGCTCATC TCTGAGCTCT TCTTAGGATG TCAAGAGTAG 127140
GTAAGGTTCT TCGCGTTGCA TCGAATTAAA CCACATGCTC CACCGCTTGT GCGGGCCCCC 127200
GTCAATTCAT TTGAGTTTTA ACCTTGCGGC CGTACTCCCC AGGCGGTCGA TTTATCACGT 127260
TAGCTACGGG CACCAAGCTC TAAGCCCAAT CCCCAAATCG ACAGCGTTTA CAGCGTGGAC 127320
TACCAGGGTA TCTAATCCTG TTTGCTCCCC ACGCTTTCGC ACATGAGCGT CAGTACATTC 127380
CCAAGGGGCT GCCTTCGCCT TCGGTATTCC TCCACATCTC TACGCATTTC ACCGCTACAC 127440
GTGGAATTCT ACCCCTCCCT A~AGTACTCT AGTTACCCAG TCTGAAATGC AATTCCTAGG 127500
TTAAGCCCAG GGCTTTCACA CCTCACTTAA ATAACCGCCT GCGTGCCCTT TACGCCCAGT 127560
TATTCCGATT AACGCTCGCA CCCTCCGTAT TACCGCGGCT GCTGGCACGG AGTTAGCCGG 127620
TG~ll~l-l-~l GTATTTAACG TCAATTTGAT GTACTATTAA CACATCAACC TTCCTCAATA 127680
CCGAAAGAAC TTTACAACCC GAAGGCCTTC TTCATTCACG CGGCATGGCT GCGTCAGGGT 127740
TCCCCCCATT GCGCAATATT CCCCACTGCT GCCTCCCGTA GGAGTCTGGA CC~-1~1~'1~A 127800
GTTCCAGTGT GGCTGGTCAT CCTCTCAGAC CAGCTAGAGA TCGCAGGCTT GGTAGGCATT 127860
TACCCCACCA ACTACCTAAT CCCACTTGGG CTCATCCTAT GGCATGCGGC CTCTCAGTCC 127520
CGCACTTTCA TCTTCCGATA ATACGCGGTA TTAGCGACAG TTTCCCGTCG TTATCCCCCT 127980
CCATAAGCCA GATTCCCAAG CATTACTCAC CCGTCCGCCA ~-lC~l~AGCA AGAAAGCAAG 128040
CTTTCTCCTG CTACCGTTCG ACTTGCATGT GTTAAGCCTG CCGCCAGCGT TCAATCTGAG 128100
CCATGATCAA A~-l~ll-AAT TCAAGTTCAA TCGCTCAATA AACTGCTTAG CTATAAATAA 128160
AATACTACTT AAAAAAGTAA TAATGAATTT TCAGTTAAGC ACCTATTAAG ACTTCAAAAT 128220
TAAAAATAGT TTTAAAACAA GTCAATCAAC AAGTGCCCAC ACAGATTGTC TGATATATTG 128280
TTAAAGAGCA AAATAAAGTG GTCGGCGAGA TAGGATTTGA ACCTACGACC CACTGGTCCC 128340
AAACCAGTTG CGCTACCAAG CTGCGCTACT CGCCGTCAGA TCTTATAAAG ATAAGATGGG 128400
GTGGCTAATG GGATTCGAAC CCACGACAAC TGGAATCACA ATCCAGGGCT CTACCAACTG 128460
AGCTATAGCC ACCATTAAAA ~-ll~ll~ACTG CATTGACCTG GCGCGCTCGA CAAGATTCGA 128520
ACTTGCGACC TTTGGCTCCG GAGGCCAACG CTCTATCCAA CTGAGCTACG AACGCGTTAC 128580
TGC~lC~-llG CGGAGGCGTA TATTAATGAT TTAATAAAAC CTTGTCTAGC A~l-l--l-l-l~AA 128640
AAAAAATGTT TGAGCGATAG ~l-l-l-lllATTC A~-l-~ll~lllA A~ATACACTA L~lll-llCGAC 128700
TATTTTTACA ACTTGGCGAA TCATTATATA TGTgGAATCA TCCAACAATT ATGAATTTGT 128760
-77.78-
SU8S i ITUTE SHEET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
TTATTACGTT CAAAATCTAG CGGTAACGTT TTATGCGA~A TTTCTATTGC ACTTAAGCCT 128820
AATTCTTCCA ACGCAACTAA ATTCATTTTG AATCCACGTT TATTATTCGA A~AAACAATT 128880
GTGCCATTAT TCGACA~AAC 1C~111LA~A TTGCGCATTA ATTTCACATG A1~1C~11GC 128940
ACATCCCAAC 1~1~LLC~AT ACGTTTAGAA TTCGA~AACG TCGGTGGATC CGCA~ATATC 129000
A~ATCA~ATT GACGATCACA 1LLLL~LAAC CATTGAAGGC AATCTGCTTG AATTAATTTA 129060
TGTgGTTTAC CTTCAATATC ATTCAAAATA AGATTTTGCT CCGCCCAATT AAGATAAGTA 129120
TTTGACATAT CAACTGTAGT TGTCGATTTA GCGCCACCAA GTGCTGCATG AACAGTGGCA 129180
GAACCTGTAT AAGCA~ATAA GTTCAAGA~A TCTTTACCCT TTGCCAACTC ACCAATCATT 129240
LL1~1L~L1A AACGGTGATC TAAGAATAAT CCA~L~L~1A AATAATCTGT CA~ATTTACC 129300
CAAAGTTGCG TGCCATATTC ATTCACATAA AAGTATTCGC CTTTATTGGC TAA~11~L~A 129360
TATTGATTTG TAC~L1"LLLG L11~L~ACGA ACTTTGAGGA TCAACTTATT CGTTTCCACA 129420
C~L~L~ACTT GCA~AGTTGC AGTAACGGCA TCTAACA~AC GCTGACGAGC TTTATTTTCA 129480
TCAATATTTT TCGGCGCTGC ATACTCTTGC ACAACAATGT AATCTGCATA ACGATCAACA 129540
GCTAAATTAT ATTCTGGCAA ATCAGCATCA TATA~ACGAT AAGCGTCTAA LL~LL~LLGC 129600
TTTGCCCATT TGCTAATTTT CTTAATATTT L1LL~-LAATC GATTAGCA~A ATCGGGGGCG 129660
ACCTCCGAAG TGCGGTTA~A TTCTAGTTCC TTTTCATCTG TAATTGCGTC AGA'L1LLC~L 129720
TCTGA~ACTT GATAATTCTT TTGCACACAA TCTAGTGGGC CALLLLLLGC TTTA~ACTGT 129780
CGGCTGGCAC GCATTCTCAA ACAATCAAGC AATGTGGATT CGCTACTA~A AACAGA~ACA 129840
TTCCAACCGC A~AATTCTTT TTTAAGTCTT TGCCCA~ATA CAGAATAGAG CGCGATTA~A 129900
GCTGGTGTTG TTCCTA~ACG TTCGCCATAA GGTGGATTAC AGATAACCGT ACCGACTTCA 129960
TTTA~ACGAG GALLL11LAA CGCTGCCACA TCAGCTTGCT GCCATTTAAT TA~ATGTGAA 130020
ACACCTGCAT TTTGTGCATT TTTCTGCGCC L1LLLL~ATA CGCGGTGATC GAGGTCA~AT 130080
CCATA~AAGT GCGGTTGAAT TTCACGTTGT '1LL1~LL~LG CTAATTCAAT CGCTTCATTT 130140
TTTACTTTTT CCCAAGCCGA TTGATTATGC GCTTTCCA~A AATCA~ATCC CCAATGTA~A 130200
CGATA~AGTT GCGGCGCAAT TTTGGCTTCC ATTTGTGCCG CTTCAATTAA AAGCGTACCT 130260
GAACCACACA TTGGATCTAC TAATGGAGAA CCCACTTGCC AACCTGAACG CATTAACAAT 130320
TGCCGCCGCG AGAGTTTCAC GTAAAGGCGC TTGACCTGCA TCTTCACGAT AGCCTCGCAA 130380
ATGTAATGCT TCCCCACTTA AATCTA~AGA AATCACTA~A TTTTCACGAT TCA~ATAAGC 130440
-77.79-
SUBST~UTE S~E~T tRULE 2
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
ATGGATACGT ACGTCTGGCT GAATTTTATC TACATCAGGA CGAGTTTTAC CTTGACGTTC 130500
AAAGTAATCG ACAATTCCAT CTTTAACGCG CATCGCACCA AATTGAGTAT GACGAATTTC 130560
i:
TTGGTTGGTT CCATTAAAAT CGACA~AGAA TGTCACTCGT TCATCA~ATT GTGCTAACCA 130620
ATTAAAGCCT GA~ACAGCCG CATA~AGATC CA~ATCACTG TA~ATTTTGG TTTCAATCAA 130680
AGGA~ATAAA ATGCGTGAAG CAAGGCGTGA CCA~AGCA~A GTGCGGTATA AA~lllC~lC 130740
ATCAGCTTGA TAATGAACGC CACCTTGAAC CACTTTTGCC TCTTGCGCAC CCAGTTCAGT 130800
GAGTTCAACT TTTAATAATT CTTCAAAGCC ACGAGAAGTC GTTGCA~ATA A~ l~AT 130860
TTAGGTACCG ATTTTGAAAA TTTTGAGGGA TTATAGCATA GAAAAAGATG ATCTAATTGA 130920
GATCATCATA GCGAGTTA~A CTGTA~AAAG A~AAGCCCTG A~llll~llAA ATCAGGGCTT 130980
TAGAATTTGT TGGTTGCGGG GGCCGGATTT GAACCGACGG CCTTCGGGTT ATGAGCCCGA 131040
CGAGCTACCA AGCTGCTCCA CCCCGCgtCT GATGGGGCGT ACTATACTCG CTTA~AATTG 131100
AaTTGCAAGA ATTAAACAAA ACTTGATGTA t~ LA ATAAAATGTT CAATATGTGG 131160
TTTTATTAAT CAACTTCGCT AAATAACACT G~'1"1'~'1"L'1"1'C AGTAAATTTT GATAGCGTAT 131220
GCAGCCCTAT TGTrGCTTAC TTTAGAATTA AAAAATGTCG ATGCTTAAAC ~lll~l~GTT 131280
CA~AACTTTT TCTATCTCAA TTATTACCGC ACTTTTGGTA GCTTGTACCT CTAACACA~n 131340
A~ACACTCAG ATTCCAACCn CCTCA~ATGG GAGTGATCCT CAACAATTCG GTGTGCA~AA 131400
TATACCAATC GAACTTATCA GCA~ACCGCT CTTGTGCCTG lLlC~lATAT AGAAAACCAA 131460
AGTGCGGTAA TAAATCAAGG CGA~llllllA ACACAGCTTT CCAATATA~A A~ATTATTCA 131520
AGTAAACTTT CCACAAATTT TTACGATAAT TATGAAAAGA ATTACA~ATT GGGTTCTTTC 131580
TGGGGCAAAT ATTAATGAAC TCACTCAATT TAATATCCAA CCACA~ATTA TGCGTGGCTT 131640
TGATGGATTT CA~AATGTGC TGATGACAGG CTATTATTCG CCTATACTTT ATGCTCGTCA 131700
TTCCCCACAA GGTCAATTTA AAAATCCAAT TTATCGTATG CCTGTAAAAA AACGTCTAAG 131760
TCGAGCACAA ATTTATGCGG GAGCATTAGC GGA~AAAGAT TAGAGTTAGC ATATAGCGAT 131820
TCAATGTTAG AAAACTTTTT ACTTGGTGTA CAAGGCAGTG GCTATGTAGA TTTTGGCGAT 131880
GGCAATCTTA ACTATTTTGC TTACGCAGGA CAAAATGGTT ACCCTTACAC GGCTATCGGG 131940
CGTTTATTAG TAGAAGATGG CGAAATTCCA A~AGA~AAAA TGTCTATTCA AGCAATTCGA 132000
GAATGGGGTA ATCGTAATCC ~l~lC~lATA CAAAGCTTGT TAGAACGCAA TGAAGCTTAT 132060
GTAll~lllA AAAATGATCC AAGTGGCA~A GTGA~AGGCT CTGCGGGCGT TC~'1'~''1"1'~'1'A 132120
-77. 80-
SU~S i 11 UTE ~E~ (RULE 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GCAATGGCTT CAGTGGCATC AGATCGCAAT ATTATCCCAT CTG~lLCl~l GCTTTTAGTC 132180
GAAGTACCCG ACATTGATAA TAACGGA~AC TGGCTTGGCA CACACA~ATT ACACTTAATG 132240
GTTGCACTTG ATGTAGGCGG TGCAGTGA~A GGTCATCACT TTGACTTATA TCGTGGTATC 132300
GGTGCTAGAG CAGGACATAT TGCAGGGCTT TCA~AACACT ACGGTAGAGT ATGGGTATTA 132360
CGGTAATGGC TAGAATAGAT AATTACGAAC AACGCTTTGG TGGCATTGGA CGACTTTATA 132420
CGCCTGATAG CTTAGCACGC TTACGCCAAG CGCATATTTG CGTAATAGGC ATTGGTGGCG 132480
TGG~LL~llG GGTCGTGGAG GCCTTAGCAC GATCTGGCAT TGGCGAACTC ACATTAATTG 132540
ATATGGATGA TATTTGCGTC ACA~ATATCA ATCGCCAACT TCCTGCGATG AGCGGCACAA 132600
TCGGCA~ATT A~AAACTGAA GTCATGTCAG AGCGAGTA~A ATTAATTAAC CCAGAATGTA 132660
CCGTCAATAT TATTGATGAT TTTATCTCGC CAGAGAATCA ATCGGATTAT CTCAACCGAG 132720
GCTATGACTA CGTCATTGAT GCCATTGACA ATGTGA~AAC TA~AGCGTCG CTGATTGCTT 13?.780
ATTGTA~ACG TAACA~AATT AATGTGATTA CTATTGGCGG TGCTGGCGGT CA~ACTGATC 132840
CAACCCAAAT TCA~ATTGCC GATCTCAGTA A~ACCATTCA AGATCCGCTG CTCGCCAAAG 132900
TGCGGTCAGT TTTACGCAAG GATTACAATT TTAGCCA~AA TCCA~AGCGT A~ATTTAGTA 132960
TCGATGCGGT ATTTTCAACA CAACCTTTAA TATTCCCACA AATGACTGAA GG~L~Ll~lA 133020
CTTCTGCCAC AATGAATTGC GCAAATGGGT TTGGCGCAGC CACAATGATT ACGGCAACCT 133080
TTG~LLLLLL TGCC~LLL~L CGTGTAATAG ATA~ATTACT A~AGA~AAAA TCTTAATCAC 133140
~l~LL~AAAA TGCACATTGA CCATA~ATGT GCALLLLLLA TTGAATGA~A CCTATTGACT 133200
TTGA~AATGA A~AATTTTCC ~'L~'L'l''L'L'l'AC TATA~AATCG TTGCAATTTA TATA~AAAGG 133260
CGTACTCTTT TTTCCCTTTG AGAATTACTA CCAACAAGTA AGGA~ACATA AATATGA~AA 133320
AACTTTTAAA AATTAGTGCC ATTTCTGCCG CACTTTTAAG TGCGCCAATG ATGGCGAATG 133380
CCGATGTATT AGCATCAGTA A~ACCTTTAG GCTTTATTGT TTCATCTATT GCAGATGGCG 133440
TAACTGGTAC ACAAGTCCTT GTTCCTGCTG GCGCCTCTCC GCATGATTAC AATTTGA~AT 133500
TATCTGATAT TCA~AAAGTA A~ATCTGCAG ATTTAGTTGT ATGGATTGGT GAAGACATTG 133560
ATTCATTCTT AGACA~ACCA ATTAGCCA~A TTGAACGTAA A~AAGTGATT ACCATTGCCG 133620
ATCTTGCGGA TGTA~AACCT TTATTAAGTA AAGCTCACCA TGAGCATTTC CATGAAGATG 133680
GCGATCATGA TCATGACCAT AAGCACGAAC ACA~ACATGA TCATA~ACAC GACCATGACC 133740
ATGATCATGA TCATA~ACAC GAGCATA~AC ACGACCACGA ACATCATGAT CACGATCATC 133800
-77. 8 1 -
SUE~S i 11 UTE S~tE~T (RULE 2~i)
CA 022l874l l997-l0-2l
096/33276 PCTrUS96/05320
ACGAGGGTTT AACAACAAAC TGGCACGTTT GGTATTCTCC AGCTATCAGC A~AATTGTTG 133860
CACA~AAAGT AGCGGATA~A TTAACTGCAC AATTCCCAGA TAAAAAAGCG TTAATTGCAC 133920
AAAATCTTTC AGATTTTAAC CGCACTTTGG CAGAACA~AG TGAAAAAATT ACGGCACAAC 133980
TTGCAAATGT TA~AGATA~A GGTTTCTACG TTTTCCACGA TGCTTATGGT TATTTCAACG 134040
ATGCTTATGG TTTAAAACAA ACGGGTTACT TTACCATCAA TCCATTAGTG GCACCGGGTG 134100
CA~AAACTTT AGCGCACATT A~AGAAGAAA TTGATGAACA TAAAGTA~AT TGCTTATTCG 134160
CAGAGCCTCA ATTTACGCCA A~AGTGATTG A~l~lLlAGC GAAAAATACT A~AGTCAATG 134220
TAGGACAACT CGACCCAATT GGCGATA~AG TTACTTTAGG TAAAAATTCT TATGCAACAT 134280
TCTTGCAATC TACTGCAGAT AGCTACATGG AATGTTTAGC TAAATAAACC TTTCTAAAAA 134340
CAATGACCGC ACATAAAAGT GCGGTCATTT ~llllll~lAA ATTTGATATT TAGTTTTATC 134400
TCCAATATCA AAATGCA~AG GCATTCGCCA 'l"l"l"l"l'~'l'ATC GCTAAAACTA A~AGTAATAC 134460
GCCAGAAATA ATAGAAAAAA TGCGTAGTGC AATAAGATTA TTTAACACCC ACGAAAACCA 134520
CAAGCAAGCC ACAAATATCG GCTGTAAATT TAGCA~AGGC ACGCGGA~AC AAAAATATTC 134580
TTTAAAACAC A~ACCACCTA AAGTAAGTAA CGCACCGCCA AGAGCCAACG CAGGATAATG 134640
ATTAATATAA AAAAGTAGTC CAATCCAAGT TGCA~ATTGA AAAAGCAATC GAAAAGATTT 134700
TAAGTA~ATG TGTAACGAAG AGGCACAACA GGTTGCCGCA ATTAATATAA ATGTGAGTGA 134760
TAAATCTGGA TACCAACTCA CTGTAAGAAC AGCCAACGCC GCTATCACAA AACCAGTTCG 134820
GTAAATAATA ACAGTCAGAT AATCTAAAAA ATCCATCGGT GATTTAATAT GTGGATCAGC 134880
CATTGTATAA ATGTTCCTTT TTATGAATTA CA~ATTAAAA ATA~ATATAT CCTAAAAGTC 134940
AGAAATAAAA AGTACAGTCA ATTTA~AAAC AGGTTCTA~A TTAACCGCAC TTTTATTATT 135000
TCAGTTTTAG CTTATCAAGA All"llllGAT GAATGCCACC AAAACTGCCG TTAGACATCA 135060
CTAAAATATG ATCCGTAGGT TGAGCCTTTG CAACAATCAT ATCCACTAAT CGATCTA~AT 135120
TTGCATTCCA ATAAGCAGGT TGTACACATT GGTTTGCAAT ATCTGCCACT TCCCAAGA~A 135180
~'l''l'~'l"l'~AGG TTGAAGCATA AACACGGCAT CAGCTCGACC AAGTGCAGGC GCGATGTCAT 135240
CTTTATGAAC ACCCATTTTC All~l~llAG AACGAGGTTC AAGCACTGCA AGAATACGAA 135300
CACCACCACC AACTTTATCT CGTA~AGCGG TTAGCGTAGC AAGAATAGCT TCTGGATGAT 135360
GCGCAAAATC ATCATA~ACC GTAATGCTAT TAACTTCGCC TTTCACTTCT A~ACGACGTT 135420
TAGCATTCAC AAAAGATCCC AACGCTTTGC ACGCATCTTC AATAGCAACG CCAGTATGAT 135480
-77.82-
SUBSTITUTE SHE~T tRULE 2~
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
GAGCGGCAGC TATTGCCATT AACGCATTAT GCATATTATG TTGTCCCACT ACATTCCATT 135540
TTACTTCTGC CA~lll-ll~l CCATGATGGA AAACCGCAAA ATGTGAAGCA TCATTTGTAA 135600
TACGTTCAGC A~ACCACTCG TTATCTTTGC CTAAAAATTG ~l~llGAGAC CAACATCCCA 135660
ATGCCAAAGT ll~llllGCA ~'ll-l~ll'~'AC TCGCCGAACT TAATACCAAG CCACTGGCTG 135720
GGATAGTTCG AATCATATGA TGAAATTGGC GTTGGATCGC TTTGAGATCA TCA~AAATAT 135780
CAGCGTGATC AAAACTAATA ll~lllACGA TAAGTGTACG TGGATTGTAA TGGACAAATT 135840
TCGAACGTTT ATCAAAGAAA GCTGTATCAT ATTCATCAGC TTCAATAATA AAATAAGGGC 135900
TATCTCCTAA ACGAGCTGAA ATGCCAAAAT TACCCGCAAT TCCGCCGATT A~AAAACCTG 135960
ATTTTAAGCC A'1-L11'~'1"1~'1' AAGACCCACG TTAGCATACC TGTGGTCGTT ~lllllCCAT 136020
GCGTACCTGA AACCGCCAAT ACCCAACGAT CGCGCAATAA ATGATCATGT AACCATTGAG 136080
GGCCAGATGT GTATTTCAAA TTATTTTCCA ACACATATTC TACGCAAGGA TTACCACGTT 136140
TCATCGCATT ACCAACAATT ACCATATCAG GCGCAGGTTG TAATTGTGCA ACATCATAAT 136200
TTGGAATAAT CTCGATACCT TG~l~ll~-lA AAAAAGTGCT CATTGGAGGG TAAACATTAG 136260
TATCGGAACC CGTTACGTGA TAGCCCATTT GTTTAGCAAT CATCGCCACA CCGCCCATAA 136320
ATGTGCCACA AATACCTAAG ATATGAATAT GTTTCATTGT Alll~l~l~l TGATTAAGGA 136380
AAACGAA~AA TATGATAAAA CAACTTCTAT GAACTTTCAA AAGAAAAGAC CATCATACCA 136440
AACTATATGA TCTATAATTA ACGCCACTGA ACTATTATTT AACCACTTCA ATAGGAATAA 136500
ACAATGAAAT TTAAGCGATA AAGCAATTTC AGAAGCACAA TGGCTCACTA TTTACA~AGA 136560
A~ATAATCAG CCGTTCTATG TAGCAAATCT TCCTGCATTA CAATTTGGAA AAAGTATTCA 136620
AGTCGATATT ATTGGGACTT CAATTCATTT TGCTGACGGT ACCCAAATTG GTTTAGTTTC 136680
AGAACAAAAA TAATCCTATA AAAAATGCCT GTGTAAAACA GGCATTTTTT TATCCGCACT 136740
TTTAAGCAAT TCGCTCA~AA CCAGCTTTCA AATCTGCAAT TAGTTCATCC ACATTTTCAA 136800
AACCAATATG CACACGAATT AATGAACCTG TAAGATTACG TTTAATATTT GGACGAATAT 136860
GTGCAATTTC TT~lG~-L-lGA TTACAAAGAA TTAGAGACTC A~ATCCTCCC CATGAATAAG 136920
CCATAGCGAA CAGTTGA~AA TGATCCATAA ATTTTGATAC TTGCTCTGAA GTTAATCGCT 136980
GGGTTAATTC A~AAGAAAAT A~ACCACTGC TTCCACTA~A ATCACGTA~A AAGAATTCAT 137040
GACCAGGGCA ACTTGGTAAA GCTGGATGGT ACACAGTTTT TACTTCTGGT TGCTCACTCA 137100
ACCATTTTGC CACTTTAATA CTGCTTTCCT GAl~ll~lll TAATCGTACC CCCA~TGTAC 137160
-77.83 -
SUBST~TUTE SHFET tRULE 2
CA 02218741 l997-l0-2l
W 096/33276 PCTAUS96/05320
GGATACCACG AGCAGTCGTA TAAGCGGAAT CTGCATCAAC CATTTGCCCC ATTAAATAGG 137220
AA1~11-~1~1 AAGTTGATCC CAAGTTCGCG CATTCGCAAC GGCAGTACCA ATCATAATAT 137280
CTGAATGACC CACTAAATAT TTCGTACCCG CCTGAATAGA AATATCAATA TCATGCTCTA 137340
ACGCTTTAAA TAGAACACCT GCCGACCAAG TATTATCAAT CATAATCACA ATATTAGGGT 137400
TCACCTTTCT TGCAGCCTTC ACAATAGTCG GAATATCGGG AATTTCCATT GTAATAGAAC -137460
TCGGTGCTTC TAAGAAAAGT A~11-11~1AT 1CG~11GAAT AAGCGTTGCA ATATCTTCAC 137520
CAATAAGAGG ATCGTAATAA GTTATATCGA TCTGCATTTT TTTCAGCACA ATATTACAGA 137580
AATATTGGGT TGGCTCGTAA GCTGCGCCAC TCATTAGCAC ATGATCGCCA GTTTTAACAA 137640
AAGAAAGAAT CGAATTAGTT ACTGCTGCTG TACCACAAGG ATAAAGATAA CAACCTGCCC 137700
CCCCCTCCAT TTCGCACATT A~A1~11~1A AAGCAAAATG TGTTAGCGTC C~l~ll~lGC 137760
CATAAAATAA TTCGCCTTTT GCTCTACGTT GAGTAGCGTG ~11~1111ATCT TCAATACTGT 137820
CAAATAGTAA TGAAGAAGCT CGCTGTA~AA CAGGGTTTAC CGA1C~-L-L~1 GAAAAACGTT 137880
TTTGACGACC AGAATGAATA AACATTGTTG AAAGATCATA 11-1--1-~1--1--1GC ATATATTTCC 137940
TTATTTAAAT TAACTTATAG GGCA~AAATA ACTATGGTTT CAATTCCTAT CCGCACCTGA 138000
TTTTACTTCA TCTGCGGTAT TAGGCAATGG A~AAAATAAA GAGAAAACAA CAAATAATTC 138060
TGACGTCTAC ACAGAATCCC TAAAATAGAT GCTAACGAGC TTTAATTTTA TCAATTATTT 138120
ATAAAAAGCG ACCTTAGGTG G~-L-L-L-L-L-L1A TCATCAGAGA TAATTTAGAA TAAACCATCT 138180
TTAGCTAAAG TGCGGTCAAT 1LL1-~1ATGA AATTCAATAT CCCAATTTTC CTAACGATCT 138240
TTCGAGTCAT TTTGATTCCT '1-L-1-L1C~LGA TTGCATTTTA TTTACCCATT GAATCATCTC 138300
CTTTCATCAC AACGCTCATT 1111-1--LATTG CAGGTGTCAC TGACTGGCTA GATGGCTATC 138360
TAGCTCGTAA ATGGAAACAG ACCACGCGCT TTGGTGCATT TCTTGATCCT GTTGCTGATA 138420
AAGTAATGGT AGTGGCTGCA CTAGTTTTAA TTGTCGAACA TCAACATACA TTTTGGATAA 138480
CCATTCCTGC CATTATTATG ATTTCTCGTG AAATTATCAT CTCCGCATTA CGTGAATGGA 138540
TGGCAGAGCT TGGGGAACGT AGCAAAATCG CA~-1~-1~-1-LG GTGGGGAAAA TGGA~AACCA 138600
CAGCGCA~AT GTTAGCACTA GGCGGATTAT TATGGCGTTA TAACAACTAT ATGGAAATAG 138660
CAGCAATTAT CTTACTTTAT ATCGCCGCTA TTTTAACTAT ATGGTCAATG ATCCAATATT 138720
TACAAGTAGC A~AAGGAAGC TTGCTAGATA ATATTCAATT ATAAATTTAA ATAAAACACA 138780
r GTTATTTTTT ATGATAACCA TCTATATTTG AGTTATTTTT AATCAAATAA AATATTTTTT 138840
-77.84-
SUBSTITUTE SHEET ~RULE 26)
~ =
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
A'1'1"1"1"1"1"1'CG TTTGACAGCA ATATATA~AT CCGTAAAATA CGCCCC~1"1G TCACGCAGTA 138900
GTGCTGATTA GTGATAAATG CGGGAATAGC TCAGTTGGTA GAGCACGACC TTGCCAAGGT 138960
CGGGGTCGCG AGTTCGAGCC '1'C~'1''1''1'CCCG CTCCAATTTG CCCGAGTGGT GGAATCGGTA 139020
GACACAAGGG ATTTAAAATC CCTCGCCTTT CGAGGCGTGC CAGTTCAAGT CTGGCTTCGG 139080
GCACCATTTA AACACCAATT CAAAGATTTT AAAATTTATT TTAAAATCAT CTAATTGGGT 139140
CGTTAGCTCA GTCGGTAGAG CAGCGGACTT TTAATCCGTT GGTCGAAGGT TCGAATCCTT 139200
CACGACCCAC CACTTAAAAA TAAAGTAAGC ACCGAAAGGT ~1L11111AT TATCTAAATC 139260
TCTGAAACTC ATATAAAAAA TCCCCGACTC AAAGAATCAG GGACTTTTAC AATCAAACGT 139320
CTTTAATTAA TTAACGCTCA TTCCAACGTT TAATAGACTC ACGAATCACT TCTTTCGCTT 139380
CTTCTACATC GCCCCAATGA GTTACTTTCG TTGAGCCAGG '1''1"1'~'1''1'AAGC GCTTTATAGT 139440
TATTGAAATG GAACTCAATT TGTTTAATTA AGTTTGCCGG TAAATCTGCT AATGAATTGT 139500
AAGCATTTCC TGTATCACGA TCATCTGCAG GAACACAAAC GATTTTATCA TCCACTTCGC 139560
CATCATCAAC AAATTTCATG ACACCAATTA CTTTAGCCTC AAGGAATACA CCTGTTGCTA 139620
ATGGTTGGCG AGTGATTAAT AACACATCTA ACTCATCGCC ATCTTCATCT AAA~111~1G 139680
GAATGAAACC ATAGTTAGTT GGTTTTGCAA AAATTGCTGG CTCAACACGA TCTAACTGGA 139740
ATGCCGCAAC TTTACGGTTC CATTCGATTT TATGGCAGCT AC~'1''1'~'LGGA ATTTCATTTA 139800
CTACATTGAT AATGCCAGCA TCTACATCGC CTGGCGTTAA AATTTGATTA A~ATCAGCCA 139860
'1"L'1"1'~'1''L'1'CC TTCATTTTAT CAAGTTAAAA AACGCAACAA GTATAGCAGn lLll~LGCGA 139920
ACTCGCAGTC TCATTTGTAG AGAAAATCAG CAAATAGATC CATCTCATAA CTATTCATAA 139980
TTTTGACCGC ACTTTATCCT AAATAAAACT CACGCAAACG TTTACTTATC ~L1111ATGA 140040
TGTAAAATAG CGCACCTTAT TACTTCCAAT TTTTTACTTA ACTTCAAGGA ACACTATGCC 140100
AACTTTAGAA AAAACATTTG AGCTCAAACA ACGTGGTTCA A~'L~'L'LC~'LC AAGAAATTAT 140160
CGCGGGTTTA ACCACTTTCT TAGCAATGGT TTATTCTGTC ATCGTGGTAC CCAATATGCT 140220
TGGTGCTGCA GGTTTCCCTG CGGAATCTGT CTTTATTGCC AC~'L~'1"1"LAG TTGCAGGATT 140280
AGGCTCTATC TTAATCGGCT TATGGGCA~A TGCACCAATG GCAATTGGTT GTGCAATTTC 140340
TCTTACTGCT TTTACAGCAT TTAGCTTAGT GATTGGTCAA AAGGTCGCCA TTCCCGTnGC 140400
GCTAGGCGCA GTATTCTTAA TGGGGGTTGT GTTTACCTTA ATTTCTACCA CAGGTATCCG 140460
TGCATGGATC TTGCGTAATT TACCATCCAA TATCGCTCAT GGAGCAGGCA TTGGTATCGG 140520
-77.85-
SUB~ 111 UTE ~i~ FET tRULE 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
A~1~11111A CTTTTAATTG CCGCA~ACGG TGTTGGTTTA GTCGTCAGCA ACCAAGCTGG 140580
CTTACCAGTA AAATTAGGCG ATTTCACCTC ATTCCCAGTC ATGATGTCCT TAATTGGCTT 140640
AGCGTTAATT ATTGGCCTTG AAAAAATGAA AATTA~AGGC GGCATTTTAT GGGTAATTAT 140700
CGCTATTACT ATCGTAGGTT TAATTTTTGA TCCA~ATGTA A~ATTTGGCG GAGAGATTTT 140760
CA~AATGCCA ACCTTTGGTG A~AATTCTCT ~11--1~11ACAA TTAGACTTTA TGGGCGCACT 140820
ACAACCCGCA ATCTTGCCTG TGGTATTTGC TTTGGTGATG ACTGCCGTAT TTGATGCAAC 140880
CGGTACAATT CGTGCAGTTG CAGGTCAAGC AGACTTGCTT GATA~AGATG GTCA~ATTAT 140940
CAATGGCGGT AAAGCCTTAA CTTCAGATTC AATCAGTAGC TTATTCTCAG GCTTATTCGG 141000
TACAGCACCA GCTGCCGTTT ATATTGAGTC AGCAGCAGGG ACAGCAGCAG GCGGTAAAAC 141060
AGGTATTACT GCTATCGTTG TTG~1-~1-~-11 ATTCCTATTA ATG~-11L-1~1 TCCAACCATT 141120
AG~11-1~11A GTGCCAGGCT ACGCAACTGC TCCAGCATTA ATGTATGTTG GTTTATTAAT 141180
GTTAAGCAAT GTAAGCAAAT TAGATTTCGA TGA'11-1C'~11' GGCGCGATGA GCGGATTAAT 141240
CTGCGCAGTG TTTATCGTAC TTACCGCGAA CATCGTAACA GGCATTATGT TAGGTTTTGC 141300
GGCATTAGTA ATTGGAAGAA TCGTGAGTGG CGATATTAAA CGCTTAAATG TAGGTACTGT 141360
GATTATTGCA ATCGTACTTG TTGCATTCTA TGCAGGCGGT TGGGCGATTT AGTAACAGAA 141420
ATAAGA~AAG GGAAAAGCCT TCCCCTCAAT TTTAATCACA AAAGTGCGGT GA~ATTTTAC 141480
CGCACTTTTT TATACTTGGA TTACTCTTTC TTCAATAAGA AAATACCGTG GATCAGATAA 141540
ATTTACATAA G~-11~1111A AAATTGGCAT TAAAATCCCT CTGGTTTACA ATTTACCAGT 141600
A~ATCTTTGC CCCGCCCAGT TTGCAACCAC TTCCCCAATG GTTGCCCCAT ATAAACCGCA 141660
CTTTTAATCT CGCAACGTTG TGCATCGCTA CCCTCTGCAG CAAGATAAAT TGCTTCTGGG 141720
CGAATACCCA CTAAACATTC GCCATCGGGT AAATTAAACT GTGCAGCATC TTTTAAAGGC 141780
ACAGAGTAAC CATTAATATC CGCCACGCCA 111-1~-1AATT TTCCATCGAA AATACTGGAT 141840
TCGCCCATAA AGTTAGCCAA A~ACAGAGAA TTTGGTCGGA GATA~AGCTC TTTCGCCGGC 141900
G~-LLLLLGCA TAATTTTACC TTTATTCATC ACAATCACTT CATCAGATAC CGCAAATGCC 141g60
T~1~11--LGAT C~-L~L~-L~AC ATA~AGCGAA GTAATGCCTA AAC~11~11~ CAATTCACGG 142020
A111-L-1-1~AC GCATAGAACG ACGTAAGTTT GCATCTAAAT TACTTAATGG TTCATCAAAC 142080
AATAGGACTT TTGGTTTCAA TACCAAAGCA CGAGCCAATG CGACACGTTG TTGTTGCCCA 142140
CCAGAAATTT GATCCACGAA ACGATCTTCA AAGCCCGCTA AATCCACTAA TTCTAAAGCC 142200
-77.86-
SUBS i ~ ~ UTE SHEET ~RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
'L~-l-ll-lACAC GCTGAGCGCG LL~ll~ll-lG CCAATGCCTT GCATTTTTAA GCCGTAGCCC lg2260
ACGTTATCGC CAATGCTCAT ATGCGGGA~A AGCGCGTAAG ATTGGA~AAC AATACAAATA 142320
TCTCGATTCT GAATAGAGGA LLll~-llACA TCTTCGCCAT CAATAAATAT TTGACCTGAT 142380
GTTGGATTTT CTAATCCTGC CACTA~ACGT AATACGGTGG TTTTACCACA GCCT.GATGGC 142440
CCTAACAATG TTACCATTGT GCCACGTTTG ATCGTTAAAT CTAAATTATC AATGACGACC 142500
GCTTTACCAA ATG~L-ll-l~l GATATTTTTT AATACTAAGA AATCATTATT ACTCATAATT 142560
TTTACCTACA ACTTAACGAG TTAATTCATT LllllCGCTT TAGAACGGGA AATACGCGTA 142620
TCGCCTACAA TCCAGTCGAA A~ACAAAATA ATTGCCATCA TCACAACAAT TAAAATAGAA 142680
CCGTATGCAA TCGCAATGCC GTA~Ll-~lCCG l~llC~ACAC GATTTAAAAT ATATGCGGTA 142740
GACGCGAGTn TCTGCTGTCA CTAAGAATAT AATCGCACTT ACC~1C~1~A TTGCACGAAC 142800
GA~ACTAGTC ACTA~AGCAG A~AGCAACGC AGGTTTTAAT AATGGCAATA CGATAAAGCA 142860
CAAl~l-lllC CACGAACTCC CTTTTA~AGA AAGCGATGCT TCATCAAGGG ATTTATCAAG 142920
CTGTCCTAAC CCAGCAATCG CTGCTCGCAT ACCAATGGGT A~ATCACGCA TTACCATTGA 142980
AATAATCACG ATAATGCCCG TACCCGTAAT ATAAAGCGGT GCATTGTTGA AGGCTAAAAT 143040
GTAAGACACC CCAGCCACAG TACCTGGCAC GGCAAAACAA AGCATAGTTA AGAACTCAAG 143100
GGA~lllLllA C~lLG~A~AT CTTTACGCAC CACAATATAC GCAATCAATA ATCCAAAGAA 143160
TGCAGTTAAT GGCGCAGCAA TACCCGCATA GATTAAGGTA TTGATTAGTG ACGGCCACGC 143220
TCCATCGCTC AATCCTTGCC CGAATAACAT GGCATAGTTT TTCAAGGTTA AAGTGTAATT 143280
TACGCCCCAG TTTACAGTGA AA~llCC'~lA GA~AATACTA CCGTAAAGTG CCATATTA~A 143340
GATTACCCAG AAGCCAAGCA TACCGATGAT GGTATATTTC AAGCCATTTG GCAGCTCTTG 143400
CACATCGCCA CGATAAGATT TCCCCGA~AC AGTGACATAA GAGCGGTTAC CAATCCA~AT 143460
GTATTGAATG ATAAAAATCG CCAACGAGAA AATTAACAAC ATCGAACCCA AAGTACTGGC 143520
TGAAGCATAA TCAAGTTGTG AACCCGCAAT ATAGAAATAA A~l-ll~l~lGG CAATCACATC 143580
GA~ACTTCCA CCTAACACTA AAGGATTACT AAAGTCCGCC AATGATTGAA TGAATACAAT 143640
TAAGA~AGAA TTTGCTAATG CTGGACGCAG TAACGGAAAA ATAATCTGAT AGAACGTTTG 143700
ATAACGATTA GCACGCAACG TATAAGACGC LL~LL~AATA GACGGGTGTA CGGATTTTAA 143,60
TGCGCCATCT AAAATCATAA AAGAAATAGG AGCAAATGCG AGAATTTGAG CAATCGCAAT 143820
CCCATTAAAA CCATAAAGCC AATTATGACT AGAAAAACCA AaATTCGTAC TTAAAAATTC 143880
-77.87-
SUE~STmJTE S~EET tRULE 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
GGTTACATAA CCAGAACGTC CGAGCATTAA AGTAACCCCA AGTCCTACAA CAAATGGGGG' 143940
CGTCACAATT GGCAAAATAG AGAAAATTTT TCCGATAAAT GCCGTTCTAC GAGCGATACG 144000
