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 a national stage application under 35 U.S.C. § 371 of international
Application No. PCT/US2019/068001, filed 12/20/2019, which claims the priority benefit of
PCT Application No. PRO 62/782,906, filed 12/20/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/08/2022, 07/12/2022,
12/02/2022 and 08/25/2025 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 1-5, 7-13 and 19 are pending and currently under examination. Claims 1-4 and 8 are amended. Claims 6, and 14-18 are cancelled by applicant without prejudice or disclaimer. Claims 10-13 are withdrawn.
Applicant's arguments, filed 08/14/2026, 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objections not reiterated from previous office actions are hereby withdrawn.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 05/15/2026 Office Action and modified in order to address the most recent amendments.
Claim Interpretation
Regarding the limitations of claims 4-5 wherein the YTHDF1 inhibitor reduces
expression of one or more lysosomal cathepsins B,D and/or L is being considered as an inherent
property of the compound. See MPEP 2112 (III).
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 1-5, 7-9 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Nishizawa (Oncogene c-Myc promotes epitranscriptome m6A reader YTHDFl expression in colorectal cancer, 2017, pgs. 7476-7486) in view of Alsaab (PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome, 2017, pgs. 1-15) and further in view of Janco (Tumor-Infiltrating Dendritic Cells in Cancer Pathogenesis, 2015, pgs. 2985-2991).
The instant claims are directed to a method for treating cancer comprising administering a YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDF1) inhibitor wherein the inhibitor is an antibodies, antibody-drug conjugates, fusion proteins, small molecule, dsRNA, siRNA, antisense oligonucleotide, aptamer, or a gene editing agent to a subject receiving an immune checkpoint inhibitor selected from a PD-L1, PD-1, CTLA4, CSG1 antibody, an IDO inhibitor, Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab, and Ipilimumab.
Nishizawa teaches a method of enhancing cancer treatment by attenuating YTHDF1 in a colorectal cancer (CRC) cell with an anticancer agent "We performed chemosensitivity assay using fluorouracil (5-FU) and oxaliplatin (L-OHP), which are anticancer drugs commonly used in the therapeutic treatment of patients with CRC (page 7478, col. 2, second para.). The results from the chemosensitivity assay showed that transfected YTHDF1 siRNA cells had a higher sensitivity to both 5-FU and L-OHP than cells transfected with negative control siRNA in HT29 cells." Nishizawa also states "[t]aken together with the present observation of YTHDF1 role in cancer cell proliferation, the data suggest the candidacy of YTHDF1 as a possible therapeutic target (page 7479, col. 2 para. 1). Nishizawa discloses "we performed a proliferation assay with the knockdown cells, which showed that the knockdown of YTHDF1 resulted in the inhibition of cell proliferation compared with cells transfected as a negative control siRNA in both SW480 and HT29 cells" (pg. 7478, col 1, para 2 and col 2, para 1).
However, Nishizawa et al. fail to disclose a method of enhancing cancer treatment wherein the subject is undergoing therapy with an immune checkpoint inhibitor or YTHDF1 activity is attenuated in an antigen presenting cell (APC) and/or dendritic cell (DC).
