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.
Claims 1 – 9, and 12 – 13 are 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 1 recites the limitation "the subject with the cancerous tumor" in line 3. There is insufficient antecedent basis for this limitation in the claim; since the determining step in the claim 1 does not require the subject to have a cancerous tumor. Moreover the determining step in claim 1 which recites “determining if the cancerous tumor exhibits an inactivating PTEN mutation;” is indefinite because it is unclear whether that determining step requires that the cancerous tumor exhibits an inactivating PTEN mutation. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of whether the subject is required to have a cancerous tumor that exhibits an inactivating PTEN mutation or not. Therefore, given the uncertainty around determining step of claim 1; claim 1 is rejected under 35 U.S.C. 112(b). Moreover, claims 2 – 5, and 12 – 13 are included in the rejection since the claims dependent from claim 1 but do not address the deficiency.
Claim 6 recites the limitation "the subject having the PTEN gene" in line 4. There is insufficient antecedent basis for this limitation in the claim; since the determining step in the claim 6 does not require the subject to have a cancerous tumor. Moreover the determining step in claim 6 which recites “determining if the subject has a PTEN gene;” is indefinite because it is unclear whether that determining step requires that the subject has PTEN gene. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of whether the subject is required to have a PTEN gene or not. Therefore, given the uncertainty around determining step of claim 6; claim 6 is rejected under 35 U.S.C. 112(b). Moreover, claims 7 – 9 are included in the rejection since the claims dependent from claim 6 but do not address the deficiency.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 – 9, and 12 – 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite a method of treating a subject with a cancerous tumor, comprising: determining if the cancerous tumor exhibits an inactivating PTEN mutation; and administering to the subject with the cancerous tumor exhibiting the inactivating PTEN mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof. The first step of the claims is a determining step, which is an abstract idea, more specifically, a mental processes, wherein after well-understood, routine, and conventional data gathering activity there is an evaluation of the collected data. Thus the determining step is a mental processes step that can be performed by a human, to diagnosis or interpret the results.
This judicial exception is not integrated into a practical application because, as stated in the 112(b) rejection both claims 1 and 6 are indefinite, because with the inclusion of the conditional term “if” in the determination step. The conditional recitation in claims 1 and 6 is interpreted to mean that there are two distinct patient populations: (1) a population that has a cancerous tumor that exhibits inactivating PTEN (claim 1) or a subject having a PTEN gene with germline inactivating mutation (claim 6) and (2) a population that does not have a cancerous tumor that exhibits inactivating PTEN (claim 1) or a subject not having a PTEN gene with germline inactivating mutation (claim 6).
For the population that has a cancerous tumor that exhibits inactivating PTEN (claim 1) or a subject having a PTEN gene with germline inactivating mutation(claim 6), this population will receive the administering of trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof which yields a claim as a whole that is sufficiently amounts to significantly more than the judicial exception of a mental process. However, for population that does not have a cancerous tumor that exhibits inactivating PTEN (claim 1) or a subject that does not have a PTEN gene with germline inactivating mutation(claim 6) the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only active step in the method as claimed by claims 1 and 6 is the judicial exception, of a mental processes step. To overcome this 101 rejection applicant may amend the claims to require the detection of the subject with the cancerous tumor (claim 1) or the subject having the PTEN gene (claim 6).
Claim Rejections - 35 USC § 102
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 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.
Claims 10 – 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent No. US 10155990 B2 to Abe et. al. (herein after Abe’990) as evidenced by Aguissa-Toure et. al. ((2012), Genetic alterations of PTEN in human melanoma, Cell. Mol. Life Sci., 69, 1475 – 1491).
