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 .
DETAILED ACTION
Applicant’s amendment filed on 24 September 2025 is entered.
Claims 176-196 are pending. Claims 194-195 remain withdrawn. Claims 176-193 and 196 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 September 2025 is being considered by the examiner.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 176-179, 182-193, and 196 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 claims contain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP §2163.
Claim 176 recites a chimeric Clostdridial Botulinum neurotoxin (BoNT) polypeptide comprising, from N-terminus to C-terminus: (a) a protease domain; (b) a linker region; (c) a translocation domain; and (d) a receptor binding domain, wherein (a) and (c) are from BoNT serotype X, and wherein (d) is not from BoNT serotype X.”
Claim 179 limits the receptor binding domain to be from a serotype selected from the group consisting of: A, B, C, and D. Claim 196 limits the receptor binding domain to be from a serotype selected from the group consisting of: E, F, and G. Dependent claims 177-178 and 182-193 do not further limit the receptor binding domain to be from a specific serotype from the BoNT serotypes A-G, and none of the dependent claims limit the receptor binding domain to a specific subtype within the BoNT serotypes A-G, and so dependent claims 177-178 and 182-193 share the same written description issues of their parent claims as discussed below.
The broadest reasonable interpretation of the chimeric BoNT polypeptide of claim 176 includes any chimeric BoNT polypeptide that has receptor binding domain that is not from BoNT serotype X.
At the present moment, 7 other serotypes are known as BoNT serotypes A-G (Specification pg. 1 ln 14), and the chimeric BoNT polypeptide of claim 176 can have a receptor binding domain from any BoNT serotypes A-G. In addition to this, each of the BoNT serotypes A-G encompass many different subtypes (specification pg. 13-15). Thus, the broadest reasonable interpretation of the chimeric BoNT polypeptide of claim 176 includes chimeric BoNTs comprising any receptor binding domain from BoNT serotypes A-G and any of the subtypes within the BoNT serotypes A-G (specification pg. 13-15). This means that the genus of chimeric BoNT polypeptides recited in claim 176 is extremely large.
Although claims 179 and 196 limit the receptor binding domains to be from serotypes A, B, C, or D, or from serotypes E, F, and G, respectively, neither claim limits the subtypes of the serotypes. Thus, the broadest reasonable interpretation of the chimeric BoNT polypeptide of claim 179 includes a chimeric BoNT comprising a receptor binding domain from any of the subtypes within the BoNT serotypes A-D (specification pg. 13-15). Likewise, the broadest reasonable interpretation of the chimeric BoNT polypeptide of claim 196 includes a chimeric BoNT comprising a receptor binding domain from any of the subtypes within the BoNT serotypes E-G (specification pg. 13-15). The genus of chimeric BoNT polypeptides recited in claims 179 and 196 is also large.
The instant specification provides some broad suggestions in combining different BoNT receptor binding domains to the BoNT serotype X protease and translocation domains (specification pg. 28 lns. 6-20), and discloses additional specific embodiments that use the receptor binding domains of BoNT serotypes A1, B1, and C1, which are provided in SEQ ID Nos: 22-24, respectively (specification pg. 28 lns. 21-22). Of these sequences, only SEQ ID NO: 22 is reduced to practice and characterization within the instant disclosure (specification pg. 15-16 bridging para. and Fig. 8). However, the disclosure fails to adequately describe any other chimeric BoNTs with receptor binding domains from other BoNT serotypes A-G and their subtypes such that one of ordinary skill in the art would not be able to determine whether Applicant had possession of the entire genus of claimed invention at the time of filing.
