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 .
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant's arguments filed 7/27/2026, with respect to the rejections under 35 U.S.C. 103, have been fully considered but they are not persuasive.
Applicant’s position is that 1) the rejections rely on improper hindsight, 2) the references alone or in combination fail to teach or suggest the presently claimed subject matter and do not provide motivation with a reasonable expectation of success to arrive at the claimed invention, and 3) the claimed invention provides unexpected technical advantages not predictable from the prior art.
Regarding 1), in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, since all of the peptide fragments and the peptide synthesis method steps used to condense the peptide fragments to make full-length semaglutide are known in the prior art, the rejections under 35 U.S.C. 103 do not rely on improper hindsight.
Regarding 2), per MPEP 2143: The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. In Ball Aerosol v. Ltd. Brands, 555 F.3d 984, 89 USPQ2d 1870 (Fed. Cir. 2009), the Federal Circuit offered additional instruction as to the need for an explicit analysis. The Federal Circuit explained that the Supreme Court’s requirement for an explicit analysis does not require record evidence of an explicit teaching of a motivation to combine in the prior art.
"[T]he analysis that "should be made explicit" refers not to the teachings in the prior art of a motivation to combine, but to the court’s analysis. . . . Under the flexible inquiry set forth by the Supreme Court, the district court therefore erred by failing to take account of ‘the inferences and creative steps,’ or even routine steps, that an inventor would employ and by failing to find a motivation to combine related pieces from the prior art." Ball Aerosol, 555 F.3d at 993, 89 USPQ2d at 1877.
As stated in the prior Office Action and reiterated herein, the above references teach each of the fragments 1, 2, 3, and 6 as recited in claim 2. As semaglutide has a well-established structure, there is only one way to combine the fragments taught by the references in order to obtain full-length semaglutide. Thus, there is sufficient motivation for one skilled in the art to combine the fragments as well as a reasonable expectation of success.
Moreover, in addition to the above teachings, it would have been further prima facie obvious to try to generate semaglutide via the steps recited in the instant claims. Bray teaches that a solution-phase and solid-phase hybrid process is more efficient to produce such peptides; a combination of SPPS, which could easily produce shorter peptide fragments, and fragment condensation in solution, which could combine the shorter peptide fragments in a specific order to create the full-length peptide, can overcome many of the problems associated with the synthesis of longer peptides via SPPS. For longer peptides for which linear SPPS is inefficient, two fragments of approximately equal size is optimal, but one should consider aspects such as fragment solubility, ease of synthesis, purity, yield, and carboxyl terminal amino acid. Further, predicting the ideal fragments from a peptide sequence is not an exact science and may require some trial and error. That said, one of ordinary skill in the art would have recognized that a peptide with a defined, given sequence only could be fragmented and condensed in a finite number of ways; moreover, after starting with two fragments of approximately equal size, as taught by Bray, one skilled in the art would recognize that said two fragments might need to be broken down into additional, smaller fragments, for the reasons described above. Therefore, it would be obvious to try each and every fragment of semaglutide possible based upon the teachings of Bray, leading to the production and condensation of the instantly claimed fragments 1, 2, 3, and 6 to produce full-length semaglutide.
Further, in response to applicant's arguments against the references individually, 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). In the instant case, the deficiencies of any one of the references listed above are remedied by the teachings of the other references and vice versa.
Consequently, the combination of Barlos, Bridon, Incisivo, and Bray teach render the prior and currently amended claims obvious; see maintained/modified art rejections below.
Regarding 3), per MPEP 716.02(b)(I): “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).” In the instant case, the data set forth merely demonstrate the generation of semaglutide from the fragments claimed, which are taught by the prior art. Further, although it is noted that the Applicant has reported the purity and yield for each fragment generated, there is no evidence to support that these results are statistically significant.
Additionally, per MPEP 716.02(C)(II), “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).” In the instant case, one would reasonably expect the yield and the purity of semaglutide to be high as has been reported in the prior art; consequently, these results are not unexpected.
Moreover, as described above, the fragmentation and condensation process instantly claimed would be entirely predictable to one skilled in the art.
For these reasons, the rejections under 35 U.S.C. 103 have been maintained/modified herein.
Election/Restrictions
Applicant's election with traverse of Group I, claims 2, 12, and 17, drawn to a four fragment-based hybrid approach for the preparation of semaglutide, in the reply filed on 11/3/2025 is acknowledged. The traversal is on the ground(s) that the instant application adheres to the principle of unity of invention under Rule 13 PCT and 37 CFR 1.475 by establishing a single special technical feature that links all claimed subject matter. This is not found persuasive.
