Ex Parte KE et al

Patent Trial and Appeal Board

Feb 8, 2016

12425763 (P.T.A.B. Feb. 8, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/425,763 04/17/2009
24353 7590 02/10/2016
BOZICEVIC, FIELD & FRANCIS LLP
Bozicevic, Field & Francis
1900 UNIVERSITY A VENUE
SUITE 200
EAST PALO ALTO, CA 94303
FIRST NAMED INVENTOR
YAOHUANGKE
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
EPIT-019 3335
EXAMINER
SKELDING, ZACHARY S
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
02/10/2016 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YAOHUANG KE and GUO-LIANG YU 1
Appeal2013-009436
Application 12/425,763
Technology Center 1600
Before MELANIE L. McCOLLUM, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.
McCOLLUM, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
antibody. The Examiner has rejected claims as indefinite and lacking
written description. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.
STATEMENT OF THE CASE
The Specification discloses an antibody that neutralizes a tumor
necrosis factor-alpha (TNF-a) (Spec. 1: 5 & 30). Claims 1-8, 10, and 13 are
1 Appellants identify the real party in interest as EPITOMICS, Inc. (App.
Br. 3).
Appeal2013-009436
Application 12/425,763
on appeal (App. Br. 1).2 Claims 1 and 10 are representative and read as
follows:
1. An antibody, comprising:
a) a heavy chain variable domain comprising an amino acid sequence
that is at least 95% identical to the amino acid sequence of SEQ ID NO. 1;
and
b) a light chain variable domain comprising an amino acid sequence
that is at least 95% identical to the amino acid sequence of SEQ ID No. 2,
wherein the antibody binds TNFa.
10. The antibody of claim 1, where said antibody comprises CDRs
that are otherwise identical to the CD Rs of the antibody shown in Fig. 1
except for up to four amino acid substitutions in said CDRs.
Claim 10 stands rejected under 35 U.S.C. § 112, second paragraph
(Ans. 3).
Claims 1-8, 10, and 13 stand rejected under 35 U.S.C. § 112, first
paragraph, as failing to comply with the written description requirement (id.
at 5).
WRITTEN DESCRIPTION
The Examiner finds:
[T]he teachings of the instant specification are insufficient to put
the skilled artisan in possession of the claimed genus of
antibodies which encompasses in its breadth an enormous genus
of antibodies with up to 6 amino acid changes in SEQ ID NO: 1
and up to 5 amino acid changes in SEQ ID NO: 2, said amino
acid changes occurring potentially anywhere in the SEQ ID
NO: 1 or 2, including all of the changes in any given Vh I Vl
CDR region or spread across multiple Vh I Vl CDR regions, and
2 Claims 11 and 12 are also pending but have been withdrawn from
consideration (Final OA 1 ). In addition, claims 9 and 14 are pending but
have been indicated to be allowable if rewritten in independent form (id. at
9).
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Application 12/425,763
further said amino acid changes including in their breadth amino
acid substitutions, deletions, or insertions.
Essentially . . . , the skilled artisan understands that, in general,
the framework residues of an antibody will be involved in
forming the overall structure of the antibody molecule, and, in
tum, are essential for positioning the CD Rs so that they can form
the antigen binding site. However, unlike the CDR residues the
framework residues are not generally expected to make direct
contact with the antigen. By contrast, the skilled artisan further
understands that the CDR residues will not only interact with the
antibody framework residues to form the antigen binding site but
also make direct contact with the antigen itself (see the teachings
of Padlan[3J and Adaif[4J ... ). Furthermore, there is extensive
guidance in the art regarding the structure of antibody framework
regions with respect to the structural contribution of particular
framework residues to formation of the antigen site (see ibid).
By contrast, the skilled artisan has no way of predicting, a priori,
the general tolerance to modification in the CDR regions of an
antibody, i.e., which CDR residues of the antibody can be
mutated without substantially diminishing, and in some cases
ablating, antigen binding (see the teachings of Vajdos,[5J
Rudikoff1:6J and Colman[7J ... ).
(Final OA 4-5.)
3 Eduardo A. Padlan, Anatomy of the Antibody Molecule, 31 MOLECULAR
IMMUNOLOGY 169-217 (1994).
