Ex Parte Zhang

Board of Patent Appeals and Interferences

Sep 1, 2011

10705109 (B.P.A.I. Sep. 1, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/705,109 11/10/2003 Dongxiao Zhang EPIT-002 4484
24353 7590 09/01/2011
BOZICEVIC, FIELD & FRANCIS LLP
1900 UNIVERSITY AVENUE
SUITE 200
EAST PALO ALTO, CA 94303
EXAMINER
GRUN, JAMES LESLIE
ART UNIT PAPER NUMBER
1641
MAIL DATE DELIVERY MODE
09/01/2011 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DONGXIAO ZHANG
__________

Appeal 2010-012282
Application 10/705,109
Technology Center 1600
__________

Before ERIC GRIMES, MELANIE L. McCOLLUM, and STEPHEN
WALSH, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a protein
identification method. The Examiner has rejected the claims as nonenabled
and obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.
Appeal 2010-012282
Application 10/705,109

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STATEMENT OF THE CASE
Claims 1, 9, 10, and 12-15 are on appeal (App. Br. 3).
1
We will focus
on claims 1 and 12, the only independent claims on appeal, which read as
follows:
1. A method of identifying an antigen that is present in first and
second samples in different amounts, comprising,
a) immunizing a first and second rabbit with a first and a second
sample of human cells or a fraction thereof to generate a first and a second
population of rabbit antibodies, respectively;
b) distinguishably labeling said first and second population of
antibodies,
c) contacting said first and second populations of labeled antibodies
with a plurality of non-human mammalian cells producing a library of
human proteins on their cell surfaces;
d) sorting a non-human mammalian cell that is differentially bound by
said first and second populations of antibodies, and
e) identifying a human protein on a surface of said non-human
mammalian cell, wherein said human protein is an antigen that is present in
said first and second samples in differing amounts.
12. A method of identifying a differentially expressed protein,
comprising,
a) distinguishably labeling a first and a second population of
polyclonal antibodies that are reactive against a cancerous human cell and a
non-cancerous human cell, respectively;
b) contacting said first and second populations of labeled antibodies
with a plurality of non-human mammalian cells producing human proteins;
and
c) identifying a non-human mammalian cell producing a protein that
is differentially bound by said first and second populations of antibodies,
wherein said protein is differentially expressed.

1
Claims 11, 16, and 17 are also pending but have been withdrawn from
consideration (App. Br. 3).
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Claims 1, 9, 10, and 12-15 stand rejected under 35 U.S.C. § 112, first
paragraph, “as containing subject matter which was not described in the
specification in such a way as to enable one skilled in the art to which it
pertains, or with which it is most nearly connected, to make and/or use the
invention” (Ans. 5).
Claims 1, 9, 10, 12, 13, and 15 stand rejected under 35 U.S.C.
§ 103(a) as obvious over Xu
2
(Ans. 9).
Claims 1, 9, 10, and 12-15 stand rejected under 35 U.S.C. § 103(a) as
obvious over Xu in view of Punnonen,
3
Handa,
4
Knight,
5
Fisher,
6
and
Kessler
7
(Ans. 12).
ENABLEMENT
The Examiner finds that “inadequate guidance is presented for how to
use the screening methodology because appellant‟s method is based on
certain assumptions that would not be believable to one of skill in the art”
(Ans. 5).
Appellant argues:
[T]he instant specification presents a working example of the
claimed method on page 25 to 30. Moreover, the antibody arts
are mature . . . and it would be straightforward to weed out false
positives and false negatives. Thus, while some

2
Xu et al., US 6,943,236 B2, Sep. 13, 2005.
3
Punnonen et al., US 6,541,011 B2, Apr. 1, 2003.
4
Kazuko Handa et al., A new procedure for establishing functional
monoclonal antibodies capable of inhibiting E- or P-selectin-dependent cell
adhesion, 14 GLYCOCONJUGATE J. 39-43 (1997).
5
Knight, US 5,675,063, Oct. 7, 1997.
6
Fisher et al., US 5,851,764, Dec. 22, 1998.
7
Kessler, US 2003/0044849 A1, Mar. 6, 2003.
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experimentation may be required to practice the method recited
in the appealed claims, that experimentation would not be
“undue”.
(App. Br. 6.)
Issue
Has the Examiner demonstrated that Appellant‟s methods are not
enabled by the Specification?
Principles of Law
When rejecting a claim under the enablement
requirement of section 112, the PTO bears an initial burden of
setting forth a reasonable explanation as to why it believes that
the scope of protection provided by that claim is not adequately
enabled by the description of the invention provided in the
specification of the application; this includes, of course,
providing sufficient reasons for doubting any assertions in the
specification as to the scope of enablement.
In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).
Analysis
We conclude that Appellant has the better position. Thus, for the
reasons stated in the Appeal and Reply Briefs, as well as the reasons
provided below, we will reverse the enablement rejection.
With regard to the Examiner‟s reliance on Goding,
8
we agree that it
states that “[r]abbits are notoriously variable in their immune responsiveness
between individuals” (Goding 255). However, Goding does not conclude
that rabbits should not be used. Instead, Goding states that, “[i]f rabbits are
used as recipients, a minimum of three should be injected, and the sera tested

