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. DETAILED ACTION This office action is in response to the application filed on 15 August 2023. Claims 1 , 8 - 9 , 13 , 16 - 19 , 21 , 32 - 33 , and 43 - 44 are amended. Claims 2 - 7 , 10 - 12 , 14 - 15 , 20 , 22 - 31 , and 32 - 42 are cancelled. Currently, claims 1 , 8 - 9 , 13 , 16 - 19 , 21 , 32 - 33 , 43 - 51 are pending. Information Disclosure Statement The information disclosure statement (IDS) submitted on 22 November 2023 was filed after the mailing date of the application on 15 August 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. 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. Claim s 1 , 8 - 9 , 13 , and 43 - 4 6 , are rejected under 35 U.S.C. 103 as being unpatentable over Chung et al. ( Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-B]indol-2-yl)-2,2,-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use , WO2019/245974A1 , 2019 , IDS entered on date 22 November 2023) in view of Zhu et al . ( Exposure-response-based product profile-driven clinical utility index for ipatasertib dose selection in prostate cancer, CPT Pharmacometrics Syst. Pharmacol . 2019 , 8 , 240-248) . Chung teaches that GDC-9545 was developed to target ER-positive breast cancer, including HER2- breast cancer and discloses that both GDC-9545 and pharmaceutically acceptable salts can be administered through various dosing regimens including 10 mg, 30 mg, 50 mg, 90 mg, 100 mg, 125 mg, and 250 mg. Additionally, Chung also discloses dosing in rat and monkey in vivo studies where exemplary dose levels were defined as 10, 30 and 100 mg/kg for rat, and 20, 60, 200 mg/kg for monkey. Chung does not disclose the combinatorial use of utilizing ipatasertib or a pharmaceutically acceptable salt at a dose of 400 mg. Zhu rectifies this deficiency by teaching the administration of 400 mg of ipatasertib in a phase II study that aimed to characterize the ipatasertib exposure-response relationship and to assess the benefit-risk to support a phase III dose selection in patients with metastatic castration-resistant prostate cancer. In this study, 200 and 400 mg daily ipatasertib doses in combination with abiraterone were evaluated in a phase II trial . I patasertib is a potent Akt inhibitor that works synergistically with the standard-of-care abiraterone in metastatic castration-resistant prostate cancer as mutations in the PI3K/Akt/mTOR signaling pathway are common . T he developed exposure-response profile illustrated an optimal benefit-risk balance for a daily dosing of 400 mg over a cycle of 28-days of ipatasertib. This was evaluated by several means including radiographic progression free survival and the 400 mg ipatasertib /abiraterone dos ing regimen proved to be the most efficacious with reasonable safety profiles . As such, it would have be en prima facie obvious , for a person of ordinary skill in the art, to consider the use of 400 mg of ipatasertib to look for synergistic treatment outcomes , which Zhu used in combination with abiraterone to treat castration-resistant prostate cancer, as mutations in the PI3K/Akt/mTOR signaling pathway is also commonly associated with HER2+ breast cancer, as noted in the specification . The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung and Zhu because both references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claim s 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Lambertini et al. ( Adjuvant anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients, JNCI J. Natl. Cancer Inst . 2019 , 111 , 1, djy094). Chung and Zhu disclose a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545, QD on a 28-day cycle, and co-administration of ipatasertib on a 28-day cycle. These references, do not, however, teach where this method is applied to a patient that is premenopausal. Lambertini overcomes this delinquency by teaching treating a cohort of HER2-positive early breast cancer patients, a total of 2862 premenopausal women, receiving adjuvant lapatinib and/or trastuzumab treatment in the BIG 2-06 phase III trial. Approximately 73% of patients were observed to have treatment-related amenorrhea with a statistically significant associated survival benefit (abstract). As such, it would have been prima facie obvious to a person of ordinary skill in the art to recruit a cohort of similar premenopausal women to see if there is a similar occurrence of treatment-related amenorrhea and corollary to therapeutic efficacy and survival rates. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, and Lambertini because all three references are in the same field of endeavor of treating cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claims 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Wedam et al. ( FDA approval summary: palbociclib for male patients with metastatic breast cancer, Clin. Cancer Res . 2020 , 26, 6, 1208-1212). Chung and Zhu disclose a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545, QD on a 28-day cycle, and co-administration of ipatasertib on a 28-day cycle. These references do not, however, teach where the patient is male. This omission is filled by Wedam who discloses the FDA approval of the expansion of palbociclib for use with those indicated with hormone receptor positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor or fulvestrant, to include men (abstract). This expansion in patient demographics came after results of PALMOA-2 and PALMA-3 trials and safety data derived from the global safety database. As such, it would have be en prima facie obvious to a person of ordinary skill in the arts to include a cohort of relevant male patients with the associated indications as part of an evaluation of a novel breast cancer therapy. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, and Wedam because all three references are in the same field of endeavor of treating cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claim 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Jerzak et al. ( HR+/HER2- advanced breast cancer treatment in the first-line setting: expert review, Curr. Oncol. 