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 the Claims
The status of the claims are as follows
Claims 1 and 3-17 are pending.
Claims 1 and 3-17 are rejected.
Priority
Acknowledgement is made that Instant Application 18/938,468, filed on 2024, Nov. 06 is a Continuation of PCT/IB23/54902, filed on 2023, May 11, which claims priority from Provisional Application 63,370,170, filed on 2022, Aug. 02, and claims priority from Provisional Application 63,350,524, filed on 2022, Jun. 09, and claims priority from Provisional Application 63,341,210, filed on 2022, May 12.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 2025, Jul. 09 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the examiner.
Claim Objections
Claim 10 is objected to for containing the phrase “(on Day 0)”. The claim is directed to azacitidine in Cycle 1 being administered 1 day prior to the administration of the BCL-2 inhibitor. This does not necessarily mean the day azacitidine is administered must be called “Day 0” to fall within the scope of the claim. Therefore, the parenthetical phrase is objected to for being ambiguous.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 3-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over DiNardo (Safety and Preliminary Efficacy of Venetoclax with Decitabine or Azacitidine in Elderly Patients with Previously Untreated Acute Myeloid Leukemia: A Non-Randomized, Open-Label, Phase 1b Study. Lancet Oncol. 2018, 19(2), 216-228. doi.org/10.1016/S1470-2045(18)30010-X) in view of Hu (WO 2021/110102 A1, published 2021, Oct. 06; international filing date, 2020, Dec. 03).
Claim 1 is directed to a method of treating myeloid malignancy in a subject, the method comprising administering to the subject a therapeutically effect amount of a BCL-2 inhibitor, in combination with a therapeutically effective amount of azacitidine, wherein the myeloid malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN); and the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1R,4R)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (hereafter referred to as “compound 1”) (Table 1, left), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
DiNardo teaches the outcome of a Phase1b study, wherein elderly patients (≥ 65 years old) with AML are treated with the oral anti-apoptotic BCL-2 protein inhibitor venetoclax (Table 1, right) in combination with either azacitidine or decitabine (title, background).
“Compound 1”
Venetoclax
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The difference between the teaching of DiNardo and the Instant Application is that DiNardo fails to teach the use of “compound 1” as the BCL-2 inhibitor to treat AML.
However, Hu teaches methods of treating cancer in a subject with a BCL-2 inhibitor, in particular “compound 1” or a pharmaceutically acceptable salt thereof (abstract). “Compound 1” exhibits potent cell killing activity against a variety of lymphoma and leukemia cell lines, including MV4-11 (AML) (page 3, paragraph 0008).
One of ordinary skill in the art would have been motivated to combine these teachings because DiNardo shows that venetoclax is an effective BCL-2 inhibitor that has been used in human trials for treating AML in combination with azacitidine, while Hu shows “compound 1” an effective BCL-2 inhibitor that kills AML cell lines in vitro. One BCL-2 inhibitor could be substituted for another BCL-2 inhibitor to treat AML with a reasonable expectation of success. Therefore, said skilled artisan would have found it prima facie obvious to treat AML by using “compound 1” in combination with azacitidine.
Claim 3 is directed to the method of claim 1, wherein AML is either treat-naïve (TN) unfit for intensive induction chemotherapy or relapsed/refractory (R/R).
DiNardo teaches venetoclax has shown promising single-agent activity in patients with relapsed or refractory AML and preclinical data suggested synergy between hypomethylating agents (e.g., azacitidine) and venetoclax, which led to the combination phase 1b study (background). DiNardo further teaches the combination of venetoclax with a hypomethylating agent seems to be a well-tolerated regimen with low early mortality and promising anti-leukemic activity in elderly, treatment-naïve patients with AML (page 227, left column, paragraph 2). DiNardo further teaches that patients in the age range of their selected patient population are more frequently refractory than younger patients to cytotoxic intensive induction chemotherapy (page 217, left column, paragraph 1).
Claim 4 is directed to the method of claim 1 comprising orally administering once daily the BCL-2 inhibitor to the patient in escalating doses, wherein the escalating doses comprise an initial dose of 5, 10, 20, or 40 mg of the BCL-2 inhibitor per day.
DiNardo teaches the venetoclax dose-escalation study was conducted with 4 cohorts (page 218, Figure 1). Venetoclax was administered on day 2 at either 20 mg, 50 mg, or 100 mg, with each cohort experiencing a 3- or 4-day ramp-up to the recommended dose of either 400 mg, 800 mg, or 1200 mg. Those cohorts in group B received azacitidine alone (75 mg/m²) on day 1 and was further administered azacitidine every subsequent day until day 7 during each cycle.
Figure 1. Dosing schedule for Group A (venetoclax and decitabine) and Group B (venetoclax and azacitidine).
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Claim 5 is directed to the method of claim 4, wherein the BCL-2 inhibitor is orally administered in two Cycles, comprising a 4-day ramp-up schedule (Cycle 1) and a subsequent cycle.
DiNardo teaches cohort 4 underwent a 4-day ramp-up schedule, wherein patients were orally administered venetoclax at 100 mg on Day 2, 200 mg on Day 3, 400 mg on Day 4, and 800 mg on Day 5 (Figure 1; page 218, right column, paragraphs 3-4).
Claim 6 is directed to the method of claim 5, wherein the 4-day ramp-up schedule (Cycle 1) is a 10-day cycle, 21-day cycle, or a 28-day cycle; and the subsequent cycle (Cycle 2) is a 10-day cycle, 21-day cycle, or 28-day cycle
DiNardo teaches Cycle 1 is a 28-day cycle (Figure 1). While DiNardo does not explicitly state that the study is comprised of Cycle 2 wherein the cycle is a 10-day, 21-day, or 28-day cycle, it is stated that when the cohort-designated maximum dose was reached, the target dose of venetoclax was continued daily in 28-day cycles (page 218, right column, paragraph 4), and blood samples were collected on day 5 of cycle 2 (page 219, right column, paragraph 2). Therefore, one of ordinary skill in the art would have known that the study is comprised of Cycle 2, wherein the cycle is a 28-day cycle.