Alsaab et al. teaches a colorectal cancer immunotherapy treatment using the checkpoint inhibitors of Ipilimumab, Nivolumab and also anti-PD-1 antibody Atezolizumab (p. 2, col. 1, last para. - col. 2, first para.). Furthermore, Alsaab discloses the use of 5-fluororacil (which is also used by Nishizawa) enhanced immunotherapy when used in combination with attenuated YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDF1) (page 13, col. 1, "Combination of PD-1 and Chemotherapeutics" section). "Recent trends in cancer treatment are moving toward combination immunotherapy, but its success depends on addressing the challenges of choosing the right drug combination, optimizing the dose and schedule of the combination regimen, and managing toxicities and side effects" (p.13, col. 1 ). Alsaab teaches (p 12, col 1, para 4) that an immune checkpoint inhibitor can be a PD-1 antibody "Targeting T-cells regulatory proteins, such as CTLA--4 and PD-1 by checkpoint blocking antibodies has been strengthened the area of cancer immunotherapy. The FDA approval of CTLA-4 antibody inhibitor (ipilimumab) and PD-1 inhibitors (Pembrolizumab, Nivolumab) have diversified the clinical activity toward wide variety solid tumor including lung cancer, renal cell cancer, and ovarian cancer. Based on clinical data these monotherapeutics have been demonstrated to be a successful immunotherapy regimen. Considering the safety and better clinical activity of monotherapy the field is moving toward the direction of discovering novel combination therapies (abstract). Various anti-cancer agents including other check point inhibitors, kinase inhibitors, chemotherapeutics, and targeting agents are used in combination with PD-1 antibody inhibitors" Furthermore, Alsaab teaches "Recent trends in cancer treatment are moving toward combination immunotherapy, but its success depends on addressing the challenges of choosing the right drug combination, optimizing the dose and schedule of the combination regimen, and managing toxicities and side effects" (page 13, col. 1, second para).
However, Alsaab et al. fail to disclose YTHDF1 activity is attenuated in an antigen presenting cell (APC) and/or dendritic cell (DC).
Janco et al teach "[d]endritic cells (DCs) play a pivotal role in the tumor microenvironment, which is known to affect disease progression in many human malignancies" (Intro., pg. 2985) Janco also discloses dendritic cells as "DCs are key decision makers, determining whether the adaptive arm of the immune system should or should not be activated. Crucial as professional APCs, they present Ags and provide a multitude of other necessary signals" (Dendritic cells, 1st para., pg. 2985) Janco also teaches that a number of studies found correlations between the presence of infiltrating immune cells in the tumor microenvironment (TME) and prognosis of many cancers, such as colorectal cancer and that dendritic cells are a component of the TME (left col, 2nd para., pg. 2985).
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 the method of Nishizawa of treating colorectal cancer cells (CRC) while considering Janco's disclosure of dendritic and antigen presenting cells because treatment of a YTHDF1 inhibitor in the tumor microenvironment impacts the tumor localized dendritic cells which are also antigen presenting cells in a combination of a YTHDF1 inhibitor and an anticancer agent with Alsaab' s disclosure of administering a PD-1, PDL-1, and CTLA-4 checkpoint antibody inhibitors to a subject with CRC because a skilled artisan would have recognized combining two methods of treating colorectal cancer into a combined therapy as prima facie obvious to try. See MPEP 2144.05(11).
A person of ordinary skill in the art would have been motivated to administer a YTHDF1 inhibitor to a subject with CRC as taught by Nishizawa and Janco with an immune checkpoint inhibitor as taught by Alsaab in a combination therapy with a reasonable expectation of success in treating a colorectal cancer.
Response to Arguments
Applicant's arguments filed 08/14/2026 have been fully considered but they are not persuasive.
Applicant argues (pg. 4) Nishizawa does not disclose or suggest use of a YTHDFl inhibitor in combination with an immune checkpoint inhibitor, as presently claimed and that Alsaab (pg. 4-5) simply does not disclose or suggest a combination of immunotherapy and a YTHDFl inhibitor as presently claimed. Applicant also argues (pg. 5) that Janco also does not disclose or suggest administering a YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDFl) inhibitor to a subject receiving treatment with the immune checkpoint inhibitor and none of the cited references, whether considered alone or in combination, disclose or suggest combination therapy with a YTHDFl inhibitor and an immune checkpoint inhibitor, as recited in claim 1.
