Rigel Pharmaceuticals, Inc.Download PDFPatent Trials and Appeals BoardOct 1, 20212021000080 (P.T.A.B. Oct. 1, 2021) 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. 15/568,206 10/20/2017 Yasumichi Hitoshi P.0311.01.US.UT 1015 74839 7590 10/01/2021 Klarquist Sparkman, LLP (Rigel) 121 SW Salmon St Suite 1600 Portland, OR 97204 EXAMINER CRUZ, KATHRIEN ANN ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 10/01/2021 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): docketing@klarquist.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte YASUMICHI HITOSHI, NAN LIN, and RAJINDER SINGH Appeal 2021-000080 Application 15/568,206 Technology Center 1600 Before LINDA M. GAUDETTE, JOHN E. SCHNEIDER, and RACHEL H. TOWNSEND, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 1–16.2 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 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interest as Rigel Pharmaceuticals, Inc. Appeal Br. 3. 2 Claims 17–27 are also pending in the application but have been withdrawn from consideration. Final Act. 2. Appeal 2021-000080 Application 15/568,206 2 CLAIMED SUBJECT MATTER Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal B cells in the blood, bone marrow, lymph nodes, and spleen. Wiestner, 125. B cell development, survival, proliferation, functional differentiation and migration are regulated by B Cell receptor (BCR) in a metabolic pathway shown in Figure 1 of Wiestner below: Figure 1 of Wiestner showing the BCR signaling and downstream pathways for the production of B cells including the various kinases involved in the process. Wiestner, 126. As shown in Figure 1 of Wiestner, certain kinases including spleen tyrosine kinases (“SYK”) and Bruton’s tyrosine kinase (“BTK”) are essential elements in the BCR pathway. Id. at 125–126. It has been found that certain Appeal 2021-000080 Application 15/568,206 3 compounds act as inhibitors of certain kinases and have been found to be effective in treatment of B-cell malignancies. Id. One kinase inhibitor that has been found effective in treating B-cell malignancies is Ibrutinib (1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one). Spec. ¶ 4. Recently, certain mutations of BTK have arisen that have led to ibrutinib- resistant diseases. Id. ¶ 5. The invention claimed in the present application is directed to “the treatment of ibrutinib-resistant disease with Syk kinase inhibitors.” Id. ¶ 1. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A method of treating an ibrutinib-resistant disease in a mammal, the method comprising administering an effective amount of a compound of Formula (I): wherein R is hydrogen, -CH2OP(O)(O-)2X+2, or - H2OP(O)(O-)2Y2+, and each X is independently a hydrogen ion or a monovalent cation, and Y2+ is a divalent cation; or a pharmaceutically acceptable salt, hydrate or solvate thereof; to the mammal. Appeal 2021-000080 Application 15/568,206 4 REFERENCES The prior art relied upon by the Examiner is: Wiestner, BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma, Hematology, 2014, 125 Wiestner, Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia, 120 Blood 4554 (2016) (“Wiestner II”) Friedberg et al., Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and lymphocytic leukemia, 115 Blood 2578 (2010) Woyach, et al., Resistance Mechanisms for the Bruton’s Tyrosine Inhibitor Ibrutinib, 370 N. Eng. J. Med. 2286 (2014) REJECTIONS The Examiner has rejected the claims as follows: Claims 1–13 have been rejected under 35 U.S.C. § 103 as unpatentable over Wiestner combined with Wiestner II and Freidberg. Claims 14–16 have been rejected under 35 U.S.C. § 103 as unpatentable over Wiestner combined with Wiestner II, Freidberg and Woyach. OPINION Wiestner Combined with Wiestner II and Friedberg The Examiner finds that Wiestner teaches the use of BTK inhibitors such as ibrutinib as a second line treatment for chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL). Final Act. 7–8. The Examiner finds that Wiestner teaches that the SYK inhibitor fostamitinib has also been used to treat leukemia. Id. The Examiner finds that Wiestner teaches that mechanisms of resistance to certain kinase inhibitors may depend on the specific kinase targeted. Id. The Examiner Appeal 2021-000080 Application 15/568,206 5 finds that Wiestner teaches that ibrutinib resistance has been observed in several patients. Id. The Examiner finds that Wiestner II teaches that fostamitinib has induced impressive responses in relapsed and refractory CLL patients. Id. at 8. The Examiner finds Wiestner teaches: Treatment of CLL cells with fostamatinib in vitro inhibits BCR and integrin signaling, antagonizes the protective effect of stromal cells, reduces migration to chemokines and adhesion to stromal components, and induces a moderate degree of apoptosis. Thus, inhibition of SYK antagonizes BCR-dependent and BCR-independent prosurvival effects in the tissue microenvironment. The therapeutic potential of SYK inhibitors in B-cell malignancies is supported by studies in mouse models; fostamatinib prevents disease progression both in TCL 1 transgenic mice (in which antigen-dependent selection appears to play a similar role as in human CLL) and in a non-Hodgkin lymphoma model that depends on cooperation between Myc and BCR-derived signals (page 4686, right column). Wiestner II teaches that the first clinical trial of a SYK inhibitor used fostamatinib in a phase 1/2 study in patients with relapsed/refractory non-Hodgkin lymphoma and CLL. The phase 1 part established a dose of 200 mg oral bid for phase 2 testing. 