Ex Parte Samaranayake et al

Patent Trial and Appeal Board

Nov 8, 2017

13858393 (P.T.A.B. Nov. 8, 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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/858,393 05/01/2013 Haritha SAMARANAYAKE Ark-GB1100804.2 1621
22925 7590 11/13/2017
PHARMACEUTICAL PATENT ATTORNEYS, LLC
55 MADISON AVENUE
4THFLOOR
MORRISTOWN, NJ 07960-7397
EXAMINER
WEHBE, ANNE MARIE SABRINA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
11/13/2017 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
following e-mail address(es):
docket @ LicensingLaw. net
administration @LicensingLaw.net
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HARITHA SAMARANAYAKE, JERE PIKKARAINEN, ANN-
MARIE MAATTA, and SEPPO YLA-HERTTUALA
Appeal 2017-003 6241
Application 13/858,393
Technology Center 1600
Before RICHARD M. LEBOVITZ, DEVON ZASTROW NEWMAN, and
DAVID COTTA, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a viral vector, ganciclovir, and
temozolomide, for treating malignant glioma. The Examiner rejected the
claims under 35 U.S.C. §§ 102 and 103 as obvious. We have jurisdiction
under 35 U.S.C. § 6(b). The Examiner is affirmed.
1 The Appeal Brief (“Appeal Br.”) identifies Fin Vector Therapies Ltd, as
the real-party-in-interest. Appeal Br. 2.
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Application 13/858,393
STATEMENT OF THE CASE
Claims 1—14, 17—25, and 27-42 are pending and stand rejected by the
Examiner. Appellants appeal all rejections. An Appeal Brief was filed Oct.
13, 2015. A notice was sent to Appellants on January 12, 2016 informing
Appellants that the claim appendix was defective and giving Appellants 30
days to correct the error. The electronic records indicate that the Examiner
entered claims on Dec. 27, 2016, which we will consider to be the claims on
appeal. In those entered claims, claim 26, which had been pending and
rejected, was canceled. We therefore consider moot the rejections of claim
26 because the Examiner entered an amendment in which the claim had been
canceled. Consequently, we have not considered and have omitted mention
of claim 26 from the rejections. A Reply Brief was filed Dec. 30, 2016.
We note that Appellants have objected to the Examiner’s procedural
handling of the prosecution. Appeal Br. 24. The Board does not have
jurisdiction over the Examiner’s actions during prosecution; matters
involving an action by the Examiner are petitionable and not under the
Board’s jurisdiction. See MPEP § 1002.02(a)(1). Appellants are urged to
raise these matters by petition, e.g., to the Director under 37 C.F.R. § 1.181,
since we will not consider them in this appeal.
Pending claims 1—14, 17—25, and 27-42 stand rejected by the
Examiner as follows:
1. Claim 41 under pre-AIA 35 U.S.C. § 102(b) as anticipated by
Ulasov et al., Br. J. Cancer, 100(7), 1154—1164, 2009 (“Ulasov”). Ans. 3.
2. Claims 9—14, 17—25, 27, 29, 31, 32, 34, 41, and 42 under pre-AIA
35 U.S.C. § 102(b) as anticipated by “Preliminary Cerepro® Phase III Results
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Meet Primary Endpoint-Operable Primary Malignant Glioma”, 1—3 (2008)2
(“Medical News”). Ans. 3.
3. Claim 33 under pre-AIA 35 U.S.C. § 102(a) as anticipated by
Chiocca et al., J. Clin. Oncol., 29 (27), 3611—3619, 2011 (“Chiocca”). Ans.
4.
4. Claims 1—14, 17—25, 27—32, and 34-40 under pre-AIA U.S.C.
§ 103(a) as obvious in view of Medical News, WO 00/28059, publ. May 18,
2000 (“Yla-Herttuala”), Wick et al., Neuro-Oncology, 11, 69-79, 2008
(“Wick”), and Rainov et al., Cancer Gene Therapy, Vol. 8(9), 662—668,
2001 (“Rainov”). Ans. 5.
In the Examiner’s Answer, the Examiner withdrew the pending
rejection of claims 1—8, 28 and 35—40 under 35 U.S.C. § 112 (b) as being
indefinite for failing to particularly point out and distinctly claim the subject
matter which the applicant regards as the invention. Ans. 7. This issue is
thus no longer a part of this appeal.