The prior art recognized several challenges concerning fusion of proteins to each other. Yu et al. (Synthetic fusion protein design and applications, Biotechnology Advances 33 (2015) 155–164) teaches that the simplest form of fusion is tandem fusion, which involves joining together the coding genes of the proteins to be fused and expressing those joined genes as a single peptide chain in a suitable host organism (Yu pg. 156 sec. Tandem Fusion para. 1 sentence 5). Yu also teaches that the order of fusion partners in a polypeptide chain is often critical (Yu pg. 156 sec. Tandem Fusion para. 1 sentence 3). However, Yu teaches that this strategy fails when the free N- or C-terminus to be tethered is essential to the one of the protein’s function and/or is not flexible or long enough to avoid steric hindrance, which may give rise to undesirable outcomes such as protein misfolding, aggregation leading to inclusion body formation, low yield in protein production, and impaired bioactivity (Yu pg. 156 sec. Tandem Fusion para. 1 sentence 7). To remediate this, linker sequences, which serve to maintain necessary distance to reduce steric hinderance and/or permit favorable domain-domain interaction, are often used to link the two proteins together (Yu pg. 156 sec. Tandem Fusion para. 1 sentence 6 through para. 2 sentence 1). However, Yu then teaches that the selection of a linker is mostly ad hoc and still remains an underexplored area in fusion protein engineering, and admits that it is hard to assume that a linker suitable for one case will be applicable to others, as each type of linker has its specific characteristics (Yu pg. 156 sec. Tandem Fusion para. 3 sentences 3-4). Yu continues to another fusion technique called domain insertion, where functional fusion proteins can be reconstituted by inserting one domain into a host protein to achieve their chimerization (Yu pg. 157 sec. Domain Insertion para. 1 sentence 3). This approach appears to be the most applicable to the instant invention’s chimerization process described in the specification. However, Yu teaches that domain insertion is more difficult to design than tandem fusion since it is mandatory to find a “cut” site on the host protein to take the insert, which could disrupt domain folding if inappropriately selected, but generally surface loops or turns that are not in the catalytic sites are selected as insertion points (Yu pg. 157 sec. Domain Insertion para. 2 sentences 1-2). However, in most cases additional efforts are required to identify optimal insertion sites by directed evolution approaches (Yu pg. 157 sec. Domain Insertion para. 2 sentence 3). The combination of Yu’s teachings indicate that there are many challenges when fusing proteins or functional domains together to form a chimeric protein, and that these challenges can lead to unpredictable results, such as protein misfolding, aggregation leading to inclusion body formation, low yield in protein production, and impaired bioactivity. In light of these known challenges and the lack of adequate written description in the disclosure, one of ordinary skill in the art would find it unpredictable to successfully fuse any given receptor binding domain from serotypes A-G or their subtypes to the C-terminus of a translocation domain from BoNT serotype X.
In conclusion, the invention recited in instant claims 176-193 and 196 lacks sufficient written description to reasonably convey to one of skill in the art that Applicant had possession of the entire genus of claimed invention.
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 176-193 and 196 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.
Regarding claim 176, the limitation “wherein (a) and (c) are from BoNT serotype X, and wherein (d) is not from BoNT serotype X” is indefinite. It is unclear how many sequence differences or mutations can be tolerated to the point where the protease/translocation domains are considered to be “from” or “not from” BoNT serotype X, and likewise where a receptor binding domain is considered to be “not from” or “from” BoNT serotype X. In other words, it is unclear if only a polypeptide sequence that behaves in the same way as the domains in BoNT serotype X, but comprises some sequence differences/mutations, is considered to be “from” BoNT serotype X, or if there is one specific polypeptide sequence, without sequence differences/mutations, is considered to be “from” BoNT serotype X within the context of the claim. The lack of clarity leaves the claim indefinite. Claims 177-193 and 196 are dependent on claim 176, and so are indefinite for the same reasons.
Regarding claim 177, the claim term “modified” renders the claim indefinite because it is unclear what the metes and bounds of the term are. For example, it is unclear if the term “modified” is meant to mean just substitutions or mutations to the polypeptide sequence of the receptor binding domain, or if the term means a change in structure to the receptor binding domain, or if the term means the addition, fusion or conjugation of other components onto the receptor binding domain. It is also unclear to what degree the receptor binding domain can be modified. The lack of clarity leaves the claim indefinite. Claim 178 is dependent on claim 177, and so is indefinite for the same reasons.
