Ex Parte Warrell et al

Board of Patent Appeals and Interferences

Feb 16, 2010

09709170 (B.P.A.I. Feb. 16, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
09/709,170 11/10/2000 Raymond P. Warrell 10412-025 4982
79089 7590 02/16/2010
Diehl Servilla LLC
77 Brant Avenue
Suite 210
Clark, NJ 07066
EXAMINER
GIBBS, TERRA C
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
02/16/2010 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 RAYMOND P. WARRELL, ROBERT E. KLEM,
and HOWARD FINGERT
__________

Appeal 2009-010167
Application 09/709,170
Technology Center 1600
__________

Decided: February 16, 2010
__________

Before TONI R. SCHEINER, ERIC GRIMES, and STEPHEN WALSH,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating cancer. The Examiner has rejected the claims as obvious. We
have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.
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STATEMENT OF THE CASE
The Specification discloses that “[i]n many types of human cancers, a
gene termed bcl-2 (B cell lymphoma/leukemia-2) is overexpressed, and this
overexpression may be associated with tumorigenicity” (Spec. 1). The
Specification discloses that “bcl-2 antisense oligomers, when administered
to patients at high doses for a short period of time, i.e., less than 14 days, …
resulted in significant therapeutic responses in the treatment of cancer
patients. These therapeutic regimens further encompassed administering the
bcl-2 antisense oligomer at high doses for the short time in combination with
one or more cancer therapeutics.” (Spec. 4).
Claims 1, 3-5, and 7-23 are on appeal. Claim 1 is representative and
reads as follows:
1. A method of treating cancer in a human comprising administering
to said human, in which such treatment is desired, a bcl-2 antisense
oligonucleotide at a dose of 0.01 to 50 mg/kg/day in more than one cycle of
therapy, each cycle of therapy consisting of 3 to 9 days, wherein each cycle
of therapy is separated by an interval of time wherein said human receives
no bcl-2 antisense oligonucleotide, and wherein said interval of time
comprises at least one day, and further comprising administering one or
more cancer therapeutics.

OBVIOUSNESS
Issue
The Examiner has rejected claims 1, 3-5, and 7-23 under 35 U.S.C.
§ 103(a) as being obvious in view of Webb,1 Waters,2 and Bennett.3

1 A. Webb et al., “BCL-2 antisense therapy in patients with non-Hodgkin’s
lymphoma,” 349 THE LANCET 1137-1141 (1997)
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The Examiner finds that Webb discloses “bcl-2 antisense therapy at a
dose from 4.6 mg/m2 to 73.6 mg/m2 in human patients with non-Hodgkin
lymphoma” (Ans. 4), and that a 14 day course of therapy resulted in an
“improvement in symptoms and tumor shrinkage” in two patients (id.). The
Examiner finds that Waters discloses bcl-2 antisense oligonucleotide therapy
in patients with non-Hodgkin’s lymphoma using repeated courses of
treatment and in combination with other therapeutic agents (id. at 5).
The Examiner finds that Bennett discloses treatment of cancer using
bcl-x (a family member of bcl-2) antisense oligonucleotides and
chemotherapeutics (id. at 5). The Examiner finds that Bennett discloses that
the optimization of treatment schedules is within the skill of one in the art
and that treatment times may vary from several days to several months (id.
at 5-6). The Examiner concludes that “[o]ne of ordinary skill in the art
would have been motivated to administer the antisense in a cycle of therapy
comprising 3 to 9 days since Bennett et al. taught that dosing is dependent
on severity and responsiveness of the disease state to be treated, with the
course of treatment lasting from several days to several months” (id. at 7).
Appellants contend that the “none of the cited art provides the claim
elements of ‘more than one cycle of therapy,’ ‘3 to 9 days,’ and ‘separated
by an interval of time wherein no bcl-2 antisense oligonucleotide is
administered’” (Appeal Br. 10). Appellants also contend that, in the absence
of impermissible hindsight, the cited references would not have suggested

