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 .
Application Status
The amendment filed on 12/18/2025 in response to the Non-Final rejection of 9/11/2025 is acknowledged and has been entered. Claims 1-2, 4-6, 8-11, 15-16, 19 and 28-33 are currently pending and under consideration.
Rejections Withdrawn in view of Applicants amendments/arguments
All previous rejections have been withdrawn in view of Applicants arguments/amendments to the instant claims, wherein claim 1 has been amended to require a determining step a first mutant allele frequency (“MAF”) value of a first ERa mutant and a second Era mutant in the patient, and administering to the patient a therapeutically effective amount of compound 1 if the first “MAF” value is greater than or equal to 0.5% and the second MAF value is less than 0.5%.
New Rejections necessitated by the Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-6, 8-11, 15-16, 19 and 28-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating PgR positive breast cancer comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a patient, wherein the method comprises determining a first mutant allele frequency (“MAF”) of an ERa mutant Y537S or a first MAF of an ERa mutant D538G and a second MAF value of a second ERa mutant, and administering to the patient a therapeutically effective amount of compound 1 if the first MAF value is greater than or equal to 0.5% and the second MAF value is less than 0.5%, wherein the compound is not administered if the MAF value for both Y537S and D538G are above 0.5%, does not reasonably provide enablement for the instant method as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed toward a method of treating cancer, generally, in a patient comprising administering compound 1, but only when a first mutant allele frequency (“MAF”) value of a first ERalpha mutant is greater than or equal to 0.5% AND a second MAF value of a second ERalpha mutant is less than or equal to 0.5%. Thus, the claims encompass a predictive method for the treatment of cancer based on parameters, MAF values, for a first and second ER alpha mutant.
Thus, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Prior Art
Regarding compound 1 as claimed, Bock et al. (US2016/0347717A1, 2016-12-01, IDS, cited in the prior office action) teach compounds and methods of using the compounds to treat breast cancer by administration of a therapeutically effective amount of the compound, wherein the breast cancer is an ER-positive breast cancer or the cancer expresses a mutant ER-a protein (abstract). With regards to the compounds, Bock et al. teach that compounds include, but are not limited to, a compound having the formula
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referred to as compound 60 which appears to be identical to compound 1 of the instant application (page 26). In particular, Brock teaches in vivo model showing the anti-tumor activity of compound 60, wherein the Patient-Derived Xenograft (PDX) tumor model, WHIM20, representing an ESR1-Y537S mutated ER+ breast cancer was propagated in mice followed by oral administration of compound 60 ever day at indicated doses (paragraphs 0859-0860 and 0876). Thus, the prior art teaches treating ER-positive breast cancer or the cancer expresses a mutant ER-a protein, but does not teach administration of the compound based on MAF values as claimed.
Regarding the ER-a mutations, Brock et al. teach that ER-a mutations include, but are not limited to, L536Q , L536R, Y537S, Y537N, Y537C and D538G (paragraph 0116). Moreover, Chandrarlapaty et al. (JAMA Oncol. 2016:2(10):1310-1315, cited in the previous office action) analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double blind phase 3 study that randomized patients from 189 centers in 24 countries with metastatic breast cancer (MBC) to exemestane plus placebo or exemestane plus everolimus and assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by the treatment arm (page 1310, Design, Setting, and Participants). Moreover, the reference teaches that an ESR1 mutation (Y537S and/or D538G) was detected in 28.8% of the samples, wherein D538G was the more prevalent mutations occurring in 21.1%, whereas Y537S occurred in 13.3% and both mutation were identified in 30 patients (5.5%) (page 312, 2nd column, 1st full paragraph). Interestingly, the reference teaches that there was a notable difference associated with mutation prevalence and line of therapy, wherein there was a 3 fold increase in mutation prevalence in patients who had failed first line therapy for metastatic disease (33% were mutant) compared with those who were initiating first-line treatment for MBC (11% were mutant), in whom exposure to AI (aromatase inhibitor exemestane) therapy only occurred in the adjuvant setting (page 312, 2nd column, 2nd full paragraph). Moreover, the reference teaches that D538G and Y537S mutations were associated with shorter overall survival (wild-type, 32.1 months; D538G, 25.99 months; V537S, 19.8 months; both mutations, 15.15 months). Finally, the reference acknowledges the ease and feasibility with which the biomarkers was able to be obtained via cfDNA (page 1314, 2nd column, last paragraph). Thus, while Chandrarlapaty et al. teach the prognostic value of ESR1 mutations, Chandrarlapaty et al. is silent regarding the predictive value of ESR1 mutations for therapeutic interventions.
Predictability in the Art
Santo et al. (Cancers 2019; 11: 1894) reviewed the emerging role of ESR1 mutations in Luminal breast cancer as a prognostic and predictive biomarker of response to endocrine therapy (title). Specifically, Santo et al. notes that a biomarker is defined as prognostic if it provides information about cancer outcome regardless of therapy, whereas a predictive biomarker is prospectively reflective of the effect of a therapeutic intervention (page 2 of 15, last paragraph). Regarding the predictive value, Santo et al. teach that the available data suggests that baseline ESR1 mutations do not hold predictive value as biomarkers for CDK4/6 inhibitor therapy, but the dynamic changes in mutational ctDNA on treatment may be a biomarker of response or resistance to CDK4/6 inhibitor treatment (page 10 of 15, Conclusion).
Thus, in view of the teachings of Santo et al., there is no clear predictive value of ERalpha mutations relating to therapeutic intervention.
Working Examples
The instant specification provides a single example of the effect of clonal Y537S and clonal D538G ESR1 mutations in subjects who started at a 450 mg dose of compound 1 (Example 2). Specifically, the specification teaches that after trying each one of the ESR1 mutants, only Y537S had a MAF value >=0.5% or when D538G had a MAF value >= 0.5% did the test predict a favorable outcome for the patient, wherein the highest clinical benefit was observed in subjects with tumors that were PgR+ and carried clonal ESR1 Y537S or D538G mutations, and not concurrently both ESR1 Y537S and D538G mutations.
Direction and Guidance
In view of the single example showing the effectiveness of only Y537S having a MAF value >=0.5% or D538G having a MAF value >= 0.5% for predicting a favorable outcome, there is minimal direction provided by the inventor for the invention as broadly claimed.
Quantity of Experimentation
In view of the unpredictability of the art in using ERalpha mutations to predict therapeutic intervention, the amount of experimentation required would be astronomical. This amounts to invention, not development; it is an undue amount of experimentation.
Thus, while the specification provides enablement for a method of treating PgR positive breast cancer comprising administering compound 1 or a pharmaceutically acceptable salt thereof to a patient, wherein the method comprises determining a first mutant allele frequency (“MAF”) of an ERa mutant Y537S or a first MAF of an ERa mutant D538G and a second MAF value of a second ERa mutant, and administering to the patient a therapeutically effective amount of compound 1 if the first MAF value is greater than or equal to 0.5% and the second MAF value is less than 0.5%, wherein the compound is not administered if the MAF value for both Y537S and D538G are above 0.5%, does not reasonably provide enablement for the instant method as claimed..
Conclusion
Therefore, No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626