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Patent 2316282 Summary

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(12) Patent Application: (11) CA 2316282
(54) English Title: REGULATORY DNA SEQUENCES OF THE HUMAN CATALYTIC TELOMERASE SUB-UNIT GENE, DIAGNOSTIC AND THERAPEUTIC USE THEREOF
(54) French Title: SEQUENCES D'ADN REGULATRICES DU GENE DE LA SOUS-UNITE TELOMERASE CATALYTIQUE HUMAINE ET LEUR UTILISATION A DES FINS DIAGNOSTIQUES ET THERAPEUTIQUES
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C12N 15/54 (2006.01)
  • A01K 67/027 (2006.01)
  • C12N 9/12 (2006.01)
  • C12N 15/11 (2006.01)
  • C12N 15/85 (2006.01)
  • C12Q 1/68 (2006.01)
  • A61K 38/00 (2006.01)
(72) Inventors :
  • HAGEN, GUSTAV (Germany)
  • WICK, MARESA (Germany)
  • ZUBOV, DMITRY (Germany)
(73) Owners :
  • BAYER AKTIENGESELLSCHAFT (Germany)
(71) Applicants :
  • BAYER AKTIENGESELLSCHAFT (Germany)
(74) Agent: FETHERSTONHAUGH & CO.
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 1998-12-22
(87) Open to Public Inspection: 1999-07-08
Examination requested: 2003-10-15
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/EP1998/008216
(87) International Publication Number: WO1999/033998
(85) National Entry: 2000-06-21

(30) Application Priority Data:
Application No. Country/Territory Date
197 57 984.1 Germany 1997-12-24

Abstracts

English Abstract




The present invention relates to regulatory DNA sequences containing promotor
sequences, in addition to intervening sequences, for the human catalytic
telomerase sub-unit gene. The invention also relates to the use of said DNA
sequences for pharmaceutical, diagnostic and therapeutic purposes, especially
in the treatment of cancer and ageing.


French Abstract

L'invention concerne des séquences d'ADN régulatrices, contenant des séquences promoteurs, ainsi que des séquences interposées, pour le gène de la sous-unité télomérase catalytique humaine. L'invention concerne en outre l'utilisation de ces séquences d'ADN à des fins pharmaceutiques, diagnostiques et thérapeutiques, avant tout pour traiter le cancer et le vieillissement.

Claims

Note: Claims are shown in the official language in which they were submitted.





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Claims

1. Regulatory DNA sequences for the gene for the human catalytic telomerase
subunit.

2. DNA sequences according to Claim 1, characterized in that the sequences are
intron sequences in accordance with SEQ ID NO 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19 and/or 20 or fragments of these sequences which
have a regulatory effect.

3. DNA sequences according to Claim 1, characterized in that the sequences are
the 5'-flanking regulatory DNA sequence for the gene for the human catalytic
telomerase subunit as depicted in Fig. 10 (SEQ ID NO 3), or fragments of this
DNA sequence which have a regulatory effect.

4. Recombinant construct which contains a DNA sequence according to one of
Claims 1 to 3.

5. Recombinant construct according to Claim 4, characterized in that it
additionally contains one or more DNA sequences which encode polypeptides
or proteins.

6. Vector which contains a recombinant construct according to Claim 4 or 5.

7. Use of recombinant constructs or vectors according to one of Claims 4 to 6
for preparing medicaments.

8. Recombinant host cells which harbour recombinant constructs or vectors
according to one of Claims 4 to 6.




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9. Process for identifying substances which affect the promoter activity,
silencer
activity or enhancer activity of the human catalytic telomerase subunit,
comprising the following steps:
A. adding a candidate substance to a host cell which harbours DNA
sequences according to one of Claims 1 to 3, which sequences are
functionally linked to a reporter gene, and
B. measuring the effect of the substance on expression of the reporter
gene.

10. Process for identifying factors which bind specifically to the DNA
according
to one of Claims 1 to 3, or to fragments thereof, characterized in that an
expression cDNA library is screened using a DNA sequence according to one
of Claims 1 to 3, or subfragments of widely differing length, as the probe.

11. Transgenic animals which harbour recombinant constructs or vectors
according to Claims 4 to 6.

12. Process for detecting telomerase-associated conditions in a patient,
comprising the following steps:
A. incubating a recombinant construct or vector according to Claims 4 to
6, which additionally contains a reporter gene, with body fluids or cell
samples,
B. detecting the activity of the reporter gene in order to obtain a
diagnostic value, and



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C. comparing the diagnostic value with standard values for the reporter
gene construct in standardized normal cells or body fluids of the same
type as the test sample.

Description

Note: Descriptions are shown in the official language in which they were submitted.



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Regulatory DNA seQUences of the gene for the human catalytic tetomerase
subunit, and their dia nostic and therapeutic use
Structure and function of the chromosome ends
The genetic material of eukaryotic cells is distributed on linear chromosomes.
The
ends of hereditary units are termed telomeres, derived from the Greek words
telos
(end) and meros (part, segment). Most telomeres consist of repeats of short
sequences
which are mainly composed of thymine and guanine (Zakian, 1995). In all the
vertebrates which have so far been investigated, the telomeres consist of the
sequence
TTAGGG (Meyne er al., 1989).
The telomeres have a variety of important functions. They prevent the fusion
of
chromosomes (McClintock, 1941) and thus the formation of dicentric hereditary
1 ~ units. Such chromosomes having two centromeres can lead to the development
of
cancer due to loss of heterozygosis or duplication, or loss of genes.
In addition, telomeres serve the purpose of distinguishing intact hereditary
units from
damaged hereditary units. Thus, yeast cells ceased their cell division when
they
contained a chromosome without a telomere (Sandell and Zakian. 1993).
Telomeres fulfil another important task in association with the replication of
eukaryotic cell DNA. In contrast to the circular genomes of prokaryotes, the
linear
chromosomes of eukaryotes cannot be completely replicated by the DNA
polymerase
complex. RNA primers are required to initiate DNA replication. After
elimination of
the RNA primers, extension of the Okazaki fragments and subsequent ligation,
the
newly synthesized DNA strand lacks the ~' end since the R\A primer cannot be
replaced by DNA at that point. Without special protective mechanisms, the
chromosomes would therefur~;: shrink with each cell division ("end-replication
problem"; Harley Et al.. l~'~t)). The non-coding telomere sequences presumably
constitute a buffer-zone for preventin~l the loss of genes (Sandell and
Zakian, 1993).


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In addition to this, telomeres also play an import role in regulating cell
ageing
(Olovnikov, 1973). Human somatic cells exhibit a limited capacity for
replication in
culture; after a certain period of time, they become senescent. In this state,
the cells
no longer divide even after having been stimulated with growth factors;
however,
S they do not die and remain metabolically active (Goldstein, 1990). Various
observations support the hypothesis that a cell determines how many more times
it
can divide on the basis of the length of its telomeres (Allsopp et al., 1992).
In summary, the telomeres consequently possess key functions in the ageing of
cells,
and in stabilizing the genetic material and preventing cancer.
The enzyme telomerase synthesizes the telomeres
As described above, organisms which possess linear chromosomes can only
replicate
1 ~ their genome incompletely in the absence of a special protective
mechanism. Most
eukaryotes use a special enzyme, i.e. telomerase, for regenerating the
telomere
sequences. Telomerase is expressed constitutively in the single-cell organisms
which
have so far been investigated. On the other hand, telomerase activity has only
been
measured in humans in germ cells and tumour cells, whereas neighbouring
somatic
tissue did not contain any telomerase (Kim et al., 1994).
Telomerase can also be designated functionally as terminal telomere
transferase,
which is located in the cell nucleus as a multiprotein complex. While the RNA
moiety of human telomerase has been known for a relatively long period of time
(Feng et al., 1995), the catalytic subunit of this enzyme group was recently
identified
in a variety of orylanisms (Lingmer et al., 1997; cf. our application PCT
EP/98/03468
which is likewise pending). These catalytic subunits of telomerase are
strikingly
homolo~~ous both among themselves and in relation to all previously known
reverse
transcnptases.
WO 98; 1459? also describes nucleic acid and amino acid sequences of the
catalytic
telomeras~ subunit


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Activation of telomerase in human tumours
It was originally only possible to demonstrate telomerase activity in humans
in germ
line cells and not in normal, somatic cells (Hastie et al., 1990; Kim et al.,
1994).
Following the development of a more sensitive detection method (Kim et al.,
1994),
a low telomerase activity was also detected in hematopoietic cells (Broccoli
et al.,
1995; Counter et al., 1995; Hiyama et al., 1995). It is true, however, that
these cells
nevertheless exhibited a reduction in the telomeres (Vaziri et al., 1994;
Counter et
al., 1995). It has still not been resolved whether the quantity of enzyme in
these cells
is not sufficient for compensating the telomere loss or whether the telomerase
activity
which is measured stems from a subpopulation, e.g. incompletely differentiated
CD34+38+ precursor cells (Hiyama et al., 1995). In order to resolve this, it
would be
necessary to detect telomerase activity in a single cell.
Interestingly, however, significant telomerase activity was detected in a
large number
of the tumour tissues which had thus far been tested (1734/2031, 85%; Shay,
1997),
whereas no activity was found in normal somatic tissue ( 1 / 196, < 1 %, Shay,
1997). In
addition various investigations have shown that the telomeres still shrank in
senescent cells which were transformed with viral oncoproteins and it was only
possible to detect telomerase in the subpopulation which survived the growth
crisis
(Counter et al., 1992). The telomeres were also stable in these immortalized
cells.
(Counter et al., 1992). Similar findings from investigations in mice (Blasco
et al.,
1996) support the assumption that reactivation of the telomerase is a late
event in
tumorigenesis.
Based on these results, a "telomerase hypothesis" was developed which links
the loss
of telomere sequences and cell ageing with telomerase activity and the
development
of cancer. In long-lived species such as humans, the shrinkin~T of the
telomeres can be
regarded as being a mechanism for suppressing tumours. Differentiated cells
which
do not contain any telomerase cease their cell division at a particular
telomere length.
If such n cell mutates, it can curly form a tumour if the cell can extend its
telomeres.

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Otherwise, the cell would continue to lose telomere sequences until its
chromosomes
became unstable and it was finally destroyed. Telomerase reactivation is
presumably
the main mechanism used by tumour cells to stabilize their telomeres.
S It follows from these observations and considerations that it should be
possible to
treat tumours by inhibiting the telomerase. Conventional cancer therapies
using
cytostatic agents or short-wave radiation damage all the dividing cells in the
body in
addition to the tumour cells. However, since only germ line cells, apart from
tumour
cells, contain significant telomerase activity, telomerase inhibitors would
attack the
tumour cells more specifically and consequently elicit fewer undesirable side
effects.
Telomerase activity has been detected in all the tumour tissues which have so
far
been tested, which means that these therapeutic agents could be employed
against all
types of cancer. The effect of telomerase inhibitors would then set in when
the
telomeres of the cells had shortened to such an extent that the genome became
unstable. Since tumour cells usually possess telomeres which are shorter than
those
of normal somatic cells, cancer cells would be the first to be eliminated by
the
telomerase inhibitors. By contrast, cells possessing long telomeres, such as
the germ
cells, would only be damaged at a much later date. Telomerase inhibitors
consequently represent a potential way forward in the treatment of cancer.
It becomes possible to obtain unambiguous answers to the question of the
nature and
points of attack of physiological telomerase inhibitors once the manner in
which
expression of the telomerase gene is regulated has also been identified.
Regulation of gene expression in eukaryotes
There are a large number of points in eukaryotic gene expression, i.e. the
cellular
flow of information from the DNA to the protein by way of the RNA, at which
regulatory mechanisms can exert an effect. Examples of individual control
;reps are
gene amplification, the recombination of gene loci, chromatin structure, DNA
methylation, transcription, post-transcriptional modifications of mRNA. mRNA
transport, translation and post-translational modifications of proteins.
Studio; which


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have been earned out to date indicate that control at the level of
transcription
initiation is of the greatest importance (Latchman, 1991 ).
A region which is responsible for regulating transcription, and which is
designated
S the promoter region, is located directly upstream of the transcription start
of a gene
which is transcribed by RNA polymerise II. Comparison of the nucleotide
sequences
of promoter regions from a large number of known genes shows that particular
sequence motifs occur regularly in this region. These elements include, inter
alia, the
TATA box, the CCAAT box and the GC box, which elements are recognized by
specific proteins. The TATA box, which is located about 30 nucleotides
upstream of
the transcription start, is, for example, recognized by the TFIID subunit TBP
("TATA
box-binding protein"), whereas particular GC-rich sequence segments are
specifically
bound by the transcription factor Sp 1 ("specificity protein 1 ").
1 S The promoter can be functionally subdivided into a regulatory segment and
a
constitutive segment (Latchman, 1991 ). The constitutive control region
comprises the
so-called core promoter which enables transcription to be initiated correctly.
This
promoter contains the sequence elements which are described as UPE's (upstream
promoter elements) which are necessary for efficient transcription. The
regulatory
control segments, which can be interlaced with the UPE's, possess sequence
elements
which can be involved in the signal-dependent regulation of transcription by
hormones, growth factors, etc. They impart tissue-specific or cell-specific
promoter
properties.
DNA segments which are able to exert an influence on gene expression over
relatively large distances are a characteristic feature of eukaryotic genes.
These
elements can be located upstream or downstream of a transcription unit, or
within the
unit, and can perform their tunction independently of their orientation. These
sequence segments may reinforce (enhancers) or attenuate (silencers) promoter
activity. In a similar way to the pronu>ter regions, enhancers and silencers
also
accommodate several binding sites for transcription factors.


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The invention relates to the DNA sequences from the 5'-flanking region of the
gene
for the catalytically active human telomerase subunit and intron sequences for
this
gene.
The invention particularly relates to the 5'-flanking regulatory DNA sequence
which
contains the promoter DNA sequence for the gene for the human catalytic
telomerase
subunit, as depicted in Fig. 10 (SEQ ID NO 3).
The invention furthermore relates to part regions of the 5'-flanking
regulatory DNA
sequence, as depicted in Fig. 4 (SEQ ID NO 1 ), which has a regulatory effect.
Intron sequences for the gene for the human catalytic telomerase subunit, in
particular those sequences which have a regulatory effect, are also part of
the subject-
matter of the present invention. The intron sequences according to the
invention are
described in detail in the context of Example 5 (cf. SEQ ID NO 4, 5, 6, 7, 8,
9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19 and 20).
The invention furthermore relates to a recombinant construct which comprises
the
DNA sequences according to the invention, in particular the 5'-flanking DNA
sequence of the gene for the human catalytic telomerase subunit, or part
regions
thereof.
Preference is given to recombinant constructs which, in addition to the DNA
sequences according to the invention, in particular the 5'-flanking DNA
sequence of
the gene for the human catalytic telomerase subunit, or part regions thereof,
also
contain one or more additional DNA sequences which encode polypeptides or
proteins.
According to a particularly preferred embodiment, these additional DNA
sequences
encode antineoplastic proteins_


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Particular preference is given to those antineoplastic proteins which inhibit
angiogenesis directly or indirectly. Examples of these proteins are:
Plasminogen activator inhibitor (PAI-1 ), PAI-2, PAI-3, angiostatin,
endostatin,
platelet factor 4, TIMP-1, TIMP-2, TIMP-3 and leukaemia inhibitory factor
(LIF).
Antineoplastic proteins which have a direct or indirect cytostatic effect on
tumours
are likewise particularly preferred. These proteins include, in particular:
perform, granzyme, IL-2, IL-4, IL-12, interferons, such as IFN-a, IFN-13 and
IFN-y, TNF, TNF-a, TNF-13, oncostatin M; tumour suppressor genes, such as p53,
retinoblastoma.
Particular preference is furthermore given to antineoplastic proteins which,
where
appropriate in addition to their antineoplastic effect, stimulate
inflammations and
thereby contribute to the elimination of tumour cells. Examples of these
proteins are:
RANTES, monocyte chemotactic and activating factor (MCAF), IL-8, macrophage
inflammatory protein (MIP-la,-f3), neutrophil activating protein-2 (NAP-2), IL-
3, IL-
5, human leukaemia inhibitory factor (LIF), IL-7, IL-11, IL-13, GM-CSF, G-CSF
and
M-CSF.
Particular preference is furthermore given to antineoplastic proteins which,
due to
their action as enzymes, are able to convert precursors of an antineoplastic
active
2~ compound into an antineoplastic active compound. Examples of these enzymes
are:
herpes simplex virus thymidine kinase, varicella zoster virus thymidine
kinase,
bacterial nitroreductase, bacterial f3-glucuronidase, plant f~-glucuronidase
from Secale
cer-eale, human glucuronidase, human carboxypeptidase, bacterial
carboxypeptidase,
s0 bacterial fl-lactamase, bacteria( cytosine deaminidase, human catalase
and/or
phosphatase, human alkaline phosphatas~, type ~ acid phosphatase, human


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lysooxidase, human acid D-aminooxidase, human glutathione peroxidase, human
eosinophil peroxidase and human thyroid peroxidase.
The abovementioned recombinant constructs can also contain DNA sequences which
encode factor VIII or factor IX, or part fragments thereof. These DNA
sequences also
include other blood clotting factors.
The abovementioned recombinant constructs can also contain DNA sequences which
encode a reporter protein. Examples of these reporter proteins are:
Chloramphenicol acetyl transferase (CAT), glow-worm luciferase (LUC), 13-galac-

tosidase (f3-Gal), secreted alkaline phosphatase (SEAP), human growth hormone
(hGH), 13-glucuronidase (GUS), green-fluorescing protein (GFP), and all the
variants
derived therefrom, aquarin and obelin.
Recombinant constructs according to the invention can also contain DNA which
encodes the human catalytic telomerase subunit and its variants and fragments
in the
antisense orientation. Where appropriate, these constructs can also contain
other
protein subunits of the human telomerase and the telomerase RNA component in
the
antisense orientation.
The recombinant constructs can, in addition to the DNA which encodes the human
catalytic telomerase subunit, and its variants and fragments, also contain
other
protein subunits of the human telomerase and the telomerase RNA component.
2~
The invention furthermore relates to a vector which contains the
abovementioned
DNA sequences according to the invention, in particular the 5'-Clanking DNA
sequences and also one or more of the other DNA sequences mentioned above.
The preferred vector for these constructs is a virus, for example a
retrovirus, an
adenovirus, an adeno-associated virus, a herpes simplex virus, a vaccina
virus, a
lentiviral virus, a Sindbis virus and a Semliki forest virus.


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Preference is also given to using plasmids as vectors.
The invention furthermore relates to pharmaceutical preparations which
comprise
recombinant constructs or vectors according to the invention; for example a
preparation in a colloidal dispersion system.
Examples of suitable colloidal dispersion systems are liposomes or polylysine
ligands.
The preparations of the constructs or vectors according to the invention in
colloidal
dispersion systems can be supplemented with a ligand which binds to the
membrane
structures of tumour cells. Such a ligand can, for example, be attached to the
construct or the vector or else be a component of the liposome structure.
l~
Suitable ligands are, in particular, polyclonal or monoclonal antibodies, or
antibody
fragments thereof, which bind, by their variable domains, to the membrane
structures
of tumour cells, or substances carrying mannose terminally, cytokines or
growth
factors, or fragments or part sequences thereof, which bind to receptors on
tumour
cells.
Examples of corresponding membrane structures are receptors for a cytokine or
a
growth factor, such as IL-l, EGF, PDGF, VEGF, TGF 13, insulin or insulin-like
growth factor (ILGF), or adhesion molecules, such as SLeX, LFA-1, MAC-I,
2> LECAM-1 or VLA-4, or the mannose-6-phosphate receptor.
The present invention includes pharmaceutical preparations which, in addition
to the
vector constructs according to the invention, can also comprise non-toxic,
inert,
pharmaceutically suitable excipients. It is possible to conceive of
administering (e.g.
intravenously, intraarterially, intramuscularly, subcutaneously,
intradermally, anally,
vaginally, nasally, transdernlally, intraperitoneally, as an aerosol or
orally) these
preparations at the site of a tumour or administering them systemically.


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The vector constructs according to the invention can be employed in gene
therapy.
The invention furthermore relates to a recombinant host cell, in particular a
recombinant eukaryotic host cell, which harbours the above-described
constructs or
vectors.
The invention furthermore relates to a process for identifying substances
which affect
the promoter activity, silencer activity or enhancer activity of the catalytic
telomerase
subunit, with this process comprising the following steps:
A. adding a candidate substance to a host cell which harbours the regulatory
DNA sequence according to the invention, in particular the 5'-flanking
regulatory DNA sequence for the gene for the human catalytic telomerase
subunit, or a part region thereof which has a regulatory effect, which
sequence
or part region is functionally linked to a reporter gene, and
B. measuring the effect of the substance on expression of the reporter gene.
The process can be employed for identifying substances which increase the
promoter
activity, silencer activity or enhancer activity of the catalytic telomerase
subunit.
The process can furthermore be employed for identifying substances which
inhibit
the promoter activity, silencer activity or enhancer activator of the
catalytic
telomerase subunit.
The invention furthermore relates to a process for identifying factors which
bind
specifically to fragments of the DNA fragments according to the invention, in
particular the 5'-flanking re~Tulatory DNA sequence of the catalytic
telomerase
subunit. This method comprises screening an expression cDNA library using the
above-described DNA sequence, or subfragments of widely differing length, as
the
probe.


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The above-described constructs or vectors can also be used for preparing
transgenic
animals.
The invention furthermore relates to a process for detecting telomerase-
associated
conditions in a patient, which process comprises the following steps:
A. incubating a construct or vector, which contains the DNA sequence according
to the invention, in particular the 5'-flanking regulatory DNA sequence for
the
gene for the human catalytic telomerase subunit, or a part region thereof
having a regulatory effect, and a reporter gene, with body fluids or cell
samples,
B. detecting the activity of the reporter gene in order to obtain a diagnostic
value;
I5 and
C. comparing the diagnosic value with standard values for the reporter gene
construct in standardized normal cells or body fluids of the same type as the
test sample;
The detection of diagnostic values which are higher or lower than the standard
comparative values indicates a telomerase-associated condition, which in turn
indicates a pathogenic condition.
Explanation of the figures:
Fig. 1: Southern blot analysis using genomic DNA from various species
A: Photograph of an ethidium bromide-stained 0.7",a> agarose gel
containing approximately 4 pg of Eco RI-cut genomic DNA. Track 1
contains Hind III-cut a~ DNA as size markers (23.5, 9.4, 6.7, 4.4, 2.3, 2.0
and 0.6 kb). Tracks 2 to 10 contain human, rhesus monkey. Sprague


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Dawley rat, BALB/c mouse, dog, bovine, rabbit, chicken and yeast
(Saccharomyces cerevisiae) genomic DNA.
B: Autoradiogram, corresponding to Fig.l A, of a Southern blot analysis
in which radioactively labelled hTC-cDNA probe of about 720 by in
length is used for the hybridization.
Fig. 2: Restriction analysis of the recombinant 7~ DNA of the phage clone P
12,
which hybridizes with a probe from the 5' region of the hTC cDNA.
The figure shows a photograph of an ethidium bromide-stained 0.4%
agarose gel. Tracks 1 and 2 contain Eco RI/Hind III-cut ~. DNA and a
1 kb ladder from Gibco as size markers. Tracks 3 - 7 each contain 250 ng
of the DNA from the recombinant phage which has been cut with Bam
HI (track 3), Eco RI (track 4), Sal I (track 5), Xho I (track 5) and Sac I
(track 7). The arrows mark the two ~, arms of the vector EMBL3 Sp6/T7.
Fig.3: Restriction analysis and Southern blot analysis of the recombinant
~, DNA of the phage clone which hybridizes with a probe from the 5'
region of the hTC cDNA.
A: The figure shows a photograph of an ethidium bromide-stained 0.8%
agarose gel. Tracks 1 and 15 contain a 1 kb ladder from Gibco as size
markers. Tracks 2 to 14 each contain 2~0 ng of cut ~, DNA from the
recombinant phage clone. The followin~~ enzymes were employed: track
2: Sac I, track 3: Xho I, track 4: Xho I, Xba I, track ~: Sac I, Xho I, track
6: Sal I, Xho I, Xba I, track 7: Sac I, Xho I, Xba I, track 8: Sac I, Sal I,
Xba I, track 9: Sac I, Sal I, BamH I, track 10: Sac I, Sal I, Xho I, track I
1:
Not I, track 12: Sma I. track 13: empty, track 14: not digested.


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B: Autoradiogram, corresponding to Fig. 3 A, of a Southern blot analysis.
A 5'-hTC cDNA fragment of about 420 by in length was used as the
probe for the hybridization.
Fig. 4: Partial DNA sequence of the 5'-flanking region and of the promoter of
the gene for the human catalytic telomerase subunit. The ATG start
codon in the sequence is printed in bold. The depicted sequence
corresponds to SEQ ID NO 1.
Fig. S: Use of primer extension analysis to identify the transcription start.
The figure shows an autoradiogram of a denaturing polyacrylamide gel
which was selected for depicting a primer extension analysis. An
oligonucleotide having the sequence
S~GTTAAGTTGTAGCTTACACTGGTTCTC 3' was used as the primer.
The primer extension reaction was loaded in track 1. Tracks G, A, T and
C constitute the sequence reactions using the same primer and the
corresponding dideoxynucleotides. The thick arrow marks the main
transcription start while the thin arrows point to three subsidiary
transcription start points.
Fig. 6: cDNA sequence of the human catalytic telomerase subunit (hTC; cf. our
pending application PCT/EP/98/03468). The depicted sequence
corresponds to SEQ ID NO 2.
Fig. 7: Structural organization and restriction map of the human hTC gene and
its > ~-flanking and 3'-flanking regions.
Exons are shown as consecutively numbered rectan~Tlia which are filled-
in in black, and introns are shown as regions which are not filled in.
Untransl<ited sequence segments in the exons are hatched. Translation
starts in exon I and ends in exon 16. Restriction enzyme cleavage sits
The figure shows a photograp


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are marked as follows: S, SacI; X, XhoI. The relative arrangement of the
five phage clones (P2, P3, P5, P 12, P 17), and of the product from the
genome walking, are shown by thin lines. As the dots indicate, the
sequence of intron 16 has only been partly deciphered.
Fig. 8: HTL splice variants.
A: Diagrammatic structure of the hTC mRNA splice variants. The
complete hTC mRNA is depicted as a rectangle with a grey background
in the upper region of the figure. The 16 exons are depicted in accordance
with their size. The translation start (ATG) and the stop codon, and also
the telomerase-specific T motif, and the seven RT motifs, are all shown.
The hTC variants are subdivided into deletion and insertion variants. The
missing exon sequences are marked in the deletions. The insertions are
shown by additional white rectangles. The sizes and origins of the
inserted sequences are given. Newly formed stop codons are marked. The
size of the insertion in variant INS2 is unknown.
B: Exon-intron transitions in the hTC splice variants. Unspliced 5 ~-
flanking and 3 ~-flanking sequences are shown as white rectangles. The
origins of the exon and intron sequences are given. Intron and exon
sequences are shown in small letters and large letters, respectively. The
donor and acceptor sequences in the splice sites are underlaid as grey
rectangles, and their exon and intron origins are also given.
Fig- 9: Identification of the transcription start by means of R-r-PCR
analysis.
The RT-PCR was carried out using a cDNA library prepared from HL 60
cells and genomic DNA as the positive control- A common 3' primer
hybridizes to a region of the exon 1 sequence. -I~i~~ positions of the
different 5' primers in the codin~~ region or the ~'-tlanking region are
given. In the negative control, no template DNA w as added to the PCR
reaction. M: DNA size marker.


CA 02316282 2000-06-21
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-15-
Fig. 10: Nucleotide sequence and structural features of the hTC promoter.
The figure depicts 11273 by of the 5'-flanking hTC gene sequence,
beginning with the translation start codon ATG (+1). The putative region
S of the translation start is underlined. Possible regulatory sequence
segments within the 4000 by upstream of the translation start are ringed.
The depicted sequence corresponds to SEQ ID NO 3.
Fig. 11: Activity of the hTC promoter in HEK-293 cells.
The first 5000 by of the 5'-flanking hTC gene region are shown
diagrammatically in the upper part of the figure. The ATG start codon is
picked out. CpG-rich islands are marked by grey rectangles. The sizes of
the hTC promoter-luciferase construct are shown on the left-hand side of
the figure. The promoterless pGL2 basic construct and the SV40
promoter construct pGL2-Pro were used as controls in each transfection.
The relative luciferase activities of the different promoter constructs in
HEK cells are shown as continuous bars on the right-hand side of the
figure. The standard deviation is indicated. The numerical values
represent the average of two independent experiments which were earned
out in duplicate.
Tab. 1: Exon-intron transitions in the hTC gene
The table lists the nucleotide sequences at the 3 ~ and S ~ splice transitions
of the hTC gene. The consensus sequences for donor and acceptor
sequences (.AG and GT) are underlaid with grey rectangles. The table
shows the intron sequences (small letters) and exon sequences (large
letters) which dank the splice acceptor and donor sites. The sizes of the
exons and introns are given in bp.
Tab. ?: Potential bindin~~ sites for DNA-binding factors in the nucleotide
sequence of intros 2


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- 16-
The search for possible DNA-binding factors (e.g. transcription factors)
was carried out using the "find pattern" algorithm from the Genetics
Computer Group (Madison, USA) GCG sequence analysis program
package. The table lists the abbreviations of the DNA-binding factors
which were identified and their location in intron 2.


CA 02316282 2000-06-21
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Tab. 2
Factors Location in intron 2


C/EBP 2925


CRE.2 2749


S 1 2378, 4094, 4526, 4787, 4835, 4995


AP-2 CS3 5099


AP-2 CS4 2213, 3699, 4667, 5878, 5938, 6059, 6180,
6496


AP-2 CS5 5350, 5798, 5880, 5940, 6061, 6182, 6375,
6498


PEA3 934, 2505


P53 2125


GR utero lobin 848, 1487, 2956


PR utero lobin 3331


Zeste-white 1577, 1619, 1703, 1745, 1787, 1829, 1871,
1913, 1955,
1997, 2039, 2081, 3518, 3709, 4765, 5014,
5055


GRE 846


MyoD-MCK right 447, 509, 558, 1370, 1595, 1900, 2028,
site/rev 2099, 4557


MyoD-MCK left 108, 118, 453, 1566, 1608, 1692, 1734,
site 1818, 1902,
1986, 2372, 2460, 2720, 3491, 5030


Ets-1 CS 6408


AP1 3784, 4406


CREB 2801


GATA-1 839, 1390, 3154


c-Myc 108, 118, 453, 1566, 1608, 1692, 1734,
1818, 1902,
1986, 2372, 2460, 2720, 3491, 5030


CACCC site 991


CCAAT site 1224


CCAC box 992


CAAT site 463, 2395


Rb site 992, 4663


TATA 3650


CDEI 106, 1564, 1606, 1690, 1732, 1816, 1900,
1984




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Examples
The human gene for the catalytic telomerase subunit (ghTC), and the regions of
this
gene located 5' and 3', were cloned, while the start point for transcription
was
determined, potential binding sites for DNA-binding proteins were identified
and
active promoter fragments were highlighted. The sequence of the hTC cDNA (Fig.
6)
has already been reported in our application PCT/EP/98/03468, which is also
pending. Unless otherwise mentioned, all the data refer to the position of the
cDNA
in this sequence.
Example 1
A genomic Southern blot analysis was used to determine whether ghTC
constitutes a
single gene in the human genome or whether there exist several loci for the
hTC gene
and possibly also ghTC pseudogenes.
In order to do this, a commercially available zoo blot from Clontech was
subjected to
Southern blot analysis. This blot contains 4 pg of Eco RI-cut genomic DNA from
nine different species (human, monkey, rat, mouse, dog, bovine, rabbit,
chicken and
yeast). With the exception of yeast, chicken and human, the DNA was isolated
from
kidney tissue. The human genomic DNA was isolated from placenta and the
chicken
genomic DNA was purified from liver tissue. An hTC cDNA fragment of about 720
by in length, which was isolated from hTC cDNA, variant Del2 (position 1685 to
2349 plus 2531 to 2590 in Fig. 6 [deletion 2; cf. Example 5 in Fig. 8]), was
used as
the radioactively labelled probe in the autoradiogram in Fig. 1. The
experimental
conditions for the blot hybridization and washing steps were taken from
Ausubel et
al. ( 1987).
In the case of the human DNA, the probe recognizes two specific DNA fragments.
The smaller Eco RI fragment, of from about 1.~ to 1.8 kb in length, probably
ori~~inates from two Eco RI cleavage sites in an intron in the ghTC DNA. On
the


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basis of this result, it is to be assumed that only one single ghTC gene is
present in
the human genome.
Example 2
In order to isolate the 5' flanking hTC gene sequence, approx. 1.5 x 106
phages from
a human genomic placenta gene library (EMBL 3 SP6/T7 from Clontech, order
number HL1067j) were hybridized on nitrocellulose filters (0.45 um; from
Schleicher and Schuell), in accordance with the manufacturer's instructions,
with a
radioactively labelled 5'-hTC cDNA fragment of about 500 by in length
(position
839 to 1345 in Fig. 6). The nitrocellulose filters were firstly incubated, at
42°C for
two hours, in 2 x SSC (0.3 M NaCI; 0.5 M Tris-HC1, pH 8.0) and then in a
20
prehybridization solution (50% formamide; 5 x SSPE, pH 7.4; 5 x Denhard's
solution; 0.25% SDS; 100 pg of herring sperm DNA/ml). For the overnight
hybridization, the prehybridization solution was supplemented with 1.5 x 106
cpm of
denatured, radioactively labelled probe/ml of solution. Nonspecifically bound
radioactive DNA was removed under stringent conditions, i.e. by means of three
five-
minute steps of washing with 2 x SSC; 0.1% SDS at from 55 to 65°C. The
filters
were evaluated by autoradiography.
The phage clones which were identified in this primary investigation were
purified
(Ausubel et al. ( 1987)). In subsequent analyses, one phage clone, i.e. P 12
turned out
to be potentially positive. A i~ DNA preparation carried out on this phage
(Ausubel et
al. ( 1987)), and the subsequent restriction digestion with enzymes which
release the
genomic insert in fragments. showed that this phage clone contains an insert
of
approx. 15 kb in the vector (Fia. 2).
In order to isolate the complete hTC gene sequence, in each case from 1 to 1.5
x 106
pha~~es were screened, in independent experiments, with in each case different
radioactively labelled probes. as described above.

~
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The phage clones which were identified in these primary investigations, and
which
were positive for the corresponding probes, were purified. The phage clone P17
was
found to contain an hTC cDNA fragment of about 250 by in length (position 1787
to
2040 in Fig. 6). The phage clone P2 was identified as containing an hTC cDNA
S fragment of about 740 by in length (position 1685 to 2349 plus 2531 to 2607
in Fig.
6 [deletion 2; cf. Example 5]). The phage clones P3 and PS were found to
contain a
3' hTC cDNA fragment of 420 by in length (position 3047 to 3470 in Fig. 6).
After
the ~, DNA had been prepared from these phages, and subsequently subjected to
restriction digestion with enzymes which release the genomic insert in
fragments, the
inserts were subcloned into plasmids (Example 4).
Example 3
In order to investigate whether the 5' end of the hTC cDNA was also present in
the
insert in the recombinant phage clone P 12, the ~, DNA from this clone was
hybridized, in a Southern blot analysis, with a radiactively labelled hTC cDNA
fragment of about 440 by in length (position 1 to 440 in Fig. 6) from the
extreme 5'
region (Fig.3).
Since the isolated ~, DNA from the positive clone also hybridizes with the
extreme 5'
end of the hTC cDNA, this phage probably also contains the 5' sequence region
flanking the ATG start codon.
Example 4
In order to subclone the entire 15 kb insert in the positive phase clone P 12
in the
form of subfra'~ments, and subsequently to sequence these fra~~ments,
restriction
endonucleases which, on the one hand. release the entire insert from EMBL3
Sp6/T7
(cf. Example 2) and, in addition, cut within the insert, were selected for
digesting the
DN.~.


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In all, two Xho I subfragments, of about 8.3 and about 6.5 kb in length;
respectively,
and three Sac I subfragments, of about 8.5, about 3.5 and about 3 kb in
length,
respectively, were subeloned into the pBluescript KS(+) vector (from
Stratagene).
The 5123 by 5'-flanking nucleotide sequence of the ghTC gene region, starting
from
the ATG start codon, was determined by analysing the sequences of these
fragments
(Fig. 4; corresponding to SEQ ID NO 1). Fig. 4 depicts the first 5123 by
(starting
from the ATG start codon). Fig. 10 depicts the entire cloned 5' sequence
(corresponding to SEQ ID NO 3).
In order to subclone the entire insert, of approx. 14.6 kb in size, in phage
clone P 17
in the form of subfragments, restriction endonucleases which, on the one hand,
release the entire insert from EMLB3 Sp6/T7 and, in addition, cut a few times
within
the insert, were selected for digesting the DNA. Three XhoI/BamHI fragments,
of 7.1
kb, 4.2 kb and 1.5 kb in size, respectively, and one BamHI fragment, of 1.8 kb
in
1 ~ size, were subcloned by means of using a combination digestion with the
enzymes
XhoI and BamHI. Combination restriction digestion with the enzymes XhoI and
XbaI
resulted in a XhoI/XbaI fragment of 6.~ kb in size, and two XhoI fragments, of
6.5 kb
and 1.5 kb in size, respectively, being cloned.
Digestion with the restriction enzyme Xhol was used to subclone the insert, of
approx. 17.9 kb in size, in phage clone P2 in the form of subfragments. In
all, three
XhoI subfragments, of 7.5 kb, 6.4 kb and 1.6 kb in length, respectively, were
cloned.
Four SacI fragments, of 4.8 kb, 3 kb, 2 kb and 1.8 kb in size, respectively,
were
additionally subcloned by digesting with the restriction enzyme SacI.
The insert, of approx. 13.s kb in size. in phav~e clone P3 was subcloned by
digesting
with the restriction enzymes Sacl anc~, or Xhol. Six SacI subfragments, of 3.2
kb,
2 kb, 0.9 kb, 0.8 kb, 0.6~ kb and (). ~ kb in length, respectively, and two
XhoI
subfragments, of 6.~ kb and 4.3 kb io l~n'~th, respectively, were obtained in
this
connection.


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The insert, of approx. 13.2 kb in size, in phage clone PS was subcloned by
digesting
with the restriction enzymes SacI and/or XhoI. In all, SacI fragments of 6.5
kb, 3.3
kb, 3.2 kb, 0.8 kb and 0.3 kb in size, and XhoI fragmente of 7 kb and 3.2 kb
in size,
were subcloned.
In order to clone the hTC genomic sequence region located 3 ' of phage clone P
17
and 5' of phage clone P2, 3 genomic walkings were earned out using the
Clontech
GenomeWalkerTM kits (catalogue number K1803-1) and various combinations of
primers. In a final volume of 50 ~l, 1 U pmol of dNTP mix were added to 1 ul
of
human GenomeWalker Library HDL (from Clontech), and a PCR reaction was
carried out in 1 xKlen Taq PCR reaction buffer and 1 xAdvantage Klen Taq
polymerase mix (from Clontech). 10 pmol of an internal gene-specific primer,
and 10
pmol of the adaptor primer AP 1 (S'-GTAATACGACTCACTATAGGGC-3 '; from
Clontech) were added as primers. The PCR was carried out in 3 steps as a
touchdown
PCR. First of all, denaturation was carried out at 94°C for 20 sec, and
the primers
were then annealed, and the DNA chain extended, at 72°C for 4 min, over
7 cycles.
There then followed 37 cycles in which the DNA was denaturated at 94°C
for 20 sec
but the subsequent primer extension took place at 67°C for 4 min. In
conclusion,
there followed a chain extension at 67°C for 4 min. After this first
PCR, the PCR
product was diluted 1:50. One ~1 of this dilution was used in a second nested
PCR
together with 10 pmol of dNTP mix in lxKlen Taq PCR reaction buffer and
1 xAdvantage Klen Taq polymerase mix and also 10 pmol of a nested gene-
specific
primer and 10 pmol of the nested Marathon Adaptor primers AP2 (5'-
ACTATAGGGCACGCGTGGT-3'; from Clontech). The PCR conditions
corresponded to the parameters which were selected in the first PCR. As the
sole
exception, only 5 cycles rather than 7 cycles were selected in the first PCR
step and
only 24 cycles, instead of 37 cycles, were run in the second PCR step. The
products
of this nested genomic walking PCR were cloned into the TA Cloning Vector
pCRII
from InVitrogen.
3 (>


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In the first genomic walking, the gene-specific primer C3K2-GSP1 (5'-
GACGTGGCTCTTGAAGGCCTTG-3') and the nested gene-specific primer C3K2-
GSP2 (5'-GCCTTCTGGACCACGGCATACC-3') were used, together with the
HDL library 4, and a PCR fragment of 1639 by in length was obtained. In the
second
genomic walking, a PCR fragment of 685 by in length was amplified from the HDL
library 4 using the gene-specific primer C3F2 (5'-
CGTAGTTGAGCACGCTGAACAGTG-3') and the nested gene-specific primer
C3F (5'-CCTTCACCCTCGAGGTGAGACGCT-3. The third genomic walking
mixture, using the gene-specific primer DELS-GSP 1 (5 '-
GGTGGATGTGACGGGCGCGTACG-3 ') and the nested gene-specific primer
CSK-GSPI (5'-GGTATGCCGTGGTCCAGAAGGC-3'), led to a 924 by PCR
fragments being cloned from the HDL library 1. In all, 2100 by of the genomic
hTC
region located 3 ' of phage clone P 17 were identified using this genomic
walking
method (see Fig. 7).
The subcloned fragments, and the genomic walking products, were sequenced in
single-stranded form. The Lasergene Biocomputing Software (DNASTAR Inc.
Madison, Wisconsin, USA) was used to identify overlapping regions and form
contigs. In all, 2 large contigs were assembled from the sequences collected
from
phage clones P 12, P 17, P2, P3 and P5, and also the sequence data from the
genomic
walking. Contig 1 consists of sequence data from phage clones P 12 and P 17
and the
sequence data from the genomic walking. Contig 2 was put together from the
sequences from phage clones P2, P3 and P5. Overlapping phage clone regions are
shown diagrammaticaly in Fig. 7. The sequence data from the 2 contigs are
shown
below. The ATG start codon in contig 1 is underlined. The TGA stop codon is
underlined in contig 2.


