METHODS OF TREATING LIVER DISEASE

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 Claims 1, 5, 6, and 8 are pending and are under examination. Priority This application is a continuation of U.S. Application No. 16/803,824, filed February 27, 2020, which is a continuation of U.S. Application No. 15/935,759, filed March 26, 2018, now abandoned, which application claims the benefit of: U.S. Provisional Application Serial No. 62/477,697, filed March 28, 2017; U.S. Provisional Application Serial No. 62/482,105, filed April 5, 2017; and, U.S. Provisional Application Serial No. 62/586,354, filed November 15, 2017. Applicant’s claim to priority is acknowledged. Information Disclosure Statement The Information Disclosure Statement(s) filed 2/8/2024 has/have been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered. 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. 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. Claims 1, 5, 6, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Harriman et al. (“Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats.” Proc. Natl. Acad. Sci. U S A.; Published online (2016, Mar. 14); 113(13): E1796–E1805) (herein after Harriman1) in view of Harriman et al. (US PG-PUB 2013/0123231) (hereinafter Harriman2), Ali et al. (“Recent advances in the development of farnesoid X receptor agonists.” Annals of Translational Medicine (2015); 3(1): 5/1-5/16), and Kinzel et al. (WO 2013/007387). Each reference cited in 02/08/2024 IDS. Claimed invention A method of treating and/or preventing non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an ACC inhibitor of Formula (I) PNG media_image1.png 160 225 media_image1.png Greyscale (“Compound I-278”) and the FXR agonist having the structure PNG media_image2.png 139 294 media_image2.png Greyscale . Prior art Harriman1 teaches that the inhibition of Acetyl CoA carboxylase (ACC) reduces hepatic steatosis. Harriman1 specifically teaches the ACC inhibitor, ND-630, having the structure PNG media_image3.png 189 258 media_image3.png Greyscale , reduces fatty acid synthesis and stimulates fatty acid oxidation in cultured cells and experimental animals when administered in a vehicle, reduces hepatic steatosis. See Title; Abstract; Fig. 2. Harriman1 suggest ND-630 for treating non-alcoholic steatohepatitis (NASH). See sentence bridging columns at p. E1801. Harriman1 describes use of structure-based drug design (SBDD) to identify a unique series of potent and efficacious allosteric protein–protein interaction inhibitors that interact within the ACC subunit dimerization and phosphopeptide acceptor site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes. Harriman1 also demonstrate that ND-630, a representative analog of this series that exhibits favorable pharmaceutical properties, is highly effective in reducing hepatic steatosis, improving insulin sensitivity, and favorably affecting dyslipidemia in rats with diet-induced obesity (DIO) and in Zucker diabetic fatty (ZDF) rats, suggesting its utility in treating a variety of metabolic disorders. Harriman1 refers to Harriman2 (US 2013/0123231) as disclosing ND-630 and methods of how to make it. See p. E1804, left column. Harriman1 further states that a patent application was also filed for analogs of ND-630. See p. E1796 right column. While Harriman1 teaches inhibition of acetyl CoA carboxylase (ACC) reduces hepatic steatosis specifically disclosing PNG media_image3.png 189 258 media_image3.png Greyscale (ND-630) as an ACC inhibitor, Harriman1 does not expressly teach PNG media_image1.png 160 225 media_image1.png Greyscale (Compound I-278) or the FXR agonists having the structure PNG media_image2.png 139 294 media_image2.png Greyscale . Harriman2 teaches how to make ND-630 and other analogs that possess ACC inhibiting activity, including Example 128 PNG media_image4.png 170 291 media_image4.png Greyscale (Compound I-278). See pp. 84 and 212; Fig. 16. Harriman2 teaches that the compounds inhibit ACC and suggest they are useful for treating NASH. See title; 0186,0203. Harriman2 thus teaches the ACC inhibitor of Example 128 (Compound I-278) for use in treating NASH. Similar to Harriman1, Ali teaches the treatment of hepatic steatosis. But Ali teaches the use of agents that are Farnesoid X receptors (FXR) agonists as the active. FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. See abstract. Several preclinical and clinical studies demonstrating beneficial effects of FXR agonists as potential therapeutic agents for the treatment of NAFLD/NASH are reported. See pp. 3 and 5. One of ordinary skill in the art would have found it obvious to treat NASH with a combination of an ACC inhibitor - such as ND-630 (Harriman1) or Compound I-278 (Harriman2) - and a FXR agonist (Ali) because each are disclosed as agents for treating NASH. Because both agents are suggested for treating NASH, it would have been logical to combine them into a single therapeutic composition to achieve the same result. Kinzel teaches novel FXR agonist for treating diseases mediated by FXR including, inter alia, NASH and Non-Alcoholic Fatty Liver Disease (NAFLD). See title; abstract; Claim 13. The compounds PNG media_image5.png 107 214 media_image5.png Greyscale is expressly taught as a FXR agonist useful for the invention. See last compound in Claim 5. Accordingly, one of ordinary skill in the art would have found it obvious to incorporate FXR agonist compounds from Kinzel (e.g., PNG media_image5.png 107 214 media_image5.png Greyscale ) into the combination suggested by Harriman1, Harriman2 and Ali. The artisan would have done so because Ali teaches that agents that are agonists of FXR are effective for treating NASH. Thus, the combination would have resulted in treating NASH with the ACC inhibitor of Harriman2 Example 128 (Compound I-278)and the FXR agonist compound of Kinzel. Accordingly, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill before the effective filing date of the claimed invention. Correspondence No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. CHRIS E. SIMMONS Examiner Art Unit 1622 /CHRIS E SIMMONS/Examiner, Art Unit 1622 /JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622