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.
Claims 176-177, 179, 182-185, and 196 are rejected under 35 U.S.C. 103 as being unpatentable over Steward et al. (US 8052979 B2, published 08 November 2011) in view of Hosomi et al. (putative botulinum neurotoxin, GenBank Accession number BAQ12790.1, publicly available 21 February 2015), as evidenced by Zhang et al. (Identification and characterization of a novel botulinum neurotoxin, Nature Communications, 8:14130, DOI: 10.1038/ncomms14130, published 03 August 2017) and David et al. (The Receptor Binding Domain of Botulinum Neurotoxin Serotype A (BoNT/A) Inhibits BoNT/A and BoNT/E Intoxications In Vivo, Clinical and Vaccine Immunology, p. 1266–1273, August 2013, Volume 20, Number 8).
Regarding claims 176, 179 and 196, Steward teaches a modified Clostridial toxin comprising an enzymatic domain (protease domain), a translocation domain, a targeting domain that is a glucagon like hormone (hormone receptor binding domain), and a protease cleavage site (linker region), which is equivalent to instant claim 176 (a)-(d) (Steward claim 1), and that the amino-to-carboxyl polypeptide order of the domains is the enzymatic domain, the protease cleavage site, the translocation domain, and the targeting domain (Steward claim 2). The enzyme domain (protease domain) and the translocation domain are taught to be from any BoNT serotype A-G (Steward claims 8-9). Steward also teaches that the targeting domain (receptor binding domain) can be the natural sequences of BoNT A-G, which meets the limitations of instant claims 179 and 196 (Steward col. 122 lns. 42-55).
However, Steward does not teach that the enzymatic domain (protease domain) and the translocation domain are from BoNT serotype X.
Hosomi teaches the sequence of GenBank accession number BAQ12790.1 is the putative botulinum neurotoxin from the whole genome sequence of Clostridium botulinum strain 111, which was considered to be a serotype B strain at the time (Hosomi lns. 27-29). However, this sequence was later characterized and determined to be the new BoNT serotype X, as evidenced by Zhang (Pg. 2 sec. Results para. 1 sentence 3), but the sequences are from the same accession number, BAQ12790.1, and thus are equivalent to each other. Therefore, the polypeptide of BAQ12790.1 would have had an enzyme domain (protease domain) and a translocation domain from a sequence that is equivalent to a BoNT serotype X, which would meet the limitations of instant claim 176 (a) and (c).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to use the Clostridium botulinum strain 111 serotype B polypeptide of sequence of BAQ12790.1 as the basis for the modified Clostridial toxin of Steward, and to have modified the targeting (receptor binding) domain to one from a different BoNT serotype A-G. One of ordinary skill in the art would have been motivated to use the Clostridium botulinum strain 111 serotype B polypeptide of sequence of BAQ12790.1 as the basis for the modified Clostridial toxin of Steward because one of ordinary skill in the art at the time of the applied prior art would have considered BAQ12790.1 to be a BoNT serotype B, and thus would have understood that the polypeptide of BAQ12790.1 was applicable in the modified Clostridial toxin of Steward because Steward taught that the enzyme domain (protease domain) and the translocation domain can be from any BoNT serotype A-G (Steward claims 8-9). Furthermore, the very same polypeptide sequence BAQ12790.1 is now considered to be BoNT serotype X, as evidenced by Zhang (Pg. 2 sec. Results para. 1 sentence 3). Therefore, the polypeptide of BAQ12790.1 would have had an enzyme domain (protease domain) and a translocation domain from a sequence that is equivalent to a BoNT serotype X, which would meet the limitation “wherein (a) and (c) are from BoNT serotype X” of instant claim 176.
