DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-9 are pending in the application and are being examined on the merits.
Applicant’s preliminary amendment to the claims, filed March 17, 2023, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Priority
This application is filed under 35 U.S.C. 371 as a national stage of international application PCT/IN2021/050924, filed September 21, 2021, which claims foreign priority under 35 U.S.C. 119(a)-(d) to Indian application no. 20241041229, filed September 23, 2020. A certified copy of the foreign priority document has been filed in this application on March 17, 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 16, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Patent citation number 4 of the IDS filed June 16, 2023 has been lined through because it is a duplicate of Patent citation number 3.
Specification/Informalities
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). See specification at p. 2, bottom; p. 3, bottom; p. 5, top; p. 7, middle; p. 9, middle; p. 10, middle; and p. 11, bottom. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825; applicants’ attention is directed to the final rulemaking notice published at 55 FR 18230 (May 1, 1990), and 1114 OG 29 (May 15, 1990). To be in compliance, applicants should identify nucleotide sequences of at least 10 nucleotides and amino acid sequences of at least 4 amino acids in the specification by a proper sequence identifier, i.e., “SEQ ID NO:” (see MPEP 2422.01). If these sequences have not been listed in the computer readable form and paper copy of the sequence listing, applicant must provide an initial computer readable form (CRF) copy of the “Sequence Listing”, an initial paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, and a statement that the content of the paper and CRF copies are the same and, where applicable, include no new matter as required by 37 C.F.R. 1.821(e) or 1.821(f) or 1.821(g) or 1.821(b) or 1.825(d).
Claim Objections
Claims 1, 2, 4, and 6-8 are objected to because of the following informalities:
Claim 1 is objected to in the recitation of “sequence encoding of Formula” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “sequence encoding a peptide of Formula.”
Claim 1 is objected to in the recitation of “a nucleotide sequence of Alanine-Valine” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “the sequence of Alanine-Valine.”
Claim 2 is objected to in recitation of “insoluble tag is optionally linked to a nucleotide sequence encoding affinity tag of Formula (III)” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “insoluble tag is optionally linked to an affinity tag in a peptide of Formula (III).”
Claim 4 is objected to in the recitation of “sequence encoding a formula (II)” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “sequence encoding a peptide of Formula (II).”
Claim 6 is objected to in the recitation of “sequence encoding Formula” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “sequence encoding a peptide of Formula.”
Claim 7 is objected to in the recitation of “sequence encoding a Formula” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “sequence encoding a peptide of Formula.”
Claim 8 is objected to in the recitation of “A conjugate of Formula IV, His6 Tag---AV---Ubiquitin--- Arg34GLP-1 (9-37) (Nucleotide Sequence)” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “A nucleic acid comprising a nucleotide sequence encoding a fusion protein of Formula IV, His6 Tag---AV---Ubiquitin--- Arg34GLP-1 (9-37) Formula IV.”
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-7 and 9 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1 (claims 2-4 dependent therefrom), 5-7, and 9 are confusing because the claims appear to use the terms “Formula (II)” and “Formula (III)” interchangeably with the term “Arg34GLP-1 (9-37) peptide”, however, the peptides of “Formula (II)” and “Formula (III)” are structurally different from the peptide of “Arg34GLP-1 (9-37) peptide.” It is suggested that applicant clarify the meanings of the claims.
Claim 6 recites the limitation "a nucleotide sequence encoding…Formula (III).” There is insufficient antecedent basis for the limitation “Formula (III)” in the claim.
Claim 7 is indefinite because the substituents “R1” and “R2” of Formula V are undefined.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-6, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Reddy et al. (WO 2018/020417 A1; cited on the IDS filed June 16, 2023; hereafter “Reddy”) in view of Xu et al. (CN 110498849 A; cited on the IDS filed June 16, 2023; hereafter “Xu”). Reference is made to a machine translation of Xu (obtained from WIPO on September 15, 2025, 6 pages; cited on the attached Form PTO-892; hereafter “Translation”).
Claims 1-6 and 9 are drawn to a process for producing Arg34GLP-1 (9-37) peptide comprising the steps of:
a) culturing a host cell comprising a nucleotide sequence encoding of Formula (II) under suitable conditions for expression, Insoluble tag---Fusion tag---Arg34GLP-1 (9-37) Formula (II) wherein, insoluble tag is a nucleotide sequence of Alanine-Valine; and
b) recovering the expressed Arg34GLP-1 (9-37) peptide.
d) coupling optionally protected Aib and His amino acid, and
e) isolating semaglutide.
