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CA 02393616 2002-06-05
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Nucleic Acids, Proteins, and Antibodies
[001] This application refers to a "Sequence Listing" that is provided only on
electronic
media in computer readable form pursuant to Administrative Instructions
Section
801(a)(i). The Sequence Listing forms a part of this description pursuant to
Rule 5.2
and Administrative Instructions Sections 801 to 806, and is hereby
incorporated in its
entirety.
[002] The Sequence Listing is provided as an electronic file (PA120PCT
seqList.txt,
7,005,066 bytes in size, created on January 12, 2001) on four identical
compact discs
(CD-R), labeled "COPY 1," "COPY 2," "COPY 3," and "CRF." The Sequence
Listing complies with Annex C of the Administrative Instructions, and may be
viewed,
for example, on an IBM-PC machine running the MS-Windows operating system by
using the V viewer software, version 2000 (see World Wide Web URL:
http://www.fileviewer.com).
Field of the Invention
[003] T]~e present invention relates to novel testes related polynucleotides,
the
polypeptides encoded by these polynucleotides herein collectively referred to
as
"testicular antigens," and antibodies that immunospecifically bind these
polypeptides,
and the use of such testicular polynucleotides, antigens, and antibodies for
detecting,
treating, preventing and/or prognosing disorders of the male reproductive
system,
particularly disorders of the testes, including, but not limited to, the
presence of
testicular cancer and testicular cancer metastases. More specifically,
isolated testicular
nucleic acid molecules axe provided encoding novel testicular polypeptides.
Novel
testicular polypeptides and antibodies that bind to these polypeptides are
provided.
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Also provided are vectors, host cells, and recombinant and synthetic methods
for
producing human testicular polynucleotides, polypeptides, and/or antibodies.
The
invention further relates to diagnostic and therapeutic methods useful for
diagnosing,
treating, preventing and/or prognosing disorders related to the testes,
including
testicular cancer, and therapeutic methods for treating such disorders. The
invention
further relates to screening methods for identifying agonists and antagonists
of
polynucleotides and polypeptides of the invention. The invention further
relates to
methods and/or compositions for inhibiting or promoting the production and/or
function of the polypeptides of the invention.
Backg~ouhd of the Ihvehtion
[004] The two primary functions of the testes are 1) production of
testosterone and 2)
production of sperm. Testosterone produced in the testes is released into the
blood
stream, where it travels to and acts on a wide range of tissues and organs
within the
male body. Disorders resulting from testosterone deficiency are manifested in
the
male reproductive system typically by symptoms of hypogonadism, which is the
failure to go through puberty. Specifically, erectile function is impaired, as
well as
libido and sperm production.
[005] Known dysfunctions of sperm production include aspermia (the failure to
produce
an ejaculate), asthenospermia (the production of an ejaculate in which less
than 50%
of spermatozoa are motile), azoospermia (the production of an ejaculate devoid
of
spermaiozoa), oligospermia (production of an ejaculate containing less than
20x100
spermatozoa per milliliter of semen), and teratospermia (the production of an
ejaculate
in which more than 50% of the spermatozoa are of abnormal shape), all of which
result in reduced fertility. Improper sperm formation may result from a
variety of
factors, including congenital defects, genetic abnormalities, injury, and
infection. For
example, contraction of the mumps virus early in male adolescence can infect
the
testicles, leading to permanent complications in sperm production.
[006] Sperm formation may also be impaired by disorders of the epididymus, a
labyrinthine tube system located in each testis where sperm mature. Common
disorders include infections (e.g., Neisseria gonorrhoea, Pseudomonas,
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Enterobacteriaceae, and Chlamydia ty~achomatis), cyst formation or other
obstructions,
or enlargement of spermatoceles (liquid filled cavities in the epididymus).
[007] During fetal development, the testes mature within the abdominal cavity
and
descend through the inguinal canal into the scrotum prior to birth. It is well
known
that the testicles reside in the scrotum because it is cooler than other
places within the
body cavity, and even minor temperature differences can have a dramatic
influence on
the ability of the testicle to make sperm. An undescended testicle, sometimes
called a
cryptorchid testicle, is a fairly common problem in male babies. Typically,
testicles
undescended at birth will move into the scrotum within the first year of life,
however
in a small percentage of cases, this migration does not occur. Early
correction of this
problem is crucial in preserving the fertility of the male, as the testicles
begin to loose
the ability to make sperm very early in life if they are not properly stored
in the
scrotum. Additionally, testicles that are undescended have a much higher risk
of
developing testicular cancer than testicles that descended spontaneously.
Testicular
cancer is the most common solid tumor in males aged 18 to 35. It typically is
extremely aggressive and spreads early. A tumor of the testicle often shows
itself by a
fast enlargement of the testicle. Bringing the testes into the scrotum will
allow for
easier and more accurate examination of the testes, hopefully resulting in
earlier
detection of tumors. Undescended testicles axe also associated with a greater
risk of
hernia.
j008] Disorders of the scrotal pouch commonly involve the small amount of
fluid lining
the pouch that allows for small movements and cushioning of the testicles.
Several
causes, such as testicular torsion, trauma, or tumors, may lead to an increase
of the
amount of liquid, causing the scrotal pouch to bulge. While this condition is
harmless,
it may cause irritation and discomfort if the bulge becomes too large.
[009] Another harmless, yet irritating disease of the testes is varicocele, a
disorder of the
small veins that run the blood from the testicle back toward the heart. Small
valves are
present in these veins to prevent blood from flowing back toward the
testicles.
Sometimes, these valves malfunction, causing backflow and subsequent
enlargement
of the small vessel network in the scrotal sac. This gives rise to dull pain
and an
uncomfortable "bag of worms" feeling around the scrotum. There is currently
considerable debate as to whether this phenomenon contributes to decreased
fertility.
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[010] Thus, the discovery of new human testicular associated polynucleotides,
the
polypeptides encoded by them, and antibodies that immunospecifically bind
these
polypeptides, satisfies a need in the art by providing new compositions which
are
useful in the diagnosis, treatment, prevention and/or prognosis of disorders
of the
testes, including, but not limited to, cryptorchid testicle, varicocele,
azoospermia,
testicular cancers, and those described in the "Reproductive System Disorders"
section
below.
Summary of the Invention
[011] The present invention relates to novel testes related polynucleotides,
the
polypeptides encoded by these polynucleotides herein collectively referred to
as
"testicular antigens," and antibodies that immunospecifically bind these
polypeptides,
and the use of such testicular polynucleotides, antigens, and antibodies for
detecting,
treating, preventing and/or prognosing disorders of the male reproductive
system,
particularly disorders of the testes, including, but not limited to, the
presence of
testicular cancer andtesticular cancer metastases. More specifically, isolated
testicular
nucleic acid molecules are provided encoding novel testicular polypeptides.
Novel
testicular polypeptides and antibodies that bind to these polypeptides are
provided.
Also provided are vectors, host cells, and recombinant and synthetic methods
for
producing human testicular polynucleotides, polypeptides, and/or antibodies.
The
invention further relates to diagnostic and therapeutic methods useful for
diagnosing,
treating, preventing and/or prognosing disorders related to the testes,
including
testicular cancer, and therapeutic methods for treating such disorders. The
invention
further relates to screening methods for identifying agonists and antagonists
of
polynucleotides and polypeptides of the invention. The invention further
relates to
methods and/or compositions for inhibiting or promoting the production and/or
function of the polypeptides of the invention.
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Detailed Description
Tables
[012] Table 1A summarizes some of the polynucleotides encompassed by the
invention
(including cDNA clones related to the sequences (Clone ID NO:Z), contig
sequences
(contig identifier (Contig ID:) and contig nucleotide sequence identifier (SEQ
ID
NO:X)) and further summarizes certain characteristics of these polynucleotides
and
the polypeptides encoded thereby. The first column provides a unique clone
identifier,
"Clone ID NO:Z", for a cDNA plasmid related to each testes associated contig
sequence disclosed in Table IA. The second column provides a unique contig
identifier, "Contig ID:" for each of the contig sequences disclosed in Table
1A. The
third column provides the sequence identifier, "SEQ ID NO:X", for each of the
contig
polynucleotide sequences disclosed in Table 1A. The fourth column, "ORF (From-
To)", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence of SEQ ID NO:X that delineate the preferred open
reading
frame (ORF) shown in the sequence listing and referenced in Table 1A as SEQ ID
NO:Y (column 5). Column 6 lists residues comprising predicted epitopes
contained in
the polypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y).
Identification of potential immunogenic regions was performed according to the
method of Jameson and Wolf (CABIOS, 4:181-186 (1988)); specifically, the
Genetics
Computer Group (GCG) implementation of this algorithm, embodied in the program
PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group
(GCG), Madison, Wisc.). This method returns a measure of the probability that
a given
residue is found on the surface of the protein. Regions where the antigenic
index score
is greater than 0.9 over at least 6 amino acids are indicated in Table 1A as
"Predicted
Epitopes." In particular embodiments, testes associated polypeptides of the
invention
comprise, or alternatively consist of, one, two, three, four, five or more of
the
predicted epitopes described in Table 1A. It will be appreciated that
depending on the
analytical criteria used to predict antigenic determinants, the exact address
of the
determinant may vary slightly. Column 7, "Tissue Distribution" shows the
expression
profile of tissue, cells, and/or cell line libraries which express the
polynucleotides of
the invention. The first number in column 7 (preceding the colon), represents
the
CA 02393616 2002-06-05
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tissue/cell source identifier code corresponding to the code and description
provided in
Table 4. Expression of these polynucleotides was not observed in the other
tissues
and/or cell libraries tested. For those identifier codes in which the first
two letters are
not "AR", the second number in column 7 (following the colon), represents the
number of times a sequence corresponding to the reference polynucleotide
sequence
(e.g., SEQ ID NO:X) was identified in the tissue/cell source. Those
tissue/cell source
identifier codes in which the first two letters are "AR" designate information
generated using DNA array technology. Utilizing this technology, cDNAs were
amplified by PCR and then transferred, in duplicate, onto the array. Gene
expression
was assayed through hybridization of first strand cDNA probes to the DNA
array.
cDNA probes were generated from total RNA extracted from a variety of
different
tissues and cell Lines. Probe synthesis was performed in the presence of 33P
dCTP,
using oligo(dT) to prime reverse transcription. After hybridization, high
stringency
washing conditions were employed to remove non-specific hybrids from the
array.
The remaining signal, emanating from each gene target, was measured using a
Phosphorimager. Gene expression was reported as Phosphor Stimulating
Luminescence (PSL) which reflects the level of phosphor signal generated from
the
probe hybridized to each of the gene targets represented on the array. A local
background signal subtraction was performed before the total signal generated
from
each array was used to normalize gene expression between the different
hybridizations. The value presented after "[array code]:" represents the mean
of the
duplicate values, following background subtraction and probe normalization.
One of
skill in the art could routinely use this information to identify normal
and/or diseased
tissues) which show a predominant expression pattern of the corresponding
polynucleotide of the invention or to identify polynucleotides which show
predominant and/or specific tissue and/or cell expression. Column 8,
"Cytologic
Band," provides the chromosomal location of polynucleotides corresponding to
SEQ
ID NO:X. Chromosomal location was determined by finding exact matches to EST
and cDNA sequences contained in the NCBI (National Center for Biotechnology
Information) UniGene database. Given a presumptive chromosomal location,
disease
locus association was determined by comparison with the Morbid Map, derived
from
Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man,
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OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins
University (Baltimore, MD) and National Center for Biotechnology Information,
National Library of Medicine (Bethesda, MD) 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/ornim/). If the putative chromosomal location of
the
Query overlapped with the chromosomal location of a Morbid Map entry, an OMIM
identification number is provided in column 9 labeled "OMIM Disease
References)".
A key to the OMIM reference identification numbers is provided in Table 5.
[013] Table 1B summarizes additional polynucleotides encompassed by the
invention
(including cDNA clones related to the sequences (Clone ID NO:Z), contig
sequences
(contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID
NO:X)),
and genomic sequences (SEQ. ID NO:B). The first column provides a unique clone
identifier, "Clone ID NO:Z", for a cDNA clone related to each contig sequence.
The
second column provides the sequence identifier, "SEQ ID NO:X", for each contig
sequence. The third column provides a unique contig identifier,- "Contig ID:"
for each
contig sequence. The fourth column, provides a BAC identifier "BAC ID NO:A"
for
the BAC clone referenced in the corresponding row of the table. The f fth
column
provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of
the
BAC clone identified in column four of the corresponding row of the table. The
sixth
column, "Exon From-To", provides the location (i.e., nucleotide position
numbers)
within the polynucleotide sequence of SEQ ID NO:B which delineate certain
polynucleotides of the invention that are also exemplary members of
polynucleotide
sequences that encode polypeptides of the invention (e.g., polypeptides
containing
amino acid sequences encoded by the polynucleotide sequences delineated in
column
six, and fragments and variants thereof).
[014] Table 2 summarizes homology and features of some of the polypeptides of
the
invention. The first column provides a unique clone identifier, "Clone ID
NO:Z",
corresponding to a cDNA disclosed in Table 1A. The second column provides the
unique contig identifier, "Contig ID:" corresponding to contigs in Table 1A
and
allowing for correlation with the information in Table 1A. The third column
provides
the sequence identifier, "SEQ ID NO:X", for the contig polynucleotide
sequences.
The fourth column provides the analysis method by which the homology/identity
disclosed in the row was determined. Comparisons were made between
polypeptides
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encoded by the polynucleotides of the invention and either a non-redundant
protein
database (herein referred to as "NR"), or a database of protein families
(herein referred
to as "PFAM") as further described below. The fifth column provides a
description of
PFAM/NR hits having significant matches to a polypeptide of the invention.
Column
six provides the accession number of the PFAM/NR hit disclosed in the fifth
column.
Column seven, "Score/Percent Identity", provides a quality score or the
percent
identity, of the hit disclosed in column five. Columns 8 and 9, "NT From" and
"NT
To" respectively, delineate the polynucleotides in "SEQ ID NO:X" that encode a
polypeptide having a significant match to the PFAM/NR database as disclosed in
the
f fth column. In specific embodiments, polypeptides of the invention comprise,
or
alternatively consist of, an amino acid sequence encoded by the
polynucleotides in
SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants
thereof.
[015] Table 3 provides polynucleotide sequences that may be disclaimed
according to
certain embodiments of the invention. The first column provides a unique clone
identifier, "Clone ID NO:Z", for a cDNA clone related to testes associated
contig
sequences disclosed in Table 1A. The second column provides the sequence
identifier, "SEQ ID NO:X", for contig polynucleotide sequences disclosed in
Table
1A. The third column provides the unique contig identifier, "Contig ID", for
contigs
disclosed in Table 1A. The fourth column provides a unique integer 'a' where
'a' is
any integer between I and the final nucleotide minus 15 of SEQ ID NO:X,
represented as "Range of a", and the fifth column provides a unique integer
'b' where
'b' is any integer between 15 and the final nucleotide of SEQ ID NO:X,
represented as
"Range of b", where both a and b correspond to the positions of nucleotide
residues
shown in SEQ ID NO:X, and where b is greater than or equal to a + 14. For each
of
the polynucleotides shown as SEQ ID NO:X, the uniquely defined integers can be
substituted into the general formula of a-b, and used to describe
polynucleotides which
may be preferably excluded from the invention. In certain embodiments,
preferably
excluded from the polynucleotides of the invention (including polynucleotide
fragments and variants as described herein and diagnostic and/or therapeutic
uses
based on these polynucleotides) are at least one, two, three, four, five, ten,
or more of
the polynucleotide sequences) having the accession numbers) disclosed in the
sixth
column of this Table (including for example, published sequence in connection
with a
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particular BAC clone). In further embodiments, preferably excluded from the
invention are the specific polynucleotide sequences) contained in the clones
corresponding to at least one, two, three, four, five, ten, or more of the
available
material having the accession numbers identified in the sixth column of this
Table
(including for example, the actual sequence contained in an identified BAC
clone).
[016] Table 4 provides a key to the, tissue/cell source identifier code
disclosed in Table
1A, column 7. Column 1 provides the key to the tissue/cell source identifier
code
disclosed in Table 1A, Column 7. Columns 2-5 provide a description of the
tissue or
cell source. Codes corresponding to diseased tissues are indicated in column 6
with
the word "disease". The use of the word "disease" in column 6 is non-limiting.
The
tissue or cell source may be specific (e.g. a neoplasm), or may be disease-
associated
(e.g., a tissue sample from a normal portion of a diseased organ).
Furthermore, tissues
and/or cells lacking the "disease" designation may still be derived from
sources
directly or indirectly involved in a disease state or disorder, and therefore
may have a
further utility in that disease state or disorder. In numerous cases where the
tissue/cell
source is a library, column 7 identifies the vector used to generate the
library.
[017] Table 5 provides a key to the OMIMTM reference identification numbers
disclosed
in Table 1A, column 9. OMIM reference identification numbers (Column 1) were
derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance
in
Man, OMIMTM. McI~usick-Nathans Institute for Genetic Medicine, Johns Hopkins
University (Baltimore, MD) and National Center for Biotechnology Information,
National Library of Medicine, (Bethesda, MD) 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseases associated with
the
cytologic band disclosed in Table 1A, column 8, as determined from the Morbid
Map
database.
[018] Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation
numbers of deposits made with the ATCC in connection with the present
application.
[019] Table 7 shows the cDNA libraries sequenced, tissue source description,
vector
information and ATCC designation numbers relating to these cDNA libraries.
[020] Table 8 provides a physical characterization of clones encompassed by
the
invention. The first column provides the unique clone identifier, "Clone ID
NO:Z",
for certain cDNA clones of the invention, as described in Table 1A. The second
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column provides the size of the cDNA insert contained in the corresponding
cDNA
clone.
Definitions
[021] The following definitions are provided to facilitate understanding of
certain terms
used throughout this specification.
[022] In the present invention, "isolated" refers to material removed from its
original
environment (e.g., the natural environment if it is naturally occurring), and
thus is
altered "by the hand of man" from its natural state. For example, an isolated
polynucleotide could be part of a vector or a composition of matter, or could
be
contained within a cell, and still be "isolated" because that vector,
composition of
matter, or particular cell is not the original environment of the
polynucleotide. The
term "isolated" does not refer to genomic or cDNA libraries, whole cell total
or
mRNA preparations, genomic DNA preparations (including those separated by
electrophoresis and transferred onto blots), sheared whole cell genomic DNA
preparations or other compositions where the art demonstrates no
distinguishing
features of the polynucleotide sequences of the present invention.
[023] As used herein, a "polynucleotide" refers to a molecule having a nucleic
acid
sequence encoding SEQ ID NO:Y or a fragment or variant thereof; a nucleic acid
sequence contained in SEQ ID NO:X (as described in column 3 of Table 1A) or
the
complement thereof; a cDNA sequence contained in Clone ID NO:Z (as described
in
column 1 of Table 1A and contained within a library deposited with the ATCC);
a
nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence
in
SEQ ID NO:B as defined in column 6 of Table 1B or a fragment or variant
thereof; or
a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B
or
the complement thereof. For example, the polynucleotide can contain the
nucleotide
sequence of the full length cDNA sequence, including the 5' and 3'
untranslated
sequences, the coding region, as well as fragments, epitopes, domains, and
variants of
the nucleic acid sequence. Moreover, as used herein, a "polypeptide" refers to
a
molecule having an amino acid sequence encoded by a polynucleotide of the
invention
as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine
peptide
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sequences which result from translation of a polyA tail of a sequence
corresponding to
a cDNA).
[024] As used herein, a "testicular antigen" refers collectively to any
polynucleotide
disclosed herein (e.g., a nucleic acid sequence contained in SEQ ID NO:X or
the
complement therof, or cDNA sequence contained in Clone ID NO:Z, or a
nucleotide
sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID
NO:B as defined in column 6 of Table 1B, or a nucleotide coding sequence in
SEQ ID
NO:B as defined in column 6 of Table 1B or the complement thereof and
fragments or
variants thereof as described herein) or any polypeptide disclosed herein
(e.g., an
amino acid sequence contained in SEQ ID NO:Y, an amino acid sequence encoded
by
SEQ ID NO:X, or the complement thereof, an amino acid sequence encoded by the
cDNA sequence contained in Clone ID NO:Z, an amino acid sequence encoded by
SEQ ID NO:B, or the complement thereof, and fragments or variants thereof as
described herein). These testicular antigens have been determined to be
predominantly expressed in testicular tissues, including normal or diseased
tissues (as
shown in Table 1A column 7 and Table 4).
[025] In the present invention, "SEQ ID NO:X" was often generated by
overlapping
sequences contained in multiple clones (contig analysis). A representative
clone
containing all or most of the sequence for SEQ ID NO:X is deposited at Human
Genome Sciences, Inc. (HGS) in a catalogued and archived library. As shown,
for
example, in column 1 of Table 1A, each clone is identified by a cDNA Clone ID
(identifier generally referred to herein as Clone ID NO:Z). Each Clone ID is
unique to
an individual clone and the Clone ID is all the information needed to retrieve
a given
clone from the HGS library. Furthermore, certain clones disclosed in this
application
have been deposited with the ATCC on October 5, 2000, having the ATCC
designation numbers PTA 2574 and PTA 2575; and on January 5, 2001, having the
depositor reference numbers TS-l, TS-2, AC-1, and AC-2. In addition to the
individual cDNA clone deposits, most of the cDNA libraries from which the
clones
were derived were deposited at the American Type Culture Collection
(hereinafter
"ATCC"). Table 7 provides a list of the deposited cDNA libraries. One can use
the
Clone ID NO:Z to determine the library source by reference to Tables 6 and 7.
Table
7 lists the deposited cDNA libraries by name and links each library to an ATCC
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Deposit. Library names contain four characters, for example, "HTWE." The name
of
a cDNA clone (Clone ID NO:Z) isolated from that library begins with the same
four
characters, for example "HTWEP07". As mentioned below, Table 1A correlates the
Clone ID NO:Z names with SEQ ID NO:X. Thus, starting with an SEQ ID NO:X, one
can use Tables l, 6 and 7 to determine the corresponding Clone ID NO:Z, which
library it came from and which ATCC deposit the library is contained in.
Furthermore,
it is possible to retrieve a given cDNA clone from the source library by
techniques
known in the art and described elsewhere herein. The ATCC is located at 10801
University Boulevard, Mantissas, Virginia 20110-2209, USA. The ATCC deposits
were made pursuant to the terms of the Budapest Treaty on the international
recognition of the deposit of microorganisms for the purposes of patent
procedure.
[026] In specific embodiments, the polynucleotides of the invention are at
least 15, at
least 30, at least S0, at least 100, at least 125, at least 500, or at least
1000 continuous
nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15
kb, 10 kb,
7.5 kb, S kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In ti further embodiment,
polynucleotides of the invention comprise a portion of the coding sequences,
as
disclosed herein, but do not comprise all or a portion of any intron. In
another
embodiment, the polynucleotides comprising coding sequences do not contain
coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the
genome). In other embodiments, the polynucleotides of the invention do not
contain
the coding sequence of more than 1000, 500, 250, 100, S0, 25, 20, 15, 10, S,
4, 3, 2, or
1 genomic flanking gene(s).
(027) A "polynucleotide" of the present invention also includes those
polynucleotides
capable of hybridizing, under stringent hybridization conditions, to sequences
contained in SEQ ID NO:X, or the complement thereof (e.g., the complement of
any
one, two, three, four, or more of the polynucleotide fragments described
herein), the
polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the
complement
thereof, andlor cDNA sequences contained in Clone ID NO:Z (e.g., the
complement of
any one, two, three, four, or more of the polynucleotide fragments, or the
cDNA clone
within the pool of cDNA clones deposited with the ATCC, described herein)
and/or
the polynucleotide sequence delineated in column 6 of Table 1B or the
complement
thereof. "Stringent hybridization conditions" refers to an overnight
incubation at 42
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degree C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM
trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution,
10%
dextran sulfate, and 20 ~.g/ml denatured, sheared salmon sperm DNA, followed
by
washing the filters in O.lx SSC at about 65 degree C.
[028] Also contemplated are nucleic acid molecules that hybridize to the
polynucleotides
of the present invention at lower stringency hybridization conditions. Changes
in the
stringency of hybridization and signal detection are primarily accomplished
through
the manipulation of formamide concentration (lower percentages of formamide
result
in lowered stringency), salt conditions, or temperature. For example, lower
stringency
conditions include an overnight incubation at 37 degree C in a solution
comprising 6X
SSPE (20X SSPE = 3M NaCI; 0.2M NaH2P04; 0.02M EDTA, pH 7.4), 0.5% SDS,
30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50
degree C with 1XSSPE, 0.1% SDS. In addition, to achieve even lower stringency,
washes performed following stringent hybridization can be done at higher salt
concentrations (e.g. 5X SSC).
[029] Note that variations in the above conditions may be accomplished through
the
inclusion and/or substitution of alternate blocking reagents used to suppress
background in hybridization experiments. Typical blocking reagents include
Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and
commercially available proprietary formulations. The inclusion of specific
blocking
reagents may require modification of the hybridization conditions described
above,
due to problems with compatibility.
[030] Of course, a polynucleotide which hybridizes only to polyA+ sequences
(such as
any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a
complementary stretch of T (or U) residues, would not be included in the
definition of
"polynucleotide," since such a polynucleotide would hybridize to any nucleic
acid
molecule containing a poly (A) stretch or the complement thereof (e.g.,
practically any
double-stranded cDNA clone generated using oligo dT as a primer).
(031] The polynucleotide of the present invention can be composed of any
polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or
DNA or modified RNA or DNA. For example, polynucleotides can be composed of
single- and double-stranded DNA, DNA that is a mixture of single- and double
13
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
stranded regions, single- and double-stranded RNA, and RNA that is mixture of
single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that
may be single-stranded or, more typically, double-stranded or a mixture of
single- and
double-stranded regions. In addition, the polynucleotide can be composed of
triple-
stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide
may also contain one or more modified bases or DNA or RNA backbones modified
for
stability or for other reasons. "Modified" bases include, for example,
tritylated bases
and unusual bases such as inosine. A variety of modifications can be made to
DNA
and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or
metabolically modified forms.
[032] The polypeptide of the present invention can be composed of amino acids
joined to
each other by peptide bonds or modified peptide bonds, i.e., peptide
isosteres, and may
contain amino acids other than the 20 gene-encoded amino acids. The
polypeptides
may be modified by either natural processes, such as posttranslational
processing, or
by chemical modification techniques which are well known in the art. Such
modifications are well described in basic texts and in more detailed
monographs, as
well as in a voluminous research literature. Modifications can occur anywhere
in a
polypeptide, including the peptide backbone, the amino acid side-chains and
the amino
or carboxyl termini. It will be appreciated that the same type of modification
may be
present in the same or varying degrees at several sites in a given
polypeptide. Also, a
given polypeptide may contain many types of modifications. Polypeptides may be
branched, for example, as a result of ubiquitination, and they may be cyclic,
with or
without branching. Cyclic, branched, and branched cyclic polypeptides may
result
from posttranslation natural processes or may be made by synthetic methods.
Modifications include acetylation, acylation, ADP-ribosylation, amidation,
covalent
attachment of flavin, covalent attachment of a heme moiety, covalent
attachment of a
nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid
derivative,
covalent attachment of phosphotidylinositol, cross-linking, cyclization,
disulfide bond
formation, demethylation, formation of covalent cross-links, formation of
cysteine,
formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation,
GPI
anchor formation, hydroxylation, iodination, methylation, myristoylation,
oxidation,
pegylation, proteolytic processing, phosphorylation, prenylation,
racemization,
14
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
selenoylation, sulfation, transfer-RNA mediated addition of amino acids to
proteins
such as arginylation, and ubiquitination. (See, for instance, PROTEINS -
STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W.