Claim 7 is directed to the method of claim 6, wherein the 4-day ramp-up schedule (Cycle 1) comprises a first dose on Day 1, second dose on Day 2, third dose on Day 3, and recommended dose on Day 4 and beyond, wherein the recommended dose on Day 4 and beyond is higher than the third dose on Day 3, the third dose on Day 3 is higher than the second dose on Day 2, and the second dose on Day 2 is higher than the first dose on Day 1.
DiNardo teaches cohort 4 underwent a 4-day ramp-up schedule, wherein patients were orally administered venetoclax at 100 mg on Day 2, 200 mg on Day 3, 400 mg on Day 4, and 800 mg on Day 5 and beyond (Figure 1; page 218, right column, paragraphs 3-4).
Claim 8 is directed to the method of claim 7, wherein the 4-day ramp-up schedule (Cycle 1) comprises the first dose on Day 1 at 12.5% of the recommended dose, the second dose on Day 2 at 25% of the recommended dose, the third dose on Day 3 at 50% of the recommended dose, and a daily dose on Day 4 and beyond at 100% of the recommended dose.
DiNardo teaches the patients of cohort 4 are administered a first dose that is 12.5% of the recommended dose; the second dose administered is 25% of the recommended dose; the third dose administered is 50% of the recommended dose; and the fourth dose administered is 100% of the recommended dose and maintained until the end of the cycle (Figure 1).
Claim 9 is directed to the method of claim 8, wherein administration of the BCL-2 inhibitor in the subsequent cycle (Cycle 2) is at the recommended dose from Day 1 of Cycle 2 with no ramp-up.
DiNardo teaches the dose of venetoclax was counting failed in 28-day cycles once the cohort-designated maximum dose was reached (page 218, right column, paragraph 4).
Claim 10 is directed to the method of claim 9, wherein azacitidine in Cycle 1 is administered 1 day prior to the administration of the BCL-2 inhibitor.
DiNardo teaches Cycle 1 is comprised of cohort B, who was administered azacitidine alone one day prior to the combination venetoclax/azacitidine (Figure 1).
Claim 11 is directed to the method of claim 9, wherein azacitidine in Cycle 2 is administered concurrently with the BCL-2 inhibitor.
DiNardo teaches administration of azacitidine on days 1-7 of each cycle (page 218, right column, paragraph 4). Venetoclax was administered from days 2-28 of each cycle (Figure 1). Therefore, azacitidine was administered concurrently with the BCL-2 inhibitor during each cycle, including Cycle 2.
Claim 12 is directed to the method of claim 11, wherein azacitidine is administered at a dose of 75 mg/m2 intravenously or subcutaneously once daily (QD).
DiNardo teaches azacitidine was administered intravenously or subcutaneously at 75 mg/m2 (page 218, right column, paragraph 4).
Claim 13 and claim 17 are directed to the method of claim 12, wherein the recommended dose of the BCL-2 inhibitor is 160 mg once daily (QD) or 320 mg (QD).
DiNardo teaches a dose-escalation study comprising the administration of a BCL-2 inhibitor at doses ranging from 20 mg to 1200 mg to determine the maximum tolerated and recommended phase 2 dose (page 216, methods). It was found that the recommended phase 2 dose was 400 mg QD, or 800 mg QD with an interrupted dosing schedule (page 222, left column, paragraph 1).
The difference between the teaching of DiNardo and the Instant Application is that DiNardo fails to teach therein the recommended dose of the BCL-2 inhibitor is 160 mg QD or 320 mg QD.
However, one of ordinary skill in the art could have arrived at the instantly-claimed dosages by quantifying the side effects caused by administration of the BCL-2 inhibitor with azacitidine. For example, DiNardo teaches treatment-related adverse events of administering venetoxclax with azacitidine (page 222, Table 2, Group B). A skilled artisan could have reasonably established that higher dosages of a BCL-2 inhibitor leads higher-grade negative side effects and therefore routinely optimize the recommended dose to mitigate those events.
Claim 14 is directed to the method of claim 1, wherein the myeloid malignancy is AML.
DiNardo teaches a method of treating AML with a combination BCL-2 inhibitor and azacitidine (title).
Claim(s) 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over DiNardo in view of Hu and in further view of NCBI Clinical Trial ID NCT02942290 (first posted 2016, Oct. 24).
The teachings of DiNardo in view of Hu are discussed above and incorporated herein by reference.
Claims 15-16 is directed to the method of claim 1, wherein the myeloid malignancy is MDS or MPN, wherein the MDS or MPN is treatment-naive or relapsed/refractory.
The difference between the teachings of DiNardo in view of Hu is that they fail to teach wherein the BCL-2 inhibitor is used to treat MDS or MPN.
However, NCT02942290 teaches a Phase 1b dose escalation study evaluating the safety and pharmacokinetics of venetoclax in combination with azacitidine in subjects with treatment-naïve higher-risk MDS (trial description, official title).
One would be motivated to combine the teaching of NCT02942290 with the teachings above because NCT02942290 discloses a new myeloid malignancy indication that can be treated with venetoclax in combination with azacitidine, the same combination therapy as taught by DiNardo. Hu teaches other BCL-2 inhibitors that may be useful in treating myeloid malignancy diseases, including “compound 1”. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to substitute “compound 1” for venetoclax to treat MDS in combination with azacitidine.
Conclusions
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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