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 .1
Status of the Claims
Claim(s) 1-5,7-14,16-19 and 21-23 are pending/under examination.
Election/Restrictions
Applicant’s election without traverse of the species alpelisib in the reply filed on March 2 2026 is acknowledged.
Information Disclosure Statements
The information disclosure statement(s) (IDSs) submitted on Sept 9 2025 and June 18 2024 is/are in compliance with the provisions of 37 CFR § 1.97. Enclosed with this Office Action is a return-copy of the PTO-1449 Forms with the Examiner's initials and signature indicating those references that have been considered.
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 1-5, 7-14, 19 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/007146 A1 (WO 146) in view of Takebe et al. Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors Oncotarget. 2021 Feb 16;12(4):268-277 and Markham Alpelisib: First Global Approval Drugs (2019) 79:1249–1253, as evidenced by Walpole et al. The weight of nations: an estimation of adult human biomass BMC Public Health 2012, 12:439. Pp. 1-6. Markham is cited on the PTO-892 form. Takebe and Walpole are cited on the IDS dated Sept 9 2025 (NPL Ref. 3). WO 146 is cited on the IDS dated Sept 9 2025 (For Ref 1).
Regarding claims 1-4 and a method of treating ovarian cancer in a subject in need comprising WO 146 administering to the subject a therapeutically effective amount of endoxifen (Z enantiomer per claim 2) and a phosphoinositide 3-kinase inhibitor (alpelisib per claims 3-4), WO 146 teaches a method of treating a subject suffering from cancer with the claimed combination of endoxifen, including a PI3K inhibitor. See claims 5-6 and 12. WO 146 teaches the claimed PI3Kc inhibitor, alpelisib. See claim 13.
While specifically teaching the claimed combination administered to a cancer subject in need, it does not exemplify an ovarian cancer subject. However, a person having ordinary skill in the art (PHOSITA) would have a rationale to treat such patients.
Takebe teaches the use of Z-endoxifen for the treatment of ovarian cancer. See title and abstract.
Markham teaches alpelisib was at the time of its publication, in clinical trials for the treatment of high grade serous ovarian cancer. See page 1253, column 1.
Prior to the filing of the instant application a PHOSITA following the teachings of WO 433, Takebe and Markham would have found it prima facie obvious to administer such a combination of endoxifen and alpelisib to treat ovarian cancer, because such a combination and treatment of ovarian cancer is/are known. The rationale to do so is per MPEP 2143 (a) combining prior art elements according to known methods to yield predictable results, i.e. where it is predictable to arrive at the claimed combination in the to treat ovarian cancer.
Regarding claims 5 and 7, WO 146 teaches various routes of administration such as oral, parenteral, etc. See paragraphs 24-25.
Regarding claims 8-9, while WO 146 does not explicitly recite the terms sustained and/or delayed release, WO 146 teaches excipients, as well as formulation forms that are known to a PHOSITA used in sustained/delayed release formulations. See paragraph 28 for examples of pharmaceutically acceptable carriers that include excipients such as starches, various types of cellulose and suppository waxes.
Regarding claim 10, WO 146 teaches the composition is administered once daily. See paragraph 22.
Regarding claims 11-14 and the ranges of endoxifen doses administered, WO 146 teaches doses (30 mg/kg, 10 mg/kg or 1 mg/kg or less) that encompass/overlap the ranges claimed. See claims 18-20. As evidenced by Walpole2 Table 3, where average body mass (kg) is 62 kg overall worldwide, a PHOSITA would routinely arrive at the claimed doses based off known human mass in kg.
Regarding claims 16-18, Markham teaches:
The recommended dose of alpelisib is 300 mg once daily taken with food. In the event of adverse reactions requiring a reduction in dose the dose of alpelisib should be reduced first to 250 mg once daily and then to 200 mg once daily. See page 1249, column 2.
Regarding claims 19 and 21, Markham teaches alpelisib is administered once daily. See page 1249, column 2. Takebe teaches oral Z-endoxifen doses daily. See abstract. Also note that WO 146 teaches a dosing or therapeutic regimen that involves one or more doses. See paragraph 22, where it notes that a given therapeutic agent which may involve one or more doses, thus allowing for multiple doses per day as claimed, or once per day dosing.