H. Freeman and Company, New York (1993); POSTTRANSLATIONAL
COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic
Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. I82:626-646
(1990);
Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992).)
[033] "SEQ ID NO:X" refers to a polynucleotide sequence described, for
example, in
Tables I or 2, while ~"SEQ ID NO:Y" refers to a polypeptide sequence described
in
column 5 of Table 1A. SEQ ID NO:X is identified by an integer specified in
column 3
of Table 1A. The polypeptide sequence SEQ ID NO:Y is a translated open reading
frame (ORF) encoded by polynucleotide SEQ ID NO:X. "Clone ID NO:Z" refers to a
cDNA clone described in column 1 of Table 1A.
[034] "A polypeptide having biological activity" refers to a polypeptide
exhibiting
activity similar to, but not necessarily identical to, an activity of a
polypeptide of the
present invention, including mature forms, as measured in a particular
biological
assay, with or without dose dependency. In the case where dose dependency does
exist, it need not be identical to that of the polypeptide, but rather
substantially similar
to the dose-dependence in a given activity as compared to the polypeptide of
the
present invention (i.e., the candidate polypeptide will exhibit greater
activity or not
more than about 25-fold less and, preferably, not more than about tenfold less
activity,
and most preferably, not more than about three-fold less activity relative to
the
polypeptide of the present invention).
[035] Table 1A summarizes some of the polynucleotides encompassed by the
invention
(including contig sequences (SEQ ID NO:X) and clones (Clone ID NO:Z) and
further
summarizes certain characteristics of these polynucleotides and the
polypeptides
encoded thereby.
Polynucleotides and Polynentides
TABLE 1A
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
,::.
OAS,
.
.
.
o ~
U
a
O
O .~ ~ ..
m ,~
00
G ~ '~ O O O N ~ O
~
.
x
~
o
~ .c ~t
~ ~ O
A ~~ N N N N N ~ ~ N N N N
~ ~
~ ~ ~ ~ ~ ~ ~ ~' ~'~'
a
~~
n :. o ~n~o ~O~ d d d
r o ~ '-'' ~ ~nV~
. N
~
~ I O O O M M M l M
Ha N l~
~xr~
~ ~ ~ ~ aoo v~x x x
.
~' a
~
M
.
-, M O1 O d'
01 O
G, cV tiA ~, N ~ ~ ~''~
a~ ~ W ~ M ~
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~a~~~
,~ a c~
o C7 w ~
C7 H
a~ 0 0 0 a O O p O p
~ O O O
v ~ +- ~ +~ +~ ~.~ N
~ M ~ .a-~O ,~ ,_,
O ,-r ~-' M
,--, ~
c<7
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"' C7 ,..~ H ci~ C7 w ~~'.1
C7 p H C7 a,
, H a
d ~ ~ ~O ~ l~o001 O '-'C'1 M dw n
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~ ~ ~ O O O O O
O O O O O O
z
o O
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v7 N
, N N oo~ O o0~n ~ , c
i 00.--,~ p~ .-~~ ~ n
M
V7 i
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A
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-, '
d ~ , ..~ ~ ,-~.-.,-~ .-~ ,-,,-~ ,--~N N
O 00 V7M ,--~O1 01 01~ O~.-a
00 0o O .-~ooM M a\O ~ N N
C ~
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~
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o
0 0~oo~ ~ o
o
Ov N .-~~DO ,.-. M
~O O
~ d ~
W
x x x
x x x x x x x x
16
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
0 0 0 ~ c.
~n ,_;
l~ l~ ,~
N
x ~
~
pp "~ ~ ~ '
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., j
c~
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N N ~ -~
01 0~a\01a\01 Ov01O O o0 O ~ O O O
O ' - - - ' ~ d' O O~
d~
d d d d d d wt~n ~n.-~ ~ ~ ~
m .mt~tmn ~n ~nv'~~n ~n~ ~O m ~ Vo ~ vo Vo
O O O O O O O O O O O O O O ~ O O O
x x x x x x x x x x O ~
~
. x . x x . x . x
.
O o_1 ~ p ~ M O ~ ~ N ~: ,-i
~ ~ ~!j
i i ~ ~ M l~ ~ N ~ Vi
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~
0 0 0 0 0 0 o
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d'N ~ l~ N l~,~ N (w p p~ Q~ ~p
~ p ,-,
N ~ ~ .-. ,-~N ,-V ~ O ~p d. N l0 ,-. ,-i
M ~- d'
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t ' ~
CJC7 ~ -~ ~ P ,-~ Ci~, % . _
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~ CJ
,
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O O O O O O O O O O O O O O
vo00
~ oMOt~000o d-
e
N N d"l~N ~ ~ O d'V~ d O N .-.
-
~ W'N N ~ ~ N i M ~ M M M
O l~~ ~ ~ i O i
dwo ,-,M ,.-W~ oo~ ~ ~ ~ ~- M a\
.~.-~ ~ N ,~ N ~n ~n
N M d-in\O (~oo~ O
N N N N N N N N M M M M M M
d'00~ O ~ M 01l0 d'O 'd' 01 I~ O~
O M N N M ~ d1~ 00O d' 01 M
Q~ool~~ 01 N N l~ N Q~ M N oo d-
M O \O~n~p ~ l~\O l~M d' l~ O I~
(~ooI~M O ~n~nl~ ~ON ~ o0 0o O~
N d'd'00rT '"~M d' M d- 01 d' M ,.,
N ooN v~l~ O ,--N l~oo ~O O o0
~ ~ ~ ~ ~ ~ ~ a
z ~ ~ v ~ o .
w w w
w w w w c~ c~c~ c~ c~ c~ c~
w w w w w w w w w w w w w . w
x x x x x x x x x x x x x x
17
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
t!7 lf7 O O M V1 t!j 00
V'1 O 00
~n ~n ~O O ~ N N ~-~
~n V~ I~ M N O O O
N ~ O N N O~
N N ~o
M
N
~M
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O> C
O cn
d
O O ~ O ,-,
,
M Q', ~ '-' 'G
'd' d~
N N N \p ~ ,~ ~ N N ~ ~ M N M N
O O O p O1 O O
~n ~n m o p~ ~ d' ~ ~ O ~ O~ O O O
N
r~ ~ x O~~r~~ x x ~d'
'-~ op M ~ I~ M p d' ~ r, ,--r \O O
i pp d- N ~' ~p M V7 V; ~ ~' N O d-0 M V~ N
S~, ~~!,~ i i v~~N '~NN ~ '~'S~ N O~
H v~ ~ p~ ~ H a C7 0 ~ ~" ~ C7 C~ ~
0 0 ~ 0 0 0 0 0 0 ~ o ~ 0 0 0 0
N \O N \O \p N 01 ~ ~n ,-W-' ~ p V7 O pip ~ O
M CV M V1 M M ~ ~ ~ lp [w M ~ N M d'
b4 ~, ~. ~ cn ' '
v~ H ~ ~ ~ ~ 0.. a U E-~ ~ v~ H U ~ 0.~
0 0 0 0 0 0 0 0 0 0
O d' M
N ~ O
N ~ N M
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M ~ M d' d' d' d' d'
\O M \O ~ \O N N M
~n O ~ M ~n ~_t N O ~n
O 0~1 t~ oho
pip ~ O o0
O
Ig
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
0 0
0
o d-
o
N ~D
01
.~
,-r
N
N
p, ,
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l~
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O
x ~ x p
p
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,-~ .-; '~s
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M N N N ~- .-, M d-N N N CV
,
op O O ~ ~
O O O O O O O O
~
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,-~ M O ~ ~n
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a ~ M
x x0 x a x x x ~MxOO x x x x x0 x
~ .
o M O N O N N
~ ~t d-
N _ ~ ..-~
v~
by ,~ ~ .rJ
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0 0 o o o o C
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d. -
CV d o0 M +.~ ~
M -
d- ~ . ,-, .-' l~
M M ~ M
1 1 i 1
1 i
O ,- N M V V7~O l~ 00d1O .--~N M
M M M M M M M M
O O O
O O O O O O O O O O O
0 oMO d' ~ ~ 0~00 00
M ~ ~ M ~ N N O N
~ .-,M N N
1 1 1 1 1 1 N 1 1
N N M O M M
t~ 00 Ov O
d- Wit'~ d- ~n
vo
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M d' O O~ - ~ M ~ ~ ~ h ~ N
M ~ l~ l~ . l~o 00 0 1 N o
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01 O ~D~ \
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, a t
w w aa~ar~ r~ w
w w w w w w w w w w w w w w
x x x x x x x x x x x x x x
19
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
'"' nj 0o O
O
M .-i
..
O
"CS ~ O a ~ ~ O N O
ox~ ~c~ x
M ~nN ~ N N N N ,-~-~ d= ~ '~ O N N ~ M
M ~ x Ov
O M ,
O O O O O 01 O O _" ~ O _" O l~ 0o pp
i
-~-a~-,N -~,~-~~ ~ p V~ N O -~ M
~ ~n ~ p O
~
O O O O , O . , ., . O O O ~ ~ '~' O
O O O O -~ M a
O O ~
~
x x x x x x x x ~ ~~ x~~ x~ x
x
N N r..1
00 ~ ~ ~i W ri
M ~M
O oo N ' .
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N M ~ , m 0 ~ , m
d- t~ ~ b0 ~ by
~ ~, ~ by ~ ~ by ;~
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~ ,~ x, ~
~ ~
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s.. >, N ,. ~ P~
-~ 0 ~
a ~ H
o o 0 0 0 o o ~ o
O ''-'O ~ ~ ~ ~ N 1'' ~O o0 '~' p ~ O
p~ ~O O
o0
1'.'N O M ~ .-~ I~ O N l~ 1-' M
- .-. M ~ O ~
- N \O
d N , ,--~ N d n ,~ ,--~ ~ ,-~ .~ ,n
'p ,-i ,~ r-~
,.-, N
O ~ ~ O ~. c~ r~ bD b4
~ cG ~ b4
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O O O O O O O O O Q 01 O O
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p
M N N d- N d' N ,_,~O p~ pp ~-' ,.,
i i ~ i i d' ~ , , ~ ~ M
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N ,~ N ~t M M
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0 o d oo
1 o -
~ ~O00\O \O~O M O O 00 ~ p
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~ Q\l~O~ O M ~n~ N
dw0 d'~O d- ~
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W W W W W W W W W W
W H E
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x x x x x x x x x x x x
~o
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
~O
N
01
O
O N
O O
N N
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N ~O
~' ~ --~ QO ~O 'O ~ N ~ N
~ ,-~
l~ ~ o0 ~1 O ~' VW 0o O ~_O
~ ~O 'x p ~
p O
I O O O M O l~ " \p
~D a V~ ~ x ~ "'
~
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o
a
N cn " ~ ~ "~ ~ ~ " oo 00
~ a ~
., gyp .- ,.-~ ~. ~,
, M
0000 ~ ' ~y .-~ N M
' ,-, O O
.-a
M M o0 ~ yp ~ ~ ~ ~:,~j~ M ~ O
~ ~:,~ ~
O O --~ ~ ~ O O O 01 O tn ~O O
O O ~O ~ ~---~ ~ O ~ O ,.~,
~ O O V~ O
O
~D
~
~ ~ ~ O p
O O a x x x O O ~i
O O ~
~ ,--i " r
r-1 "'
N ,~ ~ M ~' . .
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bA a; ' 'M-' ~ ~ N ~
by by ~ -' ~ y~,i.,,
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O O ~ O O O O O
M 00 O N *''+~ +~ ,-, M ,-~
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O ~ ~ O ~ ~ M .-i
V~
U a~ x a~ ~ H ~ 7 x L a
w ~ ~ H ~
C 7
N M d- n
O O O O~ O Q O O O O O
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N Ov ~ ~ N N N O N
N M M i
~ i ~O M ~
i i i ,
M ~ N
M
M N ~ M
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M _N oo d- N ~n (~ ~r7 r
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M ~ M 00 M l0 lp 00 N
~ d\
~7 ~ a a
d
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x x x x x x x
21
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
~O ~O lQ ~O 00
~ N
~O ~O ~ lp ~D p~ O
O x x N O ,~, x ~ O x
~ ~ a "C? '~ 't3
a
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"
a
~ ~ ~
crj N N N l N ~ N N ~' N M
~ d'
N
pp o0 0000 00 00 00 00 oow 0oso
~ o0
~ M M ~ M -~
M
O O O O O O p ~ ~
''~
Ot~ O O o Ono 0 o O o o o o
a x x x~ xx x x x x x x x
; . ~
~ ~ N
vD N o0 O
~ l~
00 01 M V~ Q\
~
M I~ N M ~
~O
~, ~ ~., ' S-, N . , ,~ ' ' ~i ~ ~,
N ~ cd ~., ~ ~' ~ v~
~ ~
H~ 0 0 0 ~ ~ ~" E .~ a v,
. 0 t7 -i,~ o
0 0 0 ~ .~ .~ ~ o H o .~
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o o o -~ o +-0
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00 0 00
0
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~ '-' N
N
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t'-, ~ t'-.v~ v~ i' v~bA ~ v~
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r~
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O O O O O O O O O O O O
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N ~
M V n .-mp ,-mp
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~
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M
DD ~O M M OO O O V7M
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N N ~ ~ N N
N M ~ vW p ~ 00 01 O ~ N M
00 00 0000 00 00 00 00 a101 a\O~
O ~ O~d- v1 I~ ~ N O l~ w 0
a1 d- ~nM vD t~ O ~n ~nN ooN
M d- O~~ N M 01 O -~d- N O
M ~ ~ ~ M M ~' 00O ~OM
o~ ~ ~ O ~D N N
O1
M ue" ~ O l~ O N o0 ~no0
N d ~ ~ i ~ ~ ~ N
C~Ca t
~ f~~ ~ Ga t~ Ga ~ f~1 ~ f~
W W W W W W W W W W W W
H H H H H H H H H H H H
x x x x x x x x x x x x
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
-~
r..,. ,--~,-i I~ Oy -' N M
\O ~ [w pp ~ . .--i O
,--,
o ~ ~ a ~ ~ ~ o;
o;
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x ~ ~ ~ ~ x a o 0
'-' ~'
N -~ N d- N ~ N
~ 01 d- N '~ N M .-
N a
0o M o0 00 00 M 00 . o0 0o M
l~ 00 d' 0o N
M V'1 M M M ~ ~ M p~ M M
O M O M ~(j
N M
~
o o o o o o o ~ o o ~ ~ o o No
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x x x x x ~Nx ~~x x x x x
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~ ~ ~ ~ a .
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N
f ~O
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~
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H
. 0 0 , 0 ~
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M ~' '~, .~ ,- N 0
."' ~~ 0
N
M h 00 ~ ~ o .~
N 0 Ov
N
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0o a1 O ~ N M d- ~n ~p ~ o0
O O O O O O O O O O O
a,
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N M N O M O
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W ~ N , M , ~-,~
i
O ~ ~ ~O ~,,~N ,-,
N -'
01 M \O
O O O O
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M O .-~ M \O 01 V7 O N O M
N d' 00 v~ W
p O ~D O~ I~ t~
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~O ~n O ~O ,~ d- O l~ N t~
Q\ O ~ l~ Q1 O~ I~ 00 Q1 O
rr ~ ~-, M \O r--~ N ~ M .~ M
'dw 0 N .-~ .~ N M ~n o0 N
N ~ d ~ ~ ~ ~ Pa U
0.1 (~ ~ U U U U U ' U U U
W W W W W W W W W W W
E-~ E-~ E- E-~ H E-~ H H H H E--
x x x x x x x x x x x
23
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
~o ~ ' W ~o ~t
-, ~ M o
~
, M
~O ~ ~ ~O o0 v~ ~ N
~ .-,
x x O x x O O ~ ~ l~ ~ ~O
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xx
a
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~=
N ~ d= N N N N N N N
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00 00 0o o0 00 00 00 00, N 0o
M 00N
vD vO ~ N ,-.
-~ -~
M M M M M M M M ~ O [w ~ M M p~
O O pp O O O O O ,-, ~ O pp
O ~O x p ,-~ O ~
~ ~ ~
O o o o O O O o O ,.~ a o ~ ~ 0
x x ~ x x x x x o 0
x x~
~ ~ ~ ~x
~ O '"''00 01 (W oo ~y= ,~ \O
r-i d: ~ N ~ -i v'i ~O 'i
'-'-' N ~ N - d= N
l~ M ~ -~ N
00
,_ ~ . V
..., d ~ M M
,
b4 N ~ ~
N ,~ ~
,~, ~...aC7~a ~~ HC7E-~ > .~,~ ~ cwa
~cr~C7 C7w ~
0 0 0 0 0 0 0 0 0 0 0 ~ o
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a ~a ~v~~ ~H c~~ H~
t!- W D l~ oo O~ O ,-1 0oN M
d' d' d- ~t d' d- ~n ~ i
n ~ n in
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~ ~ ~ ~ O ~ ~
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d- l~ M N d" M N M N 01 M
1 1 7 i ~' 1 1 ~ 1
O> ~ d- 1 ~ 1 1 ~ ~ 1
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N ~ ~ -~ ~ N N ,-, N
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O~ 01 01 01 Q1 01 01 Q1 01D1 a1
0 ~ I~ O Q1 00~ 00
N ~ N t oo v
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N ~ ue ue
d d ~ O d ~ O O
M l~ - l0 - -
01
M ~ M N 00l~ .--i
O>
N
Q
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W
W W W W W W , W W
W
x
x x x x x x x x x
104
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
r;
" ~ ~ 00
a< ~' ov ~, ~: ,-.
00
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O M O O Q1
U~ V~ C/~
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l~ ' 01 O
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M ~ M M M M M ~ M M l~ M d'
a ~o a a ~ a
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a;
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-i 00 ~ d1 ~ ~--i ~ M N
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P p C
... ., , C7 7
d- V~ ~OI~ 0001O .~N M d-V~ ~O I~ o0
V7 ~ ~ N N ~
01 a1D\ O~Q1D1Q1a1O> Q\O~ O~ a\ a\
O M I~~-'M ppdd''N 00N 110 N
N ~f' M p N d-~ N N O ~ ~O N
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M .-WO d'00\ptnM 01 M 01 V'7 M N
l0 M ~ l~ V1N '~01M
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OW o 0ot~ t~~ M oo,--.,--~o ~ ~ N
O
00 ~ ~ ~ ~ ~ ~ ~ ~ ~ a1 ~ D\
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Ov M ooN N N O a1d-d- N ,-, O O N
w W U U U U U f~paW PaGa 0. ~I
x x x x ~ ~ x x ~ ~ x x x
105
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[036] The first column in Table 1A provides a unique "Clone ID NO:Z" for a
cDNA
clone related to each contig sequence disclosed in Table 1A. This clone ID
references
the cDNA clone which contains at least the 5' most sequence of the assembled
contig,
and at least a portion of SEQ ID NO:X was determined by directly sequencing
the
referenced clone. The reference clone may have more sequence than described in
the
sequence listing or the clone may have less. In the vast majority of cases,
however,
the clone is believed to encode a full-length polypeptide. In the case where a
clone is
not full-length, a full-length cDNA can be obtained by methods known in the
art
and/or as described elsewhere herein.
[037] The second column in Table 1A provides a unique "Contig ID"
identification for
each contig sequence. The third column provides the "SEQ ID NO:X" identifier
for
each of the testes associated contig polynucleotide sequences disclosed in
Table 1A.
The fourth column, "ORF (From-To)", provides the location (i.e., nucleotide
position
numbers) within the polynucleotide sequence "SEQ ID NO:X" that delineate the
preferred open reading frame (ORF) shown in the sequence listing and
referenced in
Table 1A, column 5, as SEQ ID NO:Y. Where the nucleotide position number "To"
is
lower than the nucleotide position number "From", the preferred ORF is the
reverse
complement of the referenced polynucleotide sequence.
[038] The fifth column in Table 1A provides the corresponding SEQ ID NO:Y for
the
polypeptide sequence encoded by the preferred ORF delineated in column 4. In
one
embodiment, the invention provides an amino acid sequence comprising, or
alternatively consisting of, a polypeptide encoded by the portion of SEQ ID
NO:X
delineated by "ORF (From-To)". Also provided are polynucleotides encoding such
amino acid sequences and the complementary strand thereto.
[039] Column 6 in Table 1A lists residues comprising epitopes contained in the
polypeptides encoded by the preferred ORF (SEQ ID NO:Y), as predicted using
the
algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186. The
Jameson-Wolf antigenic analysis was performed using the computer program
PROTEAN (Version 3.11 for the Power Macintosh, DNASTAR, Inc., 1228 South
Park Street Madison, WI). In specific embodiments, polypeptides of the
invention
comprise, or alternatively consist of, at least one, two, three, four, five or
more of the
predicted epitopes as described in Table 1A. It will be appreciated that
depending on
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the analytical criteria used to predict antigenic determinants, the exact
address of the
determinant may vary slightly.
[040] Column 7 in Table IA provides an expression profile and library code:
count for
each of the contig sequences (SEQ ID NO:X) disclosed in Table 1A,' which can
routinely be combined with the information provided in Table 4 and used to
determine
the normal or diseased tissues, cells, and/or cell line libraries which
predominantly
express the polynucleotides of the invention. The first number in column 7
(preceding
the colon), represents the tissue/cell source identifier code corresponding to
the code
and description provided in Table 4. For those identifier codes in which the
first two
letters are not "AR", the second number in column 7 (following the colon)
represents
the number of times a sequence corresponding to the reference polynucleotide
sequence was identified in the tissue/cell source. Those tissue/cell source
identifier
codes in which the first two letters are "AR" designate information generated
using
DNA array technology. Utilizing this technology, cDNAs were amplified by PCR
and
then transferred, in duplicate, onto the array. Gene expression was assayed
through
hybridization of first strand cDNA probes to the DNA array. cDNA probes were
generated from total RNA extracted from a variety of different tissues and
cell lines.
Probe synthesis was performed in the presence of 33P dCTP, using oligo(dT) to
prime
reverse transcription. After hybridization, high stringency washing conditions
were
employed to remove non-specific hybrids from the array. The remaining signal,
emanating from each gene target, was measured using a Phosphorimager. Gene
expression was reported as Phosphor Stimulating Luminescence (PSL) which
reflects
the level of phosphor signal generated from the probe hybridized to each of
the gene
targets represented on the array. A local background signal subtraction was
performed
before the total signal generated from each array was used to normalize gene
expression between the different hybridizations. The value presented after
"[array
code]:" represents the mean of the duplicate values, following background
subtraction
and probe normalization. One of skill in the art could routinely use this
information to
identify normal and/or diseased tissues) which show a predominant expression
pattern
of the corresponding polynucleotide of the invention or to identify
polynucleotides
which show predominant and/or specific tissue and/or cell expression. The
sequences
disclosed herein have been determined to be predominantly expressed in
testicular
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tissues, including normal and diseased testicular tissues (See Table 1A,
column 7 and
Table 4).
[041] Column 8 in Table 1A provides a chromosomal map location for certain
polynucleotides of the invention. Chromosomal location was determined by
fording
exact matches to EST and cDNA sequences contained in the NCBI (National Center
for Biotechnology Information) UniGene database. Each sequence in the UniGene
database is assigned to a "cluster"; all of the ESTs, cDNAs, and STSs in a
cluster are
believed to be derived from a single gene. Chromosomal mapping data is often
available for one or more sequences) in a UniGene cluster; this data (if
consistent) is
then applied to the cluster as a whole. Thus, it is possible to infer the
chromosomal
location of a new polynucleotide sequence by determining its identity with a
mapped
UniGene cluster.
[042] A modified version of the computer program BLASTN (Altshul et al., J.
Mol.
Biol. 215:403-410 (1990), and Gish et al., Nat. Genet. 3:266-272 (1993)) was
used to
search the UniGene database for EST or cDNA sequences that contain exact or
near-
exact matches to a polynucleotide sequence of the invention (the 'Query'). A
sequence
from the UniGene database (the 'Subject') was said to be an exact match if it
contained a segment of 50 nucleotides in length such that 48 of those
nucleotides were
in the same order as found in the Query sequence. If all of the matches that
met this
criteria were in the same UniGene cluster, and mapping data was available for
this
cluster, it is indicated in Table 1A under the heading "Cytologic Band". Where
a
cluster had been further localized to a distinct cytologic band, that band is
disclosed;
where no banding information was available, but the gene had been localized to
a
single chromosome, the chromosome is disclosed.
[043] Once a presumptive chromosomal location was determined for a
polynucleotide of
the invention, an associated disease locus was identified by comparison with a
database of diseases which have been experimentally associated with genetic
loci. The
database used was the Morbid Map, derived from OMIMTM (supra). If the putative
chromosomal location of a polynucleotide of the invention (Query sequence) was
associated with a disease in the Morbid Map database, an OMIM reference
identification number was noted in column 9, Table 1A, labeled "OMIM Disease
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References)". Table 5 is a key to the OMIM reference identification numbers
(column
1), and provides a description of the associated disease in Column 2.
