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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11 December 2025 has been entered.
Status of Application, Amendments and/or Claims
The amendment of 11 December 2025 has been entered in full. Claims 1, 2, and 18 are amended.
Claims 4, 6, 9, 11, 12, 14, 20, 22, 25, 27, 28, and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 15 January 2025.
Claims 1-3, 5, 7, 8, 10, 13, 15-19, 21, 23, 24, 26, 29, and 31-33 are under consideration in the instant application as they read upon the elected species of (i) the peptide amino acid sequence of SEQ ID NO: 42 and (ii) NASH.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 26 January 2026 and 11 December 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Maintained 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.
1. Claims 1-3, 5, 7, 8, 10, 13, 15-19, 21, 23, 24, 26, 29, and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (Diabetologia 60(Suppl 1): S50, abstract #109, 2017; cited on the PTO-892 of 03 April 2025) and Oh et al. (US 2018/0311315; cited on the IDS of 25 April 2024). The basis for this rejection is set forth at pages 3-9 of the previous Office Action of 11 September 2025 and at pages 7-10 of the Office Action of 03 April 2025 and is reiterated herein below for convenience.
Choi et al. teach the generation of a long-acting GLP-1/glucagon/GIP triple agonist, HM15211 (see background). Choi et al. disclose that HM15211 consists of a triple agonist peptide, TA211, conjugated to the human aglycoslated Fc fragment via a short PEG linker (see background). Choi et al. state that HM15211 is administered to diet-induced obesity (DIO) mice and methionine choline-deficient (MCD) diet mice (a well-established NASH model) (see material and methods). Choi et al. teach that HM15211 treatment reduces both liver triglycerides (TG) and NAFLD activity score (NAS) in MCD mice (see results). Choi et al. disclose that HM15211 could provide a favorable therapeutic profile, as well as dosing convenience as compared to existing therapeutics for the treatment of obesity and obesity-related liver disease, including NASH (see conclusion and background).
Choi et al. do not teach that the triple agonist peptide comprises the instant amino acid sequence of SEQ ID NO: 42.
Oh et al. teach the generation of a GLP-1/glucagon/GIP triple agonist peptide conjugated to an immunoglobulin Fc via a PEG (polyethylene glycol) linker (page 2, [0019-0024; Example 2, page 19, [0554-0555]). Oh et al. indicate that the elements are joined to each other through covalent bonds (page 10, [0463], [0479], [0481]). Oh et al. disclose that the PEG linker in the agonist peptide conjugate may have a molecular weight between 1 kDa to 100 kDa (page 11, [0482]; page 19, [0554]). Oh et al. teach that the triple agonist peptide comprises the amino acid sequence of SEQ ID NO: 42 (page 14, [0552]; page 16, Table 1; page 19, [0559]). It is noted the amino acid sequence of SEQ ID NO: 42 of Oh et al. is 100% identical to the elected amino acid sequence of SEQ ID NO: 42 of the instant claims, including the requirement of an aminoisobutyric acid (Aib) at the second amino acid (see sequence alignment, below). Oh et al. also indicate the C-terminus of the peptide may be amidated (page 7, [0268]).
Qy= instant SEQ ID NO: 42
Db= SEQ ID NO: 42 of Oh et al.
US-16-024-014-42
Filing date in PALM: 2018-06-29
Sequence 42, US/16024014
Publication No. US20180311315A1
GENERAL INFORMATION
APPLICANT: HANMI PHARM. CO., LTD.