The claims involve a viral vector and the drugs ganciclovir (“GCV”),
and temozolomide (“TMZ”) for cancer therapy. Both methods and vectors
are claimed. For illustrative purposes, we reproduce claim 9 below.
9. A method of cancer therapy comprising: administering to
an immune competent human a vector having a functional gene,
a prodrug which can be converted into a first cytotoxic agent by
an expression product of the gene, and a second cytotoxic agent
in an amount sufficient to provide anti-cancer efficacy above
that provided by the first cytotoxic agent alone, wherein the
dosage regimen comprises beginning the second cytotoxic
2 https://www.medicalnewstoday.eom/releases/l 16938.php (posted online on
Aug. 10, 2008).
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agent therapy no later than 7 days after the prodrug therapy has
finished.
1. ANTICIPATION REJECTION BASED ON ULASOV
Claim 41 is directed to a kit comprising “a viral gene therapy vector
and temozolomide, said viral vector and said temozolomide present in an
amount effective to treat brain cancer in a human patient.”
The Examiner found that Ulasov describes 1) a recombinant
adenoviral vector expressing the El A gene under transcriptional control of
the survivin promoter, serving as the viral gene therapy vector of claim 41,
and 2) temozolomide, a cytotoxic agent, in amounts effective to treat
malignant glioma as required by the claim. Ans. 3.
Appellants contend that Ulasov’s vector is not a gene therapy vector
as required by the claim, but an oncolytic vector. Appeal Br. 10-11.
Appellants state that “that the term ‘gene therapy’ is consistently used for
vectors which deliver expressible genes to host cells for expression” and
does not overlap with lytic vector which “by design kills the host.” Id. at 11.
Appellants’ argument does not persuade us that the Examiner erred.
Ulasov’s vector, as found by the Examiner uses the “survivin promoter to
drive El A expression and binds to heparin sulphate proteoglycans expressed
on malignant glioma.” Ulasov 1155. Thus, the vector delivers an
expressible gene to a host cell — where El A is the expressible gene made
expressible by the survivin promoter — meeting Appellants’ own definition
of a gene therapy vector. App. Br. 11. Appellants appears to attempt to
change this definition in the Reply Brief by further requiring that a gene
therapy vector requires “long-term” expression. Reply Br. 11. However, we
are not persuaded that the term “gene therapy” should be construed to
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require “long-term” expression. Moreover, new arguments are prohibited in
a Reply Brief (37 C.F.R. § 41.41(a)(2)), and, even if considered, we simply
do not find it credible that one of ordinary skill in the art would not have
considered Ulasov’s vector — which delivers an expressible gene to a cell for
a therapeutic purpose — to be a gene therapy vector.
Appellants did not identify a reversible error in the Examiner’s
rejection. The anticipation rejection of claim 41 is affirmed.
2. ANTICIPATION REJECTION BASED ON MEDICAL NEWS
Vector claims
Claims 41 and 42 are directed to a kit comprising a viral gene therapy
vector and temozolomide, “said viral vector and said temozolomide present
in an amount effective to treat brain cancer in a human patient.” The
Examiner found that Medical News discloses a vector having a functional
thymidine kinase gene (HSV-tk) and a cytotoxic agent, temozolomide, as
required by the claims. Ans. 3^4.
Appellants attempt to distinguish Medical News by arguing that the
timing of administration of the drug differs from the claim. Appeal Br. 15.
However, this argument is unavailing because the claim is directed to the
vector and the drug; the claims are not limited to when such agents are
administered, and thus cannot be distinguished over the prior art for this
reason.
Appellants also argue “the reference fails to inherently anticipate the
claim because it teaches that whatever dose [of temozoloamide] the study in
fact used, it provided no benefit, and indeed imparted a (slight) detriment.”
Id. Appellants calculate the number of adverse events worsened from 83%
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to 84% when gene therapy was added. Id., 16. Accordingly, Appellants
contend that Medical News does not disclose an effective amount of
temozolomide.
This argument is not persuasive. First, Appellants have not
demonstrated that the stated 1 % increase in adverse events is statistically
significant. Thus, it cannot be concluded that the number of adverse events
between standard care and gene therapy is statistically significant and
meaningful. An argument made by counsel in a brief does not substitute for
evidence lacking in the record. Estee Lauder, Inc. v. L ’Oreal, S.A., 129 F.3d
588, 595 (Fed. Cir. 1997).
