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 of Group I, drawn to a process of the preparation of glucagon-like peptide-1 agonist peptide, in the reply filed on 11/24/2025 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Claims 14-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/24/2025.
Specification
The disclosure is objected to because of the following informalities: pseudoproline is misspelled as “pusedoproline” several times on page 7 (see Table 1).
Appropriate correction is required.
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.
Claims 1-13 are 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. Specifically, the steps are general, and they do not specify which protected peptide is synthesized and which protected amino acids and dipeptides are used. As such, any protected peptide and any protected amino acids or dipeptides may be used. This represents a lack of union between the body of the claims and the subject matter that Applicant regards as the invention. Specifically, the language of the preamble and embodiments in the specification suggest that Applicant regards subject matter directly related to the synthesis of liraglutide and semaglutide as the subject matter of the invention, but the language of the claims is general and can be used for any protected peptide. Here, Applicant has not particularly pointed out and distinctly claimed the subject matter which they regard as the invention, as there is a lack of direct connection between the body of the claims and the subject matter regarded as the invention. It is suggested that Applicant revise the claim language to distinctly claim the subject matter they regard as the invention. More specifically, it is advised that Applicant distinctly claim the synthesis of the peptides that they regard as the invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 3, 6-8, and 10-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20210009631 A1 (filed 06/18/2020 claiming priority to EP17209828.7, filed 12/21/2017), hereinafter Schoenleber et al.
With regard to claim 1, Schoenleber et al. teach a process of the preparation of glucagon-like peptide-1 agonist peptide represented by the following formula: H(Aib)EGTFTSDVSSYLEGQAAK(R)EFIAWLVRGRG (see Table 1). The method comprises synthesizing a protected peptide on a solid phase by stepwise coupling of a protected amino acid and a protected dipeptide (see claims 43, 52, and 70), the protected dipeptide comprising pseudoproline dipeptide (see claim 53), cleaving the protected peptide from the solid phase (see [0038]), and deprotecting the protected peptide to obtain the peptide (see [0038]), wherein R is -AEEA-AEEA-γ-Glu-octadecanedioic acid (see claim 83), referred to as AEEAc-AEEAc-g-Glu-17-carboxyheptadecanoyl (see claim 83). It is worth noting that, as written, the histidine is at the N terminus of the peptide and would be protonated under physiological conditions (bound to a hydrogen), and the glycine is at the C terminus and would be bound to an OH. As such, it is the examiner’s position that the leftmost H and rightmost OH groups of formula (1) of the instant application are merely a notational difference between formula (1) and Table 1 of Schoenleber et al.
With regard to claim 2, Schoenleber et al. teach the process discussed above wherein the pseudoproline dipeptide is Fmoc-Val-Ser(Psi(Me,Me)pro)-OH (see [0207]).
With regard to claim 3, Schoenleber et al. teach the process discussed above wherein the dipeptide derivative can be Boc-His(Boc)Aib-OH (see [0197]).
With regard to claim 6, Schoenleber teach the process described above wherein the non-pseudoproline dipeptide can be Boc-His(Trt)-Aib-OH or Boc-His(Trt)-Ala-OH and Trt is referred to as “1-Trit” (see [0197]).
With regard to claim 7, Schoenleber teach the process described above wherein the coupling of the non-pseudoproline dipeptide with the protected amino acid is carried out in presence of a coupling reagent consisting of DEPBT and DIPEA (see [0184-0187]).
With regard to claim 8, Schoenleber et al. teach the process discussed above wherein the protected amino acid is Fmoc-Lys(Alloc)-OH) (see [0323]).
With regard to claim 10, Schoenleber et al. teach the process discussed above wherein the peptide is semaglutide (see claim 43).
With regard to claim 11, Schoenleber et al. teach the process discussed above wherein the R group is -AEEA-AEEA-γ-Glu-octadecanedioic acid and the process comprises coupling -AEEA-AEEA-γ-Glu-octadecanedioic acid with a carboxyl protecting group moiety (see claim 43), which can be t-butyl ester (see claim 63), with the epsilon amino side chain of Lysine (see [0108], [0329]) after step a) recited above (see claims 43, 47, 48, and 63).
With regard to claim 13, Schoenleber et al. teach the method discussed above wherein there is a step of purification after cleaving the peptide from the solid phase and deprotecting the protected peptide to obtain the peptide (see [0249]).
Claims 1, 2, 9, and 13 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent No. 11117946 (published 04/04/2019, filed on the IDS submitted on 09/27/2023), hereinafter Loidl et al.