TITLE OF INVENTION: LONG-ACTING CONJUGATE OF TRIPLE GLUCAGON/GLP-1/GIP RECEPTOR
TITLE OF INVENTION: AGONIST
FILE REFERENCE: Q240631
CURRENT APPLICATION NUMBER: US/16/024,014
CURRENT FILING DATE: 2018-06-29
PRIOR APPLICATION NUMBER: PCT/KR2016/015555
PRIOR FILING DATE: 2016-12-30
PRIOR APPLICATION NUMBER: KR 10-2015-0191082
PRIOR FILING DATE: 2015-12-31
PRIOR APPLICATION NUMBER: KR 10-2016-0163737
PRIOR FILING DATE: 2016-12-02
SEQ ID NO 42
LENGTH: 40
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Trigonal agonist
FEATURE:
NAME/KEY: MISC_FEATURE
LOCATION: (2)
OTHER INFORMATION: Xaa is aminoisobutyric acid (Aib)
FEATURE:
NAME/KEY: MISC_FEATURE
LOCATION: (16)..(20)
OTHER INFORMATION: amino acids at positions 16 and 20 form a ring
Query Match 99.5%; Score 221; Length 40;
Best Local Similarity 100.0%;
Matches 40; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 YXQGTFTSDYSKYLDEKRAKEFVQWLLDHHPSSGQPPPSC 40
||||||||||||||||||||||||||||||||||||||||
Db 1 YXQGTFTSDYSKYLDEKRAKEFVQWLLDHHPSSGQPPPSC 40
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of treating NASH comprising administering the long-acting GLP-1/glucagon/GIP triple agonist, HM5211, as taught by Choi et al. by substituting Choi et al.’s triple agonist with the GLP-1/glucagon/GIP triple agonist comprising the amino acid sequence of SEQ ID NO: 42 as taught by Oh et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the long-acting conjugate comprising the amino acid sequence of SEQ ID NO: 42 of Oh et al. is also a potent GLP-1/glucagon/GIP triple agonist in vitro and in vivo (page 20, Table 2; page 21, Table 3, [0569], [0570-0573]; Figures 1-2) and the simple substitution of one known equivalent element for another obtains predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
(i) At the bottom of page 2 of the Response of 11 December 2025, Applicant argues that Choi provides no information regarding the peptide included in HM15211 (size, sequence, activity, etc.). Applicant states since peptides without any information are extremely broad in scope, one skilled in the art would have no clue what properties or size of peptide could be included in HM15211. Applicant indicates, for example, Choi provides no information on whether a very short peptide with fewer than 5 amino acids could exhibit the same efficacy, whether it is hydrophobic or hydrophilic, or whether it can function regardless of physical properties such as pI value. Applicant submits that even combining Oh with Choi, it is impossible to apply SEQ ID NO: 42 to HM15211 and expect efficacy.
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner acknowledges that Choi et al. do not disclose the specific identity of the peptide in the long-acting GLP-1/glucagon/GIP triple agonist, “HM15211”. However, Choi et al. teach that HM15211 consists of a triple agonist peptide, TA211, conjugated to the human aglycoslated Fc fragment via a short PEG linker (see background).
Oh et al. also teach the generation of a GLP-1/glucagon/GIP triple agonist peptide conjugated to an immunoglobulin Fc via a PEG (polyethylene glycol) linker (page 2, [0019-0024; Example 2, page 19, [0554-0555]). Oh et al. teach that the triple agonist peptide comprises the amino acid sequence of SEQ ID NO: 42, which is 100% identical to the elected amino acid sequence of SEQ ID NO: 42 of the instant claims, including the requirement of an aminoisobutyric acid (Aib) at the second amino acid (page 14, [0552]; page 16, Table 1; page 19, [0559]).
Therefore, the long-acting GLP-1/glucagon/GIP triple agonists of both Choi et al. and Oh et al. have the same function and are comprised of similar components: peptide, PEG linker, and Fc fragment.
The person of ordinary skill in the art would have been motivated to modify the method of treating NASH comprising administering the long-acting GLP-1/glucagon/GIP triple agonist, HM5211, as taught by Choi et al. by substituting Choi et al.’s triple agonist with the GLP-1/glucagon/GIP triple agonist comprising the amino acid sequence of SEQ ID NO: 42 as taught by Oh et al and would have expected success because the long-acting conjugate comprising the amino acid sequence of SEQ ID NO: 42 of Oh et al. is also a potent GLP-1/glucagon/GIP triple agonist in vitro and in vivo (page 20, Table 2; page 21, Table 3, [0569], [0570-0573]; Figures 1-2). The simple substitution of one known equivalent element for another obtains predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
Furthermore, Oh et al. clearly teach the GLP-1/glucagon/GIP triple agonist peptide comprising the instant amino acid sequence of SEQ ID NO: 42 is a functional triple agonist (page 20, Table 2; page 21, Table 3, [0569], [0570-0573]; Figures 1-2). Oh et al. disclose that the high-fat diet-induced obesity mouse groups administered with a high-dose of the long-acting conjugate of SEQ ID NO: 42 showed (i) a decrease in body weight by 57.0% (compared to that before administration) and (ii) a significant decrease in body fat (compared to a group administered excipient) (page 21, [0572-0573]). Therefore, the skilled artisan would have expected that replacing the long-acting GLP-1/glucagon/GIP triple agonist, HM5211, as taught by Choi et al. with the structurally similar and biologically active GLP-1/glucagon/GIP triple agonist comprising the amino acid sequence of SEQ ID NO: 42 as taught by Oh et al. would treat a liver disease, such as NASH. Contrary to Applicant’s arguments, it is noted that conclusive proof of efficacy is not required to show a reasonable expectation of success (OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See also MPEP §2143.02.
