Ex Parte Xia et al

Board of Patent Appeals and Interferences

Jan 28, 2009

10242092 (B.P.A.I. Jan. 28, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HAIYING XIA and ZHIDA HUANG
__________

Appeal 2008-3329
Application 10/242,092
Technology Center 1600
__________

Decided: January 28, 2009
__________

Before DEMETRA J. MILLS, LORA M.GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 21-27, 29, and 30. We have jurisdiction
under 35 U.S.C. § 6(b).

Appeal 2008-3329
Application 10/242,092

STATEMENT OF THE CASE
The claims are directed to a rabbit monoclonal antibody having
specific affinity for the human progesterone receptor, as well as a method for
selecting a monoclonal antibody that is suitable for immunohistochemical
analysis of human progesterone receptor. Claims 21 and 25 are
representative of the claims on appeal, and read as follows:
21. A rabbit monoclonal antibody having a specific affinity for human
progesterone receptor that is higher than that of murine monoclonal antibody
lA6, wherein the rabbit monoclonal antibody specifically binds an epitope
within amino acids 412-562 of the progesterone receptor B form present in a
fresh tissue section and present, in the absence of a tissue section processing
step involving proteolytic digestion or heat treatment for antigen retrieval, in
a formalin-fixed, paraffin-embedded tissue section after processing steps of
deparaffinization and rehydration.

25. A method for selecting a monoclonal antibody for
immunohistochemistry analysis of a human progesterone receptor, said
method comprising the steps of:
a) contacting a rabbit monoclonal antibody of a plurality of rabbit
monoclonal antibodies with a formalin-fixed, paraffin-embedded tissue
section that contains the progesterone receptor, in the absence of a tissue
section processing step involving proteolytic digestion or heat treatment for
antigen retrieval, and after processing steps of deparaffinization and
rehydration; and
b) detecting specific binding of the monoclonal antibody to the
progesterone receptor in the absence of antigen retrieval to select the
monoclonal antibody from the plurality of monoclonal antibodies for
immunohistochemistry analysis of the progesterone receptor.

The Examiner relies on the following evidence:
Press et al. “Comparison of different antibodies for detection of progesterone
receptor in breast center,” 67 Steroids 799-813 (2002).

We reverse.
2
Appeal 2008-3329
Application 10/242,092

ISSUE (Written Description)
The Examiner finds that claims 21-27, 29, and 30 fail to comply with
the written description requirement of 35 U.S.C. § 112, first paragraph.
Appellants contend that the claimed antibody was described as to the
antigen used, i.e., the PR B 412-562 antigen, which was recombinantly
produced, and thus the claims are compliance with the written description
rejection.
Thus, the issue on Appeal is: Is the description of the antigen used to
produce the claimed antibody, i.e., the PR B 412-562 antigen, which was
recombinantly produced, sufficient to meet the written description
requirement of 35 U.S.C. § 112, first paragraph, of the claims to the
antibody?

FINDINGS OF FACT
FF1 The Specification teaches that “the assessment of estrogen and
progesterone receptors (ER and PR) status in breast cancer is widely used
for the prediction of response to endocrine therapy and as a prognostic
marker.” (Spec. 2.)
FF2 Immunohistochemical methods, in which ER and PR antibodies are
used to test for the receptors on formalin-fixed, paraffin-embedded tissues,
are considered to be a specific, sensitive, and economical method for
determining receptor status (id.). One drawback of the
immunohistochemical methods, however, is that it requires heat
pretreatment of the sample, required for target retrieval, to be accurate (id. at
3
Appeal 2008-3329
Application 10/242,092

