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 Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites the limitation of, “LIAD,” in line 4 of page 3 of the claims but fails to define “LIAD” within the claim. Additionally, the acronym “LIAD” is not defined in the specification. Moreover as evidenced by google LIAD can possible be a misspelling of several different terms which include Lung Adenocarcinoma (LUAD) or Li-Fraumeni Syndrome (LFS). Since the acronym “LIAD” is not described in either the specification, the claim, nor the state of the art; the recitation of “LIAD” within claim 5 is indefinite and ambiguous. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention in regards to a tumor being associated with LIAD. Therefore, given the uncertainty around the term “LIAD”; claim 5 is rejected under 35 U.S.C. 112(b).
Claim Rejections - 35 USC § 103
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 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 1 – 5, and 9 – 18 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Publication US 2019/0202789 A1 to Dar et. al. (herein after Dar’789; cited ISR form) in view of Jung et. al. ((2020), Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex, Experimental & Molecular Medicine, 52, 183 – 191; cited on the IDS dated 05/02/2023).
Regarding claims 1 – 5, and 9 – 18, Dar’789 teach new kinase inhibitors of formula (I) having the structure:
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(page 8 paragraph 0135) in methods of treating cancer (page 8 paragraph 0134). Moreover, Dar’789 teach that the compounds of the disclosure as polypharmacological kinase inhibitors target biological networks at multiple nodes and through multiple pathways (page 5 paragraph 0063). Additionally, Dar’789 teach that the compounds of the disclosure are “sorafelogs" that is compounds that are related to the FDA approved kinase inhibitor sorafenib (page 5 paragraph 0063). Specifically Dar’789 teach
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(claims 1, 11, and 18) (page 19 paragraph 0195); wherein instant X is F (claim 9), instant R is a phenyl substituted with C3F7 (claim 10). Dar’789 teach that the compounds of the disclosure can be administered (claim 14) orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes (claim 15) (page 21 paragraph 0216).
Additionally, Dar’789 teach that suitable subjects for the treatment include mammals (claim 16) and human (claim 17) (page 21 paragraph 0217). Furthermore, Dar’789 teach that cancer include colorectal cancer, gastric (stomach) cancer, an endometrial cancer; a lung cancer; a liver cancer; a hepatocellular carcinoma; a hepatocellular adenoma; a hepatoblastoma; a melanoma; a bladder carcinoma; an ovarian cancer; a medulloblastoma; an adenocortical carcinoma; a pancreatic cancer; a NSCLC; a liver adenoma; a LIAD; a hepatoblastoma; or a cancer of the uterus, pancreas, prostate, stomach, bladder, anus, or esophagus (claim 5) (page 21 paragraph 0128). Furthermore, Dar’789 teach that the compounds were screened in MTT assays using TT human MT cells (claim 12) (page 44 paragraph 0373), and in vivo (claim 13) using Drosophila MTC models (page 45 paragraphs 0385 – 0387), and xenograft mice (claim 16) (page 49 paragraphs 0414 – 0417). Moreover, Dar’789 teach that example compound APS6-45 was administered (claim 14) p.o. (claim 15) for five days to female nude mice (5-6 weeks) when tumors volume was achieved at ~ 120 mm3 (page 49 paragraph 0417).
However, Dar’789 fails to teach whether the cancers or tumors treated have a dysregulated Wnt signaling pathway (claims 1 and 18) comprising a mutation in one or more genes selected from the group consisting of CTNNB1 (claims 2 and 3); wherein the tumor encodes β-catenin comprising an N-terminal phosphodegron mutation or exon 3 indels (claim 4).
