Ex Parte Weichselbaum et al

Board of Patent Appeals and Interferences

Aug 27, 2010

11576310 (B.P.A.I. Aug. 27, 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.
11/576,310 03/29/2007 Ralph R. Weichselbaum 092234-9016-US01 9113
26753 7590 08/27/2010
ANDRUS, SCEALES, STARKE & SAWALL, LLP
100 EAST WISCONSIN AVENUE, SUITE 1100
MILWAUKEE, WI 53202
EXAMINER
ANDERSON, JAMES D
ART UNIT PAPER NUMBER
1614
MAIL DATE DELIVERY MODE
08/27/2010 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 RALPH R. WEICHSELBAUM,
ZAHRA SHAFAEE, and WEI DU
__________

Appeal 2010-003888
Application 11/576,310
Technology Center 1600
__________

Before ERIC GRIMES, LORA M. GREEN, and STEPHEN WALSH,
Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL1

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.
Appeal 2010-003888
Application 11/576,310

2
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 1-3, 5, 9, 10, 12-21, 23-33, 36-40, and 42.2
We have jurisdiction under 35 U.S.C. § 6(b).

STATEMENT OF THE CASE
Claim 1 is representative of the claims on appeal, and reads as
follows:
1. A method of inhibiting growth of cancer cells expressing the
hedgehog signaling pathway comprising, contacting the cells with effective
amounts of a hedgehog inhibitor and an antimicrotubule chemotherapeutic
agent to inhibit the growth of the cells.

Claims 1-3, 5, 9, 10, 12-21, 23-33, 36-40, and 42 stand rejected under
35 U.S.C. § 103(a) as being rendered obvious by the combination of Safran,3
Thayer,4 and Beachy.5
We affirm.
ISSUE
Has the Examiner established by a preponderance of the evidence that
the combination of Safran, Thayer, and Beachy renders the method of claim
1 obvious? And if yes, have Appellants demonstrated unexpected results,

2 Claims 4, 6, 22, 34, 35, and 41 are also pending, but stand withdrawn from
consideration. (App. Br. 5.)
3 Safran et al., Paclitaxel as a radiation sensitizer for locally advanced
pancreatic cancer, 43 CRITICAL REVIEWS IN ONCOLOGY/HEMATOLOGY 57-
62 (2002).
4 Thayer et al., Hedgehog is an early and late mediator of pancreatic cancer
tumorigenesis, 425 NATURE 851-856 (2003).
5 Beachy, US Patent No. 6,432,970 B2, issued Aug. 13, 2002.
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that when weighed with the evidence of obviousness, are sufficient to
demonstrate the unobviousness of claim 1?

FINDINGS OF FACT
FF1 The Specification teaches that “[t]herapy for cancer has largely
involved the use of chemotherapy, in which highly toxic chemicals are given
to the patient, and/or radiotherapy, in which toxic doses of radiation are
directed at the patient.” (Spec. 1, ¶3.)
FF2 The Specification further notes that “[c]ombination therapies, which
employ two or more agents with differing mechanisms of action and
differing toxicities, have been useful for circumventing drug resistance and
increasing the target cell population.” (Id. at 2, ¶5.)
FF3 According to the Specification:
The present invention provides methods of treating and
preventing hyperproliferative diseases, especially cancers, by
combining a hedgehog inhibitor with chemotherapy and/or
radiation therapy. That is, hedgehog inhibitors may potentiate
tumor response to radiation, to chemotherapy, or to a combined
treatment of radiation and chemotherapy. Thus, hedgehog
inhibitors may improve the efficacy of radiotherapy and/or
chemotherapy.

(Id. at 2, ¶7.)
FF4 The Specification also teaches that the “hedgehog signaling pathway
is overexpressed in many pancreatic adenocarcinomas.” (Id. at 5, ¶21.)
FF5 Example 7 of the Specification investigates “the potential cytotoxic
interaction between cyclopamine and chemotherapeutic agents,” the results
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of which are shown in Figure 2 of the application. (Id. at 41, ¶131.) Figure
2 is reproduced below:

Specifically:
Figure 2 shows colony formation following exposure to
cyclopamine, taxol (3.5 nM), cisplatin (0.8 μMol), and
gemcitabine (7.3 nM). In Mia PaCa-2 cells, cyclopamine (4
µM) gave a survival of 29% and taxol (3.5 nM) demonstrated
survival of 91%. The combination of taxol (3.5 nM) and
cyclopamine (4 µM) yielded a survival of 7% (p<.001).
Cisplatin alone (0.8 µM) gave 35% survival, and the
combination of cyclopamine (2 µM) and cisplatin (0.8 µM)
gave 11% survival. P=0.56. Gemcitabine (7.3 nM)
demonstrated 35% survival and in combination with
cyclopamine (2 µM) demonstrated 41% survival. P=0.7.