Second, the fact that the gene therapy might have caused an increase
in adverse events does not mean that the temozolomide dosage was
ineffective. Out of a number of potential causes, Appellants did not
adequately explain why the occurrence of adverse events indicates that the
drug was ineffective when combined with gene therapy.
Third, temozolomide was administered as part of standard care
treatment option (“Standard care was surgery and radiotherapy or surgery
and radiotherapy followed by temozolomide.” Medical News 2). Thus, the
Examiner reasonably found that the temozolomide was administered in an
effective amount because its dosage was the known and conventional
amount delivered to treat cancer. Appellants did not provide adequate
evidence to rebut this reasonable determination.
Accordingly, we affirm the anticipation rejection of claims 41 and 42.
Method claims
Claim 9
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Claim 9 is directed to a method comprising administering a vector
having a functional gene, a prodrug, and a second cytotoxic agent, where the
method comprises “beginning the second cytotoxic agent therapy no later
than 7 days after the prodrug therapy has finished.”
The Examiner found that Medical News teaches administering HSV-
tk, ganciclovir, and temozolomide, meeting the corresponding limitations of
the functional gene, prodrug, and second cytotoxic agent as required by the
claim. Ans. 4. With respect to the claimed requirement of beginning the
temozolomide no later than 7 days after the prodrug has finished, the
Examiner found that Medical News “states that the temozolomide is
administered following surgical resection of the tumor, and that the cerepro
[vector comprising HSV-tk] is also administered after resection of the tumor.
Thus, the administration of the two cytotoxic agents appears to be around the
same time and over-lapping, after-surgical resection.” Id., 13.
We agree with Appellants that the Examiner did not establish that
temozolomide was administered within the recited time period. Medical
News states that temozolomide was administered after surgery or radiation
and that ganciclovir (the prodrug) was provided after surgery, but there is no
disclosure about the relative timing of each, particularly that temozolomide
is administered after the prodrug therapy is done. Consequently, the
anticipation rejection of claim 9—14 and 17—25 is reversed.
Claim 27
Independent claim 27 is directed to a method which comprises the
following limitation:
. . . treating brain cancer in an immunocompetent human patient
by administering temozolomide to said immunocompetent
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human patient, the improvement comprising: administering to
said immunocompetent human patient a viral vector in an
amount effective to increase expression of a mismatch repair
protein, and administering said temozolomide
contemporaneously with said increased expression of mismatch
repair protein.
The Examiner did not explain how the disclosure in Medical News
met the claimed requirement of “administering said temozolomide
contemporaneously with said increased expression of mismatch repair
protein.” Appeal Br. 13. Consequently, because the Examiner did not meet
the burden of establishing that all the limitations of claim 27 are met by
Medical News, we reverse the anticipation rejection of claim 27, and
dependent claims 29, 31, 32, 34, 41, and 42.
3. ANTICIPATION REJECTION BASED ON CHIOCCA
Claim 33 depends from independent claim 27 and further recites that
“wherein said brain cancer is selected from the group consisting of:
glioblastoma multiforme and anaplastic astrocytoma.” The Examiner found
that the effective filing date of the claim was Jan. 18, 2012, because the
United Kingdom priority document relied upon for the earlier filing date of
Jan. 18, 2011, disclosed a genus of gliomas, but did not expressly describe
the treatment of the glioblastoma multiforme species. Ans. 15. The
Examiner states that this species was not introduced until Jan. 18, 2012.
Thus, Examiner found that Chiocca, published Aug. 15, 2011, qualifies as
prior art against claim 33. Id.
Appellants contend that a claim “need not have in haec verba support
in the Specification.” Appeal Br. 9. Appellants argue:
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In the instant case, glioblastoma multiforme is well-known in
the art. Indeed, glioblastoma multiforme is the most-prevalent
species of malignant glioma. The instant provisional application
need not recite “glioblastoma multiforme” in haec verba
because it was well-known in the art as the most-prevalent
species of the genus taught by the provisional.
Id., 10.
This argument does not persuade us that Examiner erred. The issue is
not whether glioblastoma multiforme is the most-prevalent species of
malignant glioma, but whether one of ordinary skill in the art would have
recognized that the inventors had possession of the claimed species at the
time of the filing date.