TABLE 1B
Clone ID SEQ CONTIG BAC ID: SEQ ID EXON
ID A ~
NO:Z NO:X ID: NO:B From-To
HCDMBO1 13 915613 AC012484 1979 1-355
HCDMCO1 16 915239 AC005789 1980 1-48
1051-2390
2839-3458
HCDMCO1 16 915239 AC005789 1981 1-1721
2187-3101
3194-3363
4200-4903
53 I O-5493
6194-6294
7366-7482
7598-7676
8092-8778
8869-9496
HCDMD23 17 676799 AC018743 1982 1-801
HCDMD23 17 676799 AC018630 1983 1-413
HCDMD23 17 676799 AC018743 1984 1-138
HCDMD23 17 676799 AC018630 1985 1-177
HEEAD64 18 741305 AC011457 1986 I-795
2400-2512
HEEAD64 18 741305 AC006116 1987 1-795
2400-2512
HEEAD64 18 741305 AC011457 1988 1-391
HEEAD64 18 741305 AC006116 1989 1-391
HEEAH07 19 851219 AC019039 1990 1-112
HEEAK84 23 780838 AC004549 1991 1-570
HEEAK84 23 780838 AC004549 1992 I-873
HEEAN24 24 676721 AC073835 1993 1-519
HEEAN24 24 676721 AC012366 1994 1-656
HEEAN24 24 676721 AC012366 1995 1-633
782-1160
HEEAN24 24 676721 AC073835 1996 1-379
HEEAS58 25 735620 AC022730 1997 1-562
HEEAU79 26 706935 AC069419 1998 1-744
HEEAU79 26 706935 AC011311 1999 1-744
HEEAU79 26 706935 AC011311 2000 1-316
HEEAU79 26 706935 AC011311 2001 1-500
3112-3179
3264-3366
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4303-4458
5803-5999
6173-6605
7699-7818
8085-8264
12380-13064
13449-14180
14198-14750
15016-15543
15578-15659
16183-16694
17010-19286
HEEAWOl 27 851213 AC003117 2002 1-384
HEEAWOl 27 851213 AC003117 2003 I-289
HEEAW13 28 656299 AC005344 2004 1-1022
HEEAW13 28 656299 AC005344 2005 1-612
HEEAW13 28 656299 AC005344 2006 1-569
HEGAA24 29 676716 AC015818 2007 1-416
HEGAA24 29 676'716 AC022319 2008 1-416
HEGAA24 29 676716 AC022596 2009 1-429
HEGAA24 29 676716 AC005324 2010 1-419
HEGAA24 29 676716 AL353996 2011 1-429
HEGAA24 29 676716 AC015818 2012 1-435
HEGAA24 29 676716 AC022596 2013 1-435
HEGAA24 29 676716 AC022319 2014 1-435
HEGAA24 29 676716 AC005324 2015 1-435
HEGAA24 29 676716 AL353996 2016 1-434
HEGAB84 31 823900 AC007040 2017 I-750
1028-1687
2050-2327
3305-3352
HEGAB84 31 823900 AC007040 2018 1-513
HEGAB84 31 823900 AC007040 2019 1-745
1107-1335
HEGAK04 33 887299 AP001319 2020 1-790
HEGAK04 33 887299 AP000485 2021 1-789
HEGAK04 33 887299 AP001319 2022 1-471
761-1159
2076-2471
3129-4172
5710-6153
HEGAK04 33 887299 AP000485 2023 1-471
HEGAK04 33 887299 APOOI319 2024 I-106
HEGAK04 33 887299 AP000485 2025 1-106
HEGA083 34 780837 AC024009 2026 1-880
I 967-2289
2746-2890
I10
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3236-3284
HEGA083 34 780837 AC040991 2027 _
1-88p'
1967-2288
2745-2889
3235-3283
HEGA083 34 780837 AC040991 2028 1-176
HEGAP31 3S 697419 U73167 2029 1-462
537-572
I I42-1632
. 1720-2993
3778-4687
5675-5764
58
7
5-6565
HEGAP31 35 697419 U90094 2030 _
_
1-462
537-572
1142-1632
1720-2993
3778-4687
5675-5764
5875-6565
HEGAP31 35 697419 U73167 2031 1-47
235
-1
145
HEGAP31 35 697419 U73167 2032 _
_
1-463
947-1439
1459-1899
1984-2068
2160-2287
2366-3007
3094-3248
3517-3657
3744-3873
3944-4147
4183-4867
HEGAP31 35 697419 U90094 2033 1-463
947-1439
1459-1899
1984-2068
2160-2287
2366-3007
3094-3248
3517-3657
3744-3873
3944-4147
4183-4867
HEGAP31 35 697419 U90094 2034 1-47
235-1145
HEGAP36 36 706951 AL160314 2035 1-558
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HEGAP36 36 706951 AC023226 2036 1-558
HEGAP36 36 706951 AL160314 2037 1-316
HEGAP36 36 706951 AC023226 2038 1-I94
HEGAY32 37 699906 AP000759 2039 1-156
199-2013
HEGAY52 38 726316 AC004863 2040 1-272
2151-2257
4711-4808
5669-5932
HEGAY52 38 726316 AC004863 2041 1-517
HEGAY52 38 726316 AC004863 2042 1-307
HEPAA44 40 509456 AP002440 2043 1-554
HEPAD40 43 509002 AC022486 2044 1-S99
HEPAD40 43 509002 AC007379 2045 1-599
HEPAD40 43 509002 AC068541 2046 1-599
HEPAD82 44 509452 AC012054 2047 1-I99
HEPAD82 44 509452 AC012054 2048 1-367
HEPAK41 47 925146 AL355987 2049 1-1171
2141-2215
2661-2998
3515-3894
HEPAK41 47 925146 AL355987 2050 1-412
HEPAM29 48 508706 AC068515 2051 1-403
HEPAM29 48 508706 AC012256 2052 1-629
HEPAN19 49 508694 AC018422 2053 1-656
HEPAN19 49 508694 AC018422 2054 1-488
HEPAP02 50 926914 AC005041 2055 1-68
87-493
711-838
997-1167
2227-2960
3326-4641
4768-5786
HEPAP02 50 926914 AC005041 2056 1-2920
3439-3667
3839-4332
HEPAP02 50 926914 AC005041 2057 1-143
HEPAP12 51 968771 AC022123 2058 I-704
HEPAS44 52 884083 AC005042 2059 1-526
2088-2310
2826-3158
3165-3449
3645-4062
5680-6042
9261-9489
9723-10014
10575-10710
112
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12839-14011
17421-17570
17625-17808
19953-20102
20972-21402
21801-22496
23146-23452
25891-26147
27915-28163
36900-37086
40102-40222
40334-40438
41262-41858
42042-42215
44623-45334
45461-45648
47989-48685
52151-52529
52651-52771
55505-56703
57348-57424
5 8261-5
8444
58449-58644
58759-59136
59195-60637
HEPAS44 52 884083 AC005042 2060 1-505
HEPBB24 54 508684 AC010862 2061 1-649
HEPBB24 54 508684 AC010862 2062 1-345
HEPBB60 55 855597 AC021139 2063 1-570
HEPBB60 55 855597 AC021139 2064 1-373
HEPBG26 56 967921 AL117692 2065 1-362
HEPBG26 56 967921 AL117692 2066 1-680
HEPBG35 57 508686 AL390242 2067 1-235
HEPBG35 57 508686 AC073965 2068 1-758
HEPBG35 57 508686 AL357055 2069 1-522
HEPBG35 57 508686 AC006286 2070 1-759
HEPBG35 57 508686 AL357055 2071 1-307
HEPBG35 57 508686 AC073965 2072 1-308
HEPBG35 57 508686 AC006286 2073 1-307
HEPBH38 59 70.7524 AC021881 2074 1-353
HEPB069 61 888697 AC004464 2075 1-565
HEPB 47 62 713836 AC015624 2076 1-243
HEPBQ47 62 713836 AC011743 2077 1-94
853-988
2270-2334
3850-4276
4554-4835
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5824-5974
7894-8034
9229-9353
10526-10939
11126-11250
12266-13223
HEPBQ47 62 713836 AC009948 2078 1-125
1141-2098
HEPB 47 62 713836 AC011743 2079 1-238
HEPB 47 62 713836 AC009948 2080 1-414
HEPB 47 62 713836 AC011743 2081 1-914
HEPB 47 62 713836 AC009948 2082 1-914
HEPB 69 63 888693 AC011799 2083 1-573
HEPB 69 63 888693 AC011799 2084 1-413
HEPCE25 66 529343 AL121747 2085 1-823
HEPCE25 66 529343 AL034548 2086 1-823
HEPCE25 66 529343 AL121747 2087 1-277
HEPCE25 66 529343 AL034548 2088 1-277
HEPCE25 66 529343 AL121747 2089 1-2350
HEPCE25 66 ' 529343 AL034548 2090 1-2350
HEPC059 67 761094 AC025879 2091 1-1719
HEPC059 67 761094 AC025879 2092 1-457
HEPCT32 68 947081 AC010458 2093 1-95
HTEAD95 73 961232 AC006445 2094 1-1321
HTEAF26 75 537271 AC022988 2095 1-319
HTEAG50 76 787500 AC026462 2096 1-310
HTEAG50 76 787500 AC026462 2097 1-250
HTEAR84 80 783328 AL133353 2098 1-222
225-361
2796-2928
4044-4119
5719-5962
7512-7571
10952-11165
11840-11870
15055-15191
17157-17497
18170-18193
19594-20180
20819-21289
21499-22434
22520-23934
HTEAR84 80 783328 AL133353 2099 1-200
456-609
5860-5998
6526-6629
8425-8724
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9151-9625
12117-12252
15026-15571
15654-16121
16221-16852
19264-19592
21596-21794
22707-22795
23248-23407
23487-23890
25183-26429
26561-27890
28380-28908
28953-29430
29490-32385
32577-35455
36789-37427
37736-38206
38250-38308
38867-39048
39075-39236
39491-39811
39971-40302
40401-40871
41105-41186
41719-41801
43440-43567
43732-44141
44689-44855
46395-46619
47357-47643
47700-47887
48174-48294
48469-48728
50284-50469
52382-52845
HTEAR84 80 783328 AL133353 2100 1-445
HTEAV43 81 927010 AL365184 2101 1-577
HTEAZ54 83 793441 AC024644 2102 I-52I
HTEAZ54 83 793441 AC008555 2103 1-797
1423-1942
2185-2716
2806-4251
HTEAZ54 83 793441 AC024644 2104 1-97
HTEBD35 84 967959 AC072024 2105 1-317
HTEBD35 84 967959 AL353796 2106 1-317
HTEBD35 84 967959 AL360172 2107 1-317
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HTEBJ78 86 . 779265 AP001177 2108 1-1021
3487-4086
4668-5157
5193-5665
5913-7625
HTEBJ78 86 779265 AC016186 2109 I-1
021
_
HTEBJ78 86 779265 AC016127 2110 _
1-1021
2300-2622
348
8-4067
HTEBJ78 86 779265 AP001164 2111 _
1-1021
2463-2587
3494-4093
4675-5164
5200-5672
5920-7633
HTEBJ78 86 779265 AC023989 2112 1-1021
2300-2622
3488-4067
HTEBJ78 86 779265 APOOII64 2113 1-340
HTEBJ78 86 779265 AC023989 2114 1-340
HTEBJ78 86 779265 AC016186 2115 1-340
HTEBJ78 86 779265 AC016127 2116 1-340
HTEBJ78 86 779265 AC023989 2117 1-490
HTEBX62 90 508150 AC068620 2118 1-584
HTEBX62 90 508150 AC068620 2119 1-2496
2639-3538
HTEBY15 92 526281 AL117259 2120 1-260
HTEBY41 94 711523 AL357093 2121 1-229
HTEBY41 94 711523 AL157736 2122 1-229
HTEBY41 94 711523 AL357093 2123 1-142
HTEBY41 94 711523 AL357093 2124 1-455
HTEBY41 94 711523 AL157736 2125 1-142
HTEBY41 94 711523 AL157736 2126 1-455
HTEBY61 95 967340 AC020663 2127 1-150
1916-2097
3254-3396
4731-5065
5605-5801
5830-6113
6544-6716
7594-8121
8494-8612
8752-9291
9401-9505
10308-10582
11826-11970
12379-12478
I16
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12796-13085
13942-14925
HTEBY6I 95 967340 AC020663 2128 1-265
HTEBZ21 96 958381 AL390764 2129 1-101
236-1007
1038-1344
1353-1493
1641-1750
1837-2006
2542-2700
3557-3720
4326-9299
9617-10008
10623-11068
11238-11714
11800-11992
12001-12566
13314-15677
15882-16457
16614-17442
17850-18427
19713-19802
HTEBZ21 96 958381 AL135843 2130 1-32
1420-1543
2122-2266
2730-3022
3914-4068
4197-4968
4999-5305
5314-5454
5602-5711
5798-5967
6503-6661
7518-7681
8287-13260
13578-13969
14584-15029
15199-15675
15761-15953
15962-16527
17275-19638
19843-20418
20575-21403
HTEBZ21 96 958381 ALI36105 2131 1-576
HTEBZ21 96 958381 AL359921 2132 1-703
1021-1412
2027-2470
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2640-3116
3202-3394
3403-3968
4716-7079
7284-7859
8016-8844
9252-9829
11115-11204
HTEBZ21 96 958381 AL136105 2133 1-32
1420-1543
2122-2266
2730-3022
3914-4068
4197-4968
4999-5305
. 5314-5454
5602-5711
' 5798-5967
6503-6661
7518-7681
8287-13260
13578-13969
14584-15029
15199-15675
15761-15953
15962-16527
17275-19638
19843-20418
20575-21403
21811-22388
23674-23763
HTEBZ21 96 958381 AL136105 2134 1-311
HTEBZ21 96 958381 AL390764 2135 1-287
HTEBZ21 96 958381 AL135843 2136 1-302
HTEBZ21 96 958381 AL136105 2137 1-1122
HTEBZ21 96 958381 AL359921 2138 1-347
661-1203
1533-2057
2287-2445
3335-3716
5741-6053
HTEBZ21 96 958381 AL136105 2139 1-347
661-1203
1533-2057
2287-2445
3335-3716
5729-6044
118
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEBZ21 96 958381 AL136105 2140 1-302
HTECA16 98 764416 AC011726 2141 1-470
HTECA16 98 764416 AC022911 2142 1-470
HTECA16 98 764416 AC011726 2143 I-500
HTECA16 98 764416 AC022911 2144 1-500
HTECA51 101 708860 AL035450 2145 I-93
1880-3178
HTECA51 101 708860 AL035450 2146 1-105
HTECC13 104 971673 AC018638 2147 1-252
3348-3556
3720-3822
3 877-4004
4927-5181
5226-5736
HTECC13 104 971673 AC018638 2148 1-130
HTECC37 106 508143 AC073270 2149 1-416
HTECC37 106 508143 AC022202 2150 1-416
HTECC80 109 796820 AC016767 2151 1-35
784-988
1186-1254
1854-2737
HTECC80 109 796820 AL353608 2152 1-140
1348-1579
1810-2502
2585-2694
2831-3054
3202-3273
3513-3903
4019-4053
4802-5008
5205-5273
5873-6756
HTECC80 109 796820 AL078621 2153 1-35
784-988
1187-1255
1855-2739
HTECC80 109 796820 AC016767 2154 1-103
HTECC96 111 959874 AC025977 2155 1-1286
HTECC96 111 959874 AC040170 2156 1-1286
HTECC96 111 959874 AC013513 2157 1-1286
HTECD17 112 508108 AC013812 2158 1-700
HTECD17 112 508108 AL136360 2159 1-707
HTECD17 I12 508108 AL132868 2160 I-712
HTECD17 112 508108 AL136360 2161 1-263
HTECD17 112 508108 AL132868 2162 1-1166
HTECD36 114 518124 AL132780 2163 1-562
736-1855
119
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
1931-2051
2232-2897
3495-3673
3759-3882
3968-4030
4121-4203
4369-4532
5620-6405
7007-7151
7615-7702
7882-8106
8655-8942
HTECD36 114 518124 AL132780 2164 1-1058
1452-2073
HTECE44 118 764830 AC026957 2165 I-198
2840-3137
3146-3
524
3811-4890
6360-6479
7798-8125
13068-13250
14052-14
2
52
HTECE44 118 764830 AC026957 2166 _
_
1-626
1734-2270
HTECE44 I18 764830 AC026957 2167 1-51
4
HTECE91 121 522984 AC021586 2168 _
1-1460
4600-4966
5827-6179
6596-7246
8893-9973
9991-10696
10851-11246
11352-11783
11934-12787
12926-13555
HTECE91 121 522984 AC021586 2169 1-310
HTECE91 121 522984 AC021586 2170 1-227
HTEDF13 122 522964 AL133499 2171 I-370
HTEDF13 122 522964 AP001579 2172 1-370
HTEDF13 122 522964 AL133499 2173 I-373
HTEDF13 122 522964 AP001579 2174 1-373
HTEDF76 125 522973 AC073612 2175 1-445
HTEDF76 125 522973 AC011601 2176 1-445
HTEDF76 125 522973 AC073612 2177 1-1099
HTEDF76 125 522973 AC011601 2178 1-1099
HTEDG16 126 925527 AC008547 2179 1-196
5138-6241
120
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEDG16 126 925527 AC008547 2180 1 -615
HTEDI82 133 536477 AL359455 2181 1-396
561-837
2703-2900
3015-3099
HTEDI82 133 536477 AL359455 2182 1-99
404-514
597-985
HTEDJ04 134 519940 AL359767 2183 1-363
411-960
HTEDJ04 134 519940 AL139377 2184 1-363
411-960
HTEDJ04 134 519940 AL359767 2185 1-1831
HTEDJ04 134 519940 AL359767 2186 1-430
HTEDJ04 134 519940 AL139377 2187 1-27
318-1304
2398-3171
3518-4027
4716-4919
6801-6956
9618-9892
9938-10400
10485-11629
14162-18670
18980-19880
20136-20686
21997-22089
23839-23999
24083-24175
25513-26022
27060-27487
27557-28168
28906-29445
31090-31363
31403-31488
31669-33499
HTEDJ04 134 519940 AL139377 2188 1-430
HTEDM08 135 960303 AF215848 2189 1-170
294-4.04
HTEDM08 135 960303 AC009314 2190 1-171
295-405
HTEDM08 135 960303 AF215848 2191 1-317
HTEDM08 135 960303 AC009314 2192 1-319
HTED031 136 870711 AC066613 2193 1-279
HTED031 136 870711 AC021238 2194 1-279
HTEDO51 137 530592 AL390816 2195 1-67
~ ~ ~ ~
5510-5778
121
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEDP15 138 870675 AC008119 2196 1-129
1226-2057
3894-4078
4353-5054
5261-6347
6614-7200
9168-9576
10127-10285
11014-11729
11817-12350
12430-12511
12645-12705
13644-13859
15181-15386
16010-16997
17664-18577
18904-19074
20351-20663
20725-20760
22661-23119
23379-23760
24351-24525
24708-25559
25582-29154
29209-29484
29561-30822
31196-31337
31407-31850
31943-32302
33856-33927
HTEDP15 138 870675 AC008119 2197 1-254
HTEDP31 139 870548 AC004674 2298 1-660
HTEDP31 139 870548 AC004674 2199 1-139
HTED 30 142 530589 AC011182 2200 1-683
.
HTED 30 142 530589 AC011181 2201 1-443
HTED 30 142 530589 AC011181 2202 1-275
HTED 83 244 530586 AC018935 2203 I-49I
HTEDR71 145 761585 AJ239328 2204 1-367
,
884-2043
2287-2859
4457-4512
4780-6360
9237-9407
20873-11661
HTEDR71 145 761585 AP000219 2205 1-367
884-2043
2287-2859
122
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
4457-4512
4780-6360
9237-9407
10903-11691
HTEDR71 145 761585 AP000341 2206 1-367
884-2043
2287-2859
4457-4512
4780-6360
923 7-9407
10903-11691
HTEDR71 145 761585 AJ239328 2207 1-241
HTEDR71 145 761585 AP000219 2208 1-241
HTEDR71 145 761585 AP000341 2209 1-241
HTEDU48 148 932315 AC026083 2210 1-1222
HTEDU48 148 932315 AC026083 2211 1-4I6
HTEDU48 148 932315 AC026083 2212 1-442
HTEEE65 158 530157 AC011830 2213 1-164
2053-2094
2375-2846
HTEEE65 158 530157 AC018502 2214 1-164
~
2053-2094
2375-2846
HTEEE65 158 530157 AC018499 2215 1-164
2053-2094
2375-2846
HTEEE65 158 530157 AC018502 2216 1-2058
'
HTEEU23 161 524059 AL355801 2217 1-359
3545-3632
6187-6329
7609-7687
HTEEU23 I61 524059 AL355801 2218 1-939
1454-1932
2912-3240
3284-3953
HTEEW73 166 917206 AL355377 2219 1-83
578-621
1159-1219
2182-2285
2508-2616
6024-6598
HTEFJ53 168 935982 AC019031 2220 1-710
HTEFJ53 168 935982 AC019031 2221 I-405
HTEF032 171 529272 AL133264 2222 1-190
1330-1629
2351-5250
5255-5600
123
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
5635-9271
9938-10152
10897-11597
11951-12840
13095-13296
13340-13626
13704-14430
I4S36-14639
15282-15909
16437-16561
18269-18449
20662-21446
21484-22073
HTEF076 172 770270 AC055733 2223 1-160
888-1009
1771-2022
HTEF076 172 770270 AC025148 2224 1-322
946-1105
1827-1948
2710-2961
HTEF076 172 770270 AC025148 2225 1-924
1228-1751
1793-2057
2224-2959
3239-3297
4754-4965
5736-6035
8675-9217
10252-11580
11720-11844
12753-13021
HTEFS60 176 836010 284469 2226 1-640
HTEFW55 178 787550 AL138975 2227 1-703
HTEFWSS 178 787550 AC011190 2228 1-703
HTEFW55 178 787550 AL162171 2229 1-118
600-642
4987-5103
8034-8072
8978-9174
9525-9958
10048-10357
10648-11468
11642-12760
12786-12888
13913-14249
14931-15063
15738-16168
124
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
16205-16345
17103-17538
20097-20865
21389-21912
24378-24502
24644-25083
27767-28008
28873-29360
31358-32060
36985-37295
38992-39029
39774-40017
44189-44310
44400-44530
46199-46350
46476-46750
47107-47593
47781-48000
48185-48492
48689-50784
HTEFW55 178 787550 AL162171 2230 1-1502
HTEFW55 178 787550 AL162171 2231 1-294
309-744
HTEFX53 181 842047 AC019054 2232 1-1177
HTEFX53 181 842047 AC019054 2233 1-272
HTEGA13 182 656077 AC016366 2234 1-124
250-1075
1645-1784
3488-3903
4325-4378
5000-5066
5729-5862
HTEGA13 182 656077 AC005237 2235 1-129
864-968
2110-2704
2874-3374
3897-4026
4152-4977
5547-5686
7392-7807
8227-8285
8903-8970
9633-9766
10230-10642
10754-10917
13200-13823
15685-15784
125
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
I 6202-16302
16342-16496
16754-16865
17467-17820
20203-20289
25130-25260
26385-26486
28046-28566
28884-28989
30114-30820
33068-33452
HTEGA13 182 656077 AC005237 2236 1-592
HTEGF95 I89 796660 AC023097 2237 1-1019
1110-1237
1879-2520
2630-2722
2971-3623
3632-3799
4789-5451
5681-5917
6015-6176
7511-7632
7814-8250
9336-9535
9998-11067
12025-12474
14608-14706
15489-15605
16481-16607
HTEGF95 189 796660 AC023097 2238 1-600
HTEGF95 189 796660 AC023097 2239 1-388
HTEGG07 190 954115 AC011842 2240 1-486
HTEGG07 190 954115 AC011842 2241 1-606
HTEGG61 191 528007 AC009220 2242 1-627
HTEGG61 191 528007 AC009220 2243 1-303
HTEGG61 191 528007 AC009220 2244 1-123
HTEGK51 I92 520046 AC008555 2245 1-797
1423-1942
2185-2716
2806-4251
HTEGU13 204 520041 AC036208 2246 1-388
3367-3638
4217-4390
4594-4868
6530-6680
7892-7971
9392-9567
126
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
10136-10429
HTEGU13 204 520041 AC036208 2247 1-156
HTEGU62 206 573885 AC036238 2248 1-402
HTEGU62 206 573885 AC036238 2249 1-256
HTEGU62 206 573885 AC036238 2250 1-150
HTEGU93 207 764831 AC026957 2251 I-198
2840-3137
3146-3524
3811-4890
6360-6479
7798-8125
13068-13250
14052-14252
HTEGU93 207 764831 AC026957 2252 1-626
1734-2270
HTEGU93 207 764831 AC026957 2253 I-514
HTEGV60 209 822954 AC013414 2254 1-138
550-714
2702-3122
3973-4262
4649-4745
5363-7228
HTEGV60 209 822954 AC016171 2255 1-127
1017-1306
1693-1789
2407-5049
HTEGV60 209 822954 AC016171 2256 1-4710
HTEGV84 210 870240 AC027120 2257 1-1730
HTEGV84 210 870240 AC023877 2258 1-1730
HTEGV84 210 870240 AC027120 2259 1-85
HTEGV84 210 870240 AC023877 2260 1-85
HTEGW41 211 573880 AL135939 2261 1-541
HTEGW94 212 794350 AC022672 2262 1-1334
1951-2103
HTEGW94 212 794350 AC022672 2263 I-5446
HTEGX74 213 783829 AC027396 2264 1-95
227-318
546-654
669-792
1355-1766
HTEGX74 213 783829 AC027396 2265 1-1730
HTEGY01 214 917214 AC009061 2266 I-123
4295-4489
5148-5404
5536-5632
HTEGY01 214 917214 AC009061 2267 1-101
HTEHB07 216 870707 AC020575 2268 1-625
127
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
1178-1625
HTEHB07 216 870707 AC027000 2269 1-625
1177-1624
HTEHC60 219 965998 AC007343 2270 1-695
HTEHC60 219 965998 AC018553 2271 1-695
HTEHC60 219 965998 AC007343 2272 1-494
HTEHC60 219 965998 AC018553 2273 1-494
HTEHE60 221 795264 AC007114 2274 1-738
HTEHE60 221 795264 AC007114 2275 1-359
HTEHE78 223 932312 AC022621 2276 1-419
HTEHE78 223 932312 AC022621 2277 1-634
HTEHE78 223 932312 AC022621 2278 1-398
HTEHF66 226 836999 AL109657 2279 ~ 67
6I 1-694
1472-1552
7387-7447
7998-8086
10739-10859
HTEHI93 232 870629 AL121926 2280 1-402
HTEHX32 253 772643 AL049742 2281 1-694
HTEIA80 257 721831 AC021473 2282 1-258
HTEIA80 257 721831 AC016310 2283 1-257
HTEIA80 257 721831 AC021473 2284 1-114
HTEIA80 257 721831 AC016310 2285 1-114
_
HTEIF40 258 958355 AL157687 2286 1-40
249-903
1489-1913
2058-2116
2558-2733
2737-2876
3462-3623
5522-5820
5917-6004
HTEIF40 258 958355 AL161668 2287 1-40
249-903
1489-1913
2058-2116
2558-2892
3479-3633
5532-5830
5927-6014
HTEIF40 258 958355 AL157687 2288 1-307
HTEIF40 258 958355 AL161668 2289 1-307
HTEIF68 259 573828 AP001887 2290 1-311
HTEIF68 259 573828 AP002008 2291 1-311
HTEIF68 259 573828 AP001887 2292 1-107
~i HTEIF68259 573828 AP002008 2293 1-357
128
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEIF68 259 573828 AP001887 2294 1-357'
HTEIF68 259 573828 AP002008 2295 1-107''
HTEIH70 261 573826 AC020908 2296 1-85 ~'
759-1469
2611-2787
3133-3229
3908-3972
4076-4239
5908-6009
6780-6924
8969-9104
9180-9480
9730-10047
10173-10906
12607-13024
HTEIH70 261 573826 AC020908 2297 1-183
HTEIK90 267 789121 AL161442 2298 1-380
HTEIK90 267 789121 AL161442 2299 1-185
1241-1480
3780-4356
5514-5666
6203-6495
6752-7126
7461-7946
10053-10148
10892-10967
12645-13553
HTEIK90 267 789121 AL161442 2300 1-323
HTEIL48 269 523681 AC026861 2301 1-38
601-692
1658-1810
2194-2275
HTEI002 274 920622 AC010632 2302 1-38
1512-1878
2899-2944
3751-4080
HTEI002 274 920622 AC010632 2303 1-523
HTEI002 274 920622 AC010632 2304 1-394
HTEI028 276 573803 AC067839 2305 1-489
HTEI028 276 573803 AC007898 2306 1-489
HTEI028 276 573803 AL359508 2307 1-346
HTEIP88 277 941155 AC068659 2308 1-5I
