Ex Parte Warrell

Board of Patent Appeals and Interferences

May 5, 2010

10738717 (B.P.A.I. May. 5, 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.
10/738,717 12/16/2003 Raymond P. Warrell JR. GEN0008-02CP 8311
79089 7590 05/05/2010
Diehl Servilla LLC
77 Brant Avenue
Suite 210
Clark, NJ 07066
EXAMINER
GIBBS, TERRA C
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
05/05/2010 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, JR.
__________

Appeal 2009-015028
Application 10/738,717
Technology Center 1600
__________

Decided: May 5, 2010
__________

Before ERIC GRIMES, DEMETRA J. MILLS, and LORA M. GREEN,
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.
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
Appeal 2009-015028
Application 10/738,717

2
overexpression may be associated with tumorigenicity” (Spec. 2). The
Specification discloses that a“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 and 4-16 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 and an antibody, wherein administration of the bcl-2
antisense oligonucleotide consists of 3 to 9 days of administration in
multiple cycles of therapy, and wherein the multiple cycles of therapy are
separated by intervals of time wherein no treatment is administered and
wherein the interval of time comprises at least one day.
OBVIOUSNESS
Issue
The Examiner has rejected claims 1 and 4-16 under 35 U.S.C.
§ 103(a) as being obvious in view of Webb,1 McLaughlin,2 and Bennett.3
The claims have been argued in two groups: claims 4-9 and 11-15 stand or

1 A. Webb et al., BCL-2 antisense therapy in patients with non-Hodgkin
lymphoma, 349 Lancet 1137-1141 (1997)
2 Peter McLaughlin et al., Rituximab Chimeric Anti-CD20 Monoclonal
Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients
Respond to a Four-Dose Treatment Program, 16(8) Journal of Clinical
Oncology 2825-2833 (1998)
3 Bennett et al., US 6,214,986 B1, Apr. 10, 2001
Appeal 2009-015028
Application 10/738,717

3
fall with claim 1; claim 16 stands or falls with claim 10. 37 C.F.R.
§ 41.37(c)(1)(vii).
The Examiner finds that Webb discloses “bcl-2 antisense therapy by
intravenous infusion in human patients with non-Hodgkin lymphoma” using
a 14-day course of therapy (Ans. 5). The Examiner finds that McLaughlin
discloses that “the chimeric monoclonal anti-CD20 antibody, rituximab, has
been approved for treatment of relapsed refractory low-grade B-cell non-
Hodgkin’s lymphoma” (id.). The Examiner finds that Bennett discloses the
treatment of cancer with bcl-x antisense oligonucleotides, and 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 it would have been obvious to one of
ordinary skill in the art to treat “cancer in a human comprising administering
a bcl-2 antisense oligonucleotide and an antibody … since Webb et al. and
McLaughlin et al. independently taught the treatment of cancer … using a
bcl-2 antisense oligonucleotide and an antibody, respectively” (id. at 6-7).
The Examiner further concludes that “[o]ne of ordinary skill in the art would
have been motivated to administer the antisense in multiple cycles of
therapy, each cycle of therapy consisting of 3 to 9 days of administration
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).
Appellant contends that Webb’s 14-day treatment cycle would not
have suggested repeated 3 to 9 day cycles of therapy with bcl-2 antisense
oligonucleotide (Appeal Br. 13), with a reasonable expectation of success
Appeal 2009-015028
Application 10/738,717

4
(Reply Br. 9). Appellant also argues that it would not have been obvious to
treat cancer with a combination of a bcl-2 antisense oligonucleotide and an
antibody (Appeal Br. 12).
The main issues with respect to this rejection are: Does the evidence
of record support the Examiner’s conclusions that the cited references would
have made it obvious to administer a bcl-2 antisense oligonucleotide in
repeated 3 to 9 day cycles of therapy, along with an antibody, with a
reasonable expectation of success?
Findings of Fact
1. Webb discloses that “[i]ntermediate or high-grade non-Hodgkin
lymphomas … respond well to combination chemotherapy … , with or
without radiotherapy…. The use of new drugs, different chemotherapy
combinations, and high-dose chemotherapy with bone-marrow or peripheral
stem-cell rescue have had an impact.” (Webb 1137, right col.)
2. 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.” (Id. at 1137.)
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.)
Appeal 2009-015028
Application 10/738,717

