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 .
Claim Status
Claims 2, 4-5, 7-8, and 10 are cancelled. Claims 1, 3, 6, 9, and 11 as filed on 06 April 2026 are pending and under examination.
Rejections and Objections Withdrawn
Rejection of claims 6 and 8 under 35 U.S.C. 102 over Bar et. al. Molecular Pharmacology. 74(3):(777-784) (2008) is withdrawn with applicant amendment of claims.
Rejection of claims 6 AND 9 under 35 U.S.C. 103 over Bar et. al. Molecular Pharmacology. 74(3):(777-784) (2008) (IDS 03/24/2023 NPL1) and Hartley et al. Cancer Immunol Res. 6(10:1260-1273. (2018) is withdrawn with applicant amendment of claims.
Substitute Specification dated 04/06/2026 is accepted and corrects minor informalities the objection to specification is withdrawn.
Rejection of claims 6 and 8-9 under 35 U.S.C. 112(a) is withdrawn with applicant amendment of claims.
Applicant’s arguments with respect to claim(s) 6 and 8-9 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
New Rejection Necessitated by Applicant Amendment
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 6 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. 14(38):1-12. (2017) (PTO-892).
Yang teaches the knockdown of P2Y6 in BV-2 cells using siRNA (Figure 4) and Yang teaches the cells were cultured which would then include a composition with the cells and an excipient by the cell being in culture (page 6 in col 2 in par 1). Yang teaches microglia are resident macrophages of the central nervous system (page 10 in col 1 in lines 8-10 of paragraph 1).
Rejection Maintained – Rejection Amendment as Necessitated by Applicant Amendment to Claims
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, 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 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, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Carleton (WO 2019/1401150 A1) (IDS), Thevananther (WO 2017/070660 A1) (IDS), Golz (WO 2004/106937 A2) (IDS), and Yebdri et. al. Eur. J. Immunol. 39:2885-2894. (2009) (IDS).
Carleton teaches the combination of anti-PD-1 and anti-IL-8 antibodies for use in cancer therapy (abstract). The antibodies of the invention are inhibitory of PD-1 and PD-L1 and IL-8 (page 14 in par 1 and page 16 in par 1 in particular the last line). Carleton teaches the combination inhibitory therapy targeting PD-1 and IL-8 pathways. Carleton teaches the combination therapy will be better than treatment with an immune checkpoint inhibitor alone (page 36 in last par).
Regarding claim 12, Carleton teaches the treatment of pancreatic cancer (page 41 in Part 2: Dose Expansion and claim 23).
Carleton does not teach a P2Y6 inhibitor for use in this combination.
These deficiencies are filled by Thevananther, Golz, and Yebdri.
Regarding claims 1-2, Thevananther teaches the use of P2Y6 inhibitors in the treatment of cancer (abstract). Thevananther teaches a number of inhibitors including MRS2578 ([0004]). Thevananther teaches the use of MRS2578 in a method of inhibiting cancer cells (claims 1-2).
Golz teaches the expression of P2Y6 in various tissues of interest including the brain (page 5 in lines 1-5) and cancers including stomach, liver, lung, cervix tumor, uterus, ovary, pancreas, and kidney (page 62 in lines 25-31 and page 63 in lines 1-5). Golz teaches the modulation of P2Y6 (page 63 in lines 4-5).
Yebdri teaches the administration of MRS2578, a P2Y6 inhibitor, decreased IL-8 secretion (abstract).
It would have been obvious at the time the application was filed to substitute the IL-8 inhibitor of the combination therapy comprising PD-1 inhibition and IL-8 inhibition for use in a method of treating cancer of Cartleton with the P2Y6 inhibitor MRS2578 taught by Thevananther and Yebdri. It would have been obvious to substitute the IL-8 inhibiting antibodies of Carleton with MRS2578 as Yebdri teaches MRS2578 when used as a P2Y6 inhibitor decreased IL-8 secretion. PD-1 antibodies and MRS2578 are both taught for use in the treatment of cancer making their combination prima facie obvious. Further, Carleton teaches the combination of targeting PD-1 and IL-8 signaling by inhibition which in combination of Yebdri teaches towards the combination of inhibition of PD-1 and MRS2578 inhibition of P2Y6. There would have been a reasonable expectation of success as both PD-1 immune checkpoint inhibitors and P2Y6 inhibitor MRS2578 are known in the art for the treatment of cancer and further Carleton teaches the treatment of pancreatic cancer and Golz teaches the presence of P2Y6 in pancreatic cancer.
Applicant Arguments
Applicant argues the amendment of the claims overcome the rejection.
Applicant argues the rejection does not establish a case for obviousness over Carleton, Thevananther, Golz, and Yebdri. Applicant argues there is no expectation of success that the combination of PD-1 with a P2Y6 inhibitor of MRS2578 would break resistance to PD-1 antibodies.
