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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 5, 2025 has been entered.
Status of the Claims
Claims 1-19 were originally filed October 27, 2023.
The preliminary amendment received October 27, 2023 amended claims 3, 5-10, 12-14, and 17-19.
The amendment received November 18, 2024 amended claims 1, 2, 4, 12, 13, and 16; canceled claims 3, 5, 7, 9, 11, 15, 18, and 19; and added new claims 20-28.
The amendment received March 10, 2025 amended claims 2, 16, 20, 24, 25, and 28; canceled claims 1, 4, 6, 8, 10, 12-14, and 17.
The amendment received July 14, 2025 amended claims 2, 16, and 20-28.
The amendment received November 5, 2025 amended claims 2, 16, 20, 24, and 25 and canceled claim 21.
Claims 2, 16, 20, and 22-28 are currently pending and under consideration.
Election/Restrictions
Applicant's election with traverse of WX-005 (i.e. SEQ ID NO: 6 – SEQ ID NO: 12 with K at residue 24 replaced with E; So is amidated serine, m = 2, n = 17, p = 1; “staple” is as shown in claims 16 and 23-26) in the reply filed on March 10, 2025 is acknowledged. The traversal is on the grounds that Bokvist et al. does not teach the presently claimed formula because Bokvist et al. teach Q at position 24 and not K. It is unclear why applicants are focusing on SEQ ID NO: 1 when SEQ ID NO: 6 was elected. Applicants then assert that Bokvist et al. only teach conjugation at residue 20 and not the presently claimed stapled peptide. This is not found persuasive because present claim 2 requires position 24 to be substituted from K to Q, A, I, or E. Present SEQ ID NO: 6 has E at residue 24. Q and E are conservative amino acid substitutions according to Dayhoff (hydrophilic). The claim language was unclear with regard to the stapled peptide. However, applicants may rely on the prior art of record in combination with Bokvist et al. for Lack of Unity (see the 35 USC 103 rejection below).
The requirement is still deemed proper and is therefore made FINAL.
Please note: it is unclear what applicants have elected for E. Applicants provide a definition of pharmaceutically acceptable salt and state that “a pharmaceutically acceptable salt may be elected as a salt prepared by reacting the polypeptide compound with glucuronic acid” and “a pharmaceutically acceptable salt may be elected as starch, which is usually used as a filler” (emphasis added). It is respectfully noted that this appears to be a typographical error and applicants meant pharmaceutically acceptable carrier in the last full paragraph on page 16. See page 16 of the response received March 10, 2025.
Please note: applicants clearly state on the record that “It is conventional to prepare a pharmaceutically acceptable base or acid addition salts based on the polypeptide compounds disclosed in the application.”. Therefore, applicants have clearly stated on the record that a pharmaceutically acceptable salt is conventional and thus obvious to one of skill in the art. Applicants clearly state on the record that “Pharmaceutically acceptable carrier is well-known as a conventional component used in the formulation of a pharmaceutical composition”. Therefore, applicants have clearly stated on the record that a pharmaceutically acceptable carrier is well-known and conventional and thus obvious to one of skill in the art. See page 16 of the response received March 10, 2025.
Priority
The present application is a 371 (National Stage) of PCT/CN2022/095859 filed May 30, 2022 which claims foreign priority to China 202210552077.4 filed May 18, 2022; China 202210138835.8 filed February 15, 2022; China 202110814116.9 filed July 19, 2021; and China 202110594662.6 filed May 28, 2021.
Drawings
No drawings are present.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Withdrawn Objections
The objection to the abstract regarding “SEQ ID NO. 11” should read “SEQ ID NO: 11” is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 20 regarding a conjunction is missing between SEQ ID NO: 8 and SEQ ID NO: 9 (see lines 10 and 11) is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 20 regarding utilizing SEQ ID NOs: 6-9 twice is redundant is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 2 regarding a conjunction is missing between n and p is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 2 regarding “Formula (P)” should be deleted and only SEQ ID NO: 12 should be utilized (e.g. in parentheses after the sequence) is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 16 regarding “formula” should be removed since no formulas are present in the claim (i.e. applicants are correctly utilizing SEQ ID NOs: and not formulas) is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 24 regarding X, X1, and X2 should be defined in order to ensure that the claim is not broadening the scope of independent claim 2 is withdrawn in view of the amendment received November 5, 2025.
The objection to claim 25 regarding X, X1, and X2 should be defined in order to ensure that the claim is not broadening the scope of independent claim 2 is withdrawn in view of the amendment received November 5, 2025.
