PIRAMAL ENTERPRISES LIMITEDDownload PDFPatent Trials and Appeals BoardDec 4, 20202020004745 (P.T.A.B. Dec. 4, 2020) Copy Citation 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 Copy with citationCopy as parenthetical citation