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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosures of the prior-filed application, Application Nos. 63/426,904, 63/430,430, PCT/US23/80440, and 18/800,392 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior-filed applications fail to support a compound comprising the amino acid sequence of SEQ ID NO: 5, wherein the threonine amino acid at position 5 is D-threonine, and the aspartic acid amino acid at position 9 is D- aspartic acid. The rationale and support for this conclusion is the same as presented in the new matter rejection below.
Therefore, the earliest effective filing date of claims 9 and 12-13 is September 26, 2025.
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 9 and 12-13 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 claims are drawn to a compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide), wherein the threonine amino acid at position 5 is D-threonine and the aspartic acid amino acid at position 9 is D- aspartic acid.
This language does not appear in the originally-filed disclosure. The specification does not disclose any of the following:
a narrative description of compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide), wherein the threonine amino acid at position 5 is D-threonine and the aspartic acid amino acid at position 9 is D- aspartic acid;
a structure or amino acid sequence representing a compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide), wherein the threonine amino acid at position 5 is D-threonine and the aspartic acid amino acid at position 9 is D- aspartic acid;
any reference to D-threonine at position 5; or
any reference to D-aspartic acid at position 9.
Therefore, claims 9-17 are not supported by express disclosure in the originally-filed disclosure.
In the Reply filed September 26, 2025, Applicant identified pages 7-8, Table 2, and Table 3 as providing support for claims 9-17.
The specification at pages 7-8, bridging paragraph, describes in general terms the importance of chiral purity to the quality of peptide pharmaceutical products and a method for quantitative determination of trace levels of D-isomer impurities. There is nothing in this section that directs one of ordinary skill in the art to the specific D-isomers of tirzepatide wherein D-threonine is present at position 5, and D-aspartic acid is present at position 9.
The specification at pages 14-16 describes in general terms the procedure for chiral HPLC-ESI-MS/MS. Table 2 presented in this section lists targeted amino acids with associated MRM conditions. All twenty naturally-occurring amino acids are listed in Table 2 with no particular reference to the tirzepatide sequence. There is nothing in this section that directs one of ordinary skill in the art to the specific D-isomers of tirzepatide wherein D-threonine is present at position 5, and D-aspartic acid is present at position 9.
The specification at pages 17-19 describes in general terms the procedure for chiral HPLC-ESI-MS/MS analysis of amino acids. Table 3 presented in this section lists chiral HPLC-ESI-MS/MS sensitivity, linearity, and accuracy data representing the quantitation of D-isomers of all 19 natural chiral amino acids supporting a range of 0.10%-1.0%. All nineteen naturally-occurring chiral amino acids are listed in Table 3 with no particular reference to the tirzepatide sequence. There is nothing in this section that directs one of ordinary skill in the art to the specific D-isomers of tirzepatide wherein D-threonine is present at position 5, and D-aspartic acid is present at position 9.
Therefore, claims 9-17 are not supported by implicit disclosure in the portions of the originally-filed disclosure cited by Applicant.
In addition, the specification at page 39 discloses the determination of chiral purity of tirzepatide following synthesis according to the methods in the specification. However, this section fails to report the results of the chiral purity analysis. There is nothing in this section that directs one of ordinary skill in the art to the specific D-isomers of tirzepatide wherein D-threonine is present at position 5, and D-aspartic acid is present at position 9.
Therefore, claims 9-17 are not supported by implicit disclosure in the originally-filed disclosure.
Accordingly, claims 9-17 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.
Response to Arguments
Applicant's arguments filed June 2, 2026, have been fully considered but they are not persuasive.
First, Applicant argues that the specification discloses the defined amino acid sequence of tirzepatide, which contains threonine at position 5 and aspartic acid at position 9. Applicant argues that the claimed compound is not a species in an open or undefined genus but rather a molecule “whose only point of variation relative to the disclosed sequence is the stereochemical configuration at two expressly-named residues.” Applicant argues that the disclosure required to demonstrate possession is “modest”. Reply, page 4, para. 2. This is not persuasive because Applicant is minimizing the number of possible stereoisomers for tirzepatide. SEQ ID NO: 5 is 39 amino acid residues in length. Each amino acid other than glycine, can exist in the L- or D-configuration. SEQ ID NO: 5 contains four glycines. Therefore, there are 235 = 3.4 x 1010 possible unique stereoisomers for tirzepatide. Applicant is claiming one single stereoisomer from among 3.4 x 1010 possible stereoisomers. Therefore, in contrast to Applicant’s characterization that the scope of the genus from which the claimed species is selected is narrow, it is significantly broad and requires specific guidance to demonstrate possession.
