Ex Parte Giaccia et al

Patent Trials and Appeals Board

Apr 15, 2019

14712731 - (D) (P.T.A.B. Apr. 15, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/712,731 05/14/2015
77974 7590 04/17/2019
Stanford University Office of Technology Licensing
Bozicevic, Field & Francis LLP
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
Amato J. Giaccia
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.
STAN-626CIPCON 1031
EXAMINER
ROARK, JESSICA HOPE
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
04/17/2019 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 AMATO J. GIACCIA, ERINN BRUNO RANKIN, JENNIFER R.
COCHRAN, DOUGLAS JONES, MIHALIS KARIOLIS, KATHERINE
FUH, and YU MIA0 1
Appeal2018-006002
Application 14/712,731
Technology Center 1600
Before RYAN H. FLAX, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.
HARDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to soluble
AXL variant polypeptides, which have been rejected for lack of written
description support, for obviousness, and for nonstatutory obviousness-type
double patenting. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm the written description and double patenting rejections.
We reverse the obviousness rejection.
1 Appellants identify the Real Party in Interest as The Board of Trustees of
the Leland Stanford Junior University. (Br. 1.) Herein we reference the
Appeal Brief filed Jan. 5, 2018 ("Br."); the Specification filed May 14, 2015
("Spec."); the Final Office Action mailed Mar. 17, 2017 ("Final Act."); and
the Examiner's Answer mailed Feb. 28, 2018 ("Ans.").
Appeal2018-006002
Application 14/712,731
STATEMENT OF THE CASE
According to the Specification, AXL is a receptor tyrosine kinase, and
GAS6 (growth arrest-specific protein 6) is the "activating ligand for AXL."
Spec. ,r,r 9, 10. The Specification states that "[t]he present invention is based
in part on the discovery that AXL and/or GAS6 related pathways are related
to tumor invasion and/or metastasis." Id. at ,r 12. The invention "provides
soluble AXL variant polypeptides, wherein said polypeptide lacks the AXL
transmembrane domain, and optionally intracellular domain and comprises
at least one amino acid modification relative to the wild-type AXL sequence,
and wherein said change increases the affinity of the AXL polypeptide
binding to GAS6." Id. at ,r 13.
Claims 1, 4, 5, and 17-19 are on appeal. Claim 1 is illustrative and
reads as follows:
1. A soluble AXL variant polypeptide, wherein said
polypeptide lacks the AXL transmembrane domain, comprises
at least one amino acid substitution relative to the wildtype
AXL sequence of SEQ ID NO: 1 wherein said substitution
increases the affinity of the AXL polypeptide binding to GAS6
and wherein the polypeptide competes for binding to GAS6
with a reference AXL variant polypeptide having a set of amino
acid substitutions of the wild-type AXL sequence (SEQ ID NO.
1) selected from the group consisting of
1) Gly32Ser, Asp87Gly, Val92Ala, and Gly127 Arg,
2) Glu26Gly, Val79Met, Val92Ala, and Gly127Glu, and
3) Gly32Ser, Ala72Val, Asp87Gly, Val92Ala, and
Gly127Arg.
Br. 10 (Claims Appendix).
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Application 14/712,731
The claims stand rejected as follows:
Claims 1, 4, 5, and 17-19 are rejected under 35 U.S.C. § 112(a) for
failure to comply with the written description requirement. Final Act. 3---6.
Claims 1, 4, 5, and 17-19 are rejected under 35 U.S.C. § 103(a) as
obvious over Graham, 2 Sasaki, 3 and Patel. 4 Id. at 8-11.
Claims 1, 4, 5, and 17-19 are rejected for nonstatutory obviousness-
type double patenting over (1) claims 1-8 of US Patent No. 8,618,254; (2)
claims 1-7 of US Patent No. 9,074,192; and (3) claims 1---6 of US Patent No.
9,266,947. Id. at 12-13.
Claims 1, 4, 5, and 17-19 are provisionally rejected for nonstatutory
obviousness-type double patenting over (1) claims 1-24, 28, and 31-84 of
US Patent Application No. 13/714,875 (now US Patent No. 9,879,061); and
(2) claims 81-98 of US Patent Application No. 14/650,854 (now US Patent
No. 9,822,347). 5 Id. at 13-14; Ans. 19.