The inventor must “convey with reasonable clarity to those skilled in
the art that, as of the filing date sought, he or she was in possession of the
invention.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563—64 (Fed. Cir.
1991). “One shows that one is ‘in possession’ of the invention by describing
the invention, with all its claimed limitations.” Lockwood v. Am. Airlines,
Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (internal citation omitted). In
describing the claimed invention, there is no requirement that the wording be
identical to that used in the specification as long as there is sufficient
disclosure to show one of skill in the art that the inventor “‘invented what is
claimed.’” Union Oil Co. v. Atlantic Richfield Co., 208 F.3d 989, 997 (Fed.
Cir. 2000) (internal citation omitted). The written description “need not
recite the claimed invention in haec verba but [it] must do more than merely
disclose that which would render the claimed invention obvious.” ICU
Med., Inc. v. Alaris Med. Sys., Inc., 558 F.3d 1368, 1377 (Fed. Cir. 2009).
Thus, as long as a person “of ordinary skill in the art would have understood
the inventor to have been in possession of the claimed invention at the time
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of filing, even if every nuance of the claims is not explicitly described in the
specification, then the adequate written description requirement is met.” In
re Alton, 76 F.3d 1168, 1175 (Fed. Cir. 1996).
In this case, Appellants have not provided evidence that one of
ordinary skill in the art, reading the United Kingdom priority document,
would have recognized that the inventors necessarily possessed the claimed
glioblastoma multiforme species. For example, Appellants did not provide
evidence that one of ordinary skill in the art reading the specification of the
priority document would have understood that the inventors invented a
method of treating glioblastoma multiforme. Appellants’ only evidence is
that glioblastoma multiforme is a prevalent species of malignant glioma, but
they have not addressed the issue of whether one of ordinary skill in the art
would have recognized, from the generic disclosure of malignant glioma,
that the inventors invented treating the undisclosed species of glioblastoma
multiforme. Claim 33 is not merely directed to the species glioblastoma
multiforme, but the claim requires treating it with a viral vector and
temozolomide contemporaneously with increased expression of mismatch
repair protein. Appellants’ evidence might establish the obviousness of
treating glioblastoma multiforme, but obviousness is not the standard.
Lockwood, 107 F.3d at 1572. Rather, it is what is conveyed to the person of
ordinary skill in the art upon reading the Specification. Appellants did not
provide persuasive evidence of what the skilled worker would have
understood upon reading the application Specification. See Vas-Cath, 935
F.2d at 1563-64; Union Oil Co., 208 F.3d at 997.
Appellants did not provide any other argument as to why claim 33 is
not anticipated by Chiocca. Because we have decided Chiocca is prior art to
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the claims, we affirm the anticipation rejection of it for the reasons given by
the Examiner.
4. OBVIOUSNESS REJECTION
The obviousness rejection is over method claims 1, 9, and 27, each
which comprise administering a viral vector, a prodrug, and a second
cytotoxic agent to a subject.
The Examiner found Medical News discloses treating patients having
malignant glioma with adenoviral vector HSK-tk (known as “Cerepro”),
ganciclovir as a prodrug, and temozolomide, meeting the corresponding
requirements of independent method claims 1, 9, and 27. Ans. 5. The
Examiner states that Medical News does not disclose the exact timing or
dosage of each treatment phase as recited in the claims. Id.
The Examiner found that Yla-Herttuala describes effective treatment
regimens for the administration of adenoviral vector encoding HSV-tk and
prodrug ganciclovir for the treatment of malignant glioma, including the
injection to the resected tumor bed with specific dosages and timing of
adenovirus and ganciclovir, meeting the corresponding limitations of the
claims. Id., 6.
The Examiner also found that Wick teaches specific dosages and
administration schedules of temozolomide for the treatment of glioblastoma
multiforme disclosing or making obvious the claims dosages and time of
administration of such agents. Id.
The Examiner cited Rainov for its teaching of the effects of
administering HSV-tk, ganciclovir, and temozolomide on malignant glioma.
Id., 6. The Examiner found that Rainov teaches co-administration of
ganciclovir and temozolomide for 14 days. Id.
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The Examiner determined it would have been obvious to one of
ordinary skill in the art to apply the treatment regimens of Yla-Herttuala,
Wick, and Rainov to that disclosed in Medical News to meet the limitations
in the claims. Id., 6—7. The Examiner found that the specific dosage
regimes and timing recited in the claims were taught in the cited prior art or
obvious from it. Id., 6, 8, 21—22.
