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 .
Status of Claims
Claims 1-6, 9-11, and 14-29 are pending.
Priority
Instant application 18/323,674, filed 05/25/2023 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 08/01/2023, 09/25/2023, 08/23/2024, and 01/08/2026 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6, 9-11, 14-24, and 26-29 in the reply filed on 01/08/2026 is acknowledged. The election of the species of ESR1 mutation Y537S and the species of gene having an oncogenic mutation TP53 is also acknowledged. However, in the course of the search, the election of species requirement was withdrawn.
In view of the election of Group I, claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/08/2026.
Claim Objections
Claim 22 is objected to because of the following informalities: claim 22 contains a typographical error in line 2. The term “sale” should instead read “salt”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-15 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 depends from the method of claim 1 and further specifies “wherein the cancer has previously been determined to have at least one mutation in the Estrogen Receptor 1 (ESR1) gene”. Claim 14 fails to further limit claim 1 because claim 1 already requires that the cancer (in the patient being treated) has at least one mutation in the Estrogen Receptor 1 (ESR1) gene. Similarly, claim 15 depends from the method of claim 14 and recites an earlier step of “determining that the patient has at least one mutation in the Estrogen Receptor 1 (ESR1) gene”. Claim 15 fails to further limit claims 1 and 14, because claim 1 already requires that the cancer (in the patient being treated) has at least one mutation in the Estrogen Receptor 1 (ESR1) gene.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 27-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NCT04432454 (first posted June 16, 2020; cited in IDS).
NCT04432454 evaluates the combination of lasofoxifene with abemaciclib in treating locally advanced and/or metastatic ER+/HER2- breast cancer with an ESR1 mutation. The cancer may have progressed on no more than 2 of the following endocrine treatments for metastatic breast cancer: an aromatase inhibitor (AI) and/or fulvestrant either as monotherapy or in combination with any commercially approved CDKi. The inclusion criteria include:
“At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. Note: the Sponsor's blood ctDNA assay must be used but tissue sequencing (if done) may be done by a validated commercial laboratory.” The lasofoxifene was administered at a dosage of 5 mg orally daily and abemaciclib was given 150 mg twice orally daily.
NCT04432454 therefore anticipates claims 27-29, which require administering a CDK4/6 inhibitor (abemaciclib) and an effective amount of lasofoxifene to a breast cancer patient, wherein the breast cancer is ER+ and has at least one ESR1 point mutation in the ligand binding domain.
Claim Rejections - 35 USC § 103
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.
Claims 1-6, 9-11, 14-22, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04432454 (first posted June 16, 2020; cited in IDS) in view of Andreano et al. (WO 2019199891 A1; published 2019; cited in IDS).
NCT04432454 evaluates the combination of lasofoxifene with abemaciclib in treating locally advanced and/or metastatic ER+/HER2- breast cancer with an ESR1 mutation. The cancer had progressed on 1st and/or 2nd lines of hormonal treatment. The inclusion criteria include: “At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. Note: the Sponsor's blood ctDNA assay must be used but tissue sequencing (if done) may be done by a validated commercial laboratory.” The lasofoxifene was administered at a dosage of 5 mg orally daily and abemaciclib was given 150 mg twice orally daily.
While NCT04432454 discloses an inclusion criterion of, inter alia, progression on fulvestrant either as monotherapy or in combination with any commercially approved CDKi, NCT04432454 fails to specifically disclose progression with a CDK4/6 selected from palbociclib or ribociclib. However, the only commercially approved CDKi for HR+/HER2- breast cancer are three CDK4/6 inhibitors: abemaciclib, palbociclib, and ribociclib.
Andreano is drawn to treatment of ER+ breast cancer in patients with ESR1 gene mutations comprising administering lasofoxifene (title, abstract). Andreano teaches embodiments wherein the patient has locally advanced or metastatic ER+/HER2- breast cancer, wherein the patient has progressed on her first hormonal treatment while on fulvestrant in combination with a CDK4/6 inhibitor (para. [0033]; claims 72-73). Andreano additionally teaches treating the patient with lasofoxifene and an effective amount of CDK4/6 inhibitor, wherein the said CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib (e.g. para. [0031], [0032], [0037], claims 51-52).
