Array BioPharma Inc.Download PDFPatent Trials and Appeals BoardNov 17, 202014355903 - (D) (P.T.A.B. Nov. 17, 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. 14/355,903 05/02/2014 Darrin Stuart 019121.00936\US 3258 22907 7590 11/17/2020 BANNER & WITCOFF, LTD. 1100 13th STREET, N.W. SUITE 1200 WASHINGTON, DC 20005-4051 EXAMINER CHONG, YONG SOO ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 11/17/2020 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): GPD@bannerwitcoff.com eofficeaction@bannerwitcoff.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte DARRIN STUART and MEGHNA DAS THAKUR ____________ Appeal 2020-002370 Application 14/355,903 Technology Center 1600 ____________ Before DONALD E. ADAMS, ULRIKE W. JENKS, and MICHAEL A. VALEK, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 1–4 and 6–33 (Appeal Br. 1). We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 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 “Array BioPharma Inc.” (Appellant’s August 15, 2019 Appeal Brief (Appeal Br.) 1). Appeal 2020-002370 Application 14/355,903 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to a method of suppressing resistance to treatment with inhibitors of BRAF” (Spec.2 1). Appellant’s independent claim 1 is reproduced below: 1. A method of treating a proliferative disease in a subject in need thereof, wherein the proliferative disease is characterized by a mutation in BRAF kinase, wherein the method comprises suppressing resistance to treatment with a BRAF inhibitor of the Formula II by administering the BRAF inhibitor of Formula II to the subject on an intermittent dosing schedule, wherein the intermittent dosing schedule comprises administering the BRAF inhibitor for a period of 1, 2, 3, 4, 5, or 6 weeks followed by a period of 1, 2, 3, 4, 5, or 6 weeks wherein treatment with the BRAF inhibitor of Formula II is withheld. (Appeal Br. 18.) 2 Appellant’s May 2, 2014 Specification. Appeal 2020-002370 Application 14/355,903 3 Claims 1–4 and 6–33 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Huang,3 Haura,4 Gumerlock,5 and Flaherty.6 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Huang discloses the compound of Appellant’s formula (II) (see Appeal Br. 5 (“[T]he compound of formula (II) in [Appellant’s] claim 1 is compound ‘9’ in Huang.”); see generally Final Act.7 4). FF 2. Huang discloses “methods for the treatment of kinase related disease, particular B-Raf kinase related diseases; for example, metastatic melanomas” (Huang ¶ 27; see generally Final Act. 4). FF 3. Huang discloses the administration of its compounds in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on 3 Huang et al., WO 2011/025927 A1, published Mar. 3, 2011. 4 Haura et al., A Phase II Study of PD-0325901, and Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer, 16 Clin. Cancer Res. 2450–2457 (2010). 5 Gumerlock, US 2007/0099856 A1, published May 3, 2007. 6 Flaherty et al., Vemurafenib, 10 Nature Reviews: Drug Discovery, 811– 812 (2011). 7 Examiner’s July 23, 2018 Final Office Action. Appeal 2020-002370 Application 14/355,903 4 the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. (Huang ¶ 50; see also id. ¶ 49 (“[T]he required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.).) FF 4. “Huang does not disclose the intermittent dosing schedule required by [Appellant’s] claims” (Appeal Br. 5–6; see also Final Act. 4 (“Huang do[es] not expressly teach intermittent dosing with the BRAF Kinase inhibitor of Formula II.”)). FF 5. Haura discloses a phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer (Haura, Title; see Appeal Br. 6 (citing Haura, Title) (“Haura describes a ‘Phase II study of PD-0325901’, which is an ‘Oral MEK Inhibitor.’”); see generally Final Act. 5). FF 6. Haura’s “phase II study initially evaluated 15 mg PD-0325901 twice daily administered intermittently (3 weeks on/1 week off; schedule A). As this schedule was not well tolerated, a second schedule was introduced as follows: 5 days on/2 days off for 3 weeks, followed by 1 week off (schedule B),” wherein “[t]he primary end point was objective response” (Haura, Abstract; see Final Act. 5 (Haura discloses intermittent administration of its MEK inhibitor, PD-0325901.); see also Appeal Br. 7). FF 7. Haura discloses that “PD-0325901 did not meet its primary efficacy end point” and recommends that “[f]uture studies should focus on PD- 0325901 schedule, rational combination strategies, and enrichment of patient selection based on mode of action” (Haura, Abstract; see id. at 2456 (“The primary