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). In this case, examiner notes Alsaab discloses Nivolumab and Ipilimumab, both of which are also named as immune checkpoint inhibitors by instant claim 7. Alsaab also discloses 5-fluororacil which is also disclosed by Nishizawa, the limitations of instant claim 8 state a YTHDF1 inhibitor is a small molecule and therefore the small molecule 5-fluororacil satisfies the limitations of the claim. The only disclosure of what qualifies as a small molecule can be found in the specification in [0007]-[0008], [0013], [0049], [0052], and [0059]. The specification at [0049] teaches, “as well as pharmacological or small molecule inhibition that interferes with the stability or activity of YTHDFl.”. Therefore, 5-fluororacil satisfies the limitation of a “small molecule” in view of the specification as previously indicated in the office action dated 05/15/2026. “Alsaab discloses the use of 5-fluororacil (which is also used by Nishizawa) enhanced immunotherapy when used in combination with attenuated YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDF1) (page 13, col. 1, "Combination of PD-1 and Chemotherapeutics" section).”
Examiner notes that instant claim 1 is a method claim wherein the only active step cited is the step of administering a YTHDF1 inhibitor, wherein the patient population is a subject who already has cancer and is already receiving immunotherapy treatment (Broad)(Instant claim 1, lines 1-2), wherein the immunotherapy treatment is an immune checkpoint inhibitor (instant claim 1, lines 3-4), “…wherein the subject is receiving treatment with an immune checkpoint inhibitor”. There is no active step for administering an immune checkpoint inhibitor in the instant claims as they are currently written.
Applicant further argues (pg. 6), in supporting an obviousness rejection under any rationale, a reasonable expectation of success is required (MPEP 2143.02). The Examiner has simply not established that it would be expected or predictable that a YTHDFl inhibitor would enhance cancer immunotherapy in a subject receiving treatment with an immune checkpoint inhibitor based upon the disclosures of the cited references.
As previously indicated in the office action dated 05/15/2026. “Alsaab discloses the use of 5-fluororacil (which is also used by Nishizawa) enhanced immunotherapy when used in combination with attenuated YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDF1) (page 13, col. 1, "Combination of PD-1 and Chemotherapeutics" section).” Furthermore, Alsaab discloses Nivolumab and Ipilimumab, both of which are also named as immune checkpoint inhibitors by instant claim 7.
Applicant argues (pg. 6-7) the magnitude of sensitization to immune checkpoint blockade using YTHDFl inhibition is simply not predictable based upon the disclosure of Nishizawa, which only shows a slight sensitization to cytotoxic compounds and does not disclose or suggest combining YTHDFl inhibition with immunotherapy, or in view of the disclosures of Alsaab and Janco which do not teach or suggest combination therapy with an immune checkpoint inhibitor and a YTHDFl inhibitor at all.
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). Furthermore, as disclosed above Alsaab discloses Nivolumab and Ipilimumab, both of which are also named as immune checkpoint inhibitors by instant claim 7 and Alsaab also discloses 5-fluororacil which is also disclosed by Nishizawa, whereas the limitations of instant claim 8 state a YTHDF1 inhibitor is a small molecule and therefore the small molecule 5-fluororacil satisfies the limitations of the claim as they are currently written. See also MPEP 2111.02 (II)
“During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963) (The claims were directed to a core member for hair curlers and a process of making a core member for hair curlers. The court held that the intended use of hair curling was of no significance to the structure and process of making.); In re Sinex, 309 F.2d 488, 492, 135 USPQ 302, 305 (CCPA 1962) (statement of intended use in an apparatus claim did not distinguish over the prior art apparatus). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (anticipation rejection affirmed based on Board’s factual finding that the reference dispenser (a spout disclosed as useful for purposes such as dispensing oil from an oil can) would be capable of dispensing popcorn in the manner set forth in appellant’s claim 1 (a dispensing top for dispensing popcorn in a specified manner)) and cases cited therein. See also MPEP § 2112 - MPEP § 2112.02.”
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Conclusion
All claims are rejected, no claims are allowed.
THIS ACTION IS MADE FINAL. 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
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
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