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 Group I and species which is BoNT fused to C2H2ZFPn (SEQ ID NO:1-4) in the reply filed on 5/1/26 is acknowledged.
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 contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located [0074], “X-C-X-C-X-H-X-H”, which falls under the rules wherein there are at least 4 specifically defined amino acids forming an unbranched sequence.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
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) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Information Disclosure Statement
The information disclosure statement filed 10/25/2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. Those non-English references have not been considered.
On the IDS filed 10/25/23, the CN document number (106069608) for Foreign Document #3 does not match the publication date. There is no translation, but the pictures of the document suggest that the document submitted was not the one that was intended.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show “red boxes” and “blue boxes” described in the Brief Description of Figure 15 (end of [0032]) in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: INTRAMUSCULAR COMPOSITIONS OF BOTULINUM NEUROTOXINS AND METHOD OF DELIVERY.
Disclosure
The disclosure is objected to because of the following informalities: In [0037], the second sentence should apparently be part of the first. In [0067[, line 4, “composing of” should be “composed of”. In [0085], line 1, “by of “ is incorrect. [0090], last sentence of p. 23, is missing a verb. In [0089], “sparsticity” appears twice but is not a recognized word in the context of neurological disorders. It appears “spasticity” may have been intended. In [0098], last sentence, “unable of self-cleavage” is incorrect. In [0137], end of line 5, it appears there should be a comma.
Appropriate correction is required. Applicant is encouraged to carefully review the specification for other grammatical errors.
The use of the term “Bac-to-Bac” in [0117], which is a trade name or a mark 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.
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.
Claim Objections
Claim 10 is objected to because of the following informalities: Claim 10 recites “sparsticity”, but this is not a recognized word in the context of the claim. It appears “spasticity” may have been intended. 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.
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 2 and 25 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 2 is indefinite because it recites “zinc finger peptide (ZFP, EKPYKCPECGKSFSASAALVAHQRTHTG, SEQ ID NO:1), TAT (GRKKRRQRRRPQ, SEQ ID NO:18), Pep-1 (KETWWETWWTEWSQPKKKRKV, SEQ ID NO:19),” however, it is unclear if the sequences in the parentheses are exemplary or limiting. That is, if the ZFP is SEQ ID NO:1, the TAT is SEQ ID NO:18 and the Pep-1 is SEQ ID NO:19, or if these are merely examples of each type of CPP. The prior art refers to multiple sequences of each type. For example, US 2005/0239705 A1, teaches three different TAT fragments in [0090], only one of which is comprised by the TAT of SEQ ID NO:18.
Claim 25 recites the limitation "The method… of claim 12,…" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 12 is drawn to a pharmaceutical formulation without mention of a method.
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.
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 1-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for wherein the botulinum toxin (BoNT) is naturally occurring, does not reasonably provide enablement for wherein the BoNT is other than one which is naturally occurring. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are drawn to a method of delivering a botulinum toxin (BoNT) to a mammal intramuscularly. The specification in [0068] defines “BoNT or a particular type or subtype thereof also encompasses their equivalent polynucleotides as well, such as those having certain level (e.g., at least 85%, 90%, 95%, 98%, or 99%) of sequence identity or modified with one or more amino acid residue addition, deletion or substitutions.” This provides no meaningful structural or functional limitation to a BoNT.
Paragraph [0104] discusses different constructs, however, they all have the heavy and/or light chain of BoNTA (see Fig. 1). While other BoNT serotypes are known ([0061]), the definition of BoNT comprises many more molecules than the known serotypes or the commercial BOTOX® ([0004]). In order for the skilled artisan to be able to use the BoNT-CPP fusion, it must function to alleviate a nerve-induced condition, such as those listed in claim 10. If it does not, the skilled artisan would not know how to use a method of intramuscular injection of the fusion protein. That is, there would be no point to it. The wide structural breadth of BoNT molecules that include non-naturally occurring variants has not been shown to be associated with any particular function such that the skilled artisan would know how to use a representative number of fusions of the genus without undue experimentation in view of the unpredictability of changing amino acids within and/or adding to or deleting amino acids from a known BoNT. The specification does not provide direction or guidance to make a representative number of BoNT for the genus that would reasonably be expected to have a practical applicability. The only species used was BoNTA (e.g., [0104]).
