Ex Parte Blatt

Board of Patent Appeals and Interferences

Nov 15, 2011

10556474 (B.P.A.I. Nov. 15, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte LAWRENCE M. BLATT
__________

Appeal 2010-009451
Application 10/556,474
Technology Center 1600
__________

Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for treating ovarian cancer. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

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Statement of the Case
Background
“The present invention features a method of treating cancer, generally
involving combination therapy with effective amounts of IP-10 and
pirfenidone or a pirfenidone analog. The methods are useful as primary
cancer therapy, or as adjuvant therapy” (Spec. 2 ¶ 0008).
The Claims
Claims 1-5, 7, and 22-24 are on appeal. Claims 1 and 22 are
representative and read as follows:
1. A method for treating ovarian cancer in an
individual, the method comprising administering a
therapeutically effective amount of IP- 10 and a
therapeutically effective amount of pirfenidone or a
specific pirfenidone analog to the individual.

22. A method for treating ovarian cancer in an
individual, the method comprising administering a
therapeutically effective amount of pirfenidone or a
specific pirfenidone analog and a therapeutically
effective amount of at least one additional antineoplastic
agent or biological response modifier to the individual.

The issue

The Examiner rejected claims 1-5, 7, and 22-24 under 35 U.S.C. §
103(a) as obvious over Tosato,
1
Markovic,
2
Krishnan,
3
and Ciardiello
4
(Ans.
4-5).

1
Tosato et al., US 5,994,292, issued Nov. 30, 1999.
2
Markovic, S., US 7,041,301 B1, issued May 9, 2006.
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The Examiner finds that “Tosato et al teaches that IP-10 is useful in
the treatment of ovarian cancer . . . Tosato et al does not teach the use of IP-
10 in combination with IFN alpha or pirfenidone. Markovic teaches the use
of INF alpha in the treatment of ovarian cancer” (Ans. 4). The Examiner
finds that “Krishnan et al teaches that pirfenidone is useful in the treatment
of cancer (glioblastoma specifically) and that the compound inhibits the
phosphorylation of the Epidermal Growth Factor Receptor” (id.). The
Examiner finds that “Ciardiello et al teaches that EGFR kinase inhibitors
(i.e. compounds that inhibit the phosphorylation of EGFR) are useful in the
treatment of ovarian cancer” (id.).
The Examiner finds it obvious
to treat ovarian cancer using IP-10, IFN alpha and
pirfenidone. Since IP-10 and IFN alpha were known to be
useful in the treatment of ovarian cancer and pirfenidone
was known to useful in the treatment of cancer and to have
activity that was known be useful in the treatment of ovarian
cancer specifically.

(Id.)
Appellant contends that the
Examiner has failed to articulate an adequate rationale for
combining the disparate references in order to select the

3
Krishnan et al., Targeted Therapy for Glioblastomas:
Pirfenidone, An Anti-fibrotic Agent that Inhibits Epidermal Growth
Factor Receptor Phosphorylation, 54 INTERNATIONAL J.
RADIATION ONCOLOGY BIOLOGY PHYSICS 217, abstract #2007
(2002).
4
Ciardiello, F. and Giampaolo, T., A Novel Approach in the
Treatment of Cancer: Targeting the Epidermal Growth Factor
Receptor, 7 CLINICAL CANCER RESEARCH 2958-2970 (2001).
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specific combination of IP-10 and pirfenidone from among
the wide variety of agents that were known, suggested, or
suspected to be useful for treating cancer and why one
would select the treatment of ovarian cancer from among the
wide variety of possible cancers.