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Contigl:
ACTTGAGCCC AGCCATGATTGCAACACCAC TGGTGACAGA70
AAGAGTTCAA ACGCCAGCCT
GGCTACGGTG


ATGAGACCCTGTCTCAAAAA AATTGAAATAATATAAAGCA CCACAGTGGA140
AAAAAAAAAA TCTTCTCTGG


S ACAAAACCAGAAATCAACAA TTTGAAAACTATACAAACAC AACAATATAC210
CAAGAGGAAT ATGAAAATTA


TTCTGAATGACCAGTGAGTC TTAAAAAGGAAATTGAAAAA CAAATGATAA280
AATGAAGAAA TTTATTTAAG


CGGAAACATAACCTCTCAAA TACAGCAAAAGCAGTGCTAA TATAGCTATA350
ACCCACGGTA GAAGGAAGTT


AGCAGCTACATCAAAAAAGT GGCGCAGTGGCTCATGCCTG ACTTTGGGAG920
AGAAAAGCCA TAATCCCAGC


GCCAAGGCGGGCAGATCGCC AGTTCGAGACCAGCCTGACC AACCTTGTCG990
TGAGGTCAGG AACACAGAGA


IO CTACTAAAAATACAAAATTA GTGGCACATGCCTGTAATCC GGAGGCTGAG560
GCTGGGCATG CAGCTACTCG


GCAGGATAACCGCTTGAACC AGGTTGCGGTGAGCCGGGAT GACTCCAGCC630
CAGGAGGTGG TGCGCCATTG


TGGGTAACAAGAGTGAAACC AAAAAAAAAAAAGTAGAAAA ACAACCTAAT700
CTGTCTCAAG ACTTAAAAAT


GATGCACCTTAAAGAACTAG GCAAACTAAACCTAAAATTG AGAAATAATA770
AAAAGCAAGA GTAAAAGAAA


AAGATCAGAGCAGAAATAAA AGATAACAATACAAAAGATC AAAGTTGGTT890
TGAAACTGAA AACAAAATTA


IS TTTTGAAAAGATAAACAAAA TTTGCCCAGACTAAGAAAAA ACCTAAATAA910
TTGACAAACC AGGAAAGAAG


ATAAAGTCAGAGATGAAAAA CAACTGATACCACAGAAATT .CTAGAGGCTA980
AGAGACATTA CAAAGGATCA


CTATGAGCAACTGTACACTA AAACCTAGAAAAAATAGATA TGCATACAAC1050
ATAAATTGAA AATTCCTAGA


CTACCAAGATTGAACCATGA AGCCCAAACAGACCAATAAC TTAAAGCCAT1120
AGAAATCCAA AATAATGGGA


AATAAAAAGTCTCCTAGCAA AGGACCCAATGGCTTCCCTG CCAATCATTT1190
AGAGAAGCCC CTGGATTTTA


2O AAAGAAGAATGAATTCCAAT CTATTCTGAAAAATAGAGGA CCAAACTCAT1260
CCTACTCAAA AAGAATACTT


TCTACATGGCCAGTATTACC AACCAGACAAAAACACATCA AACAAAAAAA1330
CTGATTCCAA AAAACAAACA


CAGAAAGAAAGAAAACTACA CCTGATGAATACTGATACAA CAAAACACTA1400
GGCCAATATC AAATCCTCAA


GCAAACCAAATTAAACAACA ATCATTCATTGTGATCAAGT CCAGGGATGG1970
CCTTCGAAAG GGGATTTATT


AAGGATGGTTCAACATATGC ATGTGATACATCATCCCAAC ACAAAAACTA1590
AAATCAATCA AAAATGAAGT


ZS TATGATTATTTCACTTTATG ATTTGATAAAATTCTGCACC AAAACCCTCA1610
CAGAAAAAGC CTTCATGATA


AAAAACCAGGTATACAAGAA CAGGCACAGTGGCTCACACC GCACTCTGGG1680
ACATACAGGC TGCGATCCCA


AGGCCAAGGTGGGATGATTG GGAGTTTGAGACTAGCCTGG GAGACCTGGT1750
CTTGGGCCCA GCAACAAAAT


CTACAAAAAACTTTTTTAAA GGCATGATGGCATATGCCTG TAGTCTGGAG1820
AAATTAGCCA TAGTCCCAGC


GCTGAGGTGGGAGAATCACT AGGTCGAGGCTGCAGTGAGC TCACTGTACT1890
TAAGCCTAGG CATGAACATG


3 CCAGCCTAGACAACAGAACA GAATAAGAAGAAGGAGAAGG AGGGAGGGAG1960
O AGACCCCACT AGAAGGGAGA


AAGGGAGGAGGAGGAGAAGG GGAGAAGTGGAAGGGGAAGG GAGGAAGAAG2030
AGGAGGTGGA GGAAGGGAAA


F~GAAACATATTTCAACATA TATATGACAGACCGAGGTAG AAAAACTGAA2100
ATAAAAGCCC TATTATGAGG


AGCCTTTCCTCTAAGATCTG AGGGCCCACTTTCACCACTG TAGTACTAGA2170
GAAAATGACA TGAT'rCAACA


AGTCCTAGCTAGAGCAATCA AGAAATAAAAGGCATCCAAA AGAAGTCAAA2240
GATAAGAGAA CTGGAAAGGA


3 TTATCCTGTTTGCAGATGAT ATCTGGAAAAGACTTAAGAC AACTATTAGA2310
S ATGATCTTAT ACCACTAAAA


GCTGAAATTTGGTACAGCAG CAATGTACAAAAATCAGTAG TTCCAACAGC2380
GATACAAAAT TATTTCTATA


SAACAATCTGAAAAAGAAAC GCTACAAATAAAATTAAACA AACCAAAGAA2950
CAAAAAAGCA GCTAGGAATT


GTGAAAGATCTCTACAATGA ATGTTGATAAAAGAAATTGA AAAAAAGAAA2520
AAACTATAAA AGAGGGCACA


AGATATTCCATGTTCATAGA AAATACTGTTAAAATGTCCA AGCAATTTAC2590
TTGGAAGAAT TACTACCCAA


4O AAATTCAATGCAATCCCTAT ATGACGTTCTTCACAGAAAT ATTCTAAGAT2660
TAAAATACTA AGAAGAAACA


TTGTACAGAACCACAAAAGA CCAAAGCTATCCTGACCAAA CTGGAAGCAT2%30
CCCAGAATAG AAGAACAAAA


CACATTACCTGACTTCAAAT AGCTATAGTAACCCAAACTA GCATAAAAAC2800
TATACTACAA CATGGTACTG


AGATGAGACATGGACCAGAG GAGAATCCAGAAACAAATCC AGTGAACTCA2870
GAACAGAATA ATGCATCTAC


TTTTTGACAAAGGTGCCAAG GGGGAAAAGATAATCTCTTC GCTGGAGGAA2940
AACATACTTT AATAAATGGT


4 CTGGATATCCATATGCAAAA AGAACTCTGTCTCTCACCAT AAATCAAAAT3010
S TAACAATACT ATACAAAAGC


GGATGAAAGGCTTAAATCTA CTTTGCAACTACTAAAAGAA AAACTCTCCA3080
AAACCTCAAA AACACCGGAG


GGACATTGGAGTGGGCAAAG TAATTCCCTGCAGGCACAGG AAAAACAGAC3150
ACTTCTTGAG CAACCAAAGC


AAATGGGATCATATCAAGTT TGCCCAGCAAAGGAAACAAT AAGAGACAAC3220
AAAAAGCTTC CAACAAAGAG


CCACAGAATGGGAGAATATA ATTCATCTRACAAGGAATTA TATATAAGGA3290
TTTGCAAACT ATAACCAGTA


S GCTCAAACTACTCTATAAGA ATAAGCTGATTTTCAAAAAT TCTGGGTAGA3360
O AAAACACCTA AAGCAAAAGA


CATTTCTCAAAATAAGTCAT AACAGGCATCTGAAAATGTG CTGATCATCA3430
ACAAATGGCA CTCAACACCA


GAGAAATGCAAATCAAAACT ATCATCTCATCCCAGTTAAA TTCAAAAGAC3500
ACTATGAGAG ATGGCTTTTA


AGGCAATAACAAATGCCAGT ATAAAAGGAAACCCTTGGAC GGAATGGAAA3570
GAGGATGTGG ACTGTTGGTG


TTGCTACCACTATGGAGAAC TTCCTCAAAAAACTAAAAAT TACAGCAATC3690
AGTTTGAAAG AAAGCTACCA


S CCATTGCTAGGTATATACTC AATCAGTGTATCAACAAGCT CCACATTTAC3710
S CAAAAAAGGG ATCTCCACTC


TGCAGCACTGTTCATAGCAG GAAGCAACCTCAGTGTCCAT ATGGAAAAAG3780
CCAAGGTTTG CAACAGACGA


AAAATGTGGTGCACATACAC TACGCAGCCATAAAAAAGAA TCAGTTGCAA3850
AATGGAGTAC TGAGATCCTG


CAGCATGGGGGGCACTGGTC GTGAAATAAGCCAGGCACAG TTTTCATGTT3920
AGTATGTTAA AAAGACAAAC


CTCCCTTACTTGTGGGAGCA CRATTGACATAGAAATAGAG GTTCTAGAGG3990
AAAATTAAAA GAGAATGGTG


E)O GGTGGGGGACAGGGTGACTA TAATTTATTGTATGTTTTAA AGAGTATAAT4060
GAGT.CAACAA AATAACTAAA


TGGGTTGTTTGTAACACAAA ATGCTTGAAGGTGACAGATA CCTGATGTGA4130
GAAAGGATAA CCCCATTTAC


TTATTACACATTGTATGCCT ATCTCATGTATGCTATAGAT CTATATTAAA4200
GTATCAAAAT ATAAACCCTA


AATTAAAATTTTAATGGCCA CTCATGTCCGTAATCCCAGC GCCGAGGCGG4270
GGCACGGTGG ACTTTGGGAG


GTGGATCACCTGAGGTCAGG CAGTCTGGCCACCATGATGA ~TACTAAAGA4390
AGTTTGAAAC AACCCTGTCT


6J TACAAAAATTAGCCAGGCGT ACCTGTAGTCCCAACTACTC GACAGGAGAA4410
GGTGGCACAT AGGAGGCTGA


TTGCTTGAACCTGGGAGGCG TGAGCCGAGATCATGCCACT CTGGGTGACA4980
GAGGTTGCAG GCACTGCAGC


GAGCAAGACTCCATCTCAAA AAAAAAGAAGATTAAAATTG GTACCGTATA4550
ACAAAAACAA TAATTTTTAT


AATATATACTCTACTATATT AATTAAAACAATTATAAAAG ACTTAATCTA4620
AGAAGTTAAA GTAATTAACC


AAATAAGAACAATGTATGTG CTTCTGAAGAAGTAAAAGTT TGGCAGAAAT4690
GGGTTTCTAG ATGGCCACGA


IO GTGAGGAGGGAACAGTGGAA TTAGACGCTCATACTCTCTG AATTTTAACC4760
GTTACTGTTG TAAGTGACTT


AAAGACAGGCTGGGAGAAGT TTCTATAAGCCCTAAAACAA TGGTGAAAGG4830
TAAAGAGGCA CTGCTAATA.~


TAATCTCTATTAATTACCAA TATCTCTAAAATCGAGCTGC ~GTCTGATCA9900
TAATTACAG:. AGAATTGGC=,


CACCGTCCTCTCATTCACGG CTTGTGTGCTTGGAGATTTT TTCGTGTTTG4970
TGCTTTTTTT CGATTGTGTG


GTTAAACTTAATCTGTATGA GAAAAATGGTGGTGATTTCC TTAGAGTACC5040
ATCCTGAAAC TCCAGAAGA
=.


75 TGGCAGGAAGCAGGTGGCTC AGCCACTTCA. 1AGACCCAGG5110
TGTGGACCTG ATCTTCAAGG
GTCTCTGGC~




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-26-
TGCAAGGCAGAGGCCTGATGACCCGAGGACAGGAAAGCTCGGATGGGAAGGGGCGATGAG 5180
AAGCCTGCCT


CGTTGGTGAGCAGCGCATGAAGTGCCCTTATTTACGCTTTGCAAAGATTGCTCTGGATACCATCTGGAAA5250


AGGCGGCCAGCGGGAATGCAAGGAGTCAGAAGCCTCCTGCTCAAACCCAGGCCAGCAGCTATGGCGCCCA5320


CCCGGGCGTGTGCCAGAGGGAGAGGAGTCAAGGCACCTCGAAGTATGGCTTAAATCTTTTTTTCACCTGA5390


S AGCAGTGACCAAGGTGTATTCTGAGGGAAGCTTGAGTTAGGTGCCTTCTTTAAAACAGAAAGTCATGGAA5960


GCACCCTTCTCAAGGGAAAACCAGACGCCCGCTCTGCGGTCATTTACCTCTTTCCTCTCTCCCTCTCTTG5530


CCCTCGCGGTTTCTGATCGGGACAGAGTGACCCCCGTGGAGCTTCTCCGAGCCCGTGCTGAGGACCCTCT5600


TGCAAAGGGCTCCACAGACCCCCGCCCTGGAGAGAGGAGTCTGAGCCTGGCTTAATAACAAACTGGGATG5670


TGGCT'GGGGGCGGACAGCGACGGCGGGATTCAAAGACTTAATTCCATGAGTAAATTCAACCTTTCCACAT5740


IO CCGAATGGATTTGGATTTTATCTTAATATTTTCTTAAATTTCATCAAATAACATTCAGGACTGCAGAAAT5810


CCAAAGGCGTAAAACAGGAACTGAGCTATGTTTGCCAAGGTCCAAGGACTTAATAACCATGTTCAGAGGG5880


ATTTTTCGCCCTAAGTACTTTTTATTGGTTTTCATAAGGTGGCTTAGGGTGCAAGGGAAAGTACACGAGG5950


AGAGGCCTGGGCGGCAGGGCTATGAGCACGGCAGGGCCACCGGGGAGAGAGTCCCCGGCCTGGGAGGCTG6020


ACAGCAGGACCACTGACCGTCCTCCCTGGGAGCTGCCACATTGGGCAACGCGAAGGCGGCCACGCTGCGT6090


IS GTGACTCAGGACCCCATACCGGCTTCCTGGGCCCACCCACACTAACCCAGGAAGTCACGGAGCTCTGAAC6160


CCGTGGAAACGAACATGACCCTTGCCTGCCTGCTTCCCTGGGTGGGTCAAGGGTAATGAAGTGGTGTGCA6230


GGAAATGGCCATGTAAATTACACGACTCTGCTGATGGGGACCGTTCCTTCCATCATTATTCATCTTCACC6300


CCCAAGGACTGAATGATTCCAGCAACTTCTTCGGGTGTGACAAGCCATGACAAAACTCAGTACAAACACC6370


ACTCTTTTACTAGGCCCACAGAGCACGGSCCACACCCCTGATATATTAAGAGTCCAGGAGAGATGAGGCT6940


2O GCTTTCAGCCACCAGGCTGGGGTGACAACAGCGGCTGAACAGTCTGTTCCTCTAGACTAGTAGACCCTGG6510


CAGGCACTCCCCCAGATTCTAGGGCCTGGTTGCTGCTTCCCGAGGGCGCCATCTGCCCTGGAGACTCAGC6580


CTGGGGTGCCACACTGAGGCCAGCCCTGTCTCCACACCCTCCGCCTCCAGGCCTCAGCTTCTCCAGCAGC6650


TTCCTAAACCCTGGGTGGGCCGTGTTCCAGCGCTACTGTCTCACCTGTCCCACTGTGTCTTGTCTCAGCG6720


ACGTAGCTCGCACGGTTCCTCCTCACATGG'GGTGTCTGTCTCCTTCCCCAACACTCACATGCGTTGAAGG6790


2S GAGGAGATTCTGCGCCTCCCAGACTGGCTCCTCTGAGCCTGAACCTGGCTCGTGGCCCCCGATGCAGGTT6860


CCTGGCGTCCGGCTGCACGCTGACCTCCATTTCCAGGCGCTCCCCGTCTCCTGTCATCTGCCGGGGCCTG6930


CCGGTGTGTTCTTCTGTTTCTGTGCTCCTTTCCACGTCCAGCTGCGTGTGTCTCTGCCCGCTAGGGTCTC7000


GGGGTTTTTATAGGCATAGGACGGGGGCGTGGTGGGCCAGGGCGCTCTTGGGAAATGCAACATTTGGGTG7070


TGAAAGTAGGAGTGCCTGTCCTCACCTAGGTCCACGGGCACAGGCCTGGGGATGGAGCCCCCGCCAGGGA7190


)O CCCGCCCTTCTCTGCCCAGCACTTTCCTGCCCCCCTCCCTCTGGAACACAGAGTGGCAGTTTCCACAAGC7210


ACTAAGCATCCTCTTCCCAAAAGACCCAGCATTGGCACCCCTGGACATTTGCCCCACAGCCCTGGGAATT7280


CACGTGACTACGCACATCATGTACACACTCCCGTCCACGACCGACCCCCGCTGTTTTATTTTA~1TAGCTA7350


CAAAGCAGGGAAATCCCTGCTAAAATGTCCTTTAACAAACTGGTTAAACAAACGGGTCCATCCGCACGGT7420


GGACAGTTCCTCACAGTGAAGAGGAACATGCCGTTTATAAAGCCTGCAGGCATCTCAAGGGAATTACGCT7990


.~S GAGTCAAAACTGCCACCTCCATGGGATACGTACGCAACATGCTCAAAAAGAAAGAATTTCACCCCATGGC7560


AGGGGAGTGGTTAGGGGGGTTAAGGACGGTGGGGGCGGCAGCTGGGGGCTACTGCACGCACCTTTTACTA7630


AAGCCAGTTTCCTGGTTCTGATGGTATTGGCTCAGTTATGGGAGACT_AACCATAGGGGAGTGGGGATGGG7700


GGAACCCGGAGGCTGTGCCATCTTTGCCATGCCCGAGTGTCCTGGGCAGGATAATGCTCTAGAGATGCCC7770


ACGTCCTGATTCCCCCAAACCTGTGGACAGAACCCGCCCGGCCCCAGGGCCTTTGCAGGTGTGATCTCCG7890


4 TGAGGACCCTGAGGTCTGGGATCCTTCGGGACTACCTGCAGGCCCGAAAAGTAATCCAGGGGTTCTGGGA7910
O


AGAGGCGGGCAGGAGGGTCAGAGGGGGGCAGCCTCAGGACGATGGAGGCAGTCAGTCTGAGGCTGAAAAG7980


GGAGGGAGGGCCTCGAGCCCAGGCCTGCAAGCGCCTCCAGAAGCTGGAAAAAGCGGGGAAGGGACCCTCC8050


ACGGAGCCTGCAGCAGGAAGGCACGGCTGGCCCTTAGCCCACCAGGGCCCATCGTGGACCTCCGGCCTCC8120


GTGCCATAGGAGGGCACTCGCGCTGCCCTTCTAGCATGAAGTGTGTGGGGATTTGCAGAAGCAACAGGAA8190


4S ACCCATGCACTGTGAATCTAGGATTATTTCAAAACAAAGGTTTACAGAAACATCCAAGGACAGGGCTGAA8260


GTGCCTCCGGGCAAGGGCAGGGCAGGCACGAGTGATTTTATTTAGCTATTTTATTTTATTTACTTACTTT8330


CTGAGACAGAGTTATGCTCTTGTTGCCCAGGCTGGAGTGCAGCGGCATGATCTTGGCTCACTGCAACCTC8900


CGTCTCCTGGGTTCAAGCAATTCTCGTGCCTCAGCCTCCCAAGTAGCTGGGATTTCAGGCGTGCACCACC8470


ACACCCGGCTAATTTTGTATTTTTAGTAGAGATGGGCTTTCACCATGTTGGTCAAGCTGATCTCAAAATC8540


S CTGACCTCAGGTGATCCGCCCACCTCAGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGCACCT8610
O


GGCCTATTTAACCATTTTAAAACTTCCCTGGGCTCAAGTCACACCCACTGGTAAGGAGTTCATGGAGTTC8680


AATTTCCCCTTTACTCAGGAGTTACCCTCCTTTGATATTTTCTGTAATTCTTCGTAGACTGGGGATACAC8750


CGTCTCTTGACATATTCACAGTTTCTGTGACCACCTGTTATCCCATGGGACCCACTGCAGGGGCAGCTGG8820


GAGGCTGCAGGCTTCAGGTCCCAGTGGGGTTGCCATCTGCCAGTAGAAACCTGATGTAGAATCAGGGCGC8890


S AAGTGTGGACACTGTCCTGAATCTCAATGTCTCAGTGTGTGCTGAAACATGTAGAAATTAAAGTCCATCC8960
S


CTCCTACTCTACTGGGATTGAGCCCCTTCCCTATCCCCCCCCAGGGGCAGAGGAGTTCCTCTCACTCCTG9030


TGGAGGAAGGAATGATACTTTGTTATTTTTCACTGCTGGTACTGAATCCACTGTTTCATTTGTTGGTTTG9100


TTTGTTTTGTTTTGAGAGGCGGTTTCACTCTTGTTGCTCAGGCTGGAGGGAGTGCAATGGCGCGATCTTG9170


GCTTACTGCAGCCTCTGCCTCCCAGGTTCAAGTGATTCTCCTGCTTCCGCCTCCCATT'rGGCTGGGATTA9290


6O CAGGCACCCGCCACCATGCCCAGCTAATTTTTTGTATTTTTAGTAGAGACGGGGGTGGGTGGGGTTCACC9310


ATGTTGGCCAGGCTGGTCTCGAACTTCTGACCTCAGATGATCCACCTGCCTCTGCCTCCTAAAGTGCTGG9380


GATTACAGGTGTGAGCCACCATGCCCAGCTCAG~.ATTTACTCTGTTTAGAAACATCTGGGTCTGAGGTAG9950


GAAGCTCACCCCACTCAAGTGTTGTGGTGTTTT:.nGCCAATGATAGAATTTTTTTATTGTTGTTAGAACA9520


CTCTTGATGTTTTACACTGTGATGACTAAGACATCATCAGCTTTTCAAAGACACACTAACTGCACCCATA9590


6S ATACTGGGGTGTCTTCTGGGTATCAGCAATCTTCATTGAATGCCGGGAGGCGTTTCCTCGCCATGCACAT9660


GGTGTTAATTACTCCAGCATAATCTTCTGCTTCCi:TTTCTTCTCTTCCCTCTTTTAAA.ATTGTGTTTTCT9730


ATGTTGGCTTCTCTGCAGAGAACCAGTGTAAGCTACAACTTAACTTTTGTTGGAACAAATTTTCCAAACC9800


GCCCCTTTGCCCTAGTGGCAGAGACi-
~ATTCACT;?.i:CACAGCCCTTTAAAAAGGCTTAGGGATCACTAAGG9870


GGATTTCTAGAAGAGCGACCTGTAATCCTAAGTATTTACAAGACGAGGCTAACCTCCAGCGAGCGTGACA9990


7O
GCCCAGGGAGGGTGCGAGGCCTGTTCAAATGCT=.GCTCCATAAATAAAGCAATTTCCTCCGGCAGTTTCT10010


GAAAGTAGGAAAGGTTACATTTAAGGTTGCGTT'_GTTAGCATTTCAGTGT.TTGCCGACCTCAGCTACAGC10080


ATCCCTGCAAGGCCTCGGGAGACCCAGAAGTTTCTCGCCCCCTTAGATCCAAACTTGAGCAACCCGGAGT10150


CTGGATTCCTGGGAAGTCCTCAGCTGTCCTGCGC-TTGTGCCGGGGCCCCAGGTCTGGAGGGGACCAGTGG10220


CCGTGTGGCTTCTACTGCTGGGCTGGAAGTCGGGCCTCCTAGCTCTGCAGTCCGAGGCTTGGAGCCAGGT10290


7S
GCCTGGACCCCGAGGCTGCCCTCCACCCTGTGCGGGCGGGATGTGACCAGATGTTGGCCTCATCTGCCAG10360


ACAGAGTGCCGGGGCCCAGGGTCA.yGG'CCGTTGTGGCTGGTGTGAGGCGCCCGGTGCGCGGCCAGCAGGA10430


GCGCCTGGCTCCATTTCCCACCCTT'"CTCGACGGGACCGCCCCGGTGGGTGATTAACAGATTTGGGGTGG10500


TTTGCTCATGGTGGGGACCCCTCGCCGCCTGAGAACCTG::AAAGAGAAATGACGGGCCTGTGTCAAGGAG10570




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-27-
CCCAAGTCGCGGGGAAGTGTTGCAGGGAGGCACTCCGGGAGGTCCCGCGTGCCCGTCCAGGGAGCAATGC10640


GTCCTCGGGTTCGTCCCCAGCCGCGTCTACGCGCCTCCGTCCTCCCCTTCACGTCCGGCATTCGTGGTGC10710


CCGGAGCCCGACGCCCCGCGTCCGGACCTGGAGGCAGCCCTGGGTCTCCGGATCAGGCCAGCGGCCAAAG10780


GGTCGCCGCACGCACCTGTTCCCAGGGCCTCCACATCATGGCCCCTCCCTCGGGTTACCCCACAGCCTAG10850


S
GCCGATTCGACCTCTCTCCGCTGGGGCCCTCGCTGGCGTCCCTGCACCCTGGGAGCGCGAGCGGCGCGCG10920


GGCGGGGAAGCGCGGCCCAGACCCCCGGGTCCGCCCGGAGCAGCTGCGCTGTCGGGGCCAGGCCGGGCTC10990


CCAGTGGATTCGCGGGCACAGACGCCCAGGACCGCGCTCCCCACGTGGCGGAGGGACTGGGGACCCGGGC11060


ACCCGTCCTGCCCCTTCACCTTCCAGCTCCGCCTCCTCCGCGCGGACCCCGCCCCGTCCCGACCCCTCCC11130


GGGTCCCCGGCCCAGCCCCCTCCGGGCCCTCCCAGCCCCTCCCCTTCCTTTCCGCGGCCCCGCCCTCTCC11200


IO
TCGCGGCGCGAGTTTCAGGCAGCGCTGCGTCCTGCTGCGCACGTGGGAAGCCCTGGCCCCGGCCACCCCC11270


GCG_ATGCCGCGCGCTCCCCGCTGCCGAGCCGTGCGCTCCCTGCTGCGCAGCCACTACCGCGAGGTGCTGC11390


CGCTGGCCACGTTCGTGCGGCGCCTGGGGCCCCAGGGCTGGCGGCTGGTGCAGCGCGGGGACCCGGCGGC11410


TTTCCGCGCGCTGGTGGCCCAGTGCCTGGTGTGCGTGCCCTGGGACGCACGGCCGCCCCCCGCCGCCCCC11480


TCCTTCCGCCAGGTGGGCCTCCCCGGGGTCGGCGTCCGGCTGGGGTTGAGGGCGGCCGGGGGGAACCAGC11550


IS
GACATGCGGAGAGCAGCGCAGGCGACTCAGGGCGCTTCCCCCGCAGGTGTCCTGCCTGAAGGAGCTGGTG11620


GCCCGAGTGCTGCAGAGGCTGTGCGAGCGCGGCGCGAAGAACGTGCTGGCCTTCGGCTTCGCGCTGCTGG11690


ACGGGGCCCGCGGGGGCCCCCCCGAGGCCTTCACCACCAGCGTGCGCAGCTACCTGCCCAACACGGTGAC11760


CGACGCACTGCGGGGGAGCGGGGCGTGGGGGCTGCTGCTGCGCCGCGTGGGCGACGACGTGCTGGTTCAC11830


CTGCTGGCACGCTGCGCGCTCTTTGTGCTGGTGGCTCCCAGCTGCGCCTACCAGGTGTGCGGGCCGCCGC11900


2O
TGTACCAGCTCGGCGCTGCCACTCAGGCCCGGCCCCCGCCACACGCTAGTGGACCCCGAAGGCGTCTGGG11970


ATGCGAACGGGCCTGGAACCATAGCGTCAGGGAGGCCGGGGTCCCCCTGGGCCTGCCAGCCCCGGGTGCG12090


AGGAGGCGCGGGGGCAGTGCCAGCCGAAGTCTGCCGTTGCCCAAGAGGCCCAGGCGTGGCGCTGCCCCTG12110


AGCCGGAGCGGACGCCCGTTGGGCAGGGGTCCTGGGCCCACCCGGGCAGGACGCGTGGACCGAGTGACCG12180


TGGTTTCTGTGTGGTGTCACCTGCCAGACCCGCCGAAGAAGCCACCTCTTTGGAGGGTGCGCTCTCTGGC12250


S
ACGCGCCACTCCCACCCATCCGTGGGCCGCCAGCACCACGCAGGCCCCCCATCCACATCGCGGCCACCAC12320


GTCCCTGGGACACGCCTTGTCCCCCGGTGTACGCCGAGACCAAGCACTTCCTCTACTCCTCAGGCGACAA12390


GGAGCAGCTGCGGCCCTCCTTCCTACTCAGCTCTCTGAGGCCCAGCCTGACTGGCGCTCGGAGGCTCGTG12960


GAGACCATCTTTCTGGGTTCCAGGCCCTGGATGCCAGGGACTCCCCGCAGGTTGCCCCGCCTGCCCCAGC12530


GCTACTGGCAAATGCGGCCCCTGTTTCTGGAGCTGCTTGGGAACCACGCGCAGTGCCCCTACGGGGTGCT12600


3
CCTCAAGACGCACTGCCCGCTGCGAGCTGCGGTCACCCCAGCAGCCGGTGTCTGTGCCCGGGAGAAGCCC12670
O


CAGGGCTCTGTGGCGGCCCCCGAGGAGGAGGACACAGACCCCCGTCGCCTGGTGCAGCTGCTCCGCCAGC12790


ACAGCAGCCCCTGGCAGGTGTACGGCTTCGTGCGGGCCTGCCTGCGCCGGCTGGTGCCCCCAGGCCTCTG12810


GGGCTCCAGGCACAACGAACGCCGCTTCCTCAGGAACACCAAGAAGTTCATCTCCCTGGGGAAGCATGCC12880


AAGCTCTCGCTGCAGGAGCTGACGTGGAAGATGAGCGTGCGGGACTGCGCTTGGCTGCGCAGGAGCCCAG12950


3
GTGAGGAGGTGGTGGCCGTCGAGGGCCCAGGCCCCAGAGCTGAATGCAGTAGGGGCTCAGAAAAGGGGGC13020
S


AGGCAGAGCCCTGGTCCTCCTGTCTCCATCGTCACGTGGGCACACGTGGCTTTTCGCTCAGGACGTCGAG13090


TGGACACGGTGATCTCTGCCTCTGCTCTCCCTCCTGTCCAGTTTGCATAAACTTACGAGGTTCACCTTCA13160


CGTTTTGATGGACACGCGGTTTCCAGGCGCCGAGGCCAGAGCAGTGAACAGAGGAGGCTGGGCGCGGCAG13230


TGGAGCCGGGTTGCCGGCAATGGGGAGAAGTGTCTGGAAGCACAGACGCTCTGGCGAGGGTGCCTGCAGG13300


4O
TTACCTATAATCCTCTTCGCAATTTCAAGGGTGGGAATGAGAGGTGGGGACGAGAACCCCCTCTTCCTGG13370


GGGTGGGAGGTAAGGGTTTTGCAGGTGCACGTGGTCAGCCAATATGCAGGTTTGTGTTTAAGATTTAATT13940


GTGTGTTGACGGCCAGGTGCGGTGGCTCACGCCGGTAATCCCAGCACTTTGGGAAGCTGAGGCAGGTGGA13510


TCACCTGAGGTCAGGAGTTTGAGACCAGCCTGACCAACATGGTGAAACCCTATCTGTACTAAAAATACAA13580


AAATTAGCTGGGCATGGTGGTGTGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCACT13650


'~S
TGAACCCAGGAGGCGGAGGCTGCAGTGAGCTGAGATTGTGCCATTGTACTCCAGCCTGGGCGACAAGAGT13720


GAAACTCTGTCTTTAAAAAAAAAAAGTGTTCGTTGATTGTGCCAGGACAGGGTAGAGGGAGGGAGATAAG13790


ACTGTTCTCCAGCACAGATCCTGGTCCCATCTTTAGGTATGAAGAGGGCCACATGGGAGCAGAGGACAGC13860


AGATGGCTCCACCTGCTGAGGAAGGGACAGTGTTTGTGGGTGTTCAGGGGATGGTGCTGCTGGGCCCTGC13930


CGTGTCCCCACCCTGTTTTTCTGGATTTGATGTTGAGGAACCTCCGCTCCAGCCCCCTTTTGGCTCCCAG14000


S
TGCTCCCAGGCCCTACCGTGGCAGCTAGAAGAAGTCCCGATTTCACCCCCTCCCCACAAACTCCCAAGAC14070
O


ATGTAAGACTTCCGGCCATGCAGACAAGGAGGGTGACCTTCTTGGGGCTCTTTTTTTTCTTTTTTTCTTT19190


TTATGGTGGCAAAAGTCATATAACATGAGATTGGCACTCCTAACACCGTTTTCTGTGTACAGTGCAGAAT19210


TGCTAACTCGGCGGTGTTTACAGCAGGTTGCTTGAAATGCTGCGTCTTGCGTGACTGGAAGTCCCTACCC19280


ATCGAACGGCAGCTGCCTCACACCTGCTGCGGCTCAGGTGGACCACGCCGAGTCAGATAAGCGTCATGCA19350


JS
ACCCAGTTTTGCTTTTTGTGCTCCAGCTTCCTTCGTTGAGGAGAGTTTGAGTTCTCTGATCAGGACTCTG19920


CCTGTCATTGCTGTTCTCTGACTTCAGATGAGGTCACAATCTGCCCCTGGCTTATGCAGGGAGTGAGGCG19490


TGGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGTTGCCCCCAGGTGTCCCTGTCACGTGTA14560


GGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTGTCCCGTGCAGCGTGATTGAGGTGTGGCCCCCGGGTGT14630


CCCTGTCACGTGTAGGGTGAGTGAGGCGCCATCCCCGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCG14700


GO
TGGTCCCCGGGTGTCCCTGTCCCGTGCAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCA14770


GGGTGAGTGAGGCGCGGTCCCCGGGTGTCCCTCTCAGGTGTAGGGTGAGTGAGGCGCGGCCCCAGGGTGT19840


CCCTGTCACGTGTAGGGTGAGTGAGGCACCGTCCCTGGGTGTCCCTCCCAGGTATAGGGTGAGTGAGGCA19910


CTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTCTCAGGTGCA19980


GGGTGAGTGAGGCGCTGTCCCTGGGTGTCCCTGTCTCGTGTAGGGTGAGTGAGGCTCTGTCCCCAGGTGT15050


E)S
CCTTGGCGTTTGCTCACTTGAGCTTGCTCCTGAATGTTTGCTCTTTCTATAGCCACAGCTGCGCCGGTTG15120


CCCATTGCCTGGGTAGATGGTGCAGGCGCAGTGCTGGTCCCCAAGCCTATCTTTTCTGATGCTCGGCTCT15190


TCTTGGTCACCTCTC~GTTCCATTTTGCT;CGGGGACACGGGACTGCAGGCTCTCGCCTCCCGCGTGCCA15260


GGCACTGCAGCCACAGCTTCAGGTCCGCTTGCCTCTGTTGGGCCTGGCTTGCTCACCACGTGCCCGCCAC15330


ATGCATGCTGCCAATACTCCTCTCCCAGCTTGTCTCATGCCGAGGCTGGACTCTGGGCTGCCTGTGTCTG15400


7O
CTGCCACGTGTTGCTGGAGACATCCCAGA."1AGGGTTCTCTGTGCCCTGAAGGAAAGCAAGTCACCCCAGC15970


CCCCTCACTTGTCCTGTTTTCTCCCAAGCTGCCCCTCTGCTTGGCCCCCTTGGGTGGGTGGCAACGCTTG15540


TCACCTTATTCTGGGCACCTGCCGCTCATTGCTTAGGCTGGGCTCTGCCTCCAGTCGCCCC~TCACATGG'5610


ATTGACGTCCAGCCACAGGTTGGAGTGTCTCTGTCTGTCTCCTGCTCTGAGACCCACGTGGAGGGCCGGT15680


GTCTCCGCCAGCCTTCGTCAGACTTCCCT~TTGGGTCTTAGTTTTGAATTTCACTGATTTACCTCTGACG15750


7J
TTTCTATCTCTCCATTGTATGCTTTTTCT"GGTTTATTCTTTCATTCCTTTTCTAGCTTC':'TAGTTTAGT.5820


CATGCCTTTCCCTCT.-",AGTGCTGCCTTAC~TGCPCCCTGTGTTTTGATGTGAAGTAATCTCAACATCAGC15890


CACTTTCAAGTGTTC'~TAAAATACTTCAAAGTGTTAATACTTCTTTTAAGTATTCTTATTCTGTGATTTT'_590'0


TTTCTTTGTGCACGCTGTGTTTTGACGTG:1AATCATTTTGATATCAGTGACTTTTAAGTAT;CTTTAG~".'10030




CA 02316282 2000-06-21
Le A 32 808-Foreign Countries
-28-
TATTCTGTGATTTCTTTGAGCAGTGAGTTATTTGAACACTGTTTATGTTC GAGTATCAAG16100
AAGATATGTA


ATACGTAGAGTATTTTAAGTTATCATTTTATTATTGATTTCTAACTCAGTTGTGTAGTGGTCTGTATAAT16170


ACCAATTATTTGAAGTTTGCGGAGCCTTGCTTTGTGATCTAGTGTGTGCATGGTTTCCAGAACTGTCCAT16290


TGTAAATTTGACATCCTGTCAATAGTGGGCATGCATGTTCACTATATCCAGCTTATTAAGGTCCAGTGCA16310
S


AAGCTTCTGTCTCCTTCTAGATGCATGAAATTCCAAGAAGGAGGCCATAGTCCCTCACCTGGGGGATGGG16380


TCTGTTCATTTCTTCTCGTTTGGTAGCATTTATGTGAGGCATTGTTAGGTGCATGCACGTGGTAGAATTT16450


TTATCTTCCTGATGAGTGAATCTTTTGGAGACTTCTATGTCTCTAGTAATCTAGTAATTCTTTTTTTAAA16520


TTGCTCTTAGTACTGCCACACTGGGCTTCTTTTGATTAGTATTTTCCTGCTGTGTCTGTTTTCTGCCTTT16590


AATTTATATATATATATATATTTTTTTTTTTTTTGAGACAGAGTCTTGGTCTGTCGCCCAGGGTGAGTGC16660
IO


AGTGGTGTGATCACAGGTCAGTGTAACTTTTACCTTCTGGCCTGAGCCGTCCTCTCACCTCAGCCTCCTG16730


AGTAGCTGGAACTGCAGACACGCACCGCTACACCTGGCTAATTTTTAAATTTTTTCTGGAGACAGGGTCT16800


TGCTGTGTTGCCCAGGCTGGTCTCAAACTCTTGGACTCAAGGGATCCATCTACCTCGGCTTCCCAAAGTG16870


CTGAATTACAGGCATGAGCCACCATGTCTGGCCTAATTTTCAACACTTTTATATTCTTATAGTGTGGGTA16990


TGTCCTGTTAACAGCATGTAGGTGAATTTCCAATCCAGTCTGACAGTCGTTGTTTAACTGGATAACCTGA17010
IS


TTTATTTTCATTTTTTTGTCACTAGAGACCCGCCTGGTGCACTCTGATTCTCCACTTGCCTGTTGCATGT17080


CCTCGTTCCCTTGTTTCTCACCACCTCTTGGGTTGCCATGTGCGTTTCCTGCCGAGTGTGTGTTGATCCT17150


CTCGTTGCCTCCTGGTCACTGGGCATTTGCTTTTATTTCTCTTTGCTTAGTGTTACCCCCTGATCTTTTT17220


ATTGTCGTTGTTTGCTTTTGTTTATTGAGACAGTCTCACTCTGTCACCCAGGCTGGAGTGTAATGGCACA17290


ATCTCGGCTCACTGCAACCTCTGCCTCCTCGGTTCAAGCAGTTCTCATTCCTCAACCTCATGAGTAGCTG17360
2O


GGATTACAGGCGCCCACCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGATAGGCTTTCACCATGT17930


TGGCCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCTGCCCGCCTTGGCCTCCCACAGTGCTGGGATT17500


ACAGGTGCAAGCCACCGTGCCCGGCATACCTTGATCTTTTAAAATGAAGTCTGAAACATTGCTACCCTTG17570


TCCTGAGCAATAAGACCCTTAGTGTATTTTAGCTCTGGCCACCCCCCAGCCTGTGTGCTGTTTTCCCTGC17690


TGACTTAGTTCTATCTCAGGCATCTTGACA'CCCCCACAAGCTAAGCATTATTAATATTGTTTTCCGTGTT17710
2S G
G


A GTAGCTTTGCCCCCGCCCTGCTTTTCCTCCTTTGTTCCCCGTCTGTCTTCTGTCTCAGGC17780
TGTTTCT


CCGCCGTCTGGGGTCCCCTTCCTTGTCCTTTGCGTGGTTCTTCTGTCTTGTTATTGCTGGTAAACCCCAG17850


CTTTACCTGTGCTGGCCTCCATGGCATCTAGCGACGTCCGGGGACCTCTGCTTATGATGCACAGATGAAG17920


ATGTGGAGACTCACGAGGAGGGCGGTCATCTTGGCCCGTGAGTGTCTGGAGCACCACGTGGCCAGCGTTC17990


CTTAGCCAGTGAGTGACAGCAACGTCCGCTCGGCCTGGGTTCAGCCTGGAAAACCCCAGGCATGTCGGGG18060
3
O


TCTGGTGGCTCCGCGGTGTCGAGTTTGAAATCGCGCAAACCTGCGGTGTGGCGCCAGCTCTGACGGTGCT18130


GCCTGGCGGGGGAGTGTCTGCTTCCTCCCTTCTGCTTGGGAACCAGGACAAAGGATGAGGCTCCGAGCCG18200


TTGTCGCCCAACAGGAGCATGACGTGAGCCATGTGGATAATTTTAAAATTTCTAGGCTGGGCGCGGTGGC18270


TCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCGGGTGGATCACGAGGTCAGGAGGTCGAGACCAT18390


CCTGGCCAACATGATGAAACCCCATCTGTACTAAAAACACAAAAATTAGCTGGGCGTGGTGGCGGGTGCC18910


JS
TGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACC'TGGGAGTTGGAAGTTGCAGTGA18980


GCCGACATTGCACCACTGCACTCCAGCCTGGCAACACAGCGAGACTCTGTCTCAAAAAAAAAAAAAAAAA18550


AAAAAAAAAAAATTCTAGTAGCCACATTAAAAAAGTAAAAAAGAAAAGGTGAAATTAATGTAATAATAGA18620


TTTTACTGAAGCCCAGCATGTCCACACCTCATCATTTTAGGGTGTTATTGGTGGGAGCATCACTCACAGG18690


ACATTTGACATTTTTTGAGCTTTGTCTGCGGGATCCCGTGTGTAGGTCCCGTGCGTGGCCATCTCGGCCT18760


GGACCTGCTGGGCTTCCCATGGCCATGGCTGTTGTACCAGATGGTGCAGGTCCGGGATGAGGTCGCCAGG18830


CCCTCAGTGAGCTGGATGTGCAGTGTCCGGATGGTGCACGTCTGGGATGAGGTCGCCAGGCCCTGCTGTG18900


AGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTGAGCTGGAGGT18970


ATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCT19090


GGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTAAGCTGGAGGTATGGAGTCCGGATGATGCA19110
4S


GGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGG19180


TGAGGTCACCAGGCCCTGCGGTGAGCTGGGTGTGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGC19250


CAGACGGTGCCAGACCATGCGGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTTG19320


CCAGGCCCTGCTGTGAGTTGGATGTGGGGTGTCCGGATGCTGCAGGTCCGGTGTGAGGTCACCAGGCCCT19390


GCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGGTGAAGGTCGCCAGGCCCCTGCTTGTG19960
S
O


AGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGT19530


GCAGTGTCCAGATGGTGCAGGTCCGGGGTGAGGTCGCCAGACCCTGCGGTGAGCTGGATGTGCGGTGTCT19600


GGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGTATGGAGTCCGGATGGTGCC19670


GGTCCGGGGTGAGGTCGCCAGACCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATGGTACAGGTCTGGAG19740


TGAGGTCGCCAGACCCTGCTGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCAGGGGTGAGGTCTC19810
SS


CAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGC19880


TGTGAACTGGATGTGCGGCGTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGG19950


AGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCGGC20020


GTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGA20090


TGCAGGTCCGGGGTGAGGTTGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGTCCG20160
GO


GGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCTGGGGTGAGGT20230


CACCAGGCCCTGCGGTGAGCTGGTTGTGCGGTGTCCGGTTGCTGCAGGTCCGGGGTGAGTTCGCCAGGCC20300


CTCGGTGAGCTGGATGTGCGGTGTCCCCGTGTCCGGATGGTGCAGGTCCAGGGTGAGGTCGCTAGGCCCT20370


TGGTGGGCTGGATGTGCCGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCTTTGGTGAGCTG20990


GATGTGCGGTGTCTGCATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCCTTGGTGGGCTGGATGTGTGGT20510
C)S


GTCCGGATGGTGCAGGTCCGGCGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATG20580


GTGCAGGTCCGGGGTGAGGTAGCCAAGGCCTTCGGTGAGCTGGATGTGGGGTGTCCGGA"'GGTGCAGGTC20650


CGGGGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCCGGGGTGAG20720


GTCACCAGGCCCTGCGGTTAGCTGGATGTGCGGTGTCTGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGG20790


CCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCAGT20860


GAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCTGGCGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGAT20930


ATGCGGTGTCGGATGGTGCAGGTCCGGGGTGAGGTCACCAGGCCCTGCGGTTAGCTGG..-.TGTG~GGTGTC21000


CGGATGGTG:~AGGTCTGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCTGT.'-
.T~CGGAT.GGTG21070


CAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTGAGCTGGATGTGCTGTATCCGGATG;~TGCAGGTCTGG21190


CGTGAGGTCGCCAGGCCCTGCGGTGAGCTGGATGTGCAGTGTACGGATGGTGCAGGTC:~GGGTGAGGTC21210
7S '


GCCAGGCCCGCGGTGGGCTGTATGTGTGTTGTCTGGATGGTGCAGGTCCGGGGTGAG:':'CGC,P.GGCCC21280


TGCGGTGAGCTGGATGTGTGGTGTCTGG~ITGCTGCAGGTCCGGGGTGAGT.T~GCCAGG~:CTCGGTGAGC21350


TGGATA'rGCGGTGTCCCCGTGTCCGAATGGTGCAGGTCCAG:~GTGAGGTCGCCAGGCC::"TGG"'GGGCTG21420



GATGTGCCG'."GTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCC:T GGTGi,GC,AT'~: 21990
':~ GCGGT




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-29-
GTCCGGATGGTGCAGGTCCG ACCAGGCCCT GATGTGGCATGTCCTTCTCG21560
GGGTGAGGTC CGGTGATCTG


