Celldex Therapeutics, Inc.

Patent Trials and Appeals Board

Jun 10, 2020

2019006094 (P.T.A.B. Jun. 10, 2020)

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.
14/790,247 07/02/2015 Tibor KELER CDJ-367DV 1450
959 7590 06/10/2020
NELSON MULLINS RILEY & SCARBOROUGH LLP
FLOOR 30, SUITE 3000
ONE POST OFFICE SQUARE
BOSTON, MA 02109
EXAMINER
DUFFY, BRADLEY
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
06/10/2020 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
ipboston.docketing@nelsonmullins.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte TIBOR KELER, HENRY C. MARSH, LIZHEN HE,
LAURA A. VITALE, and LAWRENCE J. THOMAS
__________

Appeal 2019-006094
Application 14/790,247
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, ELIZABETH A. LAVIER, and
MICHAEL A. VALEK, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a
method for inducing or enhancing an immune response using an antibody to
CD27. The Examiner rejected claim 10 as failing to comply with the written
description requirement. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Celldex
Therapeutics, Inc. (see Appeal Br. 2).
2 We reviewed and refer to the Specification of Aug. 7, 2015 (“Spec.”);
Final Action of Sept. 12, 2017 (“Final Act.”); Appeal Brief of Oct. 9, 2018
(“Appeal Br.”); and Examiner’s Answer of Dec. 31, 2018 (“Ans.”). A
telephonic oral hearing was held on June 2, 2020.
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Statement of the Case
Background
“Interactions between T cells and antigen-presenting cells involve a
variety of accessory molecules that facilitate in the generation of an immune
response. One such molecule is CD27, which binds CD70 and belongs to
the tumor necrosis factor receptor (TNF-R) superfamily” (Spec. 1:11–14).
“Agonistic monoclonal antibodies against CD27 have recently been shown
to promote T cell responses and show promise as anti-cancer therapeutics”
(id. at 1:30–31). “[T]here is a need in the art for further insight into the
specific functional properties that make anti-CD27 antibodies therapeutically
effective, as well as improved therapeutic antibodies against CD27 which
are more effective for treating and/or preventing diseases” (id. at 2:2–5).
The Claim
Claim 10 is on appeal and reads as follows:
10. A method for inducing or enhancing an immune response
against an antigen in a subject comprising administering to the
subject a monoclonal antibody which binds to human CD27, in
an amount effective to induce or enhance an immune response
against an antigen, wherein the antibody comprises heavy and
light chain variable region sequences having at least 95%
identity to SEQ ID NOs: 37 and 43, respectively.

The Issue
The Examiner rejected claim 10 under 35 U.S.C. § 112(a) as failing to
comply with the written description requirement (Ans. 3–7).
The Examiner finds that:
With respect to antibodies that have sequences with 95%
identity to SEQ ID NOs: 37 and 43, as evidenced below, the 6
antibody complementarity-determining regions (CDRs) are
primarily responsible for the functions of an antibody, and the
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claimed antibodies include antibodies with multiple CDR
modifications, including deletions, insertions and substitutions
. . .
The specification fails to adequately describe the genus, as a
whole, because the skilled artisan could not immediately
envision, recognize or distinguish as least most of its members
from other antibodies, as the specification fails to describe its
members as sharing any particularly identifying (i.e.,
substantial) structural feature, which correlates with any one
particularly identifying functional feature that is also shared by
many, if not all, of these variants.
(Ans. 5). The Examiner finds that “while the instant specification
establishes that an antibody comprising the six CDRs of antibody mAb 1F5
binds CD27, the specification does not establish which residues in the CDRs
are required for binding” (id. at 6). The Examiner finds “the disclosed
species would not be considered representative of the claimed genus [i.e.,
antibodies comprising heavy and light chain variable region sequences
having at least 95% identity to SEQ ID NOs: 37 and 43 that bind human
CD27] as the CDR modifications encompassed by the claim is significantly
broader and structurally distinct from the CDR modifications set forth in the
species disclosed in the specification” (id. at 7).
Appellant contends the
antibodies of claim 10 are defined in terms of a particular
structure (i.e., full-length heavy and light chain variable region
sequences) and functional effect (i.e., binding to human CD27
and inducing or enhancing an immune response against an
antigen). Thus one of skill in the art could, indeed, readily
distinguish members of the claimed genera of antibodies from
other antibodies.
(Appeal Br. 3–4). Appellant identifies three species of antibodies where the
“variable heavy chains of antibodies 1H8 and 3H12 share 93.3% and 97.5%
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identity, respectively, with the variable heavy chain of antibody 1F5.
Additionally, the variable light chains of antibodies 1H8 and 3H12 share
97.2'% and 100% identity, respectively, with the variable light chain of
antibody 1F5” (id. at 4). Appellant contends the “three antibodies (i.e., 1F5,
1H8, and 3H12) possess common functional features. For example, all three
antibodies (1) bind CD27 with similar affinities . . . (2) block binding of
sCD70 . . . (3) compete for binding to CD27 . . . and (4) induce complement
dependent cellular cytotoxicity (CDCC)” (id.).
The issue with respect to this rejection is: Does a preponderance of the
evidence of record support the Examiner’s conclusion that claim 10 fails to
comply with the written description requirement?

