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 .
Applicant’s response filed on 4/21/2026 is acknowledged and fully considered.
Status of Application, Amendments, And/Or Claims
The amendments of claims 1,9-11,13, 16 and 18-19, and the cancellation of claims 2-6 and 8 have been made of record.
Claims 1, 7 and 9-19 are pending and under consideration to the extent they read on the elected species.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 4/6/2026 and 5/1/2026 have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: the examiner suggests that syntax of claim 1 can be improved by deleting the term “and” before the term “a pharmaceutically acceptable excipient. Appropriate correction is required.
Response to Arguments
Claim Rejections - 35 USC § 112
The rejection of 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of applicants’ incorporation of limitations of claim 8 (previously not included in the rejection). However, upon further consideration a new ground of rejection has been made by the examiner.
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 9-19 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 composition comprising a triple agonist of SEQ ID NO: 42 subcutaneously and a composition comprising a farnesoid X receptor orally, and therefore the written description is not commensurate in scope with a method of treating any liver disease comprising administering a pharmaceutical composition comprising a triple agonistic long-acting conjugate of formula Z-Lx-Fc or triple agonist; a pharmaceutically active excipient and a farnesoid X receptor agonist, wherein Z is amino acid sequence of SEQ ID NO:21, 22, 42, 43, 50, 64-77 and 95-102.
The claims broadly encompass a method of treating any liver disease using a single pharmaceutical composition comprising a triple agonist comprising an amino acid sequence of SEQ ID NO:21, 22, 42, 43, 50, 64-77 and 95-102, an excipient and a farnesoid X receptor agonist.
The specification at pg.77-82 discloses administering a triple agonist having amino acid sequence of SEQ ID NO: 42 subcutaneously and a farnesoid X receptor orally to a choline deficient fat diet (CD-HFD) mouse model known for NASH and fibrosis that was fed a choline deficient, high fat and high cholesterol that induces steatohepatitis and fibrosis. However, the claim requires a combination a triple agonist and a farnesoid X receptor agonist in a single pharmaceutical composition that can treat any liver disease that may be not liver fibrosis and NASH. To provide adequate written description and evidence of possession of a claimed pharmaceutical composition, the specification must provide sufficient guidance for the claimed invention that includes treating any liver disease. 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 treating.
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 subcutaneously and an FXR agonist and ACC inhibitor orally 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, previously presented) 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. However, none of the art discloses using a single pharmaceutical composition comprising a triple agonist (GLP-1 receptor agonist, GCG receptor agonist and GIP receptor agonist) and a farnesoid X receptor agonist administering subcutaneously or orally that can treat any liver disease not including NASH and liver 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 administering subcutaneously with or without FXR agonist and/or ACC inhibitor administering orally for treating non-alcoholic fatty liver or fibrosis of liver. The specification does not describe a single pharmaceutical composition a triple agonist and a farnesoid X receptor inhibitor that can treat any liver disease in a subject in need thereof. 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).
As discussed above, the skilled artisan cannot envision the detailed genus of “ a method of treating any liver disease comprising administering a single pharmaceutical composition comprising a triple agonistic long acting conjugate having amino acid sequence of SEQ ID NO: 21, 22, 42, 43, 50, 64-77 and 95-102, an excipient and a farnesoid X receptor agonist” 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 subcutaneously; an agonist of cilofexor for oral administration; and an Acetyl-CoA carboxylase inhibitor Firsocostat for oral administration, 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 § 112-scope of enablement
Claims 1, 7 and 9-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating NASH or liver fibrosis comprising a composition having a polypeptide of SEQ ID NO: 42 administering subcutaneously and a farnesoid X receptor agonist administering orally, does not reasonably provide enablement for treating any liver disease (not including NASH or liver fibrosis) comprising a pharmaceutical composition comprising a polypeptide of SEQ ID NO: 42 and a farnesoid X receptor agonist together with a pharmaceutically acceptable excipient to a subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
In In re Wands, 8USPQ2d, 1400 (CAFC 1988) page 1404, the factors to be considered in determining whether a disclosure would require undue experimentation include: (1) Nature of the invention, (2) the state of the prior art, (3) the predictability or lack thereof in the art, (4) the amount of direction or guidance present, (5) the presence or absence of working examples, (6) the breath of the claims, (7) the quantity of experimentation needed, (8) relative skill of those in the art.
The instant disclosure fails to meet the enablement requirement for the following reasons:
Claims 1, 7 and 9-19 are drawn to a method of treating any liver disease comprising a single pharmaceutical composition comprising a polypeptide selected from SEQ ID NO: 21, 22, 42, 43, 50, 64-77 and 95-102, and a farnesoid X receptor agonist together with a pharmaceutically acceptable excipient to a subject in need thereof.