CGTGGTATAG AGCGCAAAGG CTAAACCA~A TACAGTAGAA ACGATGCCCA CAAAGCCCGA 144060
TAAGA~AAGC GAATTGGTAA TTACGCGGAC AATATAGCTC TGCGTTAAAA TTCGCATCAC 144120
ll~ll~lGGC GCAAAGGTAT CGCCGTCATA A~ACATTGAA ACGAAAATCG CCAATGTTGG 144180
ATAAACGATA AAGAAGA~AA TGAGCAAGAT AATGCA~AGC A~AGAAGCGA TGATAAATTT 144240
ATCACCTTGC ATCACTTTTA GTTTTGCCAA TGAAAGTGTC GCCAATGCGG TATATCCCAC 144300
AAGTAACACA ATCACAGAAT AGCCCATACT AAllll~lAC ACCGTCGCAC TGATAAACAT 144360
AAACAGTACA GAAAGTGCGG TCA~AAATAG ~'l'~'l'~'l"l"l''L'l' GCTTGGGTTT GCTGTGGCAA 144420
TCTCAATAAC GGCAAAGCAC CATACACAAT TACAGGCAGG AACCAAGCCC AAGTTAAATT 144480
GAAAGAAGCC CAGCCCATTG CCTCTAAATA TTATCTGAAG TACTTTCAAA CA~ACCGTAA 144540
TCAAGTGCAT TGGAAGGCAG AAGTGCA~AC GCTAACAAGG ATA~AATAAT CCA~AAATAA 144600
GCAGAATGCA TTATGGAAAG lllLlllGCG TTCATACAAC CTCGCAGTAA AGAAAACCTG 144660
ACTTTCGCCT AGGGTAAGTA GGCCCTAGGA TAATTACAGT AACTCCCCTA TTGGGGAGTA 144720
AAAAGCTGTC CCAAAGGGGA ACTACTATTA CGATAATTAG CCGTGGGTAT ACTTACTCAC 144780
GGCTATGATT GTCACGAAAA CTATTTCGCC AATTTAACTT CTTGAACCCA TTTTTCAATT 144840
AAGGCTTTGC ~ TGCACCGTAT TTTTCAAAGT CATAATTGAT TAATTTGAGT 144900
TTATTTGGAT CAAATGCAGT TGGCGATTGT TCTGCGGTCG TGTTAGTTAA GATTTGTAAA 144960
GAATCCCCTT GTTTCCAAGC TAAll~ll~A ~~ "l"lG ATAAAGCCCA ATCGACGAAT 145020
AATTTTGCAT TATCAATATT ACGCGCACCT TTTAAGAnAC TCACGCCACC TAATTCATAG 145080
CCC~llC~ll CGCACGGCAC AACTAATTCT AATGGCGCAC CATTGCGTTT TTCTAAAGCA 145140
TAAlC~l~LA AGAAACCCAC CCCAATTGTC nTTCGCCACG CGCAGAGTTA CGTGATGGCG 145200
TGATACCCGA TTTGGTATAT TGAGAAACAT TAGGATGTAA ~'l'~''l''l''l"l'AGG A~ATCGAATG 145260
C~l~lrlllC GCCCCATAAT TGAACGAAAG TTGCCAATGC AGTGTAAGCA GTACCCGCAC 145320
TTTGAGGGTC TGCAATTTGA ACTTCACCTT TTAAGCGTGG ATCGGTTAAG TCTTTCCAGC 145380
ATTTTGGCAC ll~lllAATA CCTAATTTTG CCAAACGTTC AGTATTCACA CCGA~ACCTA 145440
AGATCCCCAT ATAAATTGAG GAAACATAAT GGC~lllC~l' TTTCGCTGGT TCACGGAAAC 145500
GTTCTACAAT TTCATCAATA TGTTTGGATT TATAAGGCTC AATTAACCCT AATTCTGCCG 145560
-77.88-
SUBSTI~UTE 5}~EET tRULE 2~)
CA 022l874l l997-l0-2l
W 096133276 PCT~US96/05320
CTTGAGCTTG AGGGTCAAAA GTACCGCCGA ACCA~ACATC CGCTTGAGGG TTALlllLll 145620
CAGCTTCAAC TTTAGCAAAA GTACTGCCTG AACCATTACG AATA~AGGAT ~Llll~ACAT 145680
CATATTTTTC GCCAAATGCT TTCGTGGTGG TTTCGCACAA AATATTGGTT GCACTACAAT 145740
ATACAACTAA ACGACCTTTA GCGTTAGCAG AACCAGAAAC AGCCAAGCCA GCAGCTAAAA 145800
GTGCGGTAGA AACAGAAAGA GAAATTTTGT TGAATTTCAT AATACATACT CCTTATTGGA 145860
TA~AATGTTT GAATCCTACT TGA~AAATAG A~ATAATACC GTGATGAAGT TCACAGTTTT 145920
TAAAATTCAA GTGAA~AAAT AnACGTGA~A TTCACCGCAC llll~LLlAT AATTGCAAGA 145980
AL-L-L-LC~L-1A CATCGA~ACA CGATTATGTC A~ATCCCTCT TGTATCATCA TCGCCATCAC 146040
AGGTGCATCT GCATCAGGCA A~AGTTCTAT CGCTTCCACT GTTCACA~AG AG~L~L~LAA 146100
TGAACTAGGC TGCCAAGA~A TTGGTATCAT TACTGAAGAC AGTTACTATA AAGATCA~AG 146160
TCATTTAGAA ATGACTGAGC GGGTA~AAAC GAATTACGAT CATCCA~ACT CTATGGATCG 146220
CGATTTACTT ATCCAACATT TAA~AAATCT A~AAAATGGC AGTGCAGTAG ATGTGCCTGT 146280
TTATAGCTAT GTAGAACATA CTCGCACCAA CGA~ACAACG CATTTCACAC CA~AACGAAT 146340
CGTAATTTTA GAAGGGATTT TATTACTTAC CGATGAACGA GTACGCCAAT TAGCCGATAT 146400
LL~L~LATTC GTAGACACAC CACTTGATAT LL~LLL~ATC CGCC~LLlAC AACGTGATAT 146460
GGAAGAACGT GGTCGCTCTC TACAATCAGT GATTGATCAA TALC~LG~AA CCGTGCGTCC 146520
AAL~LL~LlA CAATTTATTG AGCCGTCTAA ACAATATGCG GATATTGTCA TTCCTCGTGG 146580
TGGTAA~AAT CGCATTGCGA TCAATATGTT AAAAGCTCAA ATCCTTCATT TATTGAATCA 146640
AAAATAGGAA ATCTTATGCG TCTTTGCGAT ACTGATATTG AACGCTATCT TGATGATGGC 146700
ATTATTTCTT TAACACCACG TCCAAATAAT GACA~AATCA ACGGTGCGAC AATTGATGTT 146760
CGCTTGGGGA ALL~LLLCCG TGTATTTCGT GAACACTCTG CACCTTTTAT TGATCTAAGC 146820
GGCCCGAAAG AAGAAGTATC CGCCCAGCTT GAATCAGTAA TGAGCGATGA AATTATTATT 146880
CCAGAGGGGG AAGCATTTTT CTTACATCCT GGTACTTTAG CCTTAGCAAC CACGCTTGAA 146940
TCCGTGA~AT TGCCAGCCAA TATTATCGGT TGGTTAGATG GCC~L-L~LLC TTTAGCCCGT 147000
TTAGGCTTAA TGGTACACGT CACCGCACAC CGTATTGATC CAGGTTGGGA AGGAAAAATC 147060
GTGCTGGAAT TTTATAATTC AGGGAAATTA CCATTAGCAT TACGCCCAAA TATGGTAATT 147120
GGTGCGTTAA ~-L-L-LL~AAGT ATTAAGTGGC GAAssAAAAC GACCATACAG TAGCCGCA~A 147180
GATGCAAAAT ATAA~AnTCA ACAAAGTGCA GTAGCCAGTC GTATTGACGA AGACAAGGAA 147240
-77 . 89-
SUBSTTTUTE S~EET tRULE 26
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TAATCGATGA A~AAGTTCGC ACTTATCGTA GGGATCGTCG CTTTGGCGAT ~llll~llll 147300
TTATATATTC AACTTTACCG CGTGCA~AGT GCTATTAATG mACAACTGGC ACAACA~AAC 147360
ATTGCCGTTC AGTCAATCAA TTTATCATTA llll~lCCCG CACTTTCCCT TGA~AATATA 147420
AAAACTACGC AATTTTCAGC TCAAAAAATT GAAGCTA7.~AT TTA~Llllll GC~l~llLlG 147480
TATGGA~ACG CAGCACTTCA TTCACTGAAT ATTCAACAGC TCAAATTAAC TCAAAACACA 147540
CA7.~AATCCTG CCAATGTATC GATAGAGATT TCGCCTTTTT CATTAAAACA GCTTTTATCA 147600
A~AAAAGTAA TATTA~ATGG CGAAAACCAT ATTCGCATTG AATTTAATAA ACCTATTTAT 147660
GGAAAAACAA A~ACTTTCCA TTTTTCTTTC CATA7.~AGCGA ATTTAGACTT CTCAACATCA 147720
GAATCAACCC CACTTCAATT TGTAGATGCA AGCCTA~ATA ATCAGCCTAT CGGTTATATT 147780
GA7.~ACTCACA CAGCCCACCA ACA~ATAGTG ACTTATATAA AACCACAATG CGATAACGAT 147840
TGTTTAGCCG TATTGA~ATA TCAACA~ATA GACAATCA~A GTGCGGTA~A TTTTTCGGGT 147900
A7iATATTTCC ~l~ll~AACG CTTATTCGCA CTATTA~ATT TGCCAGA~AT GTTAAGTGGA 147960
CACGCCGATT TTGATCTTGA TTTCAGCTTT TCATCTTCCT CGCTTATTCA AGGA~AATTA 148020
AA~ AG CGCA~AATGG CGA~ATTCTT GGTGTGAATT TATTGGATAT GGTAGCGCAA 148080
TATTTCCCGA TTAATTACAA CAATGATTTG TTACA~AACA AAGAATTA7.~A CACTCGCTTT 148140
GAACAATTTT ACTTACAATT A~lll~lC~AA CA~AATCAAC TCATTGCTGA AAAAATCGAA 148200
TTA~AAACGC CCGCACTTTT GGGGCAAGGA A~AGGCATCA TTGATTTA~A TCGAATGGAA 148260
TGCAATGTGG ATATTAATTT A7~ATTCTACG GATCAACGCT ATCA~AATTT GACACTTCCA 148320
ATCAATTTTT TTGGTAACTG CAATTCTCCA CAATACAAAA TTAATTTTAC GAAGA7~ATTC 148380
CGCCATCAAT TAATTGATGC GATTA~AGAA AAGTTACGTT AATGTCGTTA TATTTA~AAG 148440
CTGA~AAAAT CCAATCATGG CGCGTGCTTA TTATGGCTTG CGCAGGATTT ATTTTTAATA 148500
CTACAGAATT TGTACCCGTT GCAATGTTAA GCGATATTGC ACA~AGTTTT GATATGCA7.~A 148560
CCGCCGATAC TGGTTTAATG ATGACAGTTT ATGCTTGGAC GGTGCTAATT ATGTCTTTGC 148620
CTGCGATGCT TGCCACGGGC AATATGGAAC GTA~AAGTCT GCTTATTAAG ~llll~ATTA 148680
TATTTATTGT TGGGCATATT TTATCGGTCA TTGCATGGAA llL~lG~ATA TTACTTCTCG 148740
CTCGAATGTG TATTGCATTA GCACATTCGG l~llllGGTC AATTACTGCC TCACTTGTGA 148800
TGCGCATCTC ACCTAAACAC AAGA7.~AACTC AAGCATTAGG AATGCTCGCT ATTGGCACCG 148860
CACTTGCCAC AATCTTAGGC TTACCGATTG GACGAATTGT CGGACAGCTC GTCGGTTGGC 148920
-77.90-
SUE~5 111 UTE 5~E~T ~RULE 2~
-
CA 022l874l l997-l0-2l
W 096~33276 PCTrUS96/05320
GGGTCACTTT TGGCATTATT GCGGTACTGG CATTATCCAT CA'1'~'1"1"1"1"1'A ATTATTCGAT 148980
TATTGCCA~A TTTACCCAGT AAAAATGCTG GCTCTATTGC AAGTTTACCC TTGCTTGCTA 149040
AACGTCCATT ATTACTTTGG CTTTACGTAA CAACGGCAAT CGTCATTTCA GCACACTTTA 149100
CTGCTTATAC TTATATCGAA CCATTTATGA TTGATGTAGG GCATTTAGAT CCA~ATTTTG 149160
CCACGGCTGT ATTATTAGTT '1''1''1'~'1''1"1'~'1' CAGGCATTGC AGCAAGCCTA TTATTTAACA 149220
GATTATACCG ATTTGCTCCC ACAAAATTTA Ll~ll~lllC GATGAGTTTA TTGATGTTCT 149280
CC~'1'~'1"1'GCT ACTCCTCTTT TCGACCA~AA CAATAATAGC AATGTTCAGC ~'1''L~'1'~'1"1"1'A 149340
TTTGGGGGAT TGGCATTTCT TGTATCGGAC TATCTCTACA AATGCGCGTA CTA~AACTTG 149400
CGCCAGATGC AACCGATGTT GCCACAGCTA TTTACTCGGG CATTTTCAAT GCAGGAATTG 149460
GCGCAGGCGC ATTATTTGGA AACCTTGCGA CAACCTATTT AGGATTA~AT GA~ATTGGTT 149520
ATACAGGCGC AGCATTAGGT TTAATCGGTT TCATCATTTT TATTACAACG CACTTA~AAT 149580
ATCGCCATAC A'L'1''L~'L'1'~'1'G CA~AACA~AT A~AAAAATAA CCGCACTTTA GTTCTCCAAA 149640
AAGAGTTTTA A~AGTGCGGT TA~ATCTTGC TAAGTTTTAT TTATCTTGCG TTTAACGTTT 149700
CG~LLL~LLA ATA~ATTTCA TCA~ACGTTT ACGTTTACGC AA'L'1'G~'L'LCG GAGTGAGTTT 149760
ATTTTTGCGT CCTGCA~ATG GGTTTGAGCC TTCTTGGAAA AGCAGACGAA TCGGTGAACC 143820
AATAATTTTT AAGCTCTTAC GATAATAATT AGATA~ATAA CGTTTATAAG AATCTGGTAG 149880
TTTATCCATT TGGTTACCGT GAACCACTAT AATCGGCGGA TTATAACCAC CTGGGTGAGC 149940
ATATTTTAAT TTAATGCGAC GACCGCCAAT CATCGGCGGT TGGTGCTCAT CCGTTGCCAT 150000
TTGCA~AATA CGAGTTA~AA GCGAAGTCGT CA'L'L'1''1"1''L~A GTGGCACAAG CATAGGCTTC 150060
TTTAATCGAA TCAAAAAGAT TACCTACACC A~'1''1'CC~'LGC AAGGCTGA~A TA~AATGCAC 150120
CCGAGCAAAA TCAATA~AAT CTA~ACGACG ATCAAGTTCA GATTTCACAC GA~L~LLL~Ac 150180
ATCTTGATCT A~ACCATCCC ATTTATTCAC GACGATCACC A~AGAACGCC CTGCATTTAA 150240
AATA~AGCCG AGCA~AGATA AATCCTGATC AGA~ATGTTC 'L~''L~'1'CGCAT CAATAGTCAG 150300
CAATACAACA TTAGCATCTT GAATCGCTTG TAAG~'1"1"L'1'A ATCACAGAGA ATTTTTCCAC 150360
TGCCA~ATGC ACTTTACCAC GCTTACGCAC ACCAGCCGTA TCAATCAAGG TATATTGCTG 150420
CCCATCACGC TCCATTGGAA TATA~ATACT GTCACGTGTC GTACCTGGCA TATCAAAAAC 150480
CACGACACGA TCTTCGCCTA A~ATACGATT GGTTA~AGTA GATTTACCCA CATTTGGACG 150540
ACCAACAATG GCAATCTTAA TATTTTTATC 'L'L~'L'L~'1''1'~'1' TCAAGTTCTT CGTCTAACGC 150600
-77.91-
SUBS i 11 UTE ~E~EET tRULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/05320
ATCATCAATT AATGCCGTAT CTTCTTCTGA ATTCAAAATC GAAll-ll~l TCCCATTCGT' 150660
~'l''l'~'l"L~'l"l'C CTCAGAAGTG CGGTCATTTT CATCGGCGTT TTCCATTTTT TCCGCAAAAG 150720
GssGCAAGTA ~ll~llCCAT TAATTGAGTA ACACCACGGC CTTGTGAGGC TGCGATTTGC 150780
TCAATTTCCC CTAAACCTAA CTGATA~AAT TCAGCACAAT GGGAATCCGC ATCAATACCA 150840
nCAGTTTTAT TTGCCACCAC CACAGTAATT ll~llllGAC GTTGGCGTAA ATAATTAGCA 150900
ATACCAATAT CAGCTGCCGT TAAACCCGCT CTAGCATCCA CAAGGA~AAG AACAATATCC 150g60
GCTTCATCAA TAGCAAGCAA AGATTGCTCC GCCATTTTTT CTTCTACACC CTCTTCCGTT 151020
CCATCAATAC CGCCAGTATC AATAACAATA AAATCATAGC CAGCAATATG TGCGTGACCA 151080
TAllll~lAT CACGAGTTAA ACCGGGA~AA TCAGCGACTA ACGCATCTCT CGTACGAGTA 151140
AGGCGATTAA ATAATGTGGA TTTTCCCACA TTTGGGCGAC CAACAAGGGC GACGACTGGA 151200
GTTGCCATAA A~AATCTCTT Allll~l~AA A~ATGGCGAC TATTATATCG GAAGTTA~AG 151260
GATTGGTAAA AAATCATTTC ATAAAGA~AA GA~AAAGCCA CAGGATACAA TCCTATGGCT 151320
TTCTAAATAC TGTTTATTTA TCTACAACTT AACGTTATAA TAATCTCGCT TTCAAGGATT 151380
CAGCTTGAAA GCGAGTGTTG CG~lllll~G CAAC~lll~A AGAGGATAAG AAAATGATTA 151440
AGATCATTAT C~ ~l'C~l~A CTACTATTAT TAGTGAGCCA GCCCGCTTAC TAATAACACG 151500
ACATACTAGG GAGTAACCGC TCCCTAGTTC TTCAAATATT A~AAGTTTAC TTTATTTTTG 151560
TCAAGATGAA TAAATTTCAG ATACAAAAAA AGCACCCTTA GGTGCTATCT TTATTTATCT 151620
TTATTTATCT TAATTGGCGG AATGGACGGG ACTCGAACCC GCGACCCCCT GCGTGACAGG 151680
CAGGTATTCT AACCAGCTGA ACTACCACTC CGAGATAAGA TATTAATTTT AAATTGGCGG 151740
AATGGACGGG ACTCGAACCC GCGACCCCCT GCGTGACAGG CAGGTATTCT AACCAGCTGA 151800
ACTACCACTC CGCTAAGTGG TGCGTATCTT AATGATGAAC ACAAATCTCG TCAATCTTTT 151860
TTTATTAAAT TTTACTTACC TGCTTA~ATT CCACACGATT AATGCACATT ATTATTGCCA 151920
AAACGTTTAT CCCAAAGGCA ATTATTTCCA ~lllllllAT TCATCATCTT TAAGAATTCT 151980
AAATGCGCTT GTAGCTCATC ATTAGTAGGT TGAAGTAATT TCA~ATTGTG CGAAAAATCT 152040
ACCGCACTTT TTAlll-ll~ CGCC~lllll TCTTGCATAA CACGGATAAC TCCAGACTCA 152100
ACAGATTCTT CTTCATCGAA TA~ATTTGTT TGCCCTCCCG TCATCATCAA ATAAACATCC 152160
GCCAAGATCT CGGCATCCAG TAACGCACCG TGCAAAGTAC GTTTGCTATT ATCAATACCT 152220
AAACGATCAC AAAGTGCATC CA~ATTATTG C~llllCCAG GATACATCTG ACGCGCCATT 152280
-77.92-
SUBS i 11 UTE ~HEE~ tRULE 26)
-
=
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96105320
TGTAGCGTAT CTGTCACCAA ACA~ATATCG TCAGTTTTCA CATTGAGGTT AAGTTTACGA 152340
AATTCATAAT CCATAAATCC AACGTCAAAG GGGGCATTGT GAATAAGCAA TTCTGCGCCA 152400
TTAATATAAT CCA~AAAATC TTGGGCAACT TCTTTGAATT CAGGTTTATC CGCTAACATT 152460
TCATCAGTAA TTCCATGAAC TTTAATCGCA TCAGGATCAn CGGGGCGATC TGGCTTAATA 152520
TAAATATGAn AATTATTACC TGTGTAacGA CGATTTATTA ATTCAACTGC ACCAATtTCA 152580
ATAATGCAGT GTCCTTCATA ATGCGCGCCA AGCTGATTCA TACCTGTAGT TTCAGTATCT 152640
AATACAATTT GGCGATTGGG ATTAATCATT TGTTCAACCT ATCTCTTTCC ATTAAAATAC 152700
TTGCCATTCT ACACAACAAC ~-l"l"l"l"l'~'l"l'A TGCCnAAACA GATTGAAATT TTTACTGATG 152760
GATCTTGCTT AGGTAATCCA GGGGCGGGCG GAATTGGTGC CGTATTGCGT TATAAACAAC 152820
ATGAA~AAAC ACTCTCCAAA GGCTATTTCC AAACCACCAA TAATCGAATG GAATTACGCG 152880
CTGTCATTGA AGCATTAAAT ACATTAAAAG AACCTTGCTT GATCACGCTT TATAGTGATA 152940
GCCAATATAT GAAAAATGGC ATAaCcAAAT GGATCTTTAA CTGGA~AAAA AATAATTGGA 153000
AAGCAAGTTC TGGAAAGCCT GTAAAAAACC AAGATTTATG GATAGCCTTA GATGAATCCA 153060
TCCAACgTCA TAAAATTAAT TGGCAATGGG TAAAAGGCCA TGCTGGACAC AGAGAAAATG 153120
AAATTTGCGA TGAATTAGCA A~AAAAGGGG CAGAAAATCC GACATTGGAA GATATGGGGT 153180
ACATAGnAGA ATAATACAAC TGATATAACG TCATATTTTT CGATACCTAA AAATATTTAA 153240
TACTTAAACC TAAAACAGAA TAAAAAATAA TCAAATTCAT TTaAAAAATG TGATCTCGAT 153300
CAGATTTCAA GnAAATTAAA ATTTTGGAGT ATTGACATCA AAAATTTTTT TTGTAAAGAT 153360
GCAGCTCGTC C~llllGGCG ATTGGACAAT TCTATTGGAG AAAAGTTCAA TCATAGATAG 153420
TAAACAACCA TAAGGnATAC AAATTATGAA AAAAACACTT GCAGCATTAA TCGTTGGTGC 153480
ATTCGCAGCT TCAGCAGCAA ACGCAGCTGT TGTTTATAAC AACGAAGGGA CTAACGTAGA 153540
ATTAGGTGGT CGTTTAAGCA TTATCGCAGA ACAAAGTAAT AGCACTGTAG ATAATCAAAA 153600
ACAGCAACAC GGTGCATTAC GCAATCAAGG TTCACGTTTC CACATTAAAG CAACTCATAA 153660
CTTCGGTGAT G~llL~lATG CACAAGGTTA TTTAGA~ACT C~11L1~11A CAAAAGCCTC 153720
TGAAAACGGT TCAGATAACT TCGGTGATAT TACAAGCA~A TATGCTTATG TTACTTTAGG 153780
AAATAAAGCA TTCGGTGAAG TAAAACTTGG TCGTGCGAAA ACTATTGCTG ATGGCATAAC 153840
AAGCGCAGAA GATAAAGAAT ATGGCGTTCT CAACAATAGT GACTATATTC CTACTAGTGG 153900
TAATACCGTT GGCTATACTT TTAAAGGTAT TGATGGTTTA GTATTAGGCG CTAATTATTT 153960
-77.93-
SUE~STITUTE ~EET ~RULE 26)
CA 02218741 l997-l0-2l
W 096/33276 PCT~US96/05320
ATTAGCACAA AAGCGTGAGG GTGCAAAAAA TACA~ATAAG CAGCCTAATG ATAAGGCTGG 154020
TGAAGTACGT ATAGGTGA~A TCAATAATGG AATTCAAGTT GGTGCAAAAT ATGATGCA~A 154080
CGACATCGTT GCA~AAATTG CTTATGGTAG AACTAACTAC A~ATATAACG AAGCTGACGA 154140
GCATACACAG CAATTA~ATG GTGTATTAGC AACTTTAGGC TA'LC~lLLlA GTGATTTAGG 154200
CTTATTAGTG TCTCTAGATA GTGGCTATGC AAAAACTAAA AACTATAAAA CTA~ACACGA 154260
AAAACGCTAT TTCGTATCTC CAGGTTTCCA ATATGAATTA ATGGAAGATA CTAATGTCTA 154320
TGGCAACTTC A~ATATGAnC GCA~ll~l~l AGATCAAGGT GAAAAAACAC GTGAACAAGC 154380
AGTATTATTC GGTGTAGATC ATA~ACTTCA CAAACAACTA TTAACCTATA TTGAaGGTGC 154440
TTACGCTAGA nCTAAAACAA CTAATGGAGG CGTAAAAACT GA~AAAGAAA AATCAGTGGG 154500
TGTAGGTTTA CGCGTTTACT TCTAATCATT TGTTAGAAAT ACATTATTAA AAGCAAGGCG 154560
AATCGAAAGA TTCGCTtTTT TTTTTGCTCA A~ATCAAGTT AAAAAATGAT TAAGTTAAAA 154620
GTGTATAAAT ATTTAGGCTA TTTTATAATT AATAAAAAAt CTGTGATATA TATCACAGAT 154680
TTTTAAATCA ATTAACTATT TAA~L~lllA CTATTAATTC T~LllC~ACT TTCCGTTTAC 154740
TACTGTGCCG ATTACTTGGT AATTTGGCGT A~ACACGGCT AAGTTTGCTA TCTTACCTTT 154800
TTCTACCGAA CCTA~ACGAT CATCTATACC AATTGCTCGT GCAGGATAAA GGTTACTCAT 154860
TCTAATGGCT TCCGCAAGAG GAATTTCGAC ATATTCTACC GCATTTTTAA TGGATTCCAT 154920
CATTGTGATT GATGCCCCTG CAATTGTGTC ATTCGCATCA TAGCAACGCC ~LL~lll~AT 154980
ATAAATTGTT TTTCCCACAA AGGTAAAACT TTCTAGTTCT GGCGGTGCGC CTGCAGCTGC 155040
AATAGAGTCA GTCACAATAC AAAGTTTGTC GCCTTTGATT TTTTTATCAA TGCGAACATT 155100
GCCGTAATTG ATATGCACAC CATCGACGAT AATGCCAGTG TA~ACATCAG AATCTAATAC 155160
TGCACCCACT ACGCCCATTT CACGTCCAGA ACTAATTGGC GACATCGCAT TATGCAAGTG 155220
AGTCGCAAAA GTTGCGCCTT TGTGGAATGC GGCTTTAGCC ACTTCATAAG TGGCATTAGA 155280
ATGGCCTACA GAGACAATAA TGCCCGCTTT CACAAAATCA GGCGTATAGT TAATGGTTGG 155340
GCG GCAATGGTCA Lllll~LAAT CACATCACCA TTTTCGCAGA GAAAATCTTT 155400
CATTTCAGGC GTAATTTCAC GAATATATTC GGGACGGTGT ACGCCTTTTT TCTCAATGCT 155460
GAGATAAGGT CCTTCAATAT GTAAACCAAG TGCTTGGTTT TTATGCTTGT TTAAATATTC 155520
ACGCATAATT TTTACCGCAC TTTTTATATT TTCATCAGGC GCGGTAATAA AAGTGGGAAG 155580
GA~ACTTGTA CAACCTGATT TTAAGTTAGT TTCCTGCATA ATTTCCAAGG TTTCAACGCT 155640
-77.94-
SUBS i 11 UTE S~EET (RULE ~6)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
AGTTTGGTCG TTAAACATCA CGCCACCACA GCCATTTAAT TGCAGATCAA TAAAACCAGC 15S700
CGTTA~ATTA TTACCTTGTA AATCAATGGT TTTGATACCT ~'1"1"1'~'1'AATT CAGCTTGGGG 155760
GATCACTGCT TCAATAATTT CACCGTTAAT AATTACAGCA A~ATCACGTA A~ACATCATA 155~20
'1"1"1"1'~'1'~'1'AA ATTACACAAT TAATTAATGC GTATTTCATA Ll~l~llC~l AATATCAACA 155880
TCAGTTTAAC ATAGCAACTA TATTGCTCTT AAACGTAAGG ACAATTTGCC CTATGATTGT 155940
TTGTGATTAT AGGGCGAATG TAATTCGCCC CTACATA~AG ATGAAGAATA GATCTCTATT 156000
TATCCTGATA ATCCGTACCA GCAACCGCGC CTTCTAATTC AGTA~AATAT TTCACGGTTT 156060
TCACTTTTAG ~'1'~'L'L~'L'L~A GATTATAGGG CGAATGTAAT TCGCCCCTAC ATA~AGATGA 156120
AGAATAGATC TCTATTTATC CTGATAATCC GTACCAGCAA CTGCGCCTTC TAATTCAGTA 156180
A~ATATTTCA CG~LLLL.AC TTTTAACTCT TGTTGAGCAG CTTCATCACA AACAAGCAAG 156240
A~ATGACGGT GCATTTGTAA TGCACTGACT GTCCATA~AT GGTTAATACT GCCTTCAACT 156300
GCAGCTTGCA CTGCCAGTGC ~LL1L1~ATGT CCTGTTGCTA A~ATCATCAC 'L'l ~'L'L~'l'GCA 156360
TCTAATAATG TGCCAACACC AATGGTTA~A GCATATTTCG GCACTTGAGT AACATCATTA 156420
TTAAAGAAGC GTGAATTTGC AATCAATGTA TCTTGCGTTA GC~L~L~LAAT ACGGGTGCGA 156480
GAACTTAATG AAGAAGCAGG TTCATTA~AT GCGATATGTC CATCTACGCC AACCCCCCCC 156540
ATA~ACAGAT GAATTTTGCC GTAGGATTTA A'L'L'L'L'L'L~'L'L CATAACGACG GCATTCTGCA 156600
TTATGGTCAT CGGTATTGCC GTTAAGAATA TTGATATTTT CAGGTAAAAT ATCGATATGA 156660
TTGAAAAAAT TGTTATACAT A~AGCTGTGG TAACTTTCAG G~'L~'1"LCCTC TGGTA~AGCC 156720
ACATATTCAT CCATATTGAA AGTCACTACG 'L~L11~A~AC TCACTTTGCC TGCTTGATAA 156780
AGTCGAATCA ~LL~1LGATA A~'1"1"L'1"LAGT GGTGTGCCAC CAGTAGGTAA CCCCAATACA 156840
A~AGGACGCT CGGCGGTAGG TTTA~AATCG TTGATACGAT TGATGATATG TTGTGCAGCC 156900
CAACAACTGA ~ L~L~L~L~1~C ~L~L~L~L~1~AAT GGAATAAAAC GCATATTAGC ~LLC~l'L'LAT 156960
TATTGACCGT GATGATCCTA TTCATATCGT AGGCTGGACT TTAGCCCACC CTACACCAAA 157020
GGATCATTAT AAGTGCGGCA A'1"1''L'L~'LATC 'LL~LL1LLAA A~AGA~ATTC TTTTGCTCCA 157080
ATAATTTACG ACAGAGCAAT AGAAGTTGCC CCCTTCCGCC CTTCGGGCAC CTTCCCCCGT 157140
A~ACAGGGGA AGGA~AGTGC TTGCTGACTT G~'L~'1"1'~'L~'L TTGTAACGGA ATA~AACAGG 157200
GGGAGGTAAG '1"1"L'1''1"1'~'LAA TTTAAATATT TATGACA~AA ATTTCGCTTT CAAGTCTTTT 157260
GCTTTTGCAA G~'1'~'L'L~'L'1'C TGTTGCTTTT GATGTCATTG GTTCACGGCA ATAACCTGCA 157320
-77.95-
SU85 i I i UTE S~EE~ ~RULE ~6)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TCCACCCCTT CTAATTTAAG CAATTCTTTG ATGGTTAAAT ATAAACCGTT CGCTAAAATG 157380
CCTTCGATTA AATCGTTGGT TACGTGTTGG ATTTCTAACG CTTCGGCTAA TTTACCCGCT 157440
TTGGTTAATT CAAAAATTTG ACGAGCACGA ACGCCGTTTA CGTTAAAGGT TGAACCAATT 157500
GCACCATCTA CCCCAAGTGA TGCTGCAGGT AACATCATTT CATCGAAACC TGCCCAAATT 157560
AAGTGGTTTG GATAAGCTTT TTTCAAACGT TCTAATAAAT AGAAATCACC TGCTGTGAAT 157620
TTTACCCCTA ATA~lllCGG ~lllllATAA AGTTCACCGA AlL~Ll~AAT GCCCATATTC 157680
ACGCCAGTTA AGAACGGGAT AGAGTACACA ATCATATTGT TGC-lvlllC AGCGATGATG 157740
~l~l~lAAT AATGTTTAAT TTCAGGGAAG CTAAATTTGT AATAGAATGG CGTCACTGCA 157800
GATAAGCAGT CGTAGCCTAA ~ll~l~llGCA TATTTACCTA ATTCCACCGC 'll~llllAAG 157860
TTTACACTAC CCACTTGAGC AATTAGTGCG ATTTGATCTT TTGCTTCATC TTTTGCAATG 157920
CGGAAGATTT ~llllllCTC TTCCGTTGAA AGCATAAAGT TTTCGCCTGT TGAACCGCCC 157980
ACATATAAGC CATCAACTTT CATTTTGTCG ATATTATGGC GGATAATTTG GCGTAAACCT 158040
TTTTCATTAA TGGTGCCATC TTCATTAAAT GACACTAATA ATGCACTGAA AATACCTTTT 158100
AAATCACGCA TAA~lllL~ CCTATTTTAT AC~11~11~A AGAATTACAT TGAGAGTTTT 158160
ll~lllAGTT TGAGCGGCAA TAl~Ll~llC GCCCTGCACT AACAAAGCAT AAATTAAATC 158220
TAATACAA~A AGCTGTGCAA TTTTGGTGCC AATAGAATCG CCTTGTAACT TGC~ll~lll 158280
ATTACCATTT ACCAAAACAT AATCAGCATA TTCTGTCACG GGGGAACGCA AACTATGCGT 15~340
CAATGCCACT ~ll~llGCAC CAllll~lll TGCGATTTTG ATGGTATGCG ~C~lll~AGC 158400
AGAATAACCA GAATGGCTTA AACCAATTGC CACATCAGAA GAGGTCAATA ATGCCGCCTG 158460
CATATACATA AAATGATTAT TACCTGAAGC ATCCACTTGA AAACCAATAC GCATCAGCTT 158520
ATTTTTAGCA TCTTCAGCCG TTACGCCAGA TGAACCCACC CCAAATAAAA AAATACGGCG 158580
TG~llllllA AGTACTTTAA CGACTTCTTC AAG~l~llll AAATCAAGTA AATTAATCGT 158640
l~l~LlC~ATT ACATTAGCAA CCGCCGTTTG CAAlllLl~l~ GCAATAGTGA GCGAATCATC 158700
ACTTGGCATA Alll~l~lll CAAGTATGCT TTCATCTTGA TTATCTTTCG TCGCAAGTTC 158760
AATAGAAAGC TCTAGTTTGA ACTCGCTGAA ACCTTTAAAA CCAATGGTTC GACAAAAACG 158820
GACGAGCGTA G~ll~lCCAA CTTGCAAATG TTTAGCGATT TCTGAAAGGG AGCATTGAGA 158880
GACTAAATCA GGCGAACGCA A~ATCGTATC GGCAATTTTT ~ ~ATT TAGTTAAACT 158940
CTGGTAAAGT GAGCCAATTT TGTTTAACAC ATTTCCCGAT TTAGCCATAA ATTGTTCCTT 159000
-77.96-
SUBS 111 UTE ~i~{E~T tRULE 2fi)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
CAGGCTTATC CAGTAAAACA TCTTTTACCC AATAAGCTGC GCCAATTAAA CCTGCATCTT 159060
GTCCAAATTT AGCGGTTTCA ATTTCACAAC AATATATCGA AGGAAAATCT TGTA~ATATT 159120
TTTCAACCAA AGATAAATAT CCCTCAGCTA ATCCCACACT GCCACCAATC GCGATTTTTT 159180
GAATATCTAA ACTAATCACT A~ATCAGCAA TTAAATTAGC AATGGCTTTC GCAGAACGCT 159240
CGACAAGTGC GGTCGCTTTT TCATCATTTT TTCTAAAACG CTCAAACACT l~llllGGAT 159300
CGCACGGTTC TTCCCATTGG GAAGA~ACTG CTTCAATTGC TCGCCCTGAA GCAATCGCTT 159360
CGACACAACC TCGACGCCCA CAACCACAGA TCGCACCATT TGGATCAGCT AATGTATGAC 159420
CAATATGCCC AGCAATACCA CGAGAACCTG TCTGCAAAAT TTGGTTCAGC ACAATCCCTC 15g480
CGCCAACTCC TGTTGAAACG GTAATA~AAA CAAAATTTGA TAC~l~ll~A GAATTTTGCA 159540
ATTGATATTC CGCATAAGTC GCAGCTTGTG CATCATTTAA TAAACCAATC GGTTTATCCG 159600
TAL~llllGC AATACTCGCT TTAAGTGGAA ATTCCGCCAA GCCACCTAAG lllllCGGAT 159660
TTAATGCACT TA~AATGCCA TTATTGATGA TCCCCGTAGA TGCTACCGCT ACATAATCAA 159720
ACTGCCCTTC ATAATCAGCA AGCAATTTGC CTAACGCTTG GTGCATTCCC TCCACGACAT 159780
TTTCACGTGG TGTATGAATT TGCTGACGTT GCTCAATTTC GCCATTTTTT ACAATCGCCG 159840
CTGCAATTTT TGTCCCACCA ATATCTAGTG CTAAACAACG CATAACTTAT CCTTATAGTG 159900
TAAAGTCkTT nTCTCACACG TCTTACGACT ATCTTGCAGA TTTCACTGAA TTAGCAAACC 159960
AACTCACAAT ATGTTCAAGA CGAGTTAAGG CTGAACCTAC AGTCACGCAA TCTGCACCAA 160020
TTTCAATTGC CACTTTTGCC AATTCTGGTG TGTTATAACG CCCCTCAGCC ATCACAAAAC 160080
AACCCGCTGA TTTTAAATCT TTCACTAATT GATAATCTGG TTCTTCTGGC ACTGCGCCAC 160140
CTGTATAACC TGACATCGTA CTGCCGACAA TATCAAAACC AAGCGCTTTA CAATACAAGC 160200
CTTCTTCTAA ATTAGGaACA ATCTGCCATT GCCAAACAGC CCA~lllC~LG GA~lllllllC 160260
ACCGCACTTT CAATATCCAC AGGACGTGGA CGGCTCGTGC CATCTACTGC AATAATATCC 160320
GCGCCAGCAT TGGCTAGATC TTCAATATCT TGTAAAAACG GCGTAATACG CACGGGACTA 160380
TCAGGCAAAT CAC~llllAC AATTCCGATA ATCGGGACAT TCACAAAAGG ACGGGTTGCT 160440
TTAAGGTTAT CAACACCCTC AATACGTAAG CCAGAACGTC CGCCCATAAC TGAAGCCTGA 160500
GCCATAGCAG A~ACGATTTC AGGTTTATCC ATTGGGCCAT CATCGACAGG TTGGCAAGaA 160560
GAAATAAGAC CATATTGAAT TTGAGA~AGC A~ll~ll~AT AAGATAATTT AGACATATA~ 160620
CACCCCTCAT TTAAATCTGA ATAAATCACT TTA~AATTAA TTTAATCCAC ACA~AACAAT 160680
-77.97-
SUB5TITUTE SHE~T tRULE 2~)
CA 02218741 1997-10-21
W O 96/33276 PCTnUS96105320
CTTTTATAAG TTGTAATATG CTTATATTTT CATCATTTAA CCTTATTATA TGAAAAATAA 160740
ATGCCATTTT AAAGAATATT TTTGAAGTGT Llll-l~ATAA ATGTGATCAA CTTCTCATTT 160800
