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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed December 5th, 2025, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
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.
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 5, and 8 – 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ji et. al. ((2019), Selonsertib (GS-4997), an ASK1 inhibitor, antagonizes multidrug resistance in ABCB1- and ABCG2-overexpressing cancer cells, Cancer Letters, 440-441, 82 – 93; cited in the office action September 8th, 2025) in view of US 2018/0311247 A1 to Di Paolo et.al. (herein after Di Paolo’247; cited in the office action March 19th, 2025).
Regarding claims 5, and 8 – 11, Ji et. al. teach that chemotherapy is an important tool to combat a variety of cancers; however, multidrug resistance (MDR)(claim 10) in cancer cells remains a major challenge that contributes to the failure of cancer chemotherapy (page 82 column 1 paragraph 1). Additionally, Ji et. al. teach that one important mechanism of MDR is mediated by the efflux pump protein, known as the ATP-binding cassette (ABC) transporters, which are located on the membrane of cancer cells (page 82 column 1 paragraph 1). Furthermore, Ji et. al. teach that decreasing the expression of ABC proteins or inhibiting the efflux function of ABC transporters by certain inhibitors is of great importance to reverse MDR in cancer cells (page 83 column 1 paragraph 1). Moreover, Ji et. al. teach that Apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase that belongs to the mitogen-activated protein kinase (MAP3K) family, is involved in severe human diseases including neurodegenerative disorders, inflammatory diseases and cancer (page 83 column 1 paragraph 2).
Additionally, Ji et. al. teach that selonsertib (GS-4997) (claim 5) of structure
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(page 84 Figure 1 A), a selective ASK1 inhibitor, has been found to significantly improve metabolic parameters associated with nonalcoholic steatohepatitis (NASH) and to reduce hepatic steatosis, inflammation, as well as fibrosis (page 83 column 1 paragraph 2). Furthermore, Ji et. al. teach for the first time that selonsertib suppressed the efflux function of ABCB1 and ABCG2, which sensitized cancer cells to chemotherapeutic drugs (page 83 column 1 paragraph 2). Moreover, Ji et. al. teach that selonsertib was tested in human epidermoid carcinoma cell line KB-3-1 and its colchicine-selected ABCB1-overexpressing KB-C2 cells, human colon cancer cell line SW620 and its doxorubicin-selected ABCB1-overexpressing SW620/Ad300 cell line, non-small cell lung cancer (NSCLC) cell line NCI-H460 and its mitoxantrone-selected ABCG2-overexpressing NCIH460/MX20 cells, and the human colon carcinoma cell line S1 and its mitoxantrone-selected derivative ABCG2-overexpressing S1-M1-80 (page 83 column 1 paragraph 4). Moreover, Ji et. al. teach that as shown in Table 1 provided here
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, selonsertib significantly lowered the IC50 values of doxorubicin and paclitaxel to KB-C2 and SW620/Ad300 cells compared to their control cell lines in a dose-dependent manner (page 84 column 2 paragraph 5). Furthermore, Ji et. al. teach that selonsertib significantly decreased the efflux of [3H]-paclitaxel in ABCB1-overexpressing cell lines KB-C2 and SW620/Ad300, and [3H]-mitoxantrone efflux in ABCG2 overexpressing cell lines NCI-H460/MX20 and S1-M1-80 (page 86 column 2 paragraph 1). Additionally, Ji et. al. teach that that selonsertib significantly increased the efficacy of doxorubicin and paclitaxel to the ABCB1 overexpressing KB-C2 and SW620/Ad300 cells compared to untreated control resistant cells in a dose-dependent manner; selonsertib also significantly reduced the IC50 values of substrate-drugs in HEK293/ABCB1 cells in a dose-dependent manner; and selonsertib sensitized ABCG2 overexpressing cell lines NCI-H460/MX20, and S1-M1-80, and the ABCG2-transfected HEK293 subline ABCG2- 482-R2, ABCG2-482-G2, and ABCG2-482-T7 to mitoxantrone, topotecan, and SN-38 in a concentration-dependent manner (page 91 column 2 paragraph 1).
However, while Ji et. al. teach that selonsertib was tested in a variety of cancer cell lines which includes non-small cell lung cancer (NSCLC) cell line NCI-H460, Ji et. al. is silent about the use of selonsertib in esophageal squamous cell carcinoma, melanoma, or Lewis lung cancer (claim 9) in combination with an Anti-PD1 humanized IgG4 antibody (claims 5 and 8).
Nevertheless, Di Paolo’247 teach therapeutics and compositions and methods of preparation of the therapeutics for treating cancers (claim 5) and allergic, autoimmune, and inflammatory disorders (page 1 paragraph 0001). Further teaching the embodiment wherein the composition includes the ASK1 inhibiting compound of the structure:
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(claim 5) referred to as 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (page 21 paragraph 0429). Moreover, Di Paolo’247 teach that compositions for the present invention can be prepared with therapeutically effective amounts of ASK1 inhibiting compounds from 1 mg to 500 mg (page 59 paragraph 0617). Additionally, Di Paolo’247 teach that it is within the purview of physician to choose the route of administration, combination of administration based on the age, weight, and response of the individual patient (page 59 paragraph 0617). Furthermore, Di Paolo’247 teach that the pharmaceutical compositions maybe administered alone or in combinations (claim 5) (page 62 paragraph 0639).