objective of this study was not met according to a prespecified criterion” and “[f]urther evaluation using a lower dose of PD-0325901 on Appeal 2020-002370 Application 14/355,903 5 the intermittent schedule may be warranted in selected patients with BRAF mutation or in other tumor contexts in which downstream signaling is reliant on MEK for tumor maintenance”). FF 8. Gumerlock discloses the treatment of cancer in human patients, wherein the cancer may be melanoma, including refractory melanoma (Gumerlock ¶ 57; see generally Ans. 4). FF 9. Gumerlock discloses the combined treatment with docetaxel [(DOC)] and an epidermal growth factor receptor kinase inhibitor using an intermittent dosing regimen (Gumerlock, Title; see Final Act. 5 (“Gumerlock teaches combined treatment that includes a kinase inhibitor, using an intermittent dosing regimen.”); Appeal Br. 12 (“Gumerlock is concerned with intermittent dosing of an EGFR inhibitor in combination with chemotherapy.”)). FF 10. Gumerlock discloses that “erlotinib HCl (also known as TARCEVATM)” is “[a] preferred example of an EGFR kinase inhibitor that can be used in practicing [Gumerlock’s] invention” (Gumerlock, Abstract). FF 11. Gumerlock discloses: Two dose escalating phase I trials (Arm A and Arm B) were conducted simultaneously. DOC was administered every 21 days in both arms (70-75 mg/m2 IV). Arm A: erlotinib given weekly days 2, 9, 16 (600-800 mg). Arm B: erlotinib given days 2-16 (150-300 mg). . . . 42 patients with advanced solid tumors were treated, including 22 [non-small-cell lung cancer (NSCLC)] patients. . . . Arm A MTD: DOC 70 mg/m2 and weekly erlotinib 600 mg. Arm B MTD[:] DOC 70 mg/m2 and erlotinib 200 mg day 2-16. Of 22 NSCLC patients, there were 4 partial responses, 4 minor responses, and 5 with stable disease. 4 N[S]CLC patients remain on therapy at 23, 22, 15, and 10 months. (Gumerlock ¶¶ 108, 113; see also Appeal Br. 12.) Appeal 2020-002370 Application 14/355,903 6 FF 12. Flaherty discloses: The emergence of BRAF inhibitors has provided an opening for exploiting the molecular underpinnings of melanoma, which has historically been a treatment-refractory tumour type. It is hoped that this approach will extend to the other solid tumours in which activating BRAF mutations can be found, and that this represents a building block for the development of targeted combination regimens. (Flaherty 812; see Final Act. 5 (“Flaherty teaches that melanoma has a history of being a treatment refractory tumor type, wherein activating BRAF tumors are found.”); see also Appeal Br. 14 (“Flaherty . . . points out that melanoma ‘has historically been a treatment-refractory tumor.’”).) FF 13. Appellant’s Figure 1 is reproduced below: Appeal 2020-002370 Application 14/355,903 7 Appellant’s Figure 1 provides a “[c]omparison of continuous and intermittent dosing of a BRAF inhibitor of formula II shows that taking away a growth advantage for the resistant cells by intermittent dosing delays or prevents the onset of resistance to the BRAF inhibitor” (Spec. 1–2). FF 14. Appellant discloses: The following Example illustrates the present invention. Example 1 Hmex1906 primary human melanoma tumors are implanted at passage 3 into nude mice. The mice were monitored until the implanted tumors reached 200-400mm3. Once this size is reached, the mice are dosed . . . with 5mg/kg of a Raf inhibitor (Compound of Formula II) for 4 weeks. Some of the mice continue treatment while others are subject to an intermittent treatment schedule of 4 weeks of treatment and 2 weeks of drug holiday.[] The results are shown in Figure 1. Resistance emerged in all mice receiving the Compound of Formula II on a continuous basis, but there is no evidence of resistance in the mice that were subject to an intermittent dosing schedule. (Spec. 5–6.) ANALYSIS Based on the combination of Huang, Haura, Gumerlock, and Flaherty, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to use an intermittent dosing regimen, such as that disclosed by Haura and Gumerlock, to administer Huang’s MEK inhibitor to patients, because Flaherty discloses “that solid tumors, with BRAF mutations, are historically treatment refractory” (see Final Act. 6–7; FF 1–11). In this regard, Examiner reasons that, at the time of Appellant’s claimed invention, a person of ordinary skill in this art would have found it prima facie obvious “to administer the claimed compound to Appeal 2020-002370 Application 14/355,903 8 treat melanoma under any dosing schedule that [was] known in the art” (Ans. 4; see FF 3 (Huang discloses