(App. Br. 7.)
Appellant contends that “the Examiner‟s speculation as to the
teachings of the cited art is not supported by adequate reasoning, in view of
Ciardiello‟s failure to provide evidence that all EGFR inhibitors can treat
ovarian cancer, and the uncertainty regarding how pirfenidone
actually exerts its anti-tumor effects” (id. at 9). Appellant contends that the
“Examiner‟s speculation is admittedly not supported by any actual evidence
regarding pirfenidone and ovarian cancer” (id.).
Appellant contends that “the Examiner has failed to show a reasonable
expectation of success that the combination of IP-10 and pirfenidone would
be effective. Appellant presented evidence showing that one of ordinary skill
in the art cannot predict whether a combination may be synergistic, additive,
or antagonistic before it is tested” (id. at 10).
Appellant contends that the “Examiner erred by ignoring Appellant's
unexpected results in the specification. Figures 1 and 2 of the specification
demonstrate that the combination of pirfenidone and IP-I0 provides
synergistic - better than additive - effects on inhibiting growth of ovarian
cancer cells” (id. at 11). Appellant contends that the “the Examiner erred by
dismissing the evidence based on lack of statistical significance. There is no
reason to question data on the basis of statistical significance without some
indication either from the data or the prior art that the results are
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unreliable” (App. Br. 15).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner‟s conclusion that Tosato, Markovic, Ciardiello, and
Krishnan render obvious the methods of claims 1, 5, and 22-24?
Findings of Fact
1. Tosato teaches that “[t]umors which may be prevented or
inhibited by preventing or inhibiting angiogenesis with IP-10 include . . .
ovarian tumors” (Tosato, col. 7, ll. 30-37).
2. Tosato teaches that the “present invention encompasses
combination therapy in which IP-10 is administered in conjunction with
another anti-angiogenic agent for inhibiting angiogenesis. Other anti-
angiogenic agents that may be administered in conjunction with IP-10
include but are not limited to angiostatin, PF4, IFN- , fumagillin, AGM-
1470, thrombospondin and the like” (Tosato, col. 5, ll. 30-36).
3. Tosato teaches that “[c]ombination therapy is not limited to the
use of IP-10 in conjunction with another anti-angiogenic agent but
encompasses therapy using IP-10 in combination with an anti-inflammatory
agent such as ibuprofen, aspirin, prednisone.” (Tosato, col. 5, ll. 50-55.)
4. Tosato teaches that
Combination therapy also encompasses the use of IP-
10 in combination with a chemotherapeutic agent such as
Taxol, cyclophosphamide, cisplatin, gancyclovir and the
like. Such a therapy is particularly useful in situations in
which the mammal to be treated has a large preexisting
tumor mass which is well vascularized. The
chemotherapeutic agent serves to reduce the tumor mass and
the IP-10 prevents or inhibits neovascularization within or
surrounding the tumor mass.
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(Tosato, col. 5, ll. 56-64.)
5. Markovic teaches “a method for treating a human patient
having a malignant tumor by administering an immunostimulatory dosage of
an -interferon composition to the patient” (Markovic, col. 2, ll. 16-19).
6. Markovic teaches that the “method is useful for treating solid
tumors, including . . . ovarian cancer” (Markovic, col. 3, ll. 42-44).
7. Krishnan teaches that “EGFR is the most frequently
overexpressed and mutated oncogene in malignant gliomas. We report here
Pirfenidone‟s potent anti-tumor effects on malignant gliomas, which is
mediated through inhibition of EGFR phosphorylation” (Krishanan,
abstract).
8. Ciardiello teaches that
A large body of experimental and clinical work supports the
view that the EGFR is a relevant target for cancer therapy.
Two therapeutic approaches have been shown most
promising and are currently being used to inhibit the EGFR
in clinical studies: (a) MAbs; and (b) small molecule
inhibitors of the EGFR tyrosine kinase enzymatic activity

(Ciardiello 2959, col. 1).
9. Ciardiello teaches that a “generally cytostatic growth inhibiting
activity of ZD1839 has been demonstrated in a wide range of human cancer
cell lines that express functional EGFRs, including . . . ovarian” (Ciardiello
2963, col. 1).
10. Ciardiello teaches that a
Phase II study in ovarian cancer patients has also been
reported recently. Patients with advanced, heavily
pretreated, ovarian cancer received p.o. OSI-774, 150 mg
daily. Major toxicities were skin rash (88% patients, 9%,
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grade 3) and diarrhea (35% patients. 6%, grade 3). Two
patients had partial responses, and 16 experienced disease
stabilization. The median survival for the patients in this
study was 242 days.