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A) and/or (G), it would have been prima facie obvious to administer an effective amount of lasofoxifene or pharmaceutically acceptable salt thereof with an effective amount of abemaciclib to a patient having ER+ breast cancer with at least one mutation in the ESR1, wherein the cancer has progressed during prior CDK4/6 inhibitor therapy, wherein the prior CDK4/6 inhibitor therapy is palbociclib or ribociclib. Each of the recited elements are taught by the combination of NCT04432454 and Andreano. A person having ordinary skill would have been motivated to administer the combination to claimed the patient population with a reasonable expectation of success in view of the combination of NCT04432454 and Andreano.
Note also MPEP 2107.03, which states “Before a drug can enter human clinical trials, the sponsor, often the applicant, must provide a convincing rationale to those especially skilled in the art (e.g., the Food and Drug Administration (FDA)) that the investigation may be successful. Such a rationale would provide a basis for the sponsor’s expectation that the investigation may be successful. In order to determine a protocol for phase I testing, the first phase of clinical investigation, some credible rationale of how the drug might be effective or could be effective would be necessary. Thus, as a general rule, if an applicant has initiated human clinical trials for a therapeutic product or process, Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility.”
Therefore claims 1-4, 22, and 26 are obvious over NCT04432454 in view of Andreano.
With respect to claims 5-6, Andreano teaches administering lasofoxifene as lasofoxifene tartrate (e.g. para. [0036], claim 75); and both NCT04432454 and Andreano teach administering 5 mg lasofoxifene/day.
With respect to claims 9-11, NCT04432454 teaches administering 150 mg abemaciclib orally at 150 mg BID.
With respect to claims 14-17, both NCT04432454 and Andreano teach determining that the patient has at least one mutation in the ESR1, wherein the mutation is selected from Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N.
With respect to claim 18, both NCT04432454 and Andreano teach treating metastatic cancer. A person having ordinary skill would reasonably expect that treating metastatic cancer includes treating visceral metastatic cancer.
With respect to claims 19-21, both NCT04432454 and Andreano teach treating patients who have progressed on one or more prior endocrine therapies, including the SERD fulvestrant.
Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04432454 (first posted June 16, 2020; cited in IDS) in view of Andreano et al. (WO 2019199891 A1; published 2019; cited in IDS), and further in view of Wander et al. (Journal of the National Comprehensive Cancer Network, Mar. 2021, pp. 1–8; cited in IDS)
The teachings of NCT04432454 in view of Andreano are disclosed above and at least those teachings are incorporated herein by reference and applied to claims 23-24. NCT04432454 and Andreano teach treating breast cancer in an ER+ patient with at least one mutation in the ESR1, wherein the patient has progressed during prior CDK4/6 inhibitor therapy.
With respect to claims 23-24, NCT04432454 and Andreano do not explicitly disclose treating patients having breast cancer with an additional oncogenic mutation in a gene other than the ESR1, or with increased expression of a gene other than the ESR1.
However, Wander teaches clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer (title, abstract), and teaches that clinical resistance to CDK4/6 inhibitors may be mediated by inactivation of RB1; overexpression of CDK6, CCNE1/2, and aurora kinase A; and mutational activation of FGFR, ERBB2, AKT1, and RAS family oncogenes (page 2, left col., 3rd para.) Wander additionally teaches that administering abemaciclib to patients after prior progression on a CDK4/6i was well tolerated and a clinical benefit was identified in a meaningful subset of patients (36.8%, page 7, right col, 2nd para.).
Applying KSR example rationale (G), it would have been prima facie obvious to administer an effective amount of lasofoxifene or pharmaceutically acceptable salt thereof with an effective amount of abemaciclib to a patient having ER+ breast cancer with at least one mutation in the ESR1, wherein the cancer has an oncogenic mutation in one or more genes other than the ESR1 gene, or wherein the cancer has increased expression of one or more genes other than the ESR1 gene. The combination of NCT04432454 and Andreano teaches that the lasofoxifene in combination with abemaciclib has utility for treating patients with prior progression on a CDK4/6i, and Wander teaches oncogenic mutations and/or increased expression in genes associated with progression on a CDK4/6i (e.g. inactivation of RB1; overexpression of CDK6, CCNE1/2, and aurora kinase A; and mutational activation of FGFR, ERBB2, AKT1, and RAS). A person having ordinary skill in the art would have enjoyed a reasonable expectation of success in treating some patients with prior progression on a CDK4/6i having an oncogenic mutation or increased expression of the genes identified in Wander.
Conclusion
Claims 1-6, 9-11, and 14-24, and 26-29 are rejected. Claim 25 is withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621