TTTAAGGGGTTGGCTGTGTTCCGGCCGCAGAGCACCGTCTGCGTGAGGAGATCCTGGCCAAGTTCCTGCA21630


CTGGCTGATGAGTGTGTACGTCGTCGAGCTGCTCAGGTCTTTCTTTTATGTCACGGAGACCACGTTTCAA21700


AAGAACAGGCTCTTTTTCTACCGGAAGAGTGTCTGGAGCAAGTTGCAAAGCATTGGAATCAGGTACTGTA21770
S


TCCCCACGCCAGGCCTCTGCTTCTCGAAGTCCTGGAACACCAGCCCGGCCTCAGCATGCGCCTGTCTCCA21890


CTTGCCTGTGCTTCCCTGGCTGTGCAGCTCTGGGCTGGGAGCCAGGGGCCCCGTCACAGGCCTGGTCCAA21910


GTGGATTCTGTGCAAGGCTCTGACTGCCTGGAGCTCACGTTCTCTTACTTGTAAAATCAGGAGTTTGTGC21980


CAAGTGGTCTCTAGGGTTTGTAAAGCAGAAGGGATTTAAATTAGATGGAAACACTACCACTAGCCTCCTT22050


GCCTTTCCCTGGGATGTGGGTCTGATTCTCTCTCTCTTTTTTTTTTCTTTTTTGAGATGGAGTCTCACTC22120
IO


TGTTGCCCAGGCTGGAGTGCAGTGGCATAATCTTGGCTCACTGCAACCTCCACCTCCTGGGTTTAAGCGA22190


TTCACCAGCCTCAGCCTCCTAAGTAGCTGGGATTACAGGCACCTGCCACCACGCCTGGCTAATTTTTGTA22260


CTTTTAGGAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCATGACCTCAGGTGATCCAC22330


CCACCTTGGCCTCCCAAAGTGCTGGGTTTACAGGCTAAGCCACCGTGCCCAGCCCCCGATTCTCTTTTAA22900


TTCATGCTGTTCTGTATGAATCTTCAATCTATTGGATTTAGGTCATGAGAGGATAAAATCCCACCCACTT22470
IS


GGCGACTCACTGCAGGGAGCACCTGTGCAGGGAGCACCTGGGGATAGGAGAGTTCCACCATGAGCTAACT22590


TCTAGGTGGCTGCATTTGAATGGCTGTGAGATTTTGTCTGCAATGTTCGGCTGATGAGAGTGTGAGATTG22610


TGACAGATTCAAGCTGGATTTGCATCAGTGAGGGACGGGAGCGCTGGTCTGGGAGATGCCAGCCTGGCTG22680


AGCCCAGGCCATGGTATTAGCTTCTCCGTGTCCCGCCCAGGCTGACTGTGGAGGGCTTTAGTCAGAAGAT22750


CAGGGCTTCCCCAGCTCCCCTGCACACTCGAGTCCCTGGGGGGCCTTGTGACACCCCATGCCCCAAATCA22820
2O


GGATGTCTGCAGAGGGAGCTGGCAGCAGACCTCGTCAGAGGTAACACAGCCTCTGGGCTGGGGACCCCGA22890


CGTGGTGCTGGGGCCATTTCCTTGCATCTGGGGGAGGGTCAGGGCTTTCCCTGTGGGAACAAGTTAATAC22960


ACAATGCACCTTACTTAGACTTTACACGTATTTAATGGTGTGCGACCCAACATGGTCATTTGACCAGTAT23030


TTTGGAAAGAATTTAATTGGGGTGACCGGAAGGAGCAGACAGACGTGGTGGTCCCCAAGATGCTCCTTGT23100


CACTACTGGGACTGTTGTTCTGCCTGGGGGGCCTTGGAGGCCCCTCCTCCCTGGACAGGGTACCGTGCCT23170
2S


TTTCTACTCTGCTGGGCCTGCGGCCTGCGGTCAGGGCACCAGCTCCGGAGCACCCGCGGCCCCAGTGTCC23290


ACGGAGTGCCAGGCTGTCAGCCACAGATGCCCAGGTCCAGGTGTGGCCGCTCCAGCCCCCGTGCCCCCAT23310


GGGTGGTTTTGGGGGAAAAGGCCAAGGGCAGAGGTGTCAGGAGACTGGTGGGCTCATGAGAGCTGATTCT23380


GCTCCTTGGCTGAGCTGCCCTGAGCAGCCTCTCCCGCCCTCTCCATCTGAAGGGATGTGGCTCTTTCTAC23450


CTGGGGGTCCTGCCTGGGGCCAGCCTTGGGCTACCCCAGTGGCTGTACCAGAGGGACAGGCATCCTGTGT23520
3 G
O


GAGGGGCAT GGGTTCACGTGGCCCCAGATGCAGCCTGGGACCAGGCTCCCTGGTGCTGATGGTGGGACA23590


GTCACCCTGGGGGTTGACCGCCGGACTGGGCGTCCCCAGGGTTGACTATAGGACCAGGTGTCCAGGTGCC23660


CTGCAAGTAGAGGGGCTCTCAGAGGCGTCTGGCTGGCATGGGTGGACGTGGCCCCGGGCATGGCCTTCAG23730


CGTGTGCTGCCGTGGGTGCCCTGAGCCCTCACTGAGTCGGTGGGGGCTTGTGGCTTCCCGTGAGCTTCCC23800


CCTAGTCTGTTGTCTGGCTGAGCAAGCCTCCTGAGGGGCTCTCTATTGCAGACAGCACTTGAAGAGGGTG23870
3 C
S


AGCTGCGGG AGCTGTCGGAAGCAGAGGTCAGGCAGCATCGGGAAGCCAGGCCCGCCCTGCTGACGTCCA23990


GACTCCGCTTCATCCCCAAGCCTGACGGGCTGCGGCCGATTGTGAACATGGACTACGTCGTGGGAGCCAG29010


AACGTTCCGCAGAGAAAAGAGGGTGGCTGTGCTTTGGTTTAACTTCCTTTTTAAACAGAAGTGCGTTTGA29090


GCCCCACATTTGGTATCAGCTTAGATGAAGGGCCCGGAGGAGGGGCCACGGGACACAGCCAGGGCCATGG29150


CACGGCGCCAACCCATTTGTGCGCACAGTGAGGTGGCCGAGGTGCCGGTGCCTCCAGAAAAGCAGCGTGG29220
4O


GGGTGTAGGGGGAGCTCCTGGGGCAGGGACAGGCTCTGAGGACCACAAGAAGCAGCCGGGCCAGGGCCTG29290


GATGCAGCACGGCCCGAGGTCCTGGATCCGTGTCCTGCTGTGGTGCGCAGCCTCCGTGCGCTTCCGCTTA29360


CGGGGCCCGGGGACCAGGCCACGACTGCCAGGAGCCCACCGGGCTCTGAGGATCCTGGACCTTGCCCCAC24930


GGCTCCTGCACCCCACCCCTGTGGCTGCGGTGGCTGCGGTGACCCCGTCATCTGAGGAGAGTGTGGGGTG29500


AGGTGGACAGAGGTGTGGCATGAGGATCCCGTGTGCAACACACATGCGGCCAGGAACCCGTTTCAAACAG29570
4S


GGTCTGAGGAAGCTGGGAGGGGTTCTAGGTCCCGGGTCTGGGTGGCTGGGGACACTGGGGAGGGGCTGCT24690


TCTCCCCTGGGTCCCTATGGTGGGGTGGGCACTTGGCCGGATCCACTTTCCTGACTGTCTCCCATGCTGT29710


CCCCGCCAGGCCGAGCGTCTCACCTCGAGGGTGAAGGCACTGTTCAGCGTGCTCAACTACGAGCGGGCGC29780


GGCGCCCCGGCCTCCTGGGCGCCTCTGTGCTGGGCCTGGACGATATCCACAGGGCCTGGCGCACCTTCGT29850


GCTGCGTGTGCGGGCCCAGGACCCGCCGCCTGAGCTGTACTTTGTCAAGGTGGGTGCCGGGGACCCCCGT29920
S
O


GAGCAGCCCTGCTGGACCTTGGGAGTGGCTGCCTGATTGGCACCTCATGTTGGGTGGAGGAGGTACTCCT24990


GGGTGGGCCGCAGGGAGTGCAGGTGACCCTGTCACTGTTGAGGACACACCTGGCACCTAGGGTGGAGGCC25060


TTCAGCCTTTCCTGCAGCACATGGGGCCGACTGTGCACCCTGACTGCCCGGGCTCCTATTCCCAAGGAGG25130


GTCCCACTGGATTCCAGTTTCCGTCAGAGAAGGAACCGCAACGGCTCAGCCACCAGGCCCCGGTGCCTTG25200


CACCCCAGTCCTGAGCCAGGGGTCTCCTGTCCTGAGGCTCAGAGAGGGGACACAGCCCGCCCTGCCCTTG25270
SS


GGGTCTGGAGTGGTGGGGGTCAGAGAGAGAGTGGGGGACACCGCCAGGCCAGGCCCTGAGGGCAGAGGTG25390


ATGTCTGAGTTTCTGCGTGGCCACTGTCAGTCTCCTCGCCTCCACTCACACAGGTGGATGTGACGGGCGC25910


GTACGACACCATCCCCCAGGACAGGCTCACGGAGGTCATCGCCAGCATCATCAAACCCCAGAACACGTAC25980


TGCGTGCGTCGGTATGCCGTGGTCCAGAAGGCCGCCCATGGGCACGTCCGCAAGGCCTTCAAGAGCCACG25550


TAAGGTTCACGTGTGATAGTCGTGTCCAGGATGTGTGTCTCTGGGATATGAATGTGTCTAGAATGCAGTC25620
6O


GTGTCTGTGATGCGTTTCTGTGGTGGAGGTACTTCCATGATTTACACATCTGTGATATGCGTGTGTGGCA25690


CGTGTGTGTCGTGGTGCATGTATCTGTGGCGTGCATATTTGTGGTGTGTGTGTGTGTGGCACGTGTGTGT25760


CCATGGTGTGTGTGCCTGTGGTGTGCATGTGTGTGTGTCTGTGACACGTGCATGTTCATGCTGTGTGCTG25830


CATGTCTGTGATGTGCCTATTTGTGGTGTGTGTGTGCATGTGTCCGTGACATATGCGTGTCTATGGCATG25900


GGTGTGTGTGGCCCCTTGGCCTTr~CTCCTTCCTCCTCCAGGCATGGTCCGCACCATTGTCCTCACGCTCT25970
C)S


CGGGTGCTGGTTTGGGGAGCTCCACATTCAGGGTCCTCACTTCTAGCATGGGTGCCCCTGTCCTGTCACA26040


GGGCTGGGCCTTGGAGACTGTA.;~CC.aGGTTTGAGAGGAGAGTAGGGATGCTGGTGGTACCTTCCTGGAC26110


CCCTGGCACCCCCAGGACCCC~~TCTGG~CTATGCCGGCTCCATGAGATATAGGAAGGCTGATTCAGGCC26180


TCGCTCCCCGGGACACACTCCTCCCAGAGCGGCCGGGGGCCTTGGGGCTCGGCAGGGGTGAAAGGGGCCC26250


TGGGCTTGGGTTCCCACCCAGTGGTCATGAGCACGCTGGAGGGGTAAGCCCTCAAAGTCGTGCCAGGCCG26320
7O


GGGTGCAGAGGTGAAGAAGTAT~~CCT~Ga,GCTTCGGTCTGGGGAGAGGCACATGTGGAAACCCACAAGGA26390


CCTCTTTCTCTGACTTCTTGA.~__ 26419




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-30-
Contig 2:
TGTGGGATTGGTTTTCATGTGTGGGATAGG TGGGATTGGT GGGGTAACAC70
TGGGGATCTG TTTTATGAGT


AGAGTTCAAGGCGAGCTTTCTTCCTGTAGTGGGTCTGCAGGTGCTCCAACAGCTTTATTGAGGAGACCAT190


ATCTTCCTTTGAACTATGGTCGGGTTTATAGTAAGTCAGGGGTGTGGAGGCCTCCCCTGGGCTCCCTGTT210
S


CTGTTTCTTCCACTCTGGGGTCGTGTGGTGCCTGCTGTGGTGTGTGGCCGGTGGGCAGGGCTTCCAGGCC280


TCCTTGTGTTCATTGGCCTGGATGTGGCCCTGGCTACGCTCCGTCCTTGG CGAGTTGGAG350
AATTCCCCTG


GCTTTCTTTCTTTCTTTTTTTCTTTCTTTTTTTTTTTTTTTGATAACAGAGTCTCGCTCTTTTTTGCCCA920


GGCTGGAGTGGTTTGGCGTGATCTTGGCTCACTGCAACCTGTGCTTCCTGAGTTCAAGCAATTCTCTTGC990


CTCAGCCTCCCAAGTAGCTGGAATTATAGGCGCCCACCACCATGCTGACTAATTTTTGTAATTTTAGTAG560
IO


AGACGAGGTTTCTCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCTCCCACCTCGGC630


CTCCCAAAGTGCTGGGATGACAGGTGTGAACCGCCGCGCCCGGCCGAGACTCGCTTCCTGCAGCTTCCGT700


GAGATCTGCAGCGATAGCTGCCTGCAGCCTTGGTGCTGACAACCTCCGTTTTCCTTCTCCAGGTCTCGCT770


AGGGGTCTTTCCATTTCATGACTCTCTTCACAGAAGAGTTTCACGTGTGCTGATTTCCCGGCTGTTTCCT890


GCGTAATTGGTGTCTGCTGTTTATCGATGGCCTCCTTCCATTTCCTTTAGGCTTTGTTTATTGTTGTTTT910
IS


TCCGGCTCCTTGAAGGAAAAGTTTCGATTATGGATGTTTGAACTTTCTTTTCTAAACAAGCATCTGAAGT980


TGCCGTTTTCCCTCTAAAGCAGGGATCCCGAGGCCCCTGGCTGTGGAGTGGCACCGGTCTGGGGCCTGTT1050


AGGAACCCGGCGCACAGCGGGAGGCTAGGTGGGGTGTGGGGAGCCAGCGTTCCCGCCTGAGCCCCGCCCC1120


TCTCAGATCAGCAGTGGCATGCi;GTGCTCAGAGGCGCACACACCCTACTGAGAACTGTGCGTGAGAGGGG1190


TCTAGATTCTGTGCTCCTTATGGGAATCTAATGCCTGATGATCTGAGGTGGAACCGTTTGCTCCCAAAAC1260
2
O


CATCCCCTTCCCCACTGCTGTCCTGTGGAAAAATCGTCTTCCACGAAACCAGTCCCTGGTACCACAATGG1330


TTGGGGACCCTGTGCTAAAGACCTGCTTCAGCAGCCTCTCGTCAGTGTTGATATATTGGCTTTTCTGTGT1900


TGAGTCCAGAATAATTACGGATTTCTGTGA.TGCTTTCCGCCGACCTCAGACCCATGGGCTATTTGTGGGC1470


GTGTTGCCTGCTCCTGGGTTGGGAAGGGTGCAGGCCCCATGTACCTTCCTGTTACTGCCTTCCAGGTTGG1540


TTCTCAGGGTTGAATCGTACTCGATGTGGTTTTAGCCCACGGCCCTGCCGCCAGCTCCTGGGGGCTGGGG1610
2S


AACATGCTGAAGCACAGAGTCACCGTGCGCGTCTTTTGATGCCTCACAAGCTCGAGGCCTCCTGTGTCCG1680


TGTTAGTGTGTGTCACGTGCCTGCTCACATCCTGTCTTGGGGACGCAGGGGCTTAGCAGGTCCCGTAGTA1750


AATGACAAGCGTCCTGGGGGAGTCTGCAGAATAGGAGGTGGGGGTGCCGGTCTCTCTCCCGCGTCTTCAG1820


ACTCTTCTCCTGCCTGTGCTGTGGCTGCACCTGCATCCCTGCAATCCCTCCAGCACTGGGCTGGAGAGGC1890


CCGGGAGCTCGAGTGCCACTTGTGCCACGTGACTGTGGATGGCAGTCGGTCACGGGGGTCTGATGTGTGG1960
3
O


TGACTGTGGATGGCGGTTGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2030


TGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2100


TGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2170


TGGTGAC'TGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2290


TGGTGACTGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG2310
3
S


TGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2380


TGTGTGG'PGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA2450


TGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGG2520


GGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCG2590


GTCGivGv'GTCTGATGTGTGGTGACTGTGGATGGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTG2660
4O


GATGGCGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGT2730


GACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGT2800


GACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGT2870


GACTGTGGATGGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGAT2990


GTGGTGACTGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGAT3010
4
S


GTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTG3080


ATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTG3150


ATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTG3220


GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTG3290


GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTAGGGTCTGATGTGTGGTGACTGTGGATGGCAGTCG3360
S
O


GTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATG3930


GCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGA3500


TGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTAGCT3570


GCAGGTGGAGTCCCAGGTGTGTCTGTAGCTACTTTGCGTCCTCGGCCCCCCGGCCCCCGTTTCCCAAACA3690


GAAGCTTCCCAGGCGCTCTCTGGGCTTCATCCCGCCATCGGGCTTGGCCGCAGGTCCACACGTCCTGATC3710
SS


GGAAGAAACAAGTGCCCAGCTCTGGCCGGGGCAGGCCACATTTGTGGCTCATGCCCTCTCCTCTGCCGGC3780


AGGTCTCTACCTTGACAGACCTCCAGCCGTACATGCGACAGTTCGTGGCTCACCTGCAGGAGACCAGCCC3850


GCTGAGGGATGCCGTCGTCATCGAGCAGGTCTGGGCACTGCCCTGCAGGGTTGGGCACGGACTCCCAGCA3920


GTGGGTCCTCCCCTGGGCAATCACTGGGCTCATGACCGGACAGACTGTTGGCCCTGGGGGGCAGTGGGGG3990


GAATGAGCTGTGATGGGGGCATGATGAGCTGTGTGCCTTGGCGAAATCTGAGCTGGGCCATGCCAGGCTG9060
6O


CGACAGCTGCTGCATTCAGGCACCTGCTCACGTT.TGACTGCGCGGCCTCTCTCCAGTTCCGCAGTGCCTT913J


TGTTCATGATTTGCTAAATGTCTTCTCTGCCAGTTTTGATCTTGAGGCCAAAGGAAAGGTGTCCCCCTCC92CJ


TTTAGGAGGGCAGGCCATGTTTGAGCCGTGTCCTGCCCAGCTGGCCCCTCAGTGCTGGGTCTGAGGCCAA4270


AGGAAACGTGTCCCCCTTCTTAGGAGGACGGGCCGTGTTTGAGCCACGCCCCGCTGAGCGGGCCTCTCAG934J


TGCTGGGTCTGTCCACGTGGCCCTGTGGCCCTTTGCAGATGTGGTCTGTCCACGTGGCCCTGTGGCTCTT941J
C
J


TGCAGATGCCTGTTAGCACTTGCTCGGCTCTAGGGGACAGTCGTGTCCACCGCATGAGGCTCAGAGACCT448:7


CTGGGCGAATTTCCTTGGCTCCCAGGGTGGGGGTGGAGGTGGCCTGGGCTGCTGGGACCCAGACCCTGTG455)


CCCGGCAGCTGGGCAGCAACTCCTGGATCACATATGCCATCCGGGCCACGGTGGGCTGTGTGGGTGTGAG46~J


CCCAGCTGGACCCACAGGTGGCCCAGAGGAGACGTTCTGTGTCACACACTCTGCCTAAGCCCATGTGTGT969J


CTGCAGAGACTCGGCCCGGCCAGCCCACGATGGCCCTGCATTCCAGCCCAGCCCCGCACTTCATCACi-_i,A970
7O


CACTGACCCC GAGGGTCTTGGCCACGTGGTCCTGCCTGTCTCAGCACCCACCGGCTCACT983;
AAAAGGGACG


CCCATGTGTC TTTCGCAGAGCTCC':CCCTG GCAGTGGCCTCTTCGACGTC49CJ
TCCCGTCTGC AATGAGGCCA


TTCCTACGCT CCACGCCGTGCGCATCAGGGGCAAGTGAGTCAGGTGGCCAGGTGCCATTG99,7
TCATGTGCCA


CCCTGCGGGT
GCTGGCAGGGCT.TC'_"GC':CACCTCTCTCCTGCCCC:'TCCCCACTGtICC'.".'S04J
GGCTGGGCGG


CTGCCCGGGG CTCCTTTTCTG CCTGGGCTGCAGGCTCCCGA511
7J CCACCAGe'~GT v CCCCCGCC
CCCTCCGGCT


GGCCCCGGAA GCTTGCGGCAGCCGGAGCGG ACACGAGGCCTGGAAAT~~~C518J
ACATGGCTCG AGCAGGTGCC


P.AGCGGGGTG CCTGCGTGGAGGACGA~GGG GTCTGGGTCA~GTGTGC;~~~-.5:'
TGGAGTTGCT CGGGGGGTGT




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-31 -
GAGCGTTTGAGCCTGCAGCTTGTCAGCTCC TGACGCTGGACACCCGGCTCTCACACGCTT5320
AAGTTACTAC


GTATCTCTCTCTCCCGATAC TATCCGATTCTCATTCCTGTCCCTGTCGTGTGACCCCCGC5390
AAAAGGATTT


GAGGGCGCGGGCTCTTCTCTCTGTGACTAGATTTCCCATCTGGAAAGTGCGGGGTTGACCGTGTAGTTTG5960


CTCCTCTCGGGGGGCCTGTGGTGGCCATGGGGCAGGCGGCCTGGGAGAGCTGCCGTCACACAGCCACTGG5530
S


GTGAGCCACACTCACGGTGGTAGAGCCACAGTGCCTGGTGCCACATCACGTCCTCTGGATTTTAAGTAAA5600


ACCACACACCTCCCGGCAGGCATCTGCCTGCGACCCTGTGTGTGCCTGGGGAGAGTGGTAGCACGGAGGA5670


AATTCGTGCACACTCAAGGTCATCAGCAAGGTCATCCGCAGTCAGGTGGAACGTGGAGGCCTCTCTCTGG5790


GATCGTCTCCAGCGGATAAAGGACTGTGCACAGCTTCGGAAGCTTTTATTTAAAAATATAACTATTAATT5810


ATTGCATTATAAGTAATCACTAATGGTATCAGCAATTATAATATTTATTAAAGTATAATTAGAAATATTA5880
IO


AGTAGTACACACGTTCTGGAAAAACACAAATTGCACATGGCAGCAGAGTGAATTTTGGCCGAGGGACACG5950


TGTGCACATGTGTGTAAGCGGCCCCCAGGCCCACAGAATTCGCTGACAAAGTCACCTCCCCAGAGAAGCC6020


ACCACGGGCCTCCTTCGTGGTCGTGAATTTTATTAAGATGGATCAAGTCACGTACCGTCCACGTGTGGCA6090


GGGCTTTGGGGAATGTGAGGTGATGACTGCGTCCTCATGCCCTGACAGACAGGAGGTGACTGTGTCTGTC6160


CTGTCCCTAGGACACGGACAGGCCCGAAGCTCTAGTCCCCATCGTGGTCCAGTTTGGCCTCTGAATAAAA6230
IS A


CGTCTTCAAAACCTGTTGCCCCAAAAACTAAGAACAGAGAGAGTTTCCCATCCCATGTGCTCACAGGGG6300


CGTATCTGCTTGCGTTGACTCGCTGGGCTGGCCGGACTCCTAGAGTTGGTGCGTGTGCTTCTGTGCAAAA6370


AGTGCAGTCCTCTTGCCCATCACTGTGATATCTGCACCAGCAAGGAAAGCCTCTTTTCTTTTCTTTCTTT6990


TTTTTTTTTTGAGACGGAACGTCACTGTTGTCTGCCTGGGCTTGAGTGCAGTGGCGCGATCTCAACTCAC6510


TGCAACCTCCGCCTCCCGGGTTCCAGCATTTCTCCTGCCTCAGCCTCCCGAGCAGCTGAGATTACAGGCA6580
2O


CCCACCCCCTGCGCCTGGCTAATTTTTGTATTTTTAGTAGAGAGGGGTTTTTGCCATGTTGGCCAGGCTG6650


GTCTCGAACTCCTGACCTCAGGTGATCCACCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAG6720


CCATCACGCCCAGCCGGAAAGCCTCTTTTTAAGGTGACCACCTATAGCGCTTCCCGAAAATAACAGGTCT6790


TGTTTTTGCAGTAGGCTGCAAGCGTCTCTTAGCAACAGGAGTGGCGTCCTGTGGGCTCTGGGGATGGCTG6860


AGGGTCGCGTGGCAGCCATGCCTTCTGTG'I'GCACCTTTAGGTTCCACGGGGCTATTCTGCTCTCACTGTT6930
2S


TGTCTGAAAACGCACCCTTGGCATCCTTGTTTGGAGAGTTTCTGCTTCTCGTTGGTCATGCTGAAACTAG7000


GGGCAAGGTTGTATCCGTTGGCGCGCAGCGGCTACATGTAGGGTCATGAGTCTTTCACCGTGGACAAATT7070


CCTTGAAAAAAAAAAAAGGAGTCCGGTTAAGCATTCATTCCGGGTCAAGTGTCTGGTTCTGTGAATAAAC7190


TCTAAGATTTAAGAAACCTTAATGAAAGAAAACCTTGATGATTCAGAGCAAGGATGTGGTCACACCTGTG7210


GCTGGATCTGTTTCAGCCGCCCCAGTGCATGGTGAGAGTGGGGAGCAGGGATTGTTTGTTCAGAGGTCTC7280
3
O


ATCTGGTATGTTTCTGAGGTGTTTGCCGGCTGAATGGTAGACGTGTCGTTTGTGTGTATGAGGTTCTGTG7350


TCTGTGTGTGGCTCGGTTTGAGTGTACGCATGTCCAGCACATGCCCTGCCCGTCTCTCACCTGTGTCTTC7420


CCGCCCCAGGTCCTACGTCCAGTGCCAGGGGATCCCGCAGGGCTCCATCCTCTCCACGCTGCTCTGCAGC7490


CTGTGCTACGGCGACATGGAGAACAAGCTGTTTGCGGGGATTCGGCGGGACGGGTGAGGCCTCCTCTTCC7560


CCAGGGGGGCTTGGGTGGGGGTTGATTTGCTTTTGATGCATTCAGTGTTAATATTCCTGGTGCTCTGGAG7630
3
S


ACCATGACTGCTCTGTCTTGAGGAACCAGACAACGTTGCAGCCCCTTCTTGGTATGAAGCCGCACGGGAG7700


GGGTTGCACAGCCTGAGGACTGCGGGCTCCACGCAGGCTCTGTCCAGCGGCCATGTCCAGAGGCCTCAGG7770


GCTCAGCAGGCGGGAGGGCCGCTGCCCTGCATGATGAGCATGTGAATTCAACACCGAGGAAGCACACCAG7840


CTTCTGTCACGTCACCCAGGTTCCGTTAGGGTCCTTGGGGAGATGGGGCTGGTGCAGCCTGAGGCCCCAC7910


ATCTCCCAGCAGGCCCTCGACAGGTGGCCTGGACTGGGCGCCTCTTCAGCCCATTGCCCATCCCACTTGC7980


ATGGGGTCTACACCCAAGGACGCACACACCTAAATATCGTGCCAACCTAATGTGGTTCAACTCAGCTGGC8050


TTTTATTGACAGCAGTTACTTTTTTTTTTTTAATACTTTAAGTTCTAGGGTACATGTGCACGACGTGCAG8120


~TTAGTTACATATGTATACATGTGCCATGTTGGTGTGCTGCACCCATTAACTCATCATTTACATTAGGTA8190


TATC.TCCTAATGCTATCCCTCCCCACTCCCCCCATCCCATGACAGGCCCTGGTGTGTGATGTTCCCCACC8260


CTGTGTCCAAGTGTTCTCATTGTTCAGTTCCCACCTGTGAGTGAGAACATGTGGTGTTTGGTTTTCTTTC8330
4S '


CT TTTGCTCAGAGTGATGGTTTCCAGCTTCGTCCATGTCCCTACAAAGGACATGAACTCATC8900
TGCAATAG


CTTTTTTATGACTGCATAGTATTCCGTGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATCGAT8970


GGACATTTGGGTTGGTTGCAAGTCTTTGCTACTGTGAATAGTGCCGCAATAAACATACGTGTGCATGTGT8540


CTTTATAGCAGCATGATTTATAATCCTTTGGGTATATACCCAGTAATGGGATGGCTGGGTCAAATGGTAT8610


T'rCTAGTTCTAGATCCTTGAGGAATCACCACACTGTCTTCCACAATGGTTGAACTAGTTTACACTCCCAC8680
S
O


CAACAGTGTAAAAGTGTTCTGGTGCTGGAGAGGATGTGGACAGCAGTTATTTTTTTATGAAAATAGTATC8750


ACTGAACAAGCAGACAGTTAGTGAAGGATGCGTCAGGAAGCCTGCAGGCCACACAGCCATTTCTCTCGAA8820


GACTCCGGGTTTTTCCTGTGCATCTTTTGAAACTCTAGCTCCAATTATAGCATGTACAGTGGATCAAGGT8890


TCTTCTTCATTAAGGTTCAAGTTCTAGATTGAAATAAGTTTATGTAACAGAAACAAAAATTTCTTGTACA8960


CACAACTTGCTCTGGGATTTGGAGGAAAGTGTCCTCGAGCTGGCGGCACACTGGTCAGCCCTCTGGGACA903C
S
S


GGATACCTCTGGCCCATGGTCATGGGGCGCTGGGCTTGGGCCTGAGGGTCACACAGTGCACCATGCCCAG9100


CTTCCTGTGGATAGGATCTGGGTCTCGGATCATGCTGAGGACCACAGCTGCCATGCTGGTAAAGGGCACC91'70


ACGTGGCTCAGAGGGGGCGAGGTTCCCAGCCCCAGCTTTCTTACCGTCTTCAGTTATTTTTCCCTAAGAG9290


TCTGAGAAGTGGGGCCGCGCCTGATGGCCTTCGTTCGTCTTCAGCTGGCACAGAATTGCACAAGCTGATG9310


GTAAACACTGAGTACTTATAATGAATGAGGAATTGCTGTAGCAGTTAACTGTAGAGAGCTCGTCTGTTGG9380
AA


AGAAATTT AAGTTTTTCATTTAACCGCTTTGGAGAATGTTACTTTATTTATGGCTGTGTAAATTGTTT9950


GACATTCAGTCCCTCGTAGACAGATACTACGTA.a.AAAGTGTAAAGTTAACCTTGCTGTGTATTTTCCCTT9520


ATTTTAGGCTGCTCCTGCGTTTGGTGGATGATTTCTTGTTGGTGACACCTCACCTCACCCACGCGAAAAC9590


CTTCCTCAGGTGAGGCCCGTGCCGTGTGTCTGTGGGGACCTCCACAGCCTGTGGGCTTTGCAGTTGAGCC9660


CCCCGTGTCCTGCCCCTGGCACCGCAGCGTTGTCTCTGCCAAGTCCTCTCTCTCTGCCGGTGCTGGATCC9730
GS


GCAAGAGCAGAGGCGCTTGGCCGTGCACCCAGGCCTGGGGGCGCAGGGGCACCTTCGGGAGGGAGTGGGT9800


ACCGTGCAGGCCCTGGTCCTG~AGAGACGCACCC.=,GGTTACACACGTGGTGAGTGCA~GGCGGTGACCTGG9370


CTCCTGCTGCTCTTTGGAAAG'."CAAG-
~,GT_GGCGGCT~CTGGGGCCCCAGTGAGACCC:CAGGAGCTGTGC9940


ACAGGGCCTGCAGGGCCGAGGCGGCAGCCTCCTCCCCAGGGTGCACCTGAGCCTGCGGAGAGCAGGAGCT10010


GCTGAGTGAGCTGGCCCACAGCGTTCGCTGCGGT~~ACGT'"CCTGCGTGGGGTTGTTT.GGGATCGGTGGGA10080
7O


GAATTTGGATTTGCTGAGTGCTGCTGTCTTGAS-
.~_.=~CGGi,GATGGCTAGGAGTGGGTT.TCAGAGTTGATT10150


TTTGTGAATCAAACTAAAATC~GGC=,~=;GGGGA~~TGGC~TCAGCACAGGGGATTGTC~AATGTGGTCCC1220


CCTCAAGGGCGCCCCACAGAG;CGGT;>GGCTTGTT:'TAA~"-
,GTGCGATTTGACGAGGGACGAGAAACCTTG1;7290


AAAGCTGTAAAGGGAACCCTCAGAAAATGTGGCCGCCAGGGGTGGTTTCAGGTGCTTTGCTGGGCTGTGT10360


TTGTGAAAACCCATTTGGACC:GCCC:CCAAGTC~ACCCTCCAGGTCCACCCTCCAGGGCCGCCCTGGGC'0430
7J TG '
"


GGGGTATG CCTGGCGTTCC AGC~~GGAG:.ACAGCAGGCTGTGCACATTTAAATCCACTA'x')500
_
TGTG'CGC


AGATTCACTCGGGGGGA~CCCAGGTCCCAAGCAr.~TGAGGGCTCAGGAGTCCTGAGGCTGCTGAGGGGAC10570


AGAGCAGACGGGGAACGCTGCTTCTGTGTGGCr.AGTTCCTGAGGGTGCTGGCCAGGGAGGTGGCTCAGAG'0640


TGTATGTTGGGGTCCCACCGG ~GGCA TCTG~'~ATGAGTCGGCAGCCATGTAACAGGAAGGGG_~i710
~.=;.,C "~T~~




CA 02316282 2000-06-21
Le A 32 805-Forei~~n Countries
-32-
TGGCCACAGG GAGCTGGGAA TGCACCAGGG GAGCTGCGCA GCTGGCCGAG
GTCCCAGGGC CAGGCCACAG 10780


GAAGGGCAGG GGGACGCCCG GGGCCACAGC AGAGGCCGCA GGAAGGGAAG
GGGATGCCCA GGCCAGAGCA 10850


GAGGCTACCG GGCACAGGGG GGCTCCCTGA GCTGGGTGAG CGAGGCTCAT10920
GACTCGGCGA GGGAACCTCC


TTGACGTGAA GCTGACGACT GGTGTTGCCC AGCTCACAGC CCAGCCAGGT10990
S CCCGCGCCTG AGCAGGAACT


CAGAACCCTC CCCTTTGTCT AAAGCACAGC AGATGCCTTC AGGGCATCTA11060
GGAGAAAACA GGCAAAGTCG


TTGAGAAACG TCTTAAAAGA AGGTGGGATG GTGGCAATTT CTTGTCCAGA11130
TTTTAGTCTG CCCCGGACCA


CAGATGAGTC TATAACGGGA TTGTGGTGTT GCCATGGGGA CACATGAGAT11200
GGACCATCAC AGAGGCCACT


GGGGCTGCAC CTCCCATCTG AGTCCTGGCT GTCCCGGGTC CAGGCCAGGT11270
TCTTGCATGC TCACCTACCT


GTCCTGCCCG GGAGACAGGG AAAGCACCCC GAAGTCTGGA GCAGGGCTGG11340
IO GTCCAGGCTC CTCAGAGCTC


CTGCCAGGCC CAGCACCCTG CTCCAAATCA CCACTTCTCT GGGGTTTTCC11910
AAAGCATTTA ACAAGGGTGT


CAGGTTACCT CCTGGGTGAC GGCCCCGCAT CCTGGGGCTG ACATTGCCCC11980
TCTGCCTTAG GACCCTGGTC


CGAGGTGTCC CTGAGTATGG CTGCGTGGTG AACTTGCGGA AGACAGTGGT11550
GAACTTCCCT GTAGAAGACG


AGGCCCTGGG TGGCACGGCT TTTGTTCAGA TGCCGGCCCA CGGCCTATTC11620
CCCTGGTGCG GCCTGCTGCT


IS GGATACCCGG ACCCTGGAGG TGCAGAGCGA CTACTCCAGG TGAGCGCACC11690
TGGCCGGAAG TGGAGCCTGT


GCCCGGCTGG GGCAGGTGCT GCTGCAGGGC CGTTGCGTCC ACCTCTGCTT11760
CCGTGTGGGG CAGGCGACTG


CCAATCCCAA AGGGTCAGAG GCCACAGGGT GCCCCTCGTC CCATCTGGGG11830
CTGAGCAGAA ATGCATCTTT


CTGTGGGAGT GAGGGTGCTC ACAACGGGAG CAGTTTTCTG TGCTATTTTG11900
GTAAAAGGAA ATGGTGCACC


AGACCTGGGT GCACTGAGGT GTCTTCAGAA AGCAGTCTGG ATCCGAACCC11970
AAGACGCCCG GGCCCTGCTG


GGCGTGAGTC TCTCAAACCC GAACACAGGG GCCCTGCTGG GCATGAGTCC12090
2O CTCTGAACCC GAGACCCTGG


GGCCCTGCTG GGCGTGAGTC TCTCCGAACC CAGAGACTTC AGGGCCCTTT12110
TGGGCGTGAG TCTCTCCGCT


GTGAGCCCCA CACTCCAAGG CTCATCCACA GTCTACAGGA TGCCATGAGT12180
TCATGATCAC GTGTGACCCA


TCAGGGGACA GGGCCATGGT GTGGGGGGGG TCTCTACAAA ATTCTGGGGT12250
CTTGTTTCCC CAGAGCCCGA


GAGCTCAAGG CCCCGTCTCA GGCTCAGACA CAAATGAATT GAAGATGGAC12320
ACAGATGCAG AAATCTGTGC


TGTTTCTTTT ATGAATAAAA AGTATCAACA-TTCCAGGCAG GGCAAGGTGG12390
2 CTCACACCTA TAATCCCAGC
S


ACTTTGGGAG GCCGAGGTGG GTGGATCACT TGAGGCCAGG AGTTTGAGGC12960
CAACCTAACC AACATAGTGA


AATTCCATTT CTACTTAAAA AATACAAAAA TTAGCCTGGC CTGGTGGCAC12530
ACGCCTGTAG TCCCCGCTAT


GCGGGAGGCT GAGGCAGGAG AATCATTTGA ACCCAGGAGG CAGAGGTTGC12600
AGTGAGCCGA GATCACACCA


CTGCACTCCA GCCTGGGCAA CAGAGTGAGA CTTCATCTTA AAAAAAAAAA12670
AAAAAGTATC AGCATTCCAA


AACCATAGTG GACAGGTGTT TTTTTATTCT GTCCTTCGAT AATATTTACT12740
3 GGTGCTGTGC TAGAGGCCGG
O


AACTGGGGGT GCCTTCCTCT GAAAGGCACA CCTTCATGGG AAGAGAAATA12810
AGTGGTGAAT GGTTGTTAAA


CCAGAGGTTT AAACTGGGGT CCTGTCGTTC TGAGTTAACA GTCCAGATCT12880
GGACTTTGCC TCTTTCCAGA


ATGCTCCCTG GGGTTTGCTT CATGGGGGAG CAGCAGGTGT GGACACCCTC12950
GTGATGGGGG AGCAGCAGGT


GCAGACGCCC TCATGATGGG GGAGTGGCAG GTGCAGACAC CCTTGTGCAT13020
GGTGCCCAGC ATGTCCCTGT


TGCAGCTCCC TCCCCACAAG GATGCCGGTC TCCTGTGCTC CCCACAGTCC13090
3 CTGCTTCCCT CTCACAGCCT
S


TACCTGGTCC TGGCCTCCAC TGGCTTTGTC TGCATGATTT CCACATTTCC13160
TGGGCTCCCA GCACCTCTTC


GCCTCTCCCA GGCACCTCTG CAGTGCTGGC CATACCAGTC AGCTGTGAAC13230
TGTCCACTGC TTATTTTGCT


CCCCATGAAA TGTATTTTTT AGGACAGGCA CCCCTGGTTC CAGCCTCTGG13300
CACAGCATCA GTGAATGTTA


TTGAAGGACA AAGGACAGAC AAACAAATCA GGAAAATGGG TTCTCTCTAA13370
ACACATTGCA AAGCCACAGA


GGCTAGTGCA GGATGGGTGG GCATCAGGTC ATCAGATGTG GGTCCAATGC13990
CAGAATATTC TGTGCTCCCA


AAGGCCACTT GGTCAGAGTG TGTGCTTGCA GAGGTGGCTC TAAAAGCTCA13510
GCAGTGGAGG CAGTGGTTCG


CCATACTCAG GGTGAACTCA CATCCTCTGT GTCTGAAGTA TACAGCAGAG13580
GCTTGAAGGG CATCTGGGAG


A.AGAAAACAG GCAAAATGAT TAAGAAAAGT GAAAAAGGAA AAGTGGTAAG13650
ATGGGAATTT TCTTGTCCAG


ATTTTAGTCT CCCAAACCAC AGCTCAGATG GTAGAATGTG GTCAGAACTG13720
ATGGACAGAA CAATAGAACA


AAACGGAAGC CCTATCTCTC AGAAACGTGT GTTAATGTGG TATGTGGCAC13790
4S AGCTGATGGA AAAGAGAGTG


TGTGTGTAAT TTTTTTTTCT GAGAAAACTG ACTGGAAGCA AATAAGTTGT13860
GTCTTTACAG CATATACCAG


AGCAGATTCT AGGTAGAAGA GGAGACACAT GCAAACAACA CCAGCAACAG13930
AAATAAAACA AAAGACTCAA


AGGGAAGGGA GGTGAACGTT CCCTGGTTTG GTGTTGGGGA AGGACACACA19000
GGGAGGCGGA TGAAACCAGT


GAGGCAACGG GCATTGCTTT CACTGCAGAG AAACTCAGCT TGCCTGAGCC14070
ACAGTGAAAA TGGCCATTCC


CTGGAGCGTT TGTGCACGTG ATTTATTTAA GGCGCCCTGT GAGGTCCTGC14190
S ACATTCATCC TCTCACTTTG
O


TTCTCCTAAC CACCTGAGAG GTAGAGGAGG AAAGGCTCCA GGGGAGCAGC14210
CGCCCTTGGT CACCCAGCTG


GCAAAGGGCA TGCATGATTG CAGCCTGGCC TCCTGCTCCG GGGCCCTTGC19280
TCTGCCCGAG GACCCCACAC


AAGTCAGACC CATAGGCTCA GGGTGAGCCG GAGCCCAAGG TCGTGTTGGG19350
GATGGCTGTG AAAGAAGAAA


TGGACGTCTG ATGCACACTT GGGAAGGTCC TACCAGCAGC GTCAAAGAAA19420
TGCATGTGAA ACTGACAGCG


AGACCCATCC CTCAAAGAAA CGCACGTGAA ACTGATGGCG AGACCTGTCC14990
SS CCATCCCTCA TGCTGG~:.''::C


TTTTCTGGGC TTGCCAAGAG CCAGCATCAG GTTGAGGCAA GCTGGAAAGA19560
CTTTTCTGGA AAGCAGCTTG


TTTGCATGGA AGTCCTCACA ATGTCCTGTG TCTTCCCAGT AATTCCACTT19630
CTGAAGTGAC CAGACATTAT


CACGGGTCTT ATTTACCATT TCCAGTGTTC CAGGCAGGGG GACTTGCCAC14700
AGCAAGTCAC GAACCTGCCC


AAATACAGGG CTAAGGAGAT ATTATGCATC ACAAAACTTG CTCTGCCATT19770
AAACATTTTT CAAAGAATTT


TTGAAGAATG TTTAATGGCA CAAAACGTTT ATTTCAATGT AGCAGTGTTC19890
AAAGCTGGAT GTAAAAGAAC


ACACCCCAGG AGCCTGCCGT GAATGTCATG TGTGTTCATC TTTGGACATG19910
GACATAC~~-.TG GGCAGTGAGT


GGTGGTGAGG CCCTGGAGGA CATCGGTGGG ATGCCTCCAT CCTGCCCCTC19980
TGGAGACACC ATGTGTGCCA


CGTGCACTCA CTGGAGCCCT GTTTAGCTGG TGCCACCTGG CTCTTCCATC15050
CCTGAGAT'.".~ AAACACAGTG


AGATTCCCCA CGCCCAACTC AGTGTTCTCC CACAAAAAAC CTGAGTCACA15120
CCTGTGTTCA CTCGAGGG-iC


GCCCGGGAGC CAGGGCTCCA CAGTTTATTA TGTGTTTTTG GCTGAGTTAT15190
6S GTGCAGATCT CATCAGG~CA


GATGATGAGT GCACAAACAC GGCCGTGCGA GGTTTGGATA CACTCAACAT15260
CACTAGCCAG GTCCTGG'G


AGTTTGGTCA TGCAGAGTCT GGATGGCATG TAGCATTTGG AGTC~ATGGA15330
GTGAGCAC~C AGCCCC~~;G


GGCTGCAGCG CATGCCCCAG G::AGGAC.=u'aG GAAGCGGGAG GAAG 15400
~CAGGA GGCTCTT T "G AGCAAG~ _' _'T


GCAGGAGGGG GCTGGGTGTG GGGCAGGCAC CTGTGTCTGA CATTCCCCCC15970
TGTGTCTCAG CTATGC~~~G


ACCTCCATCA GAGCCAGTCT CACCTTCAAC CGCGGCTTCA AGGCTGGGAG15540
GAACATGC~'f CGCAAACT,:T
'


TTGGGGTCT: 15610
GCGGCTGAAG TGTCACAGCC TGTTTCTGGA TTTG~AGGTG AGCAGGCTv:,
TGGTCAGC.',C


AGAGTTCAGA GTTCAGGAGG T~TGTG~~GCA AGTATGTGTG TGTGTGTGTG15680
CGCGCGT~':~ TGCAAGG'::'G


ATGGTGACTG GCTGCACGTA AGAGTGC=.CA TGTACGCATA TACA~GTGAG15750
CACATACATG TGTGCAT~:'G


TGTACATGAA GGCATGGCAG TGTGTGC-',CA GGTGTGCAAG GGCA:AAGTG15820
TGTGCACAI'G CGAATGC-",'.A


CCTGACATGC ATGTGTGTTC GTGCACAGTC GTGTGGGCAT TCAC~TGAGG15890
7S TGCATGCGTG TGGGTGT~~:A


GTGTGAGTAG CATGTGTGCA CATP.AC=;"GT ATTGAGGGGT CCTC~TGTTC15960
ACCCCGCT:~.G G'rCCTC=,:,':A


CCAGTGCCAC TCCTTACAGG ATGAGACGGG GTCCCAGGCC TTGGTGGGCT16030
GAGGCTCTW, AGCTGC,:;;C


CTGAGGGCAT TGT~CCATCT GGGCATCCGC GTCCACTCCC TCTC~TGTGG16100
GCTTCTG'."_~." CCACT~'::"~


TCTCCTGTGG GCATT"'ACAT Ci:~CTCU yCT CCCTCTCTCC TGTG~;;CATC16170
CGCGTCCa,::' CCCCC:'~.":'."