TGGAAATAAA ACTCGTA~AA CTATTTTA~A 'l"l"l'~'l"l"l"L'L'L TACTCTTAGA ATTGCTCTCG 160860
AATCCTATTT TGGGGGAGAA AACATACATT TTTGGCCTAA ATTGATTCTC ATATTACGGG 160920
GTTAATcTAT GCCCCTTTCC AACATAAGTT CACACAGGAG CGAATATGAT GAAATTGACA 160980
AAACTTTTCC TTGCCACCGC CA'LlLClllA GGCGTATCTT CTGCTGtTCT TGCCGCTGAT 161040
TATGACTTGA AATTCGGTAT GAATGCTGGA ACTTCATCAA ATGAATATAA AGCGGCAGAA 161100
ATGTTTGCCA AAGAAGTCAA AGAAAAATCA CAGGGTAAAA TTGAAATTTC ACTTTATCCA 161160
AGTTCACAAT TAGGTGATGA CCGTGCAATG TTAAAACAAT TAAAAGACGG ~Ll~L~lCGAC 161220
TTTACCTTTG CAGAATCTGC TCGCTTCCAG ~L~LlllACC CTGAAGCGGC AGTATTTGCC 161280
TTACCTTATG TTATTAGCAA CTACAATGTT GCACAAAAAG CCTTATTCGA TACAGAATTC 161~40
GGTAAAGATT TAATTAAAAA AATGGATAAA GATCTTGGCG TGACTTTACT TTCCCAAGCT 161400
TATAACGGAA CTCGCCAAAC GACTTCAAAT CGTGCAATCA ACAGTATTGC AGATATGAAA 161460
GGCTTA~AAC LlC~L~LGCC AAATGCAGCA ACA~ACTTAG CCTATGCTAA ATATGTTGGT 161520
GCATCACCAA CACCAATGGC ALlll~lGAA GTTTATCTTG CGTTACAAAC CAATGCCGTC 161580
GATGGTCAAG AAAACCCGTT AGCAGCGGTG CAAGCACAAA AATTCTATGA AGTGCAAAAG 161640
TTCTTAGCAA TGACTAATCA TATTTTGAAT GACCAACTTT ATTTAGTAAG CAACGAGACT 161700
TATAAAGAAC TCCCTGAAGA TCTTCAAAAA GTCGTAAAAG ATGCTGCCGA AAATGCAGCA 161760
AAATATCACA CTAAATTATT CGTAGATGGA GAGA~AGATT TAGTCACATT CTTTGAAAAA 161820
CAAGGCGTGA AAATTACACA TCCTGATCTT GTTCCATTTA AAGAATCAAT GAAGCCGTAT 161880
TATGCTGAGT TTGTAAAACA AACTGGTCAA AAAGGTGAAT CAGCTTTAAA ACA~ATTGAA 161940
GCAATCAATC CATAATCCCT CTTTAGTGTG CCGTAATGGC CCTACATTCC CTTATTCTTC 162000
ATCAAACGGA GTGAGTATGA AATATATTAA TAAGCTTGAG GAATGGCTGG GTGGCGCATT 162060
ATTTATCGCC ATTTTCGGTA TTCTTATCGC TCAAATTCTT TCACGCCAAG TTTTTCATTC 162120
TCCGTTAATT TGGAGTGAAG AACTCGCCAA GCTCTTATTT GTTTACGTGG GTATGTTGGG 162180
TATCAGCGTT GCTGTGAGAA AACAAGAACA CGTATTTATT GALllLlLAA CTAATCTAAT 162240
GCCCGAAAAA ATCAGAAAAT TCACA~ATAC ~Lll~lACAA TTATTAGTCT TTATATGTAT 162300
TTT ATTCATTTCG GTATTCGTAC TTTTAACGGT GCATCATTCC CTATTGATGC 162360
-77.98-
SUBS 111 UTE ~HEET tRULE 2h~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
CTTAGGAGGC ATTTCTGAAA AATGGATTTT CGCAGCACTG C~L~ll~LCG CAATATTAAT 162420
GAL~lllCGC TTTATCCAAG CGCA~ACCCT A~ACTTTAAG ACTGGGAAAA GCTATTTACC 162480
TGCAACTTTC TTTATCATAA GTGCGGTCAT TTTATTTGCG ATTTTATTTT TCGCGCCAGA 162540
TTGGTTCAAA GTATTGCGTA TTAGCAATTA TATA~AACTC GGTTCAAGTT CAGTCTATGT 162600
CGCCTTACTC GTTTGGCTAA TCATTATGTT TALCG~L~lC CCTGTAGGTT GGTCCTTATT 162660
TATTGCTACT CTACTTTATT TTTCTATGAC ACGTTGGAAC GTCGTA~ATG CCGCAACTGA 162720
AAAATTAGTC TATAGCCTAG ACAGCTTCCC ATTACTTGCC GTGCCATTTT ATATTTTAAC 162780
GGGCATTCTA ATGAATACAG GTGGGATTAC CGAACGTATT TTTAATTTTG CTA~AGCCTT 162840
ACTCGGTCAT TACACAGGAG GAATGGGACA CGTTAATATC GGCGCAAGTT TALl~LL~LC 162900
TGGTATGTCA GGTTCAGCAC TTGCTGATGC GGGGGGCTTA GGTCAATTGG A~ATCA~AGC 162960
AATGCGTGAT GCTGGTTATG ACGATGATAT TTGCGGAGGA ATTACTGCTG ~ll~LL~lAT 163020
TATTGGGCCA TTAGTTCCGC CAAGTATTGC AATGATTATT TACGGTGTAA TTGCCAATGA 163080
ATCTATCGCA AAA~L~lllA TTGCAGGTTT TATTCCAGGT GTATTAATTA CTTTAGCTTT 163140
AATGGCAATG AATTATCGCA TTGCAAAAAA ACGAGGTTAT CCACGTACAC CAAAAGCTAC 163200
GAGAGAaCAA CTTTGCAGCA GCTTTAAACA Al~llLLlGG GCAATCTTAA CGCCGTTATT 163260
AATTATCGGT GGTATTTTTT CAGGCTTATT CAGTCCAACA GAATCTGCCA TTGTTGCAGC 163320
AGCATACTCT GTAATTATTG GTAAATTCGT GTATA~AGAA TTAACCTTAA AAAGCTTATT 163380
TAATAGTTGC ATAGAAGCAA TGGCAATTAC GGGCGTAGTC GCCTTAATGA TTATGACCGT 163440
GA~LLL~LLl GGCGATATGA TTGCGCGTGA ACAAGTCGCA ATGC~l~LLG CTGATGTGTT 163500
TGTTGCCGTT GCCGATTCGC CTTTAACCGT ATTGATAATG ATTAACGCAC TGTTACTTTT 163560
TCTTGGAATG TTCATTGATG CCCTAGCATT ACAATTTTTA GTATTACCAA TGCTTATTCC 163620
TATCGCAATG CAGTTCAATA TTGACTTAAT ~LL~llLGGT GTAATGACCA CATTAAATAT 163680
GATGGTTGGT ATTCTTACCC CACCAATGGG AATGGCTCTC Lll~lL~LLG ~LC~L~lAGG 163740
AAATATGTCA GTTTCCACGG TAACCAAAGG CGTATTACCG TTCTTGATTC C~111LC~L 163800
CACATTAGTA TTAATCACGA TTTTCCCACA AATCATCACA TTTGTGCCAA ATCTATTGAT 163860
ACCATAATAA AAAGTGCGGT TGAAAAACAT TAAATTTTTT AACCGCACTT TCALC~LLLL 163920
CGTAAGTTAC ATCTGCCGTA TCTTACAATA CAAAAGGGTG CAATAACTGC ACTTTATCAA 163980
CGCCTATTCA ATGCC~lLlA ATGAATAGAA AACTGTAAAC ACAACTCA~A ATGGGGTTTA 164040
-77.99-
SUBSmUTE SHE~T ~RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
TTATGAAACT AACTA~AACA GCATTATGTA CTGCACTTTT TGCCACCTTT A~lllLl~AG 164100
CGAACGCACA AACTTATCCT GATTTGCCAG TGGGGATCAA AGGAGGAACA GGCGCATTAA 164160
TTGGCGACAC AGTTTATGTG GGATTAGGTT CTGGTGGCGA TA~ATTCTAT ACCTTAGACC 164220
TAAAAGATCC TTCAGCACAA TGGAAAGAAA TTGCTACATT TCCGGGTGGC GAACGCAATC 164280
AACCTGTTGC AGCCGCAGTG GATGGAAAAC TTTATGTATT CGGTGGTTTA CAAAAAAATG 164340
AAAAAGGCGA ACTTCAACTC GTTAATGACG CTTATCGCTA TAACCCAAGC GATAATACTT 164400
GGATGAAACT TCCTACTCGT TCTCCCCGTG GTTTAGTAGG ATCAAGTGGT GCATCTCACG 164460
GAGATA~AGT TTATATTTTA GGCGGCTCTA ATCTCTCTAT ATTTAATGGC TTCTTCCAAG 164520
ACACTGTGGC AGCAGGTGAA GATAAAGCGA AAAAAGATGA AATCGCAGCA GCTTATTTCG 164580
ATCAACGTCC AGAAGATTAT 'l'l~'l''l"l'ACAA CAGAATTATT GAGCTATGAA CCATCAACCA 164640
ATA~ATGGCG CAATGAAGGT CGTATTCCAT TCTCTGGTCG TGCTGGTGCA GCCTTTACAA 164700
TTCAAGGTAA TGAGCTAGTG ~ll~l~AATG GCGA~ATTAA ACCTGGACTT CGCACCGCTG 164760
AAACCCATCA AGGTAAATTC ACTGCTAAAG GTGTGCAATG GAAAAACTTA CCTGACTTAC 164820
CTGCTCCA~A AGGCAAATCA CAAGATGGTT TAGCTGGTGC GCTTTCAGGC TATAGTAACG 164880
GTCATTATTT AGTCACTGGC GGCGCAAATT TTCCAGGTTC AATCAAACAA TTCAAAGAAG 164940
GAAAACTTCA CGCACATA~A GGTTTAAGCA AAGCTTGGCA TAACGAAGTT TATACGTTGA 165000
ATAATGGTAA ATGGCGCATT GTTGGGGAAT TACCAATGAA TATTGGTTAT GGTTTTTCTG 165060
TATCTTACAA CAATAAAGTT TTACTGATTG GCGGTGAAAC TGATGGAGGT AAGGCTTTAA 165120
CTAGCGTCAA AGCAATAAGC TATGACGGTA AAAAATTAAC CATCGAATAA TTTATCACAG 165180
AATAGTGCAT AAAATTTATA ATAATCAAAA GCGGCGAAAT TTATCGCCGC TTTATGCAAA 165240
ATA~AAGTAA TTAAAGCAAA ATTAAGACAA ATTTTGACCG CACTTTAAAT GCGCTATAAA 165300
GAGCTGGCAT TTTTATTAAT AAGATTTAGC GATGTTATTT ATTCCACCAC CACTACTCTG 165360
TTTATTCATT GCCATAGCAA TGTATTTTTT GCCA~AGATT GCTAGTTATT CTGTCCATTT 165420
TTCAGTGATT ~'l''l"l''l''l'~'l''l'A TTTCCCTTTC A~ llGATT GCTTTAAGCA GCGTTATGCA 165480
ATCTTTATAT GTAAAACCTC CATTAATCCT CGTGACTTTA AAGGCACAAC A~AATTAGTT 165540
TCCACAGGCA TATTTCGATT TAGCCGTAAC CCAATGTATT TAAGTTTGCT GTTAATTTTG 165600
CTTGCTTGGA CGCTTTGGTT AGGTAATAGT TTGGCTTGGT TAGGCGTAAT TATCTTTATA 165660
TTAGTGATAA ACCAGTTTCA AATAGCCCGA GAAGAAACCT ATTTGGAAAG TA~ATTTGGC 165720
-77.100-
SUBST~UTE SHEET ~RULE 26~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GATGAATATC ~lC~llACAA ACA~AAAGTA AGACGTTGGC TATA~AAAAA CACCTTCACA 165780
AGGAAGGTGT TTTTATCA~A TTA~ACTCTA llllllCGGT GCCTGCATAA AGCGGAAGAA 165840
ATCACTATCT GGTTTTAAAA TCATTATATT GTCAGAATTT GCA~AACTCG CTTCATAGGC 165900
TTTTAAGCTA CGCACA~AAG TA~AGAATTG TG~ll~ll~A GCA~AAGCAT CTGAATATAA 165960
TTTTGCTGCA GCTGCATCGC CTGAACCTCG TAAll~ll~l GCAGTTTTAT TTGCATTAGC 166020
AAGAATTAAC GTCACTTTGC GATCTACATC AGCTTGAATA AATGCTGCTT lll~lllCCC 166080
TTGAGAACGA TGTTCACGCG CCACTGCATC ACGTTCTGCA CGCATACGTT GGTA~ATTGA 1661.40
AGAAGAGACT TCATCTGGTA AATTAATTTG TTTTACACGC ACATCGATCA CTTCAATACC 166200
TAATTCTGCC GTACTGTCTT GTCCTGAACT TA~AGCTTTT TTTGCCCCTT CCATTAATTC 166260
TCCACGTGTA CCAGA~ACAA TATCTTTAAT CGTGCGTGAA CCAATTTCAG AACGTAAACG 166320
GTCGTTTACT TTACGACTTA ATA~ATTTGC AGCTTGAGCA TAATCGCCAC CGCCAGTAGA 166380
TGTGTAGAAT CGACCA~AAT CACTGATTTT CCATTTCACA TAAGAATCCA CTAGCA~ATC 166440
'l"l"l"l"l"l'~'l'~'A ACAGTAACAA AAC~l~llGC AGAGCCATCT A~AGTACGAA TACGTGCATC 166500
TAAAACTTTG ATGCTATCAA TTA~AGGCAC TTTA~AATGC AAGCCCG~Ll CATATACAAC 166560
CA~lll~llA TCAGCATCAC GCTGTACTTT GTTA~ATCGT AACATAATGC CACGCGTACC 166620
llCC~llACA ACGACGATAC TAGAATA~AC GACTGCCGCA ATCACGA~AA TAACAGGTAA 166680
TA~AAATCTA CGCATTAGTT A~ATCTCCCT TGACGAATCG GCGCAACGGT AGTCGGCTGA 166740
GGCTGATAAG AATTTTGACG TTCTGGTGCA GTA~AAGCAG GCGAAGAATT GACCGCACTT 166800
GGCGCACTTG TTACCGATTT TTTGCCCATA ATTTGCTCTA GCGGTAACAC AGTTAAATTA 166860
TTACCATTAT TGCCATCAAG CATTACTTTT GGGGTATTTG CCATCACTTT TTCCATCGTC 166920
TGAATATATA AACGCTCACG CAGTA~ATCT GGCGCAGCCT TA~ATTCTGG CAACAAGCGT 166980
TGCA~ACGTT CCACTTCACC TTTTGCATCT AACACGATAC GATCTTTATA AGCTGTTGCT 167040
TCTTCAAGAA TACGTTGCGC ATCACCACGT GCAATCGGTT CTTTCTCACG CGCATAGGCT 167100
TCCGCTTCAC GAATA~AACG TTGTTCATCT TCCTGCGCTT TAATTGCATC ATCA~ACGCA 167160
'L~llllAcTT CTTCAGGTGG GCGCGCAGAT TGGAAGTTCA CATCAATAAC CTCAAGTCCC 167220
ATATCATAGG ATTTGATAAT TTCATTCAAA GCTTTCCAAG TATTTTCACG CACGACAGAG 167280
CGACCTGTGG TTAAAATATC ATTCATAGAC ATATGCCCAA TAACATAACG TAATGCACTA 167340
l~l~lCGCTT GATTCA~ACT ATCATCTGCA lll~llACGC TA~AAAGATA TTTTGCAGGA 167400
-77.101-
SUBSTITUTE S~tEET (RULE
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96105320
TCTTGCACAC GATATTGCAC GGTCATTTCC ACTTTTACCA TATTTTCATC TTGAGTCAGC 167460
ATTGCACCTT GTGTACGCAA ~l~llllACT TGCTCCACAT TTACTGGCAA TACTTTATCT 167520
ACA~ATGTTG ~lllC~AGTT CAAACCAGGT TGAACAATAG AATGTAACTC GCCAAAACGA 167580
AGCACCACAC CGCGTTCAGC ~l~LllAATG GTGTAAAAAC CGTTTACGCC CCAAATAATC 167640
GCACCAATCG CTACAGCAAG TGGAATAACT TTACCAAAAT GA~ATGGCGT ATTGCCTTGA 167700
GAACTGCCAT TATTTTGACC G~'1'~-1"1"1L'1'A TTTCCACCAC CTAATTTTTT AAGCAGATTA 167760
TTAAAAATCT CCTCAATATC TGGTGGAGAT TG~l~llGAT TTCCACGATT TTGATTGTTA 167820
TTCCATCCAT TATTATTGGA TGAATTTCCC GGCTGTTGGT CGTTGCTTTG CCCTGGTTTA 167880
CTCCAAGGAT CGCGATCTGA ACCGTTCTGT GACATTTCAT TCTCCATTTG TCA~AAAATT 167940
GTTAAGAGTT TAGCTAAATA AATGGGGCAC GTCTATGA~A ATACAAGGCT TTTTAGGCAA 168000
TAAAAAATCC TTGATTTTAT ATAAGGATTT TTTTGATTAA TTCACTTCAT A~AGAACATA 168060
AGT 'l~llllATCT GTA~ACTTTC TCTATTCCAT TCATAAAAGT GCGGTAATTT 168120
ll~ll~ATGA TTGACAAAAG CGGCTAAATA AATAGGGAGT TCATCAGTAA ACCACAACTG 168180
CCCCTGCGGA CAATAATCTG AAAAAATTTT ~ A GGAAAATGAC GAACATTGGA 168240
TAATTTTACG ATCCCA~ATC CTTGAGATTT CAATACAGCC TCTCGCAAAC ACCAACAACG 168300
ATA~AAAGCG TTCAAAGAAT CCTGCTGATG ATGAAACCAA TCA~TTTCTT CTTTTGGTGC 168360
AATATGTTCC ATCAACGCCG TAAAATTTCT TATTTTAGGA AATTCAATAT CAATTCCCAC 168420
CGCACTTTTT TCTTCATTTC TAATATCTAA TATTACCGCC ACCCAATCAC CAGAATGGCT 168480
AATATTAAAA TCTATTCGCT CATCAAGAAA ATAAGGTCTG CCACTTTCAG TACGATGAAT 168540
TTGAGATAAA AGTGCGGTGG ATTTTCCTGC TATTTTTAGA AGTTGGAAAA GTAATAAATG 168600
CGCAAGCCGA CGACACTGAT GACGCTGAAA AACACGGGAG CTATCCGTTT CAATTTGATA 163660
TAGATTTTCT GGAATCAGTT CATCGGGTAA GGATTCCAAA GAAAAAGGTT GATTTATATT 168720
GCCGTAGGCG ATGTAGGTTG TCATA~AATA A~AGCACCAT TCAAAGGTGC TTTTATATTA 168780
AAAGGATTTA ~-L-l-l'G'l'~'l~'l- AAATTAGCGA ATCACTAATT CCGCCACAGA AACACCGACC 168840
AAGCAAGCAA CAACAACCCC AATTA~ACCT GGCACCATAA AACTGTGGTT A~AATAATAT 168900
TTACCAATTT 'l'-l'~'l'l~'l'ACC CGTTACGTCA AAGTTTACTG TTGCAATATC TGACGGATAA 168960
TTTGGAATGA AGArATACGC ATAAGTTGCA GGCATTA~AC CAACTAAGAT TGGCGCAGGA 169020
ATACCTAAAC CAATACCAAC AGGTAATAAC ATTACGGCTG TTGCTGCTTG GCTATTAATT 169080
-77.102-
SUBSmUTE SHEET ~RULE 26)
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
ACAACTGAGA CTGCAAATAA CGCCAATGCG AATGTCCAAG GGTAAGTTTG CACCATATCA 169140
GTAATCGCGG CTTTAAATTC TGGCATTGCA TATTTGAAGT AAGTGTCGCT CATCCACGCA 169200
ATACCATAAA TTGCAATCGC TGCTACCATA CCTGACTTAA ATACCACACC ATTTTGCACG 169260
ATTTGAGGAT TC~llllC~l TGCAAGTA~A ATCACACCAC CAAAACAAAG CATCATCATT 169320
TGAATGATAA GTGACATTGA AATTGCTTTT CCGCTACCGA TAGTGCGAAT TTCAGGAATC 169380
ATCGCAATCG CAACAATCAC AACTA~AGCA AGTAAAAATA GGTAAACAGA LllllllGCC 169440
CCTTGCGGAA GGGTTTCATT CAA1~L1~1A CTGGTAGTAT TTAAAATACG TTCGCGCCAT 169500
ACTGGATCTT GTAAACGACG TTGATATTCA GGA1~11~11 CTAACTCTTT ACCACGACGC 169560
ATACTGTATA AAGAAAGTGC AATCGTACCC GCTAAGGTTG CAGGAACGGT TACGCAAATA 169620
ATATCTAATA AACTAATATG CTCAAAAGCG GGCATTGCTG TAATTTTACC TAGATAAAAT 169680
ACAACAGCTG CAGAAAGTGG GCTTGATGTG ATGGCTAATT GCGATGCTAC CGAAGACGCT 169740
GCCATTGGAC GTTCTGGACG AA1111~111 TTCAATGCAA CATCGCCGAT GATTGGCATA 169800
AL1~1~1AAA CAGAGTGACC TGTACCAAGC ATAAAGGTTA ATAAATAGAC GACTAATGGG 169860
CCGAGTAAAG TGACACGTTT TGGATTTTTA CGGAGAATGC GTTCAGCAAT TTGTAACATA 169920
AATTTCAAAC CGCCAGCTGC TTCAAGTACG GATGCGCAAG TCACCACTGC AAGAATGATA 169980
AGCATAACAT CAATCGGTGC TTCCCCACTG GCATACGAAA TACGAAAACC TCGATAGCAA 170040
GACCGATACC AGAAACAACA CCTAATCCGA TACCGCCGTA ACGGCTACCG ATATAGAGCA 170100
TTAATAGTAA AAATAAAAAT TCTAAATA~A GCATA~ACAC CTCAAAAATG GAAAACTATG 170160
CAAATAATAC 1L~L1L11AG GCATATAACT AAATTATTTT TTAAAATTTA AACCAAGATT 170220
TTAAGTAAAC GATAATTTAG ATCAATTTTT ATGAAAAGGA AAAATAAAAA GTGCGGTAAT 170280
TTTAAAGAGG ATTATTAGAA AAAAAATTAG CGACTTAAAA CGTCGCCCAA CTTAAAATTA 170340
TTGATTGTTT TGCACGTAAT CAATCGCAGA TTGAACAGTG GTAATTTTTT CAG~11~1LC 170400
ATCAGGAATT TCAATATCAA AL1~L1~LLC TAAAGCCATT ACTAATTCAA CTGTGTCTAA 170460
TGAATCTGCA CCTAAATCTT CAACAAAAGA AGCTTCAGGT TTAACATCTT CTTCTTTAAC 17~5Z0
ACCTAATTGT TCAACGATGA 1LLLL1~1~AC GCGTTCTTCA ATACTCATTT GTTTTTCCTA 170580
~11L~11AGTT TTAACTCATA AAAGAGTGGT TAGTGTATGT A~1L1111AGT AACTTGCAAC 170640
TATTTTATGG TCTGGTCGCA CCACAAAATA GGCAATGTGA ACACACACAT CAAATATAGT 170700
TACGTACCTT TGCATACGCT CAAGGCGTAA CCAAGTTACA TTGCGAGCGG GATTTTAGCA 170760
-77.103-
SUBST~TUTE S~{EET (RULE 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
TTATCTAAAA TCTTTGGCTA TGATTTTATT GCTTAGAAAT CCCCCATA~A TCAATGTCAA 170820
ATTTTAGCTT AAGTATAAGC CACCATTCAC GTGTAACGTT GTTCCCGTGA TATAACCTGC 170880
ATCATCAGAA GCTAAGAAAG CAACGGCTTT AGCTATGTCT TTnGCTTCGC CTAAACGTCC 170940
AGCTGGAACA TTAGATAAGA TCCCCGCTTT TkGTTCATCC GTAAGCACTT CTGTCATATC 171000
TGTTGCAATA AAACCAGGAG CAACCACATT TACAGTAATA CCACGTGCAG CTA~l~l~lll 171060
CGCTAAAGAT TTAGAAAAAC CAACCACACC CGCTTTTGCC GCACAATAGT TA~lll~lCC 171120
TGGATTACCC GTTGAACCAA CCACTGAACC AATATTGATG ATACGACCAA AAC~llLlll 171180
CATCATTGAA CGTAACATGG CTTTAGAAAG ATGATACACC GAAGTTAAGT TAGTTTGCAT 171240
AATATCAAAC CATTCCTCAT CTTTCATACG CATCAATAAA TTATCGCGAG TAATACCTGC 171300
GTTATTCACG AGAATATCAA TATCGCCAAA ATCATTTTTA A'lll~ll~AA GTAAGGTTTC 171360
GATAGATTCT TTATCCGTTA CGTTTAAAAC TAAACCTTTA CCTTTATCCC CTAAATAAGC 171420
CGAGATCGCC TCTGCACCCT TTTCAGAGGI TGCTGTACCA ATTACAAATG CAC-lll~l~A 171480
ACTAAGTTCT TCTGCAATCG CACGACCGAT ACCACGGGTA GATCLl~l~A CTAAAGCAAT 171540
TTTACCTTGC Allllll~ll CCTTTTACTT ACACTAAAAA 'l''l'~'l"l'~'l'ACC GCATTGAATG 171600
ATGCAACATC ATTTACAGAT ATTGCTTGTA AATCACCCAC AATGCGTTTG GTTAAACCAT 171660
TTAATACTTT ACCTGGCCCC ACTTCAGCAA GCACTAGAAC GCCATCTTGC GCCATTTTTT 171720
CAACTGTTTC AGTCCAACGA ACTGGACTAT ATAACTGACG CACAAGTGCG GTACGAATTT 171780
CGGTGCCTTC AGTTTCAGCT TTCACATCAA CGTTATTTAA TACCGATATT GTTGGTGTAT 171840
TAATTTGAAT ATTCTCAAGT GTTACCGCTA ATTGCTCGGC TGCAGGTTTC ATTAATGCAC 171900
AGTGAGAAGG TACGCTCACA GCTAACGGCA ATGCACGTTT CGCCCCTGCT TCTTTACATA 171960
ATGCAGCCGC ACGCTCAACT GCAGCTTTCG CACCCGCAAT AACTACTTGA CCCGGTGAGT 172020
TAAAGTTCAC CGCAGATACG ACTTCGCCTT CCTCTGCTTG TTTGCAAGCA TTAATAATTG 172080
CTTCATTATC TAAACCAATG ATTGCATACA TTGCGCCAGT GCCTTCAGGC ACAGCTTGTT 172140
GCATTAATTT TCCGCGCAAT TCCACTAATT TAATCGCATC TTGGA~ATCC AACACGCCAG 172200
CACAAACTAA CGCAGAATAC TCACCTAAGC TATGACCTGC CATCACTTCT G~lllLAATT 172260
GAGGA~ATTT ~lL~lllC-AT ACGCGATAAA TAGCGACTGA AGCAGCTAAA AGTGCGGGCT 172320
GAGTTTGCCA AGTTTTATTA A~ll~ll-AG CTGGACCTTG TTGAACAAGA TACCATAAAT 172380
CATAACCAAG CGCATCAGAT G~ll~lllAA Al~lll~AAT AACGATTGGA TATTCAGTTG 172440
-77.10~-
SUB ST7T~JTE ~ EET ~RULE 26
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
CAAGATCAGC AAGCATACCG ACAGTTTGGG AGCCTTGACC TGGGAAGACC ATTGCGAATT 172500
TTTTCATTAT ~Llll~lCCT A'1"1'~ 1"1 1 L 1"1' AATTGAAAAT T~'1"1'~'L'LCGG TAATTA~AAT 172560
CGGGTTTCGC CGATGGCGAG CTTACTTTTT CTTTGCTTCG CCAAAGAAAA AGTAAGCA~A 172620
AAGA~AGGCG CCCCTACTTT TCL'L'1'~'L'L'1'C ~LLL~LLCCA TTGAATTTGC CTTAACGGAA 172680ATTTtCTGAA CTCGCTACGC TCA~ACAGAC GA~AATTTCC TACA~ATTCA ATTCCACAAA 172740
GGTGGAAAAG AAGGGAACCC AA'L'L'1'~'1"L~'L TTATCCGATT TAAAGTGCGG TCAAAACTCA 172800AAATATTTTT '1~L1~L1AAA ATGAATTTAA AATTAACCGC A~''L'L'L'L'LA~A TAATGCTCTG 172860ATA~ATTCGG GGCCCCATAT AAATCACCTT TGCGACTTTC AATTTTCAGG CAATTTGCGT 172920
~L~1LL~AGC GCAGCGAGTT CAGCA~ATTG CCGTTAAGAA AATTGAAACA AAGCAAAGAA 172980
CAGCGATTTA ACTGGGGCGT ~'1"L'L'L~'L'L'LG CCTACTTTCT TTTACACGAG TA~AAGAAAG 173040TGAGTCGCCG TCAGGCGAAC CCCTGACATT TAACACA~AA AGTGCGGTCA ATTTTTACCG 173100
CACTTTAAAA TCATCAATAA TTATATCA~A TCAACTAAAA TCTCACTAAC GCTGAACCCC 173160
AAGTCCAACC ACCGCCA~AG GCTTCTAATA ATAGTAACTG CCCACGTTGA ATACGGCCAT 173220
CTCGAATAGC CTCATCTA~A GCAACAGGAA CAGTTGCTGC ACTGTTATTA GCGTATTTAT 173280
CTAACGTTAC CACCACTTGC GACATATCCA TTTCTAATTT TTTAGCTGTT GCTGTAATAA 173340
TACGTAAATT TGCTTGGTGT GGCACAAGCC AGTCTAAATC rL'1''L'L'L'1'ATCT AAATTATTGG 173400
CTAAAAGTGT TTCTTCCACC ACATTTGAAA GTTCACGAAC TGCCAATTTG AAC~'L'1"LC~'1' 173460
TACCTTGCAT CTCGATATAG CCAGATTTTT CTATACCACG TTCTGGCTGA GCTAAAACAA 173520
GGGCATTATT TTTATCTGCT GAAGCGTGTA AATGGGTGGA GATAATTCCT T~'L'1'~'L'L~AC 173580
TCGCTTCTAA AATTACAGCA CCCGCACCAT CACCA~ATAG CACAACAGTG CTGCGATCTG 173640
TTTCATCTAA TTTACGAGAA TTGAGATCTG AGCCTATCAC TAAGGCTTTT TTCACTTTGC 173700
CTGCACGAAT AAATTGATCA GCTACGCTCA AAGCATAGAC A~AGCCTGTG CAAGCTGCCG 173760
CCAAATCAAA AGaAATCGCA TCATCAATAT TTAATA~ACC TTGCACTTGG CAAGCCGCAC 173820
TTGGATAAGC ATGTGAGTGA CTTGTAGTTG CAACAATAAT CAGTTCAATA TCTTGAGGAT 173880
TAATTTGAGC AGCTTCGATC GCA'1"1"1''1''L'LG CCGCTTCA~A TCCCATTGTT GCAACAGTTT 173940
CATCTTCCGC TGCGATACGA CGTTCACGGA TACCAGAACG AGTGACAATC CATTCATCTG 174000
ATGTATCAAC CA'1''L'1"L'L'1'~'1' AAATCCGCAT TTGTGCGAAT ATGGCTCGGC AGATAGCTAC 174060
CGGTGGATAA AATTCTACTA TTCATACTCA ATAAGATAAG CGATTA~AAA GGAAAAAATC 174120
-77.105-
SUBSmUTE S}~EET tRULE :2~i3
-
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/0~320
TATGGACTAT CGCCAAGTAA GAGATAAGAC CACACCGGAT TATTTTCCGA TGTTAAAGGA 174180
ATGCAGATAG TAATACGGGG ACCAACGTCC CCGCCCATCA CATCTAACGC CAAGGTTAGA 174240
CGGTTCAAGT GAACACCTAT AAGTAAAAAA TTACTTATTG ATCACTTTAC GACCACGATA 174300
GTAACCGTCT GCAGTTACGT GGTGGCGTAA GTGAGTTTCA CCGCTTGCTT TATCTACTGA 174360
TACAGCAGCA ~L~ AAAG CATCGTGTGA ACGACGCATA TCACGACGTG AACGAGATTT 174420
~Ll-l~ll-ll~l TGAACAGCCA TTGGCTATAC TCCTAAATTT AATTTACTTT TGCTTTA~AT 174480
TAGCTAATAC AGCGAACGGG TTCGGTTTTT TTGCCAATTC TTCAGGCAAT ACGCCAAAAA 174540
C~l~-l-LCCTG CGCGGACACT TCACAGTGTT CAGATGAATG CATTGGTACA AGCGGCAAAG 174600
CTAAAATTAG CTCATCTTCC ACCGTGCCAA TTAAATCTAT TTCGCCAAAC TCATTGAACT 174660
CGATTGGCTC ATAAATTTCG GGCAAGTCAT CAGCCTGATC CCAATTAGCC ACTGGACTAT 174720
AAGTAAACTC ACATTCCAAT ~Lll~ll-l~l AAG~LlC~l--l ACAACGCTGA CATTCAAGAT 174780
CGACATCAAT CTGTACTTTA CCTTTCATCA CCACTAATTT TTGTGGATCA ACATAAAACG 174840
ATAATGTTAC CTGTGCATCG CTGAGCACGT TTACCACTGA TTCCGCCAAA CGCTCAAGCT 174900
GATTTGCCGC ATAATAACCA ACATAATCAA GCC~-L~LllG AGCATCTTTT ATGGGATCAA 174960
CAGTGAGGGG TAGTTTTk~C T~TTG~TAG GGCGTGAATA TTACCTGTTG TTGCGAAGAT 175020
AGTCA~AGGG AAATCACATT TTTTATTGGA TAACTCAATA AAGGAAATTA TCCGCTAACT 175080
AAAAAGGTTG GAACTATAAC A~AAATTGCT ATAATCACGC ~L-lL-l--l-lll AACAAGGAAA 175140
GATAATGATG ACTTCAAATT CTTATTGGCA ACGCTTAAAA GTGGCATTTC AATATGTCAT 175200
GCCACAAATT TATTTAACTC AAATTGCTGG CTGGTTTGCT A~ACA~AAAT GGGGCAAAAT 175260
AACACATTTT GTAATTAAAG CTTTTGCGAA AAAATACAAC ATTGATATGA GCATTGCGCA 175320
AAAAGAACAA LLl--l~l-GATT ACGCAAGTTT TAATGAATTT TTTATTCGTC CGTTAAAAGA 175380
AAACGCACGT CCAATTAATC AAAATCCAAC CGCACTTTGT TTACCAGCAG ACGGTCGCAT 175440
TAGTGAGTGC GGTCATATTG ACGATAATCT TTTATTGCAA GCTAAGGGGC AL-l-l-ll-lCAG 175500
CCTAGAAGAC TTATTGGCAG AAGATAAAGA ATTAGTGGAA ACCTTTAAAA ATGGGGAATT 175560
TGTAACTACT TAT~L-LL~l-C CTCGTGATTA TCACCGAGTG CATATGCCAT GCGATGCTAC 175620
GCTACGCAAA ATGATTTATG TGCCGGGTGA TTTATTCTCT GTGAACCCAT TTTTAGCCCA 175680
ACATGTACCA AATTTATTTG CACGTAATGA ACGTGTGATT TGTGTATTTG ATACTGAATT 175740
TGGCACAATG GTACAAATTT TAGTGGGTGC AACCATCACT GCAAGTATTG GCACAACTTG 175800
-77. 1 06-
SUBS 111 UTE ~E~T (RULE 263
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GGCAGGCGTA ATTAATCCTC CACGCCACAA CGAAGTGA~A ACTTGGACTT ATGAAGGCGA 175860
AAGTGCGGTC AAATTATTGA AAGGTCAAGA AATGGGGTGG TTCCAACTTG GTTCGACAGT 175920
AATTAATTTA TTCCAAGCAA ATCAAGTGCG TTTAGCTGAT CATTTAAGCG TTAATGAACC 175980
TGTTCGCATG GGCGAAATCT TGGCATATAA AAAATA~ACA GGATTTATTT CCATA~ATGA 176040
CAGA~ACA~A TCCTGA~AGT AGATATTTCT CA~-Ll~lllA AAGGCAGTAT AACCTTACTG 176100
C~L1111~11 CTTTCATTTG AACAATTAAC GCATTGTTAC A~ATTCCTCT GAACCTGTTG 176160
GATGAATTGC CACCGTATTG TCA~AATCAG ~Llll~llGC ACCCATTTTG ATTGCTACAG 176220
CA~ATCCTTG AATCATTTCA TCTACACCAA AACCAATACC ATGTA~ACCC ACAACTTTTT 176280
CATCTTTACC CACACA~ACT AATTTCATTT TGCACGGTTG GCGATGTTGA GTTACCGCAG 176340
TGTACATCGC TGTGA~AGAA GATTTATATA CCTTAACATT TTCTGCGCCG TACTGCTCAA 176400
TCGCTTGCGG TTCAGTTA~A CCTACAGTGC CGATAGGCGG ATGGCTA~AT ACAACGGTTG 176460
GAACTA~ACT GTAATCTA~A TAtTCAGTCG GTTTATTATT A~ATA~ACGC TCAGA~AGGC 176520
GACGACCTGC TGCAACTGCA ACTGGTGTTA ATTCAATGCC ~llllC~ATA ATATCGCCTA 176580
CCGCATA~AT GCCTTTCACA TTAGTATTTT GATATTTATC TACTTTGACA TAGCCATGTT 176640
~'~LlC~lllC TACGCCAGCA llll~lAAGC CAATTTTATC L~lC~llGGA ACACGACCCG 176700
CAGCCCA~AT AACGCAATCT ACGGTAACAT CAGATTGACC ATCACATCTT ACAGTAAGTG 176760
AACCATCTGC ALLllllACA ATTTCAGATG GGGTAGAATT GGTATGTAAT TGAATTCCAT 176820
CTTGCGCAAG CACTTCCACT AAL~lll~lA CGATTAATGG ATCCTGATTA CGCATTGGCG 176880
CATGGCGACG CACTAATA~A l~l~LllCCA CGCCTAAGCT ATTTAATACG CCAGA~AGTT 176940
CAACAGCAAT ATAGCCTGCA CCAATAACAG CAGCACGTTT TGGTAATTCG GTTAATGCAA 177000
AGA~ACCATC TGAATCAATG CCGTATTCTT ~LC~lllAAT ATTTGGACGA TATGGACGAC 177060
CACCAGTTGC GATTA~AATA TGATCTGCGG TTA~Ll~llC ~Llll~lACCA TCAGCAAGTG 177120
TTACTTCAAT GGTATGGGCA TCGACA~ATT TTCCGA~ACC ATTAATTACA TCAATATTAT 177180
TTTTCGCTAA TACATTATTA TAAGATGTAT GGATACGACT AATATAGGCT TGGCGACTTT 177240
CAATCAGTTT TGA~AAATCA AALlllllCA CTTCAACATC A~AACCATAA TCTGGCGCAT 177300
AArLl~ll~AT TGCTTCTGCA ATATGCGCAC CATA~AACAT CA~llLLLlA GGTACACAAC 177360
CGACATTTAC ACAAGTTCCG CCAAGATGTT TTGCtTCAAT GATTGCACAT TTTTTtCCAT 177420
AGCTTGCTGC TCGATTTAGA GACGCAATAC CGCCACTGCC ACCGCCAATA GCAATATAAT 177480
-77. 1 07-
SUBS i 11 UTE SH~Fr (RULE 2~i3
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
CATAATGTTT AGTCATAGTT TGAACCTTTT TTA~ACTAAA Alllllll~l ATTCTGCCTA 177540
ATTTTTATAA AGAATGCTAT AAATTGATGT AATTGGTTTT ATGAATATTT TTTACTCTTT 177600
TGAACAGATG ATTAGTTTGA AATGATTTTA TGTGAAGCCT AGTATGTAGA ATGAAATAGC 177660