3). The Specification thus notes that it would be desirable to have a test
system that does not require the heat pretreatment (id.).
FF3 The Specification thus discloses high affinity rabbit monoclonal
antibodies for ER (clone SP1) and PR (clone SP2) (id. at 4).
FF4 According to the Specification, “general[ly], it has been found that a
rabbit monoclonal antibody has higher affinity than a mouse monoclonal
antibody,” thus “it was hypothesized that rabbit monoclonal antibodies
would be effective for immunohistochemistry testing.” (Id. at 7.)
FF5 For the antigen,
the PR gene encoding human PR B Form 412-562 aa was
amplified by polymerase chain reaction (PCR) from human
uterus PCR ready cDNA. The PR gene was then ligated into an
expression plasmid. The presence of the PR gene in the
plasmid was verified by DNA sequencing and the expressed PR
412-562 aa recombinant protein in E. Coli was confirmed by
the protein size on the Commasie blue stained SDS-
polyacrylamide gel and western blotting. The affinity purified
recombinant protein was used as immunogen.

(Id. at 10-11.)
FF6 Positive clones were tested for tissue staining screen and the two best
clones were selected “which gave strong signal and very low background in
tissue staining without heat pretreatment.” (Id. at 18.) The clone that
produced the antibody with the strongest staining was named clone SP2
(id.).
FF7 The Examiner rejects claims 21-27, 29, and 30 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 reasonably convey to one skilled in the
4
Appeal 2008-3329
Application 10/242,092

relevant art that the inventor(s), at the time the application was filed, had
possession of the claimed invention.” (Ans. 3.)
FF8 The Examiner finds that the Specification “does not provide sufficient
recitation of distinguishing identifying characteristics of the genus of
antibodies, or even for the single disclosed functional species of SP2
antibody.” (Id. at 4.)
FF9 According to the Examiner, the Specification “provides no guidance
as to what modifications or structure are important for the predictable
function of [SP2] or any other monospecific antibody.” (Id.)
FF10 The Examiner finds further that the Specification “does not identify
the epitope bound by the SP2 antibody and only localizes binding to the
sequence comprising amino acid residues 412-562 of the human
progesterone receptor B isoform.” (Id. at 5.)
FF11 The Examiner notes that “[a] sequence of 151 amino acid residues,
having numerous differences (about 38 mismatches) between the human
sequence and the corresponding sequence in rabbits, has many potential
unpredictable immunogenic epitopes therein which could be recognized as
foreign in rabbits.” (Id.)
FF12 The Examiner finds that “[g]iven the lack of guidance to the relevant
epitope and unpredictability of the relevant structures of the epitopes and of
the fine specificities of the antibodies elicited in a rabbit, even of the SP2
antibody, one would not know or be able to predict or envision what epitopic
fragments were important for function.” (Id.) Thus, the Examiner finds that
the “description has not provided any guidance for a structure/function
correlation identifying the genus because one does not know and cannot
5
Appeal 2008-3329
Application 10/242,092

envision the structure of the antibody or the epitope to be bound thereby.”
(Id. at 5-6.)
FF13 Citing Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991), the
Examiner finds that “the skilled artisan cannot envision the detailed
chemical structure of the encompassed genus of antibodies and therefore
conception is not achieved until reduction to practice has occurred,
regardless of the complexity or simplicity of the method of isolation.” (Ans.
6.)
FF14 The Examiner thus finds:
However, as set forth above, appellant only teaches a single
species of undefined structure and properties. Here, a single
species of undefined structure and properties is not found to
describe a genus of molecules, a genus with unknown structures
and properties other than that they share the property of binding
to unknown and unpredictable formalin-resistant epitope(s) in a
151 amino acid sequence.
Therefore, only the SP2 antibody, if provided via a
deposit in compliance with the Deposit rules, but not the full
breadth of the claims, has the potential to meet the written
description provision of 35 U.S.C. $1 12, first paragraph.

(Id. at 6-7.)