4 It appears that the Examiner is referring to Adair et al., US 5,859,205,
Jan. 12, 1999 (3/27/12 OA 6; Final OA 4; Ans. 9).
5 Felix F. Vajdos et al., Comprehensive Functional Maps of the Antigen-
Binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning
Mutagenesis, 320 J. MOL. BIOL. 415-28 (2002).
6 Stuart Rudikoff et al., Single Amino Acid Substitution Altering Antigen-
Binding Specificity, 79 PROC. NATL. ACAD. SCI. USA 1979-83 (1982).
7 P .M. Colman, Effects of Amino Acid Sequence Changes on Antibody-
Antigen Interactions, 145 RESEARCH IN IMMUNOLOGY 33-36 (1994).
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Appeal2013-009436
Application 12/425,763
Findings of Fact
1. The Specification states:
An immunoglobulin light or heavy chain variable region consists
of a "framework" region (FR) interrupted by three hypervariable
regions, also called "complementarity determining regions" or
"CDRs" .... The framework region of an antibody, that is the
combined framework regions of the constituent light and heavy
chains, serves to position and align the CDRs. The CDRs are
primarily responsible for binding to an epitope of an antigen.
(Spec. 5: 8-18.)
2. The Specification discloses a TNFa neutralizing antibody
compnsmg:
a heavy chain variable domain compnsmg an amino acid
sequence that is at least 95% identical to the amino acid sequence
of SEQ ID NO. 1, and a light chain variable domain comprising
an amino acid sequence that is at least 95% identical to the amino
acid sequence of SEQ ID No. 2.
fLJ ~<- (). ""l""I '"'IL\ VU. dl 7. LL-LU.)
3. In particular, the Specification discloses:
[T]he antibody may comprise a) a heavy chain variable domain
comprising an amino acid sequence that is identical to the amino
acid sequence of SEQ ID NO. 1 and b) a light chain variable
domain comprising an amino acid sequence that is identical to
the amino acid sequence of SEQ ID NO. 2.
(Id. at 13: 9-12.)
4. The Specification also discloses a monoclonal antibody
comprising a variable domain comprising:
a heavy chain variable domain comprising the CDRl ( ... SEQ
ID NO: 3), CDR2 ( ... SEQ ID NO: 4), and CDR3 ( ... SEQ ID
NO: 5)[] regions of SED ID NO: 1; and a light chain variable
domain comprising the CDRl ( ... SEQ ID NO: 6), CDR2 ( ...
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Application 12/425,763
SEQ ID NO: 7), and CDR3 ( ... SEQ ID NO: 8) regions of SEQ
ID NO: 2; or a variant of the variable domain that is otherwise
identical to the variable domain except for up to 6 amino acid
substitutions (i.e., 1, 2, 3, 4, 5 or 5 [sic] substitutions) in the CDR
regions (i.e., the 6 CDR regions, collectively, may contain up to
a total of 6 amino acid substitutions), where the monoclonal
antibody neutralizes TNFa activity.
(Id. at 10: 1-11.)
5. In addition, the Specification discloses that exemplary amino
acid substitutions are shown in Tables 1 and 2, as well as in Figure 1, which
lists 73 substitutions, including substitutions in the CDRs (id. at 10: 16 to
12: 2). The Specification states that an "antibody having any of these
substitutions should neutralize TNFa activity as antibodies with all of these
substitutions have been shown to neutralize TNFa activity," that "TNFa-
neutralizing antibodies containing amino acids at these positions are
disclosed in [Couto8]," and that "subject antibody may be a humanized
version of the antibodies disclosed in [Couto]" (id. at 12: 2-8).
6. Couto is directed to "monoclonal antibodies that neutralize
TNFa activity" (Couto iJ 7).
7. Couto discloses that "FIG. lA. shows a sequence alignment of
the heavy chain amino acid sequences of 44 exemplary rabbit TNFa
neutralizing antibodies" and that "FIG. IB. shows a sequence alignment of
the light chain amino acid sequences of 44 exemplary rabbit TNFa
neutralizing antibodies" (id. iii! 9-10).
8 Couto et al., US 2006/0216293 Al, Sept. 28, 2006.
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Application 12/425,763
8. Couto also discloses that the "light chains set forth in [FIG. lB]
are partnered with corresponding heavy chains in FIG. lA to provide
antibodies that neutralizes TNFa" (id. iJ 10).