With regard to claim 1, Loidl et al. teach a process for the preparation of glucagon-like peptide-1 agonist peptide given by the following formula: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser- Tyr-Leu-Glu-Gly-Gln-Ala-Ala-B.sup.1-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly (liraglutide) (see column 25 lines 26-45). Here, the moiety bound to the Lysine can be Lys(N.sup.ε-(γ-glutamyl(OtBu)-(N.sup.α-hexadecanoyl))) (see column 25 lines 35-39). Further, they teach that the method comprises stepwise Fmoc-based Solid Phase Peptide Synthesis using suitably protected amino acid derivatives or dipeptide derivatives (see column 25, lines 26-46), wherein one or more pseudoproline dipeptides are introduced, namely Fmoc-Val-Ser(Psi(Me, Me)pro)-OH (see column 25 lines 40-42), and at the end of the synthesis, the peptide is cleaved from the resin and the protecting groups are removed (see column 26 lines 17-19).
With regard to claim 2, Loidl et al. teach the method discussed above wherein the pseudoproline dipeptide is Fmoc-Val-Ser(Psi(Me,Me)pro)-OH (see column 25 lines 40-42).
With regard to claim 9, Loidl et al. teach the method discussed above wherein the peptide is liraglutide (see column 25 lines 26-45).
With regard to claim 13, Loidl et al. teach the method discussed above wherein crude peptide obtained by the method of the present invention can be subjected to further purification by one or more preparative process steps (see column 25 lines 26-45).
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 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over US 20210009631 A1 (filed 06/18/2020 claiming priority to EP17209828.7, filed 12/21/2017), hereinafter Schoenleber et al., as applied to claims 1 and 3 above, and in further view of China Patent No. 109311961 (published 02/05/2019, relying on the English translation filed on the IDS submitted on 05/18/2023), hereinafter Li et al.
Schoenleber et al. teach the method discussed above and applied to claims 1 and 3. Schoenleber et al. do not teach the method wherein the non-pseudoproline dipeptide comprises at least one selected from the group consisting of Boc-Arg(Pbf)Gly-OH and Boc-Glu(OtBu)Gly-OH.
Li et al. teach a method for synthesizing semaglutide, the method comprising stepwise coupling of dipeptide fragments and tripeptide fragments with an amino acid N-terminus Fmoc protection to obtain semaglutide (see [0025], [0119]). They further teach that their method, which includes the use of Boc-Glu(OtBu)Gly-OH in the synthesis of the peptide, led to a 56.1% yield of Boc-His(trt)-Aib-Glu(OtBu)-Gly-OH with a purity of 96.8% (see [0201-0205]). Boc-His(trt)-Aib-Glu(OtBu)-Gly-OH is then used as a peptide in the preparation of the peptide resin in Example 31 (see [0249]-0252]). Using the peptides of this invention, Li et al. teach that the synthesis of dipeptide fragments, tripeptide fragments, tetrapeptide fragments, pentapeptide fragments, or combinations thereof with Gly-resin can be carried out simultaneously during the semaglutide synthesis process, shortening the synthesis time (see [0131]). This provides a motivation to use the aforementioned peptides, including Boc-His(trt)-Aib-Glu(OtBu)-Gly-OH, in order to shorten the synthesis time. Here, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Li et al. and Schoenleber et al. to synthesize semaglutide with Boc-His(trt)-Aib-Glu(OtBu)-Gly-OH on account of the shortened synthesis time taught by Li et al.
With regard to claim 4, Schoenleber et al. teach the process described and applied above wherein the non-pseudoproline dipeptide derivative can be Boc-His(Boc)Aib-OH, but Schoenleber et al. does not teach that the non-pseudoproline dipeptide can be Boc-Arg(Pbf)Gly-OH or Boc-His(Trt)Ala-OH.
As discussed above, Li et al. teach the aforementioned method wherein the non-pseudoproline dipeptide can be Boc-Glu(OtBu)-Gly-OH (see [0201]-[0205]). Given the reasoning provided above, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to combine the references of Li et al. and Schoenleber et al. to synthesize semaglutide wherein the non-pseudoproline dipeptide is Boc-Glu(OtBu)-Gly-OH.
With regard to claim 5, Schoenleber et al. teach the process as described and applied to claims 1-4, 6-8, and 10, 12, and 13 above. Schoenleber et al. do not explicitly teach the process wherein the non-pseudoproline dipeptide comprises no more than 3 types of dipeptide. With regard to the use of non-pseudoproline dipeptides, Schoenleber et al. teach that the coupling of His derivatives is preferably carried out by using an amino acid derivative, like Fmoc-His(1-Trt)-OH, or a similar non-pseudoproline dipeptide to optimize racemization (see [0197]). Specifically, they teach the use of the following non-pseudoproline dipeptides: Fmoc-His(1-Trit)-Aib-OH, Boc-His(1-Trit)-Aib-OH, Boc-His(Boc)-Aib-OH, Fmoc-His(Boc)-Aib-OH, Fmoc-His(1-Trit)-Ala-OH, Boc-His(1-Trit)-Ala-OH, Boc-His(Boc)-Ala-OH, or Fmoc-His(Boc)-Ala-OH (see [0197]). Here, Schoenleber et al. imply the use of a single amino acid derivative, like Fmoc-His(1-Trt)-OH, or a single non-pseudoproline dipeptide, like Boc-His(Boc)-Aib-OH, in order to optimize racemization. Seeing as they do not require a non-pseudoproline dipeptide, as a preferred embodiment utilizes Boc-His(Boc)-OH in place of the dipeptide (see [0197]), Schoenleber et al. teach embodiments that have fewer than 3 types of non-pseudoproline dipeptides.