Regarding claims 10 – 11, Abe’990 teach a method for predicting therapeutic efficacy of a chemotherapy using an antitumor agent comprising a PI3K/AKT/ mTOR inhibitor on a cancer patient on the basis of an expression level of PHLDA1 and/or PIK3C2B in tumor cells isolated from the cancer patient (column 2 lines 17 – 21). Furthermore, Abe’990 teach a method wherein the PI3K/AKT/mTOR inhibitor is an imidazo-oxazine compound represented by formula (I) or its pharmaceutically
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acceptable salt (column 2 lines 36 – 54). More specifically, Abe’990 teach compound k, that is trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (claims 10 and 11)(column 3 lines 63 – 64). Moreover, Abe’990 teach in example 4 that of the 37 cell lines from human breast cancer describe in Example 1, 36 cell lines (KPL-3C is excluded) have been known to have PIK3CA mutation or PTEN deletion (column 16 lines 56 – 58). Furthermore, while Abe’990 is silent about an inactivating PTEN mutation; as evidenced by Aguissa-Toure et. al. PTEN is classified as a tumor suppressor because its activity is lost by deletion, mutation, or through epigenetic changes (page 1475 column 2 paragraph 1); thus PTEN deletion which would result in the inactivation of PTEN.
Regarding claim 10, the preamble, “for treating a subject” recited in line 3 is interpreted as an intended use drawn to a composition. 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)(MPEP2111.02(II)). However, since the recitations of, “for treating a subject” recited in claim 10 do not provide a structural limitations for the composition the recitations are interpreted as intended use.
Regarding claim 11, the preamble, “for us in treating a subject” recited in line 2 is interpreted as an intended use drawn to a composition. 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)(MPEP2111.02(II)). However, since the recitations of, “for us in treating a subject” recited in claim 11 do not provide a structural limitations for the composition the recitations are interpreted as intended use.
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 10 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020256096 A1 to Koba et. al. (herein after Koba’096; English translation used cited on IDS dated 07/31/2023) in view of Zhu et. al. ((2001), PTEN Induces G1 Cell Cycle Arrest and Decreases Cyclin D3 Levels in Endometrial Carcinoma Cells1, Cancer Research, 61, 4569 – 4575).
Regarding claims 1 – 5, and 10 – 13, Koba’096 teach an imidazooxazine compound, trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (hereinafter also referred to as “Compound 1”) as an extremely potent and highly selective oral allosteric AKT inhibitor (translation page 3 paragraph 0003). Moreover, Koba’096 teach that Compound 1 can be used for tumors that have abnormalities, in the FGFR, PTEN, PIK3CA, or AKT genes (translation page 63 paragraph 0094). Furthermore, Koba’096 teach that genetic abnormalities include gene amplification, gene mutation, chromosomal translocation /insertion/inversion, gene fusion, and gene rearrangement (translation page 63 paragraph 0094). Additionally, Koba’096 teach that genetic abnormalities may be detected by methods known to those skilled in the art, such as DNA sequencing including pyrosequencing, NGS (next generation sequencing), PCR-based methods including allele-specific PCR chain reaction, microarray-based comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH) (translation page 64 paragraph 0094).
Additionally, Koba’096 teach a method for treating a malignant tumor in a human comprising administration of Compound 1 wherein the dosage regimen is 4mg/body/day to 160 mg/body/day (claims 12 and 13) of compound 1 for 4 consecutive days with one course lasting 7 days followed by a prescribed 3-day washout period (claims 4) (translation page 9 paragraph 0013). While instant claim 13 recites a dosage range from about 1 to 160 mg/day of the free base; this range lies within the dosage range 4mg/body/day to 160 mg/body/day taught by Koba’096. Moreover even when the differences between the free base mass and the pharmaceutical salt mass are taken into consideration. Thus in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)(MPEP 2144.05(I)). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)(MPEP 2144.05(I)).
Moreover, given that claim 12 merely recites “a therapeutically effective amount,” the range of 4mg/body/day to 160 mg/body/day taught by Koba’096 renders obvious claim 12; since claim 12 does not require a specific range to be administered and only requires that the amount of compound 1 administered is effective.
Furthermore, Koba’096 teach a method wherein compound 1 or a salt thereof is administered consecutively for four days from day 1 to day 4, from day 8 to day 11, and from day 15 to day 18 over three courses of 21 days, with one course being seven days in the administration schedule, and prescribed drug holidays are given from day 5 to day 7, from day 12 to day 14, and from day 19 to day 21 (claims 3 and 5) (translation page 15 paragraph 0022). Additionally, Koba’096 teach in example 2, that compound 1 was administered, at 15 mg/kg/day (claims 10 – 12) (non-translation page 54 Figure 2) to nude mice carrying AN3CA tumors human AN3CA tumor transplanted subcutaneously Human endometrial cancer-derived cell line AN3CA (American Type Culture Collection (ATCC) (translation page 102 paragraph 0126). Moreover, Koba’096 teach that in the example 2 in vivo study there was no significant weight loss and there was excellent antitumor effects (translation page 106 paragraph 0132).
