Ex Parte Wallach et al

Patent Trial and Appeal Board

Jan 17, 2013

10423927 (P.T.A.B. Jan. 17, 2013)

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.
10/423,927 04/28/2003 David Wallach WALLACH=12C 1478
1444 7590 01/17/2013
Browdy and Neimark, PLLC
1625 K Street, N.W.
Suite 1100
Washington, DC 20006
EXAMINER
GAMBEL, PHILLIP
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
01/17/2013 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 PATENT TRIAL AND APPEAL BOARD
__________

Ex parte DAVID WALLACH, JACEK BIGDA, IGOR BELETSKY,
IGOR METT, and HARTMUT ENGELMANN
__________

Appeal 2011-005314
Application 10/423,927
Technology Center 1600
__________

Before LORA M. GREEN, JEFFREY N. FREDMAN, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

Opinion for the Board filed by SNEDDEN,
Administrative Patent Judge.

Opinion Concurring filed by FREDMAN,
Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a DNA
molecule. The Examiner has rejected the claims as lacking adequate written
description and as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm-in-part.
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STATEMENT OF THE CASE
“Tumor necrosis factor (TNF) is a pleiotropic cytokine, produced by a
number of cell types, mainly by activated macrophages.” (Spec., ¶ [0003].)
The various effects of TNF are all signaled by the binding of TNF to TNF
receptors (TNF-Rs). (Id., ¶ [0003].) There are two forms of TNF-Rs, a 55-
kilodalton TNF-R and a 75-kilodalton TNF-R, referred to as p55 (or TBP-I
1
)
and p75 TNF-R (or TBP-II), respectively. (Id., ¶ [0005].) “The cell-killing
activity of TNF is thought to be induced by the p55 receptor,” although “this
p55 receptor activity can be assisted by the p75 receptor.” (Id., ¶ [0007].)
Appellants‟ invention relates to DNA molecules encoding the antigen
binding portion of “[a]ntibodies to [TNF-Rs] which inhibit the cytocidal
effect of TNF but not its binding to the TNF-Rs.” (Id., Abst.) Claim 1, the
sole independent claim on appeal, reads as follows:
1. A DNA molecule comprising a DNA sequence encoding a
peptide which inhibits the cytocidal effect of TNF but does not
block TNF binding to the p75 TNF receptor,
said peptide comprising the antigen binding portion of a
monoclonal antibody that binds to the fourth cysteine rich
domain of the p75 TNF receptor, which domain consists of the
sequence of amino acid residues 163 to 185 of SEQ ID NO:2,
or to the region between said fourth cysteine rich domain of the
p75 TNF receptor and the cell membrane, which region consists
of the sequence of amino acid residues 201-257 of SEQ ID
NO:2.

1
Terlizzese et al., In vitro comparison of inhibiting ability of soluble TNF
receptor p75 (TBP II) vs. soluble TNF receptor p55 (TBP I) against TNF-
alpha and TNF-beta, 16 J INTERFERON CYTOKINE RES. 1047-53 (1996);
available at http://www.ncbi.nlm.nih.gov/pubmed/8974008.
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The claims stand rejected as follows:
I. Claims 1-4 and 6-10 under 35 U.S.C. § 103(a) as obvious over the
combination of Wallach
2
and Queen.
3

II. Claims 1-3 and 6-10 under 35 U.S.C. § 112, first paragraph, written
description.
The Examiner withdrew, on appeal, the rejection of claims 1-4 and 6-
10 under 35 U.S.C. § 103(a) in view of Bigda.
4
(Ans. 3).
I.
Issue
The Examiner has rejected claims 1-4 and 6-10 under 35 U.S.C.
§ 103(a) as obvious over the combination of Wallach and Queen. The
Examiner finds that Wallach discloses “a variety of antibodies that bind the
human p75 TNF receptor, including antibodies with blocking and non-
blocking properties, as well as their use in immunoassays, affinity
purification and as pharmaceutical compositions, including antibody 67.”
(Ans. 10.) The Examiner finds that Wallach “differs from the claimed
invention by not disclosing the identification or isolation of nucleic acids
encoding antibodies of interest at the time the invention was made.” (Id.)
The Examiner relies on the teaching of Queen and finds as follows:
Queen et al. teach that at the time the invention was made
methods of producing recombinant antibodies starting from
hybridoma and antibody producing cells (see entire document).