As stated in the prior Election/Restriction requirement, the claims collectively are drawn to multiple methods of use. Per 37 CFR 1.475(b), unity of invention is limited to a single product and process of use. The instant claims are drawn to multiple processes of use. Therefore, unity of invention is lacking.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 1-20 are pending. Claims 1, 3-11, 13-16, and 18-20 are hereby withdrawn as non-elected inventions. Claims 1-6 and 11 are currently amended.
Priority
The present application is the 371 national stage entry of PCT/IN2021/050425, filed 4/30/2021, which claims priority to IN202141015767, filed 4/2/2021, and IN202041019091, filed 5/5/2020. The priority date of 5/5/2020 is acknowledged.
New - Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
1. Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 7/27/2026.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
2. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
See [0067]
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66
738
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and
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134
770
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;
[0083]
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92
810
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and
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102
674
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; and
[0099 (see arrows)]
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858
836
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and
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96
602
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.
Also see [0132, 0141, 0150, 0163, 0172, 0193, 0205, 0213, 0245, 0250, 0259].
3. Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specifically, the file size must be listed in bites.
4. Other: It appears that SEQ ID NO: 5 and SEQ ID NO: 40 are the same fragment.
New - Specification
The amendment filed 7/27/2026 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: The Sequence Listing includes SEQ ID NO: 41, which consists of the fragment Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Val-Ser(Oxa). However, this fragment has not been found in the Specification as originally filed.
Applicant is required to cancel the new matter in the reply to this Office Action.
The disclosure is objected to because of the following informalities: “[0080]” does not appear at the beginning of the line, see below:
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362
872
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Also see [0121, 0149, 0161, 0171, 0172].
Additionally, the SEQ ID NO’s introduced in [0083] appear to cover part of the actual amino acid sequence such that the sequence of fragment-3 is obscured, see below:
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196
780
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Appropriate correction is required.
Maintained/Modified - 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) 2, 12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Barlos et al. (WO 2019069274 A1, published 4/11/2019), Bridon et al. (WO0069900A2, published 11/23/2000), Incisivo et al. (WO2020074583A1, published 4/16/2020), and Bray (Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat Rev Drug Discov. 2003 Jul;2(7):587-93.).
Barlos teaches a process for preparing GLP-1 or GLP-2 peptides, including semaglutide, comprising coupling in solution at least a first fragment and at least a second fragment that have been generated from solid phase peptide synthesis (Abstract; Pg 1, “Field of the Invention”, first paragraph; Pg 4, top schematic; Pg 8, second and third paragraphs). One such peptide fragment generated through solid phase synthesis is “His-Aib-Glu-Gly” (SEQ ID NO: 54) or “P1-His-Aib-Glu-Gly-OH” (SEQ ID NO: 55; Pg 45; lines 30-31), wherein P1 is a protecting group. Barlos teaches that the N-terminal His can be protected with a protecting group such as Boc or Fmoc (Pg 17, lines 25-26). Barlos further teaches that during synthesis, the side chains of various amino acids are conjugated to protecting groups to prevent unwanted side reactions; examples include His(Boc), His(Trt), Glu(OtBu), Trp(Boc), and Gly(OtBu) (for example see Pg 20, line16 – Pg 21, line 17; Pg 23, line 17 – Pg 25, line 21; Pg 27, line 21 – Pg 29, line 24; Pg 31, line 22 – Pg 33, line 28). In order to generate SEQ ID NO: 54 of Barlos, one would synthesize the instant fragment 1 using Fmoc- or Boc-His(Boc)- or His(Trt)-Aib-Glu(OtBu)-Gly-OH.
Barlos further teaches amino acid sequence modified by the incorporation of one or more pseudoprolines, artificially created dipeptides that minimize aggregation during Fmoc solid phase synthesis; psuedoprolines can include, for example, serine-(oxa) (Pg 14, lines 14-17). Psuedoprolines serve as temporary side-chain protection for Ser and also served as solubilizing building blocks to increase solvation and coupling rates during synthesis and subsequent chain assembly (Pg 15, lines 1-5).
Barlos teaches multiple examples wherein semaglutide fragments produced by solid phase synthesis are dissolve in solvents in the presence of a coupling agent (Pg 52, lines 19-29). The side chains can subsequently be deprotected (Pg 53, lines 28-33).
Barlos further teaches that crude GLP peptide can be purified by preparative HPLC (Pg 44, lines 8-9).
Barlos does not teach other peptide fragments corresponding to the instant fragment 2 , 3, or 6.
Bridon teaches methods for making and protecting peptides and their derivatives and fragments thereof from peptidase activity (Abstract). A subset of the peptides taught by Bridon include glucagon peptides, derivatives, and fragments thereof; one such fragment is Thr-Phe-Thr-Ser-Asp-Val-Ser (SEQ ID NO: 360; Sequence Listing, final page of attached reference).
