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 .
The response filed 3-11-2026 has been entered into the record.
Status of Claims
Claims 1-10 are pending.
Sequence Requirements
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § § 1.821-1.825 for the reason(s) set forth below. Figure 1, recites sequences that are not followed by a proper sequence identifier either in the Figure per se or in the Description of the Figure. Correction is required. Full compliance with the sequence rules is required in response to this office action.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 16/094,254, filed o 5-17-2017.
Election/Restrictions
Applicant’s election of species of mutation E1191M in the reply filed on 3-11-2026 without traverse is acknowledged.
Information Disclosure Statement
The information disclosure statement has been considered. An initialed copy is enclosed.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms UNIPROT®, NEUPAGETM, BENZONASE®, BOTEST®, which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Applicant should review the specification for any other trademarks/names that are not in compliance and provide the appropriate generic terminology as applicable.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1-10 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, or for pre-AIA the applicant regards as the invention.
As to claim 1 and all the claims dependent thereon, the claims state a “di-chain chimeric neurotoxin”, however the claims provide for a single chimeric polypeptide. Does applicant mean the active form of the neurotoxin ? As such, the metes and bounds of “di-chain” are indefinite because the claims only set forth a single polypeptide chain.
As to claims 3, 4 and 5, the substitutions are prima facie indefinite because claim 1 does not comprise a defined reference sequence of each of the domains for which substitutions can arise. Furthermore, it is unclear if the reference sequence number refers to the full-length chimeric neurotoxin or a subpart thereof.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 6, 7, 8, 9, 10, 11, 15 and 16 of U.S. Patent No. 11,434,265 in view of Dong et al (WO 2013/180799; of record on PTOL-1449). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims anticipate the instantly claimed invention.
The ’265 patent claims chimeric neurotoxins. ‘265 patent describes the domains as corresponding to the first amino acid residue of the 310 helix and the N-terminal residues of the Hc domain corresponding to the second amino acid residue of the 310 domain helix it is clear from the specification that those residues in correspond to the instantly claimed residues of A1 and B1 of the claims of the instant application and are clearly set forth in the boundaries of the domains in dependent claim 6 of the patent. Thus, while the language is different the claims are drawn to the same invention. Additionally, each of the amino acid substitutions including the elected E1191M substitution is obvious over the Hc domain of B1 which corresponds to residues 860-1291 of SEQ ID NO:2 as set forth in claim 8, 9, 10 and 12. SEQ ID NO:12 is obvious over the substitutions into base sequence residues 860-1291 of SEQ ID NO:2 as set forth in claim 10. The ‘265 patent specification defines neurotoxin as encompassing the single chain and enzymatically cleaved polypeptide. See paragraph bridging pages 6-7. However, tne the patented claims do not specify that the neurotoxin is the “active” or enzymatically cleaved form of the neurotoxin.
Dong et al teach that the botulinum neurotoxin can be in a single chain or a di-chain form. The di-chain form results from the naturally occurring protease processing of a protease cleavage site located between the protease domain and the translocation domain. The protein is maintained in the di-chain by the presence of a disulfide bond. (see page 17, paragraph [0063]).
The di-chain form of the neurotoxin polypeptide of the ‘265 patented claims also known is the biologically active form of the pharmaceutical/drug according to Dong et al and as such the di-chain form of the chimeric neurotoxins of the ‘265 patent are prima facie obvious over the single chain chimeric neurotoxin of the patent.
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-11, 18 and 19 of copending Application No. 19/309,183 (reference application in view of Dong et al (WO 2013/180799; of record on PTOL-1449).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘183 application render obvious the instantly claimed cleaved (i.e. di-chain) chimeric neurotoxin as the specification
The patent specification defines neurotoxin as encompassing the single chain and enzymatically cleaved polypeptide. See paragraph bridging pages 6-7. The substitutions set forth in claims 8, 9 and 10 of the ‘183 application as depending on claim 6 therein define the same structure of the elements of the claims of the instant application.
Dong et al teach that the botulinum neurotoxin can be in a single chain or a di-chain form. The di-chain form results from the naturally occurring protease processing of a protease cleavage site located between the protease domain and the translocation domain. The protein is maintained in the di-chain by the presence of a disulfide bond. (see page 17, paragraph [0063]).
The cleaved/enzymatically processed form of the neurotoxin or chimeric neurotoxin is the biologically active form of the pharmaceutical/drug and as such is prima facie obvious over the single chain chimeric neurotoxin of the patent in view of the definition of neurotoxin to encompass both those embodiments. The instantly claimed pharmaceutical compositions and kits of claims 6, 7, 9 and 10 herein are also anticipated by composition and kit claims of the ‘183 application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 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.
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 2, 3, 4, 5, 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Dong et al (WO2013/180799; of record in PTOL-1449).