2 Graham et al., WO 2008/098139 A2, published Aug. 14, 2008.
3 Sasaki et al., Structural Basis for Gas6-Axl Signalling, 25(1) EMBO J. 80-
87 (2006).
4 Patel et al., Engineering an APRIL-Specific B Cell Maturation Antigen,
279(16) J. BIOL. CHEM. 16727-35 (2004).
5 The Examiner withdrew the rejection of claims 1 and 17 as anticipated
under 35 U.S.C. § 102(b) by Graham, and the provisional rejection of claims
1, 4, 5, and 17-19 on the ground of nonstatutory obviousness-type double
patenting over claims 1-5, 9, 23, 27, 28, 31, 38, 40, 45--47, 49, 55, 73, and
75 of US Patent Application No. 14/650,852, in view of the abandonment of
that application. (Ans. 20.)
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Application 14/712,731
DISCUSSION
Written Description
Claims 1, 4, 5, and 17-19 are rejected for failure to comply with the
written description requirement. Ans. 3. The Examiner acknowledges that
the Specification discloses numerous variants that fall within the scope of
independent claim 1, but notes that all of these variants have amino acid
substitutions in the Igl domain. Id. at 6-9. The Examiner points to the
breadth of the claims, stating that the claimed genus "is highly variable
because a significant number of structural differences between genus
members are permitted." Id. at 7. The Examiner concludes:
This limited disclosure of soluble human AXL variants with
specific amino acid substitutions at specific positions in the first
lg domain of the AXL extracellular domain is insufficient to
show that Applicant was in possession of the necessary
common attributes or features possessed by the members of the
genus, which encompasses unidentified substitutions at any
position within any portion of the AXL extracellular domain.
The specification does not describe the physical or chemical
characteristic[ s] for the undefined substitution variants nor does
the specification disclose any correlation between the structures
of the undefined variants or any correlation of structure with
enhanced affinity for binding GAS6 beyond that of the
exemplified variants.
Id. 7-8.
Appellants respond that the Specification discloses at least 25 unique
variant polypeptides that meet the criteria of the claims, and that this "large
number of variants demonstrates that Appellants were in possession of the
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Application 14/712,731
necessary common attributes or features possessed by the members of the
genus as currently broadly claimed."6 Br. 5.
In determining whether disclosed species are representative of a
claimed genus, one factor considered is "how large a genus is involved and
what species of the genus are described in the patent." AbbVie Deutschland
GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir.
2014). Here, the only structural limitations recited in claim 1 are the lack of
the AXL transmembrane domain and the at least one amino acid
substitution. Ans. 9; Br. 10 (Claims Appendix). The claims thus cover
structurally diverse polypeptides, e.g., polypeptides with or without the
cytoplasmic domain, and with or without the Ig2 and two fibronectin
domains. Ans. 9. Further, given the "comprising" language in the claims,
the recited amino acid substitution( s) can occur in any domain of the
polypeptide, so long as the functional limitations of the claims are met. Id.
In view of the breadth of the claims, we are not persuaded by
Appellants' argument that "25 unique variants" disclosed in the specification
that meet the criteria of the claims "demonstrate[] that Appellants were in
possession of the necessary common attributes or features possessed by the
members of the genus as currently broadly claimed." Br. 5. Appellants
have not articulated what common attributes or structural features unite the
disclosed variants such that one of skill in the art would visualize or
recognize other members of the genus. AbbVie, 759 F.3d at 1299. Instead,
we agree with the Examiner that "[t]he specification does not describe the
6 We agree with the Examiner that claims 18 and 19 add functional
limitations to claim 1, and it is not clear that all of the disclosed variants
meet the functional limitations of these claims. Ans. 10.
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physical or chemical characteristic[ s] for the undefined substitution variants
nor does the specification disclose any correlation between the structures of
the undefined variants or any correlation of structure with enhanced affinity
for binding GAS6 beyond that of the exemplified variants." Ans. 8.
Appellants further argue that "if a set of amino acid substitutions in
the context of a specific known polypeptide sequence have [sic] been
provided, and demonstrated to have a specific function of interest, i.e.
enhanced binding to GAS6, then a person of ordinary skill in the art would
readily recognize that additional amino acid substitutions could be made to
that sequence without unduly altering the structure or function of the
polypeptide." Br. 6. We are not persuaded by this argument. First, it is not
supported by evidence. See Johnston v. IVAC Corp., 885 F.2d 1574, 1581
(Fed. Cir. 1989) (noting that attorney argument is "no substitute for
evidence"). Second, claim 1 is not limited to polypeptides that include
amino acid substitutions that have already been demonstrated to meet the
functional limitations of the claims, but rather encompass polypeptides with
unidentified substitutions as well.
