Ex Parte Xu

Patent Trial and Appeal Board

Dec 12, 2016

12665746 (P.T.A.B. Dec. 12, 2016)

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.
12/665,746 06/10/2010 Hanmei Xu JIAN.6678-NY 3541
5409 7590 12/14/2016
SCHMEISER, OLSEN & WATTS
22 CENTURY HILL DRIVE
SUITE 302
LATHAM, NY 12110
EXAMINER
HADDAD, MAHER M
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
12/14/2016 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):
AZ5409@IPLAWUSA.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HANMEI XU1
Appeal 2015-007840
Application 12/665,746
Technology Center 1600
Before ERIC B. GRIMES, JOHN E. SCHNEIDER, and RYAN H. FLAX,
Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to an
agent for inhibiting angiogenesis which have been rejected as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
The present invention is directed to small peptides that inhibit
angiogenesis, which is the formation of new blood vessels. Spec. 2. The
angiogenic inhibitors can be used to treat tumors. Id.
1 Appellant identifies the Real Party in Interest as the inventor, Hanmei Xu.
Appeal Br. 2.
Appeal 2015-007840
Application 12/665,746
Claims 1, 12—15, and 17 are on appeal. Claim 1 is illustrative and
reads as follows:
1. A highly efficient antiangiogenesis agent
comprising: a polypeptide, wherein the polypeptide is selected
from the group consisting of SEQ ID NO 2, SEQ ID NO 4,
SEQ ID NO 7, SEQ ID NO 8 and SEQ ID NO 9, wherein said
polypeptide is modified by polyethyleneglycol, heparin,
dextran, polyvinylpyrrolidone, polyethyleneglycolpoly-amino
acid copolymer, palmitic acid polysialic acid, liposomes, or
nanotechnology.
Each of SEQ ID NOs 2, 4, 7, 8, and 9 includes an RGD (Arg-Gly-
Asp) sequence connected to a longer sequence via a “linker.” Spec.2 4—5.
The claims stand rejected as follows:
Claims 1, 12—15, and 17 stand rejected under 35 U.S.C. § 112, first
paragraph, as failing to comply with the written description requirement.
Claims 1, 12—15, and 17 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Xu3 in view of Yokoyama.4
Claims 1, 12—15, and 17 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Yokoyama in view of Wickstrom5 and Parry.6
2 Substitute Specification filed May 21, 2014.
3 Xu et al., CN 1699408 Al, published Nov. 23, 2005 (“Xu”) (citations are
to the English translation).
4 Yokoyama et al., US 6,825,167 Bl, issued Nov. 30, 2004 (“Yokoyama”).
5 Wickstrom et al., An Endostatin-derived Peptide Interacts with Integrins
and Regulates Actin Cytoskeleton and Migration of Endothelial Cells, 279 J.
Bio. Chem. 20178 (2004) (“Wickstrom”).
6 Parry et al., In Vitro and in Vivo Evaluation of64Cu-Labeled DOTA-Linker-
Bombesin (7—14) Analogues Containing Different Amino Acid Linker
Moieties, 18 Bioconjugate Chem. 1110 (2007) (“Parry”).
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Application 12/665,746
THE WRITTEN DESCRIPTION REJECTION
Issue
The Examiner finds that the term “linker” is not adequately described
in the Specification. Final Act. 4. The Examiner finds that,
the specification provides neither a representative number of
species (linkers having one or more different amino acids) to
describe the claimed genus, nor does it provide a description of
structural features that are common to species (one or more
different amino acids). The specification provides no structural
description of linkers having one or more different amino acids;
in essence, the specification simply directs those skilled in the
art to go figure out for themselves what the claimed linkers
having one or more different amino acids looks like. The
specification’s disclosure is inadequate to describe the claimed
genus of linkers having one or more different amino acids.
Id.
