Ex Parte Yla-Herttuala

Patent Trial and Appeal Board

Mar 23, 2017

13969763 (P.T.A.B. Mar. 23, 2017)

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
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/969,763 08/19/2013 Seppo YLA-HERTTUALA FKD - 61/692,828 6511
22925 7590 03/27/2017
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EXAMINER
PAK, MICHAEL D
ART UNIT PAPER NUMBER
1646
NOTIFICATION DATE DELIVERY MODE
03/27/2017 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SEPPO YLA-HERTTUALA
Appeal 2016-0073951
Application 13/969,763
Technology Center 1600
Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and JOHN E.
SCHNEIDER, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to treating cancer comprising
administering a cytotoxic compound and a decoy receptor which binds to
vascular endothelial growth factor (“VEGF”). The Examiner rejected the
claims as anticipated under 35 U.S.C. §§ 102(b)/(e) and obvious under 35
U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 134. The
rejections are affirmed.
STATEMENT OF THE CASE
Appellant appeals from the Examiner’s final rejection of claims 1—11.
The claims stand rejected by the Examiner as follows:
1 The Appeal Brief (“Appeal Br.”) at page 1 lists FKD Therapies Oy as the
real-party-in-interest.
Appeal 2016-007395
Application 13/969,763
1. Claims 1—6 and 8—10 under 35 U.S.C. § 102(e) as anticipated by
Baldwin.2 Examiner’s Answer (“Ans.”) 3.
2. Claims 1—5 under 35 U.S.C. § 102(b) as anticipated by Hu.3 Ans.
3.
3. Claims 1—11 under 35 U.S.C. § 103(a) as obvious in view of
Byrne,4 Hu, Sallinen,5 and Baldwin. Ans. 5.
Claim 1, the only independent claim on appeal, is reproduced below:
1. In a method of treating cancer by administering a cytotoxic
compound, the improvement comprising administering a decoy
receptor which binds to Vascular Endothelial Growth Factor,
wherein said decoy receptor is in a form adequate to ensure
efficient dimerization of said decoy receptor, said cytotoxic
compound and said decoy receptor administered in amounts
which are together effective to treat said cancer.
1. REJECTION BASED ON BALDWIN
The Examiner found that Baldwin describes treating ovarian cancer,
2 Megan E. Baldwin, U.S. Pat. App. Publ. 2013/0344065 Al, publ. Dec. 26,
2013.
3 Limin Hu, Hofmann, J., Holash, J., Yancopoulos, G.D., Sood, A.K., and
Jaffe, R.B., Vascular Endothelial Growth Factor Trap Combined with
Paclitaxel Strikingly Inhibits Tumor and Ascites, Prolonging
Survival in a Human Ovarian Cancer Model, 11 Clin. Cancer Res., 6966—71
(2005).
4 Annette T. Byrne, Ross, L., Holash, J., Nakanishi, M., Hu, L., Hofmann,
J.I., Yancopoulos, G.D., and Jaffe, R.B., Vascular Endothelial Growth
Factor-Trap Decreases Tumor Burden, Inhibits Ascites, and Causes
Dramatic Vascular Remodeling in an Ovarian Cancer Model, 9 Clin.
Cancer Res., 5721-28 (2003).
5 Hanna Sallinen et al., Antiangiogenic Gene Therapy With Soluble
VEGFR-1, -2, and -3 Reduces the Growth of Solid Human Ovarian
Carcinoma in Mice, 17 Mol. Ther., 278—84 (2009).
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Application 13/969,763
as required by claim 1. Final Office Action (“Final Act.”) 5. The Examiner
found that Baldwin describes administering a cytotoxic compound (taxane)
and a soluble receptor trap from a VEGF receptor (VEGF-Trap) that serves
as the claimed “decoy receptor which binds to Vascular Endothelial Growth
Factor.” Id. The VEGF-Trap described in Baldwin comprises an Fc region
which the Examiner found ensures efficient dimerization of said decoy
receptor as required by the claims. Id. See Spec. 2:18—19 (“All constructs
contain an immunoglobulin Fc domain to ensure efficient dimerization of
the soluble decoy receptors”). The Examiner also found that Baldwin
describes gene therapy using a viral vector comprising the VEGF-Trap as
required by rejected claim 6. Id.
The filing date of the Baldwin U.S. Application is August 29, 2013.
Baldwin’s application is a continuation of an earlier filed application and a
PCT Application filed April 5, 2011. It also claimed benefit of a
provisional application filed April 15, 2010. The U.S. Application was
published December 26, 2013. The corresponding PCT application
published October 20, 2011.6 Neither the Examiner nor Appellant made an
express determination as to whether Baldwin was entitled to the priority date
of April 15, 2010.