2023 , 30 , 5425-5447.) and in further view of Shao et al. ( MR imaging phenotypes and features associated with pathogenic mutation to predict recurrence or metastasis in breast cancer, BMC Cancer 2023 , 23 , 97, 1-13). While Chung and Zhu teach a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545 and ipatasertib, these references do not teach testing for estrogen receptor (ER), prostaglandin receptor (PR), and Ki67 mutations in the patient. Jerzak cures a portion of this omission by teaching routinely performing ER/PR testing during the first-line treatment of HR+/HER2- advanced breast cancer while administering ribociclib and aromatase inhibitor therapy as part of a simplified approach to monitoring breast cancer detection and tracking of progression during the therapy period (abstract, Fig. 3). Shao completes this by teaching genetic testing for breast-related gene mutations in 54 patients with breast cancers alongside comparative evaluation of tumors. Ki67 was observed to have a near significant difference between pathogenic mutations and non-pathogenic mutations where women younger than 40 had more pathogenic gene mutations than women over than 40. Pathogenic mutations were therefore more likely to be associated with the triple-negative phenotype than another and were observed in more unfavorable biological behavior in cancer. Additionally, these pathogenic mutations, including Ki67, were more likely to be associated with recurrence or metastasis (results). As such, it would have been prima facie obvious to a person of ordinary skill in the art to combine any experimental therapy, such as the claimed GDC-9545 and abemiciclib combination, with monitoring of ER, PR, and Ki67 levels to provide corollary data possibly predictive of patient outcomes. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, Jerzak, and Shao because all four references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claims 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Davis et al. ( Circulating tumour DNA characterization of invasive lobular carcinoma in patients with metastatic breast cancer, eBioMedicine 2022 , 86 , 104316). While Chung and Zhu disclose a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545 and ipatasertib, these references do not teach applying the method to patients with a mutation or loss of PTEN. Davis redresses this by teaching an analysis of circulating tumor DNA to examine invasive lobular carcinoma and invasive ductal carcinoma histologies and associated genomic mutations including PTEN. They observe, for patients with HR+ HER2- metastatic breast cancer, a higher frequency of PTEN mutations was observed in invasive lobular carcinoma but no significant difference between standard-of-care therapies and an impact on survival. Nonetheless, the differences in genomic profiles across the various breast cancer histologies can guide future precision medicine treatment . As such, it would have be en prima facie obvious to a person of ordinary skill in the art, to consider profiling genomic alterations in the different breast cancer histologies while applying a combinatorial therapy to correlate results and improve patient survival outcomes. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, and Davis because all three references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claims 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Tserga ( Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness, Virchows Arch 2016 , 469 , 35-43) and Dannemann ( Phosphatidylinositol 4,5-bisphosphate (PIP 2 )-specific AKT1 is oncogenic, Int. J. Cancer 2010 , 127 , 1, 239-244). While Chung and Zhu teach a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545 and ipatasertib, these references do not teach application of the method to a patient with tumor containing mutation of AKT1 corresponding to position E17, L52, or Q79. Tserga rectifies this by teaching that AKT1 mutations are commonly observed in breast, ovarian, and colon carcinomas, with the hot spot mutation being p.Glu17Lys, causing substitution of glutamic to lysine. This is supported by the work of Dannemann, identifying the mechanical consequence as greater kinase binding affinity to phosphorylated lipids of phosphatidylinositol. This mutation has been described in 3% of breast cancer cases and correlated with tumor grade and immunoreactivity for HER2. As such, it would have been prima facie for a person of ordinary skill in the art to consider screening patients for this genetic mutation to explore the corollary influence on therapy outcomes. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, Tserga, and Dannemann because all four references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claims 32 - 33 and 49 - 5 1 are rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claims 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Harbeck et al. ( Breast cancer, Nat. Rev. Dis. Primers 2019 , 5, 1, 66). While Chung and Zhu teach a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545 and ipatasertib, these references do not teach the application of the method on patients who had received other chemotherapies or tamoxifen prior to administration. Harbeck addresses this paucity by teaching the mainstays of treatment for HR+/HER2- advanced breast cancer in postmenopausal women prior to 2016 being either endocrine therapy with tamoxifen, cdk4/6 inhibitors, aromatase inhibitors (anastrozole, exemestane, or letrozole) or fulvestrant. Since 2016, Harken notes that CDK4/6 inhibitors, beginning with palbociclib , emerged as first-line treatment of HR+/HER2- metastatic breast cancer in postmenopausal women, followed by ribociclib in 2018 and abemaciclib in 2019. Ribociclib was further approved for first-line treatment in premenopausal women in 2020 . Harbeck notes that management of early breast cancer is based on tumor burden and subtype, that all patients with estrogen receptor-positive disease receive endocrine therapy after surgery and that patients with a high risk of reoccurrence (e.g., high-risk gene expression signature results with 0-3 involved lymph nodes), chemotherapy , such as the combinatorial approach being claimed by the applicant, is highly recommended (management). As such, it would have be en prima facie obvious to a person of ordinary skill in the art to design experiments, utilizing the claimed combination therapy, with patient cohorts as described above with cohorts that had received the established standard-of-care treatments including endocrine therapy agents. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, and Harbeck because all three references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claims 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Guarneri et al . ( HER2DX genomic test in HER2-positive/hormone receptor-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab: a correlative analysis from the PerELISA trial, eBioMedicine , 2022 , 85 , 104320 ). While Chung and Zhu teach a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545 and ipatasertib, they do not teach application of the method where the patient has a reduction in Ki67 in a patient sample after combination therapy. Guarneri a ddress es this paucity in their evaluation of a chemotherapy-free neoadjuvant regimen in HER2-positive/HR+ breast cancer utilizing Ki-67 evaluation . Patients were initially treated with letrazole alone and histology done to determine Ki-67 protein expression. Those with endocrine therapy sensitive disease , defined as those with greater than 20% of Ki-67 as compared to prior to treatment received a combination of trastuzumab and pertuzumab . T he outcome show ed a correlation to the percentage of patients achieving a pathological complete response as compared to those who did not undergo the same treatment. Guarneri notes that these results would assist patients in selecting treatment strategies without chemotherapy in early-stage and advanced HER2-positive/HR+ breast cancer to achieve outstanding long-term survival outcomes. As such, it would be prima facie obvious to a person of ordinary skill in the art to consider monitoring patients ’ Ki-67 protein expression levels as a corollary metric to evaluate their pathological outcomes. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, and Guarneri because all three references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Zhu as applied to claims 1 , 8 - 9 , 13 , and 43 - 4 6 above, and further in view of Saura et al. ( A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors, Cancer Discov . 2017 , 102-113 ). While Chung and Zhu teach a method of treating ER+ and HER2-negative breast cancer utilizing a combination therapy of GDC-9545 and ipatasertib or GDC-9545 alone, they do not teach administration of ipatasertib independently as a fixed QD administration. Saura rectifies this by teaching the use of ipatasertib in a phase I study where patients with a variety of tumors including breast, colorectal, prostate, and ovarian were exposed to 200 mg daily, correlating with a tumor growth inhibition of 90% while PD studies confirmed that multiple targets were inhibited . As such, it would be prima facie obvious to a person of ordinary skill in the art to consider the administration of ipatasertib individually in a daily regimen as a possible comparator to a similarly scheduled individual GDC-9545 administration. The person of ordinary skill in the art at the time of the effective filing date of the instant application would have had a reasonable expectation of success in combining the teachings of Chung, Zhu, and Saura because all three references are in the same field of endeavor of treating/diagnosing cancer and more specifically cancers characterized by particular genetic mutations, as described above. 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 . Claim s 1 , 3 , 9 , and 13 are rejected on the ground of nonstatutory double patenting a s being unpatentable over claim s 1 , 3 , 11 , and 13 of U.S. Patent No. 18/449,793 (“Co-pending ‘793”) in view of Kim et al. ( Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomized, double-blind, placebo-controlled, phase 2 trial, Lancet Oncol. 2017 , 18 , 1360-1372) and Harbeck et al. ( Breast cancer, Nature Reviews Disease Primers 2019 , 5 , 66, 1-31) . Although the claims at issue are not identical, they are not patentably distinct from each other because both applications claim QD dosing of GDC-9545 at 10, 30 50, or 100 mg, in the same HER2-negative locally advanced breast cancer or metastatic breast cancer models in a patient having ER+ and HER2-negative locally advanced breast cancer or metastatic breast cancer on a 28-day cycle, in combination with either abemeciclib/ribociclib or ipatasertib. Abemeciclib and ribociclib have been reported by Harbeck to have been used as standard-of-care adjuvant therapy in conjunction with endocrine therapy. Kim has explored ipatasertib in combination with paclitaxel as a first-line therapy for metastatic triple-negative breast cancer. Both illustrate the potential benefits of using a combination approach toward breast cancer therapy with other theranostic agents without obvious liabilities. As such, it would have be en prima facie for a person of ordinary skill in the art to modify the cited claims in this rejection of Co-pending ‘793 and consider utilizing either abemciclib/ribociclib or ipatasertib in combination with GDC-9545 to explore synergistic therapeutic effects for breast cancer treatments . Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT Allen Chao whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-7001 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday 0700-1300 . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ALLEN CHAO/ Examiner, Art Unit 1622 /JAMES H ALSTRUM-ACEVEDO/ Supervisory Patent Examiner, Art Unit 1622