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 .
Claim Rejections - 35 USC § 103
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Medscape (ripretinib Rx https://web.archive.org/web/20200614140745/https://reference.medscape.com/drug/qinlock-ripretinib-4000074; publication online 6/13/2020).
Scope of prior art
On page 1, Medscape discloses that ripretinib is indicated for advanced gastrointestinal stromal tumor at a dose of 150mg/day. On page 2, with regards to Hepatic impairment, Medscape discloses that no dose adjustment is necessary for mild hepatic impairment. Regarding moderate or severe hepatic impairment, Medscape states that the recommended dosage has not been established.
Ascertaining the difference
Claims limit the subject population to individuals with pre-existing Child-Pugh class C severe hepatic impairment. While Med scape teaches 150mg dose for mild hepatic impairment (no dose adjustment is necessary), it teaches that the proper dose adjustment for treatment of subjects with severe hepatic impairment has not been established.
Obviousness
At issue is whether a person of ordinary skill in the art would have found it obvious to determine a proper dose for treatment of subjects GIST with pre-existing severe hepatic impairment.
A person of ordinary skill in the art would have found it obvious treat an individual with advanced gastrointestinal stromal tumor in a subject in need thereof by administering to said subject 150mg/day of ripretinib. Medscape teaches that 150mg dose is sufficient for treatment of the stromal tumor and that mild hepatic impairment does not affect the recommended dosage. While no dose recommendation for moderate to severe hepatic impairment is provided, a skilled practitioner would have found it obvious to determine the proper dose. It would have been obvious to start with 150mg daily dose suggested for advanced gastrointestinal stromal tumor and to adjust the dose if needed. For dose modification Medscape teaches starting with 150mg/day and reducing to 100mg/day if the dose is not well tolerated. According to Medscape guidance the currently claimed 150mg/day dose is the dose a skilled practitioner would start with in an effort to optimize the dose for a given subject. Administration of a 150mg dose to a subject with pre-existing Child-Pugh class C severe hepatic impairment is therefore obvious.
While Medscape recites “severe hepatic impairment” not “Child-Pugh class C severe hepatic impairment”, both recitations are directed to advanced liver disfunction.
Reply to applicant’s remarks
Applicants have traversed the rejection of record in the reply filed on 7/27/26. The arguments presented have been fully considered and found to be not persuasive.
The first argument is that art teaches away from administration of a recommended dose to subjects with severe hepatic impairment. The support for this argument is the dose recommendations for GIST approved drugs. Applicants provide dose recommendations for Imatinib Sunitinib and Regorafenib. Out of the three, only Imatinib is recommended at a reduced dose for subjects with severe hepatic impairment. For the other two the dose for such subjects has not been established. A single example is not seen as being sufficient to constitute a teaching away. Since art teaches a 150mg dose is sufficient for treatment GIST, and art also teaches starting with the recommended dose and adjusting as needed, Examiner maintains that it would have been obvious to treat any subject with GIST (including those with severe hepatic impairment) with a 150mg dose and to adjust the dose if it is not well tolerated.
Applicants second argument is directed to unexpected results derived from administration of a 150mg dose to a subject with severe hepatic impairment (page 3 of remarks, first paragraph). This argument is not persuasive because it is not supported by the experimental data and conclusions provided in the specification. In discussing the modeling experiments for subjects with severe HI (no experiments with 150mg have been conducted on severe HI subjects), applicants conclude on page 59:
“The increased exposure of combined ripretinib plus DP-5439 in patients with severe HI, a potentially vulnerable population, supports dose adjustment to 50mg QD in such patients”
Applicant’s modeled predicted PK parameters suggest reducing the dose to 50mg for severe HI patients. This represents the expected result. There are no other results in the specification that indicate that unexpectedly, when a 150mg dose administered to actual subjects with GIST and severe HI, there is no need for dose reduction.
Conclusion
Claim 6 is pending
Claim 6 is rejected
THIS ACTION IS MADE FINAL. 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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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
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