2 Justin S. Waters et al., “Phase I Clinical and Pharmacokinetic Study of
Bcl-2 Antisense Oligonucleotide Therapy in Patients With Non-Hodgkin’s
Lymphoma,” 18 JOURNAL OF CLINICAL ONCOLOGY 1812-1823 (2000)
3 Bennett et al., US 6,214,986 B1, Apr. 10, 2001
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the cycle of therapy required by the claims (id.) and would not have
provided a reasonable expectation of success (Reply Br. 9).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that the cited references would
have made obvious the method of claim 1 with repeated 3- to 9-day cycles
of therapy separated by a day of nontreatment?
Findings of Fact
1. Webb discloses that a bcl-2 “antisense oligonucleotide was
administered for 2 weeks to nine patients who had BCL-2-positive relapsed
non-Hodgkin lymphoma” (Webb 1137).
2. Webb discloses that “[d]uring the course of the study, the daily
dose of BCL-2 antisense was increased incrementally from 4.6 mg/m2 to
73.6 mg/m2” (id.).
3. Webb discloses that
[i]n two patients, computed tomography scans showed a
reduction in tumour size (one minor, one complete response).
In two patients, the number of circulating lymphoma cells
decreased during treatment. In four patients, serum concen-
trations of lactate dehydrogenase fell, and in two of these
patients symptoms improved. We were able to measure BCL-2
levels by flow cytometry in the samples of five patients, two of
whom had reduced levels of BCL-2 protein.
(Id. at 1137.)
4. Webb discloses that a two-week treatment was given and that a
second course was considered if there was evidence of tumor response (id. at
1138).
5. Webb discloses that patient 1 was given two courses of treatment
(id. at 1139).
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6. Webb discloses that “six of eight patients who were treated with
chemotherapy after antisense treatment went on to achieve a partial
remission” (id. at 1140).
7. Waters discloses treating patients with non-Hodgkin’s lymphoma
with “a 14-day subcutaneous infusion of G3139, an … oligonucleotide
complementary to … the bcl-2 open reading frame” (Waters 1812).
8. Waters discloses that the “patients were treated at doses ranging
from 4.6 mg/m2/d to 195.8 mg/m2/d” (id. at 1813).
9. Waters discloses that the “only hematologic toxicity that seemed to
be unequivocally related to G3139 therapy was thrombocytopenia (Table 2).
… In all of these cases, the platelet count fell progressively during the
course of the G3139 infusion and recovered after discontinuation of
treatment.” (Id. at 1813.)
10. Waters discloses that
[a]lthough this was primarily a safety study, there was evidence
for clinical antitumor activity and for specific downregulation
of Bcl-2 protein in target tissues. Three patients with low-grade
lymphoma had an objective reduction in overall tumor bulk
after treatment, and one of them had a complete remission that
has been sustained for 36 months.
(Id. at 1819.)
11. Waters discloses that “[o]ne course of treatment was planned per
patient, but additional courses of treatment were considered in the event of a
tumor response. A second course was administered to patients no. 2, 17, and
21.” (Id. at 1813.)
12. Waters discloses that there “is great potential for the further
development of bcl-2 antisense oligonucleotides in the treatment of
malignant disease. One of the most interesting possibilities is their use as
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chemosensitizing agents … [in] malignancies characterized by Bcl-2
overexpression.” (Id. at 1821.)
13. Bennett discloses “[a]ntisense compounds … targeted to nucleic
acids encoding bcl-x.... Methods of using these compounds for modulation
of bcl-x expression and for treatment of diseases associated with expression
of bcl-x are also provided.” (Bennett, abstract)
14. Bennett discloses that the
formulation of therapeutic compositions and their subsequent
administration is believed to be within the skill of those in the
art. Dosing is dependent on severity and responsiveness of the
disease state to be treated, with the course of treatment lasting
from several days to several months, or until a cure is effected
or a diminution of the disease state is achieved.… Persons of
ordinary skill can easily determine optimum dosages, dosing
methodologies and repetition rates.
(Id. at col. 16, l. 59 to col. 17, l. 2.)
15. Appellants have provided a declaration under 37 C.F.R. § 1.132
of Steven Craig Novick (filed July 16, 2007, Appeal Br. 21).
16. Dr. Novick states that the
results reported in Webb and Waters are not impressive, and
therefore, one skilled in the art reviewing these references
would not be motivated to provide a shorter course of therapy,
especially since most of [sic] all of the patients in the studies
did not respond satisfactorily, despite 14 days of treatment.
Those skilled in the art that develop drugs and treatment
regimens do not routinely shorten cycles of therapy. To be
motivated to do so (and to go against accepted treatment
schedules) would require convincing results, which simply are
not reported in Webb and Waters.
(Novick Declaration, ¶ 9.)
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Principles of Law
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that is was obvious under § 103.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
The obviousness “analysis 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.
“It is not inventive to discover the optimum or workable ranges by
routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
“Obviousness does not require absolute predictability of success.…
For obviousness under § 103, all that is required is a reasonable expectation
of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).
“[W]hen unexpected results are used as evidence of nonobviousness,
the results must be shown to be unexpected compared with the closest prior
art.” In re Baxter-Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).
Analysis
Claim 1 is directed to a method of treating cancer comprising
administering a bcl-2 antisense oligonucleotide in more than one cycle of
therapy, each lasting 3 to 9 days and separated by at least one day. (Claim 1
also requires a particular range of antisense dosages and administration of an
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additional cancer therapeutic, but Appellants do not dispute that the prior art
would have made obvious those limitations.)
Webb and Waters both disclose treatment of cancer by administering
bcl-2 antisense oligonucleotides for a 14-day cycle, and disclose repeated