Bridon further teaches methods of making said peptides, derivatives and fragments thereof. Bridon teaches that peptide fragments may be synthesized by standard methods of solid phase peptide chemistry known to those of ordinary skill in the art; further, multiple fragments may be synthesized then linked together to form larger fragments (Pg 62, “3. Synthesis of therapeutic peptides used in the present invention”, first paragraph). In subsequent examples demonstrating the synthesis of glucagon/GLP-1 peptides, the individual amino acids with protecting groups are described and added sequentially in the desired order to achieve the desired fragment, which include Fmoc-Thr(tBu), Fmoc-Ser(tBu), and Asp(OtBu) (see, for example, Examples 24 and 25). Thus, generating the peptide SEQ ID NO: 360, one would produce Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu); the difference this peptide fragment and the instant fragment 2 is that the C-terminal Ser is not Ser(Oxa)-OH.
Incisivo teaches a process for the manufacture of GLP-1 analogues with high yield and purity by fragment condensation on the solid phase (Abstract). Incisivo teaches that the branched structure and low solubility of semaglutide hampers its synthesis and purification (Pg 2, final paragraph). One strategy to circumvent this issue is to generate fragments and perform fragment condensation on the solid phase.
Incisivo teaches fragments can be prepared by stepwise SPPS, CSPPS, or LPPS and then coupling two or more fragments. In Scheme 2, “fragment B” is comprised of an N-terminal fragment C and C-terminal fragment D (Pg 17, very bottom – top of Pg 18). Fragment C can consist of Fmoc-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly16-OH (Pg 18, fifth paragraph beneath the chemical formula at the top of the page, or the instant fragment 3). Fragment D can consist of Gln(Trt)-Ala-Ala-Lys(Pal-Glu-OtBu)-Glu(OtBu)-Phe-Ile-Ala-Trp(tBu)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-resin (SEQ ID NO: 13); the difference SEQ ID NO: 13 and the instant fragment 6 is that the protecting group of Trp is tBu rather than Boc; moreover, Incisivo does not teach the addition of OtBu to the C-terminal Gly attached to the resin.
In summary:
Barlos teaches the methods of making semaglutide, wherein shorter peptide fragments are generated through solid phase peptide synthesis and combined through fragment condensation in solution by dissolving said fragments in solvent with a coupling agent to generate the full-length sequence; the protecting groups can subsequently be deprotected and the crude semaglutide purified through preparative HPLC; and the peptide His-Aib-Glu-Gly and protected amino acids required to generate the instant fragment 1 (Boc-His(Boc or Trt)-Aib-Glu(OtBu)-Gly-OH) are also taught;
Bridon teaches the peptide Thr-Phe-Thr-Ser-Asp-Val-Ser and protected amino acids to generate the fragment (Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)). The difference between the peptide taught by Bridon and the instant fragment 2 is that the protecting group of the C-terminal Ser is tBu instead of Oxa. However, Barlos teaches that amino acid sequences of the invention can be modified by the incorporation of one or more pseudoprolines, artificially created dipeptides that minimize aggregation during FMOC solid phase synthesis; psuedoprolines can include Serine-(oxa), among others, to protect Ser side-chains and increase solvation and coupling rates during synthesis and subsequent chain assembly. Thus, one would be motivated to incorporate Ser(Oxa) at the C-terminal end of the instant fragment 2 for the reasons taught by Barlos. Moreover, it would be a simple substitution to exchange one type of protecting group (Ser(tBu)) for another type of protecting group (Ser(Oxa)) as both types of protecting groups serve to prevent reactions from occurring at the side-chain -OH group of Ser. Thus, the teachings of Bridon and Barlos would lead one skilled in the art to arrive at the instant fragment 2 (Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(Oxa)); and
Incisivo teaches the peptides 1) Fmoc-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly16-OH, the instant fragment 3, and 2) Gln(Trt)-Ala-Ala-Lys(Pal-Glu-OtBu)-Glu(OtBu)-Phe-Ile-Ala-Trp(tBu)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-resin, wherein X2 is N-(17-carboxy-1-oxoheptadecyl)-L-γ-glutamyl-2-[2-aminoethoxy)ethoxy]acetyl-2-[2-(2-aminoethoxy)exthoxy]acetyl for the synthesis of semaglutide (Pg 16, third line from bottom of the page). The difference between Gln17-Ala-Ala-Lys-(X2)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gln31 and the instant fragment 6 is that the protecting group of Trp is tBu rather than Boc and Gly does not have an OtBu protecting group. However, Barlos teaches additional protected amino acids used to generate semaglutide and other GLP-1 peptides, such as Trp(Boc) and Gly(OtBu), wherein Gly(OtBu) is specifically taught in reference to peptide fragments wherein Gly is at the C-terminus. Regarding the substitution of Trp(tBu) for Trp(Boc), one skilled in the art would recognize that it would be a simple substitution to exchange one type of protecting group (Trp(tBu))for another type of protecting group (Trp(Boc)) as both types of protecting groups serve to prevent reactions from occurring at the side-chain of Trp. Moreover, one would be motivated to make the substitution and have a reasonable expectation