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 .
Election/Restrictions
Applicant’s election of species (a) Z peptide of SEQ ID NO: 42; (b) FXR agonist: Cilofexor; and (c) Acetyl-CoA carboxylase inhibitor: Firsocostat in the reply filed on 11/3/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The requirement is still deemed proper and is therefore made FINAL.
Status of Application, Amendments, And/Or Claims
Claims 1-19 are pending and under consideration to the extent they read on the elected species.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 1/13/2023, 12/18/2024 and 3/17/2025 have been considered.
Specification
The disclosure is objected to because of the following informalities: the specification is objected for using different terms regarding FXR agonist throughout the specification, for example at pg. 9, paragraph[00128], and pg. 49, paragraph [00669] terms like M790, M780, M450, M-480 and many others. Applicants should provide a chemical name with an shortened terms.
Appropriate correction is required.
Claim Objections
Claim 12 is objected to because of the following informalities: claim 12 lists many farnesoid X receptor agonists as without chemical names as an acronym and they are not searchable, for example M-480: appears to be a polyurethane or something else; M450 appears to be several products including “M450 Celanese celcon”. Therefore, a proper search cannot be performed. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, and 12-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description in this case only sets forth a method for treating a non-alcoholic fatty liver disease or cholestatic liver disease in a subject in need thereof comprising administering an effective amount of a pharmaceutical composition comprising a triple agonist of SEQ ID NO: 42 or a long-acting conjugate comprising an Fc and the peptide of SEQ ID NO: 42; and pharmaceutically acceptable excipient, wherein the pharmaceutical composition is combined with a farnesoid X receptor agonist, and therefore the written description is not commensurate in scope with “a method of treating of any liver disease in a subject in need thereof comprising administering any triple agonistic long acting conjugate having formula Z-Lx-Fc in a pharmaceutical composition combined with a farnesoid X receptor agonist, wherein Z represented by General Formula 1: Xaa 1-Xaa2-Xaa3-Gly-Thr-Phe-Xaa7-Ser-Asp-Xaa 10-Ser-Xaa 12-Xaa 13-Xaa 14-Xaa 15- Xaa 16-Xaa 17-Xaa 18-Xaa 19-Xaa20-Xaa21 -Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28- Xaa29-Xaa30-R1 (General Formula 1, SEQ ID NO: 103), wherein each variant position can be substituted from 2-6 amino acids and wherein the pharmaceutical composition is further combined with an acetyl -CoA carboxylase inhibitor comprising CP-640186 derivatives, sprochromanone derivatives, spirolactam derivatives…….amino-oxazole derivatives, axobenzimidazole derivatives”.
The claims broadly encompass millions of variants of triple agonist (Z) of Formula 1 in a conjugate represented as Z-Lx-Fc in a pharmaceutical composition, and the pharmaceutical composition further comprising thousands of derivatives of acetyl-CoA carboxylase inhibitors (claim 14) for treating any liver disease in a subject in need thereof. The claims do not require that a triple agonist (Z) variant possess any particular feature or structure that may treat a liver disease.
The specification at pg.62-69 (Table 1), discloses triple agonists 1-100 that can be conjugated with an Fc via a PEG linker. The listed triple agonists in Table 1 are represented by substitution of either one, two or three amino acids out of 30 amino acid long peptide. However, the claim requires a combination of millions of options requiring substitutions at each and all amino acids of a 30 amino acid long peptide for treating any liver disease. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. Some of the factual considerations that are weighed when determining a written description include the level of skill and knowledge in the art, the disclosure of complete or partial structures, the disclosure of physical and or chemical properties, adequate disclosure of the functional characteristics, the correlation between structure and function, and disclosure of methods of making.