Further, Schoenleber et al. teach that the use pseudoproline dipeptides in the synthesis of semaglutide is beneficial because pseudoproline dipeptides advantageously suppress peptide aggregation and hence the formation of by-products due to inefficient synthesis (see [0206], [0208]). Here, they provide a clear motivation to use, try, or experiment to use a greater share of pseudoproline dipeptides as opposed to non-pseudoproline dipeptides on account of their advantageous ability to suppress peptide aggregation. Given this motivation, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to try to experiment to maximize the number of pseudoproline dipeptides and, thereby, minimize the number of non-pseudoproline dipeptides with a reasonable expectation of conferring greater ability to suppress aggregation. As such, Schoenleber et al. provide a clear motivation to try the process described above wherein the non-pseudoproline dipeptide comprises no more than 3 types of dipeptide. This practice of routine optimization would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant application and would have reasonably led to embodiments with no more than 3 types of dipeptide with a reasonable expectation of decreasing aggregation.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over US Application No. 16/955,532 (filed 06/18/2020 claiming priority to EP17209828.7, filed 12/21/2017), hereinafter Schoenleber et al., as applied to claims 1 and 10 above and in further in view of China Patent No. 110922470 (published 03/27/2020, relying on the English translation filed on the IDS submitted on 05/18/2023), hereinafter Lyu et al., as evidenced by Musaimi et al. with regard to the definition of semaglutide (Al Musaimi, Othman et al. “2017 FDA Peptide Harvest.” Pharmaceuticals (Basel, Switzerland) vol. 11,2 42. 7 May. 2018).
Schoenleber et al. teach the process described above and applied to claims 1-8, 10, 11, and 13.
With regard to claim 12, Schoenleber et al. teach the process discussed above wherein the R group is -AEEA-AEEA-γ-Glu-octadecanedioic acid and the process comprises coupling Fmoc-AEEA, Fmoc-Glu-OtBu, and octadecanedioic acid mono-t-butyl ester building blocks to the epsilon amino side chain of Lysine after step a) recited above (see claims 43, 47, 48, 51, and 63). Schoenleber et al. do not teach that the process comprising sequentially coupling Fmoc-AEEA-OH, Fmoc-AEEA-OH, and -AEEA-AEEA-γ-Glu-octadecanedioic acid mono-tert-butyl ester with the epsilon-amino side chain of Lys after step (a).
Lyu et al. teach a method of synthesizing semaglutide comprising sequentially coupling Fmoc-AEEA-OH, Fmoc-AEEA-OH, and -AEEA-AEEA-γ-Glu-octadecanedioic acid mono-tert-butyl ester to the side chain of Lys (see page 2, paragraph 7; page 3, paragraph 1). Lyu et al. teach that by using their method, racemic impurities can be well controlled, and the purity of the semaglutide crude peptide can be improved (see page 4, paragraph 2). Additionally, they teach that their method is simple because it requires few deprotection steps (see page 4, paragraph 2). Given that the method of Lyu et al. can lead to these benefits, a person having ordinary skill in the art prior to the effective filing date of the instant application would have a motivation to combine the references of Lyu et al. and Schoenleber et al. in synthesizing semaglutide with a reasonable expectation of improved purity relative to other known methods. As such, it would have been obvious to one of ordinary skill prior to the effective filing date of the instant application to combine the references of Lyu et al. and Schoenleber et al. to synthesize semaglutide with a reasonable expectation of improved purity relative to other known methods (see page 4, paragraph 2).
With regard to the limitation that the side chain group is coupled to the epsilon-amino side chain of Lys, Musaimi et al. teach that acylation occurring at the epsilon-amino side is inherent to semaglutide. More specifically, Musaimi et al. defines semaglutide as follows: Semaglutide contains a linear sequence of 31 amino acids, with a moiety pending from the ε-amino function of Lys, which is Lys20/K26 depending on the numbering system (see page 4, paragraph 7). As such, the moiety connected to semaglutide is inherently pending from the epsilon-amino function of Lys. The reference of Lyu et al. meets all of the limitations of claim 12, as it teaches that the moiety is attached after the peptide is synthesized (after step a) and before cleavage and deprotection of the semaglutide. Here, it is the position of the examiner that the moiety attached to the Lys is inherently pending from its epsilon-amino function. Otherwise, it is not semaglutide as known in the art and defined by Musaimi et al.
Conclusion
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/BRENDAN P. OLISS/Examiner, Art Unit 1658
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654