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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 21, 2025 has been entered.
3. Claim 1 is pending.
Claims 2-7 have been cancelled.
Claim 1 has been amended.
Claim 1 is examined on the merits.
4. The species requirement between species (treated cancer), as set forth in the Election/Restriction action mailed on March 13, 2024, is hereby withdrawn in light of the cancellation of the claims that previously cited those species.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 112
5. The rejection of claim 1 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn, see Table 1 spanning pages 40-43 within Specification filed March 26, 2025. Claims 2-6 have been cancelled.
New and Maintained Grounds of Rejection
Claim Rejections - 35 USC § 112
6. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claim 1 is rejected 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, see Figure 2A caption on page 31; Figures 7B-7D captions on page 32; Figure 8B; Figure 9C; Figure 10 and corresponding drawings.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The claimed invention reads on treating, preventing or ameliorating mesothelioma in a subject with a composition comprising a BAP1 inhibitor and a DRL, wherein the DRL is a TRAIL receptor ligand selected from a group consisting of TRAIL, recombinant TRAIL (dulanermin), mapatumauab, drozitumumab, conatumumab, lextumumab, tigatuzumab, Medi-3038, Medi-3039, LBY-135, or a combination thereof.
However, Applicants’ specification does not seem to provide any level of prevention of mesothelioma. The state of the art reveals “[t]here’s no way to completely prevent mesothelioma. But there are things you can do that might lower your risk.”, see American Cancer Society, 7 pages (last revised/publicly available November 16, 2018).
Preventing a disease is a complex a process. In terms of preventing mesothelioma, one can limit exposure to asbestos and to high doses of radiation during treatment for another cancer, see pages 2-4 of the American Cancer Society document. While it is art known that clinicians are capable of implementing both screening, surveillance, the type of screening test used and the intervals at which it is performed are based on risk stratification, which also serves as the basis for selecting potential candidates for possible prevention. However, like most screening procedures determining whether a population will eventually be struck with a disease is not fool proof.
The specification provides insufficient guidance in regard to the issues raised above and provides insufficient working examples which would provide guidance to one skilled in the art. There seems to be no evidence provided which would allow one of skill in the art to prevent mesothelioma with the administration on a BAP1 small molecule inhibitor and a DRL. In view of the above, one of skill in the art would be forced into undue experimentation identifying all the anti-C5 antibodies with pharmacological products or variants thereof as a preventative therapeutic modality for a host of C5-related diseases.
Granted the Office does not require that experiments under the scope of the claims produce positive and astonishing results, the experiments must be within the scope of the Forman factors (see Ex parte Forman, 230 USPQ 546, BPAI, 1986). There would also need to be some valid amount of direction or guidance, as well as presence or absence of working examples presented in the specification that would enable one skilled in the art to perform the method as presented in the recited claims.
Given the lack of evidence, one skilled in the art would not reasonably conclude that administering the said composition comprising the said BAP1 inhibitor and one of the DRLs would be effective in preventing mesothelioma. Therefore, one of skill in the art would conclude that the claimed regimen would result in an unpredictable outcome. Thus, one of skill in the art could not practice the broadly claimed method with a reasonable expectation of success.
Thus, undue experimentation would be required to implement the instantly claimed method. One skilled in the art would be forced into undue experimentation in order to practice the broadly claimed invention. Furthermore, the complexity and unpredictability of the art to which the invention retains, i.e., in vivo human therapy, suggests the need for some guidance of how to effectively use the claimed methodology to achieve human therapeutic efficacy. There would also need to be some valid amount of direction or guidance, as well as presence or absence of working examples presented in the specification that would enable one skilled in the art to perform the method as presented in the recited claims. It appears that undue experimentation would be required of one skilled in the art to practice the instant claimed invention using the teachings of the specification. See Ex parte Forman, 230 USPQ 546 BPAI, 1986.
The specification provides insufficient guidance with regard to these issues and provides no working examples, other than those mentioned herein which would provide guidance to one skilled in the art. For the above reasons, it appears that undue experimentation would be required to use the claimed invention to prevent mesothelioma with any BAP1 small molecule inhibitor and a death receptor ligand as cited in claim 1.
Claim Rejections - 35 USC § 103
8. 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.
9. 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.
10. Claim(s) 1 are rejected is/are 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). Claims 2-6 have been cancelled.
Applicant sets forth the criteria required for establishing ground for an obviousness rejection and supporting case law, see Remarks submitted November 21, 2025, page 4.
Applicant concludes arguments stating “…the rejection fails to consider the specific constellation of elements in amended claim 1. Specifically, the Arlen and Zucali and Katz disclosures all fail to teach or suggest…” the claimed invention because the prior art fails to teach or suggest each and every feature, see paragraph bridging pages 4 and 5 of the Remarks.
Applicant’s arguments and points of view have been carefully considered, but fail to persuade.
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.
The combination of all the references teaches each and every limitation set forth in claim 1. Concisely, Arlen teaches treating mesothelioma with DRLs in combination with another anti-cancer agent or regimen. Levine teaches producing an anti-cancer effect with the administration of small molecules, BAP1 shRNAs and GSK126 to treat cancer including malignant mesotheliomas. Katz teaches in vivo treatment of malignant pleural mesothelioma (MPM) with BAP1 small inhibitor, sorafenib, while Zucali makes clear a combinatorial approach to treating MPM is a successful strategy for MPM treatment, see all documents in their entirety, as well as the instant rejection herein.
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.
11. 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. Claims 2-6 have been cancelled.
Applicant sets forth the criteria required for establishing ground for an obviousness rejection and supporting case law, see Remarks submitted November 21, 2025, page 4.
Applicant concludes arguments stating “…the rejection fails to consider the specific constellation of elements in amended claim 1. Specifically, the Arlen and Zucali and Katz disclosures all fail to teach or suggest…” the claimed invention because the prior art fails to teach or suggest each and every feature, see paragraph bridging pages 4 and 5 of the Remarks.
Applicant’s arguments and points of view have been carefully considered, but fail to persuade.
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.
The combination of all the references teaches each and every limitation set forth in claim 1. Concisely, Zucali teaches DRLs and a combinatorial approach to treating malignant pleural mesothelioma (MPM) is a successful strategy for MPM treatment. Katz teaches in vivo treatment of MPM with BAP1 small inhibitor, sorafenib, while Peng teaches additional small molecules, siRNAs, see all documents in their entirety, as well as the instant rejection herein.
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
12. 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
11 December 2025
/Alana Harris Dent/Primary Examiner, Art Unit 1643