(Ciardiello, 2965, col. 2.)
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“If a person of ordinary skill can implement a predictable variation, §
103 likely bars its patentability.” Id. at 417. As noted by the Court in KSR,
“[a] person of ordinary skill is also a person of ordinary creativity, not an
automaton.” 550 U.S. at 421.
Analysis
Claim 1
Tosato teaches treatment of ovarian cancer with IP-10 (FF 1) as well
as combination therapies with IP-10 for cancer treatment (FF 2-4).
Krishnan teaches that pirfenidone has anti-tumor activity by
modulating EGFR activity (FF 7). Ciardiello teaches that EGFR inhibitors
are useful in cancer therapy (FF 8). In particular, Ciardiello teaches that two
different EGFR inhibitors inhibited growth of ovarian cancer cells (FF 9)
and stabilized patients with ovarian tumors (FF 10).
Applying the KSR standard of obviousness to the findings of fact, we
conclude that an ordinary artisan would have reasonably found it obvious to
use pirfenidone as a chemotherapeutic treatment for ovarian cancer, since
Krishnan teaches that pirfenidone inhibits EGFR and treats a form of cancer,
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and since Ciardiello teaches that EGFR inhibitors function in the treatment
of ovarian cancer. We further conclude that the ordinary artisan would have
found it obvious to combine pirfenidone with other known ovarian cancer
treatments such as IP-10, as shown by Tosato‟s teaching to combine IP-10
with other chemotherapeutic agents (FF 2-4). Such a combination is merely
a “predictable use of prior art elements according to their established
functions.” KSR, 550 U.S. at 417.
Appellant contends that the
Examiner has failed to articulate an adequate rationale for
combining the disparate references in order to select the
specific combination of IP-10 and pirfenidone from among
the wide variety of agents that were known, suggested, or
suspected to be useful for treating cancer and why one
would select the treatment of ovarian cancer from among the
wide variety of possible cancers.