The state of the prior art and the predictability or lack thereof in the art: 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 subcutaneously and an FXR agonist and ACC inhibitor orally 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, previously presented) 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. However, the art does not disclose using a single pharmaceutical composition comprising a triple agonist (GLP-1 receptor agonist, GCG receptor agonist and GIP receptor agonist) and a farnesoid X receptor agonist together to administer either subcutaneously or orally that can treat any liver disease besides NASH and liver fibrosis. Therefore, a large amount of experimentation would be required to make a single pharmaceutical composition comprising a triple agonistic long-acting conjugate selected from SEQ ID NO: 21, 22, 42, 43, 50, 64-77 and 95-102, farnesoid X receptor agonist and a pharmaceutically acceptable excipient to enable the invention as broadly being claimed.
The amount of direction and guidance present and the presence or absence of working examples: Given the teachings found in the art, detailed teachings are required to be present in the disclosure in order to enable the skilled artisan to practice the invention as claimed. These teachings are absent. 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 administering subcutaneously with or without FXR agonist and/or ACC inhibitor administering orally for treating non-alcoholic fatty liver or fibrosis of liver. The specification does not describe a single pharmaceutical composition a triple agonist and a farnesoid X receptor inhibitor that can treat any liver disease in a subject in need thereof. Therefore, it is unpredictable how one of the skill in the art can practice the instantly claimed invention.
The breadth of the claims and the quantity of experimentation needed: Due to the large quantity of experimentation necessary to treat any liver disease (that does not include NASH or liver fibroses) to administer a single pharmaceutical composition comprising a triple agonistic long-acting conjugate selected from SEQ ID NO: 21, 22, 42, 43, 50, 64-77 and 95-102, farnesoid X receptor agonist and a pharmaceutically acceptable excipient to a subject in need thereof, the lack of direction/guidance presented in the specification regarding treating any liver disease comprising administering a pharmaceutical composition comprising selecting polypeptide from SEQ ID NO: 21, 22, 42, 43, 50, 64-77 and 95-102, farnesoid X receptor agonist and a pharmaceutically acceptable excipient to a subject in need thereof, the absence of working examples directed to same, the complex nature of the invention, the state of the prior art which establishes the unpredictability about the same, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claim Rejections - 35 USC § 103-maintained
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, 7 and 9-19 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 including non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) comprising administering a triple agonist of SEQ ID NO: 42, a farnesoid X receptor agonist and pharmaceutically acceptable excipient in a single pharmaceutical composition, and further comprising an acetyl-CoA carboxypeptidase (ACC) inhibitor, wherein the triple agonist comprises amino acid sequence selected from SEQ ID NO:21, 22, 42, 43, 50, 64-77 and 95-102 (claims 9-12), 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 firsocostat 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.
Applicants argue that Kim is the closest art but it does not disclose the sequence of a long-acting triple agonist and it does not disclose the combination of cilofexor/ firsocostat. They argue that Kim does not disclose the specific combination of the claimed invention. Applicants argue that Norlin teaches the combined effect of Semaglutide +cilofexor_ firsocostat but not the long-acting triple agonist. They argue that Norlin may provide the direction of combination therapy that combination did not treat fibrosis. They argue that Trevaskis confirms NASH treatment with GLP-1/Glucagon receptor agonist with FXR agonist and an ACC inhibitor but they did not use a triple agonist, in particular with the amino acid sequence of SEQ ID NO: 42. They argue that Oh teaches the triple agonist of SEQ ID NO: 42 but do not teach the combination of cilofexor, or further with the addition of ACC inhibitor. They argue that the instantly claimed combination of a long-acting triple agonist having SEQ ID NO: 42 with FXR agonist and/or ACC inhibitor provides better NAFLD score (Fig. 1) or hydroxyproline (Fig. 2).
Applicant’s arguments have been fully considered but they are not persuasive because Norlin et al. 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 cilofexor, firsocostat or both to GLP-1/GCG agonist further reduced liver lipid by 82%, 88% and 91%, respectively (see abstract) and this result is considered surprising result. Kim et al. teach a long acting triple agonist comprising GLP-1/GIP/Glucagon (HM 1521) administration to a subject having liver inflammation and liver fibrosis reduces inflammation and fibrotic effects (see the title). Therefore, one skill in the art would substitute incretin Semaglutide or dual agonist (GLP-1/glucagon receptor) a triple agonist HM1521 to treat NASH and fibrosis in a subject and the treatment result would be synergistic (surprising). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claim is allowed.
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/GYAN CHANDRA/Primary Examiner, Art Unit 1674
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