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 .
This is the First Office Action on the Merits of US18/270,520 filed on 06/30/2023 which is a 371 of PCT/IB2022/050013 filed on 01/03/2022 which claims foreign priority to INDIA 202141000174 filed on 01/04/2021. The Filing Receipt received on 06/20/2024 is controlling.
Claims 2-4 are canceled.
Claims 1, and 5-16 are pending and under examination in this office action.
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:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "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.
If the "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 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
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). See page 1 (Formula-I, lines6-10); page 1, lines 21-25; page 15, lines 3-6;
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.
Information Disclosure Statement
The IDS filed on 01/04/2024 has been considered by the examiner. References not in the English language are considered only to their English language machine translations which are provided with the Reference.
Claim Objections
Claims 5 and 11-16 are objected to because of the following informalities:
Claim 5 should amended: “comprises
Claims 11-16 recite Teduglutide which appear to be a misspelling for Teduglutide. 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.
Claims 1, and 5-16 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.
Claim 1 recites the limitation "the Wang resin" in line 3. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference to a Wang resin in the claim.
Claim 1 recites the limitation "coupling of side chain protected amino acids" in line 5. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference to side chain protected amino acids in the claim.
Claim 1 recites the limitation "by removal of protected groups" in line 7. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference to protected groups in the claim.
Claim 1 recites the limitation "cleavage of peptide from the resin" in lines 7-8. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference to a peptide attached to the resin.
Claims 10-16 are indefinite because they depend from claim 1 and are not remedial.
Independent claim 5 recites the limitation "from the solid support" in line 1. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference to a solid support in the claim.
Also, claim 5 is an improper use claim because it recites “using” but without an active method step.
Claims 6-7 are indefinite because they depend from claim 5 and are not remedial.
Independent claim 8 is an improper use claim because it recites a use but without an active method step. Claim 9 is indefinite as it depend from claim 8 and is not remedial
Also, claim 9 recites the limitation "the protection group" in line 1. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference to a protection group in the claim 9 or claim 8.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 5-6, 8-10, 12-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over The Pallin Dissertation (University of Edinburgh, November 1993), as evidenced by Wang (Journal of American Chemical Society 1973 Vol 95, No 4), in view of Neumann et al in Prevention of aspartimide formation during peptide synthesis using cyanosulfurylides as carboxylic acid-protecting groups (Nature Vol 11, No: 982, published February 20, 2020).
Regarding claim 1, Pallin discloses a process for the preparation of peptides comprising the steps of:
a) anchoring of first amino acid, aspartic acid to the Wang resin through its side chain carboxylic group. Note that a Wang resin is a standard polystyrene support in solid-phase peptide synthesis (SPPS) for creating peptides with a C-terminal acid, using Fmoc chemistry, where amino acids are added sequentially to the resin, deprotected, and coupled, finally cleaved with acid (like TFA) to yield the peptide, making it popular for its compatibility with mild Fmoc deprotection and relatively easy cleavage. (See page 16 showing 4-alkoxybenzyl alcohol resin, which is a Wang resin, as evidenced by the Wang reference). Pallin discloses that generally, the first amino acid at the carboxyl terminus is attached to a resin. (page 2).
b) sequential coupling of side chain protected amino acids to prepare the peptide, in the presence of coupling agent. Pallin disclose that activation of side chain carboxylic acids, specifically noting for aspartic acid, must be suppressed. (See page 19, Section 1.2.2)
c) obtaining crude peptide by removal of protective groups and cleavage of peptide from the resin.
Regarding claim 5-6 and 12-13, Pallin discloses a process for the cleavage of a peptide from the solid support using a cleavage solution, wherein the cleavage solution comprises of an antioxidant, amino acids and TFA cocktail. (See page 74, Section 3.2.7 “Cleavage of the Peptide from the Resin”). Pallin discloses that the “peptide was cleaved from the resin using aqueous TFA, with appropriate scavengers” (See page 47).
Regarding claims 14 and 16, Pallin discloses a process for the preparation of a peptide wherein the peptide is purified after cleavage from the resin. (See page 74, Section 3.2.7 “Cleavage of the Peptide from the Resin” and 3.2.8 “The Preparation of Purified Peptide for Amino Acid Analysis”).