Norlin et al. (IDS, Diabetes, June 2020; 69(supplement 1) teach treating non-alcoholic steatohepatitis in a diet-induced mouse by using GLP-1 receptor agonist Semaglutide, an FXR agonist and AC inhibitor. Trevaskis et al. (IDS, Diabetes, June 2020, 69(supplement 1) teach administering a GLP-1/Glucagon receptor agonist with an FXR agonist and ACC inhibitor for treating NASH (nonalcoholic steatohepatitis). Neuschwander-Tetri et al. (IDS, Hepatology 2003, 38: 1008-1017) teach that insulin resistance is commonly associated with nonalcoholic steatohepatitis and the use of PPAR-gamma ligand Rosiglitazone improves NASH (see Figure 4). Kim et al. (IDS, Diabetes, June 01, 2020 (supplement_1); 1804-P) teach use of a long-acting triple agonist HM15211 (triple agonist-L-Fc, see Abdelmalek et al. Contemporary Clin. Trial. 130(2023)107176) results in anti-inflammatory and anti-fibrotic effects in an AMLN/TAA induces liver inflammation and Fibrosis mice and therefore, they suggest that the use of a long-acting GLP-1/GIP/Glucagon agonist for treating NASH, a severe form of NAFLD which is characterized by hepatic steatosis, inflammation and fibrosis.
In the instant case, the specification (at pg. 77-80, Example 4) only adequately discloses that the administration of a long-acting conjugate of amino acid sequence of SEQ ID NO: 42 with or without FXR agonist and/or ACC inhibitor for treating non-alcoholic fatty liver or fibrosis of liver. The specification does not describe various variants representative of a combination of 30 amino acids, 25 amino acids or even 20 amino acids in a 30 amino acid long peptide of SEQ ID NO: 103 (see claim 1) that can treat any liver disease. The specification also only discloses ACC inhibitors as 1,4-disubstitued cyclohexane, firsocostat analog. The specification does not disclose ACC derivatives including (4-peridinyl)-pepoerazine derivative, spirochromanone derivatives, pseudopeptide pyrrolidione derivatives and others. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1 "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states an adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.
As discussed above, the skilled artisan cannot envision the detailed genus of “ a method of treating any liver disease comprising a triple agonistic long acting conjugate of Formula 1: Z-lx-Fc having variants at every position of peptide Z of SEQ ID NO: 103 and derivatives of ACC inhibitors” and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of making a mutation. The compound itself is required. See Fiers v.Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen v.Baird, 30 Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 148 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class.
Therefore, only a method of treating NAFLD or NASH comprising administering a triple agonist comprising amino acid sequence of SEQ ID NO: 42 or a long-acting conjugate peptide of SEQ ID NO: 42 with an Fc; an agonist of cilofexor; and an Acetyl-CoA carboxylase inhibitor Firsocostat, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
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.
Claim(s) 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (IDS, Diabetes, 2020, 69(Supplement_1): 1804P in view of Norlin et al. (IDS, Diabetes 2020, June; 69(Supplement 1); 1810-p or Trevaskis et al. (IDS, Diabetes, 2020, June; 69(Supplement 1); 1813-P and Oh et al. (US Pat. No. 10,370,426).
The instantly claimed invention is broadly drawn to a method of treating a liver disease non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) comprising administering a triple agonist of SEQ ID NO: 42 in a pharmaceutical composition combined with an agonistic FXR receptor agonist and further comprising an acetyl-CoA carboxypeptidase (ACC) inhibitor, wherein the triple agonist comprises amin acid sequence of SEQ ID NO: 42 (claims 1-11), wherein the FXR agonist is Cilofexor (claim 12), and wherein ACC inhibitor is firsocostat (claims 13-14) and wherein the administration to the subject treats liver inflammation, NASH, NAFLD and liver fibrosis (claims 15-19).
Kim et al. teach a long acting triple agonist comprising GLP-1/GIP/Glucagon administration to a subject having liver inflammation and liver fibrosis reduces inflammation and fibrotic effects (see the title). They teach that nonalcoholic steatohepatitis is a severe form of nonalcoholic fatty liver disease (NAFLD) and that the disease is characterized by hepatic steatosis, inflammation, and fibrosis (lines 1-2). They teach a long-acting triple agonist, HM1521 which is a GLP-1/GIP/Glucagon conjugated to an Fc by a PEG linker (as evidence by Abdelmalek et al., Contemporary Clinical trials 130, (2023) 107176). It is noted that Abdelmalek et al. is applied to support the skill of the art and not as a prior art. Kim et al teach that the administration of HM15211 to mice fed with AMLN diet and concomitantly treated with thioacetamide for 16 weeks results in reduced liver inflammation and fibrosis as compare to control. Kim et al. do not teach administering an FXR agonist and an ACC inhibitor and they teach that the GLP-1/GIP/Glucagon triple agonist comprises amino acid sequence of SEQ ID NO: 42.