9. Adair "relates to humanised antibody molecules[ and] to
processes for their production," a "humanised antibody molecule" being "a
molecule having an antigen binding site derived from an immunoglobulin
from a non-human species, and remaining immunoglobulin-derived parts of
the molecule being derived from a human immunoglobulin" (Adair, col. 1,
11. 8-15).
10. In describing the prior art, Adair states:
[I]t was found that transfer of the CDR regions alone ... was not
sufficient to provide satisfactory antigen binding activity in the
CDR-grafted product. ... These results indicate that changes to
residues of the human sequence outside the CDR regions, in
particular in the structural loop adjacent to CDRl, may be
necessary to obtain effective antigen binding activity for CDR-
grafted antibodies which recognise more complete antigens.
(Id. at col. 2, 11. 47-65.)
11. Thus, Adair discloses "a CDR-grafted antibody heavy chain
having a variable region domain comprising acceptor framework and donor
antigen binding regions wherein the framework comprises donor residues at
at least one of [the specified] positions" (id. at col. 3, 1. 64, to col. 4, 1. 1 ).
Principles of Law
"The 'written description' requirement states that the patentee must
describe the invention; it does not state that every invention must be
described the same way. As each field evolves, the balance also evolves
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Application 12/425,763
between what is known and what is added by each inventive contribution."
Capon v. Eshhar, 418 F.3d 1349, 1358 (Fed. Cir. 2005).
Precedent illustrates that the 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.
Id. at 1359. "It is not necessary that every permutation within a generally
operable invention be effective in order for an inventor to obtain a generic
claim, provided that the effect is sufficiently demonstrated to characterize a
generic invention." Id.
Analysis
The Specification "discloses a TNFa neutralizing antibody" (Finding
of Fact (FF) 2). In particular, the Specification discloses an antibody
comprising "a) a heavy chain variable domain comprising an amino acid
sequence that is identical to the amino acid sequence of SEQ ID NO. 1 and
b) a light chain variable domain comprising an amino acid sequence that is
identical to the amino acid sequence of SEQ ID NO. 2" (FF 3). In addition,
the Specification recites that the antibody may comprise:
a heavy chain variable domain comprising an amino acid
sequence that is at least 95% identical to the amino acid sequence
of SEQ ID NO. 1, and a light chain variable domain comprising
an amino acid sequence that is at least 95% identical to the amino
acid sequence of SEQ ID No. 2.
(FF 2.) The Specification also discloses the location and sequence of the
three CD Rs of each of the heavy and light chain variable domains (FF 4).
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Application 12/425,763
In addition, the Specification discloses 73 amino acid substitutions,
including substitutions in the CDRs (FF 5). Citing to Couto, the
Specification states that an "antibody having any of these substitutions
should neutralize TNFa activity as antibodies with all of these substitutions
have been shown to neutralize TNFa activity" (FF 5). We conclude that the
Examiner has not provided sufficient basis to doubt this assertion. In
addition, we conclude that the Examiner has not adequately explained why
these examples fails to support the scope of the present claims.
The Examiner argues, however, that "[t]here does not appear to be an
antibody in [Couto] 'which contains 73 amino acid ... substitutions relative
to the antibody defined by SEQ ID NOS: 1 and 2. '" (Ans. 7.) Instead, the
Examiner argues that Couto "discloses four antibodies (see the 'Group F'
antibodies) in Figures IA and B, each appearing to have a sub-set of the
framework and CDR mutations set forth in the Tables 1 and 2 of the instant
specification" (id.). We are not persuaded.
According to Appellants:
The antibody defined by SEQ ID NOS: 1 and 2 has 42 amino
acid substitutions (not 73 amino acid substitutions) relative to
[Couto's] 858 antibody. The remaining substitutions (31 of
them) shown in Tables 1 and 2 are derived from variants of the
858 antibody that have already been tested for binding against
TNFa.
(Reply Br. 2; see also 3127 /12 OA 4, in which the Examiner identifies the
presently claimed antibody as a homo log of Couto' s "rabbit-derived anti-
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Application 12/425,763
TNFa antibody referred to as the '848' antibody"9). Given the disclosure in
Couto of 44 exemplary antibodies (FF 7-8), we conclude that the Examiner
does not adequately explain why all 73 amino acid substitutions are not
supported. However, in any event, the Examiner does not adequately
explain why 42 exemplary amino acid substitutions would not support the
present claims.