One of ordinary skill in the art would have been motivated to modify the targeting (receptor binding) domain of BAQ12790.1 described above to one from a different BoNT serotype A-G because changing the targeting domain of a BoNT would reduce undesirable dispersal of the toxin to areas not targeted for treatment, thereby reducing undesirable side effects associated with diffusion of a Clostridial toxin to an unwanted location (Steward col. 3 lns. 21-24 and 31-33). Thus, by modulating the targeting (receptor binding) domain, one of ordinary skill in the art would have been able to adapt the modified Clostridial toxin of Steward to target different receptor proteins because different serotypes bind to different receptors, as evidenced by David (Pg. 1272 para. 2 sentence 2).
Regarding claim 177, Steward teaches that the BoNT A-G targeting domain (receptor binding domain) can be modified (Steward col. 45 lns. 36-43).
Regarding claims 182, Steward teaches that artificial flexible spacers (or several in tandem) can be placed between the different domains which can be used to adjust the length of a polypeptide region in order better expose a protease cleavage site to facilitate cleavage of that site (Steward col. 133 lns. 9-16), and the flexible spacers can be adjacent to the protease cleavage site, thereby linking the two into one region (Steward col. 134 lns. 16-20).
Regarding claims 183-185, Steward teaches the exogenous protease cleavage site is a thrombin cleavage site (Steward claim 12), which is presented as SEQ ID NO: 94 of Steward (Steward table 9), which aligns 100% to SEQ ID NO: 50 of instant claim 185 (see Sequence Search Results dated 27 February 2025).
Response to Arguments
Applicant's arguments filed 24 September 2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that claim 176 has been amended to limit the claimed chimeric BoNTs to comprise from N-terminus to C-terminus, domains (a)-(d) thereby overcoming the 112a written description rejection of claims 176-19 and 182-193 (Remarks pg. pg. 7 sec. I), although the order that the domains of the chimeric BoNT polypeptide are fused together is now limited as Applicant asserts, the full genus of claimed receptor binding domains is still not adequately described. The broadest reasonable interpretation of the chimeric BoNT polypeptide of claim 176 includes any chimeric BoNT polypeptide that has receptor binding domain that is not from BoNT serotype X. At the present moment, 7 other serotypes are known as BoNT serotypes A-G (Specification pg. 1 ln 14), and the chimeric BoNT polypeptide of claim 176 can have a receptor binding domain from any BoNT serotypes A-G. In addition to this, each of the BoNT serotypes A-G encompass many different subtypes (specification pg. 13-15). Thus, the broadest reasonable interpretation of the chimeric BoNT polypeptide of claim 176 includes chimeric BoNTs comprising any receptor binding domain from BoNT serotypes A-G and any of the subtypes within the BoNT serotypes A-G (specification pg. 13-15). This means that the genus of chimeric BoNT polypeptides recited in claim 176 is extremely large. The instant specification provides some broad suggestions in combining different BoNT receptor binding domains to the BoNT serotype X protease and translocation domains (specification pg. 28 lns. 6-20), and discloses additional specific embodiments that use the receptor binding domains of BoNT serotypes A1, B1, and C1, which are provided in SEQ ID Nos: 22-24, respectively (specification pg. 28 lns. 21-22). Of these sequences, only SEQ ID NO: 22 is reduced to practice and characterization within the instant disclosure (specification pg. 15-16 bridging para. and Fig. 8). However, the disclosure fails to adequately describe any other chimeric BoNTs with receptor binding domains of other BoNT serotypes A-G and their subtypes such that one of ordinary skill in the art would not be able to determine whether Applicant had possession of the entire genus of claimed invention at the time of filing.