Applicant argues synergy and unexpected success by pointing to Figure 5 of the instant application. Figure 5 is to a treatment of pancreatic cancer model that was completely unresponsive to treatment with an anti-PD-1 antibody alone or treatment with MRS2578 alone but responded to a combination therapy of MRS2578 with an anti-PD-1. Applicant argues this makes the combination of the known treatments for cancer non-obvious.
Applicant argues the substitution of an IL-8 inhibitor with a P2Y6 inhibitor is non-obvious. Applicant argues P2Y6 affects at least 3 different cytokines (IL-6, CXCL2, IL-8, and TLR2). Applicant argues the substitution of an IL-8 inhibitor with a P2Y6 inhibitor that has inhibitor activity beyond IL-8 would be highly unpredictable when compared to targeted interference of just IL-8. Applicant argues P2Y6 inhibition would be different from an IL-8 blockade as a monotherapy and further complicated by the therapy of Carleton being a combination therapy further comprising an immune checkpoint inhibitor. Applicant argues the results in a tumor microenvironment would be unpredictable with no reasonable expectation of success. Applicant argues IL-8 inhibition is not equivalent to inhibition P2Y6 as known in the art at the time the application was filed.
Applicant argues Yebdri in relation to the rejection maintained that Yebdri is in the context of inflammatory disease and only speculates about its use as a target in inflammatory disease while being silent to cancer.
Applicant argues Carleton only provides outlines for future clinical trials while not providing the efficacy of the combined therapy of PD-1 inhibition and IL-8 inhibition.
Applicant argues Thevananther does not teach or suggest combining P2Y6 inhibition with other anti-cancer agents. Applicant argues Thevananther does not support P2Y6 biological activity in relation to IL-8 inhibition. Applicant argues P2Y6 inhibition and MRS2578 inhibitor are not in the abstract as pointed to by the examiner and that MRS2578 is infrequently mentioned in Thevananther and only present in a long list of 18 possible inhibitors. Applicant argues there is no clear pointing towards MRS2578 as a P2Y6 inhibitor. Applicant argues Thevananther singles out AF-353 or PPADs. Applicant argues Thevananther teaches towards the inhibition of P2X3 and not P2Y6.
Applicant argues Golz does not teach the combination of P2Y6 modulation with other anti-cancer agents. Applicant argues Golz provides evidence of elevated P2Y6 on a number of cancers but does not provide evidence of P2Y6 being a cause or consequence of tumor formation. Applicant argues Golz teaching the use of P2Y6 modulation in cancer is only a wish and not evidence of the treatment of cancer being effective. Applicant argues Golz teaches modulation and not clearly inhibition or activation.
Response to Arguments
Applicant's arguments filed 04/06/2026 have been fully considered but they are not persuasive.
The amendment of the claims do not overcome the rejection, see the amended rejection of record.
Carleton explicitly teaches the combination therapy will be better than treatment with an immune checkpoint inhibitor alone (page 36 in last par). The patient population of the claims is not to a patient population that is resistant to PD-1 targeted therapy. The claims are to cancer patients that are fully or partially non-responsive to immune checkpoint therapy.
Regarding the results of Figure 5. The applicant has shown pancreatic patients that were fully nonresponsive to PD-1 antibody treatment and not responsive to MRS2578 treatment responded to a combination treatment of PD-1 antibody with MRS2578. This is not commensurate with the scope of the claims. Claims 1 and 3 are to any cancer, only claim 12 is limited to pancreatic cancer. Claims 1, 3, and 12 are to a method using any immune checkpoint inhibitor and any P2Y6 inhibitor, applicant has not shown results for all of these combinations of therapies. The claims are also to a method of partial and completely unresponsive, not the completely unresponsive to treatment shown in Figure 5.
Regarding applicant’s argument that P2Y6 inhibition in general and MRS2578 specifically would have unpredictable results in the cancer environment and as a replacement for IL-8 inhibition in a method of treating cancer. Thevananther teaches methods of treating cancer by the administration of MRS2578. Thevananther is one of skill in the art teaching the expected result of it inhibiting cancer cells (claim 1 of Thevananther). One of skill in the art would be taught by Thevananther that administration of MRS2578 to cancer would treat cancer. The teachings of the art pointed to by the applicant support that MRS2578 does act as an inhibitor of IL-8. It was known in the art that MRS2578 was an inhibitor of IL-8 and the teachings of Thevananther would inform one of skill in the art that it should be administered to cancer patients.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Carleton is relied upon to teach a combination therapy to pancreatic cancer patients that comprises immune checkpoint inhibition with IL-8 inhibition explicitly teaching that response would improve when an anti-PD-1 antibody is used with another treatment.