cycles of treatment. Bennett also discloses the treatment of human cancer
with antisense oligonucleotides and states that a person of ordinary skill in
the art “can easily determine optimum dosages, dosing methodologies and
repetition rates” for such treatments. Bennett also discloses that the course
of treatment may last from several days to several months.
In view of these disclosures, it would have been obvious to one of
skill in the art to modify the prior art 14-day bcl-2 antisense oligonucleotide
treatment cycle to provide repeated 3- to 9-day cycles of treatment. Such a
modification is disclosed by Bennett to be a variable for which optimization
is routine and well within the skill of those in the art. A person of ordinary
skill in the art would reasonably expect that, for example, two 7-day cycles
of treatment, separated by one day of nontreatment, would provide a similar
therapeutic effect as the 14-day treatments disclosed by Webb and Waters.
Appellants argue that the cited references do not suggest repeated 3-
to 9-day cycles of therapy (Appeal Br. 13). Appellants argue that “[a]t most,
one would obtain the generally accepted 14-day bcl-2 ASO [antisense
oligonucleotides] treatment cycle (as taught by Webb) perhaps followed by a
second generally accepted 14-day bcl-2 ASO treatment cycle (as taught by
Waters), perhaps further comprising one or more cancer therapeutics (as
taught by Bennett)” (id. at 21). Appellants argue that the Novick
Declaration establishes “that one skilled in the art would not have shortened
the 14-day cycle in Webb, regardless of reduced bcl-2 levels in Webb or
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Bennett’s boilerplate language regarding optimal dosing of ASOs. Rather,
the skilled artisan would have continued with longer courses of therapy
given the overall unsatisfactory results provided in Webb and Waters.” (Id.)
This argument is not persuasive. First, claim 1 does not require
shortening the overall period of treatment from that taught by the prior art.
The claim encompasses fourteen days of ASO treatment; it just requires that
the fourteen days be split into two seven-day treatments, separated by a day
of nontreatment. As discussed above, a person of ordinary skill in the art
would reasonably expect the two treatment regimens to provide similar
results.
In addition, Bennett discloses that treatment protocols with antisense
oligonucleotides and chemotherapeutic agents would be routinely optimized
by one of skill in the art. One of skill in the art would reasonably expect that
the optimal treatment protocol when using a combination of antisense
oligonucleotides and chemotherapeutics would differ from the optimal
protocol when administering antisense oligonucleotides alone, as taught by
Webb and Waters, and therefore it would have been obvious to optimize the
combination therapy suggested by the references.
Appellants also contend that the Examiner erred in finding that the
references provide a reasonable expectation of success (Reply Br. 9).
Appellants argue that “[n]o showing has been made that reducing the time of
administration below 14 days (in particular the claimed 3-9 days) would be
efficacious in the treatment of cancer” (id.).
This argument is not persuasive. In accord with In re O’Farrell,
obviousness only requires a reasonable expectation of success, but not an
absolute predictability of success. As discussed above, claim 1 does not
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require shortening the overall length of treatment from that taught by the
references, only splitting a continuous fourteen-day treatment into, for
example, two seven-day treatments separated by a day of nontreatment.
Appellants have not provided evidence showing that a skilled worker would
have expected a single day of nontreatment to interfere with the therapeutic
efficacy of Webb’s or Waters’ treatment.
Appellants contend that the “invention is based, in part, on the
discovery that short treatment cycles and/or high doses of bcl-2 ASO, alone
or in combination with other therapeutic agents, unexpectedly provides
greater ameliorative effects with less toxicity in human patients suffering
from cancer compared to previous treatment regimens.” (Appeal Br. 13).
This argument is not persuasive. In accord with In re Baxter-Travenol
Labs., unexpected results must be shown in comparison to the closest prior
art. Here, Appellants have pointed to no evidence of record that provides a
comparison of the method of claim 1 with the treatment methods disclosed
in the prior art. Therefore, the record does not establish that the claimed
method is unexpectedly superior to the methods taught by the closest prior
art.
With regard to claim 5, Appellants argue that claim 5 is nonobvious
“for the additional reason that Waters, which enlarged the study of Webb,
clearly states that the maximum tolerated does of bcl-2 ASO was 4.1
mg/kg/day. See page 1815.” (Appeal Br. 24.)
Claim 5 depends on claim 1 and further requires administering 5 to 7
mg/kg/day of bcl-2 antisense oligonucleotide. Waters discloses that “DLTs
[dose-limiting toxicities] were observed in patients treated at doses of 147.2
mg/m2/d and above.… The maximum-tolerated dose was therefore
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considered to be 147.2 mg/m2/d (approximately 4.1 mg/kg/d).” (Waters
1815, right col.)
The Examiner did not respond in the Answer to Appellants’ argument
with respect to claim 5. We agree with Appellants that Bennett’s general
direction to optimize dosages, when viewed in light of Waters’ disclosure
that the maximum-tolerated dose of a bcl-2 antisense oligonucleotide was
4.1 mg/kg/d, would not have led a person of ordinary skill in the art to the
dosage range recited in claim 5. We therefore reverse the rejection of claim
5.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
cited references would have made obvious the method of claim 1 with
repeated 3- to 9-day cycles of therapy separated by a day of nontreatment.
But the evidence does not support the Examiner’s conclusion that the cited
references would have suggested the dosage range recited in claim 5.
SUMMARY
We affirm the rejection of claim 1 under 35 U.S.C. § 103(a) as being
obvious in view of Webb, Waters, and Bennett. Claims 3, 4, and 7-23 fall
with claim 1 because they were not argued separately. 37 C.F.R.
§ 41.37(c)(1)(vii). We reverse the rejection of claim 5.
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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).

AFFIRMED-IN-PART

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