(ii) At the top of page 3 of the Response, Applicant asserts that even assuming HM15211 has a peptide-PEG-Fc structure as in Oh, the active site in such as triple agonist conjugate is the peptide. Applicant indicates that the properties and activity of the peptide are important. Applicant contends that selecting and applying a specific sequence from Oh to Choi, which provides no disclosure regarding the active-site peptide, exceeds what would be obvious to those skilled in the art and cannot be done without hindsight bias to SEQ ID NO: 42 (see top and bottom of page 3 of the Response). Applicant argues that there is no basis in Oh to select SEQ ID NO: 42 from among the 102 disclosed sequences. Applicant states that SEQ ID NO: 42 is not even included among the top 30 sequences with the highest GLP-1 receptor activity and is also not included among the top 20 sequences for GIP receptor activity. Applicant submits that those skilled in the art seeking to select a peptide acting on all three receptors from Oh would not reasonably select SEQ ID NO: 42, which, according to Oh, does not exhibit remarkably high activity for two of the three receptors.
Applicant’s arguments have been fully considered but are not found to be persuasive. First, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Second, although Applicant argues that there is no basis in Oh to select SEQ ID NO: 42 from among the 102 disclosed sequences, Applicant is reminded that Oh et al. disclose a finite list of GLP-1/glucagon/GIP triple agonists, including the peptide comprising the amino acid sequence of SEQ ID NO: 42 (Table 2). The comprehensiveness of the list of triple agonist peptides does not negate the fact that a peptide comprising the amino acid sequence of SEQ ID NO: 42 is taught as one of those triple agonist peptides. There are a finite number of identified, predictable solutions and one skilled in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Furthermore, one skilled the art actually would be guided to select the triple agonist of SEQ ID NO: 42 of Oh et al. based upon its relative potency ratios disclosed in Tables 2 and 3 (pages 20-21 of Oh et al.). Specifically, the peptide of SEQ ID NO: 42 has one of the highest potencies across all three GLP-1, Glucagon, and GIP (see Tables 2 and 3). Oh et al. also teach that high-fat diet-induced obesity mouse groups administered with a high-dose of the long-acting conjugate of SEQ ID NO: 42 showed (i) a decrease in body weight by 57.0% (compared to that before administration) and (ii) a significant decrease in body fat (compared to a group administered excipient) (page 21, [0572-0573]; Figures 1-2).
(iii) At the bottom of page 3, Applicant argues that although the Examiner has cited Figures 1 and 2 of Oh as further basis, neither Figure 1 nor Figure 2 tests only the long-acting conjugate of SEQ ID NO: 42. Applicant adds that experimental results for other sequences are also included, and Table 3 confirms activity for several sequences other than SEQ ID NO: 42 in conjugate form.
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner is unclear how Applicant has concluded that Figure 1, Figure 2, and Table 3 do not show the test results for only the long-acting conjugate of SEQ ID NO: 42. Specifically, contrary to Applicant’s arguments, Figure 1 of Oh et al. clearly demonstrates the body weight changes in two obesity mouse model groups only administered the conjugate comprising the amino acid sequence of SEQ ID NO: 42 (at two different dosages) (see bottom key). Likewise, Figure 2 of Oh et al. shows mesenteric fat amounts in two obesity mouse model groups only administered the conjugate comprising the amino acid sequence of SEQ ID NO: 42 (at two different dosages) (see bottom key).
Additionally, at page 21 of Oh et al., Table 3 indicates the relative potency ratio of a long-acting conjugate of the triple agonist of SEQ ID NO: 42 (see the third conjugate listed in the table).
Thus, Figures 1, 2, and Table 3 of Oh et al. show the experimental results of a long-acting conjugate of the triple agonist of SEQ ID NO: 42.
