PIRAMAL ENTERPRISES LIMITED

Patent Trials and Appeals Board

Dec 4, 2020

2020004745 (P.T.A.B. Dec. 4, 2020)

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.
14/904,407 01/11/2016 Veena AGARWAL 062299-5004-US 9535
28977 7590 12/04/2020
MORGAN, LEWIS & BOCKIUS LLP (PH)
1701 MARKET STREET
PHILADELPHIA, PA 19103-2921
EXAMINER
BORI, IBRAHIM D
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
12/04/2020 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
judith.troilo@morganlewis.com
phpatentcorrespondence@morganlewis.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte VEENA AGARWAL, GIRIDHARAN PERIYASAMY,
MAGGIE RATHOS, ANKITA SRIVASTAVA, and
SREESHA SRINIVASA
__________

Appeal 2020-004745
Application 14/904,407
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
of treating melanoma. The Examiner rejected the claims as indefinite and as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as PIRAMAL
ENTERPRISES LIMITED (see Appeal Br. 3). We have considered and
refer to the Specification of Jan. 11, 2016 (“Spec.”; we number the pages of
the Specification sequentially from the title page); Final Action of June 25,
2019 (“Final Act.”); Appeal Brief of Nov. 12, 2019 (“Appeal Br.”);
Examiner’s Answer of April 8, 2020 (“Ans.”); and Reply Brief of June 8,
2020 (“Reply Br.”).
Appeal 2020-004745
Application 14/904,407

2
Statement of the Case
Background
“Melanoma is the most serious type of skin cancer . . . Unfortunately,
no effective treatment exists for metastatic melanoma” (Spec. 1). “40-60 %
of melanomas carry an activating mutation in the gene encoding the serine-
threonine protein kinase B-raf (BRAF)” (id. at 2). “BRAF inhibitors have
been found to be effective in tumor shrinkage in the majority of patients with
BRAF mutant melanoma at low nanomolar concentrations” (id. at 2). “A
few examples of potent BRAFV600 inhibitors include . . . vemurafenib . . .
dabrafenib” (id.). “Cyclin-dependent kinases (CDKs) are a family of
enzymes which become activated in specific phases of the cell cycle” (Spec.
7). “Aberrant expression and overexpression of these kinases are evidenced
in many disease conditions such as cancer” (id.).
The Claims
Claims 1, 3, 8, 12, 13, and 22–25 are on appeal. Independent claim 1
is representative and reads as follows:
1. A method of treating melanoma comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt thereof;

wherein Ar is 2-chloro-4-trifluoromethylphenyl; and a therapeutically
effective amount of at least one anticancer agent selected from
vemurafenib, dabrafenib, and trametinib.

Appeal 2020-004745
Application 14/904,407

3
The Issues
A. The Examiner rejected claims 3, 12, and 13 under 35 U.S.C. § 112(b)
as indefinite (Final Act. 2–3).
B. The Examiner rejected claims 1, 3, 8, 12, 13, and 22–25 under 35
U.S.C. § 103(a) as obvious over Chellappan,2 Dong,3 and Sivakumar4 (Final
Act. 3–9).
C. The Examiner rejected claims 1, 3, 12, 13, and 22 under 35 U.S.C.
§ 103(a) as obvious over Kwong5 and Sivakumar (Final Act. 11–15).

A. 35 U.S.C. § 112(b), indefiniteness
The Examiner finds “Claims 3 and 12–13 recite[] the limitation ‘the
CDK inhibitor’ (claim 3) and ‘said CDK inhibitor’ (claims 12-13). There is
insufficient antecedent basis for the limitation ‘CDK inhibitor’ in claim 1,
from which claims 3 and 12–13 depend” (Final Act. 3).
We summarily affirm the indefiniteness rejection because Appellant
does not dispute the merits of this rejection. See Manual of Patent
Examining Procedure § 1205.02 (“If a ground of rejection stated by the
examiner is not addressed in the appellant’s brief, that ground of rejection
will be summarily sustained by the Board.”)