GTGATAGAAA AAGAGGAAGA TTGTTCAATC TTCCTCACTG TAGATATGTG ATTAATTAGA 177720
ATATTGGTTT ATCGCAGCCG CAA ll~llG ATCTTGATAA ATAll~ll~A CAATATCATT 177780
AAAAGTTTGA GATAGCACTT TATGAATTTC ATCATTGCCC GCATTAAATA CGCCCTCTTG 177840
TGAGTGCGTG ACATTAAATG ATTTATTATA CGAACCTTTC GCACCTTGTA CATAAACTGT 177900
CGCTTGAATT TTGGTATTAA GTTTATAACG AAGATTACCT ~ lACTT GCGTACCAAA 177960
TTCACGCACA TCCACAGTTA CCCACGCATT TGAACCATTT AATTGCCCAA CTCTAAAACC 178020
TTTACTAATT AAATTTTGCT GCATCACTTG CTGA~ATAAT TGTGTAACAC TTGGGGATGC 178080
ATTTAATTTA ATCAGTTCCC C~l~lllCGT ATAACTCGCA ATCTCTTGTA TTGCACGGCT 178140
Al~llll~ll GTCACAGATA CAACGGCAGT TCGATTAACA TTCATTGAAG CACTTGGTGC 178200
AGGCGGTGTA AATGCTAATA TATTTGATTG TGCTTGGCAG CCTGCAAGAA ATAATGTAGC 178260
CGCTAGAATA CCTACTGATG ATAATGTTTT AA~llll~lll ACTAATGCCA TAATTTCCCC 178320
ATAAATCAAT TAGAATTGTG CTATTCTTAC AAA~llC~ll ATTAATGTAT AGC~lll~AT 178380
TTTAGTTTTT GTGGAGAACT TATAATGTCA ATTCAACAAA TTATTGAGCA AAAAATTCAA 178440
AAAGAATTTC AACCGCACTT TTTAGCAATA GAAAATGAAA GCCATTTACA TCACTCTAAT 178500
CGAGGTTCTG AATCACATTT TA~ATGCGTT ATTGTCAGCG CAGACTTTAA AAATATTCGA 178560
AAAGTACAAC GTCATCAGCG TATTTATCAA TTATTGAACG AAGAATTAAA TCATAGTATT 178620
CACGCATTAG CATTACATTT ATTCACTCCA GAAGAATGGA AAGCACA~AA TGA~ACTGTA 178680
CCGCACTCAA CAAAATGTGC AGGTATTGGT CGTTAATTTT GTTATAAAAA TGTAACATTT 178740
TTGATATATC GCAAAAAGTT CTAACAAAAA ACC~l~l~ll TAAGTAGCGA AAAACAGAGA 178800
TTTTCGCTAG AATGAGGCGT TTAATTTAGT CCAAATTCGA lll~lCGGTA AAATTATTAA 178860
CTGTGAAATC AATCCATTTG A~llllllAT TTTGTGACAT TAAL~lllll TTAGCGGTTT 178920
GTCACACTCA AACGTGAGAT TGCTTCTAGG GTATTTTTAC TATATTAGCA ATTGTATTTT 178980
TAACCTTGAA AAGTAGTGCA AATAGTATGA TTACAATTAA GA~AGGTTTG GATCTCCCAA 179040
TTGCGGGA~A ACCAGCACAA GTAATCCATA GCGGCAACGC TGTGAATCAA GTTGCGATTC 179100
TAGGTGAGGA GTATGTGGGG ATGC~lC~ll CAATGAAGGT GCGCGAAGGC GA~l~ll~lGA 179160
-77.108-
SUBSmUTE SHEET tRULE 26
-
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/OS320
AAAAAGGTCA AGTACTTTTT GAAGACAAAA AAAATCCTGG TGTAATTTTT ACAGCCCCTG 179220
CAAGCGGTAC CATCACTGCA ATCAATCGTG GCGAAAAACG TGTATTACAA ~L~L~L~L~1~A 179280
TTAATGTAGA AGGTGATGAA AAAATCACTT TTGCAAAATA TAGCACAGaA CAATTGAATA 179340
CA~LLL~1LC TGAACAAGTA AAACAAAACT TGATAGAATC TGGCTTATGG ACGGCATTAC 179400
GTACTCGTCC ATTTAGTA~A GTTCCATCCA TTGAAAGTGA AGCATCTTCT A'L'L'L'1"1'~'LAA 179460
ATGCGATGGA TACCAATCCA TTAGCAGCCG ATCC~L~L~L CGTATTAAAA GAATATTCGC 179520
AAGACTTCAC TAACGGTTTA ACCGTATTAA ~LC~1~L~TT CCCTTCAAAA CCATTACACT 179580
TATGTA~AGC AGGCGATTCT AATATTCCAA CTGCTGATCT TGAAAATTTA CAGATTCATG 179640
ATTTTACTGG TGTTCATCCA GCTGGTCTTG TAGGGACGCA TATTCACTTT ATTGATCCTG 179700
TCGGTATTCA AAAAACTGTA TGGCATATCA ATTATCAAGA TGTGATCGCT GTAGGTA~AT 179760
TATTTACAAC AGGCGAACTT TATTCAGAAC GAGTAATTTC TCTTGCAGGT CCTCAAGTGA 179820
AAGAACCTCG TTTAGTACGT ACAACAATCG GTGCTAATCT TTCTCAATTA ACCCAAAATG 179880
AATTAAGTGC AGGTAAAAAT CGTGTAATTT CTGGCTCAGT '1~LLL~LGGT CA~ATAGCAA 179940
AAGATTCACA TGATTATTTA GGTCGCTATG CTTTGCAAGT ATCAGTAATC GCTGAAGGTA 180000
ATGAAAAAGA A'L'1"L'L'L'LGGT TGGATTATGC CACAAGCCAA TAAATATTCT GTGACTCGTA 180060
CCGTATTAGG GCCACTTCAG TA~AAAATTG TTTAATTTTA CTACTTCAGA AAATGGTGGC 180120
GAACGTGCAA TGGTGCCAAT CGGTAGCTAT GAGCGCGTAA TGCCATTGGA CATTTTACCT 180180
ACATTATTAT TACGTGATTT AATCGTGGGC GATACCGATG GTGCTCAAGA GTTAGGTTGT 180240
CTGGAATTAG ACGAAGAAGA CTTGGCGTTA '1~L1~1LLCG TTTGTCCAGG CA~ATATGAA 180300
TACGGTTCAA TCTTGCGTCA AGTCTTAGAT AAGATTGAGA AGGAAGGTTA AAAATGGGTT 180360
TGAAAAATCT TTTTGAAAAA ATGGAACCCG C~'L'L'L'L'L~CC CGGTGGTAAA TACAGCAAGC 180420
TTTATCCGAT CTTTGAATCG ATTTATACCT TGCTTTATAC ACCAGGTACG GTAACGCACA 180480
AAAACACTCA C~'L'LC~'1'~AT GCGTTAGATT CAAAACGTAT GATGATTACG GTTTTCCTTG 180540
C~'L'1'~'L'LCCC TGCGATTTTC TATGGGATGT ACAATGTGGG TAACCAAGCG ATTCCAGCGT 180600
TAAATCAATT AGGCAATTTA GATCAACTAA TTGCTAACGA TTGGCACTAT GCTCTTGCAA 180660
GTTCATTAGG TTTAGATTTA ACTGCCAATG CAACTTGGGG CTCTAAAATG GCTCTTGGAG 180720
CAATTTTCTT TTTACCAATT TACTTAGTGG TATTTACCGT TTGTACTATT TGGGAATTGT 180780
TA~L~L~ GGTTCGTGGT CACGAAGTAA ATGAaGGAAT GTtCGTTTCA ACCATTTTAT 180840
-77.109-
SUE~S i 1 1 UTE S~EET ~RULE 2fi3
CA 02218741 l997-l0-2l
W 096/33276 PCTrUS96/05320
TTGCCTTGAT CGTTCCACCA ACATTGCCAC TATGGCAAGC CGCATTAGGT ATTACTTTTG 180900
GTATCATTGT TGCAAAAGAA ATTTTTGGTG GCGTAGGTCG TAACTTTATG AACCCTGCAC 180960
TTG~-lG~lCG TGC~ll~llA TTCTTCGCAT ATCCAGCTCA AATTTCAGGC GATACGGTTT 181020
GGACTGCCGC AGATGGTTTC TCTGGTGCAA CCGCACTTTC ACAGTGGTCA CAAGGTGGTC 181080
AAGGTGCATT GCAACATACC GTAACAGGGG CTCCAATTAC TTGGATGGAT G~1-L-11-~1'1G 181140
GTAACTTACC TGGTTCAATG GGGGAAGTTT CTACCCTTGC AATTTTAATT GGCGGTGCTG 181200
TTATTGTATT CACTCGCATT GCAGCTTGGC GCATTATTGC TGGTGTGATG ATTGGCATGA 181260
TTGCAACCTC AAC~-l--l~-ll-l- AACCTAATTG GCTCAGAGAC TAACCCTATG TTCTCAATGC 181320
CTTGGCATTG GCA~l-l-L~ll- TTAGGTGGAT TTGCATTGGG TATGGTATTT ATGGCGACCG 181380
ATCCTGTTTC AGCATCTTTT ACTAATACTG GTAAATGGTG GTACGGTGCA TTAATTGGCG 181440
TAATGGCTGT ATTAATTCGT ACTGTAAACC CAGCCTATCC AGAAGGAATG ATGTTAGCGA 181500
TTTTATTTGC AAACTTATTT GCACCGATTT TCGACTACAT C~-~ lCAA GCAAATATCA 181560
AACGTCGGAG AGCAAGAACA AATGGCTAAG TTTAATAAAG ACAGCGTAGG CGGCACAATC 181620
~-l-l~-l-l~-lGC TACTACTGAG TTTAGTTTGT TCCATTATTG TTG~-lG~-l-lC CGCAGTAATG 181680
TTAAAGCCTG CACAAGAAGA ACAAAAGTTA CTCGATAAAC AAAAAAATAT CTTAAATGTA 181740
GCTGGTCTTT TACAAGAAAA CACGAATGTA AAAGAAACTT ATGCAAAATT TATCGAGCCC 181800
C~ll--lC~llG ATTTAGCAAC GGGTGAATAC ACACAACAAG CAGATGATAG CCAACAAGCA 181860
ATTCCTGCTG ATGCGGATAA AGCACGTATT C~ll~l-C~lA GCAAAACAAC TGAAGTTTAT 181920
CTTGTAAAAG ATGAACAGGG TCAAACTCAA CAAGTTATTT TACCAATTTA TGGCACTGGC 181980
TTGTGGTCAG TGATGTATGG CTTAGTATCT GTTCAACCAG ATGGTAATAC TATTAATGGA 18''040
ATCACTTACT ATCAACACGG AGAAACACCG GGATTGGGCG GAGAAATTGA AAATCCAAAC 182100
TGGGCAAGTC TATTTAAAGG TAAAAAATTA TTTGATGAGC AACATCAACC TGCCATTCGT 182160
ATTGTGAAAG GTCAAGCTCC ACAAGATGAA CATAGCATTG ATGGTTTATC TGGTGCAACT 182220
TTAACAGGTA ATG~-l-~ll~A AGGTACCTTT AATTATTGGT TCAGCAAAGA TGGCTTTGGT 182280
CCATATCTTG AAAAACTTCA TTCAGGAGCA AACTAATGTC TGGAAAAACA AGTTATAAAG 182340
Al~-l-~-l-l~l-l AGCGCCAATT GCTAAAAACA ACCCTATTGC ATTGCAAATC TTAGGGATTT 182400
GTTCTGCATT AGCTGTAACA ACAAAATTAG AAACTGCTTT TGTTATGGCG ATTGCAGTTA 182460
CCTTAGTAAC TGGATTATCA AACTTATTTG TTTCCCTAAT CCGCAATTAT ATCCCTAACA 182520
-77.110-
SUBSTITUTE ~EET tRULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
GCATTCGTAT TATTGTACAG CTCGCAATCA TCGCTCGCTT GTtATCGTAG TGGATCA~AT 182580
TCTAAAAGCC TATGCTTATG GTTTATCTAA ACAACTTTCA GTA1LC~11G GTTTGATTAT 182640
TACTAACTGT ATCGTAATGG GGCGTGCTGA AGCATTTGCG ATGA~ATCCC CTCCAGTTGA 182700
AA~1111~1A GATGGTATCG GA~ATGGCTT AGGTTATGGT TCAATGTTAA TTATCGTAGC 182760
AL1111CC~1 GAACTTATCG GTTCAGGTAA ATTATTTGGT ATGACGATTT TCGA~ACTAT 182820
TCAAAATGGT GGCTGGTATC AAGCA~ATGG TTTATTCCTA CTTGCACCAA GTGCATTCTT 182880
TATCATCGGA LL1~L~ATCT GGGGATTAAG AACTTGGA~A CCAGAACAAC AGGAGAAGTA 182940
ATCAATGGAA CATTATATTA GCCTATTTGT TAAGGCAGTC TTCATTGA~A ATATGGCACT 183000
ll~lll~llC TTAGGAATGT GTA~1L1~11 AGCGGTATCT AAAAAGGTGT CCCCTGCGTT 183060
'LG~1~1LGGG ATTGCGGTAA ~111C~1L~1 TGGGATCGCA GTGCCAGTAA ACCAATTAAT 183120
TTATGCA~AT GTACTA~AAG AGAATGCTTT AATTGAAGGT GTAGATTTAT CATTCTTA~A 183180
CTTCATCACT TTCATTGGGG TTATTGCTGG TTTAGTGCAA ATTCTTGA~A TGGTATTAGA 183240
TA~ATTTATG CCA1~1~111 ATAACGCATT AGGGATTtCT TACCTTTAAT CGCAGTA~AC 183300
TGTGCGATCT TTGGTGGGGT AL~111~ATG GTTCAACGTG ATTACAATTT CCCTGAATCT 183360
A1C~1~1ATG GTTTCGGCTC AGGTTTAGGT TGGATGTTAG CGATTGTAGC GCTTGCTGGC 183420
TTAACGGAAA AAATGA~ATA CGCTGATATT CCTGCTGGAT TA~AAGGTTT AGGTATTACC 183480
TTTATCTCTG TTGGTTTAAT GGCACTAGGC TTTATGTCTT TCTCTGGTAT TCAATTATAA 183540
GGAGTGTAAT CAATGAGCGA TTCAGTAATT CTTGCACTCG GTATTGCCGC ATTCACGGTT 183600
ATTGTATTAG TGTTAGTGGC AATCATCTTA TTTGCGA~AT CA~AATTAGT CGATTCTGGT 183660
GATATTACTA TCGACATCAA TGACGATCCT GAAAAAGCGA TCACATTACC TGCAGGTGGC 183720
A~ATTATTAG GGGCTTTAGC AAGTA~AGGT ATTTtCGTGT CTTCTGCTTG CGGCGGCGGT 183780
GG~1~11~1G GTCAATGTAT TGTTA~AGTG A~AAATGGTG GCGGAGA~AT TCTTCCAACC 183840
GAA~111~1C ACATTAACAA ACGTGAAGCA A~AGAGGGAT ATCGCTTAGC TTGTCAAGTT 183900
AATGTA~AAG GTAATATGGA AGTTGAACTT CCAGAAGA~A TCTTCGGCGT GA~AAAATGG 183960
GAATGTACTG TTATTTCTAA CGATAACA~A GCAACCTTTA TCA~AGAGCT TA~ATTGGCT 184020
A'11C~1~AAG GCGAGGAAGT GCCTTTCCGT GCAGGTGGTT ATATCCAAAT CGAAGCTGAA 184080
CCACATGTGG TGAACTATAA AGATTTCGAT ATTCCAGAAG AATACCACGA AGACTGGGAT 184140
A~ATATGATT TATGGCGTTA 1~L~L~1AAA GTGGACGAGC ATATTATCCG TGCTTACTCA 184200
-77.111-
SU8S 111 UTE S}~EET ~RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
ATGGCTTCAT ACCCTGAAGA GA~AGGTATC ATTATGCTTA ACGTTCGTAT TGCGACTCCA 184260
CCACCACGCC AACCTGATGC GCCTCCGGGT CA~ATGTCTT CTTACATTTG GTCATTAAAA 184320
GCAGGAGATA AAGTCACAAT TTCTGGTCCA TTTGGTGAAT TCTTTGCGAA AGAAACTGAT 184380
GCAGAAATGG TATTTATCGG TGGTGGTGCG GGTATGGCTC CAATGCGTTC ACATATCTTC 184440
GACCAATTAA AACGTTTACA TTCTA~ACGT AA~ATGTCGT TCTGGTATGG TGCACGTTCT 184500
AAACGTGAAA TATTCTATCA AGAAGACTTT GACCAATTAC AAGCTGAAAA TCCAAACTTT 184560
GTATGGCACG TGGCACTTTC AGATGCATTG CCTGAAGATA ATTGGACTGG CTATACAGGC 184620
tTTATTCACA ATGTACTTTA TGAAAACTAC TTGAAAAATC ATGAAGCACC AGAAGACTGT 184680
GAATACTATA TGTGTGGGCC TCCAGTGATG AATGCAGCTG TAATTAAAAT GTTGAAAGAT 184740
CTTGGTGTTG AAGATGAAAA CATTTTATTA GATGACTTTG GTGGCTGATT TTAGTTAATC 184800
AATTCATCAT AAAAGCTGcC CGCACTTTGT GATAAAGTGC GGnCsAAATT TAAGATGTTT 184860
TTAAACATTT TCTATGATTA CAGGTAAGTT Ll~ll~AGTT TGCCAGTAAT TCACCAATTT 184920
AGGAAATCCA GATGAAAAAA TTAATAAGCG GTATCATAGC GGTAGCAATG GCATTAAGTC 184980
TTGCTGCTTG TCAAA~AGAA ACAAAAGTTA l~l-lllAAG CGGTAAAACA ATGGGGACAA 185040
CTTATCATGT TAAATACCTT GATGATGGTT CAATAACAGC AACATCTGAA AAGACGCATG 185100
AAGAAATTGA AGCAATCTTA AAAGATGTAA ACGCGAAAAT GTCCACTTAC AAAAAAGATT 185160
CGGAATTGAG CCGCTTCAAT CAAAATACCC AAGTGAACAC ACCGATTGAG ATTTCAGCAG 185220
ATTTTGCCAA AGTATTAGCT GAAGCGATTC GTTTAAATAA AGTGACCGAA GGCGCGTTGG 185280
ATGTAACTGT TGGCCCTGTC GTGAATTTAT GGGGATTTGG TCCTGAAAAA CGCCCCGAAA 185340
AGCAACCTAC ACCAGAACAA TTAGCTGAAC GCCAAGCGTG GGTTGGCATT GATA~AATTA 185400
CCCTAGATAC TAACAAAGAA AAAGCTACAT TAAGTAAAGC A~ll~l-AA GTTTACGTAG 185460
ATTTATCGTC AATTGCTAAA GGCTTTGGCG TTGATCAGGT GGCTGAA~AG TTAGAACAAT 185520
TA~ATGCTCA GAATTACATG GTTGAAATCG GCGGTGAAAT TCGTGCGA~A GGAAAAAATA 185580
TTGAAGGTAA ACCTTGGCAG ATTGCCATTG AA~AACCAAC TACAACAGGC GAAAGAGCGG 185640
TTGAAGCGGT CATTGGATTA AACAATATGG GAATGGCAAG TTCTGGCGAT TACCGTATTT 185700
ACTTTGAAGA AAATGGCAAA CGCTTTGCGC ACGAAATTGA TCCGAAAACA GGTTATCCAA 185760
TTCAGCATCA TTTAGCCTCA ATTACGGTAC TTGCACCAAC CTCAATGACT GCAGATGGCT 185820
TATCTACAGG GTTATTTGTG CTGGGGGAAG ACAAGGCGTT AGAAGTGGCT GAGAAAAATA 185880
-77.1 12-
SUBSmUTE ~H~ET tRULE 2~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
ATCTTGCCGT TTATTTAATC ATTAGAACAG ATAATGGTTT TGTTACCA~A TCATCCTCTG 185940
CTTTCAAAAA ATTAACAGAA ACA~AAGAAT AGTTATGCAA ACTTTATTTT TTACTTTAAT 186000
CG~LLLC~LC GCAATTATAT TGTTGATGTC TATCGGATTT ATTATCAAAA AACAAAGTTT 186060
A~AAGGCAGC TGCGGTGGTT TATCTACCCT TGGTATTGCC A~AGCTTGCG ATTGTGATAA 186120
ACCTTGCGAC ACGCnTCAaT CAAAATTAGA TGCAGGCGAT GrACAAGCGA AAGCTGAATA 186180
TGAGCAAAAA TTTGCGAAAA AAGATGATGA CTCGCAATTT TATCAAGTGA AATAACTTGC 186240
TCAAAAATGA CCGCACTTTA TGTGCAAAAT A~AATTAACG GCAAAATTAT TTTGCCGTTT 186300
TCTCATTCAA TGACCAATGT GCTTCGCCTT AACCGAAGTT ACGGGAGAAC TATGTTAATT 186360
TCAAATACTT ATAATCAACA CTTTCCTCAA TTGACGCAAG AGCAGCTTGC GAGAAATGCG 186420
ACA~AAAAAG TCATTTGTGG TATGTCTGGT GGCGTGGATT ~Ll~-l~-L~LC AGCGTTTATT 186480
CTTCAACAGC AAGGCTATCA GGTGGAAGGC ~l~LLLATGr A~AACTGGGA AGAAGATGAT 186540
GATACGGATT ATTGTACTGC CGCAGCTGAT CTTGCAGATG CTCAGGCTGT ATGTGATAAG 186600
TTGGGGATCA AACTACATAA AATTAATTTT GCGGCAGAAT ATTGGGATAA L~L~LLL~AG 186660
CAL-L-L-L-L-LAA CCGAATATAA AGCAGGGCGC ACGCCGAACC CAGATATTTT GTGTAATAAA 186720
GAAATTAAAT TTAAAGCATT TTTAGAATAT GCAGCTGAAG ATCTCGGTGC AGATTATATT 186780
GCAACAGGGC ATTATGTACG TAGAGCGGGA GATAATGAAA ATGCAAAACT ATTACGTGGT 186840
TTAGATCCCA ATA~AGATCA AAGTTATTTT CTTTATACTT TAAGCCATAA ACAAGTGGGG 186900
CA~AGTTTAT TCCCC~LLGG TGAAATCGAG AAGCCCATTG TTCGTGCTAT TGCTGAAGAT 186960
CTTGGCTTAA TTACGGCGAA GAAAAAAGAT TCTACAGGGA Lll~llLLAT TGGTGAGCGT 187020
A~ATTTAAGG ALLL~LlAGC ACGCTATTTA CCAGCTCAAC CAGGTAATAT TCGCACTGTA 187080
GATGATGAAA TTATTGGTCG CCATGATGGA TTAATGTATC ACACATTGGG ACAACGCAAA 187140
GGATTAGGCA TTGGTGGTCT AAAAAATGCG GGAGATGAAG ~LLG~LATGT AGTAGATAAA 187200
GATGTAGAAA ATAATGAACT TATTGTCGCA CAAGGTCACG ATCATCCTCG TTTATTTTCA 187260
AAAGGATTGA TTGCCAGCCA ATTACATTGG GTTGATCGCG AACCAATTCG AGAGTCATTA 187320
CGTTGCACGG TGAAAACGCG TTATCGCCAA CAAGATATTC ~Ll~l~L~AT TGAACCAATT 187380
GATGATGA~A CCATTCGAGT TALLLLL~AT GAACCTCAAT CAGCAGTAAC CCCAGGGCAA 187440
TCTGCCGTAT TTTACCTTGG CGAAGTTTGT TTGGGTGGCG GTATTATCGC AGA~AGAATA 187500
TAAAACAAAG ATGACTAAAA GCGCGTAAAA TGCGCTTTTA AACTATTTAT TCAAACCAAA 187560
-77.1 13-
SUE~S i 11 UTE SHEE~ ~RULE 26
CA 02218741 1997-10-21
W 096/33276 PCTAuS96/05320
TGACGCTCGC CATTCGTCCC GTTTGATTGT CCCTGCGATA AGAAAAGAAC 'l"ll"l'~'l"lLll' 187620
CGTTGAATGT ACAGTGATTT CCACCATAAA TTTGCGTAAT ACCTAGATTG TTTAATCGCT 187680
GAGTTGCAAT TTGATAAAGA TTACTCAGGT ATTTACCTTC TTCGATTGCA TCAGGTTGAA 187740
AGGCGAGTTT GG-lllll-A TCTACTACAA CAAACTTTTC TACAACATCA ATCCCAACTT 187800
GAAAGGCCTT TGGACCTATT GCAGGGCCAA ACCACGCGAT AATATCTTCA GGTTTAGCTT 187860
GAAAATATTT CA~L~lll-l TCTAGTACAC CATCGCATAA ACCACGCCAG CCAGCATGTG 187920
TTGCAGCCAC TTCATTGCCA GAl~ll~lAG TGAATAGAAC TGGCA~ACAG TCTGCCGTCA 187980
TAACAACGCA AACTTGATTG GGAACATTTG TATAAACTGC ATCCGCTTCA AGALlll~lC 188040
CTGAATAAGG TAATTGAATC ACTCGAGTAC L~l~l~lllG AGTTAGA~AT ATAGGTGTTT 188100
GTGGCAAACC AAA'Lllll~l ACTAATAAAG TGCGGTTGGT TTTTACCGCA ~Llll~llAT 188160
CACCGACATG ATCGCCTAAG TTGAAACTCA AATAAGGCGC TAAGCTCACA CCCCCTTCAC 188220
GAGTAGTGGT AAAGGCATGA ATALl~lllG GAACATTCCA ATTGGGGTTA ATTGCTTGCA 188280
TATTAATAAT CTAACTCATC TTGATGTTCG AGATAGTCGG CTTTGAGGGC ATTAAGCAAT 188340
TCAACGAAAT CATCTGGTAA TGGTGCATAC CATTCCATCA ~L~LCCC~l~l GATTGGATGA 188400
GCTAAGCGTA ACATGACCGC ATGTAAAGCT TGGC~LllGA AATTACGCAA TACTTCCATA 188460
AAGTCTTCAC TCGCATTTTT TGGTGGACGA GGGCGTCCGC CATAGGTTTG ATCGCCTAGC 188520
AGTGGATGGG CAATATGTGC CATATGAACG CGGATTTGAT GGGTGCGCCC C~'l"l"l'-''l'AAA 188580
CGTAAACGTA AACGGGTGTA GTTACGGTAA TTTTCCATAA TACGATAGTG GGTAACAGCG 188640
G~llllCCCA TTGGATGAAC CGCCATTAAA GTACGTTTGG TTGCATGACG AGCCATAGGT 188700
TGATCTACTG TGCCACCTTT AGTCATAATG CCTGAAGCGA CTGCTTCATA TTCGCGCGTA 188760
ATTTTACGTT $TTGTAGGTC ACGTACTAAC TTAGTTTGAG CAGGAATGGT TTTAGCaACA 188820
ACCATTAGAC ~L~llGlATC TTTATCTAAT CGATGCACAA TTCCTGCTCT CGGTACTTCT 188880
ACAATCGGCG GATAATGATA GAGTAACGCA TTGAGCACGG TTCCATTTGG ATTGCCAGCA 188940
CCAGGGTGTA CCACAAGATC TTTTGGTTTG TTAATCACAA TAATATCATC ATCTTCATAC 189000
ACGATATTCA ATGGAATATT TTCTGCTTCA AAAC~L~lll CATCTTCCAC TTCAACAATA 189060
ATCTCTATTC TCTCTCCTCC AAGCACTTTC TCACGCGGAA TATTAGTAAT GCG~LC~llA 189120
AGTTTTACGA GATCGGCTTC AATCCATGTT TTTAATCGGG AACGAGAATA TTCAGGGAAC 189180
AACTCTGCAA ~L~lLlGGTC TAAACGTTGT CCCATTTGTT CTGGCTGCAC TTCAGCCGAA 189240
-77.1 14-
SU8S 111 UTE S~tEET (RULE ~6)
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/05320
AGGGTAATTT GTGGCATA~A TAGCTCTCAA AAATTTTAAA AGTTGGCTTA TTGATTAATG 189300
TTCTATACAA TAGCGGACAA TTGTATCTTA TTTATTGGTT TTCGTAAAAA TTAAGGAAAA 189360
AACAATGCGT A~AATA~AAT CTTTGGCATT GCTTGCCGTG GCAGCATTGG TTATTGGATG 189420
TTCAAGTGGT TCA~AAGATG TTGAACAAGC ATCGGTAAAT GAATTATACA CA~AAGGTAC 189480
AACATCATTA CAAGAAGGTA GTTACTCTGA AGCCATTCGC TATTTA~AAG CGACGACTGA 189540
GCGTTTTCCA GGTAGCGTTT ATCAAGAACA AGCAATGTTA GATTTAATTT ATGCA~ATTA 189600
TAAAACACAA GATTATACGC AAGTATTATT GATGGTAGAT AG~111-1-1AC ATCAATTTAC 189660
ACA~AGCCCA AATCAAGCCT ATGCGGTATA TATGGCTGGC TTAACTAATG CAGCAACAGG 189720
CGATAATTTC ATTCAAGATT TTTTTGGAAT TGACCGTGCT ACACGTGA~A CAACCTCTAT 189780
GCGTACCGCT TTTTCTAATT TCCA~AACTT A~L1C~-1~-1A TTCCCTAATA GCCCTTACTC 189840
ACAAGATGCT TTAGCTCGTA TGGCTTATAT TA~AGATGCA CTGGCTCGTC ACGAATTAGA 189900
GATTGCA~AA TTCTATGCAA AACGTA~AGC GTGGGTAGCA GTTGCA~ATC GTGTGGTAGG 189960
AATGTTAAAA CAATATCCTG ATACTA~AGC aACTTATGAA GGATTATTTC TGATGCAGGA 190020
AGCTTATGAA A~AATGGGTT TAACCGCATT AGCA~ATGAT ACTCA~AAAA TTATTGATGC 190 080
GAATA~AGAT AAAACTTTTG CACCAATTGA A~AACCA~AC GAGCCAGACT TAAAAGTGCC 190140
AGCAGTA~AA TAGCAATAAC TGCAGAAAAA TCGAATACTC TCTGCACCCT AAAAATTGAA 190200
TA~AATTTAA ACTAATTAAG GTGCAGATTT TTTTATTTTT TATCAACTGA AAATGCTTTA 190260
CCATAATTTG CACA~ATAAT CTGAGCAGCA TTATA~AGCG TTGTATCAGG TGTTA~ACTT 190 320
AACGTATGTT ~1-~-1-1-1-1-GCTT TTTAGGTGCT GCCCGCAAAC CCTGTCCCCA A~ATTCATCA 190 380
TAGA~ATCAG TTCGTATTTG AGTTAAATGA TAATTTGCAC AATTCAAAAT CTTATACTGA 190440
CGAACAGAAC GTGCATAACG TTTAGGCTCA GGATA~ACAT ACAATCCCCT ATCTA~ATTC 190 500
ACCACAGCAT CA~AATGTAC AATTTGTGGC TCTTGGTTAT CCACCCAGAT CGATTCACTA 190560
TCGATGTAAT AATTCACATT CTTTACCA~A CGTATATATC CG~-1~C~1AC ATCAGTCGGC 190620
GGTGCCAGCT TCACATCATT 11~-1-1-~'AGCC TTTTGGATTT GAGCAGAACA AGCGGTAAGT 190680
AACCCAAGTG ATAATGTTAA AATAATTTTT TTCATTATTT ACTCCTTATG TTAGCTGACA 190740
TTTATTCTAG AATTTTACAG TGTGTCCATA ACCTTCTAGG ALl~llllAA TAL~ll~lAA 190800
GGAL-L~-1--L-1A GTTGGCGGTA ATACATTTTC AAGCTCATAA TCTAACCCAA GGGTTTTCCA 190860
TTTATGCACA CCTAATCGAT GATAAGGAAG AAGTTCAACT TTTTCAATAT TGGTCATACC 1909 20
-77.115-
SUBS 1 1 1 UTE S~{EET tRULE 2~
CA 02218741 1997-10-21
W 096t33276 PCTtUS96/05320
TTCAATAAAC TGACCTAATA AATGCACATC GTGATCGCTA TCAGTATAAC CAGGAACCAC 190980
AACATAACGA ATCCAGGTAT GTTGATTACG TTTTTGCA~A TATTTTGCAA ATTCAAGGGT 191040
ACGTTTATTT GGCACCCCAA TAAGATTTTG ATGAACTTGA TCATTAAGTT CTTTTAAATC l91100
AAGTAAAACA AGATCTGTTA CATCTAATAA TTCATCAATA ATATGATCAT AATGACGTAC 191160
A~AACCATTT GTATCTAAGC AAGTATTAAT CCCTTCCTCT TTACAAGCAC GGAACCAATC 191220
GCGTACAAAC TCTGCTTGTA ACACAGCCTC GCCACCAGAT GCTGTGACAC CACCGCCAGT 191280
AGCATTCATA AAATGGCGAT AAGTCACGAC ~Ll~lLL~ATT AAATCTTCGA CACTGATTTC 191340
TTTACCACCT TCAAGATCCC AAGTATCACG ATTGTGGCAA TATTTGCAGC GCATCAAGCA 191400
GCCTTGCATA AATAAAATAA AACGAATACC TGGCCCATCT ACAGTGCCAC AGGATTCAAA 191460
AGAGTGAATT CGTCCAAGAA CTGACATACA TAAATTTCCT A~AATTAGAT ATAGCTAAAT 191520
TTTACCAAAG ATTTAGTCTA TA~AAAATGA GCCTGATTTA AATCAGGCTC ATACATATTA 191580
TGTTCCCGCC AAAGTGCGGT CA~AAATAAA CAl~LllllA CATTGACTCT GTGAAAGTTC 191640
TAGTAATTAC ~'L~'L'l'~'L'l'~'l' TG~L~lLlAG TTAAAGAGTT APAAACGTACT GCGTAACCTG 191700
ATACACGGAT AGTCAATTGT GGATATTTAT CCGGATTTTC CATTGCATCT AATAACATTT 191760
CACGGTTTAA CACGTTCACA TTTAAGTGTT GGCCACCTTC AACCGTTGCT TCGTGGTGGA 191820
AGTAACCATC CATTAAGCCA GCAAGGTTGC GAC~ll~lGC TTCTGCATCT TTACCTAAGG 191880
CATTTGGTAC GATTGAGAAG GTATAAGAAA TACCATCTTT CGCGTAAGCA AATGGAAGTT 191940
TAGCTACAGA AGTTAATGAT GCTACCGCAC ~LLLllGGTC ACGACCGTGC ATTGGGTTCG 192000
CACCTGGTCC GAATGGTGCA CCAGCACGAC GACCATCAGG GGTGTTACCC ~'l"l"l"l'~'l"l'AC 192060
CATAAACTAC GTTAGAAGTA ATGGTTAATA CAGATTGTGT AGGCACTGCA TTGCGGTAAG 192120
TTTTAAGTTT TTGAATTTTC TTCATAAAAC GTTCAACTAA GTCACAAGCG ATGTCATCAA 192180
CACGGTTATC ATTGTTACCA TATTGTGGAT ATTCACCTTC GATTTCAAAG TCGATTGCTA 192240
CGTTAGTTGC AACAACATTG CCATCTTTAT CTTTGATGTC GCCACGAACT GGTTTAACTT 19?.300
TCGCATATTT GATTGCTGAA AGTGAGTCAG CCGCAACAGA AAGACCTGCG ATACCACAAG 192360
CCATAGTACG GTATACATCA CGATCATGTA ATGCCATTAA TGCGGCTTCG TATGAATATT 192420
TATCGTGCAT ATAGTGGATT ACGTTTAAGG CAGTCACATA Ll~l"l"llGCC AACCAATCCA 192480
TA~AGCTATC CATACGAGTC ATTACTGTAT CGA~ATCTAA TACTTCATCA GTAATTGGTG 192540
CA~LlllCGG ACCTACTTGC ATACCTAATT TTTCATCGAT ACCGCCGTTG ATTGCGTATA 192600
-77.1 16-
SU~SmUTE ~}~EET tRULE 26
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/05320
ACAATGTTTT CGCTAAGTTT GCACGTGCAC CGAAGAATTG CA'111~111A CCCACAATCA 192660
TTGGTGATAC ACAACATGCG ATTGCGTAGT CA'1'C~'1''1'~'1"1' GAAGTCTGGA CGCATTA~AT 192720
CA'1'C~'1''1''1"1'C GTATTGAACT GATGAGGTAT CAATCGATAC TTTTGCACAG A~ACGTTTGA 192780
A~'L'1''L'1'~AGG TAATTGTTCA GACCAAAGAA TGGTTAAGTT TGGCTCTGGA GAAGTACCCA 192840
1~11~1AAAG G~1~1~1A~A ATACGGAATG TATTTTTGGT TACTAATGTA CGACCATCTA 19 2900
AACCCATACC TGCGATGGTT TCAGTTGCCC ACATTGGGTC ACCAGAGAAT AATTGATCGT 192960
ATTCAGGTGT ACGTAAGA~A CGAACCATAC GAAGTTTCAT AACTAAGTGG TCAACTAATT 193020
CTTGCGCTTC AGTTTCAGTA ATTTTTCCTG CTTTTA~ATC AC~'1''LC~ATG TACACGTCAA 193080
TA~AGGTTGC GGTACGACCG AATGACATTG CAGCACCATT TTGTGATTTT ATTGCAGCAA 193140
GATAAGCA~A GTACATCCAT TGAATGGCTT CTTGAGCATT AGTTGCTGGG TTAGA~ATAT 19 3200
CATAACCATA GCTTGCTGCC A'1''1''L~'1"1''L'1'A ATTGACCTAA TGCACGGTGT L~Ll~LGCGA 193260
'L11~LL~ACG TA~ACGAATT GTTGCTTCAA GATTTACGCC A'L~'1''L~'LA~A 'L~'L'L'L'L'L~'LA 193320
AAGAAGAGAA TTGTGCGTAT TTA'L~'L'L'1'~A TTAAGA~ATC TACACCATAA AGTGCTACAC 193380
GACGGTAGTC ACCGATGATA CGACCACGAC CATAAGCATC TGGAAGACCA GTTAATACCC 193440
CAGATTTACG GCAACGTA~A ATATCTGGCG TGTA~ACATC GAATACACCT TGGTTATGTG 193500
TTTTACGGTA TTCAGTGAAG A'L'L'L'1''L'1''L~'A CTTTTGGATC AAGTTCACGA CCATA~ACTT 193560
TACAAGAACC TTCCACCATT TTGATACCAC CGAATGGCAT AATGGCACGT TTTA~AGGTT 193620
CATCAGTTTG AAGACCAACG A'1''1''1''L'L'L~'1'A AA'L~'L'L'1'~'L'L AATGTAACCA GGTGCGTGAG 193680
AGATAATGGT AGATGGTGTA TGTTCATCAA AATCTAATGG CGCGTGAGTA CG~'L L'L l ~AA 193740
TTTTAATACC TTCCATCACA GATTCCCA~A GCTTGGTTGT TGCTTCGGTT GGACCTGCTA 193800
AGA~AGAGTC ATCGCCTTCA TAAGGGGTAT A~11L1LL1G GATA~AGTCA CGTACATTGA 193860
CA'1''1"L'1'~'1"1'G CCAATCGCCA CCAGCA~AAC CAGCCCACGC CAATTTTTGC ATTTCATTAA 193920
GTTCTGACAT AGTCATTTCC '1LL~11AATT AATA~ATA~A TCTTTAATGT GTTTTGGTTA 193980
AATAACGTTG GAATACACCA ATACAAATTG CCCCGCCGAC AATATTTCCC AACGTTACAG 194040
GGATTA~ATT CTTCACGATG A~ATGGTACA AATCTA~ATC TGCGTATTTC ATCGGATCAA 194100
CACCGATTTG TTGCCA~AAT TCAGGTGTAC TA~AATGTGC GGTAATAATT CCCATCGGAA 194160
TCATA~ACAT ATTAGCCACA CA~'1'~'L'L~'AA ATCCTGACGC GACA~ACA~A CCAATCGGCA 194220
TAATCATAAT A~ATGCTTTG TCTGTAACAG TCTTACCAGA ATAAGACATC CAAACCGCCA 194280
-77.117-
SUBS 111 UTE S}~E~T (RULE 2~)
CA 02218741 1997-10-21
W 096133276 PCTAUS96/05320
CACACACCAT AATGTTACAT AAAATACCTA GGTTAAAAGC TTCA~ACCAA GTGTGATGAA 194340
TTTTATGTTG GGCGGTTGCA AGAATTGTTA AACCCCATTG GCCATTTGCT GCCATTGTTT 194400
GTCCACTAAA CCAAATAACA GCCGCAATAA ATAAACCACC AACGAAGTTG CCTAAATACA 194460
CCACGATCCA ATTTCGAATC A'lll~l~lCG TGGTGATTCT ACCGCCTACA CGGGCGACTA 194520