Sequence Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising a sequence of SEQ ID NO: 1” requires only a 2mer of SEQ ID NO: 1, “comprising the sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with any N-/C-terminal additions or any 5’/3’ additions, “consisting of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 and the same length as SEQ ID NO: 1, and “selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3.
Maintained Rejections
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.
Claims 2, 16, 20, and 22-28 are rejected under 35 U.S.C. 103 as being unpatentable over Bokvist et al. U.S. Patent Application Publication 2016/0199438 published July 14, 2016; Shen et al. U.S. Patent Application Publication 2016/0317623 published November 3, 2016; Li et al., 2020, Novel Stapling by Lysine Tethering Provides Stable and Low Hemolytic Cationic Antimicrobial Peptides, Journal of Medicinal Chemistry, 63: 4081-4089; Yang et al., 2020, New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice, Bioconjugate Chemistry, 31: 1167-1176; and Lear et al., 2019, Engineering PEG-fatty acid stapled, long-acting peptide agonists for G protein-coupled receptors, Methods in Enzymology, 622: 183-200.
For present claims 2, 16, 20, and 22-28, Bokvist et al. teach GLP-1/GIP dual agonists comprising YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS wherein the C-terminus can be amidated (i.e. S-NH2) and carriers wherein residue 20/Lys is utilized for conjugation (please refer to the entire specification particularly the abstract; paragraphs 1, 3, 8, 9, 12-36, 54; Examples; claims). Residue 17 is I (see present SEQ ID NOs: 1-4). Residue 24 is Q (see claim 2 and present SEQ ID NO: 7). Q and E are conservative amino acid substitutions according to Dayhoff (hydrophilic) (i.e. present SEQ ID NOs: 6 and 10).
However, Bokvist et al. do not teach stapled polypeptides.
For present claims 2, 16, 20, and 22-28, Shen et al. teach stapled GLP-1/GIP dual agonists wherein the staple is attached at least about two, three, or four residues apart and substituting residues to cysteine for conjugation including residue 17 (e.g. 17 and 20 or 20 and 24 based on Shen et al. and Bokvist et al. utilizing residue 20 for conjugation) (please refer to the entire reference particularly the abstract; paragraphs 5-7, 10, 12, 15, 34-70, 75, 76, 123, 124, 180-209, 226-228, 288; Tables 4, 5).
However, Bokvist et al. does not teach utilizing lysine for attachment of a staple.
For present claims 2, 16, 20, and 22-28, Li et al. teach utilizing lysine for stapling peptides (please refer to the entire reference particularly the abstract; Figure 1; Table 1; Scheme 1).
However, Bokvist et al. do not teach the specific staple as presently claimed.
For present claims 2, 16, 20, and 22-28, Yang et al. teach stapled GLP-1 dual agonists comprising variations of the presently utilized staple (please refer to the entire reference particularly Figures 1, 2, 5).
For present claims 1, 16, 20, and 22-28, Lear et al. teach stapled GLP-1 agonists comprising variations of the presently utilized staple (please refer to the entire reference particularly the abstract; Figures 1, 4; section 2).
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." See In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979); In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963); and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990). Compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977); In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) and; Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007).
All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions and the combination would have yielded predictable results (i.e. stapling instead of conjugation to a single residue to increase half-life, utilizing lysine for conjugation, utilizing a specific staple) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. GLP-1/GIP dual agonist stapling to increase half-life) was recognized as part of the ordinary capabilities of one skilled in the art. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 103 as being unpatentable over Bokvist et al.; Shen et al.; Li et al.; Yang et al.; and Lear et al. for claims 2, 16, 20, and 22-28 were considered but are not persuasive for the following reasons.
Applicants contend that the cited references do not teach substituting amino acids for lysine stapling or staples separated by 2-3 residues. Applicants contend that stapling is unpredictable and there is no motivation to combine the references. Applicants contend that compounds with I17K substitutions exhibit unexpected results.
Applicants’ arguments are not convincing since the teachings of Bokvist et al.; Shen et al.; Li et al.; Yang et al.; and Lear et al. render the modified polypeptide of the instant claims prima facie obvious.
Bokvist et al. teach GLP-1/GIP dual agonists comprising YAibEGTFTSDYSIAibLDKIAQKAFVQWLIAGGPSSGAPPPS wherein the C-terminus can be amidated (i.e. S-NH2) and carriers wherein residue 20/Lys is utilized for conjugation (please refer to the entire specification particularly the abstract; paragraphs 1, 3, 8, 9, 12-36, 54; Examples; claims). Residue 17 is I (see present SEQ ID NOs: 1-4). Residue 24 is Q (see claim 2 and present SEQ ID NO: 7). Q and E are conservative amino acid substitutions according to Dayhoff (hydrophilic) (i.e. present SEQ ID NOs: 6 and 10).
