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 RCE filed 20 August 2026 for application 18/449,793 filed 15 August 2023. Claims 1-10, 12, 14-17, 19, 22-34 and 38-47 are canceled. Claims 55-56 are amended. Currently, claims 11, 13, 18, 20-21, 35-37 and 48-56 are pending.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 20 August 2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 20 August 2026 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.
REJECTIONS – MAINTAINED & NEW
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Maintained) Claims 11, 13, 20-21, 35-37, and 48-56 are rejected under 35 U.S.C. 103 as being unpatentable over Chung et al. (Solid forms of 3-(1R,3R)-1-(2,6-djfluoro-4-((1-(3-fluoropropyllazetidine-3-yl)amino)phenyl)-3-metyl-1,3,4,9-tetrahydro-2H-pyridof3,4-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, WO 2019/245974A1, 2019; entered in the IDS on 22 November 2023) in view of Bardia et al. (Phase lb dose-escalation/expansion trial of Ribociclib in combination with Everolimus and Exemestane in postmenopausal women with HR+, HER2⁺ advanced breast cancer, Clin. Cancer Res. 2020, 26, 6417-6428).
Chung discloses methods of treating ER+, HER2+, HER2, TN (para. 0388), locally advanced or metastatic breast cancers (para. 0390) through the administration of an effective amount of GDC-9545, which can include 30 mg (para. 0393), QD on 28-day cycles (para. 0726), in a combinational therapy (para. 0398) with CDK4/6 inhibitors Abemaciclib and Ribociclib (para. 0402), where Abemaciclib can be dosed 150-450 mg, BID daily in 28-day cycles (para. 0403), and Ribociclib can be dosed 250-750 mg, QD daily in 28-day cycles (para. 0404). The receiving patient may have previously been treated, with a 1L, 2L, 3L or more line therapy with an AKT inhibitor, CDK4/6 inhibitor, PARP inhibitor, or aromatase inhibitor (para. 0395) and may be refractory to the anti-cancer therapy (para. 0396).
Chung does not, however, disclose where the cancer is inoperable.
Bardia rectifies this deficiency by teaching the clinical design and results of a phase lb dose-escalation/expansion study of triplet therapy with Ribociclib, mTOR inhibitor Everolimus, and endocrine therapy Exemestane for postmenopausal women with HR+, HER2, pretreated, advanced breast cancer. Within the key inclusion data included postmenopausal and adult women (≥18 years of age) with HER2 locally advanced or metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy who experienced recurrence during, or within 12 months of ending, adjuvant treatment with letrozole or anastrozole, or progression during or within one month of stopping, letrozole or anastrozole treatment for advanced breast cancer, with radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrollment (pg. 6418 - Patient Population).
While the combinational therapy is different as the target includes HR+ breast cancer, the framework of treatment, utilizing a CDK4/6 inhibitor in combination with another treatment to target HER2- breast cancer, broadly reads upon the methods of claim 11 and 13.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the addition of inoperable cancers as an inclusive criterion in the selection of patients based on the prior clinical trial patient inclusion criteria in a clinical trial for the treatment of advanced breast cancer using a combinational therapy which included a CDK4/6 inhibitor.
(Maintained) With regards to the limitation of claim 20, wherein the patient is premenopausal, is met by Bardia who teaches the inclusion of both postmenopausal and adult women who are ≥18 years of age, necessarily premenopausal (pg. 6418- Patient Population).
(Maintained) Pertaining to the limitations of claim 21, wherein the patient is tested for the presence of a mutation of one or more of estrogen receptor, prostaglandin receptor, or Ki67, are met as Chung discloses treatment of a patient diagnosed with ER+PR+ breast cancer (para. 0728).
(Maintained) With respect to the limitation of claim 35, wherein the patient has been previously treated with tamoxifen, is met by Chung who discloses that the patients of the described methods may have had previous treatment with one or more anti-cancer agents including tamoxifen (para. 0394).
(Maintained) Concerning the limitations of claim 36, wherein the patient has been previously treated with an aromatase inhibitor or an aromatase inhibitor in combination with a CDK4/6 inhibitor, are met as Chung discloses that the patients of the described methods may have been previously treated with one or more anti-cancer agents including letrozole, anastrozole, or exemestane, which are aromatase inhibitors (para. 0394).
(Maintained) Regarding the limitations of claim 37, wherein the patient has been previously treated with fulvestrant, is met as Chung discloses that a patient may have been previously treated with fulvestrant (para. 0395).
(Maintained) With regards to the limitations of claim 48, wherein the patient is premenopausal, is met by Bardia who teaches the inclusion of both postmenopausal and adult women who are ≥18 years of age, necessarily premenopausal (pg. 6418- Patient Population).
(Maintained) Pertaining to the limitations of claim 49, wherein the patient is tested for the presence of a mutation of one or more of estrogen receptor, prostaglandin receptor, or Ki67, are met as Chung discloses treatment of a patient diagnosed with ER+PR+ breast cancer (para. 0728).