Claim 8 is drawn to a conjugate of Formula IV, His6 Tag---AV---Ubiquitin--- Arg34GLP-1 (9-37) (Nucleotide Sequence).
Regarding the nucleotide sequences of Formula II, Formula III, and Formula IV of instant claims 1-3 and 8, Reddy teaches an improved recombinant process for the preparation of a peptide involving the use of a ubiquitin fusion tag (p. 2, third full paragraph).
Reddy teaches fusion of ubiquitin to the N-terminus of a protein increases yield of unstable or poorly expressed proteins (paragraph bridging pp. 1-2).
Reddy teaches modulating solubility of a ubiquitin fusion construct by adding a suitable SI tag to the N-terminus of the ubiquitin fusion construct (p. 8, third full paragraph). Reddy teaches suitable SI tags (p. 8, SI tags 10-13) that include the sequence alanine-valine (e.g., SI tag GAIFLGAV). Given a broadest reasonable interpretation, Formula (II), Formula (III), and Formula (IV) encompass additional amino acids at the N-terminus and C-terminus of the alanine-valine insoluble tag, and the alanine-valine of the SI tags of Reddy are considered to be the “Insoluble tag” of Formula II and Formula III in claim 1 and “AV” in Formula IV in claim 8. According to Reddy, the suitable SI tags can be used for expression of the fusion protein as insoluble form (p. 9, last full paragraph).
Reddy teaches the suitable affinity tag includes a polyhistidine-tag (p. 9, second full paragraph) and teaches a 6XHis affinity tag (p. 26, first paragraph).
Reddy teaches the “peptide” of the ubiquitin fusion is intended to refer to any peptide comprising two or more amino acid residues connected by peptide linkage and encompasses GLP-1 analogs (p. 24, second and fourth full paragraphs).
Reddy teaches an embodiment of the fusion protein as being a ubiquitin fusion tag with GLP-1 analog along with combination of affinity tag and SI tag (p. 11, middle) and teaches ligating ubiquitin fusion construct to nucleotide encoding a combination of affinity tag and SI tag in an expression vector (p. 2, middle).
Regarding the process steps of instant claims 1 and 6, Reddy teaches (bridging pp. 3-4; p. 12, top) a process for producing protein or peptide comprising the steps of:
a) inducing transformant prokaryotic cells which comprise expression vector and ubiquitin fusion construct in fermentation culture medium; wherein the said ubiquitin fusion tag is linked to SI tag,
b) culturing the transformant prokaryotic cells under condition suitable for accumulation of fusion protein;
c) recovering the ubiquitin fusion protein or peptide;
d) optionally, purifying the ubiquitin fusion protein or peptide;
e) enzymatically cleaving the ubiquitin fusion protein or peptide; and
f) recovering the protein or peptide;
g) optionally, purifying the protein or peptide.
Regarding instant claim 4, Reddy teaches using multiple copies of ubiquitin fusion construct cloned together – either under a single promoter or multiple promoters, for the expression (p. 3, middle).
Regarding instants claims 5 and 9, Reddy teaches increase in accumulation of resulting ubiquitin fusion protein or peptide by inducing transformant prokaryotic cells having expression vector and ubiquitin fusion construct in culture medium with chemical agent (p. 12, middle).
The difference between Reddy and instant claims 1-6, 8, and 9 is that Reddy does not teach Arg34GLP-1(9-37) as recited in claims 1, 2, 5, 6, 8, and 9.
Xu teaches the GLP-1 analog, semaglutide, and its intermediate peptide Arg34GLP-1 (9-37) (Translation, p. 1, middle). Xu teaches a recombinant production method for intermediate peptide Arg34GLP-1 (9-37) (Translation, p. 1, middle).
In view of the combination of Reddy and Xu, it would have been obvious to one of ordinary skill in the art before the effective filing date for the peptide and GLP-1 analog of Reddy to be the Arg34GLP-1(9-37) of Xu. One would have been motivated and would have expected success for the peptide and GLP-1 analog of Reddy to be Arg34GLP-1(9-37) because Reddy taught “an improved recombinant process” for producing peptides generically and “GLP-1 analogs” specifically, and Xu taught the GLP-1 analog intermediate peptide Arg34GLP-1 (9-37), which is suitable for recombinant production.