Pirazzini et al. (Pharmacol. Rev. 69:200-235, Apr. 2017) discusses that there are 7 recognized serotypes of BoNT and that there are subtypes within the serotypes and these are all naturally occurring proteins (p. 201, col. 2, last paragraph, and p. 219, col. 1 first full paragraph). However, Pirazzini et al. states (p. 202, col. 1, last paragraph), “The limited data available on the biologic properties of the novel BoNTs indicate that even minor differences in the amino acid sequence can significantly change their activity and toxicity (Wang et al., 2013; Whitemarsh et al., 2013; Kull et al., 2015).” Further (p. 205, col. 1, first paragraph):
The known BoNTs bind with high affinity to the presynaptic plasma membrane of skeletal and autonomic cholinergic nerve terminals in numbers estimated to be, for BoNT/A1 or /B1, in the order of hundreds of molecules per square micrometers at the rat neuromuscular junction (NMJ) (Dolly et al., 1984). This restricted tropism is extraordinary, particularly considering that the presynaptic plasma membrane of cholinergic peripheral nerve terminals represents an infinitesimal part of the total surface area of cells and tissues exposed to body fluids. Such neurospecificity and affinity of binding, together with their catalytic activity, is at the basis of the BoNTs toxicity and, at the same time, of their pharmacological and therapeutic use.
Also, there is high sequence similarity between different human, rat and mouse BoNTs (Tables 1-3), showing sequence conservation. An important property of BoNTs is that they are not cytotoxic and do not cause axonal damage, which makes them suitable therapeutics (p. 215, col. 1, first full paragraph). Pirazzini et al. notes (p. 217, col. 1, first full paragraph), “BoNTs are very particular therapeutics endowed with unique properties among pharmaceutical drugs. They are “natural products”, purified from living
bacteria of the genus Clostridium, but they are also “biopharmaceuticals”, i.e., exogenous proteins with a well-defined biologic activity.” The Abstract begins, “The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown.”
Therefore, based on the minimal teachings of variants of BoNT in the specification and prior art, all of which are naturally occurring, the lack of guidance and direction in the specification about how these naturally occurring BoNT could be altered while retaining their particular critical activities, the unpredictability about what effect amino acid changes of BoNT would have on function, the complex function of the toxin dictated by its binding to cholinergic nerve terminals, and the presence of unknown properties of BoNT as discussed by Pirazzini et al., it would require undue experimentation to use the invention commensurate in scope with the claims.
Claims 1-11 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 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 claims are drawn to a method of delivering a botulinum toxin (BoNT) to a mammal intramuscularly. The specification in [0068] defines “BoNT or a particular type or subtype thereof also encompasses their equivalent polynucleotides as well, such as those having certain level (c.g., at least 85%, 90%, 95%, 98%, or 99%) of sequence identity or modified with one or more amino acid residue addition, deletion or substitutions.” The specification, however, is limited to fusion proteins comprising the heavy and/or light chain of BoNTA ([0104] and Fig. 1). While other BoNT serotypes are known ([0061]), the definition of BoNT comprises many more molecules than the known serotypes or the commercial BOTOX® ([0004]).
The specification discloses naturally occurring BoNT as they relate to the different known serotypes, in particular BoNTA. These BoNT meet the written description provision of 35 USC 112(a). However, the claims are directed to or encompass sequences that have some sequence identity to a known BoNT or have modified amino acid sequences, wherein the modifications are without limit. None of these sequences meets the written description provision of 35 USC 112(a).
Pirazzini et al. (Pharmacol. Rev. 69:200-235, Apr. 2017) discusses that there are 7 recognized serotypes of BoNT and that there are subtypes within the serotypes and these are all naturally occurring proteins (p. 201, col. 2, last paragraph, and p. 219, col. 1 first full paragraph). However, it is cautioned that (p. 202, col. 1, last paragraph), “The limited data available on the biologic properties of the novel BoNTs indicate that even minor differences in the amino acid sequence can significantly change their activity and toxicity….”
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the naturally occurring BoNT serotypes, the skilled artisan cannot envision the detailed chemical structure of the encompassed BoNTs, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only wherein the BoNT is naturally occurring, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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.