PRINCIPLES OF LAW
“The burden of showing that the claimed invention is not described in
the application rests on the PTO in the first instance.” In re Edwards, 568
F.2d 1349, 1354 (CCPA 1978). To comply with the written description
requirement, the Specification must “convey with reasonable clarity to those
skilled in the art that, as of the filing date sought, [the inventor] was in
6
Appeal 2008-3329
Application 10/242,092

possession of the invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555,
1563-64 (Fed. Cir. 1991). “[T]he determination of what is needed to support
generic claims to biological subject matter depends on a variety of factors,
such as the existing knowledge in the particular field, the extent and content
of the prior art, the maturity of the science or technology, the predictability
of the aspect at issue, and other considerations appropriate to the subject
matter.” Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005).
For antibody claims, which are defined by their function rather than
the structure of the antibody per se, the Court of Appeals for the Federal
Circuit, our reviewing court, has adopted the USPTO Written Description
Guidelines
as persuasive authority for the proposition that a claim directed
to “any antibody which is capable of binding to antigen X”
would have sufficient support in a written description that
disclosed “fully characterized antigens.” Synopsis of
Application of Written Description Guidelines, at 60, available
at http://www.uspto.gov.web.menu.written.pdf (last visited Jan.
16, 2003) (emphasis added).

Noelle v. Lederman, 353 F.3d 1343, 1349 (Fed. Cir. 2004); see also Enzo
Biochem Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
Therefore, “as long as an applicant has disclosed a ‘fully characterized
antigen,’ either by its structure, formula, chemical name, or physical
properties, or by depositing the protein in a public depository, the applicant
can then claim an antibody by its binding to that described antigen.” Noelle,
355 F.3d at 1349.

7
Appeal 2008-3329
Application 10/242,092

ANALYSIS
Appellants argue that the claimed antibody was described as to the
antigen used, i.e., the PR 412-562 antigen, which was recombinantly
produced, and thus the claims are compliance with the written description
rejection (App. Br. 3).
We agree. The Specification describes a “rabbit monoclonal antibody
having a specific affinity for human progesterone receptor that is higher than
that of murine monoclonal antibody lA6, wherein the rabbit monoclonal
antibody specifically binds an epitope within amino acids 412-562 of the
progesterone receptor B form present in a fresh tissue section and present, in
the absence of a tissue section processing step involving proteolytic
digestion or heat treatment for antigen retrieval, in a formalin-fixed,
paraffin-embedded tissue section after processing steps of deparaffinization
and rehydration,” that is, antibody SP1, and also describes the immunogen
that was used to produce the antibody (FF5).
The Examiner appears to be requiring that the Specification disclose
both the specific epitope recognized by the antibody (see, e.g., FF10), as
well as the structure of the antibody (see, e.g., FF9). All that is required,
however, for adequate written description of an antibody is the disclosure of
a fully characterized antigen, which requirement is met by the Specification
(FF5). We decline to read into that requirement that the Specification also
disclose the specific epitope bound by the antibody, or the structure of the
antibody.
8
Appeal 2008-3329
Application 10/242,092

To the extent that the Examiner is concerned about the ability of the
skilled artisan to reproduce the claimed antibody, that concern is more one
of enablement than written description.

CONCLUSIONS OF LAW
We find that the description of the antigen used to produce the
claimed antibody, i.e., the PR B Form 412-562 antigen, which was
recombinantly produced, is sufficient to meet the written description
requirement of 35 U.S.C. § 112, first paragraph, of the claims to the
antibody.
The rejection of claims 21-27, 29, and 30 under 35 U.S.C. § 112, first
paragraph, as failing to comply with the written description requirement, is
therefore reversed.

ISSUE (Enablement)
The Examiner concludes that claims 21-27, 29, and 30 do not meet the
enablement requirement of 35 U.S.C. § 112, first paragraph.
Appellants contend that the Specification provides thorough teachings
and working exemplifications describing how to make and use the claimed
monoclonal antibody and claimed selection methods.
Thus, the issue on Appeal is: Are the teachings and working
exemplifications in the Specification describing how to make and use the
claimed monoclonal antibody and claimed selection methods sufficient to
enable the claimed antibodies and methods?