2
Wallach et al., EP 0 398 327 A1, published Nov. 22, 1990.
3
Queen et al., US 5,530,101, issued Jun. 25, 1996.
4
Bigda et al., Dual Role of the p75 Tumor Necrosis Factor (TNF) Receptor
in TNF Cytotoxicity, 180 J. EXP. MED. 445-460 (1994).
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Queen et al. teach that immunoglobulin gene structure
and organization were well understood in the art at the time the
claimed invention was made and that strategies for cloning the
DNAs encoding immunoglobulin variable regions genes were
well established in the art at the time the claimed invention was
made, as were methods for the production of DNA constructs
comprising expression vectors containing DNAs encoding
immunoglobulin variable regions. The determination and
manipulation of the nucleic acid sequences encoding antibodies
of interest was an outcome and product(s) of such engineering.
(Ans. 11.)
In reaching a conclusion of obviousness, the Examiner finds “[i]t
would have [been] prima facie obvious to one of ordinary skill in the art at
the time the claimed invention was made to employ the methods of Queen et
al. to obtain nucleic acids encoding the anti-TNF p75 receptors antibodies of
interest, including the antibody 67 specificity, taught by Wallach.” (Ans.
12.)
Appellants contend that antibody 67 is described by Wallach merely
as an “arbitrary name.” (Id. at 28.) Appellants further contend that
“[a]ntibody 67 is the name of one antibody among the large list of antibodies
disclosed in … [Wallach] that bind to the TNF p75 receptor” and that “[t]his
name would mean nothing to one of ordinary skill the art” reading Wallach
because Wallach does not refer “to any deposit of a hybridoma by this name
and no sequence information or even epitope specificity is disclosed for it.”
(Id.)
The issue presented is: Does the evidence of record support the
Examiner‟s conclusion that cited prior are renders claim 1 obvious?
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Findings of Fact
FF1. Wallach discloses monoclonal antibodies to TBP-II identified
by hybridoma clone numbers. (See e.g., Wallach, pp. 12-14 and 16-17.)
FF2. Wallach discloses that TBP-II or an unspecified fragment may
be used for the production of antibodies. (See e.g., Wallach, p. 6. ll. 57-58
and p. 11, ll. 20-45.)
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).
Analysis
In the present case, Wallach provides names for antibodies where the
names are arbitrary (FF1) and completely devoid of any structural meaning
sufficient to inform a person of ordinary skill in the art as to which region of
p75 TNF receptor the antibodies bind (FF2). The claims require binding
either to the region including amino acids 163 to 185 of SEQ ID NO:2, or to
the region which consists of amino acids 201-257 of SEQ ID NO:2. Thus,
while Wallach provides evidence that p75 TNF receptor antibodies exist, a
person of ordinary skill in the art would not have necessarily produced DNA
encoding an antibody capable of binding to the specific regions of p75 TNF
receptor recited in the claims using the techniques disclosed by Queen. See
Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1269 (Fed. Cir. 1991)
(“Inherency, however, may not be established by probabilities or
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possibilities. The mere fact that a certain thing may result from a given set of
circumstances is not sufficient.”) We therefore find that the Examiner has
not established that the ordinary artisan would have inherently and
predictably selected the recited regions of p75 TNF receptor in order to
produce DNA encompassed by the claim.
Conclusion of Law
The evidence of record does not support the Examiner‟s conclusion
that cited prior are renders claim 1 or dependent claims thereto obvious.
II.
Issue
The Examiner finds that claims 1-3 and 6-10 fail to comply with the
written description requirement of 35 U.S.C. § 112, first paragraph. The
Examiner concedes that DNA encoding the monoclonal antibody produced
from the deposited CNCM No. 1-1368 hybridoma could have been derived
using “known procedures of selecting, isolating and linking the particular
DNAs from this particular hybridoma/cell line at the time the invention was
made.” (Ans. 16.) As such, claim 4, which is directed to DNA derived from
the CNCM No. 1-1368 hybridoma, is not subject to this written description
rejection. (See Ans. 16.) However, the Examiner finds that “the
specification is insufficiently representative to provide adequate written
descriptive support for the genus of such diverse DNA molecules required to
practice the claimed invention.” (Id.)
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Appellants contend that Example 13 of the Written Description
Training Materials
5
supports a finding that
there is written description for the entire genus of antibodies
that are capable of binding to “antigen X,” even if the
specification does not describe an actual reduction to practice of
an antibody that binds to antigen X, by description of a method
of making such an antibody or by deposit, and even if the
specification does not describe any physical or chemical
properties of the claimed antibody, and even if the specification
does not disclose a correlation between the function of binding
to antigen X and the structure of the claimed antibody.
(App. Br. 16.) And if “one is in possession of a monoclonal antibody
against antigen X, one is also in possession of the hybridoma that produces
such a monoclonal antibody, as one cannot produce such a monoclonal
antibody by the conventional method without a hybridoma that encodes and
expresses it.” (Id. at 17.) One is also in possession of the DNA encoding
the antibody because the “hybridoma includes DNA encoding the amino
acid sequence of the antibody.” (Id.)
Appellants further contend that, in the present case, the
specification discloses how to make all hybridomas that
produce monoclonal antibodies binding to an antigen whose
sequence is specifically disclosed and having the desired
properties; one such hybridoma has been deposited and the
sequence is thus effectively available as part of the written
description of the present specification. Applicants were as
much in possession of the undeposited hybridomas as they were
of the antibodies produced thereby.

