Ex Parte Bissery

Board of Patent Appeals and Interferences

Dec 16, 2010

10747410 (B.P.A.I. Dec. 16, 2010)

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.
10/747,410 12/30/2003 Marie-Christine Bissery 3806.0281-10 6613
22852 7590 12/16/2010
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
MARX, IRENE
ART UNIT PAPER NUMBER
1651
MAIL DATE DELIVERY MODE
12/16/2010 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARIE-CHRISTINE BISSERY
__________

Appeal 2010-004121
Application 10/747,410
Technology Center 1600
__________

Before ERIC GRIMES, FRANCISCO C. PRATS, and STEPHEN WALSH,
Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of treating cancer. The Patent Examiner rejected the claims on the
ground of obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.
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STATEMENT OF THE CASE
Claims 24-34 and 36-42, which are all the pending claims, are on
appeal. Claim 24 is representative and reads as follows:
24. A method of treating a cancer in a human patient comprising
administering an effective amount of a combination of docetaxel and
cyclophosphamide to the patient, wherein the combination of
docetaxel and cyclophosphamide has greater anticancer activity in the
human patient than the optimum dose of docetaxel alone against said
cancer in the human patient or the optimum dose of
cyclophosphamide alone against said cancer in the human patient.

The Examiner claims 24-34 and 36-42 under 35 U.S.C. § 103(a) as
unpatentable over Bissery 1992,2 Bissery 1991,3 Eagan,4 Jett,5 Omura,6 and
Speicher.7

2 Bissery, M.C., et al., In vivo evaluation of Taxotere (RP56976,
NSC628503) in combination with cisplatinum, doxorubicin, or vincristine,
Abstract 2645, 33 PROC. AMER. ASSOC. CANCER RES. 443 (1992).
3 Marie-Christine Bissery et al., Experimental Antitumor Activity of
Taxotere (RP 56976, NSC 628503), a Taxol Analogue, 51 CANCER RES.
4845-4852 (1991).
4 Robert T. Eagan et al., A Randomized Comparative Trial of Sequential
Versus Alternating Cyclophosphamide, Doxorubicin, and Cisplatin and
Mitomycin, Lomustine, and Methotrexate in Metastatic Non-Small-Cell Lung
Cancer, 6 J. CLIN. ONCOL. 5-8 (1988).
5 James R. Jett et al., Treatment of Limited-Stage Small-Cell Lung Cancer
With Cyclophosphamide, Doxorubicin, and Vincristine With or Without
Etoposide: A Randomized Trial of the North Central Cancer Treatment
Group, 8 J. CLIN. ONCOL. 33-38 (1990).
6 George Omura et al., A Randomized Trial of Cyclophosphamide and
Doxorubicin With or Without Cisplatin in Advanced Ovarian Carcinoma,
57 CANCER 1725-1730 (1986).
7 Lisa A. Speicher et al., Combined Antimicrotubule Activity of
Estramustine and Taxol in Human Prostatic Carcinoma Cell Lines,
52 CANCER RES. 4433-4440 (1992).
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Claims 25-34 and 36-42 have not been argued separately and
therefore stand or fall with claim 24. 37 C.F.R. § 41.37(c)(1)(vii).