(iv) At the middle of page 4 of the Response, regarding references WO 2021/126695 and WO 2019/125938 cited by Applicant to evidence that not all triple agonists would necessarily have treatment efficacy of liver diseases, Applicant states that since receptor activity is substantially exhibited by the peptide rather than PEG-Fc, the properties of the triple agonist peptide without PEG-Fc, disclosed in WO 2021/126695 and WO 2019125938, should be considered as objective evidence. Applicant argues that as shown in these references, a triple agonist does not necessarily exhibit a NASH effect and those skilled in the art would not be able to reasonably predict that a NASH therapeutic effect would be achieved merely by replacing the triple agonist of HM15211 with that of Oh.
Applicant’s arguments have been fully considered but are not found to be persuasive. Specifically, although Applicant cites WO 2021/126695 and WO 2019/125938 as evidence that not all triple agonists would necessarily have treatment efficacy of liver diseases (pointing to the lack of significance of the peptides in Examples 2 and 3 of WO 2021/126695 in controlling insulin and triglycerides (Table 8) and the lack of significance of ALT improvement of substances in Example 1 of WO 2019/125938 (citing Table 8 of ‘938), the Examiner does not find this argument persuasive. Specifically, in WO 2021/126695, Table 7 indicates that the compounds of Examples 1-3 dose-dependently reduce body weight and fat. Table 8 in WO 2021/126695 also demonstrates that the compounds of Examples 1-3 “reduce blood glucose, insulin (as a sign of increasing insulin sensitivity), cholesterol and triglycerides” (page 36, [0144]). The disclosure of WO 2021/126695 even indicates that the compounds of Examples 1-3 can be used to treat NASH (pages 2-3, [0008]; page 19, [0074]).
Similarly, the disclosed compounds in WO 2019/125938 dose-dependently reduce body weight (Table 7); and “reduce blood glucose, plasma insulin (as a sign of increasing insulin sensitivity) and plasma cholesterol, as well as improve liver health demonstrated by decrease of plasma ALT and liver triglycerides” (page 34, lines 9-12; Table 8). The disclosure of WO 2019/125938 also teaches that the compounds can be used to treat NASH (pages 2, lines 31-32; page 3, lines 8-12; page 13, lines 5-8).
Although the agonist compounds in the ‘695 and ‘938 references are structurally different from the agonists of Choi et al. and Oh et al. and do not comprise a PEG linker or an Fc fragment, they are GLP-1/glucagon/GIP triple agonists that reduce blood glucose, insulin, cholesterol, and triglycerides and are disclosed to treat NASH. Therefore, contrary to Applicant’s arguments, the ‘695 and ‘938 references provide evidence that shows there is a reasonable expectation of success, supporting a conclusion of obviousness.
As discussed in-depth above and in previous Office Actions, Oh et al. teach the GLP-1/glucagon/GIP triple agonist peptide comprising the instant amino acid sequence of SEQ ID NO: 42 is a functional triple agonist in vitro and in vivo (page 20, Table 2; page 21, Table 3, [0569], [0570-0573]; Figures 1-2). Oh et al. disclose that high-fat diet-induced obesity mouse groups administered with a high-dose of the long-acting conjugate of SEQ ID NO: 42 showed (i) a decrease in body weight by 57.0% (compared to that before administration) and (ii) a significant decrease in body fat (compared to a group administered excipient) (page 21, [0572-0573]). The skilled artisan would have expected that replacing the long-acting GLP-1/glucagon/GIP triple agonist, HM5211, as taught by Choi et al. with the structurally similar and biologically active GLP-1/glucagon/GIP triple agonist comprising the amino acid sequence of SEQ ID NO: 42 as taught by Oh et al. would treat a liver disease, such as NASH. Oh et al. disclose a finite list of GLP-1/glucagon/GIP triple agonists, including the peptide comprising the amino acid sequence of SEQ ID NO: 42 (Table 2). The comprehensiveness of the list of triple agonist peptides does not negate the fact that a peptide comprising the amino acid sequence of SEQ ID NO: 42 is taught as one of those triple agonist peptides. There are a finite number of identified, predictable solutions and one skilled in the art has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
It is also noted that conclusive proof of efficacy is not required to show a reasonable expectation of success (OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See also MPEP §2143.02.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
2. Claims 1-3, 5, 7, 8, 10, 13, 15-19, 21, 23, 24, 26, 29, and 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the following U.S. Patent Nos in view of Bifari et al. (Pharmacol Res 137: 219-229, 2018) and Choi et al. (Diabetologia 60(Suppl 1): S50, abstract #109, 2017):
a. claims 1-14 of U.S. Patent 10,370,426
b. claims 1, 3-16, and 18-34 of U.S. Patent 11,332,508
Each of the ‘426 and ‘508 patent claims recite an isolated peptide that is a GLP-1/glucagon/GIP triple agonist peptide, pharmaceutical compositions, and methods of treating metabolic syndrome. Specifically, the patent claims recite peptide amino acid formulas and that the peptide comprises the amino acid sequence of SEQ ID NO: 42 (see claims 3, 4, 10 of the ‘436 patent and claims 5, 6, 11, 18, 19 of the ‘508 patent). It is noted the amino acid sequence of SEQ ID NO: 42 of the ‘426 and ‘508 patents is 100% identical to the amino acid sequence of SEQ ID NO: 42 of the instant application.