AAGTTAAAGT AGAAGAAGTG AATAATTCAG ATCCTAAAAT CACCACCATA ATTACGCCCA 194580
AGGAGAAGAC TAATCCACCT ACTAACTTGG TTAATCCCCA AGGTGCGCCT GCACTAGCAG 194640
'l"l"l'~'l'~'l"l'~'l' CGTGTAAAAT ACAAAGGCTA AGGCAATACA AGCACCGGCA CTAATACCGG 194700
ACATAAACGA TAAAAATGGA CGTTTATTTG CTTTATAAGT TGCTGTATTT TCTGCATAAT 194760
CCGTTGCTTC AACAGGTGTG AGCGCAACAG AAGATAGTTT TTGATTTTCT GATGCCATAA 194820
TCAAACTCCA ACTATTGACA TTGAAAAAGT TGATGAAAAT TTAATACTTT TAACAAGTTT 194880
ACGACTACAA ATACTTCTAT AATTGGTGCT ATTTTACTCT CCTCCCCTTT CATTGCAAAG 194940
AAAAGCAAAA ATTATTTCAA CAAACTTTGA TATTTTGCAA G~'1''1"1'~'1"1''1'A ATTAAAGACA 195000
AAATTCCCAT ATTAATATTC GCTCAATTTC ATACATTCAG AGTAAGTAAA GTACTTAATT 195060
TGAAACTTGT TTTATTCGCG TAATACCGTG AATTCCCCCA GATAATCATC CA~llllC~A 195120
AAACCTTGAT TATTCACAAC AGGCAAATTC ATAATTTTTT CAAACGAACC AGATTAAGTG 195180
TATAGACTTG CTATTTTGAG TAATTAATAG CATTATTTTG Al~lllll~A AGAAAAAGGC 195240
GAl~lll~lC ATAAAATAAT GATTTAAGTG CGGTTAAAAT TTGGTTAATT TTAAGTGCAC 195300
ll~lllATAC AGGAGCAGAT TATGTATTAT GGTTTAGATA TTGGTGGCAC GAAAATAGAG 195360
CTTGCCGTAT TCAATGAAAA ATTGGAAAAA TTATATTCTG AACGGGTGCC AACACCTAAA 195420
ACCGACTATG AAGAATGGCT TAACACGATT GTGGATTTAG TGAATCGTGC TGATGAAAAG 195480
'l"llG~l~AGG TGGGCACCGT AGGTTTGGGC GTACCTGGTT TTGTTAATCA ACAAACTGGA 195540
TTAGCCGAAA TTGCCAATAT lC~l~lGGCA GATAATAAAC CAATTTTATG CGAlll~l~l 195600
ACGCGTTTGG GCCGTGAAGT GCGGGCAGAA AATGACGCAA All~llllGC GTTATCTGAA 195660
GCATGGGATA CGGAAAATCA GCAATATTCG ACTGTACTTG GTTTAATTCT TGGGACTGGT 195720
TTTGGTGGTG G-lll~lCTT AAACGGTAAA GTTCATTCAG GTCAAGTGGG AATGGCGGGA 195780
GAGCTTGGTC ATTTACAATT AAATTATCAT GCTTTGAAAT TATTGGGATG GGATAACGCC 195840
CCAATTTATC AATGCGGTTG CGGCAACAAG G~ll~lll~G ATAATTATCT GTCTGGTCGC 195900
GGTTTTGAAA TGCTTTATCA AGATTTGAAA GGCGAAACAT TATCTGCTCG TAAAATTATT 195960
-77.1 18-
SUBS i I i UTE ~}~E~T (RULE Z6)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/OS320
AA~LLL~Ll~L ATCAAAGCAA TGA~AGTGCG GTAGATTTTG TGAATCTTTT TGTTGAGTTG 196020
GCGGCGATTT CTATTGGCAA TATCATTACG GCATTTGATC CGCATATGAT l~l~LLAGGT 196080
GGTGGATTAT CTAATTTTGA TTACCTTTAT GAGGCTTTAC CAAAAGCnCT TCCGCCTCAT 196140
TTGATGCGAA AAGCAAAAGT TCCGCCAATT AAAAAAGCGA AACACGGCGA TTCTGGTGGT 196200
GTGCGTGGTG CGGCAGCGTT ~~ AACC AAATAATTCA ACAAACTAGT GGGGCGTATT 196260
CAAATAATAC GCCCTTTATT TTGGAAAATA TTTAGAATAT TGTGAATTTA TTAGATTTTT 196320
T~11~LL1~1 GTTTCTTTCT TTAGAGAAAT TATTAAAAAA TCTCGCCTTT TCATTGAAAA 196380
GCCATACAAT CAAATTATTT ATCGCTTGAG GGATGATTAT GGAATTTGAA TTTTCAAAAA 196440
TGTTAGAAGA AGTGCTAACT TGGATAGTCG CACACCTTGA TGGACCTTTA TGGGATGCCA 196500
CCATTATTAT TTTGCTTGGG ACTGGTCTAT TTTTTACCAT TACAACAGGA TTTGTGCAGT 196560
LCC~lLLATT CCCAGCAAGC ~LLC~L~AAA TGTGGTTTGG LC~LlCGGTG GAGGGGAGTT 196620
CATTAACACC TTTCCAAGCG TTTACAACAG GTCTTGCGAG CCGCGTTGGT GTGGGTAACA 196680
TTGGTGGGGT TGCAACGGCA ATCGCCTTAG GGGGCGAAGG CGCAGTGTTT TGGATGTGGG 196740
TAACGGCATT TATTGGTATG TCGAGTGCTT TCGCTGAATC TACCCTTGCT CAATTATTTA 196800
AAATTCAAGA TAAAGATGGA TCA~lLCC~LG GCGGCCCTGC TTATTATATT GTGCAAGGTT 196860
TAAAATCACG TTGTATGGCA GTGGCTTTTG CGCTTGCATT AATTTTTACA TTTGGTTTTG 196920
CCTTTAATTC TGTGCAGGCA AACTCTATTG TTGAAGCAAC CAGCAATGCG TGGAATTGGA 196980
AAGGGGAATA L~LCG~LATT TCATTAGTAA TTTTTACCGC ACTTATTATT TTCGGTGGCG 197040
TTAAGCGTAT TGCGATTATT TCGAGCAACC TTGTACCAAT GATGGCACTT TTCTATTTGA 197100
TTATGGCGGT AATTATTCTT GGCATGCATA TTGATATGAT CCCTTCCGTG ATTCATCGTA 197160
'lL~LL~AAAG TGCATTTAGT TTTGATGCTG CCGCTGGCGG AATGTTTGGT GCATTGGTAT 197220
CGAAAGCAAT GATGATGGGG ATTA~ACGTG GTTTATTCTC A~ACGAAGCA GGGATGGGAT 197280
CTGCGCCTAA TTCGGCTGCA GCAGCTCACG TTAAGCATCC AGTTAGCCAA GGTTTAGTGC 197340
AAATGCTCGG G~1~11L~11 GATACAATGA LC~Lll~lAC TTGTACTGCC GTTATTATTT 197400
TGCTTTCGAA TAATTATGGT AGCGA~ACGC TCAAAAGTAT ~L~~ ACG CA~AATGCTT 197460
TGCAATACCA CATAGGTGAA TTTGGGGCGC ATTTCCTGGC GTTTATCTTA TTGTTATTCG 197520
CTTATTCTTC TATTATTGGT AACTATGCTT ATGCGGAAAG CAACATCCGT TTTATCAAGA 197580
ATAAACCTTG GTTGGTCTTG TTGTTCCGTT TAATGGTGCT ATTTTTCGTG TATTTCGGTG 197640
-77.119-
SUE~S i 11 UTE SHEET (RULE 2~i)
CA 022l874l l997-l0-2l
W O 96/33276 PCTnUS96/05320
CGGTTCGCTC TGGTAATGTG GTGTGGAATT TCGCAGATAC GGTGATGGCT GTCATGGCAA 197700
TCATTAACTT GATCGCAATT TTGATGTTGT CGCCAATCGT ATGGA~ATTA ATGAAAGATT 197760
ATCAACGCCA GCTTAAAGAA GGA~AAACGC CAGAGTTTAA AATTGATGAA TACCCTGAAT 197820
TACGTAAGAA AATATTTGAT TCCCGCATTT GGAAATAAAG ATAAAATGGC TAGAAAGAGA 197880
TTATCTACCT TTCCAAAAAG AGTTAGATTA TTATTTAAAG A~ALlllll~ ATATTGTTTC 197940
AGGCTTGGTT CTTCTAGTTC AGACTGAATA AACTATTGCC GGCACTTTTT ACCGCCCTCG 198000
TGCCGGCTAT CCCAAACTGC TTTGAAAACT GACCGCTCTT TAGCTTACTT CAAAAATTCC 198060
GCATGATAGG CAATATGCTC GCCAATAAAA CTGGCGATGA AGTAATAGCT GTGATCATAG 198120
CCTTTATGGA AGCGCACATC GACTGGCTGA TTTGCCACTC GACAGGTTTC TATA~AATCT 198180
TCGGTACGCA All~l~lCGG TAAAAACTCA TCTTCCAAGC CCTGATCAAT GCGCATACCT 198240
TGCACTTTAT AGC~ll~llG AATGAGCGAG CTGGCATCAT ATTGCTGCCA TTTTTCACGA 198300
TCTTCCCCTA AATAGGCAGA AAAGGCTTTT TCTCCCCAAG GCACAAGGCT TGGCGACAAA 198360
ATGGGCGAAA AGGCAGAAAC GCTTTGATAA CGTTCCCGAT TTCGCAGTGC CAATACCAAT 198420
GCACC~l~lC CACCCATTGA A~l~lCC~ATA ATGGAACGTT TGCC~ll~l AGGGAAATTT 198480
GCTT~TCA A~TCAG~-C~ TTCATTCAAG ATATAATCA-T ACATTTGATA AllC~lCGCC 198540
CAAGGCTGCT CGGTCGCATT AAGATAAAAG CCCGCTCCCT GCCCTA~ATC GTAAGCCGCA 198600
TCATTCGGCA CTTGCTCTCC ACGAGGGCTT GTATCGGGAG CAACAACAAT CACTTGATGT 198660
TCTGCCGCGT AACGCTGGAA GCCTGATTTG GTAATGAAAT TTTGCTCAGT ACAAGTTAAG 198720
CCTGAAAGCC AATA~ATCAC ACCAAGCGGT CGA~ lG GATTATTTGG CAAATAAACG 198780
GCAAATTTCA TTTCACATTG AA~l~lllGA GCATTATGCG CCCAAACTTG CTGCGAACCG 198840
CCAAAAATTT GA'l~ll~llC AATTAGTTTC ATAGCGTACC TTAGTAGTGA ATAACAGTAC 198900
GGATTGATTT ACCTTCGTGC ATTAATTCAA AGGCTTCATT AATTTTATCA AGTGGCATTG 198960
TGTGAGTCAC AAACG~ll~l AACTGGATGT CGC~lll~AT TGAATCTTCC ACCATTTGCG 199020
GAAGTTCAGA GCGACCTTTC ACGCCACCAA ATGCCGAACC TTTCCAAACA CGGCCTGTTA 199080
CCAATTGGAA CGGACGCGTT GA~ATTTCTT GTCCTGCACC CGCTACGCCG ATGATAATGG 199140
ATTGTCCCCA GCCACGGTGA GCA~lll~lA ATGCTTGACG CATTACGTTT ACATTACCGA 199200
TACATTCAAA GGTATGGTCA ATGCCCCATT TATTAATATC TAACAACACA ~l~-l"l'-l'~ATCG 199260
,GCTTATCGTA ATCATTAGGG TTTA~ACAAT CCGTTGCACC A~A~L~llll GCCAACTCAA 199320
-77. 1 20-
SUBSTIl~JTE ~tEET tRULE 26)
CA 022l874l l997-l0-2l
W 096r33276 PCTrUS96/05320
ATTTTGCAGG ATTGGTATCA ATAGCGATAA TGCGACCTGC TTTGGCTTGA CGCGCACCTT 199380
GCACTACCGC TAAACCAATC GCACCCAAGC CAAACACGGC AACAGAGTCG C~'1--1'~'1"L~'LA 199440
CTTTTGCTGT ATTATGCACC GCACCAATAC CTGTAGTGAC ACCGCAGCCG AGCAAACACA 199500
~L1~-L-LC~-LG GTTCGCTTCA GGGTTGATTT TCGCCAGTGA AACTTCCGCA ACAACTGAGT 199560
ATTCACTGAA GGTTGAACAG CCCATATAGT GATAGATCGG CTGACCTTGA TAAGA~AAAC 199620
~1~LC~1-GCA ATCAGGCATT AAGCCTTTAC CTTGCGTGTC ACGCACTGAG ACGCATAAGT 199680
TGGTTTTACC CGAGCGGCAA AACTCACATT CGCCACATTC AGCTGTATAA AGAGGAATGA 199740
CGTGATCGCC CGGTTTTACG CTTAACACAC CTTCGCCAAC CGCAACAACC ACACCCGCAC 199 800
~-L'1'C~-L~'LCC TAGCACCACA GGGAATACCC CTTCAGGATC GCTTCCTGAT AACGTAAACG 199 860
CATCAGTATG GCAAACGCCC GTGTGAGTGT TGCGGATTAA CACTTCACCT TTGCGTGGCA 199920
TTTCTACGTC GATTTCTACA ATTTGTAAGG GTTGATTTGG GGCGAATGCT ACCGCCGCAC 1999 80
GAGATTTGAT GGTTGAATTG A'L'L'1'~'L'1"1'AA TTTCCATTGT TTTTCCTCTT AATTCATTGA 200040
CAAAGTTGCC TTACGTAAGC AAGATAGCAA CAGTTTACAC TTTAGAGTTC ACTCTAAAGC 200100
AA~'1'~'L'L'L-1''1- TTATCATTTT TGTTTA~AGG GAATAAAAAG TGACTTACAC CACCGCTAAA 200160
GCTGCTGA~A A~ATAGGCAT TTCCGCCTAC ACCTTACGCT TTTATGACAA AGAAGGCTTG 200220
TTACCTAATG TCGGACGTGA TGAATACGGT AATCGCCGTT TTACCGACAA GGATTTGCAA 200280
TGGTTGAGTT TATTACAATG CTTGAAAAAT ACAGGAATGA GCTTAAAAGA CATCAAACGC 200340
TTTGCGGAAT GTACCATCAT TGGCGACGAT ACTATTGAAG AACGCCTTTC CTTATTTGAA 200400
AATCAAACAA AAAATGTA~A GTGTCA~ATT GCCGAATTAA AACGTTATTT AGATTTGCTT 200460
GAATACAAAT TAGC~-L-L-L-1-A CCAAAAAGCG A~AGCACTAG GCTCGGTA~A AGCTGTGAAT 200520
TTACCGCA~A ~L-LC~-L~AAAC GAGCTA~AAG GGTAAAAGTG TTCACATCAC AGAATTAGAA 200580
GAAAAATACA ATTTTTAGAG ATAGATAAAT TTTAACTTTT TTATTACATA AATAAGTTAA 200640
AAATCAGGTT TTGTGATCAA GATCAGGATA ACATA~AAAT AA1-~'LCCGAT AGCTATTGTT 200700
CTAAATGGCT AAAAAGAGTA TATTCCGAGC CA~ATTTTTT ~-1-LL1L-LACA GAACGGAGTT 200760
TATTATGTTT GGTTTATCCC CCGCTCAACT GATTATTTTA TTAGTCGTTA TTTTATTGAT 200820
TTTTGGCACG aAAAAATTAA GAAATGCTGG CTCAGATCTT GGTGCAGCAG TGA~AGGTTT 200880
CA~AAAGGCG ATGAAAGAAG ATGAAA~AGT A~AAGATGCG GAATTTAAGT CTATAGATAA 200940
TGAAACAGCG TCTGCAAAAA AAGGA~AATA TA~AAGAGAA AGGAACAGGC TTAATCCGTG 201000
-77.121-
SUBSTiTUTE S~EET tRULE 2~i)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
TTTGATATTG GTTTTTCAGA ACTTATTTTA CTAATGGTTT TGGGATTGGT TGTATTAGGC 201060
CCGA~ACGTT TGCCTATAGC AATTCGCACT GTAATGGATT GGGTAAAAAC AATTCGTGGT 201120
TTAGCTGCTA ACGTTCA~AA TGAGTTGAAA CAAGAGCTAA AATTGCAAGA ATTACAAGAT 201180
AGTATTAAAA AAGCGGAATC CCTTAACTTG CAAGCCCTTT CACCAGAATT GAGTAAAACG 201240
GTGGAAGAAT TAAAAGCTCA AGCAGATAAG ATGAAAGCGG AGCTAGAAGA TA~AGCAGCT 201300
CAAGCTGGTA CAACGGTGGA AGATCAAATC AAAGAAATCA AAAGTGCGGC TGAAAATGCA 201360
GAAAAGTCTC AAAATGCAAT CTCAGTTGAG GAGGCTGCAG A~ACTTTATC TGAAGCAGAA 201420
AGAACACCTA CAGATTTGAC CGCACTTGAA ACTCACGAGA AAGTAGAACT GAACACACAT 201480
TTATCTAGCT ATTATCCTCC TGATGATATT GAAATCGCTC CAGCGTCAAA ATCTCAATCT 201540
TCAAAAACTA AATCATAGCG A~lllllATG AGTAATGTGG ATGAATCTCA ACCTTTAATT 201600
ACGCACCTTG TTGAACTAAG A~ACCGTTTA TTACGCTGTG TGALll~L~l AGTGTTGGTT 201660
Lll~ll~CTT TGGTGTATTT TTCCAATGAT ATTTATCATT TTGTTGCTGC ACCTTTAACG 201720
GCTGTTATGC CAAAAGGCGC AACAATGATT GCAACCAATA TTCAAACGCC lLl~lllACG 201780
CCAATTAAAT TAACTGCGAT TGTTGCAATT TTTATTTCTG LCC-llATTT GCTTTATCAA 201840
ATTTGGGCTT TTATTGCACC TGCTTTATAT CAGCACGA~A AACGGATGAT TTATCCGTTG 201900
TTAllllC~A GTACGATTTT ATTTTATTGC GGTGTTGCTT TTGCTTACTA TATC~L~lll 201960
C~l~lL~LAT TCAGCTTCTT TACACAAACA GCCCCAGAAG GCGTTACCAT CGCAACAGAT 20'020
ATTAGTAGTT ATTTAGATTT TGCTTTAGCG TTATTTTTAG ~LLllGGCGT Ll~LlLl~AA 202080
GTGCCAATTG CGATTATTCT ACTTTGCTGG ACTGGTATTA CCACTGTAAA GG~L~llLCC 202140
GAAAAACGCC CTTATATTAT TGTTGCGGCA LlllllATTG GTATGCTTTT AACGCCTCCT 202200
GAL~LLllLl CACAAACTTT GCTTGCCATA CCGATGTGCT TG~L~lllGA GCTCGGTCTA 202260
TTGGTCGCTC GATTTTATCA ACCAAAAGAC GACGA~AGTG CGGTTAAAAA TAATGATGAA 202320
TCAGAAAAAA CACAATGATG AACTGAATTG TTAATCGTAT GGGGGCTTTG CCCCCGTTTT 202380
TATTATATTG ATATAACCCT AAllll~lll TTTCATAAAA CATATTTTCG TAGTGATTTA 202440
CTAGAAATAT GATTTGTAAT CTGCTCTATA TTTTTATTGA AAATATCATT ACCTGATGGT 202500
'l"l"l'~'L~'LC~'l' TTTTTATTTT TTATCTAATA AATACGATAT TTTTTAGATA AL11~111AC 202560
TTTTTCCTTT TCTTTAAATT TCCTTTATAA AAATGGTTGC AAGATTAAAT TAGCCATTGC 202620
ATALl~L~lA TGCGCCTCAC GAGGCGAATA CAATAAAAAT ACAATACACA CAACATCAAC 202680
-77. 1 22-
SUB~TtTUTE 5}tE~T tRULE 26)
-
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
AAAGAGGGAA ATTCATTATG TCA~AAGTTG CTTCCTTAGA CGCATTTTTA ACA~AAGTTG 202740
CTCAACGCGA TGGTTATCAA CCTGAATTTT TACAAGCGGT TCGCGAGGTA TTCACATCAA 202800
TTTGGCCTTT TTTAGAAGCC AATCCTA~AT A'1'C~'1"1'~AGA AGCATTATTA GAACGTTTAG 202860
TTGAGCCTGA ACGTGCATTT CAATTCCGTG TGGCGTGGAC TGACGATA~A GGGCAAGTGC 202920
AAGTA~ACAG AGCA111C~1 GTACAATTTA ATAGTGCCAT AGGCCCATTT A~AGGGGGAA 202980
TGC~111CCA TCCATCAGTA AATTTATCTA TCTTA~AATT CTTAGGTTTT GAGCA~ATCT 203040
TTA~AAATGC TTTAACAACA TTGCCTATGG GCGGGGCA~A AGGCGGTTCA GATTTTGATC 203100
CTA~AGGCAA ATCTGATGCT GAAGTTATGC ~'L'L'L'L'LGCCA AGCATTAATG GCTGAACTTT 203160
ATCGTCACGT AGGAGCTGAT ACAGATGTTC CCGCAGGCGA TATAGGCGTC GGTGGGCGCG 203220
AAGTTGGCTA TTTAGCTGGC TATATGA~AA AATTATCA~A CCAATCAGCC '1'~'L~'L'L'L'L~'A 203280
CTGGTCGCGG 'L~'1''1"1'~'1"L'LC GGTGGTAGTT TAALLC~LCC GGAAGCAACG GGATATGGAT 203340
TAATTTATTT TGCTCAAGCA ATGCTTGCTG A~AAAGGCGA TAGTTTTGCA GGTA~AGTAG 203400
TTTCAGTTTC TGGTTCTGGT AATGTAGCAC AATATGCTAT TGA~AAAGCA TTAl~L~LLG 203460
GTGCA~AAGT AGTAACTTGT TCTGATTCAT CAGGTTATGT TTATGAtCCA AATGGATTTA 203520
CTACTGA~AA ATTAGCCGCA CTTTTCGATA TTA~AAATAC A~AACGTGGG CGTGTGA~AG 203580
ATTATGCAGA ACAGTTTGGT TTGCAATATT TTGAAGGTAA ACGCCCTTGG GAAGTGCAAG 203640
TTGATATTGC G~'L'LC~'1''L~'1' GCAACTCA~A ATGAATTAGA A~'1"L'L~'LGAT GCACAACGTT 203700
TAATTA~AAA TGGTGTGA~A TTAGTGGCTG AAGGTGCGAA TATGCCAACA ACAATTGAAG 203760
CAACAGAAGC ATTACTAGCT GCAGATGTAT TATTTGGCCC GGGTA~AGCT GCCAACGCTG 203820
GTGGTGTTGC TACTTCTGGT TTAGA~ATGG CACA~AGTTC ACAACGTTTA TATTGGACAG 203880
CGGAAGAAGT GGACGCTCAA TTACATCGCA TTATGTTAGA TATTCACGCA AACTGTAAAA 203940
AATACGGCAC AATTGAAGGT CAAGAAAACA,TTAACTATGT TGTTGGGGCA AATGTAGCAG 204000
G~'L'1''L~'1''LAA GGTGGCTGAT GCAATGTTAG CCCAAGGCGT TTATTAACAA ATA~AAAAGT 204060TAAACTAAAT AACCGCACTG TAATAAAGTG CGGTTATTTT TTTAGGATGA AATTTGAATA 204120
TAAGA~AGCG ACATTTTGTC GCCTTAGATA TTATTTATTT TGAATTGTTT TCGTCACAAT 204180
GATTAATATC ACTGCATTTG CCGTALAGAT ACACGTTATG C~'1''1"L'L'1'AAT TTTATGCCGT 204240A'L'L'L'L'1'~'ACT GATTTCACGC TGACGTTGTT CAATAATATT ATCCGTAAAT TCAAATACTT 204300TACCGCAATC TTCACAAATA ATATGATCGT GA~L~L~L~ L TGGAGCAAGC TCA~AAACGG 204360
-77.123-
SUBSTTTUTE S~ EET (RULE 2~
:
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/05320
ATTTATTTCC CTCAAAATTA TGACGGATTA CAATATGCGC TTCATCAAAT TGATTAAGCA 204420
CACGATAAAC TGTGGCTAAT CCAATTTCAC AAC~-l-l~llC CAGGAAAATT TTATAAACAT 204480
CTTCTGCAGA AAAATGTTCA TTTTTATGAT TTTGCATTAA AGCGAGAATA GTTAAGCGAG 204540
G~l-~l~-lAAT TTTTAATCCC A~ll--ll-llGA GTAATTTAAT ATTTCCTTCA GACATAATTT 204600
TCCTTCCTAT TATGCACA~A ATGCTAAGCC AATTCAGCTA AGCACATTTC ATCATAAATT 204660
TGTTTACACC A1-1-1-11~-1AC ACGCTCTGCG GTAAGCTCTG GTTGGCGATC TTCATCAATA 204720
CATAATCCGA TGAAAGTGCC ATCTTCCAAT AAGGCTTTCG AAGCTTCAAA ATTATAGCCT 204780
~l~l~-l-l-GGCC AAl--l-lC~-lAC CACAATTGCA CCGTGTGGCT CTATAATATC GCGCACAGTT 204840
CCGATAGCAT CACAGAAATA ATCTGCATAA l~-L-l~-L-l~AT CGCCACAACC GAAAATACCT 204900
ACAAGTTTAT CTGTAA~ATC AAlll~llCG AGTGTTGGGA AAAAGTCATC CCAGTCTGCT 204960
TGTGCTTCGC CGTAATACCA AGTTGGGATA CCGAAAAGCA AGAAATCGTA TGCTTCAATA 205020
l~l--l-~ll-LGC TACTTTTGGC AATATCACGA ATATCAATTA AATCACTACC TAA~ll~-l-lll 205080
TGGATTTGTT TTGCGATGTT TTCAGTATTT CCAGTATCAC TACCATAAAA AAGACCAACT 205140
ATTGCCATTT TTATTTCCTT TTTTATATTA AATTTAATCT ATTGATTATA AGGCTTATCC 205200
AAATTTGGCG AACTATATCA TAAAAGCATT CTCACTTAAA CTACTTAATT CTTATTTAGA 205260
AAl-CG-ll-lAA TTGCACGAAT AACAAAATCA G~-l-l-l-l--lC~G CGTGAACCCA GTGTCCACTG 205320
CCATTAATCG TAAAGGCAGT TGCATTAGGA AAll~-l-L~lA GAA~l-l-lll-lC GCTATTTTCT 205380
ATTTTTATAT AAGAGGAATT TCCACCCTTA ATAAAAAGAG TTGGCGTAAA TACACGTACT 205440
TTTTCCCAAT CCATAATATT GGCATAATTG TTAAAAAGCG CGGTAAGATT AAAACGA~AA 205500
CAATCAGCTG AATTAACATC AAAAGATTTC AACATAAATT GTACAACGTC TTCATCATTA 205560
All-l~l--lG-l--l TTAAAATCGG TTTGGCTTGC TGACGATTTT CAGGCTTTGC A1-11111ACC 205620
GCAAATAGGC CATTAAAAAC ATCTTTATGA CCAAATCCCT CATAAGGCAT AGGCGACATA 205680
TCAATTACGA TTAATTTTTC GACTAATTCT GGGCAAAGTG CGGTGATTTT CATGGCGGTT 205740
TTTCCCCCCA TAGAATGACC AATTAATATC ACTTTGGATA AATTTAAGTG GCGGATTACT 205800
GCGATAACAT CTTCAGCCAT CAGTTGATAA TTCATTTTTT CCGAATGAAA ACTATGGCCG 205860
TGATTGCGTA AATCAATACG TAAAATACTG TAATGTTCAC TAAAAGCTCT CGCGATAACG 205920
CCGAGATTAT CCATATCGCC GAATAAACCG TGAATAAAAA TTA~AACAGG TGTATTAATC 205980
~-l-ll~-l-l-l-lA CTTGATGAAA TTGATAATTG AGTAATGATT TTGCCATAAT TTTTACGTGA 206040
-77.124-
SUBS-~ I I UTE SH EF~ (RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GAATTTGTAA AGAAGTCGTT ATAATTGA~A A~AATTTTAG CA~ACAGAGA GATA~AAATG 206100
AAGATCATTG AAGTAGATGA AGAATTATAC CAATATATTG CGAGCCAAAC CCGCTCTATT 206160
GGAGA~AGTG CTTCGGATAT TTTACGCCGT TTGCTTAGTT TACCTGTGCA TACTTCAATT 206220
GTTAATGATT TAATTATTAC TTCAGCAGAA ACAGATCA~A AGCCA~AACA GGCTATCAAT 206280
GTGA~AGAAG TA~ATATCAA AACAACAAAA AAGCAATCAA TAACCGCAAT TAATCAGATT 206340
GTAGA~AAAG TCCAAACTTT ATTA~ATTCA ACTGAATTTC AAGAAGAAAG TAAGGCTGTT 206400
GTAC~l-ll~l TAGCGATTTT ACGTGTGCTT TATCGTACAA ATCCTGAAAG TTTTGCGCAA 206460
GCAACGGAAT CTTTACAAGG ACGTACTCGA GTTTACTTTG CACGCGATGA AGCGACATTA 206520
TTAATGGCAG GTAACCATAC TAAACCA~AA CA~ATTCCAG ATACGCCTTA TTGGGTTATT 206580
ACCAATACAA ATAGTGGACG A~AAATGTTA ATGCTAGAAG GTGCAATGCA ATCTATGGAA 206640
TTACCTGA~A CATTGATTGA TGAAGTGCGA TCATATTTCA CGGTA~ATTA ATAATGTATC 206700
CTTGGCAAGA TTTTGCTATT CAACCTGATT TCTCAGATAA AATCGCTTTG CGTACTACGC 206760
AGGGCGATAT GCTTACTTGG ATAGAATTGA CTACA~AGAT TAACCAAACA GTGGCTTTTT 20 b 820
TACA~AAAAA AGGCGTA~AT GCAGAAAGTG CGGTTGCTTT TGTGGGA~AA AATTCAGAGA 206880
A~ATTTTATT TTTATATCTG GCGACAATTC AGCTTGGCGC A~AAGTTTTA GGCATAAACC 206940
CTG~llllCC ACAAGA~AAA ATTGCA~AAT TATGTGAGTT TTATCA~ATT GALlllL~ll 207000
TTTATGATAA AGATTTACTG AATTTGCAAG AAATTGATGT TTTTACTCAA A~AGCCGATT 207060
lllLlC~lCC TGCGACGATG ACGCTAACGT CTGGCTCGAC AGGTTTACCA AAAGCAGTTG 207120
TGCATAATGT CCAAGCACAT TTGGATAATG CA~AAGGGGT ATGTAACTTA ATGAAGTTTG 207180
ATTGTAATCA ATCTTGGTTA CTTTCATTAC CCTTATATCA C~lll~AGGG CAAGGTATTG 207240
TTTGGCGTTG GTTATATTGC GGTGCACAAT TACATTTCCC AGAAGATGAT TTTTATGCTT 207300
CATTATTAAA GACGACCCAC ~'L'l"l'~'L~'l''l'G TGCCAACGCA ATTACAGCGT TTATTAGATT 207360
ATTTACAGGA A~ATCCGAGC ATTTCATTTG CTACACGCCA TATTTTACTG GGCGGTGCGC 207420
ATATTCCGAC AGAACTTACA CAAAATATGT TGA~ATATGG TATCGA~ACG TATTCTGGCT 207480
ACGGAATGAC GGAAATGGCT TCGACAGTTT TTGCTA~AAA ATCTGACAGA A~ACAAGGCG 207540
TAGGGCAACC GCTCTTAGGT AGAGAGTATT GTTTAGTAAA TGATGA~ATT TGGCTGA~AG 207600
GTGCAGGTTT GGCGATGGGT TATTGGAAAG ATCGACAAAT l~llC~ATTA ACGAATAACC 207660
AAGGCTGGAT TCAGACA~AA GATA~AGGCA TTTGGCAAGA GGGCGAACTT GTTATTATCG 207720
-77 . 1 25 -
SU8S~ I I UTE ~ EET (RULE ~6
CA 02218741 1997-10-21
W 096/33276 PCTAUS96/OS320
GACGACTTGA TAATATGTTT ATTTCAGGTG GCGA~AATAT TCAGCCAGAA GA~ATTGAAC 207780
AAGTGATTAT TCAACATTCT TCAGTTAATC AAGTATTTGT TTTACCACAA A7.~AAACA~AG 207840
AATTTGGTCA GCGTCCTGTC GCTTTAGTGG ATTTTAATGA GCCCTTTAGC A~AAGTGCGG 207900
TTGAAAATTT AALC;lll-lll TTACAAGATA AACTTGCACG TTTTA7.~ACAA CCTATTGCAT 207960
ATTATCCTTT GCCACTGATG CTTGAGA7~AG GCATTAAGAT CTCACGTA7~A CAGCTTGCTG 208020
AL LG~ l l GGC A~AGCGAGAT GAGATA7iATT AATTTACCAT TTAGATTAGG GA~AAATAAT 208080
GATTAGGA~A CTTATGA~AA TACCTCCATT TTTTACCGCA (:LLlllGCCT CGGCAATGTT 208140
TACCCTTAGC GTTTCGCAAG GGGTATTGGC GGCA~ATTCA ACA~ATGTAT TACCAACGGA 208200
GCAATCGCTT A7.~AGCCGATT TGGCTAACGC TCA~A~AATG AGTGAGGGGG AGGCA~AAA 208260
TAG~lL~llA GCAGAATTAC A~ACATCAAT TGATTTATTG CAGCA~ATTC AAGCCCAACA 208320
A~ATCAAT GATGCATTGC A~ACAACATT AAGCCATTCA GAGAGTGA7.~A TTAGA~AGAA 208380
TAATGCAGAA ATTCAAGCAT TA~AAAAACA ACAAGA~ACG GCAACAAGTA CTGATGATAA 208440
TGCGCAATCA CAGGACTATT TACA7.~AATAG TCTCACTAAG TTA~ATGATC AATTACAAGA 208500
TACGCA7.~AAC GCATTAAGCA CAGCA7.~ATGC ACAATTGGCA GGGCA~AGTT CTALLLI :L~A 208560
ACGAGCACAA GCGGCATTAA CAGA~AATGT TGTACGCACA CAGCA~ATCA ATCAACAATT 208620
AGCCAATAAT GATATTGGTA GCACATTGCG AAAACAATAT CAGATTGATT TACAACTGAT 208680
TGATTTA7.~AG AATAGTTATA ATCA7~AACTT ATTA~AAAT AATGATCAGC LLL(_LLlACT 208740
CTATCA7.~AGC CGATATAACC TATTGAATTT ACGTTTGCAA GTACAGCAGC A~AATATTAT 208800
TGCGATTCAA GAAGTCATTA ATCA~AAAAA TCTTCAGCAA TCACA7~AATC AAGTAGAACA 208860
AGCTCAGCAA CAGCA7.~AAAA CTGTGCA7.~aA TGATTACATT CAAA~AGAAC TTGATCGCAA 208920
TGCACAGCTT GGTCAGTATT TATTACAACA AACAGA~AAA GCGAATTCAT TAACTCAAGA 208980
TGAGTTAAGA ATGCGGAATA TTTTAGATAG CCTCACTCAA ACTCAACGTA CTATTGATGA 209040
ACA~ATTAGT GCATTACAAG GCACGTTAGT TCTTTCACGT ATTATCCAGC AACA7.~AACA 209100
A7.~AATTACCG ACTAACTTAA ATATTCAAGG TTTATCA~AA CA~ATTGCCG ATTTGCGTGT 209160
ACATATTTTT GACATTACTC A7.~AAACGCAA TGAACTTTAT GATCTAGATA ACTATATTAA 209220
TA7.~AGTTGAA AGTGAAGATG GA~AACAATT TACTGAGGCA GA7.~AGAACGC AAGTTAPAAC 209280
GCTATTAACT GAGCGTCGGA AAATGACATC TGATCTGATT A~ATCTTTAA ATAATCAATT 209340
AAATCTCGCG A~L l l ~ l L l GG AATTAACACA GCTGCA~ATT ACACA7.~ATCA GTGATCA7.~AT 209400
-77. 1 26-
SUBS 111 UTE S~tEET ~RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
TCAATCTAAA TTAGAGCAGC A~A~1-1111G GGTGAAAAGT AATAATCCTA TTAATTTAGA 209460
TTGGGTAAAA ATGCTGCCAA GAGCTTTAAT TGAACAGTTT AATGGTATGT TGAAAAAATT 209520
AGGTTTTCCA ACTAATTATG ACAATTTACC TTATTTGCTG ATGTATTTCT TAGGGTTATT 209580
TATTGTAGGC GGTGCAATTT TTAAATTTAA AAATCGTATT AAACAACAAT TAAACAAAAT 209640
TAATCGTGAA ATACATCGTT TAGATACAGA TAGTCAGTGG AGTACTCCAC TTGCCCTGTT 209700
ATTAACAGCG TTTTTAACGC TTTCTAGTAC ACTTTGGTTT TTAGCAGTTT GCCAAATGAT 209760
CGG~11~-11-1 11~1-L~A~AA ATCCAGAAGA ATTTTGGCAT TGGTCATTTA GTATGGCGGG 209820
TTATTGGTGG ~ 1-1ACAT TTTGGATTTC AL-L~-L-LCC~-1~ CCAAATGGTA 'L-L-L-L-l~L-LAA 209880
TCATTTTGAA TCTTCAAAAG AGAATGCACA AC~'L'L-L-LC~-L G~1-~-1LATCC AGCGCATTAT 209940
'1~L-L~-1GGTT GTATTGCTTT TA~ATACTTC ~1'~-L~-L'L'LAGC AATGTCACTG ATGCAGGTTT 210000
AGCTAATGAT GTGTTAGGTC AAATTAATAC TATTGCGGCT CTAATTTTCT GTGCGGCGAT 210060
TATTGCCCCT CGTTTTAATC GAGTACTTCG CTCTTATGAA CCTGAAACAA ATAAACATCA 210120
~1-LG~-1-LAATA AGAATTGTAC AAATTGGTTT TAGATTAATT CCTGTGGGAT TAATCGTACT 210180
TA~L-L~1L-LLA GGCTATTACT ACACCGCTTT AAATTTAATT GAGCATTTTA TTCATTCTTA 210240
TATTGCTTGG TGTGTATGGT GGTTAGTACG CAATACGATT TACCGTGGTA TTACGGTTTC 210300
'1'-1~-LC~'1'C~'1' TTAGCACATC GCCGTTTAGC AGAAAAACGT CGTCA~AAAG CACTTGAAAA 210360
TAATTATGAA AATATATCCT CTGATGATGT GGTTGCAGTG GGAGAGCCAG AGGAAAGTTT 210420
GGCGTTAAAT GATGTGCGTA GCCAATTATT AC~'L-L-L-L~-LA GA~1~-L~-LL1A TTTGGACAGC 210480
ATTATTAGGG A1~1-L~-1ACT ATGTATGGTC AGATTTAGTC ACCGTAGTGA GCTATTTACG 210540
TGAAATTACA CTTTGGCAAC AAACCACGAC AACCGATGCT GGCACTGTAA TGGAAAGCAT 210600
TACTTTATTT AAL~LL~-LLG TTGCTTTGGT TATCGTAGGA ATTACTTATG TGTTGGTTCG 210660
TAATATTTCA GGCATTTTGG AAGTATTAAT 'L-L-L-L'L~-LCGC GTGAATCTTT CACAAGGTAC 210720
GCCTTATACG ATTACGACAC TACTTACTTA TATTTTTATC GCCATTGGTG GTGCGTGGGC 210780
ATTTGCAACC TTAGGGATGT CTTGGTCAAA ATTACAATGG TTATTCGCCG CA~'LL-L~'l~'L 210840
TGGTCTTGGT TTTGGTATGC AAGAGATTTT TGCAAACTTT GTGTCAGGTA TCA1111~1-1 210900
ATTTGAACGC CCAATCCGAG TTGGCGATGT GGTTACCATT AATGAAGTGA GCGGTACTGT 210960
AGCGAAAATT CGTATCCGTG CAATTACATT GATTGATTTT GATCGCA~AG AAGTGATTGT 211020
GCCAAATA~A '1'~'L-L-L-1~-1'~A CTGGTCAAGT GACCAACTGG GCATTATCTA ACACTATGAC 211080
-77. 1 27-
SUBS i 11 UTE S~}E~T tRULE 2~i3
CA 02218741 l997-l0-2l
W 096/33276 PCTnUS96/05320
ACGTTTAGTG ATTAGCGTTG GTGTTGCTTA LG~ll~lGAT TTAACACTCG TGCGCCAATT 211140
ATTACTTCAA GCAGCTGATG AACAACCGAC TATTTTACGC GATCCTAAAC CATCTGCTTA 211200