5
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.)
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. McLaughlin discloses a “multiinstitutional trial of the chimeric
anti-CD20 antibody, IDEC-C2B8” in treating patients with lymphoma
(McLaughlin, abstract).
8. McLaughlin discloses that the IDEC-C2B8 antibody is also known
as Rituximab (id. at 2825, right col.).
9. McLaughlin discloses that the “response rate of 48% with IDEC-
C2B8 is comparable to results with single-agent cytotoxic chemotherapy.
Toxicity was mild.… Further investigation of this agent is warranted,
including its use in conjunction with standard chemotherapy.” (Id.).
10. McLaughlin discloses that “[b]y virtue of the modest toxicities of
this agent, which do not overlap with the toxicities of standard chemotherapy,
this agent lends itself to integration with chemotherapy programs” (id. at
2831).
11. McLaughlin discloses that
[t]here is already some early experience with this antibody in
conjunction with chemotherapy with cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP): the toxicity
of CHOP plus Rituximab appeared comparable to that of CHOP
alone, so the combination seems feasible. The response rate
(73% CRs [complete responders] and 27% PRs [partial
Appeal 2009-015028
Application 10/738,717

6
responders]) was respectable, although in the range of what
might be achieved with CHOP alone. Further experience with
chemotherapy plus Rituximab programs seems warranted.
(Id. at 2831.)
12. 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.)
13. 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.)
14. Appellant has provided a declaration under 37 C.F.R. § 1.132 of
Steven Craig Novick (filed June 4, 2007).
15. Dr. Novick states that the
results reported in Webb 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 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 when response is suboptimal. To be
motivated to do so (and to go against accepted treatment
schedules) would require convincing results, which simply are
not reported in Webb.
(Novick Declaration, ¶ 9.)
Appeal 2009-015028
Application 10/738,717

7
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 it 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 to a human a bcl-2 antisense oligonucleotide and an antibody,
where the antisense oligonucleotide is administered in 3- to 9-day cycles of
therapy separated by at least one day.
Appeal 2009-015028
Application 10/738,717

8
Webb discloses the treatment of lymphoma by administering a bcl-2
antisense oligonucleotide (bcl-2 ASO) for a 14 day cycle and discloses
repeated cycles of treatment. McLaughlin discloses the treatment of
lymphoma by administering Rituximab antibody. Bennett discloses the
treatment of human cancer with antisense oligonucleotides and states that,
for such treatment plans, a person of ordinary skill in the art “can easily
determine optimum dosages, dosing methodologies and repetition rates.”
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
ordinary skill in the art to treat lymphoma with both a bcl-2 ASO and
Rituximab antibody to achieve the combined benefits of both anti-lymphoma
agents. It would also have been obvious to one of skill in the art to modify
the prior art 14-day bcl-2 ASO treatment schedule 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 within the skill 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 without treatment,
would provide a therapeutic effect similar to that of the 14-day treatment
disclosed by Webb.
Appellant argues that the cited references do not suggest the
combination of a bcl-2 ASO with an antibody (Appeal Br. 12). Appellant
argues that although McLaughlin “stated that investigation of combination
therapy was warranted based on earlier reports of synergism between
rituximab and some chemotherapeutic agents, these agents are described as
Appeal 2009-015028
Application 10/738,717

9
‘standard chemotherapy’,” and bcl-2 ASO treatment is non-standard (id.,
citing McLaughlin at 2831).
This argument is not persuasive. Webb discloses treatment with a bcl-
2 ASO followed by chemotherapy (FF 6). Webb also discloses that
lymphoma is typically treated with a combination of different anticancer
therapies (FF 1). McLaughlin suggests that rituximab treatment be
combined with other cancer treatments. In view of these disclosures, it
would have been obvious to a skilled worker to treat lymphoma with a
combination of rituximab and a bcl-2 ASO because the prior art disclosed
both agents individually for treatment of lymphoma and the references show
that cancer is commonly treated with a combination of different therapies.
Appellant argues that the cited references do not suggest repeated 3-
to 9-day cycles of therapy (Appeal Br. 13). Appellant argues that the
Novick Declaration establishes that, in view of the results in Webb, “rather
than reducing the course of therapy, one skilled in the art would be
motivated to continue with the longer course of therapy, perhaps with a
higher dose of bcl-2 ASO, or add to the regimen a second, third or fourth (or
more) course of therapy, or some combination thereof” (id. at 14).
This argument is not persuasive. First, claim 1 does not require
shortening the period of treatment from that taught by the prior art. Claim 1
encompasses fourteen days of ASO treatment; it just requires that the
fourteen days be split into, for example, two seven-day treatments, separated
by a day without treatment. As discussed above, a person of ordinary skill
in the art would reasonably expect the two treatment regimens to provide
similar results.
Appeal 2009-015028
Application 10/738,717