Regarding claim 10, the preamble, “for treating a subject” recited in line 3 is interpreted as an intended use drawn to a composition. 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)(MPEP2111.02(II)). However, since the recitations of, “for treating a subject” recited in claim 10 do not provide a structural limitations for the composition the recitations are interpreted as intended use.
Regarding claim 11, the preamble, “for us in treating a subject” recited in line 2 is interpreted as an intended use drawn to a composition. 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)(MPEP2111.02(II)). However, since the recitations of, “for us in treating a subject” recited in claim 11 do not provide a structural limitations for the composition the recitations are interpreted as intended use.
Regarding claim 1, while Koba’096 does not specifically recite determining if the cancerous tumor exhibits an inactivating PTEN mutation; Koba’096 does teach that use of compound 1 can be used for tumors that have abnormalities, in the FGFR, PTEN, PIK3CA, or AKT gene (translation page 63 paragraph 0094) and that genetic abnormalities include gene mutation (translation page 63 paragraph 0094). Thus it would have been obvious to determine if the tumor exhibits any of a FGFR, PTEN, PIK3CA or AKT mutation and to treat any or all of them with a reasonable expectation of success because the trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol is known to be effective against these mutations. Moreover, in regards to claim 1, while Koba’096 does not explicitly recite a step comprising determining if the cancerous tumor exhibits an inactivating PTEN mutation before administration; Koba’096 does teach that genetic abnormalities may be detected by methods that are known to those skilled in the art (translation page 64 paragraph 0094). Thus it would have been obvious to one of ordinary skill in the art to incorporate a determination step into a method of treatment as a way of maximizing the probability of positive patient outcomes.
However, Koba’096 fails to explicitly teach the determination of whether any of the cancer lines contained an inactivating PTEN mutation (claim 1).
Nevertheless, Zhu et. al. teach that the PTEN tumor suppressor gene is inactivated by mutations in tumors of the endometrium, brain, prostate, and others (page 4569 column 1 paragraphs 2). Additionally, Zhu et. al. teach that in tumors, inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K (page 4569 column 1 paragraphs 2). Moreover, Zhu et. al. teach that PTEN mutations occur at the earliest stages of endometrial carcinogenesis, whereas such mutations are late events in the tumorigenic progression in other tissues such as brain and prostate (page 4569 column 2 paragraphs 2). Furthermore, Zhu et. al. teach that familial syndromes with germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance (page 4569 column 2 paragraphs 2).
Additionally, Zhu et. al. teach that the endometrial carcinoma cell lines AN3CA, RL-95, and Hec1A were obtained from American Type Culture Collection (ATCC) (Manassas, VA) and sequence analysis of PTEN in these cell lines was performed (page 4569 column 2 paragraph 5). Moreover, Zhu et. al. teach that two of the cell lines contained mutations in PTEN of which AN3CA was one and contained a deletion of a single bp in codon 130, leading to truncation of the protein at codon 133 with a loss of the second PTEN allele, and RL-95 contained two mutations, a 1-bp deletion in codon 321 and a 1-bp insertion in codon 323 (claim 2) (page 4570 column 2 paragraph 1). Thus Zhu et. al. suggest that the cell line AN3CA from ATCC naturally contains PTEN mutations. Accordingly, since Koba’096 teach the administration of compound 1 to nude mice carrying AN3CA tumors human AN3CA tumor transplanted subcutaneously Human endometrial cancer-derived cell line AN3CA (American Type Culture Collection (ATCC) (translation page 102 paragraph 0126) and since this cell lines derive from the same vendor one of ordinary skill in the art would have a reasonable expectation that the cell lines taught by Koba’096 also contained the PTEN mutations screened for and detected by Zhu et. al.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Koba’096, that is to treat a cancer tumor, comprising determining whether the cancerous tumor has a PTEN inactivating mutation and administering to the cancerous tumor with a PTEN inactivating mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol in view of Zhu et. al. that is especially when the cancer tumor is derived from AN3CA cells. One of ordinary skill in the art would have been motivated to make this modification because inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K. One of ordinary skill in the art would have had a reasonable expectation of success because in the example 2 in vivo study after administration of trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol there was no significant weight loss and there was excellent antitumor effects. Moreover, as taught about the cell line AN3CA cells from ATCC contain contained mutations in PTEN.
