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 .
Election/Restrictions
Applicant's election without traverse of provisionally electing Group I, claims 1-5, 7 and 11 in the reply filed on 6/13/25 is acknowledged.
Claims 10, 12, 15, 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/13/25.
Applicant’s election of the following species in the reply filed on 6/13/25 is acknowledged:
PNG
media_image1.png
273
726
media_image1.png
Greyscale
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)).
Consistent with applicant’s statement that claims 1, 4-7 and 11 read on or recite the elected species, page 2 of 6/13/25 reply (however noting that claim 6 is cancelled), claims 2 and 3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Priority
The instant application, filed 09/20/2023 is a National Stage entry of PCT/CN2022/082552 , International Filing Date: 03/23/2022
claims foreign priority to 202110321851.6, filed 03/25/2021
claims foreign priority to 202110553745.0, filed 05/20/2021.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 9/20/23 and 8/19/24 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Claim Status
Claims 1-5, 7, 10-12, 15, 16 are pending.
Claims 6, 8, 9, 13, 14, 17 are cancelled.
Claims 10, 12, 15, 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 2 and 3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 4, 5, 7 and 11 are pending and under examination.
Claims 1, 4, 5, 7 and 11 are rejected.
Claim 4 is objected to.
Claim Objection
Claim 4 is objected to because of the following informalities: in lines 4 and 19 “followings” should be amended to “following” for grammatical correctness. Appropriate correction is required.
Claim Interpretation
Each of claims 7 and 11 in their respective last two lines set forth an “optionally” as to the pharmaceutical composition further comprising of one or more pharmaceutically acceptable carriers. Per MPEP 2111.04, which states in part, “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure,” given the use of “optionally” the presence of any carriers is not required for these claimed pharmaceutical compositions.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 sets forth 14 A40 alternatives, and then after an “or” near the end of the claim sets forth only three of these alternatives. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. This alternative listing makes the claim unclear because one does not know with certainty what the scope of the claim is. If applicant wants a claim with a broad range of these structures, and also a claim with a narrower range of these A40 structures, then having two separate claims would be a solution.
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.
Claim(s) 1, 4, 5, 7 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over US PGPUB 20160199438 (‘438) in view of (WO 2020/207477, published 10/15/20, (Wu, supplied in 9/20/23 IDS, in Chinese so corresponding US PGPUB 2022/0168396 (‘396) is used as reference for citation of relevant teachings).
Claim 1 is directed to a compound represented by formula I or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof, wherein A40 binds via a peptide bond to the Ser at position 39 of the sequence set forth in claim 1 as formula I, A40 being a lysine to which at its epsilon nitrogen is bound an “R1”, this encompassing a genus comprising numerous possible structures including fatty acids linked to the lysine set forth in claim 1 as follows:
PNG
media_image2.png
146
642
media_image2.png
Greyscale
PNG
media_image3.png
379
561
media_image3.png
Greyscale
The ‘438 SEQ ID NO:3 comprises the same first 39 amino acids as instant SEQ ID NO:2, and lacking the C-terminal lysine of instant claim 1. The lysine of the ‘438 SEQ ID NO:3, at position 20, “is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γGlu).sub.1-CO—(CH.sub.2).sub.18—CO.sub.2H; and the C-terminal amino acid is amidated as a C-terminal primary amide,” para 21, see also para 20.
Such a conjugated moiety also is depicted in claim 15:
PNG
media_image4.png
527
730
media_image4.png
Greyscale
This ‘438 peptide is known variously as tirzepatide, LY3298176, Mounjaro, Zepbound, and GIP/GLP-1RA. The ‘438 teaches that its use of “non-natural amino acids can have unexpected effects on the balance of agonist activity between GIP and GLP-1. Non-natural amino acids also increase the likelihood that a peptide may be seen as foreign and set off undesirable immune reactions, such as human immunogenicity and injection site reactions,” para 8, this in its SEQ ID NO:3 represented by two Aib non-natural amino acids. This peptide thus is an improvement in the field, and the ‘438 also teaches, “Fatty acids, through their albumin binding motifs, can improve the pharmacokinetics of a peptide by extending the half-life, for example. While use of fatty acids can improve peptide half-life, it was discovered by Applicants as part of the present invention that the length, composition, and placement of the fatty acid chain and the linker between the peptide and the fatty acid chain can have unexpected effects on the balancing of the GIP and GLP-1 agonist activity,” para 9. The ‘438 provides data of different species and their effect on multiple properties and effects.
The ‘438, however, does not teach shifting the position of the acylating moiety1 to the C-terminus by adding a lysine there, and similarly bonding the same acylating moiety to that lysine’s epsilon nitrogen.
The moiety conjugated to the lysine at position 20 of the ‘438 tirzepatide falls within the genus of moieties of instant claim 1, however it is attached to a lysine at position 20 of the ‘438 SEQ ID NO:3 rather than at a lysine at position 40 as instantly claimed.
Wu teaches a “series of pharmaceutical compositions containing polypeptide dual agonist compounds and pharmaceutically acceptable salts thereof, wherein same have dual agonist effects on a human glucagon-like peptide-I (GLP-1) receptor and a human blood glucose-dependent insulinotropic polypeptide (GIP) receptor,” Abstract of the ‘396 (all following paragraph numbers and claim numbers also refer to the ‘396). Wu thus is in the same field as the ‘438 and applicant’s claimed subject matter.
Wu teaches sequences having very substantial similarity with the sequence of instant claim 1, with an X40 after the sequence Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser of the claim 1 GLP-1 analog, claim 1. Whereas that claim 1 X40 “is a natural amino acid, an unnatural amino acid, or a peptide fragment consisting of a natural amino acid or an unnatural amino acid, or X40 is absent,” per claim 3, depending from claim 1, the X40 is Lys, Y1 or absent, and “Y1 is Lys, Om, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of { [2-(2-amino-ethoxy )-ethoxy ]-acetyl} a -(y-Glu )6 - CO-(CH2)c----COOH; a is an integer between 1-3; b is an integer between 1-2; and c is an integer between 10-30,” and per claim 20, depending from claim 3, the claim 3 GLP-1 analog is characterized in that Y1 is K (-OEG-OEG-γGlu-C18-OH) or K (-OEG-OEG-γGluC20-OH):
PNG
media_image5.png
953
979
media_image5.png
Greyscale
These structures also are set forth in claim 26 which depends from claim 13, which depends from claim 1, so are clearly particularly identified. (Among others, Wu SEQ ID Nos: 59 and 81-83, also listed in claim 22, further clearly provide particularly identified examples of sequences having at the C-terminus a lysine to which is appended acylating moieties.)
The second structure depicted above is identical with the structure conjugated to the lysine at position 20 of the ‘438 peptide known as tirzepatide. This second structure also is identical to the acetylating moiety structure of the elected species, discussed further below.
Wu teaches modifications of sequences of polypeptide dual agonist compounds which comprise at position 40 of the polypeptides a lysine, from which at its epsilon nitrogen are attached acylating (fatty acid) structures including the same structure as found in the ‘438 SEQ ID NO:3, albeit for the latter this is attached to the lysine at position 20.
Wu also evaluated several of its compounds having the acylating (fatty acid) structure from the lysine at position 40 versus position 20, see Table 5, and the results teach that for compounds 28 versus 27 and 74 versus 75 when at position 40 the overall activities for human GLP-1R and GIPR were superior to corresponding sequences having the acylating (fatty acid) structure at position 20 (and for 62 versus 60 the results were close, with the position 20 sequence slightly better). Also of interest is that per Table 5 the activities for compounds 28 and 74, both with acylating (fatty acid) structure at position 40, exhibited much better activities than for the known therapeutic compound semaglutide.
One of ordinary skill in the art, recognizing the superior results of Wu when positioning the acylating (fatty acid) structure from a lysine that is added to the dual agonist sequence at the C-terminus, that is, at position 40, would have been motivated to apply such approach/technique to other similar therapeutic compounds, such as that of the ‘438, in order to improve the performance by such modification (that is, adding a lysine at the C-terminus of the 39 amino acid sequence of tirzepatide of the ‘438 primary reference). This would result in the instantly claimed SEQ ID NO:2 amino acid sequence, and from the epsilon amino group of that terminal lysine one of ordinary skill in the art would reasonably have appended a known acetylating moiety, such as from those taught to be more effective by the cited references. Wu contained a known technique applicable to the ‘438 compounds, and as taught by Wu, this moving to this position is a routine modification and the results indicate that this approach yields favorable results, including versus the same acylating (fatty acid) structure at position 20, so this variable of moving an acylating (fatty acid) structure such as to the position at 40, by adding a lysine at that position, is a result-effective variable. Such one of ordinary skill in the art would have recognized that applying the known technique would have yielded predictable results and resulted in an improved product for therapeutic use in the field.
There would have been a reasonable expectation of success given the results set forth in Wu when considered in combination with the teachings of the ‘438.
Accordingly, claim 1, in which the generic R1 encompasses the acylating (fatty acid) structures of both the ‘438 and Wu’s depicted structures, would have been obvious.
With regard to the elected species:
PNG
media_image6.png
319
903
media_image6.png
Greyscale
,
having found the positioning of the lysine at the C-terminus of the ‘438 tirzepatide sequence obvious per above, the particular acylating structure of this species is identical both to that used in the ‘438, see its claim 15 above, and also to the last acetylating moiety of Wu claim 26, the following from page 55 thereof (see also re Wu claim 20, above):
PNG
media_image7.png
341
442
media_image7.png
Greyscale
.
Because this is a known acetylating moiety taught in the prior art for use with very similar compounds, using it on the modified tirzepatide amino acid sequence at the C-terminus lysine, obvious per above, also would have been obvious based on using a known moiety for its intended purpose.
Claim 4 depicts A40 structures including
PNG
media_image8.png
157
486
media_image8.png
Greyscale
this beyond the epsilon nitrogen of the lysine meeting the structure of Wu below para 41:
PNG
media_image9.png
279
832
media_image9.png
Greyscale
as well as being encompassed by the Wu formulas for the acylating (fatty acid) structures, however also comprising amidation of the C-terminal carboxylic acid moiety of that lysine. Because multiple sequences of Wu also indicate amidation of the C-terminal carboxylic acid moiety of the position 40 lysine, see for example the sequences of compound 28 on page 7, ending in NH2, and of compound 74 on page 8, ending in NH2, claim 4 would have been obvious.
Claim 5 is rejected on the same bases as claims 1 and 4, please note formula I-7 on page 10 of the claims has the same acylating (fatty acid) structure applied when rejecting claim 4, and the sequence and adding the lysine at position 40 are rejected above for claim 1.
Because both the ‘438, at para 47, and Wu, at Abstract, para 52, and claim 23, inter alia, teach pharmaceutical compositions, claims 7 and 11 would have been obvious when also applying the bases for rejection of claim 1 as to claim 7, and claims 1, 4 and 5 as to claim 11.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Wednesday-Friday and on Monday/Tuesday on alternating weeks, but will promptly answer messages upon his return to work.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MELISSA FISHER, can be reached on 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH FISCHER/Examiner, Art Unit 1658
1 Throughout this action the structure conjugated to an amino acid is referred to either as “acylating moiety” or “acylating (fatty acid) structure”. These often include a linker, which is part of the structure.
Prosecution Insights