Shen et al. teach stapled GLP-1/GIP dual agonists wherein the staple is attached at least about two, three, or four residues apart and substituting residues to cysteine for conjugation including residue 17 (e.g. 17 and 20 or 20 and 24 based on Shen et al. and Bokvist et al. utilizing residue 20 for conjugation) (please refer to the entire reference particularly the abstract; paragraphs 5-7, 10, 12, 15, 34-70, 75, 76, 123, 124, 180-209, 226-228, 288; Tables 4, 5). Shen et al. teach methods of extending the half-life of GLP-1 and/or GIP via stapling with half-life extending molecules wherein the staple is at least about 4 amino acids apart (please refer to the entire specification particularly the abstract; paragraphs 5-7, 15, 123, 124). Shen et al. is utilized to teach utilizing residue 17 for stapling. Shen et al. teach that residue 17 in a GLP-1/GIP dual agonist can be hydrophilic.
Bokvist et al. teach modifying lysine to generate long-acting GLP-1/GIP dual agonists (please refer to the entire specification particularly paragraph 46).
Li et al. teach utilizing two lysines for stapling to increase stability (please refer to the entire reference particularly the abstract; Figure 1; Scheme 1).
Yang et al. teach stapled, long-acting and highly potent GLP-1 receptor agonists wherein half-life and potency were increased via stapling (please refer to the entire reference particularly the abstract; Figures 1, 2A).
Lear et al. teach stapled, long-acting GLP-1 agonists and GIP with improved half-life (please refer to the reference particularly Table 1; sections 2.1, 2.2).
Therefore, utilization of stapling to improve GLP-1 receptor agonists and/or GIP agonists half-life, stability, and potency is well-known in the prior art. Thus, providing motivation to alter the GLP-1/GIP dual agonists of Bokvist et al. with a staple (i.e. alternative to the lysine modification utilized by Bokvist et al. to enhance half-life).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions and the combination would have yielded predictable results (i.e. stapling instead of conjugation to a single residue to increase half-life, utilizing lysine for conjugation, utilizing a specific staple) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. GLP-1/GIP dual agonist stapling to increase half-life) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because “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.”. See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Cysteines and lysines are commonly utilized in the prior art for both conjugation and stapling (see the references in the above art rejection of record). See Dinh et al., 2015, Antimicrobial activity of doubly-stapled alanine/lysine-based peptides, Bioorganic & Medicinal Chemistry Letters, 25: 4016-4019; Moiola et al., 2019,Stapled Peptides – A Useful Improvement for Peptide-Based Drugs, 24: 3654 (35 pages); Chen et al., 2020, Stapled and Xenopus Glucogon-Like Peptide 1 (GLP-1)-Based Dual GLP-1/Gastrin Receptor Agonists with Improved Metabolic Benefits in Rodent Models of Obesity and Diabetes, Journal of Medicinal Chemisty, 63: 12595-12613; Kim et al., 2018, Photoswitching of Cell Penetration of Amphipathic Peptides by Control of a-Helical Conformation, Biomacromolecules, 19: 2863-2869; and Tan et al., 2016, Stapled peptide design: principles and roles of computation, Drug Discovery Today, 21(10): 1642-1653.
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." See In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) and In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989).
Li et al. Table 1 does not show unpredictability. Li et al. Table 1 shows that ALL stapled peptides have activity (MIC/minimum inhibitory concentration) to both Gram + and Gram – bacteria. Li et al. in describing Table 1 reads “All the cross-linked peptides exhibited comparable activity with their linear counterpart 1. All had antimicrobial activity at mg/mL levels against Gram-positive and Gram-negative bacteria.” (see page4083, left column). If applicants are relying on the results for MRSA, it is respectfully noted that MRSA is drug-resistant methicillin-resistant Staphylococcus aureus and the majority of antimicrobial peptides would actually be expected to not have antimicrobial activity against MRSA. In addition, a prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." See Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005)). See MPEP § 2121. Conclusive proof of efficacy is not required to show a reasonable expectation of success. See 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.’"). See also 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")). Obviousness does not require absolute predictability, but at least some degree of predictability is required.
Statements from applicants attorneys do not negate the necessity of a 37 CFR 1.132 Declaration. See MPEP § 716. Furthermore, it is respectfully noted that tirzepatide is not a stapled peptide. Thus, the comparison is lacking regarding a proper control (e.g. tirzepatide stapled with an amino acid other than lysine, etc.).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lear et al., 2020, Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist, Molecules, 25: (12 pages).
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/AMBER D STEELE/Primary Examiner, Art Unit 1658