Nevertheless, Jung et. al. teach Wnt signaling orchestrates various biological processes, such as cell proliferation, differentiation, organogenesis, tissue regeneration, and tumorigenesis (page 183 column 1 paragraph 1). Jung et. al. teach an overview of the ongoing effort to inhibit Wnt signaling and suggest potential approaches to target Wnt signaling for cancer therapies proposed from recent studies (page 183 column 1 paragraph 1). Jung et. al. teach that the CTNNB1 gene (claims 2 – 3) encoding β-catenin is predominantly mutated in hepatocellular carcinoma, endometrial cancer, and pancreatic cancer (page 184 column 2 paragraph 2). Additionally, Jung et. al. teach that in human cancer, the phosphorylation sites (Ser/Thr) in the N-terminal domain of CTNNB1/β-catenin are mutational hotspots (claim 4) demonstrating that escape from destruction complex-mediated β-catenin protein degradation is a key process for Wnt signaling-induced tumorigenesis (page 184 column 2). Specifically, Jung et. al. teach in Table 1 Wnt/β-catenin signaling inhibitors in current and past clinical trials, with the combination of OMP-54F28 and Sorafenib in Phase 1 trial for the treatment of hepatocellular (Liver) cancer (page 185 Table 1). Now while Jung et. al. fails to teach the results of the study; Jung et. al. does suggest that the use of sorafenib for the treatment of hepatocellular carcinoma; which Jung et. al. does teach has the CTNNB1 gene as the predominate mutant.
Therefore, it would have been obvious before the effective filing date of the instant application to apply the method of Dar’789 to treat a tumor with the disclosed compound in view of Jung et. al. that is wherein the tumor has a dysregulated Wnt signaling pathway. One of ordinary skill in the art would have been motivated to make this modification, because the compounds of Dar’789 are related to the FDA approved kinase inhibitor sorafenib. One of ordinary skill would have had a reasonable expectation of success because sorafenib is suggested in a phase 1 clinical trial study against hepatocellular carcinoma; which Jung et. al. does teach has the CTNNB1 gene as the predominate mutant.
Claims 6 – 8 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Publication US 2019/0202789 A1 to Dar et. al. (herein after Dar’789; cited ISR form) and Jung et. al. ((2020), Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex, Experimental & Molecular Medicine, 52, 183 – 191; cited on the IDS dated 05/02/2023) as applied to claims 1 – 5, and 9 – 18 above, and further in view of Ganesh et. al. ((2018), RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade, Molecular Therapy, 26, 2567 – 2579.
The teachings of Dar’789 and Jung et. al. as they relate to claim 1 from which claims 6 – 8 depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Dar’789 and Jung et. al. fail to teach a method further comprising contacting the tumor with an immune checkpoint inhibitor (claim 6) either simultaneously (claim 7) or sequentially (claim 8) with a compound of Formula (I).
Nevertheless, Ganesh et. al. teach that tumors evade the immune system, in part, by activating molecular checkpoints that dampen antitumor host defense responses (page 2567 column 1 paragraph 2). Ganesh et. al. teach that while recent development and commercialization of cancer immunotherapeutics (claim 6), including PD-1-, PD-L1-, and CTLA-4-targeting antibodies, have led to dramatically increased response rates in melanoma and several other tumor types; most tumors remain insensitive to checkpoint blockade immunotherapy (page 2567 column 1 paragraph 2). Additionally, Ganesh et. al. teach that mutations in Wnt-related genes correlated strongly to a low T cell signature in a large panel of human colorectal tumors (page 2567 column 2 paragraph 2). Moreover, Ganesh et. al. teach other efforts to sensitize cancers to checkpoint blockade are in early clinical evaluation, including combining with standard-of-care chemotherapy, radiotherapy, or targeted small molecule inhibitors of epigenetic modifiers and signaling kinases (page 2567 column 2 paragraph 1). Furthermore, Ganesh et. al. teach the development of a potent RNAi trigger targeting CTNNB1, the gene that encodes β-catenin, that selectively silences CTNNB1 in tumors and causes rapid tumor growth inhibition in diverse Wnt-dependent preclinical models (page 2568 column 1 paragraph 1).