9
Appeal 2008-3329
Application 10/242,092

FINDINGS OF FACT
FF15 The Examiner rejects claims 21-27, 29, and 30 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, particularly the invention commensurate in scope with these
claims.” (Ans. 7.)
FF16 The Examiner made the following findings with respect to the factors
set out in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). 1
FF17 The Direction and Guidance provided by Appellants/Working
Examplest: The Examiner finds that the only guidance provided by the
Specification is “a single species of antibody of unknown structure and
properties which functions as intended by appellant.” (Ans. 7.)
FF18 State of the Art/The level of Skill in the Art and Lack of Predictibility:
The Examiner notes that the Specification teaches methods of screening
antibodies, but finds that “the reproducibility of making another antibody of
similar characteristics to the SP2 antibody is not known and is entirely
unpredictable.” (Id. at 7.) The Examiner relies on Press, finding that it
teaches that
after conventional immunization with N-terminally truncated A
isoform of the human progesterone receptor (PR), which

1 The factual considerations discussed in Wands are: (1) the quantity of
experimentation necessary to practice the invention, (2) the amount of
direction or guidance presented, (3) the presence or absence of working
examples, (4) the nature of the invention, (5) the state of the prior art, (6) the
relative skill of those in the art, (7) the predictability or unpredictability of
the art, and (8) the breadth of the claims.
10
Appeal 2008-3329
Application 10/242,092

comprises the same sequence used by appellant and which is
even less similar (about 63 mismatches) in sequence to the
corresponding sequence in the protein found in the mouse,
none of the isolated murine anti-PR monoclonal antibodies
performed in the screening method as functional for PR
detection without antigen retrieval in formalin-fixed and
paraffin embedded tissue sections after deparaffinization and
rehydration (see page 810).

(Ans. 8.) Thus, according to the Examiner, Press supports that it is
unpredictable whether generation of antibodies having the characteristics of
the SP2 antibody could be reproduced (id.). The Examiner notes further that
in Press, it was only after immunization with a formalin fixed PR a isoform
that two antibodies were elicited that allowed for PR detection without initial
antigen retrieval (id.).
FF19 Undue Experimentation: The Examiner finds that the amount of
experimentation required to determine functional structures or modifications
for usable antibodies other than the SP2 antibodies would be undue (id. at 7).
FF20 The Examiner also objects to the Specification, and rejected claims
21-27, 29, and 30 under 35 U.S.C. § 112, first paragraph, “as failing to
provide an adequate written description of the invention and failing to
provide an enabling disclosure, because the specification does not provide
evidence that the disclosed biological materials (which may be enabled) are:
(1) known and readily available to the public; (2) reproducible from the
written description; or, (3) deposited in compliance with the criteria set forth
in 37 C.F.R. §§ 1.801-1.809.” (Ans. 9.)
11
Appeal 2008-3329
Application 10/242,092

FF21 The Examiner concludes it would require an “undue experimentation
to reproduce the monoclonal antibody species chemically as produced by the
hybridoma designated SP2 and encompassed by the claims.” (Id.)
FF22 The Examiner notes that a suitable deposit would satisfy the
enablement requirement for the antibody species produced by the hybridoma
(id.).
FF23 Press discloses two antibodies, PgR636 and PgR1294, that do not
require antigen retrieval, i.e., heat pretreatment, for the
immunohistochemical detection of progesterone receptors in formalin fixed
and paraffin embedded tissue samples (Press Abstract).
FF24 The antibodies were prepared using formalin treated, full-length PR-A
as the antigen (id. at 800, second column-801, first column).
FF25 Press teaches that in “parallel experiments, we used unfixed PR as
antigen and screened hybridomas for IHC [immunohistochemical] detection
of PR in formalin-fixed paraffin tissue sections. None of the Mabs isolated
from these other cell fusions was able to specifically stain for PR in the
absence of antigen retrieval.” (Id. at 810, first column.)
FF26 Thus, Press appears to teach that full length, unfixed PR A was used
as the antigen in the parallel experiments (FF25), and not N-terminally
truncated A isoform of the human progesterone receptor, as found by the
Examiner (FF18).

