DETAILED ACTION
Notice of 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 .
Status of Application
Claims 1-2, 4-9, 16-18, 21, 24, 29-30, 40, 43, 46, 52 and 68 are pending and subject to examination on the merits.
Priority
The instant application is a CON of PCT/US2023/031703 filed 31 August 2023 which claims benefit of US provisional application 63402841 filed 31 August 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09 May 2025 has been considered by the examiner. See initialed and signed PTO/SB/08.
Claim Objections
Claim 1 is objected to because of the following informalities: the first time an acronym is used in a claim set, it should be spelled out in full. Thus, GCH1 should be spelled out as “GTP cyclohydrolase 1 (GCH1)”. Appropriate correction is required.
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 1-2, 4-9, 18, 21, 24, 29-30, 40, 43, 46, 52 and 68 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 join inventor regards as the invention.
Claims 1 and 9 recite a GCH1 cleaving polypeptide comprising an amino acid sequence that is is at least 70% to SEQ ID NO: 9 or 1, respectively, and comprises one or more amino acid substitutions selected from those listed in each of claims 1 and 9.. However, it not clear if the GCH1 cleaving polypeptide has 70% identity to SEQ ID NO: 1 and 9 before the recited mutations or if it has 70% identity (and higher) after/inclusive of the recited mutations are made in SEQ ID NO: 1 and 9.
For examination purposes, it will be construed that the aminotransferase has the 70% identity to SEQ ID NO: 1 and 9 prior to the mutations being introduced. However, clarification is requested.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-2, 4-9, 16, 18, 21, 24, 29-30, 40, 43, 46, 52 and 68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' MPEP 2111.03. I. states that “t]he transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps”. In the instant case, the examiner has broadly interpreted the claims to encompass any variant of GCH1 cleaving polypeptides having at least 70% sequence identity to SEQ ID NOs: 1, 9, and 10-23, or any variant of the GCH1 cleaving polypeptides of SEQ ID NO:1 or 9, wherein the variant comprises substitutions of selected from N59, N61, A73, A75, I102, I115, K164, A166, Y168, I175, K193, D199, I235, F248, N260, L262, F264, A277, R324, R354, L364, P368, S395, S413, L428, Y430, and N439 relative to SEQ ID NO: 9; or comprises amino acid substitutions selected from N59, N61, E72, A73, A75, I102, E113, I115, I119, D161, N164, A166, T167, Y168, Y171, P174, I175, K193, Y199, N210, A218, N235, S240, F248, K252, N260, L262, F264, A277, S280, Y314, R324, R354, L364, P368, S395, S413, L428, Y430, and N439 relative to SEQ ID NO: 1. In addition, for claim 16, the sequences need only 70% sequence identity to SEQ ID NOs: 10-23, thus permitting approximately 1321-137 amino acid substitutions per sequence (depending if the sequences have 439 or 458 amino acids). Therefore, the claims are drawn to a genus of GCH1 cleaving polypeptides variants having unknown structure except the specific substitutions as in claim 5, but even here, the additional substitutions result in the rest of the GCH1 cleaving polypeptides having an enormous variation in structures.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The recitation of “GCH1 cleaving polypeptides” fails to provide a sufficient description of the genus of polypeptides as it merely describes the functional features of the genus without providing any definition of the structural features of the species within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
Clostridium botulinum neurotoxin X catalytic domain (e.g. CGH1 cleaving polypeptide) having the amino acid sequence of SEQ ID NO:1 was known in the art. Dong (US 2020/0224185 – cited herein) discloses Clostridium botulinum neurotoxin X catalytic domain having the amino acid sequence of SEQ ID NO:3, which is identical to instant SEQ ID NO:1 (See Supplemental Content, 20260923_110203_us-19-064-858-1.rapbm file, Result #1), and wherein SEQ ID NO: 1 is the wild-type sequence Clostridium botulinum neurotoxin X catalytic domain. However, wild-type Clostridium botulinum neurotoxin X catalytic domain does not possess the ability to cleave GCH1 polypeptides. Rather, this is novel function for a known protease, which has been evolved to have this function, such as in instant SEQ ID NO: 9 is a variant of instant SEQ ID NO: 1, having 16 amino acid changes. The claims, however, allow for an unlimited number of substitutions (e.g. comprises at least one selected from). In addition, the starting enzyme minimally must possess at least 70% identity to SEQ ID NO: 1, or 9-23. Thus, the claims are drawn to a huge and variable genus of enzymes having CGH1 cleaving activity, but which must have a novel function.
Fransceus (J Ind Microbiol Biotechnol. 2017 May;44(4-5):687-695 – cited herein) reviews protein engineering techniques, such as random mutagenesis and recombination, directed evolution and iterative or combinatory saturation “hotspots”. Fransceus states that “a recurring problem, however, is choosing which amino acid positions should be targeted. Answering this question is not an easy feat and requires substantial insight in the relationship between an enzyme’s sequence or structure and its properties.” Sanavia (Computational and Structural Biotechnology Journal, Volume 18, 2020, Pages 1968-1979 – cited herein) discloses challenges in the prediction of protein stability in the occurrence of multiple mutations. “Multiple-point mutations are common variations of the protein sequence that may be needed in protein engineering when a single-point mutation is not enough to yield the desired stability change. Dealing with multiple-site variations adds another level of complexity beyond the prediction of the effect of a single variant on protein stability, since it requires the learning of many types of combinatorial effects”.