Appellant contends that the linkers are adequately described in the
Specification. Appeal Br. 10. Appellant argues that the Sequence Listing
for the claimed peptides meets the requirements of the USPTO rules in that
it specifically identifies the location of the linker sequences. Id. Appellant
goes onto point out that the Specification teaches that the linker comprises
one or more different amino acids. Id. Appellant concludes by arguing that,
[a] person skilled in the art, knowing both the compositions of
each of the limited number of amino acids, and knowing
methods for connecting each of the amino acids to one another,
would inherently understand as being disclosed in the current
application that the linker described by the Appellants [sic]
specification would inherently encompass each combination of
the known amino acids containing one or more different amino
acids which may be linked between the sequenced portions
disclosed in the Sequence Listing. Thus, a person skilled in the
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Application 12/665,746
art would understand that the Appellant identified at the
specific un-sequenced locations, that a chain of amino acids,
having one or more different amino acids, could be inserted or
connected in-between specified sequenced amino acids.
Appeal Br. 11.
The issue with respect to this rejection is whether the linker portion of
the claimed peptides has been described in the Specification in such a way as
to reasonably convey to one skilled in the art that the application was filed
showed possession of the claimed invention.
Principles of Law
“[T]he test requires an objective inquiry into the four comers of the
specification from the perspective of a person of ordinary skill in the art.
Based on that inquiry, the specification must describe an invention
understandable to that skilled artisan and show that the inventor actually
invented the invention claimed.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598
F.3d 1336, 1351 (Fed. Cir. 2010) (enbanc).
A “sufficient description of a genus instead requires the disclosure of
either a representative number of species falling within the scope of the
genus or stmctural 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.” Id.
at 1350.
“One needs to show that one has tmly invented the genus, i.e., that
one has conceived and described sufficient representative species
encompassing the breadth of the genus. Otherwise, one has only a research
plan, leaving it to others to explore the unknown contours of the claimed
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Application 12/665,746
genus.” AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759
F.3d 1285, 1300 (Fed. Cir. 2014).
Analysis
We agree with the Examiner that the Specification does not contain an
adequate written description of the linker element. While Appellant has
identified the location of the linker relative to the rest of the peptide
sequences, the Specification does not give any structure or physical or
chemical properties of the linker other than to say that it contains one or
more different amino acids. Ans. 9. As the Examiner points out,
[t]he specification provides neither a representative number of
species (linkers having one or more different amino acids) to
describe the claimed genus, nor does it provide a description of
structural features that are common to species (one or more
different amino acids). The specification provides no structural
description of linkers having one or more different amino acids
in the highly efficient antiangiogenesis agent; in essence, the
specification simply directs those skilled in the art to go figure
out for themselves what the claimed linkers having one or more
different amino acids look[] like. The specification’s disclosure
is inadequate to describe the claimed genus of linkers having
one or more different amino acids with the capability of having
highly efficient antiangiogenesis agent.
Ans. 3.
Appellant contends that the written description requirement has been
met in that the location of the linker has been set forth in the sequence listing
and the Specification teaches that the linker comprises one or more different
amino acids. Appeal Br. 10. Appellant goes on to argue that,
[a] person skilled in the art, knowing both the compositions of
each of the limited number of amino acids, and knowing
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Application 12/665,746
methods for connecting each of the amino acids to one another,
would inherently understand as being disclosed in the current
application that the linker described by the Appellants
specification would inherently encompass each combination of
the known amino acids containing one or more different amino
acids which may be linked between the sequenced portions
disclosed in the Sequence Listing. Thus, a person skilled in the
art would understand that the Appellant identified at the
specific un-sequenced locations, that a chain of amino acids,
having one or more different amino acids, could be inserted or
connected in-between specified sequenced amino acids.
Appeal Br. 11.
We are unpersuaded. As the Examiner points out, the general
knowledge of the known amino acids and how to link them in a chain is not
the same as knowing which amino acids can be used to form a linker that
creates a highly effective anti-angiogenic agent. Ans. 11. One skilled in the
art would not conclude that Appellant had in Appellant’s possession the full
genus of linkers that could be used to create the claimed anti-angiogenic
agent at the time the application was filed. Id.