Although the claims of ‘426 and ‘508 patents recite administering the triple agonist peptide, the patent claims do not recite treating subjects with NASH. The ‘426 and ‘508 patent claims also do not recite that triple agonist peptide is in the form of a long-acting conjugate with a PEG linker and immunoglobulin Fc fragment.
Bifari et al. review several GLP-1 analogs available and indicate that they demonstrate the clinical benefit on NAFLD and NASH—both diseases of which have metabolic features (Figure 2; page 221 and Table 1; page 223, column 2, last paragraph through the top of page 224; page 224, column 1, last paragraph). Bifari et al. point out that GLP-1 analogs reduce the levels of inflammatory cytokines, such as TNFα, IL-1β, and IL-6 (page 223, column 2, last paragraph). Bifari et al. conclude that the overall effect of GLP-1 analog administration results in liver function improvement and NASH amelioration (page 225, column 1, 1st and 2nd full paragraphs).
Choi et al. teach the generation of a long-acting GLP-1/glucagon/GIP triple agonist, HM15211 (see background). Choi et al. disclose that HM15211 consists of a triple agonist peptide, TA211, conjugated to the human aglycoslated Fc fragment via a short PEG linker (see background). Choi et al. state that HM15211 is administered to diet-induced obesity (DIO) mice and methionine choline-deficient (MCD) diet mice (a well-established NASH model) (see material and methods). Choi et al. teach that HM15211 treatment reduces both liver triglycerides (TG) and NAFLD activity score (NAS) in MCD mice (see results). Choi et al. disclose that HM15211 could provide a favorable therapeutic profile, as well as dosing convenience as compared to existing therapeutics for the treatment of obesity and obesity-related liver disease, including NASH (see conclusion and background).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the isolated GLP-1/glucagon/GIP triple agonist peptide and methods of treating metabolic syndrome of the ‘426 and ‘508 claims by also administering the triple agonist peptide to treat NASH and formulating the peptide into a long-acting conjugate (with a PEG linker and an Fc fragment), as taught by Bifari et al. and Choi et al. The person of ordinary skill in the art would have been motivated to make those modifications and would have expected success because the administration of other GLP-1 agonists were known to successfully treat NASH at the time of filing of the instant application and the generation of a long-acting conjugate increases therapeutic efficacy with fewer adverse events (Bifari et al. and entirety of Choi et al.). Additionally, the simple substitution of one known equivalent element for another obtains predictable results and a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
3. Claims 1-3, 5, 7, 8, 10, 13, 15-19, 21, 23, 24, 26, 29, and 31-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the following U.S. Patent Nos in view of Choi et al. (Diabetologia 60(Suppl 1): S50, abstract #109, 2017):
a. claims 1-5, 7-24 of U.S. Patent 10,400,020
b. claims 1, 3-17, and 19-41 of U.S. Patent 10,981,967
Each of the ‘020 and ‘967 patent claim sets recite a conjugate comprising a chemical formula of X-La-F, wherein X is a GLP-1/glucagon/GIP triple agonist peptide, La is a polyethylene glycol linker, and F is an immunoglobulin Fc region. The claims of the patents also recite pharmaceutical compositions and a method of treating metabolic syndrome. Furthermore, the patent claims recite that the agonist peptide comprises the amino acid sequence of SEQ ID NO: 42 (see claims 2, 7, 8 of the ‘020 patent and claims 5, 6, 14, 19, 20 of the ‘967 patent). It is noted the amino acid sequence of SEQ ID NO: 42 of the ‘020 and ‘967 patents is 100% identical to the amino acid sequence of SEQ ID NO: 42 of the instant application.