The specification is limited to specific variants of the Clostridium botulinum neurotoxin X catalytic domain of SEQ ID NO:1, wherein the variants have been evolved to have substitutions in positions N59, N61, A73, A75, I102, I115, K164, A166, Y168, I175, K193, D199, I235, F248, N260, L262, F264, A277, R324, R354, L364, P368, S395, S413, L428, Y430, and N439. While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the above example described above is not enough and does not constitute a representative number of species to describe the whole claimed genus. Therefore, the specification fails to describe a representative species of the claimed genus in terms of structure and function.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 1-2, 4-9, 16, 18, 21, 24, 29-30, 40, 43, 46, 52 and 68.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-2, 4, 16, 18, 21, 24, 29-30, 40, 43, 46, 52 and 68 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dong et al. (US 20200224185 – cited herein).
Dong et al. teach:
Regarding claims 1-2, 4, 16, 18, 21, 24 a GCH1 cleaving polypeptide, namely, a modified botulinum toxin (BoNT X) polypeptide comprising SEQ ID NO: 3 (See claim 17), which has 96% sequence identity to instant SEQ ID NO: 9 and has a substitution of K164N, I235N (See Supplemental Content, 20260923_110203_us-19-064-858-9.rapbm file, Result #22).
Regarding claims 29-30, the modified a botulinum toxin polypeptide comprises fusion protein, wherein the fusion partner is a delivery domain, e.g. a Hn or Hc translocation domain (See claim 62; paragraphs 0109 to 0113, 0123).
Regarding claims 40, 43, 46, 52 and 68, nucleic acids encoding, expression vectors, host cells and methods of delivering the proteins are taught (See claims 102-105); and methods of delivering said modified a botulinum toxin polypeptide to patients (See claim 148).
Query Match 96.0%; Score 2164; Length 439;
Best Local Similarity 96.4%;
Matches 423; Conservative 5; Mismatches 11; Indels 0; Gaps 0;
Qy 1 MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT 60
Qy 61 NDLNIPSEPIMRADAIYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLKLISSSVP 120
||||||||||| ||||||||||||||||||||||||||||||||||||||||:|||||:|
Db 61 NDLNIPSEPIMEADAIYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIP 120
Qy 121 LPLVSNGALTLSDNETIAYQENNNIVSNLQANLVIYGPGPNIAKNAAYGLDSTLISNGEG 180
||||||||||||||||||||||||||||||||||||||||:|| || ||| || ||||||
Db 121 LPLVSNGALTLSDNETIAYQENNNIVSNLQANLVIYGPGPDIANNATYGLYSTPISNGEG 180
Qy 181 TLSEVSFSPFYLKPFDESDGNYRSLVNIVDKFVKREFVPDPASTLMHELVHVTHILYGIV 240
|||||||||||||||||| ||||||||||:||||||| |||||||||||||||| ||||
Db 181 TLSEVSFSPFYLKPFDESYGNYRSLVNIVNKFVKREFAPDPASTLMHELVHVTHNLYGIS 240
Qy 241 NRNFYYNFDTGEIETSRQQNSLIFEELLTFGGIDSKAISPLIIKKIIETAKNNYTTLISE 300
|||||||||||:||||||||||||||||||||||||||| ||||||||||||||||||||
Db 241 NRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKKIIETAKNNYTTLISE 300
Qy 301 RLNTVTVENDLLKSIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR 360
||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||
Db 301 RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR 360
Qy 361 KHYLKERPIDPIYVNILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFI 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 KHYLKERPIDPIYVNILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFI 420
Qy 421 KICPRNGLLYNAIYRNSKN 439
|||||||||||||||||||
Db 421 KICPRNGLLYNAIYRNSKN 439
Regarding the claimed activity of GCH1 cleaving, or those recited in claims 21 and 24, said activity must necessarily be an inherent function of the Stenmark et al. polypeptide because as noted in MPEP 2112.01(I) and (II):
Where the claimed and prior art products are identical or substantially identical in
structure or composition, or are produced by identical or substantially identical
processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
AND
“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Because SEQ ID NO: 3 of Stenmark comprises at least two substitutions that are identical to the claimed substitution positions, then necessarily, the claimed function must be present.
It is further noted regarding claim 16, the following sequences of Dong et al. also teach with the same substitutions as above are as follows (See Supplemental Content, filed ending in .rabpm for each sequence):
SEQ ID NO: 19 has 91.4% sequence identity to instant SEQ ID NO: 10 (Result #19)
SEQ ID NO: 3 has 95.8% sequence identity to instant SEQ ID NO: 11 (Result #21).
SEQ ID NO: 19 has 91.2% sequence identity to instant SEQ ID NO: 12 (Result #19).
SEQ ID NO: 19 has 91.1% sequence identity to instant SEQ ID NO: 13 (Result #19).
SEQ ID NO: 19 has 91.2% sequence identity to instant SEQ ID NO: 14 (Result #20).
SEQ ID NO: 19 has 91.5% sequence identity to instant SEQ ID NO: 15 (Result #19).
SEQ ID NO: 19 has 91.7% sequence identity to instant SEQ ID NO: 16 (Result #19).
SEQ ID NO: 19 has 90.6% sequence identity to instant SEQ ID NO: 17 (Result #19).
SEQ ID NO: 3 has 94.5% sequence identity to instant SEQ ID NO: 18 Result #22).
SEQ ID NO: 19 has 90.4% sequence identity to instant SEQ ID NO: 19 (Result #19).
SEQ ID NO: 3 has 94.3% sequence identity to instant SEQ ID NO: 20 (Result #22).
SEQ ID NO: 19 has 90.3% sequence identity to instant SEQ ID NO: 21 (Result #19).
SEQ ID NO: 3 has 94.7% sequence identity to instant SEQ ID NO: 22 (Result #22).
SEQ ID NO: 19 has 90.7% sequence identity to instant SEQ ID NO: 23 (Result #19).
Conclusion
Claims 1-2, 4-9, 16, 18, 21, 24, 29-30, 40, 43, 46, 52 and 68 are rejected.
Claim17 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 28 September 2026