(App. Br. 7.)
We are not persuaded by the asserted large number of combinations.
That the prior art “discloses a multitude of effective combinations does not
render any particular formulation less obvious. This is especially true
because the claimed composition is used for the identical purpose taught by
the prior art.” Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed.
Cir. 1989). In the instant case, Ciardiello teaches that EGFR inhibitors are
useful treatments for ovarian cancer (FF 9-10) and Krishnan teaches that
pirfenidone is an EGFR inhibitor (FF 7). Along with Tosato‟s teaching that
IP-10 may be used to treat ovarian cancer (FF 1) in combination with other
agents (FF 2-4), this provides a reason for the combination of pirfenidone
and IP-10. Appellant has provided no evidence that the selection of the two
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compounds was in any way unpredictable, unexpected or otherwise not
routine. It is the essence of the Supreme Court's holding in KSR that the
“combination of familiar elements according to known methods is likely to
be obvious when it does no more than yield predictable results.” KSR, 550
U.S. at 416.
Appellant contends that “the Examiner‟s speculation as to the
teachings of the cited art is not supported by adequate reasoning, in view of
Ciardiello‟s failure to provide evidence that all EGFR inhibitors can treat
ovarian cancer, and the uncertainty regarding how pirfenidone
actually exerts its anti-tumor effects” (App. Br. 9). Appellant contends that
the “Examiner‟s speculation is admittedly not supported by any actual
evidence regarding pirfenidone and ovarian cancer” (id.).
We are not persuaded. The Examiner has provided evidence that two
different EGFR inhibitors functioned to treat ovarian cancer (FF 9-10).
With regard to the remaining EGFR inhibitors in Ciardiello, Appellant has
not identified any teaching that suggests that any EGFR inhibitor is
ineffective against ovarian cancer. The balance of the evidence therefore
supports the position of the Examiner, since there is evidence that two EGFR
inhibitors treat ovarian cancer (FF 9-10) and no evidence that any EGFR
inhibitors, and in particular the EGFR inhibitor pirfenidone, fail to treat
ovarian cancer.
Appellant contends that “the Examiner has failed to show a reasonable
expectation of success that the combination of IP-10 and pirfenidone would
be effective. Appellant presented evidence showing that one of ordinary skill
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in the art cannot predict whether a combination may be synergistic, additive,
or antagonistic before it is tested” (App. Br. 10).
We are not persuaded. The Examiner has demonstrated that
pirfenidone is a successful treatment for glioma as an EGFR inhibitor (FF 7)
and that EGFR inhibitors have been successful treatments for ovarian cancer
(FF 9-10). The Examiner also has shown that IP-10 is suggested as a
treatment for ovarian cancer (FF 1) and that Tosato teaches a combination of
IP-10 with other agents (FF 2-4). Thus, the ordinary artisan would have
been apprised of the reasonable likelihood that both IP-10 and pirfenidone
function in ovarian cancer treatment. Kubin stated that “[r]esponding to
concerns about uncertainty in the prior art influencing the purported success
of the claimed combination, this court [in O’Farrell] stated: „[o]bviousness
does not require absolute predictability of success … all that is required is a
reasonable expectation of success.”‟ In re Kubin, 561 F.3d 1351, 1360 (Fed.
Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988)).
Appellant contends that the “Examiner erred by ignoring Appellant‟s
unexpected results in the specification. Figures 1 and 2 of the specification
demonstrate that the combination of pirfenidone and IP-I0 provides
synergistic - better than additive - effects on inhibiting growth of ovarian
cancer cells” (App. Br. 11). Appellant contends that the “the Examiner erred
by dismissing the evidence based on lack of statistical significance. There is
no reason to question data on the basis of statistical significance without
some indication either from the data or the prior art that the results are
unreliable” (id. at 15).
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We are not persuaded. We need not address the Examiner‟s statistical
argument because there is no evidence that the results were unexpected.
That is, neither the Specification nor any expert declaration state that the
results of figure 1 have any unexpected quality. The only statement that the
results were unexpected derives from the arguments of counsel. See In re
Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“It is well settled that unexpected
results must be established by factual evidence. Mere argument or
conclusory statements… [do] not suffice.”) Also see In re Pearson, 494 F.2d
1399, 1405 (CCPA 1974) (“Attorney‟s argument in a brief cannot take the
place of evidence.”).
In addition, when we review figure 1 of the Specification, the doses
which Appellant contends are unexpected represent doses which are
reasonably interpreted as ineffective in killing the tumor cells. That is, the
doses from 23.43 to 375 micrograms/ml fail to achieve the desired result,
which is elimination and death of the tumor cells. Only the doses from 750
to 3000 microgram/ml achieve the goal of killing tumor cells and no
difference is apparent in these doses. Therefore, that ineffective and
insufficient doses do not work well in treatment does not reasonably
represent an unexpected result.
Finally, even for the lower doses, the results are somewhat
ambiguous. Appellant does not identify their source for the specific
numbers used in their analysis, so we are uncertain if they are accessing raw
data unavailable to the Examiner or simply measuring lines on figure 1. To
the extent that there are small differences in the effect of the combination
relative to the effects of each drug alone, these differences are not clearly
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unexpected. See In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (“[I]t is
not enough to show that results are obtained which differ from those
obtained in the prior art: that difference must be shown to be an unexpected
difference”).
Claim 5
Appellant contends that “[w]here three agents are involved rather than
two, the number of possible combinations increases exponentially” (App.
Br. 16). Appellant contends that for “reasons similar to those described
above . . . the Examiner has failed to provide a rationale for why one of
ordinary skill in the art would select IP-10, pirfenidone, and IFN-alpha from
among the thousands or millions or billions of potential combinations of
agents known, suggested or suspected to be useful for treating cancer” (id).
We are not persuaded for the reasons given above. To reiterate, the
“combination of familiar elements according to known methods is likely to
be obvious when it does no more than yield predictable results.” KSR, 550
U.S. at 416. Here, we have already explained why it would have been
obvious to treat ovarian cancer with IP-10 and pirfenidone. The Examiner
relies upon Markovic to teach the use of interferon alpha treatment of
ovarian cancer (FF 5-6) and Tosato specifically teaches that IP-10 may be
combined with interferon alpha for treatments (FF 2).
Claims 22-24
Appellant contends that “the Examiner‟s speculation as to the
teachings of the cited art is not supported by adequate reasoning, in view of
Ciardiello‟s failure to provide evidence that all EGFR inhibitors can treat
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ovarian cancer, and the uncertainty regarding how pirfenidone actually
exerts its anti-tumor effects” (App. Br. 17).
We are not persuaded for the reasons given above. In particular, the
Examiner has provided evidence for a reasonable expectation of success in
the combination (FF 7-10) and no rebuttal evidence has been presented. See
Kubin, 561 F.3d at 1360.
Conclusion of Law
The evidence of record supports the Examiner‟s conclusion that
Tosato, Markovic, Ciardiello, and Krishnan render obvious the methods of
claims 1, 5, and 22-24.
SUMMARY
In summary, we affirm the rejection of claims 1, 5, and 22-24 under
35 U.S.C. § 103(a) as obvious over Tosato, Markovic, Krishnan, and
Ciardiello. Pursuant to 37 C.F.R. § 41.37(c)(1), we also affirm the rejection
of claims 2-4 and 7 as these claims were not argued separately.

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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