Regarding Applicant’s arguments that a skilled person would be able to determine whether a polypeptide is or is not from BoNT/X in view of the specification’s disclosure that BoNT/X comprises the same general domain arrangement of other BoNTs, but has the least protein sequence identity (<31%) to any other BoNTs among pairwise comparisons within the BoNT family (Remarks pg. 8 sec. II para. 3), broadly describing the general sequence identity differences between BoNT/X and other BoNT serotypes is insufficient to clearly indicate whether any given protease, translocation, and/or receptor binding domain are or are not from BoNT serotype X. Notably, claim 176 does not limit the protease, translocation, and/or receptor binding domains to be derived from BoNTs. These domains can be any protease, translocation, and/or receptor binding domains that are available to one of ordinary skill in the art. However, it is unclear how one of ordinary skill in the art can determine if their given protease, translocation, and/or receptor binding domains would be classified as being “from” or “not from” BoNT serotype X. Claim 176 also does not limit the protease, translocation, and/or receptor binding domains to be of any specific sequence identity to those domains in BoNT/X or to any other BoNT serotype.
Regarding Applicant’s arguments that the specification discloses that a modified Clostridial Botulinum neurotoxin (BoNT) encompasses a BoNT comprising any modifications in the amino acid sequence, such as truncation, addition, substitutions, etc., thus one of ordinary skill in the art would understand the metes and bounds of the term “modified” as it relates to an amino acid sequence (Remarks pg. 8 sec. II para. 4), the section of the specification Applicant cites (cited as [107] in PG Pub. US20220177867A1, corresponding to pg. 21 lns. 15-22 of specification filed 9/24/2025) is not a special definition that limits the claim term “modified”. It is still unclear what the metes and bounds of the term “modified” are, and to what degree the receptor binding domain can be modified. For example, if a “modified” receptor domain may comprise any modification of the amino acid sequence as Applicant asserts, this means that in one embodiment the modified domain may comprise a sequence that is completely different from the base receptor domain sequence it modified, making the term “modified receptor binding domain” so broad as to encompass modified domains which do not possess any binding abilities after modification, or in another embodiment the receptor domain may be fused or conjugated to any polypeptide components or domains in existence, which could dramatically change the sequence, structure, and function of the receptor binding domain. One of ordinary skill in the art would not be able to determine whether or not the modification to the receptor binding domain would still require the receptor binding domain to function as the original sequence did, or to what degree the modification may be made to the receptor binding domain so as to be considered a “modified” receptor binding domain rather than a completely different domain altogether, or if a domain with any given amino acid sequence that is not exactly the same as the receptor binding domain sequence of claim 176 is considered to be modified.
Regarding Applicant’s arguments that cited reference Zhang does not qualify as prior art because it was published after the effective filing date (Remarks pg. 9 last para.), MPEP §2124 states “In certain circumstances, references cited to show a universal fact need not be available as prior art before the effective filing date of applicant’s claimed invention. In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962). Such facts include the characteristics and properties of a material or a scientific truism. Some specific examples in which later publications showing factual evidence can be cited include situations where the facts shown in the reference are evidence.” Zhang is used in the 103 rejection as an evidentiary reference providing evidence that Hosomi’s sequence BAQ12790.1 is actually characterized as being BoNT serotype X, not serotype B as Hosomi had originally suggested. Since Zhang is used to describe characteristics of the BoNT polypeptide it does not need to antedate the effective filing date.
Regarding Applicant’s arguments that one of ordinary skill in the art would recognize that a BoNT that is not involved in the pathogenicity of C. botulinum would not have an enzymatic and/or a translocation domain, so one of ordinary skill in the art would not have had reason to modify Steward’s chimeric BoNT with Hosomi’s because such a modification would render the chimeric BoNT inactive (Remarks pg. pg. 10 para. 2), Hosomi’s BAQ12790.1 clearly indicates that the sequence comprises an enzymatic domain “Peptidase_M27” at amino acids 5-404, and a translocation domain “Toxin_trans” at amino acids 559-871 (Hosomi lns. 40-48). Therefore, one of ordinary skill in the art would recognize that Hosomi’s BoNT would have enzymatic and translocation domains. Thus, one of ordinary skill in the art would understand that modifiying Steward’s chimeric BoNT with Hosomi’s would not render the resultant modified chimeric BoNT inactive.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander M Duryee whose telephone number is (571)272-9377. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/Alexander M Duryee/Examiner, Art Unit 1657 /LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657