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 .
Response to Amendment
The amendment to the claims filed on September 14, 2026, does not comply with the requirements of 37 CFR 1.121(c)(3) because the text of withdrawn claims 12 and 13 is omitted.
Election/Restrictions
Applicant’s election of Group I in the reply filed on April 10, 2026, 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)).
Claims 12-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Bokvist et al. (U.S. Patent No. 9,474,780 B2) in view of Coskun et al. (LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Molecular Metabolism, (2018) 18: 3-14), Frias et al. (Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. The Lancet, (2018) 392: 2180-2193), Wang (Instability, stabilization, and formulation of liquid protein pharmaceuticals. International Journal of Pharmaceutics 185 (1999) 129-188), Manning et al. (Stability of Protein Pharmaceuticals: An Update. Pharmaceutical Research, Vol. 27, No. 4, April 2010, 544-575), Barnett et al. (Probing the Tryptophan Environment in Therapeutic Proteins: Implications for Higher Order Structure on Tryptophan Oxidation. Journal of Pharmaceutical Sciences 108 (2019) 1944-1952), Stadelmeir et al. (WO 2017/162653 A1), and Center for Drug Evaluation and Research, U.S. Food & Drug Administration (ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin Guidance for Industry, Guidance for Industry. May 2021. Docket Number: FDA-2017-D-5767, downloaded from www.fda.gov/regulatory-information/search-fda-guidance-documents/andas-certain-highly-purified-synthetic-peptide-drug-products-refer-listed-drugs-rdna-origin on June 11, 2026; hereafter “The FDA”).
Determining the scope and contents of the prior art.
Bokvist et al. teach the GIP and GLP-1 co-agonist peptide tirzepatide (SEQ ID NO: 1) (Example 1 in Bokvist et al.)1. Tirzepatide is a 39 amino acid linear peptide conjugated to a C20 fatty diacid moiety via a linker connected to the lysine residue at position 20. Tirzepatide also contains two non-coded amino acid residues at positions 2 and 13 (Aib, a-amino isobutyric acid), and an amidated C-terminus (structure at top of columns 9-10). Tirzepatide functions as a dual glucose-dependent insulinotropic (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist (column 16, lines 23-31). Bokvist et al. teach that the pharmacokinetic profile of tirzepatide supports once-weekly dosing in humans (column 21, lines 10-30). Bokvist et al. teach that tirzepatide may be useful for treating type 2 diabetes (T2D) (claim 17). Later publication of Phase 1 and Phase 2 clinical trials support the use of tirzepatide as a treatment for T2D (see Coskun et al. and Frias et al.).
Ascertaining the differences between the prior art and the claims at issue.
Neither Bokvist et al., Coskun et al., nor Frias et al. teach a compound comprising tirzepatide wherein the tryptophan at position 25 is oxidized to N’-formylkynurenine.
Resolving the level of ordinary skill in the pertinent art.
The FDA has established guidance for industry regarding synthetic peptide drugs "ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin". According to this guidance, peptide-related impurities include amino acid sequences related to, but different from, that of the active ingredient, as a result of insertion, deletion, or other modifications (e.g., oxidation or glycosylation) to the amino acid sequence, and residues of the peptide (page 6). The FDA guidance requires that an ANDA must be submitted for any new peptide-related impurity above 0.5% of the substance. Peptide-related impurities should be measured, characterized, and assessed for effects on safety and efficacy (page 8).
It has long been understood in the prior art that oxidation of tryptophan side chains is common degradation pathway for pharmaceutical peptides that lead to peptide-related impurities. See for example Wang (Section 3.2.2), Manning et al. (page 551, column 2), Barnett et al. (page 1944). Barnett et al. in particular teach that oxidation of tryptophan can lead to formation of N-fomylkynurenine (Figure 1):
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Peptide-related impurities characterized by oxidized tryptophan have been reported in the prior art for GLP1 peptides in particular. Stadelmeir et al. teach improved methods of purification of the therapeutic GLP-1 peptide liraglutide (page 1, lines 5-7, 29-31). Stadelmeir et al. teach that liraglutide impurities include derivatives wherein the indole moiety in the side chain of tryptophan at position 25 is oxidized by the addition of one or two oxygens or wherein tryptophan at position 25 is oxidized by the replacement with kynurenine. These derivatives include Trp(O)25-liraglutide, Trp(2O)25-liraglutide, and Kyn25-liraglutide (page 11, lines 22-33). Stadelmeir et al. teach compositions comprising liraglutide and not more than 0.1% of Trp(O)25-liraglutide, Trp(2O)25-liraglutide, or Kyn25-liraglutide (page 27, line 18 - page 28, line 29). Stadelmeir et al. teach purification and analytical methods for isolating, detecting, and measuring Trp(O)25-liraglutide, Trp(2O)25-liraglutide, and Kyn25-liraglutide (Example 7).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to characterize peptide-related impurities of tirzepatide, including impurities comprising an oxidized tryptophan such as those taught for related peptide liraglutide by Stadelmeir et al. The rationale for obviousness is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP § 2143.01(G)). The relevant findings for this rationale are as follows.