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
12
Appeal 2008-3329
Application 10/242,092

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.” In re Wright, 999 F.2d 1557, 1561-62
(Fed. Cir. 1993).
“[T]o be enabling, the specification . . . must teach those skilled in the
art how to make and use the full scope of the claimed invention without
‘undue experimentation.’” Wright, 999 F.2d at 1561, (emphasis added),
quoted in Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365, (Fed.
Cir. 1997). Thus, “there must be sufficient disclosure, either through
illustrative examples or terminology, to teach those of ordinary skill how to
make and how to use the invention as broadly as it is claimed.” In re Vaeck,
947 F.2d 488, 496 & n. 23, (Fed. Cir. 1991), quoted in Enzo Biochem, Inc. v.
Calgene, Inc., 188 F.3d 1362, 1374, (Fed. Cir. 1999). Moreover, the test of
whether the experimentation required is undue “is not merely quantitative,
since a considerable amount of experimentation is permissible, if it is merely
routine.” Wands, 858 F.2d at 737.

ANALYSIS
Appellants argue that the Specification “provides thorough teachings
and working exemplification describing how to make and use the claimed
monoclonal antibody and claimed selection method.” (App. Br. 6.)
We find that Appellants have the better argument. The Specification
teaches the immunogen used to make the claimed antibody (FF5), and
further teaches that two clones were obtained, of which the SP2 clone
produced the antibody with the strongest staining (FF6). Thus, given the
13
Appeal 2008-3329
Application 10/242,092

guidance provided in the Specification, while it may require a considerable
amount of routine experimentation to obtain additional rabbit monoclonal
antibodies having the claimed characteristics, such experimentation would
not be undue.
We have considered the Press reference, but contrary to the finding of
the Examiner that none of the isolated murine anti-PR monoclonal
antibodies performed in the screening method as functional for PR detection
without antigen retrieval in formalin-fixed and paraffin embedded tissue
sections (FF18), it appears that the immunogen used was actually the full
length PR A receptor (FF25, FF26). Thus, Press does not support the
Examiner’s conclusion that it would be unpredictable to produce antibodies
having the claimed characteristics using the immunogen taught by the
Specification, i.e., recombinantly produced PR B 412-562 antigen.
Moreover, because we conclude that the Examiner has not established
that one could not reproduce the claimed antibody, and as none of the claims
on appeal specifically require the rabbit monoclonal antibody produced by
clone SP2, we also conclude that Appellants need not deposit the SP2
antibody to satisfy the enablement requirement.

CONCLUSIONS OF LAW
Thus, we conclude that the teachings and working exemplifications in
the Specification describing how to make and use the claimed monoclonal
antibody and claimed selection methods are sufficient to enable the claimed
antibodies and methods.
14
Appeal 2008-3329
Application 10/242,092

We thus reverse the rejection of claims 21-27, 29, and 30 under 35
U.S.C. § 112, first paragraph, as not meeting the enablement requirement;
and also reverse the rejection of claims 21-27, 29, and 30 under 35 U.S.C. §
112, first paragraph, as failing to provide an adequate written description of
the invention and failing to provide an enabling disclosure, because the
specification does not provide evidence that the disclosed biological material
(which may be enabled) are: (1) known and readily available to the public;
(2) reproducible from the written description; or, (3) deposited in
compliance with the criteria set forth in 37 C.F.R. §§ 1.801-1.809.

REVERSED

RICHARD ARON OSMAN
4070 CALLE ISABELLA
SAN CLEMENTE, CA 92672

dm

15