Further, we find that Appellants' argument is not consistent with the
state of the art. For example, the Examiner stated, citing US Patent No.
6,737,056 to Presta ("Presta"), that "[t]he art generally recognized that
changes to amino acid residues outside the exact contact area for binding of
one polypeptide to another could have dramatic, and opposite, effects on the
binding affinity ( or other function), and that those effects were dependent on
both the position altered and upon the amino acid substation introduced."
Ans. 4--5; see also Non-Final Office Action, mailed July 25, 2016, at 6. The
Examiner further stated, again citing Presta, that "the effect of mutations in
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and outside of an lg domain on binding affinity for a particular counter-
receptor generally was not predictable a priori." Ans. 9. We adopt these
findings, and agree with the Examiner that the prior art demonstrates that
"without actually conducting the mutational analysis for the larger genus of
soluble AXL polypeptides lacking the transmembrane region, the skilled
artisan would not be able to envision which other 'at least one substitution'
would maintain the recited functional activities." Id. Accordingly, we
sustain the written description rejection.
Obviousness
Claims 1, 4, 5, and 17-19 are rejected as obvious over the
combination of Graham, Sasaki, and Patel. The Examiner finds that Graham
teaches soluble AXL fusion proteins, including fusion proteins that bind
GAS6 with higher affinity compared to wild-type AXL. Ans. 12-13. The
Examiner acknowledges, however, that "Graham does not exemplify any
affinity-enhancing mutations or show that the resulting variant AXL-Fc
fusion protein would bind GAS6 with the affinities recited in claims 18 and
19." Id. at 13 ( emphasis omitted).
The Examiner finds that Sasaki teaches crystallography mapping of
the AXL-GAS6 binding interaction, and discloses mutations within the
major and minor contact sites between AXL and GAS6 that affect the
affinity of the AXL/GAS6 interaction. Id. The Examiner finds that "[i]n
view of the teachings of Sasaki, the ordinary artisan at the time the invention
was made would have found it obvious to substitute amino acids within or
near the major and minor contact sites for GAS6 to enhance the binding
affinity of the AXL-Fc inhibitors of Graham for GAS6." Id. The Examiner
cites Patel because it "evidences that techniques for making mutations at
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specific location[ s] were routine in the art at the time the invention was
made, including using alanine substitution scanning to monitor which
residues contributed to the affinity of a protein for binding another protein."
Id. at 14.
The Examiner concludes:
The teachings of Graham to produce higher affinity
variants combined with the teachings of Sasaki regarding
residues in the binding sites would have motivated the ordinary
artisan to make at least alanine substitutions at each of those
positions. . . . Thus, the ordinary artisan would have been
motivated to prepare an AXL-Fc polypeptide with at least the
Val92Ala substitution and would have observed that this
substitution necessarily enhanced binding affinity to GAS6.
In addition, given that the same variant would be produced, it
would necessarily compete with one of the three reference
variants now recited in claim 1.
Id. at 14 ( emphasis in original).
In response, Appellants argue, inter alia, that "alanine substitution has
been generally considered by one skilled in the art as a tool for identifying
substitutions that are likely to 'lower the binding activity' of a protein," and
that "Patel's own data demonstrate that [the] overwhelming majority of
alanine substitutions made in Patel caused diminished binding or change of
binding specificity." Br. 8. Appellants therefore conclude that"[ o ]ne
skilled in the art would not have been motivated to use [the] alanine
scanning method to look for substitutions that are likely to maintain or
increase the binding of the AXL to GAS6." Id. at 8-9 (emphasis in
original).
On the present record, we agree with the Examiner that an "ordinary
artisan at the time the invention was made would have found it obvious to
substitute amino acids within or near the major and minor contact sites for
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Application 14/712,731
GAS6 to enhance the binding affinity of the AXL-F c inhibitors of Graham
for GAS6," including the amino acid at residue 92. See, e.g., Ans. 13.
