DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment and Argument
2. Claim 1 is pending.
Claim 1 has been amended.
Claim 1 is examined on the merits.
3. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 112
4. The rejection of claim 1 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the in vitro treatment of malignant pleural mesothelioma (MPM) cell lines with death receptor ligand (DRL), recombinant TRAIL (rTRAIL); rTRAIL in the presence of LCL161, an inhibitor of apoptosis proteins (IAPs); and BAP1 shRNA with rTRAIL, does not reasonably provide enablement for preventing mesothelioma in a subject with the administration of a composition comprising a BAP small molecule inhibitor and a DRL has been withdrawn in light of the Examiner’s reconsideration and the amendment to the claim, see In the Claims submitted April 9, 2026, page 2.
New and Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
5. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
6. 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, 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.
7. The rejection of claim(s) 1 under 35 U.S.C. 103 as being unpatentable over Arlen et al., US Patent 11,279,768 B1 (effectively filed April 4, 2016), and further in view of Zucali et al., (Cancer Treatment Reviews 37: 543-558, 2011) and Levine et., WO 2015/196064 A1 (published 23 December 2015) and Katz et al., (Cancer Biology & Therapy 8(24): 2406-2416, December 15, 2009) is maintained.
Applicant asserts, “[c]laim 1 has been amended to focus on embodiments of the invention that are directed to methods of treating or ameliorating mesothelioma in subject, wherein the mesothelioma comprises a wild-type BAP1 gene.”, see Remarks submitted April 9, 2026, page 4, 1st paragraph.
Applicant follows this assertion with a summary of their teachings pointing out specific pages and Example 4 beginning on page 47 stating alleged novelty of the claim, see pages 4 and 5.
“Applicant’s attorney respectfully traverses…[the pending] rejection stating “…the cited art does not teach or suggest a therapy that uses BAP1 inhibitors in combination with DRL ligands to specifically treat mesotheliomas that comprises a wild-type BAP1 gene.”, see page 5, 1st full para. And notably, Applicant cites each prior art reference with alleged deficiencies and/or negligible teachings, see page 5 of the Remarks, 1st full para.
Applicant further avers the criteria for establishing a proper obviousness rejection, see page 5, last full para. to page 6, 1st full para. And in conclusion, “Applicant's attorney notes that the synergistic effects of the claimed combination therapy discussed in Example 4 were quantifiably described using a delta area under the curve (AUC) metric (i.e., where dAUC = AUCexpected, additive – AUCobserved,combination). The synergy observed with the claimed combination therapy further provides objective technical evidence of nonobviousness under MPEP § 716.02, because Applicant's disclosure demonstrates that the claimed invention provides superior properties not expected from prior art.”, see page 6 of the Remarks, 2nd para.
Applicant’s arguments, citations from the Specification and points of view have been carefully considered, but fail to persuade.
Arlen teaches not only short interfering nucleic acid, but also additional small molecule inhibitors able to silence gene expression, as well as sensitize the apoptotic pathway, see column 14, line 16-column 16, line 24. Levine teaches shRNA targeting BAP1 to reduce BAP1 expression in vitro.”, see page 27, lines 21-27; page 35, lines 12-15. Katz further teaches BAP1 small inhibitor, sorafenib treat in vivo malignant pleural mesothelioma, see entire document. The combination of all the references teaches each and every limitation set forth in claim 1.
It is art known BAP1 is a key regulator of the apoptotic pathway. Therefore, one of ordinary skill in the art would understand and expect the small molecule inhibitors taught by Arlen and Levine would target the expression of wild-type BAP1 and not mutant forms of BAP1. Thus, it is obvious that the treated mesothelioma comprises a wild type BAP1 gene and can be treated with the combination of therapeutic agents, shRNA and sorafenib.
Applicants have not presented any scientific evidence that would dissuade the Office from the combination of references. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are
sufficient to render the claims prima facie obvious.