583-821
4529-4916
5879-6079
6298-6442
7345-7447
129
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
7836-8136
8423-8833
12S2S-12677
13528-13727
14268-14602
14605-14655
15410-I
5666
17282-18408
HTEIP88 277 941155 AC0121$3 2309 1-Sl
S83-821
4528-491
S
5878-6078
6297-6441
7344-7446
7835-8135
8422-8832
12525-12677
13529-13728
14269-14603
14606-14656
1S4I0-15666
17282-18408
HTEIP88 _277 941155 AC0686S9 2310 1-482
HTEIP88 277 941155 AC012183 2311 1-482
HTEIP88 277 941155 AC0686S9 2312 1-1254
HTEIP88 277 9411SS AC012183 2313 1-1254
HTEIP92 278 523892 AC0132S2 2314 1-368
HTEIP92 278 523892 AC0132S2 2315 1-9S2
HTEIP92 278 523892 AC013252 2316 1-413
HTEI 74 279 765794 ACOS581S 2317 1-681
HTEI 74 279 765794 AC026801 2318 1-681
HTEI 74 279 765794 AC008690 2319 1-681
HTEI 74 279 765794 AC055815 2320 1-43S
HTEI 74 279 765794 AC026801 2321 1-435
HTEIQ74 279 765794 AC008690 2322 1-43S
HTEIR33 280 928058 AL139I30 2323 I-I64
346-423
S45-673
1188-1349
3339-3655
4129-4219
6133-6265
8323-8553
HTEIR33 280 928058 AL139130 2324 1-196
418-S29
69S-927
1596-1660
130
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
I75I-1803
2056-2085
2710-2770
3176-4018
5037-5258
HTEIU75 282 779163 AL390863 2325 1-51
469-1032
HTEIU75 282 779163 AL136370 2326 1-51
469-1032
HTEIV86 285 784657 AC021467 2327 1-44
1339-1
S03
21 SO-2290
3993-4708
HTEIV86 285 784657 AC009761 2328 I-112
759-899
2602-3318
HTEIX85 288 864251 AL161614 2329 1-2924
3023-4030
5001-S
171
7210-7434
7618-7734
9610-9764
10165-10247
11951-12426
12489-12966
12976-14097
14682-14894
15043-15480
15790-16240
18111-18240
19064-19538
21727-21871
22803-22927
HTEIYS2 289 963536 AC067940 2330 1-358
HTEIY52 289 963536 AC067940 2331 1-304
HTEIY69 290 577783 AC013615 2332 1-1089
HTEIY69 290 577783 AC019281 2333 ' 1-1089
HTEIY69 290 577783 AC013615 2334 I-386
HTEIY69 290 577783 AC019281 2335 1-386
HTEJB81 295 870644 AC005230 2336 1-267
506-723
867-1915
24366-24674
28859-29337
45854-46053
HTEJB81 295 870644 AC005230 2337 1-S05
HTEJC28 296 573774 AL358214 2338 1-298
131
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEJE15 298 908360 AC016632 2339 1-220
361-469
1509-2194
HTEJE15 298 908360 AC016639 2340 1-220
3 62-470
1510-2195
HTEJE15 298 908360 AC0089I4 2341 1-220
361-469
1512-2197
HTEJG24 301 526278 AL139237 2342 1-430
HTEJG24 301 526278 AC025004 2343 1-430
HTEJG24 301 526278 AC021S40 2344 1-430
HTEJJ43 302 774243 AC018519 2345 I-214
309-383
1911-2211
2693-2983
3679-4166
4899-4949
9474-9544
HTEJJ43 302 774243 AC018519 2346 1-611
HTEJM56 304 952255 AC025036 2347 1-148
HTEJM56 304 952255 AC027300 2348 1-158
HTEJM56 304 952255 AC016327 2349 1-165
HTEJM56 304 952255 AC016327 2350 1-195
HTEJN49 306 558383 AL354888 2351 1-250
HTEJN49 306 558383 AC067884 2352 1-250
HTEJN49 306 558383 AL033527 2353 1-250
HTEJN49 306 558383 AL354888 2354 1-391
HTEJN49 306 558383 AC067884 2355 1-391
HTEJN49 306 558383 AL033527 2356 1-392
~
HTEJT37 310 530596 AC011318 2357 1-170
4244-4812
HTEJT37 310 530596 AC027296 2358 1-404
HTEJT37 310 530596 AC012340 2359 1-404
HTEJX78 314 806395 AL136373 2360 1-131
694-1754
HTEJX78 314 806395 AL357392 2361 1-112
67
5-1735
HTEJX78 314 806395 AC013593 2362 _
1-131
694-1754
HTEJX78 314 806395 AL357392 2363 1-3661
5981-6371
6517-7301
8141-8268
9332-9897
11527-11603
11625-11713
132
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
13194-13546
14430-14533
16668-16939
HTEJX78 314 806395 AL136373 2364 1-217
HTEJX78 314 806395 AC013S93 2365 1-3662
5982-6372
6S 18-7302
8142-8269
9333-9446
9450-9898
11528-11604
11626-11714
13195-13547
14428-14534
16669-16940
18704-20067
20193-20457
20794-22689
HTEKC07 317 920925 AL3S9708 2366 1-546
HTEKC07 317 920925 AL139318 2367 1-546
HTEKD04 319 519938 AC026S2S 2368 1-1001
1500-1654
1958-2325
HTEKF35 325 573749 AC016878 2369 1-152
2683-2792
HTEKF35 325 573749 AC023911 2370 1-152
2683-2792
HTEKF3S 325 573749 AC011272 2371 1-152
2681-2790
HTEKF3S 325 573749 AC023911 2372 1-128
HTEKF3S 325 573749 ACOlI272 2373 1-128
HTEKF68 326 772997 AL3S7117 2374 1-634
HTEKF68 326 772997 AC023219 2375 1-634
HTEKI70 328 503039 AC009648 2376 1-230
1002-1211
1349-1470
2451-2575
2924-3218
3509-3805
HTEKI70 328 503039 AC009648 2377 1-103
188-274
326-447
2665-2749
3400-4013
HTEK049 331 723148 AC021S27 2378 1-159
330-389
747-1508
133
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
1628-1889
2484-3286
HTEK049 331 723148 AC006211 2379 1-159
330-389
747-1508
1628-1889
2484-3286
HTEK049 331 723148 AC021527 2380 1-233
HTEK049 331 723148 AC006211 2381 1-233
HTEK 26 332 870627 AC069404 2382 1-343
HTEKQ85 333 784444 AP000879 2383 1-39
770-842
2822-3250
3862-4296
HTEK 85 333 784444 AP000879 2384 1-355
HTEKS20 336 846714 AL137023 2385 1-1052
HTEKS20 336 846714 AL137023 2386 1-868
1143-1650
HTEKS76 338 767658 AC073366 2387 1-121
756-1172
HTEKS76 338 767658 AC012683 2388 1-121
756-1172
HTEKS76 338 767658 AC069546 2389 1-121
756-1172
HTEKX06 339 935945 AC020603 2390 1-434
HTEKX06 339 935945 AC020603 2391 1-89
HTEKX08 340 959876 AC064835 2392 1-2215
HTEKX28 34_1 920927 AC027120 2393 1-1730
HTEKX28 341 920927 AC069399 2394 1-1153
HTEKX28 341 920927 AC023877 2395 1-1730
HTEKX28 341 920927 AC027120 2396 1-85
HTEKX28 341 920927 AC023877 2397 1-85
HTEKZ50 343 524054 AC008552 2398 1-424
HTEKZ50 343 524054 AC008385 2399 1-424
HTEKZ50 343 524054 AC008385 2400 1-435
HTELD47 345 934272 AC017113 2401 1-883
888-1012
1959-2108
2538-3546
5010-5154
6554-6734
HTELD47 345 934272 AL109804 2402 1-885
890-1014
1960-2109
2553-3562
5027-5172
6576-6756
134
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTELD47 345 934272 AC017113 2403 1=1019
HTELD47 345 934272 AL109804 2404 1-493 ~,
810-1071
1154-2175
HTELG47 349 757740 AC024231 2405 1-377
458-535
HTELG47 349 757740 AC016891 2406 1-377
458-535
HTELG47 349 757740 AC024231 2407 1-533
HTELG47 349 757740 AC016891 2408 1-533
HTELG57 350 870621 AL356494 2409 1-2375
2863-3250
3804-3987
HTELG57 350 870621 AL353662 2410 _
1-2375
2863-3250
3804-3987
HTELG57 350 870621 AL356494 2411 1-538
HTELG57 350 870621 AL356494 2412 1-85
637-1181
HTELG57 350 870621 AL353662 2413 1-538
HTELG57 350 870621 AL353662 2414 1-85
637-1181
HTELH44 352 766462 AC006480 2415 1-266
1371-2150
HTELH44 352 766462 AC006480 2416 1-369
HTELI03 353 923071 AC068698 2417 1-587
HTELI03 353 923071 AC005157 2418 1-587
HTELI03 353 923071 AC068698 2419 1-276
HTELI03 353 923071 AC068698 2420 1-427
HTELI03 353 923071 AC005157 2421 1-427
HTELI03 3S3 923071 AC005157 2422 1-273
HTELJ89 3S5 966134 AL023S85 2423 1-117
211-466
HTELJ89 355 966134 AC024690 2424 1-123
217-474
HTELJ89 35S 966134 AL358783 2425 1-123
217-474
HTELJ89 355 966134 AL023585 2426 I-122
217-474
HTELJ89 355 966134 AL022101 2427 1-123
217-474
HTELI~14 356 794339 299716 2428 1-56
2209-2313
3622-3727
3907-4268
' 5968-6088
6723-7099
135
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTELK14 356 794339 299716 2429 1-29I
HTELK14 356 794339 299716 2430 1-100
161-616
2777-2861
3555-3660
5314-57
69
HTELK50 357 870552 AC025953 2431 _
1-75
1003-1162
HTELK50 357 870552 AL355516 2432 1-77
1002-1161
HTELK50 357 870552 AC015873 2433 1-77
1002-1161
HTELK68 358 923055 AL110504 2434 1-658
HTELK68 358 923055 AL110504 2435 I-346
HTELK68 358 923055 AL110504 2436 1-420
HTELL48 359 783824 AC027195 2437 1-649
HTELL48 359 783824 AC027195 2438 1-105
HTELL48 359 783824 AC027195 2439 1-729
HTEL020 363 926910 AL031597 2440 1-346
524-615
HTEL073 365 761806 AL078613 2441 1-96
242-666
HTEL093 366 934344 AC012391 2442 1-400
HTEL093 366 934344 AC023283 2443 1-270
HTEL093 366 934344 AC012308 2444 1-400
HTEL093 366 934344 AC023283 2445 1-314
1245-1274
HTEL093 366 ' 934344 AC012308 2446 1-317
HTELO93 366 934344 AC012308 2447 1-235
HTELQ87 369 761768 AC024958 2448 1-404
2868-3
I92
HTELQ87 369 761768 AC018422 2449 1-404
2868-3192
HTELT72 371 761598 AC011237 2450 1-633
697-899
1405-1529
1983-2165
2371-2490
4239-4353
6793-6880
6993-8390
8442-8767
9115-9434
HTELT72 371 761598 AF214633 2451 1-633
697-899
1405-1529
1983-2165
136
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
2371-2490
4239-4353
6793-6880
6993-8387
8439-8764
9112-9431
HTELT72 371 761598 AC011237 2452 1-2683
2788-2900
3022-3162
3429-3503
3651-3777
4664-5070
5348-5888
6053-6296
6742-6875
7101-7249
7462-8011
8400-9118
9860-10566
10670-11294
HTELT72 371 761598 AF214633 2453 1-2685
2790-2902
3024-3164
3431-3505
3653-3779
4666-5072
5351-5891
6056-6299
6745-6878
7104-7252
7465-8014
8403-9121
9863-10569
10673-11487
12212-12665
12994-13576
14033-14265
14998-15123
HTELT72 371 761598 AC011237 2454 1-367
HTELT72 371 761598 AF214633 2455 1-367
HTELU01 373 .915339 AL033517 2456 1-375
HTELV10 375 963576 AC010339 2457 1-256
HTELV10 375 963576 AC008674 2458 . 1-256
HTELVIO 375 963576 AC008674 2459 1-95
HTELW29 379 952241 AC009131 2460 1-780
HTELW29 379 952241 AC009131 2461 1-246
HTELW29 379 952241 AC009131 2462 1-270
137
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTELX52 38I 963506 AL390858 2463 1-70
733-1332
HTELX52 381 963506 AC026025 2464 I-70
733-1332
HTELX52 381 963506 AL390858 2465 1-457
HTELX52 381 963506 AC026025 2466 1-457
HTELX72 382 761599 AC009682 2467 1-263
HTELX72 382 761599 AL358940 2468 1-263
HTELY64 383 764834 AL356056 2469 1-445
HTELY64 383 764834 AL136982 2470 1-445
HTELY64 383 764834 AL356056 2471 1-328
HTELY64 383 764834 AL356056 2472 1-371
HTELY64 383 764834 AL136982 2473 1-78
179-861
HTELY64 383 764834 AL136982 2474 1-371
HTEMA54 386 911666 AL359692 2475 1-1487
HTEMB26 387 827055 AC004900 2476 1-112
HTEMB26 387 827055 AC004900 2477 1-2372
2882-2974
3048-3578
4547-4806
5624-6285
7400-7547
10800-11164
11907-12010
16372-16542
17325-17552
19368-19662
22876-23302
28256-28683
31524-31990
35872-36237,
36287-36728
37997-38535
38707-38829
3 9160-3
9466
40178-40339
40353-40480
40782-41520
42009-42538
HTEMB26 387 827055 AC004900 2478 1-1968
HTEMB34 389 870589 AL354940 2479 1-649
HTEMB34 389 870589 AL157708 2480 1-649
HTEMB34 389 870589 AL359554 2481 1-649
HTEMB83 391 775593 AL050341 2482 1-294
621-1371
3345-3753
138
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEMC75 393 848193 AC074117 2483 1-93
3 I7-475
850-1162
1511-2098
2194-4316
4373-4717
4836-5053
5192-5313
5403-5497
5798-6033
6121-6210
6370-6841
7244-7310
7582-7935
8489-8606
9212-9266
HTEMC75 393 848193 AC074117 2484 1-70
485-599
880-966
1279-1414
2072-2489
3066-3209
3281-4159
' 4400-4694
4931-6271
HTEMD10 394 963546 AC005858 2485 1-655
HTEMJ34 397 786377 AC021491 2486 1-124
290-781
1447-1562
1650-1767
2309-2417
3273-3466
3935-4120
5213-5358
6216-6605
7621-7744
8491-8761
9044-9175
9353-9523
9966-10843
11395-11839
HTEMJ34 397 786377 AC021491 2487 1-228
3662-4225
HTEMJ54 398 963531 AC026334 2488 1-1272
1874-2420
4782-5167
5373-5502
139
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
5508-5671
5752-6010
6478-6836
7094-7292
7526-8820
9237-9731
HTEMJ54 398 963531 AC060226 2489 1-1272
HTEMJ54 398 963531 AC060226 2490 1-547
HTEMJ54 398 963531 AC026334 2491 1-424
HTEMJ54 398 963531 AC060226 2492 1-424
HTEMN08 401 958374 AP001016 2493 1-248
HTEMN08 401 958374 AC011077 2494 1-248
HTEMN08 401 958374 AP002381 2495 1-248
HTEMN08 401 958374 AC011077 2496 1-339
HTEMN08 401 958374 AP001016 2497 1-339
HTEMN08 40I 958374 AP002381 2498 1-339
HTEMN95 402 789113 AC005540 2499 1-157
1565-1735
HTEMP48 405 767863 AL121747 2500 1-181
315-683
1416-1776
1804-2673
2940-3611
3880-4030
4596-4924
5925-6032
6514-6965
7032-7135
7196-7771
8229-8385
9347-9435
11732-13123
HTEMP48 405 767863 AL049761 2501 1-573
2229-2431
2486-2797
3011-3299
3434-3924
4487-4614
5864-6151
6385-6768
6786-7099
7437-7594
7761-8029
8318-9645
9767-10324
10882-10944
11032-11505
140
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
12853-13033
13167-13535
14268-14627
14656-15525
15792-16463
16731-16911
17448-17776
18777-18886
19366-19817
19884-19987
20048-20606
21085-21248
22199-22289
24584-25975
HTEMP48 405 767863 AL121747 2502 1-1738
HTEMP48 405 767863 AL049761 2503 1-1738
HTEMP48 405 767863 AL049761 2504 1-267
HTEMP49 406 932319 AC005848 2505 1-50
276-606
3099-3179
3390-3458
4162-4388
HTEMU17 411 789623 AL159141 2506 I-210
345-515
4335-4446
9330-9443
9841-9904
11140-12334
12776-13144
13501-13916
17369-18981
HTEMU17 411 789623 AL118559 2507 1-369
.
HTEMU17 411 789623 ALI59141 2508 1-318
HTEMU17 41I 789623 AL118559 2509 1-4I6
HTEMU17 411 789623 AL118559 2510 1-231
HTEMZ04 415 927021 AC068707 2511 1-102
574-851
HTEMZ04 415 927021 AC068707 2512 1-202
HTENB03 417 923050 AL157814 2513 1-490
HTENB03 417 923050 AL157814 2514 1-30
1784-1887
2320-2867
HTENB03 417 923050 AL157814 2515 1-550
HTENC22 418 775544 AC069539 2516 1-890
999-I3I4
1794-4625
HTENC22 418 775544 AC069539 2517 1-416
141
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTENC22 418 775544 AC069539 2518 1-129
~ _
HTENF08 419 958378 AC018682 2519 1-752
HTENF08 419 958378 AC018682 2520 1-252
HTENI58 423 917213 AL121980 2521 1-716
HTENI58 423 917213 AL121980 2522 1-179
373-573
HTENK69 427 844557 AC063919 2523 1-696
1146-1317
1506-1768
HTENI~69 427 844557 AC073439 2524 1-696
1146-1317
1506-1768
HTEN050 429 969213 AC009874 2525 1-315
1284-1411
1668-1749
3993-4056
4183-4346
5547-6161
6198-6612
6660-6806
7328-7394
7459-7881
8005-8503
8700-8977
9207-9362
10056-10514
12312-12436
HTEN050 429 969213 AC009874 2526 1-1809
1985-2077
2851-7606
HTENP80 431 775387 AL035453 2527 1-408
4407-4511
HTENP80 431 775387 AL035453 2528 1-342
HTENQ05 432 928244 AC024952 2529 1-126
1960-2212
2845-2947
6326-6450
9966-10000
12088-12311
13031-13145
13786-13869
14356-14874
HTENQ05 432 928244 AC018638 2530 1-123
666-828
4839-5113
6402-6995
7727-7910
142
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
9744-9996
10630-10732
I41I2-14236
17737-17771
19858-20081
20801-20915
21556-21640
22127-22645
HTEN OS 432 928244 AC024952 2531 1-368
HTEN OS 432 928244 AC018638 2532 1-368
HTEN OS 432 928244 AC018638 2533 1-374
HTENS22 435 785996 AP001034 2534 1-964
1560-2151
HTENS22 435 785996 AC015840 2535 I-965
1070-1278
1561-2152
HTENS22 435 785996 AC015840 2536 1-422
HTENS43 436 784936 ACOlI959 2537 I-189
439-1562
HTENS43 436 784936 AF1312I6 2538 1-188
440-1562
HTENS91 437 870515 AC016771 2539 1-688
HTENS91 437 870515 AC048382 2540 1-1000
HTENS91 437 870515 AC016771 2541 1-53
468-636
1619-1744
2423-2651
2790-3043
4364-4636
7345-7727
HTENS91 437 870515 AC048382 2542 1-255
HTENX77 440 771409 AP000484 2543 1-1719
HTENX77 440 771409 AP000484 2544 1-255
HTENX77 440 771409 AP000484 2545 1-103
2060-2420
4856-5151
HTENY35 442 884043 AC006208 2546 1-1385
1465-3 044
3323-3377
3821-3917
4057-4165
4748-4778
4805-5177
5224-5464
5956-6173
6207-7085
8138-8296
143
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
8758-9056
9162-9263
9638-9764
10225-10392
10853-11247
11548-12281
12417-12970
HTENY35 442 884043 AC006208 2547 I-1425
1603-1678
1783-1875
2028-3154
3258-3740
3768-4488
4764-4913
5252-5382
5827-5905
6172-6319
6397-6466
6957-7076
7473-7606
8554-8608
8714-8741
8840-8984
HTEOF9I 450 918571 AL133387 2548 1-1187
HTEOF91 450 918571 AL135794 2549 1-1189
HTEOF9I 450 918571 AL133387 2550 1-47
231-264
3SS-857
HTEOF91 450 918571 AL135794 2551 1-146
HTEOF9I 450 918571 AL133387 2552 I-140
_
HTEOF91 450 918571 AL135794 2553 1-47
23 I-264
355-857
HTEOK02 453 918590 AL136084 2554 I-486
HTEOK02 453 918590 AL136084 2555 I-181
2911-3377
HTEON67 455 954114 AC004533 2556 I-347
HTEOU45 456 915138 AC016309 2557 1-708
HTEOU45 456 915138 AC016309 2558 1-1634
HTEOV90 457 870532 AL359092 2559 I-116
HTEOV90 457 870532 AC009453 2560 1-143
HTEOV90 457 870532 AC025036 2561 1-148
HTEOV90 457 870532 AC011953 2562 1-126
HTEOV90 457 870532 AC027300 2563 I-158
HTEOV90 457 870532 AC022231 2564 I-151
HTEOV90 457 870532 AC023242 2565 1-86
HTEOV90 457 870532 AC048342 2566 1-130
144
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEOV90 457 870532 AL121656 2567 1-2346
2487-3703
3832-4167
HTEOV90 457 870532 AC048342 2568 1-118
HTEOW39 459 870566 AL356464 2569 1-142
570-728
1523-1638
1741-1926
HTEOW39 459 870566 AL356797 2570 1-142
570-728
1523-1638
1741-1926
HTEOW39 459 870566 298304 2571 1-142
570-728
1523-1638
1742-1926
HTEOW39 459 870566 AL356464 2572 1-538
HTEOW39 459 870566 AL356464 2573 1-437
HTEOW39 459 870566 AL356797 2574 1-136
HTEOW39 459 870566 AL356797 2575 1-437
HTEOW39 459 870566 298304 2576 1-538
HTEOW39 459 870566 298304 2577 1-437
HTEPA08 461 958391 AL133480 2578 1-918
1739-2284
2588-2821
HTEPA08 461 958391 AC021645 2579 1-918
1739-2284
2588-2821
HTEPA08 461 958391 AL133480 2580 1-640
HTEPA08 461 958391 AL133480 2581 1-331
HTEPA08 46I 958391 AC02I645 2582 1-331
HTEPA08 461 958391 AC021645 2583 1-640
HTEPC76 465 767824 AC008403 2584 1-270
797-964
1044-1123
1229-1342
1467-1845
2640-2987
3113-4431
4439-4555
5060-5233
5373-5488
6011-6410
6946-7068
7284-7513
8720-8791
8874-9044
145
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
9864-10381
10706-10846
12118-12821
12983-13117
13377-14044
14066-15218
16961-17324
HTEPC76 465 767824 AC008403 2585 1-1468
HTEPC76 465 767824 AC008403 2586 1-583
HTEPJ79 472 774212 AC073569 2587 1-370
HTEPJ79 472 774212 AC073595 2588 1-371
HTEPJ79 472 774212 AC007949 2589 1-371
HTEPM33 474 870561 AL132776 2590 1-42
1020-1195
2173-2338
6839-7029
11880-12103
HTEPM33 474 870561 AL132776 2591 1-173
HTEPM33 474 870561 AL132776 2592 1-791
HTEPM52 475 806471 AC022744 2593 I-600
HTEPM52 475 806471 AC009588 2594 1-600
HTEPM52 475 806471 AC022744 2595 1-197
HTEPM52 475 806471 AC009588 2596 1-86
404-641
1062-1413
1506-1869
2725-3045
3625-4106
HTEPP29 478 917207 AC064831 2597 1-467
HTEPP29 478 917207 AC023103 2598 I-470
HTEPP29 478 917207 AC036199 2599 1-470
HTEPT25 483 870509 AC074256 2600 1-408
HTEPZ10 488 963433 AC011028 2601 1-543
HTE B03 490 922941 AC023331 2602 1-393
HTE B03 490 922941 AL358236 2603 1-391
HTEQB03 490 922941 AL359374 2604 1-391
HTE B03 490 922941 AL358236 2605 1-220
HTE B03 490 922941 AC023331 2606 1-292
HTEQB03 490 922941 AL359374 2607 1-116
130-210
HTE B03 490 922941 AL359374 2608 I-290
HTEQD40 491 915198 AL121906 2609 1-158
414-924
975-1601
HTEQD40 491 915198 AL121906 2610 1-776
856-949
1390-1468
146
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
1591-2048
2412-2463
2503-2918
3174-3270
HTE D40 491 915198 AL121906 2611 I-411
HTE D69 492 918579 AL157399 2612 1-712
HTE D69 492 918579 AC018476 2613 1-712
HTE D69 492 918579 AC007949 2614 1-711
HTEQD69 492 918579 AC018476 2615 1-922
1159-1246
1288-1481
1547-1649
1673-1758
2026-2482
2668-3297
HTEQD69 492 918579 AC018476 2616 1-145
541-677
1557-1852
HTEQD69 492 918579 AC007949 2617 1-145
541-677
1555-1850
HTE D69 492 918579 AC007949 2618 1-314
HTE J42 497 806495 AC007405 2619 1-510
HTEQ081 498 806504 AC010766 2620 1-198
316-378
3441-3601
HTEQO81 498 806504 ALI63636 2621 1-I98
316-378
3442-3
602
HTEQ081 498 806504 AL163195 2622 1-I98
316-378
3442-3602
HTEQ081 498 806504 AC010766 2623 1-301
HTE 081 498 806504 AC010766 2624 1-S91
HTE 081 498 806504 AL163636 2625 1-591
HTE 081 498 806504 AL163636 2626 1-177
HTE 081 498 806504 AL163195 2627 1-293
HTE 081 498 806504 AL163195 2628 1-591
HTE R94 502 966486 AC010980 2629 1-1047
HTEQT63 503 924799 AC026410 2630 1-1820
HTLAB44 SOS 530579 AC006549 2631 1-530
HTLAB44 505 530579 AC000097 2632 1-530
HTLAB44 SOS 530579 AC006547 2633 1-530
HTLAB44 505 530579 AC006549 2634 1-42
147-212
380-436
699-747
147
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
821-1197
HTLAB44 505 530579 AC006549 2635 1-311
HTLAB44 505 530579 AC000097 2636 1-42
147-212
3 80-43
6
699-747
821-1197
HTLAB44 505 530579 AC000097 2637 1-311
HTLAB44 505 530579 AC006547 2638 1-42
147-212
380-436
699-747
821-1197
HTLAB44 505 530579 AC006547 2639 1-314
HTLAB73 506 575019 AC000078 2640 1-341
2484-3046
3397-3489
4877-5165
5231-5303
5477-5578
6429-7030
7187-7509
7842-8148
HTLAB73 506 575019 AC000078 2641 1-507
HTLAC81 507 679414 AC019258 2642 1-200
HTLAC81 507 679414 AP002807 2643 1-204
HTLAC81 507 679414 AC034259 2644 1-204
HTLAD21 509 761758 AC024029 2645 1-37
1140-1255
2004-2115
2586-2801
3347-3460
4242-4320
4959-5284
HTLAD21 509 761758 AC019121 2646 1-37
1140-1249
2584-2799
3342-3460
4243-4321
4956-5281
HTLAD21 509 761758 AC019121 2647 1-336
HTLAD21 509 761758 AC024029 2648 1-336
HTLAV67 512 530742 AC005258 2649 1-326
HTLAV67 512 530742 AC005258 2650 1-278
HTLAV67 512 530742 AC005258 2651 1-89
HTLBF14 516 971661 AC018638 2652 1-252
- 3348-3556
148
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
3 720-3
822
3 877-4004
4927-5181
5226-5736
HTLBF14 516 971661 AC018638 2653 1-130
HTLBG83 517 527942 AP002840 2654 1-102
1010-1888
2064-2785
HTLBG83 517 527942 AC016056 2655 1-290
HTLBG83 517 527942 AC009466 2656 1-94
1419-1520
2428-3306
3482-4203
HTLBG83 SI7 527942 AP000880 2657 1-94
1419-1520
2428-3306
3482-4203
HTLBG83 517 527942 AC009466 2658 1-998
HTLBG83 517 527942 AP002840 2659 1-368
HTLBG83 517 527942 AP000880 2660 1-368
HTLBG83 517 527942 AC009466 2661 1-368
HTLBG83 517 527942 AP000880 2662 1-996
HTLCA95 S I8 911655 AC012616 2663 1-1151
HTLCA95 518 911655 AC012616 2664 1-284
HTLCX76 520 767667 AC011736 2665 1-97