8
James W. Goding, Monoclonal Antibodies: Principles and Practice 250-
261 (Academic Press Inc. 1983).
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individually” (id.). This would be understood by one of ordinary skill in the
art, as reflected by the fact that Appellant describes immunizing rabbits in
triplicate for each cell type (although antisera from only two rabbits of each
group were used due to the death of one of the rabbits) (Spec. 25).
With regard to the Examiner‟s reliance on Krueger,
9
we agree that it
states that “[c]ancer antigens are weak or nonimmunogenic molecules”
(Krueger 367). However, as noted by Appellant, the claims do not require
identification of all antigens that are differentially expressed, merely the
identification of a protein (App. Br. 7). The Examiner has not adequately
explained why it would not have been believable that an immunogenic
antigen, even a weak one, could be identified by the claimed methods. In
this regard, we note that the Specification indicates that Appellant‟s
“experiments demonstrated that identification of rabbit cells expressing
tumor specific surface markers is possible by using competitive immuno-
staining with differentially labeled antibody probes” (Spec. 29-30 (emphasis
added)).
OBVIOUSNESS
The Examiner concludes that Xu suggests the methods of claims 1
and 12 (Ans. 9-11).
Appellant argues that “Xu does not teach using two populations of
antibodies raised against a first and a second sample of human cells to
contact non-human mammalian cells producing human proteins and