Moreover, Ganesh et. al. teach that in the antitumor study C57BL/6 mice were subcutaneously allografted with 1x106 B16F10 cells or Neuro2A cells before treatment with DCR-BAT/DCR-Placebo followed by CTLA4/PD-1 ab (claim 8) as described in Figure 1 (page 2570 Figure 2). Furthermore, Ganesh et. al. teach that in C57BL/6 mice were subcutaneously allografted with 1x106 B16F10 cells there was 87 % tumor growth inhibition for the combination therapy of DCR-BAT and CTLA4/PD-1 ab (page 2570 Figure 2A) and in C57BL/6 mice were subcutaneously allografted with Neuro2A cells there was 74 % tumor growth inhibition for the combination therapy of DCR-BAT and CTLA4/PD-1 ab (page 2570 Figure 2B). While Ganesh et. al. is silent about the administration of the DCR-BAT and CTLA4/PD-1 ab simultaneously as recited in claim 7, given the skill level of one of ordinary skill in the pharmaceutical arts, it would have been within the purview of the skilled artisan to attempt to administer the combination therapy simultaneously in an attempt to optimize the treatment regimen.
Therefore it would have been obvious before the effective date of the instant application to apply the method of Dar’789 to treat a tumor with the disclosed compound in view of Jung et. al. that is wherein the tumor has a dysregulated Wnt signaling pathway and further in view of Ganesh et. al. to include an immune checkpoint inhibitor either administered sequentially or simultaneously. One of ordinary skill in the art would have been motivated to make this modification to cause rapid tumor growth inhibition in diverse Wnt-dependent cancers. One of ordinary skill in the art would have had a reasonable expectation of success because the treatment strategy of kinase inhibition with an immune checkpoint inhibitor has been shown to have 74 % and 87 % tumor growth inhibition as compared to the monotherapy of inhibiting a kinase.
Claims 29 – 30 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Publication US 2019/0202789 A1 to Dar et. al. (herein after Dar’789; cited ISR form) in view of Anwar et. al. ((2018), p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis, Nature Communications, 9, 1 – 13).
Regarding claims 29 – 30, Dar’789 teach new kinase inhibitors of formula (I) having the structure:
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(page 8 paragraph 0135) in methods of treating cancer (page 8 paragraph 0134). Specifically Dar’789 teach
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(claim 30) (page 19 paragraph 0195); wherein instant X is F; instant R is a phenyl substituted with C3F7. Furthermore, Dar’789 teach that cancer includes breast cancer (page 21 paragraph 0128). Moreover, Dar’789 teach that the compounds of the disclosure as polypharmacological kinase inhibitors target biological networks at multiple nodes and through multiple pathways (page 5 paragraph 0063). Additionally, Dar’789 teach that the compounds of the disclosure are “sorafelogs" that is compounds that are related to the FDA approved kinase inhibitor sorafenib (page 5 paragraph 0063). Furthermore, Dar’789 teach that the compounds of the disclosure were screened in MTT assays using TT human MT cells (claim 12) (page 44 paragraph 0373).
However, Dar’789 fails to teach whether the cancers or tumors treated have cytoplasmic EZH2 (claims 29).
Nevertheless, Anwar et. al. teach the overwhelming majority of breast cancer deaths occur due to metastasis with breast cancer patients with distant metastases at the time of diagnosis have significantly worse prognosis with a 5-year survival rate of 23.4% (page 2 column 1 paragraph 1). Furthermore, Anwar et. al. teach that the frequency of cytoplasmic pEZH2(T367) increased significantly with breast cancer progression, as it was absent in normal lobules and detected in 57% of invasive carcinomas and in 74% of breast cancer distant metastasis (Chi-square p = 0.0001, Fig. 1b) (page 2 column 2 paragraph 2). Moreover, Anwar et. al. teach that in the 104 primary invasive carcinomas, high cytoplasmic pEZH2 (T367) was significantly associated with higher histological grade (p = 0.028), ER- (p = 0.0003), PR- (p = 0.0002), and triple negative status (p = 0.0006) (page 2 column 2 paragraph 2).
Additionally, Anwar et. al. teach that ectopic expression of T367A-EZH2 significantly reduced the lung metastatic burden and ability to metastasize compared to WT-EZH2 (page 4 column 2 paragraph 3). Furthermore, Anwar et. al. teach that T367 phosphorylation is critical for the metastasis-promoting function of EZH2 in breast cancer (page 4 column 2 paragraph 3).Thus, Anwar et. al. teach that based on their study, targeting this oncogenic mechanism, that is the phosphorylation of p38 by EZH2, in a subset of ER- breast cancers with high pEZH2(T367) expression using combined EZH2 and p38 inhibition may offer a therapeutic opportunity to interrupt breast cancer metastasis to distant sites (page 10 column 2 paragraph 4).