612-718
913-1065
5655-5767
6173-6351
6803-6954
9565-9706
13178-13360
13963-14058
17351-17653
19337-19476
22288-22405
22711-22769
24564-24601
25844-25947
26983-27370
28050-28233
29000-29163
HTLCX76 520 767667 AC027618 2666 1-97
612-718
913-1065
5657-5768
6174-6352
149
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
6807-6958
9568-9709
13178-13216
HTLCX76 520 767667 AC027618 2667 1-89
HTLCX76 520 767667 AC011736 2668 1-152
HTLCX76 520 767667 AC027618 2669 1-40
3350-3648
7546-7581
HTLCZ48 522 572959 AC015497 2670 1-402
HTLCZ48 522 572959 AL353695 2671 1-405
HTLCZ48 522 572959 AC015497 2672 1-140
HTLCZ48 522 572959 AL353695 2673 I-140
HTLCZ96 523 815897 AL118498 2674 1-160
1685-1871
2742-2910
5414-5599
6883-6914
8226-8271
9277-9733
11311-11543
HTLDE64 526 908613 AC005087 2675 1-207
524-773
945-1056
3251-3659
HTLDE64 526 908613 AC005087 2676 1-232
HTLDE64 526 908613 AC005087 2677 1-232
HTLD 25 531 870057 AL355315 2678 1-1401
HTLD 25 531 870057 AL359388 2679 1-1401
HTLD 25 531 870057 AL355315 2680 1-636
HTLDQ25 531 870057 AL3553I5 2681 1-II2
128-185
HTLDQ25 531 870057 AL359388 2682 1-112
128-185
HTLD 25 531 870057 AL359388 2683 1-636
HTLDS55 532 891322 AC020663 2684 1-64
584-868
2241-2367
2459-2539
4278-4416
4580-4698
4790-4886
8560-8662
9190-9487
10204-10263
10348-10678
HTLDS55 532 891322 AC020663 2685 1-309
HTLDS55 532 891322 AC020663 2686 1-304
ISO
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
849-1240
2947-3164
HTLDZ14 538 573401 AL133318 2687 1-403
HTLDZ14 538 573401 AL133318 2688 1-353
HTLDZ14 538 573401 AL133318 2689 1-381
HTLEB14 539 573464 AL353647 2690 1-1046
1485-
1639
HTLEB14 539 573464 AL138784 2691 _
1-1046
1485-1639
HTLEB14 539 573464 AC022786 2692 1-1046
1485-1639
HTLEB14 539 573464 AL353647 2693 1-116
HTLEB14 539 573464 AL138784 2694 1-116
HTLED72 540 906989 AC011442 2695 1-281
HTLEG65 542 870154 AC026083 2696 1-1655
HTLEG91 543 870257 AL031406 2697 1-114
HTLEG91 543 870257 294160 2698 1-114
HTLEG91 543 870257 AL031406 2699 1-945
HTLEG91 543 870257 294160 2700 1-945
HTLEI47 545 573460 AC025959 2701 1-307
650-751
1100-1209
HTLEI47 545 573460 AC009451 2702 1-307
650-751
1100-
120
9
HTLEI47 545 573460 AC025963 2703 _
_
1-307
650-751
1100-1209
HTLELOl 549 917022 AC024631 2704 1-496
699-1081
1222-1331
1385-1614
1658-1771
1784-2779
3025-3737
HTLELO1 549 917022 AC053481 2705 1-84
142-371
415-528
541-1535
1780-2492
3204-3300
3678-5015
HTLELOl 549 917022 AC027821 2706 1-50
213-300
859-1126
1195-1903
2104-2487
ISI
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
2628-2737
2791-3020
3064-3182
3190-4185
4433-5145
5857-5953
6331-7971
7973-8232
8452-8515
HTLELOl 549 917022 AC036181 2707 1-84
141-370
414-532
540-1535
1776-2488
3200-3296
3674-5593
5809-6696
HTLELOl 549 917022 AC036181 2708 1-524
687-774
1333-1600
1669-2377
2578-2962
3103-3212
3266-3495
3539-3657
3665-4659
4905-5617
6332-6428
6806-8442
8444-87.03
8918-9805
HTLELO1 549 917022 AC023133 2709 1-524
688-775
1333-1600
1669-2321
2574-2957
3098-3207
3261-3490
3534-3652
3660-4655
4896-5608
6320-6416
6792-8432
8434-8693
8908-9796
HTLELOl 549 917022 AC067923 2710 1-104
267-354
152
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
913-1180
1249-1956
2157-2540
2681-2790
2844-3073
3117-3235
3243-4238
4484-5196
5908-6004
6382-8301
8517-9404
HTLELO1 549 917022 AC015818 2711 1-940
HTLELO1 549 917022 AC003976 2712 1-524
688-775
1334-1601
1670-2378
2579-2962
3103-3212
3266-3495
3539-3657
3665-4659
4905-5617
6332-6428
6806-8442
8444-8703
8918-9804
HTLELOI 549 917022 AC021317 2713 I-529
HTLELO1 549 917022 AC036181 2714 I-358
-
HTLELO1 549 917022 AC053481 2715 I-297
HTLELOl 549 917022 AC036181 2716 I-371
HTLELO1 549 917022 AC036181 2717 1-371
HTLELOI 549 917022 AC023133 2718 1-243
HTLEL01 549 917022 AC036181 2719 I-243
HTLELO1 549 917022 AC023133 2720 1-371
HTLELO1 549 917022 AC067923 2721 1-371
HTLELO1 549 917022 AC015818 2722 1-527
HTLELO1 549 917022 AC015818 2723 1-554
559-639
HTLELO1 549 917022 AC003976 2724 1-371
HTLELO1 549 917022 AC003976 2725 I-243
HTLELO1 549 917022 AC021317 2726 1-1419
1443-1741
1748-2500
HTLELOI 549 917022 AC021317 2727 1-103
HTLEL31 551 669950 AF053356 2728 1-71
234-304
320-826
153
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
878-1099
1233-1683
2077-3297
HTLEL3I 551 669950 AF053356 2729 1-434
HTLEL31 551 669950 AF053356 2730 1-152
HTLEQ07 555 953706 AC009485 2731 1-159
352-455
634-742
1105-1433
HTLE 07 555 953706 AC009485 2732 1-550
HTLES54 557 574884 AC007732 2733 1-694
HTLES54 557 574884 AC007732 2734 1-102
HTLES54 557 574884 AC007732 2735 1-1969
HTLET56 558 911654 AL356984 2736 1-1371
HTLET78 559 836820 AC048358 2737 1-64
135-253
439-619
880-1007
1334-1548
1691-2473
HTLET78 559 836820 AC027307 2738 1-64
135-253
439-619
880-1007
1335-1549
1692-2474
HTLET78 559 836820 AC027307 2739 1-80
HTLET93 560 573454 AC021744 2740 1-105
HTLEV33 561 527956 AC024257 2741 1-1156
HTLEV33 561 527956 AC024257 2742 1-496
HTLEV33 561 527956 AC024257 2743 1-529
HTLEW21 563 573458 AC008392 2744 I-80
1758-1900
3780-4202
4434-4597
4677-4747
HTLEW21 563 573458 AC027218 2745 1-80
1754-1896
3776-4198
4430-4593
4673-4743
HTLEW21 563 573458 AC027218 2746 1-872
HTLEW21 563 573458 AC008392 2747 1-872
HTLEY11 564 967309 AC036174 2748 1-88
1369-1453
2944-3069
3655-4026
154
CA 02393616 2002-06-05
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HTLEZ14 566 791662 AC006549 2749 1-530
HTLEZ14 566 791662 AC000097 2750 1-530
HTLEZ14 566 791662 AC006547 2751 1-530
HTLEZ14 566 791662 AC006549 2752 1-42
147-212
380-436
699-747
821-1197
HTLEZ14 566 791662 AC006549 2753 1-311
HTLEZ14 566 791662 AC000097 __ 1-42
2754
147-212
380-436
699-747
821-1197
HTLEZ14 566 791662 AC000097 2755 1-311
HTLEZ14 566 791662 AC006547 2756 1-42
147-212
380-436
699-747
821-1197
HTLEZ14 566 791662 AC006547 2757 1-314
HTLEZ15 567 934288 AC021163 2758 1-212
773-858
1055-1178
HTLEZ15 567 934288 AC011495 2759 1-210
774-859
1056-1155
HTLEZ15 567 934288 AC021163 2760 1-150
HTLEZ15 567 934288 AC021163 2761 1-334
HTLEZ15 567 934288 AC011495 2762 1-150
HTLEZ15 567 934288 AC011495 2763 1-325
HTLFC20 570 917128 AL354944 2764 1-116
1049-1279
1947-2369
2924-3064
3498-9096
10048-10150
10917-11052
11221-11920
12125-12310
12501-12633
12868-13122
13980-14176
16118-16486
16537-17101
17616-18267
18312-19168
155
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20650-20901
21433-21866
23387-23568
23660-23748
HTLFC20 570 917128 AL354944 2765. 1-259
'
HTLFC20 570 917128 AL354944 2766 1-101
HTLGD25 578 870136 AC025865 2767 1-1491
HTLGD25 578 870136 AC019225 2768 1-1491
HTLGD25 578 870136 AL160006 2769 1-1491
HTLGD25 578 870136 AC019225 2770 1-480
HTLGD25 578 870136 AC025865 2771 1-481
HTLGD25 578 870136 AL160006 2772 1-481
HTLGD69 579 835493 AC013713 2773 1-1128
HTLGD69 579 835493 AL157875 2774 1-1128
HTLGD69 579 835493 AC013713 2775 1-362
5379-5440
HTLGD69 579 835493 AC013713 2776 1-493
HTLGD69 579 835493 AL157875 2777 1-362
5379-5440
HTLGM07 582 952254 AC003688 2778 1-81
236-691
773-1054
1662-1893
2248-2282
3053-3219
3774-4061
423 8-4344
4469-4939
5460-5564
5664-6980
HTLGM07 582 952254 AC003688 2779 1-85
509-995
1324-1425
1574-1640
HTLGM07 582 952254 AC003688 2780 1-265
HTLHE72 587 963471 AL353608 2781 1-510
HTLHE72 587 963471 AL353608 2782 1-628
HTLHE72 587 963471 AL353608 2783 1-907
HTLHL82 588 958334 AL162377 2784 1-246
3348-4249
HTLH094 589 968685 AC006445 2785 1-1321
HTLHP80 592 870156 AL132868 2786 1-784
HTLHP80 592 870156 AL132868 2787 1-135
HTLIIC11 600 966043 AC008649 2788 1-504
1236-1319
2515-2917
4549-4998
156
CA 02393616 2002-06-05
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5053-5186
5694-5778
6477-6722
9052-9536
9591-9714
9993-10115
HTLII~11 600 966043 AC008649 2789 1-370
376-776
HTLIP19 601 958351 AC067784 2790 1-74
3587-3742
4069-4200
4639-4740
5740-5808
6262-6401
HTLIP19 601 958351 AC018595 2791 1-147
393-578
1688-1771
4090-4246
4573-4704
5143-5249
6244-6312
6446-6554
6763-6903
HTLIP19 601 95835'1 AC018595 2792 1-140
HTLIY52 606 942161 AC011448 2793 1-194
424-1198
193 8-2018
3137-3317
5423-5732
5894-6019
6299-6608
7425-7771
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9697-9815
9872-9959
10811-11127
11264-11754
11867-12454
12539-13980
14020-14373
14522-15107
15641-15786
18585-22176
22246-22801
24994-25641
26099-26401
28795-29074
157
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
29176-29432
29653-29854
31298-31468
31507-32203
32864-33359
34805-34936
35464-35750
35878-36319
36610-37065
37680-38123
. 38902-39124
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43593-43745
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48694-49237
49352-49706
52310-52618
53725-54348
54650-55016
56425-56525
56655-57164
58248-59197
59662-60112
60732-61475
62024-62173
69325-69730
HTLIY52 606 942161 AC011448 2794 1-544
HTLIY52 606 942161 AC011448 2795 1-293
HTLJA24 608 934279 AC006237 2796 1-77
1994-2263
3098-3450
3551-4203
HTLJA24 608 934279 AC006237 2797 1-1048
1633-2065
2080-2333
2374-2524
4212-4459
5299-5463
7313-7346
HTLJA24 608 934279 AC006237 2798 1-101
HTLJC71 609 922923 AC009516 2799 1-2009
HTLJC71 609 922923 AC007957 2800 1-1747
HTLJC71 609 922923 AC018751 2801 1-2009
HTLJC71 609 922923 AC023490 2802 1-2009
HTLJC71 609 922923 AC009516 2803 1-375
HTLJC71 609 922923 AC009516 2804 1-494
HTLJC7I 609 922923 AC007957 2805 1-205
158
CA 02393616 2002-06-05
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HTLJC71 609 922923 AC018751 2806 1-494
HTLJC71 609 922923 AC023490 2807 1-375
HTLJC71 609 922923 AC018751 2808 I-375
HTLJJ75 612 924755 AL354888 2809 1-1283
HTLJJ75 612 924755 AL033527 2810 1-448
451-1733
HTLJJ75 612 924755 AL354888 2811 1-699
HTLJJ75 612 924755 AL033527 2812 1-696
HTLJL23 613 922994 AL031587 2813 1-151
441-552
1214-1667
1820-2290
2375-2664
4552-5062
5224-5492
6136-6319
6684-7594
7786-8096
8297-8930
8932-10855
HTLJL23 613 922994 AL031587 2814 1-135
2617-2705
3232-3371
5671-5793
HTTAD55 614 835652 AC021558 2815 1-260
HTTAD55 614 835652 AC021558 2816 1-599
HTTAE49 615 723331 AC023266 2817 1-491
HTTAE49 615 723331 AC023266 2818 1-276
HTTAE49 615 723331 AC023266 2819 1-1777
HTTAJ50 617 509657 AC022148 2820 1-287
HTTAJ50 617 509657 AC022148 2821 1-392
HTTAN57 618 509453 AC010299 2822 l-304
HTTAS96 619 961057 AC074073 2823 1-254
HTTAS96 619 961057 AC022621 2824 1-320
HTTAS96 619 961057 AC022621 2825 1-272
HTTAS96 619 961057 AC022621 2826 1-195
HTTAU82 620 797726 AC009618 2827 1-342
HTTAU82 620 797726 AL390022 2828 1-510
HTTAU82 620 797726 AC006517 2829 1-191
443-741
2568-2781
3248-3544
3716-3884
HTTAU82 620 797726 AC006927 2830 1-191
443-741
2568-2778
3317-3427
159
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
3717-3885
HTTAU82 620 797726 AC009618 2831 I-731
HTTAU82 620 797726 AL390022 2832 1-728
HTTAU82 620 797726 AC006517 2833 1-115
HTTAU82 620 797726 AL390022 2834 I-383
HTTAU82 620 797726 AC006517 2835 1-76
848-890
1618-2210
HTTAU82 620 797726 AC006927 2836 1-89
HTTAU82 620 797726 AC006927 2837 1-76
848-890
1618-2210
HTTBH54 622 530563 ACOI3443 2838 1-305
HTTBJ94 623 530564 AC012306 2839 1-371
2517-2948
3269-3389
4036-4139
4655-4747
6026-6302
6920-7056
7205-7304
8993-12574
HTTBN67 624 578085 AF235102 2840 1-227
HTTBN67 624 578085 AF235102 2841 1-117
290-371
1962-2328
HTTCAIS 625 869705 AC005833 2842 1-412
HTTCA15 625 869705 AC005833 2843 1-559
HTTCD71 627 530393 AL049844 2844 1-74
381-637
1227-1614
1677-3333
4088-4213
4220-4876
5053-5406
5474-5917
6045-6442
HTTCD71 627 530393 AL049844 2845 1-263
HTTCD71 627 530393 AL049844 2846 1-885
~
HTTCL35 628 529672 AC024375 2847 1-253
1273-1795
HTTCL35 628 529672 AC024375 2848 1-418
HTTDF50 630 526385 AC022335 2849 1-1306
-
HTTDF50 630 526385 AC022335 2850 1-156
HTTDI21 633 869686 AC074236 2851 1-485
HTTDI21 633 869686 AC009269 2852 1-192
206-468
160
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
1229-1713
2228-2407
2998-3211
3314-3817
4343-4938
5571-5768
HTTDI21 633 869686 AC009269 2853 l-104
HTTDI21 633 869686 AC009269 2854 1-559
HTTDL45 636 523452 AC007390 2855 1-75
417-583
1679-1765
2788-3466
4413-4490
4941-5105
5400-5517
6071-6185
8399-8718
9893-10500
HTTDL45 636 523452 AC007390 2856 1-803
HTTDL45 636 523452 AG007390 2857 1-186
901-2187
2559-2605
2853-4188
4215-6320
6739-7105
7892-8398
8852-9356
9561-10277
10360-10560
12504-12595
13356-13552
13845-13905
15014-15064
15377-15953
16401-16466
16831-17031
17378-18339
18502-18552
19127-19426
19501-19804
20934-21502
21567-21695
21900-21988
22836-23379
23660-23743
23890-24076
24682-24916
161
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
26831-27787
28708-30551
32927-33109
HTTDL89 637 959837 AC004803 2858 1-376
HTTDL89 637 959837 AC004765 2859 1-376
471-1538
2707-3361
HTTDL89 637 959837 AC004803 2860 1-1068
HTTDL89 637 959837 AC004803 2861 1-2019
3153-3257
3637-3880
4449-46
S S
4695-4983
5401-6067
7497-7573
8470-8588
8874-9327
9904-10065
11619-11681
12466-12581
12911-13213
14830-14911
16048-17861
17889-18018
18305-18362
18566-18740
19076-19167
HTTDL89 637 959837 AC004765 2862 1-264
HTTDN85 639 783444 AC078852 2863 1-442
HTTDN85 639 783444 AC022763 2864 1-443
HTTDN85 639 783444 AC078852 2865 1-538
HTTDN85 639 783444 AC022763 2866 1-538
HTTDR91 641 790336 AC005740 2867 1-176
1646-1818
4524-4697
5747-5899
8660-9945
10558-10883
11064-11295
11314-11646
14324-14496
15739-15886
16611-16794
18676-21241
22938-23085
23224-24224
24447-24843
162
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
25199-25490
2SS1S-27062
HTTDR91 641 790336 ACOOS740 2868 1-S40
HTTDR91 641 790336 ACOOS740 2869 1-398
HTTDR92 642 573666 AC023098 2870 1-368
HTTDR92 642 573666 AC003046 2871 1-368
HTTDR92 642 573666 AC023098 2872 1-368
HTTDR92 642 573666 AC023098 2873 1-62
1717-2020
231 S-2432
3271-3381
4686-4832
HTTDR92 642 573666 AC003046 2874 I-62
1728-2020
231 S-2432
3271-3381
4686-4832
HTTDR92 642 573666 AC003046 2875 1-368
HTTDS02 643 920589 AL139100 2876 1-309
2987-3113
4207-4877
SS73-5677
5684-S84S
93 82-949
S
11034-11269
14694-14786
16010-16116
16799-17013
17078-17196
18023-18134
19046-I956S
20157-20645
HTTDS02 643 920589 AL139100 2877 1-121
HTTDX84 644 921100 AC016912 2878 1-137
839-1199
467
9-4860
HTTDX84 644 921100 AC018682 2879 _
1-137
840-1200
4680-4861
HTTDZ91 646 523206 AL137229 2880 1-14S
S72-661
4888-5112
6942-7339
7820-7914
8041-8423
8957-9106
11434-11806
163
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
11986-12491
13542-13680
14277-16062
HTTDZ91 646 523206 AL137229 2881 1-1790
HTTEH58 648 747943 AC068781 2882 1-387
HTTEH58 648 747943 AC068365 2883 1-387
HTTEH58 648 747943 AC073466 2884 1-387
HTTEH58 648 747943 AC068365 2885 1-813
HTTEH58 648 747943 AC073466 2886 1-813
HTTEH58 648 747943 AC068781 2887 1-813
HTTELSO 649 745985 AL359551 2888 1-443
HTTELSO 649 745985 AL360010 2889 1-227
3577-4019
4331-4797
HTTELSO 649 745985 AL360010 2890 1-556
HTTEV62 651 573614 AC018706 2891 1-120
327-596
HTTEY64 652 974107 AL121759 2892 1-457
HTTEY64 652 974107 AL121759 2893 1-182
1815-1886
HTTEY64 652 974107 AL121759 2894 1-413
HTTEZ34 653 771602 AL356116 2895 1-508
HTTEZ34 653 771602 AC017067 2896 1-244
4587-5158
5672-6138
HTTEZ34 653 771602 AL356116 2897 1-467
HTTFB60 654 869666 AC023818 2898 1-2041
2271-2442
2475-6107
HTTFB60 654 869666 AC023818 2899 1-353
HTTFB60 654 869666 AC023818 2900 1-120
HTTFG35 655 778426 AC019205 2901 1-231
428-607
HTTFG35 655 778426 AL133336 2902 1-231
428-607
HTTFG35 655 778426 AC068247 2903 1-231
428-607
HTTFG35 655 778'426 AC019205 2904 1-974
HTTFG35 655 778426 AL133336 2905 1-974
HTTFG35 655 778426 AC068247 2906 1-974
HTTFL89 658 974346 AC005551 2907 1-436
HTTFL89 658 974346 AC005S51 2908 1-135
1535-1715
2043-2114
5528-6140
HTTFM17 659 750942 AC009994 2909 1-422
164
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
658-1260
2947-3758
HTTFM17 659 750942 AC009994 2910 1-155
HTTFS59 661 825922 AP001332 2911 1-1736
1937-2284
2596-2760
3034-3162
4857-4934
5196-5338
6131-6244
6276-6756
7170-7308
7537-7569
7659-7709
HTTFS59 661 825922 AC013606 2912 1-1738
1938-2285
2478-2580
2594-2758
3036-3160
HTTFS59 661 825922 AC015685 2913 1-1737
HTTFS59 661 825922 AC013606 2914 1-489
HTTFS59 661 825922 AC015685 2915 1-487
HTTFT08 662 934460 AC013726 2916 1-43
317-418
1097-2127
2193-2346
2456-2503
2713-3159
3231-6093
HTTFT08 662 934460 AC013726 2917 1-536
HTTFV93 663 925544 AL139410 2918 1-1222
1338-1532
HTTFV93 663 925544 AL353760 2919 1-1222
1338-1532
HTTFZ70 664 974066 AL355594 2920 1-115
207-368
516-876
1441-1565
2014-2187
2404-2951
3705-5973
6008-8387
HTTFZ70 664 974066 AL033383 2921 1-1004
2982-3105
3372-3514
4034-4609
5643-5817
165
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
9019-9176
10736-10817
12053-12475
13292-13391
14259-14546
15423-15497
16340-16660
17244-17630
17683-17864
17981-18128
18264-18585
18678-18767
20206-20356
20955-21122
22834-23358
23679-23944
24217-24406
24565-24684
25085-25439
26585-26758
26975-27139
28275-30550
30582-33232
36611-37091
37344-38113
46301-46465
55718-55969
66431-66687
HTTFZ70 664 974066 AL138831 2922 1-1004
2982-3105
3372-3514
4034-4609
5643-5817
9019-9176
10736-10817
12053-12475
13292-13391
14259-14546
15423-15497
16340-16660
17244-17630
17683-17864
17981-18128
18264-18585
18678-18767
20206-20356
20955-21122
166
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
22836-23360
23681-23946
24219-24408
24567-24686
24778-24939
25087-25441
26585-26758
26975-27139
28275-30550
30582-33232
36611-37091
37344-38113
46301-46465
55718-55969
66431-66687
HTTFZ70 664 974066 AL033383 2923 1-375
HTTFZ70 664 974066 AL355594 2924 1-266
539-728
HTTFZ70 664 974066 AL033383 2925 1-205
HTTFZ70 664 974066 AL13883I 2926 1-375
HTTFZ70 664 974066 AL138831 2927 1-205
HTTIG04 666 926752 AC012609 2928 1-458
HTTIG04 666 926752 AC026406 2929 I-458
HTTIG04 666 926752 AC012609 2930 1-661
HTTIG04 666 926752 AC026406 2931 1-661
HTTIH23 667 869636 AC040970 2932 1-1041
1186-1881
2845-2973
HTTIH23 667 869636 AC011676 2933 1-1041
1185-1880
2844-2972
5523-5631
6840-71
I 1
7196-7890
8274-9038
9916-10234
HTTIH23 667 869636 AC040970 2934 _
1-740
HTTIH23 667 869636 AC011676 2935 1-400
HTTIH80 668 869635 AC006443 2936 1-385
HTTIH80 668 869635 AC006443 2937 1-201
HTTIN23 670 869634 AC002549 2938 1-566
HTTIU05 671 931015 AC008663 2939 1-461
3399-3527
4652-5129
5447-6031
6123-6401
6651-7418
167
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
8095-9142
HTTIU05 671 931015 AC010339 2940 1-76
1203-1680
1998-2582
2674-2952
3202-3969
4646-5693
HTTIU05 671 931015 AC022259 2941 1-585
HTTIU05 671 931015 AC008663 2942 1-101
HTTIU05 671 931015 AC008663 2943 1-130
HTTIU05 671 931015 AC010339 2944 1-130
HTTIU05 671 931015 AC022259 2945 1-478
HTTIU05 671 931015 AC022259 2946 1-280
HTTIW81 672 922817 AL357149 2947 1-433
HTTIW81 672 922817 AL357149 2948 1-399
HTTIZOS 673 930994 AC012246 2949 1-443
HTTIZOS 673 930994 AC012246 2950 1-646
HTTJA11 674 839725 AC068403 2951 1-440
HTTJA11 674 839725 AC067775 2952 1-440
HTTJAll 674 839725 AC068403 2953 1-288
HTTJA11 674 839725 AC067775 2954 1-288
HTTJA47 675 869618 AP002091 2955 1-276
3023-3207
HTTJA47 675 869618 AP002091 2956 1-149
HTTJA47 675 869618 AP002091 2957 1-179
HTTJH13 676 869615 AC013436 2958 1-324
HTTJH13 676 869615 AC004859 2959 1-324
HTTJH13 676 869615 AC013436 2960 1-209
HTTJH13 676 869615 AC013436 2961 1-65
191-304
339-660
~ 712-888
HTTJH13 676 869615 AC004859 2962 1-209
~
HTTJH13 676 869615 AC004859 2963 1-65
191-304
339-660
712-888
HTTJMO1 677 913799 AC009469 2964 1-310
383-487
HTTJ 06 678 934130 AC022202 2965 1-1086
HTTJQ06 678 934130 AL136969 2966 1-308
973-1308
4938-4961
8196-8326
11508-12593
13039-13501
168
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
15003-15234
17040-17530
20304-20729
25068-25578
25828-26705
26728-26816
26831-27320
28927-29311
29405-29614
30437-31474
HTTJ 06 678 934130 AC022202 2967 1-461
HTTJ 06 678 934130 AL136969 2968 1-98
HTTJ 06 678 934130 AL136969 2969 1-377
HTTJX68 679 974063 AC026318 2970 1-312
987-1439
3651-3801
HTTJX68 679 974063 AC023910 2971 I-453
HTTJX68 679 974063 AC026318 2972 1-241
HTTJX68 679 974063 AC026318 2973 1-128
HTTJY08 680 958170 AL355586 2974 1-453
HTTJY08 680 958170 AL355307 2975 I-453
HTTJY08 680 958170 AL023584 2976 1-453
HTTJY08 680 958170 AL355586 2977 1-349
HTTJY08 680 958170 AL355307 2978 1-349
HTTJY08 680 958170 AL023584 2979 1-349
HTTKF89 682 960928 AL035425 2980 1-524
HTTI~F89 682 960928 AL035425 2981 1-133
HTTI~F89 682 960928 AL035425 2982 1-418
HTTKI~06 684 974311 AC046137 2983 1-1282
1645-2164
3070-3680
3888-3943
3999-4329
5064-5333
6343-6658
6733-6987
7096-7247
7432-7831
8006-8123
8293-8756
9804-9858
HTTKK06 684 974311 AL138965 2984 1-1284
1646-2165
3071-3681
3889-3944
4000-4499
5065-5333
169
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
6343-6662
6733-6987
7096-7247
7432-7831
8006-8123
8293-8756
9803-9857
HTTKL80 685 974316 AC027572 2985 1-495
HTTKN21 686 974310 AC024563 2986 1-495
HTTKN21 686 974310 AC010318 2987 1-495
HTTKN21 686 974310 AC008626 2988 1-495
HTTKN2I 686 974310 AC024563 2989 1-276