The instant application was filed August 19, 2013 and claims benefit
to a provisional application filed August 24, 2012. Baldwin’s PCT
application was published October 20, 2011 which is less than a year before
the instant application’s provisional filing date and, thus, is not a statutory
bar to patentability.
6 The Examiner did not cite the published PCT Application.
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The inventor, Seppo Yla-Herttuala, M.D., provided several
declarations under 37 C.F.R. § 1.131 in an attempt to antedate the published
U.S. application by establishing a reduction to practice of the claimed
invention before Baldwin’s PCT filing date and before Baldwin’s
provisional application filing date, respectively. Appellant argues that it was
not necessary to provide evidence that the invention was reduced to practice
prior to Baldwin’s provisional application’s filing date because the Examiner
did not provide a copy of the provisional application7 nor establish that
Baldwin’s published application was entitled to such date. Appeal Br. 5—6.
We do not need to reach the issue of entitlement to the provisional
application filing date because, as discussed in more detail below, the
declarations filed to antedate Baldwin’s published application are
ineffective. It is noted that the declarations filed March 13, 2015, July 17,
2015, and October 8, 2015 all contain the same information and all are
ineffective in antedating Baldwin. The March 13, 2015 and July 17, 2015
declarations did not contain an English translation of the “laboratory animal
printed form.” This was corrected in a declaration executed October 6, 2015
(“Yla-Herttuala Oct. 2015 Decl.”).
We note that the Examiner indicated that the Oct. 2015 declaration
was not considered, but yet commented that Appellant did not discuss the
information within the Declaration. Ans. 8. We considered the declaration
because it is the same as the other two declarations, differing only in having
7 It was not necessary for the Examiner to provide a copy of the provisional
application because it was readily available to Appellant. See Ex parte
Yamaguchi, 88 USPQ2d 1606, 2008 WL 4233306 (BPAI
2008)(Precedential Opinion).
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Application 13/969,763
attestments to different dates of the reduction to practice of the claimed
invention and in being accompanied by an English translation of the
laboratory animal printed form.
Legal Principles
37 C.F.R. § 1.131(a):
When any claim of an application or a patent under
reexamination is rejected, the inventor of the subject matter of
the rejected claim, the owner of the patent under reexamination,
or the party qualified under § 1.42 or § 1.46, may submit an
appropriate oath or declaration to establish invention of the
subject matter of the rejected claim prior to the effective date of
the reference or activity on which the rejection is based.
37 C.F.R. § 1.131(b):
The showing of facts . . . shall be such, in character and
weight, as to establish reduction to practice prior to the effective
date of the reference, or conception of the invention prior to the
effective date of the reference coupled with due diligence from
prior to said date to a subsequent reduction to practice or to the
filing of the application. Original exhibits of drawings or records,
or photocopies thereof, must accompany and form part of the
affidavit or declaration or their absence must be satisfactorily
explained.
Discussion
Under 37 C.F.R. § 1.131(a), a publication can be antedated and
eliminated as prior art by establishing “invention of the subject matter of the
rejected claim prior to the effective date of the reference or activity on which
the rejection is based.” “The showing of facts . . . shall be such, in character
and weight, as to establish reduction to practice prior to the effective date of
the reference.” 37 C.F.R. § 1.131(b).
In this case, Seppo Yla-Herttuala, M.D., the named inventor of the
instant application, provided a Declaration in which he declared that he
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“conceived the claimed invention and reduced it to practice not later than 14
April 2010.” Yla-Herttuala Oct. 2015 Decl. 1. The experiments described
in his declaration were performed in Kuopio, Finland and recorded in
Finnish. Id. at 1—2. The laboratory animal printed form which accompanied
his Declaration is an English translation. Id. Dr. Yla-Herttuala stated that a
tumor was formed by injection of an ovarian cancer line into a mouse. Id. at
2. The mouse was administered soluble VEGF receptors (“decoy receptor
which binds to Vascular Endothelial Growth Factor”) and paclitaxel
(“cytotoxic compound”). Id. Dr. Yla-Herttuala testified that the soluble
receptors form dimers as required by the claim. Id.
Claim 1 is directed to “a method treating cancer” by administering
“said cytotoxic compound and said decoy receptor administered in amounts
which are together effective to treat said cancer.” Consequently, in order to
show reduction to practice of the claimed invention, it must be shown in the
Declaration that soluble receptor and cytotoxic compound treated the cancer
(e.g., reduced tumor volume, weight; reduced tumor microvessels;
prolonged survival) (see Spec. 3:9-22; 4: 1—11). However, Dr. Yla-
Herttuala did not make a statement in his declaration that the cancer was
treated. He stated that “[assessment includes measurement of tumor size by
MRI,” but there was no statement in the Declaration of the results of the
assessment. Yla-Herttuala Oct. 2015 Decl. 2. In the English translation of
the Laboratory Animal Printed Form, we observe recorded weights and MRI
information, but none of this is explained. It is also not evident whether any
kind of control was performed.