of success given that Barlos had previously demonstrated that incorporation of Trp(Boc) into similar peptide fragments could be used to successfully generate semaglutide. Further, regarding the inclusion of Gly(OtBu) at the C-terminus of a peptide fragment, one skilled in the art would recognize that a C-terminal protection group would be necessary after removal of the peptide from the resin in order to direct subsequent chemical reactions to occur at the N-terminus of the peptide, where it would be desirable to add the next peptide fragment. Moreover, one skilled in the art would be motivated to use the teachings of Barlos in order to determine what protecting group to use as Barlos also describes methods for generating semaglutide through the generation of smaller fragments that are subsequently condensed in solution to make the full-length peptide. One would have a reasonable expectation of success as Barlos had used this approach previously to successfully generate semaglutide. Thus, Incisivo teaches the instant fragment 3 (Fmoc-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly16-OH), and the teachings of Incisivo and Barlos would lead one skilled in the art to arrive at the instant fragment 6 (Gln17-Ala-Ala-Lys-(X2)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly(OtBu), wherein X2 is N-(17-carboxy-1-oxoheptadecyl)-L-γ-glutamyl-2-[2-aminoethoxy)ethoxy]acetyl-2-[2-(2-aminoethoxy)exthoxy]acetyl).
Thus, regarding claim 2, it would have been prima facie obvious to combine prior art elements according to known methods to yield predictable results based upon the teachings of Barlos, Bridon, and Incisivo, which collectively teach the instant fragments 1, 2, 3, and 6 and render the synthesis of semaglutide from said fragments obvious. Each of the peptide fragments taught by Barlos, Bridon, and Incisivo is taught as part of a method of making semaglutide through a combination of solid phase synthesis to make smaller peptide fragments that are then condensed to make full-length semaglutide. Thus, the only difference between the teachings of the prior art and the instant claim 2 is that the fragments as taught are not actually combined. However, it would be obvious to combine them in a method of making semaglutide because in order to generate semaglutide one necessarily needs to condense the fragments in a certain order. Moreover, the methods of fragment condensation are taught by each of the references cited above, thereby allowing one of ordinary skill in the art to combine the fragments via fragment condensation in solution and to produce semaglutide. The semaglutide produced from the combination of these fragments would be indistinguishable from the semaglutide produced from other fragments taught by Barlos, Bridon, and Incisivo. Thus, the combination of fragments leading to semaglutide as claimed would yield predictable results readily recognized by one skilled in the art.
Moreover, it would have been prima facie obvious to try to generate semaglutide via the steps recited in the instant claims. At the time of filing, the art recognized that it was difficult to synthesize longer peptides. Bray teaches that a solution-phase and solid-phase hybrid process is more efficient to produce such peptides (Pg 590, left column, second paragraph); a combination of SPPS, which could easily produce shorter peptide fragments, and fragment condensation in solution, which could combine the shorter peptide fragments in a specific order to create the full-length peptide, can overcome many of the problems associated with the synthesis of longer peptides via SPPS. For longer peptides for which linear SPPS is inefficient, two fragments of approximately equal size is optimal, but one should consider aspects such as fragment solubility, ease of synthesis, purity, yield, and carboxyl terminal amino acid. Further, predicting the ideal fragments from a peptide sequence is not an exact science and may require some trial and error (Pg 590, right column, second paragraph).
Thus, one of ordinary skill in the art would have recognized that a peptide with a defined, given sequence only could be fragmented and condensed in a finite number of ways; moreover, after starting with two fragments of approximately equal size, as taught by Bray, one skilled in the art would recognize that said two fragments might need to be broken down into additional, smaller fragments, for the reasons described above. Therefore, it would be obvious to try each and every fragment of semaglutide possible based upon the teachings of Bray, leading to the condensation of the instant fragments 1, 2, 3, and 6 in solution.
Regarding claim 12, Barlos teaches that dehydrating agents (coupling agents) such as DIC and HBTU and an acid catalyst are used to facilitate the condensation reaction in solution (Pg 9, lines 18-20).
Regarding claim 17, Barlos teaches examples of liquid phase fragment condensation wherein the protected peptide is dissolved in NMP (Pg 52, lines 6-29).
Conclusion
No claims are 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 Sara Konopelski Snavely whose telephone number is (571)272-1841. The examiner can normally be reached Monday - Friday 9-6pm EST.
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 L Fisher can be reached at 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.
/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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