HTTKN21 686 974310 AC010318 2990 1-276
HTTKN21 686 974310 AC008626 2991 1-276
HTTKS13 688 926795 AC023593 2992 1-494
HTTKS13 688 926795 AC012406 2993 1-195
510-647
1298-1791
2210-2419
2689-291
I
3871-4132
4236-4418
5740-5922
9461-9715
10556-10634
HTTKS13 688 926795 AC023593 2994 1-207
480-702
1662-1923
HTTKS13 688 926795 AC012406 2995 I-87
HTTKV17 689 830008 AC005027 2996 1-993
2319-3110
3184-3327
3609-3791
4475-4927
8332-9120
9164-9583
10780-11193
12543-14416
HTTKV17 689 830008 AC005027 2997 1-2780
HUDAM29 690 529157 AL161451 2998 1-354
HUDAM29 690 529157 AL161451 2999 1-238
HUDBZ78 691 739638 AC018638 3000 1-I23
666-828
4839-5113
6402-6995
7727-7910
9744-9996
170
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
10630-10732
14112-14236
17737-17771
19858-20081
20801-20915
21556-21640
22127-22645
HtTDBZ78 691 739638 AC018638 3001 1-368
HUDBZ78 691 739638 AC018638 3002 1-374
HUDBE95 694 795796 AC019073 3003 1-780
5430-5615
7641-7685
10826-10887
11255-11332
12359-12669
13590-13776
16097-16197
16225-16569
17409-17588
17614-18145
18212-18277
20025-20135
21203-21289
21668-21798
22067-22836
22902-23233
23289-24983
HUDBE95 694 795796 AC009079 3004 1-780
1966-2659
5432-5617
7643-7687
10830-10891
11259-11336
12363-12673
13594-13780
16101-16201
16229-16573
17510-17593
17618-18149
18216-18281
20020-20130
21198-21284
21663-21793
22060-22829
22895-23226
23282-24977
HUDBE95 694 795796 AC019073 3005 1-464
171
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HUDBE95 694 795796 AC009079 300 1-454
6
HUDAI~19 700 671974 AC024249 _ 1-882
3007
1119-1964
HTTI~C85 702 956206 AC007246 3008 1-445
HTTI~C85 702 956206 AC007246 3009 1-653
HTTI~C85 702 956206 AC007246 3010 I-766
HTTJN26 704 869612 AC010761 _ 1-545
3011
730-2324
2733-2817
2910-2993
3334-3705
4186-4362
HTTJN26 704 869612 AC010761 3012 1-158
HTTJN26 704 ~ 869612 AC010761 3013 1-244
HTTIXOS 706 931024 AL138955 3014 1-492
646-1277
1480-2938
HTTIX05 706 931024 ALI36I04 3015 1-493
647-1278
1481-2939
HTTIXOS 706 931024 AL136104 3016 1-124
HTTIN11 709 965920 AC073580 3017 1-815
HTTIN11 709 965920 AL109916 3018 1-815
HTTIN11 709 965920 AC073580 3019 1-436
HTTIN11 709 965920 AC073580 3020 1-228
HTTIN11 709 965920 ALI09916 3021 1-436
HTTIN11 709 965920 AL109916 3022 1-228
HTTIE08 710 958169 AC026405 3023 I-4307
HTTIE08 710 958169 AC020566 3024 1-575
HTTIE08 710 958169 AC016901 3025 1-6684
HTTIE08 710 958169 AC020566 _ 1-34
3026
1050-1364
HTTIE08 710 958169 AC016901 3027 1-131
1868-2214
2273-2385
3084-3172
HTTIB 12 711 969568 AC026576 3028 1-71 S
HTTHJ56 712 944914 AC013715 3029 I-241
407-704
1629-1750
3363-3439
6942-7140
7436-7629
11318-11960
HTTFG12 713 751809 AC068289 3030 1-1168
HTTFG12 713 751809 AC068289 3031 1-104
HTTEQ59 715 ~ 739445 AC018654 3032 1-113
~ ~
172
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
608-2226
2955-3217
3366-4135
4148-4842
HTTEQ59 715 739445 AC022073 3033 1-113
608-2226
2955-3217
3366-4135
4148-4842
HTTE O1 716 917156 283845 3034 1-684
HTTEQOl 716 917156 283845 3035 I-504
658-707
1786-3045
3351-4099
HTTE059 717 900662 AC046168 3036 1-2879
HTTE053 7I8 728344 AC074116 3037 1-280
905-4002
HTTE053 718 728344 AL162722 3038 1-280
905-3688
HTTE053 718 728344 AC074116 3039 1-99
HTTE053 718 728344 AL162722 3040 1-99
HTTEJ56 719 573669 AC068707 3041 I-134
1054-1276
1688-1740
2572-2856
2936-3012
3748-3941
4846-4969
5395-5467
5675-6158
HTTEJ56 719 573669 AC068707 3042 1-1098
HTTEBOS 720 932294 AL031672 3043 1-1512
HTTEBOS 720 932294 AL031672 3044 1-489
HTTEBOS 720 932294 AL031672 3045 1-692
4641-5166
6143-6251
8784-8849
11398-I
1796
11851-12038
13499-13858
14606-14716
17177-17863
19079-19195
19315-19699
20154-20572
22216-22455
22597-23544
173
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTTD059 721 744438 AL160282 3046 1-671
781-2678
2858-2994
3178-3347
3426-3693
HTTDM42 722 460948 AC073619 3047 1-421
704-793
1909-2043
HTTDM42 722 460948 AL354745 3048 1-421
704-793
1910-2044
2204-2966
3204-4359
HTTDM42 722 460948 AL354745 3049 1-904
HTTDM42 722 460948 AL354745 3050 1-233
HTTDL81 723 694222 AL022328 3051 1-481
729-828
1094-1193
1289-1396
1553-1617
1798-1929
2089-2152
2247-4100
4146-4381
4518-4577
4865-4961
5157-5580
5725-6072
HTTDL81 723 694222 AL022328 3052 1-723
~
HTTDL81 723 694222 AL022328 3053 1-81
162-241
315-880
1024-1324
1365-1937
2215-2794
HTTDL7S 724 766551 AC068013 3054 1-384
HTTDL75 724 766551 AC068471 3055 1-697
HTTDL75 724 766551 AC074378 3056 1-697
HTTDL75 724 766551 AC074378 3057 1-495
HTTCQ95 726 796674 AC026065 3058 1-100
772-894
1216-1581
1841-2015
2208-2519
3025-3350
3659-4132
6075-6743
174
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTTBR42 730 714220 AL1S7409 3059 1-570
4245-4986
~
HTTBR42 730 714220 AL1S7409 3060 1-312
HTTB082 732 780164 AC044902 3061 1-436
477-893
HTTB082 732 780164 AC009S9S 3062 1-436
477-893
HTTB082 732 780164 AC044902 3063 1-256
HTTBM03 733 925409 AC031984 3064 1-766
2180-2586
3286-3634
3651-3858
3 895-4311
HTTBM03 733 925409 ALOS0318 3065 1-766
217 8-25
84
3284-3632
3649-3856
3893-4309
4861-SOOS
7178-7361
11400-11880
12124-123
92
13017-13267
15332-15583
15793-16031
16947-17288
18668-18837
19381-19764
21255-21574
22689-22887
23670-23952
27931-28039
28646-28948
29548-29705
30258-32335
HTTBM03 733 925409 AL390374 3066 1-766
2178-2S
84
3284-3632
3649-3856
3893-4309
4861-SOOS
7178-7362
11063-11173
11400-11880
12124-12392
13017-13268
15332-1SS83
175
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
15795-16033
16952-17289
18674-18843
19387-19770
21261-21580
22695-22893
23676-23958
27937-28045
28652-28954
29556-29713
30266-32343
HTTBM03 733 925409 AC031984 3067 1-145
HTTBM03 733 925409 AL050318 3068 1-151
HTTBM03 733 925409 AL050318 3069 1-195
HTTBM03 733 925409 AL390374 3070 1-195
HTTBI80 734 781590 AC008628 3071 1-162
1001-1703
HTTBI80 734 781590 AC010226 3072 1-162
1001-1703
HTTBH95 735 530559 AL121759 3073 1-182
1815-1886
HTTBH95 735 530559 AL121759 3074 1-457
HTTAQ60 738 742377 AC055720 3075 1-643
842-1218
HTTAQ60 738 742377 AC024145 3076 1-643
842-1223
HTTA 60 738 742377 AC055720 3077 1-679
HTTA 60 738 742377 AC024145 3078 1-679
HTTAQ60 738 742377 AC024145 3079 1-135
HTTAP21 740 671488 AL023803 3080 1-198
4122-4247
8722-8781
12640-12742
15684-15778
17532-17609
17745-18841
19072-19205
20937-21397
21427-21993
22264-22342
24544-24618
28047-28160
30396-30560
32340-33565
HTTAP21 740 671488 AL023803 3081 1-293
HTTAP21 740 671488 AL023803 3082 1-414
HTTAP09 741 826343 AC023593 3083 1-437
176
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTTAP09 741 826343 AC012406 3084 1-437
HTTAP09 741 826343 AC012406 3085 1-786
1865-1938
HTTAP09 741 826343 AC023593 3086 1-787
1865-1938
HTTAC77 745 772735 AC021291 3087 1-779
HTTAA94 746 793001 AL031255 3088 1-908
HTTAA94 746 793001 AL031255 3089 1-480
HTTAA39 747 710355 AC016691 3090 1-526
564-1577
HTTAA39 747 710355 AC015719 3091 1-1149
HTTAA39 747 710355 AC016691 3092 1-496
HTTAA39 747 710355 AC016691 3093 1-106
HTTAA39 747 710355 AC015719 3094 1-840
HTLIP06 748 934207 AL162586 3095 1-2160
2297-2470
HTLIP06 748 934207 AL162426 3096 1-2160
2297-2472
3211-3477
3629-4087
HTLIP06 748 934207 AC007430 3097 1-2160
2297-2472
3211-3477
3629-4087
HTLIP06 748 934207 AL162586 3098 1-136
294-491
2350-2692
3660-3898
HTLIP06 748 934207 AL162426 3099 1-136
294-491
2351-2693
3661-3899
HTLIP06 748 934207 AC007430 3100 1-136
294-491
2351-2693
3661-3899
HTLIP06 748 934207 AL162426 3101 I-118
HTLIP06 748 934207 AC007430 3102 1-118
HTLHS69 753 870152 AC009095 3103 1-220
227-466
573-1448
HTLHSOS 754 933720 AL121753 3104 1-77
91-640
2531-2639
3380-3625
3692-4433
4677-4862
177
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
5043-5355
5532-5893
6299-10579
12966-13230
14676-15242
15749-15996
16066-16393
16675-17238
17381-17885
18029-18260
19347-19477
20064-20199
20849-21010
HTLHS05 754 933720 AL356652 3105 1-77
91-640
2531-2639
3380-3625
3 692-443
3
4677-4862
5043-5355
5532-5893
6299-10590
12979-13243
14689-15255
I 5762-16052
16079-16406
16688-17251
17394-17898
18042-18273
19363-19509
20088-20188
20863-21024
HTLHS05 754 933720 AL121753 3106 1-437
HTLHS05 754 933720 AL121753 3107 1-638
793-854
HTLHS05 754 933720 AL356652 3108 1-437
HTLHS05 754 933720 AL356652 3109 1-638
793-854
HTLHJ51 756 865399 AC027421 3110 1-I46
1403-3399
HTLHJ51 756 865399 AC025860 3111 1-146
1402-3398
HTLHJ51 756 865399 AL353622 3112 1-146
1402-3
3 98
HTLHB93 757 945862 AL161656 3113 1-585
HTLHB93 757 945862 AL035460 3114 1-585
HTLHB93 757 945862 AL161656 3115 1-29
178
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
92-45 9
544-844
HTLHB93 757 945862 AL161656 3116 1-7
54
HTLHB93 757 945862 AL035460 3117 _
1-29
92-45 9
544-844
HTLHB93 757 945862 AL035460 3118 1-754
HTLGS10 759 963458 AC055863 3119 1-34
227-316
895-1294
1518-1678
1917-2553
HTLGR32 760 928245 AC013403 3120 1-1399
HTLGR32 760 928245 AC013403 3121 1-391
HTLGR32 760 928245 AC013403 3122 1-126
HTLGP84 761 782194 AC020934 3123 1-58
591-853
900-1357
HTLGC43 763 870228 AL118524 3124 1-903
936-2052
HTLGC43 763 870228 AL118524 3125 1-497
HTLEQ92 764 932882 AC009109 3126 1-303
1003-1241
2173-2763
HTLEQ92 764 932882 AC010531 3127 1-303
1003-1241
2173-2763
2907-3967
4804-4849
4950-7755
HTLEQ92 764 932882 AC009109 3128 1-722
HTLE 92 764 932882 AC010531 3129 1-1592
HTLEP21 765 671151 AC016774 3130 1-138
467-569
810-930
1056-1149
1553-1686
1774-2544
HTLEP21 765 671151 AC010789 3131 1-138
468-570
811-931
1057-1150
1554-1687
1775-2546
HTLEP21 765 671151 AC016774 3132 1-594
1023-1155
1772-2162
179
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2448-2739
j
2975-3438''
~
3681-4096
~
4814-4865
5289-5389
5443-5627
7000-7166
7396-8248
8876-9167
10516-10689
11193-11857
12200-12372
12455-12745
13874-14148
14398-14684
15738-15861
16053-16243
17510-17938
18019-18179
18259-18528
18587-18676
18960-19577
19606-20010
20036-21667
22067-26217
26261-26631
26869-27524
27631-28143
28212-28560
29119-29156
29687-30245
30256-31203
31798-33971
HTLEP21 765 671151 AC010789 3133 1-595
1024-1156
1773-2165
2447-273
8
2974-3437
3680-4095
4813-4864
5288-5388
5442-5626
6999-7165
7395-8247
8875-9166
10515-10688
11192-11856
180
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
12199-12371
12454-12755
13981-14147
14397-14683
15737-15860
16052-16242
17509-17937
18018-18178
18258-18527
18586-18675
18959-19576
19605-20009
20035-21666
22243-26224
26240-26630
26868-27523
27630-28149
28212-28560
29119-29156
29688-30247
30269-31205
31800-33973
HTLDO01 772 913669 AC002056 3134 1-1300
HTLDO01 772 913669 AC000036 3135 1-1300
2
362-2937
HTLDO01 772 913669 AC002056 3136 __
_
1-375
HTLDO01 772 913669 AC000036 3137 1-829
1755-2331
3054-3393
5260-5322
HTLDO01 772 913669 AC000036 3138 1-375
HTLCZ79 775 572853 AC004064 3139 1-285
HTLCZ79 775 572853 AL161939 3140 1-285
HTLCZ79 775 572853 AL118502 3141 1-285
HTLCZ79 775 572853 AC004064 3142 1-97
HTLCZ79 775 572853 AC004064 3143 1-471
571-1561
HTLCZ79 775 572853 AL161939 3144 . 1-471
571-1561
_
HTLCZ79 775 572853 AL118502 3145 1-471
571-1561
HTLC002 777 921045 AC066588 3146 1-242
2043-2258
HTLCG65 778 413333 AC015549 3147 1-167
HTLCG65 778 413333 AC006060 3148 1-171
3245-3475
3590-3742
181
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
4110-4269
X242-5535
6465-6516
HTLCG59 779 530039 AC027712 3149 1-46
3805-3943
5188-5370
6708-6843
7531-7689
8008-8127
8669-8788
9234-9406
9698-10187
10689-15514
HTLCG59 779 530039 AL356097 3150 1-46
3805-3943
5188-5370
6709-6844
7530-7688
8007-8126
8668-8787
9234-9406
9698-10187
10693-15517
HTLCG59 779 530039 AC027113 3151 1-46
3805-3944
5189-5371
6709-6844
7530-7688
8007-8126
8668-8787
9233-9405
9697-10186
10692-15518
HTLCG59 779 530039 AC027712 3152 1-595
HTLCG59 779 530039 AL356097 3153 1-595
HTLCG59 779 530039 AC027113 3154 1-S95
HTLBH67 781 751985 AC008439 3155 1-62
293-400
452-976
1016-1058
1463-1534
1886-2026
2110-2249
2401-2463
3324-4027
4192-4288
4694-5330
182
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
S48S-S6S0
5813-6262
6273-6401
6475-6559
6728-6847
6979-7205
7573-7676
7730-8146
8334-8866
8885-9392
HTLBH67 781 7S198S AC008781 3156 I-8S
2S4-371
SOS-731
1098-1201
12SS-1671
1718-2387
2408-2915
3113-3244
3382-4278
4504-4538
4650-S64S
HTLBH67 781 7SI98S AC022420 3157 1-62
29S-403
4SS-979
1019-1061
1466-1537
1890-2030
2114-2253
2405-2467
3328-4030
4195-4291
4697-5333
5488-S6S3
5816-6265
6276-6404
6478-6562
6731-6850
6982-7208
7S7S-7678
7732-8148
8195-8864
8885-9392
9590-9721
9859-10754
10980-11014
11126-12121
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183
CA 02393616 2002-06-05
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294-399
451-975
1015-1057
1462-1533
1885-2025
2109-2248
2400-2462
3323-4026
4191-4287
4693-5329
5484-5649
5812-6264
6275-6403
6477-6561
6730-6849
6981-7207
7575-7678
7732-8148
8201-8868
8887-9394
9592-9723
9861-10759
10985-11019
11131-12126
HTLBH67 781 751985 AC00878I 3159 1-292
HTLBH67 781 751985 AC022420 3160 1-323
1372-1431
1657-1821
2377-2485
4488-4700
4954-5061
6224-6547
6819-6965
7268-7333
8088-8593
9897-10068
10109-10623
10645-10680
10812-10871
10982-11123
11345-11383
11877-12000
12310-13467
HTLBH67 781 751985 AC022420 3161 1-292
HTLBH67 781 751985 AC005368 3162 I-292
HTLBC07 782 954111 AC015841 3163 1-668
HTLBC07 782 954111 AC018617 3164 1-672
184
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTLBC07 782 954111 AC004S86 3165 1-672
~
HTLBC07 782 954111 AC015841 3166 1-124
HTLBC07 782 954111 ACOI86I7 3167 1-124
HTLBC07 782 954111 AC004586 3168 1-514
681-994
1116-1732
1974-2431
2451-3123
3603-3698
4469-4606
5033-5496
6293-6890
6965-8015
8053-8130
HTLBC07 782 954111 AC004586 3169 1-77
3689-3807
3960-4294
4692-4820
5674-5809
6237-6334
713 8-7247
8211-8309
8720-8861
9797-10087
10098-1021
S
10448-11237
11311-11550
11566-11654
12306-12914
12929-13575
13587-13703
14256-14391
14535-14763
17193-17450
HTLAB29 789 879168 AC026362 3170 1-389
508-653
1079-1226
1867-2043
213 6-223
9
2359-3327
3438-3958
4003-5312
HTLAB29 789 879168 AC026362 3171 1-336
HTFBE02 790 920507 AC022536 3172 1-31
340-421
1097-1262
2446-2621
185
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
3069=3161
3571-3791
4947-5076
5905-6987
HTFBE02 790 920507 AC022536 3173 1-102
HTE S95 791 972746 AL133284 3174 1-1005
HTE S95 791 972746 AL133284 3175 1-258
HTE S90 792 973426 AP000635 3176 1-692
HTE S90 792 973426 AP000610 3177 1-691
HTEQS90 792 973426 AP001547 3178 1-691
HTE S90 792 973426 AP000635 3179 1-543
HTE S90 792 973426 AP000610 3180 1-197
HTE S90 792 973426 AP001547 3181 1-197
HTE S90 792 973426 AP000610 3182 1-543
HTE S90 792 973426 AP001547 3183 1-543
HTEQP03 793 870516 AC018931 3184 1-238
672-970
6605-6665
HTEQP03 793 870516 AC018931 3185 1-323
373-560
HTE B08 795 958291 AL139106 3186 1-831
HTE B08 795 958291 AL162721 3187 1-831
HTE B08 795 958291 AL139106 3188 1-324
HTEQB08 795 958291 AL162721 3189 1-261
805-1128
HTEOE28 801 870581 AL139243 3190 1-1106
HTENY44 802 870588 AC027544 3191 1-197
710-864
1263-1380
2382-2706
3184-3394
3970-4082
HTENY44 802 870588 AC027544 3192 1-570
HTENY44 802 870588 AC027544 3193 1-322
HTENV06 803 933294 AL121753 3194 1-498
HTENV06 803 933294 AL356652 3195 1-498
HTENV06 803 933294 AL121753 3196 1-116
HTENV06 803 933294 AL356652 3197 1-104
HTENL95 808 795314 AC022930 3198 1-32
79-745
880-1680
1782-2276
2861-3730
4861-5265
HTENL95 808 795314 AC069217 3199 1-32
79-745
186
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
880-1679
HTENL95 808 795314 AF238376 3200 1-32
79-745
880-1680
HTENL95 808 795314 AC022930 3201 1-150
215-626
662-1438
23 51-2999
HTENL95 808 795314 AC022930 3202 1-297
HTENL95 808 795314 AC069217 3203 1-297
HTENL95 808 795314 AF238376 3204 1-297
HTENL95 808 795314 AC069217 3205 I-495
HTENL95 808 795314 AF238376 3206 1-495
HTENA08 810 958380 297985 3207 1-460
851-1242
1372-1475
2276-2373
HTENA08 810 958380 297985 3208 1-264
HTEMY05 811 880592 AC019326 3209 I-734
1378-6434
HTEMY05 811 880592 AF129408 3210 1-734
1378-7065
HTEMY05 81I 880592 AC019326 3211 1-579
HTEMY05 811 880592 AF129408 3212 1-756
HTEMU66 813 944419 AC006510 3213 1-1150
HTEMU66 813 944419 AL022167 3214 1-1796
HTEMU66 813 944419 AC018903 3215 1-631
HTEMU66 813 944419 AC068470 3216 1-706
HTEMU66 813 944419 AL049186 3217 1-912
HTEMU66 813 944419 AC022305 3218 I-686
HTEMU66 813 944419 AL049186 3219 1-87
HTEMN80 816 775543 AP001386 3220 1-2970
3001-4307
HTEMN80 816 775543 AP002785 3221 1-2974
3005-4311
HTEMN80 816 775543 AP001386 3222 1-300
HTEMN80 8I6 775543 AP002785 3223 1-236
HTEMI51 818 870613 AL365214 3224 I-94
3508-4007
HTELV29 821 806421 AC068938 3225 1-643
HTELV29 821 806421 AC073407 3226 1-2055
3690-3915
3928-4379
4421-5222
7704-8003
11303-11530
I87
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
12021-12259
12917-14410
HTELV29 821 806421 AC073407 3227 1-350
HTELP07 822 952274 AC041014 3228 1-118
490-918
HTELP07 822 952274 AC041014 3229 1-332
HTELA02 824 918699 AC021688 3230 1-687
1014-1336
HTEKI62 826 812862 AC005848 3231 1-164
343-428
578-2903
3020-3168
4072-4415
5074-5526
5
547-5780
HTEI~I62 826 812862 AC005848 3232 _
1-863
1241-1590
1666-2167
2328-2424
2500-2950
3000-3341
3351-3962
3976-3995
4276-5430
5485-5585
5616-5892
6622-6727
7156-8018
HTEKD77 828 772397 AC018865 3233 1-1638
HTEJV94 829 793039 AC058807 3234 1-946
HTEJV94 829 793039 AC003669 3235 1-946
HTEJN12 831 653252 AL096763 3236 1-118
1052-1310
3744-4364
4488-4515
5291-5447
6507-7124
7157-7605
7842-8575
HTEJL30 832 696784 AG012379 3237 1-2084
HTEJL30 832 696784 AC009697 3238 I-2084
HTEJL30 832 696784 AC012379 3239 1-142
HTEJL30 832 696784 AC009697 3240 1-719
HTEJL30 832 696784 AC012379 3241 1-719
HTEJL30 832 696784 AC009697 3242 1-I42
HTEJB07 834 953801 AC073625 3243 1-494
2402-2532
188
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
HTEJB07 834 953801 AC007394 3244 1-430
HTEJB07 834 953801 AC073625 3245 1-1712
1727-2677
HTEJB07 834 953801 AC007394 3246 1-1712
17
27-2677
HTEIS34 835 887112 AC069257 3247 _
1-635
725-895
1011-1169
1645-2361
2527-3215
3399-3766
3 842-4045
HTEIS34 835 887112 AC026308 3248 1-635
725-895
1011-1169
1645-2361
2527-3215
3399-3766
3 842-4045
HTEIS34 835 887112 AC069257 3249 1-165
HTEIS34 835 887112 AC069257 3250 1-380
HTEIS34 835 887112 AC026308 3251 1-381
HTEIS34 835 887112 AC026308 3252 1-486
HTEIS25 836 870660 AC053512 3253 1-252
304-440
462-606
851-994
HTEIS25 836 870660 AL360086 3254 1-253
305-441
463-607
852-995
HTEHX57 845 734976 AC023756 3255 1-91
1173-1400
3751-4383
4431-4890
5497-5769
5920-6396
HTEHX57 845 734976 AP001152 3256 1-452
1059-1331
1482-1958
HTEHX57 845 734976 AC011007 3257 1-79
3753-3901
9145-9297
9344-9538
13689-14081
14559-14683
15765-15992
I89
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
17822-18243
18342-18974
19022-19481
20088-20360
20511-20987
HTEHX57 84S 734976 AC023756 3258 1-1701
I83I-4730
HTEHX57 845 734976 AP001152 3259 1-1702
1835-4742
HTEHX57 845 734976 ACOlI007 3260 1-1701
HTEHV11 846 967439 AL021331 3261 1-569
HTEHVII 846 967439 AL021331 3262 1-690
HTEHS17 847 664436 AC010255 3263 1-184
308-529
2761-3109
HTEHS17 847 664436 AC010255 3264 1-502
HTEHS17 847 664436 AC010255 3265 1-130
310-1003
1040-1331
HTEGU55 850 931017 298752 3266 1-2035
HTEGU55 8S0 931017 298752 3267 1-465
HTEGU55 8S0 931017 Z987S2 3268 1-415
HTEGC30. 856 690998 AC073079 3269 I-504
HTEF046 8S9 719280 AC068790 3270 1-31
136-656
HTEF046 859 719280 AC024438 3271 1-31
136-942
1083-4020
HTEF028 860 685383 AC023123 3272 1-119
151-982
1019-1286
1442-1755
1908-2137
2256-2608
2974-3413
4977-5488
5507-8584
8676-10198
HTEF028 860 685383 AC006534 3273 1-I19
151-982
1019-1286
1442-1755
1986-2137
2256-2608
2974-3413
4977-5488
5507-8584
190
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
8676-10198
HTEF028 860 685383 AC023123 3274 1-546
601-659
HTEF028 860 685383 AC006534 3275 1-230
234-264
HTEF028 860 685383 AC023I23 3276 I-237
~
239-272
HTEF028 860 685383 AC006534 3277 1-546
601-659
HTEET22 866 675071 AC022930 3278 I-649
1562-2338
2374-2785
2850-2999
HTEET22 866 675071 AC069217 3279 1-777
813-1224
1289-1366
HTEET22 866 675071 AF238376 3280 I-38
1258-1452
3186-3304
3555-3746
6146-6232
8I 1 I-8262
9292-9751
10190-10839
11752-12528
12564-12975
13040-13189
HTEET22 866 675071 AC022930 3281 1-460
HTEET22 866 675071 AC022930 3282 1-405
1536-2405
2990-3484
3586-4386
4521-5187
5234-5265
HTEET22 866 675071 AC0692I7 3283 1-402
HTEET22 866 675071 AF238376 3284 1-408
HTEEF25 867 677513 AC012330 3285 1-344
HTEEF25 867 677513 AC008132 3286 1-344
HTEEF25 867 677513 AC023491 3287 1-344
HTEEF25 867 677513 AC008103 3288 1-583
683-2302
5090-5245
5708-5746
5973-6045
HTEEF25 867 677513 ACO23490 3289 1-582
682-2297
HTEEF25 867 677513 AC008079 3290 1-583
191
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
683-2302
4878-5241
5704-5742
5969-6041
HTEEF2S 867 677513 AC007325 3291 1-S83
683-2306
4881-5244
5707-S74S
5972-6044
HTEEF2S 867 677513 AC007708 3292 1-S82
682-2297
HTEEF2S 867 677513 AC007324 3293 1-S82
,.682-2301
5089-5244
5707-S74S
5972-6044