Regarding claims 6 – 9, Koba’096 teach an imidazooxazine compound, trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (hereinafter also referred to as “Compound 1”) as an extremely potent and highly selective oral allosteric AKT inhibitor (translation page 3 paragraph 0003). Moreover, Koba’096 teach that Compound 1 can be used for tumors that have abnormalities, in the FGFR, PTEN, PIK3CA, or AKT genes (translation page 63 paragraph 0094). Furthermore, Koba’096 teach that genetic abnormalities include gene amplification, gene mutation, chromosomal translocation /insertion/inversion, gene fusion, and gene rearrangement (translation page 63 paragraph 0094). Additionally, Koba’096 teach that genetic abnormalities may be detected by methods known to those skilled in the art, such as DNA sequencing including pyrosequencing, NGS (next generation sequencing), PCR-based methods including allele-specific PCR chain reaction, microarray-based comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH) (translation page 64 paragraph 0094).
Additionally, Koba’096 teach a method for treating a malignant tumor in a human comprising administration of compound 1 for 4 consecutive days with one course lasting 7 days followed by a prescribed 3-day washout period (claim 8) (translation page 9 paragraph 0013). Furthermore, Koba’096 teach a method wherein compound 1 or a salt thereof is administered consecutively for four days from day 1 to day 4, from day 8 to day 11, and from day 15 to day 18 over three courses of 21 days (claim 7 and 9), with one course being seven days in the administration schedule, and prescribed drug holidays are given from day 5 to day 7, from day 12 to day 14, and from day 19 to day 21 (claims 7and 9) (translation page 15 paragraph 0022). Additionally, Koba’096 teach in example 2, that compound 1 was administered, at 15 mg/kg/day (non-translation page 54 Figure 2) to nude mice carrying AN3CA tumors human AN3CA tumor transplanted subcutaneously Human endometrial cancer-derived cell line AN3CA (American Type Culture Collection (ATCC) (translation page 102 paragraph 0126). Moreover, Koba’096 teach that in the example 2 in vivo study there was no significant weight loss and there was excellent antitumor effects (translation page 106 paragraph 0132).
Regarding claim 6, while Koba’096 does not specifically teach determining if a subject has a PTEN gene with a germline inactivating PTEN mutation; Koba’096 does teach that use of compound 1 can be used for tumors that have abnormalities, in the FGFR, PTEN, PIK3CA, or AKT gene (translation page 63 paragraph 0094) and that genetic abnormalities include gene mutation (translation page 63 paragraph 0094). Thus it would have been obvious to one of ordinary skill in the art that the scope of abnormalities of the PTEN gene and more specifically gene mutation would include germline inactivating PTEN mutations.
Moreover, in regards to claim 6, while Koba’096 does not explicitly teach a step comprising determining if the cancerous tumor exhibits a germline inactivating PTEN mutation before administration; Koba’096 does teach that use of compound 1 can be used for tumors that have abnormalities, in the FGFR, PTEN, PIK3CA, or AKT gene (translation page 63 paragraph 0094) and that genetic abnormalities include gene mutation (translation page 63 paragraph 0094). Furthermore, gene mutations encompasses both germline inactivating mutations as well. Thus it would have been obvious to determine if the tumor exhibits any of a FGFR, PTEN, PIK3CA or AKT mutation and to treat any or all of them with a reasonable expectation of success because the trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol is known to be effective against these mutations.
However, Koba’096 fails to explicitly teach a method comprising determining of the subject has a PTEN gene with a germline inactivating mutation and administering to the subject having the PTEN gene with germline inactivating mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (claim 6).