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.
Claim(s) 1-5, 7-10 and 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/015673 A1 (WO ‘673, cited in the IDS filed 10/26/2023).
WO ‘673 teaches in Example 6 ([0155]-[0159]) the intramuscular injection of a fusion protein comprising cell penetrating peptide (CPP), ZPF, fused to botulinum toxin A (BoNTA-ZPF; Protein ID 6). Figure 1 shows the IDs of the different BoNTA constructs. The ZFP is C2H2ZPF of SEQ ID NO:1 (Table 3, [0077]), which is identical to instant SEQ ID NO:1. Construct ID 1 used in Example 6 comprises both a BoNTA light chain (LC) and heavy chain (HC) with three ZFP peptides at the N-terminus of the light chain and three at the C-terminus of the HC (see also claim 16). Claim 27 is drawn to administering a BoNT LC to a mammal comprising intramuscularly applying a formulation comprising a chimeric polypeptide, including that of construct ID 6 (claim 16). This construct has the sequence of SEQ ID NO:15. Further, the construct was produced in insect cells, specifically in Spodoptera frugiperda Sf9 insect cells (Example 5, [0150]-[0152]). Claim 33 specifies the mammal is in need of treatment of conditions including dystonias, sparsticity, and hemifacial spasms. Note that intramuscular injection is necessarily “under a skin” (see instant claim 9).
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.
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, 7-11 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/015673 A1 (WO’673) as applied to claims 1-5, 7-9 and 25 above, and further in view of SELF (https://www.self.com/story/does-your-face-need-workout. SELF Magazine, 22 Sept. 2015).
WO ‘673 teaches in Example 6 ([0155]-[0159]) the intramuscular injection of a fusion protein comprising cell penetrating peptide (CPP), ZPF, fused to botulinum toxin A (BoNTA-ZPF; Protein ID 6). Figure 1 shows the IDs of the different BoNTA constructs. The ZFP is C2H2ZPF of SEQ ID NO:1 (Table 3, [0077]), which is identical to instant SEQ ID NO:1. Construct ID 1 used in Example 6 comprises both a BoNTA light chain (LC) and heavy chain (HC) with three ZFP peptides at the N-terminus of the light chain and three at the C-terminus of the HC (see also claim 16). Claim 27 is drawn to administering a BoNT LC to a mammal comprising intramuscularly applying a formulation comprising a chimeric polypeptide, including that of construct ID 6 (claim 16). This construct has the sequence of SEQ ID NO:15. Further, the construct was produced in insect cells, specifically in Spodoptera frugiperda Sf9 insect cells (Example 5, [0150]-[0152]). Claim 33 specifies the mammal is in need of treatment of conditions including dystonias, sparsticity, and hemifacial spasms. Note that intramuscular injection is necessarily “under a skin” (see instant claim 9). Either topical or intramuscular administration of the chimeric BoNT polypeptide can be at a mucosal membrane of the eye, ear, nose, mouth, lip, urethral opening, anus or tongue ([0105]). WO ‘673 does not teach wherein the mammal being administered the BoNT-CPP fusion is in need of muscle shaping.
SELF teaches that it is desirable to shape muscles, as suggested by the subtitle: There's a new way to shape up your complexion and it starts with targeting your facial muscles. The article goes on to discuss methods of doing so to look more attractive.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have intramuscularly administered the fusion protein of WO’673 to a person who desired to be more attractive, including anywhere that shaping their muscles would accomplish this, e.g., especially in their face (SELF). As most people desire to be more attractive, most mammals can be considered in need to muscle shaping. Alternatively, because a subject with dystonia has involuntary muscle contractions, which may result in the contracting muscles becoming large, this would have led to the subject being in need of muscle shaping.
Claim(s) 1, 3, 9-11 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0246266 (Lee) in view of FDA: Highlights of Prescribing Information for BOTOX® (https://www.accessdata.fda.gov/drugsatfda_
docs/label/2017/103000s5302lbl.pdf, 04/2017)
Lee teaches botulinum toxin conjugated to a cell penetrating peptide.