In sum, the Declaration is not effective to antedate Baldwin because
Dr. Yla-Herttuala did not establish that the combination of the soluble
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VEGF receptor and taxane achieved the result required by claim 1, namely,
treatment of cancer. As indicated by the Examiner, there is no discussion in
the Appeal Brief as to why the Yla-Herttuala Declaration is effective to
antedate Baldwin.
Appellant did not provide any other basis to distinguish Baldwin.
Consequently, we affirm the rejection of claims 1—6 and 8—10 as anticipated
by Baldwin.
2. REJECTION BASED ON HU
The Examiner found that Hu describes administering VEGF-Trap
(“decoy receptor which binds to Vascular Endothelial Growth Factor”) and
paclitaxel (“cytotoxic compound”) to treat cancer in a human ovarian cancer
model OVCAR-3 cell in mice as required by claim 1. Final Act. 6. Hu
states that the VEGF-Trap was obtained from Regeneron Pharmaceuticals.
Hu 6967. The Examiner cited Holash8 as evidence that the Regeneron
VEGF-Trap utilized in Hu contained the Fc region to achieve the claimed
dimerization and did “not initiate VEGF signal transduction” as recited in
claim 5. Final Act. 6—7.
Appellant contends:
Neither Hu nor Byrne, however, say exactly what fragments are
included in VEGF-Trap™, nor whether these fragments have
been modified to include dimer binding sites, nor modified to be
soluble in normal saline.
Appeal Br. 9.
8 Jocelyn Holash et al., J., Davis, S., Papadopoulos, N., Croll, S.D., Ho, L.,
Russell, M., Boland, P., Leidich, R., Hylton, D., Burova, E., Ioffe, E.,
Huang, T., Radziejewski, C., Bailey, K., Fandl, J.P., Daly, T., Wiegand, S.J.,
Yancopoulos, G.D., and Rudge, J.S .VEGF-Trap: A VEGF blocker with
potent antitumor effects, 99 Proc. Natl. Acad. Sci., 11393—98 (2002).
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Appellant’s argument is not supported by adequate evidence. Hu
discloses:
Specifically, we showed that a novel, soluble VEGF decoy
receptor, the VEGF Trap, comprised of fragments of VEGF
receptor (VEGFR)-1 (fltl) and VEGFR2 (flkl, KDR), could
markedly decrease visible ascites formation and reduce tumor
burden by—63% in a xenogeneic nude mouse model of advanced
human ovarian cancer (4).
Hu 6966. Thus, Hu describes the fragments present in its decoy receptor.
Reference 4 cited in Hu (“(4)”) is Byrne which has similar disclosure
to Hu regarding the use of VEGF-Trap to treat an ovarian cancer model.
Because Appellant questioned the structure of VEGF-Trap, the Examiner
identified a reference cited in Byrne — Holash — for the description of its
structure. Byrne is authored by a group of scientists which included Holash
from Regeneron. Holash discloses three different constructs of VEGF Trap,
each which has an Fc region. Holash Fig. 1. One of these constructs, VEGF
Trap R1R2, comprises both VEGFR-1 and VEGFR-2 {id), which, thus,
would be reasonably understood to the version of the VEGF-Trap utilized by
Hu and Byrne because both publications mention the presence of VEGFR1
and VEFGR2 fragments. Appellant has given no reason to doubt that the
VEGF-Trap would include the Fc region, when all the constructs of it shown
in Regeneron’s publication by Holash have it. In fact, each of Hu, Byrne,
and Holash include inventors from Regeneron, the supplier of VEGF-Trap.
Holash from Regeneron is a named co-author on all three publications.
Appellant also argues that “[i]n teaching that VEGF-Trap™ includes
tyrosine kinases, Hu (2005) implies that VEGF Trap™ initiates [signal]
transduction.” Appeal Br. 9. Appellant did not identity disclosure in Hu
that “implies” that VEGF-Trap initiates signal transduction. Hu describes
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utilizing “fragments” of the VEGF receptors, but does not state that such
fragments possessed tyrosine kinase activity. Figure 1 of Holash clearly
shows that the kinase domain of the receptor is absent from VEGF Trap. As
explained by Holash:
The clinical promise of initial anti-VEGF approaches highlights
the need to optimize blockade of this pathway. Previous studies
have found that one of the most effective ways to block the
VEGF signaling pathway is to prevent VEGF from binding to its
normal receptors by administering decoy VEGF receptors ....