Nevertheless, Zhu et. al. teach that the PTEN tumor suppressor gene is inactivated by mutations in tumors of the endometrium, brain, prostate, and others (page 4569 column 1 paragraphs 2). Additionally, Zhu et. al. teach that in tumors, inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K (page 4569 column 1 paragraphs 2). Moreover, Zhu et. al. teach that PTEN mutations occur at the earliest stages of endometrial carcinogenesis, whereas such mutations are late events in the tumorigenic progression in other tissues such as brain and prostate (page 4569 column 2 paragraphs 2). Furthermore, Zhu et. al. teach that familial syndromes with germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance (page 4569 column 2 paragraphs 2).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Koba’096, that is to treat a cancer tumor, comprising administering to the cancerous tumor trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol in view of Zhu et. al. that is to determining whether the cancerous tumor has a germline PTEN inactivating mutation. One of ordinary skill in the art would have been motivated to make this modification because inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K and because germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance. One of ordinary skill in the art would have had a reasonable expectation of success because in the example 2 in vivo study after administration of trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol there was no significant weight loss and there was excellent antitumor effects in cancer cells with PTEN mutations that are somatic.
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 – 13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 8 of U.S. Patent No. US 8772283 B2 to Nakamura et. al. (herein after Nakamura’283) in view of Koba et. al. (herein after Koba’096; English translation used cited on IDS dated 07/31/2023) and ((2001), PTEN Induces G1 Cell Cycle Arrest and Decreases Cyclin D3 Levels in Endometrial Carcinoma Cells1, Cancer Research, 61, 4569 – 4575).
Nakamura’283 recite an imidazooxazine compound represented by Formula (I) or a salt thereof,
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(reference claims 1 – 4). More specifically, Nakamura’283 recite an imidazooxazine compound selected from the group consisting of the following (a) to (t), or a salt thereof which includes (m) that is trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (instant claims 1, 6, 10, and 11)(reference claim 5). Additionally, Nakamura’283 recite a pharmaceutical composition comprising an effective amount of an imidazooxazine compound according to (reference) claim 1 or a salt thereof and a pharmaceutical carrier (reference claim 6). Moreover, Nakamura’283 recite a method for treating a cancer, comprising administering to a mammal, the imidazooxazine compound according to (reference) claim 1 or a salt, in an affective amount (instant claim 12) for cancer treatment wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, liver cancer, prostate cancer, stomach cancer, lung cancer, ovarian cancer, head and neck cancer, urinary tract cancer, and endometrial cancer (reference claim 8).
However, Nakamura’283 fails to recite a method of treating comprising: determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation (instant claim 6); and administering to the subject with the cancerous tumor exhibiting the inactivating PTEN mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof (instant claim 1).
Nevertheless, the teachings of Koba’096 and Zhu et. al. as they relate to limitations of claims 1 and 6, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of Nakamura’283 for a method for treating a cancer, comprising administering trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol in view of Koba’096 and Zhu et. al. for a method further comprising determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation. One of ordinary skill in the art would have been motivated to make this modification because inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K and because germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance. One of ordinary skill in the art would have had a reasonable expectation of success because in the example 2 in vivo study after administration of trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol there was no significant weight loss and there was excellent antitumor effects in cancer cells with PTEN mutations that are somatic.
Claims 1 – 13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 8 of U.S. Patent No. US 9375434 B2 to Ichikawa et. al. (herein after Ichikawa’434) in view of Koba et. al. (herein after Koba’096; English translation used cited on IDS dated 07/31/2023) and ((2001), PTEN Induces G1 Cell Cycle Arrest and Decreases Cyclin D3 Levels in Endometrial Carcinoma Cells1, Cancer Research, 61, 4569 – 4575).
Ichikawa’434 recite a method for potentiating one or more antitumor agents, comprising administering an imidazooxazine compound represented by Formula (I), or a pharmaceutically acceptable salt thereof in combination with one or more antitumor agents, wherein said imidazooxazine compound is in an amount, effective for potentiating the effect of said one or more antitumor agents, to a patient in need of such treatment,
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(reference claims 1 – 4).