Therefore, it would have been obvious before the effective filing date of the instant application to apply the method of Dar’789 to treat a tumor with the disclosed compound in view of Anwar et. al. that is wherein the tumor has cytoplasmic EZH2. One of ordinary skill in the art would have been motivated to make this modification to treat metastatic tumor cells, since Dar’789 specifically teaches their compounds as useful for treating a variety of cancers as kinase inhibitors capable of targeting a variety of kinases. One of ordinary skill would have had a reasonable expectation of success because the combination of EZH2 and p38 inhibition interrupted breast cancer metastasis; therefore, as kinase inhibitors capable of targeting a variety of kinases Dar’789 it is within reason that these compounds can inhibit EZH2 and p38 or related kinases.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 18, and 29 – 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 20 of U.S. Patent No. US 11066370 B2 to Dar et. al. (herein after Dar’370) in view of Jung et. al. ((2020), Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex, Experimental & Molecular Medicine, 52, 183 – 191; cited on the IDS dated 05/02/2023), Ganesh et. al. ((2018), RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade, Molecular Therapy, 26, 2567 – 2579), and Anwar et. al. ((2018), p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis, Nature Communications, 9, 1 – 13).
Dar’370 recites a compound of Formula (I) having the following structure:
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(reference claim 1); wherein reference R is a substituted phenyl (reference claim 2); wherein the phenyl is substituted 1 time with C2F5 (reference claims 3 and 7) wherein reference R is
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(reference claim 4); wherein reference R3 is F (reference claims 5 and 7); wherein reference R6 is Me (reference claims 6 and 7); wherein reference R1-2 and 4-5 are H, reference X is NH, reference Y is
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, and reference Z is CH (reference claim 7). Dar’370 recites a method of treating cancer in a subject, said method comprising administering to a subjects a compound of Formula (I) having the following structure:
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(reference claim 10; instant claims 1, 18, and 30); wherein reference R is a substituted phenyl (reference claim 11); wherein the phenyl is substituted 1 time with C2F5 (reference claim 12) wherein reference R is
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(reference claim 14; instant claims 10 – 11); wherein reference R3 is F (reference claim 14; instant claim 9); wherein reference R6 is Me (reference claim 15) wherein reference R1-2 and 4-5 are H, reference X is NH, reference Y is
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, and reference Z is CH (reference claim 16; instant claim 11); wherein the administering is carried orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes (reference claim 17; instant claims 14 and 15) wherein the subject is mammal (reference claim 18; instant claim 16) or human (reference claim 19; instant claim 17); and wherein the cancer is selected from the group consisting of colorectal cancer (instant claim 5), hepatocellular (liver) cancer (instant claim 5), and melanoma (reference claim 20).
However, Dar’370 fails to recite the cancers or tumors having a dysregulated Wnt signaling pathway (claims 1 and 18) comprising a mutation in one or more genes selected from the group consisting of CTNNB1 (claims 2 and 3); wherein the tumor encodes β-catenin comprising an N-terminal phosphodegron mutation or exon 3 indels (claim 4). Moreover, Dar’370 fails to recite a method further comprising contacting the tumor with an immune checkpoint inhibitor (claim 6) either simultaneously (claim 7) or sequentially (claim 8) with a compound of Formula (I). Additionally, Dar’370 fails to recite a method wherein the cancer or tumor has cytoplasmic EZH2 (claim 29).
Nevertheless, the prior art teachings of Jung et. al., Ganesh et. al., and Anwar et. al. as they relate to the instant claims limitations are given previously in the prior art rejections and are incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Dar’370, that is to apply the compounds in view of Jung et. al., Ganesh et. al., and Anwar et. al. to treat a cancer or tumor with a dysregulated Wnt signaling pathway or cytoplasmic EZH2. One of ordinary skill in the art would have been motivated to make this modification, because the compounds of Dar’789 are related to the FDA approved kinase inhibitor sorafenib. One of ordinary skill would have had a reasonable expectation of success because sorafenib is suggested in a phase 1 clinical trial study against hepatocellular carcinoma; which Jung et. al. does teach has the CTNNB1 gene as the predominate mutant.