With regard to claim 22 and the limitation of administration of the combination for at least 28 days, WO 146 teaches administration for at least once monthly dosing, which suggests administration for at least 28 days. See claim 24.
With regard to claim 23 and a single tablet of the combination, WO 146 teaches the combination composition is a tablet. See claim 28.
Claims 1-5, 7-14, 19 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/003433 (WO 433).
WO 433 is cited on the IDS dated June 18 2024 (For Ref 14).
Regarding claims 1-4, WO 433 teaches a sustained release composition comprising Z-endoxifen (see claim 1) further suggests, and alpelisib (see paragraphs 341, 346 and 349). Regarding claims 1-4, WO 433 teaches a specific embodiment, where the disorder to be treated is ovarian cancer. See paragraph 295.
While WO 433 does not teach a specific exemplification of Z-endoxifen with alpelisib, specifically treating ovarian cancer, it does teach the combination of the two as noted above with an embodiment to treat ovarian cancer.
Prior to the filing of the instant application a PHOSITA following the teachings of WO 433 would have found it prima facie obvious to form such a combination, despite the working examples of WO 433 not disclosing one was done. The rationale to do so is per MPEP 2143 (a) combining prior art elements according to known methods to yield predictable results, i.e. where it is predictable to arrive at the claimed combination.
Regarding claims 5 and 7, WO 433 teaches oral administration. See paragraph 25, 27 etc.; claims 50, 52, 54 and 59.
Regarding claims 8-9, WO 433 teaches a sustained release composition, see claims 1-69; WO 433 teaches a delayed release formulation, see multiple references including Figures 1-2, paragraph 38-40, etc.
Regarding claim 10, WO 433 suggests concurrent chemotherapy. See paragraph 452. A person having ordinary skill in the art (PHOSITA) would routinely optimize concurrent chemotherapy to daily administration of both endoxifen and PI3K inhibitor (alpelisib).
Regarding claims 11-14 and the ranges of endoxifen doses administered, WO 433 teaches dose ranges that encompass/overlap those claimed. See paragraph 35 and claim 71.
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Regarding claims 19 and 21, where endoxifen or PI3K inhibitor is administered two to four times a day, or once per day, WO 433 dosing once, twice or three times a day. See paragraph 332. See also claim 70, noting once, twice per day, every 2, 3, 4, 5, 6 and 7 days.
Regarding claim 22 and for at least 28 day administration, WO 433 teaches administration of the sustained release combination composition in overlapping days ranges. See claim 69.
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Regarding claim 23 and the limitation of a single tablet, WO 433 teaches sustained release tablets. See paragraph 170. While not explicitly teaching a combination with alpelisib, as WO 433 teaches a combination of endoxifen and alpelisib, it would be routine for a PHOSITA to formulate the two into a single tablet.
Claim(s) 1-5, 7-14, 16-19 and 21-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/003433 (WO 433) in view of Markham Alpelisib: First Global Approval Drugs (2019) 79:1249–1253. WO 433 is cited on the IDS dated June 18 2024 (For Ref 14). Markham is cited on the PTO-892 form.
While WO 433 renders obvious the subject matter of claims 1-5, 7-14, 19 and 21-23, it does not teach the subject matter of claims 16-18, where the PI3K inhibitor (alpelisib) at doses of no less than 50 mg and more than 400 mg; no less than 10 mg and more than 600 mg; and no less than 150 mg and more than 300 mg.
To address this, Markham teaches:
The recommended dose of alpelisib is 300 mg once daily taken with food. In the event of adverse reactions requiring a reduction in dose the dose of alpelisib should be reduced first to 250 mg once daily and then to 200 mg once daily. See page 1249, column 2.
Prior to the filing of the instant application a PHOSITA following the teachings of WO 433 and Markham would have found it prima facie obvious to form such a combination with the particular doses of alpelisib to treat ovarian cancer, because such a combination and particular dose of alpelisib is known. The rationale to do so is per MPEP 2143 (a) combining prior art elements according to known methods to yield predictable results, i.e. where it is predictable to arrive at the claimed combination in the claimed dose to treat ovarian cancer.
Conclusion and Correspondence
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a 371 of PCT/US2022/019674 03/10/2022
PCT/US2022/019674 has PRO 63/159,548 03/11/2021
2 Walpole et al. The weight of nations: an estimation of adult human biomass BMC Public Health 2012, 12:439. Pp. 1-6.
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