More specifically, Ichikawa’434 recite a method wherein an imidazooxazine compound selected from the group consisting of the following (a) to (t), or a salt thereof which includes (m) that is trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (instant claims 1, 6, 10, and 11)(reference claim 3). Additionally, Ichikawa’434 recite an antitumor pharmaceutical composition comprising an imidazooxazine compound according to formula (I) or a salt (reference claim 4); a pharmaceutical composition comprising an effective amount of an imidazooxazine compound according to formula (I) or a salt thereof and a pharmaceutical carrier (reference claim 7; instant claim 12). Moreover, Ichikawa’434 recite method for treating a malignant tumor in which AKI ( serine/threonine-specific kinase) is frequently activated or highly expressed, comprising administering to a patient a combination of an imidazooxazine compound or a pharmaceutically acceptable salt thereof and one or more antitumor agents in an amount effective for treatment of said malignant tumor, wherein said imidazooxazine compound is represented by Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective for potentiating the effect of said one or more antitumor agents (reference claim 8) wherein said malignant tumor in which AKI serine/threonine-specific kinase is frequently activated or highly expressed is a cancer selected from the group consisting of head and neck cancer, esophagus cancer, stomach cancer, colon cancer, rectum cancer, hepatocarcinoma, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma, soft-tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, and a brain tumor (reference claim 12).
However, Ichikawa’434 fails to recite a method of treating comprising: determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation (instant claim 6); and administering to the subject with the cancerous tumor exhibiting the inactivating PTEN mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof (instant claim 1)
Nevertheless, the teachings of Koba’096 and Zhu et. al. as they relate to limitations of claims 1 and 6, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of Ichikawa’434 for a method for treating a cancer, comprising administering trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol in view of Koba’096 and Zhu et. al. for a method further comprising determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation. One of ordinary skill in the art would have been motivated to make this modification because inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K and because germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance. One of ordinary skill in the art would have had a reasonable expectation of success because in the example 2 in vivo study after administration of trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol there was no significant weight loss and there was excellent antitumor effects in cancer cells with PTEN mutations that are somatic.
Claims 1 – 13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7 of U.S. Patent No. US 10155990 B2 to Abe et.al. (herein after Abe’990) in view of Koba et. al. (herein after Koba’096; English translation used cited on IDS dated 07/31/2023) and Zhu ((2001), PTEN Induces G1 Cell Cycle Arrest and Decreases Cyclin D3 Levels in Endometrial Carcinoma Cells1, Cancer Research, 61, 4569 – 4575).
Abe’990 recite a method for identifying a cancer patient as likely to sufficiently respond to chemotherapy using an antitumor agent comprising a PI3K/AKT/mTOR inhibitor and for treating said patient, comprising a) measuring an expression level of PHLDA1 and/or PIK3C2B in a biological sample containing tumor cells isolated from the cancer patient, wherein the cancer patient is suffering a cancer selected from the group consisting of breast cancer, ovarian cancer and uterine cancer; and b) identifying a cancer patient as likely to sufficiently respond to chemotherapy using the antitumor agent comprising a PI3K/AKT/mTOR inhibitor when the expression level of PHLDA1 measured in step a) is equal to or lower than a predetermined cutoff point, or when the expression level of PIK3C2B measured in step a) is equal to or higher than a predetermined cutoff point, wherein the predetermined cutoff point for the expression level of PHLDA1 is the mean or median value of the PHLDA1 expression levels of cancer patients or a value at which the p-value of the log-rank test conducted for the therapeutic efficacy is less than 0.1 and wherein the predetermined cutoff point for the expression level of PIK3C2B is the mean or median value of the PIK3C2B expression levels of cancer patients or a value at which the p-value of the log-rank test conducted for the therapeutic efficacy is less than 0.1; and c) administering the antitumor agent comprising a PI3K/ AKT/mTOR inhibitor, to said cancer patient, wherein the PI3K/AKT/mTOR inhibitor is an imidazo-oxazine compound represented by formula (I) or its pharmaceutically acceptable salt
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(reference claims 1 – 3; and 5 – 7) wherein the imidazooxazine compound represented by formula (I) is any of the following compounds (a) to (t), which includes (m) that is trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol (instant claims 1, 6, 10, and 11)(reference claim 4).