9
Pamela Krueger et al., A new small cell lung cancer (SCLC)-specific
marker discovered through antigenic subtraction of neuroblastoma cells, 52
CANCER IMMUNOL. IMMUNOTHER. 367-377 (2003).
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identifying a non-human mammalian cell producing a protein that is
differentially bound by the two populations of antibodies” (App. Br. 15).
Issue
Has the Examiner set forth a prima facie case that Appellant‟s
methods would have been obvious?
Findings of Fact
1. The Specification states: “By „fraction of a cell‟ is meant a
subset of the total constituents of a cell that has been separated from other
constituents of the cell using any means, e.g., physical or biochemical
mean[s].” (Spec. 10.)
2. The Specification also states: “By plurality is meant more than
1.” (Id. at 15.)
3. Xu relates to polypeptides “comprising at least a portion of a
prostate-specific protein” (Xu, col. 1, ll. 35-38).
4. Xu states that “a „prostate-specific polypeptide‟ or „prostate-
specific protein,‟ refers generally to a polypeptide sequence . . . that is
expressed in a substantial proportion of prostate tissue samples . . . at a level
that is at least two fold . . . greater than the level of expression in other
normal tissues” (id. at col. 28, ll. 1-11).
5. To identify polypeptides disclosed therein, Xu discloses the
formation of human prostate tumor and normal human pancreas cDNA
expression libraries, using the libraries to perform cDNA library subtraction,
isolating clones from the resulting subtracted prostate tumor-specific cDNA
library, and determining their mRNA expression levels using microarray
technology (id. at col. 80, l. 20, to col. 85, l. 13).
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6. Xu also discloses that “polynucleotide sequences or fragments
thereof which encode polypeptides of the invention . . . may be used in
recombinant DNA molecules to direct expression of a polypeptide in
appropriate host cells” (id. at col. 49, ll. 53-57).
7. In addition, Xu discloses the use of various “host cells such as
CHO, COS, HeLa, MDCK, HEK293, and W138” (id. at col. 52, ll. 63-64).
8. Xu also discloses antibodies “that exhibit immunological
binding to a [disclosed] tumor polypeptide” (id. at col. 55, ll. 7-10).
9. To prepare antibodies, Xu discloses: “[A]n immunogen
comprising the polypeptide is initially injected into any of a wide variety of
mammals (e.g., . . . sheep . . . ). . . . Polyclonal antibodies specific for the
polypeptide may then be purified from such antisera.” (Id. at col. 56, ll. 26-
40.)
10. In particular, Xu discloses expression of the human protein
antigen P501S in mammalian host cells (id. at col. 117, ll. 12-41).
11. In addition, Xu discloses: “FACS analysis of P501S transiently
infected CHO-K cells, demonstrated surface expression of P501S.
Expression was detected using rabbit polyclonal antisera raised against a
P501S peptide.” (Id. at col. 117, ll. 42-48.)
12. Xu also discloses:
Surface expression of P501S was examined by FACS analysis.
Cells were stained with the polyclonal anti-P501S peptide
serum at 10 g/ml, washed, incubated with a secondary FITC-
conjugated goat anti-rabbit Ig antibody (ICN), washed and
analyzed for FITC fluorescence using an Excalibur
fluorescence activated cell sorter. For FACS analysis of
transduced cells, B-LCL were retrovirally transduced with
P501S. To demonstrate specificity in these assays, B-LCL
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transduced with an irrelevant antigen (P703P) or nontransduced
were stained in parallel. . . . The rabbit polyclonal serum
generated against the peptide of SEQ ID NO: 519 was shown to
specifically recognize the surface of cells transduced to express
P501S, demonstrating that the epitope recognized by the
polyclonal serum is extracellular.
(Id. at col. 130, ll. 9-28.)
13. In addition, Xu discloses:
In further studies, rabbits were immunized with peptides
derived from the P501S sequence and predicted to be either
extracellular or intracellular. . . . To determine specific
reactivity with P501S, FACS analysis was employed, utilizing
either B-LCL transduced with P501S or the irrelevant antigen
P703P, of B-LCL infected with vaccinia virus-expressing
P501S. . . . Rabbit polyclonal serum generated against the
peptide of SEQ ID NO: 548, which corresponds to amino acids
181-198 of P501S, was found to recognize a surface epitope of
P501S. Rabbit polyclonal serum generated against the peptide
SEQ ID NO: 551, which corresponds to amino acids 543-553 of
P501S, was found to recognize an epitope that was either
potentially extracellular or intracellular since in different
experiments intact or permeabilized cells were recognized by
the polyclonal sera. Based on similar deductive reasoning,
[other] sequences . . . , which correspond to [other regions] . . .
of P501S, can be considered to be potential surface epitopes of
P501S recognized by antibodies.
(Id. at col. 131, ll. 12-38.)
Principles of Law
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993) (citation omitted).
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Analysis
The Examiner relies on various teachings in Xu (Ans. 9-11). Among
these teachings, Xu discloses a FACS analysis that contacts populations of
polyclonal antibodies raised in rabbits against first and second human
peptides (e.g., the peptides of SEQ ID NOs: 548 and 551) with a plurality of
mammalian cells (that is, more than one mammalian cell (FF 2)) producing
human proteins (e.g., P501S and P703P) to determine which epitopes of a
protein are extracellular (FF 13). Although this analysis uses B-LCL cells,
Xu also discloses a FACS analysis using CHO-K cells (FF 11), which the
Examiner indicates are hamster derived (Ans. 11). In addition, the Examiner
finds that the “polyclonal antibodies were labeled for use in FACS analysis”
and that “substitution of different fluorescent labels for different antibody
populations, or direct labeling of a given antibody population, are
notoriously old, well known, and conventional alternatives in the art
motivated by, among other considerations, choice” (Ans. 10; see also
FF 12)).
However, the Examiner has not adequately explained how Xu
suggests using first and second antibody populations to identify a human
protein on a surface of a mammalian cell that is present in first and second
samples in differing amounts, as required by claim 1. In addition, the
Examiner has not adequately explained how Xu suggests contacting first and
second antibody populations, which are reactive against a cancerous human
cell and a non-cancerous human cell, respectively, with a plurality of
mammalian cells producing human proteins, as required by claim 12.
Moreover, the Examiner has not adequately explained how Punnonen,
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Handa, Knight, Fisher, and Kessler overcome these deficiencies (Ans. 12-
15).
CONCLUSION
The Examiner has not demonstrated that Appellant‟s methods are not
enabled by the Specification, nor has the Examiner set forth a prima facie
case that Appellant‟s methods would have been obvious. We therefore
reverse the enablement rejection and both of the obviousness rejections.

REVERSED

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