the administration of “therapeutically effective amounts [of its MEK inhibitor] via any of the usual and acceptable modes known in the art”)). Examiner further reasons: [I]f a particular disease (melanoma in this case) is known to be refractory or resistant to a known active agent, which the Gumerlock reference clearly teaches, it would be obvious for one of ordinary skill in the art to select intermittent dosing so as to limit or minimize the developing resistance. (Ans.8 4.) In this regard, Examiner reasons that a person of ordinary skill in this art would utilize routine experimentation to optimization the intermittent dosing schedule to treat Huang’s patients with MEK inhibitor and, thus, Appellant’s intermittent administration schedule would have been prima facie obvious to those of ordinary skill in this art (see generally Final Act. 7). We are not persuaded. As Appellant explains, “Haura expressly states that PD-0325901 did not meet its primary efficacy endpoint” (Appeal Br. 16; see also FF 7). In addition, although Haura discloses, “schedule A,” an intermittent dosing schedule that is encompassed by Appellant’s claimed invention, Haura discloses that schedule A was discontinued because it “was not well tolerated” (see Appeal Br. 16; see also FF 6). Thus, Haura recommends further studies, i.e. experimentation, to develop an effective therapeutic dosing regimen (see FF 7). Given the foregoing, we agree with Appellant’s contention “that a person of ordinary skill [in this art] would [not] have been motivated to apply the methods of Haura [to Huang] in order to arrive at the presently claimed methods” (Appeal Br. 16). 8 Examiner’s November 22, 2019 Answer. Appeal 2020-002370 Application 14/355,903 9 Further, as Appellant explains, Gumerlock discloses “a compound that is clearly unrelated to the compound recited in [Appellant’s] . . . claims, both structurally and with respect to its mechanism” and “neither of Gumerlock’s dosing schedules teaches or suggests the intermittent do[s]ing schedule recited in [Appellant’s] claim 1” (Appeal Br. 13). Thus, even if one were to assume, purely arguendo, that the skilled artisan might somehow apply the Gumerlock dosing schedules to the compound recited in the present claims - which is both structurally and mechanistically unrelated to Gumerlock’s -the resulting schedule would differ significantly from [Appellant’s] claimed intermittent dosing. And modifying Gumerlock in light of the teachings of Haura would not change the conclusion of non-obviousness, since, as already discussed, there would be no expectation of success given the failure of the Haura study. (Id.) We also agree with Appellant’s contention that Flaherty fails to disclose a particular dosing schedule and, therefore, fails to cure the deficiencies in the combination of Huang, Haura, and Gumerlock (see id. at 16). In sum, Examiner established that because proliferative diseases, such as melanoma, that are characterized by a mutation in BRAF kinase have a history of being treatment refractory, a person of ordinary skill in this art would have found it prima facie obvious to try intermittently dosing Huang’s compound according to the dosing methodology set forth for different compounds in the combination of Haura and Gumerlock. As discussed above, however, the combination of Haura and Gumerlock, at best, provides a general intermittent dosing approach and invites a person of ordinary skill in the art to explore the use an intermittent dosing schedule to develop an effective therapy. Appeal 2020-002370 Application 14/355,903 10 [A]n invention is not obvious to try where vague prior art does not guide an inventor toward a particular solution. A finding of obviousness would not obtain where “what was ‘obvious to try’ was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.” . . . This expresses the same idea as the KSR requirement that the identified solutions be “predictable.” Bayer Schering Pharma AG v. Barr Laboratories, Inc., 575 F.3d 1341, 1347 (Fed. Cir. 2009) (citations omitted); see also In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) (“‘[O]bvious to try’ is not the standard under § 103.”). CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. The rejection of claims 1–4 and 6–33 under 35 U.S.C. § 103(a) as unpatentable over the combination of Huang, Haura, Gumerlock, and Flaherty is reversed. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–4, 6–33 103 Huang, Haura, Gumerlock, Flaherty 1–4, 6–33 REVERSED Copy with citationCopy as parenthetical citation