Moreover, the modification of the primary reference in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213
USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old
elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art
invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Arlen teaches combinatorial methods of treating human cancers, including mesothelioma with a death receptor ligand (DRL) and another therapeutic agent or regimen, see page 3, column 3, lines 37-43, 52-57; column 4, line 13- column 5, line 14; and column 26, lines 43-49. In particular, exemplary DRLs taught by Arlen are tumor necrosis factor a (TNF-alpha), TRAIL (Apo2L), CD95 (Fas, APO-I) ligand, DR6 ligand as well as fragments, variants, and derivatives of said ligands, see column 4, lines 29-37; paragraph bridging columns 4 and 5. Examples of antibody agents that activate the extrinsic apoptotic pathway directed to cellular death receptors, but not limited to are “anti-CD95 antibody, anti-TRAIL -R1 (DR4) antibody, anti-TRAIL-R2 (DR5) antibody, anti-DR6 antibody, anti TNF-R1/2 antibody and anti-TRAMP (DR3) antibody as well as fragments or derivatives thereof. In some embodiments, the antibody is an anti- TRAIL-R1 (D4) antibody. An exemplary anti-TRAIL-R1 (D4) antibody includes, but is not limited to, mapatumumab (HGS-ETR1). Mapatumumab is an agonistic monoclonal antibody to TRAIL-R1 with apoptosis promoting and potential antitumor activities. Mapatumumab selectively binds to and activates the TRAIL cell receptor, thereby inducing apoptosis and reducing tumor growth. In another embodiment, the antibody is an anti-TRAIL-R2 (D5) antibody. An exemplary anti-TRAIL-R2 (D5) antibody includes, but is not limited to, lexatumumab (HGS-ETR2). Lexatumumab is a fully human monoclonal agonistic antibody directed against TRAIL-R2 with potential antitumor activity. Mimicking the natural ligand TRAIL, lexatumumab binds to and activates TRAIL-R2, which may trigger apoptosis in and inhibit the growth of TRAIL -R2-expressing tumor cells. Additional monoclonal antibodies that bind cellular death receptors include conatumumab (AMG655), dulanermin (AMG 951, APO2L TRAIL, PRO1762, RG3639, rhApo2L/ TRAIL), tigatuzumab (CS1008), TRAIL R (DR4-Specific Altrimer, Anaphore), HGS TR2J, LBY135, drozitumab (PR085780, apomab), SL231, SM164 with TRAIL R2, TAS266, and the like.”, see column 5, lines 15-47; and column 13, lines 15-32.
Arlen does not teach the claimed method, wherein the individual is treated with a BRCA1-associated protein 1 (BAP1) inhibitor.
However, Levine teaches BAP1 shRNAs and BAP1 inhibitor, GSK126, see page 6, lines 25-28; page 10, lines 3-8; and page 27, segment 6.1. These therapeutic agents were implemented in in vitro assays, as well as in vivo, see page 6, lines 25-28; page 10, lines 3-8; and page 27, segment 6.1.
Katz teaches treating a malignant pleural mesothelioma (MPM) tumor-bearing xenograft nude mice with a mock BAP1 inhibitor, sorafenib, see abstract; Pilot…segment bridging pages 2408 and 2409. The MPM cell line that formed subcutaneous tumors within the mice was MSTO-211H, see page 2408, Pilot…segment bridging pages 2408 and 2409; and page 2415, Xenograft…segment.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of all the references to treat mesothelioma, as well as MPM with a composition comprising a DRL and a known BAP1 inhibitor. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the mock BAP1 inhibitor of Katz with the known BAP1 inhibitors of Levine. One of ordinary skill in the art would have because this particular type of cancer has been successfully treated with each agent and combinatorial treatment with anticancer agents and TRAIL have been successfully implemented in in vitro studies, see all documents in their entireties; Katz’s abstract and page 2407, Human MPM…section. And Zucali teaches combinatorial anticancer therapeutics to treat MPM in xenograft models and patients, see entire document. Zucali also teaches death receptor ligands, “[t]umor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein belonging to the TNF family of death ligands...TRAIL-R targeting is an excellent strategy for selective cancer therapy and oncology trials with TRAIL and TRAIL-R human agonistic antibodies have been initiated.”, see page 549, 2nd column, Tumor…section.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings in Zucali combinatorial treatment including a DRL has been effective, see Zucali, Tumor…and The intrinsic…segments spanning pages 549 and 550; and Arlen, wherein it is hypothesized such a combination may result in enhanced therapeutic efficacy (see col. 3, lines 27-43; and col. 7, lines 35-43), see Zucali, wherein the therapeutic agents have been known before Applicants’ effective filing date and all references in their entireties.
8. The rejection of claim(s) 1 is/are under 35 U.S.C. 103 as being unpatentable over Zucali et al., (Cancer Treatment Reviews 37: 543-558, 2011), and further in view of Katz et al., (Cancer Biology & Therapy 8(24): 2406-2416, December 15, 2009) and Peng et al. (Cancer Letters 369: 167-174, 1 December 2015) is maintained.
Applicant asserts, “[c]laim 1 has been amended to focus on embodiments of the invention that are directed to methods of treating or ameliorating mesothelioma in subject, wherein the mesothelioma comprises a wild-type BAP1 gene.”, see Remarks submitted April 9, 2026, page 4, 1st paragraph.
Applicant follows this assertion with a summary of their teachings pointing out specific pages and Example 4 beginning on page 47 stating alleged novelty of the claim, see pages 4 and 5.
“Applicant’s attorney respectfully traverses…[the pending] rejection stating “…the cited art does not teach or suggest a therapy that uses BAP1 inhibitors in combination with DRL ligands to specifically treat mesotheliomas that comprises a wild-type BAP1 gene.”, see page 5, 1st full para. And notably, Applicant cites each prior art reference with alleged deficiencies and/or negligible teachings, see page 5 of the Remarks, 1st full para.
Applicant further avers the criteria for establishing a proper obviousness rejection, see page 5, last full para. to page 6, 1st full para. And in conclusion, “Applicant's attorney notes that the synergistic effects of the claimed combination therapy discussed in Example 4 were quantifiably described using a delta area under the curve (AUC) metric (i.e., where dAUC = AUCexpected, additive – AUCobserved,combination). The synergy observed with the claimed combination therapy further provides objective technical evidence of nonobviousness under MPEP § 716.02, because Applicant's disclosure demonstrates that the claimed invention provides superior properties not expected from prior art.”, see page 6 of the Remarks, 2nd para.