However, Abe’990 fails to recite a method of treating comprising: determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation (instant claim 6); and administering to the subject with the cancerous tumor exhibiting the inactivating PTEN mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof (instant claim 1)
Moreover, Abe’990 fails to recite a method wherein the administering is daily for at least 21 days (claims 3 and 7); wherein the administering is for 4 consecutive days followed by a 3-day drug holiday in a week (claims 4 and 8); wherein the administering is repeated for a total period of at least 21 days (claim 5); and wherein the administering for 4 consecutive days followed by the 3-day drug holiday is repeated for a total period of at least 21 days (claim 9).
Nevertheless, the teachings of Koba’096 and Zhu et. al. as they relate to limitations of claims 1 and 6, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of modify the invention of Ichikawa’434 for a method for treating a cancer, comprising administering trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol in view of Koba’096 and Zhu et. al. for a method further comprising determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation. One of ordinary skill in the art would have been motivated to make this modification because inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K and because germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance. One of ordinary skill in the art would have had a reasonable expectation of success because in the example 2 in vivo study after administration of trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol there was no significant weight loss and there was excellent antitumor effects in cancer cells with PTEN mutations that are somatic.
Claims 1 – 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28 – 34 of copending Application No. 18/699669 to Ichikawa et. al. (herein after Ichikawa’669) in view of WO 2020256096 A1 to Koba et. al. (herein after Koba’096; English translation used cited on IDS dated 07/31/2023).
Ichikawa’669recite a method of treating a subject with a cancer having an aberration in PTEN, the method comprising: administering to the subject an effective amount of 4-( 4-(3-((2-(tertbutylamino)ethyl)amino )-6-( 5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidinl-yl)-5,5-dimethyl-5H-pyrolo[2,3-d]pyrimidin-6(7H)-one (TAS0612) or a pharmaceutically acceptable salt thereof (reference claim 28). Furthermore, Ichikawa’669 recite the method of (reference) claim 28 wherein the subject is determined to have the aberration in PTEN prior to administering TAS0612 or a pharmaceutically acceptable salt thereof (reference claim 31); wherein the aberration in PTEN is PTEN loss of gene or variants which lead to loss of function (reference claim 34; instant claim 1 and 6).
However, Ichikawa’669 fails to recite a method of treating comprising: administering to the subject with the cancerous tumor exhibiting the inactivating PTEN mutation trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol or a pharmaceutically acceptable salt thereof (instant claims 1 and 6)
Moreover, Ichikawa’669 fails to recite a method wherein the administering is daily for at least 21 days (claims 3 and 7); wherein the administering is for 4 consecutive days followed by a 3-day drug holiday in a week (claims 4 and 8); wherein the administering is repeated for a total period of at least 21 days (claim 5); and wherein the administering for 4 consecutive days followed by the 3-day drug holiday is repeated for a total period of at least 21 days (claim 9).
Nevertheless, the teachings of Koba’096 and Zhu et. al. as they relate to limitations of claims 1 and 6, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the invention of modify copending Ichikawa’434 for a method for treating a cancer, comprising administering trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol in view of Koba’096 for a method further comprising determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation further, that is, in a dosage regimen wherein trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol is administered for 4 consecutive days with one course lasting 7 days followed by a prescribed 3-day washout period for 21 days. in view of Koba’096 and Zhu et. al. for a method further comprising determining if the cancerous tumor exhibits an inactivating PTEN mutation or with a germline inactivating mutation. One of ordinary skill in the art would have been motivated to make this modification because inactivating mutations in PTEN led to increased activity of AKT/PKB, one of the most well-characterized downstream effectors of PI3K and because germ-line mutations in PTEN have a predisposition to develop endometrial hyperplasia and carcinoma, as well as breast and thyroid cancers, macrocephaly, and hamartomas in multiple tissues with widely variable penetrance. One of ordinary skill in the art would have had a reasonable expectation of success because in the example 2 in vivo study after administration of trans-3-amino-1-met