10
In addition, Bennett discloses that treatment protocols with antisense
oligonucleotide agents would be routinely optimized by those of skill in the
art. One of skill in the art would expect that the optimal treatment protocol
with a combination of antisense oligonucleotides and anticancer antibodies
would differ from one with the administration of antisense oligonucleotides
alone, as taught by Webb, and therefore it would have been obvious to
optimize the combination therapy suggested by the references.
Appellant also contends that the Examiner erred in finding that the
references provide a reasonable expectation of success (Reply Br. 9).
Appellant argues 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, not absolute
predictability, of success. As discussed above, claim 1 does not 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 without treatment. Appellant has
not provided evidence showing that a skilled worker would have expected a
single day without treatment to interfere with the therapeutic efficacy of
Webb’s treatment protocol.
Appellant further argues that “bcl-2 ASO given for 3-9 days in
multiple cycles of therapy separated by at least one day…, in combination
with an antibody, … has been shown to be an effective anti-cancer treatment
having surprising mechanistic effects” (Appeal Br. 19). Appellant cites the
Appeal 2009-015028
Application 10/738,717

11
Pro4 reference as showing that an “encouraging objective rate of 60% was
observed in patients with follicular lymphoma previously treated with
rituximab, ‘confirming a suggestion from earlier preclinical data of
synergy’” between a bcl-2 ASO and rituximab (id.; citing Pro at 5).
To the extent Appellant is arguing unexpected results, 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,
Appellant has not pointed to evidence of record that shows that the method
of claim 1 is unexpectedly superior to the bcl-2 ASO treatment method
disclosed by Webb. Therefore, the record does not establish that the claimed
method is unexpectedly superior to the closest prior art.
Appellant argues claim 10 separately (Appeal Br. 21). Claim 10
depends from claim 1 and further requires that “the antibody is administered
at a dose which is below the effective dose when the antibody is
administered without the bcl-2 antisense oligonucleotide.”
The Examiner finds that “[o]ne of ordinary skill in the art would have
been motivated to administer the antibody at a dose which is below the
effective dose when the antibody is administered alone because one of
ordinary skill in the art would readily accept that the purpose of combination
therapy is to administer less of a drug because of the theoretical additive
effect” (Ans. 8).

4 Barbara Pro et al., Phase II multicenter study of oblimersen sodium, a
Bcl-2 antisense oligonucleotide, in combination with rituximab in patients
with recurrent B-cell non-Hodgkin lymphoma, British Journal of
Hematology 1-5 (2008). Appellants cite Pro as “Epub ahead of print”
(Appeal Br. 18); no volume number is provided but a copy of the reference
is included in the Appeal Brief’s Evidence Appendix.
Appeal 2009-015028
Application 10/738,717

12
Appellant argues that McLaughlin discloses that the combination of
rituximab and chemotherapy (CHOP) was in the range of what would be
achieved with chemotherapy alone and thus teaches away from
administering a bcl-2 antisense oligonucleotide with a reduced dose of
antibody (Appeal Br. 21).
Appellant’s argument is not persuasive. Claim 10 requires that the
amount of antibody is reduced but does not require any particular degree of
reduction. We agree with the Examiner that it would have been obvious to
one of ordinary skill in the art to optimize the dosages of the bcl-2 ASO and
rituximab antibody in the treatment suggested by the references, including
administering a reduced amount of antibody in order to reduce antibody-
associated toxicity while maintaining effectiveness of the combined therapy.
Conclusion of Law
The evidence of record supports the Examiner’s conclusions that the
cited references would have made it obvious to administer a bcl-2 antisense
oligonucleotide in repeated 3 to 9 day cycles of therapy along with an
antibody, with a reasonable expectation of success.
SUMMARY
We affirm the rejection of claims 1 and 4-16 under 35 U.S.C.
§ 103(a).
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
Appeal 2009-015028
Application 10/738,717

13

lp

DIEHL SERVILLA LLC
77 BRANT AVENUE
SUITE 210
CLARK NJ 07066