HTEEF2S 867 677513 AC008018 3294 1-S82
682-2301
4877-5240
5703-5741
5968-6040
HTEEF2S 867 677513 AC007981 3295 1-340
HTEEF2S 867 677513 AC008103 3296 1-603
HTEEF2S 867 677513 AC008103 3297 1-233
HTEEF2S 867 677513 AC023490 3298 1-603
HTEEF2S 867 677513 AC008079 3299 1-4S2
11SS-1470
1497-1744
6815-7114
8000-8325
8749-9359
10364-1OS77
IOS86-10884
11714-12079
14576-14752
169SS-17117
17240-17567
21365-21630
23483-23784
23982-24078
24280-24312
2SS97-25744
2S9S2-26024
26254-26692
27187-27493
27543-27657
27931-28344
192
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
31056-31145
31243-31541
31698-31846
33652-33750
34559-34729
34936-35276
36328-36748
36956-37092
37601-37650
38741-38979
40580-41206
HTEEF25 867 677513 AC008079 3300 1-233
HTEEF25 867 677513 AC007325 3301 1-603
HTEEF25 867 677513 AC007325 3302 1-235
HTEEF25 867 677513 AC007708 3303 I-603
HTEEF25 867 677513 AC007324 3304 1-234
HTEEF25 867 677513 AC007324 3305 1-603
HTEEF25 867 677513 AC008018 3306 1-233
HTEEF25 867 677513 AC008018 3307 1-603
HTEEF25 867 677513 AC007981 3308 1-488
HTEEB82 868 780161 AC026140 3309 1-8I
1974-2064
2695-2852
2934-3354
4059-4360
4682-4800
HTEEB82 868 780161 AL033531 3310 1-81
1974-2064
2695-2852
2934-3354
4059-4845
HTEEB82 868 780161 AC026140 3311 1-212
HTEEB82 868 780161 AL033531 3312 1-669
HTEEB82 868 780161 AL033531 3313 1-212
HTEDX39 869 530201 AC005726 3314 1-257
HTEDX39 869 530201 AC005726 3315 1-124
HTEDX39 869 530201 AC005726 3316 1-81
754-902
1011-1476
1836-2127
3328-3518
371 S-3773
43 07-4426
4S I 6-4946
5049-5097
5496-5623
6425-6598
193
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HTEDX04 870 927850 AF111169 3317 1-136
1693-1823
1913-2092
2493-2707
4607-4680
HTEDX04 870 927850 AF111169 3318 1-347
HTEDX03 87.1 925353 AC005300 3319 1-202
HTEDX03 871 925353 AC006946 3320 1-202
HTEDX03 871 925353 AC006946 3321 1-168
HTEDW96 872 881958 AC017028 3322 1-477
786-1004
HTEDW96 872 881958 AC017028 3323 1-867
HTEDW59 873 530448 AC025868 3324 1-217
HTEDW59 873 530448 AC025868 3325 1-264
363-446
HTEDV86 874 785818 AL356801 3326 1-763
HTEDV86 874 785818 AL356801 3327 1-142
HTED075 878 767024 AL049541 3328 1-910
HTEDJ92 880 522827 AL390815 3329 1-295
HTEDI01 883 961028 AC019205 3330 1-224
HTEDH30 887 522936 AL049697 3331 I-57
1807-1921
2559-262
5
HTEDH30 887 522936 AL049697 3332 _
1-365
381-1034
HTEDH17 888 522938 AC026124 3333 1-413
HTEDH17 888 522938 AC012597 3334 1-413
HTEDH06 889 869427 AC006251 3335 1-718
767-1512
1639-2023
2398-2655
2926-2990
3300-3357
4357-4395
5163-5275
5927-6337
6945-7074
7156-7444
HTEDH06 889 869427 AC006251 3336 1-163
460-673
787-898
4433-4791
6955-7223
7246-7642
11004-11548
12185-12593
13374-13482
194
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14491-14587
15381-16043
16395-16546
18407-18623
19528-19762
19852-20715
21495-21936
HTEDH06 889 869427 AC006251 3337 1-400
HTEDF96 892 614726 AC021163 3338 1-540
655-1021
1053-1143
1354-1536
1692-1762
1924-2030
2867-2962
3191-4078
413 5-4228
4365-4458
4565-4675
4747-4815
4901-4977
5232-5675
6013-6910
HTEDF96 892 614726 AC006942 3339 1-541
656-1023
1055-1145
1356-1538
1694-1764
1926-2032
3194-4081
413 8-4231
4368-4461
4568-4678
4750-4818
4904-4980
5235-5678
6016-6914
7138-7281
7453-7737
7813-8322
8835-9123
9152-10108
10204-10288
- 10387-10448
11252-11414
11496-11676
11746-12218
195
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12336-12436
13243-13426
13626-13767
13891-14067
14442-14596
15655-15742
16852-17292
17660-17764
18610-18921
19197-19405
19407-19499
20302-20404
20510-20780
21329-21458
HTEDF96 _892 614726 AC021163 3340 1-288
HTEDF96 892 614726 AC006942 3341 1-
288
HTEDF22 895 908406 AL138891 3342 _
1-822
HTEDF22 895 908406 AC002418 3343 1-823
HTEDF22 895 908406 AC004386 3344 1-823
HTEDF22 895 908406 AL138891 3345 1-155
HTEDF22 895 908406 AC002418 3346 1-142
HTECE66 896 522997 AL159160 3347 1-61
5520-5850
HTECE66 896 522997 AL390071 3348 1-61
620-770
5508-5838
HTECE66 896 522997 AL390071 3349 1-259
HTECE62 897 523002 AC069401 3350 1-158
259-547
1614-2136
HTECE62 897 523002 AC005232 3351 1-158
259-547
1614-2136
HTECE51 899 870723 AC016976 3352 1-301
HTECE51 899 870723 AC058805 3353 1-301
HTECE51 899 870723 AC027764 3354 1-301
HTECE51 899 870723 AC016976 3355 1-425
HTECE51 899 870723 AC027764 3356 1-425
HTECE31 901 508104 AC069360 3357 1-283
HTECE31 901 508104 AC023850 3358 1-283
HTECE3I 901 508104 AC069360 3359 1-409
HTECE3I 901 508104 AC023850 3360 1-
409
HTECD94 903 527210 AC025959 3361 _
1-58
828-1050
2944-3114
3238-3330
HTECD94 903 527210 AC025963 3362 1-127
196
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951-1008
1778-2000
3894-4064
4188-4280
HTECD94 903 527210 AC009451 3363 1-127
951-1008
1781-2003
3897-4067
4191-4283
HTECD94 903 527210 AC025959 3364 1-151
HTECD94 903 527210 AC025963 3365 1-151
HTECD94 903 527210 AC009451 3366 1-151
HTECD88 904 527214 AC024631 3367 1-560
HTECD88 904 527214 AC017098 3368 1-560
HTECD88 904 527214 AC024631 3369 1-263
HTECD88 904 527214 AC017098 3370 1-869
1451-4175
HTECD88 904 527214 AC024631 3371 1-869
1451-4174
HTECD88 904 527214 AC017098 3372 1-263
HTECD70 905 527203 AC013471 3373 1-243
3350-3433
HTECD65 906 533795 AL157899 3374 1-119
4379-4589
HTECD65 906 533795 AL137800 3375 I-119
4380-4590
HTECD65 906 533795 AL1S7899 3376 1-489
540-886
HTECD65 906 533795 AL137800 3377 1-489
540-2889
HTECDIS 908 523029 AC019082 3378 1-405
HTECD15 908 523029 AC019082 3379 1-136
545-583
824-1177
HTECC71 909 508142 AC060234 3380 1-364
HTECC45 910 508124 AC034305 3381 1-320
HTECC45 910 508124 AC034305 3382 1-539
HTECC26 911 508144 AL158090 3383 I-168
2574-2660
3463-3623
HTECC09 912 678659 AC069004 3384 1-91
238-330
1468-1597
1773-1835
2685-2851
2987-3081
3275-3440
197
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4518-4928
6204-6550
6951-7273
7923-8577
HTECC09 912 678659 AC069004 3385 1-816
HTECC08 913 960439 AC008397 3386 1-436
HTECC08 913 960439 AC008397 3387 1-314
HTECC08 913 960439 AC008397 3388 1-555
HTECA39 915 508132 AC036150 3389 1-412
HTECA39 915 508132 AP001883 3390 I-412
HTECA39 915 508132 AC036150 3391 1-496
541-1674
HTECA39 915 508132 AP001883 3392 1-461
HTECA39 915 508132 AC036150 3393 l-461
HTECA39 915 508132 AP001883 3394 1-496
541-1674
HTEBJ02 920 921321 AL031727 3395 1-1383
HTEBJ02 920 921321 AL031727 3396 I-576
HTEAX06 922 960792 AC015559 3397 1-949
HTEAX06 922 960792 AC015559 3398 1-65
86-509
733-1 178
2992-3574
4191-4337
4759-4850
6000-6163
6241-6337
6731-6852
6932-7048
7138-7271
8386-8513
9167-9300
9384-9468
9527-9830
10006-10582
11005-11153
11315-11469
11660-11810
14929-15256
15410-15569
16041-16200
16626-16799
17095-17498
17712-18272
HTEAX06 922 960792 AC015559 3399 1-188
1981-2138
3446-3545
198
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3751-3867
3900-4028
4262-4369
HTEAV22 923 679394 AC016757 3400 1-1823
HTEAV22 923 679394 AC016757 3401 1-1229
2106-2702
3129-4275
HTEAR93 927 503298 AC009967 3402 1-411
1914-2289
2844-2962
3628-4209
4664-4925
5258-5353
HTEAR93 927 503298 AC009967 3403 1-241
348-492
1563-1872
1875-2138
HTEAR93 927 _503298 AC009967 3404 1-315
HTEAG47 931 503623 AL139384 3405 1-939
HTEAG47 931 503623 AL16271I 3406 1-939
1988-2462
5032-5242
HTEAG47 931 503623 AC011695 3407 1-939
HTEAG47 931 503623 AL139384 3408 1-475
HTEAG47 931 503623 AL1627I1 3409 1-310
HTEAG47 931 503623 AL139384 3410 1-198
HTEAG47 931 503623 AL162711 3411 1-198
HTEAG47 931 503623 AC011695 3412 1-198
HTEAG47 931 503623 AC011695 3413 1-475
HTEAG08 932 960469 AC069236 3414 1-329
HTEAG08 932 960469 AC069236 3415 1-454
HTEAB50 933 724751 AL391056 3416 1-162
524-688
735-874
1577-1774
2049-2216
2395-2540
3191-3424
HTEAB50 933 724751 AC007779 3417 1-162
524-688
749-849
1579-1776
2050-2217
2396-2541
3192-3425
HTEAB50 933 724751 AC007779 3418 1-130
HEPCB04 935 941270 AL023581 3419 1-394
199
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541-679
HEPB085 937 783362 AC010192 3420 _
1-1410
HEPB085 937 783362 AC010192 3421 1-844
HEPAX40 939 535627 AP000872 3422 1-919
HEPAX40 939 535627 AP001316 3423 1-918
HEPAX40 939 535627 AC020735 3424 1-918
HEPAX40 939 535627 AP000872 3425 1-239
HEPAX40 939 535627 AP0013I6 3426 1-239
HEPAX40 939 535627 AC020735 3427 1-239
HEPAP34 942 703336 AC023500 3428 1-861
1078-1553
1584-2086
2457-5820
5956-6035
6220-6390
6480-6573
HEPAP34 942 703336 AC023500 3429 1-90
204-285
394-540
757-840
1060-1090
HEPAP34 942 703336 AC023500 3430 1-44
976-1138
1382-1480
1506-1645
2208-2505
2848-2978
3094-3276
4404-4939
5843-5881
HEPAJ14 945 657440 AL158843 3431 1-749
HEPAJ14 945 657440 AL158843 3432 I-548
HEPAJ04 946 933091 AC078837 3433 1-358
HEPAJ04 946 933091 AC015937 _ 1-295
3434
1964-2131
2295-2696
HEPAJ04 946 933091 AC007993 3435 1-295
1964-2131
2295-2696
HEPAJ04 946 933091 AC015937 3436 1-152
343-406
656-852
HEPAJ04 946 933091 AC007993 3437 1-152
~
343-406
656-852
HEPAE58 947 509130 AL356017 3438 1-422
489-1010
200
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1016-1105
4311-4768
4930-5657
12468-12775
12982-13085
17810-19506
19953-20359
20615-20935
21563-21594
21625-21685
21806-22238
HEPAE58 947 509130 AL117187 3439
1-422
489-1009
1015-1104
4310-4767
4929-5656
12467-12774
12981-13084
17809-19505
19952-20358
20614-20934
21562-21593
21624-21684
21805-22237
HEPAE02 948 921389 AC004887 3440 1-573
HEGBA01 951 915596 AC006333 3441 1-164
HEGBA01 951 915596 AC006333 3442 1-1132
HEGBA01 951 915596 AC006333 3443 1-106
HEGAQ91 953 789940 AL031319 3444 1-429
1170-1866
7200-7527
8540-8925
HEGAL55 954 731654 AL133367 3445 1-S1
740-1103
3374-3642
5341-6839
HEGAL55 954 731654 AL139300 3446 1-51
740-1103
3374-3642
5340-6838
HEGAL55 954 731654 AL133367 3447 1-680
HEGAL55 954 731654 AL139300 3448 1-535
HEGAL55 954 731654 AL139300 3449 1-680
HEGAJ08 955 959216 AC013472 3450 1-162
207-664
1217-1396
1663-1842
201
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2264-3540
3892-4029
HEGAC02 9S6 918992 293016 3451 1-1S4
1660-2193
4376-4S
18
4613-4754
S 136-5690
HEGAC02 956 918992 293016 3452 1-196
HEEAY84 957 782706 AC058792 3453 1-366
744-1 I96
HEEAY84 9S7 782706 AC024408 3454 1-366
744-1196
HEEAY84 9S7 782706 AL136091 3455 1-366
744-1196
HEEAY84 9S7 782706 AC024408 3456 1-379
HEEAY84 9S7 782706 AL136091 3457 1-379
HEEAY84 9S7 782706 ACOS8792 3458 1-379
HEEAX09 958 912065 AL35S987 3459 1-380
897-1234
1680-1754
2724-3894
HEEAX09 958 912065 AL3S5987 3460 1-412
HEEAW40 9S9 7106SS AL132982 3461 I-47S
741-1367
HEEAP59 960 738892 AC019120 3462 1-389
91S-1330
HEEAP59 960 738892 AC019120 3463 1-520
HEEAH94 962 794257 AC044789 3464 1-S96
HEEAH94 962 794257 AC009877 3465 1-621
HEEAH94 962 794257 AC039056 3466. 1-618
HEEAH94 962 794257 AC009877 3467 1-I8S
HEEAH94 962 794257 AC009877 3468 1-358
HEEAH94 962 794257 AC0390S6 3469 1-358
HEEAH94 962 794257 AC0390S6 3470 1-185
HEEAH76 963 769950 AC010600 3471 . 1-83S
1917-2695
HEEAH76 963 769950 AC010600 3472 1-427
HEEAH76 963 769950 AC010600 3473 1-S16
HEEAHS7 964 734488 AC069029 3474 I-S61
661-1152
HEEAHS7 964 734488 AC069029 3475 1-150
HEEAGSl 966 930810 U73637 3476 1-4S6
624-1143
1468-3366
5719-5910
11252-11421
16310-16521
202
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WO 01/55317 PCT/USO1/01329
16547-16574
18633-20907
HEEAG51 966 930810 AFOI5416 3477 1-456
677-1130
1469-3367
5720-5912
6136-6235
11254-11423
16312-16523
16549-16576
18636-19929
HEEAG51 966 930810 AF015416 3478 1-727
HEEAG51 966 930810 U73637 3479 1-280
HEEAG51 966 930810 AF015416 3480 1-280
HEEAD13 968 470886 AC020558 3481 1-162
5477-5629
8588-8704
8974-9372
9931-10402
11053-11250
11813-11910
12288-12575
HEEAD13 968 470886 AC073621 3482 1-153
3113-3228
3498-3896
4455-4926
5578-5775
6338-6435
6813-7100
10158-10763
11954-11987
HEEAD13 968 470886 AC073621 3483 1-428
HCDMF96 970 796196 AC004676 3484 1-80
563-871
1053-1408
1467-2070
4385-4481
4889-4977
5408-5903
6173-6232
6875-7016
9420-10150
11107-11627
HCDMF96 970 796196 AC004676 3485 1-126
HCDMF96 970 796196 AC004676 3486 I-323
HCDMC86 972 785134 AC007337 3487 ~ 1-74
~ ~ ~ ~
578-1317
203
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WO 01/55317 PCT/USO1/01329
HCDMC86 972 785134 AC009039 3488 1-74
579-1318
HCDMC86 972 785134 AC007337 3489 1-278
HCDMC86 972 785134 AC009039 3490 1-278
HCDMC22 975 672815 AC012204 3491 1-74
HCDMB91 977 789551 AL358472 3492 1-348
HCDMB42 978 713300 AC024971 3493 1-274
HCDMB42 978 713300 AL078591 3494 1-283
HCDMB41 979 711996 AC024481 3495 1-588
HCDMB27 980 682389 AC027783 3496 1-298
HCDMB27 980 682389 AC027576 3497 1-298
HCDMB03 983 923316 AL030997 3498 1-325
HCDMB03 983 923316 AL030997 3499 1-340
HCDMB03 983 923316 AL030997 3500 1-268
HCDMA20 984 669201 AC016874 3501 1-72
1460-2583
HCDMA20 984 669201 AC016721 3502 1-72
1460-2583
HCDMA20 984 669201 AC016874 3503 1-98
HCDMA20 984 669201 AC016721 3504 1-454
HCDMA20 984 669201 AC016874 3505 1-458
HCDMA20 984 669201 AC016721 3506 1-98
[044] Table 1B summarizes additional polynucleotides encompassed by the
invention
(including cDNA clones related to the sequences (Clone ID NO:Z), contig
sequences
(contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID
NO:X)),
and genomic sequences (SEQ ID NO:B). The first column provides a unique clone
identifier, "Clone ID NO:Z", for a cDNA clone related to each contig sequence.
The
second column provides the sequence identifier, "SEQ ID NO:X", for each contig
sequence. The third column provides a unique contig identifier, "Contig ID:"
for each
contig sequence. The fourth column, provides a BAC identifier "BAC ID NO:A"
for the
BAC clone referenced in the corresponding row of the table. The fifth column
provides
the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC
clone
identified in column four of the corresponding row of the table. The sixth
column, "Exon
From-To", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides
of the
invention that are also exemplary members of polynucleotide sequences that
encode
polypeptides of the invention (e.g., polypeptides containing amino acid
sequences encoded
204
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
by the polynucleotide sequences delineated in column six, and fragments and
variants
thereof). .
TABLE 2
205
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WO 01/55317 PCT/USO1/01329
~ O N O ~ 00~n O O
~N O
N N --~ N M c~M
z N
H
0
l~ ~ ~ O~ 01 l~ O N M I~ \O
~D
M N N N
z
w
o ~ v so s o
o
~ ~ .-r O O O I~ N ~O (r01 ~ N
v0 '
O O O o0 l~ M M d p1
~O
w
~
i
r V
V
~
G
7
~H
_ ~ _
.-i '~'~,, .r-,'-: .., Q1
M N M V7 N
-, N 01
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M I
Q\
y ~ U o w ~ ~ ~ N ~ d
~ ~
w ~ ~ ~ o t~ o ~ o '~ U
o ~ ~ 0 0 0
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w ~ ~o te ~ ~ ~ ~ ~~ te '~te w
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... .. ..
0
'"' ~ O .~
~~ ~
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~,' , ~ u ~ O
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~ ~ ,~', ~
v~
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~
G~7 ~ ~ O O ~ ~ ~ V~-' ~' .
T3 ~' Si +' ~ U f0 ~ ,-
~ U r
,, , r .,
O O ~ ~ 'O ~ ~ CCl
O .~i 01 O ~'' ~ _O N
bA i"' O p pp -~
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00 ~ ~ 1~ ~ ~ M -r
~. s"'~x r ~" ~ b4
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x '"'
O
O l~ O N O W " C~
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cn .,~
O Q' ~ ~,,O N U O ~N ~ O 'G
V~ *' '4j V N
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00 cd cd cd c~3 ~ cd0o ~ cti
x ~ ~ ~ .i x ~ '~' i ~
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N N N M M M
blJ ~ ~ O~ ~ ~--~M O I~ M
. 00 O .-a _
p ~ ~ N ~ M N 001 oMO O
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l~ l~ ~-'~n l~ .-i M O O
A ~ N
U o 0 o n o 0 o ~ o
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o
x ~ ~ ~ ~ o
~
N W W W W ~
o ~ ~ W U"
vz x x x x x x x x x
206
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
a1 M O~ ~O ~O ~O t~ l~ O N d- t~
--~ O~ v7 oo Omn
~
N ~ ~O O ~D d- M t~ N M oo N N I~
~ ~D t~ O O
M .--~.-~V~ .--m p ~- 1U ~D ~n ~n
M N N d' M
M N
~ ~ ~ ~ ~ N N ~ 0o N ~O ~n a,
M 00 a\ M
N v0
d .- ~D ~ O O M O 01
' , N -~ l~ M
(~
M -~ M M N N v~ ~n d' M N
M
N
0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0
M t~ O N M N O~ O O O O
O N l~ O O
00 O N d' V7 M M M ~ M N ~ M N
00 N ~O \O
Q\
O '-' ~ ~
~n _b0 _b4
M
O 00 '~ d' ~O ~O
M ~ -
_ U ~ r.,
~ ~ ~ ~ ~
o ~ o o
d ~ U d- d-
O ~ ~ ~ O N M O N M
'
,_, ~' ~ ,~ O M ~ O M ~t
~ w w
an 0. ~o ~- ~ - p bn p en
, a ., U ., U
~ ~ k ~
p
U ;~ 'C3~ ~ ,~, ''~ ~ ~~ v~ r
cd ~ ~i ~' .~ ~--' ~ i ' h n
~' p V y vW ~
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CA 02393616 2002-06-05
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[045] Table 2 further characterizes certain encoded polypeptides of the
invention, by
providing the results of comparisons to protein and protein family databases.
The first
column provides a unique clone identifier, "Clone ID NO:", corresponding to a
cDNA
clone disclosed in Table 1 A. The second column provides the unique contig
indentifier, "Contig ID:" which allows correlation with the information in
Table 1 A.
The third column provides the sequence identifier, "SEQ ID NO:X", for the
contig
polynucleotide sequences. The fourth column provides the analysis method by
which
the homology/identity disclosed in the row was determined. The fifth column
provides a description of PFam/NR hits having significant matches identified
by each
analysis. Column six provides the accession number of the PFam/NR hit
disclosed in
the fifth column. Column seven, "Score/Percent Identity", provides a quality
score or
the percent identity, of the hit disclosed in column five. Comparisons were
made
between polypeptides encoded by polynucleotides of the invention and a non-
redundant protein database (herein referred to as "NR"), or a database of
protein
families (herein referred to as "PFam"), as described below.
[046] The NR database, which comprises the NBRF PIR database, the NCBI GenPept
database, and the SIB SwissProt and TrEMBL databases, was made non-redundant
using the computer program nrdb2 (Warren Gish, Washington University in Saint
Louis). Each of the polynucleotides shown in Table 1A, column 3 (e.g., SEQ ID
NO:X
or the 'Query' sequence) was used to search against the NR database. The
computer
program BLASTX was used to compare a 6-frame translation of the Query sequence
to the NR database (for information about the BLASTX algorithm please see
Altshul
et al., J. Mol. Biol. 215:403-410 (1990), and Gish et al., Nat. Genet. 3:266-
272
(1993)). A description of the sequence that is most similar to the Query
sequence (the
highest scoring 'Subject') is shown in column five of Table 2 and the database
accession number for that sequence is provided in column six. The highest
scoring
'Subject' is reported in Table 2 if (a) the estimated probability that the
match occurred
by chance alone is less than 1.0e-07, and (b) the match was not to a known
repetitive
element. BLASTX returns alignments of short polypeptide segments of the Query
and
Subject sequences which share a high degree of similarity; these segments are
known
as High-Scoring Segment Pairs or HSPs. Table 2 reports the degree of
similarity
between the Query and the Subject for each HSP as a percent identity in Column
7.
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The percent identity is determined by dividing the number of exact matches
between
the two aligned sequences in the HSP, dividing by the number of Query amino
acids in
the HSP and multiplying by 100. The polynucleotides of SEQ ID NO:X which
encode
the polypeptide sequence that generates an HSP are delineated by columns 8 and
9 of
Table 2.
[047] The PFam database, PFam version 5.2, (Sonnhammer et al., Nucl. Acids
Res.,
26:320-322, (1998)) consists of a series of multiple sequence alignments; one
alignment for each protein family. Each multiple sequence alignment is
converted into
a probability model called a Hidden Markov Model, or HMM, that represents the
position-specific variation among the sequences that make up the multiple
sequence
alignment (see, e.g., R. Durbin et al., Biological sequence analysis:
probabilistic
models of proteins and nucleic acids, Cambridge University Press, 1998 for the
theory
of HMMs). The program HMMER version 1.8 (Sean Eddy, Washington University in
Saint Louis) was used to compare the predicted protein sequence for each Query
sequence (SEQ ID NO:Y in Table 1A) to each of the HMMs derived from PFam
version 5.2. A HMM derived from PFam version 5.2 was said to be a significant
match to a polypeptide of the invention if the score returned by HMMER 1.8 was
greater than 0.8 times the HMMER 1.8 score obtained with the most distantly
related
known member of that protein family. The description of the PFam family which
shares a significant match with a polypeptide of the invention is listed in
column 5 of
Table 2, and the database accession number of the PFam hit is provided in
column 6.