Combination of surgery and chemotherapy
The method of claim 1 comprises “Resectioning said malignant
glioma tumor to remove at least part of said malignant glioma tumor and
expose tumor bed tissue.” The method further requires chemotherapy,
namely, administration of adenoviral vector and temozolomide.
Appellants contend that the art taught “that brain surgery and
chemotherapy are each debilitating and potentially fatal. The art thus
teaches to allow a patient ample time to physically recover from one before
pursuing the other. See Specification at 7:8—12.” Appeal Br. 19. Appellants
also contend that “the art avoided combining the two because the
combination was believed inordinately dangerous, and the artisan did not see
any counterbalancing benefit.” Id. To support this argument, Appellants
cited teachings in Wick
[that] “high daily doses can be tolerated only for short periods
of time” because chemotherapeutics cause “dose-limiting
hematologic toxicity.” See Wick (2009) at p.71 col. 2. Wick
thus teaches a variety of regimens which balance dose size
against dose length. See Table 1.
Id.
Thus, Appellants conclude that while “Wick teaches varying the dose,
it fails to teach surgery, nor using a vector-prodrug to increase mismatch
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repair expression, nor administering chemotherapy during that transient
window. . . . Wick thus corroborates the inventors’ allegation that the art
taught away from combining surgery and chemotherapy.” Id., 20.
Appellants’ contention that that “art taught away from combining
surgery and chemotherapy” is not supported by the evidence in this record.
First, Appellants cite to the Specification at page 7, lines 8—12 to
support this contention. We reproduce the passage below:
In current treatment protocols used in human clinical trials,
TMZ is commenced after completing 14 days of GCV therapy.
In most cases, there had been a considerable gap in time
between completing GCV therapy and beginning TMZ therapy.
This gap was thought helpful, as it enabled the patient to
recover somewhat from the physiological stress imposed by
GCV, before imposing the added stress of TMZ therapy.
This passage of the Specification does not support the contention that
“brain surgery and chemotherapy are each debilitating and potentially fatal”
and therefore would not be combined as alleged by Appellants. Appeal Br.
19. Indeed, there is no mention of brain surgery in this paragraph.
Wick describes studies designed to improve the effect of
temozolomide in treating malignant glioma “with the goal of improving
antitumor activity and overcoming resistance.” Wick, Abstract. Appellants’
contention that Wick “corroborates the inventors’ allegation that the art
taught away from combining surgery and chemotherapy” is contrary to the
actual teachings in Wick. We reproduce a portion of Table 2 from Wick:
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Table 2. C3i:>k7(: of .r:]>"r:rnai:':ve b'frooA'olornicjo dosing regimens in v'/ft.b newly rjirignosed hign-gsade gjiorrvi
Median Median
PF5, OS,
Study n Patient Population Schedule Months Months
Carols et ai. (2COyy-f! 38 Newly Dx GBM After' surgery and RTr 15iJ mg/ni'5 days 1-5. then 10 16
75 mg/ms days 6-10 q28d
Table 2 shows a study by Caroli (2007) of patients with glioblastoma
(GBM) treated with surgery, radiotherapy (RT), and temozolamide.
As summarized in Table 2 reproduced above, Wick expressly cited a
study by Caroli in which surgery was combined with chemotherapy using
temozolomide. Appellants’ argument about a teaching away from
combining the two is therefore is inconsistent with Wick’s teaching and
lacks credibility.
Appellants also assert that “Yla-Herttuala (2000) used surgery without
chemotherapy.” Appeal Br. 19. This is incorrect. Yla-Herttuala teaches:
All patients underwent craniotomy and tumour resection . . .
GCV treatment (5mg/kg/d) was delivered intravenously
through the subclavian vein twice a day for 14 days. The
medication started 14 days or 5 days after the tumour resection
and gene transfer in retrovirus or adenovirus patients,
respectively.
Yla-Herttuala 4:18—26. Thus, there is an explicit teaching in Yla-Herttuala
of tumor surgery (“tumour resection”) with GCV chemotherapy.
See also Ans. 19—20 for the Examiner’s fact-supported determination
“that surgical resection of tumors and administration of a chemotherapeutic
such as temozolomide represents a standard of care in the treatment of
brain.”