Norlin et al. teach a triple combination therapy comprising a GLP-1 agonist Semaglutide with an FXR agonist and an ACC inhibitor (see the title). Norlin et al teach that the FXR agonist is Cilofexor and the ACC inhibitor is firsocostat (Abstract). They teach that the administration of triple therapy (semaglutide +Cilofexor + ACC inhibitor) improved NAS score by 75% as compared to Semaglutide alone (about 13%). They teach that the liver fibrosis also got improved with the triple therapy. They teach that the triple therapy also reduced liver fat and improved liver fibrosis.
Trevaskis et al. teach coadministration of a GLP-1/Glucagon receptor agonist with an FXR agonist and ACC inhibitor reverses nonalcoholic steatohepatitis (NASH)in diet induced mice model. They teach that the FXR agonist is cilofexor and the ACC inhibitor is firsocostat (abstract). They teach that the administration of cilofexor, firsocostat or both to GLP-1/GCG agonist further reduced liver lipid by 82%, 88% and 91%, respectively (see abstract). They teach that GLP-1/GCG effectively reduced hepatic lipid and the addition of an FXR agonist and ACC inhibitor further improved pre-to-post NAS and fibrosis stage in DIO-NASH mice.
Neither Kim et al. Norlin et al nor Trevaskis et al teach that the triple agonist (GLP-1/GIP/Glucagon) comprises amino acid sequence of SEQ ID NO: 42.
Oh et al. teach a triple agonist (GLP-1/GIP/GCG) for treating obesity and diabetes type 2, wherein the triple agonist comprises amino acid sequence of SEQ ID NO: 76 which is 100% identical to the instantly claimed triple agonist of SEQ ID NO: 42 (see sequence alignment).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a triple agonist of amino acid sequence of SEQ ID NO: 42 as taught by Oh et al to replace the long-acting triple agonist taught by Kim et al for treating a liver disease including liver fibrosis as taught by Kim et al. It would have been obvious to one of the ordinary skill in the art to further include the FXR agonist cilofexor and the ACC inhibitor firscostat as taught by Norlin et al and Trevaskis et al with a triple agonist (GLP-1/GIP/Glucagon) of SEQ ID NO: 42 for treating NASH or liver fibrosis as taught by Kim et al. Additionally, one would have been motivated to do so because Oh et al teach that the triple agonist of amino acid sequence of SEQ ID NO:42 interacts with GLP-1, GIP and Glucagon receptors and reduces body weight; and Kim et al teach that a long-acting triple agonist being able to reduce liver fat and treat fibrosis. Also, Norlin et al and Trevaskis et al. teach that the addition of an FXR agonist and an ACC inhibitor further reduces lipid content, and liver inflammation and fibrosis as compared to semaglutide or GIP/GLP-1 agonists. Further, one would have a reasonable expectation of success in using an FXR agonist and an ACC inhibitor as taught by Norlin et al or Trevaskis et al. along with a triple agonist. One would have reasonably replaced the triple agonist of Kim et al in a long-acting conjugate with the triple agonist having amino acid sequence of SEQ ID NO: 42 as taught by Oh et al because they are functionally equivalent Oh et al teach the peptide of SEQ ID NO: 42 as a triple agonist. Therefore, the instantly claimed invention would have been obvious over the combined teachings of the prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GYAN CHANDRA whose telephone number is (571)272-2922. The examiner can normally be reached Mon-Friday 8:30AM-5:00P.
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, Vanessa Ford can be reached at 571-272-0857. 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.
/GYAN CHANDRA/Primary Examiner, Art Unit 1674