2 Chellappan et al., Interaction between BRAF inhibitor PLX-4720 and CDK
inhibitors can sensitize melanoma cells with BRAF V600E mutation, Cancer
Research, 72 Cancer Res. Abstract 5598 (2012).
3 Dong, J., Overcoming Resistance to BRAF and MEK Inhibitors by
Simultaneous Suppression of CDK4, in Melanoma – From Early Detection
to Treatment (IntechOpen, DOI: 10.5772/53620) (2013).
4 Sivakumar et al., WO 2007/148158 A1, published Dec. 27, 2007.
5 Kwong et al., Oncogenic NRAS signaling differentially regulates survival
and proliferation in melanoma, 18 Nature Medicine 1503–10 (2012).
Appeal 2020-004745
Application 14/904,407

4
B. & C. 35 U.S.C. § 103(a) over Chellappan, Dong, and Sivakumar or
Kwong and Sivakumar
Because the same issue is dispositive for both obviousness rejections,
they will be addressed together.
The Examiner finds Chellappan teaches “therapy of melanomas with
BRAFV600E mutation . . . wherein a combination of CDKi and BRAFi, led
to sensitization of BRAFV600E mutated melanoma cells to BRAFi by, for
example, decreasing cell viability” (Final Act. 4). The Examiner finds
Chellappan teaches “i) olomoucine and roscovitine as exemplary CDKis;
and ii) PLX-4720 as exemplary BRAFi” (id. at 4–5).
The Examiner acknowledges that Chellappan “does not explicitly
disclose, wherein: i) the CDKi is a compound of formula I; and ii) the
BRAFi is vemurafenib or dabrafenib” (Final Act. 5).
The Examiner finds Dong teaches “i) BRAFi such as dabrafenib; and
ii) MEKi such as trametinib . . . [and] a combination of BRAFi or MEKi
with an endogenous CDKi (INK4A) or a CDKi, significantly suppress
growth and enhances apoptosis in melanoma cells” (Final Act. 5). Each of
dabrafenib and trametinib are anticancer agents recited in claim 1 that are
used in combination with the claimed formula I compound. The Examiner
finds Sivakumar teaches “compounds of formula I as CDKis” and teaches
“using the inventive CDKi compounds in order to inhibit the growth of
cancer cell lines” (id. at 6). The Examiner finds Sivakumar teaches
“inventive CDKi compounds may be used alone or in combination therapy
with other known anticancer” agents (id.).
Appeal 2020-004745
Application 14/904,407

5
The Examiner finds that “it [would have been] obvious to substitute
one known element (a CDKi + BRAFi combination, e.g., CDKi of
Sivakumar . . . for another
(i.e., a CDKi + BRAFi combination of Chellappan) for the predictable result
of treating BRAFV600E mutated melanoma in a subject suffering from
BRAFV600E mutated melanoma” (Final Act. 6–7; emphasis omitted).
The issues with respect to this rejection are:
(i) Does a preponderance of the evidence of record support the
Examiner’s conclusion that Chellappan, Dong, and Sivakumar or Kwong
and Sivakumar render the claims obvious?
(ii) If so, has Appellant provided evidence of unexpected results that
outweighs the evidence supporting the prima facie case of obviousness?
Findings of Fact
1. Chellappan teaches “BRAF V600E mutation happens in 60% of
all melanomas cases and this mutation is responsible to poor prognosis of
the disease. BRAF is part of the MAPK signaling pathway” (Chellappan 1).
2. Chellappan teaches “Our objective is to evaluate if the
combination of BRAF inhibitors and CDKs inhibitors can suppress the
acquired resistance of V600E melanoma cells to BRAF inhibitors”
(Chellapan 1).
3. Chellappan teaches “Olomoucine and Roscovitine were the
CDKs inhibitors used in this study, while PLX-4720 was BRAF inhibitor”
(Chellappan 1).
4. Chellappan teaches the “combination of Olomoucine and PLX-
4720 or Roscovitine and PLX-4720 could sensitize the BRAF V600E
mutated melanoma cell line SKMel 28” (Chellappan 1–2).
Appeal 2020-004745
Application 14/904,407