LlLlllAACT LllG~lGCAA GTACACTGGA TCACGAGTTA C~L~lllATG TAGAACAAGT 211260
TGGGGATCGC ACCAGTACTA CAGATGCCCT TAATCGCCGT ATTAATGAAT TATTTGCAGA 211320
ACATAATATT GATATTGCCT TTAATCAATT AGATGTATTT ATCAAAAATA ATGATACAGG 211380
CGAAGAAATT C~LL11~11~ ATGTAAAAAA ATAAGGGCAA ATTATGGCTG GTAATACAAT 211440
TGGACAACTT TTCC~L~L~A CAACCTTTGG AGAGTCACAT GGTATTGCAT TAGGCTGTAT 211500
CGTTGATGGC GTGCCACCAA ATCTCGAATT ATCCGAGAAA GATATTCAGC CAGATTTAGA 211560
L~lC~lAAA CCAGGAACAT CTCGATATAC GACGCCTCGT CGTGAAGATG ACGAAGTTCA 211620
AATTTTATCT G~L~l~lllG AAGGAAAAAC CACAGGCACA AGTATTGGGA TGATCATTAA 211680
AAATGGAGAT CAGCGTTCGC AAGATTATGG TGACATTAAA GALC~lllCC GCCCAGGTCA 211740
TGCGGATTTT ACCTATCAGC AAAAGTATGG AATCCGTGAT TATCGTGGCG GTGGGCGTTC 211800
GTCAGCACGT GAAACAGCGA TGCGGGTTGC TGCAGGGGCT ATTGCGAAAA AATATTTACG 211860
CGAACATTTT GGCATTGAGG TGCGAGGTTT TTTAAGCCAA ATCGGTAATA TAAAAATTGC 211920
TCCGCAGAAA GTGGGACAAA TTGATTGGGA AAAGGTAAAC AGTAATCCAT L~ll~ CC 211980
TGATGAAAGT GCGGTAGAAA AATTCGATGA ATTGATCCGT GAACTTAAAA AAGAAGGAGA 212040
TTCTATTGGC GCAAAACTTA CTGTTATTGC AGAAAATGTA CCTGTAGGAT TGGGCGAGCC 212100
AGTATTTGAC CGTTTAGATG CCGATCTTGC TCACGCATTA ATGGGAATTA ATGCAGTAAA 212160
AGGTGTAGAA ATTGGCGATG GCTTTGCTGT GGTTGAACAA CGAGGTTCGG AACATCGTGA 212220
TGAAATGACA CCTAATGGCT TTGAAAGTAA TCATGCAGGC GGTATTTTAG GCGGAATTAG 212280
TTCAGGACAA CCAATTATCG CCACTATTGC ACTAAAACCA ACTTCAAGCA TTACGATTCC 212340
TG~LC~ll~A ATCAATCTTA ATGGTGAAGC CGTAGAAGTT GTAACAAAAG GTCGTCACGA 212400
'l'C~'l''l'~'L~'l'G GGGATTCGTG CTGTGCCAAT TGCGGAAGCT ATGGTGGCGA Ll~l~llATT 212460
AGATCATCTC TTAC~lLllA AGGCACAGTG TAAATAATCC TGTACCTAGG GTAGTATACT 212520
CTAGGTTAGT TCTTCAATAG GACTGAACCT AGGATATACT TACCTACAGC AAAACTTTAG 212580
AATGAATAAA ATTTTATTAA AAACAACCAT AATTTTTACC GCA~Llll~L CTCTGAACGT 212640
TGTTGCGTCT CCTCTAGATT GGCAAAAAGT GAAACGCCCT ATTCCAAGTG AAGATGGTAA 212700
AGCAAGTCCT ATTGGTAGTT ATACCAACGG GTGTATTATT GGAGCACAAG CATTACCGCC 212760
-77.128-
SU8STTTUTE SHEET (RULE 26
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GA~AGGTGAA GGTTACCAAG TGATTCGCAT GAATCGCAAT CGTTATTATG GTCATCCAAA 212820
TATGATTCAG TATCTTGAAC GTTTGGGGCA GCGAGCTA~A GCTGCTGGGT TGCCAACGAT 212880
GTTAGTAGGC GATATTGCCA TGCCCGGTGG TGGGCGGTTT TTAACGGGTC ATGCTAGCCA 212940
TCAGATGGGA TTAGATGCGG ATA'1"1'-1G~'L-1' AAGAATGGGC GA~ATGTCAG ATGCCGATGC 213000
GCTCAATTCT GATGGTA~AG GTTTATTAGT TGTGGATAGA AAGGCGCAAC GAGTAGATGA 213060
GCGCGTGTGG AATAGCAATC ATGCGACGTT AATCAAGTTA GCTGCGCAAG ATCCAAATGT 213120
GACGCGTATT ~11-1~-1LAATC CTGCGATTAA GGTAAAATTA TGTCAAACCG CTGGCAATGA 213180
TCGCGGTTGG CTACACAAAA ~1-LC~1C~11G GCATGGACAC AACTCTCATT TTCATGTTCG 213240
TTTAACTTGC CCAGCAGATG CATCTTATTG TGA~AATCAA GCGCCTGTGC CTG~LG~lGA 213300
TGGTTGTGGA GACGAATTAT ATTCTTGGTT TGAACCGCCA AAACCAGGCA CTTCAGTGAG 213360
CAAACCTAAA GTTACACCGC CTGAGCCGTT TTTGTGCCA~ CAGATTTTGA ACTCACCGAA 213420
TCGGAGAGAA TGGTTAGAAT AGCATTGAGG TAAATCAATA TGGATATCGG CATTGATCTT 213480
TTAGCAATAT ~l~-l-l'-l'-L~'l~-L TG~'l"l-l L~'LC GCATCATTTA TCGATGCAAT TGCTGGCGGT 213540
GGTGGATTAA TCACCATTCC AGCGTTACTC ATGACAGGTA TGCCACCAGC AATGGCGTTA 213600
GGCACCAACA AATTGCAAGC TATGGGCGGT GCATTATCCG CAAGCCTTTA 'l'-L-L~-l--LGCGA 213660
AAAAGAGCGG TCAATTTACG CGATATTTGG TTTATTTTGA ~1-L-LGG~-L-1-1-L CTTAGGTTCT 213720
GCCCTAGGTA CATTATTAAT TCAATCAATT GACGTGGCGA TTTTCAAAAA AATGCTTCCT 213780
TTTTTGATTT TAGCCATTGG TCTATATTTT TAATTTACTC CTAAATTAGG TGATGAAGAT 213840
CGAAAACAAC GATTAAGTTA 1~L~-L-1ATTT G~-L~-L-L-L-LAG TTAGCCCATT TTTAGGTTTT 213900
TATGATGGCT TCTTTGGGCC AGGGACTGGC TCAATCATGA GTTTAGCCTG TGTTACTTTG 213960
CTAGGATTTA ATCTCCCGAA AGCGGCAGCA CATGCA~AAG TGATGAACTT CACTTCGAAC 214020
CTTGCTTCTT TTGCACTTTT CTTATTGGGC GGACA~ATTC TTTGGA~AGT GG~L1LC~LG 214080
ATGATGGCTG GGAGCATTTT AGGTGCA~AT TTAGGTGCCA AAATGGTGAT GACGA~AGGT 214140
AAAACCTTGA TTCGACCGAT G~-LL~1-1ATC A'L~-L~-L1'-L-LA TGATGACGGC TA~AATGGTT 214200
TACGATCAGG GTTGGTTTCA TTTTTAATTC GGA~AGCGCG CA~AAGTGCG GTTAAAATTA 214260
ATTACATTTT ATTATGTCGG ATAATCAACA A~ATTTACGT TTGACGGCGA GAGTGGGCTA 214320
TGAAGCGCAC TTTTCATGGT CGTATTTAAA GCCTCAATAT TGGGGGATTT GGCTTGGTAT 214380
,~L~ ~1L~LL1~ ~LL~LL~LLAG CATTTGTGCC '1"1"11C~1~LG CGCGATAAAT TGACGGGAAA 214440
-77.129-
SU85TI~UTE S~EET tRULE 2~
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96/05320
ATTAGGTATT TGGATTGGGC ATA~AGCAAA GAAACAGCGT ACGCGTGCAC A~ACTAACTT 214500
GCAATATTGT TTCCCTCATT GGACTGAACA ACAACGTGAG CAAGTGATTG ATA~AATGTT 214560
TGCGGTTGTC GCTCAGGTTA '1'~'1"1"1'G~'1'AT TGGTGAGATT GCCATCCGTT CAAAGAAACA 21~620
TTTGCAAAAA CGCAGCGAAT TTA1'CG~'1'~"1' TGAACATATC GAACAGGCAA AAGCTGAAGG 214680
AAAGAATATT ATTCTTATGG TGCCACATGG CTGGGCGATT GATGCGTCTG GCATTATTTT 214740
GCACACTCAA GGCATGCCAA TGACTTCTAT GTATAATCCA CACCGTAATC CATTGGTGGA 214800
TTGGCTTTGG ACGATTACAC GCCAACGTTT CGGCGGAAAA ATGCATGCAC GCCAAAATGG 214860
TATTAAACCT TTTTTAAGTC A'1'~'1''1'C~'LAA AGGCGAAATG GGTTATTACT TACCCGATGA 214920
AGATTTTGGG GCGGAACAAA GCGTATTTGT TGA'L'L'1'~'1''1"1' GGGACTTATA AAGCGACATT 214980
ACCAGGGTTA AATAAAATGG CAAAACTTTC TAAAGCCGTT GTTATTCCAA 'l~l LlC~lCG 215040
TTATAACGCT GAAACGGGCA AATATGAAAT GGAAATTCAT CCTGCAATGA ATTTAAGTGA 215100
TGATCCTGAA CAATCAGCCC GAGCAATGAA CGAAGAAATA GAA'L~''1''L'L'1'G TTACGCCAGC 215160
GCCAGAGCAA TATGTTTGGA TTTTGCAATT ATTGCGTACA AGGAAAGATG GCGAAGATCT 215220
TTATGATTAA AAATAGGGTT TGAAAGTCAT A'L'L~'LC~AAA ACGGATATTC AATAAGGTAA 215280
ATAAGAAATG GAAGAAAAAA TTCGGCTGAC GCAATACAGC CATGGTGCAG GTTGAGGCTG 215340
TAAAATTTCG CCTAAGGTGT TAGGGACAAT TTTACATTCA GAACTGGAAA AATTTTATGA 215400
WCCAAATCTG ATCGTTGGCA ATGAAACTGC AGACGATGCG GCGGTGTATG ATCTTGGTAA 215460
TGGAACTGCA ATTATCAGTA CCACAGACTT TTTCATGCCG ATTGTGGATG ATCCTTTTGA 215520
'1"LL'1'GGACGA ATTGCTGCGA CCAATGCCAT CAGTGATATT TTTGCTATGG GCGGTAAGCC 215580
GATAATGGGA ATTGCTATTT TAG~'1"1''1"LCC AACCAATGTA TTACCTGCAG AAGTTGCACA 215640
GAAAATTGTT GATGGTGGGC GTTTTGCTTG CCATCAAGCG GGGATTGCTT TGGCGGGTGG 215700
ACATTCCATT GATTCGCCTG AACCTATTTT TGGTTTAGCC GTGACAGGCG TGATTGACAC 215760
TGAAAAAGTG AAACGTAATG CTTCTGCAAA ATCAGGTTGT AAGCTTTATA TGACGAAACC 215820
GCTTGGTATT GGTATTTTGA CGACGGCGGA AAAAAAAGGA AAACTAAAAC CAGAACATCA 215880
AGGTTTAGCC ACTGCCGCTA TGTGCCAAAT GAATTCTATT GGTAGTCAAT TTTCCCAAGT 215940
GGATGGCGTC ACCGCAATGA CGGATGTCAC TGGATTTGGT TTA~L~LG~1~C ATTTAATTGA 216000
AATCTGTGAA GGTTCAAATC TAAGTGCGGT A~'L'L'L'L'1''1'CG GACAAAATTA A~ACCTTGGA 216060
,CGGTGTAAAA GATTATATTG CTCAAGGTTG CGTACCGGGT GGAACAGGGC GTAATTTTGA 216120
_77.130-
SUBSTTTUTE SHE~T tRuLE 2~1
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
CAGTTATGGA CATAAAGTTG GGATATTGAC GGAAGAACAA AAAGCGATTT TGTGTGATCC 216180
TCAAACATCA GGCGGCTTAT TAGTGGCAGT TGAGCTTAAT AGCGTTCAAA CAGTAATTGA 216240
CATAGCCAAA GATGCGGGGA TTGATTTATA TGAAGTGGGT AAATTGAAAC CTAAATCAGA 216300
ATCCGATATC ~11~11~AAG TAAAATAAGG AATTTTAATC GATCCTCCCT AATGATTAAT 216360
TAAATTACCA TGATCCACAT AGCAAAAAAC CTTGGAATAT CCCAAGGTTT TTTAGATTAT 216420
CATTAAATAT AATGAATTAT GCGCCTAAAC G~'1'~'1"1"1'AAT ACGAGCTGAT TTACCTGAAC 216480
GTTCACGTAA GTAGTAAAGT TTAGCTTTAC GTACCGCACC TTTACGTTTA ACTGCGATAG 216540
AATCTACAGC TGGAGAGTGA GTTTGGAATA CACGCTCAAC GCCTACGCCG TTAGATACTT 216600
TACGTAAAGT AAATGCTGAG TGCAAGCCAC GGTTACGAAT TGCAATAACC ACGCCTTCGA 216660
ATGCTTGCAA ACGACGTTTG CTACCTTCAA CCACCCATAC TTTAACTTCT AAAGTATCAC 216720
CTGGGCGGAA GCTAGGTACG '1"1"1"1'~'1"1"1"1'A A'L'L~'L'1'~''L'LG TTCAAGTTGT TTGATAATGT 216780
TAGACATTGT TTGATCCTTT ATTGATCCTA GATGTAACTG AAACTAACTG TTATGCTCGG 216840
CTTGCGCCTC TTTTAACAGC TTAC~'L'L~'1"1' CGTCAGTCAG AGCTAGGCCT TCTAAGAGCT 216900
CAGGGCGTCG GAGCCACGTT ~L~L~LAGCG A'L'1'~'L'L'L'LAA TCGCCATTTC CGAATTTCTT 216960CGTGATGTCC CGACATCAGC ACGGGTGGTA CAGTTAATCC TTCTAACACT 'L~'L~'1'~'LAG 217020
TGTAATGCGG GCAATCTAAT AAACCATCTG CA~AAGAATC '1''L~'L'L~'1'GCC GAGGCTTGTT 217080TGCCTAATAC ACCGGGAATA AAACGTGCAA CAGCATCAAT TAATGTCATT GCCGGCAATT 217140
CCCCACCGGT CAGAACGTAA TCGCCGATTG ACCATTCTTC ATCAATTTCA GTTTGAATCA 217200
ACC~'1"L~'ATC AATCCCTTCG TAACGTCCAC ATACTAAAAT CAA'L'L'L~'1'~A TTTTGAGCAA 217260
G~'LCG~'L'1'AC GCCGCCTTGA TCGAGTTTAC GTCCTTGTGG CGAAAGGTAA ATCACCTTTG 217320
CGCCTTCTCC TGCCGCAGCT TTTGCAGTAT GAATCGCATC CCGTAAAGGT TGCACCATCA 217380
TTAGCATTCC TGGGCCACCA CCATAAGGGC GATCGTCCAC GGTTTTATGC TTGTCGAATG 217440
TAAAATCTCT TGGATTCCAA CATTCAACTT TCAGAAGATT A'L~'L'1"L'LACG GCTCTACCTG 217500
TAACCCCAAA TTCCGTAATT GCTTTAAACA TTTCGGGGAA TAATGAAATT ACCCCTATCC 217560
ACATAAAAAG CCTACTACAT TAC~'1"1"L~'LG CATACTTGAG ATTAGAAACC AGCGTCCCAA 217620
TCCACTTCAA TA~'L'L'L'LC~'1' GGTGAGATCG A~L~L~L~L~L~A CTACTTGTTC ATACAAAAAC 217680
GGAATTAACC G~'1'~'L'1'~'L'1''1' TCCAAAAGCA TCTTTGGTAT TGGCTTTAAC CACTAATACA 217740
TCATTAGAAC CCGTTTCCAT CA'L'L'1'~'1'~'L'1' A~'1'~'L'LCC~'A TTGTATAACC TTCTAAGTTT 217800
-77.131-
SUBSmUTE S}~EET (RUI E 2~i~
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
ACGACTGTAC AACCGATTAA ATCGTGCCAG TAATAATCGC C~'1'~'1"1'~'1'AG TTCTGGGA~A 217860ACAGATAAAT CTACACCAAT TTCAACATTC GCTA~AATTT GTGCAGCTTC ACGGTCATCA 217920
ACGCCTTTTA ATTTAACGAT GATTTCGTGA TTATGATAAC GCCAGTTTTC TAATTCAATT 217980
GATTGCCATT CGCCTTTGAT TTTTA~AAAC CAAGGTTGAT AATCA~AAAT GCTTTCAGCT 218040
'1'~'1'-1'~'1'~'1"1'G ATGAATAAAT ACGCAACCAC CCACGAATAC CGTAGGTTGA GCCTAATTTG 218100
CCCACAACTT CAATATGTTG TTGTTCCATA '11111~ACCT ATCTTAGTTT GAGAACTAAA 218160
TCAAAAAGCA AAATTATGCT G~''1"1"1''1"1'~'1'G ~11~1111AC CAAGCTCGCA ACACGATCAG 218220
AAAGTGAAGC ACCTTGAGCA ACCCAGTGAT TTACACGCTC AAGATTAATG CGAAGACGTT 218280
CTGCATTACC TTGTGCAATT GGATTGAAGA AACCTACACG TTCAATGAAG CGACCGTCAC 218340
GAGGTGAACG ACTGTCAGCG ACTACGATTT GATAAAATGG GC'~'1"1"1"1''1"1'A GCTCCGCCAC 218400
GAGATAAACG AATGGTTACC ATAACCTTCC TCTAAATGTT TAATTACTAA AAGAATATTC 218460
TCAAATTCGA AAGTGATTTG AGAATATAGC TTA~''1"1''1"1"1''L ~1~1~1ATAT ATAGACAAAA 218520
AGCCTGCGAA TTTTATACTT TTCAAGCAAA ATTGCAAGTT TTGTATGCAT AAAGTAGGTT 218580
GTA'1"1'C~'1'1''1' TAATTATCAT TCACAATTTA '1"1"L'1'~'1"1''L'1'A CGATATAATA CGAGGCATCC 218640
AG~''L~'1''1''1''1'A GGTCAAATTT ACGCGTATAG CGGTATTTTA GCTTGATAAA ATATCAGTTA 218700
AATGAGGTTT ATATATGAAA ATTAGTTTTC A'L'1'~''1'~'1'~'1"1' AATTGGATTA GCATCATTTA 218760
'1''1'G~'1'~'1"1'~'A ACAAGGTGTA ATAGCTAATC C~'1'~'1"1'CTCA TCAATCAATA TCCACTGAAT 218820
CAGCTGAGGC TTTGAAGCAA CAATTTTCAA TGGCTTTAGC TAAACAAGAT AAACAACAAA 218880
TTACAAATTT ACA~IU~AA CTTACCGCAC 'l''l''l"l'l''l'~'l''L''l' ACCTCCCCAA '1''1"1'~'1"1'GATA 218940
ATCAGATCCA AATAAGCGAA AAA~nCCTCA CTCGCATTTT TAAAACAGAT AAAAATCTCA 219000
CGCCTAbATT TCTTGATTAC TTATACTTTG AGCCAATA~A TA~'1'~'1"1'~AT GCTAATTTAA 219060
TTCAGGAAAT GAAGAAAAAC TTACTGGTGT ~111111AGC AAATGATCAG GCA~AAATTT 219120
ATATTCGTCA AACAGATAAT TCAGAGCAAT TTGTTCAGAC TTTAATGGAG CGGGGAGCAA 219180
AAGCAGATCA AATTATATTA CTGTCTTTGA ATGCCA~AGG TATATTTCAA AAAATTATTG 219240
AACA~ATACG TCAAGATTTT CCGAATCAGA CTA'1"1"1"1''1''1'C GATTACTGAA AATCGTATTA 219300
GTTTGATTAC TC~11~11~A GAAATTAAGT CTCGCCTTGC TTTAGCAAAT ATGATGTTCA 219360
ATCGCCAATT TAAAGGTGTG GAAGTTGATG A'1"1''1'~'1'~ATA TTTAGATCAA CCTCGAGAAA 219420ATTTACAGCA CAATAATGAT GCAATTCGTT ACA~AACCTT TCAAGCAATG CTAGAAGGTT 219480
-77.132-
SUBST~UTE SHEET tRULE ;~6)
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/0~320
TAAATTAATC CCTTACCAAT AGGAGTTTTT ATGCTTTTAT CCA~AAAATC AGCCTCCTTT 219540
GCACTCAGTG CATTTGCGAT G~L111~ACT AGTGTAGCTC TTGCCAAAGA GGCACCACAA 219600
GCTCACAAAG CTGTGGAATT AAGTATTTTG CATATCAATG ATCACCATTC TTATTTAGAA 219660
CCGCACGA~A CACGGATTAA TTTAAATGGT CAGCAAACCA AAGTGGATAT TGGTGGTTTT 219720
TCTGCTGTCA ATGCAAAACT TAACAAATTG CGTAAAAAAT ACAA~AATCC ATTAGTACTG 219780
CATGCAGGCG ATGCCATTAC TGGTACACTT TACTTCACGC TGTTTGGTGG TTCTGCAGAT 219840
GCAGCTGTGA TGAATGCAGG TAATTTCCAT TATTTTACTT TAGGTAATCA TGAATTTGAC 219900
GCGGGTAATG AAGGGTTATT AAAACTGCTT GAACCATTAA AAATCCCAGT GCTTTCAGCT 219960
AATGTGATTC CTGATAAAAA TTCAATTTTG TATAACAAAT GGA~ACCTTA CGATATTTTC 220020
ACTGTGGATG GAGAAAAAAT TGCCATTATC GGTTTAGATA CTGTGAATAA AACAGTGAAT 220080
TCCTCTTCTC CGGGTAAGGA TGTGAAGTTC TACGATGAAA TTGCTACTGC ACA~ATTATG 220140
GCAAATGCGC TAAAACAGCA AGGAATTAAT AAAATTATCC TACTTTCACA CGCAGGTAGT 220200
GAAA~AAATA TCGAAATTGC TCAAAAAGTA AATGATATTG ATGTGATCGT TACTGGCGAT 220260
TCACATTATT TATACGGAAA TGATGAATTA CGTAGTTTAA AACTTCCAGT AATCTATGAA 220320
TATCCACTTG AATTTAAAAA TCCAAATGGA GACCCTGTAT TTGTAATGGA AGGCTGGGCT 220380
TATTCTGCCG TGGTGGGGGA TTTGGGTGTT A~ATTCAGTC CTGAAGGTAT AGCGTCTATT 220440
ACTCGTAAAA TTCCTCATGT GTTAATGAGT TCTCATAAAC TTCAAGTGAA AAATGCGGAA 220500
GGTAAATGGA CGGAATTAAC TGGCGATGAA CGTAAAAAAG CACTTGATAC TTTAAAATCA 220560
ATGAAGAGTA TTTCACTTGA TGATCATGAT GCA~AAACAG ACATGCTTAT TTCAAAATAT 220620
A~AAGTGAAA AAGATCGTTT AGCACAAGAA ATTGTTGGTG TCATCACAGG TTCTGCAATG 220680
CCGGGTGGTT CAGCAAACCG TATCCCAAAT AAAGCAGGCT CAAATCCAGA AG~lL~lATT 220740
GCAACGCGTT TTATTGCAGA AACAATGTAT AACGAACTCA AAACAGTGGA TTTAACTATT 220800
CAAAATGCTG GCG~1~1ACG CGCAGATATT TTACCGGGTA ATGTAACCTT TAACGATGCT 220860
TATACTTTCT TACCTTTCGG GAATACGTTA TATACCTATA AAATGGAAGG TTCATTAGTG 220920
A~ACAAGTGC TTGAAGATGC AATGCAATTT G~1L1G~11G ATGGCTCTAC AGGCGCATTC 220980
CCTTATGGTG CAGGTATTCG TTATGAAGCG AATGAAACAC CAAATGCGGA AGGTAAGCGT 221040
TTAGTGAGTG TTGAAGTCTT GAATA~ACAA ACCCAACAAT GGGAACCGAT TGATGATAAC 221100
AAACGTTATC TTGTCGGAAC AAATGCTTAT GTTGCAGGCG GTA~AGACGG TTATAAAACC 221160
-77.133-
SUBSTlTtJTE S~E}~T tRULE 2fi~
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96/05320
TTTGGTAAAT TATTTAACGA TCCAAAATAT GAAGGCGTTG ATACCTACTT ACCTGATGCA 221220
GAAAGTTTCA TAAAATTTAT GAAAAAACAT CCGCACTTTG AGGCTTACAC TTcATcAAAT 221280
GTGAAATTTA ATGCTTCAAC TGATGCATTA CCTAAAAAAT AAAATTGAAA AATAGGCTAA 221340
AAATAGCGCG TATTTAACGC GCTATTTTTG TTATTAGTCC TAGGTTTGAA GACTTCATAG 221400
ATGATTAAGA ATTTTAACTA TTCCATATTT AGATGCTTTC TCGTGGAAAA TA~ATTCCCT 221460
ATAGAGGTTG AAAAATAGGG TGATTTATTG CGATAATCTA CCCCATTTTT TGGGAGATcT 221520
TTCTATCTTC TGCATTTTTA CGCAGTTTAT TTTCATTAGA AATGATCGAA TTTTATTTCA 221580
CTTTTAATTT AATTAGATAA AGAACAATGG CGGAAAAACG TAATATTTTT TTAGTAGGAC 221640
CAATGGGTGC AGGTAAAAGT ACTATCGGTC GTCAATTAGC ACAACAGCTT AATATGGATT 221700
TTATTGATTC CGATGCAGTG ATTGAAGAAC GTACGGGCGC GGATATTAGC TGGATTTTTG 221760
ATTTGGAAGG CGAAGACGGC TTCCGAAAAC GTGAAGAACG CATTATTAAC GAACTCACAC 221820
AAATGCAAGG TATTGTACTT TCAACTGGTG GGGGAGCAGT G~lll~lAAG GAAAACCGTA 221880
ATTATTTATC AGCACGTGGT ATTGTGATTT ATTTAGAAAC AACGGTGGAA AAACAATTCC 221940
AACGCACTCA ACGTGATAAA AAACGTCCAT TGCTCCAAGA TGCAGAGAAT C~lC~L~AAG 222000
TATTGGAAGA TTTAGCA~AA ATTCGCAATC CGCTTTATGA AGAAATTGCG GACATCACTT 222060
TGCCAACCGA TGAACAAAAT GCCAAAATAA TGGTA~ATCA AAlL~ll~AT TTAATTGATA 222120
ATATGAATGG GTTGAATGGT GCACTTTAAA CACACCTAAG GATAAATTAT GCTGTGCGTC 222180
AACGTGGAAT TGCAAGAGCG TCGCTATCCT ATTTTAATTG GTAGCGGATT GTTACAAGAT 222240
GAACGTAGTT ACCCGATTAA ACGTGGAGAT CGCGTGATGA TTGTAACGAA TCCCACGGTT 222300
GCACAGTTTT ATCTTGATAC AGTCATCTAT GC~llGGAAA AACGTGGTTG CGTAGTCGAT 222360
CAl~lLllAT TGCCAGATGG CGA~AAATAC A~AACACTTG AATCTTTAAA CTTAATTTTC 222420
ACCGCACTTT TGCAAGGTAA TCATGGGCGA GATACCACGA TTATTGCATT GGGCGGTGGC 222480
GTAATTGGCG ATGTTGCTGG CTTTGCTGCG GCAAGTTATC AGCGCGGCGT GCGTTTAATT 222540
CAAATTCCAA CAACATTGCT TTCACAAGTG GAll~Ll~AG TGGGCGGTAA AACGGCGGTT 222600
AATCATGAAT TAGGCAAAAA TATGATTGGC GCGTTCTATC AGCCATCAAT GGTTATTATT 222660
GATACGCTCA CGCTTAATAC ACTTCCTA~A CGTGAAGTAA ACGCGGGGCT TGCCGAAGTT 222720
ATCAAATATG GTGCCATTTT AGATTACGAA llllllGAAT GGCTAGAGCA ACATATTGAT 222780
GAACTTGTCG CTTTGCATCC TGAGGCGCTT CAACATTGTA TTTCTCGTTG TTGCCAAATT 222840
-77. 1 34-
SUBSTITUTE S~EET (RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/0~320
A~AGCAGATG TTGTCGCGAG AGATGA~ACA GAAAAAGGCG ATCGTGCATT GCTTAATCTT 222900
GGACATACTT TTGGACATGC CATTGAAACT CACTTAGGTT ATGGAAACTG GCTTCATGGT 222960
GAAGCTGTTT CTACGGGAAT GATGATGGCA GCGGCGCTTT CGGAAGAACT TGGAGATATT 223020
TCTATTGCAG A1-~1~-1~-1CG CCTTGAAAAA TTACTTGCTC GTGCCAATTT GCCCACCGTA 223080
TCTCCAGATA CGATGCAGCC GGAGGACTAT TTACCGCATA TGATGCGTGA TAAA~AAGTT 223140
CTATCGGGTA AATTGCGTCT GGTATTACTC AAATCTCTAG GTCAAGCTTA TGTGGCGAAT 223200
GATACCGAAC ATACCCTCGT GTTAAACGCA A11C~1C~1--1- GTACTCAAAC GGATTAAGAT 223260
GTTACGTCCG AAAAAACAAT CTTTAAAACC TAAGTTAAAA CACCGTCCAT TTTTA~AATG 223320
GGCGGGGGGA AAA~111C~L-1 TAACGGACGA GATAAATAAA GCCTTTCCAA ACAA L~AA~ 223380
CTGCTTAATT GAGCCATTTG TGGGCGCTGG AGCAGTATTT CTTAATTCTA ATTTTGAACG 223440
CTATATTTTG GCAGATATCA ATCCTGATTT AATCAATCTA TTCAATATTG TGAAAGnAAA 223500
TGTAGATGGT TATATTGAAG ATTGTAAGCC GATTTTCTTC GCTGATGATG CCAATACACC 223560
CGATTATTAC TATGCTAAAC~GTCGCCAATT CAATGCATCA ACAGAACCTT TCGAACGTTC 223620
GATTATTTTT TTGTATTTGA A1C~-1--1-1--1GG TTTTAATGGA TTATGCCGTT ATAACAGCAA 223680
GAATGAATTT AATGTACCTT TTGGTGCTTA CAAAACTCAT TATTTTCCAG AGGATGAATT 223740
ACGTTATTTT GCGCATAAAG CGCAAAGTGC G~L~1111LA TGCTGTGATT TTCAAAAAAC 223800
TTTTGAATTT GCCGATAAGG ATTCGGTGAT TTATTGTGAT CCACCTTATG CTCCGCTACA 223860
ACAAGAGACT AATTTTACTG GTTATGCGGG CAATGAGTTT GGACTGGCGC AGCAACGTGC 223920
TTTGGCAGAT TTAGCGAAAT CTATACAAAA AGAAA~ACAA ATTTCGATAT TGATCTCGAA 223980
TCACGATACT AAATTTACGC GTGA~ATTTA TAACGGTGCT AAATTTAAAC GGGTAAAAGT 224040
CCAACGTTCT ATTAGCCA~A ACCCAGA~AA ACGCGTAAAA GTGAAAGAAT TGATTGCGAT 224100
ATTTGGTGCT CGTAAATAAT AAAAATAACC CTTACTTTAT ACTA~AAGTA CCAAAATCGT 224160
AATTTTAAAA CCACAATAAA ATAATATATT ATGTATTACC ATTTATCTCT TACAGTACCT 224220
ATATACTTTT TTGATACTAA CTCAAAATAC TCACAAGTCT GTAATTTTAC CTGTAATCCT 224280
111~1111AT CAGAATGATT ATCTAGAAAA CTCATCCAAT CATCAGAATA ATTAACAAAT 224340
AATTATTATC CTATAGTAGA ATGTAAATTA TTTTAATAAC GCCTTATTTG TACTGTGGAT 224400
AATTCATCAA AATTTAAGCC TGTTATGCTT TA11-~1-1LAG TGTATAACAA ATAGGATAAA 224460
AATGGAAAAA GCA~AACCAT CCAAGCAAAG A~ATTTTAAT CACTGTCAAG GAGTACATTA 224520
-77.135-
SUBS I ~ I UTE SHE~ ~RULE 26~
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96/05320
TTGAATTTGG TAATA~ACCG TTAGGTTTAA AAGATACTAC ACCCAAATGC CACTGCCCTA 224580
TTTGTGCTCA AGTTTTATTT GAGA~AAATG TTAATACAGT GCCATCCTCT AATAGCAATT 224640
TTTCTAATTA CCCAAAAAGC GAATTCTGCC CCATA~AATT A~ACTA~AGC AATTTATACC 224700
AATCATATTT TCCATTATCA CCA~ATAAAA CGCATGGACT GAATTA~AAA ATTTATTCAG 224760
AAAAAATTGG CAAAAATATT ATCGTCA~AT TA~l~ llG GCAAAAAACT TATAACCTAT 224820
TGAATTTATT ATATTAGCTA ATCAACA~AA AATTTGGGAA TACGATAAAC TTGAAGAGTA 224880
TCAAATTCCT TATATTCTAT TAACATTAGC AGACTGTCCT AACCA~AAAG GAACATATAA 224940
AAATAAACGT CACTGCTGGT TTAGATTTTG GTTTGATGCT TCAATTCA~A GATATGAAGA 225000
TATTTGGAAT AATAGTTCTT TACCAGTATT GTGGACAACC TATTATTACC TATCAGGGAA 225060
ACA~AGAAAA CCTTCAGAAA TA~ATCTAAA A~ACATGAAT TATTTCATCA TGGATAAAAC 225120
Tll-llAGAA CAAGAAATAT TACTTCCCCA ATTTATTATT CA~AATATAG AACGGTGGTT 225180
TA~AACACAC AAllll~lAT AGACAAGTCA GCACCTAATA CTATTTCATG ACGAAGATCG 225240
C~1L111~11 TAAAAAGGCA AAAATAATGC TATTAATCAA CCATGCCAGT AATGTCGCCA 225300
CCAACAAATC TATTGGGTAA TGCATGCCTA ATCGCACACG GCTAATCAAC ATCAATAAGC 225360
CCCACACTGC AATACCCACC ACCAGCAATT TTGCTTTA~A AGAACGGTTA CCCAATAATT 225420
GGGTAAAGCC AACAGCAAGC ATTAGCCAAG TTGCTGCA~A AATCGTATGT CCAGAAGGGA 225480
ACGAATACCC C~lll~ATTT TCATAATGAT GAACTAACCA AGCTGGTGTA ATGGCATCCA 225540
TCGAATAAAA ATTCTTAGCT ATTTCAGCAC GCA~AGTGCG GTCATTTTTA TAA~AGTTTT 225600
CAGGCGTTGA ATGAGTTTGC TCAGCTAGAT A~ACGGTGAA TGGACGAGGT TCTTCAAATA 225660
ATGCTTTTGC CC~l~lllll GCGGCTTGAG TTGCAATAAC TGAAATCCCC ATCACAATTA 225720
CGCCTAATAT CCAll~llll GGATTTTTAA ATAAAAACGC AAACA~AAGC GTAAACAACA 225780
CACAGGTGAT CAACGCATAA GGTACGCTAC CCGTTTCAGT GAGCAAATAA AGCCAATAAT 225840
CAGCTTGAGT TAATTGGCTA TTACCATGCC ACTGATAGGA AATACCCCAA ATAAAAAATG 225900
GTACAAGACA AAGTAATAAC GTATATAATG ACAGCCTTTT GAACATGCTC GCCCCTTGAT 225960
AACAAAAATA ACGCGCGCAT TCTAACAGAA ATGACTACGA ATAAGGATCA CTTTATGGCA 226020
AAAATTCAGC TAGTTGCGCA AGCCAATTTA CCCACTGAAT ACGGTATTTT CAAAATGGTG 226080
GGATTTGAAT TCCCAGATAC AAAAAAAGAA CATGTAGCCT TAGTGATGGG CGATATTTCT 226140
AATGCTGATG AACCTGTATT AGCACGTATC CATTCTGAAT GTTTAACTGG CGATGCGCTT 226200
77.136-
SUBS i H UTE SHEET (RULE 2~)
CA 022l874l l997-l0-2l
W 096133276 PCTnUS96/05320
CACAGCTTAA AATGCGATTG TGG~-L-LC~AA CTGGCGACAG CATTA~AACA AATTCAAGAA 226260
GAAGGTCGCG GAGTCTTAAT TTATCATCGT GAAGAAGGTC GCGGAATTGG TTTGATTAAT 226320
AAAATCCGTG CTTATTCTTT ACAAGATA~A GGAATGGATA CCATTGAAGC TAATCTTGCT 226380
TTAGGTTTCA AAGCGGATGA ACGCAACTTT GAA~L~-L~LG CCGATATGTT TGAGCTACTT 226440
GGTGTAAAAA AAGTTCGCTT AATGACCAAC AACCCAGAAA AAGTAGA~AC CATGA~AAAA 226500
GCAGGTATCA ACGTGGTTGA ACGAGTA~CG CTTAATGTAG GCGA~AACCG CTACAACACA 226560
A~ATATCTTG ATACA~AAGC GA~AAAAATG GGGCATTACA TTGTGCATAA CAATGACGAA 226620
CAACATTTAA TGACCTGTCC ACATTGCCAG GAAGAGATTA TTTAACA~AT AAGATATGTT 226680
TA~AAAGCCA TACTGTTATA TTGAACAGTA TGG~L1-L-L-L-L ATTTAAACTT TATGTTATGG 2267gO
AATAATCAAA AGA~1LL-L-11A GCATATTGCT A~AAACGGGA AACCCCGTCT CGTATTCCAA 226800
AGATCGGGGC TTATCAGGAG TAAGTAAAAT GA~AAAAATT GC~ L 'L-1--1 -L~'A 'L-L L L ~-L L ~AT ' 226860
TA1~1~-1-L~1 TTAGTTAGCT GTTCCGGAAC AGTTATCTAA GATAATCGCA AGGGGACGAT 226920
GTAGGAGTTG TCCCCAATGC CTCCACCAAT CTTAAAGAAT ~L~1L1C~-L-1G ATTGCAAGGG 226980
CAATTATTGA CTTTGAACCT TTCTCCACAA ATCTTTACTG TAAATGACAC CGACAGAATT 227040
TACTTGCGCA CCCATTATAC TCGGTACAAG ATA~ACAGGC GTACTATATT GA~AAATAGG 227100
TAACACTAAA TG~-L~-11-~-1L GAACTATCCC TTTTAATTTC GCGTAATTTT CTAACCGCAC 227160
~11-1-1-1CGGAT ATCGTCGTCA TTGCACTTTC AAATA~ACGA TCAAATTCCG CATTTTTATA 227220
GCCATTTTTG TTATCTGGGC TTTTTGAATA GAATAAATTT AGA~ATGCTG CAGGATCATT 227280
AAAATCAGCA CACCAGCCAG AACGAATTAA TTGAAAATCG C~Llll~lGC GGGCGGTTTG 227340
CAATTCTTGC CAGCTCATCC CTTGATTTTC AACTCGTAAT A~ATCAGATT GTGATAATTG 227400
ATGATTTAAT CGCATTGCAA TGGTTTGATT CAGAGATAAA TCATCATA~C GAATACGTAA 227460
TTTCAATGGA CGAGTTTCAC TAATTTGATT TTGGGAAAAG AG~-1~-L-L~1G CAACAACTGG 227520
CTCCCAAACA GATTCTTGCT CACCTAGCAT AGATTTTGGC AAAAAAGTAT TGTTAGGATA 227580
AAGATGAGCA ATATCTGCAA CCA~ATTATT GGTAGAAATC ATCGA~ACAA TCG~ L L L-L~-L 227640
TACCGCACTT 1L1L~-1AACA CAGGATCGGA AAGATTAAAC TCATAGAAGT AAGTACAAAG 227700
TTGCGGATAA TCTTGGATAT TCTGATTGAC 11L11LCGGA TTCATTACAA CATCAAAATC 227760
AGACAAATCT GCATCAACGG AAA1-1-L1L1G ATACTTCACT TGCTGAAATA TCA~-l l-L-L-LC 227820
TTTCGCCCAA TAATAAGGAT TGGTAGTTAA AATGTGCTGA TTTTCAGCCT GC~L11~LAA 227880
-77. 1 37-
SUBS i 11 UTE S~tEET (RULE 2~i)
.
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
TTGATATGCA CCATTGCTGA TA~ATATTTC AGTCGATTTA GCATAGTGAG GCA~AAGACT 227940
GACATGTGCC AGCATAGAAG GTAAATATGG CGATGCTTTA TCTAATTCAA TGCGTAAAGT 228000
GCGGTCATTT TCGGCAAACA ATCCTAGGGA TTCAACAGGT AACGCTTTTT CCAATACTGC 228060
CTTCGCATTT TTCAGATTCA TA~AAGCCAA ATAATTTTTA AGTGGGCTTT CAGATTGAGA 228120
AA~1~1-L1GC CAAGATTGTA CAAAATCTGA TGCAGTGATA GGCTCGCCAT TTGACCATTT 228180
AGCATTTTCA CGCA~AGTGA A~ATCCAAGT TTTATTGTCT TCGGTTTGCC AA'1'111~1GC 228240
TACAGCTGGA ACAAGATTAC CCTGCACATC ATAAGCTGTT AATCCTTCAA A~AGATCTCG 228300
TAATAATTGA ~111~11~11 CG~L11~1~C TTGCCAAGGT TGCA~AGTCA AATCGCTATA 228360
AACGCCACGT TTTAATTCAA CTCGGTTAGA TTCCAATTGA GTALLlllll ~L~L-l-AAT 228420
TTGTGGCGAA ATAGGCTTAG GACTATCCAA TTTATCACAA GCCACCACCG TAAAAATAAT 228480
AGAAAAAATA ACCGCACTTC GTTGGCACAA AGCGAACAAA TTATTCATTT TCGGTTTTAA 228540
TCCA~AATAA GAAGAACCAA AACTTAATAC AAATCAACGC AACAATAACA CTACGCCCTA 228600
TTACACTTGG CGTGA~ATAA AAACCAATTA GTAGCATTGT GGTAACA~AA GTCAAAATAA 2286~0
AAATTTTGGT AL1L11~111 AATGATCGAT TTTCATGA~A GGACTTGAGA L~lllLl~AT 228720
A~ATACTTGT GCCTAAAAAC CA11~11~1'A AGC~L111GA A~-1111~1G AAGA~AAATA 228780
AAGTAAGTAA TAAAAAAGGC GTGGTAGGCA AAAGAGGAAG GA~AAATCCC AATGATGCCA 228840
ATTGCAAGTG AAAGA~AACC TAAAATAATG TA~ATAATTT TCATAATGTT CCTAATAAAA 228900
AAGGAAAATG CAAACTATTA TTACTGATTT TTTAGATTTT TCAACCTTGA TATTATAGAA 228960
TTTGCCGTCA CATAAAAAAA CA~1111~AA A~AAGGAACA TTTATGTCTA TGTCAAATCC 229020
ATTACTTAAC ATTCAAGGCC TACCGCCATT TTCACA~ATC AAGCCAGAAC ACATTCGACC 229080
AGCTGTTGAA AAATTAATTC AAGATTGTCG CAATACGATA GAACAAGTGT TAAAACAACC 229140
GCACTTTACT TGGGAAAATT TCATTTTGCC TTTAACGGAA ACTAATGATC GCTTAAATCG 229200
TGCTTGGTCG CCC~lll~lC ATCTCAATTC AGTAAAAAAT AGCACTGAAT TACGTGAAGC 229260
CTATCAAACG TGCTTGCCGT TA~111~LGA ATACAGCACT TGGGTTGGTC AGCATAAGGG 229320
GCTTTATAAT GCCTATTTAG CGTTAAAAAA TAGTGCTGAA TTTGCCGATT ATTCGATTGC 229380
ACA~AAGA~A GCCATTGAAA ATTCACTGCG TGATTTTGAA CTTTCAGGCA TTGGGCTTTC 229440
CGAAGAGAAA CAACAACGTT ATGGCGA~AT TGTGGCACGC TTATCGGAAT TA~ATTCACA 229500
ATTTAGCAAT AACGTATTAG ATGCCACCAT GGGTTGGGAA AAACTCATTG A~AACGAAGC 229560
-77.138-
SUBS 1 i 1 UTE SHEET (RULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
AGAACTTGCT GGTTTACCTG AATCCGCACT ACAAGCTGCA CAACAATCTG CCGA~AGTAA 229620
AGGATTAAAG GGCTATCGTT TTACGTTAGA AATCCCAAGT TATTTGCCTG TGATGACTTA 229680
CTGCGAAAAT CGTGCATTGC GTGAAGAAAT GTACCGTGCT TATGCAACAC GTGCCTCTGA 229740
ACAAGGCCCT AACGCTGGCA AATGGGACAA CAGTA~AGTT ATGGAAGAAA TTCTGACGTT 229800
ACGCGTTGAA CTGGCAAAAT TACTCGGTTT TAATACTTAT ACCGAACTTT CACTTGCCAC 229860
A~AAATGGCA GAAAACCCAC AACAAGTGCT TGA1L1~11A GATCATCTTG CCGAACGTGC 229920
CAAACCACAA GGCGAAAAAG AACTGCAAGA ATTGAAAGGT TACTGCGAAA AAGAATTTGG 229980
TGTCACTGAA CTTGCACCTT GGGATATTGG TTTTTACAGC GA~AAACA~A AACAACATTT 230040
ATACGCCATT AATGATGAAG AACTTCGCCC ATA1L11C~A GAAAATCGCG TGATTTCAGG 230100
A~11~111~AA TTAATTAAAC GCATTTTTAA TATTCGTGCA GTGGAACGCA AAGGTGTGGA 230160
TACTTGGCAT AAAGATGTAC ~'L'1''1'~'1"1"1'~A TTTAATCGAT GA~AATGATC AACTCCGTGG 230220
CA~'LL1~1AT CTTGATTTAT ATGCACGCGA ACACAAACGT GGTGGTGCGT GGATGGATGA 230280
CTGTATCGGA CGTAAGCGTA AACTGGATGG CAGCATTGAA ACGCCTGTGG CTTATTTAAC 230340
CTGTAACTTC AACGCACCGA TAGGGAATAA ACCAGCGTTA TTTACTCACA ATGAAGTCAC 230400
CACGCTATTC CACGAATTTG GGCACGGAAT CCATCATATG CTCACGCAAA TTGATGTATC 230460
CGATGTGGCG GGAATAAATG GCGTGCCTTG GGATGCTGTG GAATTACCAA GTCAATTTAT 230520
GGAAAACTGG TGCTGGGAAG AAGAGGCTTT GGC~LLLATT TCAGGACATT ACGAAACAGG 230580
CGAGCCGTTG CCAAAAGAAA AACTCACGCA ATTGTTA~AA GCGAAAAATT TCCAAGCTGC 230640
GATGTTTATC TTACGTCAGC TTGAATTTGG TALLLLL~AT TTCCGTTTAC ATCACACCTT 230700
TGATGCGGAA A~AACCAATC AAATTTTGGA TACACTTAAA TCAGTGA~AT CACAAGTTGC 230760
CGTCATAAAA GGCGTAGATT GGGCAAGAGC GCCACACAGC TTCAGCCATA TTTTTGCAGG 230820
GGGCTACGCC GCAGGTTATT ACAGCTATTT ATGGGCTGAA GTATTATCGG CTGATGCTTA 230880
TTCACGCTTT GAAGAAGAAG GTATTTTCAA CCCAATCACC GGCAAATCAT TCTTAGATGA 230940
AATTCTCACC CGTGGCGGCT CAGAAGAACC AATGGAACTC TTCA~ACGCT TCCGTGGCCG 231000
TGAACCGCAA TTAGATGCGT TGTTAAGACA TA~AGGAATT ATGAACTAAT ACGTCAAACT 231060
ATAGGGCATG CACAACATGC C~'L'L'L~'L~'AA ATATTTTCCT CGACATAAAA ACATAGTAAA 231120
TTTTAACCGC ACTTTATCTA GACAA~ACCT GCA~ACGAGA CATTATTTTT ACAAATAGCT 231180
GTAAGATAAA CGCATAGAAA TTCACGCAGA ATAAACTAAT TTCCTGTATA ATTTTTCACA 231240
-77.139-
SUBSl 11 UTE ~HE~T (RULE 2~i~
CA 022l874l l997-l0-2l
W 096133276 PCTrUS96/05320
TATCTATCCA ACTCATTACA CAAAATATTC TGAGGATTTT ATGGCTGCTG CAATTCAACA 231300
ACGTGCCGAA CTTCAACGCC GTATTTGGCA AATTGCTAAT GATGTGCGAG GCTCGGTCGA 231360
TGGCTGGGAT TTCAAACAAT ATGTGCTTGG CACACTTTTT TACC~-LlllA TTAGCGAAAA 231420
TTTTGCCAAT TACATTGAAG CGGGCGATGA AAGCGTAAAT TATGCCCAAT TACCTGATGA 231480
AATCATTACA CAGATGCCAT TAAAACGAAA GGCTACTTTA TTTACCCAAG CCAATTATTT 231540
AAGAATGTTG CGGCTAATGC TGGCAGCAAT CCTAATTTGA ATACTGATTT AAAACAGATT 231600
TTTACTGATA TTGAAAACTC AGCGACGGGC TTTCCGTCTG AACAAGATAT TAAAGGGTTA 231660
TTTGCCGATT TTGATACCAC CAGCAATCGC TTAGGCAATA CCGTAAAAGA TAAAAACGAC 231720
CGCTTAACGG ~l~ll-llGAA AGGCGTGGCT GAACTTGATT TTGGCAAATT TGAAGATAAC 231780
CACATTGATT TATTTGGCGA TGCATACGAA TATCTTATTT CTAACTATGC CGCCAATGCA 231840
GGCAAATCTG GTGGCGAATT TTTTACCCCA CAAAGTGTTT CCAAACTCAT TGCTCAAATT 231900
GCAATGCACG GGCAAACCTC GGTCAATAAA ATTTATGACC CTGCAGCAGG TTCTGGCTCA 231960
CTTTTGCTTC AAGCCAAAAA ACAATTTGAT GAACATATTA TTGAAGAAGG ~LlLlL~GGG 232020
CAGGAAATTA ACCATACCAC ATACAACCTT GCCCGTATGA ATAl~lllll GCATAACATC 232080
AACTACGACA AGTTTGATAT TGCTTTAGGC AACACCTTAA TGGAACCACA ATTTGGCGAT 232140
AATAAACCTT TCGATGCCAT 'i~lllC~AAC CCGCCTTACT CCGTGAAATG GGCTGGCTCC 232200
GACGATCCAA CATTGATTAA TGATGAACGA TTTGCCCCCC GCAGGCGTGC TTGCACCAAA 232260
ATCCAAAGCG GACTTTGCCT TTATTTTACA TGCGTTAAGT TA~L~llL~AG CAAAAGGCCG 232320
CGCGGCGATT GTTTCCTTCC CTGGTATTTT TTATCGTGGC GGTGCCGAGC AAAAAATTCG 232380
TCAATATTTG GTGGATAATA ACTATGTGGA CGCGGTGATT GCGCTTGCGC CAAATCTCTT 232440
TTTTGGCACC AGTATTGCGG TGAATATTTT GGTGCTTTCC AAACACAAAC CCAATTTATC 232500
GATGCCAGCG GTTTATTTAA ATCTGCCACT AATAACCACA TTTTAGAAGA GGAACATATC 232560
GAGCAAATCC TCAAACTGTT TGCCGATAAA GAGGATGTGC CGCATTTGGC AAAATCCATA 232620
TC~LllGAAG AAATCGCCCA AAATGACTAC AACCTTGCAG TAA~LlC~lA TGTGGAACAA 232680
AAAGACACTC GTGAAGTGAT TAATATTGAT GAACTCAATG CTCAAATTCG TGaAACTGTT 232740
ACCAATATTG ACCACTTGCG TGCGGAAATT GACAAGATTG TTGCAGAAAT TGAAGGGTAA 232800
AATGTAGGGT GGGCTTCAGC CCAnaTTTAC GATAACAGGT AGTGGGCTAA AGCCCaCCCT 232860
ACGAGGAACA ATAAAAAAAC ACCATGAAAA ACAACCGCAC llllllAGAA AAATTATTGG 232920
-77. 1 40-
SUB5 i 11 UTE ~}~EET (RULE 2~)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
AGGG~1~-L~A GGTTGAGTGG AAGCCTTTAG ATGAAGTTGC CAATATCGTC AATAAtGCAA 232980
GA~AACCAGT CAAATCATCC TTACGAGTGT CAGGGAATAT TCCATATTAT GGTGCTA~TA 233040
ATATCCAAGA TTATGTCGAA GGATATACTC ACGAGGGCGA ATTTGTATTA ATTGCTGAAG 233100
A1G~11~-1GC TAGTCTAGAA AATTACTCTA TTCAATGGGC TGTAGGTAAA TTTTGGGCAA 233160
ATAACCACGT CCATGTAGTA AATGGCAAAG A~AAATTAAA TAA1C~-1-1-11 TTATACCATT 233220
ATTTAACTAA TATGAATTTC ATTCCATTCT TAGCTGGAAA GGAACGTGCA A~ATTAACAA 233280
AAGCTA~ACT GCAACA~ATT CCAATCCCCA TCCCCCCACT CTCCGTCCAA ACCGAAATCG 233340
TA~AAATTTT GGACGCATTG ACAGCACTTA CCAGCGAGCT TACCAGCGAG CTTACCAGCG 233400
AGCTTACCAG CGAGCTTATA CTACGCCAGA AACAGTATGA ATACTATCGA GAAAAATTGT 233460
TA~ATATTGA TGA~ATGAAC AAGGTTATTG AA~1LG~1~A TGTAGGGCCT ~LlC~lATGT 233520
GTA~ACGAAT TCTTAAAAAC CA~ACAGCAA GCTCTGGAGA TATTCCATTT TATAAGATTG 233580
GAACTTTTGG GA~AAAGCCT GATGCCTATA TTTCAAATGA G~-L-1-1-1C~AA GAATATAAAC 233640
AAAAATATAG CTATCCTAAA A~AGGAGATA TTCTTATATC TGCTAGCGGA ACTATTGGTA 233700
GAACAGTTAT ATTTGATGGA GAAAATTCTT ATTTTCAAGA TAGCAATATC GTCTGGATTG 233760
ATAATGATGA AA~L~LC~-1L CTTAATAAAT ATTTATATCA TTTCTATAAG ATTGCTA~AT 233820
GGGGAATTGC AGAAGGAGGC ACCATTCAAC GTTTATATAA CGACAATTTG A~AAAAGTAA 233880
AAATTTCTAT TCCTCCATTA AAGGAACAAC ACCGCATCGT TTCAATCCTA GATA~ATTTG 233940
AAACCTTAAC CAATTCCATC ACTGAAGGCT TACCTTTAGC GATTGAACAA AGCCA~AAGC 234000
GGTATGAATA TTACCGAGAA TTGCTATTAA AL-L-1~-1-C~1A ACCCGTAGTG GGCTTCAGCC 234060
CACCAATTAA CCATAACAAA CGGTGGGTTA AAGCTCACCC TACAATGTAA TGAGAATATT 234120
TTTATGGTGG GCTAAAGCCC ACCCTACGAA CTACAATTTG GAATAATATA TGTCTAATTA 234180
TCGGCGCGAT TTTACTAAAG GTGGATTATA 1-L-L-L-L-L~ACA AL-L~-L-LL-LAC AAGATAGAAC 234240
A~AATCTTAT CTAACTGACT ATATCAATGA ATTTAGATCT GCATATAAAC A~A~l--L~-L~A 234300
ACATTATCCA TTCGA~ACAG TAGCAATTTG TATTTTGCCC GATCATATTC ATTTACTGAT 234360
GCAATTACCT GA~AATGATG ATAATTACGC AATACGCATC GCATATTTAA AAACACAATT 234420
TACACGACAA CTTCCA~AAG AATGCCGACA ATTTAATA~A AATAGACA~A AATATCGAGA 234480
ATCAGGTATT TGGCAACGCC GATTTTGGGA GCATTTAATT CGTGATGATA AAGATTTAGC 234540
GAATCATTTA GATTATATTT ATTACAATCC TGTGA~ACAC GGCTATGTTG AGGTAGTAAA 234600
-77.141-
SUBSTI~VTE S}tEET ~RULE 2~
CA 022l874l l997-l0-2l
W 096/33276 PCTruS96/05320
AGATTGGCCG TATTCTTCCT TCCATCGTGA TGTGAAAGCA GAGATTTATC CTGAAGATTG 234660
GGGAGGCAAC CCAGATTTGA AAATTAAAGG TGATATATAA CAATACTGTA GGGTGGGCTT 234720
CAGCCCACAA TTAACCATAA CAAACGGTGG GCTAAAGCcc ACCCTACAAT GTAATGAGAA 234780
TATTTTTATG ATGGGCTAAA GCCCACCCTA CGAACTGAAT AACTGAAAAA TATACTAAGG 234840
AAAAACCATG ACCCAATACA AAACTATCGC TGAATCCAAT AATTTTATCG TTTTAGATCA 234900
ATATAATAAA TTTGTGGAAG AATCTAATGC TGGTTATCAA ACGGAAAGGA GCCTTGAGCG 234960
TGAGTTTATT CGTGATTTAC AGGCTCAAGG CTATGAGTAT TTACAATGGC TTAATAATCA 235020
CGATGAACTG ATTAAAAACT TACGGGCGCA ATTACAACGC TTAAATAACG TG~Llll~LC 235080
CGATGCAGAA TGGCAACGTT TTTTAGAGGA ATATTTGGAT AAACCGAGCG ATAATCTGAT 235140
TGAGAAAACC CGCAAAATTC ACGATGATTA TATTTATGAT lll~l~LlCG ATAACGGACG 235200
CATTCAGAAC ATCTATTTGC TTGATAAGAA AAATCTTGCC AATAATTCTC TGCAAGTCAT 235260
CAATCAATTT AAGCAAACTG GCAGCTATGA TAATCGTTAT GATGTGACAA TTTTGGTGAA 235320
TGGTTTACCC CTTTATTGAA TTAAAAAAAC GCGGCGTGGC GAllC~l~AA GCCTTTAACC 235380
AAATTCACCG TTACAGCAAA GAAAGTTTCA ATAAAGaAAA Ll~l~l~lll AAATATATTC 235440
AGALllll~l CATTTCTAAT GGCACGGATA CTCGCTATTT TGCTAATACG ACTAAACGCA 235500
ATAAGAATAG CTACGACTTC ACAATGAATT GGGCAACGGC AAAAAATACT CTGATTAAAG 235560
ATTTAAAGGA TTTTACCGCG A~Lll~llGC AAAAGAATAC TTTGCTCAAT GTGTTGGTAA 235620
ATTACTGCGT GTTTGATGTG AGTGATACGT TGTTAATTAT GCGTCCGTAT CAAATTGCCG 235680
CAACAGAACG TATTTTATGG AAAATtCAAA llL~llACTT AGCA~AAAAT TGGAGTAATC 235740
GTGAAAGTGG TGGCTATATT TGGCATACCA CAGGTTCAGG CAAAACCCTC ACCAGTTTTA 235800
AAGC~L~lCG CCTTGCGACT GAACTTGATT TTATTGATAA A~L~1L1111 GTGGTCGATC 235860
GTAAAGACTT AGACTACCAA ACGATGAAAG AATATCAGCG LLlllCGCCT GATAGCGTGA 235920
ATGGGTCGGA AAGTACCGCT GGGCTTAAAC GCAATATTGA AAAAGATGAT AACA~AATTA 235980
TCGTAACCAC CATTCAAAAA TTGAATAATT TAATGAAAAG TGAAGAAAAC ~L~L-lATTT 236040
ATCAAAAACA GGTGGTCTTT AllllC~ATG AAGCACATCG CTCTCAATTT GGCGAAGCAC 236100
AAAAAAATCT AAAACGTAAA TTCAAAAAAT TCTATCAATT TGGTTTTACT GGCACGCCTA 236160
TTTTCCCTGA AAACGCATTA GGTGCGGAAA CGACAGCAAG TGTGTTCGGT GCGGAATTGC 236220
ATTCTTATGT GATTACCGAT GCTATTCGTG ATGACAAAGT ACTGAAATTC AAAGTCGATT 236280
-77. 1 42-
SUBSmUTE ~HEET tRULE :Z6
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
ACAACGATGT CCGCCCACAA TTTA~AGCCT TAGAAACAGA AAAAGATCCT GAAAAATTGA 236340
CCGCACTTGA GCAGA~ACAA GC~L111LAC ACCCTGAGCG TATTAAAGAA ATCTCGCAAT 236400
ATTTGCTTAA CAATTTTA~A CAGAaAACCC ACCG~-ll~AA TGCCACAGGT A~AGGCTTTA 236~60
ATGCAATGTT TGCGGTAAGC AGTGTAGAAG CAGCAAAACG TTATTACGAA ACCTTACA~A 236520
ATTTACAGGC AGAGCAGGAA TATCCGTTAA A~ATTGCAAC AAL~llllCG TTTGCCGCCA 236580
ATGAAGA~CA AGATGCGATT GGCGATATTC CAGATGAGAC CTTTGAACCC ACTGCTCTAA 236640
ACAGTACGGC AAAAGAATTT TTAACA~AAG CCATTGATGA TTACAATCAC TACTTTGGCA 236700
CGAATTATGG CGTAGATAGT CAATCATTCC AA~ATTACTA TCGCGATCTT GCCAAACGTG 236760
TGA~AAATCA GGAAGTGGAT TTACTGATTG LG~lCGGAAT ~Ll~llAACA GGCTTTGATG 236820
CCCCTACGTT GAATACTCTT TTCGTGGACA A~AACTTGCG TTATCACGGA TTAATGCAGG 236880
-L-lll~lCG CACCAACCGC ATTTATGACA CAACTAAAAC CTTTGGGAAT ATCGTCACTT 236940
TCCGCGATTT GGAACAAAAT ACCATTGATG CAATCACGCT ATTTGGCGAT AA~AATACGA 237000
AGAATGTCGT ACTAGA~AAA AGCTACGACA GCTATTTTAA CGGTGATGAC AATCAACGTG 237060
GCTATGCAGA AATCGTGA~A GAATTA~AAG A~AGCTTTCC TGATCCAACA GAAATCGA~A 237120
CAGAGCAAGA TAA~AAAGAG TTTGTAAAAT TATTTGGCGA ATATTTGCGT GTCGAAAATA 237180
TTTTGCAAAA TTACGATGAG TTTGCAGCAT TGCAAGCCTT ACAAGCGGTC GATTTAAATG 237240
ATCCGATTGC AATGGA~AAA TTCAAGCAAG TACATTATGT GAATGATGAA CA~ATTGCAG 237300
AAATGCTGAA AGTACCCACT TTACCAGTAA GAGCGGAGCA AGATTATCGT TCAACTTATA 237360
ATGATATTCG CGATTGGTTA CGCCA~AGAA AAGAGGGGAA TGATAAGGAT AATTCGCCGA 237420
TA~ATTGGGA TGATGTCGTG TTTGAAGTGG ATTTATTA~A ATCTCAAGAA ATCAATTTGG 237480
ATTATATTCT TGCGTTAATT TTCGAACATC ATAAGA~AAA CCAAGACAAA GAGGTGTTAA 237540
TTGATGA~AT CCGCCGCACA ~LlC~-lL~AA GTTTGGGTAA CCGTGCGAAA GAGAGCTTGA 237600
TTGTCGATTT TATCAACCAA ACA~ATTTAG ATGATATTCC CGATA~AGCG ACTTTAATTG 237660
ACTCATTCTT CCTATTTGCT CAAGCAGAAC AGCGAAAAGA AGCAGAATCC TTAATTCAAG 237720
AAGAAAATTT GAATGTCGAT GCAGCA~AAC GCTATATCAG CACTTCATTA A~ACGGGAAT 237780
ATGCCAGTGA AAACGGCACG GCACTTAATG AAGTATTGCC A~AAATGAGT CTACTTAAGC 237840
CACAATATCT CACTAAAAAG CAGAAGATTT TCCA~AAAAT TGCTGCATTT GTAGAGAAAT 237900
TTA~AGGGGT TGGAGGAAAG ATTTA~ATTT AATATATCAA CAATTAGACA TCTTATTAAG 237960
-77.143-
SUB5 i 11 UTE 5~}E~T ~RULE 26)
_
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
ACATA~AGGC ATTATGAATT ATGAATTAAT AATACAAAAC ATACTGGTCA ATATTTAACT 238020
A~1C~1GATA ATAAAAACAG CTCCAATTTA TACTTGGAGC 1~11-1L11AT ATCGATA~AC 238080
TTA~1111LA CGTGCTAAAA TTCGATTTGC ACACTCTGCT GCAGCTGTTA AGCCACCTGC 238140
CATCATAATA ATATCTTTAA TCACTA~ACG ACCAACTCCA GATAAATAAG GGAAACCATA 238200
GGCTGGCGTT GGTAAATCTC CACCTAGATT AGGCACCCAA GCCTCGGGCG TTGTGATTAA 238260
A~ATGACAGC GTGACTATTG ACATGCCAAA TGTCAGTAGG CCTCCTGCCA AACCTGCCGT 238320
TGCATTCCAA ATACCAGCTA AAGTAAGAAT ACCAACAGTA ACAATAATTG CTCCAATAAT 238380
GTAAGAAGCC GTATAGGTGC CA1111~111 ATGCCATTCG A1~111111G CAACCATTTT 238440
~1C~11~AGGA 11111~1~1A GTGTATATTC CATCACTAAC TCTCCTTTAT CATTCGGCAC 238500
TAAATTTGGC C~L1111~AT ACATATAGCT AAAAAACGGG CTATTTGATA CAAAGTGAGC 238560
AATTCCATCT GCCTCATATT GACAAACTTT CAAACCACCG ATCCATGCCA TTACAATAAA 238620
AATAGCAATA CGGATAAAAT TAATAAATTG ACGCTGCATT GGTGCAACAA TTCTCGCGAC 238680
A~ATTCAACA AATGTATTAA ATACTGACAT ATA~ATTTCC ACATAAAAGT AAATAAAATT 238740
GAGAGCCTAA TTCTACTCGC TTTAATATTA AAAAGCAAAA TCAATTCCCT TTAATAAAAG 238800
ATAAATAACG GAGAAATTTG AAAAGTTTTA CTAATTAAAA TAAAATTTGA TTTTCCCATT 238860
TTAAGCCTCT TTATTATCTT TAAATCACAT GTAAATAATC TTTACACAAC TACCTTATAA 238920
TATTAAAATT TACAAAATTT AAGCAAATCC TCCACATCTT CTAACCAAAG ATTTCCAATT 239980
TTATCAATCA ATTCTCCACA ATTAAAAACA TCAGAATTTT TAGCCGCACT TTCTA~AGTA 239040
TCCGCTAATT GACGTAAATG ATTTAACCCT ACCGATGCCG CTGCGCCTTT AATTTTATGG 239100
GCGGTATCTT ~1~111~111 CATATTATCT TTTGATAATT GAGCCAGATA ATTTGGCATA 239160
~111~11L~A ATAAAGATAA A1L11~1A~A ATTTGGGATT TTCCAAGTGT TTCTATCAGC 239220
GCTAAATCAA A~1~L1~L~A AAGCTCATTA TCATCATTCA TTTCTATAAT AGATTCGCTT 239280
TCATCCGCAA AAAATTGCTG TAGACAATGG TGTAAATCCT TAATTGA~AT GGGTTTACGT 239340
AATACGCCAT CCATGCCCAT TTCTA~ATAT TCTTGCTCGC TTTGCATAAC ATTGGCGGTA 239400
AAAGCAATCA TTGGCGGTAA AAAATCATAA ATACCGTTTT CATAGTTCTC TCGCAAATAT 239460
-
TGGGCAATTT CAAAACCACT CATATCTGGT AATTTAATAT CGAGCAATAG AATGTCATAA 239520
ACA11L1L~1 CAAATA~AGT AATCGCCTGC TTGCCATTTG TCGCAACATC AACATGATGC 239580
CCAAGTTTTT CTAAAATAGT TTTTGCAACC ATAATATTGA GATCAACATC TTCCACTAAA 239640
-77.144-
SUBSTrrUTE SI~EET tRULE 2~)
-
CA 022l874l l997-l0-2l
W 096133276 PCTAUS96/OS320
AGAGTATTCA AGGATGGTAT ATTTTnCTTA ACAGATTCTT TTTCAGA~AT TTCCTGAGCG 239700
TGGAGAGTnA GATGGA~AGT CGCGCCTTTT C~1C~11~AC TTTCAACTGT TA~ATCCCCT 239760
TCCCATTAAC TGAGCAAGAT TTTTAGA~AT AGCCAACCCA ATACCGCTAC CCGCACTTTG 239820
CTGGCGGCTT TCTTTCACTT GATAATACAT TTCA~AAATA l'~'L'l''l"l"l'~'L'L CTTCAGGTGA 239880
AATCCCCATT CCTGTATCTT TCACAATA~A ATGGTAACAA TCCTGATTTC TCATAATTTT Z39940
AAGAATAATA TTTCCCTGAT CCGTAAACTT CACCGCATTA CTAATTAAGT TCCACAAAAT 240000
TTGGCTCAAG CGAACACGAT CAAGATTCAA CCAATTAGGC A~ATTAGGTT CAAGCTCTAA 240060
AGAAAAAATA AGALlLLLLl CTTTGGCGAG GA~ACTAGCA A~ATTATA~A TALC~LLLAA 240120
TAAGGCAGGG AAAL~L~LLG GCTGGCGATT TAATTCAATT CGGCTGGCAT CAALLLLLLC 240180
CAAATCAATA ATATCGCTAA AAATATAGCC TA~ACTGACC GcACTTATGT TGATAGTTTT 240240
TAAATAATTA CGCTGGAGAT CATCCAATTC ATCATCAAGT A~AATCTGGC TAAGCCCGAC 240300
AATCCCATTC AATGGCGTGC GA~ATTCATG GCTTATTGTG GCAAGTAAGG TACTTTTATC 240360
ACGGCTATTT ~LlLL~LAACT TTTCCAATGC TTGGGATAAT LLLLL~l~AG CAGCAATTCG 240420
CTCGGCGACC TCATTTTCCA ATCGATTAAC CGAGCTAGAA AGATCAAGAC GAGAATGTTC 240480
AA~LLLLL~l ACTAATA~AG TGAAAAAATA AATAACA~AA GGCGCAGTGA GTAAGCCA~A 240540
AGTTACCGAA CGAAAAATAT CTACCCAAGA TATCTGATGA ACAATA~ATA GACTAAATAA 240600
AATCTGAGTA CA~AGAGCTA A~ACCGCGAG AATCATCACG CCTAAAAGAG A~AAACGAAG 240660
ACGCCCAAGA CGAATAACCC AATCCACATA ACTCTGAGCA AAATATTTGA AALLLlL~AT 240720
CA~ATCTCCT AAAACATTAT TATCGTTATA A~AAAAACCT GTGCATATAG GCTTTATTAT 240780
ATCCATAAAG TAAACGAGAT TGTTATTACT ATGTATGCGT AAGA~ATGAA A~ACTTAATC 240840
TTTATTAATT AT~L~LlL~A CTAAAATTTG TAATTCAGGA ATAACTTGCT CTTCA~ACCA 240900
AGGALL~Lll GTTACCCAAA GCTGATTACG TGGGGAAGGG TGCACGAGAG GCATAAAGTG 240960
CGGTAAGAAT TGACGATAAT TTTTAACAGT GTTAGTTACA TTATCTTTAT TTTCGGGTAA 241020
ATAATATTTC TGTGCATATT GCCCAATAAG AATAGTGAGC TGAATATTAG GTAGATTCCC 241080
TA~AATCATT GGATGCCATC TTTCTGCA~A ACCTTGACGA GGTGGTAAAT CACCCGATTT 241140
ACCTTTTCCA GGATAATAGA AATCCATTGG AAGAACCGCA AATATCCCAG AATTATA~AA 241200
ATAATCGTAA TCTACTCCCA ACCATTCTCG CAGACGATCA CCGCTTTTAT CATTCCAATA 241260
CA~ACGAGAT TGCTCAGCTT TTAACCCAGG AGCTTGACCA ACAATATTAA TTCGAGCTGT 241320
-77.145-
SUBST~TUTE S~{EET tRUI E 2~i)
CA 022l874l l997-l0-2l
W 096/33276 PCTAUS96/05320
TTTAGGAGCC GAAAATA~AG GGA~AATTCC ACC3-11~1C~1A AAATCTTTAT TTTGAGGATC 241380
AGCGATAATA CTTGAAGTTA TTTCGTCTAA ATTTTTAAGC ATAATGAAGG AGATTAGAAA 241440
TGAATATATA AAGTCTATTT GA~AAATATG AAAAATCAAA ACTCTA~ATG ATGTA~ATAG 241500
GTATATTTAT TAAAACTATA TTGTAGGCAA TACAAAACTA AAAACTTGAT ATTGAAATAC 241560
AATCTCTATT TTCTACTTTA A~lCCllll~A TGA~ATAATG AATA~ATTCC CA~AAGCTAA 241620
AACCCCATAT clllC~ACAC GGGGCCCTTC l~lllllATT TAACTTAGAT AAGTATTTGG 241680
TAACCTGGCG GTGCCCTACT CTCACATGGG GAAACCCCAC ACTACCATCG GCATTACAGC 241740
GTTTCACTTC TGAGTTCGGT ATGGTCTCAG GTGGGTCCAC CGCACTATCG CCGCCAGGAT 241800
AA~ll~lllC~A TAA~lCC,l~l 'lll~lCllll AlC_l~lCc~lC l~llll~TCT C_lCC,llACTC 241860
A~lC_lllCCT CTACCTTTCA C_lCC,ll~llA TTGGTCACAA GCTGAATCCG AllllC_lllC 241920
TATTAAGTCT TCTATATTTA C_llllc_lllG TTTAGTCTTT TAC_llc_l~ll TCGCTCTGCT 241980
TTTATTTGCT TCGC_Llll~A lCl~llACTT CACTTAGCTC CCAAAAACAC TTGAGCGTTG 242040
TATAGTTAAG CC_~lc-lCGGGC AATTAGTATT GGTTAGCTCA ATGACTCACA TCACTTACAC 242100
ACCCAACCTA TCTACGTCGT AGTCTACAAC AACCCTTACT GACTTA~AGT CAGGGATGAC 242160
TCATCTCTTG GCAAGTTTCG TGCTTAGATG CTTTCAGCAC TTAl~l~llC CGCATTTAGC 242220
TACCCGGCAA TGCGTCTGGC GACACAACCG GAACACCAGT GATGCGTCCA ~lCCG~LC~l 242280
CTCGTACTAG GAGCAGCCCC AATCAATCAT CCTACGCCCA CGGCAGATAG GGACCGAACT 242340
GTCTCACGAC GTTCTA~ACC CAGCTCGCGT ACCACTTTAA ATGGCGAACA GCCATACCCT 242400
TGGGACCTAC TTCAGCCCCA GGATGTGATG AGCCGACATC GAGGTGCCAA ACACCGCCGT 242460
CGATATGAAC TCTTGGGCGG TATCAGCCTG TTATCCCCGG AGTACCTTTT ATCCGTTGAG 242520
CGATGGCCCT TCCATTCAGA ACCACCGGAT CACTATGACC TA~lllC~lA CCTGCTCGAC 242580
'll~l~l~l~l CGCAGTTAAG CTTGCTTATA CCATTGCACT AACCTCACGA 'l~lCCC,ACCG 242640
TGATTAGCAA AC~llC~lGC TCCTCCGTTA CGCTTTGGGA GGAGACCGCC CCAGTCA~AC 242,00
TACCCACCAG ACACTGTCCG AGACCACGTT TCGTCATCTT CGTTAGAACA TCA~ACGTTA 242760
AAGGGTGGTA TTTCAAGGTC GCCTCCACAA TGACTGGCGT CACTGCTTCA AAGGCTCCCA 242820
CCTATCCTAC ACATCAAAAT TCAATGTTCA GTGTCAAGCT ATAGTA~AGG TTCACGGGGT 242880
CTTTCCGTCT AGCCGCGGGT ACACCGCATC TTCACGGCGA TTTCAATTTC ACTGAGTCTC 242940
GGGTGGAGAC AGCCTGGCCA TCATTATGCC ATTCGTGCAG GTCGGAACTT ACCCGACAAG 243000
-77. 1 46-
SUBSTlTUTE SHEET ~RULE 2~)
-
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96/05320
GAATTTCGCT ACCTTAGGAC CGTTATAGTT ACGGCCGCCG TTTACTGGGG CTTCGATCAG 243060
GTG~Ll~l~l TTCGATGACA CCATCAATTA AC~L-lC~'AGC ACCGGGCAGG CATCACACCC 243120
TATACGTCCA CTTTCGTGTT TGCAGAGTGC 'L~'L~'l"l"l''l''l'A ATA~ACAGTT GCAGCCAGCT 243180
GGTATCTTCG ACCGGTTCAA CCTTCAGGGG CTAGCCCTTA CAATCTACGC CGGCGCACCT 243240
L~lCCCGAAG TTACGGTGCT ATTTTGCCTA GTTCCTTCAC CCGAGTTCTC TCAAGCGCCT 243300
GAGTATTCTC TACCTGACCA C~L~l~lCGG TTTTCAGTAC GGTTTAGTAA AGCCTTTCGC 243360
TTAGTGGCTT TTCCTGGAAG TGTGGTATCA GTTACTTCAG CTCCGTAGAG C~LC~l ATC 243420
A~L~1~1~1~1 GTTAAGGAAG TCCGGATTTG CCTA~ACTTC CCACCTACCA ACTTA~ACGC 243480
ACATATCCAA CAGTGCGATA ACCTAACCTA ~''LCC~'LCCCC ACATCGCAGC TTTACCAAGT 243540
ACAGGAATAT TAACCTGTTT CCCATCGACT ACG~LLLL~A GCCTCGCCTT AGGAGCCGAC 243600
TCACCCTGCC CCGATTAACG TTGGACAGGA ACCCTTGGTC TTCCGGCGAA CGG~LLlLLC 243660
ACCC~'L'L'L'LA TCGTTACTTA TGTCAGCATT CGCACTTGTG ATACGTCCAG CCCACCTCTC 243720
GATGAACCTT CTTCCGCTTA CACAACGCTC CCCTACCCAA CAGAATA~AT TCTGATGCCG 243780
CAG~LLCG~L GCTATATTTC AGCCCCGTTA CAL~LlCCGC GCAGGCCGAC TCGACTAGTG 243840
AGCTATTACG ~LLL~LLLAA ATGATGGCTG CTTCTAAGCC AACATCCTAG ~L~L~lAAGC 243900
~'L'LCC~ACTT CGTTTCCCAC TTAATATAGA CTTGGGGACC TTAGCTGGCG GTCTGGGTTG 243960
'L'L'LCC~L~LC CACGACGGAC GTTAGCACCC G~C~'L~L~'LC TCCTGAGTAT CA~L~LLLGG 244020
TATTCGTAGT TTGCATCGGG TTGGTAAGCC GGGATGGCCC CCTAGCCGAA ACAGTGCTCT 244080
ACCCCCA~AG GTGTCACCTC AAGGCTCTAC CTA~ATAGAT TTCGGGGAGA ACCAGCTATC 244140
TCCCGGTTTG ATTGGCCTTT CACCCCCAGC CACAAGTCAT CCGCTAATTT TTCAACATTA 244200
GTCGGTTCGG TCCTCCAGTT AGTGTTACCC AACCTTCAAC CTGCCCATGG CTAGATCACC 244260
GGGTTTCGGG TCTATACCTT GCAACTATTC GCCCAGTTAA GACTCGGTTT CCCTTCGGCT 244320
CCCCTATTCG GTTAACCTCG CTACA~AATA TAAGTCGCTG ACCCATTATA CAAAAGGTAC 244380
GCAGTCACAA GGTTGCCCTC GCTCCCACTG CTTGTACGTA CAAGGTTTCA GGTTCTATTT 244440
CACTCCCCTC ACCGGGGTTC TTTTCGCCTT TCCTTCACAG TACTGGTTCA CTATCGGTCA 244500
ATCAGGAGTA TTTAGCCTTG GAGGATGGGC CCCCCTTCTT CA~ACAGGAT ATCACGTGTC 244560
CCGCCCTACT TCTCGTTAGC TTAGTACCAC AATATGGTTT TTAGATACGG GATTATCACC 244620
~L~LLLGATT GTGCTTCCCA ACACATTCTC CTCACTATAT TGCTATCACT TACTGGCTCT 244680
-77. 1 47-
SU~STITUTE S~}EET (RULE 2~i)
CA 022l874l l997-l0-2l
W 096133276 PCTnUS96/0~320
TTCGCTTTCG CTCGCCGCTA CTGACGAAAT CTCGGTTGAT LlCllllCCT CGGGGTACTT 244740
AGA1~111~A GTTCTCCCGG TTTGCCTCAA CAAGCTATGA ATTCACTTGT TGATAGTAGA 244800