Findings of Fact
1. The Specification teaches “[a]n ‘antibody’ refers, in one
preferred embodiment, to a glycoprotein comprising at least two heavy (H)
chains and two light (L) chains inter-connected by disulfide bonds, or an
antigen binding portion thereof” (Spec. 23:22–25). The Specification
explains the “VH and VL regions can be further subdivided into regions of
hypervariability, termed complementarity determining regions (CDR),
interspersed with regions that are more conserved, termed framework
regions (FR). Each VH and VL is composed of three CDRs and four FRs”
(Spec. 23:29–32). The Specification teaches “[a]ntibodies interact with
target antigens predominantly through amino acid residues that are located
in the six heavy and light chain complementarity determining regions
(CDRs)” (Spec. 44:22–24) and that “antibody heavy and light chain CDR3
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domains play a particularly important role in the binding specificity/affinity
of an antibody for an antigen” (Spec. 48:1–3).
2. The Specification teaches:
the invention provides anti-CD27 antibodies that induce or
enhance effector cell function (e.g., cell killing via either
ADCC and/or CDC). In one embodiment, the antibody induces
at least about 30% specific lysis of CD27 expressing cells via
ADCC at an antibody concentration of 10 μg/ml and/or induces
at least about 30%CDC of CD27 expressing cells at a
concentration of 10 μg/ml. Particular antibodies falling within
this class exhibiting ADCC effector function include, e.g., (e.g.,
mAb comprising heavy and/or light chain variable region
sequences comprising . . . SEQ ID NOs:37 and/or 43 (mAb
1F5).
(Spec. 4:21–29).
3. The Specification teaches that the antibodies encompass
“conservative sequence modifications” (Spec. 9:27) as well as providing
literal support for the 95% requirement3 by teaching “[i]solated antibodies
which include heavy and light chain variable regions having . . . at least 95%
. . . or more sequence identity to any of the above sequences” (Spec. 10:15–
18).
4. The Specification teaches that “[c]onservative amino acid
substitutions include ones in which the amino acid residue is replaced with
an amino acid residue having a similar side chain. Families of amino acid
residues having similar side chains have been defined in the art” (Spec.

3 We recognize that the Examiner’s written description rejection is not based
on new matter, but rather a failure to provide descriptive support for the full
scope of the claim, so we cite this portion of the Specification simply to note
that literal support for this limitation does exist.
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31:14–17). The Specification explains that “[m]ethods of identifying
nucleotide and amino acid conservative substitutions which do not
eliminate antigen binding are well-known in the art (see, e.g., Brummell et
al., Biochem. 32: 1180-1187 (1993); Kobayashi et al. Protein Eng.
12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:412-
417 (1997))” (id. at 25–28).
5. The Specification teaches the “comparison of sequences and
determination of percent identity between two sequences can be
accomplished using a mathematical algorithm” (Spec. 32:10–12), and list a
number of prior art algorithms to perform this analysis (see Spec. 32:13 to
33:3).
6. The Specification further teaches that:
Methods for identifying residues that can be altered without
removing antigen binding are well-known in the art (see, e.g.,
Marks et al. (Biotechnology (1992) 10(7):779-83 (monoclonal
antibodies diversification by shuffling light chain variable
regions, then heavy chain variable regions with fixed CDR3
sequence changes), Jespers et al.(1994) Biotechnology
12(9):899-903 (selection of human antibodies from phage
display repertoires to a single epitope of an antigen), Sharon et
al. (1986) PNAS USA 83(8):2628-31 (site-directed mutagenesis
of an invariant amino acid residue at the variable-diversity
segments junction of an antibody); Casson et al. (1995) J.
Immunol. 155(12):5647-54 (evolution of loss and change of
specificity resulting from random mutagenesis of an antibody
heavy chain variable region).
(Spec 48:30 to 49:6).
7. The Specification also teaches that “in another embodiment,
mutations can be introduced randomly along all or part of an anti-CD27
antibody coding sequence, such as by saturation mutagenesis, and the
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resulting modified anti-CD27 antibodies can be screened for binding
activity” (Spec. 31:29–32).
8. Figure 15 of the Specification is reproduced in part below:

This portion of Figure 15 of the Specification shows alignment of the heavy
chain of antibodies 1H8 and 3H12 with 1F5. Appellant asserts, and the
Examiner acknowledges, that the 1H8 and 3H12 sequences share 97.2% and
100% identity with the 1F5 sequence, respectively (see Final Act. 7–8). The
Examiner further acknowledges that the light chain sequences of 1H8 and
3H12 share 93.3% and 97.5% identity respectively with 1F5 (see Final Act.
8; cf. Figure 16 of Specification).
9. Table 1 of the Specification is reproduced in part below:

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Table 1 shows that antibodies 1F5, 1H8, and 3H12 bind CD27 with half max
values of 0.059 µg/ml, 0.064 µg/ml, and 0.085 µg/ml respectively (see Spec.
75:10–20).
10. The Specification teaches that “several of the antibodies
(including 1F5, 1H8, 3H12 and 1A4 ) had the property of blocking or at
least significantly inhibiting the binding of sCD70” (Spec. 76:11–12).
11. The Specification teaches “a first set of the human mAbs
(comprising mAbs 1F5, 1H8 and 3H12) cross-competed with each other” for
binding to CD27 (Spec. 77:15–16).
12. Figure 11 of the Specification is reproduced below:

Figure 11 shows that “a number of the anti-CD27 antibodies displayed
significant CDCC activity,” including 1F5, 3H8 and 3H12 (Spec. 78:3–4).
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Principles of Law
An adequate written description must contain enough
information about the actual makeup of the claimed products —
“a precise definition, such as by structure, formula, chemical
name, physical properties, or other properties, of species falling
within the genus sufficient to distinguish the genus from other
materials,” which may be present in “functional” terminology
“when the art has established a correlation between structure
and function.”
Amgen, Inc. v. Sanofi, 872 F.3d 1367, 1378 (Fed. Cir. 2017) (citing Ariad
Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010) (en
banc)).
The Federal Circuit has found that “a sufficient description of a
genus . . . requires the disclosure of either a representative number of species
falling within the scope of the genus or structural features common to the
members of the genus so that one of skill in the art can ‘visualize or
recognize’ the members of the genus.” Ariad, 598 F.3d at 1351 (quoting
Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1568–69
(Fed. Cir. 1997)).