Although the claims of the ‘020 and ‘967 patents recite administering a conjugate comprising the triple agonist peptide of SEQ ID NO: 42, the patent claims do not recite treating subjects with NASH.
Choi et al. teach the generation of a long-acting GLP-1/glucagon/GIP triple agonist, HM15211 (see background). Choi et al. disclose that HM15211 consists of a triple agonist peptide, TA211, conjugated to the human aglycoslated Fc fragment via a short PEG linker (see background). Choi et al. state that HM15211 is administered to diet-induced obesity (DIO) mice and methionine choline-deficient (MCD) diet mice (a well-established NASH model) (see material and methods). Choi et al. teach that HM15211 treatment reduces both liver triglycerides (TG) and NAFLD activity score (NAS) in MCD mice (see results). Choi et al. disclose that HM15211 could provide a favorable therapeutic profile, as well as dosing convenience as compared to existing therapeutics for the treatment of obesity and obesity-related liver disease, including NASH (see conclusion and background).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the conjugate comprising a GLP-1/glucagon/GIP triple agonist peptide of SEQ ID NO: 42 and methods of treating metabolic syndrome of the ‘020 and ‘967 claims by also administering the conjugate to treat NASH, as taught by Choi et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the administration of other long-acting GLP-1 agonist conjugates were known to successfully treat NASH at the time of filing of the instant application, as well as increase therapeutic efficacy with fewer adverse events (entirety of Choi et al.). Additionally, the simple substitution of one known equivalent element for another obtains predictable results and a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
4. Claims 1-3, 5, 7, 8, 10, 13, 15-19, 21, 23, 24, 26, 29, and 31-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the following copending Application Nos. in view of Bifari et al. (Pharmacol Res 137: 219-229, 2018) and Choi et al. (Diabetologia 60(Suppl 1): S50, abstract #109, 2017):
a. claims 1-6, 8, 9, 23-25, 30, 32, 34-37, 41-43, 61-63 of 17/416,880
b. claims 4-15, 18-22 of 17/700,055
c. claims 38-58, 61-72 of 17/926,912
d. claims 12-22 of 18/032,076
e. claims 1-4, 6-20 of 18/565,628
Each of the claim sets of the ‘880, ‘055, ‘912, ‘076, and ‘628 applications recite an isolated peptide that is a GLP-1/glucagon/GIP triple agonist peptide; a long-acting conjugate comprising the peptide, an ethylene glycol linker, and an immunoglobulin Fc fragment; pharmaceutical compositions; and/or a method of treating a metabolic syndrome or liver disease comprising administering the peptide or conjugate thereof. Specifically, the applications’ claims recite peptide amino acid formulas and that the peptide comprises the amino acid sequence of SEQ ID NO: 42. It is noted the amino acid sequence of SEQ ID NO: 42 of the ‘880, ‘055, ‘912, ‘076, and ‘628 applications is 100% identical to the amino acid sequence of SEQ ID NO: 42 of the instant application.
However, the claims of the ‘880, ‘055, ‘912, ‘076, and ‘628 applications do not recite treating NASH by administering the triple agonist peptide of SEQ ID NO: 42 or conjugate thereof.
Bifari et al. review several GLP-1 analogs available and indicate that they demonstrate the clinical benefit on NAFLD and NASH—both diseases of which have metabolic features (Figure 2; page 221 and Table 1; page 223, column 2, last paragraph through the top of page 224; page 224, column 1, last paragraph). Bifari et al. point out that GLP-1 analogs reduce the levels of inflammatory cytokines, such as TNFα, IL-1β, and IL-6 (page 223, column 2, last paragraph). Bifari et al. conclude that the overall effect of GLP-1 analog administration results in liver function improvement and NASH amelioration (page 225, column 1, 1st and 2nd full paragraphs).