Furthermore, Di Paolo’247 teach that cancer includes esophageal squamous cell carcinoma, head and neck cancer, melanoma (claim 9), pancreatic cancer, urological cancer, and prostate cancer (claim 5) (page 58 paragraph 0590). In addition, Di Paolo’247 teach that the cancer can include cancers that are resistant to treatment from the beginning of treatment, or may become resistant during the course of treatment (claim 10) (page 7 paragraph 0074). Likewise, Di Paolo’247 teach that the administration of such an anti-cancer agent or treatment, that is as an anti-cancer agent, can be concurrent (claim 11) with the administration of the composition (page 60 paragraph 0626). Moreover, Di’ Paolo’247 teach that in some foregoing embodiments, the combination of a BTK inhibitor and one or more inhibitor as described herein, may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, and/or surgery (page 58 paragraph 0592). Additionally, Di Paolo’247 teach that method of the disclosure can further comprises administering a composition comprising Anti-PD-1 antibody such as nivolumab, that is nivolumab (claim 8) (page 62 paragraph 0647). Thus Di Paolo’247 teach the preparation of 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide of structure
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in a method of preparation of drugs for treatment.
While Di Paolo’247 fails to teach an example wherein 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide was specifically used to treat esophageal squamous cell carcinoma Di Paolo’247 does clearly suggest the use of the instant compound in the treatment of the cancer esophageal squamous cell carcinoma. Therefore, following the direct suggestion of the reference, it would have been prima facie obvious to have treated any of the cancer types mentioned by Di Paolo with any of the drug combinations suggested. Since the reference is clearly directed towards combinations for the treatment of cancer (see title) and since the reference suggests treating ESCC with the instantly claimed drug in combination treatments.
Therefore, it would have been obvious before the effective filing date of the instant application to take apply the results of Ji et. al. that is to use selonsertib as an ASK1 inhibitor in view of Di Paolo’247 in a method of treating esophageal squamous cell carcinoma, head and neck cancer, melanoma, pancreatic cancer, urological cancer, and prostate cancer in combination with an Anti-PD-1 humanized aIgG4 antibody. One of ordinary skill in the art would have a motivation to make this modification to expand the chemotherapeutics options for this patient population through sensitizing the cancer cells to chemotherapeutic drugs. One of ordinary skill in the art would have had a reasonable expectation of success because selonsertib significantly increased the efficacy of doxorubicin and paclitaxel to the ABCB1 overexpressing KB-C2 and SW620/Ad300 cells compared to untreated control resistant cells in a dose-dependent manner; selonsertib also significantly reduced the IC50 values of substrate-drugs in HEK293/ABCB1 cells in a dose-dependent manner; and selonsertib sensitized ABCG2 overexpressing cell lines NCI-H460/MX20, and S1-M1-80, and the ABCG2-transfected HEK293 subline ABCG2- 482-R2, ABCG2-482-G2, and ABCG2-482-T7 to mitoxantrone, topotecan, and SN-38 in a concentration-dependent manner.
Response to Arguments
Applicant’s arguments, see page 3 paragraphs 2 – 3, filed December 5th, 2025, with respect to prior art rejections, of claims 5, and 8 – 11 are have been fully considered but are unpersuasive.
Applicant argues that Ji is silent as to immunotherapies, and there is no reason, based on the teaching of Ji or Di Paolo, alone or in combination, to conjecture that Selonsertib would have any effect on Anti-PD-1 immunotherapies (See Applicant’s remarks page 3 paragraph 2).
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). As stated above, the combination of Ji et. al. and Di Paolo’247, was use to reject the instant claims 5, and 8 – 11. Additionally, Di Paolo’247 specifically taught embodiment wherein the composition includes the ASK1 inhibiting compound of the structure:
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referred to as 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide (page 21 paragraph 0429) and Anti-PD-1 antibody such as nivolumab, that is nivolumab (page 62 paragraph 0647) for the treatment of cancers which include esophageal squamous cell carcinoma, head and neck cancer, melanoma, pancreatic cancer, urological cancer, and prostate cancer (page 58 paragraph 0590).
Moreover, the applicant argues the novel and non-obvious uses of Selonsertib for specific combination therapies against specific types of cancer and that the instant disclosure has characterized a previously-unknown inhibitory activity of Selonsertib directed at RSK4 enzyme (See applicant’s remarks page 3 paragraph 3).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Selonsertib inhibition activity directed at the RSK4 enzyme) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, the examiner contends that "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present (MPEP 2112.01 (II)). Thus since Ji et. al. teach the use of Selonsertib has an anti-cancer agent; one of ordinary skill in the art would have a reasonable expectation that selonsertib interacted with the RSK4 enzyme.
Moreover applicant argues that Selonsertib “enhances the efficacy of cancer immunotherapies,” as presented in instant Figures 11 and 12 (see applicant’s arguments page 2 paragraph 5 and page 3 paragraph 1).
The examiner contends that unexpected results as presented by the applicant is unpersuasive because for Figure 11 the standard deviation difference was seen only in comparison with the DMSO control and not between the sample that only contains Selonsertib or anti-PD-1, in B16F10 a melanoma cell line (Figure 11 B and C). Additionally, in the Lewis lung cancer mouse model (Figure 12) while there is a standard deviation difference noted between Selonsertib/PD-1 and the DMSO sample there is no significant difference between Selonsertib/PD-1 and the samples that only contain Selonsertib or anti-PD-1. Additionally, the examiner argues that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986)(MPEP 716.02). Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977)(MPEP 716.02(c )).
Moreover, given that the applicant argues that Selonsertib “enhances the efficacy of cancer immunotherapies,” (see applicant’s arguments page 2), the examiner argues that the results presented are not commensurate in scope with the claimed invention. The instant claims recite a method of treating esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, urothelial carcinoma, lung cancer or melanoma comprising administering Selonsertib with an anti-PD1 humanized IgG4 antibody. However, will the prior art suggest the use of selonsertib to treat each of these cancers the combination with all anti-PD-1 has not been demonstrated by the applicant. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)(MPEP 716.02(d)).
Conclusion
Claims 5, and 8 – 11 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682