Second, Applicant argues that the specification provides “blaze” marks in Table 2 and in Table 3. Applicant argues that these sections identify “by name and with individualized analytical parameters, the precise D-amino acid species recited in claim 9.” Reply, pages 4-5, bridging para. This is not persuasive because the sections replied upon by Applicant disclose analytical parameters for every amino acid and therefore do not direct POSITA to the claimed stereoisomer which contains a D-isomer only at Thr5 and Asp9. Table 2 presents the MRM transition conditions for all twenty naturally-occurring amino acids, and Table 3 presents HPLC-ESI-MS/MS sensitivity, linearity, and accuracy data for the D-isomers of all nineteen natural chiral amino acids. Neither table references the tirzepatide sequence or distinguishes Thr5 and Asp9 in any way. Furthermore, there is more than one aspartic acid and more than one threonine in tirzepatide with nothing in the tables to indicate a sequence position. Therefore, it is unclear how disclosure of MRM transition conditions and HPLC-ESI-MS/MS sensitivity, linearity, and accuracy data for all amino acids directs POSITA to a species with a D-isomer at only two of the 34 possible amino acid positions in tirzepatide.
Third, Applicant argues that the specification expressly teaches that undesirable D-isomers can be introduced as impurities in amino acid starting materials, and provides a method to detect D-threonine and D-aspartic acid at the claimed positions. Reply page 5, para. 1. This is argument is not persuasive because this guidance is entirely generic and does nothing to direct POSITA to the single claimed species from amongst the over 3.4 x 1010 possible stereoisomers.
For these reasons, the rejection is maintained.
Claim Rejections - 35 USC § 102 - withdrawn
The rejection of claims 9, 11-12, and 16 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Yadav et al. (WO 2023/089594 A1) is withdrawn in view of the amendment filed June 2, 2026.
Claim Rejections - 35 USC § 103 - withdrawn
The rejection of claims 13 and 17 under 35 U.S.C. 103 as being unpatentable over Yadav et al. (WO 2023/089594 A1) is withdrawn in view of the amendment filed June 2, 2026.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Kobierski et al. (WO 2024/112617 A2)1.
Determining the scope and contents of the prior art.
Kobierski et al. teach methods for the manufacture of tirzepatide (identical to instant SEQ ID NO: 5) (see Examples 1 and 2).
Ascertaining the differences between the prior art and the claims at issue.
Kobierski et al. do not teach a compound comprising the amino acid sequence of SEQ ID NO: 5 (tirzepatide), wherein the threonine amino acid at position 5 is D-threonine and the aspartic acid amino acid at position 9 is D- aspartic acid.
Resolving the level of ordinary skill in the pertinent art.
Kobierski et al. teach methods for determining chiral purity of pharmaceutical peptide products by using chiral high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) (page 3, paragraph 1; pages 7-8, bridging paragraph; page 14, line 25 - page 20, line 7; page 39, lines 13-25).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification does not provide explicit evidence of the formation of specific D-isomers of tirzepatide wherein D-threonine is present at position 5, and D-aspartic acid is present at position 9.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use assess the chiral purity of tirzepatide following solid phase peptide synthesis as suggested by Kobierski et al. In doing so, one of ordinary skill in the art would identify chiral impurities, including those comprising a D-threonine at position 5 and D-aspartic acid at positions 9. 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, Kobierski et al. teach that there is a need for efficient synthesis of high purity tirzepatide to meet the commercial need for this drug in the treatment of type 2 diabetes (page 1). In addition, Kobierski et al. teach that determination of chiral purity is critical to the evaluation of the quality of peptide pharmaceutical products (pages 7-8, bridging paragraph). One of ordinary skill in the art would have been motivated to evaluate the chiral purity of tirzepatide because Kobierski et al. teach that tirzepatide has pharmaceutical use (page 1) and that D-isomers can be introduced as impurities in the amino acid starting materials, during peptide synthesis, and during product shelf life (pages 7-8, bridging paragraph). 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 the chiral purity of tirzepatide manufactured according to the procedures of Kobierski et al. could be successfully evaluated because Kobierski et al. teach methods for determining chiral purity of pharmaceutical peptide products by using HPLC-ESI-MS/MS (page 3, paragraph 1; pages 7-8, bridging paragraph; page 14, line 25 - page 20, line 7; page 39, lines 13-25). Kobierski et al. demonstrate that this method can quantitate trace levels of D-isomers to a 0.1%-1.0% range for all nineteen chiral amino acids (Table 3). Therefore, there was a reasonable expectation of success that this method could identify compounds of SEQ ID NO: 5 wherein any position is a D-amino acid, including D-threonine at position 5 and D-aspartic acid at position 9.
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 12, the method would be applied to compositions comprising tirzepatide and impurities.
Regarding claim 13, Kobierski et al. demonstrate that this method can quantitate trace levels of D-isomers to a 0.1%-1.0% range for all nineteen chiral amino acids (Table 3). Therefore, there was a reasonable expectation of success that this method could identify compounds of SEQ ID NO: 5 wherein any position is a D-amino acid, including D-threonine at position 5, and D-aspartic acid at position 9.
Response to Arguments
The rejection is maintained because the earliest effective filing date of the claims is September 26, 2025, for the reasons presented above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 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 BRADLEY/Primary Examiner, Art Unit 1654
1 Kobierski et al. (WO 2024/112617 A2) was published on May 30, 2024, which is more than one year prior to the earliest effective filing date of claims 9-17, September 26, 2025.
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