(Maintained) With respect to the limitations of claim 50, wherein the patient has been previously treated with tamoxifen, is met by Chung who discloses that the patients of the described methods may have had previous treatment with one or more anti-cancer agents including tamoxifen (para. 0394).
(Maintained) Concerning the limitation of claim 51, wherein the patient has been previously treated with an aromatase inhibitor or an aromatase inhibitor in combination with a CDK4/6 inhibitor, are met as Chung discloses that the patients of the described methods may have been previously treated with one or more anti-cancer agents including letrozole, anastrozole, or exemestane, which are aromatase inhibitors (para. 0394).
(Maintained) Regarding the limitation of claim 52, wherein the patient has been previously treated with fulvestrant, is met as Chung discloses that a patient may have been previously treated with fulvestrant (para. 0395).
(Maintained) With regards to the limitation of claim 53, wherein the patient has not undergone breast conserving surgery or had a mastectomy before treatment with Giredestrant and Abemaciclib, is met as Bardia teaches the inclusion of women with locally advanced or metastatic breast cancer not amenable to curative treatment by surgery.
(Maintained) With respect to the limitation of claim 54, wherein the patient has not undergone breast conserving surgery or had a mastectomy before treatment with Giredestrant and Ribociclib, is met as Bardia teaches the inclusion of women with locally advanced or metastatic breast cancer not amenable to curative treatment by surgery.
(Maintained) Concerning the limitation of claim 55, wherein the ER+ and HER2-negative inoperable laBC or mBC comprises an ESR1-mutation, is met as Chung discloses that studies have identified mutations in ESR1 (i.e., the gene that encodes for Erα) affecting the ligand-binding doman of the ER, where mutant ER can drive transcription and proliferation in the absence of estrogen, suggesting that LBD-mutant forms of ER may be involved in mediating clinical resistance to some endocrine therapies, and that ER antagonists that are efficacious against these ligand- independent, constitutively-active ER-mutated receptors may possess substantial therapeutic benefit (para. 0707). Chung also discloses that GDC-9545 also demonstrated nonclinical activity in ER-positive breast cancer models of ESR1-wildtype and ESR1-mutation bearing disease (para. 0721).
(Maintained) Concerning the limitation of claim 56, wherein the ER+ and HER2-negative inoperable laBC or mBC comprises an ESR1-mutation, is met as Chung discloses that studies have identified mutations in ESR1 (i.e., the gene that encodes for Era) affecting the ligand-binding domain of the ER, where mutant ER can drive transcription and proliferation in the absence of estrogen, suggesting that LBD-mutant forms of ER may be involved in mediating clinical resistance to some endocrine therapies, and that ER antagonists that are efficacious against these ligand- independent, constitutively-active ER-mutated receptors may possess substantial therapeutic benefit (para. 0707). Chung also discloses that GDC-9545 also demonstrated nonclinical activity in ER-positive breast cancer models of ESR1-wildtype and ESR1-mutation bearing disease (para. 0721).
(Maintained) Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Bardia as applied to claim 11, 13, 20-21, 35-37, and 48-56 above, and further in view of O'Kane et al. (A single-centre analysis of 30 patients with relapsed germ cell tumours treated with the TI-CE regimen, Bone Marrow Transplantation 2016, 51, 6, 856-859).
Chung teaches a method of treating ER+ and HER2- breast cancer utilizing a combination therapy of GDC-9545, dosed QD on a 28-day cycle, and co-administration of Abemaciclib or Ribociclib, dosed BID on the same 28-day cycle, for patients who have been previously treated with a 1L or 2L line therapy with a CDK4/6 inhibitor and are refractory to the anti-cancer therapy, while Bardia teaches the inclusion of patients with inoperable cancers.
They do not, however, teach the application of this dosing regimen over a range of 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, and 72 cycles.
O'Kane rectifies this deficiency by teaching a TI-CE regimen applied from 1998 to 2015 at the National Adult SCT center at St James's Hospital in Dublin. The TI aspect, two cycles of taxol (paclitaxel/ifosfamide) followed by three cycles of the CE aspect (carboplatin/etospide) as a means to treat germ cell tumors, common malignancies in young men between 15-35 years. With a cohort of 30 patients, a total of 81 out of a planned 90 cycles were performed, with a 72% survival rate (discussion). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant application. MPEP § 2144.05.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider an extended treatment period to observe the longitudinal outcomes including ORRs, survival rates, and AEs.
(Maintained) Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Bardia as applied to claim 11, 13, 20-21, 35-37, and 48-56 above, and further in view Lambertini et al. (Adjuvant anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients, J. Natl. Cancer Inst. 2019, 111, 1djy094).
Chung teaches a method of treating ER+ and HER2⁻ breast cancer utilizing a combination therapy of GDC-9545, dosed QD on a 28-day cycle, and co-administration of Abemaciclib or Ribociclib, dosed BID on the same 28-day cycle, for patients who have been previously treated with a 1L or 2L line therapy with a CDK4/6 inhibitor and are refractory to the anti-cancer therapy, while Bardia teaches the inclusion of patients with inoperable cancers.