OBVIOUSNESS
The Issue
The Examiner’s position is that (1) Bissery 1992 shows that
combination therapies in the treatment of cancer were recognized in the art;
(2) Bissery 1991 taught the effectiveness of docetaxel for treating various
cancers, and disclosed that both docetaxel and cyclophosphamide were used
against early stage B16 melanoma; (3) each of Eagan and Jett disclosed
cyclophosphamide in combination therapy for treating small cell lung
cancer; (4) Omura disclosed the combination of cyclophosphamide,
doxorubicin and cisplatin in treating ovarian cancer; (5) Speicher taught
paclitaxel, a compound closely related to docetaxel, in combination with
other chemotherapeutic agents for treating cancer; and (6) Speicher taught
“that the rationale for using the combination therapy is to decrease the
dosage of the chemotherapeutic agents and to maximize cytotoxicity to
cancer cells.” (Ans. 4.) The Examiner concluded that it would have been
obvious to combine docetaxel and cyclophosphamide for treating cancer in
humans because it is prima facie obvious to combine two compositions
known to be useful for the same purpose to form a third composition useful
for the same purpose. (Id.) The Examiner found that one of ordinary skill in
the art would have expected the results to be at least additive. (Id.) The
Examiner found that the Specification did not demonstrate unexpected
results in this regard. (Id. at 4-5.) Ultimately, the Examiner concluded that
the prior art evidence showed that combination therapy with docetaxel and
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cyclophosphamide would have had “the expected benefit of improving the
effectiveness of the treatment of a cancer by maximizing cytotoxicity to the
cancer cells and reducing side effects as well as avoiding multidrug
resistance by using chemotherapeutic agents targeting different cellular
pathways.” (Id. at 5.)
Appellant contends that the rejection fails to establish a prima facie
case of obviousness because it does not show “that one skilled in the art
would have predicted, based on the cited references, that the combination of
docetaxel and cyclophosphamide would result in greater anticancer activity
than either or both drugs alone.” (App. Br. 13.) Appellant further contends
that the Examiner failed to support the “conclusion that one skilled in the art
would have reasonably expected . . . at least additive results.” (Id.)
According to Appellant, “the Examiner’s mere conclusory statement
is contrary to several established principles of combination chemotherapy.”
(Id. at 13-14, citing Scripture,8 Beijnen,9 and McLeod.10) According to
Appellant, the Examiner’s references “fail to even teach or suggest the
claimed combination of docetaxel and cyclophosphamide, let alone provide
any guidance as to whether the pharmacodynamic interactions between
docetaxel and cyclophosphamide will be, e.g., (1) synergistic . . . , (2)
antagonistic . . . , (3) additive . . . , or (4) sequence-dependent . . . .” (Id. at
14.)

8 Charity D. Scripture et al., Drug interactions in cancer therapy, 6 NATURE
REVIEWS CANCER 546-558 (2006).
9 Jos H Beijnen et al., Drug interactions in oncology, 5 LANCET ONCOL.
489-496 (2004).
10 Howard L. McLeod, Clinically relevant drug-drug interactions in
oncology, 45 BR. J. CLIN. PHARMACOL. 539-544 (1998).
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“[A]lthough Eagan, Jett, and Omura disclose combination
chemotherapies comprising cyclophosphamide, none . . . compare the
anticancer activity of the combinations . . . [to] the individual drugs
administered alone. . . . Thus, these references . . . are irrelevant.” (Id. at
15-16.) Appellant contends that although Speicher disclosed a greater than
additive effect for the combination of estramustine and paclitaxel, Speicher
also disclosed that a “similar combination comprising paclitaxel and . . .
vinblastine, showed ‘no additive cytotoxicity,’” and in view of these
contradictory results, “one skilled in the art would not predict that the results
of any given combination chemotherapy would ‘be at least additive’ as
alleged by the Examiner . . . .” (Id. at 16-17.)
Appellant asserts this is “the first disclosure that the combination of
docetaxel and cyclophosphamide results in greater anticancer activity than
either or both drugs administered alone.” (Id. at 17, citing Table 1.)
The Examiner responds that “the data of Table 1 fail to provide
conclusive results in this regard” and that the showing of an effect against
one cancer is not commensurate in scope with claims to treating any kind of
cancer. (Ans. 6-7.) The Examiner also responds that the information in
Scripture, Beijnen, and McLeod is not specific to the claimed invention. (Id.
at 5-6.)
The issues with respect to this rejection are:
do the references support a prima facie case of obviousness against
the claimed combination therapy; and, if so,
has Appellant rebutted the prima facie case?

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Findings of Fact
We adopt the Examiner’s findings of fact.

Principles of Law
“It is prima facie obvious to combine two compositions each of which
is taught by the prior art to be useful for the same purpose, in order to form a
third composition which is to be used for the very same purpose.” In re
Kerkhoven, 626 F.2d 846, 850 (CCPA 1980).