(1) There was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. In the instant case, Bokvist et al., Coskun et al., and Frias et al. teach that tirzepatide is therapeutically valuable for the treatment of type 2 diabetes. As a result, one of ordinary skill in the art would be motivated to characterize the peptide-impurity profile of tirzepatide according to the guidance provided by the FDA. One of ordinary skill in the art would have been motivated to identify, measure, and purify peptide-related impurities of tirzepatide in order to develop a product that meets the regulatory requirements of the FDA. One of ordinary skill in the art would be motivated to consider peptide-related impurities caused by common degradation pathways such as tryptophan oxidation as reported by Wang, Manning et al., and Barnett et al. In particular, one of ordinary skill in the art would be motivated to identify specific impurities related to those reported for related therapeutic peptides. In the case of tirzepatide, one of ordinary skill in the art would consider the impurities formed by other GLPs such as liraglutide. According to Stadelmeir et al. these include impurities wherein the tryptophan at position 25 is oxidized. Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
(2) There was reasonable expectation of success. One of ordinary skill in the art would predict that tirzepatide impurities wherein the tryptophan at position 25 is oxidized could be successfully identified, measured, and purified because Stadelmeir et al. teach methods for doing so in a related peptide, liraglutide (Example 7). Stadelmeir et al. demonstrate methods for quantitating and isolating trace levels of Trp(O)25-liraglutide, Trp(2O)25-liraglutide, and Kyn25-liraglutide (Example 7). Stadelmeir et al. teach tryptophan at position 25 is oxidized by the replacement with kynurenine, Kyn25-liraglutide (page 11, lines 22-33). Barnett et al. teach that tryptophan is replaced by N-formylkynurenine en route to formation of kynurenine (Figure 1). Therefore, it would have been obvious to isolate impurities wherein the tryptophan at position 25 is replaced with N-formylkynurenine and kynurenine. Therefore, there was a reasonable expectation of success that similar methods could identify compounds of tirzepatide wherein the tryptophan at position 25 is oxidized.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
Therefore, claim 9 is obvious over the cited art.
Regarding claim 11, Stadelmeir et al. teach compositions comprising the desired drug and trace amounts of the peptide-related impurity (page 27, line 18 - page 28, line 29).
Response to Arguments
Applicant's arguments filed September 14, 2026, have been fully considered but they are not persuasive.
(1) The 8-reference rejection under 103 does not teach tirzepatide with position 25 oxidized to N-formylkynurenine.
Applicant is correct that no single reference discloses the claimed compound. However, the prior art recognized tryptophan oxidation as a common degradation pathway for peptides in general, and oxidation of tryptophan at position 25 in a related peptide in particular. Based on this knowledge POSITA would be motivated to identify, isolate, and purify tirzepatide degradation products having oxidation of tryptophan at position 25. Stadelmeir et al. teach that tryptophan is replaced with kynurenine in liraglutide (page 11, lines 22-33). Barnett et al. teach that a mechanism for kynurenine replacement of tryptophan involves N-formylkynurenine as an intermediate (Figure 1). Therefore, in identifying, isolating, and purifying tirzepatide degradation products having oxidation of tryptophan at position 25, POSITA would obtain impurities wherein the tryptophan at position 25 is replaced with N-formylkynurenine and kynurenine.
(2) The combination of Stadelmeir and Barnett teaches away from the present claims as it teaches a POSITA to expect that tirzepatide would oxidize to kynurenine rather than N-formylkynurenine.
Applicant’s argument that the prior art teaches away from the claim is not persuasive because the prior art of Stadelmeir and Barnett does not criticize, discredit, or otherwise discourage the solution claimed (MPEP § 2145(D)(1)). The teaching in Stadelmeir and Barnett raises the expectation that in identifying, isolating, and purifying tirzepatide degradation products having oxidation of tryptophan at position 25, POSITA would obtain impurities wherein the tryptophan at position 25 is replaced with N-formylkynurenine and kynurenine.
For these reasons, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 8:30 am - 5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA M MARCHETTI BRADLEY/Primary Examiner, Art Unit 1654
1 Tirzepaptide is identical to instant SEQ ID NO: 5 and will be used interchangeably throughout.
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