Therefore, the invention of claims 1-6, 8, and 9 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Reddy in view of Xu as applied to claims 1-6, 8, and 9 above, and further in view of Lau et al. (J. Med. Chem. 58:7370-7380, 2015; cited on the attached Form PTO-892; hereafter “Lau”) and Christensen et al. (WO 2010/029159 A1; cited on the attached Form PTO-892; hereafter “Christensen”).
Claim 7 is drawn to a process for the preparation of semaglutide, comprising the steps of:
a) culturing a host cell comprising a nucleotide sequence encoding a Formula (II) or Formula (III) under suitable conditions for expression, Insoluble tag---Fusion tag--- Arg34GLP-1 (9-37) Formula (II) Affinity Tag---Insoluble tag---Fusion tag---Arg34GLP-1 (9-37) Formula (III), wherein, insoluble tag is nucleotide sequence of Alanine-Valine;
b) recovering the expressed Arg34GLP-1 (9-37) peptide;
c) acylating an epsilon amino group one lysine residue in the expressed Arg34GLP-1 (9-37) with an acylating agent of Formula (V), which is optionally activated,
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d) coupling optionally protected Aib and His amino acid, and
e) isolating semaglutide.
The relevant teachings of Reddy and Xu as applied to claims 1-6, 8, and 9 are set forth above.
Regarding the process steps of claim 7, Reddy teaches (bridging pp. 3-4; p. 12, top) a process for producing protein or peptide comprising the steps of:
a) inducing transformant prokaryotic cells which comprise expression vector and ubiquitin fusion construct in fermentation culture medium; wherein the said ubiquitin fusion tag is linked to SI tag,
b) culturing the transformant prokaryotic cells under condition suitable for accumulation of fusion protein;
c) recovering the ubiquitin fusion protein or peptide;
d) optionally, purifying the ubiquitin fusion protein or peptide;
e) enzymatically cleaving the ubiquitin fusion protein or peptide; and
f) recovering the protein or peptide; and
g) optionally, purifying the protein or peptide, and
Reddy further teaches a process for acylating a peptide at a lysine residue to produce a GLP-1 analog and isolating the acylated peptide (beginning at p. 18, bottom).
Xu further teaches combining the intermediate peptide Arg34GLP-1(9-37) and His-Aib in a basic aqueous solution to produce the semaglutide main peptide chain (Translation at p. 4, top).
The difference between the combination of Reddy and Xu and instant claim 7 is that the combination does not teach acylating Arg34GLP-1 (9-37) with an acylating agent of Formula (V).
Lau teaches the structure of the GLP-1 analog semaglutide (p. 7373, Figure 2, reproduced below), which is acylated at Lys26 with a C18 diacid γGlu-2xOEG acylating agent (p. 7374, Table 3). The C18 diacid γGlu-2xOEG acylating agent of Lau is encompassed by Formula V of instant claim 7.
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Christensen teaches a method for acylating GLP-1 analog peptides with various acylating agents (see, e.g., Examples 6-8, 12, 15, 17, 19, and 20) including selective acylation of GLP-1 analog peptide at Lys26 (see Examples 12, 15, 17, 19, and 21).
In view of the combination of Reddy, Xu, Lau, and Christensen, it would have been obvious to one of ordinary skill in the art before the effective filing date to prepare semaglutide from the recombinantly produced Arg34GLP-1(9-37) (according to the combined method of Reddy and Xu as described above) by acylating Lys26 with the C18 diacid γGlu-2xOEG acylating agent of Lau and coupling with His-Aib. One would have been motivated to do so in order to complete the preparation of semaglutide from the intermediate peptide Arg34GLP-1(9-37). One would have expected success because Lau teaches semaglutide is acylated with a C18 diacid γGlu-2xOEG acylating agent at Lys26 and Christensen teaches a method for selective acylation of a GLP-1 analog peptide at Lys26, and Xu teaches semaglutide has N-terminal His7-Aib8 and teaches a method for coupling Arg34GLP-1(9-37) with His-Aib.
Therefore, the invention of claim 7 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 1-9 are pending in the application.
Claims 1-9 are rejected.
No claim is in condition for allowance.
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/David Steadman/Primary Examiner, Art Unit 1656