6
5. Chellappan teaches “treatment with the BRAF inhibitor and the
CDKs inhibitors can sensitize BRAF V600E melanoma cells by decreasing
cell viability, downregulation of survival pathways induced by the BRAF
inhibitor and preventing Rb phosphorylation. This strategy may overcome
the acquired resistance of BRAF-mutated melanoma after treatment with its
inhibitors” (Chellappan 2).
6. Dong teaches: “Melanoma is one of the most prevalent
malignancies and has a very poor prognosis. Mutations in v-raf murine
sarcoma viral oncogene homolog B1 (BRAF) occur in approximately
50% of melanomas” (Dong 3).
7. Dong teaches: “Based on our previous work and recent insights
into molecular mechanisms of resistance to BRAF and MEK inhibitors, we
hypothesize that simultaneous suppression of CDK4 is an effective strategy
to overcome resistance to BRAF and MEK inhibitors (Dong 3–4).
8. Dong teaches “the first combination trial of a selective BRAF
inhibitor (dabrafenib, GSK2118436) with a MEK inhibitor (trametinib,
GSK1120212) is underway and has achieved clinical responses in 17% and
disease control in 67%, in patients who failed prior single-agent treatment
with a BRAF inhibitor” (Dong 6).
9. Dong teaches “melanoma combination treatments that include
CDK4 inhibitors may overcome treatment resistance and enhance efficacy”
(Dong 19).
10. Sivakumar teaches “90% of all neoplasias are associated with
CDK hyperactivation leading to the inactivation of the Rb pathway, CDKs
are attractive targets for the development of anti-tumor drugs” (Sivakumar
1:25–27).
Appeal 2020-004745
Application 14/904,407

7
11. Sivakumar teaches “the enantiomerically pure compounds of
the present invention may be used in combination with known anti-cancer,
cytostatic, and cytotoxic agents. . . . For example, the CDK inhibitor
olomoucine has been found to act synergistically with known cytotoxic
agents in inducing apoptosis” (Sivakumar 33:2–8).

12. Sivakumar teaches the CDK inhibitor compound reproduced
below:

Sivakumar teaches synthesis of the compound above, specifically “(+)-
trans-2-(2-Chloro-4-trifluoromethyl-phenyl)-5, 7-dihydroxy-8-(2-
hydroxymethyl-1-methylpyrrolidin-3-yl)-chromen-4-one” (Sivakumar
61:10–26).
13. Figure 5 of the Specification is reproduced below:
Appeal 2020-004745
Application 14/904,407

8

In figure 5, the cells treated with vemurafenib at 1 μM showed
30 % inhibition while the cells treated with compound A
[Voruciclib] at 0.3 μM showed only 2 % inhibition of cells.
However, when the cells were treated with vemurafenib in
combination with compound A at this suboptimal
concentration, notable synergistic effect of 52 % inhibition of
cells with a combination index value of 0. 77 was observed.
When the cells were treated with compound A (3μM) in
combination with vemurafenib (1 μM), it showed 91 %
inhibition of cells with a combination index of 0.9. The
exhibited synergistic data represents the mean for two
independent experiments, each performed in triplicate.
(Spec. 43).
14. Figures 10a and 12a of the Specification are reproduced below:

Appeal 2020-004745
Application 14/904,407

9
Figure 10a shows “the combination of compound A (voruciclib) and
dabrafenib shows a strong synergy (CI <0.5) in A375 cell line” (Spec. 50).
Figure 12a shows “the combination of compound A (voruciclib) and
trametinib shows a strong synergy (CI <0.5) in A375 cell line” (Spec. 50).
15. Kwong teaches “in vivo administration of PD-0332991 and
either selumetinib [] or GSK1120212 [] induced potent synergy in iNRAS
allograft tumors, resulting in not just tumor stasis but a clear regression,
including two complete responses (no residual palpable tumor)” (Kwong
1508, col. 1).
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).
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472–
1473 (Fed. Cir. 1984).
Analysis
We adopt the Examiner’s findings regarding the scope and content of
the prior art (Ans. 3–9) and agree with the conclusion that the method of
claim 1 would have been prima facie obvious over Chellappan, Dong, and
Sivakumar (FF 1–12). Appellant presents arguments disputing the prima
facie case of obviousness which we find unpersuasive (App. Br. 9–11).
However, we do not find it necessary to address these prima facie
arguments in detail because as discussed below, we conclude that the
evidence of unexpected results, when considered with the evidence of
Appeal 2020-004745
Application 14/904,407