Conclusion of Law
We conclude that the Examiner has established that the pending
claims fail to satisfy the written description requirement of 35 U.S.C. § 112,
first paragraph.
THE OBVIOUSNESS REJECTIONS
Xu combined with Yokoyama
The Examiner finds that Xu teaches the use of the peptides of SEQ ID
NO: 2 and 4 for tumor treatment. Ans. 4. The linker used are defined as
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Application 12/665,746
having one or more different amino acids. Id. The Examiner finds that the
disclosed peptides are highly efficient angiogenesis inhibitors. Ans. 4—5.
The Examiner finds that Yokoyama teaches that endostatin can be modified
by attaching an RGD motif at either the N or C terminus without
compromising activity and that the RGD sequence increases endothelial cell
attachment. Ans. 6. The Examiner also finds that Yokoyama teaches that
the peptides can be formulated with compounds such as polyethyleneglycol
(“PEG”) and can be coupled to a carrier using liposomes. Id. The Examiner
concludes by finding that,
[f]rom the combined teachings of the references, it is apparent
that one of ordinary skill in the art would have had a reasonable
expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to
one of ordinary skill in the art at the time the invention was
made, as evidenced by the references, especially in the absence
of evidence to the contrary.
Ans. 7.
Appellant contends that neither Xu nor Yokoyama teaches
modification of the peptides as required by the claims. Appeal Br. 12.
Appellant argues that as used in the Specification, the term modification
refers to binding or linking the modification compounds to the amino acids
at either end of the polypeptide chain. Appeal Br. 13—14. Appellant goes on
to argue that the portion of Yokoyama cited by the Examiner discusses the
use of PEG to encapsulate the peptides, not to bind to the peptides. Appeal
Br. 14. Appellant goes on to argue that the Examiner has failed to provide
sufficient explanation as to why one skilled in the art would modify the
peptide of Xu using the compounds disclosed in Yokoyama. Appeal Br. 15.
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The issue with respect to this rejection is whether the Examiner has
established by a preponderance of the evidence that the present claims would
have been obvious over Xu combined with Yokoyama.
Findings of Fact
We adopt as our own the Examiner’s findings and analysis. The
following findings are included for emphasis and reference convenience.
FF1. Xu discloses small peptide inhibitors of angiogenesis which
have an anti-tumor effect. Xu 5.
FF2. The peptides of Xu may contain the amino acid sequence Arg-
Gly-Asp at either end resulting in peptide that have a binding effect on
integrin affinity and inhibit angiogenesis. Id.
FF3. Xu discloses the use of a peptide linker, Gly-Gly-Gy-Gly,
between the Arg-Gly-Asp peptide sequence and the polypeptide
angiogenesis inhibitor. Xu 2.
FF4. One of the polypeptide disclosed in Xu as an antiangiogenic
agent has the peptide sequence Ile-Val-Arg-Arg-Ala-Asp-Arg-Ala-Ala-Val-
Pro-Gly-Gly-Gly-Gly-Arg-Gly-Asp. Xu claim 3.
FF5. The instant Specification teaches that polypeptide
corresponding to SEQ ID NO:4 is useful as an antiangiogenic agent and has
the following sequence: Ile-Val-Arg-Arg-Ala-Asp-Arg-Ala-Ala-Val-Pro-
linker-Arg-Gly-Asp. Spec. 4.
FF6. Yokoyama discloses binding a targeting moiety to an
antiangiogenic polypeptide to facilitate the interaction and/or binding of the
antiangiogenic polypeptide to endothelial cells. Yokoyama col. 2,11. 8—12.
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Application 12/665,746
FF7. The targeting moiety useful in Yokoyama includes the peptide
Arg-Gly-Asp (RGD). Yokoyama col. 2,11. 19-48.
FF8. The preferred anti-angiogenic polypeptides used in Yokoyama
include endostatin. Yokoyama col. 2,11. 53—54.
FF9. Yokoyama teaches that “[preferred delivery systems for a
peptide can include coupling the peptide to a carrier or an intact attenuated
microbe, such as an inactivated virus or attenuated bacterium, e.g.,
weakened Salmonella, preparing a multiple antigen peptide, using liposomes
or other immunostimulating complexes.” Yokoyama col. 22,11. 21—26.