A scavenger in the context of an aqueous TFA cleavage solution used for peptide synthesis is a reagent that is added to prevent the cleaved protecting groups from reattaching to the peptide. The choice of scavenger is crucial as it depends on the amino acid composition of the peptide. For peptides containing Cys, Met, or Trp, which are particularly susceptible to alkylation, scavengers like 1,2-ethanedithiol (EDT) are recommended to protect the indole side-chain of Trp and the thioether of Met. For Cys-containing peptides, EDT helps keep the sulfhydryl group in a reduced state, preventing oxidation and disulfide bond formation. For peptides with Arginine (Arg) protected by Pmc or Mtr, more complex and potent scavenger mixtures may be necessary, especially for peptides with multiple Arg residues.
Regarding claim 8, Pallin discloses a process for the preparation of a peptide, wherein mono protected Histidine is used. (See page 71, Section 3.2.2 “Side Chain Protection of Fmoc Amino Acids During Synthesis”).
Regarding claim 9, Pallin discloses wherein the protection group used is tert- Butyloxycarbonyl (Boc). (See page 5, Table 1).
However, Pallin differs from the present claims because while it discloses synthesis of a peptide it does not disclose Teduglutide.
Also, regarding claim 10, Pallin does not disclose wherein the first amino acid is Fmoc-Asp-OtBu.
Regarding claims 1, 5-6, 8-10, 12-14, and 16, Neumann et al disclose peptide synthesis using commercially available Fmoc-Asp(OH)-OtBu in a process of chemically synthesizing Teduglutide. (See page 6, right col., headed “Chemical synthesis of teduglutide”) Teduglutide is a 33 amino acid peptide having an aspartic acid residue at the COOH end (C-terminal) of the peptide and a side chain carboxylic group. (See FIG4). Neumann et al disclose that peptide synthesis of Teduglutide was hindered especially because the aspartic acid residues are prone to aspartimide contaminates.
The base-promoted aspartimide formation occurs during Fmoc removal or peptide coupling (Fig. 1a). The undesired formation of aspartimides during SPPS results in poor yielding or even inaccessible peptide sequences, a problem that—although often encountered—remains unsatisfactorily addressed. It frequently results in costly and time-consuming purification steps in both research and industry. Aspartimide formation is highly sequence-dependent, with glycine, asparagine, aspartic acid, and cysteine in the preceding position showing the highest propensity for aspartimide formation.
Neumann et al disclose a method of using a stable C-C bond that masks the side-chain carboxylic acid of aspartic acid. (See Fig1b legend).
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to combine the chemical peptide synthesis methods of the cited references to synthesize Teduglutide as the type of peptide to be synthesized for the rationale that Teduglutide has been successfully chemically synthesized for therapeutic use. It would have been obvious to synthesize Teduglutide because Neumann et al disclose it has been successfully synthesized using the method of coupling the first amino acid to a resin and using commercially available Fmoc-Asp(OH)-OtBu to make Fmoc-Asp(CSY)-OtBu in a process of chemically synthesizing Teduglutide.
Further, one of ordinary skill in the art would have been motivated to use anchoring of the first amino acid of the peptide of Teduglutide being an aspartic acid to the Wang resin through its side chain carboxylic group for the rationale of being able to synthesize the 33 amino acid peptide in one linear peptide rather than in fragments which need to be coupled afterwards. As evidenced by Neumann et al, Teduglutide has a first amino acid which is an aspartic acid residue at the COOH end (C-terminal) of the peptide and a side chain carboxylic group. (See FIG4).
In view of the high skill in the art it is considered that one of ordinary skill in the art having the cited references before the effective filing date would have had a reasonable expectation of success to anchor the first amino acid of Teduglutide being an aspartic acid residue to the Wang resin using Fmoc-Asp(OH)-OtBu as shown in Neumann et al and using standard protecting groups and scavengers to avoid contaminants in the cleavage reaction to arrive at the presently claimed invention.
Conclusion
No claim is allowed.
Related prior art which may be applied in a future office action:
Behrens, et al (WO 2005014049 A2);
New t-butyl based aspartate protecting groups preventing aspartimide formation in Fmoc SPPS (J Pept Sci. 2015 Aug;21(8):680-7. Epub 2015 Jun 15);
Albericio et al in “Solid-phase synthesis of peptides with C-terminal asparagine or glutamine: An effective, mild procedure based on N x =fluorenylmethyoxycarbonyl (Fmoc) protection and side-chain anchoring to a tris(alkoxy)benzylamide (PAL) handle”, International Journal of Peptide and Protein Research, Vol 35, No 3, March 01, 1990, pages 284-286); and
US20090156478; US20060182714; US20090240028; US20120088716.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa 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.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658