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
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.
Claims 1-24 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03987074 (published at clinicaltrials.gov on June 12, 2019) in view of Dufour et al. (“Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges,” Gut 2020, 10, 1877-1884; Epub May 7, 2020), NCT03449446 (published at clinicaltrials.gov on May 22, 2019), and NCT03987451 (published at clinicaltrials.gov on June 12, 2019).
NCT03987074 teaches a method of treating NASH comprising administering 0.24 mg - 2.4 mg semaglutide (dose escalation every 4 weeks) by once weekly subcutaneous injection and 20 mg firsocostat by once daily oral administration (see § Arm, page 3), satisfying all of the limitations of independent claim 1 and dependent claims 2-3 except for the requirement that the patients also have cirrhosis (F4).
NCT03987074 teaches a method of treating NASH comprising administering 0.24 mg - 2.4 mg semaglutide (dose escalation every 4 weeks) by once weekly subcutaneous injection and 30 mg or 100 mg cilofexor by once daily oral administration (see § Arm, page 3), satisfying all of the limitations of independent claim 11 and dependent claims 12-13 except for the requirement that the patients also have cirrhosis (F4).
NCT03987074 teaches a method of treating NASH comprising administering 0.24 mg - 2.4 mg semaglutide (dose escalation every 4 weeks) by once weekly subcutaneous injection, 20 mg firsocostat by once daily oral administration, and 30 mg cilofexor by once daily oral administration (see § Arm, page 3), satisfying all of the limitations of independent claims 1, 11, and 18, and dependent claims 2-6, 12-13, and 19 except for the requirement that the patients also have cirrhosis (F4).
Although NCT03987074 excludes patients with F4 cirrhosis, it would have been obvious at the time the application was filed to extend the study to include this patient population in view of the state of the prior art as reviewed by Dufour et al. In a review of combination therapies for NASH, Dufour et al. teach that treatment for NASH “represents a major unmet need” (p. 1, para. 1). Dufour et al. teach (p. 1, para. 2): “It is now well accepted that fibrosis stage is a major predictor of liver-related morbidity and mortality. FDA and EMA guidance documents indicate that for clinical approval of new drugs for the treatment of NASH, trials should include patients who have significantly higher risk of progression to cirrhosis and hepatic decompensation, as defined as those who have biopsy-proven NASH with stage 2 fibrosis or higher.” Consistent with this guidance, Dufour et al. report that numerous clinical trials using combination therapy underway at the time of the review include patients with F4 cirrhosis (Table 1). In fact, NCT03449446 teaches a method of treating NASH in subjects with compensated cirrhosis (F4) comprising administering 20 mg firsocostat by once daily oral administration and 30 mg cilofexor by once daily oral administration (see § Arm, Experimental: SEL Placebo + Firsocostat + Cilofexor). NCT03987451 teaches a method of treating NASH in subjects with compensated cirrhosis (F4) comprising administering semaglutide, dose escalation to 2.4 mg once weekly by subcutaneous injection (see § Arm, Criteria).
Therefore, one of ordinary skill in the art would have been motivated to include NASH patients with F4 cirrhosis in the protocol of NCT03987074 in order to treat the patients most at risk of morbidity and mortality and to obtain data relevant for drug approval. There would have been a reasonable expectation of success given that Dufour et al. report that numerous clinical trials using combination therapy underway at the time of the review include patients with F4 cirrhosis (Table 1). Most importantly, the prior art discloses separate clinical trials with firsocostat + cilofexor (NCT03449446), and with semaglutide (NCT03987451) involving NASH patients with cirrhosis (F4).
With respect to claim 7, 14, and 21, NCT03987074 teaches treatment for 24 weeks (see § Arm, page 3) and NCT03449446 and NCT03987451 teach treatment for 48 weeks (see § Arm), which fall within the claimed range.
With respect to claims 8, 15, and 22, NCT03449446 teaches that the key inclusion criteria are: Liver biopsy consistent with NASH and cirrhosis (F4) in the opinion of the central reader (see § Criteria). NCT03987451 teaches that the key inclusion criteria are: Histologic evidence of NASH and fibrosis stage 4 according to the NASH CRN classification based on central pathologist evaluation of a liver biopsy obtained within 360 days prior to screening (see § Criteria).
With respect to claims 9, 16, and 23, NCT03987074 teaches that the patients exhibit screening laboratory parameters, as determined by central laboratory:
Alanine aminotransferase (ALT) ≤ 5 x upper limit of the normal range (ULN);
Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Modification of Diet in Renal Disease (MDRD) study equation HbA1c ≤ 9.5%;
International normalized ratio (INR) ≤ 1.2, unless due to therapeutic anti-coagulation therapy Platelet count ≥ 100,000/μL; and/or
Total bilirubin < 1.3 x ULN unless alternate etiology such as Gilbert's syndrome present Calcitonin ≤ 100 ng/L.
With respect to claims 10, 17, and 24, the claimed effects are inherent to the prior art method of administering the same compounds, to the same patients in the same manner.
With respect to claim 20, it would have been obvious to combine the 20 mg firsocostat and 30 mg cilofexor into a single solid dosage form because both are administered by once daily oral administration (see § Arm, page 3). Combining the active agents in a single solid dosage form would benefit the patient for convenience and improve consistency of administration.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7:30 am - 3:30 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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