The Examiner also argues:
The working examples of the instant specification are solely
devoted to showing the in vivo activity of an antibody
comprising SEQ ID NO: 1 and 2. There are no working
examples of any anti-TNFa binding antibodies having up to six
61 up to 5 amino acid residue changes in SEQ ID NO: 1 I SEQ
ID NO: 2, particularly where the mutations occur in a single Vh
I Vl CDR or spread across multiple Vh I Vl CDR regions.
(Ans. 8.) However, as noted above, we conclude that the Examiner does not
provide sufficient basis to doubt the assertion that an "antibody having any
of [the recited] substitutions[, particularly the 42 differences relative to the
858 antibody,] should neutralize TNFa activity" (FF 5).
In addition, the Examiner argues that "of the 73 potential substitutions
58 are framework residues" (Ans. 8). However, this means that 15 of the
proposed substitutions are in the CD Rs (see Spec. 10-12, in which Tables 1
and 2 list proposed substitutions at 15 CDR positions). The Examiner does
9 We note that the Examiner refers to "848" (3/27/12 OA 4). However, we
did not find an "848" antibody in Couto. Instead, we found "858," as
identified by Appellants (Reply Br. 2), listed among the Group F antibodies
(Couto, Figs. IA & lB).
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Application 12/425,763
not adequately explain why 15 proposed CDR substitutions are insufficient
to support substitutions in the CDRs.
The Examiner also argues that, according to Adair, the "CDR grafting
process more often than not results in an antibody with no ability to bind its
cognate antigen thereby necessitating a step-by-step adding back of certain
parental antibody framework residues known in the art to be critical for
recapitulating the three-dimensional structure of the original antigen binding
site" (Ans. 9). However, the present claims do not require that CDR grafting
be used to obtain sequences having 95% identity to SEQ ID NOs: 1 and 2.
On the contrary, the Specification discloses specific point substitutions that
can be used (FF 5).
In addition, the Examiner argues:
There are several reasons why the skilled artisan would be highly
uncertain that the teachings ofBurks[lOJ ... and Chen[llJ ... lend
any meaningful insight into the structural relationship between
the particular amino acids residues contained within the CDRs of
SEQ ID NOs: 1 and 2 of the instant claims and the ability of the
an antibody comprising a heavy chain at least 95% identical to
SEQ ID NO: 1 and light chain at least 95% identical to SEQ ID
NO: 2 to bind TNFa.
(Ans. 11.) However, we do not even find it necessary to rely on Burks and
Chen, as cited by Appellants, as the Examiner has not set forth a prima facie
case of unpatentability.
10 Elizabeth A. Burks et al., In Vitro Scanning Saturation Mutagenesis of an
Antibody Binding Pocket, 94 PROC. NATL. ACAD. SCI. USA 412-17 (1997).
11 Gang Chen et al., In Vitro Scanning Saturation Mutagenesis of all the
Specificity Determining Residues in an Antibody Binding Site, 12 PROTEIN
ENGINEERJNG 349-56 (1999).
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Application 12/425,763
With regard to the Examiner's reliance on Vajdos, Colman, and
Rudikoff, as well as Chen, we do not doubt that there may be substitutions,
even conservative substitutions, that can be made to SEQ ID NOs: 1 and 2
that would have a deleterious effect or even abolish TNFa binding (Ans. 12-
17). However, the written description requirement does not require the
description of every antibody having the claimed 95% identity that binds (or
does not bind) to TNFa. In the present case, we conclude that the Examiner
has not adequately explained why the disclosure of SEQ ID NOs: 1 and 2,
the location and sequences of the CDR regions therein, and exemplary
substitutions fails to support the claimed genus.
Conclusion
The Examiner has not set forth a prima facie case that the
Specification fails to provide written descriptive support for the present
claims. We, therefore, reverse the written description rejection.