5
Example 13, “Antibodies to a Single Protein,” Written Description
Training Materials, Revision 1, March 25, 2008, available at
http://www.uspto.gov/web/menu/written.pdf.
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(Id. at 17-18, citing Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956
(Fed Cir. 2002).)
The issue presented is:
Does Appellants‟ Specification contain a written description sufficient
to show they had possession of the full scope of their claimed invention at
the time the application was filed?
Additional Findings of Fact
The following findings of fact (“FF”) are supported by a
preponderance of the evidence of record.
FF3. The Specification discloses the deduced amino acid sequence of
the p75 receptor as SEQ ID NO: 2. (Spec. 15, ¶ [0045], and Figures 2A-C.)
FF4. The Specification identifies protein regions
corresponding to residues 163-201 of SEQ ID NO: 2 and residues
202-257 of SEQ ID NO: 2 as recognized by the claimed antibodies.
(See e.g., Id. 4, ¶¶ [0009]-[0010].)
FF5. The “67 epitope” refers to a region of the p75 TNF-R that
“may extend between about amino acids pro-141 and thr-179 in the
p75 TNF-R (residues 163-201 of SEQ ID NO:2) or a corresponding
region in another member of the TNF/NGF family.” (Id.)
FF6. The Specification discloses a general method for the production
of monoclonal antibodies using hybridomas. (Id., ¶¶ [0061]-[0062].)
FF7. Hybridoma “TBP-II 67” was deposited with the Collection
National de Cultures de Microorganismes (CNCM), Institut Pasteur, 25, rue
du Docteur Roux, 75724 Paris Cedex 15, France, on October 11, 1993 and
assigned Nos. I-1368. (Id., ¶ [0076].)
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FF8. The Specification discloses a “stalk” region of p75 TNF-
R (id.at 5, ¶ [0014]), where a “„stalk-antibody‟ recognizes a region
downstream of the fourth cysteine rich domain, more particularly the
region extending from about amino acid 181 to about amino acid 235”
of SEQ ID NO:2 (id.at 17, ¶ [0055]).
Principles of Law
[W]hether a patent complies with the written description
requirement will necessarily vary depending on the context.
Specifically, the level of detail required to satisfy the written
description requirement varies depending on the nature and
scope of the claims and on the complexity and predictability of
the relevant technology. For generic claims, [the court has] set
forth a number of factors for evaluating the adequacy of the
disclosure, including “the existing knowledge in the particular
field, the extent and content of the prior art, the maturity of the
science or technology, [and] the predictability of the aspect at
issue.”
Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351
(Fed. Cir. 2010) (citing Capon v. Eshhar, 418 F.3d 1349, 1357-59 (Fed. Cir.
2005)).
“[S]equences are representative of the scope of the genus claims, i.e.,
if they indicate that the patentee has invented species sufficient to constitute
the genera, they may be representative of the scope of those claims.” Enzo
Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 967 (Fed. Cir. 2002).
Disclosure of an amino acid sequence effectively puts those of skill in the art
in possession of the entire genus of DNA sequences that encode the amino
acid sequence. See In re Wallach, 378 F.3d 1330, 1333 (Fed. Cir. 2004).
A functional description is inadequate because “[o]ne skilled in the art
… cannot, as one can do with a fully described genus, visualize or recognize
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the identity of the members of the genus. A definition by function … does
not suffice to define the genus because it is only an indication of what the
gene does, rather than what it is.” Regents of the University of California v.
Eli Lilly and Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997).
Analysis
Claim 1 is directed to DNA encoding the antigen binding portion of
the recited p75 TNF-R antibodies. The Examiner does not dispute that
Appellants were in possession of DNA encoding antibodies produced by the
CNCM No. I-1368 hybridoma by virtue of a biological deposit made under
the Budapest Treaty (FF5-FF6; Ans. 16). See, Enzo Biochem, Inc. v. Gen-
Probe Inc., 323 F.3d at 965 (“[R]eference in the specification to a deposit
[of a nucleotide sequence] in a public depository, which makes its contents
accessible to the public when it is not otherwise available in written form,
constitutes an adequate description of the deposited material sufficient to
comply with the written description requirement of § 112, ¶ 1.”). What is
disputed is whether the DNA of CNCM No. I-1368 hybridoma is
representative of a genus of DNA molecules encompassed by claim 1.
Claim 1 encompasses a genus of DNA molecules that includes DNA
encoding the antigen binding portion of monoclonal antibodies that bind to
two domains of the p75 TNF receptor: the first domain defined by amino
acid residues 163 to 185 of SEQ ID NO: 2; and the second domain defined
by amino acid residues 201-257 of SEQ ID NO: 2. However, there is no
evidence of record that supports a finding that hybridomas capable of
producing antibodies that bind to residues 202-257 of SEQ ID NO: 2 have
been deposited. (See e.g., FF3-FF8.) Appellants have also not adequately
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explained how possession of antibodies binding to one domain of the p75
TNF receptor (i.e., the “67 epitope”; FF5-FF8) shows possession of DNA
molecules encoding antibodies that bind to each domain recited by the
claims (i.e., residues 202-257 of SEQ ID NO: 2). In view of the above, we
find that the genus of DNA molecules encoding antibodies that bind to
residues 202-257 of SEQ ID NO: 2 are defined solely by function. In the
absence of a correlation between structure and function, a description that
defines a claimed genus only by function does not satisfy § 112. Eli Lilly,
119 F.3d at 1568; Wallach, 378 F.3d at 1335 (A “functional description can
be sufficient only if there is also a structure-function relationship known to
those of ordinary skill in the art.”).
Conclusion of Law
Appellants have not shown that the Examiner erred in finding that the
Specification does not adequately describe the claimed genus of DNA
molecules in order to show possession to a skilled worker at the time the
application was filed.
SUMMARY
We reverse the rejection of claims 1-4 and 6-10 under 35 U.S.C.
§ 103(a) as obvious over the combination of Wallach and Queen.
We affirm the rejection of claims 1-3 and 6-10 under 35 U.S.C. § 112,
first paragraph, written description.