Analysis
In analyzing claim 10 in view of the Specification, we appreciate “the
purpose of the written description requirement is to ‘ensure that the scope of
the right to exclude, as set forth in the claims, does not overreach the scope
of the inventor’s contribution to the field of art as described in the patent
specification.’” Ariad, 598 F.3d at 1353 (citing Univ. of Rochester v. G.D.
Searle & Co., Inc., 358 F.3d 916, 920 (Fed. Cir. 2004)).
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Claim 10 sets forth a method in which a monoclonal antibody
composed of a heavy and light chain sequences with at least 95% identity to
SEQ ID Nos: 37 and 43, respectively, that binds to CD27 and functions to
induce or enhance immune response to an antigen.
The Specification teaches that the inventor’s contribution
encompasses particular antibody sequences that function to bind CD27 (FF
2). The Specification teaches that the essential binding regions in
antibodies, termed CDR sequences, were known (FF 1). The Specification
teaches that some conservative amino acids may be substituted in the
claimed amino acid sequences without eliminating function, and that it was
well known how to identify such conservative changes (FF 4, 6). Claim 10
limits the number of conservative substitutions permitted by requiring 95%
identity (cf. FF 3, 5), a value which permits no more than about seven
substitutions in the heavy chain sequence and no more than about six
substitutions in the light chain sequence (see FF 8). Lastly, the Specification
teaches three different species of VH and VL sequences that function to bind
CD27 (FF 8).
We find that claim 10 recites a sufficiently precise definition and
structural formula that would allow the ordinary artisan to identify anti-
CD27 antibodies that fall within the scope of claim 10 from those antibodies
that do not fall within the scope of claim 10. That is, claim 10 does
“particularly point out and distinctly circumscribe the outer boundaries of a
claimed invention,” AbbVie Deutschland Gmbh & Co., KG v. Jassen
Biotech, Inc. , 759 F.3d 1285, 1300 (Fed. Cir. 2014). Claim 10 establishes
this boundary both by providing specific amino acid sequences of SEQ ID
Nos: 37 and 43 and by requiring other antibodies to retain 95% identity with
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those amino acid sequences. In addition, claim 10 requires a functional
activity of antibodies of binding to CD27 that serves to further delimit the
genus of antibodies encompassed by claim 10.
Abbvie further explains that to satisfy the written description
requirement, “merely drawing a fence around a perceived genus is not a
description of the genus. One needs to show that one has truly invented the
genus, i.e., that one has conceived and described sufficient representative
species encompassing the breadth of the genus.” Id. The instant
Specification provides three representative species, 1H8, 3H12, and 1F5 (FF
8–12). The Specification further demonstrates that these species exhibit
both the structure recited in claim 10 (i.e., comprises heavy and light chain
variable region sequences having at least 95% identity to SEQ ID NOs: 37
and 43) as well as the recited function (i.e., they bind to human CD27 and
induce/enhance an immune response) (FF 8–12). Thus, Appellant’s
description correlates the structure of these species to the claimed function.
The Specification also provides a detailed explanation of methods that allow
the generation of other functional species that also fall within the scope of
claim 10 (FF 4, 6).
We recognize that the Examiner asserts “one of skill in the art would
not consider any of the disclosed species as representative of the disclosed
genus of antibodies that bind CD27 which can have 5 positions deleted,
inserted or substituted or any combination thereof in a single CDR” (Ans. 7).
We also recognize that the Examiner has cited references regarding
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unpredictability, and specifically cites Winkler4 as teaching that “a single
amino acid change in a CDR can result in unpredictable and substantial
changes in antibody specificity” (Ans. 6).
However, we are not persuaded that an exemplary species with,
essentially, a novel CDR is necessary to establish a reasonable number of
species for written description purposes. Instead, we agree with Appellant
that as of
the relevant priority date, it was well within the ordinary skill in
the art to identify and test amino acid residues within the CDR
domains of a given antibody that are amenable to amino acid
substitution and still retain the claimed functions (i.e., binding
to human CD27 and the ability to induce or enhance an immune
response).
(Appeal Br. 5). “[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.” Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005).
In Invitrogen Corp. v. Clontech Laboratories, Inc., 429 F.3d 1052,
1073 (Fed. Cir. 2005), there was evidence “that the sequences for these and
other representative [species] were known” and that the opposing party had
“not adduced contrary evidence establishing a genuine issue of fact.” Id.
We note that the Examiner here also does not provide evidence that, as of
the instant filing date, an ordinary artisan in the field of antibody technology,
would have found insufficient description in the Specification of an antibody

4 Winkler et al., Changing the Antigen Binding Specificity by Single Point
Mutations of an Anti-p24 (HIV-1) Antibody, 165 J. Immunology 4505–14
(2000).
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that comprises heavy and light chain variable region sequences having at
least 95% identity to SEQ ID NOs: 37 and 43 and binds human CD27 in an
amount effective to induce or enhance an immune response. To the extent
that there would be some unpredictability in any particular altered antibody
sequence,
it is almost always possible to so construe a claim as to have it
read on inoperative embodiments. . . . , but the alternative of
requiring an applicant to be so specific in his claims “as to
exclude materials known to be inoperative and [which] even
those not skilled in the art would not try” would result in
claims which would fail to comply with 35 U.S.C. § 112,
second paragraph, because they would be so detailed as to
obscure, rather than to particularly point out and distinctly
claim, the invention.
In re Smythe, 480 F.2d 1376, 1385 (CCPA 1973). In this case, while claim
10 excluding inoperative embodiments might not be indefinite, it would be
narrower than the scope supported by the disclosure in the Specification.
Thus, Appellant has demonstrated descriptive support for the embodiments
encompassed by claim 10.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that claim 10 fails to comply with the written
description requirement.

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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
10 112(a) Written
Description
10
Overall
Outcome
10

REVERSED