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Rainov
Appellants contend:
[T]he references teach a reasonable expectation not of success,
but failure. This is because both Medical News Today (2008)
and Rainov (2001) describe studies which show the claimed
combination would have increased risk, but no offsetting
benefit.
Appeal Br. 21.
Appellants, citing Figure 28, contend that “Rainov . . . demonstrates
that adding chemotherapy to ganciclovir confers no benefit.” Id.
Appellants state:
Figure 2B shows results for cells which express thymidine
kinase. Control saline (invert triangles) not surprisingly resulted
in the largest tumor size. Temozolomide (squares) had no
effect; Rainov concedes the distance between the control and
temozolomide curves is “not significantly different.” See pg.
664 col. 1 and Fig.2B legend. In contrast, ganciclovir (circles)
results in significantly smaller tumor size. Adding
temozolomide to ganciclovir (triangles) confers no added
benefit.
Id., 22.
Appellants have misunderstood Rainov.
Appellants have taken the statement by Rainov that a control saline
and temozolomide were “not significantly different” out of content. Such
statement was made by Rainov with reference to Figure 2A, not Figure 2B,
and the statement was made regarding cells which were not transfected with
HSV-tk, but rather served as a control. Rainov explains:
The size ofU87 control tumors in nude mice treated with TMZ,
GCV, with both drugs, or with saline (control) was not
significantly different (Fig 2A). Tumors expressing HSV-tk and
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treated with TMZ and GCV were significantly smaller than
those treated by TMZ, but not by GCV (Fig 2B). As determined
by tumor weight, the burden of HSV-tk expressing tumors was
significantly smaller than that of U87 control tumors after
treatment with the single agents TMZ or GCV or with their
combination (Fig 3).
Rainov 664 (emphasis added).
Thus, the statement about the lack of a significant difference referred
to tumors that lacked HSV-tk. Tumors transfected with HSV-tk were
significantly smaller than tumors lacking HSV-tk. Id.
Appellants make the same mistake in the Reply Brief:
Rainov thus concludes, “The size of U87 control tumors in
nude mice treated with TMZ, GCV, with both drugs, or with
saline (control) was not significantly different.”[]
Reply Br. 16.
Again, Rainov is referring to tumors that lack HSV-tk, not those
expressing HSV-tk. Appellants repeat this error on page 17 of the Reply
Brief.
While Rainov did not report a significant difference between the sizes
of tumors treated with HSV-tk and GCV, and HSV-tk, GCV, and TMZ,
Rainov observed synergy between the drugs with respect to the
concentration of each on the growth of cells, e.g., lower concentrations of
TMZ were effective when HSV-tk was present than when it was absent from
cells. Id., 663. Rainov stated that “Surprisingly, sensitivity to TMZ was
also increased in U87-t£ [transfected with HSV-tk] cells compared to U87
control cells (P< .05).” Id., 664. Furthermore, Rainov found: “Synergistic
effects are also demonstrated for GCV and TMZ in both U87-/C and U87
glioma cells as shown in Figure 1.” Id.
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Rainov reported:
Rigorous examination by this method of data from cell culture
allowed us to clearly identify a synergy between the two drugs
at all effect levels. This was additionally proven in an animal
study utilizing exactly the same cell clones and drugs.
Id., 666.
Based on the studies, Rainov concluded:
Summarizing our data, the demonstration of synergy between
HSV- ikJGCN gene therapy and chemotherapy with TMZ
suggests a possible enhanced therapeutic concept for future
studies in human malignant glioma.
Rainov 667.
Despite this clear and explicit statement in Rainbov that synergy was
observed, including in an animal study, Appellants argue:
Rainov’s failure to find synergy might have been due to any of
several factors. First, he didn’t use a viral gene therapy vector.
Rather, he used a cell line (U87MG-/T) which carries a
thymidine kinase gene. . . . Whatever the reason, Rainov []
teaches a lack of synergy.
Appeal Br. 23.
