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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/16/2026 has been entered.
Claim Status
Claims 1-33, 35-95, and 97-103 have been cancelled and claims 34, 96, and 104 have been amended, as requested in the amendment filed on 02/16/2026. Following the amendment, claims 34, 96, and 104 are pending in the instant application.
Claims 34, 96, and 104 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 34, 96, and 104 have an effective filing date of May 4, 2020 corresponding to PRO 63/019,914.
Drawings - Objection Withdrawn
Applicant has submitted replacement drawing sheets for Figures 2C, 3, 4B/E, 6K, 12A/C/J/K, 13A, and 16A/C. The replacement drawing sheets are clear and legible. As such, the objection to the drawings is withdrawn.
Specification - Withdrawn
The specification was objected to regarding the abstract. Upon further consideration in view of Applicant’s arguments presented on Pages 5-6 of Remarks (02/16/2026), the abstract as presented on the first page of WO 2021/225963 A2 and A3 (corresponding to abstract of U.S. Publication US 2023/0301998 A1) is of acceptable format and as such the objection to the abstract is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 34-37, 87-94, 96-97, and 99-104 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the recitation of the term “modulation” in independent claim 34. Applicant has amended claim 34 to remove the recitation of “modulation” and it is further noted that claims 35-37, 87-94, 97, and 99-103 have been cancelled, rendering their rejection moot. As such, the rejection of claims 34-37, 87-94, 96-97, and 99-104 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim 94 was rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends. Claim 94 has been cancelled, rendering the rejection moot. As such, the rejection of claim 94 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 34, 36, 87-91, and 94-97 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash") as evidenced by non-patent literature by Tanaka et. al. (Mol. Cancer Res., 2009, 7(4), 557-569; previously cited on PTO-892; herein after referred to as “Tanaka”) and non-patent literature by Ascierto et. al. (Seminars in Oncology, 2010, 37(5), 508-516; previously cited on PTO-892; herein after referred to as “Ascierto”).
Claims 35, 37, and 103-104 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash") as evidenced by non-patent literature by Tanaka et. al. (Mol. Cancer Res., 2009, 7(4), 557-569; previously cited on PTO-892; herein after referred to as “Tanaka”) and non-patent literature by Ascierto et. al. (Seminars in Oncology, 2010, 37(5), 508-516; previously cited on PTO-892; herein after referred to as “Ascierto”), as applied to claims 34, 36, 87-91, 94-97, and 104 above, and in further view of non-patent literature by Zhang et. al. (J. Cell. Mol. Med., 2018, 23, 1333-1342; herein after referred to as “Zhang”).
Claims 92-93 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash") as evidenced by non-patent literature by Tanaka et. al. (Mol. Cancer Res., 2009, 7(4), 557-569; previously cited on PTO-892; herein after referred to as “Tanaka”) and non-patent literature by Ascierto et. al. (Seminars in Oncology, 2010, 37(5), 508-516; previously cited on PTO-892; herein after referred to as “Ascierto”), as applied to claims 34, 36, 87-91, 94-97, and 104 above, and in further view of US 2017/0283807 A1 (previously cited on PTO-892; herein after referred to as “Mounir”).
Claims 99-101 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash") as evidenced by non-patent literature by Tanaka et. al. (Mol. Cancer Res., 2009, 7(4), 557-569; previously cited on PTO-892; herein after referred to as “Tanaka”) and non-patent literature by Ascierto et. al. (Seminars in Oncology, 2010, 37(5), 508-516; previously cited on PTO-892; herein after referred to as “Ascierto”), as applied to claims 34, 36, 87-91, 94-97, and 104 above, and in further view of US 2017/03211285 A1 (previously cited on PTO-892; herein after referred to as “Kobayashi”) and publicly available sequences from UniProt (previously cited on PTO-892).
Claims 99-100 and 102 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash") and US 2017/03211285 A1 (previously cited on PTO-892; herein after referred to as “Kobayashi”) as evidenced by non-patent literature by Tanaka et. al. (Mol. Cancer Res., 2009, 7(4), 557-569; previously cited on PTO-892; herein after referred to as “Tanaka”), non-patent literature by Ascierto et. al. (Seminars in Oncology, 2010, 37(5), 508-516; previously cited on PTO-892; herein after referred to as “Ascierto”), and publicly available sequences from UniProt (previously cited on PTO-892), as applied to claims 34, 36, 87-91, 94-97, 99-101, and 104 above, and in further view of non-patent literature by Choubey et. al. (Frontiers in Bioscience, 2008, 13, 598-608; previously cited on PTO-892; herein after referred to as “Choubey”).