Dong et al teach single chain and di-chain (biologically active) forms of a botulinum neurotoxin (BoNT) comprising a protease domain, a protease cleavage site, a translocation domain and a modified receptor binding domain of serotype B (B-Hc) wherein the B-Hc domain comprises one or more substitution mutations corresponding to substitution mutations in serotype B, strain 1, selected from the group consisting of V1118M; Y1183M; E1191M; E1191I; E1191Q; E1191T; S1199Y; S1199F; S1199L; S1201V; and combinations thereof (see page 49, claim 1) wherein the modified B-Hc is of strain 1 (page 50, claim 15). Dong et al specifically claim the combination of E1191M and S1199Y (see page 49, claim 5). Dong et al teach that the protease domain, translocation domain and protease cleave site are selected from other serotypes including serotype A strain 1 (see page 51, claim 18 as depending on claim 16). Such a BoNT polypeptide is necessarily chimeric. Dong et al teach pharmaceutical compositions comprising such, and where the pharmaceutical composition comprises a pharmaceutically acceptable excipient (page 55, claims 58 and 59. Dong et al teach the kits comprising the pharmaceutical compositions and directions for administration of such (see claim 60). Dong et al teach the domain structure of each of the serotypes (see pages 18-19 ,Table 1).
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Dong et al teach the sequence of the neurotoxin domain structure and the structure of the di-chain active form at Figure 2F from amino terminal to carboxy terminal. Dong et al teach the sequences can be in a single chain or a di-chain form. Typically, the neurotoxins are arranged in a linear amino-to carboxyl single polypeptide order of the protease domain, the protease cleavage site, the translocation domain and the modified receptor binding domain (see page 17, paragraph [0064]). The sequence of BoNT/B-Hc (Okra / strain 1) residues 857-1291, GenBank: AB232927.1 (SEQ IDNO:1) in Figure 8. The Okra/B1 strain is the same as the sequence set forth in B1INP5 in Figure 1 of the instant application. The sequence of serotypes A, B, C1, D, E, F and G are found in subsequent Figures and represented by SEQ ID NOS:3-9 (page 11, paragraphs [0032-0040]). The BoNT neurotoxin of the instant claims provides for BoNT/A1 of the protease domain, the cleavages site and translocation domain LHN fused to mutated or WT Hc domain from BoNT/B1. The fusion set forth in claim 18 of Dong et al as depending from claim 16 as depending from claim 15 as depending from claim 1 and using the domain structure of Table 1 all of Dong et al would result in a chimeric neurotoxin comprising residues 1-871 of serotype A (corresponding to the LHN domain of the instant claims) fused to residues E859-E1291 of serotype B with selected mutations individually or in combination as set forth in claim 1. Dong et al specifically calls out the fusion of A1/B1 as a contemplated embodiment within the scope of claim 18 therein. Dong et al also teach that the neurotoxin encompasses both the single chain and Di-chain form of the neurotoxin. The hybrid A1/B1 neurotoxin represented by Dong et al differs in the fusion site by an amino acid (fuses 1-K871 of A1 to E859-1291 of B1) with the mutants as compared to instant claim 1 as the instant chimeric BoNTA1/B1 fuses 1-N872 of A1 to I860-1291 of B1 (residue amino acid N to I fusion). The instant specification does not provide any unexpected property as a result of the shifted fusion point.
It would have been obvious to one having ordinary skill in the art that the time of filing the invention to modify the contemplated variant neurotoxins of Dong et al by varying the fusion junction of the A1/B1 of Dong et al to result in the instantly claimed fusion point, as the critical domain structures remain intact and the instant di-chain chimeric neurotoxins would be an obvious variation of the structure of the prior art achieved with routine experimentation and useful for the same purposes according to Dong et al. The claimed pharmaceutical compositions with excipients, in a kit with instructions are obvious over the modified botulinum neurotoxin of Dong et al which teach that the modified toxins can be included in those compositions and kits for well established therapeutic purposes.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Dong et al (WO2013/180799; of record in PTOL-1449) as applied to claims 1, 3, 4, 5, 6 and 7 above and further in view of Uniprot Accession Number P0DPI1 which replaced A5HZZ9 cited in the specification as serotype AI (SEQ ID NO:1) available 2010.
The teachings of Dong et al are set forth supra. Dong et al teach the sequence of serotype B1 Figure 11, SEQ ID NO:4. Dong et al teach serotype A, but do not specify it is serotype A1.
UniProt Accession Number P0DPI1 teaches the sequence of BoNT/A1 which was previously known as A5HZZ9 and cited in the specification. P0DPI1 is 100% identical as compared with the disclosed SEQ ID NO:1.
It would have been prima facie obvious to one of ordinary skill in the art to use domain residues 1-872 of the sequence of serotype A1 (P0DPI1/A5HZZ9) in the modified di-chain chimeric fusion (A1/B1 with mutants) of Dong et al to arrive at the instantly claimed di-chain A1/B1 mutant of SEQ ID NO:12 because the sequence of serotype A1 was known and available to the art at the time of filing. The selection of any strain of any serotype A strain is obvious over the teaching of Dong et al that serotype A was desirable and A1 was particularly called taught.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Patricia Duffy whose telephone number is (571)272-0855. The examiner can normally be reached 8:00 am - 4 pm.
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/Patricia Duffy/Primary Examiner, Art Unit 1645
/YVONNE L EYLER/Director, TC 1600
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