This argument is not supported by the evidence. First, Rainov — as
indicated in the passages reproduced above — found that the two drugs acted
synergistically on the growth of cells. In other words, lower doses were
effective to achieve the same results. Second, Appellants’ statement that
Rainov did not use viral gene therapy vector is not fully accurate. Rainov
used a plasmid containing HSV-tk —the same viral vector described in the
instant application — to transfect cells as a model for improving the “HSV-
tkJGCV gene therapy paradigm.” Rainov 663. The resulting cells or tumors
are referred to by Rainov as “HSV-tk expressing” cells or tumors, or more
simply, U87-tk. Id., 664. Thus, contrary to Appellants’ arguments, the HSV
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viral gene therapy vector was present in the cells and tumors. The cells and
tumors expressing HSV-tk were considered to “provide[ ] evidence that
HSV-tkJ GCV gene therapy and TMZ chemotherapy can be combined for
enhanced cytotoxicity of malignant glioma.” Id.
Appellants also makes arguments about the difference between
introducing a vector in cells after diagnosing cancer in contrast to using cells
which already have a vector. Id., 20. However, the rejection is not under
Section 102 as anticipation, but is rather one based on obviousness. The
Examiner recognized such differences and based the rejection on Rainov
along with additional references.
Appellants also contend that “Rainov’s preliminary in vitro screens
found synergy, but his follow-up in vivo testing contradicted that.” Reply
Br. 18.
To begin with, we find this an odd statement because in the Appeal
Brief, and elsewhere in the Reply Brief, as discussed above, Appellants
denied synergy was reported in Rainov. Such inconsistency challenges the
credibility of Appellants’ argument, or at least, their clarity, i.e., Appellants
may not be clearly explaining their allegations regarding what “synergy”
was lacking in Rainov.
Nonetheless, Rainov said such synergy was repeated in an animal
study:
Rigorous examination by this method of data from cell culture
allowed us to clearly identify a synergy between the two drugs
at all effect levels. This was additionally proven in an animal
study utilizing exactly the same cell clones and drugs.
Id., 666.
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Moreover, we find the “synergy” issue to be a red herring, i.e., even if
there is no synergy observed or added benefit, both Medical News and
Rainov suggest using the HSV-tk system with both GCV and TMZ:
Summarizing our data, the demonstration of synergy between
HSV- tk/ GCV gene therapy and chemotherapy with TMZ
suggests a possible enhanced therapeutic concept for future
studies in human malignant glioma. Despite many still
unknown variables, the present results were clearly defined in a
glioma cell culture system and confirmed in animal
experiments, and therefore justify further investigation.
Rainov 667.
On the primary endpoint, the group given Cerepro (R) and
temozolomide showed an improvement of 68% in median
survival time compared with standard care surgery and
radiotherapy controls (350 days vs 208 days). Against the same
controls, treatment with Cerepro (R) alone showed an improved
median survival trend approaching 50%, similar to those given
treatment with temozolomide alone after surgery and
radiotherapy (300 days and 307 days respectively vs 208 days
with standard care). Improvements in the combined Cerepro (R)
[to clarify for Appellants, the use of Cerepro means the viral
vector HSV-tk and GCV because the purpose of the vector is to
convert GCV into an active drug] and temozolomide treatment
group (n= 58) and temozolomide alone group (n=76) were
significant (p<0.05).
Medical News 2.
Thus, two publications teach the merit of the claimed combination
therapy of HSC-tk, GCV, and TMZ. Appellants are asking us to ignore and
disregard this evidence and instead adopt attorney argument that one of
ordinary skill in the art would never have combined both TMZ and GCV,
despite express teachings in at least two prior art publications suggesting
such that combination be administered. Appellants fail to persuasively
explain why the skilled artisan would disregard the suggestion in these two
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Application 13/858,393
publications to combine all three agents, HSC-tk, GCV, and TMZ, as
therapy for brain cancer. Consequently, we find that Appellants’ statement
that Rainov teaches to avoid the combination of GCV and TMZ (Appeal Br.
22) to be unsupported by the evidence in this record.
Summary
For the foregoing reasons, we affirm the obviousness rejection of
rejected claims 1—14, 17—25, 27—32, and 34-40.
SUMMARY
1. The rejection of claim 41 as anticipated by Ulasov is affirmed.
2. The rejection of claims 41 and 42 as anticipated by Medical News
is affirmed. The rejection of claims 9-14, 17—25, 27, 29, 31, 32, 34, 41, and
42 as anticipated by Medical News is reversed.
3. The rejection of claim 33 as anticipated by Chiocca is affirmed.
4. The rejection of claim 1—14, 17—25, 27—32, and 34-40 as obvious
in view of Medical News, Yla-Herttuala, Wick, and Rainov is affirmed.
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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