10
obviousness based on Chellappan, Dong, Sivakumar or Kwong, and
Sivakumar, successfully overcomes the prima facie case of obviousness.
Appellant contends the three drug combinations claimed for treatment
of melanoma, voruciclib (compound of formula I) with one of vemurafenib,
dabrafenib, and trametinib, demonstrate synergy (Appeal Br. 11–12; FF 13–
14). Appellant contends “that a showing of a majority of combination
indexes of less than 0.5 for the claimed combinations are unexpected results,
which are not predicted by any of the cited references” (id. at 12).
We agree. The Specification asserts that the three drug combinations
claimed yield synergistic results and demonstrates those results using both
dose response curves and the Chou-Talalay method (see Spec. 8).
The Examiner responds by citing other references, including Kwong,
Giridharan,6 and Rathos,7 that demonstrate drug combinations other than
those claimed also yield synergistic results. We find these references
inapposite. While it is certainly true that scientists have published other
cancer drug combinations that yield synergistic results, that does not provide
an expectation or predictability that the particular cancer drugs recited in
claim 1 would have shown synergistic or unexpected results. Indeed, it is
likely that many such drug combinations are never reported in the literature
because of a failure to demonstrate any synergy or benefit.
We recognize that Kwong, in particular, teaches that treatment of
complementary pathways may result in synergism (see Kwong 1509, col. 2),
but we do not agree that this teaching rises to a level that two particular
inhibitors would necessarily be expected to demonstrate synergism.

6 Giridharan et al., US 2010/0152129 A1, published June 17, 2010.
7 Rathos et al., US 2010/0305057 A1, published Dec. 2, 2010.
Appeal 2020-004745
Application 14/904,407

11
The Examiner has not provided a persuasive reason as to why the
synergistic result would necessarily have been expected. “[W]hen an
applicant demonstrates substantially improved results, as [is the case] here,
and states that the results were unexpected, this should suffice to establish
unexpected results in the absence of evidence to the contrary.” In re Soni,
54 F.3d 746, 751 (Fed. Cir. 1995) (emphasis omitted). The Examiner has
not provided any persuasive basis to question the unexpected results.
We also find the Examiner’s argument regarding the comparison with
the closest prior art unavailing. The closest prior art would have been each
drug alone, not some other drug combination, because a drug combination
with one of the claimed drugs and some other drug would provide no
particular expectation regarding the claimed combinations. And Appellant’s
evidence does properly compare the combination of drugs to the drugs
alone, and demonstrates that the results are synergistic, not additive (FF 13–
14).
We also agree with Appellant that requiring a comparison with
Sivakumar’s CDKi of compound 43 and the trametinib BRAFi is not the
correct comparison because it “would amount to requiring comparison of the
results of the invention with the results of the invention.” In re Chapman,
357 F.2d 418, 422 (CCPA 1966).
Conclusion of Law
(i) A preponderance of the evidence of record supports the Examiner’s
conclusion that Chellappan, Dong, and Sivakumar as well as Kwong and
Sivakumar render the claims obvious.
(ii) However, Appellant has provided evidence of unexpected results
that outweighs the evidence supporting the prima facie case of obviousness.
Appeal 2020-004745
Application 14/904,407

12
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
3, 12, 13 112(b) Indefiniteness 3, 12, 13
1, 3, 8, 12, 13,
22–25
103(a) Chellappan,
Dong,
Sivakumar
1, 3, 8, 12,
13, 22–25
1, 3, 12, 13, 22 103(a) Kwong,
Sivakumar
1, 3, 12, 13,
22
Overall
Outcome
3, 12, 13 1, 8, 22–25

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