The highest-affmity VEGF blocker described to date is a soluble
decoy receptor created by fusing the first three Ig domains of
VEGFR1 to the constant region (Fc portion) of human IgGl,
resulting in a forced homodimer that has picomolar binding
affinity....
Holash 11393 (endnotes omitted). Thus, it is counter intuitive to utilize a
kinase domain in VEGF Trap because the purpose of the construct is to
block receptor kinase activity by trapping VEGF and preventing it from
binding and stimulating the kinase activity of the endogenous receptor.
Appellant states that Applicant has not been afforded the opportunity
to provide rebuttal evidence to Holash. We disagree. Applicant petitioned
to have the finality of the Final Office Action withdrawn, but the petition
was denied and the decision stated that the citation of Holash was done in
response to arguments and did not impact the original grounds of rejection.
Decision on Petition (mailed Apr. 8, 2016). We have reviewed the record
after the Final Rejection, and did not find an attempt by Applicant to rebut
Holash nor did we find evidence regarding Holash that the Examiner had
declined to consider. Appellant had the opportunity after the Final rejection
was issued, as well as in the Appeal Brief, to explain why Holash is not
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evidence of the structure of VEGF Trap. In the Reply Brief, Appellant
states:
I thus sense that the Examiner knows as well as I do that
Holash doesn’t enable Hu’s proprietary fragment mixture, and
arguably actively misrepresents how to make it, to make that
proprietary mixture difficult for competitors to copy. This is, I
sense, why the Examiner has adamantly refused to afford
Applicant the opportunity to introduce rebuttal evidence.
Reply Br. 8.
Appellant did not explain how Holash misrepresented VEGF-Trap
when Figure 1 clearly shows the structure of the various constructs with this
name, including the construct comprising fragments of VEGF receptor
(VEGFR)-1 (fltl) and VEGFR2 (flkl, KDR) that is referenced in Hu and in
rejected claim 2.
In sum, for the aforementioned reasons, we affirm the rejection of
claims 1—5 as anticipated by Hu.
3. REJECTION BASED ON BYRNE, HU, SALLINEN, AND BALDWIN
The Examiner found that Byrne describes administering an adenoviral
vector comprising the nucleic acid encoding the VEGF-Trap high affinity
soluble decoy receptor to treat cancer in OVCAR-3 model in mice, meeting
the corresponding limitation of claim 6 of a gene therapy vector. Final Act.
9.
The Examiner found Byrne did not administer the gene therapy vector
in combination with a cytotoxic compound as required by the claim, but
suggested it (“Currently, we are investigating the effects of combining
VEGF-Trap treatment with a chemotherapeutic agent. ... We anticipate that
by combining therapies, we will be able to further reduce tumor burden and
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will prolong response and survival.” Byrne 5726.) Final Act. 9. The
Examiner further cited the teachings in Hu and Baldwin of combination
therapy using a VEGF-Trap and a cytotoxic drug as evidence of the
obviousness of administering a cytotoxic drug with Byrne’s viral gene
therapy vector prompted by his suggestion to do. Id. Sallinen was also cited
by the Examiner for administering the same type of VEGFR gene therapy
construct as in Byrne. Id.
Appellant contends that the rejection is improper because Sallinen
(misspelled in the Appeal Brief as “Salinnen”) “notes that the only phase III
trial carried out so far combining chemotherapy and transgene therapy was
closed prematurely because the combination ‘showed no clinical benefit’.
See 278 col. 2. Salinnen [sic] accordingly teaches the claimed combination
would have a reasonable expectation of failure, not success.” Appeal Br. 7.
This argument is not persuasive. Sallinen’s discussion of a phase III
trial had to do with p53 gene therapy, a different target than the claimed
VEGF receptor target of the rejected claims and the cited prior art. See
Sallinen 278. Sallinen’s own experiments show success with adenoviral
gene therapy with three soluble VEGF receptors. Id. at 282, 283. Based on
this success, Sallinen concluded:
These results warrant further development of the combined
antiangiogenic gene therapy to define the best dose and schedule
for such a treatment, and suggest that this approach could be
utilized in clinics along with other anticancer therapies.
Id. at 283. Accordingly, Appellant’s argument about an expectation of
failure is inconsistent with Sallinen’s own suggestion of combining gene
therapy with other anticancer therapies. Appellant’s further statement that
Sallinen “chose to use only the decoy receptor” (Appeal Br. 8) is misleading
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because, as the above-quoted passage indicates, Sallinen, once having
completed its experiments with the viral gene therapy vector alone,
suggested combination therapy — the same combination therapy to which
rejected claim 1 is directed.
For the foregoing reasons, we affirm the obviousness rejection of
claim 1, and dependent claims 2—11 which fall with claim 1 because they
were not separately argued. 37 C.F.R. § 41.37(c)(l)(iv).
TIME PERIOD
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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