Thevananther is relied upon to teach inhibition of P2Y6 in the treatment of cancer, it teaches a number of inhibitors including MRS2578 which while in the working example of the applicant is not recited in the instant claims. Regarding sections cited by the Examiner, the entire document is relied upon in the rejection and the abstract of Thevananther sates “P2Y purinergic receptor subtypes” and throughout the document references P2Y6 subtypes includes P2Y6 and teaches P2Y6 inhibition is done through MRS2578 ([0004] and claims 1 and 10). Claims 1 and 2 of Thevananther also explicitly teaches a method of inhibiting cancer cells by administering MRS2578. There are multiple inhibitors taught by Thevananther and all of their use is explicitly taught in a method of treating cancer, all of them would be prima facie obvious to use in a combination with known treatments of cancer baring unexpected results.
Golz is relied upon to teach that P2Y6 was known in the art as a target for treatment of cancer. Golz is not relied upon for teaching the inhibition of P2Y6, but it does in fact explicitly teach pharmaceutical compositions comprising inhibitors of P2Y6 in the abstract. Golz is teaching multiple diseases and its teachings are to activation or inhibition in the context of multiple disease not just cancer (claims 1).
Yebdri is not relied upon to teach the use of P2Y6 inhibition in cancer. It is relied upon to teach the link between P2Y6 and IL-8 and the use of MRS2578 as a therapeutic. Regarding Yebdri, inflammation and cancer, Yebdri teaches the use of Human acute monocyte leukemia cells (page 2891 in col 2 in last paragraph). Inflammation is well known in the art to be associated with the development and progression of cancer (Singh et. al. Ann Afr Med 18(3):121-126. (2019) (PTO-892) (Abstract).
Regarding the operability of the teachings of Carleton and Golz, when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). Specifically, in In re Antor Media Corp., the court stated: "Consistent with the statutory framework and our precedent, we therefore hold that, during patent prosecution, an examiner is entitled to reject claims as anticipated by a prior art publication or patent without conducting an inquiry into whether or not that prior art reference is enabling. As long as an examiner makes a proper prima facie case of anticipation by giving adequate notice under § 132, the burden shifts to the applicant to submit rebuttal evidence of nonenablement." In re Antor Media Corp., 689 F.3d at 1289, 103 USPQ2d at 1559. (See MPEP 2121).
While Carleton and Golz do not show the methods in practice they are presumed to be operable and provide clear teaching to one of skill in the art the use of PD-1 inhibition in combination with IL-8 inhibition and the use of P2Y6 inhibition in a method of treating cancer.
New Rejection Necessitated by Applicant Amendment
Claims 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. 14(38):1-12. (2017) (PTO-892), Che et. al. J Cell Biochem. 119:3044-3057. (2018) (PTO-892), and Wang et al. Cancer Immunology Research. 2(9):846-856. (2014) (PTO-892).
Yang teaches the knockdown of P2Y6 in BV-2 cells using siRNA (Figure 4) and Yang teaches the cells were cultured which would then include a composition with the cells and an excipient by the cell being in culture (page 6 in col 2 in par 1). Yang teaches microglia are resident macrophages of the central nervous system (page 10 in col 1 in lines 8-10 of paragraph 1).
Yang teaches P2Y6 contributes to microglia activation and phagocytosis and the role of P2Y6 and microglia in the central nervous system disease and neuroinflammation(Abstract).
Yang does not teach the presence of an immune checkpoint inhibitor.
This deficiency is filled by Che and Wang.
Che teaches PD-1/PD-L1 signaling affects activation of microglia in the central nervous system (abstract). Che teaches the isolation of microglia, the culturing of the cells, and the measurement of PD-1 and PD-L1 on the microglia using PD-1 and PD-L1 binding antibodies (abstract and page 3048 in col 1 in last paragraph). This would be a composition comprising the cells of claim 6 and an antibody that binds PD-1 or PD-L1. Che does not identify the antibody they use in their methods.
Wang teaches FACS using PD-L1 binding antibody nivolumab, which is an immune checkpoint inhibitor, to measure PD-L1 in samples (abstract and page 847 in col 1 in the last paragraph and Figure 3).
It would have been obvious at the time the application was filed to combine the cultured microglia that knockdown P2Y6 with the method of measuring PD-L1 of Che and Wang using PD-L1 binding antibodies IHC and FACS. One of skill in the art would have been motivated by the teaching of Yang that P2Y6 impacts microglia activation and phagocytosis and the teachings of Che that PD-1/PD-L1 signaling affects activation of microglia in the central nervous system. One of skill in the art would have been motivated to identify if the knockdown of P2Y6 in microglia would impact PD-1/PD-L1 in microglia and Wang teaches nivolumab works for measuring PD-L1. There would have been a reasonable expectation of success as Che teaches the measurement in microglia and the methods of IHC and FACS are well known in the art.
Conclusion
No claims allowable.
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.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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