It is reported that ([0003]), “Botulinum toxin causes paralysis by blocking a signal inducing muscle convulsion or contraction, and due to this function, is used for medical treatment or cosmetic purposes, since approved by the FDA in 1989. For medical treatment, botulinum toxin is used as an injection for a medical purpose to treat a neuromuscular disorder such as strabismus, torticollis or blepharospasm, for a cosmetological purpose to reduce wrinkles, frown or glabellar lines and a square jaw, and for other purposes to treat hyperhidrosis or migraines” “Also, since muscle paralysis caused by such botulinum toxin is mostly induced by injections, a variety of research has been conducted to find a different, effective delivery means that can provide convenience to a user, which however is still inadequate.” ([0005]) The inventors found that adding a cell-penetrating peptide to a botulinum toxin can mediate intracellular delivery (e.g., [0016]). The botulinum toxin serotype may be A ([0023]). The conjugate may be used to treat facial spasms, eyelid spasms, torticollis, blepharospasm, cervical dystonia, oropharynx dystonia, spasmodic dysphonia, for example ([0036] and [0038]). The conjugate provides increased safety because, as explained in [0043], “[W]hile even several picograms (pg) of botulinum toxin type A expresses serious toxicity, the cell-penetrating botulinum toxin of the present invention is subjected to toxicity attenuation to express toxicity at a microgram (μg) level, and thus can guarantee sufficient safety from the toxicity of botulinum toxin.” The cell-penetrating protein (CPP) is TD1 of SEQ ID NO:1 : Lys Ala Met Ile Asn Ile Asn Lys Phe Leu Asn Gln Cys (claim 1). It may be fused to the N-terminus of the light chain ([0013]). Administration may be "local”, i.e., direct administration onto a site or near the location of the body needing treating, and be used to treat diseases including cervical dystonia, pharynx central muscle tension dyskinesia, face and eyelid convulsions ([116]-[117]). Lee does not teach intramuscular injection and does not directly teach wherein the mammal being administered the fusion protein is in need of muscle shaping.
FDA: Highlights of Prescribing Information for BOTOX® states it has been approved by the FDA (initial approval 1989) for treatment of overactive bladder, cervical dystonia, migraines, blepharospasm and strabismus (p. 1, Indications and Usage). Administration is intramuscular (p. 1, Dosage and Administration).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have administered the botulin toxin (BoNT)-TD1 fusion protein for treatment of, for example, cervical dystonia or blepharospasm, by intramuscular injection in view of the approval by the FDA for intramuscular BT injection for treatment for a variety of muscle misfunction conditions. The skilled artisan would have been motivated to use the BoNT-TD1 fusion of Lee because there would have been a reasonable expectation of increased safety compared to administration of BT alone. Further, because a subject with cervical dystonia has involuntary neck muscle contractions, the neck muscles may become in large, leading to the subject being in need of muscle shaping.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Read et al., (Res. Devel. Disabil. 68:35041, 2017), teaches intramuscular injection of botulinum toxin-A (Botox®) to children with bilateral spastic cerebral palsy (BCP) to reduce spasticity (p. 36, first paragraph, and p. 37, 4th paragraph). It is reported (p. 36, third paragraph):
Intramuscular BoNT-A injections temporarily reduce muscle activity by preventing the release of acetylcholine at the neuro muscular junction, resulting in reduced spasticity and muscle tone in children with CP [cerebral palsy] (Brin, 1997). The pharmacological effects of BoNT-A commence 2–4 days following injection, with the expected peak effect at 3 weeks (Boyd et al., 2000). The neuromuscular blockade lasts 2–4 months (de Paiva, Meunier, Molgo, Aoki,&Dolly, 1999), depending on the severity of spasticity, patient antibody resistance and dosage of BoNT-A administered (Boyd et al., 1999; Yap, Majnemer, Benaroch,&Cantin, 2010). A systematic review reported significant improvements in dynamic equinus gait on the Physician’s Rating Scale (PRS), characterised by improved heel strike and maximum ankle dorsiflexion in stance and swing following a single injection episode of intramuscular BoNT-A injections (Boyd&Hays, 2001).
Read is cited to show that even 20 years prior to the effective filing date of the instant invention, BoNT was being injected intramuscularly for therapeutic purposes, including for spasticity.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice .
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
August 3, 2026
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