With regard to the above-listed claim rejections, Applicant argues on Pages 7-11 of Remarks that independent claim 34 has been amended to incorporate the subject matter of previous claims 35, 36, 87, and 103, and thus claim 34 now includes subject matter not rejected over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash"), non-patent literature by Tanaka et. al. (Mol. Cancer Res., 2009, 7(4), 557-569; previously cited on PTO-892; herein after referred to as “Tanaka”), and non-patent literature by Ascierto et. al. (Seminars in Oncology, 2010, 37(5), 508-516; previously cited on PTO-892; herein after referred to as “Ascierto”), which was the base rejection for all of the claims. Furthermore, it is noted that claims 35-37, 87-94, 97, and 99-103 have been cancelled, rendering their rejection(s) moot. Thus, in view of the instant claim amendments, the above-listed claim rejections under 35 U.S.C. 103 are withdrawn.
Claim Rejections - 35 USC § 103 - New
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 34, 96, and 104 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/100535 A1 (previously cited on PTO-892; herein after referred to as "Barbash") in view of non-patent literature by Frederick H. Wilson (Mol. Cancer Ther., 2017, 16, Abstract IA24; herein after referred to as "Wilson") and non-patent literature by Barbarino et. al. (J. Cell. Mol. Med., Published Online 04/17/2020, 24, 5565-5577; herein after referred to as "Barbarino").
Barbash is drawn to a combination of a Type II protein arginine methyltransferase (Type II PRMT) inhibitor and immuno-modulatory agent and methods for treating cancer in a human in need thereof, the methods comprising administering to the human a combination of a Type II PRMT inhibitor and an immuno-modulatory agent (Abstract). Increasing evidence suggests that PRMT5 is involved in tumorigenesis; PRMT5 protein is overexpressed in a number of cancer types (i.e., modulation of PRMT5 activity in cancers) including lymphoma, glioma, breast and lung cancer and PRMT5 overexpression alone is sufficient to transform normal fibroblasts (Page 4, Lines 1-4; emphasis added). PRMT5 has been postulated to play a role in differentiation, cell death, cell cycle progression, cell growth and proliferation; while the primary mechanism linking PRMT5 to tumorigenesis is unknown, emerging data suggest that PRMT5 contributes to regulation of gene expression (histone methylation, transcription factor binding, or promoter binding), alteration of splicing, and signal transduction wherein PRMT5 methylation of the transcription factor E2Fl decreases its ability to suppress cell growth and promote apoptosis (Page 5, Lines 9-15). "Type II protein arginine methyltransferase inhibitor" or "Type II PRMT inhibitor" means an agent that inhibits protein arginine methyltransferase 5 (PRMT5) and/or protein arginine methyltransferase 9 (PRMT9) (Page 13, Lines 8-10). Barbash teaches that the Type II PRMT inhibitor is Compound C (also known as GSK3326595; Pages 42-43), and in other embodiments the Type II PRMT inhibitor is a nucleic acid (e.g., a siRNA) (Page 44, Lines 6-8). In one embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a Type II protein arginine methyltransferase (Type II PRMT) inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of an immuno-modulatory agent, wherein the immuno-modulatory agent is selected from: an anti-CTLA4 antibody or antigen binding fragment thereof, an anti-PD1 antibody or antigen binding fragment thereof, an anti-PD-L1 antibody or antigen binding fragment thereof, and an anti-OX40 antibody or antigen binding fragment thereof; in one aspect, the Type II PRMT inhibitor is a protein arginine methyltransferase 5 (PRMT5) inhibitor or a protein arginine methyltransferase 9 (PRMT9) inhibitor, wherein the Type II PRMT inhibitor is Compound C, and the immuno-modulatory agent is an anti-PD1 antibody or antigen binding fragment thereof, which can be pembrolizumab or nivolumab (Page 64, Lines 6-30). Methods are provided for treating cancer in a human in need thereof, the methods comprising administering to the human a therapeutically effective amount of a pharmaceutical composition comprising a Type II protein arginine methyltransferase (Type II PRMT) inhibitor, which may be a PRMT5 inhibitor of Compound C, and a pharmaceutical composition comprising an immuno-modulatory agent, which may be an anti-PD1 antibody (Pages 68-69). Barbash also teaches that Compound C induced a cytotoxic response in a subset of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), glioblastoma, breast and bladder cancer cell lines at concentrations above 100 nM in a 6-day growth/death assay wherein the majority of breast cancer lines had low Ymin-T0 values, suggesting that PRMT5 inhibition results in a complete growth inhibition in breast cancer models, while the rest of the cell lines exhibited a partial cytostatic response (Page 96, Lines 17-23; Figure 8). Additionally, Barbash notes that (i) the combination of PRMT5 inhibitor and ibrutinib (immunomodulatory drug; small molecule kinase inhibitor) demonstrated synergistic anti-proliferative activity in the majority of MCL lines tested (Page 102, Lines 26-28) and (ii) treatment of A20 xenograft tumors with the combination of anti-OX-40 antibody and Compound C resulted in moderate survival advantage, highlighting the potential synergistic interaction between two agents (Page 110, Lines 25-27; Figures 28-29). Thus, the teachings of Barbash indicate that PRMT5 inhibition alone is capable of attenuating tumor growth, and further suggests synergistic effects would be reasonably expected when PRMT5 inhibitors are combined with immunomodulatory drugs. In addition to the exemplary cancers listed above, Barbash provides additional cancers for treatment which include, for example, melanoma, breast cancer, lung cancer, mesothelioma, etc. (Pages 78-79).
