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 claims 1-5 in the reply filed on 12/15/2025 is acknowledged.
Claims 6-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/15/2025.
Priority
This application is a 371 of PCT/CN2022/077631 (2/24/2022) which claims priority to CN202110217647.X (2/26/2021) as reflected in the filing receipt issued on 1/17/2024.
The certified copy of the foreign priority document is not in English. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 8/25/2023 and 12/15/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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 1-2 and 4-5 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 4 recites the broad recitation “the first protease cleavage site and the second protease cleavage site”, and the claim also recites “preferably, the first protease cleavage site and the second protease cleavage site are selected from any one of the following” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term “short” in claim 1 is a relative term which renders the claim indefinite. The term “short” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification, p. 6, states that “preferably, the short linker peptide has no more than 5 amino acids”. However, this preferred embodiment is not limiting. It would not be clear to a person of ordinary skill in the art that a “short” linker peptide must be 5 amino acids or less, and the term is not defined in the specification so as to provide an objective assessment of what is considered a short linker peptide.
Claims 2 and 5 are included in this rejection because they depend on a rejected claim and do not clarify the issue.
Claim Rejections - 35 USC § 102
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 and 4-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ichtchenko et al., US 2011/0206616 A1.
Regarding claim 1, Ichtchenko teaches Clostridium botulinum neurotoxins (Abstract). The propeptide of Ichtchenko comprises a polypeptide fragment including a tag sequence (p. 8 para. 48), a protease cleavage site (p. 8 para. 49), and a short (7 amino acid) linker sequence (p. 10 para. 62; see Fig. 1). The tag, protease cleavage site, and linker are at the N-terminus of a second polypeptide fragment, which comprises the neurotoxin light and heavy chain regions (p. 5 para. 18; see Fig. 1). The C. botulinum neurotoxin light region comprises a metalloprotease activity domain (p. 1 para. 5-7) and the heavy chain comprises receptor binding and translocation activity (p. 1 para. 5; p. 2 para. 8). Ichtchenko teaches that the light and heavy chains are connected by an intermediate region comprising a highly specific protease cleavage site (p. 5 para. 18, see Fig. 18). Thus, as seen in Fig. 1 BoNT/Aadtev, Ichtchenko teaches a single-chain neurotoxin polypeptide comprising a first fragment with a tag, protease cleavage site, and short linker peptide; and a second fragment comprising a metal-ion dependent protease activity domain (neurotoxin light chain), a second protease cleavage site, and a receptor binding/translocation domain (neurotoxin heavy chain).
Regarding claim 2, Ichtchenko teaches a polypeptide, BoNT/Aadtev, wherein the first and second protease cleavage sites are identical, both are TEV (ENLYFQ) (see Fig. 1; p. 50 para. 204). Regarding claim 4, Ichtchenko teaches that the intermediate region of the neurotoxin propeptide is not cleaved by proteases endogenous to the expression system or host cell (p. 27 para. 80), and the cleavage site may be a tobacco etch virus (TEV) protease site (p. 50 para. 204; Fig. 1).
Regarding claim 5, Ichtchenko teaches that the first functional amino acid structural region is derived from neurotoxin light chain, which comprises a Zn2-+ protease activity domain (p. 1 para. 5-7) and the second functional amino acid structural domain is derived from neurotoxin heavy chain, which comprises receptor binding and translocation activity (p. 1 para. 5; p. 2 para. 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 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ichtchenko et al., US 2011/0206616 A1.
Ichtchenko teaches the neurotoxin polypeptide of claim 1 as discussed above.
Regarding claim 3, Ichtchenko teaches that the linker (spacer) positioned upstream of the light chain region may comprise 2-40 amino acid residues (p. 10 para. 62). When claimed ranges "overlap or lie inside the ranges disclosed by the prior art", a prima facie case of obviousness exists. See MPEP 2144.05(I). Therefore, a linker peptide of no more than 5 amino acid residues is considered obvious in view of Ichtchenko, which teaches linkers with 5 or fewer amino acid residues.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-11 of copending Application No. 18/852,908 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to single-chain neurotoxin polypeptides.
Regarding claim 1, claim 1 of ‘908 is directed to a botulinum toxin protein composition. Claim 10 of ‘908 recites that the recombinant botulinum toxin protein is prepared by cleaving a single-chain polypeptide with a first protease to remove a tag protein, and forming at least one dimer after cleavage with a second protease, wherein the single-chain polypeptide comprises: (I) a first polypeptide fragment comprising:
(a) a tag protein;
(b) a structural region comprising a first protease cleavage site; and
(c) a short linker peptide; and
(II) a second polypeptide fragment comprising:
(d) a first functional amino acid structural region comprising a metal ion-dependent protease activity domain;
(e) a structural region comprising a second protease cleavage site; and
(f) a second functional amino acid structural region comprising a receptor-binding domain capable of binding to a surface receptor of a target cell and/or a translocation domain capable of mediating the transfer of the polypeptide across a vesicle membrane,
wherein preferably, the first functional amino acid structural region is a light chain of BoNT/A, and the second functional amino acid structural region is a heavy chain of BoNT/A.
Regarding claims 2-5, the limitations of these dependent claims are recited in claims 1, 10, and 11 of copending 18/852,908.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11-13 of copending Application No. 18/547,850
(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are directed to single-chain neurotoxin polypeptides.
Regarding claim 1, claim 1 of ‘850 recites a method using a modified toxin polypeptide precursor comprises:
(I) a first polypeptide fragment comprising:
(a) a tag protein;
(b) a structural region comprising a first protease cleavage site;
(c) a short linker peptide, wherein the short linker peptide has five or less amino acid residues; and
(II) a second polypeptide fragment comprising:
(d) a first functional amino acid structural region comprising a metal ion-dependent protease activity domain;
(e) a structural region comprising a second protease cleavage site; and
(f) a second functional amino acid structural region comprising a receptor-binding domain that can bind to the surface receptor of a target cell and/or a translocation domain that can mediate the transfer of the polypeptide across the vesicle membrane of the target cell; and
wherein the first protease cleave site and the second protease cleave site are identical or different.
Regarding claims 2-5, the limitations of these dependent claims are recited in claims 1 and 11-13 of copending 18/547,850.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-5 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY F EIX whose telephone number is (571)270-0808. The examiner can normally be reached M-F 8am-5pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMILY F EIX/Examiner, Art Unit 1653
/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653