Principles of Law
“The factual predicates underlying an obviousness determination
include the scope and content of the prior art, the differences between the
prior art and the claimed invention, and the level of ordinary skill in the art.”
In reRouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1998).
Analysis
Claim 1 is representative of the rejected claims and relates to an anti-
angiogenic agent comprising a peptide having the three amino acid group
Arg-Gly-Asp at one end, followed by a linker comprising one or more
different amino acids and then one of five specified antiangiogenic peptides.
The agent has been modified by polyethyleneglycol, heparin, dextran,
polyvinylpyrrolidone, polyethyleneglycol-poly-amino acid copolymer,
palmitic acid, polysialic acid, liposomes, or nanotechnology.
We agree with the Examiner that the subject matter of claim 1 would
have been obvious to one skilled in the art at the time the invention was
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Application 12/665,746
made. Both Xu and Yokoyama teach the use of the three amino acid group
Arg-Gly-Asp at one end of an antiangiogenic agent to enhance the
effectiveness of the agent. FF2 and 4. Xu teaches that the antiangiogenic
compound may comprise the same amino acid complex as SEQ ID NO: 4 of
the instant invention. Xu also teaches the use of a linker (GGGG) between
the Arg-Gly-Asp sequence and the anti-angiogenic sequence. FF3.
Yokoyama teaches that an antiangiogenic peptide having an additional
amino acid sequence Arg-Gly-Asp can be coupled to liposomes. FF6—9.
Appellant contends that the references do not teach modification of
the polypeptide as defined by the Specification. Appeal Br. 12. Appellant
contends that modification requires that the modification compound be
bound or linked to the peptide chain at either end of the chain. Id.
Appellant argues that while Yokoyama discloses the use of PEG and other
modification compounds, the compounds are not bound or linked to the
polypeptide. Appeal Br. 14—15. With respect to liposomes, Appellant
argues that Yokoyama only teaches that the liposomes are used to couple the
agent with a carrier and that this is not the same as a modification. Reply
Br. 10.
We are unpersuaded. We agree with the Examiner that Yokoyama
discloses modification of the peptide agent by coupling that agent to a
carrier using a liposome. Ans. 15. That Yokoyama does not refer to the
coupling using a liposome as a modification does not preclude such a
finding.
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Conclusion of Law
We conclude that the Examiner has established by a preponderance of
the evidence that the subject matter of claim 1 would have been obvious
over Xu combined with Yokoyama.
Claims 12—15, and 17 have not been argued separately and therefore
fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
Yokoyama combined with Wickstrom and Parry
In rejecting the pending claims over Yokoyama combined with
Wickstrom and Parry, the Examiner reiterates his findings with respect to
Yokoyama discussed above. Ans. 7. The Examiner also finds that,
Yokoyama teaches and claims the use of a composition [that]
comprises a RGD-containing peptide linked to endostatin in a
method to inhibit or prevent undesirable endothelial cell
proliferation or migration (see claims 12, 14, 15 and 21).
Yokoyama further teaches that preferred delivery systems for a
peptide can include coupling the peptide to a carrier using
liposomes (see the entire document, in particular see col., 22,
lines 20-25).
Ans. 7. The Examiner finds that Wickstrom teaches that the polypeptide Ile-
Val-Arg-Arg-Ala-Asp-Arg-Ala-Ala-Val-Pro (“ES-2”) displayed “reduced
ability to migrate toward the bFGF stimulus and inhibited tubular
morphogenesis as described earlier for endostatin.” Ans. 7. The Examiner
finds that Parry discloses the use of linkers comprising Gly-Gly-Gly, Gly-
Ser-Gly, Gly-Ser-Ser, and Gly-Glu-Gly and that their use leads to lower
background tissue uptake. Id. The Examiner concludes that,
[t]hose skilled in the art would have had a reason to use the ES-
2 peptide of Wickstrom as a substitute for the treatment taught
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by Yokoyama et al and link the ES-2 via the amino acid linkers
of Parry et al because, like the endostatin taught in Yokoyama
et al, ES-2 inhibits cell migration and tubular morphogenesis,
wherein the amino acid linker lead [sic] to lower background
tissue uptake. Substituting a known element for another, to
yield the known result, is obvious.
