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 .
CONTINUING DATA
This application is a 371 of PCT/US2020/038760 06/19/2020
PCT/US2020/038760 has PRO 62/864,413 06/20/2019
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 9, 2026 has been entered.
Claims 1, 6-17, 20-25, 27, and 29-38 are pending. Applicant’s election without traverse of the species venetoclax in the reply filed on December 17, 2024 is acknowledged.
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.
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, 6-17, 20-25, 27, 29-34, and 36-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over DiNardo (Lancet Oncol., vol. 19(2), pp. 216-228, January 2018, cited on IDS) in view of Cogle (The Oncologist 2015;20:1404-1412, cited on IDS) and Etter (US 8846628B2, 2014, cited on IDS).
It is noted that 5-azacytidine is also known as azacytidine or azacitidine.
DiNardo teaches a method of treating AML comprising oral administration of venetoclax and subcutaneous or intravenous azacytidine 75 mg/m2 (days 1-7 of each 28-day cycle). Venetoclax synergizes with azacytidine. See Introduction. The dose of venetoclax was 400 mg, 800 mg, or 1200 mg daily in 28-day cycles. The regiment was well-tolerated and 60% of patients achieved remission. See abstract. Oral administration of venetoclax began on day 2 of cycle 1, which meets the limitation of claims 22-25, 27, and 29-30 when azacytidine is administered for one day, then venetoclax is administered for one day, then optionally repeating. Page 218, right column. Patients were 65 years over and were ineligible for standard induction therapy. See page 216, Methods. Comorbidities in the elderly decrease tolerance to intensive therapies. Page 217, Introduction. Median age was 75 years (page 221, Results).
DiNardo does not teach oral administration of azacytidine and does not teach treatment of MDS.
Cogle teaches that azacytidine can be administered orally for treating of MDS or AML. See abstract. Dosing of oral azacytidine was 120-600 mg/day for 7 days or 300 mg for 14 days, or 200 mg BID for 14 days. Page 1407, Figure 2. Multiple cycles were carried out. Page 1406, last two paragraphs. Oral administration of azacytidine avoids injection-site reactions and may enhance patient convenience. Page 1406, end of first column. Oral administration also allows for alternative doses and extended dosing schedules, which may decrease toxicity and increase efficacy. Page 1406, top of right column. The MTD of oral azacytidine was 480 mg on days 1-7 of a 28-day cycle, but lower doses allowed for extended low-dose administration over periods of 14 or 21 days. See Conclusion. 7-day oral azacytidine dosing was clinically active. Page 1407, end of left column. Azacitidine for injection is approved for high-risk MDS according to IPSS (page 1405, left column).
Etter teaches a non-enteric coated tablet containing 5-azacytidine (claim 1). The amount of 5-azacytidine is 120 to 480 mg (claim 23) or about 300 mg (claim 24). The composition is used for treating myelodysplastic syndrome or acute myelogenous leukemia (claim 28), including refractory MDS (column 58, lines 32-46). The composition can be used along with an additional therapeutic agent (column 7, lines 45-50).
It would have been obvious to one of ordinary skill in the art at the time the application was filed to treat AML or MDS, including refractory MDS, using a combination of venetoclax and oral azacytidine because oral administration of azacytidine avoids injection site reactions and is convenient. Both AML and MDS are treated using azacytidine and azacytidine synergizes with venetoclax, so the skilled artisan would have employed the combination. The skilled artisan either would have substituted the iv azacytidine in DiNardo’s method with oral azacytidine for convenience, or would have added venetoclax to Cogle’s or Etter’s methods to achieve a synergistic treatment. The skilled artisan would have had a reasonable expectation of success because oral azacytidine is effective as taught by Cogle and Etter. It would have been obvious to treat a high-risk MDS patient because azacytidine is approved for high-risk patients and Cogle teaches that relatively high amounts (480 mg) of oral azacytidine can be tolerated. It would have been obvious to treat a patient who was 75 years or older, or 18 years or older with comorbidities because DiNardo teaches that these patient populations are ineligible for standard induction therapy and benefit from the combination therapy. Cogle and Etter do not teach that azacytidine is administered at 200 mg/day, but Cogle and Etter teach ranges which encompass 200 (120-480 or 120-600 mg). MPEP 2144.05 states that in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
It would have been obvious to one of ordinary skill in the art at the time the application was filed to treat patients which were ineligible for intensive chemotherapy due to age over 75 years or at least 65 years with comorbidities because the combination of venetoclax plus azacitidine has been shown to be effective for those patients.
