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 .
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.
This office action is a response to applicant’s communication submitted July 16, 2024 wherein claims 6 and 8-12 were preliminarily amended. This application claims benefit of provisional application 63/494,739 filed April 6, 2023.
Claims 1-12 are pending in this application.
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.
Claims 1 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over M.D. Anderson Cancer Center (NCT04128501, Clinicaltrials.gov, 2021, cited on PTO-892), hereinafter referred to as Anderson in view of FDA label (VENCLEXTA®, FDA label, 2021, cited on PTO-892), hereinafter referred to as FDA, and Zhao (Annals of Hematology, 2022, IDS filed July 16, 2024).
Regarding claims 1 and 6-8: Anderson suggests giving venetoclax and azacitidine after a stem cell transplantation for the treatment of acute myeloid leukemia may help control high risk leukemia and prevent it from coming back after the transplant (pg. 6, middle of page, brief summary). Anderson teaches the administration of venetoclax and azacitidine given as maintenance therapy or eradication of minimal residual disease in patients with high risk acute myeloid leukemia (AML) after hematopoietic stem cell transplantation (HSCT) (pg. 6, primary objective I). The method comprises administering azacitidine subcutaneously on days 1-5 and venetoclax orally once daily on days 1-7 after allogeneic stem cell transplantation (pg. 7, outline). Treatment repeats every 4-8 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity (pg. 7, outline).
Anderson does not teach wherein the subject receives 200 mg venetoclax. Anderson does not explicitly teach a 28 day cycle wherein the method is practiced for six cycles and wherein following the six cycles venetoclax is administered in the absence of azacitidine for eighteen cycles.
However, FDA highlights prescribing information of venetoclax (i.e. VENCLEXTA®) in combination with azacitidine (pg. 1, col. 1, indications and usage). FDA teaches dosing schedule for venetoclax includes a ramp-up schedule comprising administering venetoclax in dosages of 20, 50, 100 , 200, and 400 mg (pg. 2, table 1). FDA teaches combination therapies in combination with azacitidine in 28 day cycles until disease progression or unacceptable toxicity (pg. 3, section 2.3, table 2, pg. 4, para. 1). FDA teaches the reduction of dosages of venetoclax for adverse reactions (pg. 7, table 5). FDA teaches reduction of dosages based on concomitant use with a strong or moderate CYP3A inhibitor, including reducing venetoclax to 70 mg, 100 mg, or 50% of the dose (i.e. 200 mg). (pg. 8, section 2.6, table 7). FDA teaches concomitant use of posaconazole (a strong CYP3A inhibitor) with 50 mg and 100 mg resulted in higher concentrations than 400 mg venetoclax administered alone (pg. 33, para. 1). Additionally Zhao teaches treatment of AML patients who relapse after allogenic hematopoietic stem cell transplantation (abstract). Zhao teaches venetoclax was Venetoclax was given to patients by oral administration at a dose of 100 mg once a day ( qd) in the first week, 200 mg qd in the second week, 300 mg qd in the third week, and a final dose at 400 mg/day as maintenance dose. Azacitidine at a dose of 75 mg/m2/day was administered subcutaneously from day 1 to day 5 per 28-day treatment cycle, up to 6 - 8 cycles (pg. 121, col. 1, last para.). Thus Zhao establishes comparable doses to the FDA in dosing subjects with relapsed AML with compatible doses to those typical prescribed.
Taken together it would have been prima facie obvious to modify the dosage of venetoclax, cycle length and amount of cycles of Anderson and arrive at the claimed invention as taught by FDA and Zhao. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation in order to continue treating the condition and adjust accordingly for toxicity issues. Additionally, wherein the art establishes dosage, cycle length, and amount of cycles can vary depending on disease progression or unacceptable toxicity, they are established in the art as result effective variables to be optimized. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (See MPEP 2144.05 (II)).
