DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is the§ 371 National Stage of International Application No. PCT/US2020/066753, filed 12/30/2020, which claims the benefit of priority to U.S.
Provisional Patent Application No. 62/953,300, filed 12/30/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/24/2022, 04/06/2023, 07/29/2025, and 01/02/2026 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of claims
Claims 1-3, 5-7 and 13-15 are pending in this application and are currently under examination. Claims 4, and 8-12 are cancelled by applicant without prejudice or disclaimer.
Applicant’s arguments, filed 01/02/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 10/02/2025 Office Action and modified in order to address the most recent amendments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5-7 and 13-15 are rejected under 35 U.S.C.103 as being unpatentable over Wang (U.S. 2012/0189539 Al) in view of Lichenstein (WO 2019/067666 Al) and further in view of Mai (Comprehensive Characterization of the Apoptotic Machinery in Glioblastoma Identifies New Therapeutic Strategies – provided by Applicants in IDS).
The instant claims are directed to a method of treating a glioblastoma comprising simultaneously administering a BCL-xL inhibitor and an MCL-1 inhibitor.
Wang et al. teaches methods of using the Bcl-2/Bcl-xL inhibitors in the treatment of diseases and conditions wherein inhibition of Bcl-2/Bcl-xL provides a benefit, like cancers (abstract). Wang also discloses a secondary therapeutic agent different from a Bcl-xL inhibitor wherein the second therapeutic agent can be a known chemotherapeutic drug, like Taxol, or radiation [0030]. Wang also teaches the second therapeutic agent can be administered simultaneously [0097]. Wang also discloses that a variety of cancers can be treated including glioblastoma [0100]. Wang teaches a dosage amount of the BCL-xL inhibitor of formula 1 from 0.005-500 mg per dose [0108]. Wang teaches additional compounds were tested for binding affinities to Bcl-2, Bcl-xL, and Mcl-1 and for cell growth inhibition with the results disclosed in table 4 [0418]
However, Wang et al. fail to disclose a BCL-xL inhibitor or a secondary therapy of an MCL-1 inhibitor combined explicitly for the treatment of a p53 wild type glioblastoma.
Lichenstein et al. teach an embodiment in which one or more active pharmaceutical agents (APIs) is administered to a subject wherein Al 155463 and MIK665 (S64315) are selected as BCL-2 pathway inhibitors [30]. Lichenstein also discloses an embodiment wherein glioblastoma is the cancer being treated [13]. Lichenstein discloses an embodiment in which an inhibitor of BCL-2 pathway inhibitor is an inhibitor of BCLXL and MCL1 [39]. Lichenstein also teaches "The synergistic effect of a combination therapy according to the disclosure can permit the use of lower dosages and/or less frequent administration of at least one agent in the combination compared to its dose and/or frequency outside of the combination. Additional beneficial effects of the combination can be manifested in the avoidance or reduction of adverse or unwanted side effects associated with the use of either therapy in the combination alone (also referred to as monotherapy)" [96]. Lichenstein also discloses the BCL-xL inhibitors of ABT-737, AT-101 (Gossypol), sabutoclax, ABT-737, navitoclax (ABT-263), and TW-37 and the MCL-1 inhibitors of AT-101, MIK665 (S64315), AMG-176 [107].
However, Lichenstein et al. fail to disclose an example of a BCL-xL inhibitor and a secondary MCL-1 inhibitor combined and administered explicitly for the treatment of g p53 wild type glioblastoma.
Mai et al. teach administering Bcl-2, Bcl-xL, and Mcl-1 chemical inhibitors ( A-1155463, and S63845, respectively) to patient derived GBM cells and that the combination of Bcl-xL + Mcl-1 inhibition displayed synergy when administered together (pg. 4, 2nd para.). Mai also discloses “It is important to note that p53 mutational status also played an important role in the sensitizing effects of TMZ. p53 is a known regulator of Puma (p53 upregulated modulator of apoptosis). As such, we observed minimal increase in Puma levels in p53 mutant GBM compared to p53 wild-type cells following TMZ treatment (Supplementary Fig. 5b)” (pg. 6 last para. to pg. 7 1st para.).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer a cancer therapy using Bcl-xL and MCL-1 inhibitors shown by Wang and Lichenstein to be beneficial in the treatment of a broad spectrum of cancers in a patient as further evidenced by Mais teaching of BCL-xL, and MCL-1 inhibitors in cancer treatment of p53 wild type GBM cancers because Wang, Lichenstein and Mai disclosed BCL-xL, and MCL-1 inhibitors provide beneficial patient outcomes when administered as a treatment for a broad spectrum of cancers. A skilled artisan following the teachings of Wang, Lichenstein and Mai would have found it obvious to treat a p53 wild type GBM cancer using a combination of BCL-xL, and MCL-1 inhibitors of S64315 and A1155463 through routine experimentation, especially when the cancer of glioblastoma is mentioned by each reference as being treatable by BCL-xL, and MCL-1 inhibitors. See MPEP 2144.05, MPEP 2144.06, and MPEP 2144.08.
A person of ordinary skill in the art prior to the filing of the instant application would have been motivated to combine Al 155463 and MIK-665 (S64315) in a combination glioblastoma therapy due to the known synergistic effects of administering a combination of BCL-xL and MCL-1 inhibitors on glioblastoma taught by Lichenstein. A person having ordinary skill in the art would have had a reasonable expectation of success in treating any glioblastoma without undue experimentation when following Wang, Mai and Lichenstein's non-limiting disclosures of BCL-xL and MCL-1 inhibitors in a cancer therapy of glioblastoma.
Response to Arguments
Applicant's arguments filed 01/02/2026 have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, applicant argues Wang does not teach or suggest dual BCL-xL/MCL-1 inhibition nor identifies an MCL-1 inhibitor as the secondary agent nor suggests dual blockade of BCL-xL and MCL-1 against glioblastoma. Applicant further argues Lichenstein draws no special link between a BCL-xL inhibitor with an MCL-1 inhibitor as a two-drug regimen independent of MPC-07 67, nor does Lichenstein provide data or guidance specific to dual BCL-xL/MCL-1 inhibition in GBM.
Wang (U.S. 2012/0189539 Al) discloses the compound activity of ABT-737 as a BCL-xL and MCL-1 inhibitor on table 2 [0403]. Wang also identifies glioma and glioblastoma as varieties of cancers which can be treated with BCL-xL and MCL-1 inhibitors [0100]. Concerning Lichenstein (WO 2019/067666 Al), the BCL-2 pathway inhibitor of ABT-737 and A1155463 are disclosed and it is further defined that a BCL-2 pathway inhibitor is an inhibitor of BCL2, BCLXL, or MCL-1. A skilled artisan would have found it prima facie obvious to administer an BCL-xL and MCL-1 inhibitor to treat a subject with GBM due to the disclosures of Wang, Lichenstein and Mai as disclosed above, to produce a synergistic response in the subject being treated with a combination of BCL-xL and MCL-1 inhibitor wherein glioblastoma is identified as a condition which can be treated by the references.
Conclusion
All claims are rejected, no claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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