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-33-
GTGGGCATCTGCGTCCACCTCCCCTCTCTG CTCTCCTGGT
TGGGCATTTG TCCTTCCTGT
CGTCCACTCC 16290


CTTGGCCGAGCCTCGGGGGCAGGCAGATGA TGACTCGCCCAGGGTGGTTC
CACAGAGTCT GCAGCTGCCG
16310


GGTGAGGGCCAGGCCGGATTTCACTGGGAA TTCTTGTCAAAATGTTCCTC
GAGGGATAGT TTTCTTGTTC
16380


CATCTGAATGGATGATAAAGCAAAAAGTAA GTTTCTACCG 16450
S AAACTTAAAA TTTCTCACTC
TCCCAGAGAG


TTTCTTGGCGACTCTAGGTGAACAGCCTCC CACCAACATCTACAAGATCCTCCTGCTGCA
AGACGGTGTG 16520


GGCGTACAGGTGAGCCGCCACCAAGGGGTG CTCCAGGGACCCTCCGCGCTCTGCTCACCT16590
CAGGCCCAGC


CTGACCCGGGGCTTCACCTTGGAACTCCTG GCAAGGAATGTCTTACGTTTTCAGTGGTGC16660
GGTTTTAGGG


TGCTGCCTGTGCACAGTTCTGTTCGCGTGGCTCTGTGCAAAGCACCTGTTCTCCATCTCTGGGTAGTGGT16730


AGGAGCCGGTGTGGCCCCAGGTGTCCCCACTGTGCCTGTGCACTGGCCGTGGGACGTCATGGAGGCCATC16800
IO


CCAGGGCAGCAGGGGCATGGGGTAAAGAGATGTTTATGGGGAGTCTTAGCAGAGGAGGCTGGGAAGGTGT16870


CTGAACAGTAGATGGGAGATCAGATGCCCGGAGGATTTGGGGTCTCAGCAAAGAGGGCCGAGGTGGGTGC16990


AGGTGAGGGTCGCTGGCCCCACCCCCGGGAAGGTGCAGCAGAGCTGTGGCTCCCCACACAGCCCGGCCAG17010


CACCTGTGCTCTGGGCATGGCTGTGCTCCTGGAACGTTCCCTGTCCTGGCTGGTCAGGGGGTGCCCCTGC17080


CAAGAATCGACAACTTTATCACAGAGGGAAGGGCCAATCTGTGGAGGCCACAGGGCCAGCTTCTGCCTGG17150
IS


AGTCAGGGCAGGTGGTGGCACAAGCCTCGGGGCTGTACCAAAGGGCAGTCGGGCACCACAGGCCCGGGCC17220


TCCACCTCAACAGGCCTCCCGAGCCACTGGGAGCTGAATGCCAGGAGGCCGAAGCCCTCGCCCCATGAGG17290


GCTGAGAAGGAGTGTGAGCATTTGTGTTACCCAGGGCCGAGGCTGCGCGAATTACCGTGCACACTTGATG17360


TGAAATGAGGTCGTCGTCTATCGTGGAAACCCAGCAAGGGCTCACGGGAGAGTTTTCCATTACAAGGTCG17930


TACCATGAAAATGGTTTTTAACCCGAGTGCTTGCGCCTTCATGCTCTGGCAGGGAGGGCAGAGCCACAGC17500
2O


TGCATGTTACCGCCTTTGCACCAGCTCCAGAGGCTTGGGACCAGGCTGTCTCAGTTCCAGGGTGCGTCCG17570


GCTCAGACCGCCCTCCTCTCTGCCTTCTCTCTCTGCCTCAAATCTTCCCTCGTTTGCATCTCCCTGACGC17690


GTGCCTGGGCCCTCGTGCAAGCTGCTTGACTCCTTTCCGGAAACCCTTGGGGTGTGCTGGATACAGGTGC17710


CACTGAGGACTGGAGGTGTCTGACACTGTGGTTGACCCCAGGGTCCAGCTGGCGTGCTTGGGGCCTCCTT17780


GGGCCATGATGAGGTCAGAGGAGTTTTCCCAGGTGAAAACTCCTGGGAAACTCCCAGGGCCATGTGACCT17850
2S


GCCACCTGCTCCTCCCATATTCAGCTCAGTCTTGTCCTCATTTCCCCACCAGGGTCTCTAGCTCCGAGGA17920


GCTCCCGTAGAGGGCCTGGGCTCAGGGCAGGGCGGCTGAGTTTCCCCACCCATGTGGGGACCCTTGGGTA17990


GTCGCTTGATTGGGTAGCCCTGAGGAGGCCGAGATGCGATGGGCCACGGGCCGTTTCCAAACACAGAGTC18060


AGGCACGTGGAAGGCCCAGGAATCCCCTTCCCTCGAGGCAGGAGTGGGAGAACGGAGAGCTGGGCCCCGA18130


TTTCACGGCAGCCAGGCTGCAGTGGGCGAGGCTGTGGTGGTCCACGTGGCGCTGGGGGCGGGGTCTGATT18200


CAAATCCGCTGGGGCTCGGCCTTCCTGGCCCGTGCTGGCCGCGCCTCCACACGGGCTTGGGGTGGACGCC18270


CCGACCTCTAGCAGGTGGCTATTTCTCCCTTTGGAAGAGAGCCCCTCACCCATGCTAGGTGTTTCCCTCC18340


TGGGTCAGGAGCGTGGCCGTGTGGCAACCCCGGGACCTTAGGCTTATTTATTTGTTTAAAAACATTCTGG18910


GCCTGGCTTCCGTTGTTGCTAAATGGGGAAAAGACATCCCACCTCAGCAGAGTTACTGAGAGGCTGAAAC16980


CGGGGTGCTGGCTTGACTGGTGTGATCTCAGGTCATTCCAGAAGTGGCTCAGGAAGTCAGTGAGACCAGG18550
3J


TACATGGGGGGCTCAGGCAGTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGTGGGTGAGGCCAGGTA18620


CATGGGGGGCTCAGGCACTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGAGGGTCAGACCAGGTACA18690


CGGGGGCTCTGATCACACGCACATATGAGCACATGTGCACATGTGCTGTTTCATGGTAGCCAGGTCTGTG18760


CACACCTGCCCCAAAGTCCCAGGAAGCTGAGAGGCCAAAGATGGAGGCTGACAGGGCTGGCGCGGTGGCT18830


CACACCTGTAGTCCCAGCACTTTGGGAGGCCGAGGCGAGAGGATCCCTTGAGCCCAGGAGTTTAAGACCA18900


GCCTGAGCAACATAGTAGAACCCCATCTCTATGAAAAATAAAAACAAAAATTAGCTGAACATGGTGGTGT18970


GCGCCTGTAGTTCCAATACTTGGGAGGCTGAAGTGGGAGGATCACTTGAGCCCAGGAGGTGGAAGCTGCA19090


GTGAGC'rGAGATTGCACCACTGTACTGCAGCCTGGGTGACAGAGTGAGAGCCCATCTCAACAACAACAAA19110


GAAGACTGACAAATGCAGTTTCTTGGAAAGAAACATTTAGTAGGAACTTAACCTACACArAGAAGCCAAG19180


TCGGTGTCTCGGTGTCAGTGAGATGAGATGATGGGTCCTCACACCATCACCCCAGACCCAGGGTTTATGC19250
4S


ACCACAGGGGCGGGTGGCTCAGAAGGGATGCGCAGGACGTTGATATACGATGACATCAAGGTTGTCTGAC19320


GA.~1GGGCAGGATTCATGATAAGTACCTGCTGGTACACAAGGAACAATGGATAAACTGGAAACCTTAGAGG19390


CCTTCCCGGAACAGGGGCTAATCAGAAGCCAGCATGGGGGGCTGGCATCCAGGATGGAGCTGCTTCAGCC19960


TCCACATGCGTGTTCATACAGATGGTGCACAGAAACGCAGTGTACCTGTGCACACACAGACACGCAGCTA19530


CTCGCACACACAAGCACACACACAGACATGCATGCATGCATCCGTGTGTGTGCACCTGTGCCCATGAGGA19600
SO


AACCCATGCATGTGCATTCATGCACGCACACAGGCACCGGTGGGCCCATGCCCACACCCACGAGCACCGT19670


CTGATTAGGAGGCCTTTCCTCTGACGCTGTCCGCCATCCTCTCAGGTTTCACGCATGTGTGCTGCAGCTC19740


CCATTTCATCAGCAAGTTTGGAAGAACCCCACATTTTTCCTGCGCGTCATCTCTGACACGGCCTCCCTCT19810


GCTACTCCATCCTGAAAGCCAAGAACGCAGGTATGTGCAGGTGCCTGGCCTCAGTGGCAGCAGTGCCTGC19880


CTGCTGGTGTTAGTGTGTCAGGAGACTGAGTGAATCTGGGCTTAGGAAGTTCTTACCCCTTTTCGCATCA19950
SS


GGAAGTGGTTTAACCCAACCACTGTCAGGCTCGTCTGCCCGCCCTCTCGTGGGGTGAGCAGAGCACCTGA20020


TGGAAGGGACAGGAGCTGTCTGGGAGCTGCCATCCTTCCCACCTTGCTCTGCCTGGGGAAGCGCTGGGGG20090


GCCTGGTCTCTCCTGTTTGCCCCATGGTGGGATTTGGGGGGCCTGGCCTCTCCTGTTTGCCCTGTGGTGG20160


GATTGGGCTGTCTCCCGTCCATGGCACTTAGGGCCCTTGTGCAAACCCAGGCCAAGGGCTTAGGAGGAGG20230


CCAGGCCCAGGCTACCCCACCCCTCTCAGGAGCAGAGGCCGCGTATCACCACGACAGAGCCCCGCGCCGT20300
GO


CCTCTGCTTCCCAGTCACCGTCCTCTGCCCCTGGACACTTTGTCCAGCATCAGGGAGGTTTCTGATCCGT20370


CTGAAATTCAAGCCATGTCGAACCTGCGGTCCTGAGCTTAACAGCTTCTACTTTCTGTTCTTTCTGTGTT20490


GTGGAAATTTCACCTGGAGAAGCCGAAGAAAACATTTCTGTCGTGACTCCTGCGGTGCTTGGGTCGGGAC20510


AGCCAGAGATGGAGCCACCCCGCAGACCGTCGGGTGTGGGCAGCTTTCCGGTGTCTCCTGGGAGGGGAGC20580


TGGGCTGGGCCTGTGACTCCTCAGCCTCTGTTTTCCCCCAGGGATGTCGCTGGGGGCCAAGGGCGCCGCC20650
GS


GGCCCTCTGCCCTCCGAGGCCGTGCAGTGGCTGTGCCACCAAGCATTCCTGCTCAAGCTGACTCGACACC20720


GTGTCACCTACGTGCCACTCCTGGGGTCACTCAGGACA~~CAAGTGTGGGTGGAGGCCAGTGCGGGCCCC20790


ACCTGCCCAGGGGTCATCCTTGAACGCCCTGTGTGGGG(';AGCAGCCTC~-.GATGCTGCTGAAGTGCAGAC20860


GCCCCCGGGCCTGACCCTGGGGGCCTGGAGCCACGCTG,~AGCCCTATGTGATTAAACGCTGGTGTCCCC20930


AGGCCACGGAGCCTGGCAGGGTCCCCAACTTCTTGAACCCCTGCTTCCCTCTCAGGGGCGATGGCTCCC21000
7O A


CACGCTTGGGAGCCTTCTGACCCCTGACCTGTGTCCTCT;.ACAGCC CCCTGGCTGCTGCCCTGAGC21070
TCTT


TCCTGGGGTCCTGAGCAAGTTCTCTCCCCGCCCC~CCG'i'CCAGCGTC:1:;TGGGCTGCCTGTCTGCTCGC21190


CCCGGTGGAGGGGTGTCTGT AGGTTCCC~CCAGCCAGGGCCACGAGGTGCAGGCCCTGCC21210
CCCTTCACTG


TGCCCGGCCACCCACACGTC TGGAGGATGCCACCTCTG;~CTCTTCTGGAACGGAGTCTG21280
CTAGGAGGGT


ATTTTGGCCCCGCAGCCCAG GTCGGAAG:TCCCGGGGA:,~,ACGCTGACTGCCCTGGAGGC21350
ACGCAGCTGA


CGCAGCCAACCCGGCACTGC CAAG~=.CCAT;CTGGAC GGCCACCCGCCCACAGCCAG21920
CCTCAGACTT TG.~"


GCCGAGAGCAGACACCAGCA GCCGGGCT:~.'_ GAGGGAGGGGCGGCCCACAC21490
GCCCTGTCAC ACGTCCCA~,~


CCAGGCCCGC TGAGTGAG'~TTTGGCCG.,G~~CTGCATGTCCGGCTGAAG21560
.-ICCGCTGGGA
GTCTGAGGCC


GCTGAGTGTC GTCCAGCC?."~.G~GCTGAG.":;:'.CAG~~ACACCTGCCGTCTT21630
~~GGCTGAGGC
CTGAGCGAGT




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-34-
CACTTCCCCACAGGCTGGCGCTCGGCTCCACCCCAGGGCCAGCTTTTCCTCACCAGGAGCCCGGCTTCCA21700


CTCCCCACATAGGAATAGTCCATCCCCAGATTCGCCATTGTTCACCCCTCGCCCTGCCCTCCTTTGCCTT21770


CCACCCCCACCATCCAGGTGGAGACCCTGAGAAGGACCCTGGGAGCTCTGGGAATTTGGAGTGACCAAAG21890


GTGTGCCCTGTACACAGGCGAGGACCCTGCACCTGGATGGGGGTCCCTGTGGGTCAAATTGGGGGGAGGT21910
S


GCTGTGGGAGTAAAATACTGAATATATGAGTTTTTCAGTTTTGAAAAAAATCTCATGTTTGAATCCTAAT21980


GTGCACTGCATAGACACCACTGTATGCAATTACAGAAGCCTGTGAGTGAACGGGGTGGTGGTCAGTGCGG22050


GCCCATGGCCTGGCTGTGCATTTACGGAAGTCTATGAGTGAATGGGGTTGTGGTCAGTGCGGGCCCATGG22120


CCTGGCTGGGCCTGGGAGGTTTCTGATGCTGTGAGGCAGGAGGGGAAGGAGGGTAGGGGATAGACAGTGG22190


GAGCCCCCACCCTGGAAGACATAACAGTAAGTCCAGGCCCGAAGGGCAGCAGGGATGCTGGGGGCCCAGC22260
lO


TTGGGCGGCGGGGATGATGGAGGGCCTGGCCAGGGTGGCAGGGATGATGGGGGCCCCAGCTGGGGTGGCA22330


GGGGTGATGGGGGGGGCTGGTCTGGGTGGCGGGGAAGATGGGGAAGCCTGGCTGGGCCCCCTCCTCCCCT22400


GCCTCCCACCTGCAGCCGTGGATCCGGATGTGCTTCCCTGGTGCACATCCTCTGGGCCATCAGCTTTCAT22470


GGAGGTGGGGGGCAGGGGCATGACACCATCCTGTATAAAATCCAGGATTCCTCCTCCTGAACGCCCCAAC22590


TCAGGTTGAAAGTCACATTCCGCCTCTGGCCATTCTCTTAAGAGTAGACCAGGATTCTGATCTCTGAAGG22610
IS


GTGGGTAGGGTGGGGCAGTGGAGGGTGTGGACACAGGAGGCTTCAGGGTGGGGCTGGTGATGCTCTCTCA22680


TCCTCTTATCATCTCCCAGTCTCATCTCTCATCCTCTTATCATCTCCCAGTCTCATCTGTCTTCCTCTTA22750


TCTCCCAGTCTCATCTGTCATCCTCTTACCATCTCCCAGTCTCATCTCTTATCCTCTTATCTCCTAGTCT22820


CATCCAGACTTACCTCCCAGGGCGGGTGCCAGGCTCGCAGTGGAGCTGGACATACGTCCTTCCTCAGGCA22890


GAAGGAACTGGAAGGATTGCAGAGAACAGGAGGGGCGGCTCAGAGGGACGCAGTCTTGGGGTGAAGAAAC22960
2O


AGCCCCTCCTCAGAAGTTGGCTTGGGCCACACGAAACCGAGGGCCCTGCGTGAGTGGCTCCAGAGCCTTC23030


CAGCAGGTCCCTGGTGGGGCCTTATGGTATGGCCGGGTCCTACTGAGTGCACCTTGGACAGGGCTTCTGG23100


TTTGAGTGCAGCCCGGACGTGCCTGGTGTCGGGGTGGGGGCTTATGGCCACTGGATATGGCGTCATTTAT23170


TGCTGCTGCTTCAGAGAATGTCTGAGTGACCGAGCCTAATGTGTATGGTGGGCCCAAGTCCACAGACTGT23240


GTCGTAAATGCACTCTGGTGCCTGGAGCCCCCGTATAGGAGCTGTGAGGAAGGAGGGGCTCTTGGCAGCC23310
2
S


GGCCTGGGGGCGCCTTTGCCCTGCAAACTGGAAGGGAGCGGCCCCGGGCGCCGTGGGCGGACGACCTCAA23380


GTGAGAGGTTGGACAGAACAGGGCGGGGACTTCCCAGGAGCAGAGGCCGCTGCTCAGGCACACCTGGGTT23950


TGAATCACAGACCAACaGGTCAGGCCATTGTTCAGCTATCCATCTTCTACAAAGCTCCAGATTCCTGTTT23520


CTCCGGGTGTTTTTTGTTGAAATTTTACTCAGGATTACTTATATTTTTTGCTAAAGTATTAGACCCTTAA23590


AAAAGGTATTTGCTTTGATATGGCTTAACTCACTAAGCACCTACTTTATTTGTCTGTTTTTATTTATTAT23660
3
O


TATTATTATTATTAGAGATGGTGTCTACTCTGTCACCCAGGTTGTTAGTGCAGTGGCACAGTCATGGCTC23730


GCTGTAGCCGCAAACCCCCAGGCTCAAGTGATCCTCCGGCCTCAGCTTCCCAGAGTGCTGGGATTACAGG23800


TGTGAGCCACTGCCCTTGCCTGGCACTTTTAAAAACCACTATGTAAGGTCAGGTCCAGTGGCTTCCACAC23870


CTGTCATCCCAGTAGTTTGGGAAGCCGAGGCAGAAGGATTGTCTGAGGCCAGGAGTTTGAGACCAGCATG23940


GGTAACATAGGGAGACCCCATCTCTACAAAAAATGCAAAAAGTTATCCGGGCGTGGGGTCCAGCATCTGT29010
~
S


AGTCCCAGCTGCTCGGGAGGCTGAGTGGGAGGATCGCTTGAGCCCGGGAGGTCPTGGCTGCAGTGAGCTG29080


TGATTGTACCATCGCACTCCAGCCTGGGCAACAGAGTGAGACCCTGTCTCAAAAAAAAAAAAAAAAAAAG29150


AAGGAGAAGGAGAAGAGAAGAAGAAGGAAGAAGGAAAGAGAAGAAGAAGGAAGAAGGAAGAAAGAAGGAG24220


AAGGAGGCCTGCTAGGTGCTAGGTAGACTGTCAAATCTCAGAGCAAAATGAAAATAACAAAGTTTTAAAG24290


GGAAAGAAAAACCCCAGCTCTTTGGACTTCCTTAGGCCTGAACTTCATCTCAAGCAGCTTCCTTCCACAG24360
4O


ACAAGCGTGTATGGAGCGAGTGAGTTCAAAGCAGAAAGGGAGGAGAAGCAGGCAAGGGTGGAGGCTGTGG'9930


GTGACACCAGCCAGGACCCCTGAAAGGGAGTGGTTGTTTTCCTGCCTCAGCCCCACGCTCCTGCCGGTCC24500


TGCACCTGCTGTAACCGTCGATGTTGGTGCCAGGTGCCCACCTGGGAAGGATGCTGTGCAGGGGGCTTGC24570


CAAACTTTGGTGGGTTTCAGAAGCCCCAGGCACTTGTGGCAGGCACAATTACAGCCCCTCCCCAAAGATG29640


CCCACGTCCTTCTCCTGGAACCTGTGAATGTGTCACCCGCAAGGCAGAGGCTGGTGAAGGCTGCAGGTGG24710
4S


AATCACGGCTGCCAGTCAGCCGATCTTAAGGTCATCCTGGATTATCTGGTGGGCCTGATATGGCCACAAG24780


GGTCCCTAGAAGTGAGAGAGGGAGGCAGGGGAGAGTCAGAGAGGGGACGTGAGAAGGACCACTGGCCACT29850


GCTGGCTTTGAGATGGAGGAGGGGGTCCCCAGCCAAGGAATGGGGGCAGCCGCTCCATGCTGGAAAAGCA29920


AGCAATCCTCCCCGGTCCTGAGGGCACACGGCCCTGCCCACGCCTCGATTTCAGGCCAGTGGGACCTGTT24990


_
TCAGCTTTCCGGCCTCCAGAGCTGTAAGATGATGCGTTTGTGTTCAGCCACTAAGCTGCAGTGATTCGTC25060
JO


ACAGCAGCAAATGGAATAGCAGTACAGGGAAATGAATACAGGGACAGTTCTCAGAGTGACTCTCAGCCCA25130


CCCCTGGG 25138


Example S
SS Comparison of the above-described genomic hTC sequence and the sequence of
the
hTC cDNA (Fig. 6; corresponding to SEQ ID NO 2) made it possible to elucidate
the
exon-mtron structure of the hTC gene. The genomic organization of the hTC gene
is
illustrated diagrammatically in Fig. 7. The coding region of the hTC gene is
composed of 16 exons which vary in size between 62 by and 1354 by (see Table 1
).
60 Exon l contains the translation start codon ATG. The translation stop codon
TGA
and the 3'-untranslated region lie on exon 16 (Fig. 8). No possible
polyadenylation
signal (AATAAA) was found either in exon l6 or in the 3195 by of the following

- CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-35-
3 '-flanking region. The exon-intron transitions were determined on the basis
of the
consensus sequence
S '-Exon Intron 3 '-Exon
Pre-mRNA A/C A G ~ G T A/G A ... N C A G ~ G
Frequency (%) ~o so so ioo ioo 95 ~o eo ioo ioo so
and listed in Table 1. With the exception of the 5' splice site between exon
15 and
intron 1 S, all the exon-intron transitions are in accord with the published
(Shapiro
and Senapathy, 1987) splice consensus sequence. The sizes of the introns are
between 104 by and 8616 bp. Since only part of intron 6 was isolated, it is
not
possible to determine the precise length of the hTC gene. Based on the part
sequence
of 4660 bp, which was obtained from intron 6, the minimum size of the hTERT
gene is 37 kb.


- CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-36-
Introns 1-5 and the 5' region of intron 6, are contained in contig 1:
Intron 1: by 11493-11596 (SEQ ID NO 4);
lntron 2: by 12951-21566 (SEQ ID NO S);
Intron 3: by 21763-23851 (SEQ ID NO 6);
Intron 4: by 24033-24719 (SEQ ID NO 7);
Intron 5: by 24900-25393 (SEQ ID NO 8);
5' region of intron 6: by 25550-26414 (SEQ ID NO 9).
The 3' region of intron 6, and introns 7-15, are located in contig 2 at the
following
positions:
3' region of intron 6: by I-3782 (SEQ ID NO 10);
Intron 7: by 3879-4858 (SEQ ID NO 11 );
Intron 8: by 4945-7429 (SEQ ID NO 12);
Intron 9: by 744-9527 (SEQ ID NO 13);
i5 Intron 10: by 9600-11470 (SEQ ID NO 14);
Intron I 1: by 11660-15460 (SEQ ID NO 15;
Intron 12: by 15588-16467 (SEQ ID NO 16);
Intron 13: by 16530-19715 (SEQ ID NO 17);
Intron 14: 19841-20621 (SEQ ID NO 18);
Intron 15: 20760-21295 (SEQ ID NO 19).
The 3'-untranscribed region is also located in contig 2 at position 21960-
25138 (SEQ
ID NO 20).
The individual sequences of the abovernentioned introns are as follows:


CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-37-
Intron 1 (SEQ ID NO 4)
GTGGGCCTCCCCGGGGTCGGCGTCCGGCTGGGGTTGAGGGCGGCCGGGGGGAACCAGCGACATGCGGAGAGCAGCGCAG
G
CGACTCAGGGCGCTTCCCCCGCAG
Intron 2 (SEQ ID NO 5)
GTGAGGAGGTGGTGGCCGTCGAGGGCCCAGGCCCCAGAGCTGAATGCAGTAGGGGCTCAGAAAAGGGGGCAGGCAGAGC
C
CTGGTCCTCCTGTCTCCATCGTCACGTGGGCACACGTGGCTTTTCGCTCAGGACGTCGAGTGGACACGGTGATCTCTGC
C
TCTGCTCTCCCTCCTGTCCAGTTTGCATAAACTTACGAGGTTCACCTTCACGTTTTGATGGACACGCGGTTTCCAGGCG
C
CGAGGCCAGAGCAGTGAACAGAGGAGGCTGGGCGCGGCAGTGGAGCCGGGTTGCCGGCAATGGGGAGAAGTGTCTGGAA
G
IO
CACAGACGCTCTGGCGAGGGTGCCTGCAGGTTACCTATAATCCTCTTCGCAATTTCAAGGGTGGGAATGAGAGGTGGGG
A
CGAGP.ACCCCCTCTTCCTGGGGGTGGGAGGTAAGGGTTTTGCAGGTGCACGTGGTCAGCCAATATGCAGGTTTGTGTT
TA
AGATTT.AATTGTGTGTTGACGGCCAGGTGCGGTGGCTCACGCCGGTAATCCCAGCACTTTGGGAAGCTGAGGCAGGTG
GA
TCACCTGAGGTCAGGAGTTTGAGACCAGCCTGACCAACATGGTGAAACCCTATCTGTACTAAAAATACAAAAATTAGCT
G
GGCATGGTGGTGTGTGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATCACTTGAACCCAGGAGGCGGAGG
C
IS
TGCAGTGAGCTGAGATTGTGCCATTGTACTCCAGCCTGGGCGACAAGAGTGAAACTCTGTCTTTAAP,AAAAAAAAGTG
TT
CGTTGA1'TGTGCCAGGACAGGGTAGAGGGAGGGAGATAAGACTGTTCTCCAGCACAGATCCTGGTCCCATCTTTAGGT
AT
GAAGAGGGCCACATGGGAGCAGAGGACAGCAGATGGCTCCACCTGCTGAGGAAGGGACAGTGTTTGTGGGTGTTCAGGG
G
ATGGTGCTGCTGGGCCCTGCCGTGTCCCCACCCTGTTTTTCTGGATTTGATGTTGAGGAACCTCCGCTCCAGCCCCCTT
T
TGGCTCCCAGTGCTCCCAGGCCCTACCGTGGCAGCTAGAAGAAGTCCCGATTTCACCCCCTCCCCACAAACTCCCAAGA
C
2O
ATGTAAGACTTCCGGCCATGCAGACAAGGAGGGTGACCTTCTTGGGGCTCTTTTTTTTCTTTTTTTCTTTTTATGGTGG
C
AAAAGTCATATAACATGAGATTGGCACTCCTAACACCGTTTTCTGTGTACAGTGCAGAATTGCTAACTCGGCGGTGTTT
A
CAGCAGGTTGCTTGAAATGCTGCGTCTTGCGTGAC'iGGAAGTCCCTACCCATCGAACGGCAGCTGCCTCACACCTGCT
GC
GGCTCAGGTGGACCACGCCGAGTCAGATAAGCGTCATGCAACCCAGTTTTGC'TTTTTGTGCTCCAGCTTCCTTCGTTG
AG
GAGAGTTTGAGTTCTCTGATCAGGACTCTGCCTGTCATTGCTGTTCTCTGACTTCAGATGAGGTCACAATCTGCCCCTG
G
2S
CTTATGCAGGGAGTGAGGCGTGGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGTTGCCCCCAGGTGTCCC
T
GTCACGTGTAGGGTGAGTGAGGCGCGGCCCCCGGGTGTCCCTGTCCCGTGCAGCGTGATTGAGGTGTGGCCCCCGGGTG
T
CCCTGTCACGTGTAGGGTGAGTGAGGCGCCATCCCCGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCGTGGTCCCCG
G
GTGTCCCTGTCCCGTGCAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAGGCGCGGTC
C
CCGGGTGTCCCTCTCAGGTGTAGGGTGAGTGAGGCGCGGCCCCAGGGTGTCCCTGTCACGTGTAGGGTGAGTGAGGCAC
C
3O
GTCCCTGGGTGTCCCTCCCAGGTATAGGGTGAGTGAGGCACTGTCCCCGGGTGTCCCTGTCACGTGCAGGGTGAGTGAG
G
CGCGGCCCCCGGGTGTCCCTCTCAGGTGCAGGGTGAGTGAGGCGCTGTCCCTGGGTGTCCCTGTCTCGTGTAGGGTGAG
T
GAGGCTCTGTCCCCAGGTGTCCTTGGCGTTTGCTCACTTGAGCTTGCTCCTGAATGTTTGCTCTTTCTATAGCCACAGC
T
GCGCCGGTTGCCCATTGCCTGGGTAGATGGTGCAGGCGCAGTGCTGGTCCCCAAGCCTATCTTTTCTGATGCTCGGCTC
T
TCTTGGTCACCTCTCCGTTCCATTTTGCTACGGGGACACGGGACTGCAGGCTCTCGCCTCCCGCGTGCCAGGCACTGCA
G
3S
CCACAGCTTCAGGTCCGCTTGCCTCTGTTGGGCCTGGCTTGCTCACCACGTGCCCGCCACATGCATGCTGCCAATACTC
C
TCTCCCAGCTTGTCTCATGCCGAGGCTGGACTCTGGGCTGCCTGTGTCTGCTGCCACGTGTTGCTGGAGACATCCCAGA
A
AGGGTTCTCTGTGCCCTGAAGGAAAGCAAGTCACCCCAGCCCCCTCACTTGTCCTGTTTTCTCCCAAGCTGCCCCTCTG
C
TTGGCCCCCTTGGGTGGGTGGCAACGCTTGTCACCTTATTCTGGGCACCTGCCGCTCATTGCTTAGGCTGGGCTCTGCC
T
CCAGTCGCCCCCTCACATGGATTGACGTCCAGCCACAGGTTGGAGTGTCTCTGTCTGTCTCCTGCTCTGAGACCCACGT
G
4O
GAGGGCCGGTGTCTCCGCCAGCCTTCGTCAGACTTCCCTCTTGGGTCTTAGTTTTGAATTTCACTGATTTACCTCTGAC
G
TTTCTATCTCTCCATTGTATGCTTTTTCTTGGTTTATTCTTTCATTCCTTTTCTAGC'TTCTTAGTTTAGTCATGCCTT
TC
CCTCTAAGTGCTGCCTTACCTGCACCCTGTGTTTTGATGTGAAGTAATCTCAACATCAGCCACTTTCAAGTGTTCTTAA
A
ATACTTCAAAGTGTTAATACTTCTTTTAAGTATTCTTATTCTGTGATTTTTTTCTTTGTGCACGCTGTGTTTTGACGTG
A
AATCATTTTGATATCAGTGACTTTTAAGTATTCTTTAGCTTATTCTGTGATTTCTTTGAGCAGTGAGTTATTTGAACAC
T
4S
GTTTATGTTCAAGATATGTAGAGTATCAAGATACGTAGAGTATTTTAAGTTATCATTTTATTATTGATTTCTAACTCAG
T
TGTGTAGTGGTCTGTATAATACCAATTATTTGAAGTTTGCGGAGCCTTGCTTTGTGATCTAGTGTGTGCATGGTTTCCA
G
AACTGTCCATTGTAAATTTGACATCCTGTCAATAGTGGGCATGCATGTTCACTATATCCAGCTTATTAAGGTCCAGTGC
A


- CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-38-
AAGCTTCTGTCTCCTTCTAGATGCATGAAATTCCAAGAAGGAGGCCATAGTCCCTCACCTGGGGGATGGGTCTGTTCAT
T
TCTTCTCGTTTGGTAGCATTTATGTGAGGCATTGTTAGGTGCATGCACGTGGTAGAATTTTTATCTTCCTGATGAGTGA
A
TCTTTTGGAGACTTCTATGTCTCTAGTAATCTAGTAATTCTTTTTTTAAATTGCTCTTAGTACTGCCACACTGGGCTTC
T
TTTGATTAGTATTTTCCTGCTGTGTCTGTTTTCTGCCTTTAATTTATATATATATATATATTTTTTTTTTTTTTGAGAC
A
S
GAGTCTTGGTCTGTCGCCCAGGGTGAGTGCAGTGGTGTGATCACAGGTCAGTGTAACTTTTACCTTCTGGCCTGAGCCG
T
CCTCTCACCTCAGCCTCCTGAGTAGCTGGAACTGCAGACACGCACCGCTACACCTGGCTAATTTTTAAATTTTTTCTGG
A
GACAGGGTCTTGCTGTGTTGCCCAGGCTGGTCTCAAACTCTTGGACTCAAGGGATCCATCTACCTCGGCTTCCCAAAGT
G
CTGAATTACAGGCATGAGCCACCATGTCTGGCCTAATTTTCAACACTTTTATATTCTTATAGTGTGGGTATGTCCTGTT
A
ACAGCATGTAGGTGAATTTCCAATCCAGTCTGACAGTCGTTGTTTAACTGGATAACCTGATTTATTTTCATTTTTTTGT
C
IO
ACTAGAGACCCGCCTGGTGCACTCTGATTCTCCACTTGCCTGTTGCATGTCCTCGTTCCCTTGTTTCTCACCACCTCTT
G
GrT~rGCCATGTGCGTTTCCTGCCGAGTGTGTGTTGATCCTCTCGTTGCCTCCTGGTCACTGGGCATTTGCTTTTATTT
CT
CTTTGCTTAGTGTTACCCCCTGATCTTTTTATTGTCGTTGTTTGCTTTTGTTTATTGAGACAGTCTCACTCTGTCACCC
A
GGCTGGAGTGTAATGGCACAATCTCGGCTCACTGCAACCTCTGCCTCCTCGGTTCAAGCAGTTCTCATTCCTCAACCTC
A
TGAGTACCTGGGATTACAGGCGCCCACCACCACGCCTGGCTAATTTTTGTATTTTTAGTAGAGATAGGCTTTCACCATG
T
1S
TGGCCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCTGCCCGCCTTGGCCTCCCACAGTGCTGGGATTACAGGTGCA
A
GCCACCGTGCCCGGCATACCTTGATCTTTTAAAATGAAGTCTGAAACATTGCTACCCTTGTCCTGAGCAATAAGACCCT
T
AGTGTATTTTAGCTCTGGCCACCCCCCAGCCTGTGTGCTGTTTTCCCTGCTGACTTAGTTCTATCTCAGGCATCTTGAC
A
CCCCCACAAGCTAAGCATTATTAATATTGTTTTCCGTGTTGAGTGTTTCTGTAGCTTTGCCCCCGCCCTGCTTTTCCTC
C
T'_TTGTTCCCCGTCTGTCTTCTGTCTCAGGCCCGCCGTCTGGGGTCCCCTTCCTTGTCCTTTGCGTGGTTCTTCTGTC
TTG
20
TTATTGCTGGTAAACCCCAGCTTTACCTGTGCTGGCCTCCATGGCA'rCTAGCGACGTCCGGGGACCTCTGCTTATGAT
GC
.?CAGATGAAGATGTGGAGACTCACGAGGAGGGCGGTCATCTTGGCCCGTGAGTGTCTGGAGCACCACGTGGCCAGCGT
TC
CTTAGCCAGTGAGTGACAGCAACGTCCGC'TCGGCCTGGGTTCAGCCTGG.~AAACCCCAGGCATGTCGGGGTCTGGTG
GCT
CCGCGGTGTCGAGTTTGAAATCGCGCAAACCTGCGGTGTGGCGCCAGCTCTGACGGTGCTGCCTGGCGGGGGAGTGTCT
G
CTTCCTCCCTTCTGCTTGGGAACCAGGACAAAGGATGAGGCTCCGAGCCGTTGTCGCCCAACAGGAGCATGACGTGAGC
C
2S
ATGTGGATAATTTTAAAATTTCTAGGCTGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCGG
G
TGGATCACGAGGTCAGGAGGTCGAGACCATCCTGGCCAACATGATGAAACCCCATCTGTACTAAAAACACAAAAATTAG
C
TGGGCGTGGTGGCGGGTGCCTGTAATCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATTGCTTGAACCTGGGAGTTGGA
A
GTTGCAGTGAGCCGACATTGCACCACTGCACTCCAGCCTGGCAACACAGCGAGACTCTGTCTCP~~4AAAAAAAAAApA
AA
AAAAAAAAAAAATTCTAGTAGCCACATTAAAAAAGTAAAAAAGAAAAGGTGAAATTAATGTAATAATAGATTTTACTGA
A
3O
GCCCAGCATGTCCACACCTCATCATTTTAGGGTGTTATTGGTGGGAGCATCACTCACAGGACATTTGACATTTTTTGAG
C
TTTGTCTGCGGGATCCCGTGTGTAGGTCCCGTGCGTGGCCATCTCGGCCTGGACCTGCTGGGCTTCCCATGGCCATGGC
T
GTTGTACCAGATGGTGCAGGTCCGGGATGAGGTCGCCAGGCCCTCAGTGAGCTGGATGTGCAGTGTCCGGATGGTGCAC
G
TCTGGGATGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCA
G
GCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGAT
G
3S
TGTGGTGTCTGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTAAGCTGGAGGTATGGAGTCCGGATGATGC
A
GGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGGGTGAGGTCAC
C
AGGCCCTGCGGTGAGCTGGGTGTGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGACGGTGCCAGACCATG
C
GGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTTGCCAGGCCCTGCTGTGAGTTGGATGTGGGG
T
GTCCGGATGCTGCAGGTCCGGTGTGAGGTCACCAGGCCCTGCTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTC
T
4O
GGGGTGAAGGTCGCCAGGCCCCTGCTTGTGAGCTGGATGTGTGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCA
G
GCCCTCGGTGAGCTGGATGTGCAGTGTCCAGATGGTGCAGGTCCGGGGTGAGGTCGCCAGACCCTGCGGTGAGCTGGAT
G
TGCGGTGTCTGGATGGTGCAGGTCTGGAGTGAGGTCGCCAGGCCCTCGGTGAGCTGGATGTATGGAGTCCGGATGGTGC
C
GGTCCGGGGTGAGGTCGCCAGACCCTGCTGTGAGCTGGATGTGCGGTGTCTGGATGGTACAGGTCTGGAGTGAGGTCGC
C
AGACCCTGCTGTGAGCTGGATATGCGGTGTCCGGATGGTGCAGGTCAGGGGTGAGGTCTCCAGGCCCTCGGTGAGCTGG
A
4S
GGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAACTGGATGTGCGGCGTCTGGATGG
T
GCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCTGGAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTC
G
CCAGGCCCTGCTGTGAGCTGGATGTGCGGCGTCTGGATGGTGCAGGTCTGGGGTGTGGTCGCCAGGCCCTCGGTGAGCT
G


CA 02316282 2000-06-21
Le A 32 $OS-Foreien Countries
-39-
GAGGTATGGAGTCCGGATGATGCAGGTCCGGGGTGAGGTTGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGAT
G
GTGCAGTCCGGGGTGAGGTCGCCAGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCTGGGGTGAGG
T
CACCAGGCCCTGCGGTGAGCTGGTTGTGCGGTGTCCGGTTGCTGCAGGTCCGGGGTGAGTTCGCCAGGCCCTCGGTGAG
C
TGGATGTGCGGTGTCCCCGTGTCCGGATGGTGCAGGTCCAGGGTGAGGTCGCTAGGCCCTTGGTGGGCTGGATGTGCCG
T
S
GTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCTTTGGTGAGCTGGATGTGCGGTGTCTGCATGGTGCAGGTCT
G
GGGTGAGGTCGCCAGGCCCTTGGTGGGCTGGATGTGTGGTGTCCGGATGGTGCAGGTCCGGCGTGAGGTCGCCAGGCCC
T
GCTGTGAGCTGGATGTGCGGTGTCTGGATGGTGCAGGTCCGGGGTGAGGTAGCCAAGGCCTTCGGTGAGCTGGATGTGG
G
GTGTCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGATATGCGGTGTCCGGATGGTGCAGG
T
CCGGGGTGAGGTCACCAGGCCCTGCGGTTAGCTGGATGTGCGGTGTCTGGATGGTGCAGGTCCGGGGTGAGGTCGCCAG
G
IO
CCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCAGTGAGCTGGAT
G
TGCTGTATCCGGATGGTGCAGGTCTGGCGTGAGGTCGCCAGGCCCTGCGGTTAGCTGGATATGCGGTGTCGGATGGTGC
A
GGTCCGGGGTGAGGTCACCAGGCCCTGCGGTTAGCTGGATGTGCGGTGTCCGGATGGTGCAGGTCTGGGGTGAGGTCGC
C
AGGCCCTGCTGTGAGCTGGATGTGCTGTATCCGGATGGTGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTGAGCTG
G
ATGTGCTGTATCCGGATGGTGCAGGTCTGGCGTGAGGTCGCCAGGCCCTGCGGTGAGCTGGATGTGCAGTGTACGGATG
G
IS
TGCAGGTCCGGGGTGAGGTCGCCAGGCCCTGCGGTGGGCTGTATGTGTGTTGTCTGGATGGTGCAGGTCCGGGGTGAGT
T
CGCCAGGCCCTGCGGTGAGCTGGATGTGTGGTGTCTGGATGCTGCAGGTCCGGGGTGAGTTCGCCAGGCCCTCGGTGAG
C
TGGATATGCGGTGTCCCCGTGTCCGAATGGTGCAGGTCCAGGGTGAGGTCGCCAGGCCCTTGGTGGGCTGGATGTGCCG
T
GTCCGGATGGTGCAGGTCTGGGGTGAGGTCGCCAGGCCCTTGGTGAGCTGGATGTGCGGTGTCCGGATGGTGCAGGTCC
G
GGGTGAGGTCACCAGGCCCTCGGTGATCTGGATGTGGCATGTCCTTCTCGTTTAAG
Intron 3 (SEQ ID NO 6)
GTACTGTATCCCCACGCCAGGCCTCTGCTTCTCGAAGTCCTGGAACACCAGCCCGGCCTCAGCATGCGCCTGTCTCCAC
T
TGCCTGTGCTTCCCTGGCTGTGCAGCTCTGGGCTGGGAGCCAGGGGCCCCGTCACAGGCCTGGTCCAAGTGGATTCTGT
G
CAAGGC'!'CTGACTGCCTGGAGCTCACGTTCTCTTACTTGTAAAATCAGGAGTTTGTGCCAAGTGGTCTCTAGGGTTT
GTA
2S
AAGCAGAAGGGATTTAAATTAGATGGAAACACTACCACTAGCCTCCTTGCCTTTCCCTGGGATGTGGGTCTGATTCTCT
C
i'CTCTTTTTTTTTTCTTTTTTGAGATGGAGTCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGGCATAATCTTGGCTCA
CT
GCAACCTCCACCTCCTGGGTTTAAGCGATTCACCAGCCTCAGCCTCCTAAGTAGCTGGGATTACAGGCACCTGCCACCA
C
GCCTGGCTAATTTTTGTACTTTTAGGAGAGACGGGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCATGACCTCAG
G
TGATCCACCCACCTTGGCCTCCCAAAGTGCTGGGTTTACAGGCTAAGCCACCGTGCCCAGCCCCCGATTCTCTTTTAAT
T
3O
CATGCTGTTCTGTATGAATCTTCAATCTATTGGATTTAGGTCATGAGAGGATAAAATCCCACCCACTTGGCGACTCACT
G
CAGGGAGCACCTGTGCAGGGAGCACCTGGGGATAGGAGAGTTCCACCATGAGCTAACTTCTAGGTGGCTGCATTTGAAT
G
GCTGTGAGATTTTGTCTGCAATGTTCGGCTGATGAGAGTGTGAGATTGTGACAGATTCAAGCTGGATTTGCATCAGTGA
G
GGACGGGAGCGCTGGTCTGGGAGATGCCAGCCTGGCTGAGCCCAGGCCATGGTATTAGCTTCTCCGTGTCCCGCCCAGG
C
TGACTGTGGAGGGCTTTAGTCAGAAGATCAGGGCTTCCCCAGCTCCCCTGCACACTCGAGTCCCTGGGGGGCCTTGTGA
C
3S
ACCCCATGCCCCAAATCAGGATGTCTGCAGAGGGAGCTGGCAGCAGACCTCGTCAGAGGTAACACAGCCTCTGGGCTGG
G
GACCCCGACGTGGTGCTGGGGCCATTTCCTTGCATCTGGGGGAGGGTCAGGGCTTTCCCTGTGGGAACAAGTTAATACA
C
AATGCACCTTACTTAGACTTTACACGTATTTAATGGTGTGCGACCCAACATGGTCATTTGACCAGTATTTTGGAAAGAA
T
TTAATTGGGGTGACCGGAAGGAGCAGACAGACGTGGTGGTCCCCAAGATGCTCCTTGTCACTACTGGGACTGTTGTTCT
G
CCTGGGGGGCCTTGGAGGCCCCTCCTCCCTGGACAGGGTACCGTGCCTTTTCTACTCTGCTGGGCCTGCGGCCTGCGGT
C
4O
AGGGCACCAGCTCCGGAGCACCCGCGGCCCCAGTGTCCACGGAGTGCCAGGCTGTCAGCCACAGATGCCCAGGTCCAGG
T
GTGGCCGCTCCAGCCCCCGTGCCCCCATGGGTGGTTTTGGGGGAAAAGGCCAAGGGCAGAGGTGTCAGGAGACTGGTGG
G
CTCATGAGAGCTGATTCTGCTCCTTGGCTGAGCTGCCCTGAGCAGCCTCTCCCGCCCTCTCCATCTGAAGGGATGTGGC
T
CTTTCTACCTGGGGGTCCTGCCTGGGGCCAG~~TTGGGCTACCCCAGTGGCTGTACCAGAGGGACAGGCATCCTGTGTG
G
AGGGGCATGGGTTCACGTGGCCCCAGATGCAGCCTGGGACCAGGCTCCCTGGTGCTGATGGTGGGACAGTCACCCTGGG
G
4S
GTTGACCGCCGGACTGGGCGTCCCCAGGGTTGACTATAGGACCAGGTGTCCAGGTGCCCTGCAAGTAGAGGGGCTCTCA
G
AGGCGTCTGGCTGGCATGGGTGGACGTGGCCCCGGGCATGGCCTTCAGCGTGTGCTGCCGTGGGTGCCCTGAGCCCTCA
C
TGAGTCGGTGGGGGCTTGTGGCTTCCCGTGAGCTTCCCCCTAGTCTGTTGTCTGGCTGAGCAAGCCTCCTGAGGGGCTC
T
CTATTGCAG


CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-40-
Intron 4 (SEQ ID NO 7)
GTGGCTGTGCTTTGGTTTAACTTCCTTTTTAAACAGAAGTGCGTTTGAGCCCCACATTTGGTATCAGCTTAGATGAAGG
G
CCCGGAGGAGGGGCCACGGGACACAGCCAGGGCCATGGCACGGCGCCAACCCATTTGTGCGCACAGTGAGGTGGCCGAG
G
TGCCGGTGCCTCCAGAAAAGCAGCGTGGGGGTGTAGGGGGAGCTCCTGGGGCAGGGACAGGCTCTGAGGACCACAAGAA
G
S
CAGCCGGGCCAGGGCCTGGATGCAGCACGGCCCGAGGTCCTGGATCCGTGTCCTGCTGTGGTGCGCAGCCTCCGTGCGC
T
TCCGCTTACGGGGCCCGGGGACCAGGCCACGACTGCCAGGAGCCCACCGGGCTCTGAGGATCCTGGACCTTGCCCCACG
G
CTCCTGCACCCCACCCCTGTGGCTGCGGTGGCTGCGGTGACCCCGTCATCTGAGGAGAGTGTGGGGTGAGGTGGACAGA
G
GTGTGGCATGAGGATCCCGTGTGCAACACACATGCGGCCAGGAACCCGTTTCAAACAGGGTCTGAGGAAGCTGGGAGGG
G
TTCTAGGTCCCGGGTCTGGGTGGCTGGGGACACTGGGGAGGGGCTGCTTCTCCCCTGGGTCCCTATGGTGGGGTGGGCA
C
IO TTGGCCGGATCCACTTTCCTGACTGTCTCCCATGCTGTCCCCGCCAG
Intron 5 (SEQ ID NO 8)
GTGGGTGCCGGGGACCCCCGTGAGCAGCCCTGCTGGACCTTGGGAGTGGCTGCCTGATTGGCACCTCATGTTGGGTGGA
G
GAGGTACTCCTGGGTGGGCCGCAGGGAGTGCAGGTGACCCTGTCACTGTTGAGGACACACCTGGCACCTAGGGTGGAGG
C
IS
CTTCAGCCTTTCCTGCAGCACATGGGGCCGACTGTGCACCCTGACTGCCCGGGCTCCTATTCCCAAGGAGGGTCCCACT
G
GATTCCAGTTTCCGTCAGAGAAGGAACCGCAACGGCTCAGCCACCAGGCCCCGGTGCCTTGCACCCCAGTCCTGAGCCA
G
GGGTCTCCTGTCCTGAGGCTCAGAGAGGGGACACAGCCCGCCCTGCCCTTGGGGTCTGGAGTGGTGGGGGTCAGAGAGA
G
AGTGGGGGACACCGCCAGGCCAGGCCCTGAGGGCAGAGGTGATGTCTGAGTTTCTGCGTGGCCACTGTCAGTCTCCTCG
C
CTCCACTCACACAG
5'-region intron 6 (SEQ ID NO 9)
GTHAGGTTCACGTGTGATAGTCGTGTCCAGGATGTGTGTCTCTGGGATATGAATGTGTCTAGAATGCAGTCGTGTCTGT
G
AT:~CG'rTTCTGTGGTGGAGGTACTTCCATGATTTACACATCTGTGATATGCGTGTGTGGCACGTGTGTGTCGTGGTG
CAT
GTATCTGTGGCGTGCATATTTGTGGTGTGTGTGTGTGTGGCACGTGTGTGTCCATGGTGTGTGTGCCTGTGGTGTGCAT
G
ZS
TGTGTGTG'rCTGTGACACGTGCATGTTCATGCTGTGTGCTGCATGTCTGTGATGTGCCTATTTGTGGTGTGTGTGTGC
AT
GTGTCCGTGACATATGCGTGTCTATGGCATGGGTGTGTGTGGCCCCTTGGCCTTACTCCTTCCTCCTCCAGGCATGGTC
C
GCACCATTGTCCTCACGCTCTCGGGTGCTGGTTTGGGGAGCTCCACATTCAGGGTCCTCACTTCTAGCATGGGTGCCCC
T
GTCCTGTCACAGGGCTGGGCCTTGGAGACTGTAAGCCAGGTTTGAGAGGAGAGTAGGGATGCTGGTGGTACCTTCCTGG
A
CCCCTGGCACCCCCAGGACCCCAGTCTGGCCTATGCCGGCTCCATGAGATATAGGAAGGCTGATTCAGGCCTCGCTCCC
C
3O
GGGACACACTCCTCCCAGAGCGGCCGGGGGCCTTGGGGCTCGGCAGGGGTGAAAGGGGCCCTGGGCTTGGGTTCCCACC
C
AGTGGTCATGAGCACGCTGGAGGGGTAAGCCCTCAAAGTCGTGCCAGGCCGGGGTGCAGAGGTGAAGAAGTATCCCTGG
A
GCTTCGGTCTGGGGAGAGGCACATGTGGAAACCCACAAGGACCTCTTTCTCTGACTTCTTGAGCT
3'-region intron 6 (SEQ ID NO 10)
3S
TGTGGGATTGGTTTTCATGTGTGGGATAGGTGGGGATCTGTGGGATTGGTTTTTATGAGTGGGGTAACACAGAGTTCAA
G
G~GAGCTTTCTTCCTGTAGTGGGTCTGCAGGTGCTCCAACAGCTTTATTGAGGAGACCATATCTTCCTTTGA.~..~.T
ATGGT
CGGGTTTATAGTAAGTCAGGGGTGTGGAGGCCTCCCCTGGGCTCCCTGTTCTGTTTCTTCC'.ACTC.TGGGGT~G'GT
GGTG
C~TGCTGTGGTGTGTGGCCGGTGGGCAGGGCTTCCAGGCCTCCTTGTGTTCATTGGCCTGGATGTG.'CCC'GG~TACG
CT
CCGTCCTTGGAATTCCCCTGCGAGTTGGAGGCTTTCTTTCTTTCTTTT:T'~'CTTTCTTTTTTTTTT.
'_'TTTTGATAACAGA
GTCTCC~TCTTTTTTGCCCAGGCTGGAGTGGTTTGGCGTGATCTTGGCTCACTGCAACCTGTGCTT"~TG.'~.GT;CA
AGCA
A"TCT~_"TGCCTCAGCCTCCCA.T1GTAGCTGGAATTATAGGCGCCCACCACCATGCTGACT.=~.ATTTT
~TA.:,"T"_'TAGTAG
A~ACGA GTTTCTCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCTC~CACCT-
'~GCCTC~CAAAGT
G~TGG:GATGACAGGTGTGAACCGCCGCGCCCGGCCGAGACTCGCTTCCTGCAGCTTCCGT~AGATC:~CAG~G_~TAG
CT.G
C'TGCAGCCTTGGTGCTGACAACCTCCGTTTTCCTTCTCCAGGTCTCGCTAGGGGTCTTT~CATTT:'ATG:.~T~TCT
TCA


CA 02316282 2000-06-21
Le A 32 805-Forei~ountries
-41 -
CAGAAGAGTTTCACGTGTGCTGATTTCCCGGCTGTTTCCTGCGTAATTGGTGTCTGCTGTTTATCGATGGCCTCCTTCC
A
TTTCCTTTAGGCTTTGTTTATTGTTGTTTTTCCGGCTCCTTGAAGGAAAAGTTTCGATTATGGATGTTTGAACTTTCTT
T
TCTAAACAAGCATCTGAAGTTGCCGTTTTCCCTCTAAAGCAGGGATCCCGAGGCCCCTGGCTGTGGAGTGGCACCGGTC
T
GGGGCCTGTTAGGAACCCGGCGCACAGCGGGAGGCTAGGTGGGGTGTGGGGAGCCAGCGTTCCCGCCTGAGCCCCGCCC
C
TCTCAGATCAGCAGTGGCATGCGGTGCTCAGAGGCGCACACACCCTACTGAGAACTGTGCGTGAGAGGGGTCTAGATTC
T
GTGCTCCTTATGGGAATCTAATGCCTGATGATCTGAGGTGGAACCGTTTGCTCCCAAAACCATCCCCTTCCCCACTGCT
G
TCCTGTGGAAAAATCGTCTTCCACGAAACCAGTCCCTGGTACCACAATGGTTGGGGACCCTGTGCTAAAGACCTGCTTC
A
GCAGCCTCTCGTCAGTGTTGATATATTGGCTTTTCTGTGTTGAGTCCAGAATAATTACGGATTTCTGTGATGCTTTCCG
C
CGACCTCAGACCCATGGGCTATTTGTGGGCGTGTTGCCTGCTCCTGGGTTGGGAAGGGTGCAGGCCCCATGTACCTTCC
T
lO
GTTACTGCCTTCCAGGTTGGTTCTCAGGGTTGAATCGTACTCGATGTGGTTTTAGCCCACGGCCCTGCCGCCAGCTCCT
G
GGGGCTGGGGAACATGCTGAAGCACAGAGTCACCGTGCGCGTCTTTTGATGCCTCACAAGCTCGAGGCCTCCTGTGTCC
G
TGTTAGTGTGTGTCACGTGCCTGCTCACATCCTGTCTTGGGGACGCAGGGGCTTAGCAGGTCCCGTAGTAAATGACAAG
C
GTCCTGGGGGAGTCTGCAGAATAGGAGGTGGGGGTGCCGGTCTCTCTCCCGCGTCTTCAGACTCTTCTCCTGCCTGTGC
T
GTGGCTGCACCTGCATCCCTGCAATCCCTCCAGCACTGGGCTGGAGAGGCCCGGGAGCTCGAGTGCCACTTGTGCCACG
T
IS
GACTGTGGATGGCAGTCGGTCACGGGGGTCTGATGTGTGG'rGACTGTGGATGGCGGTTGGTCACAGGGGTCTGATGTG
TG
GTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTG
G
ATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGT
G
GGGTCTGATGTGGTGACTGTGGATGGCAGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGAT
G
TGGTGACTGTGGATGGCAGTCG1'GGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGA
CT
2O
GTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATG
G
CGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTC
A
CAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACA
G
GGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTTGGTCCCGGGG
G
TCTGATGTGTGGTGACTGTGGATGGCGATCGGTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTC
T
2S
GATGTGTGG'rGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTG
GT
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGA
T
GGCGGTTGGTCCCGGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGATGGCA
G
TCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGG
G
TCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATG
T
3O
GGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGG
T
GACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGGTGACTGTGGA
T
GGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTAGGGTCTGATGTGTGGTGACTGTGGATGGCAGTC
G
GTCACAGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTG
G
GGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGATGTGTGGTGACTGTGGATGGCGGTCGTGGGGTCTGA
T
3S
GTGGTGACTGTGGATGGTGATCGGTCACAGGGGTCTGATGTGTGGTAGCTGCAGGTGGAGTCCCAGGTGTGTCTGTAGC
T
ACTTTGCGTCCTCGGCCCCCCGGCCCCCGTTTCCCAAACAGAAGCTTCCCAGGCGCTCTCTGGGCTTCATCCCGCCATC
G
GGCTTGGCCGCAGGTCCACACGTCCTGATCGG~.AGAAACAAGTGCCCAGCTCTGGCC'vGGGCAGGCCACATTTGTGG
CTC
ATGCCCTCTCCTCTGCCGGCAG
40 Intron 7 (SEQ ID NO 11)
GTCTGGGCACTGCCCTGCAGGGTTGGGC~.~GGACTCCCAGCAGTGGGTCCTCCCCTGGGCAATCACTGGGCTCATGT;
~CG
GACAGACTGTTGGCCCTGGGGGGCAGTGGGGGGAATGAGCTGTGATGGGGGCATGA'IG.~~.GCTG'_"G"_'GCCTT
GGCGAF~TC
TGAGCTGGGCCATGCCAGGCTGC~ACAG~T'GCTGCATTCAGGCACCTGCTCACGTTTG::CTGCGC~GCCTCTCTCCA
~TT
CCGCAGTGCCTTTGTTCATGATTTGCTA-
_~.TG''CTTCTCTGCCAGTTTTGATCTTGA~GCCAAAGGAAAGGTGTCCC'CT
4~
CCTTTAGGAGGGCAGGCCATGTTTGAGC~~TGTCCTGCCCAGCTGGCCCCTCAGTGCT~GGTCTGAGGCC=;AAGGAA.
aCG
TGTCCCCCTTCTTAGGAGGACGGGCCGTG ~'TTCAGCCACGCCCCGCTGAGCGGGCC'~:;:'CAGTGC'~GGGT
C'"GT CCA .GT


CA 02316282 2000-06-21
Le A 32 805-Forei~~n Countries
- 42 -
GGCCCTGTGGCCCTTTGCAGATGTGGTCTGTCCACGTGGCCCTGTGGCTCTTTGCAGATGCCTGTTAGCACTTGCTCGG
C
TCTAGGGGACAGTCGTGTCCACCGCATGAGGCTCAGAGACCTCTGGGCGAATTTCCTTGGCTCCCAGGGTGGGGGTGGA
G
GTGGCCTGGGCTGCTGGGACCCAGACCCTGTGCCCGGCAGCTGGGCAGCAACTCCTGGATCACATATGCCATCCGGGCC
A
CGGTGGGCTGTGTGGGTGTGAGCCCAGCTGGACCCACAGGTGGCCCAGAGGAGACGTTCTGTGTCACACACTCTGCCTA
A
GCCCATGTGTGTCTGCAGAGACTCGGCCCGGCCAGCCCACGATGGCCCTGCATTCCAGCCCAGCCCCGCACTTCATCAC
A
AACACTGACCCCAAAAGGGACGGAGGGTCTTGGCCACGTGGTCCTGCCTGTCTCAGCACCCACCGGCTCACTCCCATGT
G
TCTCCCGTCTGCTTTCGCAG
Intron 8 (SEQ ID NO 12)
IO
GTGAGTCAGGTGGCCAGGTGCCATTGCCCTGCGGGTGGCTGGGCGGGCTGGCAGGGCTTCTGCTCACCTCTCTCCTGCC
C
CTTCCCCACTGNCCTTCTGCCCGGGGCCACCAGAGTCTCCTTTTCTGGCCCCCGCCCCCTCCGGCTCCTGGGCTGCAGG
C
TCCCGAGGCCCCGGAAACATGGCTCGGCTTGCGGCAGCCGGAGCGGAGCAGGTGCCACACGAGGCCTGGAAATGGCAAG
C
GGGGTGTGGAGTTGCTCCTGCGTGGAGGACGAGGGGCGGGGGGTGTGTCTGGGTCAGGTGTGCGCCGAGCGTTTGAGCC
T
GCAGCTTGTCAGCTCCAAGTTACTACTGACGCTGGACACCCGGCTCTCACACGCTTGTATCTCTCTCTCCCGATACAAA
A
IS
GGATTTTATCCGATTCTCATTCCTGTCCCTGTCGTGTGACCCCCGCGAGGGCGCGGGCTCTTCTCTCTGTGACTAGATT
T
CCCATCTGGAAAGTGCGGGGTTGACCGTGTAGTTTGCTCCTCTCGGGGGGCCTGTGGTGGCCATGGGGCAGGCGGCCTG
G
GAGAGCTGCCGTCACACAGCCACTGGGTGAGCCACACTCACGGTGGTAGAGCCACAGTGCCTGGTGCCACATCACGTCC
T
CTGGATTTTAAGTAAAACCACACACCTCCCGGCAGGCATCTGCCTGCGACCCTGTGTGTGCCTGGGGAGAGTGGTAGCA
C
GGAGGAAATTCGTGCACACTCAAGGTCATCAGCAAGGTCATCCGCAGTCAGGTGGAACGTGGAGGCCTCTCTCTGGGAT
C
2O
GTCTCCAGCGGATAAAGGACTGTGCACAGCTTCGGAAGCTTTTATTT_~1AAAATATAACTATTAATTATTGCATTATA
AGT
AATCACTAATGGTATCAGCAATTATAATATTTATTAAAGTATAAT'rAGAAATATTAAGTAGTACACACGTTCTGGAAA
AA
CACAAATTGCACATGGCAGCAGAGTGAATTTTGGCCGAGGGACACGTGTGCACATGTGTGTAAGCGGCCCCCAGGCCCA
C
AGAATTCGCTGACAAAGTCACCTCCCCAGAGAAGCCACCACGGGCCTCCTTCGTGGTCGTGAATTTTATTAAGATGGAT
C
AAGTCACGTACCGTCCACGTGTGGCAGGGCTTTGGGGAATGTGAGGTGATGACTGCGTCCTCATGCCCTGACAGACAGG
A
2S
GGTGACUGTGTCTGTCCTGTCCCTAGGACACGGACAGGCCCGAAGCTCTAGTCCCCATCGTGGTCCAGTTTGGCCTCTG
A
ATAAAAACGTCTTCAAAACCTGTTGCCCCAAAAACTAAGAACAGAGAGAGTTTCCCATCCCATGTGCTCACAGGGGCGT
A
TCTGCTTGCGTrGACTCGCTGGGCTGGCCGGACTCCTAGAGTTGGTGCGTGTGCTTCTGTGCAAAAAGTGCAGTCCTCT
T
GCCCATCACTGTGATATCTGCACCAGCAAGGAAAGCCTCTTTTCTTTTCTTTCTTTTTTTTTTTTTGAGACGGAACGTC
A
CTGTTGTCTGCCTGGGCTTGAGTGCAGTGGCGCGATCTCAACTCACTGCAACCTCCGCCTCCCGGGTTCCAGCATTTCT
C
3O
CTGCCTCAGCCTCCCGAGCAGCTGAGATTACAGGCACCCACCCCCTGCGCCTGGCTAATTTTTGTATTTTTAGTAGAGA
G
GGGTTTTTGCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCACCCACCTCGGCCTCCCAAAGTGCT
G
GGATTACAGGTGTGAGCCATCACGCCCAGCCGGAA_AGCCTCTTTTTAAGGTGACCACCTATAGCGCTTCCCGAAAATA
AC
AGGTCTTGTTTTTGCAGTAGGCTGCAAGCGTCTCTTAGCAACAGGAGTGGCGTCCTGTGGGCTCTGGGGATGGCTGAGG
G
TCGCGTGGCAGCCATGCCTTCTGTGTGCACCTTTAGGTTCCACGGGGCTATTCTGCTCTCACTGTTTGTCTGAA.~.AC
GCA
3S
CCCTTGGCATCCTTGTTTGGAGAGTTTCTGCT_"CTCGTTGGTCATGCTGAAACTAGGGGCAAGGTTGTATCCGTTGGC
GC
GCAGCGGCTACATGTAGGGTCATGAGTCTTTC.~CCGTGGACAAATTCCTTGAAAAAAAAAAAAGGAGTCCGGTTAAGC
AT
TCATTCCGGGTCAAGTGTCTGG T TCTGTGAA'~'.-"Lrlr, ~ T CTAAGA T
TTAAGAAA'~CTTAATGAAAGAAAACCTTGA T GaTTC
AGAGCAAGGATGTGGTCACACCTGTGGCTGC-
.~CT~T'rTCAGCCGCCCCAGTGCATGGTGAGAGTGGGGAGCAG,CG:~TTG
TTTGTTCAGAGGTCTCATCTGGTATGTTTCT
_~:':GG'1G':'TTGCCGGCTGAATGGTAGACGTGTCGTTTGTGTGTA: G.~GGT
4O TCTGTGTCTGTGTGTGGCTCGGTTTGAGTGT-
.'GC=,TGTCCAGCACATGCCC'"GCCCGTCTCTC=,CC:';GTGTC~_'"_'C~CGC
CCCAG
Intron 9 (SEQ ID NO 13)
GTGAGGCCTCCTCTTCCC ~AGG~GGGCTT: G;:= :' ~G ~ GGTTGATTTGCTTTTG:..TGCATTCAGT«
:'T. ~~.TA':'TCC : = ~TGC
4S TCTGGAGACCA'_"GACTGCTCTG~CTTGAGGA_=.:CA
~=~Cr".AGGTTGCAGCCCC'.":'CTTGGTA'."G-_=:G~.~.GCACGG~=..;GGG


-. CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
- 43 -
TTGCACAGCCTGAGGACTGCGGGCTCCACGCAGGCTCTGTCCAGCGGCCATGTCCAGAGGCCTCAGGGCTCAGCAGGCG
G
GAGGGCCGCTGCCCTGCATGATGAGCATGTGAATTCAACACCGAGGAAGCACACCAGCTTCTGTCACGTCACCCAGGTT
C
CGTTAGGGTCCTTGGGGAGATGGGGCTGGTGCAGCCTGAGGCCCCACATCTCCCAGCAGGCCCTCGACAGGTGGCCTGG
A
CTGGGCGCCTCTTCAGCCCATTGCCCATCCCACTTGCATGGGGTCTACACCCAAGGACGCACACACCTAAATATCGTGC
C
S
AACCTAATGTGGTTCAACTCAGCTGGCTTTTATTGACAGCAGTTACTTTTTTTTTTTTAATACTTTAAGTTCTAGGGTA
C
ATGTGCACGACGTGCAGGTTAGTTACATATGTATACATGTGCCATGTTGGTGTGCTGCACCCATTAACTCATCATTTAC
A
TTAGGTATATCTCCTAATGCTATCCCTCCCCACTCCCCCCATCCCATGACAGGCCCTGGTGTGTGATGTTCCCCACCCT
G
TGTCCAAGTGTTCTCATTGTTCAGTTCCCACCTGTGAGTGAGAACATGTGGTGTTTGGTTTTCTTTCCTTGCAATAGTT
T
GCTCAGAGTGATGGTTTCCAGCTTCGTCCATGTCCCTACAAAGGACATGAACTCATCCTTTTTTATGACTGCATAGTAT
T
IO
CCrTGGTGTATATGTGCCACATTTTCTTAATCCAGTCTATCATCGATGGACATTTGGGTTGGTTGCAAGTCTTTGCTAC
T
GTGAATAGTGCCGCAATAAACATACGTGTGCATGTGTCTTTATAGCAGCATGATTTATAATCCTTTGGGTATATACCCA
G
TAATGGGATGGCTGGGTCAAATGGTATTTCTAGTTCTAGATCCTTGAGGAATCACCACACTGTCTTCCACAATGGTTGA
A
CTAGTTTACACTCCCACCAACAGTGTAAAAGTGTTCTGGTGCTGGAGAGGATGTGGACAGCAGTTATTTTTTTATGAAA
A
TAGTATCACTGAACAAGCAGACAGTTAGTGAAGGATGCGTCAGGAAGCCTGCAGGCCACACAGCCATTTCTCTCGAAGA
C
IS
TCCGGGTTTTTCCTGTGCATCTTTTGAAACTCTAGCTCCAATTATAGCATGTACAGTGGATCAAGGTTCTTCTTCATTA
A
GGTTCAAGTTCTAGATTGAAATAAGTTTATGTAACAGAAACAAAAATTTCTTGTACACACAACTTGCTCTGGGATTTGG
A
GGAAAGTGTCCTCGAGCTGGCGGCACACTGGTCAGCCCTCTGGGACAGGATACCTCTGGCCCATGGTCATGGGGCGCTG
G
GCTTGGGCCTGAGGGTCACACAGTGCACCATGCCCAGCTTCCTGTGGATAGGATCTGGGTCTCGGATCATGCTGAGGAC
C
ACAGCTGCCATGCTGGTAAAGGGCACCACGTGGCTCAGAGGGGGCGAGGTTCCCAGCCCCAGCTTTCTTACCGTCTTCA
G
O
TTATTTTTCCCTAAGAGTCTGAGAAGTGGGGCCGCGCCTGATGGCCTTCGTTCGTCTTCAGCTGGCACAGAATTGCACA
A
GCTGATGGTP.AACACTGAGTACTTATAATGAATGAGGAATTGCTGTAGCAGT'TAACTGTAGAGAGCTCGTCTGTTGG
AAA
GAAi-
1TTTAAGTTTTTCATTTAACCGCTTTGGAGAATGTTACTTTA'rTTATGGCTGTGTAAATTGTTTGACATT.CAGTCCC

TCGTAGACAGATACTACGTAAAAAGTGTAAAGTTAACCTTGCTGTGTATTTTCCCTTATTTTAG
ZS Intron 10 (SEQ ID NO 14)
GTGAGGCCCGTGCCGTGTGTCTGTGGGGACCTCCACAGCCTGTGGGCTTTGCAGTTGAGCCCCCCGTGTCCTGCCCCTG
G
CACCGCAGCGTTGTCTCTGCCAAGTCCTCTCTCTCTGCCGGTGCTGGATCCGCAAGAGCAGAGGCGCTTGGCCGTGCAC
C
CAGGCCTGGGGGCGCAGGGGCACCTTCGGGAGGGAGTGGGTACCGTGCAGGCCCTGGTCCTGCAGAGACGCACCCAGGT
T
ACACACGTGGTGAGTGCAGGCGGTGACCTGGCTCCTGCTGCTCTTTGGAAAGTCAAGAGTGGCGGCTCCTGGGGCCCCA
G
3O
TGAGACCCCCAGGAGCTGTGCACAGGGCCTGCAGGGCCGAGGCGGCAGCCTCCTCCCCAGGGTGCACCTGAGCCTGCGG
A
GAGCAGGAGCTGCTGAGTGAGCTGGCCCACAGCGTTCGCTGCGGTCACGTTCCTGCGTGGGGTTGTTTGGGATCGGTGG
G
AGAATTTGGATTTGCTGAGTGCTGCTGTCTTGAACCACGGAGATGGCTAGGAGTGGGTTTCAGAGTTGATTTTTGTGAA
T
CAAAC1'AAAATCAGGCACAGGGGACCTGGCCTCAGCACAGGGGATTGTCCAATGTGGTCCCCCTCAAGGGCGCCCCAC
AG
AGCCGGTGGGCTTGTTTTAAAGTGCGATTTGACGAGGGACGAGAAACCTTGAAAGCTGTAAAGGGAACCCTCAGAAAAT
G
3S
TGGCCGCCAGGGGTGGTTTCAG~TGCTTTGCTGGGCT~TGTTTGTGAAAACCCATT".'GGACCCGCCCTCCAAGTCCA
CC~
TCCAGGTCCACCCTCCAGGGCC~CCCTGGGCTGGGGGTATGCCTGGCGTTCCTTGTG~CGCAGCCCGGAGCACAGCAGG
C
TGTGCACATTTAAATCCACTAA;~ATTCACTCGGGGG:~AGCCCAGGTCCCAAGCAACT;,AGGGCTCAGGAGTCCTGA
GGCT
GCTGAGGGGACAGAGCAGACGG~GAACGCTGCTTCT~TGTGGCAAGTTCCT~AGGGT.~CTGGCCAGGGAGGTGGCTCA
GA
GTGTATGTTGGGGTCCCACCGG=:GGC=,GF_~CTCTG_''-:'iCT'GATGAGTCGGCAGCCA~
~TAACAGGAAGGGGTGGCCAC.-';,~
4O
GGAGCTGGGAATGCACCAGGGG~.GCT~CGCAGCTGG~CGAGGTCCCAGGGCCAGGC':ACAGGAAGGGCAGGGGGACG
CCC
GGGGCCACAGCAGAGGCCGCAG,~AAGGGr~GGGGATCCCCAGGCCAGAGCAGAGGC"'=,CCGGGCACAGGGGGGCTC
CC"'G
AGCTGGGTGAGCGAGG CTCATG:=.CTCC.GC ~AGGGA.=,C ~ T C,~TTGACGTGA.AGCTGr.':
~ACTGGTGTTGCCC.~~,GCTCACA.~
CCCAGCCAGGTCCCGCGCC'_"GACAGGAACTCAGAACCCTCCCCTTTGTCTA.%,AGC:',CAGCAGATGCCTTCAGG
GCATC~
AG~CAGAAAACAGGCA~,AGT CGT'~GAG.=,AA CGTCT'."P.:'~.:~,A;~~GGTGGGAT.CGTGG
C:'.:,, T TTCTTGTCCAGA'?'TTTAG T C :'
4S
GCCCCGGACCACAGA"_'GAGTCT:',TAACGGGATTGTG:~'"GTTGCCATGGGGACACAT':'."~GATGGACCATC
ACAGAGGCC=,;
TGGGGCTGCACC'TCC:C=,'"C"'G~, :TCC':GGCTGTCC': ~::C. _CAGGCCAGG'~'TCT'r~..
'°,TGCTCACCTACCTGTCCTGC:C ='


CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-44-
GGGAGACAGGGAAAGCACCCCGAAGTCTGGAGCAGGGCTGGGTCCAGGCTCCTCAGAGCTCCTGCCAGGCCCAGCACCC
T
GCTCCAAATCACCACTTCTCTGGGGTTTTCCAAAGCATTTAACAAGGGTGTCAGGTTACCTCCTGGGTGACGGCCCCGC
A
TCCTGGGGCTGACATTGCCCCTCTGCCTTAG
Intron 11 (SEQ ID NO 15)
GTGAGCGCACCTGGCCGGAAGTGGAGCCTGTGCCCGGCTGGGGCAGGTGCTGCTGCAGGGCCGTTGCGTCCACCTCTGC
T
TCCGTGTGGGGCAGGCGACTGCCAATCCCAAAGGGTCAGAGGCCACAGGGTGCCCCTCGTCCCATCTGGGGCTGAGCAG
A
AATGCATCTTTCTGTGGGAGTGAGGGTGCTCACAACGGGAGCAGTTTTCTGTGCTATTTTGGTAAAAGGAAATGGTGCA
C
CAGACCTGGGTGCACTGAGGTGTCTTCAGAAAGCAGTCTGGATCCGAACCCAAGACGCCCGGGCCCTGCTGGGCGTGAG
T
IO
CTCTCAAACCCGAACACAGGGGCCCTGCTGGGCATGAGTCCCTCTGAACCCGAGACCCTGGGGCCCTGCTGGGCGTGAG
T
CTCTCCGAACCCAGAGACTTCAGGGCCCTTTTGGGCGTGAGTCTCTCCGCTGTGAGCCCCACACTCCAAGGCTCATCCA
C
AGTCTACAGGATGCCATGAGTTCATGATCACGTGTGACCCATCAGGGGACAGGGCCATGGTGTGGGGGGGGTCTCTACA
A
AATTCTGGGGTCTTGTTTCCCCAGAGCCCGAGAGCTCAAGGCCCCGTCTCAGGCTCAGACACAAATGAATTGAAGATGG
A
CACAGATGCAGAAATCTGTGCTGTTTCTTTTATGAATAAAAAGTATCAACATTCCAGGCAGGGCAAGGTGGCTCACACC
T
IJ
ATAATCCCAGCACTTTGGGAGGCCGAGGTGGGTGGATCACTTGAGGCCAGGAGTTTGAGGCCAACCTAACCAACATAGT
G
AAATTCCATTTCTACTTAAAAAATACAAAAATTAGCCTGGCCTGGTGGCACACGCCTGTAGTCCCCGCTATGCGGGAGG
C
TGAGGCAGGAGAATCATTTGAACCCAGGAGGCAGAGGTTGCAGTGAGCCGAGATCACACCACTGCACTCCAGCCTGGGC
A
ACAGAGTGAGACTTCATCTTAAAAAAAAAAAAAAAAGTATCAGCATTCCAAAACCATAGTGGACAGGTGTTTTTTTATT
C
TGTCCTTCGATAATATTTACTGGTGCTGTGCTAGAGGCCGGAACTGGGGGTGCCTTCCTCTGAAAGGCACACCTTCATG
G
2O
GAAGAGAAATAAGTGGTGAATGGTTGTTAAACCAGAGGTTTAAACTGGGGTCCTGTCGTTCTGAGTTAACAGTCCAGAT
C
TGGACTTTGCCTCTTTCCAGAATGCTCCCTGGGGTTTGCTTCATGGGGGAGCAGCAGGTGTGGACACCCTCGTGATGGG
G
GAGCAGCAGGTGCAGACGCCCTCATGATGGGGGAGTGGCAGGTGCAGACACCCTTGTGCATGGTGCCCAGCATGTCCCT
G
TTGCAGCTCCCTCCCCACAAGGATGCCGGTCTCCTGTGCTCCCCACAGTCCCTGCTTCCCTCTCACAGCCTTACCTGGT
C
CTGGCCTCCACTGGCTTTGTCTGCATGATTTCCACATTTCCTGGGCTCCCAGCACCTCTTCGCCTCTCCCAGGCACCTC
T
ZS
GCAGTCCTGGCCATACCAGTCAGCTGTGAACTGTCCACTGCTTATTTTGCTCCCCATGAAATGTATTTTTTAGGACAGG
C
ACCCCTGGTTCCAGCCTCTGGCACAGCATCAGTGAATGTTATTGAAGGACAAAGGACAGACAAACAAATCAGGAAAATG
G
GTTCTCTCTAAACACATTGCAAAGCCACAGAGGCTAGTGCAGGATGGGTGGGCATCAGGTCATCAGATGTGGGTCCAAT
G
CCAGAATATTCTGTGCTCCCAAAGGCCACTTGGTCAGAGTGTGTGCTTGCAGAGGTGGCTCTAAAAGCTCAGCAGTGGA
G
GCAGTGGTTCGCCATACTCAGGGTGAACTCACATCCTCTGTGTCTGAAGTATACAGCAGAGGCTTGAAGGGCATCTGGG
A
3O
GAAGAAAACAGGCAAAATGATTAAGAAAAGTGAAAAAGGAAAAGTGGTAAGATGGGAATTTTCTTGTCCAGATTTTAGT
C
TCCCAAACCACAGCTCAGATGGTAGAATGTGGTCAGAACTGATGGACAGAACAATAGAACAAAACGGAAGCCCTATCTC
T
CAGAAACGTGTGTTAATGTGGTATGTGGCACAGCTGATGGAAAAGAGAGTGTGTGTGTAATTTTTTTTTCTGAGAAAAC
T
GACTGGAAGCAAATAAGTTGTGTCTTTACAGCATATACCAGAGCAGATTCTAGGTAGAAGAGGAGACACATGCAAACAA
C
ACCAGCAACAGAAATAAAACAAA.~1GACTCAAAGGGAAGGGAGGTGAACGTTCCCTGGTTTGGTGTTGGGGAAGGACA
CAC
3S
AGGGAGGCGGATGAAACCAGTGAGGCAACGGGCATTGCTTTCACTGCAGAGAAACTCAGCTTGCCTGAGCCACAGTGAA
A
ATGGCCATTCCCTGGAGCGTTTGTGCACGTGATTTATTTAAGGCGCCCTGTGAGGTCCTGCACATTCATCCTCTCACTT
T
GTTCTCCTAACCACCTGAGAGG'~AGAGGAGG~~vGGCTCC.aGGGGAGCAGCCGCCCTTGGTCACCCAGCTGGCAAAG
GGC
ATGCATGATTGCAGCCTGGCCT~CTGCTCCGGGGCCCTTG~TCTGCCCG:~GGACCCCACACAAGTCAGACCCATAGGC
TC
~GGGTGAGCCGGAGCCCAAGGi~GTGTTGGGGA':GGC':GT~AAAGAAGA_=,ATGGACGTCTGATGCACACTTGGGA
AGGTC
4O
~TACCAGCAGCGTCAAAGAAA"'~CATGTGAA.1CTGACAGC~AGACCCATCCCTCAAAGAAACGCACGTGAAACTGAT
GGC
~AGACCTGTCCCCATCCCTCAi'~CTGGCTCC'~".'TTCTGGG~TTGCCAAG.=,GCCAGCATCAGGTTGAGGCAAGC
TGGAAAG
=;CTTTTCTGGAAAG~AGCTTG =' _' :'GCATGG~..y~ :'CCT~:AC.-~,ATGTCCTG
:'GTCTTCCCAGTAATTCCACTTCTGAAGTGA
~CAGACATTATCACGGGTCTT ~.:'?'TACCATTr~;.~AGT~;TT
.'CAGGCAGG:~GGACTTGCCACAGCAAGTCACGAACCTGCC
,AA~1TACAGGGCTAAGGAGAT_°~. = TAT. GCAT~~ ",.~.-
'..A.~A':TT.~CTCTGCCA'~TAAACATTTTTCAAAGAATTTTTGAAGAAT
4S pTTTAATGGCACAAP.ACGTTT='; TTCAATGT:;~ ;':AGTGTT
~AAAGCTGG.,TG'rAAAAGAACAGACCCCAGGAGCCTGCCG
!'GAATGTCATGTGT.CTTCAT~': "'~~GACaT:~ "=.'=~''A':AT
~GGCAGTGA:~TGGTGGTGAGGCCCTGGAGGACATCGGTGG


CA 02316282 2000-06-21
Le A 32 $OS-Foreign Countries
-45-
GATGCCTCCATCCTGCCCCTCTGGAGACACCATGTGTGCCACGTGCACTCACTGGAGCCCTGTTTAGCTGGTGCCACCT
G
GCTCTTCCATCCCTGAGATTCAAACACAGTGAGATTCCCCACGCCCAACTCAGTGTTCTCCCACAAAAAACCTGAGTCA
C
ACCTGTGTTCACTCGAGGGACGCCCGGGAGCCAGGGCTCCACAGTTTATTATGTGTTTTTGGCTGAGTTATGTGCAGAT
C
TCATCAGGGCAGATGATGAGTGCACAAACACGGCCGTGCGAGGTTTGGATACACTCAACATCACTAGCCAGGTCCTGGT
G
GAGTTTGGTCATGCAGAGTCTGGATGGCATGTAGCATTTGGAGTCCATGGAGTGAGCACCCAGCCCCCTCGGGCTGCAG
C
GCATGCCCCAGGCAGGACAAGGAAGCGGGAGGAAGGCAGGAGGCTCTTTGGAGCAAGCTTTGCAGGAGGGGGCTGGGTG
T
GGGGCAGGCACCTGTGTCTGACATTCCCCCCTGTGTCTCAG
Intron 12 (SEQ ID NO 16)
IO
G'fGAGCAGGCTGATGGTCAGCACAGAGTTCAGAGTTCAGGAGGTGTGTGCGCAAGTATGTGTGTGTGTGTGTGCGCGC
GT
GCCTGCAAGGCTGATGGTGACTGGCTGCACGTAAGAGTGCACATGTACGCATATACACGTGAGCACATACATGTGTGCA
T
GTGTGTACATGAAGGCATGGCAGTGTGTGCACAGGTGTGCAAGGGCACAAGTGTGTGCACATGCGAATGCACACCTGAC
A
TGCATGTGTGTTCGTGCACAGTCGTGTGGGCATTCACGTGAGGTGCATGCGTGTGGGTGTGCAGTGTGAGTAGCATGTG
T
GCACATAACATGTATTGAGGGGTCCTCGTGTTCACCCCGCTAGGTCCTCAGCACCAGTGCCACTCCTTACAGGATGAGA
C
IS
GGGGTCCCAGGCCTTGGTGGGCTGAGGCTCTGAAGCTGCAGCCCTGAGGGCATTGTCCCATCTGGGCATCCGCGTCCAC
T
CCCTCTCCTGTGGGCTTCTGTGTCCACTCCCCCTCTCCTGTGGGCATTTACATCCACTCCACTCCCTCTCTCCTGTGGG
C
ATCCGCGTCCACTCCCCCTCTCTGTGGGCATCTGCGTCCACCTCCCCTCTCTGTGGGCATTTGCGTCCACTCCCTCTCC
T
GGTTCCTTCCTGTCTTGGCCGAGCCTCGGGGGCAGGCAGATGACACAGAGTCTTGACTCGCCCAGGGTGGTTCGCAGCT
G
CCGGGTGAGG~CCAGGCCGGATTTCACTGGGAAGAGGGATAGTTTCTTGTCAAAATGTTCCTCTTTCTTGTTCCATCTG
A
2O
?TGGATGATA~'~.AGCAAAAAGTAAAAACTTAAAATCCCAGAGAGGTTTCTACCGTTTCTCACTCTTTCTTGGCGACT
CTAG
Intron 13 (SEQ ID NO 17)
GTGAGCCGCCACCAAGGGGT~CAGGCCCAGCCTCCAGGGACCCTCCGCGCTCTGCTCACCTCTGACCCGGGGCTTCACC
T
TGGAACTCCTGGGTTTTAGGGGCAAGGAATGTCTTACGTTTTCAGTGGTGCTGCTGCCTGTGCACAGTTCTGTTCGCGT
G
GCTCTGTGCAAAGCACCTGTTCTCCATCTCTGGGTAGTGGTAGGAGCCGGTGTGGCCCCAGGTGTCCCCACTGTGCCTG
T
GCACTGGCCGTGGGACGTCATGGAGGCCATCCCAGGGCAGCAGGGGCATGGGGTAAAGAGATGTTTATGGGGAGTCTTA
G
CAGAGGAGGCTGGGAAGGTGTCTGAACAGTAGATGGGAGATCAGATGCCCGGAGGATTTGGGGTCTCAGCAAAGAGGGC
C
GAGGTGGGTGCAGGTGAGGGTCGCTGGCCCCACCCCCGGGAAGGTGCAGCAGAGCTGTGGCTCCCCACACAGCCCGGCC
A
GCACCTGTGCTCTGGGCATGGCTGTGCTCCTGGAACGTTCCCTGTCCTGGCTGGTCAGGGGGTGCCCCTGCCAAGAATC
G
3O
ACAACTTTATCACAGAGGGAAGGGCCAATCTGTGGAGGCCACAGGGCCAGCTTCTGCCTGGAGTCAGGGCAGGTGGTGG
C
ACAAGCCTCGGGGCTGTACCAAAGGGCAGTCGGGCACCACAGGCCCGGGCCTCCACCTCAACAGGCCTCCCGAGCCACT
G
GGAGCTGAATGCCAGGAGGCCGAAGCCCTCGCCCCATGAGGGCTGAGAAGGAGTGTGAGCATTTGTGTTACCCAGGGCC
G
AGGCTGCGCGAATTACCGTGCACACTTGATGTGAAATGAGGTCGTCGTCTATCGTGGAAACCCAGCAAGGGCTCACGGG
A
GAGTTTTCCATTACAAGGTCGTACCATGAAAATGGTTTTTAACCCGAGTGCTTGCGCCTTCATGCTCTGGCAGGGAGGG
C
AGAGCCACAGCTGCATGTTACCGCC'_"TTGCACC~ GCTCCAGAGG:'?'TGG
GACCAGGCTGTCTCAGTTCCAGGGTGCGTCC
GGCTCAGACCG:~CCTCCTCTCTGC''_'"'CTCTCTCTGCCTCAAATCTTCC~~TCGTTTGCATCTCCCTGACGCGTG
CCTGGG
CCCTCGTGCA.%~ ~~CTGCTTGACTCC :'T "CCGGA.=_A CCCTTGGG GTGTG C".' GG=.TAC
AGGTGCCACTGAGGACTGGAGGTGT
CTGACACTGTG~TTGACCCCAGGG~~CAGCTGG~GTGCTTGGGG~CTCCTTGGGCCATGATGAGGTCAGAGGAGTTTTC
C
CAGGTGAAAA~ :'u.CTGGGAAACT~~
~.=,GGGCC.TGTGACCTGCCA:'.CTG"T:"~TCC~ATA':'TCAGCTCAGTCTTGTCCTC
ATTTCCCCAC~,GGGTCTCTAGCT:CGAGGAGCTCCCGTAGAGG'~C._~TG~G::TCAGGGCAGGGCGGCTGAGTTTC
CCCAC
CCATGTGGGGA."CCTTGGGTAG~'~»~TGATTC~G"_':,GCCCTG.A,~G..~~~C;~
AGATGCGA"'GGGCCACGGGCCGTTTCCA
A.ACACAGAGTC=.GGCACGTGGP=.G~~CCAGGA.'-
_~~CCCTTCC~T~CACG~A:GAGTGGGAGAACGGAGAGCTGGGCCCCG
ATTTCACGGCA'CCAGGCTGCAG':i:~GCGAGG~"_'GTGGTGGT~C;CGTG~C=~CTGGGGGCGGGGTCTGATTCAA
ATCCGC
TGGGGCTCGGC .TTCCTGGC~C~"_ ~ ~ i GGCCG~ ~ ~CTCCACA~~ ~~C-r'_':~G,~ ~TGGA~GC~~
~CGACCTCTAGCAGGTGGC
TATTTCTCCC:'~TGGAAGAGAGCC,~;'CACCC=.~'.GCTAGGTG:'"'"'"~C'"'C. GGTCAGG.-"-
.~~CGTGGCCGTGTGGCAACC


CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-46-
CCGGGACCTTAGGCTTATTTATTTGTTTAAAAACATTCTGGGCCTGGCTTCCGTTGTTGCTAAATGGGGAAAAGACATC
C
CACCTCAGCAGAGTTACTGAGAGGCTGAAACCGGGGTGCTGGCTTGACTGGTGTGATCTCAGGTCATTCCAGAAGTGGC
T
CAGGAAGTCAGTGAGACCAGGTACATGGGGGGCTCAGGCAGTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGTGGG
T
GAGGCCAGGTACATGGGGGGCTCAGGCACTGGGTGAGATGAGGTACACGGGGGGCTCAGGCAGAGGGTCAGACCAGGTA
C
ACGGGGGCTCTGATCACACGCACATATGAGCACATGTGCACATGTGCTGTTTCATGGTAGCCAGGTCTGTGCACACCTG
C
CCCAAAGTCCCAGGAAGCTGAGAGGCCAAAGATGGAGGCTGACAGGGCTGGCGCGGTGGCTCACACCTGTAGTCCCAGC
A
CTTTGGGAGGCCGAGGCGAGAGGATCCCTTGAGCCCAGGAGTTTAAGACCAGCCTGAGCAACATAGTAGAACCCCATCT
C
TATGAAAAATAAAAACAAAAATTAGCTGAACATGGTGGTGTGCGCCTGTAGTTCCAATACTTGGGAGGCTGAAGTGGGA
G
GATCACTTGAGCCCAGGAGGTGGAAGCTGCAGTGAGCTGAGATTGCACCACTGTACTGCAGCCTGGGTGACAGAGTGAG
A
IO
GCCCATCTCAACAACAACAAAGAAGACTGACAAATGCAGTTTCTTGGAAAGAAACATTTAGTAGGAACTTAACCTACAC
A
CAGAAGCCAAGTCGGTGTCTCGGTGTCAGTGAGATGAGATGATGGGTCCTCACACCATCACCCCAGACCCAGGGTTTAT
G
CACCACAGGGGCGGGTGGCTCAGAAGGGATGCGCAGGACGTTGATATACGATGACATCAAGGTTGTCTGACGAAGGGCA
G
Gr'1TTCATGATAAGTACCTGCTGGTACACAAGGAACAATGGATAAACTGGAAACCTTAGAGGCCTTCCCGGAACAGGG
GCT
AATCAGAAGCCAGCATGGGGGGCTGGCATCCAGGATGGAGCTGCTTCAGCCTCCACATGCGTGTTCATACAGATGGTGC
A
IS
CAGAAACGCAGTGTACCTGTGCACACACAGACACGCAGCTACTCGCACACACAAGCACACACACAGACATGCATGCATG
C
ATCCGTGTGTGTGCACCTGTGCCCATGAGGAAACCCATGCATGTGCATTCATGCACGCACACAGGCACCGGTGGGCCCA
T
GCCCACACCCACGAGCACCGTCTGATTAGGAGGCCTTTCCTCTGACGCTGTCCGCCATCCTCTCAG
Intron 14 (WEQ ID NO 18)
ZO
GTATGTGCAGGTGCCTGGCCTCAGTGGCAGCAGTGCCTGCCTGCTGGTGTTAGTGTGTCAGGAGACTGAGTGAATCTGG
G
CTTAGGAAGTTCTTACCCCTTTTCGCATCAGGAAGTGGTTTAACCCAACCACTGTCAGGCTCGTCTGCCCGCCCTCTCG
T
GGGGTGAGCAGAGCACCTGATGGAAGGGACAGGAGCTGTCTGGGAGCTGCCATCCTTCCCACCTTGCTCTGCCTGGGGA
A
GCG~~TGGGGGGCCTGGTCTCTCCTGTTTGCCCCATGGTGGGATTTGGGGGGCCTGGCCTCTCCTGTTTGCCCTGTGGT
GG
GATTGGGCTGTC'TCCCGTCCATGGCACTTAGGGCCCTTGTGCAAACCCAGGCCAAGGGCTTAGGAGGAGGCCAGGCCC
AG
ZS
GCTACCCCACCCCTCTCAGGAGCAGAGGCCGCGTATCACCACGACAGAGCCCCGCGCCGTCCTCTGCTTCCCAGTCACC
G
TCCTCTGCCCCTGGACACTTTGTCCAGCATCAGGGAGGTTTCTGATCCGTCTGAAATTCAAGCCATGTCGAACCTGCGG
T
CCTGAGCTTAACAGCTTCTACTTTCTGTTCTTTCTGTGTTGTGGAAATTTCACCTGGAGAAGCCGAAGAAAACATTTCT
G
TCGTGACTCCTGCGGTGCTTGGGTCGGGACAGCCAGAGATGGAGCCACCCCGCAGACCGTCGGGTGTGGGCAGCTTTCC
G
GTGTCTCCTGGGAGGGGAGCTGGGCTGGGCCTGTGACTCCTCAGCCTCTGTTTTCCCCCAG
Intron 15 (SEQ ID NO 19)
GCAAGTGTGGGTGGAGGCCAGTGCGGGCCCCACCTGCCCAGGGGTCATCCTTGAACGCCCTGTGTGGGGCGAGCAGCCT
C
AGATGCTGCTGAAGTGCAGACGCCCCCGGGCCTGACCCTGGGGGCCTGGAGCCACGCTGGCAGCCCTATGTGATTAAAC
G
CTGGTGTCCCCAGGCCACGGAGCCTGGCAGGGTCCCCAACTTCTTGAACCCCTGCTTCCCATCTCAGGGGCGATGGCTC
C
3S
CCACGCTTGGGAGCCTTCTGACCCCTGACCTGTGTCCTCTCACAGCCTCTTCCCTGGCTGCTGCCCTGAGCTCCTGGGG
T
CCTGAGCAAGTTCTCTCCCCGCCCCGCCGCTCCAGCGTCACTGGGCTGCCTGTCTGCTCGCCCCGGTGGAGGGGTGTCT
G
TCCCTTCACTGAGGTTCCCACCAGCCAGGGCCACGAGGTGCAGGCCCTGCCTGCCCGGCCACCCACACGTCCTAGGAGG
G
TTGGAGGATGCCACCTCTGGCCTCTTCTGGAACGGAGTCTGATTTTGGCCCCGCAG
3'-untranscribed region (SEQ ID NO 20)
ATCTCATGTTTGAATCCTAATGTGCACTGCATAGACACCACTGTATGCAATTACAGAAGCCTGTGAGTGAACGGGGTGG
T
GGTCAGTGCGGGCCCATGGCCTGGCTGTGCA'rTTACGGAAGTCTATGAGTGAATGGGGTTGTGGTCAGTGCGGGCCCA
TG
GCCTGGCTGGGCCTGGGAGGTTTCTGATGCTGTGAGGCAGGAGGGGAAGGAGGGTAGGGGATAGACAGTGGGAGCCCCC
A
C;~~CTGGAAGACATAACAGTAAGTCCAGGCCCGAAGGGCAGCAGGGATGCTGGGGGCCCAGCTTGGGCGGCGGGGATG
ATG
-~S
G~.GGGCCTGGCCAGGGTGGC:,GGGATGATGGGGGCCCCAGCTGGGGTGGCAGGGGTGATGGGGGGGGCTGGTCTGGG
TGG


CA 02316282 2000-06-21
Le A 32 80S-Foreign Countries
-47-
CGGGGAAGATGGGGAAGCCTGGCTGGGCCCCCTCCTCCCCTGCCTCCCACCTGCAGCCGTGGATCCGGATGTGCTTCCC
T
GGTGCACATCCTCTGGGCCATCAGCTTTCATGGAGGTGGGGGGCAGGGGCATGACACCATCCTGTATAAAATCCAGGAT
T
CCTCCTCCTGAACGCCCCAACTCAGGTTGAAAGTCACATTCCGCCTCTGGCCATTCTCTTAAGAGTAGACCAGGATTCT
G
ATCTCTGAAGGGTGGGTAGGGTGGGGCAGTGGAGGGTGTGGACACAGGAGGCTTCAGGGTGGGGCTGGTGATGCTCTCT
C
S
ATCCTCTTATCATCTCCCAGTCTCATCTCTCATCCTCTTATCATCTCCCAGTCTCATCTGTCTTCCTCTTATCTCCCAG
T
CTCATCTGTCATCCTCTTACCATCTCCCAGTCTCATCTCTTATCCTCTTATCTCCTAGTCTCATCCAGACTTACCTCCC
A
GGGCGGGTGCCAGGCTCGCAGTGGAGCTGGACATACGTCCTTCCTCAGGCAGAAGGAACTGGAAGGATTGCAGAGAACA
G
GAGGGGCGGCTCAGAGGGACGCAGTCTTGGGGTGAAGAAACAGCCCCTCCTCAGAAGTTGGCTTGGGCCACACGAAACC
G
AGGGCCCTGCGTGAGTGGCTCCAGAGCCTTCCAGCAGGTCCCTGGTGGGGCCTTATGGTATGGCCGGGTCCTACTGAGT
G
IO
CACCTTGGACAGGGCTTCTGGTTTGAGTGCAGCCCGGACGTGCCTGGTGTCGGGGTGGGGGCTTATGGCCACTGGATAT
G
GCGTCATTTATTGCTGCTGCTTCAGAGAATGTCTGAGTGACCGAGCCTAATGTGTATGGTGGGCCCAAGTCCACAGACT
G
TGTCGTAAATGCACTCTGGTGCCTGGAGCCCCCGTATAGGAGCTGTGAGGAAGGAGGGGCTCTTGGCAGCCGGCCTGGG
G
GCGCCTTTGCCCTGCAAACTGGAAGGGAGCGGCCCCGGGCGCCGTGGGCGGACGACCTCAAGTGAGAGGTTGGACAGAA
C
AGGGCGGGGACTTCCCAGGAGCAGAGGCCGCTGCTCAGGCACACCTGGGTTTGAATCACAGACCAACaGGTCAGGCCAT
T
IS
GTTCAGCTATCCATCTTCTACAAAGCTCCAGATTCCTGTTTCTCCGGGTGTTTTTTGTTGAAATTTTACTCAGGATTAC
T
TATATTTTTTGCTAAAGTATTAGACCCTTAAAAAAGGTATTTGCTTTGATATGGCTTAACTCACTAAGCACCTACTTTA
T
TTGTCTGTTTTTATTTATTATTATTATTATTATTAGAGATGGTGTCTACTCTGTCACCCAGGTTGTTAGTGCAGTGGCA
C
AGTCATGGCTCGCTGTAGCCGCAAACCCCCAGGCTCAAGTGATCCTCCGGCCTCAGCTTCCCAGAGTGCTGGGATTACA
G
GTGTGAGCCACTGCCCTTGCCTGGCACTTTTAAAAACCACTATGTAAGGTCAGGTCCAGTGGCTTCCr'~CACCTGTCA
TCC
2O
CAGTAG'fTTGGGAAGCCGAGGCAGAAGGATTGTCTGAGGCCAGGAGTTTGAGACCAGCATGGGTAACATAGGGAGACC
CC
AT.'CTCTIaCAAAAP.ATGCAAAAAGTTATCCGGGCGTGGGGTCCAGCATCTGTAGTCCCAGCTGCTCGGGAGGCTGA
GTGGG
AGGATCGCTTGAGCCCGGGAGGTCATGGCTGCAGTGAGCTGTGATTG'fACCATCGCACTCCAGCCTGGGCAACAGAGT
GA
GACCCTGTCTC GAAGGAGAAGGAGAAGAGAAGAAGAAGGAAGAAGGAAAGAGAAGAAGAAG
C~AAGAAGGAAGAAAGAAGGAGAAGGAGGCCTGCTAGGTGCTAGGTAGACTGTCAAATCTC?~GAGCAAAATGAAAATA
ACA
2J
AAGTTTTAAAGGGAAAGAAAAACCCCAGCTCTTTGGACTTCCTTAGGCCTGAACTTCATCTCAAGCAGCTTCCTTCCAC
A
GAC.~AGCGTGTATGGAGCGAGTGAGTTCAAAGCAGAAAGGGAGGAGAAGCAGGCAAGGGTGGAGGCTGTGGGTGACAC
CA
GCCAGGACCCCTGAAAGGGAGTGGTTGTTTTCCTGCCTCAGCCCCACGCTCCTGCCGGTCCTGCACCTGCTGTAACCGT
C
GATGTTGGTGCCAGGTGCCCACCTGGGAAGGATGCTGTGCAGGGGGCTTGCCAAACTTTGGTGGGTTTCAGAAGCCCCA
G
GCACTTGTGGCAGGCACAATTACAGCCCCTCCCCAAAGATGCCCACGTCCTTCTCCTGGAACCTGTGAATGTGTCACCC
G
3O
CAAGGCAGAGGCTGGTGAAGGCTGCAGGTGGAATCACGGCTGCCAGTCAGCCGATCTTAAGGTCATCCTGGATTATCTG
G
TGGGCCTGATATGGCCACAAGGGTCCCTAGAAGTGAGAGAGGGAGGCAGGGGAGAGTCAGAGAGGGGACGTGAGAAGGA
C
CACTGGCCACTGCTGGCTTTGAGATGGAGGAGGGGGTCCCCAGCCAAGGAATGGGGGCAGCCGCTCCATGCTGGAAAAG
C
:~AGCAATCCTCCCCGGTCCTGAGGGCACACGGCCCTGCCCACGCCTCGATTTCAGGCCAGTGGGACCTGTTTCAGCTT
TC
CGGCCTCCAGAGCTGTAAGATGATGCGTTTGTGTTCAGCCACTAAGCTGCAGTGATTCGTCACAGCAGCAAATGGAATA
G
3S ~AGTACAGGGAAATGAATACAGGGACAGTTCTCAGAGTGACTCTCAGCCCACCCCTGGG


CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-48-
Characterization of the exons showed, interestingly, that the functionally
important
hTC protein domains which are described in our Patent Application
PCT/EP/98/03469 are arranged on separate exons. The telomerase-characteristic
T
motif is located on exon 3. The RT (reverse transcriptase) motifs I-7, which
are
important for the catalytic function of the telomerase, are located on the
following
exons: RT motifs I and 2 on exon 4, RT motif 4 on exon 9, RT motif 5 on exon
10,
and RT motifs 6 and 7 on exon 11. RT motif 3 is shared by exons 5 and 6 (see
Fig. 8).
Elucidation of the exon-intron -structure of the hTC gene also shows that the
four
deletions or insertion variants of the hTC cDNA which were described in our
Patent
Application PCT/EP/98/03469, as well as three additional hTC insertion
variants
which are described in the literature (Kilian et al., 1997), in all
probability represent
alternative splicing products. As shown in Fig. 8, the splicing variants can
be divided
into two groups: deletion variants and insertion variants.
The hTC variants in the deletion group lack specific sequence segments. The 36
by
in-frame deletion in variant DEL1 in all probability results from using an
alternative
3' splice acceptor sequence in exon 6, resulting in a part of RT motif 3 being
lost. In
variant DEL2, the normal 5' splice donor and 3' splice acceptor sequences of
introns
6, 7 and 8 are not used. Instead exon 6 is fused directly to exon 9, resulting
in a
displacement arising in the open reading frame and a stop codon appearing in
exon
10. Variant Del3 is a combination of variants 1 and 2.
The insertion variant group is characterized by the insertion of intron
sequences
which lead to premature cessation of translation. Instead of the 5' splice
donor
sequence of intron 5, which is normally used, use is made, in variant INS l,
of an
alternative, 3'-located splice site, resulting in the insertion of the first
38 by from
intron 4 between exon 4 and exon 5. The insertion, in variant I'.~iS2, of a
region of the
intron 11 sequence likewise results from using an alternative 5' splice donor
sequence m intron 11. Since this variant was only described inadequately in
the


CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-49-
literature (Kilian et al., 1997), it is not possible to determine the precise
alternative S'
splice donor sequence in this variant. The insertion of intron 14 sequences
between
exon 14 and exon 15 in variant INS3 comes from using an alternative 3' splice
acceptor sequence, resulting in the 3' part of intron 14 not being spliced.
The hTC variant INS4 (variante 4), which is described in our Patent
Application
PCT/EP/98/03469, is characterized by exon 15, and the 5' part region of exon
16,
being replaced by the first 600 by of intron 14. This variant can' be
attributed to the
use of an alternative internal 5 ' splice donor sequence in intron 14 and an
alternative
3 ' splice acceptor sequence in exon 16, resulting in an altered C terminus.
The in vivo generation of hTC protein variants which are probably non-
functional
and which could interfere with the function of the complete hTC protein
constitutes a
possible mechanism, in addition to transcription regulation, for controlling
hTC
protein function. The function of the hTC splicing variants is not yet known.
Although most of these variants presumably encode proteins without reverse
transcriptase activity, they could nevertheless play a crucial role as
transdominant-
negative telomerase regulators by, for example, competing for interaction with
important binding partners.
The search for possible transcription factor binding sites was carried out
using the
"find pattern" algorithm from the Genetics Computer Group (Madison, USA) GCG
Sequence Analysis program package. This resulted in the identification of a
variety
of potential binding sites for transcription factors in the nucleotide
sequence of intron
2, which binding sites are listed in Tab. 2. In addition, an Sp 1 binding site
was found
in intron 1 (pos. 43), and a c-Myc binding site was found in the 5'-
untranslated region
(cDNA position 29-34, cf. Fig. 6).


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Example 6
In order to ascertain the start points) of hTC transcription in HL 60 cells,
the 5' end
of the hTC mRNA was determined by means of primer extension analysis.
2 Itg of polyA+ RNA from HL-60 cells were denaturated at 65°C for 10
min. 1 ul of
RNasin (30-40 U/ml) and 0.3-1 pmol of radioactively labelled primer
(5'GTTAAGTTGTAGCTTACACTGGTTCTC 3'; 2.5-8x105 cpm) were added for
primer annealing, and the whole was incubated, at 37°C for 30 min, in a
total volume
of 2U pl. After the addition of 10 Ill of 5xreverse transcriptase buffer (from
Gibco-
BRL), 2 pl of 10 mM dNTPs, 2 Ill RNasin (see above), 5 pl of 0.1 M DTT (from
Gibco-BRL) 2 pl of ThermoScript RT (15 U/pl; from Gibco-BRL) and 9 ~1 of
i~EPC-treated water, primer extension took place, at 58°C for 1 h, in a
total volume
flacunaJ. The reaction was stopped by adding 4 pl of 0.5 M EDTA, pH 8.0, and
the
RNA was degraded, at 37°C for 30 min, after having added 1 pl of
RNaseA
(10 mg/ml). 2.5 pg of sheared calf thymus DNA and 100 pl of TE were then
added,
and the mixture was extracted once with 150 pl of phenol/chloroform (1:1). The
DNA was precipitated, at -70°C for 45 min, after adding 15 pl of 3 M Na
acetate and
450 pl of ethanol, and then centrifuged at 14,000 rpm for 15 min. The
precipitate was
washed once with 70% ethanol, dried in air and dissolved in 8 ~1 of sequencing
stop
solution. After 5 min of denaturation at 80°C, the samples were loaded
onto a 6%
polyacrylamide gel and fractionated electrophoretically (Ausubel et al., 1987)
(Fig. 5).
In this connection, a main transcription start site was identitied which is
located
1767 by 5' of the ATG start codon of the hTC cDNA sequence (nucleotide
position
3346 in Fig. 4). In addition to this, the nucleotide sequence around this main
transcription start (TTA+iTTGT) represents an initiator element ( Inr). which,
in 6 out
of 7 nucleotides, matches the consensus motif (PyPyA+iNaltPyPy) (Smale, 1997)
of
an initiator element.


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It was not possible to identify any unambiguous TATA box in the immediate
vicinity
of the experimentally identified main transcription start, which means that
the hTC
promoter has probably to be classified in the family of TATA-less promoters
(Smale,
1997). However, a potential TATA box from nucleotide position 1306 to
nucleotide
S position 1311 (Fig. 4) was found by means of bioinformatics analysis. The
subsidiary
transcription starts which were additionally observed around the main
transcription
start have also been described in the case of other TATA-less promoters (Geng
and
Johnson, 1993), for example in the strongly regulated promoters of some cell
cycle
genes (Wick et al., 1995).
Example 7
In addition to the start point of the hTC transcript which was described in
Example 6
and identified in HL60 cells, a further transcription start region was also
identified in
HL60 cells. With the aid of RT-PCR analyses, the region of the hTC gene
transcription start in HL60 cells was localized to by -60 to by -105.
The cDNA for this was synthesized using a First Strand cDNA Synthesis kit
(Clontech), in accordance with the manufacturer's instructions, and employing
0.4 ~g
of HL60 cell polyA RNA (Clontech) and the gene-specific primer GSP 13
(5 '-CCTCCAAAGAGGTGGCTTCTTCGGC-3 ', cDNA position 920-897). In a final
volume of 50 pl, 10 pmol dNTP mix were added to 1 pl of cDNA, and a PCR
reaction was carried out in 1 xPCR reaction buffer F (PCR-Optimizer kit from
InVitrogen) and using one unit of platinum Taq DNA polymerase (from
Gibco/BRL).
10 pmol of each of the 5' and 3' primers defined below were added as primers.
The
PCR was carried out in 3 steps. A two-minute denaturation at 94°C was
followed by
36 PCR cycles in which the DNA was first of all denatured at 94°C for
4~ sec and,
after that, the primers were annealed, and the DNA chain was extended at
68°C for
~ min. The cycles were concluded by a chain extension at 68°C for 10
min. In all, six
different 5' PCR primers (primer HTRTSB:
~'-CGCAGCCACTACCGCGAGGTGC-3', cDNA position 10~ to 126; primer CSS:


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5'-CTGCGTCCTGCTGCGCACGTGGGAAGC-3', 5'-flanking region -49 to -23;
primer PRO-TEST 1: 5 '-CTCGCGGCGCGAGTTTCAGGCAG-3 ', 5 '-flanking
region -74 to -52; primer PRO-TEST2: 5 '-CCAGCCCCTCCCCTTCCTTTCC-3 ',
5'-flanking region -112 to -91; primer PRO-TEST4:
S 5'-CCAGCTCCGCCTCCTCCGCGC-3', 5'-flanking region -191 to -171; primer
RP-3A: 5'-CTAGGCCGATTCGACCTCTCTCC-3', 5'-flanking region -427 to
-405) were combined with the 3' PCR primer CSRback
(5'-GTCCCAGGGCACGCACACCAG-3', cDNA position 245 to 225). Genomic
DNA was also employed for the PCR, as a control, in addition to the Oligo dT-
and
GSP 13-primed cDNAs. As Fig. 9 shows, a PCR product was only obtained with the
primer combinations HTRTSB-CSRback, CSS-CSRback and PRO-TEST1-CSRback,
indicating that the start point for hTC transcription lies in the region
between bp-60
and bp-1 O5.
Example 8
Several extremely GC-rich regions, so-called CpG Islands, are located in the
isolated
5'-flanking region, of about 11.2 kb in size, of the hTC gene. One CpG Island,
having
a GC content of > 70%, extends from by - 1214 into intron 2. Two further GC-
rich
regions having a GC content of > 60% extend from by -3872 to by -3113 and from
by -5363 to by -3941, respectively. The positions of the CpG Islands are shown
graphically in Fig. 11.
The search for possible transcription factor binding sites was carried out
using the
"Find Pattern" algorithm from the Genetics Computer Group (Madison, USA) GCG
Sequence Analysis program package. This resulted in the identification of a
variety
of potential binding sites in the region up to -900 by upstream of the
translation start
codon ATG: five Sp l binding sites, one c-Myc binding site, and one CCAC box
(Fig. IO). In addition, a CCAAT box and a second c-Myc binding site were found
at
positions -1788 and -3995, respectively, of the 5'-flanking region.


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Example 9
In order to analyse the activity of the hTC promoter, PCR amplification was
used to
generate four hTC promoter sequence segments of differing length, which
segments
were cloned into the Promega vector pGL2 5' in front of the luciferase
reporter gene.
The 8.5 kb SacI fragment which was subcloned from phage clone P 12 was
selected
as the DNA source for the PCR amplification. In a final volume of 50 pl, 10
pmol of
dNTP mix were added to 35 ng of this DNA, and a PCR reaction was carried out
in
IxPCR reaction buffer (PCR-Optimizer kit from InVitrogen) and using one unit
of
platinum Taq DNA polymerase (from Gibco/BRL). In each case 20 pmol of the 5'
and 3' primers which are defined below were added as primers. The PCR was
carried
out in three steps. A two-minute denaturation at 94°C was followeed by
30 PCR
cycles in which the DNA was first of all denaturated at 94°C for 45
sec, after which
the primers were annealed, and the DNA chain was extended, at 68°C for
5 min. The
cycles were concluded by a chain extension at 68°C for l0 min. The
selected 3' PCR
primer was in each case the primer PK-3A
(5'-GCAAGCTTGACGCAGCGCTGCCTGAAACTCG-3', position ~3 to -65),
which primer recognizes a sequence region 42 by upstream of the ATG START
codon. A promoter fragment of 4051 by in size (NPKB) was amplified by
combining
the PK-3A primers with the 5' PCR primer PK-5B
(5 '-CCAGATCTCTGGAACACAGAGTGGCAGTTTCC-3 ', position -4093 to
-4070). Combining the pair of primers PK-3A and PK-5C
(5 '-CCAGATCTGCATGAAGTGTGTGGGGATTTGCAG-3 ', position -3120 to
-3096) led to the amplification of a promoter fragment of 3078 by in size
(NPK15).
Use of the primer combination PK-3A and PK-5D
(5 '-GGAGATCTGATCTTGGCTTACTGCAGCCTCTG-3 ', position -2110 to
-2087) amplified a promoter fragment of 2068 by in size (NPK22). Finally,
using the
primer combination PK-3A and PK-5E
(5'-GGAGATCTGTCTGGATTCCTGGGAAGTCCTCA-3', position -1125 to
-1 102) led to the amplification of a promoter fragment of 1083 by in size
(NPK27).


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The PK-3A primer contains a HindIII recognition sequence. The different 5'
primers
contain a BgIII recognition sequence.
The resulting PCR products were purified using the Qiagen QIA quick spin PCR
purification kit, in accordance with the manufacturer's instructions, and then
digested
with the restriction enzymes BgIII and HindIII. The pGL2 promoter vector was
digested with the same restriction enzymes, and the SV40 promoter contained in
this
vector was released and removed. The PCR promoter fragments ligated into the
vector, which was then transformed into competent DHSa bacteria (from
Gibco/BRL). DNA for the promoter activity analyses, which are described below,
was isolated from transformed bacterial clones using the Qiagen plasmid kit.
Example 10
The activity of the hTC promoter was analysed in transient transfections in
eukaryotic cells.
All the work with eukaryotic cells was carried out at a sterile workstation.
CHO-K1
and HEK 293 cells were obtained from the American Type Culture collection.
CHO-K1 cells were kept in DMEM Nut Mix F-12 cell culture medium (from Gibco-
BRL, order number: 21331-020) containing 0.15% streptomycin/penicillin, 2 mM
glutamine and 10% FCS (from Gibco-BRL).
HEK 293 cells were cultured in DMOD cell culture medium (from Gibco-BRL, order
number: 41965-039) containing 0.15% streptomycin/penicillin, 2 mM glutamine
and
10% FCS (from Gibco-BRL).
CHO-K1 and HEK 293 cells were cultured at 37°C in a water-saturated
atmosphere
while being gassed with 5% COZ. When the cell lawn was confluent, the medium
was sucked off, after which the cells were washed with PBS ( 100 mM KH~P04 pH


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7.2; 1 SO mM NaCI) and released by adding a trypsin-EDTA solution (from Gibco-
BRL). The trypsin was inactivated by adding medium and the cell count was
determined using a Neubauer counting chamber in order to plate out the cells
at the
desired density.
For the transfection, in each case 2x 105 HEK 293 cells were plated out, per
well, in a
24-well cell culture plate. The HEK 293 medium was removed after 3 hours. For
the
transfection, up to 2.5 pg of plasmid DNA, 1 pg of a CMV 13-Gal plasmid
construct
(from Stratagene, order numner: 200388), 200 p.l of serum-free medium and 10
pl of
l0 transfection reagent (DOTAP from Boehringer Mannheim) were incubated at
room
temperature for 15 minutes and then dropped uniformly onto the HEK 293 cells.
1.5
ml of medium were added after 3 hours. The medium was changed after 20 hours.
After a further 24 hours, the cells were harvested for determining the
luciferase
activity and the f3-Gal activity. For this, the cells were lysed, at room
temperature for
15 minutes, in the cell culture lysis reagent (25 mM Tris [pH 7.8J containing
H3P0.~;
2 mM CDTA; 2 mM DTT; 10% glycerol; 1% Triton X-100). Twenty pl of this cell
lysate were mixed with 100 pl of luciferase assay buffer (20 mM Tricin; 1.07
mM
(MgC03)4 Mg(OH)2'SH20; 2.67 mM MgS04; 0.1 mM EDTA; 33.3 mM DTT;
270 pM coenzyme A; 470 pM luciferin, 530 pM ATP), and the light generated by
the luciferase was measured.
In order to measure the !3-galactosidase activity, equal quantities of cell
lysate and (3-
galactosidase assay buffer ( 100 mM sodium phosphate buffer, pH 7.3; 1 mM
MgCl2;
50 mM f3-mercaptoethanol; 0.665 mg of ONPG/ml) were incubated at 37°C
for at
least 30 minutes or until a slight yellow coloration appeared. The reaction
was
stopped by adding 100 ul of 1 M Na2C03, and the absorption was determined at
420 nm.
In order to analyse the hTC promoter, four hTC promoter sequence segments of
differing length were cloned 5' in front of the luciferase reporter gene (cf.
Example
9).


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The relative luciferase activities of two independent transfections in HEK 293
cells,
using the constructs NPKB, NPK15, NPK22 and NPK27, are plotted in Fig. 11.
Each
experiment was carned out in duplicate. The standard deviation has also been
given.
The construct NPK 27 exhibits a luciferase activity which is 40 times higher
than the
basal activity of the promoterless luciferase control construct (pGL2-basic)
and from
2 to 3 times higher than that of the SV40 promoter control construct
(pGL2PR0).
lnterestingly, a luciferase activity which was from 2 to 3 times lower than
that
obtained with the NPK 27 construct was observed in cells which were
transfected
with longer hTC promoter constructs (NPKB, NPK15, NPK22). Similar results were
also observed in CHO cells (data not shown).


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References
Allsopp, R. C., Vazire, H., Pattersson, C., Goldstein, S., Younglai, E.V.,
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Blasco, M. A., Rizen, M., Greider, C. W. and Hanahan, D. (1996). Differential
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1 S Broccoli, D., Young, J. W. and deLange, T. (1995). Telomerase activity in
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Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., Avilion, A.A., Chiu, C.-
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Geng, Y., and Johnson, L.F. (1993). Lack of an initiator element is
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Goldstein, S. (1990). Replicative senescence: The human fibroblast comes of
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Harley, C. B., Futcher, A. B., Greider, C.W., 1990. Telomeres shorten during
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Hastie, N. D., Dempster, M., Dunlop, M. G., Thompson, A. M., Green, D.K. and
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Shay, J.W.,
Ishioka, S. and Yamakido, M. (1995). Activation of telomerase in human
lymphocytes and
hematopoietic progenitor cells. J. Immunol. 155, 3711-3715.
Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C. B., West, M.D., Ho,
P.L.C., Coviello,
G.M., Wright, W.E., Weinrich, S.L. and Shay, J.W. (1994). Specific association
of human
telomerase activity with immortal cells and cancer. Science 266, 2011-2015.
Latchman, D.S. (1991). Eukaryotic transcription factors. Academic Press
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Lingner, J., Hughes, T.R., Shevchenko, A., Mann, M., Lundblad, V. and Cech
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Smale, S.T. (1997). Transcription initation from TATA-less promoters within
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Shay, J. W. (1997). Telomerae and Cancer. Ciba Foundation Meeting: Telomeres
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Vaziri, H., Dragowska, W., Allsopp, R. C,, Thomas, T. E., Harley, C.B. and
Landsdorp, P.M.
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of telomeric DNA with
age. Proc. Natl. Acad. Sci. 91, 9857-9860.
Wick, M., Haronen, R., Mumberg,~ D., Burger, C., Olsen, B.R., Budarf, M.L.,
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SEQUENCE LISTING
<110> Bayer AG
<120> Regulatory DNA sequences from the 5i region of the gene
for the human catalytic telomerase subunit, and
their diagnostic and therapeutic use
<130> LeA32805-Foreign Countries
1
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<141>
<160> 20
IS
<170> PatentIn Vers. 2.0
<210> 1
<211> 5126
2n <212> DNA
<213> Homo sapiens
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gagctctgaaccgtggaaacgaacatgacccttgcctgcctgcttccctgggtgggtcaa60


25 gggtaatgaagtggtgtgcaggaaatggccatgtaaattacacgactctgctgatgggga120


ccgttccttccatcattattcatcttcacccccaaggactgaatgattccagcaacttct180


tcgggtgtgacaagccatgacaaaactcagtacaaacaccactcttttactaggcccaca240


gagcacgggccacacccctgatatattaagagtccaggagagatgaggctgctttcagcc300


accaggctggggtgacaacagcggctgaacagtctgttcctctagactagtagaccctgg360


3o caggcactcccccaaattctagggcctggttgctgcttcccgagggcgccatctgccctg420


gagactcagcctggggtgccacactgaggccagccctgtctccacaccctccgcctccag480


.Jcctcagcttctccagcagcttcctaaaccctgggtgggccgtgttccagcgctactgtc540


tcacctgtcccactgtgtcttgtctcagcgacgtagctcgcacggttcctcctcacatgg600


ggtgtctgtctccttccccaacactcacatgcgttgaagggaggagattctgcgcctccc660


3J agactggctcctctgagcctgaacctggctcgtggcccccgatgcaggttcctggcgtcc720


ggctgcacgctgacctccatttccaggcgctccccgtctcctgtcatctgccggggcctg780


ccggtgtgttcttctgtttctgtgctcctttccacgtccagctgcgtgtgtctctgcccg340


ctagggtctcggggtttttataggcataggacgggggcgtggtgggccagggcgctcttg900


ggaaatgcaacatttgggtgtgaaagtaggagtgcctgtcctcacctaggtccacgggca960


caggcctggggatggagcccccgccagggacccgcccttctctgcccagcactttcctgc1020


ccccctccctctggaacacagagtggcagtttccacaagcactaagcatcctcttcccaa1080


aagacccagcattggcacccctggacatttgccccacagccctgggaattcacgtgacta1140'


cgcacatcatgtacacactcccgtccacgaccgacccccgctgttttattttaatagcta1200


caaagcagggaaatccctgctaaaatgtcctttaacaaactggttaaacaaacgggtcca1260
45


tccgcacggtggacagttcctcacagtgaagaggaacatgccgtttataaagcctgcagg1320


catctcaagggaattacgctgagtcaaaactgccacctccatgggatacgtacgcaacat1380


gctcaaaaagaaagaatttcaccccatggcaggggagtggttaggggggttaaggacggt1440


gggggcggcagctgggggctactgcacgcaccttttactaaagccagtttcctggttctg1500


5o atggtattggctcagttatgggagactaaccataggggagtggggatgggggaacccgga1560


ggctgtgccatctttgccatgcccgagtgtcctgggcaggataatgctctagagatgccc1620


acgtcctgattcccccaaacctgtggacagaacccgcccggccccagggcctttgcaggt1680


gtgatctccgtgaggaccctgaggtctgggatccttcgggactacctgcaggcccgaaaa1740


gtaatccaggggttctgggaagaggcgggcaggagggtcagaggggggcagcctcaggac1800


55 gatggaggcagtcagtctgaggctgaaaagggagggagggcctcgagcccaggcctgcaa1860


gcgcctccagaagctggaaaaagcggggaagggaccctccacggagcctgcagcaggaag1920


gcacggctggcccttagcccaccagggcccatcgtggacctccggcctccgtgccatagg1980


agggcactcgcgctgcccttctagcatgaagtgtgtggggatttgcagaagcaacaggaa2040


acccatgcactgtgaatctaggattatttcaaaacaaaggtttacagaaacatccaagga2100


cagggctgaagtgcctccgggcaagggcagggcaggcacgagtgattttatttagctatt2160


ttattttatttacttactttctgagacagagttatgctcttgttgcccaggctggagtgc2220


agcggcatgatcttggctcactgcaacctccgtctcctgggttcaagcaattctcgtgcc2280


tcagcctcccaagtagctgggatttcaggcgtgcaccaccacacccggctaattttgtat2340


ttttagtagagatgggctttcaccatgttggtcaagctgatctcaaaatcctgacctcag2400


65 gtgatccgcccacctcagcctcccaaagtgctgggattacaggcatgagccactgcacct2460


ggcctatttaaccattttaaaacttccctgggctcaagtcacacccactggtaaggagtt2520


catggagttcaatttcccctttactcaggagttaccctcctttgatattttctgtaattc2580


ttcgtagactggggatacaccgtctcttgacatattcacagtttctgtgaccacctgtta2640


tcccatgggacccactgcaggggcagctgggaggctgcaggcttcaggtcccagtggggt2700


tgccatctgccagtagaaacctgatgtagaatcagggcgcaagtgtggacactgtcctga2760


atctcaatgtctcagtgtgtgctgaaacatgtagaaattaaagtccatccctcctactct2820


actgggattgagccccttccctatccccccccaggggcagaggagttcctctcactcctg2880


tggaggaaggaatgatactttgttatttttcactgctggtactgaatccactgtttcatt2940


tgttggtttgtttgttttgttttgagaggcggtttcactcttgttgctcaggctggaggg3000


agtgcaatggcgcgatcttggcttactgcagcctctgcctcccaggttcaagtgattctc3060
7J


ctgcttccgcctcccatttggctgggattacaggcacccgccaccatgcccagctaattt3120


tttgtatttttagtagagacgggggtgggtggggttcaccatgttggccaggctggtctc3180


gaacttctgacctcagatgatccacctgcctctgcctcctaaagtgctgggattacaggt3240




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gtgagccaccatgcccagctcagaatttactctgtttagaaacatctgggtctgaggtag3300


gaagctcaccccactcaagtgttgtggtgttttaagccaatgatagaatttttttattgt3360


tgttagaacactcttgatgttttacactgtgatgactaagacatcatcagcttttcaaag3420


acacactaactgcacccataatactggggtgtcttctgggtatcagcaatcttcattgaa3480


tgccgggaggcgtttcctcgccatgcacatggtgttaattactccagcataatcttctgc3590


ttccatttcttctcttccctcttttaaaattgtgttttctatgttggcttctctgcagag3600


aaccagtgtaagctacaacttaacttttgttggaacaaattttccaaaccgcccctttgc3660


cctagtggcagagacaattcacaaacacagccctttaaaaaggcttagggatcactaagg3720


to ggatttctagaagagcgacctgtaatcctaagtatttacaagacgaggctaacctccagc3780


gagcgtgacagcccagggagggtgcgaggcctgttcaaatgctagctccataaataaagc3840


aatttcctccggcagtttctgaaagtaggaaaggttacatttaaggttgcgtttgttagc3900


atttcagtgtttgccgacctcagctacagcatccctgcaaggcctcgggagacccagaag3960


tttctcgcccccttagatccaaacttgagcaacccggagtctggattcctgggaagtcct4020


cagctgtcctgcggttgtgccggggccccaggtctggaggggaccagtggccgtgtggct4080
15


tctactgctgggctggaagtcgggcctcctagctctgcagtccgaggcttggagccaggt4140


gcctggaccccgaggctgccctccaccctgtgcgggcgggatgtgaccagatgttggcct4200


catctgccagacagagtgccggggcccagggtcaaggccgttgtggctggtgtgaggcgc4260


ccggtgcgcggccagcaggagcgcctggctccatttcccaccctttctcgacgggaccgc4320


,7o cccggtgggtgattaacagatttggggtggtttgctcatggtggggacccctcgccgcct4380


gagaacctgcaaagagaaatgacgggcctgtgtcaaggagcccaagtcgcggggaagtgt4440


tgcagggaggcactccgggaggtcccgcgtgcccgtccagggagcaatgcgtcctcgggt4500


tcgtccccagccgcgtctacgcgcctccgtcctccccttcacgtccggcattcgtggtgc4560


ccggagcccgacgccccgcgtccggacctggaggcagccctgggtctccggatcaggcca4620


gcggccaaagggtcgccgcacgcacctgttcccagggcctccacatcatggcccctccct4680
25


cgggttaccccacagcctaggccgattcgacctctctccgctggggccctcgctggcgtc4740


cctgcaccctgggagcgcgagcggcgcgcgggcggggaagcgcggcccagacccccgggt4800


ccgcccggagcagctgcgctgtcggggccaggccgggctcccagtggattcgcgggcaca4860


gacgcccaggaccgcgctccccacgtggcggagggactggggacccgggcacccgtcctg4920


3o ccccttcaccttccagctccgcctcctccgcgcggaccccgccccgtcccgacccctccc4980


gggtccccggcccagccccctccgggccctcccagcccctccccttcctttccgcggccc5040


cgccctctcctcgcggcgcgagtttcaggcagcgctgcgtcctgctgcgcacgtgggaag5100


ccctggccccggccacccccgcgatg
5126


<210> 2
35 <211> 4042
<212> DNA
<213> Homo Sapiens
<400> 2


40 gtttcaggcagcgctgcgtcctgctgcgcacgtgggaagccctggccccggccacccccg60


cgatgccgcgcgctccccgctgccgagccgtgcgctccctgctgcgcagccactaccgcg120


aggtgctgccgctggccacgttcgtgcggcgcctggggccccagggctggcggctggtgc180


agcgcggggacccggcggctttccgcgcgctggtggcccagtgcctggtgtgcgtgccct240


gggacgcacggccgccccccgccgccccctccttccgccaggtgtcctgcctgaaggagc300
45


tggtggcccgagtgctgcagaggctgtgcgagcgcggcgcgaagaacgtgctggccttcg360


gcttcgcgctgctggacggggcccgcgggggcccccccgaggccttcaccaccagcgtgc420


gcagctacctgcccaacacggtgaccgacgcactgcgggggagcggggcgtgggggctgc480


tgctgcgccgcgtgggcgacgacgtgctggttcacctgctggcacgctgcgcgctctttg540


tgctggtggctcccagctgcgcctaccaggtgtgcgggccgccgctgtaccagctcggcg600
50


ctgccactcaggcccggcccccgccacacgctagtggaccccgaaggcgtctgggatgcg660


aacgggcctggaaccatagcgtcagggaggccggggtccccctgggcctgccagccccgg720


gtgcgaggaggcgcgggggcagtgccagccgaagtctgccgttgcccaagaggcccaggc780


gtggcgctgcccctgagccggagcggacgcccgttgggcaggggtcctgggcccacccgg840


gcaggacgcgtggaccgagtgaccgtggtttctgtgtggtgtcacctgccagacccgccg900
55


aagaagccacctctttggagggtgcgctctctggcacgcgccactcccacccatccgtgg960


gccgccagcaccacgcgggccccccatccacatcgcggccaccacgtccctgggacacgc1020


cttgtcccccggtgtacgccgagaccaagcacttcctctactcctcaggcgacaaggagc1080


agctgcggccctccttcctactcagctctctgaggcccagcctgactggcgctcggaggc1140


tcgtggagaccatctttctgggttccaggccctggatgccagggactccccgcaggttgc1200


cccgcctgccccagcgctactggcaaatgcggcccctgtttctggagctgcttgggaacc1260


acgcgcagtgcccctacggggtgctcctcaagacgcactgcccgctgcgagctgcggtca1320


ccccagcagccggtgtctgtgcccgggagaagccccagggctctgtggcggcccccgagg1380


aggaggacacagacccccgtcgcctggtgcagctgctccgccagcacagcagcccctggc1440


aggtgtacggcttcgtgcgggcctgcctgcgccggctggtgcccccaggcctctggggct1500
65


ccaggcacaacgaacgccgcttcctcaggaacaccaagaagttcatctccctggggaagc1560


atgccaagctctcgctgcaggagctgacgtggaagatgagcgtgcgggactgcgcttggc1620


tgcgcaggagcccaggggttggctgtgttccggccgcagagcaccgtctgcgtgaggaga1680


tcctggccaagttcctgcactggctgatgagtgtgtacgtcgtcgagctgctcaggtctt1740


tcttttatgtcacggagaccacgtttcaaaagaacaggctctttttctaccggaagagtg1800


tctggagcaagttgcaaagcattggaatcagacagcacttgaagagggtgcagctgcggg1860


agctgtcggaagcagaggtcaggcagcatcgggaagccaggcccgccctgctgacgtcca1920


gactccgcttcatccccaagcctgacgggctgcggccgattgtgaacatggactacgtcg1980


tgggagccagaacgttccgcagagaaaagagggccgagcgtctcacctcgagggtgaagg2040


cactgttcagcgtgctcaactacgagcgggcgcggcgccccggcctcctgggcgcctctg2100
75


tgctgggcctggacgatatccacagggcctggcgcaccttcgtgctgcgtgtgcgggccc2160


aggacccgccgcctgagctgtactttgtcaaggtggatgtgacgggcgcgtacgacacca2220


tcccccaggacaggctcacggaggtcatcgccagcatcatcaaaccccagaacacgtact2280


gcgtgcgtcggtatgccgtggtccagaaggccgcccatgggcacgtccgcaaggccttca2340




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-62-
agagccacgtctctaccttg 2400
acagacctcc
agccgtacat
gcgacagttc
gtggctcacc


tgcaggagaccagcccgctg
agggatgccg
tcgtcatcga
gcagagctcc
tccctgaatg
2460


aggccagcagtggcctcttcgacgtcttcc gtgccaccacgccgtgcgca2520
tacgcttcat


tcaggggcaagtcctacgtccagtgccagg ctctccacgc2580
ggatcccgca
gggctccatc


tgctctgcagcctgtgctacggcgacatgg gtttgcggggattcggcggg2640
agaacaagct


acgggctgctcctgcgtttggtggatgatttcttgttggtgacacctcacctcacccacg2700


cgaaaaccttcctcaggaccctggtccgaggtgtccctgagtatggctgcgtggtgaact2760


tgcggaagacagtggtgaacttccctgtagaagacgaggccctgggtggcacggcttttg2820


ttcagatgccggcccacggcctattcccctggtgcggcctgctgctggatacccggaccc2880



tggaggtgcagagcgactactccagctatgcccggacctccatcagagccagtctcacct2940


tcaaccgcggcttcaaggctgggaggaacatgcgtcgcaaactctttggggtcttgcggc3000


tgaagtgtcacagcctgtttctggatttgcaggtgaacagcctccagacggtgtgcacca3060


acatctacaagatcctcctgctgcaggcgtacaggtttcacgcatgtgtgctgcagctcc3120


catttcatcagcaagtttggaagaaccccacatttttcctgcgcgtcatctctgacacgg3180
IS


cctccctctgctactccatcctgaaagccaagaacgcagggatgtcgctgggggccaagg3240


gcgccgccggccctctgccctccgaggccgtgcagtggctgtgccaccaagcattcctgc3300


tcaagctgactcgacaccgtgtcacctacgtgccactcctggggtcactcaggacagccc3360


agacgcagctgagtcggaagctcccggggacgacgctgactgccctggaggccgcagcca3420


2o acccggcactgccctcagacttcaagaccatcctggactgatggccacccgcccacagcc3480


aggccgagagcagacaccagcagccctgtcacgccgggctctacgtcccagggagggagg3540


ggcggcccacacccaggcccgcaccgctgggagtctgaggcctgagtgagtgtttggccg3600


aggcctgcatgtccggctgaaggctgagtgtccggctgaggcctgagcgagtgtccagcc3660


aagggctgagtgtccagcacacctgccgtcttcacttccccacaggctggcgctcggctc3720


caccccagggccagcttttcctcaccaggagcccggcttccactccccacataggaatag3780
25


tccatccccagattcgccattgttcacccctcgccctgccctcctttgccttccaccccc3840


accatccaggtggagaccctgagaaggaccctgggagctctgggaatttggagtgaccaa3900


aggtgtgccctgtacacaggcgaggaccctgcacctggatgggggtccctgtgggtcaaa3960


ttggggggaggtgctgtgggagtaaaatactgaatatatgagtttttcagttttgaaaaa4020


aaaaaaaaaaaaaaaaaaaaas 4042
3O


<210> 3


<211> 11276


<212> DNA


<213> Homosapiens
~5


<400> 3


acttgagcccaagagttcaaggctacggtgagccatgattgcaacaccacacgccagcct60


tggtgacagaatgagaccctgtctcaaaaaaaaaaaaaaaaattgaaataatataaagca120


O tcttctctggccacagtggaacaaaaccagaaatcaacaacaagaggaattttgaaaact180


atacaaacacatgaaaattaaacaatatacttctgaatgaccagtgagtcaatgaagaaa240


ttaaaaaggaaattgaaaaatttatttaagcaaatgataacggaaacataacctctcaaa300


acccacggtatacagcaaaagcagtgctaagaaggaagtttatagctataagcagctaca360


tcaaaaaagtagaaaagccaggcgcagtggctcatgcctgtaatcccagcactttgggag420


45 gccaaggcgggcagatcgcctgaggtcaggagttcgagaccagcctgaccaacacagaga480


aaccttgtcgctactaaaaatacaaaattagctgggcatggtggcacatgcctgtaatcc540


cagctactcgggaggctgaggcaggataaccgcttgaacccaggaggtggaggttgcggt600


gagccgggattgcgccattggactccagcctgggtaacaagagtgaaaccctgtctcaag660


aaaaaaaaaaaagtagaaaaacttaaaaatacaacctaatgatgcaccttaaagaactag720


aaaagcaagagcaaactaaacctaaaattggtaaaagaaaagaaataataaagatcagag780
50


cagaaataaatgaaactgaaagataacaatacaaaagatcaacaaaattaaaagttggtt840


ttttgaaaagataaacaaaattgacaaacctttgcccagactaagaaaaaaggaaagaag900


acctaaataaataaagtcagagatgaaaaaagagacattacaactgataccacagaaatt960


caaaggatcactagaggctactatgagcaactgtacactaataaattgaaaaacctagaa1020


aaaatagataaattcctagatgcatacaacctaccaagattgaaccatgaagaaatccaa1080
55


agcccaaacagaccaataacaataatgggattaaagccataataaaaagtctcctagcaa1140


agagaagcccaggacccaatggcttccctgctggattttaccaatcatttaaagaagaat1200


gaattccaatcctactcaaactattctgaaaaatagaggaaagaatacttccaaactcat1260


tctacatggccagtattaccctgattccaaaaccagacaaaaacacatcaaaaacaaaca1320


6O aacaaaaaaacagaaagaaagaaaactacaggccaatatccctgatgaatactgatacaa1380


aaatcctcaacaaaacactagcaaaccaaattaaacaacaccttcgaaagatcattcatt1440


gtgatcaagtgggatttattccagggatggaaggatggttcaacatatgcaaatcaatca1500


atgtgatacatcatcccaacaaaatgaagtacaaaaactatatgattatttcactttatg1560


cagaaaaagcatttgataaaattctgcacccttcatgataaaaaccctcaaaaaaccagg1620


tatacaagaaacatacaggccaggcacagtggctcacacctgcgatcccagcactctggg1680
65


aggccaaggt cttgggcccaggagtttgagactagcctgggcaacaaaat1740
gggatgattg


gagacctggtctacaaaaaacttttttaaaaaattagccaggcatgatggcatatgcctg1800


tagtcccagctagtctggaggctgaggtgggagaatcacttaagcctaggaggtcgaggc1860


tgcagtgagc tcactgtactccagcctagacaacagaacaagaccccact1920
catgaacatg


gaataagaag agaagggagaagggagggagaagggaggaggaggagaagg1980
aaggagaagg


aggaggtgga aaggggaaggggaagggaaagaggaagaagaagaaacata2040
ggagaagtgg


tttcaacata tatatgacagaccgaggtagtattatgaggaaaaactgaa2100
ataaaagccc


agcctttcct gaaaatgacaagggcccactttcaccactgtgattcaaca2160
ctaagatctg


tagtactaga agagcaatca agaaataaaaggcatccaaa2220
agtcctagct gataagagaa


ctggaaagga ttatcctgtttgcagatgat atctggaaaa2280
agaagtcaaa atgatcttat


gacttaagac gatacaaaat2340
accactaaaa
aactattaga
gctgaaattt
ggtacagcag


caatgtacaa tatttctatattccaacagc aaaaagaaac2400
aaatcagtag aaacaatctg


caaaaaagca 2460
gctacaaata
aaattaaaca
gctaggaatt
aaccaaagaa
gtgaaagatc


tctacaatga aaaaaagaaa2520
aaactataaa
atgttgataa
aagaaattga
agagggcaca




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-63-
agatattccatgttcatagattggaagaataaatactgtt tactacccaa2580
aaaatgtcca


agcaatttacaaattcaatgcaatccctattaaaatacta tcacagaaat2640
atgacgttct


agaagaaacaattctaagatttgtacagaaccacaaaaga ccaaagctat2700
cccagaatag


cctgaccaaaaagaacaaaactggaagcatcacattacctgacttcaaattatactacaa2760


agctatagtaacccaaactacatggtactggcataaaaacagatgagacatggaccagag2820


gaacagaatagagaatccagaaacaaatccatgcatctacagtgaactcatttttgacaa2880


aggtgccaagaacatactttggggaaaagataatctcttcaataaatggtgctggaggaa2940


ctggatatccatatgcaaaataacaatactagaactctgtctctcaccatatacaaaagc3000


to aaatcaaaatggatgaaaggcttaaatctaaaacctcaaactttgcaactactaaaagaa3060


aacaccggagaaactctccaggacattggagtgggcaaagacttcttgagtaattccctg3120


caggcacaggcaaccaaagcaaaaacagacaaatgggatcatatcaagttaaaaagcttc3180


tgcccagcaaaggaaacaatcaacaaagagaagagacaacccacagaatgggagaatata3240


tttgcaaactattcatctaacaaggaattaataaccagtatatataaggagctcaaacta3300


IS ctctataagaaaaacacctaataagctgattttcaaaaataagcaaaagatctgggtaga3360


catttctcaaaataagtcatacaaatggcaaacaggcatctgaaaatgtgctcaacacca3420


ctgatcatcagagaaatgcaaatcaaaactactatgagagatcatctcatcccagttaaa3480


atggcttttattcaaaagacaggcaataacaaatgccagtgaggatgtggataaaaggaa3540


acccttggacactgttggtgggaatggaaattgctaccactatggagaacagtttgaaag3600


20 ttcctcaaaaaactaaaaataaagctaccatacagcaatcccattgctaggtatat~ctc3660


caaaaaagggaatcagtgtatcaacaagctatctccactcccacatttactgcagcactg3720


ttcatagcagccaaggtttggaagcaacctcagtgtccatcaacagacgaatggaaaaag3780


aaaatgtggtgcacatacacaatggagtactacgcagccataaaaaagaatgagatcctg3840


tcagttgcaacagcatggggggcactggtcagtatgttaagtgaaataagccaggcacag3900


25 aaagacaaacttttcatgttctcccttacttgtgggagcaaaaattaaaacaattgacat3960


agaaatagaggagaatggtggttctagaggggtgggggacagggtgactagagtcaacaa4020


taatttattgtatgttttaaaataactaaaagagtataattgggttgtttgtaacacaaa4080


gaaaggataaatgcttgaaggtgacagataccccatttaccctgatgtgattattacaca4140


ttgtatgcctgtatcaaaatatctcatgtatgctatagatataaaccctactatattaaa4200


3o aattaaaattttaatggccaggcacggtggctcatgtccgtaatcccagcactttgggag4260


gccgaggcgggtggatcacctgaggtcaggagtttgaaaccagtctggccaccatgatga4320


aaccctgtctctactaaagatacaaaaattagccaggcgtggtggcacatacctgtagtc4380


ccaactactcaggaggctgagacaggagaattgcttgaacctgggaggcggaggttgcag4440


tgagccgagatcatgccactgcactgcagcctgggtgacagagcaagactccatctcaaa4500


35 acaaaaacaaaaaaaagaagattaaaattgtaatttttatgtaccgtataaatatatact4560


ctactatattagaagttaaaaatCaaaacaattataaaaggtaattaaccacttaatcta4520


aaataagaacaatgtatgtggggtttctagcttctgaagaagtaaaagttatggccacga4680


tggcagaaatgtgaggagggaacagtggaagttactgttgttagacgctcatactctctg4740


taagtgacttaattttaaccaaagacaggctgggagaagttaaagaggcattctataagc4800


cctaaaacaactgctaataatggtgaaaggtaatctctattaattaccaataattacaga4860
40


tatctctaaaatcgagctgcagaattggcacgtctgatcacaccgtcctctcattcacgg4920


tgctttttttcttgtgtgcttggagattttcgattgtgtgttcgtgtttggttaaactta4980


atctgtatgaatcctgaaacgaaaaatggtggtgatttcctccagaagaattagagtacc5040


tggcaggaagcaggtggctctgtggacctgagccacttcaatcttcaagggtctctggcc5100


45 aagacccaggtgcaaggcagaggcctgatgacccgaggacaggaaagctcggatgggaag5160


gggcgatgagaagcctgcctcgttggtgagcagcgcatgaagtgcccttatttacgcttt5220


gcaaagattgctctggataccatctggaaaaggcggccagcgggaatgcaaggagtcaga5280


agcctcctgctcaaacccaggccagcagctatggcgcccacccgggcgtgtgccagaggg5340


agaggagtcaaggcacctcgaagtatggcttaaatctttttttcacctgaagcagtgacc5400


SO aaggtgtattctgagggaagcttgagttaggtgccttctttaaaacagaaagtcatggaa5460


gcacccttctcaagggaaaaccagacgcccgctctgcggtcatttacctctttcctctct5520


ccctctcttgccctcgcggtttctgatcgggacagagtgacccccgtggagcttctccga5580


gcccgtgctgaggaccctcttgcaaagggctccacagacccccgccctggagagaggagt5640


ctgagcctggcttaataacaaactgggatgtggctgggggcggacagcgacggcgggatt5700


caaagacttaattccatgagtaaattcaacctttccacatccgaatggatttggatttta5760
55


tcttaatattttcttaaatttcatcaaataacattcaggactgcagaaatccaaaggcgt5820


aaaacaggaactgagctatgtttgccaaggtccaaggacttaataaccatgttcagaggg5880


atttttcgccctaagtactttttattggttttcataaggtggcttagggtgcaagggaaa5940


gtacacgaggagaggcctgggcggcagggctatgagcacggcagggccaccggggagaga6000


gtccccggcctgggaggctgacagcaggaccactgaccgtcctccctgggagctgccaca6060


ttgggcaacgcgaaggcggccacgctgcgtgtgactcaggaccccataccggcttcctgg6120


gcccacccacactaacccaggaagtcacggagctctgaacccgtggaaacgaacatgacc6180


cttgcctgcctgcttccctgggtgggtcaagggtaatgaagtggtgtgcaggaaatggcc6240


atgtaaattacacgactctgctgatggggaccgttccttccatcattattcatcttcacc6300


cccaaggactgaatgattccagcaacttcttcgggtgtgacaagccatgacaaaactcag6360
65


tacaaacaccactcttttactaggcccacagagcacggsccacacccctgatatattaag6420


agtccaggagagatgaggctgctttcagccaccaggctggggtgacaacagcggctgaac6480


agtctgttcctctagactagtagaccctggcaggcactcccccagattctagggcctggt6540


tgctgcttcccgagggcgccatctgccctggagactcagcctggggtgccacactgaggc6600


7o cagccctgtctccacaccctccgcctccaggcctcagcttctccagcagcttcctaaacc6660


ctgggtgggccgtgttccagcgctactgtctcacctgtcccactgtgtcttgtctcagcg6720


acgtagctcgcacggttcctcctcacatggggtgtctgtctccttccccaacactcacat6780


gcgttgaagggaggagattctgcgcctcccagactggctcctctgagcctgaacctggct6840


cgtggcccccgatgcaggttcctggcgtccggctgcacgctgacctccatttccaggcgc6900


tccccgtctcctgtcatctgccggggcctgccggtgtgttcttctgtttctgtgctcctt6960
75


tccacgtccagctgcgtgtgtctctgcccgctagggtctcggggtttttataggcatagg7020


acgggggcgtggtgggccagggcgctcttgggaaatgcaacatttgggtgtgaaagtagg7080


agtgcctgtcctcacctaggtccacgggcacaggcctggggatggagcccccgccaggga7140


cccgcccttctctgcccagcactttcctgcccccctccctctggaacaca 7200
gagtggcagt




CA 02316282 2000-06-21
Le A 32 805-Forei~~n Countries
-64-
ttccacaagcactaagcatcctcttcccaaaagacccagcattggcacccctggacattt7260


gccccacagccctgggaattcacgtgactacgcacatcatgtacacactcccgtccacga7320


ccgacccccgctgttttattttaatagctacaaagcagggaaatccctgctaaaatgtcc7380


tttaacaaactggttaaacaaacgggtccatccgcacggtggacagttcctcacagtgaa7440


gaggaacatgccgtttataaagcctgcaggcatctcaagggaattacgctgagtcaaaac7500


tgccacctccatgggatacgtacgcaacatgctcaaaaagaaagaatttcaccccatggc7560


aggggagtggttaggggggttaaggacggtgggggcggcagctgggggctactgcacgca7620


ccttttactaaagccagtttcctggttctgatggtattggctcagttatgggagactaac7680


cataggggagtggggatgggggaacccggaggctgtgccatctttgccatgcccgagtgt7740



cctgggcaggataatgctctagagatgcccacgtcctgattcccccaaacctgtggacag7800


aacccgcccggccccagggcctttgcaggtgtgatctccgtgaggaccctgaggtctggg7860


atccttcgggactacctgcaggcccgaaaagtaatccaggggttctgggaagaggcgggc7920


aggagggtcagaggggggcagcctcaggacgatggaggcagtcagtctgaggctgaaaag7980


IS gg gggagggcctcgagcccaggcctgcaagcgcctccagaagctggaaaaagcggggaa8040


gggaccctccacggagcctgcagcaggaaggcacggctggcccttagcccaccagggccc8100


atcgtggacctccggcctccgtgccataggagggcactcgcgctgcccttctagcatgaa8160


gtgtgtggggatttgcagaagcaacaggaaacccatgcactgtgaatctaggattatttc8220


aaaacaaaggtttacagaaacatccaaggacagggctgaagtgcctccgggcaagggcag8280


2o ggcaggcacgagtgattttatttagctattttattttatttacttactttctgagacaga8340


gttatgctcttgttgcccaggctggagtgcagcggcatgatcttggctcactgcaacctc8400


cgtctcctgggttcaagcaattctcgtgcctcagcctcccaagtagctgggatttcaggc8460


gtgcaccaccacacccggctaattttgtatttttagtagagatgggctttcaccatgttg8520


gtcaagctgatctcaaaatcctgacctcaggtgatccgcccacctcagcctcccaaagtg8580


25 ctgggattacaggcatgagccactgcacctggcctatttaaccattttaaaacttccctg8640


ggctcaagtcacacccactggtaaggagttcatggagttcaatttcccctttactcagga8700


gttaccctcctttgatattttctgtaattcttcgtagactggggatacaccgtctcttga8760


catattcacagtttctgtgaccacctgttatcccatgggacccactgcaggggcagctgg8820


9aggctgcaggcttcaggtcccagtggggttgccatctgccagtagaaacctgatgtaga8880


atcagggcgcaagtgtggacactgtcctgaatctcaatgtctcagtgtgtgctgaaacat8940
30


gtagaaattaaagtccatccctcctactctactgggattgagccccttccctatcccccc9000


ccaggggcagaggagttcctctcactcctgtggaggaaggaatgatactttgttattttt9060


cactgctggtactgaatccactgtttcatttgttggtttgtttgttttgttttgagaggc9120


ggtttcactcttgttgctcaggctggagggagtgcaatggcgcgatcttggcttactgca9180


gcctctgcctcccaggttcaagtgattctcctgcttccgcctcccatttggctgggatta9240
35


caggcacccgccaccatgcccagctaattttttgtatttttagtagagacgggggtgggt9300


ggggttcaccatgttggccaggctggtctcgaacttctgacctcagatgatccacctgcc9360


tctgcctcctaaagtgctgggattacaggtgtgagccaccatgcccagctcagaatttac9420


tctgtttagaaacatctgggtctgaggtaggaagctcaccccactcaagtgttgtggtgt9480


tttaagccaar_gatagaatttttttattgttgttagaacactcttgatgttttacactgt9540
40


gatgactaagacatcatcagcttttcaaagacacactaactgcacccataatactggggt9600


gtcttctgggtatcagcaatcttcattgaatgccgggaggcgtttcctcgccatgcacat9660


ggtgttaattactccagcataatcttctgcttccatttcttctcttccctcttttaaaat9720


tgtgttttctatgttggcttctctgcagagaaccagtgtaagctacaacttaacttttgt9780


tggaacaaattttccaaaccgcccctttgccctagtggcagagacaattcacaaacacag9840
45


ccctttaaaaaggcttagggatcactaaggggatttctagaagagcgacctgtaatccta9900


agtatttacaagacgaggctaacctccagcgagcgtgacagcccagggagggtgcgaggc9960


ctgttcaaatgctagctccataaataaagcaatttcctccggcagtttctgaaagtagga10020


aaggttacatttaaggttgcgtttgttagcatttcagtgtttgccgacctcagctacagc10080


SO atccctgcaaggcctcgggagacccagaagtttctcgcccccttagatccaaacttgagc10140


aacccggagtctggattcctgggaagtcctcagctgtcctgcggttgtgccggggcccca10200


ggtctggaggggaccagtggccgtgtggcttctactgctgggctggaagtcgggcctcct10260


agctctgcagtccgaggcttggagccaggtgcctggaccccgaggctgccctccaccctg10320


tgcgggcgggatgtgaccagatgttggcctcatctgccagacagagtgccggggcccagg10380


55 gtcaaggccgttgtggctggtgtgaggcgcccggtgcgcggccagcaggagcgcctggct10440


ccatttcccaccctttctcgacgggaccgccccggtgggtgattaacagatttggggtgg10500


tttgctcatggtggggacccctcgccgcctgagaacctgcaaagagaaatgacgggcctg10560


tgtcaaggagcccaagtcgcggggaagtgttgcagggaggcactccgggaggtcccgcgt10620


gcccgtccagggagcaatgcgtcctcgggttcgtccccagccgcgtctacgcgcctccgt10680


6o cctccccttcacgtccggcattcgtggtgcccggagcccgacgccccgcgtccggacctg10740


gaggcagccctgggtctccggatcaggccagcggccaaagggtcgccgcacgcacctgtt10800


cccagggcctccacatcatggcccctccctcgggttaccccacagcctaggccgattcga10860


cctctctccgctggggccctcgctggcgtccctgcaccctgggagcgcgagcggcgcgcg10920


ggcggggaagcgcggcccagacccccgggtccgcccggagcagctgcgctgtcggggcca10980


ggccgggctcccagtggattcgcgggcacagacgcccaggaccgcgctccccacgtggcg11040
65


gagggactggggacccgggcacccgtcctgccccttcaccttccagctccgcctcctccg11100


cgcggaccccgccccgtcccgacccctcccgggtccccggcccagccccctccgggccct11160


cccagcccctccccttcctttccgcggccccgccctctcctcgcggcgcgagtttcaggc11220


agcgctgcgtcctgctgcgcacgtgggaagccctggccccggccacccccgcgatg 11276


<210> 4


<211> 104


<212> DNA


<213> Homosapiens


75 <400> 4


gtgggcctccccggggtcggcgtccggctggggttgagggcggccggggggaaccagcga60


catgcggagagcagcgcaggcgactcagggcgcttcccccgcag 104




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-65-
<210> 5
<211> 8616
<212> DNA
<213> Homo Sapiens
<400>
S


gtgaggaggtggtggccgtcgagggcccaggccccagagctgaatgcagtaggggctcag60


aaaagggggcaggcagagccctggtcctcctgtctccatcgtcacgtgggcacacgtggc120


to ttttcgctcaggacgtcgagtggacacggtgatctctgcctctgctctccctcctgtcca180


gtttgcataaacttacgaggttcaccttcacgttttgatggacacgcggtttccaggcgc240


cgaggccagagcagtgaacagaggaggctgggcgcggcagtggagccgggttgccggcaa300


tggggagaagtgtctggaagcacagacgctctggcgagggtgcctgcaggttacctataa360


tcctcttcgcaatttcaagggtgggaatgagaggtggggacgagaaccccctcttcctgg420


gggtgggaggtaagggttttgcaggtgcacgtggtcagccaatatgcaggtttgtgttta480
IS


agatttaattgtgtgttgacggccaggtgcggtggctcacgccggtaatcccagcacttt540


gggaagctgaggcaggtggatcacctgaggtcaggagtttgagaccagcctgaccaacat600


ggtgaaaccctatctgtactaaaaatacaaaaattagctgggcatggtggtgtgtgcctg660


taatcccagctacttgggaggctgaggcaggagaatcacttgaacccaggaggcggaggc720


tgcagtgagctgagattgtgccattgtactccagcctgggcgacaagagtgaaactctgt780
2~


ctttaaaaaaaaaaagtgttcgttgattgtgccaggacagggtagagggagggagataag840


actgttctccagcacagatcctggtcccatctttaggtatgaagagggccacatgggagc900


agaggacagcagatggctccacctgctgaggaagggacagtgtttgtgggtgttcagggg960


atggtgctgctgggccctgccgtgtccccaccctgtttttctggatttgatgttgaggaa1020


25 cctccgctccagcccccttttggctcccagtgctcccaggccctaccgtggcagctagaa1080


gaagtcccgatttcaccccctccccacaaactcccaagacatgtaagacttccggccatg1140


cagacaaggagggtgaccttcttggggctcttttttttctttttttctttttatggtggc1200


aaaagtcatataacatgagattggcactcctaacaccgttttctgtgtacagtgcagaat1260


tgctaactcggcggtgtttacagcaggttgcttgaaatgctgcgtcttgcgtgactggaa1320


3o gtccctacccatcgaacggcagctgcctcacacctgctgcggctcaggtggaccacgccg1380


agtcagataagcgtcatgcaacccagttttgctttttgtgctccagcttccttcgttgag1440


gagagtttgagttctctgatcaggactctgcctgtcattgctgttctctgacttcagatg1500


aggtcacaatctgcccctggcttatgcagggagtgaggcgtggtccccgggtgtccctgt1560


cacgtgcagggtgagtgaggcgttgcccccaggtgtccctgtcacgtgtagggtgagtga1620


ggcgcggcccccgggtgtccctgtcccgtgcagcgtgattgaggtgtggcccccgggtgt1680
35


ccctgtcacgtg.tagggtgagtgaggcgccatccccgggtgtccctgtcacgtgtagggt1740


gagtgaggcgtggtccccgggtgtccctgtcccgtgcagggtgagtgaggcactgtcccc1800


gggtgtccctgtcacgtgcagggtgagtgaggcgcggtccccgggtgtccctctcaggtg1860


tagggtgagtgaggcgcggccccagggtgtccctgtcacgtgtagggtgagtgaggcacc1920


gtccctgggtgtccctcccaggtatagggtgagtgaggcactgtccccgggtgtccctgt1980
40


cacgtgcagggtgagtgaggcgcggcccccgggtgtccctctcaggtgcagggtgagtga2040


ggcgctgtccctgggtgtccctgtctcgtgtagggtgagtgaggctctgtccccaggtgt2100


ccttggcgtttgctcacttgagcttgctcctgaatgtttgctctttctatagccacagct2160


gcgccggttgcccattgcctgggtagatggtgcaggcgcagtgctggtccccaagcctat2220


45 cttttctgatgctcggctcttcttggtcacctctccgttccattttgctacggggacacg2280


ggactgcaggctctcgcctcccgcgtgccaggcactgcagccacagcttcaggtccgctt2340


gcctctgttgggcctggcttgctcaccacgtgcccgccacatgcatgctgccaatactcc2400


tctcccagcttgtctcatgccgaggctggactctgggctgcctgtgtctgctgccacgtg2460


ttgctggagacatcccagaaagggttctctgtgccctgaaggaaagcaagtcaccccagc2520


5o cccctcacttgtcctgttttctcccaagctgcccctctgcttggcccccttgggtgggtg2580


gcaacgcttgtcaccttattctgggcacctgccgctcattgcttaggctgggctctgcct2640


ccagtcgccccctcacatggattgacgtccagccacaggttggagtgtctctgtctgtct2700


cctgctctgagacccacgtggagggccggtgtctccgccagccttcgtcagacttccctc2760


ttgggtcttagttttgaatttcactgatttacctctgacgtttctatctctccattgtat2820


gctttttcttggtttattctttcattccttttctagcttcttagtttagtcatgcctttc2880
SS


cctctaagtgctgccttacctgcaccctgtgttttgatgtgaagtaatctcaacatcagc2940


cactttcaagtgttcttaaaatacttcaaagtgttaatacttcttttaagtattcttatt3000


ctgtgatttttttctttgtgcacgctgtgttttgacgtgaaatcattttgatatcagtga3060


cttttaagtattctttagcttattctgtgatttctttgagcagtgagttatttgaacact3120


gtttatgttcaagatatgtagagtatcaagatacgtagagtattttaagttatcatttta3180


ttattgatttctaactcagttgtgtagtggtctgtataataccaattatttgaagtttgc3240


ggagccttgctttgtgatctagtgtgtgcatggtttccagaactgtccattgtaaatttg3300


acatcctgtcaatagtgggcatgcatgttcactatatccagcttattaaggtccagtgca3360


aagcttctgtctccttctagatgcatgaaattccaagaaggaggccatagtccctcacct3420


65 gggggatgggtctgttcatttcttctcgtttggtagcatttatgtgaggcattgttaggt3480


gcatgcacgtggtagaatttttatcttcctgatgagtgaatcttttggagacttctatgt3540


ctctagtaatctagtaattctttttttaaattgctcttagtactgccacactgggcttct3600


tttgattagtattttcctgctgtgtctgttttctgcctttaatttatatatatatatata3660


ttttttttttttttgagacagagtcttggtctgtcgcccagggtgagtgcagtggtgtga3720


tcacaggtcagtgtaacttttaccttctggcctgagccgtcctctcacctcagcctcctg3780


agtagctggaactgcagacacgcaccgctacacctggctaatttttaaattttttctgga3840


gacagggtcttgctgtgttgcccaggctggtctcaaactcttggactcaagggatccatc3900


tacctcggcttcccaaagtgctgaattacaggcatgagccaccatgtctggcctaatttt3960


caacacttttatattcttatagtgtgggtatgtcctgttaacagcatgtaggtgaatttc4020


caatccagtctgacagtcgttgtttaactggataacctgatttattttcatttttttgtc4080
t


ac cgcctggtgcactctgattctccacttgcctgttgcatgtcctcgttccc4140
agagacc


ttgtttctcaccacctcttgggttgccatgtgcgtttcctgccgagtgtgtgttgatcct4200


ctcgttgcctcctggtcactgggcatttgcttttatttctctttgcttagtgttaccccc4260


tgatctttttattgtcgttgtttgcttttgtttattgagacagtctcactctgtcaccca4320




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-66-
ggctggagtgtaatggcacaatctcggctcactgcaacctctgcctcctcggttcaagca4380


gttctcattcctcaacctcatgagtagctgggattacaggcgcccaccaccacgcctggc4440


taatttttgtatttttagtagagataggctttcaccatgttggccaggctggtctcaaac4500


tcctgacctcaagtgatctgcccgccttggcctcccacagtgctgggattacaggtgcaa4560


gccaccgtgcccggcataccttgatcttttaaaatgaagtctgaaacattgctacccttg4620


tcctgagcaataagacccttagtgtattttagctctggccaccccccagcctgtgtgctg4680


ttttccctgctgacttagttctatctcaggcatcttgacacccccacaagctaagcatta4740


ttaatattgttttccgtgttgagtgtttctgtagctttgcccccgccctgcttttcctcc4800


tttgttccccgtctgtcttctgtctcaggcccgccgtctggggtccccttccttgtcctt4860



tgcgtggttcttctgtcttgttattgctggtaaaccccagctttacctgtgctggcctcc4920


atggcatctagcgacgtccggggacctctgcttatgatgcacagatgaagatgtggagac4980


tcacgaggagggcggtcatcttggcccgtgagtgtctggagcaccacgtggccagcgttc5040


cttagccagtgagtgacagcaacgtccgctcggcctgggttcagcctggaaaaccccagg5100


catgtcggggtctggtggctccgcggtgtcgagtttgaaatcgcgcaaacctgcggtgtg5160


IS gcgccagctctgacggtgctgcctggcgggggagtgtctgcttcctcccttctgcttggg5220


aaccaggacaaaggatgaggctccgagccgttgtcgcccaacaggagcatgacgtgagcc5280


atgtggataattttaaaatttctaggctgggcgcggtggctcacgcctgtaatcccagca5340


ctttgggaggccaaggcgggtggatcacgaggtcaggaggtcgagaccatcctggccaac5400


atgatgaaaccccatctgtactaaaaacacaaaaattagctgggcgtggtggcgggtgcc5460



tgtaatcccagctactcgggaggctgaggcaggagaattgcttgaacctgggagttggaa5520


gttgcagtgagccgacattgcaccactgcactccagcctggcaacacagcgagactctgt5580


ctcaaaaaaaaaaaaaaaaaaaaaaaaaaaaattctagtagccacattaaaaaagtaaaa5640


aagaaaaggtgaaattaatgtaataatagattttactgaagcccagcatgtccacacctc5700


atcattttagggtgttattggtgggageatcactcacaggacatttgacattttttgagc5760


tttgtctgcgggatcccgtgtgtaggtcccgtgcgtggccatctcggcctggacctgctg5820


ggcttcccatggccatggctgttgtaccagatggtgcaggtccgggatgaggtcgccagg5880


ccctcagtgagctggatgtgcagtgtccggatggtgcacgtctgggatgaggtcgccagg5940


ccctgctgtgagctggatgtgtggtgtctggatggtgcaggtcaggggtgaggtctccag6000


gccctcggtgagctggaggtatggagtccggatgatgcaggtccggggtgaggtcgccag6060


3~ gccctgctgtgagctggatgtgtggtgtctggatggtgcaggtcaggggtgaggtctcca6120


ggccctcggtaagctggaggtatggagtccggatgatgcaggtccggggtgaggtcgcca6180


ggccctgctgtgagctggatgtgtggtgtctggatggtgcaggtctggggtgaggtcacc6240


aggccctgcggtgagctgggtgtgcggtgtctggatggtgcaggtctggagtgaggtcgc6300


cagacggtgccagaccatgcggtgagctggatatgcggtgtccggatggtgcaggtctgg6360


ggtgaggttgccaggccctgctgtgagttggatgtggggtgtccggatgctgcaggtccg6420


gtgtgaggtcaccaggccctgctgtgagctggatgtgtggtgtctggatggtgcaggtct6480


ggggtgaaggtcgccaggcccctgcttgtgagctggatgtgtggtgtctggatggtgcag6540


gtctggagtgaggtcgccaggccctcggtgagctggatgtgcagtgtccagatggtgcag6600


gtccggggtgaggtcgccagaccctgcggtgagctggatgtgcggtgtctggatggtgca6660


ggtctggagtgaggtcgccaggccctcggtgagctggatgtatggagtccggatggtgcc6720


ggtccggggtgaggtcgccagaccctgctgtgagctggatgtgcggtgtctggatggtac6780


aggtctggagtgaggtcgccagaccctgctgtgagctggatatgcggtgtccggatggtg6840


caggtcaggggtgaggtctccaggccctcggtgagctggaggtatggagtccggatgatg6900


caggtccggggtgaggtcgccaggccctgctgtgaactggatgtgcggcgtctggatggt6960


gcaggtctggggtgtggtcgccaggccctcggtgagctggaggtatggagtccggatgat7020


gcaggtccggggtgaggtcgccaggccctgctgtgagctggatgtgcggcgtctggatgg7080


tgcaggtctggggtgtggtcgccaggccctcggtgagctggaggtatggagtccggatga7140


tgcaggtccggggtgaggttgccaggccctgctgtgagctggatgtgctgtatccggatg7200


5o gtgcagtccggggtgaggtcgccaggccctgctgtgagctggatgtgctgtatccggatg7260


gtgcaggtctggggtgaggtcaccaggccctgcggtgagctggttgtgcggtgtccggtt7320


gctgcaggtccggggtgagttcgccaggccctcggtgagctggatgtgcggtgtccccgt7380


gtccggatggtgcaggtccagggtgaggtcgctaggcccttggtgggctggatgtgccgt7440


gtccggatggtgcaggtctggggtgaggtcgccaggcctttggtgagctggatgtgcggt7500


gtctgcatggtgcaggtctggggtgaggtcgccaggcccttggtgggctggatgtgtggt7560


gtccggatggtgcaggtccggcgtgaggtcgccaggccctgctgtgagctggatgtgcgg7620


tgtctggatggtgcaggtccggggtgaggtagccaaggccttcggtgagctggatgtggg7680


gtgtccggatggtgcaggtccggggtgaggtcgccaggccctgcggttagctggatatgc7740


ggtgtccggatggtgcaggtccggggtgaggtcaccaggccctgcggttagctggatgtg7800


6o cggtgtctggatggtgcaggtccggggtgaggtcgccaggccctgctgtgagctggatgt7860


gctgtatccggatggtgcaggtccggggtgaggtcgccaggccctgcagtgagctggatg7920


tgctgtatccggatggtgcaggtctggcgtgaggtcgccaggccctgcggttagctggat7980


atgcggtgtcggatggtgcaggtccggggtgaggtcaccaggccctgcggttagctggat8040


gtgcggtgtccggatggtgcaggtctggggtgaggtcgccaggccctgctgtgagctgga8100


tgtgctgtatccggatggtgcaggtccggggtgaggtcgccaggccctgcggtgagctgg8160



atgtgctgtatccggatggtgcaggtctggcgtgaggtcgccaggccctgcggtgagctg8220


gatgtgcagtgtacggatggtgcaggtccggggtgaggtcgccaggccctgcggtgggct8280


gtatgtgtgttgtctggatggtgcaggtccggggtgagttcgccaggccctgcggtgagc8340


tggatgtgtggtgtctggatgctgcaggtccggggtgagttcgccaggccctcggtgagc8400


tggatatgcggtgtccccgtgtccgaatggtgcaggtccagggtgaggtcgccaggccct8460


tggtgggctggatgtgccgtgtccggatggtgcaggtctggggtgaggtcgccaggccct8520


tggtgagctggatgtgcggtgtccggatggtgcaggtccggggtgaggtcaccaggccct8580


cggtgatctggatgtggcatgtccttctcgtttaag 8616


<210> 6
<211> 2089
<212> DNA
<213> Homo Sapiens


CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-67-
<400> 6


gtactgtatccccacgccaggcctctgcttctcgaagtcctggaacaccagcccggcctc60


agcatgcgcctgtctccacttgcctgtgcttccctggctgtgcagctctgggctgggagc120


caggggccccgtcacaggcctggtccaagtggattctgtgcaaggctctgactgcctgga180


gctcacgttctcttacttgtaaaatcaggagtttgtgccaagtggtctctagggtttgta240


aagcagaagggatttaaattagatggaaacactaccactagcctccttgcctttccctgg300


gatgtgggtctgattctctctctcttttttttttcttttttgagatggagtctcactctg360


ttgcccaggctggagtgcagtggcataatcttggctcactgcaacctccacctcctgggt420


to ttaagcgattcaccagcctcagcctcctaagtagctgggattacaggcacctgccaccac480


gcctggctaatttttgtacttttaggagagacggggtttcaccatgttggccaggctggt540


ctcgaactcatgacctcaggtgatccacccaccttggcctcccaaagtgctgggtttaca600


ggctaagccaccgtgcccagcccccgattctcttttaattcatgctgttctgtatgaatc660


ttcaatctattggatttaggtcatgagaggataaaatcccacccacttggcgactcactg720


cagggagcacctgtgcagggagcacctggggataggagagttccaccatgagctaacttc780
IS t
t


agg catttgaatggctgtgagattttgtctgcaatgttcggctgatgagagtg840
ggctg


tgagattgtgacagattcaagctggatttgcatcagtgagggacgggagcgctggtctgg900


gagatgccagcctggctgagcccaggccatggtattagcttctccgtgtcccgcccaggc960


tgactgtggagggctttagtcagaagatcagggcttccccagctcccctgcacactcgag1020


20 tccctggggggccttgtgacaccccatgccccaaatcaggatgtctgcagagggagctgg1080


cagcagacctcgtcagaggtaacacagcctctgggctggggaccccgacgtggtgctggg1140


gccatttccttgcatctgggggagggtcagggctttccctgtgggaacaagttaatacac1200


aatgcaccttacttagactttacacgtatttaatggtgtgcgacccaacatggtcatttg1260


accagtattttggaaagaatttaattggggtgaccggaaggagcagacagacgtggtggt1320


25 ccccaagatgctccttgtcactactgggactgttgttctgcctggggggccttggaggcc1380


cctcctccctggacagggtaccgtgccttttctactctgctgggcctgcggcctgcggtc1440


agggcaccagctccggagcacccgcggccccagtgtccacggagtgccaggctgtcagcc1500


acagatgcccaggtccaggtgtggccgctccagcccccgtgcccccatgggtggttttgg1560


gggaaaaggccaagggcagaggtgtcaggagactggtgggctcatgagagctgattctgc1620


3o tccttggctgagctgccctgagcagcctctcccgccctctccatctgaagggatgtggct1680


ctttctacctgggggtcctgcctggggccagccttgggctaccccagtggctgtaccaga1740


gggacaggcatcctgtgtggaggggcatgggttcacgtggccccagatgcagcctgggac1800


caggctccctggtgctgatggtgggacagtcaccctgggggttgaccgccggactgggcg1860


tccccagggttgactataggaccaggtgtccaggtgccctgcaagtagaggggctctcag1920


aggcgtctggctggcatgggtggacgtggccccgggcatggccttcagcgtgtgctgccg1980
35


tgggtgccctgagccctcactgagtcggtgggggcttgtggcttcccgtgagcttccccc2040


tagtctgttgtctggctgagcaagcctcctgaggggctctctattgcag 2089


<210> 7


211> 687


~~<212>
DNA


213> Homo
Sapiens


<400> 7


45 gtggctgtgctttggtttaacttcctttttaaacagaagtgcgtttgagccccacatttg60


gtatcagcttagatgaagggcccggaggaggggccacgggacacagccagggccatggca120


cggcgccaacccatttgtgcgcacagtgaggtggccgaggtgccggtgcctccagaaaag180


cagcgtgggggtgtagggggagctcctggggcagggacaggctctgaggaccacaagaag240


cagccgggccagggcctggatgcagcacggcccgaggtcctggatccgtgtcctgctgtg300


5o gtgcgcagcctccgtgcgcttccgcttacggggcccggggaccaggccacgactgccagg360


agcccaccgggctctgaggatcctggaccttgccccacggctcctgcaccccacccctgt420


ggctgcggtggctgcggtgaccccgtcatctgaggagagtgtggggtgaggtggacagag480


gtgtggcatgaggatcccgtgtgcaacacacatgcggccaggaacccgtttcaaacaggg540


tctgaggaagctgggaggggttctaggtcccgggtctgggtggctggggacactggggag600


55 gggctgcttctcccctgggtccctatggtggggtgggcacttggccggatccactttcct660


gactgtctcccatgctgtccccgccag 687


<210> 8


<211> 494


<212> DNA


60 <213> HomoSapiens


<400> 8


gtgggtgccggggacccccgtgagcagccctgctggaccttgggagtggctgcctgattg60


gcacctcatgttgggtggaggaggtactcctgggtgggccgcagggagtgcaggtgaccc120
65


tgtcactgttgaggacacacctggcacctagggtggaggccttcagcctttcctgcagca180


catggggccgactgtgcaccctgactgcccgggctcctattcccaaggagggtcccactg240


gattccagtttccgtcagagaaggaaccgcaacggctcagccaccaggccccggtgcctt300


gcaccccagtcctgagccaggggtctcctgtcctgaggctcagagaggggacacagcccg360


7o ccctgcccttggggtctggagtggtgggggtcagagagagagtgggggacaccgccaggc420


caggccctgagggcagaggtgatgtctgagtttctgcgtggccactgtcagtctcctcgc480


ctccactcacacag 494


<210> 9


<211> 865


<212> DNA


<213> HomoSapiens




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-68-
<400> 9


gtaaggttcacgtgtgatagtcgtgtccaggatgtgtgtctctgggatatgaatgtgtct60


agaatgcagtcgtgtctgtgatgcgtttctgtggtggaggtacttccatgatttacacat120


ctgtgatatgcgtgtgtggcacgtgtgtgtcgtggtgcatgtatctgtggcgtgcatatt180
t


gtggtgtgt gtgtgtgtggcacgtgtgtgtccatggtgtgtgtgcctgtggtgtgcatg240


tgtgtgtgtctgtgacacgtgcatgttcatgctgtgtgctgcatgtctgtgatgtgccta300


tttgtggtgtgtgtgtgcatgtgtccgtgacatatgcgtgtctatggcatgggtgtgtgt360


ggccccttggccttactccttcctcctccaggcatggtccgcaccattgtcctcacgctc420


to tcgggtgctggtttggggagctccacattcagggtcctcacttctagcatgggtgcccct480


gtcctgtcacagggctgggccttggagactgtaagccaggtttgagaggagagtagggat540


gctggtggtaccttcctggacccctggcacccccaggaccccagtctggcctatgccggc600


tccatgagatataggaaggctgattcaggcctcgctccccgggacacactcctcccagag660


cggccgggggccttggggctcggcaggggtgaaaggggccctgggcttgggttcccaccc720


IS agtggtcatgagcacgctggaggggtaagccctcaaagtcgtgccaggccggggtgcaga780


ggtgaagaagtatccctggagcttcggtctggggagaggcacatgtggaaacccacaagg840


acctctttctctgacttcttgagct
865


<210> 10
<211> 3782
2~ <212> DNA
<213> Homo sapiens
<400> 10


25 tgtgggattggttttcatgtgtgggataggtggggatctgtgggattggtttttatgagt60


ggggtaacacagagttcaaggcgagctttcttcctgtagtgggtctgcaggtgctccaac120


agctttattgaggagaccatatcttcctttgaactatggtcgggtttatagtaagtcagg180


ggtgtggaggcctcccctgggctccctgttctgtttcttccactctggggtcgtgtggtg240


cctgctgtggtgtgtggccggtgggcagggcttccaggcctccttgtgttcattggcctg300


gatgtggccctggctacgctccgtccttggaattcccctgcgagttggaggctttctttc360
3~


tttctttttttctttctttttttttttttttgataacagagtctcgctcttttttgccca420


ggctggagtggtttggcgtgatcttggctcactgcaacctgtgcttcctgagttcaagca480


attctcttgcctcagcctcccaagtagctggaattataggcgcccaccaccatgctgact540


aatttttgtaattttagtagagacgaggtttctccatgttggccaggctggtctcgaact600


35 cctgacctcaggtgatcctcccacctcggcctcccaaagtgctgggatgacaggtgtgaa660


ccgccgcgcccggccgagactcgcttcctgcagcttccgtgagatctgcagcgatagctg720


cctgcagccttggtgctgacaacctccgttttccttctccaggtctcgctaggggtcttt780


ccatttcatgactctcttcacagaagagtttcacgtgtgctgatttcccggctgtttcct840


gcgtaattggtgtctgctgtttatcgatggcctccttccatttcctttaggctttgttta900


ttgttgtttttccggctccttgaaggaaaagtttcgattatggatgtttgaactttcttt960


tctaaacaagcatctgaagttgccgttttccctctaaagcagggatcccgaggcccctgg1020


ctgtggagtggcaccggtctggggcctgttaggaacccggcgcacagcgggaggctaggt1080


ggggtgtggggagccagcgttcccgcctgagccccgcccctctcagatcagcagtggcat1140


gcggtgctcagaggcgcacacaccctactgagaactgtgcgtgagaggggtctagattct1200


gtgctccttatgggaatctaatgcctgatgatctgaggtggaaccgtttgctcccaaaac1260
45


catccccttccccactgctgtcctgtggaaaaatcgtcttccacgaaaccagtccctggt1320


accacaatggttggggaccctgtgctaaagacctgcttcagcagcctctcgtcagtgttg1380


atatattggcttttctgtgttgagtccagaataattacggatttctgtgatgctttccgc1440


cgacctcagacccatgggctatttgtgggcgtgttgcctgctcctgggttgggaagggtg1500


caggccccatgtaccttcctgttactgccttccaggttggttctcagggttgaatcgtac1560


tcgatgtggttttagcccacggccctgccgccagctcctgggggctggggaacatgctga1620


agcacagagtcaccgtgcgcgtcttttgatgcctcacaagctcgaggcctcctgtgtccg1680


tgttagtgtgtgtcacgtgcctgctcacatcctgtcttggggacgcaggggcttagcagg1740


tcccgtagtaaatgacaagcgtcctgggggagtctgcagaataggaggtgggggtgccgg1800


55 tctctctcccgcgtcttcagactcttctcctgcctgtgctgtggctgcacctgcatccct1860


gcaatccctccagcactgggctggagaggcccgggagctcgagtgccacttgtgccacgt1920


gactgtggatggcagtcggtcacgggggtctgatgtgtggtgactgtggatggcggttgg1980


tcacaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtggtgact2040


gtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtctga2100


6o tgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggcggtcgtg2160


gggtctgatgtggtgactgtggatggcagtcgtggggtctgatgtgtggtgactgtggat2220


ggcggtcgtggggtctgatgtggtgactgtggatggcagtcgtggggtctgatgtgtggt2280


gactgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggt2340


ctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtggatgg2400


65 cggtcgtggggtctgatgtggtgactgtggatggcggtcgtggggtctgatgtgtggtga2460


ctgtggatggtgatcggtcacaggggtctgatgtgtggtgactgtggatggcggtcgtgg2520


ggtctgatgtgtggtgactgtggatggtgatcggtcacaggggtctgatgtgtggtgact2580


gtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggttggtcccggggg2640


tctgatgtgtggtgactgtggatggcgatcggtcacaggggtctgatgtgtggtgactgt2700


ggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatg2760


tgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggcggtcgtg2820


gggtctgatgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtggat2880


ggcggttggtcccgggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgat2940


gtggtgactgtggatggcagtcgtggggtctgatgtgtggtgactgtggatggcggtcgt3000


75 ggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtg3060


gatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgt3120


ggtgactgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggtgatcggtc3180


acaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtgact3240


gtggatggcggtcgtggggtctgatgtggtgactgtggatggcggtcgtggggtctgatg3300




CA 02316282 2000-06-21
Le A 32 805-Forei , Countries
-69-
tgtggtgactgtggatggcggtcgtagggtctgatgtgtggtgactgtggatggcagtcg3360


gtcacaggggtctgatgtgtggtgactgtggatggcggtcgtggggtctgatgtgtggtg3420


actgtggatggcggtcgtggggtctgatgtgtggtgactgtggatggcggtcgtggggtc3480


tgatgtgtggtgactgtggatggcggtcgtggggtctgatgtggtgactgtggatggtga3540


tcggtcacaggggtctgatgtgtggtagctgcaggtggagtcccaggtgtgtctgtagct3600


actttgcgtcctcggccccccggcccccgtttcccaaacagaagcttcccaggcgctctc3660


tgggcttcatcccgccatcgggcttggccgcaggtccacacgtcctgatcggaagaaaca3720


agtgcccagctctggccggggcaggccacatttgtggctcatgccctctcctctgccggc3780


ag
3782


<210> 11


<211> 980


<212> DNA


<213> Homosapiens
IS


<400> 11


gtctgggcactgccctgcagggttgggcacggactcccagcagtgggtcctcccctgggc60


aatcactgggctcatgaccggacagactgttggccctggggggcagtggggggaatgagc120


tgtgatgggggcatgatgagctgtgtgccttggcgaaatctgagctgggccatgccaggc180



tgcgacagctgctgcattcaggcacctgctcacgtttgactgcgcggcctctctccagtt240


ccgcagtgcctttgttcatgatttgctaaatgtcttctctgccagttttgatcttgaggc300


caaaggaaaggtgtccccctcctttaggagggcaggccatgtttgagccgtgtcctgccc360


agctggcccctcagtgctgggtctgaggccaaaggaaacgtgtcccccttcttaggagga420


cgggccgtgtttgagccacgccccgctgagcgggcctctcagtgctgggtctgtccacgt480


ggccctgtggccctttgcagatgtggtctgtccacgtggccctgtggctctttgcagatg540


cctgttagcacttgctcggctctaggggacagtcgtgtccaccgcatgaggctcagagac600


ctctgggcgaatttccttggctcccagggtgggggtggaggtggcctgggctgctgggac660


ccagaccctgtgcccggcagctgggcagcaactcctggatcacatatgccatccgggcca720


3o cggtgggctgtgtgggtgtgagcccagctggacccacaggtggcccagaggagacgttct780


gtgtcacacactctgcctaagcccatgtgtgtctgcagagactcggcccggccagcccac840


gatggccctgcattccagcccagccccgcacttcatcacaaacactgaccccaaaaggga900


cggagggtcttggccacgtggtcctgcctgtctcagcacccaccggctcactcccatgtg960


tctcccgtctgctttcgcag 980


<210> 12
<211> 2485
<212> DNA
<213> Homo Sapiens
<400> 12
gtgagtcaggtggccaggtgccattgccctgcgggtggctgggcgggctggcagggcttc60


tgctcacctctctcctgccccttccccactgnccttctgcccggggccaccagagtctcc120


ttttctggcccccgccccctccggctcctgggctgcaggctcccgaggccccggaaacat180


ggctcggcttgcggcagccggagcggagcaggtgccacacgaggcctggaaatggcaagc240


ggggtgtggagttgctcctgcgtggaggacgaggggcggggggtgtgtctgggtcaggtg300


tgcgccgagcgtttgagcctgcagcttgtcagctccaagttactactgacgctggacacc360


cggctctcacacgcttgtatctctctctcccgatacaaaaggattttatccgattctcat420


tcctgtccctgtcgtgtgacccccgcgagggcgcgggctcttctctctgtgactagattt480


cccatctggaaagtgcggggttgaccgtgtagtttgctcctctcggggggcctgtggtgg540



ccatggggcaggcggcctgggagagctgccgtcacacagccactgggtgagccacactca600


cggtggtagagccacagtgcctggtgccacatcacgtcctctggattttaagtaaaacca660


cacacctcccggcaggcatctgcctgcgaccctgtgtgtgcctggggagagtggtagcac720


ggaggaaattcgtgcacactcaaggtcatcagcaaggtcatccgcagtcaggtggaacgt780


ggaggcctctctctgggatcgtctccagcggataaaggactgtgcacagcttcggaagct840
SS t


t aatataactattaattattgcattataagtaatcactaatggtatcagca900
tatttaaa


attataatatttattaaagtataattagaaatattaagtagtacacacgttctggaaaaa960


cacaaattgcacatggcagcagagtgaattttggccgagggacacgtgtgcacatgtgtg1020


taagcggcccccaggcccacagaattcgctgacaaagtcacctccccagagaagccacca1080


6o cgggcctccttcgtggtcgtgaattttattaagatggatcaagtcacgtaccgtccacgt1140
t


g tttggggaatgtgaggtgatgactgcgtcctcatgccctgacagacagga1200
ggcagggc


ggtgactgtgtctgtcctgtccctaggacacggacaggcccgaagctctagtccccatcg1260


tggtccagtttggcctctgaataaaaacgtcttcaaaacctgttgccccaaaaactaaga1320


acagagagagtttcccatcccatgtgctcacaggggcgtatctgcttgcgttgactcgct1380


65 gggctggccggactcctagagttggtgcgtgtgcttctgtgcaaaaagtgcagtcctctt1440


gcccatcactgtgatatctgcaccagcaaggaaagcctcttttcttttctttcttttttt1500


ttttttgagacggaacgtcactgttgtctgcctgggcttgagtgcagtggcgcgatctca1560


actcactgcaacctccgcctcccgggttccagcatttctcctgcctcagcctcccgagca1620


gctgagattacaggcacccaccccctgcgcctggctaatttttgtatttttagtagagag1680


gggtttttgccatgttggccaggctggtctcgaactcctgacctcaggtgatccacccac1740


ctcggcctcccaaagtgctgggattacaggtgtgagccatcacgcccagccggaaagcct1800


ctttttaaggtgaccacctatagcgcttcccgaaaataacaggtcttgtttttgcagtag1860


gctgcaagcgtctcttagcaacaggagtggcgtcctgtgggctctggggatggctgaggg1920


tcgcgtggcagccatgccttctgtgtgcacctttaggttccacggggctattctgctctc1980


actgtttgtctgaaaacgcacccttggcatccttgtttggagagtttctgcttctcgttg2040


gtcatgctgaaactaggggcaaggttgtatccgttggcgcgcagcggctacatgtagggt2100


catgagtctttcaccgtggacaaattccttgaaaaaaaaaaaaggagtccggttaagcat2160


tcattccgggtcaagtgtctggttctgtgaataaactctaagatttaagaaaccttaatg2220


aaagaaaaccttgatgattcagagcaaggatgtggtcacacctgtggctggatctgtttc2280




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-70-
agccgccccagtgcatggtgagagtggggagcagggattgtttgttcagaggtctcatct2340


ggtatgtttctgaggtgtttgccggctgaatggtagacgtgtcgtttgtgtgtatgaggt2400


tctgtgtctgtgtgtggctcggtttgagtgtacgcatgtccagcacatgccctgcccgtc2460


tctcacctgtgtcttcccgccccag
2485


<210> 13


<211> 1984


<212> DNA


<213> Homosapiens
1


<400> 13


gtgaggcctcctcttccccaggggggcttgggtgggggttgatttgcttttgatgcattc60


agtgttaatattcctggtgctctggagaccatgactgctctgtcttgaggaaccagacaa120


IS ggttgcagccccttcttggtatgaagccgcacgggaggggttgcacagcctgaggactgc180


gggctccacgcaggctctgtccagcggccatgtccagaggcctcagggctcagcaggcgg240


gagggccgctgccctgcatgatgagcatgtgaattcaacaccgaggaagcacaccagctt300


ctgtcacgtcacccaggttccgttagggtccttggggagatggggctggtgcagcctgag360


gccccacatctcccagcaggccctcgacaggtggcctggactgggcgcctcttcagccca420


2o ttgcccatcccacttgcatggggtctacacccaaggacgcacacacctaaatatcgtgcc480


aacctaatgtggttcaactcagctggcttttattgacagcagttacttttttttttttaa540


tactttaagttctagggtacatgtgcacgacgtgcaggttagttacatatgtatacatgt600


gccatgttggtgtgctgcacccattaactcatcatttacattaggtatatctcctaatgc660


tatccctccccactccccccatcccatgacaggccctggtgtgtgatgttccccaccctg720


tgtccaagtgttctcattgttcagttcccacctgtgagtgagaacatgtggtgtttggtt780
25 t


tctttcctt gcaatagtttgctcagagtgatggtttccagcttcgtccatgtccctaca840


aaggacatgaactcatccttttttatgactgcatagtattccgtggtgtatatgtgccac900


attttcttaatccagtctatcatcgatggacatttgggttggttgcaagtctttgctact960


gtgaatagtgccgcaataaacatacgtgtgcatgtgtctttatagcagcatgatttataa1020


tcctttgggtatatacccagtaatgggatggctgggtcaaatggtatttctagttctaga1080
3~ t


ccttgagga atcaccacactgtcttccacaatggttgaactagtttacactcccaccaa1140


cagtgtaaaagtgttctggtgctggagaggatgtggacagcagttatttttttatgaaaa1200


tagtatcactgaacaagcagacagttagtgaaggatgcgtcaggaagcctgcaggccaca1260


cagccatttctctcgaagactccgggtttttcctgtgcatcttttgaaactctagctcca1320


attatagcatgtacagtggatcaaggttcttcttcattaaggttcaagttctagattgaa1380
35


ataagtttatgtaacagaaacaaaaatttcttgtacacacaacttgctctgggatttgga1440


ggaaagtgtcctcgagctggcggcacactggtcagccctctgggacaggatacctctggc1500


ccatggtcatggggcgctgggcttgggcctgagggtcacacagtgcaccatgcccagctt1560


cctgtggataggatctgggtctcggatcatgctgaggaccacagctgccatgctggtaaa1620


gggcaccacgtggctcagagggggcgaggttcccagccccagctttcttaccgtcttcag1680
40


ttatttttccctaagagtctgagaagtggggccgcgcctgatggccttcgttcgtcttca1740


gctggcacagaattgcacaagctgatggtaaacactgagtacttataatgaatgaggaat1800


tgctgtagcagttaactgtagagagctcgtctgttggaaagaaatttaagtttttcattt1860


aaccgctttggagaatgttactttatttatggctgtgtaaattgtttgacattcagtccc1920


tcgtagacagatactacgtaaaaagtgtaaagttaaccttgctgtgtattttcccttatt1980
45


ttag 1984


<210> 14
<211> 1871
<212> DNA
<213> Homo sapiens
<400>
14


gtgaggcccgtgccgtgtgtctgtggggacctccacagcctgtgggctttgcagttgagc60


55 cccccgtgtcctgcccctggcaccgcagcgttgtctctgccaagtcctctctctctgccg120


gtgctggatccgcaagagcagaggcgcttggccgtgcacccaggcctgggggcgcagggg180


caccttcgggagggagtgggtaccgtgcaggccctggtcctgcagagacgcacccaggtt240


acacacgtggtgagtgcaggcggtgacctggctcctgctgctctttggaaagtcaagagt300


ggcggctcctggggccccagtgagacccccaggagctgtgcacagggcctgcagggccga360


60 ggcggcagcctcctccccagggtgcacctgagcctgcggagagcaggagctgctgagtga420


gctggcccacagcgttcgctgcggtcacgttcctgcgtggggttgtttgggatcggtggg480


agaatttggatttgctgagtgctgctgtcttgaaccacggagatggctaggagtgggttt540


cagagttgatttttgtgaatcaaactaaaatcaggcacaggggacctggcctcagcacag600


gggattgtccaatgtggtccccctcaagggcgccccacagagccggtgggcttgttttaa660


agtgcgatttgacgagggacgagaaaccttgaaagctgtaaagggaaccctcagaaaatg720
65


tggccgccaggggtggtttcaggtgctttgctgggctgtgtttgtgaaaacccatttgga780


cccgccctccaagtccaccctccaggtccaccctccagggccgccctgggctgggggtat840


gcctggcgttccttgtgccgcagcccggagcacagcaggctgtgcacatttaaatccact900


aagattcactcggggggagcccaggtcccaagcaactgagggctcaggagtcctgaggct960


gctgaggggacagagcagacggggaacgctgcttctgtgtggcaagttcctgagggtgct1020


ggccagggaggtggctcagagtgtatgttggggtcccaccgggggcagaactctgtctct1080


gatgagtcggcagccatgtaacaggaaggggtggccacagggagctgggaatgcaccagg1140


ggagctgcgcagctggccgaggtcccagggccaggccacaggaagggcagggggacgccc1200


ggggccacagcagaggccgcaggaagggaaggggatgcccaggccagagcagaggctacc1260


gggcacaggggggctccctgagctgggtgagcgaggctcatgactcggcgagggaacctc1320
75


cttgacgtgaagctgacgactggtgttgcccagctcacagcccagccaggtcccgcgcct1380


gagcaggaactcagaaccctcccctttgtctaaagcacagcagatgccttcagggcatct1440


aggagaaaacaggcaaagtcgttgagaaacgtcttaaaagaaggtgggatggtggcaatt1500


tcttgtccagattttagtctgccccggaccacagatgagtctataacgggattgtggtgt1560




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-71-
tgccatgggg acacatgaga tggaccatca cagaggccac tggggctgca cctcccatct 1620
gagtcctggc tgtcccgggt ccaggccagg ttcttgcatg ctcacctacc tgtcctgccc 1680
gggagacagg gaaagcaccc cgaagtctgg agcagggctg ggtccaggct cctcagagct 1740
cctgccaggc ccagcaccct gctccaaatc accacttctc tggggttttc caaagcattt 1800
aacaagggtg tcaggttacc tcctgggtga cggccccgca tcctggggct gacattgccc 1860
ctctgcctta g 1871
<210> 15
<211> 3801
lO <212> DNA
<213> Homo Sapiens
<400>
15


gtgagcgcacctggccggaagtggagcctgtgcccggctggggcaggtgctgctgcaggg60
15


ccgttgcgtccacctctgcttccgtgtggggcaggcgactgccaatcccaaagggtcaga120


ggccacagggtgcccctcgtcccatctggggctgagcagaaatgcatctttctgtgggag180


tgagggtgctcacaacgggagcagttttctgtgctattttggtaaaaggaaatggtgcac240


cagacctgggtgcactgaggtgtcttcagaaagcagtctggatccgaacccaagacgccc300


gggccctgctgggcgtgagtctctcaaacccgaacacaggggccctgctgggcatgagtc360
2O


cctctgaacccgagaccctggggccctgctgggcgtgagtctctccgaacccagagactt420


cagggcccttttgggcgtgagtctctccgctgtgagccccacactccaaggctcatccac480


agtctacaggatgccatgagttcatgatcacgtgtgacccatcaggggacagggccatgg540


tgtggggggggtctctacaaaattctggggtcttgtttccccagagcccgagagctcaag600


gccccgtctcaggctcagacacaaatgaattgaagatggacacagatgcagaaatctgtg660
25


ctgtttcttttatgaataaaaagtatcaacattccaggcagggcaaggtggctcacacct720


ataatcccagcactttgggaggccgaggtgggtggatcacttgaggccaggagtttgagg780


ccaacctaaccaacatagtgaaattccatttctacttaaaaaatacaaaaattagcctgg840


cctggtggcacacgcctgtagtccccgctatgcgggaggctgaggcaggagaatcatttg900


aacccaggaggcagaggttgcagtgagccgagatcacaccactgcactccagcctgggca960
3O


acagagtgagacttcatcttaaaaaaaaaaaaaaaagtatcagcattccaaaaccatagt1020


ggacaggtgtttttttattctgtccttcgataatatttactggtgctgtgctagaggccg1080


gaactgggggtgccttcctctgaaaggcacaccttcatgggaagagaaataagtggtgaa1140


tggttgttaaaccagaggtttaaactggggtcctgtcgttctgagttaacagtccagatc1200


35 tggactttgcctctttccagaatgctccctggggtttgcttcatgggggagcagcaggtg1260


tggacaccctcgtgatgggggagcagcaggtgcagacgccctcatgatgggggagtggca1320


ggtgcagacacccttgtgcatggtgcccagcatgtccctgttgcagctccctccccacaa1380


ggatgccggtctcctgtgctccccacagtccctgcttccctctcacagccttacctggtc1440


ctggcctccactggctttgtctgcatgatttccacatttcctgggctcccagcacctctt1500


4O cgcctctcccaggcacctctgcagtgctggccataccagtcagctgtgaactgtccactg1560


cttattttgctccccatgaaatgtattttttaggacaggcacccctggttccagcctctg1620


gcacagcatcagtgaatgttattgaaggacaaaggacagacaaacaaatcaggaaaatgg1680


gttctctctaaacacattgcaaagccacagaggctagtgcaggatgggtgggcatcaggt1740


catcagatgtgggtccaatgccagaatattctgtgctcccaaaggccacttggtcagagt1800


45 gtgtgcttgcagaggtggctctaaaagctcagcagtggaggcagtggttcgccatactca1860


gggtgaactcacatcctctgtgtctgaagtatacagcagaggcttgaagggcatctggga1920


gaagaaaacaggcaaaatgattaagaaaagtgaaaaaggaaaagtggtaagatgggaatt1980


ttcttgtccagattttagtctcccaaaccacagctcagatggtagaatgtggtcagaact2040


gatggacagaacaatagaacaaaacggaagccctatctctcagaaacgtgtgttaatgtg2100


SO gtatgtggcacagctgatggaaaagagagtgtgtgtgtaatttttttttctgagaaaact2160


gactggaagcaaataagttgtgtctttacagcatataccagagcagattctaggtagaag2220


aggagacacatgcaaacaacaccagcaacagaaataaaacaaaagactcaaagggaaggg2280


aggtgaacgttccctggtttggtgttggggaaggacacacagggaggcggatgaaaccag2340


tgaggcaacgggcattgctttcactgcagagaaactcagcttgcctgagccacagtgaaa2400


atggccattccctggagcgtttgtgcacgtgatttatttaaggcgccctgtgaggtcctg2460
55


cacattcatcctctcactttgttctcctaaccacctgagaggtagaggaggaaaggctcc2520


aggggagcagccgcccttggtcacccagctggcaaagggcatgcatgattgcagcctggc2580


ctcctgctccggggcccttgctctgcccgaggaccccacacaagtcagacccataggctc2640


agggtgagccggagcccaaggtcgtgttggggatggctgtgaaagaagaaatggacgtct2700


6O gatgcacacttgggaaggtcctaccagcagcgtcaaagaaatgcatgtgaaactgacagc2760


gagacccatccctcaaagaaacgcacgtgaaactgatggcgagacctgtccccatccctc2820


atgctggctccttttctgggcttgccaagagccagcatcaggttgaggcaagctggaaag2880


acttttctggaaagcagcttgtttgcatggaagtcctcacaatgtcctgtgtcttcccag2940


taattccacttctgaagtgaccagacattatcacgggtcttatttaccatttccagtgtt3000


ccaggcagggggacttgccacagcaagtcacgaacctgcccaaatacagggctaaggaga3060
65


tattatgcatcacaaaacttgctctgccattaaacatttttcaaagaatttttgaagaat3120


gtttaatggcacaaaacgtttatttcaatgtagcagtgttcaaagctggatgtaaaagaa3180


cacaccccaggagcctgccgtgaatgtcatgtgtgttcatctttggacatggacatacat3240


gggcagtgagtggtggtgaggccctggaggacatcggtgggatgcctccatcctgcccct3300


ctggagacaccatgtgtgccacgtgcactcactggagccctgtttagctggtgccacctg3360
7O


gctcttccatccctgagattcaaacacagtgagattccccacgcccaactcagtgttctc3420


ccacaaaaaacctgagtcacacctgtgttcactcgagggacgcccgggagccagggctcc3480


acagtttattatgtgtttttggctgagttatgtgcagatctcatcagggcagatgatgag3540


tgcacaaacacggccgtgcgaggtttggatacactcaacatcactagccaggtcctggtg3600


75 gagtttggtcatgcagagtctggatggcatgtagcatttggagtccatggagtgagcacc3660


cagccccctcgggctgcagcgcatgccccaggcaggacaaggaagcgggaggaaggcagg3720


aggctctttggagcaagctttgcaggagggggctgggtgtggggcaggcacctgtgtctg3780


acattcccccctgtgtctcag 3801




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-72-
<210> 16
<211> 880
<212> DNA
<213> Homo sapiens
<400> 16


gtgagcaggctgatggtcagcacagagttcagagttcaggaggtgtgtgcgcaagtatgt60


gtgtgtgtgtgtgcgcgcgtgcctgcaaggctgatggtgactggctgcacgtaagagtgc120


lp acatgtacgcatatacacgtgagcacatacatgtgtgcatgtgtgtacatgaaggcatgg180


cagtgtgtgcacaggtgtgcaagggcacaagtgtgtgcacatgcgaatgcacacctgaca240


tgcatgtgtgttcgtgcacagtcgtgtgggcattcacgtgaggtgcatgcgtgtgggtgt300


gcagtgtgagtagcatgtgtgcacataacatgtattgaggggtcctcgtgttcaccccgc360


taggtcctcagcaccagtgccactccttacaggatgagacggggtcccaggccttggtgg420


gctgaggctctgaagctgcagccctgagggcattgtcccatctgggcatccgcgtccact480
IS


ccctctcctgtgggcttctgtgtccactccccctctcctgtgggcatttacatccactcc540


actccctctctcctgtgggcatccgcgtccactccccctctctgtgggcatctgcgtcca600


cctcccctctctgtgggcatttgcgtccactccctctcctggttccttcctgtcttggcc660


gagcctcgggggcaggcagatgacacagagtcttgactcgcccagggtggttcgcagctg720


2o ccgggtgagggccaggccggatttcactgggaagagggatagtttcttgtcaaaatgttc780


ctctttcttgttccatctgaatggatgataaagcaaaaagtaaaaacttaaaatcccaga840


gaggtttctaccgtttctcactctttcttggcgactctag gg0


<210> 17
<211> 3186
25 <212> DNA
<213> Homo sapiens
<400> 17


gtgagccgccaccaaggggtgcaggcccagcctccagggaccctccgcgctctgctcacc60
3~


tctgacccggggcttcaccttggaactcctgggttttaggggcaaggaatgtcttacgtt120


ttcagtggtgctgctgcctgtgcacagttctgttcgcgtggctctgtgcaaagcacctgt180


tctccatctctgggtagtggtaggagccggtgtggccccaggtgtccccactgtgcctgt240


gcactggccgtgggacgtcatggaggccatcccagggcagcaggggcatggggtaaagag300


atgtttatggggagtcttagcagaggaggctgggaaggtgtctgaacagtagatgggaga360
35


tcagatgcccggaggatttggggtctcagcaaagagggccgaggtgggtgcaggtgaggg420


tcgctggccccacccccgggaaggtgcagcagagctgtggctccccacacagcccggcca480


gcacctgtgctctgggcatggctgtgctcctggaacgttccctgtcctggctggtcaggg540


ggtgcccctgccaagaatcgacaactttatcacagagggaagggccaatctgtggaggcc600


acagggccagcttctgcctggagtcagggcaggtggtggcacaagcctcggggctgtacc660


aaagggcagtcgggcaccacaggcccgggcctccacctcaacaggcctcccgagccactg720


ggagctgaatgccaggaggccgaagccctcgccccatgagggctgagaaggagtgtgagc780


atttgtgttacccagggccgaggctgcgcgaattaccgtgcacacttgatgtgaaatgag840


gtcgtcgtctatcgtggaaacccagcaagggctcacgggagagttttccattacaaggtc900


45 gtaccatgaaaatggtttttaacccgagtgcttgcgccttcatgctctggcagggagggc960


agagccacagctgcatgttaccgcctttgcaccagctccagaggcttgggaccaggctgt1020


ctcagttccagggtgcgtccggctcagaccgccctcctctctgccttctctctctgcctc1080


aaatcttccctcgtttgcatctccctgacgcgtgcctgggccctcgtgcaagctgcttga1140


ctcctttccggaaacccttggggtgtgctggatacaggtgccactgaggactggaggtgt1200


ctgacactgtggttgaccccagggtccagctggcgtgcttggggcctccttgggccatga1260


tgaggtcagaggagttttcccaggtgaaaactcctgggaaactcccagggccatgtgacc1320


tgccacctgctcctcccatattcagctcagtcttgtcctcatttccccaccagggtctct1380


agctccgaggagctcccgtagagggcctgggctcagggcagggcggctgagtttccccac1440


ccatgtggggacccttgggtagtcgcttgattgggtagccctgaggaggccgagatgcga1500


tgggccacgggccgtttccaaacacagagtcaggcacgtggaaggcccaggaatcccctt1560
ss


ccctcgaggcaggagtgggagaacggagagctgggccccgatttcacggcagccaggctg1620


cagtgggcgaggctgtggtggtccacgtggcgctgggggcggggtctgattcaaatccgc1680


tggggctcggccttcctggcccgtgctggccgcgcctccacacgggcttggggtggacgc1740


cccgacctctagcaggtggctatttctccctttggaagagagcccctcacccatgctagg1800


6o tgtttccctcctgggtcaggagcgtggccgtgtggcaaccccgggaccttaggcttattt1860


atttgtttaaaaacattctgggcctggcttccgttgttgctaaatggggaaaagacatcc1920


cacctcagcagagttactgagaggctgaaaccggggtgctggcttgactggtgtgatctc1980


aggtcattccagaagtggctcaggaagtcagtgagaccaggtacatggggggctcaggca2040


gtgggtgagatgaggtacacggggggctcaggcagtgggtgaggccaggtacatgggggg2100


65 ctcaggcactgggtgagatgaggtacacggggggctcaggcagagggtcagaccaggtac2160


acgggggctctgatcacacgcacatatgagcacatgtgcacatgtgctgtttcatggtag2220


ccaggtctgtgcacacctgccccaaagtcccaggaagctgagaggccaaagatggaggct2280


gacagggctggcgcggtggctcacacctgtagtcccagcactttgggaggccgaggcgag2340


aggatcccttgagcccaggagtttaagaccagcctgagcaacatagtagaaccccatctc2400


tatgaaaaataaaaacaaaaattagctgaacatggtggtgtgcgcctgtagttccaatac2460


ttgggaggctgaagtgggaggatcacttgagcccaggaggtggaagctgcagtgagctga2520


gattgcaccactgtactgcagcctgggtgacagagtgagagcccatctcaacaacaacaa2580


agaagactgacaaatgcagtttcttggaaagaaacatttagtaggaacttaacctacaca2640


cagaagccaagtcggtgtctcggtgtcagtgagatgagatgatgggtcctcacaccatca2700


ccccagacccagggtttatgcaccacaggggcgggtggctcagaagggatgcgcaggacg2760
75


ttgatatacgatgacatcaaggttgtctgacgaagggcaggattcatgataagtacctgc2820


tggtacacaaggaacaatggataaactggaaaccttagaggccttcccggaacaggggct2880


aatcagaagccagcatggggggctggcatccaggatggagctgcttcagcctccacatgc2940


gtgttcatacagatggtgcacagaaacgcagtgtacctgtgcacacacagacacgcagct3000




CA 02316282 2000-06-21
Le A 32 805-Foreign Countries
-73-
actcgcacacacaagcacacacacagacatgcatgcatgcatccgtgtgtgtgcacctgt3060


gcccatgaggaaacccatgcatgtgcattcatgcacgcacacaggcaccggtgggcccat3120


gcccacacccacgagcaccgtctgattaggaggcctttcctctgacgctgtccgccatcc3180


tctcag 3186


<210> 18


<211> 781


<212> DNA


<213> HomoSapiens



<400> 18


gtatgtgcaggtgcctggcctcagtggcagcagtgcctgcctgctggtgttagtgtgtca60


ggagactgagtgaatctgggcttaggaagttcttaccccttttcgcatcagg8agtggtt120


taacccaaccactgtcaggctcgtctgcccgccctctcgtggggtgagcagagcacctga180



tggaagggacaggagctgtctgggagctgccatccttcccaccttgctctgcctggggaa240


gcgctggggggcctggtctctcctgtttgccccatggtgggatttggggggcctggcctc300


tcctgtttgccctgtggtgggattgggctgtctcccgtccatggcacttagggcccttgt360


gcaaacccaggccaagggcttaggaggaggccaggcccaggctaccccacccctctcagg420


agcagaggccgcgtatcaccacgacagagccccgcgccgtcctctgcttcccagtcaccg480



tcctctgcccctggacactttgtccagcatcagggaggtttctgatccgtctgaaattca540


agccatgtcgaacctgcggtcctgagcttaacagcttctactttctgttctttctgtgtt600


gtggaaatttcacctggagaagccgaagaaaacatttctgtcgtgactcctgcggtgctt660


gggtcgggacagccagagatggagccaccccgcagaccgtcgggtgtgggcagctttccg720


gtgtctcctgggaggggagctgggctgggcctgtgactcctcagcctctgttttccccca780


g 781


<210> 19


<211> 536


<212> DNA


<213> HomoSapiens


<400> 19


gcaagtgtgggtggaggccagtgcgggccccacctgcccaggggtcatccttgaacgccc60



tgtgtggggcgagcagcctcagatgctgctgaagtgcagacgcccccgggcctgaccctg120


ggggcctggagccacgctggcagccctatgtgattaaacgctggtgtccccaggccacgg180


agcctggcagggtccccaacttcttgaacccctgcttcccatctcaggggcgatggctcc240


ccacgcttgggagccttctgacccctgacctgtgtcctctcacagcctcttccctggctg300


ctgccctgagctcctggggtcctgagcaagttctctccccgccccgccgctccagcgtca360


ctgggctgcctgtctgctcgccccggtggaggggtgtctgtcccttcactgaggttccca420


ccagccagggccacgaggtgcaggccctgcctgcccggccacccacacgtcctaggaggg480


ttggaggatgccacctctggcctcttctggaacggagtctgattttggccccgcag 536


<210> 20


<211> 3179


<212> DNA


<213> HomoSapiens


<400> 20


atctcatgtttgaatcctaatgtgcactgcatagacaccactgtatgcaattacagaagc60


ctgtgagtgaacggggtggtggtcagtgcgggcccatggcctggctgtgcatttacggaa120


gtctatgagtgaatggggttgtggtcagtgcgggcccatggcctggctgggcctgggagg180


tttctgatgctgtgaggcaggaggggaaggagggtaggggatagacagtgggagccccca240


ccctggaagacataacagtaagtccaggcccgaagggcagcagggatgctgggggcccag300



cttgggcggcggggatgatggagggcctggccagggtggcagggatgatgggggccccag360


ctggggtggcaggggtgatggggggggctggtctgggtggcggggaagatggggaagcct420


ggctgggccccctcctcccctgcctcccacctgcagccgtggatccggatgtgcttccct480


ggtgcacatcctctgggccatcagctttcatggaggtggggggcaggggcatgacaccat540


cctgtataaaatccaggattcctcctcctgaacgccccaactcaggttgaaagtcacatt600


ccgcctctggccattctcttaagagtagaccaggattctgatctctgaagggtgggtagg660


gtggggcagtggagggtgtggacacaggaggcttcagggtggggctggtgatgctctctc720


atcctcttatcatctcccagtctcatctctcatcctcttatcatctcccagtctcatctg780


tcttcctcttatctcccagtctcatctgtcatcctcttaccatctcccagtctcatctct840


tatcctcttatctcctagtctcatccagacttacctcccagggcgggtgccaggctcgca900


gtggagctggacatacgtccttcctcaggcagaaggaactggaaggattgcagagaacag960


gaggggcggctcagagggacgcagtcttggggtgaagaaacagcccctcctcagaagttg1020


gcttgggccacacgaaaccgagggccctgcgtgagtggctccagagccttccagcaggtc1080


cctggtggggccttatggtatggccgggtcctactgagtgcaccttggacagggcttctg1140


7o gtttgagtgcagcccggacgtgcctggtgtcggggtgggggcttatggccactggatatg1200


gcgtcatttattgctgctgcttcagagaatgtctgagtgaccgagcctaatgtgtatggt1260


gggcccaagtccacagactgtgtcgtaaatgcactctggtgcctggagcccccgtatagg1320


agctgtgaggaaggaggggctcttggcagccggcctgggggcgcctttgccctgcaaact1380


ggaagggagcggccccgggcgccgtgggcggacgacctcaagtgagaggttggacagaac1440


agggcggggacttcccaggagcagaggccgctgctcaggcacacctgggtttgaatcaca1500


gaccaacaggtcaggccattgttcagctatccatcttctacaaagctccagattcctgtt1560


tctccgggtgttttttgttgaaattttactcaggattacttatattttttgctaaagtat1620


tagacccttaaaaaaggtatttgctttgatatggcttaactcactaagcacctactttat1680


ttgtctgtttttatttattattattattattattagagatggtgtctactctgtcaccca1740




CA 02316282 2000-06-21
Le A 32 805-Forei;~n Countries
-74-
ggttgttagtgcagtggcacagtcatggctcgctgtagccgcaaacccccaggctcaagt1800


gatcctccggcctcagcttcccagagtgctgggattacaggtgtgagccactgcccttgc1860


ctggcacttttaaaaaccactatgtaaggtcaggtccagtggcttccacacctgtcatcc1920


cagtagtttgggaagccgaggcagaaggattgtctgaggccaggagtttgagaccagcat1980


gggtaacatagggagaccccatctctacaaaaaatgcaaaaagttatccgggcgtggggt2040


ccagcatctgtagtcccagctgctcgggaggctgagtgggaggatcgcttgagcccggga2100


ggtcatggctgcagtgagctgtgattgtaccatcgcactccagcctgggcaacagagtga2160


gaccctgtctcaaaaaaaaaaaaaaaaaaagaaggagaaggagaagagaagaagaaggaa2220


gaaggaaagagaagaagaaggaagaaggaagaaagaaggagaaggaggcctgctaggtgc2280



taggtagactgtcaaatctcagagcaaaatgaaaataacaaagttttaaagggaaagaaa2340


aaccccagctctttggacttccttaggcctgaacttcatctcaagcagcttccttccaca2400


gacaagcgtgtatggagcgagtgagttcaaagcagaaagggaggagaagcaggcaagggt2460


ggaggctgtgggtgacaccagccaggacccctgaaagggagtggttgttttcctgcctca2520


IS gccccacgctcctgccggtcctgcacctgctgtaaccgtcgatgttggtgccaggtgccc2580


acctgggaaggatgctgtgcagggggcttgccaaactttggtgggtttcagaagccccag2640


gcacttgtggcaggcacaattacagcccctccccaaagatgcccacgtccttctcctgga2700


acctgtgaatgtgtcacccgcaaggcagaggctggtgaaggctgcaggtggaatcacggc2760


tgccagtcagccgatcttaaggtcatcctggattatctggtgggcctgatatggccacaa2820


gggtccctagaagtgagagagggaggcaggggagagtcagagaggggacgtgagaaggac2880


cactggccactgctggctttgagatggaggagggggtccccagccaaggaatgggggcag2940


ccgctccatgctggaaaagcaagcaatcctccccggtcctgagggcacacggccctgccc3000


acgcctcgatttcaggccagtgggacctgtttcagctttccggcctccagagctgtaaga3060


tgatgcgtttgtgttcagccactaagctgcagtgattcgtcacagcagcaaatggaatag3120


cagtacagggaaatgaatacagggacagttctcagagtgactctcagcccacccctggg3179



Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 1998-12-22
(87) PCT Publication Date 1999-07-08
(85) National Entry 2000-06-21
Examination Requested 2003-10-15
Dead Application 2008-12-22

Abandonment History

Abandonment Date Reason Reinstatement Date
2007-12-24 FAILURE TO PAY APPLICATION MAINTENANCE FEE
2008-01-11 R30(2) - Failure to Respond
2008-01-11 R29 - Failure to Respond

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of a document - section 124 $100.00 2000-06-21
Application Fee $300.00 2000-06-21
Maintenance Fee - Application - New Act 2 2000-12-22 $100.00 2000-11-15
Maintenance Fee - Application - New Act 3 2001-12-24 $100.00 2001-11-27
Maintenance Fee - Application - New Act 4 2002-12-23 $100.00 2002-11-22
Request for Examination $400.00 2003-10-15
Maintenance Fee - Application - New Act 5 2003-12-22 $150.00 2003-11-25
Maintenance Fee - Application - New Act 6 2004-12-22 $200.00 2004-11-23
Maintenance Fee - Application - New Act 7 2005-12-22 $200.00 2005-11-21
Maintenance Fee - Application - New Act 8 2006-12-22 $200.00 2006-11-17
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
BAYER AKTIENGESELLSCHAFT
Past Owners on Record
HAGEN, GUSTAV
WICK, MARESA
ZUBOV, DMITRY
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 2000-06-21 1 75
Claims 2000-06-21 3 68
Drawings 2000-06-21 15 828
Representative Drawing 2000-10-03 1 21
Cover Page 2000-10-03 1 55
Description 2000-06-21 74 5,371
Drawings 2000-10-24 15 863
Assignment 2000-06-21 3 147
PCT 2000-06-21 14 554
Correspondence 2000-10-24 5 160
Prosecution-Amendment 2003-10-15 1 42
Prosecution-Amendment 2007-07-11 5 212

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