(Id. at 41, ¶131)
FF6 According to the Specification, “[c]onsidered together, these data
suggest a greater than additive effect between taxol and cyclopamine, an
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additive effect with cisplatin and cyclopamine, and a potentially protective
effect between cyclopamine and gemcitabine.” (Id.)
FF7 The Examiner’s statement of the rejection may be found at pages 4-6
of the Answer.
FF8 As the claims stand or fall together (App. Br. 9), we focus our analysis
on claim 1.
FF9 Specifically, the Examiner finds that Safran teaches that paclitaxel (an
antimicrotubule chemotherapeutic agent) “is a radiation sensitizer for locally
advanced pancreatic cancer.” (Ans. 4.)
FF10 The Examiner notes that Safran fails to teach the administration of a
hedgehog inhibitor. (Id.)
FF11 The Examiner cites Thayer for teaching that “hedgehog is an early
and late mediator of pancreatic cancer tumorigenesis and further teach that
cyclopamine [a hedgehog inhibitor] induces apoptosis and blocks
proliferation of pancreatic cancer cell lines both in vitro and in vivo.” (Id.)
FF12 Thayer additionally notes:
Pancreatic cancer, the fourth highest cause of death from
cancer in the United States, remains an incurable and rapidly
lethal disease, with a 5-yr survival rate of less than 3%. Many
factors contribute to this poor prognosis, but ultimately it is our
lack of knowledge of the molecular determinants involved in
the pathogenesis and progression of this tumour that has limited
our ability to design effective treatments. Identification of a
role for the HH [hedgehog] pathway in the initiation and
maintenance of pancreatic cancer suggests that this pathway
may hold promise for new diagnostic and therapeutic
approaches.

(Thayer, p. 855, first column.)
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FF13 The Examiner cites Beachy for teaching that the administration of
cyclopamine to treat pancreatic cancer would have been obvious to the
ordinary artisan. (Ans. 5.)
FF14 The Examiner thus concludes that it would have been obvious to the
ordinary artisan to use a combination of radiation, paclitaxel, and
cyclopamine to treat pancreatic cancer. (Id. at 5-6.)

PRINCIPLES OF LAW
As the Supreme Court pointed out in KSR Int' l Co. v. Teleflex
Inc., 550 U.S. 398, 418 (2007), “a patent composed of several elements is
not proved obvious merely by demonstrating that each of its elements was,
independently, known in the prior art.” Rather, the Court stated:
[I]t can be important to identify a reason that would have
prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention
does . . . because inventions in most, if not all, instances rely
upon building blocks long since uncovered, and claimed
discoveries almost of necessity will be combinations of what, in
some sense, is already known.

Id. at 418-419 (emphasis added); see also id. at 418 (requiring a
determination of “whether there was an apparent reason to combine the
known elements in the fashion claimed by the patent at issue”) (emphasis
added).
While holding that some rationale must be supplied for a conclusion
of obviousness, the Supreme Court nonetheless rejected a “rigid approach”
to the obviousness question, and instead emphasized that “[t]hroughout this
Court’s engagement with the question of obviousness, our cases have set
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forth an expansive and flexible approach . . . .” Id. at 415. The Court also
rejected the use of “rigid and mandatory formulas” as being “incompatible
with our precedents.” Id. at 419; see also id. at 421 (“Rigid preventative
rules that deny factfinders recourse to common sense, however, are neither
necessary under our case law nor consistent with it.”).
The Court thus reasoned that the analysis under 35 U.S.C. § 103 “need
not seek out precise teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.” Id. at 418; see
also id. at 421 (“A person of ordinary skill is also a person of ordinary
creativity, not an automaton.”).
The burden of demonstrating unexpected results rests on the party
asserting them, and “it 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.” In re Klosak, 455 F.2d 1077, 1080 (CCPA
1972). “Mere improvement in properties does not always suffice to show
unexpected results.” In re Soni, 54 F.3d 746, 751 (Fed. Cir. 1995).
Moreover, a showing of unexpected results must be commensurate in scope
with the breadth of the claims. In re Grasselli, 713 F.2d 731, 743 (Fed. Cir.
1983); see also In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978)
(“[O]bjective evidence of non-obviousnesss must be commensurate in scope
with the claims . . . .”)