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TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED-IN-PART

cdc

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CONCURRING OPINION
FREDMAN, Administrative Patent Judge.

I fully concur with the opinion of the Majority regarding the reversal
of the prior art rejection. I concur with the Majority‟s result affirming the
written description rejection, but I differ with the Majority‟s analysis of the
written description issue. In my opinion, the Examiner‟s rejection is
consistent with the reasoning of Centocor Ortho Biotech, Inc. v. Abbott
Laboratories, 636 F.3d 1341, 1351 (Fed. Cir. 2011).
Principles of Law
“[T]he asserted claims constitute a wish list of properties that a fully-
human, therapeutic TNF- antibody should have: high affinity, neutralizing
activity, and the ability to bind in the same place as the mouse A2 antibody.”
Centocor, 636 F.3d at 1351. “The specification at best describes a plan for
making fully-human antibodies and then identifying those that satisfy the
claim limitations. But a „mere wish or plan‟ for obtaining the claimed
invention is not sufficient.” Id.
While our precedent suggests that written description
for certain antibody claims can be satisfied by disclosing a
well-characterized antigen, that reasoning applies to
disclosure of newly characterized antigens where creation of
the claimed antibodies is routine. … Claiming antibodies
with specific properties … can result in a claim that does not
meet written description even if the [target] protein is
disclosed because antibodies with those properties have not
been adequately described.