Lambertini reinforces this 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 BIG2-06 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, before the effective filing date, to potentially recruit a cohort of similar premenopausal women to see if there is a similar occurrence of treatment-related amenorreha and corollary to therapeutic efficacy and survival rates.
(Maintained) Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Bardia as applied to claim 11, 13, 20-21, 35-37 and 48-56 above, and further in view Jerzak et al. (HR+/HER2- advanced breast cancer treatment in the first-line setting: expert review, Curr. Oncol. 2023, 30, 5425-5447) and 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).
Chung teaches a method of treating ER+ and HER2- breast cancer utilizing a combination therapy of GDC-9545, dosed QD on a 28-day cycle, and co-administration of Abemaciclib or Ribociclib, dosed BID on the same 28-day cycle, for patients who have been previously treated with a 1L or 2L line therapy with a CDK4/6 inhibitor and are refractory to the anti-cancer therapy, while Bardia teaches the inclusion of patients with inoperable cancers.
Jerzak reinforces this 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 further reinforces this by teaching genetic testing for breast-related gene mutations in 54 patients with breast cancers alongside comparative evaluation of tumors. Ki67 was observed 0 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 40. Pathogenic mutations were therefore more likely to be associated with the TN 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, before the effective filing date, to combine any experimental therapy, such as the claimed GDC-9545 and Abemaciclib combination, with monitoring of ER, PR, and Ki67 levels to provide corollary data possibly predictive of patient outcomes.
(Maintained) Claims 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Chung and Bardia as applied to claim 11, 13, 20-21, 35-37 and 48-56 above, and further in view Harbeck et al. (Breast cancer, Nat. Rev. Dis. Primers 2019, 5, 1, 66).
Chung teaches a method of treating ER+ and HER2 breast cancer utilizing a combination therapy of GDC-9545, dosed QD on a 28-day cycle, and co-administration of Abemaciclib or Ribociclib, dosed BID on the same 28-day cycle, for patients who have been previously treated with a 1L or 2L line therapy with a CDK4/6 inhibitor and are refractory to the anti-cancer therapy, while Bardia teaches the inclusion of patients with inoperable cancers.
Harbeck reinforces this by teaching the mainstay of treatment for HR+/HER2- advanced breast cancer in postmenopausal women prior to 2016 being either endocrine therapy with Tamoxifen, aromatase inhibitors (Anastrozole, Exemestane, or Letrozole) or Fulvestrant. Since 2016, Harken notes that CDK4/6 inhibitors, beginning with Pabociclib, 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. These studies are done in comparison to vehicle cohorts in clinical trials, i.e., patients who receive either a placebo or no treatment (management).
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to design experiments, utilizing the claimed combination therapy, with patient cohorts as described above, with a vehicle cohort, and other cohorts that had received the established standard-of-care treatments including endocrine therapy agents or CDK4/6 inhibitors which have been established for the past two decades.
Response to Arguments
The office kindly thanks the Applicant for their consideration and arguments to the previous office action. Responses are detailed below.
Applicant’s arguments, see pg. 5 – objections to the claims/specification, filed 20 August 2026, with respect to claim 55 have been fully considered and are persuasive. The objection of claim 55 has been withdrawn.
Applicant’s arguments, see pg. 6-7 – double patenting, filed 20 August 2026, with respect to claims 11 and 13 have been fully considered and are persuasive. The double patenting rejection of claims 11 and 13 has been withdrawn.
Applicant's arguments filed 20 August 2026 have been fully considered but they are not persuasive.
On pgs. 5-6, rejections under 35 U.S.C. § 103, filed 20 August 2026, the Applicant argues:
… Bardia teaches a combination comprising the aromatase inhibitor, exemestane, in combination with ribociclib AND the mTOR inhibitor, everolimus… fails to teach any combination with Abemaciclib… same outcome would be expected for a patient treated with GDC-9545 and abemaciclib… teaches triplet combination specifically… nothing in Bardia suggests that treatment with a selective estrogen receptor degrader (SERD), like GDC-9545 in combination with abemaciclib or ribociclib as a doublet would be effective…. replacing any of the agents … would be effective or safe… mTOR inhibitor is needed to yield an effective treatment and that the triplet combination is only effective with ribociclib, exemestane, and everolimus…
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Bardia presents a case where combinatorial therapy including a CDK4/6 inhibitor on patients who have already demonstrated disease progression despite prior single agent therapy. By doing so, Bardia motivates the person of ordinary skill in the art to consider combinatorial therapy for such patients, not that success is limited only to the parameters of the Bardia study. Rather, it is the teachings of Chung where the combinatorial study of abemaciclib or ribociclib with GDC-9545 is obtained which are reinforced by experimental results of Bardia who concludes that triplet therapy with endocrine therapy, mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women that encountered CDK4/6 resistance (abstract).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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