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ANALYSIS
Appellants argue that Safran “contains no suggestion that paclitaxel
would potentiate the activity of any chemotherapeutic agent, let alone the
activity of a hedgehog inhibitor,” and nor do Thayer and Beachy. (App. Br.
10.) According to Appellants, “nothing in the art of record provides a
rationale for choosing the claimed treatment combination from among all of
the thousands upon thousands of possible combinations of chemotherapeutic
agents available.” (Id.) Appellants rely on the Declaration of Dr. Ralph
Weichselbaum, submitted with the Reply Brief, as evidence “that there are,
in fact, thousands upon thousands of different combinations of
chemotherapeutic agents.” (Reply Br. 9.)
Claim 1 is drawn to a method of inhibiting the growth of cancer cells
by contacting the cells with effective amounts of a hedgehog inhibitor, such
as cyclopamine, and a microtubule chemotherapeutic agent, such as
paclitaxel (taxol), such that growth of the cells is inhibited. Safran teaches
that paclitaxel, along with radiation, may be used in the treatment of
pancreatic cancer. (FF9.) Thayer and Beachy provide evidence that the
hedgehog inhibitor cyclopamine may also be used to treat pancreatic cancer.
(FF11 and 13.) Thus, we agree with the Examiner that it would have been
obvious to combine the treatment of Safran with the treatment of Thayer and
Beachy to arrive at a method of inhibiting the growth of pancreatic cancer
cells through the use of radiation, paclitaxel, and cyclopamine. The ordinary
artisan would have had reason for combining the references because they all
relate to the treatment of pancreatic cancer, and as the use of combination
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therapies in the treatment of cancer is well known and routine in the art.
(See, e.g., FF2.)
We recognize that the combination may be one of many possible
combinations of agents known to be useful in the treatment of pancreatic
cancer. That fact, however, does not make it any less obvious. KSR, 550
U.S. at 419 (“What matters is the objective reach of the claim. If the claim
extends to what is obvious, it is invalid under § 103.”).
Appellants assert further, citing Example 7 and Figure 2 of the
Specification, that they have “demonstrated that the combination of a
hedgehog inhibitor, such as cyclopamine, and an antimicrotubule agent, such
as taxol, has a greater than additive effect in inhibiting the growth of cancer
cells expressing the hedgehog signaling pathway.” (App. Br. 11.)
Appellants assert further that Examples 6 through 8 of the Specification,
when taken together, “show that the hedgehog inhibitor, e.g. cyclopamine,
and antimicrotubule agent, e.g. taxol, act together to produce a greater than
additive effect on the inhibition of cancer cell growth that is not due to
apoptosis.” (Reply Br. 10.) According to Appellants the “greater than
additive effect of this combined treatment would have been unexpected and
not obvious to those of ordinary skill in the art at the time the present
application was filed.” (App. Br. 11.)
Example 7 of the Specification compares one concentration of a single
hedgehog inhibitor, cyclopamine (2µM) and one concentration of taxol (3.5
nM), an antimicrotubule chemotherapeutic agent, to a single concentration
of cisplatin (0.8 µM) and a second concentration of cyclopamine (2µM), and
to a single concentration of gemcitabine (7.3 nm) and the second
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concentration of cyclopamine (2µM). Thus we agree with the Examiner that
the purported unexpected results are not commensurate in scope with the
claims. (Ans. 10) For instance, the Example notes that the single
combination of taxol and cyclopamine at specified concentrations has a
greater than additive effect, but Appellants have not presented any evidence
or reasoning to show that one would expect the same results when the taxol
and cyclopamine are present in different concentrations or different ratios of
taxol to cyclopamine.

CONCLUSION OF LAW
We conclude that the Examiner has established by a preponderance of
the evidence that the combination of Safran, Thayer, and Beachy renders the
method of claim 1 obvious. We conclude further that Appellants have not
demonstrated unexpected results, that when weighed with the evidence of
obviousness, are sufficient to demonstrate the unobviousness of claim 1.
We thus affirm the rejection of claim 1 under 35 U.S.C. § 103(a). As
claims 2, 3, 5, 9, 10, 12-21, 23-33, 36-40, and 42 stand or fall with that
claim, we affirm the rejection as to those claims as well.

Appeal 2010-003888
Application 11/576,310

11
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)(1)(iv)(2006).

AFFIRMED

alw

ANDRUS, SCEALES, STARKE & SAWALL, LLP
100 EAST WISCONSIN AVENUE, SUITE 1100
MILWAUKEE, WI 53202