Claims 2, 9, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (NCT04128501, Clinicaltrials.gov, 2021, cited on PTO-892), hereinafter referred to as Anderson, FDA (VENCLEXTA®, FDA label, 2021, cited on PTO-892) and Zhao (Annals of Hematology, 2022, IDS filed July 16, 2024) as applied to claims 1 and 6-8 above in view of Ueda (Biol. Blood Marrow Transplant, 2016, cited on PTO-892).
Regarding claims 2, 9, and 11: As discussed above, the prior art render obvious a method of claims 1 and 6-8. As discussed above the prior art establishes venetoclax dosages, cycle length, and cycle time are optimizable variables.
The prior art does not teach administering 20 mg/m2 of azacitidine.
However, Ueda teaches low-dose azacitidine (AZA) for treatment of AML relapse after allogeneic hematopoietic cell transplant (HCT, pg. s212, col. 2, abstract 294 title). Ueda teaches treatment with low dose azacitidine ranged from 16-100 mg/m2/day for 5 days (pg. s213, col. 1, last para.). Ueda teaches low-dose AZA appears to be comparable to higher doses for the treatment of AML relapse after HCT (pg. s213, col. 2, para. 3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to further optimize the concentration of azacitidine and arrive at a concentration of 20 mg/m2 azacitidine as suggested by Ueda. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes that low-dose aza is comparable to higher doses for the treatment of AML after receiving HCT in order to reduce toxicity.
Claims 3-5, 10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson (NCT04128501, Clinicaltrials.gov, 2021, cited on PTO-892), hereinafter referred to as Anderson, FDA (VENCLEXTA®, FDA label, 2021, cited on PTO-892), Zhao (Annals of Hematology, 2022, IDS filed July 16, 2024), and Ueda (Biol. Blood Marrow Transplant, 2016, cited on PTO-892) as applied to claims 1-2 and 6-9, and 11 above in view of Zeghondy (Clinical Lymphoma, Myeloma & Leukemia, cited on PTO-892) and Sato (Cancer Chemotherapy and Pharmacology, 2022, cited on PTO-892).
Regarding claims 3-5, 10, and 12: As discussed above, the prior art render obvious a method of claims 1 and 6-8. As discussed above the prior art establishes venetoclax dosages, cycle length, and cycle time are optimizable variables. FDA teaches reduction of dosages based on concomitant use with a strong or moderate CYP3A inhibitor, including reducing venetoclax to 70 mg, 100 mg, or 50% of the dose (i.e. 200 mg). (pg. 8, section 2.6, table 7). FDA teaches concomitant use of posaconazole (a strong CYP3A inhibitor) with 50 mg and 100 mg resulted in higher concentrations than 400 mg venetoclax administered alone (pg. 33, para. 1).
The prior art while providing recommended dosages in the concomitant use of CYP3A inhibitors, such as posaconazole, does not explicitly provide a reason for doing so.
However, Zeghondy teaches venetoclax is metabolized by CYP3A, and potency increases 2- to 7-fold, empowering its effect (pg. s225, col. 1, last para.). Zeghondy teaches fluconazole can potentiate the effect of venetoclax in vivo (pg. s225, col. 1, last para.). Zeghondy teaches the addition of fluconazole, a moderate CYP3A4 inhibitor, to a pre-fixed low dose venetoclax in order to increase the chance of response (pg. s225, col. 2, para. 2). Zeghondy teaches it is known in the art that venetoclax-posaconazole in untreated AML patients resulted in an ORR of 67% (col. 2, para. 1). Additionally Sato teaches administration of venetoclax to a subject that underwent stem cell transplantation that was also taking posaconazole concomitantly (abstract). Sato teaches the patient was taking posaconazole as prophylaxis for fungal infection (pg. 280, col. 2, para. 2). Sato teaches with the concomitant use of posaconazole a CYP3A inhibitor, venetoclax dose should be reduced from 500 to 50 mg (pg. 282, col. 2, para. 3).
Taken together it would have been prima facie obvious to modify the method by administering to a subject who was concomitantly undergoing treatment with a CYP3A inhibitor as taught by Zeghondy and Sato. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to prophylactically treat fungal infections and to potentiate venetoclax, allowing for lower doses.
Conclusion
No claims are allowed in this action.
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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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