INDEFINITENESS
The Examiner finds that claim 10 is open to more than one
interpretation. In particular, the Examiner finds:
On the one hand the language of dependent claim 10, "except for
up to four amino acid substitutions in said CDRs" could be
interpreted to mean that of the up to 6 or up to 5 amino acid
changes in SEQ ID NOs: 1 and 2 of claim 1, no more than 4/6 or
415 changes may be a substitution in a CDR region. [l 2J
On the other hand, the language of dependent claim 10, "except
for up to four amino acid substitutions in said CDRs" could
12 This proposed interpretation does not appear to be mentioned in the
Examiner's Answer (Ans. 4). However, for completeness, we mention all
three of the Examiner's proposed interpretations.
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Application 12/425,763
alternatively be interpreted to mean that of the up to 6 or up to 5
amino acid changes in SEQ ID NOs: 1 and 2 of claim 1, 6/6 or
515 changes may be substitutions into CD Rs, however, any single
CDR, i.e., Vh CDRl or Vh CDR3, can have no more than four
amino acid substitutions[.]
Yet another possible interpretation of the language of dependent
claim 10 is that "except for up to four amino acid substitutions in
said CDRs" means considering the CDRs of the antibody
displayed in Fig. 1, i.e., Vh CDRl, Vl CDRl, Vh CDR2, Vl
CDR2, Vh CDR3 and Vl CDR3, the antibody of claim 10 can
have the up to 6 or up to 5 amino acid changes in SEQ ID NOs: 1
and 2 but no more than four of these 11 amino acid changes in
total can be a substitution in Vh CDRl, Vl CDRl, Vh CDR2, Vl
CDR2, Vh CDR3 and/or Vl CDR3, i.e., at least 7 of the total
amino acid changes encompassed in breadth of claim 1 must be
in non-CDR regions.
(Final OA 2-3.)
Principles of Law
"[T]he definiteness of the language employed must be analyzed-not
in a vacuum, but always in light of the teachings of the prior art and of the
particular application disclosure as it would be interpreted by one possessing
the ordinary level of skill in the pertinent art." In re Moore, 439 F.2d 1232,
1235 (CCPA 1971).
Analysis
Appellants argue that, "[ u ]pon reading the specification, one of skill in
the art would recognize that 'except for up to four amino acid substitutions
in said CDRs' means that six CDR regions, collectively, can contain up to a
total of four amino acid substitutions" (App. Br. 4). In particular, Appellants
argue that this "concept is explicitly explained on page 10, lines 7-11," of
the Specification (id.). We agree.
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Application 12/425,763
As noted by Appellants, the Specification discloses "a variant of the
variable domain that is otherwise identical to the variable domain except for
up to 6 amino acid substitutions (i.e., 1, 2, 3, 4, 5 or 5 [sic] substitutions) in
the CDR regions (i.e., the 6 CDR regions, collectively, may contain up to a
total of 6 amino acid substitutions)" (FF 4). In view of this disclosure, we
agree with Appellants that one of ordinary skill in the art would interpret the
language of claim 10 to mean that the six CDR regions, collectively, may
contain up to a total of four amino acid substitutions.
The Examiner responds:
[T]he metes and bounds of claim 10 remain unclear because
(i) the teachings of the instant specification at page 10, lines 7-
11, do not provide an explicit, clear definition of what is meant
by "except for up to four amino acid substitutions in said CD Rs,"
and further because (ii) the meaning of the phrase "(i.e., the 6
CDR regions, collectively, may contain up to a total of 6 amino
acid substitutions)" is ambiguous.
(Ans. 4.) We are not persuaded.
First, it is not clear to us, nor does the Examiner adequately explain,
how the recitation that "the 6 CDR regions, collectively, may contain up to a
total of 6 amino acid substitutions" is ambiguous. In addition, when there is
any ambiguity in the claim, it is entirely appropriate to look to the entire
Specification, and not merely explicit definitions, to resolve the ambiguity.
Here, to the extent that claim 10 could be interpreted in the alternative
way(s) suggested by the Examiner, we agree with Appellants that the
Specification clarifies how claim 10 should be interpreted, that is, that the
six CDR regions, collectively, may contain up to a total of four amino acid
substitutions.
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Conclusion
The evidence does not support the Examiner's conclusion that
claim 10 is indefinite. We, therefore, reverse the indefiniteness rejection.
SUMMARY
We reverse the written description rejection of claims 1-8, 10, and 13,
as well as the indefiniteness rejection of claim 10.
REVERSED
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