Ans. 7—8.
Appellant contends that the references do not teach modification of
the antiangiogenic polypeptide with the claimed compositions. Appeal Br.
17. In addition, Appellant contends that there is a teaching away in the
references from substituting the endostatin disclosed in Yokoyama with the
ES-2 polypeptide disclosed by Wickstrom. Appeal Br. 18—19. Specifically
Appellant argues that Wickstrom teaches that the peptide ES-2 promotes cell
adhesion which is the opposite of Yokoyama. Id. Appellant argues that this
teaching would lead one skilled in the art away from the combination
advanced by the Examiner. Appeal Br. 19.
The issue with respect to this rejection is whether the Examiner has
established by a preponderance of the evidence that the pending claims
would have been obvious over Yokoyama combined with Wickstrom and
Parry.
Findings of Fact
FF10. The polypeptide of Yokoyama “inhibits proliferation and/or
migration of endothelial cells, attaches to endothelial cells, and/or inhibits
tumor growth, and preferably is enhanced in these properties relative to the
corresponding non-chimeric antiangiogenic polypeptide.” Yokoyama col 2,
11. 43^17.
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FF11. Wickstrom discloses an endostatin-derived peptide ES-2 which
is “an inhibitor of endothelial cell migration and tube formation” and that “it
is plausibly an important sequence motif for the anti-angiogenic activity of
endostatin.” Wickstrom 20178, right col., third para.
FF12. Wickstrom teaches that the ES-2 peptide inhibited directed cell
migration, however, random cell migration was essentially unaffected or
modestly increased. Wickstrom 20184
FF13. Wickstrom teaches that “the observed inhibition of tubular
morphogenesis in endostatin- and ES-2-treated cells could reflect the loss of
directed cell migration.” Wickstrom 20185, left col.
Principles of Law
“‘It is impermissible within the framework of section 103 to pick and
choose from any one reference only so much of it as will support a given
position, to the exclusion of other parts necessary to the full appreciation of
what such reference fairly suggests to one of ordinary skill in the art.’” In re
Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986) (quoting In re Wesslau, 353
F.2d 238, 241 (CCPA 1965)).
Although a reference that teaches away is a significant factor to
be considered in determining unobviousness, the nature of the
teaching is highly relevant, and must be weighed in substance.
A known or obvious composition does not become patentable
simply because it has been described as somewhat inferior to
some other product for the same use.
In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
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Analysis
Appellant’s argument regarding Yokoyama’s lack of teaching
regarding modifying the polypeptide is discussed above and will not be
repeated.
Turning to Appellant’s argument regarding Wickstrom discouraging
one skilled in the art from combining its teachings with Yokoyama, we are
unpersuaded. While Wickstrom states that ES-2 does not inhibit random
cell migration, Wickstrom also teaches that it is effective in inhibiting
directed cell migration and that such inhibition appears to be tied to
inhibition of tubular morphogenesis. FF12 and 13. In addition, Wickstrom
teaches that because the ES-2 sequence is an inhibitor of endothelial
migration and tube formation, it is plausibly an important sequence motif for
the anti-angiogenic activity of endostatin. FF11. The teachings of
Wickstrom that ES-2 performs in a manner similar to endostatin itself would
lead one skilled in the art to use the ES-2 peptide in place of endostatin in
the modified polypeptides of Yokoyama.
Conclusion of Law
We conclude that the Examiner has established by a preponderance of
the evidence that the pending claims would have been obvious over
Yokoyama combined with Wickstrom under 35 U.S.C. § 103(a).
SUMMARY
We affirm the rejection under 35 U.S.C. § 112, first paragraph.
We affirm both rejections under 35 U.S.C. § 103(a).
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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
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