Analysis
We agree with the Examiner that the prior art suggested treating
cancer in humans with a combination of docetaxel and cyclophosphamide.
We also agree that there would have been a reasonable expectation of
successfully treating cancer with the combination, and that improving the
effectiveness of the treatment of a cancer by maximizing cytotoxicity to the
cancer cells, reducing side effects, and avoiding multidrug resistance by
using chemotherapeutic agents targeting different cellular pathways would
have been expected benefits. The references establish that combination
chemotherapy was conventional. For example, Jett explained:
“[c]ombination chemotherapy with or without thoracic radiation has been
standard therapy for SCC [small cell carcinoma] since the mid-1970s,” and
“[w]ith the reported efficacy of single-agent etoposide against SCC, it was
only natural to add this agent to a previously accepted standard combination
therapy of CAV [cyclophosphamide, doxorubicin, and vincristine].” (Jett
36.)
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The claims on appeal, however, define a method in which the
combination has greater anticancer activity than the optimum dose of either
drug alone. We agree with the Examiner that a person of ordinary skill in
the art would have reasonably expected additive effects for the claimed
combination therapy. See, e.g., Merck & Co., Inc. v. Biocraft Labs., Inc.,
874 F.2d 804, 809 (Fed. Cir. 1989) (“Given the prior art teaching that both
amiloride and hydrochlorothiazide are natriuretic, it is to be expected that
their co-administration would induce more sodium excretion than would
either diuretic alone”).
Like the Examiner, we find Scripture, Beijnen, and McLeod not
specific to the claimed combination, and we agree that the more specific
evidence in Bissery 1992, Bissery 1991, Eagan, Jett, Omura, and Speicher
suggests the claimed combination therapy would be successful. Eagan, Jett,
and Omura all evidence that cyclophosphamide was regularly used in
combination chemotherapy, Speicher evidences that taxol, an analog of
docetaxel, was used in combination chemotherapy, and Bissery 1992
evidences that docetaxel was used in combination chemotherapy.
We are not persuaded by Appellant that Speicher disclosed hit-or-miss
results, and that Speicher stands for the failure of prediction. Speicher
described its plan to “investigate[] the hypothesis that taxol used in
combination with EM [estramustine] would be a logical approach to enhance
cytotoxicity through combined, though distinct, antimicrotubule activity.”
(Speicher 4433.) Speicher demonstrated the correctness of their hypothesis:
taxol used in combination with estramustine had greater than additive
cytotoxic effects, which Speicher attributed to the known fact that the two
drugs had different microtubule protein targets. (Id. at 4438.) Speicher
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distinguished the comparison negative result: “[s]uch is not the case with
vinblastine and taxol, with both drugs interacting directly with tubulin.”
(Id.) Appellant has not provided any evidence that a person of ordinary skill
would have expected docetaxel and cyclophosphamide to behave like drugs
that have the same target. The evidence shows they were known to have
different targets: Omura refers to cyclophosphamide as an alkylating agent
(Omura 1729), and Bissery 1991 explains that docetaxel inhibits
microtubule depolymerization (Bissery 1991 at 4845).
We conclude that the rejection set out a prima facie case of
obviousness for an expected additive effect. Under these circumstances, it
was Appellant’s burden to rebut that case. See e.g., In re Susi, 440 F.2d 442,
446 (CCPA 1971) (“to overcome a finding of prima facie obviousness by
establishing that the claimed compositions are superior to what one of
ordinary skill in the art would expect, it was up to appellant to bring forward
reasonable evidence”); In re Diamond, 360 F.2d 214, 217 (CCPA 1966)
(where the evidence showed that synergy was expected because combined
drugs targeted different cellular mechanisms, and no evidence to the
contrary was produced, “[w]e are not convinced of the non-obviousness of
the combination of two drugs, A5MP and a glucocorticoid . . . particularly
since the record supports the [PTO’s] contention that the drugs selected are
two of the commonly used drugs in the treatment of such collagen
diseases”).
We agree with the Examiner that Table 1’s demonstration of an effect
against one kind of cancer in mice is not evidence of an unexpected result
supporting claims of the treatment scope claimed. “Establishing that one (or
a small number of) species gives unexpected results is inadequate proof, for
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it is the view of this court that objective evidence of non-obviousness must
be commensurate in scope with the claims which the evidence is offered to
support.” In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978) (quotations
omitted).

CONCLUSIONS
The prior art references support a prima facie case of obviousness
against the claimed combination therapy.
Appellant has not rebutted the prima facie case of obviousness.

SUMMARY
We affirm the rejection of claims 24-34 and 36-42 under 35 U.S.C.
§ 103(a) as unpatentable over Bissery 1992, Bissery 1991, Eagan, Jett,
Omura, and Speicher.
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
alw

FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER LLP
901 NEW YORK AVENUE, NW
WASHINGTON DC 20001-4413