However, it is noted that Barbash does not explicitly disclose a PRMT5 inhibitor that is a shRNA that is capable of decreasing PRMT5 expression by at least 10% nor a tumor that is melanoma having an MTAP deletion. These deficiencies are remedied by Wilson and Barbarino.
Wilson teaches that cell lines harboring a highly-recurrent alteration (homozygous deletion of the gene encoding methylthioadenosine phosphorylase or MTAP) show selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77 (Paragraph 2). Homozygous loss of MTAP occurs as a passenger event in cancer due to its proximity to the commonly-deleted tumor suppressor gene CDKN2A; MTAP is lost in >40% of glioblastomas and in 25-30% of melanomas, urothelial carcinomas, and pancreatic adenocarcinomas (in addition to other cancers) (Paragraph 3). The authors teach that loss of MTAP leads to increased intracellular levels of MTA, which in turn specifically inhibits the catalytic activity of PRMT5; since PRMT5 activity is essential for cell viability, MTAP-deleted cells may have some degree of basal inhibition of PRMT5 activity that confers heightened sensitivity to further reduction in PRMT5 activity with gene depletion (i.e., reduced activity via reduced expression of PRMT5) (Paragraph 4; emphasis added). The authors suggest a potential role for PRMT5 inhibition in multiple malignancies, either as a single agent or possibly in combination with other therapies (Paragraph 5). Thus, Wilson suggests that cancers/tumors having MTAP deletions (e.g., melanoma) are more sensitized to PRMT5 inhibition.
Barbarino teaches that protein arginine methyltransferase 5 (PRMT5) inhibition has recently emerged as a potential therapy against methylthioadenosine phosphorylase (MTAP)-deficient cancers, in which the accumulation of the substrate 5'-methylthioadenosine (MTA) inhibits PRMT5 activity, thus sensitizing the cells to further PRMT5 inhibition; considering that the MTAP gene is frequently co-deleted with the adjacent cyclin-dependent kinase inhibitor 2A (CDKN2A) locus in malignant mesothelioma (MM), the authors assessed whether PRMT5 could represent a therapeutic target also for MM (Abstract). Administration of exogenous MTA and stable PRMT5 knock-down, by short hairpin RNAs (shRNAs), selectively reduced the growth of MTAP-deleted MM cells; additionally, PRMT5 knock-down in MTAP-deficient MM cells reduced the expression of E2F1 target genes involved in cell cycle progression and of factors implicated in epithelial-to-mesenchymal transition, and the authors conclude that PRMT5 targeting could represent a promising new therapeutic strategy against MTAP-deleted MMs (Id.). Figure 3 shows PRMT5 silencing by shRNA in MTAP-negative and MTAP-positive MM cells, wherein the shPRMT5 inhibitor reduced expression of PRMT5 by ≥50% in all MM cell lines (Page 5572). Furthermore, Figure 4 shows that the shPRMT5 inhibitor selectively affected the growth of MTAP-deleted MM cells wherein the number of cells and number of cell colonies (i.e., cell growth) for all MTAP-deleted MM cells was reduced by >50% when exposed to shPRMT5 (Page 5573). Thus, MTAP-deleted cancer cells are specifically sensitive to PRMT5 knock-down by shRNA.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of treatment disclosed by Barbash (comprising the administration of a PRMT5 inhibitor in combination with an immune-modulatory agent), in cases wherein the tumor to be treated is melanoma having a MTAP deletion, as suggested by Wilson, wherein the PRMT5 inhibitor is a shRNA that inhibits/reduces PRMT5 expression by at least 10%, as suggested by Barbarino, because the references together establish PRMT5 inhibition is a therapeutic approach to cancer (as established by Barbash, Wilson, and Barbarino), MTAP-negative/MTAP-deleted cancers are selectively sensitive to PRMT5 inhibition (as established by Barbarino), and the combination of PRMT5 inhibitors with other agents is a suggested approach (as taught by Barbash and Wilson) wherein combination of PRMT5 inhibition with immunomodulatory agents could provide additive/synergistic therapeutic effects (as suggested by Barbash). One of ordinary skill in the art would have been motivated try to modify the methods of Barbash, based on the teachings of