11 patients with CLL, 6 (55%) achieved a partial response (PR). The response rate in CLL was the highest, ahead of DLBCL (22%), mantle cell lymphoma (11%), and follicular lymphoma (10%)(page 4686, right column). Id. at 9. The Examiner finds that while neither Wiestner reference teaches the use of fostamitinib disodium, Friedberg teaches that compound. Id. at 9–10. The Examiner concludes: It would have been obvious to treat an ibrutinib-resistant cancer with the administration of either fostamatinib disodium and/or fostamatinib. One would have been motivated to administer [disodium] fostamatinib and/or fostamatinib because Appeal 2021-000080 Application 15/568,206 6 it is known in the art that mechanisms of resistance likely will differ depending on which kinase is targeted. Recently, acquired mutations in BTK and in phospholipase C gamma 2 (PLC 2), a direct downstream target of BTK, were identified in 6 CLL patients who developed resistance to ibrutinib. Five patients showed a cysteine-to-serine mutation in BTK (C481S) at the binding site of ibrutinib that disrupts the covalent binding between the drug and the kinase and thereby dramatically decreases the potency of ibrutinib and therefore in administering the Syk inhibitor (such as fostamatinib disodium and/or fostamatinib) in order to effectively treat CLL as well as enhance the effects of ibrutinib with a reasonable expectation of success. Id. at 10–11. The Examiner goes on to quote In re Kerkhoven, 626 F.2d 846 (CCPA 1980): It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (CCPA 1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art. Therefore, it would have been prima facie obvious to combine fostamatinib and fostamatinib disodium composition cojointly in a formulation to treat CLL. Id. at 11. Appellant contends that the art does not teach that SYK plays a role in “ibrutinib resistance and makes no suggestion of treating patients having ibrutinib-resistant disease with any kinase inhibitor, much less a Syk inhibitor such as fostamatinib.” Appeal Br. 4. Appellant argues that the statement in Wiestner concerning mechanisms of resistance being dependent on the targeted kinase “is mere musing - it does nothing to suggest or guide Appeal 2021-000080 Application 15/568,206 7 the ordinary artisan specifically to any new kinase inhibitor to overcome resistance to another.” Id. Appellant contends that the discussion in Wiestner of SYK inhibitors and fostamatinib in particular would not lead one skilled in the art to use fostamatinib to treat an ibrutinib-resistant patient, or provide any motivation for doing so. Id. The issue before us is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 1–13 would have been obvious to one of ordinary skill in the art at the time the invention was made over Wiestner combined with Wiestner II and Friedberg. We adopt the Examiner’s findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer regarding this rejection. We find the Examiner has established a prima facie showing that the subject matter of the claims would have been obvious over Wiestner combined with Wiestner II and Friedberg to a person of ordinary skill in the art at the time the invention was made. Appellant has not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness are incorrect. Only those arguments made by Appellant in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv)). We have identified claim 1 as representative; therefore, claims 2–13 fall with claim 1. We address Appellant’s arguments below. Appellant contends that none of the references teach or suggest the use of fostamatinib to treat an ibrutinib-resistant patient. Appeal Br. 4. Appellant contends that Wiestner’s statement about resistance being Appeal 2021-000080 Application 15/568,206 8 dependent on the kinase targeted is “mere speculation” and is unsupported by the evidence. Id. We are not persuaded by Appellant’s arguments. Wiestner teaches that ibrutinib acts to disrupt the BCR pathway by inhibiting the action of BTK kinase. Wiestner Figure 1, Table 1. Wiestner teaches that ibrutinib- resistance is due to a mutation in the BTK kinase which prevents ibrutinib from binding to the BTK. Id. at 130. Wiestner and Wiestner II both teach that fostamatinib is a SYK inhibitor and can be used to treat CLL. Wiestner 129–130, Table 1; Wiestner II, 4688, Table 2. Wiestner teaches that SYK kinase occurs upstream from BTK in the BCR pathway. Wiestner, Figure 1. We find that one skilled in the art would have understood from Wiestner that fostamatinib acts on a different part of the BCR pathway than ibrutinib and would have been led to use fostamatinib in situations where ibrutinib was no longer effective. Therefore, we agree with the Examiner that when the teachings of the references are viewed as a whole, it would have been obvious to one skilled in the art to administer fostamatinib to patients who developed resistance to ibrutinib. Ans. 13. We conclude that a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 1–13 would have been obvious to one of ordinary skill in the art at the time the invention was made over Wiestner combined with Wiestner II and Friedberg. Wiestner Combined with Wiestner II, Friedberg, and Woyach Appellant’s sole argument with respect to this rejection is that Woyach does not correct the deficiencies of Wiestner, Wiestner II, and Friedberg. Appeal Br. 6. As discussed above, we do not find a deficiency in the teaching of Wiestner, Wiestner II, and Friedberg. Therefore, we affirm this rejection. Appeal 2021-000080 Application 15/568,206 9 CONCLUSION The Examiner’s rejections are affirmed. More specifically, The rejection of claims 1–13 under 35 U.S.C. § 103 as unpatentable over Wiestner combined with Wiestner II and Freidberg is affirmed. The rejection of claims 14–16 under 35 U.S.C. § 103 as unpatentable over Wiestner combined with Wiestner II, Freidberg and Woyach is affirmed. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–13 103 Wiestner, Wiestner II, Friedberg 1–13 14–16 103 Wiestner, Wiestner II, Friedberg, Woyach 14–16 Overall Outcome 1–16 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). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation