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Claims 10, 12, 15, 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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:
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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or recite the elected species, page 2 of 6/13/25 reply (however noting that claim 6 is cancelled), claims 2 and 3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
Claim Status
Claims 1-5, 7, 10-12, 15, 16, 18 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Claims 10, 12, 15, 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (method claims), there being no allowable generic or linking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Claims 2 and 3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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, 11 and 18 are pending and under examination.
Claims 1, 4, 5, 7, 11 and 18 are rejected.
NOTE: Claim 16 was properly indicated as withdrawn in the text of the 12/1/25 Office action, however the first page form contained a typographical error that erroneously indicated claim 16, which is a method claim, was under examination. Claim 16 was and is properly withdrawn given applicant’s election of Group I, drawn to compounds.
Claim Objection
Response to Arguments
Applicant’s arguments, see page 14, filed 2/27/26, and claim amendment, with respect to the objection to claim 4 have been fully considered and are persuasive. The objection to claim 4 has been withdrawn.
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
Response to Arguments
Applicant’s arguments, see page 14, filed 2/27/26, and claim amendment, with respect to the rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph have been fully considered and are persuasive. The rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph has been withdrawn.
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.
Response to Arguments
Applicant's arguments filed 2/27/26 have been fully considered but they are not persuasive.
Regarding arguments and assertions pertaining to Tables 2 and 3 of the instant application, these are not persuasive because only two of applicant’s compounds are evaluated. The results of these two compounds are not demonstrated to be representative of the compounds encompassed by the instant claims. The same applies to the bolded statement on page 16 pertaining to comparison to LY3298176.
As to arguments on pages 16-17, applicant appears to attribute the good results of the ‘438 to acylation at position 20, as well as the length, etc. of the fatty acid of this acylation. However, as made clear in the references applied, in this art changing the position and structure of acylation with a fatty acid-comprising moiety were known and evaluated, and differences in multiple aspects of performance were reasonably expected.
As to arguments on pages 17-18, and elsewhere, in response to applicant's arguments against the references individually (such as pointing to sequence differences between Wu and the ‘438), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is an obviousness, not an anticipation, rejection.
The excerpts on page 18 from the ‘438 are not dispositive of the entirety of the teachings of the ‘438, and do not appear relevant to the bases for combining the teachings of the references. As to predictability, this need not be rigorously absolute, just reasonable. Given the basic underlying amino acid sequence, such as of the ‘438 – which sequence binds to GIP and GLP-1, it was reasonable to expect that changing the location of acylation would still provide for some level of activity.
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:
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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:
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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):
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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:
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,
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):
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.
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
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this beyond the epsilon nitrogen of the lysine meeting the structure of Wu below para 41:
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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.
Claim(s) 18 is 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 parent 18283164 9/20/23 IDS, in Chinese so corresponding US PGPUB 2022/0168396 (‘396) is used as reference for citation of relevant teachings), as applied above to claim 1, and further in view of Lau et al., J. Med. Chem. 2015, 58, 7370−7380 (Lau).
The rejection of claim 1 is set forth above.
Neither the ‘438 nor Wu teach the particular acylating structure of claim 18, that is the middle structure therein:
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in which there are two sets of -C(=O)(CH2)[O(CH2)2]3NH, the first attached to the lysine epsilon nitrogen, and the second between the first set and gamma glutamic acid. The examiner notes that when oriented in the opposite direction, each ‘set’ is a modification of an OEG group in which an additional (CH2)O is added.
The level of ordinary skill in the art is high.
Lau teaches the evaluations used to develop semaglutide, and extensively teaches the inclusion of OEG units, often combined with gamma glutamic acid, in forming a linking structure to an acylating group, the latter often a fatty acid moiety (referred to as a protractor), see Table 1 and Figure 1, pages 7371 and 7372. Lau’s evaluations, in which differing linkers and protractors provide different performance results, further establishes motivations to modify known sequences with acylating moieties at different positions, toward identifying the best combination of desired properties, and establish that these portions of the acylating (fatty acid) structures are result-effective variables.
Lau teaches that “attachment of long fatty acids to peptides has successfully extended the half-life of native short-acting GLP-1 to the once daily profile of liraglutide,” and reports “a series of acylated GLP-1 analogues where increased albumin affinity relative to liraglutide has led to a profile suitable for once-weekly administration,” page 7370. Lau also teaches that the long-acting GLP-1RAs “have better glucose lowering effect and less effect on gastric emptying,” Id., providing a motivation for further improving longer acting therapeutics that include agonism of GLP-1 receptors. Lau teaches the common use of OEG joined with gamma glutamic acid as parts of linkers, see Figures 1 and 2, pages 7372 and 7373.
As part of Lau’s extensive evaluations, the acylation position was compared, Table 4, page 7375. With the attachment of a C18 diacid via a γGlu-2xOEG linkage, analogue 43, very favorable results were obtained for GLP-1R binding and potency, see discussion page 7374.
Lau, closely focused on GLP-1 analogues, clearly teaches various linkers that join an amino acid of a therapeutic peptide to a fatty acid moiety, to improve performance of the therapeutic peptide. Lau in particular teaches the importance of evaluating different structures of linkers combined with fatty acid moieties, clearly demonstrating differences in performance related to structures that differ, albeit not exceedingly from lower performing compounds. Modifications of the linker and the fatty acid are recognized as result-effective variables.
Based on the above teachings, it is well known in the art to provide acylating (fatty acid) structures to improve half-life of therapeutic peptides in the blood, this largely attributed to the fatty acid portion of the appended structures binding albumin in the blood. The substantially different results when using different linkers, as well as positioning at different positions, is taught by Lau. One of ordinary skill in the art would have been motivated to modify and evaluate the linker and/or fatty acid structures of Wu when applying Wu’s technique to the ‘438 therapeutic peptide, in order to obtain better performing resultant compounds. Those modified linker structures would reasonably include where the number of (CH2)2O units was varied, such as between that of OEG, comprising two (CH2)2O units end to end, and the number of those units longer PEG structures, also taught by Lau, see Figure 1, to more comprehensively evaluate the effect of additional (CH2)2O units between these evaluated linking portions, these structures per above having been shown to be result-effective variables. There would have been a reasonable expectation of success given the reasoning and results set forth in Wu and Lau, when applied to the particular SEQ ID NO:3 of the ‘438.
An additional basis for the obviousness of the elected species is close structural similarity founded on the expectation that compounds similar in structure will have similar properties, per MPEP 2144.09, “A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities.” Here the compounds taught in Wu versus the elected species differ by the successive addition of the same chemical group, for the elected species adding an additional (CH2)2O unit to each of the two OEGs of Wu (and also of Lau).
Accordingly, based on one or both of the above bases, claim 18 would have been obvious and is rejected.
Conclusion
No claim is allowed.
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 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.
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/JOSEPH FISCHER/Primary 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.
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