Wilson and Barbarino, to arrive at such a method of treatment (i.e., inhibiting/suppressing tumor growth) for melanoma having a MTAP deletion, said method comprising administering, generally: (i) a therapeutically effective amount of a PRMT5 inhibitor capable of reducing PRMT5 expression by at least 10%, wherein the PRMT5 inhibitor is a shRNA; and (ii) a therapeutically effective amount of an immunotherapeutic agent, and one of ordinary skill in the art would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Barbash discloses methods of treating cancer, including melanoma, wherein the method comprises administering (i) a therapeutically effective amount of a PRMT5 inhibitor, including nucleic acid inhibitors, and (ii) a therapeutically effective amount of an immuno-modulatory agent (e.g., anti-PD-1 antibody) wherein Barbash further suggests additive/synergistic effects when a PRMT5 inhibitor and an immune-modulatory agent are administered together.
(2) Wilson discloses that cancers/tumors having MTAP deletions (e.g., melanoma) are more sensitized to PRMT5 inhibition and suggests using PRMT5 inhibition in combination with other therapies as a therapeutic approach to MTAP-deleted cancers/tumors.
(3) Barbarino discloses that MTAP-deleted cancer cells (MM cancer cells) are specifically sensitive to PRMT5 knock-down by shRNA, identifying a nucleic acid inhibitor of PRMT5, and successful killing of MTAP-deleted cancer cells.
Thus, to one of ordinary skill in the art, it would have been obvious to try the method of treatment disclosed by Barbash (comprising the administration of a PRMT5 inhibitor in combination with an immune-modulatory agent), in cases wherein the tumor to be treated is melanoma having a MTAP deletion, as suggested by Wilson, wherein the PRMT5 inhibitor is a shRNA that inhibits/reduces PRMT5 expression by at least 10%, as suggested by Barbarino, because the references together establish PRMT5 inhibition is a therapeutic approach to cancer (as established by Barbash, Wilson, and Barbarino), MTAP-negative/MTAP-deleted cancers are selectively sensitive to PRMT5 inhibition (as established by Barbarino), and the combination of PRMT5 inhibitors with other agents is a suggested approach (as taught by Barbash and Wilson) wherein combination of PRMT5 inhibition with immunomodulatory agents could provide additive/synergistic therapeutic effects (as suggested by Barbash).
Response to Arguments
Applicant’s arguments with respect to the previous claim rejections of record under 35 U.S.C. 103 have been considered, but are moot because the new ground of rejection relies on references not previously applied in the rejection(s) of record.
In response to applicant's argument on Page 8 of Remarks that Example 10 of the specification demonstrates that the significantly improved therapeutic efficacy was observed in the combination of a PRMT5 inhibitor and anti-PD-1 therapy, but not in the combination of the PRMT5 inhibitor and anti-CTLA4 antibody and as such indicates a select set of immune checkpoint components that are regulated by a PRMT5 inhibitor, it is noted that:
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
More specifically, with regard to the point above, it is noted that Barbash discloses an embodiment wherein a PRMT5 inhibitor is administered with an immune-modulatory agent that is an anti-PD-1 antibody, wherein said anti-PD-1 antibody may more specifically be pembrolizumab or nivolumab (see, for example, Page 64, Lines 6-30). Wilson and Barbarino are solely relied upon (i) to establish that MTAP-deleted tumors (e.g., melanoma) are indicated for treatment with PRMT5 inhibitors and (ii) that shRNA (i.e., shPRMT5) reduces PRTM5 expression and is a reasonable PRMT5 inhibitor for use in therapeutic approaches to MTAP-deleted cancers, respectively. As such, the argued improved therapeutic efficacy would flow naturally following the suggestions of the prior art. As such, the argument with regard to Example 10 of the specification is deemed not persuasive in view of the new grounds of rejection presented above.
Conclusion
Claims 34, 96, and 104 are pending. Claims 34, 96, and 104 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
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