Moreover, one of ordinary skill in the art would have been motivated to make this modification to treat metastatic tumor cells, since Dar’789 specifically teaches their compounds as useful for treating a variety of cancers as kinase inhibitors capable of targeting a variety of kinases. One of ordinary skill would have had a reasonable expectation of success because the combination of EZH2 and p38 inhibition interrupted breast cancer metastasis; therefore, as kinase inhibitors capable of targeting a variety of kinases Dar’789 it is within reason that these compounds can inhibit EZH2 and p38 or related kinases.
Claims 1 – 18, and 29 – 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4, 6 – 7, 9, 12, and 14 – 17 of U.S. Patent No. US 10519113 B2 to Dar et. al. (herein after Dar’113; cited on IDS dated 05/02/2023) in view of Jung et. al. ((2020), Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex, Experimental & Molecular Medicine, 52, 183 – 191; cited on the IDS dated 05/02/2023), Ganesh et. al. ((2018), RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade, Molecular Therapy, 26, 2567 – 2579), and Anwar et. al. ((2018), p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis, Nature Communications, 9, 1 – 13).
Dar’113 recites a compound of Formula (I) having the following structure:
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(reference claim 1); wherein reference R is
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(reference claim 2); wherein the reference R16 is C1-C6 alkyl substituted from 2 to 13 times with F (reference claim 3); more specifically wherein reference R16 is selected from the group consisting of C2F5 and C3F7 (reference claim 4); wherein reference R3 is F (reference claim 6); wherein reference X is NH and reference Y is
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(reference claim 7). Dar’113 recites the compound of reference claim 1 wherein the compound is selected from the group consisting of
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(reference claim 9).
Dar’113 recites a method of treating cancer in a subject, said method comprising administering to a subject a compound of Formula (I) having the following structure:
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; wherein reference R is
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; wherein the reference R16 is C1-C6 alkyl substituted from 2 to 13 times with F; more specifically wherein reference R16 is selected from the group consisting of C2F5 and C3F7; wherein reference R3 is F; wherein reference X is NH and reference Y is
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(reference claim 12). Dar’113 recites the method according to reference claim 12 wherein the compound is selected from the group consisting of
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(reference claim 14), wherein the administering is carried orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes (reference claim 15; instant claims 14 and 15) wherein the subject is mammal (reference claim 16; instant claim 16) or human (reference claim 17; instant claim 17).
However, Dar’113 fails to recite the cancers or tumors having a dysregulated Wnt signaling pathway (claims 1 and 18) comprising a mutation in one or more genes selected from the group consisting of CTNNB1 (claims 2 and 3); wherein the tumor encodes β-catenin comprising an N-terminal phosphodegron mutation or exon 3 indels (claim 4). Moreover, Dar’113 fails to recite a method further comprising contacting the tumor with an immune checkpoint inhibitor (claim 6) either simultaneously (claim 7) or sequentially (claim 8) with a compound of Formula (I). Additionally, Dar’113 fails to recite a method wherein the cancer or tumor has cytoplasmic EZH2 (claim 29).
Nevertheless, the prior art teachings of Jung et. al., Ganesh et. al., and Anwar et. al. as they relate to the instant claims limitations are given previously in the prior art rejections and are incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Dar’113, that is to apply the compounds in view of Jung et. al., Ganesh et. al., and Anwar et. al. to treat a cancer or tumor with a dysregulated Wnt signaling pathway or cytoplasmic EZH2. One of ordinary skill in the art would have been motivated to make this modification, because the compounds of Dar’789 are related to the FDA approved kinase inhibitor sorafenib. One of ordinary skill would have had a reasonable expectation of success because sorafenib is suggested in a phase 1 clinical trial study against hepatocellular carcinoma; which Jung et. al. does teach has the CTNNB1 gene as the predominate mutant. Moreover, one of ordinary skill in the art would have been motivated to make this modification to treat metastatic tumor cells, since Dar’789 specifically teaches their compounds as useful for treating a variety of cancers as kinase inhibitors capable of targeting a variety of kinases. One of ordinary skill would have had a reasonable expectation of success because the combination of EZH2 and p38 inhibition interrupted breast cancer metastasis; therefore, as kinase inhibitors capable of targeting a variety of kinases Dar’789 it is within reason that these compounds can inhibit EZH2 and p38 or related kinases.