11~11~ATCT ACTGGGTTTC CCCATTCGGA TATCTTGGAT TAAACGCCTC TTATCGACTC 244860
ATCCAAGCTT TTCGCAGATT AGCACGTCCT TCTTCGCCTC TGATTGCCAA GGCATCCACC 244920
TTGTACGCTT AGTCACTTAA CTATACAACC TCAAATGTTT TCAATCACTT TACGTTTTCA 244980
CTTCAAAGTG CGGTCAATTT GATGCGTATT TTCATTCAAC TAAACACTTG ATTGCTTTTG 245040
TTCAATCAAG A~1111111AC AAAACAGGTT 11~LL1L1AG A~11LC~L1L TCA~1L~L~1 245100
CTTTCACTTT A~L~L111GC CTACTCAGAC 111~1~1CGA AAATCTCTTG TTTTCAGCTT 245160
GTTTCCAATT TTTTA~AGAA CAGTAAGACA ATCTAATAAA GTTATCTTTA ATTGGCGTCC 245220
CCACGGGGAT TCGAACCCCG GTTACCGCCG TGAAAGGGCG A1~1C~1AGG CCTCTAGACG 245280
ATGGGGACAT CAATTAAAGA TACTCTATTT 1~LL111ATC TTTTAACGtT TAL L 1 L L ~AA 245340
CGTTGCTTTC G~L1C~1111 TAA1~11~LC TACAACTATC AGCCAATCTG TGTGAGCACT 245400
CG~L~1~1~1 C~1~11~AGT AAGGAGGTGA TCCAACCGCA GGTTCCCCTA CGGTTACCTT 245460
GTTACGACTT CACCCCAGTC ATGAATCATA CC~1-G~LAAA CGCCCTCCAA AAGGTTAAGC 245520
TATCTACTTC TGGTACAACC CACTCCCATG GTGTGACGGG CG~-1~1~1AC AAGGCCCGGG 245580
AACGTATTCA CCGCGACATT CTGATTCGCG ATTACTAGCG ATTCCGACTT CATGGAGTCG 245640
AGTTGCAGAC TCCAATCCGG ACTTAGACGT ACTTTATGAG ATTCGCTCCA CCTCGCAGCT z45700
TCGCTTCCCT CTGTATACGC CATTGTAGCA C~1~L~1AGC CCTACTCGTA AGGGCCATGA 245760
TGACTTGACG TCATCCCCAC CTTCCTCCAG TTTATCACTG GCA~1~1C~1 TTGAGTTCCC 245820
GACCAAGTCG CTGGCAACAA AGGATAAGGG TTGCGCTCGT TGCGGGACTT AACCCAACAT 245880
TTCACAACAC GAGCTGACGA CAGCCATGCA GCACCTGTCT CTAAGTTCCC GAAGGCACAA 245940
GCTCATCTCT GAG~1~L1~1 TAGGATGTCA AGAGTAGGTA AG~L1~LLCG CGTTGCATCG 246000
AATTAAACCA CATGCTCCAC CGCTTGTGCG GGCCCCCGTC AATTCATTTG AGTTTTAACC 246060
TTGCGGCCGT ACTCCCCAGG CGGTCGATTT ATCACGTTAG CTACGGGCAC CAAGCTCTAA 246120
GCCCAATCCC CAAATCGACA GCGTTTACAG CGTGGACTAC CAGGGTATCT AA~Lc~L~l"l L 246180
GCTCCCCACG CTTTCGCACA TGAGCGTCAG TACATTCCCA AGGGGCTGCC TTCGCCTTCG 246240
GTATTCCTCC ACATCTCTAC GCATTTCACC GCTACACGTG GAATTCTACC CCTCCCTAAA 246300
GTACTCTAGT TACCCAGTCT GAAATGCAAT TCCTAGGTTA AGCCCAGGGC TTTCACACCT 246360
-77.148-
SUBS 111 UTE SHE~T (RULE 26~
-
CA 02218741 1997-10-21
W 096/33276 PCTnUS96/05320
CACTTA~ATA ACCGCCTGCG TGCCCTTTAC GCCCAGTTAT TCCGATTAAC GCTCGCACCC 246420
TCCGTATTAC CGCGGCTGCT GGCACGGAGT TAGCCGGTGC 'l 'l ~'l"l'~'l'~'l'A TTTAACGTCA 246480
ATTTGATGTA CTATTAACAC ATCAACCTTC CTCAATACCG AAAGAACTTT ACAACCCGAA 246540
GGC~11~11C ATTCACGCGG CATGGCTGCG TCAGGGTTCC CCCCATTGCG CAATATTCCC 246600
CACTGCTGCC 1CCC~1AGGA GTCTGGACCG 1~L~1~AGTT CCAGTGTGGC TGGTCATCCT 246660
CTCAGACCAG CTAGAGATCG CAGGCTTGGT AGGCATTTAC CCCACCAACT ACCTAATCCC 246720
ACTTGGGCTC ATCCTATGGC ATGCGGCCTC TCAGTCCCGC ACTTTCATCT TCCGATAATA 246780
CGCGGTATTA GCGACAGTTT CCC~LC~11A TCCCCCTCCA TAAGCCAGAT TCCCAAGCAT 246840
TACTCACCCG TCCGCCACTC GTCAGCAAGA AAGCAAGCTT 1~1C~LGCTA CCGTTCGACT 246900
TGCA1~1~11 AAGCCTGCCG CCAGCGTTCA ATCTGAGCCA TGATCAAACT CTTCAATTCA 246960
AGTTCAATCG CTCAATAAAC TGCTTAGCTA TAAATA~AAC ACTACTTAAA A~AGTAATGA 247020
TGAATTTTCA GTTAAGCACC TATTAAGACT TCAAAATTAA AAATAGTTTT A~AACAAGTC 247080
AATCAACAAG TGCCCACACA GA11~1~LGA TATATTGTTA AAGAGCAAAA AATAACGACG 247140
CACTTGGAAA CTTAAAAAAC TTCACAACAG TGC~1C~11G TGTGCGGTGC ATTATAGAGA 247200
TTTTCAAATC CCTTGCAAGT A~1L1111~1 AAAAATATTT A~AAAAATGA 'l ~ L L L'L~ATG 247260
GAAATATAAA CATTTTATTA AAAAGTGCGG TTAGAATAGT CA~ACTTTTA TTGCTATTAT 247320
TTCTTACGTA ATGAAACtTC TCCACCATTA AACATCTGAA TTTTATTGCC ACATAATACT 247380
TTTAAATAAC CACGTTCATC TATGCCTTGT TCAATACCTG AAATAACGCC TTGCTCAGTA 247440
AGCACATTTA TTTCACTATT TGAAAACGCA TTATATGATT GCCATGCTTG TTGAAATTCC 247500
TCATCAATAC CA1111~L1C A~AGATATTT AAACGTGTAT ATAhATGTTG TATAAGTTTG 247560
GGTAATAAAG L11~LCGCTC TACATCAGGA TCAATTTCAC ACACTTCCGC ATAAGGCTGA 247620
CTAATTTCTG L1L~LLLLGA CAACGACACA TTAATACCTA TGCCAATCAC TAAATTGAGC 247680
ATGCCATTTT TATGATTAGC AATTTCAACT AAAATGCCAC CTAACTTTCT TTCATCAAAC 247740
AAAATATCAT TTGGCCATTT CACTTGTACA TTTAGCACTT CCGCAATCGC CA~ACCGATG 247800
ACTA~ACTTA ACCCCTCAAT TGA1111LLA GGATCAAATG CCCAATA~AA ACTA~ACATG 247860
ATTTGCCCGG CAAAAGGCGA TAACCATTGG CGACCACGCC GACCTCGTCC TGCAGTTTGA 247920
TATTCAGCCA CACAAAGATC GC~L111LLL AATGAAAGAA TALLLL~LAG TATCCATTCA 247980 r
TTTGTAGAGG AAATAATCGG CTGATAATGG ATACTATAAG GA~AAAGTGC GGTTGAAATT 248040
-77. 1 49-
SUBSTITUTE S} tF:~T (RULE 2
CA 022l874l l997-l0-2l
W 096/33276 PCT~US96/05320
TGCTGAGGAT TTAATAAAGG AAGCATTGGC ACTAAGCGAT AATCTTGTCC ATCAACGAGA 248100
ATATCCAAAC CAATTTCACG TAAll~l"l'GA ATAl~llC~l CTAGATTTTT AGAAAATTTT 248160
TCCAATTCAG ACCGCACTTT CGGCTGACAA TCCGCTA~AT ATGTCAATAA CGTAAAATTC 248220
ATCATTCATT CCTTATGGCA AATAGTATGA A~ATCATAGC ATAAATCCTA A~ATTnnGTT 248280
TTCAAAATAA AGTGAAATCT GTATAATCTC GTCGCAATAT TTTTTAACTT CAACTTATTA 248340
GCGAGAATAT TGCAATGTCA TTACGCATTA AACAAGAnGC CCTTACTTTT GACGATGTTC 248400
TACTCGTCCC AGCTCACTCA ACTGTGCTTC CA~ATACTGC CAACCTTTCA ACTCAACTTA 248460
CTAAAGAAAT TcGTTTAAAT ATCCCAATGC TTTCAGCAGC AATGGaTACC GTAACTGA~A 248520
CCAAACTTGC GAl~l~lllA GCACAAGAAG GCGGTATTGG CTTTATTCAT AAAAATATGA 248580
CGATCGAACG CCAAGCAGAT CGCGTGCGTA AAGTA~AAAA ATTCGAAAGT GGTATCGTTT 248640
CTGAACCAGT AA~l~llllA CCAAATTTAA CGCTTGCCGA ACTTGCTGAA ATGGTGAAGA 248700
AAAACGGATT TGCGGGCTAC C~l~ll~lAG ATGGGGAAAA TAATTTAATC GGTATCATTA 24~760
CTGGCCGTGA TACACGTTTC GTAAAAGATT TAAGCAAAAC AGTTTCACAA GTAATGACGA 248820
A~AAAGAAGA CTTGGTGACC GTAAAAGAAG GGGCGAGTCG CGAAGAAATT TTGGaATTAA 248880
TGCATCAACA CC~l~ll~AA AAAGTATTAG TGGTTAATGA TAGTTTCAAA CTTAAAGGTA 248940
TGATTACCGT TAAAGACTTC CAAAAAGCAG AACA~AAACC AAATGCATGT AAAGATGAAT 249000
TCG~lC~lll ACGTGTCGGT GCGGCTGTAG GTGCAGGTGC TGGCAACGAA GAACGTATTG 249060
ATGCCTTAGT GAAAGCAGGC GTAGATGTAC TATTAATTGA 'l"l'~'L'l'~'l'~AC GGTCACTCAG 249120
AAGGCGTATT ACAACGCGTT CGTGAAACTC GTGCAAAATA TCCA~ATTTG CCTATCGTTG 249180
CAGGTAACGT AGCAACGGCT GAAGGCGCAA TTGCATTAGC AGACGCAGGT GCAAGTGCTG 249240
TAAAAGTAGG TATTGGTCCT GGTTCAATTT GTACAACTCG TATTGTAACT GGCGTAGGTG 249300
TTCCACAAAT TACCGCTATC GCAGATGCAG CTGCTGCATT AAAAGATCGT GGTATTCCTG 249360
TAATTGCTGA CGGTGGTATC CGTTTCTCTG GCGATATTGC AAAAGCTATC GCTGCTGGTG 249420
CAAGCTGTGT AATGGTTGGC TCGATGTTTG CGGGTACAGA AGAGGCtCCA GGTGAAATCG 249480
AACTTTATCA AGGTCGTGCA TTTA~ATCTT ACCGTGGTAT GGGCTCATTA GGTGCCATGG 249540
CGAAAGGCTC ATCAGACCGT TATTTCCAAT CGGATAACGC GGCAGATA~A CTCGTACCGG 249600
AAGGTATTGA AGGCCGTATT CCATATA~AG GTTACTTAAA AGAAATCATC CACCAACAAA 249660
TGGGTGGCTT AC~'1''1'L1"1'~'1' ATGGGCTTAA CGGGCTGTGC AACTATTGAT GAACTACGCA 249720
-77.150-
SU~S i 11 UTE ~EET tRULE 26)
CA 02218741 1997-10-21
W 096/33276 PCTrUS96/05320
CCAAAGCGGA A~LLl~llCGC ATTAGCGGTG CAGGCATTAA AGAAAGCCAC GTTCACGATG 249780
TTGCTATTAC TAAAGAAGCA CCTAACTATC GTATGGGCTA ATCTTTAAGG TGGGCTTTAG 249840
CCTGCCTTTT G~L~lllAAA GTGCGGTTGG tTTTTGCAAA GTTTTAAATA ATATGAACCG 249900
CTTACACTAT CAATAATAAG AGCATTATAA ATGACA~ATA TCCACTATCA CA~AATCCTA 249960
ALC~lC~ACT TTGGTTCACA ATACACTCAA CTGATTGCGC ~-LC~l~l~CG TGA~ATCGGT 250020
GTGTACTGCG AACTTTGGGC TTGGGATGTA ACCGAACAAn A~ATCCGTGA ATTTGCTCCC 250080
GAACTTTATC AAGGTCGTGC ATTTAAATCT TACCGTGGTA TGGGCTCATT AGGTGCCATG 250140
GCGAAAGGCT CATCAGACCG TTATTTCCAA TCGGATAACG CGGCAGATAA ACTCGTACCG 250200
GAAGGTATTG AAGGCCGTAT TCCATATAAA GGTTACTTAA AAGA~ATCAT CCACCAACAA 250260
ATGGGTGGCT TAC~-l-L~LlG TATGGGCTTA ACGGGCTGTG CAACTATTGA TGAACTACGC 250320
ACCAAAGCGG AALL-l~L-LCG CATTAGCGGT GCAGGCATTA AAGA~AGCCA CGTTCACGAT 250380
GTTGCTATTA CTA~AGAAGC ACCTAACTAT CGTATGGGCT AATCTTTAAG GTGGGCTTTA 250440
GCCTGCCTTT TG~-L~LLLAA AGTGCGGTTG ~L-L-L-LlGCAA AGTTTTA~AT AATATGAACC 250500
GCTTACACTA TCAATAATAA GAGCATTATA AATGACAAAT ATCCACTATC ACAAAATCCT 250560
AATCCTCGAC LL-l-G~-L-L~AC AATACACTCA ACTGATTGCG CGTCGTGTGC GTGAAATCGG 250620
TGTGTACTGC GAACTTTGGG CTTGGGATGT AACCGAACAA CAAATCCGTG AATTTGCTCC 250680
AACGGGTATC ALL~-L-L-L~LG GCA~-LC~LGA AAGCACAACT GAAGA~AATA GCC~1C~LGC 250740
ACCGGAATAT GTATTTAATG ~L~L~LACC AGTATTAGGC ATTTGCTATG GAATGCAAAC 250800
GATGGCGATG CAACTTGGCG GCTTAACCGA AAC~-L~-LGAT CACAGAGAGT TCGGCTATGC 250860
~L-LCC~-L-L-L~-L CTTGAAAATT CCACCGCACT TTTTGCAAAT CTTAACGATA ATTTAACCGC 250920
TTCTGAGCCA AAATTAGACG TTTGGATGAG CCACGGCGAT AAGGTAACGC GCTTACCAGA 250980
AAACTTCAAA GTAACTGGCA CAACGCTAAC CTGCCCAATT GCTGCGATGT CTGATGAAAG 251040
CCGTCGTTTC TACGGTGTGC AGTTCCACCC TGAAGTAACG CATACTAAAA AAGGCTTGGA 251100
ATTATTAACC AA~lLC~lAG TA~ACATCTG TGGTTGCGAA ACCA~ATGGA CAGCAGA~AA 251160
CATTATCGAA GATGCCGTTG CTCGCATTAA AGAGCAAGTG GGCGATGATG AAGTGATTTT 251220
AGGCTTATCT GGTGGTGTGG A~L~LL~-L~L GGTTGCATTA CTTTTACACC GTGCTATCGG 251280
CA~AAACTTA CACTGCGTAT TTGTGGATAA CGGTTTACTC CGCTTACACG AAGGCGACCA 251340
AGTCATGGAA ATGTTTGGCG ATAAATTCGG TTTAAACATC A~-LC~L~-Ll-G ATGCTGAAAG 251400
-77. 1 5 1 -
SU8STITUTE S}{EET ~RULE 26)
CA 022l874l l997-l0-2l
W 096/33276 PCTrUS96105320
~1C~1-11~11A GGTGAACTTG CAGGCGTATC~TGATCCTGA~ GCGAAACGTA AAATTATCGG 251460
TAAAGTGTTC GTGGATGTAT TCGATGATGA ATCGA~AAAA CTCACTAATG TGAAATGGTT 251520
GGCACAAGGT ACGATTTACC CTGACGTAAT CGAATCTGCA GCAAGCA~AA CTGGTAAAGC 251580
ACATGTGATT A~ATCACACC ACAACGTAGG TGGCTTACCA GACTATATGA AACTTGGTTT 251640
AGTTGAACCT TTACGTGAAT TATTTAAAGA TGAAGTACGT A~AATCGGTT TAGCATTAGG 251700
CTTACCAGCT GAAATGATCA ACCGCCACCC ATTCCCTGGC CCAGGCTTAG GTGTGCGTGT 25~760
ATTAGGCGAA GTGAAAAAAG AATACTGCGA TTTATTACGC CGTGCGGATG CGATCTTTAT 251820
CGAAGAATTA CGCAACAGCG ~11G~1ATGA AAAAACCAGC CAAGCCTTCA GCGTATTCTT 251880
ACCAGTGA~A TCTGTAGGTG TGATGGGCGA TGGCCGTA~A TACGATTGGG TTATTTCCCT 251940
ACGCGCGGTA GAAACAATCG ATTTTATGAC CGCACATTGG GCACATTTGC CTTATGATTT 252000
ATTAGGCA~A ~1~1~1AACC GTATCATCAA CGAAGTGAAT GGAATTTCCC GC~LC~1ATA 252060
CGACATCAGC GGAAAACCAC CCGCAACAAT CGAGTGGGAA TAAAAAATCA CTTTTTCAGA 252120
TA~111~1AA TTATTTCAGT AACTTTAATA AGTGCGGTTA ATTTTCACCG CA~11L~LLL 252180
LL~LL1AAAA GCCCTTCTAT GCCAATCACA ATGAGACTTA ACCAAATAGG CACATAAGTA 252240
AAATAGTCAC TTGTGGTTAT TTGATTATCT AGCACA~AGA CAGCTATTAA AAAAAGCAAT 252300
ATGGGTTCAA TATAACTCAA CACCGCA~AA ATACTAACTG GAA~LLL~LLG GCTTGATTTT 252360
AAGTTGGCTG AAAGCGAAAT CGCACTCACA ATACCAAGTG CTGGTAGCAA TAACCAATAA 252420
CGATATTCTT GCGTAACCAA AGAAAGCGTA TCGCTTTGAG AAAGAATATA AATAAAACAA 252480
GGAATCGAAA TTAAAATAAT ATCCAATGTA ALLC~L1~1A GAGCAGGGAT TTTCATCCAT 252540
TTACGGCTTA GATAATAAAA TGGATAAACC GTACA~ACCC ACAAGCTTGT CCATGAAAAA 252600
CTTTGAGTGT GCCATAATTC ATGTGCAACA CCGCAGCAGC CAGTAAAAGC GCGATTTTCT 252660
GAATA~ATGA TAAACGTTCT TTTAACCAAG CCCATCCTAA AACAGCCATA ATCAGCGGAA 252720
AAAGA~AATA TCCCATCGCA ATATTTATCC CTTCGCCATT TAGCGGTGCC CACATA~AGA 252780
GCCAGAATTG ACTTCCCGCA TCTAGTGTCC CCAGTAAAAA TA~AACCCAA CGCGTCCAAC 252840
TTTTTCCTAA AGTTGTCGTA ATAAGAGACA A~AGAGAGCG GCAACCAATA GTCGGAAATA 252900
GAATTA~AAG TAACCCAAAG ATCATGGTCA GCATACGCCA CGCAAAAACA TCCGTTCCGC 252960
TAAGTGGTTG GAGCCATATA CTA~ATAAAT ACAATATGCC AAATA~ACAT TGTGAAAAAA 253020
TGCACAATAA TATGCCTTGA GTGACTACTT TCATCTTGAA CTTCATTCAT CTCATCAATG 253080
-77.152-
SUBST~TUTE ~HEET ~RULE 2b~
CA 022l874l l997-l0-2l
W 096~3276 PCTAUS9610S320
TGATTATTAT AAAAGCCCAA GGCAATAAAA AATCTCAACT TTA~ llA TTGTGATAAT 253140
A11111~1~A ATAGTTACAT TTTTGAGA~A TTATCTTATG CA~ACACTGG ATAAATTAGA 253200
TCGTCATATT TTGAATGTAT TACAACAAGA TGCCATGATT CCGTTA~AAG AACTGTCAGA 253260
GAAAGTGAAT AGTTCCGTTG CAAC~l~l~A ACGACGTGTG CAATCATTAA CTGATTCAGG 253320
CATTATTACA A~ACGAGTTG CA~ll~lllC CCCA~AAGCC GTTGGGCGTA CGATTAGCGT 253380
Alll~l~ATG GTCGAAATGG ATAATCAACA TTCTTATTAT CAAGAGCAAT TTGAACGGAA 253440
AATGCGTCAA GAAGACGAAG TGGTGAGCTG TTACGA~ATC TCAGGGGACT ATGATTTTAT 253500
GTTGCTACTC CATGCA~AAG ATATGGA~AG CTATCACGCA TTCACACGCC GAGTATTGAC 253560
GGGTGAATTT CATGTAAGAA CTTATA~AAG TTTATTTGTA ATGAATTTTA CCAAAGCAGA 253620
TAGTGGAATT ATCTTATAGA ACAAGTGCGG TAAATTTTTA CCGCACTTTG TGTATGATTA 253680
GTTTAGTTTT GTC~llL~ll TTAAGAATAA ATACCCAAGT ATTGCCGA~A CCGTTGATCC 253740
AAGTAGAATA CCTAAACGAG A~AGAGTATT GACACTTTCC CCCGCATTAG CATCA~ACGC 253800
AAGGCTTGCT AAGAACATTG ACATCGTA~A ACCGATTCCA CATA~AACCG CAACAGCAAA 253860
AAlll~lllA AAATTAATTC CATCCGGTnA TTTAGCTAAT CCCAATTTAA CAGAAATATA 253920
ACTAAATCCA AATATACCGA ~lG~lllACC AATAATTaAA CCG-llGCTA TAGCCAATAA 253980
TAATGGCGAC GAAATCATAT TCACATCTAT GCCTGCA~AA CTCACACCAG CATTGGCAAA 254040
TGCGrAAAGT GGTAAAATAA CGA~AGATGA CCAAGAGGCT rAAATATGCT CGA~ATCATC 254100
TAATGGGCGT T~lC~lllll TACCTTTCAA TGGAATGCTA AAACCAATAA TAACGCCTGC 254160
TA~AGTAGCA TGCACACCAG ACTTTAATAC GGAAGCCCAT AAAATTGCAC CTACGACCAT 254220
ATAAGCGCAA AGTGCAGA~A CTCTGA~ACG ATTTAGTAAT ATCAGcACAA TAATTGCCAC 25~280
GGCAGAAAAA ATTAGTGCTT GCACACTCAA TCCGTGCGAG AAAAATAATG CAATAACAAC 254340
TATCGCACCG AGGTCATCAA TAATAGCAAG GGCAAGTA~A AATATTTTCA GTGGAAGTGG 254400
CA~ll~lllA CTCAATAACG CCATAATTCC CAGTGCAAAA GCAATGTCTG TTGCCATTGG 254460
AATTGCCCAG CCATTAGCTA AACTTGGATC ll~lllAGCG ATA~ACCAAT A~ACTACAGC 254520
CGGTATAACC ATTCCGCCAA TAGCTGCAAT AGCAGGGA~A ATAGCTTGTT GATAGGTAGA 254580
AAGCGCGCCT TCA~ATAATT ~'l''l"l''l"l"l'~AC TTCCATTCCC ACTAATACAA A~AACACCGC 254640
CATAAAACCA TCGTTAATCC AGTGAATTAA GGTTTTATTA ATTGAGA~AC TACCAATTTG 254700
TA~ACTTACA GGCA~ATTTA A~AAATCATT ATATTGGTTG CTTAACGGCG AATTAGCCAG 254760
-77.153-
SU85 11 i UTE ~ EET tRULE 2~i~
,
CA 02218741 l997-l0-2l
W 096133276 PCTrUS96/05320
CAACATCGCA ACAACAGCTG AAAAAAGCAA TAATATACCG CCAGCAGATT CTAATTTAAA 254820
AAAACGTTGG ATCAGTTTTA TCACATAAAC CCCTTTAAAA ATACATAGCA AAAAATTCAC 254880
AAAGGAAGCA TCCTAGCATA Ll-l--lC~AAGT TAAAGGAAAA AGTGCGGTAG ALll-l~-l-CGG 254940
GATTTTTAGC GAATTGTCGA TAAAATGCCA TATATTGTGA CAAAATTCAC ATTTTTAATT 255000
TTACACAATA GAGATTTTAT CTA~Lll~-lA GTAGAATGCG GACCTTTTAT TTTTAGAATC 255060
AAAAACTATG TTTTCACGCA AAGATATTAT ~-l-l-l--lAGGA ATGATGATCT TCGCCTTATT 255120
TTTAGGTGCG GGTAATATCA TTTTTCCGCC TATGGAAGGA TTTTCCTCAG GACAACATTG 255180
GACGAGTGCT TCCTTAGGCT ~L-l~-l-l-ll-AAC TGGC~Ll--l--l-A ATGCCATTTA TTACGCTTGT 255240
GGTGGTAGCG ATTTTAGGTC GTGGCGAAGA ACTTACTAAA GATTTACCAA AATGGGCTGG 255300
CACAGGTTTC ~-LC~-llATAC TTTATTTAAC CATTGGCTCT ACCTTTGCAA TGCCCCGCAT 255360
CACTAATGTT GCTTATGAAA TGGCGTGGTT GCCTTTAGGC TTAACAGAAA ATAATGCGAA 255420
~L~-llC~L-l-Ll GTATTCTCAC TCATTTTTAA CTTAATCGCG ATGGGCTTTA TGATTAGCCC 255480
AAATACGATC ATTTCAAGCG TGGGTAAATT TATGACACCA GCTTTATTAG TGTTACTTAT 255540
TGCTGTAGCA ATTACCGTAT TTATTTCGCC TTTATCTGAA ATTCAAGCGC CAAGTAATGC 255600
TTATGAAAAT AGCCATTCTT TATTAATCGG TTTAACTAGC GGCTATCAAA CGATGGATGT 255660
ACTTGCAGCC ATCGCTTTCG GTGGAATTGT CGCCCGAGCA TTATCAGCGA AAAATGTGAC 255720
AAAAACCAAA GATATTGTGA AATACACCAT TTCAGCAGGA ~Ll-l-~l-LL~AG TCATCTTACT 255780
TGCGGGTTTA TAL-l--Ll-l-CGC L-l--l-l-~-l-ATCT AGGCGCAACT AGTGCTGCAG TTGCAGAAGG 255840
GGCAACGAAT GGTGGACAAA L-l-l-l-~l-~-lCG TTATGTAAAT GTCTTATTCG GTTCAGCTGG 255900
GACTTGGATT ATGGCAGGTA TTALl-~L~-ll AGCGAGCTTA ACAACACTTG TTGGTGTAAC 255960
TAGCGCATCT GCTGATTATT TTTCAAAATT ~-L~L~-lGCGT ~L-L l L~'-L-l-ATC CATTCTGGGC 256020
CGCACTTTTT ACCGCAATGA CAATCACTGT TTCACAATAT GGTTTAACGG ATCTACTTCG 256080
CATAACGATC CCAGCCTTGT TATTAATTTA CCCAGTAGCC ATTGTGCTTG TTTTATTGCA 250-140
ATTCTTACGA AAAAAACTTC CATCAATAAA ATTTACATAC AATAGTACAT TGCTCGTTAC 256200
A~-L-L-L~11-1-L AGTTTATGTG ACAGCTTAAA TAACGTTAAA ATGTTACCAG AAAGCATCAA 256260
TTCATTATTG AAACACTTCC ~-L~-lLl-~ATC TGAAGGAATG GCTTGGTTGG TTCCGACTTT 256320
AGTAATGTTA GTTGCAAGCA TTTTTATTGG AAAAGCATTG CATAAAACCC ATTCTTAATC 256380
TCACAAAGTG TTTTATTTAT CAGCCCTGTG CCGTA~AACT CCGTCCTTCA GGGCGGAGAT 256440
-77. 1 54-
SUBSmUTE S~{EET tRULE 2~)
CA 022l874l l997-l0-2l
W 096/33276 PCTnUS96/OS320
ATAAGGCACA GGGCTGATAA ATTTCTAACC GCA~L~lllC AAAAATCAAA TTAATTTAAC 256500
AGGTACTTTT ACGACTAATT TTTTAATTTT ~ CCATTCACTA CACAGCAAGG 256560
CTTGTGCGGT TCATAAGGAT AGAATACAGC GAACATTTTT GGTTTCATTG TGACGGTGAA 256620
TTTATCATCA ATATCTGCAC A~AGTTGATA ATCATCCGCT ~LC~ll~lAAT CTTCATACTT 256680
AGATAAATTC GGATAGGTTG CACCCACTTC GATATTTTCC GTGCCACGAA TAAGCACTTG 256740
TACATCTAAG TATTCATGAT GTAATTCTGC LLllllACTG ~LlG~ll~l~ CA~LlL~l~G 256800
TTCCATTACG TTCATATA~A TTTGATCGTT AATATCATGG CGACCATTCT CTAACGCATT 256860
CAAATCTAAC GTATTTA~AT AATCACATAC TTCAGCAATC ACTTTTGGTA AACCAACTTT 256920
AAAATTTGGG l"lG~l"lA~AC TGCTAATAAT CATAGAATTT TCCTTATAGT GGATAAAAGT 256980
TACACTATGA TACCAAGTCA GTTA~ATGAA ATAAAGCCAC CGATTACATC AL~l~l~llG 257040
ATTAATCCAA TTAGCTCTTG TAGTACCGAG TGGAAGAGAG CAAATATCTT GCCAACTTAT 257100
TGACGCATAA AGTCTA~ACA ATGA~ATTAC GGCATTAACA CAAGCATTTT CAGAAAAAAT 257160
ATTATCAAGA GGCTTATGAG GACCTGTA~A ATGAAAAATA TTAGGAGAAG TATCAAGAGT 257220
ATTAATTGAA ATCATATGAA CTAATTGTAA TGTTGAATAG CGTTTAGCAA AATAAAGTTG 257280
AAGATCATTT TGCCACGATT CAGAaATATC TCCTGTATGT A~AATA~AAA CAGAGAGATT 257340
TTCATTGTGC ATTAATA~AG ATTTCAGTGT AATTTCTACA TTAAGGAAGA TAATTAGCAT 257400
CACTAGCCAT CATTACATTA TATTTCATAT A~AAGAACCT A~TTTCAGAG AGrACAATCA 257460
ATTTTTAGGA GGAAAATACT GTCGAAACAA TGATAATTAA GTTGGTAATG TGAAATAAAG 257520
TTAGCCATTA AAGCCA~ACA LC~l~LATA~ TGCACGGGCT TTALll-l-~lA CATTAGCGTG 257580
CGGCTATCAA AAGAAATTTT TAAACGCCCA AAGTGCGGTC ALLL~L~L~LC~A AAGATTTCTT 257640
TTGCTAGTCG CAATCTGGGA AATAAGGCAT L~LLLllAAT ATA~ATTTTA AGGAAAACAT 257700
TGTGAATCCA ATTGTTAAAC AATTTA~ATA CGGTCAGCAT ACCGTTACTC TAGAAACTGG 257760
TGCGATTGCA CGTCAAGCAA CGGCTGCGGT TATGGCAAGC ATGGACGATA CCACGGTATT 257820
CGTGACTGTT GTTGCTAAAA AAGATGTGAA AGAAGGTCAA GA~LL~llCC CATTAACCGT 257880
AAACTACCAA GAGCGTACTT ATGCGGCGGG TAAAATCCCG GGTGGTTTCT TCAAACGTGA 257940
AGGTCGTCCA TCTGAAGGCG AAACTTTAAT TGCACGTTTA ATTGACCGTC CAATTCGTCC 258000
ATTATTCCCA GAAGGTTTCT TCAATGA~AT CCAAGTTGTG GCAACTGTGG ~LLL~L~lAAA 258060
CCCACAAATC AGCCCAGACT TAGTGGCAAT GATCGGTGCT TCTGCAGCAT TAACCTTATC 258120
-77.155-
SUBS i I i UTE SHE~T (RULE 26
CA 02218741 1997-10-21
W 096t33276 PCT~US96105320
TGGTGTGCCT TTCAACGGCC CTATCGGTGC AGCGCGTGTT GGTTTTATCG ACAACCAATT 258180
CGTATTAAAC CCAACTATGG CAGAACA~AA ACAAAGCCGT TTGGACTTAG TGGTTGCAGG 258240
CACTGACAAA GCCGTATTAA TGGTTGAATC TGAAGCTGAT ATTTTAACTG AAGAACAAAT 258300
GTTAGCAGCG GTCGTATTCG GTCATCAACA ACAACAAGTT GTAGTTGAAG CAATCAAAGA 258360
ATTTGCAAAA GAAGCGGGCA AACCACGTTG GGATTGGGTT GCACCACAAC CAAACACAGA 258420
TTTAATCAAC AAAGTA~AAG CGATTGCTGA AGCACGTTTA GGCGATGCAT ACCGCATTAC 253480
TGAAAAACAA TTACGTTACG AACAGATCGA TGCGATTAAA GCGGATGTAA yTGCGCAAAT 258540
CACAGCTGAA GATGAAGAAA yCAGCGAAGG TAAAATCGTG GATATTTTCA CCGCACTTGA 258600
AAGCCAAATC GTTC~lG~lC GTATCATTGC AGGCGAACCA CGTATTGACG GTCGTACCGT 258660
TGATACTGTT CGTGCATTAG ATATTTGCAC lG~l~lATTA CCACGTACTC ACGGTTCTGC 258720
GATTTTTACT CGTGGCGAAA CGCAAGCATT AGCTGTTGCA ACCTTAGGTA CCGAACGTGA 258780
TGCACAAATC ATTGATGAAT TAACGGGTGA ACGTCAAGAT CA~ll~llAT TCCATTATAA 258840
TTTCCCTCCA TAll~l~lAG GCGAAACAGG TATGATCGGC TCGCCAAAAC GTCGTGAGAT 258900
CGGTCACGGT CGTTTAGCAA AACGTGGTGT AGCGGCTGTT ATGCCAAGCC TTGCAGAATT 258960
CCCGTATGTT GTGCGTGTAG TATCTGAAAT CACTGAATCT AACGGTTCTT CTTCTATGGC 259020
~ ~lATGT GGTGCGTCTT TAGCATTAAT GGATGCGGGC GTTCCAATCA AAGCTGCTGT 259080
TGCAGGTATC GCAATGGGCT TAGTGAAAGA AGAAGAAAAA TTTGTGGTGC TTTCAGATAT 259140
TTTAGGCGAT GAAGACCATT TAGGCGATAT GGACTTTAAA GTGGCTGGTA CACGTGAAGG 259200
TGTAACCGCC CTTCAAATGG ACATCAAAAT TGAAGGTATC ACCCCTGAAA TTATGCAAAT 259260
TGCATTAAAC CAAGCGAAAA GTGCACGTAT GCACATTCTT GGTGTAATGG AACAAGCAAT 259320
TCCTGCTCCA CGTGCTGATA lll~l~ACTA CGCACCGCGC ATCTATACAA TGAAAATCGA 259380
TCCTAAGAAA ATCAAAGATG TGATTGGTAA AGGTGGTGCA ACAATCCGTT CACTAACTGA 259440
AGAAACTGGT ACATCAATTG ACATTGATGA CGATGGTACA GTGAAAATTG CCGCAGTAGA 259500
CAGCAATGCA GCGAAAAACG TAATGGGACG TATTGAAGAA ATCGTTGCAG AAGTTGAAGC 259560
TGGCGTAATT TACAAAGGTA AAGTCACTCG TCTTGCTGAT TTTGGTGCAT TCGTCGCAAT 259620
CGTTGGAAAT AAAGAAGGTT TAGTTCATAT TTCTCAAATT GCTGAAGAGC GTGTAGA~AA 259680
AGTTAGCGAT TACCTTCAAG TGGGTCAAGA AGTA~ACGTA AAA~ll~llG AAATCGATCG 259740
TCAAGGTCGT ATTCGTTTAA CAATGAAAGA CTTGGCTCCA A~ACAAGAAA CTGAAATTAA 259800
-77.156-
SUBSmUTE ~{~EET tRULE 26)
CA 02218741 1997-10-21
W 096133276 PCTrUS96/05320
CCAAGAAGAT TCTGTCGAAG AACAGGAATA ATCTTGGAAT ATAGAATCAA AACTTGGTAG 259860
CATTCGCTGC CAA~11L1~1 1~11L1CCAA CTTTTAGGCA TAAAGAAAGC AAATGCGGTG 25g920
TTTTCGCTTA TCTCGCCATT TTATAGTCTA TTTATTTAGC TTATGTGCGA TCTTACTCCT 259980
TGCTGGCTGT GTTCAGTCTA GGGGCGGTTT '1~1~1~1AAA AATCATGTCG TGTTGGCTGA 260040
ACAAAACCCG AATACTCACT TTGAACAAGA AGTGATGATC GTGCGATTAA GCCAAGTACT 260100
ACTGGTTGGA AAAATGAGTA ATGAAGAACG CGCATCGCTA CATTTTGAAC GTGGCGTACT 260160
CTATGATTCT CTTGGATTAT GGGGACTTGC TCGTTATGAT CTTACTCAAG CCCTTGCATT 260220
ACAGCCGAAA ATGGCATCTG TGTACAATTA CTTAGGGCTT TATTTATTGC TTGAAGAAGA 260280
TTACGACGGC GCATTGGATG CTTTCAATAC G~L~111~AA TTAGATTCAG GTTATGACTA 260 40
TACCCACCTT AATCGTGGTT TA~ATTTTTA TTATGTAGGG CGCTACCATC TTGCTCAGCA 260400
AGA11L~11A CAGTTCTACC AAGCCGATAA AAAAGATCCC TA'1C~1~1~1 TATGGCTATA 260460
TTTGAACGAA CAAAAATTAA AACCACAAGA AGCCCAAACA AAC~11~11G AACGAGCAAA 260520
AGGGCTATCA GAGGACTTCT GGGGTACACA TA1C~11~AA TATTACTTAG GACACATCTC 260580
TGTAGAAGAA TTGCAACAAC GTGCAAGTGA ATTTGCCGAA AATTCACAAC AATATGCTGA 260640
AATTCTCACA GAAACCTATT TTTATCTAGC AAAACAAAAA CTCAATGTAG GGCTAGTAGA 260700
TGAAGCAGCA GCTTTATTTA AACTAGCTAT GGCAAATCAG GTTTATAACT TTGTTGAGTA 260760
1C~1111GCC GC~111~AAC TCATGAAATT AAAACCGGTT CAAACAGAAG ACGAAAAAGA 260820
AGAGAAAAGT GCGGTAACAA AAGCGATTGT TTTCTAAAAA TCAATCCAAA ACTTACCGCT 260880
CTTTGCAGTA GAACGAATAG AAAAATTCAT TCGCTCTGCT CAACTTAATA AACCGAAGGC 260940
~1~111~AGC 111C~L1ATT TATATTCGAG TATTTTAATG ACTGACAAAA TTACTTTCAA 261000
TGACTTAGGC TTACCTGAGT TCATCTTAAA AG~1~111~L GACTTAGGTT TTGAAACACC 261060
TTCTCCAATT CAACAATCTT GTATCCCGCA TTTGCTCAAT GGCAATGATG TGCTAGGTAT 261120
GGCACAAACA GGTAGTGGTA AAACCGCTGC CTTTGCACTG CCTTTACTCG CGCAAATTGA 261180
TCCAAGTGAA AAACATCCAC AAATGTTAGT AATGGCACCT ACACGCGAAC TTGCTATTCA 261240
AGTTGCCGAT GCGTGCGAAC TA111~11AA ATATGCACAG GGCACTCGCA TTGTTACCTT 261300
ATATGGTGGC CAACGTTATG ACATCCAACT TCGTGCATTA AAACAAGGCG CACAAGTGGT 261360
TGTGGGTACA CCAGGCCGTA 11~L1~ACCA TA11C~1CGC GGAACATTAA AT~lll~l~A 261420
A~11C~1111 ATCGTATTAG ATGAAGCCGA TGA~ATGCTA CGCATGGGTT TCATTGATGA 261480
-77.157-
SUBS 111 UTE S~{EET tRULE 2~)
. CA 02218741 1997-10-21
, . . .
DEMANDES OU ~3R~VETS VOLUMINEI~X
LA PRÉ~;~3YTE PARTIE DE C~ E DEMANDE OU CE BREVET
COMPRE~lD PLUS D'UN TOME.
CECI EST LE TC~ME ¦ DE S
NO~E: Pour les tomes additiorlels, veuillez c~ntac~er le 8~reau canadi~n des
brevets
~2J~7~1
JUMBO APPLICATIO~S/PATENTS - .
THtS SECTION OF THE APPLICATIONJPATENT CONTAINS MORE
THAN ONE VOLUME
T~IS ~S VOLUME f / OF 5_~
.
NO~E: For addibcnal ~ srnes-pleas~ c~ntac~~the Canadian PatPnt Off~ca