However, we agree with Appellants that the Examiner has not persuasively
established that a person of ordinary skill in the art would have been
motivated to substitute wildtype amino acids with alanine for the purpose of
increasing the binding affinity of AXL to GAS6. Specifically, the record
demonstrates that the alanine scanning technique was used to identify
residues that contribute to the binding interface between two proteins. See,
e.g., Patel at Abstract ("[S]hotgun alanine scanning of BCMA was used to
map critical residues for either APRIL or BAFF binding."). Here, however,
Sasaki already identified residues important to the AXL-GAS6 binding
interface. See, e.g., Ans. 13. Moreover, as the Examiner acknowledges,
"most alanine-scanning results in lower affinity binding." Id. at 16. Thus
we find insufficient evidence on the record to support the conclusion that a
skilled artisan would have been motivated to use alanine scanning to
substitute valine with alanine at position 92 for purposes of "affinity
enhancement." Id. at 15.
The motivation to substitute valine with alanine at position 92 was
key to the Examiner's findings that a person of ordinary skill in the art
would have achieved a polypeptide meeting the claimed functional features.
See, e.g., Ans. 14 (finding that a polypeptide with at least the Val92Ala
substitution would necessarily have enhanced binding affinity to GAS6 and
would necessarily compete with one of the three reference variants recited in
claim 1 ). However, because we find insufficient evidence on the record to
support the conclusion that a skilled artisan would have been motivated to
substitute valine with alanine at position 92, we also find insufficient
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evidence on the record to support that a person of ordinary skill in the art
would have arrived at an AXL polypeptide that meets the claimed functional
limitations. Therefore, we find that the Examiner has not established a
prima facie case of obviousness for the pending claims.
Nonstatutory Obviousness-Type Double Patenting
On appeal, Appellants do not address the Examiner's nonstatutory
obviousness-type double patenting rejections. See, e.g., Br. 1-10.
Arguments not presented in a brief are waived. See 37 C.F.R.
§ 4I.37(c)(l)(iv) (2015) ("Except as provided for in§§ 41.41, 41.47 and
41.52, any arguments or authorities not included in the appeal brief will be
refused consideration by the Board for purposes of the present appeal.").
Accordingly, in view of Appellants' lack of response, we summarily
affirm the uncontested nonstatutory obviousness-type double patenting
rejections of claims 1, 4, 5, and 17-19 over (1) claims 1-8 of US Patent No.
8,618,254; (2) claims 1-7 of US Patent No. 9,074,192; and (3) claims 1---6 of
US Patent No. 9,266,947.
The Examiner also provisionally rejected claims 1, 4, 5, and 17-19
over claims 1-24, 28, and 31-84 of US Patent Application No. 13/714,875
(the "'875 application"). Final Act. 13; Ans. 19. The '875 application has
now issued as US Patent No. 9,879,061 (the "'061 patent," issued Jan. 30,
2018), with four claims (hence, the rejection is no longer deemed to be
"provisional"). In view of Appellants' lack of response to this rejection, we
summarily affirm the rejection over issued claims 1--4 of the '061 patent.
The Examiner also provisionally rejected claims 1, 4, 5, and 17-19
over claims 81-98 of US Patent Application No. 14/650,854. Final Act. 14.
This application has now issued as US Patent No. 9,822,347 (the "'347
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patent," issued Nov. 21, 2017), with three claims (hence, the rejection is no
longer deemed to be "provisional"). In view of Appellants' lack of response
to this rejection, we summarily affirm the rejection over issued claims 1-3 of
the '347 patent.
SUMMARY
We affirm the rejection of claims 1, 4, 5, and 17-19 under 35
U.S.C. § 112(a) for failing to comply with the written description
requirement.
We reverse the rejection of claims 1, 4, 5, and 17-19 under 35
U.S.C. § 103(a) as obvious over Graham, Sasaki, and Patel.
We affirm the rejections of claims 1, 4, 5, and 17-19 for nonstatutory
obviousness-type double patenting over (1) claims 1-8 of US Patent No.
8,618,254; (2) claims 1-7 of US Patent No. 9,074,192; (3) claims 1-6 of US
Patent No. 9,266,947; (4) claims 1--4 of US Patent No. 9,879,061; and (5)
claims 1-3 of US Patent No. 9,822,347.
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)(l)(iv).
AFFIRMED
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