Column 7 provides the score returned by HMMER version 1.8 for the alignment.
Columns 8 and 9 delineate the polynucleotides of SEQ ID NO:X which encode the
polypeptide sequence which shows a significant match to a PFam protein family.
[048] As mentioned, columns 8 and 9 in Table 2, "NT From" and "NT To",
delineate the
polynucleotides of "SEQ ID NO:X" that encode a polypeptide having a
significant
match to the PFam/NR database as disclosed in the fifth column of Table 2. In
one
embodiment, the invention provides a protein comprising, or alternatively
consisting
of, a polypeptide encoded by the polynucleotides of SEQ ID NO:X delineated in
columns 8 and 9 of Table 2. Also provided are polynucleotides encoding such
proteins, and the complementary strand thereto.
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(049] The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y are
sufficiently accurate and otherwise suitable for a variety of uses well known
in the art
and described further below. For instance, the nucleotide sequences of SEQ ID
NO:X
are useful for designing nucleic acid hybridization probes that will detect
nucleic acid
sequences contained in SEQ ID NO:X or the cDNA contained in Clone ID NO:Z.
These probes will also hybridize to nucleic acid molecules in biological
samples,
thereby enabling immediate applications in chromosome mapping, linkage
analysis,
tissue identification and/or typing, and a variety of forensic and diagnostic
methods of
the invention. Similarly, polypeptides identified from SEQ ID NO:Y rnay be
used to
generate antibodies which bind specifically to these polypeptides, or
fragments
thereof, and/or to the polypeptides encoded by the cDNA clones identified in,
for
example, Table 1A.
[050] Nevertheless, DNA sequences generated by sequencing reactions can
contain
sequencing errors. The errors exist as misidentified nucleotides, or as
insertions or
deletions of nucleotides in the generated DNA sequence. The erroneously
inserted or
deleted nucleotides cause frame shifts in the reading frames of the predicted
amino
acid sequence. In these cases, the predicted amino acid sequence diverges from
the
actual amino acid sequence, even though the generated DNA sequence may be
greater
than 99.9% identical to the actual DNA sequence (for example, one base
insertion or
deletion in an open reading frame of over 1000 bases).
[051] Accordingly, for those applications requiring precision in the
nucleotide sequence
or the amino acid sequence, the present invention provides not only the
generated
nucleotide sequence identified as SEQ ID NO:X, and a predicted translated
amino acid
sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA
containing
cDNA Clone ID NO:Z (deposited with the ATCC on October 5, 2000, and receiving
ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on
January 5, 2001, having the depositor reference numbers TS-l, TS-2, AC-l, and
AC-2;
and/or as set forth, for example, in Table 1A, 6 and 7). The nucleotide
sequence of
each deposited clone can readily be determined by sequencing the deposited
clone in
accordance with known methods. Further, techniques known in the art can be
used to
verify the nucleotide sequences of SEQ ID NO:X.
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[052] The predicted amino acid sequence can then be verified from such
deposits.
Moreover, the amino acid sequence of the protein encoded by a particular clone
can
also be directly determined by peptide sequencing or by expressing the protein
in a
suitable host cell containing the deposited human cDNA, collecting the
protein, and
determining its sequence.
RACE Protocol For Recovery of Full-Length Genes
[053] Partial cDNA clones can be made full-length by utilizing the rapid
amplification of
cDNA ends (RACE) procedure described in Frohman, M.A., et al., Proc. Nat'l.
Acad.
Sci. USA, 85:8998-9002 (1988). A cDNA clone missing either the 5' or 3' end
can be
reconstructed to include the absent base pairs extending to the translational
start or
stop codon, respectively. In some cases, cDNAs are missing the start codon of
translation. The following briefly describes a modification of this original
5' RACE
procedure. Poly A+ or total RNA is reverse transcribed with Superscript II
(Gibco/BRL) and an antisense or complementary primer specific to the cDNA
sequence. The primer is removed from the reaction with a Microcon Concentrator
(Amicon). The first-strand cDNA is then tailed with dATP and terminal
deoxynucleotide transferase (Gibco/BRL). Thus, an anchor sequence is produced
which is needed for PCR amplification. The second strand is synthesized from
the
dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), an oligo-dT
primer containing three adjacent restriction sites (XhoI, SaII and CIaI) at
the 5' end and
a primer containing just these restriction sites. This double-stranded cDNA is
PCR
amplified for 40 cycles with the same primers as well as a nested cDNA-
specific
antisense primer. The PCR products are size-separated on an ethidium bromide-
agarose gel and the region of gel containing cDNA products the predicted size
of
missing protein-coding DNA is removed. cDNA is purified from the agarose with
the
Magic PCR Prep kit (Promega), restriction digested with XhoI or SaII, and
ligated to a
plasmid such as pBluescript SKII (Stratagene) at XhoI and EcoRV sites. This
DNA is
transformed into bacteria and the plasmid clones sequenced to identify the
correct
protein-coding inserts. Correct 5' ends are confirmed by comparing this
sequence with
the putatively identified homologue and overlap with the partial cDNA clone.
Similar
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methods known in the art and/or commercial kits are used to amplify and
recover 3'
ends.
[054] Several quality-controlled kits are commercially available for purchase.
Similar
reagents and methods to those above are supplied in kit form from GibcoBRL for
both 5' and 3' RACE for recovery of full length genes. A second kit is
available from
Clontech which is a modification of a related technique, SLIC (single-stranded
ligation
to single-stranded cDNA), developed by Dumas et al., Nucleic Acids Res.,
19:5227-32
(1991). The major differences in procedure are that the RNA is alkaline
hydrolyzed
after reverse transcription and RNA ligase is used to join a restriction site-
containing
anchor primer to the first-strand cDNA. This obviates the necessity for the dA-
tailing
reaction which results in a polyT stretch that is difficult to sequence past.
[055] An alternative to generating 5' or 3' cDNA from RNA is to use cDNA
library
double-stranded DNA. An asymmetric PCR-amplified antisense cDNA strand is
synthesized with an antisense cDNA-specific primer and a plasmid-anchored
primer.
These primers are removed and a symmetric PCR reaction is performed with a
nested
cDNA-specific antisense primer and the plasmid-anchored primer.
RNA Ligase Protocol For Generating The S' or 3' End Sequences To Obtain Full
Length
Genes
[056] Once a gene of interest is identified, several methods are available for
the
identification of the 5' or 3' portions of the gene which may not be present
in the
original cDNA plasmid. These methods include, but are not limited to, filter
probing,
clone enrichment using specific probes and protocols similar and identical to
5' and 3'
RACE. While the full length gene may be present in the library and can be
identified
by probing, a useful method for generating the 5' or 3' end is to use the
existing
sequence information from the original cDNA to generate the missing
information. A
method similar to 5' RACE is available for generating the missing 5' end of a
desired
full-length gene. (This method was published by Fromont-Racine et al., Nucleic
Acids
Res., 21(7):1683-1684 (1993)). Briefly, a specific RNA oligonucleotide is
ligated to
the 5' ends of a population of RNA presumably containing full-length gene RNA
transcript. A primer set containing a primer specific to the ligated RNA
oligonucleotide and a primer specific to a known sequence of the gene of
interest, is
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used to PCR amplify the 5' portion of the desired full length gene which may
then be
sequenced and used to generate the full length gene. This method starts with
total
RNA isolated from the desired source, poly A RNA may be used but is not a
prerequisite for this procedure. The RNA preparation may then be treated with
phosphatase if necessary to eliminate 5' phosphate groups on degraded or
damaged
RNA which may interfere with the later RNA ligase step. The phosphatase, if
used, is
then inactivated and the RNA is treated with tobacco acid pyrophosphatase in
order to
remove the cap structure present at the 5' ends of messenger RNAs. This
reaction
leaves a 5' phosphate group at the 5' end of the cap cleaved RNA which can
then be
ligated to an RNA oligonucleotide using T4 RNA ligase. This modified RNA
preparation can then be used as a template for first strand cDNA synthesis
using a
gene specific oligonucleotide. The first strand synthesis reaction can then be
used as a
template for PCR amplification of the desired 5' end using a primer specific
to the
ligated RNA oligonucleotide and a primer specific to the known sequence of the
testicular antigen of interest. The resultant product is then sequenced and
analyzed to
confirm that the 5' end sequence belongs to the relevanttesticular antigen.
[057] The present invention also relates to vectors or plasmids, which include
such DNA
sequences, as well as the use of the DNA sequences. The material deposited
with the
ATCC (deposited with the ATCC on October 5, 2000, and receiving ATCC
designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on January
5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, and AC-2;
and/or
as set forth, for example, in Tables 1A, 6 and 7) is a mixture of cDNA clones
derived
from a variety of human tissue and cloned in either a plasmid vector or a
phage vector,
as shown, for example, in Table 7. These deposits are referred to as "the
deposits"
herein. The tissues from which some of the clones were derived are listed in
Table 7,
and the vector in which the corresponding cDNA is contained is also indicated
in
Table 7. The deposited material includes cDNA clones corresponding to SEQ ID
NO:X described, for example, in Table 1A (Clone ID NO:Z). A clone which is
isolatable from the ATCC Deposits by use of a sequence listed as SEQ ID NO:X,
may
include the entire coding region of a human gene or in other cases such clone
may
include a substantial portion of the coding region of a human gene.
Furthermore,
although the sequence listing may in some instances list only a portion of the
DNA
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sequence in a clone included in the ATCC Deposits, it is well within the
ability of one
skilled in the art to sequence the DNA included in a clone contained in the
ATCC
Deposits by use of a sequence (or portion thereof) described in, for example
Tables 1 A
or 2 by procedures hereinafter further described, and others apparent to those
skilled in
the art.
[058] Also provided in Table 7 is the name of the vector which contains the
cDNA
clone. Each vector is routinely used in the art. The following additional
information
is provided for convenience.
[059] Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap
XR
(U.S. Patent Nos. 5,128,256 and 5,286,636), Zap Express (U.S. Patent Nos.
5,128,256
and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res.
16:7583-
7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res. 17.9494
(1989))
and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are
commercially
available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road,
La
Jolla, CA, 92037. pBS contains an ampicillin resistance gene and pBK contains
a
neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and
Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector.
Both phagemids may be transformed into E. coli strain XL-1 Blue, also
available from
Stratagene.
[060] Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were
obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897.
All
Sport vectors contain an ampicillin resistance gene and may be transformed
into E.
coli strain DH10B, also available from Life Technologies. See, for instance,
Gruber,
C. E., et al~, Focus 15:59- (1993). Vector Iafmid BA (Bento Soares, Columbia
University, New York, NY) contains an ampicillin resistance gene and can be
transformed into E. coli strain XL-1 Blue. Vector pCR~2.1, which is available
from
Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin
resistance gene and may be transformed into E. coli strain DH10B, available
from
Life Technologies. See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-
9686
(1988) and Mead, D. et al., Bio/Technology 9: (1991).
(061] The present invention also relates to the genes corresponding to SEQ ID
NO:X,
SEQ ID NO:Y, and/or the deposited clone (Clone ID NO:Z). The corresponding
gene
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can be isolated in accordance with known methods using the sequence
information
disclosed herein. Such methods include preparing probes or primers from the
disclosed sequence and identifying or amplifying the corresponding gene from
appropriate sources of genomic material.
[062) Also provided in the present invention are allelic variants, orthologs,
and/or
species homologs. Procedures known in the art can be used to obtain full-
length genes,
allelic variants, splice variants, full-length coding portions, orthologs,
and/or species
homologs of testes associated genes corresponding to SEQ ID NO:X or the
complement thereof, polypeptides encoded by SEQ ID NO:X or the complement
thereof, and/or the cDNA contained in Clone ID NO:Z, using information from
the
sequences disclosed herein or the clones deposited with the ATCC. For example,
allelic variants and/or species homologs may be isolated and identified by
making
suitable probes or primers from the sequences provided herein and screening a
suitable
nucleic acid source for allelic variants and/or the desired homologue.
[063] The polypeptides of the invention can be prepared in any suitable
manner. Such
polypeptides include isolated naturally occurring polypeptides, recombinantly
produced polypeptides, synthetically produced polypeptides, or polypeptides
produced
by a combination of these methods. Means for preparing such polypeptides are
well
understood in the art.
[064] The polypeptides may be in the form of the secreted protein, including
the mature
form, or may be a part of a larger protein, such as a fusion protein (see
below). It is
often advantageous to include an additional amino acid sequence which contains
secretory or leader sequences, pro-sequences, sequences which aid in
purification,
such as multiple histidine residues, or an additional sequence for stability
during
recombinant production.
[065] The polypeptides of the present invention are preferably provided in an
isolated
form, and preferably are substantially purified. A recombinantly produced
version of
a polypeptide, including the secreted polypeptide, can be substantially
purified using
techniques described herein or otherwise known in the art, such as, for
example, by the
one-step method described in Smith and Johnson, Gene 67:31-40 (1988).
Polypeptides of the invention also can be purified from natural, synthetic or
recombinant sources using techniques described herein or otherwise known in
the art,
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such as, for example, antibodies of the invention raised against the
testicular
polypeptides of the present invention in methods which are well known in the
art.
[066] The present invention provides a polynucleotide comprising, or
alternatively
consisting of, the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA
sequence
contained in Clone ID NO:Z. The present invention also provides a polypeptide
comprising, or alternatively, consisting of, the polypeptide sequence of SEQ
ID NO.:Y,
a polypeptide encoded by SEQ ID NO:X or a complement thereof, a polypeptide
encoded by the cDNA contained in Clone ID NO:Z, and/or the polypeptide
sequence
encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of
Table
1B. Polynucleotides encoding a polypeptide comprising, or alternatively
consisting of
the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X,
a polypeptide encoded by the cDNA contained in Clone ID NO:Z and/or a
polypeptide
sequence encoded by a nucleotide sequence in SEQ ID NO:B as defined in column
6
of Table 1B are also encompassed by the invention. The present invention
further
encompasses a polynucleotide comprising, or alternatively consisting of, the
complement of the nucleic acid sequence of SEQ ID NO:X, a nucleic acid
sequence
encoding a polypeptide encoded by the complement of the nucleic acid sequence
of
SEQ ID NO:X, and/or the cDNA contained in Clone ID NO:Z.
[067] Moreover, representative examples of polynucleotides of the invention
comprise,
or alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or
more of the sequences delineated in Table 1B column 6, or any combination
thereof.
Additional, representative examples of polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more
of the complementary strands) of the sequences delineated in Table 1B column
6, or
any combination thereof. In further embodiments, the above-described
polynucleotides of the invention comprise, or alternatively consist of,
sequences
delineated in Table 1B, column 6, and have a nucleic acid sequence which is
different
from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B
(see
Table 1B, column 5). In additional embodiments, the above-described
polynucleotides
of the invention comprise, or alternatively consist of, sequences delineated
in Table
1B, column 6, and have a nucleic acid sequence which is different from that
published
for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In
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additional embodiments, the above-described polynucleotides of the invention
comprise, or alternatively consist of, sequences delineated in Table 1B,
column 6, and
have a nucleic acid sequence which is different from that contained in the BAC
clone
identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by
these
polynucleotides, other polynucleotides that encode these polypeptides, and
antibodies
that bind these polypeptides are also encompassed by the invention.
Additionally,
fragments and variants of the above-described polynucleotides and polypeptides
are
also encompassed by the invention.
[068) Further, representative examples of polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more
of the sequences delineated in column 6 of Table 1B which correspond to the
same
Clone ID NO:Z (see Table 1B, column 1), or any combination thereof.
Additional,
representative examples of polynucleotides of the invention comprise, or
alternatively
consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more
of the
complementary strands) of the sequences delineated in column 6 of Table 1B
Which
correspond to the same Clone ID NO:Z (see Table 1B, column 1), or any
combination
thereof. In further embodiments, the above-described polynucleotides of the
invention
comprise, or alternatively consist of, sequences delineated in column 6 of
Table 1B
which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a
nucleic acid sequence which is different from that of the BAC fragment having
the
sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional
embodiments, the above-described polynucleotides of the invention comprise, or
alternatively consist of, sequences delineated in column 6 of Table 1B which
correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a
nucleic
acid sequence which is different from that published for the BAC clone
identified as
BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-
described polynucleotides of the invention comprise, or alternatively consist
of,
sequences delineated in column 6 of Table 1B which correspond to the same
Clone ID
NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is
different
from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B,
column 4). Polypeptides encoded by these polynucleotides, other
polynucleotides that
encode these polypeptides, and antibodies that bind these polypeptides are
also
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encompassed by the invention. Additionally, fragments and variants of the
above-
described polynucleotides and polypeptides are also encompassed by the
invention.
[069] Further, representative examples of polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more
of the sequences delineated in column 6 of Table 1B which correspond to the
same
contig sequence identifer SEQ ID NO:X (see Table 1B, column 2), or any
combination
thereof. Additional, representative examples of polynucleotides of the
invention
comprise, or alternatively consist of, one, two, three, four, five, six,
seven, eight, nine,
ten, or more of the complementary strands) of the sequences delineated in
column 6
of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X
(see Table 1B, column 2), or any combination thereof. In further embodiments,
the
above-described polynucleotides of the invention comprise, or alternatively
consist of,
sequences delineated in column 6 of Table 1B which correspond to the same
contig
sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic
acid
sequence which is different from that of the BAC fragment having the sequence
disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments,
the
above-described polynucleotides of the invention comprise, or alternatively
consist of,
sequences delineated in column 6 of Table 1B which correspond to the same
contig
sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic
acid
sequence which is different from that published for the BAC clone identified
as BAC
ID NO:A (see Table 1B, column 4). In additional embodiments, the above-
described
polynucleotides of the invention comprise, or alternatively consist of,
sequences
delineated in column 6 of Table 1B which correspond to the same contig
sequence
identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic acid
sequence
which is different from that contained in the BAC clone identified as BAC ID
NO:A
(See Table 1B, column 4). Polypeptides encoded by these polynucleotides, other
polynucleotides that encode these polypeptides, and antibodies that bind these
polypeptides are also encompassed by the invention. Additionally, fragments
and
variants of the above-described polynucleotides and polypeptides are also
encompassed by the invention.
[070] Moreover, representative examples of polynucleotides of the invention
comprise,
or alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or
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more of the sequences delineated in the same row of Table 1B column 6, or any
combination thereof. Additional, representative examples of polynucleotides of
the
invention comprise, or alternatively consist of, one, two, three, four, five,
six, seven,
eight, nine, ten, or more of the complementary strands) of the sequences
delineated in
the same row of Table 1B column 6, or any combination thereof. In preferred
embodiments, the polynucleotides of the invention comprise, or alternatively
consist
of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the
complementary strands) of the sequences delineated in the same row of Table 1B
column 6, wherein sequentially delineated sequences in the table (i.e.
corresponding to
those exons located closest to each other) are directly contiguous in a 5' to
3'
orientation. In further embodiments; above-described polynucleotides of the
invention
comprise, or alternatively consist of, sequences delineated in the same row of
Table
1B, column 6, and have a nucleic acid sequence which is different from that of
the
BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B,
column
5). In additional embodiments, the above-described polynucleotides of the
invention
comprise, or alternatively consist of, sequences delineated in the same row of
Table
1B, column 6, and have a nucleic acid sequence which is different from that
published
for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In
additional embodiments, the above-described polynucleotides of the invention
comprise, or alternatively consist of, sequences delineated in the same row of
Table
1B, column 6, and have a nucleic acid sequence which is different from that
contained
in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4).
Polypeptides
encoded by these polynucleotides, other polynucleotides that encode these
polypeptides, and antibodies that bind these polypeptides are also encompassed
by the
invention.
[071] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more
of the sequences delineated in column 6 of Table 1B, and the polynucleotide
sequence
of SEQ ID NO:X (e.g., as defined in Table 1B, column 2) or fragments or
variants
thereof. Polypeptides encoded by these polynucleotides, other polynucleotides
that
encode these polypeptides, and antibodies that bind these polypeptides are
also
encompassed by the invention.
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[072] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more
of the sequences delineated in column 6 of Table 1B which correspond to the
same
Clone ID NO:Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ
ID
NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. In
preferred embodiments, the delineated sequences) and polynucleotide sequence
of
SEQ ID NO:X correspond to the same Clone ID NO:Z. Polypeptides encoded by
these polynucleotides, other polynucleotides that encode these polypeptides,
and
antibodies that bind these polypeptides are also encompassed by the invention.
[073] In further specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, one, two, three, four, five, six, seven, eight,
nine, ten, or more
of the sequences delineated in the same row of column 6 of Table 1B, and the
polynucleotide sequence~of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or
fragments or variants thereof. In preferred embodiments, the delineated
sequences)
and polynucleotide sequence of SEQ ID NO:X correspond to the same row of
column
6 of Table 1B. Polypeptides encoded by these polynucleotides, other
polynucleotides
that encode these polypeptides, and antibodies that bind these polypeptides
are also
encompassed by the invention.
[074] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of a polynucleotide sequence in which the 3' 10
polynucleotides
of one of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of the sequence of SEQ ID NO:X are directly contiguous.
Nucleic
acids which hybridize to the complement of these 20 contiguous polynucleotides
under
stringent hybridization conditions or alternatively, under lower stringency
conditions,
are also encompassed by the invention. Polypeptides encoded by these
polynucleotides and/or nucleic acids, other polynucleotides andlor nucleic
acids that
encode these polypeptides, and antibodies that bind these polypeptides are
also
encompassed by the invention. Additionally, fragments and variants of the
above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by
the invention.
[075] In additional specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides
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of one of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X are
directly
contiguous Nucleic acids which hybridize to the complement of these 20
contiguous
polynucleotides under stringent hybridization conditions or alternatively,
under lower
stringency conditions, are also encompassed by the invention. Polypeptides
encoded
by these polynucleotides and/or nucleic acids, other polynucleotides and/or
nucleic
acids encoding these polypeptides, and antibodies that bind these polypeptides
are also
encompassed by the invention. Additionally, fragments and variants of the
above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by
the invention.
[076] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides
of the sequence of SEQ ID NO:X and the 5' 10 polynucleotides of the sequence
of one
of the sequences delineated in column 6 of Table 1B are directly contiguous.
Nucleic
acids which hybridize to the complement of these 20 contiguous polynucleotides
under
stringent hybridization conditions or alternatively, under lower stringency
conditions,
are also encompassed by the invention. Polypeptides encoded by these
polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic
acids
encoding these polypeptides, and antibodies that bind these polypeptides are
also
encompassed by the invention. Additionally, fragments and variants of the
above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by
the invention.
[077] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides
of a fragment or variant of the sequence of SEQ ID NO:X and the 5' 10
polynucleotides of the sequence of one of the sequences delineated in column 6
of
Table 1 B are directly contiguous. Nucleic acids which hybridize to the
complement of
these 20 contiguous polynucleotides under stringent hybridization conditions
or
alternatively, under lower stringency conditions, are also encompassed by the
invention. Polypeptides encoded by these polynucleotides and/or nucleic acids,
other
polynucleotides and/or nucleic acids encoding these polypeptides, and
antibodies that
bind these polypeptides are also encompassed by the invention. Additionally,
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fragments and variants of the above-described polynucleotides, nucleic acids,
and
polypeptides, are also encompassed by the invention.
[078) In further specific embodiments, polynucleotides of the invention
comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides
of one of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of another sequence in column 6 are directly contiguous.
Nucleic
acids which hybridize to the complement of these 20 contiguous polynucleotides
under
stringent hybridization conditions or alternatively, under lower stringency
conditions,
are also encompassed by the invention. Polypeptides encoded by these
polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic
acids
encoding these polypeptides, and antibodies that bind these polypeptides are
also
encompassed by the invention. Additionally, fragments and variants of the
above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by
the invention.
[079] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' 10
polynucleotides
of one of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of another sequence in column 6 corresponding to the same
Clone ID
NO:Z (see Table 1B, column 1) are directly contiguous. Nucleic acids which
hybridize , to the complement of these 20 lower stringency conditions, are
also
encompassed by the invention. Polypeptides encoded by these polynucleotides
and/or
nucleic acids, other polynucleotides and/or nucleic acids encoding these
polypeptides,
and antibodies that bind these polypeptides are also encompassed by the
invention.
Additionally, fragments and variants of the above-described polynucleotides,
nucleic
acids, and polypeptides are also encompassed by the invention.
[080] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of, a polynucleotide sequence in which the 3' IO
polynucleotides
of one sequence in column 6 corresponding to the same cdntig sequence
identifer
SEQ ID NO:X (see Table 1B, column 2) are directly contiguous. Nucleic acids
which
hybridize to the complement of these 20 contiguous polynucleotides under
stringent
hybridization conditions or alternatively, under lower stringency conditions,
are also
encompassed by the invention. Polypeptides encoded by these polynucleotides
and/or
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nucleic acids, other polynucleotides and/or nucleic acids encoding these
polypeptides,
and antibodies that bind. these polypeptides are also encompassed by the
invention.
Additionally, fragments and variants of the above-described polynucleotides,
nucleic
acids, and polypeptides are also encompassed by the invention.
[081] In specific embodiments, polynucleotides of the invention comprise, or
alternatively consist of a polynucleotide sequence in which the 3' 10
polynucleotides
of one of the sequences delineated in column 6 of Table 1B and the 5' 10
polynucleotides of another sequence in column 6 corresponding to the same row
are
directly contiguous. In preferred embodiments, the 3' 10 polynucleotides of
one of the
sequences delineated in column 6 of Table IB is directly contiguous with the
5' 10
polynucleotides of the next sequential exon delineated in Table 1B, column 6.
Nucleic
acids which hybridize to the complement of these 20 contiguous polynucleotides
under
stringent hybridization conditions or alternatively, under lower stringency
conditions,
are also encompassed by the invention. Polypeptides encoded by these
polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic
acids
encoding these polypeptides, and antibodies that bind these polypeptides are
also
encompassed by the invention. Additionally, fragments and variants of the
above-
described polynucleotides, nucleic acids, and polypeptides are also
encompassed by
the invention.
[082] Many polynucleotide sequences, such as EST sequences, are publicly
available
and accessible through sequence databases and may have been publicly available
prior
to conception of the present invention. Preferably, such related
polynucleotides are
specifically excluded from the scope of the present invention. Accordingly,
for each
contig sequence (SEQ ID NO:X) listed in the third column of Table 1A,
preferably
excluded are one or more polynucleotides comprising a nucleotide sequence
described
by the general formula of a-b, where a is any integer between I and the final
nucleotide minus 15 of SEQ ID NO:X, b is an integer of 15 to the final
nucleotide of
SEQ ID NO:X, where both a and b correspond to the positions of nucleotide
residues
shown in SEQ ID NO:X, and where b is greater than or equal to a + 14. More
specifically, preferably excluded are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where a and b are
integers as defined in columns 4 and 5, respectively, of Table 3. In specific
241
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
embodiments, the polynucleotides of the invention do not consist of at least
one, two,
three, four, five, ten, or more of the specific polynucleotide sequences
referenced by
the Genbank Accession No. as disclosed in column 6 of Table 3 (including for
example, published sequence in connection with a particular BAC clone). In
further
embodiments, preferably excluded from the invention are the specific
polynucleotide
sequences) contained in the clones corresponding to at least one, two, three,
four,
five, ten, or more of the available material having the accession numbers
identified in
the sixth column of this Table (including for example, the actual sequence
contained in
an identified BAC clone). In no way is this listing meant to encompass all of
the
sequences which may be excluded by the general formula, it is just a
representative
example. All references available through these accessions are hereby
incorporated by
reference in their entirety.
TABLE 3
242
CA 02393616 2002-06-05
WO 01/55317 PCT/USO1/01329
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332
DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 3
~~ TTENANT LES PAGES 1 A 332
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