The limitations of claim 20 are inherent properties of the combination of azacytidine and venetoclax. Limitations (f)-(n) in claim 21 are inherent properties of administration of azacytidine.
Claim(s) 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over DiNardo in view of Cogle and Etter as applied to claims 1, 6-17, 20-25, 27, and 29-33 above, and further in view of Aldoss (haematologica 2018; 103e407).
DiNardo, Cogle and Etter teach as set forth above, but do not teach treatment of refractory AML.
Aldoss teaches treatment of relapsed/refractory acute myeloid leukemia using the combination of venetoclax and azacitidine (Table 1). Aldoss concludes that that the combination had excellent activity and safety in r/r AML. See last paragraph.
It would have been obvious to one of ordinary skill in the art to carry out the method suggested by DiNardo in view of Cogle and Etter, wherein the patient had relapsed/refractory AML because the combination of azacitidine and venetoclax has been shown to be effective and safe in that patient population.
Response to Arguments
Applicant argues that the all-oral AZA in combination with venetoclax can be administered without hospitalization requirements and represents an unexpected advantage. This argument is not persuasive because Cogle also mentions advantages of oral administration, including patient convenience and lack of injection site reactions. The better patient experience and reduced risk of infection are not unexpected.
Applicant argues that the skilled artisan would not have had a reasonable expectation of success for using oral AZA at the specific doses of 200 mg or 300 mg. This argument is not persuasive because Cogle and Etter provide guidance for the amount of oral AZA needed as a monotherapy, which includes 300 mg specifically and broader ranges which encompass 200 mg. The skilled artisan would have used this guidance as a starting point and optimized the dose using routine optimization, administering the amount of AZA which was most effective balanced with safety concerns. Dose escalation studies are known in the art. For example, DiNardo illustrates dosing schedules for the combination of venetoclax with azacitidine. The examiner could find no evidence of unexpected results or evidence that optimizing a dose within known ranges is so unpredictable that the skilled artisan would not have had a reasonable expectation of success. The level of skill in the art is very high. The cited references contain guidance for an exemplary dose and ranges of doses, and for dose optimization in the context of combination therapy, so the skilled artisan had ample guidance.
Applicant argues that Etter does not mention venetoclax so there is no guidance that would lead the skilled artisan to select venetoclax from countless other therapeutic agents. This argument is not persuasive because DiNardo teaches the combination of AZA and venetoclax. The skilled artisan would combine AZA and venetoclax because DiNardo teaches that the combination is synergistic.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6-17, 20-25, 27, 29-33, and 36-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of US Patent 12447171. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application claims treating AML using azacytidine and another agent (claim 1), wherein the additional agent is venetoclax (claim 15), and wherein the azacytidine is administered orally in the form of a non-enteric coated tablet (claim 9). The agents can be administered concomitantly or sequentially (claim 3), and can be in one dosage form or separate (claim 4). Azacytidine can be administered at a dose of about 200 mg or 300 mg (claim 8) for 14 days in a 28-day cycle (claim 10). Azacytidine can be administered orally daily for 1, 2, 3, etc. days followed by an optional treatment holiday of 14 days (claims 11-12). AZA is administered for the first 14 days of a 28 day cycle and the addition agent which can be venetoclax is administered once daily in the 28 day cycle (claim 26). Venetoclax is administered orally (claim 16).
The reference claims also require administration of an LSD-1 inhibitor, which is not required by the current claims. The current claims do not exclude administration of the LSD-1 inhibitor. The reference claims anticipate the current claims.
Applicant requested to defer this issue until the application is otherwise in condition for allowance.
Conclusion
No claims are 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.
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/LAYLA D BERRY/Primary Examiner, Art Unit 1693
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