Claims 1 – 18, and 29 – 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4, 6 – 7, 9, 12, and 14 – 17 of copending Application No. 16/325218 to Dar et. al. (herein after Dar’218; cited on IDS dated 05/02/2023 as US 2019/0202789 A1) in view of Jung et. al. ((2020), Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex, Experimental & Molecular Medicine, 52, 183 – 191; cited on the IDS dated 05/02/2023), Ganesh et. al. ((2018), RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade, Molecular Therapy, 26, 2567 – 2579), and Anwar et. al. ((2018), p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis, Nature Communications, 9, 1 – 13).
Dar’218 recites a compound of Formula (I) having the following structure:
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(reference claim 1); wherein reference R is
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(reference claim 2); wherein the reference R16 is C1-C6 alkyl substituted from 2 to 13 times with F (reference claim 3); more specifically wherein reference R16 is selected from the group consisting of C2F5 and C3F7 (reference claim 4); wherein reference R3 is F (reference claim 6); wherein reference X is NH and reference Y is
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(reference claim 7). Dar’218 recites the compound of reference claim 1 wherein the compound is selected from the group consisting of
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(reference claim 9).
Dar’218 recites a method of treating cancer in a subject, said method comprising administering to a subject a compound of Formula (I) having the following structure:
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; wherein reference R is
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; wherein the reference R16 is C1-C6 alkyl substituted from 2 to 13 times with F; more specifically wherein reference R16 is selected from the group consisting of C2F5 and C3F7; wherein reference R3 is F; wherein reference X is NH and reference Y is
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(reference claim 12). Dar’218 recites the method according to reference claim 12 wherein the compound is selected from the group consisting of
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(reference claim 14), wherein the administering is carried orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes (reference claim 15; instant claims 14 and 15) wherein the subject is mammal (reference claim 16; instant claim 16) or human (reference claim 17; instant claim 17).
However, Dar’218 fails to recite the cancers or tumors having a dysregulated Wnt signaling pathway (claims 1 and 18) comprising a mutation in one or more genes selected from the group consisting of CTNNB1 (claims 2 and 3); wherein the tumor encodes β-catenin comprising an N-terminal phosphodegron mutation or exon 3 indels (claim 4). Moreover, Dar’218 fails to recite a method further comprising contacting the tumor with an immune checkpoint inhibitor (claim 6) either simultaneously (claim 7) or sequentially (claim 8) with a compound of Formula (I). Additionally, Dar’218 fails to recite a method wherein the cancer or tumor has cytoplasmic EZH2 (claim 29).
Nevertheless, the prior art teachings of Jung et. al., Ganesh et. al., and Anwar et. al. as they relate to the instant claims limitations are given previously in the prior art rejections and are incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify copending Dar’218, that is to apply the compounds in view of Jung et. al., Ganesh et. al., and Anwar et. al. to treat a cancer or tumor with a dysregulated Wnt signaling pathway or cytoplasmic EZH2. One of ordinary skill in the art would have been motivated to make this modification, because the compounds of Dar’789 are related to the FDA approved kinase inhibitor sorafenib. One of ordinary skill would have had a reasonable expectation of success because sorafenib is suggested in a phase 1 clinical trial study against hepatocellular carcinoma; which Jung et. al. does teach has the CTNNB1 gene as the predominate mutant. Moreover, one of ordinary skill in the art would have been motivated to make this modification to treat metastatic tumor cells, since Dar’789 specifically teaches their compounds as useful for treating a variety of cancers as kinase inhibitors capable of targeting a variety of kinases. One of ordinary skill would have had a reasonable expectation of success because the combination of EZH2 and p38 inhibition interrupted breast cancer metastasis; therefore, as kinase inhibitors capable of targeting a variety of kinases Dar’789 it is within reason that these compounds can inhibit EZH2 and p38 or related kinases.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1 – 18, and 29 – 30 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682