Choi et al. teach the generation of a long-acting GLP-1/glucagon/GIP triple agonist, HM15211 (see background). Choi et al. disclose that HM15211 consists of a triple agonist peptide, TA211, conjugated to the human aglycoslated Fc fragment via a short PEG linker (see background). Choi et al. state that HM15211 is administered to diet-induced obesity (DIO) mice and methionine choline-deficient (MCD) diet mice (a well-established NASH model) (see material and methods). Choi et al. teach that HM15211 treatment reduces both liver triglycerides (TG) and NAFLD activity score (NAS) in MCD mice (see results). Choi et al. disclose that HM15211 could provide a favorable therapeutic profile, as well as dosing convenience as compared to existing therapeutics for the treatment of obesity and obesity-related liver disease, including NASH (see conclusion and background).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the GLP-1/glucagon/GIP triple agonist peptide of SEQ ID NO: 42 or conjugate thereof of the ‘880, ‘055, ‘912, ‘076, and ‘628 application claims by administering the peptide or conjugate to treat NASH, as taught by Bifari et al. and Choi et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because the administration of other GLP-1 agonists (including long-acting GLP-1 agonist conjugates) were known to successfully treat NASH at the time of filing of the instant application, as well as increase therapeutic efficacy with fewer adverse events (see Bifari et al. and entirety of Choi et al.). Additionally, the simple substitution of one known equivalent element for another obtains predictable results and a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
These are provisional nonstatutory double patenting rejections.
5. Claims 1-3, 5, 7, 8, 10, 13, 15-19, 21, 23, 24, 26, 29, and 31-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the following copending Application Nos.:
a. claims 100, 125-137, 139-140 of 17/282,661
b. claims 1-10, 13-15 of 18/040,869
c. claims 27-46 of 18/041,151
Although the claims at issue are not identical, they are not patentably distinct from each other because all sets of claims recite a method of treating NASH or a subject with NASH comprising administering the same GLP-1/glucagon/GIP triple agonist peptide of SEQ ID NO: 42 or a long-acting conjugate thereof.
Claim 1 of the instant application is directed to a method for prevention or treatment of liver disease (elected species of NASH), comprising administering a pharmaceutical composition to a subject in need thereof, comprising: a pharmaceutically acceptable excipient; and a peptide comprising the amino acid sequence of SEQ ID NO: 42 (elected species). Instant claim 2 recites that the peptide is in the form of a long-acting conjugate that comprises the peptide, an ethylene glycol linker, and an immunoglobulin Fc fragment.
Each of the claims sets of the ‘661, ‘869, and ‘151 applications recite (a) a method of treating a metabolic syndrome or liver disease or (b) treating a patient with a metabolic syndrome or liver disease, comprising administering a pharmaceutical composition comprising (i) an isolated peptide that is a GLP-1/glucagon/GIP triple agonist peptide; or (ii) a long-acting conjugate comprising the peptide, an ethylene glycol linker, and an immunoglobulin Fc fragment; and wherein the metabolic syndrome or liver disease is NASH. Specifically, the applications’ claims recite peptide amino acid formulas and that the peptide comprises the amino acid sequence of SEQ ID NO: 42. It is noted the amino acid sequence of SEQ ID NO: 42 of the ‘661, ‘869, and ‘151 applications is 100% identical to the amino acid sequence of SEQ ID NO: 42 of the instant application.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
(i) In response to the double patenting rejections, at page 5 of the Response of 11 December 2025, Applicant requests the rejections to be held in abeyance until at least one allowable claim is identified.
The rejections are maintained and held in abeyance until all other issues are resolved. However, Applicant is encouraged to submit terminal disclaimers at Applicant's earliest convenience.
Conclusion
No claims are allowable.
The art made of record and not relied upon is considered pertinent to applicant's disclosure:
* “Efocipegtrutide” record entry in GSRS database; dated 25 August 2025 (see https://gsrs.ncats.nih.gov/ginas/app/ui/substances/TUI1MDD9F6; teaches that one synonym of efocipegtrutide is “HM12511” (long acting GLP-1/GIP/glucagon triple agonist; also teaches that “subunit 3” is 100% identical to the instant amino acid sequence of SEQ ID NO: 42 (see pages 1, 3, 5, 6). Therefore, the “efocipegtrutide” entry clearly identifies HM15211 as being the long acting GLP-1/GIP/glucagon triple agonist that comprises a peptide sequence 100% identical to the instant amino acid sequence of SEQ ID NO: 42))
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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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BEB
Art Unit 1647
11 February 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647