Id. at 1352.
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Analysis
In my view, the central issue in this written description requirement is
the functional requirement in claim 1 that the peptide, encoded by the DNA,
comprise “the antigen binding portion of a monoclonal antibody that binds .
. . amino acid residues 163 to 185 of SEQ ID NO: 2” and also functions to
inhibit “the cytocidal effect of TNF but does not block TNF binding to the
p75 TNF receptor.” I do not dispute that an antibody and therefore a peptide
portion of an antibody which binds to amino acids 163 to 185 of SEQ ID
NO: 2 is described.
However, I conclude that the functional requirement that this peptide
also inhibits the cytocidal effect of TNF without blocking TNF binding to
the p75 TNF receptor is the sort of wish list of properties which fails to
satisfy the written description requirement since claiming “antibodies with
specific properties, e.g., an antibody that binds to human TNF-α with A2
specificity, can result in a claim that does not meet written description even
if the human TNF-α protein is disclosed because antibodies with those
properties have not been adequately described.” Centocor, 636 F.3d at 1352.
The absence of description in the Specification of a routine method
for obtaining antibodies with the functional properties of claim 1 is
evidenced by Example 8, where anti-p75 antibodies alone as well as other
antibodies (67, 32, and 318) result in continued cell viability (i.e. inhibit
cytocidal effect of TNF), while anti-p55 antibodies reduce cell viability (see
Spec. 29, ll. 1-16; Fig. 4, 6). There is, however, no disclosure in the
Specification of what antibody structures, antigens, or other information is
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necessary to obtain the functional result inhibiting TNF without blocking
TNF binding to the p75 TNF receptor. Consequently, the instant
claims merely recite a description of the problem to be solved
while claiming all solutions to it and, as in Eli Lilly and Ariad’s
claims, cover any compound later actually invented and
determined to fall within the claim's functional boundaries—
leaving it to the pharmaceutical industry to complete an
unfinished invention.

Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed.
Cir. 2010).
The Specification provides no information on how the function of
“inhibit[ing] the cytocidal effect of TNF” operates without “block[ing] TNF
binding to the p75 TNF receptor” (Claim 1). While such allosteric effects
are known to exist, the Specification fails to provide any structural or
functional relationships for reliably, routinely or even rarely generating
peptides and antibodies which have the functional property of inhibiting
TNF‟s cytocidal effects without blocking TNF binding to the p75 receptor.
Appellants contend that “possession of one such hybridoma was
sufficient to obviate the present written description rejection for claim 4”
(App. Br. 21).
Where a single specific inhibitor, Ik , was taught by the Specification,
Ariad finds that “a vague functional description and an invitation for further
research does not constitute written disclosure of a specific inhibitor”
insufficient to satisfy the written description requirement. Ariad, 598 F.3d at
1356. Similarly, in the instant case, the possession of a single species of
antibody, without any structure or reliable methodology to produce other
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antibodies which necessarily share the functional property of “inhibit[ing]
the cytocidal effect of TNF” without “block[ing] TNF binding to the p75
TNF receptor” lacks written description.
This is precisely the sort of situation where Appellants have expressed
a wish. A wish for an antibody with certain functional properties. It is a fine,
useful and desirable wish, but a wish nonetheless. There is no description of
the antigen necessary to obtain this antibody. There is, at best, a single
example of such an antibody with no structural description of the antibody
itself. There is no description in the Specification of any method which
could be reliably used to obtain this antibody. Centocor mandates that a
“„mere wish or plan‟ for obtaining the claimed invention is not sufficient.”
Centocor, 636 F.3d at 1351. Here, Appellants‟ Specification lacks even a
plan, retaining only the wish.
For these reasons, I concur with the result of the Majority in affirming
the written description rejection.