Applicant’s arguments, citations from the Specification and points of view have been carefully considered, but fail to persuade.
Katz further teaches BAP1 small inhibitor, sorafenib treat in vivo malignant pleural mesothelioma, see entire document. Peng teaches siRNA targeting BAP1 to reduce BAP1 expression in vitro.”, see 168, 1st column (col.), Cell… and RNA…segments; page 169, 2nd col.; Figure 3C, 3H on page 171; page 170, 2nd col., 1st complete sentence; Figure 4B, 4C, 4E on page 172; and Table S1.
It is art known BAP1 is a key regulator of the apoptotic pathway. Therefore, one of ordinary skill in the art would understand and expect the small molecule inhibitors taught by Katz and Peng would target the expression of wild-type BAP1 and not mutant forms of BAP1. Thus, it is obvious that the treated mesothelioma comprises a wild type BAP1 gene and can be treated with the combination of therapeutic agents, siRNA and sorafenib.
Applicants have not presented any scientific evidence that would dissuade the Office from the combination of references. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are
sufficient to render the claims prima facie obvious.
Moreover, the modification of the primary reference in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213
USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old
elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art
invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Zucali teaches several combinations of death receptor therapeutics with additional anticancer therapeutics to treat MPM in xenograft models and patients, see entire document. Zucali also teaches death receptor ligands, “[t]umor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein belonging to the TNF family of death ligands...TRAIL-R targeting is an excellent strategy for selective cancer therapy and oncology trials with TRAIL and TRAIL-R human agonistic antibodies have been initiated.”, see page 549, 2nd column, Tumor…section.
Zucali teaches “two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. This study demonstrated, in contrast with previous reports, that MPM cell lines (nine of thirteen) are sensitive to TRAIL and that cisplatin synergistically enhances Mapatumumab- or Lexatumumab-mediated apoptosis in a caspase-dependent fashion and is also effective at promoting apoptosis when used in combination with either Mapatumumab or Lexatumumab in MPM tumor cells that are resistant to cisplatin, Mapatumumab or Lexatumumab single-agent therapy. “, see page 549, 2nd column, Tumor…section.
Zucali does not teach the in vivo administration of both, the taught DRLs and an BAP1 inhibitor to the same subject.
However, Katz teaches the in vitro treatment with a mock BAP1 small molecule inhibitor agent, sorafenib in combination with DRL, TRAIL to human MPM cell lines. Katz also teaches treating a MPM tumor-bearing xenograft nude mice with the said agent that mirrors the effect of BAP1 inhibition, see abstract; Pilot…segment bridging pages 2408 and 2409; and page 2415, Xenograft…segment. And Peng teaches small molecule inhibitors of BAP1, BAP1 siRNAs, see page 168, 1st column, Cell… and RNA…segments; and Table S1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of both references to treat mesothelioma, as well as MPM with a composition comprising a DRL and an actual BAP1 inhibitor because this particular type of cancer has been successfully treated with each type of agent and combinatorial treatment with a mock BAP1 and TRAIL has been implemented in in vitro studies utilizing MSTO-211H cells, see both documents in their entireties; Katz’s abstract and page 2407, Human MPM…section. It would have been obvious to one of ordinary skill in the art before the effective filing date to substitute the mock BAP1, an agent capable of producing a similar effect with an actual BAP1 inhibitor.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings in Katz, which “…suggest[s] the combination of sorafenib [a mock BAP1 inhibitor] plus TRAIL as possible therapy for clinical testing in MPM.”, which “…may be synergistic with TRAIL in some MPM tumors”, (see last sentence in the abstract; page 2411, 1st sentence); and Arlen, wherein it is hypothesized such a combination may result in enhanced therapeutic efficacy (see col. 3, lines 27-43; col. 7, lines 35-43), see Zucali, wherein the therapeutic agents have been known before Applicants’ effective filing date.
One of ordinary skill in the art would have been motivated to substitute the mock agent of Katz with the well known BAP1 therapeutic agent of Peng with a reasonable expectation of success by the teachings in Peng, wherein endogenous BAP1 was depleted by two specific siRNA, see page 169, 2nd column, BAP1…segment; page 170, 1st column, full paragraph and 1st sentence in 2nd column; Fig.3 on page 171; and Fig. 4 on page 172.
Conclusion
9. 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.
10. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached on 8AM-8PM, Monday through Friday.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
Alana Harris Dent
23 June 2026
Levine uses BAP1 shRNA to silence BAP1 expression and Katz uses sorafenib to inhibit BAP1 expression. One of skill in the art would understand that both of Levine and Katz are targeting the expression of the wild-type BAP1 not a mutant BAP1 (see if they say anything in specific about mutant forms, I doubt it). thus, its obvious that mesothelioma comprising a wild type BAP1 can be treated with the combination including either shRNA or sorafenib. Good final.
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