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 .
Please note that the instant application has been transferred to examiner Ganapathirama Raghu (571-272-4533), Art Unit: 1652, and all future correspondence regarding this application must be addressed to said examiner.
Application Status
In response to Non-Final Office Action mailed on 05/19/2025, applicants' response, arguments and amendments filed on dated 11/18/2025 is acknowledged; in said response applicants’ have amended claims 2-3, 7, 13, 16-17, 19, 22 and 25, canceled claims 18 and 20-21 and added new claims 30-41. Thus, amended claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are pending in this application and is now under consideration for examination. Rejections and/or objections not reiterated from previous office action are hereby withdrawn.
Information disclosure statement
The information disclosure statements (IDS) submitted on 11/18/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statement is considered and initialed by the examiner.
Withdrawn-Claim Rejections-35 USC § 112(b)
Previous rejection of claims 3, 7, 13, 16-19, and 25 rejected under 35 U.S.C. 112(b), is being withdrawn due to claim amendments.
Withdrawn-Claim Rejections: 35 USC § 102
Previous rejection of claims 2-3, 7, and 19-22 rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Hunt (US 2008/0113051 A1; Published: 05/15/2008; Effectively Filed: 11/13/2006), is being withdrawn due to claim amendments.
New-Claim Rejections: 35 U.S.C. 112(d)
Necessitated by claim amendments
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 38-41 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 38-41 recites “…method of claim 2, wherein the clostridial neurotoxin comprises a L domain from a BoNT/A, a HN domain from a BoNT/A, and a Hc domain from a BoNT/B (as in claim 37); method of claim 38, wherein the clostridial neurotoxin comprises a Hc domain corresponding to amino acid residues 860-1291 of SEQ ID NO: 2 (as in claim 39) and method of claim 39, wherein the Hc domain comprises an amino acid substitution selected from the group consisting of: V1118M; Y1183M; E1191M; E1191I; E1191Q; E1191T; S1199Y; S1199F; S1199L; S1201V; E1191C; E1191V, E1191L; E1191Y; S1199W; S1199E; S1199H; W1178Y; W1178Q; W1178A; W1178S; Y1183C; and Y1183P…and S1199W; E1191V and S1199Y; and E1191V and W1178Q (as in claims 40-41); ” and depends from independent claim 2; said independent claim 2 recites “… wherein the clostridial neurotoxin comprises a botulinum neurotoxin A (BoNT/A); examiner takes the position that independent claim 2 is limited to clostridial botulinum neurotoxin A (BoNT/A) and new dependent claims 38-41 reads on chimeric clostridial botulinum neurotoxins and not limited to clostridial botulinum neurotoxin A (BoNT/A). Therefore, new dependent claims 38-41 that depend from independent claim 2 and does not further limit the scope of independent claim 2. Dependent claims 38-41 broadens the scope of independent claim 2.
Applicants may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The U.S. Court of Appeals for the Federal Circuit indicated that although the requirements of pre-AIA 35 U.S.C. 112, 4th paragraph, are related to matters of form, non-compliance with pre-AIA 35 U.S.C. 112, 4th paragraph, renders the claim unpatentable just as non-compliance with other paragraphs of 35 U.S.C. 112 would. See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92, 79 USPQ2d 1583, 1589-90 (Fed. Cir. 2006) (holding a dependent claim in a patent invalid for failure to comply with pre-AIA 35 U.S.C. 112, 4th paragraph). Therefore, if a dependent claim does not comply with the requirements of 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, the dependent claim should be rejected under pre-AIA 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as unpatentable rather than objecting to the claim. See also MPEP § 608.01(n),subsection III, “Infringement Test” for dependent claims.
Maintained-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.
Maintained-Written Description
Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are directed in part to a method for treating post-operative surgical pain that requires (i) a genus of clostridial neurotoxins, (ii) a genus of botulinum neurotoxins, and (iii) a genus of botulinum neurotoxins serotype (see also Claim Rejections - 35 U.S.C. 112(d) above for claims interpretation).
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is no structural limitation with regard to the members of the genera of clostridial neurotoxins, botulinum neurotoxins, and botulinum neurotoxins serotype A required by the claims. There is no disclosure of the structural features required in any clostridial neurotoxin, botulinum neurotoxin, or botulinum neurotoxin serotype A such that the neurotoxin can treat post-operative surgical pain.
The total number of clostridial neurotoxins, botulinum neurotoxins, and botulinum neurotoxins serotype A required by the claimed method are immeasurable given that there are currently no structural limitations. A sufficient written description of a genus of proteins may be achieved by a recitation of representative numbers of proteins defined by their amino acid sequence, or a recitation of structural features common to members of each genus, which features constitute a substantial portion of each genus. However, in the instant case, there is no recited structural feature, and there is no information as to which are the structural elements that are essential for the treatment of post-operative surgical pain, which are the remaining structural elements required in the recited genera in addition to those recited in the claims such that the desired treatment of post-operative surgical pain is displayed, or a correlation between structure and function which would provide those unknown structural features.
Due to the fact that the specification only discloses a few methods for treating post-operative surgical pain utilizing a singular species (i.e., AbobotulinumtoxinA) of the multiple genera of proteins required by the claims, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Applicants have traversed the above written-description with the following arguments: (see pages 12-13 of Applicants’ REMARKS dated 11/18/2025).
Applicants argue: “…Applicant traverses in view of the present claim amendments. Applicant respectfully notes that amended claims 2 and 19, recite, among other things, "wherein the clostridial neurotoxin comprises a botulinum neurotoxin A (BoNT/A)." Clostridial neurotoxins comprise structural domains as described in the specification for various exemplary neurotoxins, including an "Hc domain" and an "LHN domain" that have clearly described functions. See Table 1. As described in the specification, the Hc domain enables binding of the neurotoxin to a receptor located on the surface of a target cell and comprises two structurally distinct subdomains, the "HCN subdomain" (N-terminal) and the "Hcc subdomain" (C-terminal). The Hcc domain of any clostridial neurotoxin functions in binding to its protein receptor. Likewise, the "LHN domain" of any clostridial neurotoxin consists of an endopeptidase domain ("L" or "light chain") responsible for translocation of the endopeptidase into the cytoplasm (HN domain of the heavy chain) and is capable of cleaving a SNARE protein. The present invention relates to administering a clostridial neurotoxin comprising a BoNT/A for treating post-surgical pain. Applicant is clearly in possession of the genus of clostridial neurotoxins comprising a BoNT/A for treating post- surgical pain as evidenced throughout the application and in the examples. For example, following administration of a clostridial neurotoxin at or proximal to a site of surgical intervention, the inventors observed SNARE protein cleavage (e.g. SNAP-25 protein cleavage) at the spinal cord (and minimal or no SNARE protein cleavage at or proximal to the site of surgical intervention), suggesting that the clostridial neurotoxin travels by retrograde transport from its site of administration to the spinal cord. This allows a clostridial neurotoxin to be administered at a site away from a(ny) site of injury (e.g., the site of surgical intervention) that may cause discomfort to a patient and thus minimize any further pain perceived by the patient.”
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 05/19/2025) and additionally for the following reasons. Contrary to applicants’ argument, claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 do not recite any specific structure, and reads on undefined and unlimited structures including variants, mutants, chimeric constructs and homologs and only partial structures corresponding to domains are recited in new claims 37-41 and the remainder of the structure is not recited; furthermore, even among clostridial botulinum neurotoxin A; the art teaches there are many sub-types i.e., a genus of botulinum neurotoxins serotype A, Fonfria et al., (Toxins, 2018, Vol. 28, pages 1-27) discloses there are structural, biochemical and physiological differences in the activities of various sub-types of clostridial botulinum neurotoxin A; see last ¶, page 4, at least 5 sub-types of BonT/A; ¶ 4.4, page 13; Conclusions, page 17; and entire document. The disclosure of the specification is still insufficient to enable the claimed method comprising a genus of Clostridial neurotoxins to its full scope or evidence of possession (also see 35 U.S.C. 112(d) rejection above for claims interpretation). Therefore, the scope of the instant claims is broad despite the guidance of the art and specification, the claims remain not commensurate with evidence of possession or in scope with the enabled invention. Examiner continues to maintain that specification only discloses a few methods for treating post-operative surgical pain utilizing a singular species (i.e., AbobotulinumtoxinA) of the multiple genera of proteins required by the claims.
There are no examples provided to encompass the numerous characteristics of the whole genus claimed by the method. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals applicants’ hope the claimed invention achieves and the problems the invention will hopefully ameliorate”). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of structures with the associated function in the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention in the claimed method.
MPEP 2163.II.A.2. (a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”;
Examiner would like to reiterate
“The basic quid pro quo contemplated by the Constitution and the Congress for granting a patent monopoly is the benefit derived by the public from an invention with substantial utility”, [u]nless and until a process is refined and developed to this point-where specific benefit exists in currently available form-there is insufficient justification for permitting an applicant to engross what may prove to be a broad field”, and “a patent is not a hunting license”,[i]t is not a reward for the search, but compensation for its successful conclusion.”
Maintained-Enablement
Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 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 a method for treating post-operative surgical pain in a patient, said method comprising administering to a patient AbobotulinumtoxinA, does not reasonably provide enablement for a method for treating post-operative surgical pain in a patient, said method comprising administering to a patient any clostridial neurotoxin, botulinum neurotoxin, or botulinum neurotoxin serotype A. 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.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are directed in part to a method for treating post-operative surgical pain that requires (i) a genus of clostridial neurotoxins, (ii) a genus of botulinum neurotoxins, and (iii) a genus of botulinum neurotoxins serotype A (see also Claim Rejections - 35 U.S.C. 112(d) above for claims interpretation).
The enablement provided is not commensurate in scope with the claims due to the lack of information regarding the structural elements required in any clostridial neurotoxin, botulinum neurotoxin, or botulinum neurotoxin serotype A such that the neurotoxin is capable of treating post-operative surgical pain. In the instant case, the specification enables a method for treating post-operative surgical pain in a patient, said method comprising administering to a patient AbobotulinumtoxinA.
The amount of direction or guidance presented and the existence of working examples. The specification discloses a few methods for treating post-operative surgical pain in a patient, said methods comprising administering to a patient AbobotulinumtoxinA, as working examples.
However, the specification fails to provide any clue as to the structural elements required in any clostridial neurotoxin, botulinum neurotoxin, or botulinum neurotoxin serotype A such that the neurotoxin is capable of treating post-operative surgical pain. No correlation between structure and function has been presented.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of clostridial neurotoxins, botulinum neurotoxins, or botulinum neurotoxins serotype A, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any clostridial neurotoxin, botulinum neurotoxin, or botulinum neurotoxin serotype A such that the neurotoxin is capable of treating post-operative surgical pain.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of isolating and purifying neurotoxins, formulating purified neurotoxins into an intradermal injection, and animal models for testing and assessing post-operative surgical pain were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of clostridial neurotoxins, botulinum neurotoxins, or botulinum neurotoxins serotype A to find those neurotoxins that are capable of treating post-operative surgical pain. In the absence of (i) a rational and predictable scheme for selecting those neurotoxins most likely to have the desired functional features, and/or (ii) a correlation between structure and function, one of skill in the art would have to test an essentially infinite number of neurotoxins to determine which ones have the desired functional characteristics.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Applicants have traversed the above enablement with the following arguments: (see pages 13-14 of Applicants’ REMARKS dated 11/18/2025).
Applicants argue: “…Applicant's invention relates to pre-operative administration of the botulinum neurotoxin in effecting a fast analgesic effect and suppressing post-operative pain. See Examples 2 and 5. Example 3 showed that intradermal administration of Dysport showed a more rapid analgesic effect than other routes tested. Cleavage of SNAP-25, a SNARE protein occurred in the spinal cord distal to the site of Dysport injection. Examples 4 and 6. The specification clearly described that the mode of action of clostridial neurotoxins relies on five distinct steps: (1) binding of the Hc domain to the cell membrane of its target neuron, followed by (2) internalization of the bound toxin into the cell via an endosome, (3) translocation of the L-chain by the HN domain across the endosomal membrane and into the cytosol, (4) proteolytic cleavage of intracellular transport proteins known as SNARE proteins by the L-chain which provides a non-cytotoxic protease function, and (5) inhibition of cellular secretion from the target cell. Specification at [0106]. Contrary to the assertions of the Office, the structural domain responsible for SNARE protein cleavage at a distal site is clearly described; SNARE protein cleavage blocked neurotransmitter and/or neuropeptide release, providing pain relief at distal sites from the site of surgical intervention. Specification at [0061]-[0063.”
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 05/19/2025) and additionally for the following reasons. Applicants’ arguments filed on 11/18/2025 for the traversal of enablement rejection are on similar lines to the arguments presented for traversing the written-description, said arguments have been fully considered but they are not persuasive. Examiner continues to maintain the rejection for reasons stated on record, supporting evidence and arguments presented above in maintaining the written-description rejection also applies to enablement rejection.
For the above cited reasons, examiner is maintaining the written-description and enablement rejection for claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41.
New-Claim Rejections: 35 USC § 103
Necessitated by claim amendments
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
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(a) 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 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hunt TJ., (US 2008/0113051 A1; Published: 05/15/2008; Effectively Filed: 11/13/2006) and further in view of Bresnahan R., (Ph.D., Thesis, Univ. of Sheffield, UK, 2018, pages 1-211), Fonfria et al., (Toxins, 2018, Vol. 28, pages 1-27), Meyer-Frießem et al., (Curr. Med. Res. Opinion., 2019, Vol. 35(10): 1793-1803) and Dong et al., (US 11,104,891 B2; priority 06/08/2017).
Regarding claims 2-3, 7, 16-17, 19, 22 and 30-36, Hunt TJ., (US 2008/0113051 A1; Published: 05/15/2008; Effectively Filed: 11/13/2006) disclose a method for alleviating pain associated with a placement or removal of a tattoo comprising the steps of administering botulinum toxin intradermally about 1-4 weeks prior to a tattoo placement or removal, wherein the botulinum toxin used can be selected from botulinum toxin types A, B, C1, D, E, F and G (¶ [0076]-[0077], Claims 1 and 6-10). Hunt TJ., also teaches that alleviating pain is defined as a reduction in pain greater than 50% via the patient reporting the degree of pain after the neurotoxin treatment as compared to the degree of pain prior to the treatment (¶ [0085]). Hunt also teaches that the method can be used to substantially alleviate pain for between 1 month (acute pain) and 27 months (chronic pain) (¶ [0086]); the dose of a neurotoxin administered is equivalent to about 1 unit to about 500 units of a botulinum toxin type A (¶ [0092]). Hunt TJ., discloses the use of botulinum toxin type A during surgical procedures and selection of optimal dose botulinum toxin type A for relieving or mitigation pain (¶ [0090-0092]); relevant paragraphs reproduced below:
[0059] In addition to having pharmacologic actions at the peripheral location, botulinum toxins can also have inhibitory effects in the central nervous system. Work by Weigand et al, (.sup.125I-labelled botulinum A Clostridial toxin:pharmacokinetics in cats after intramuscular injection, Naunyn-Schmiedeberg's Arch. Pharmacol. 1976; 292, 161-165), and Habermann, (.sup.125I-labelled Clostridial toxin from clostridium botulinum A: preparation, binding to synaptosomes and ascent to the spinal cord, Naunyn-Schmiedeberg's Arch. Pharmacol. 1974; 281, 47-56) showed that botulinum toxin is able to ascend to the spinal area by retrograde transport. As such, a botulinum toxin injected at a peripheral location, for example intramuscularly, may be retrograde transported to the spinal cord.
[0082] Further, the botulinum toxin of the present invention may comprise a first element comprising a binding element able to specifically bind to a neuronal cell surface receptor under physiological conditions; a second element comprising a translocation element able to facilitate the transfer of a polypeptide across a neuronal cell membrane, and a third element comprising a therapeutic element able, when present in the cytoplasm of a neuron, to inhibit exocytosis of acetylcholine from the neuron. The therapeutic element can cleave a SNARE protein, thereby inhibiting the exocytosis of acetylcholine from the neuron. The SNARE protein can be selected from the group consisting of syntaxin, SNAP-25 and VAMP; As used herein, the term “Clostridial Botulinum neurotoxin (BoNT) protease domain” means a BoNT domain that can execute the enzymatic target modification step of the intoxication process. Thus, a BoNT protease domain specifically targets a C. Botulinum toxin substrate and encompasses the proteolytic cleavage of a C. Botulinum toxin substrate, such as, e.g., SNARE proteins like a SNAP-25 substrate, a VAMP substrate and a Syntaxin substrate.
[0090] In some embodiments, the methods comprise the step of locally administering a neurotoxin (e.g., a botulinum toxin).
[0091] Treatments such as salabrasion and dermabrasion surgery can lighten and sometimes fully clear tattoos, but these and other destructive modalities can cause permanent scarring. Laser tattoo removal is the treatment of choice for removal of amateur and professional tattoos of all colors and in all skin types. Because of the small size of tattoo particles, pulses in the nanosecond domain are required for tattoo removal. Q-SWITCHED lasers deliver pulses in the nanosecond domain and are the optimal devices for tattoo removal.
[0092] In some embodiments, the dose of a neurotoxin administered is equivalent to about 1 unit to about 500 units of a botulinum toxin type A. In some embodiments, the dose of a neurotoxin administered is equivalent to about 1 unit to about 300 units of a botulinum toxin type A. In some embodiments, the dose of a neurotoxin administered is equivalent to about 1 unit to about 150 units of a botulinum toxin type A. In some embodiments, the dose of a neurotoxin administered is equivalent to about 1 unit to about 75 units of a botulinum toxin type A. In some embodiments, the dose of a neurotoxin administered is equivalent to about 1 unit to about 40 units of a botulinum toxin type A. In some embodiments, the dose of a neurotoxin administered is in an amount of between about 0.1 unit and about 5 units.
However, Hunt TJ., (US 2008/0113051 A1) is silent regarding herein the distal site to the surgical incision is at least 15 cm to 100 cm from the site of surgical intervention (as in claim 13); wherein the clostridial neurotoxin comprises a L domain corresponding to amino acid residues 1-448 of SEQ ID NO: 1… wherein the clostridial neurotoxin comprises a Hc domain corresponding to amino acid residues 860-1291 of SEQ ID NO: 2… wherein the Hc domain comprises an amino acid substitution selected from the group consisting of: V1118M; Y1183M; E1191M; E1191I; E1191Q; E1191T; S1199Y; S1199F; S1199L; S1201V; E1191C; E1191V, E1191L; E1191Y; S1199W; S1199E; S1199H; W1178Y; W1178Q; W1178A;… (as in claims 37-41).
Regarding claims 2-3, 16-17, 19, 22 and 30-36, Bresnahan R., (Ph.D., Thesis, Univ. of Sheffield, UK, 2018, pages 1-211), provide teaching, suggestion for pre-emptive/prior to surgery use of clostridial toxins including BonT/A and chimeric toxins to mitigate post-surgical pain (see ¶ 7.5 Conclusions, pages 180-181); Bresnahan R., also discloses the molecular mechanisms, biochemical properties, mode of action and physiological effects of clostridial toxins including BonT/A (see Abstract; pages 32-20; and entire document).
Regarding claims 2-3, 16-17, 19, 22 and 30-36, Fonfria et al., (Toxins, 2018, Vol. 28, pages 1-27),also provide teaching, suggestion for pre-emptive/prior to surgery use of clostridial toxins including BonT/A and chimeric toxins to mitigate post-surgical pain and in wound healing following surgery (see Abstract; Wound healing, ¶ 3.4; ¶ 7, Conclusions, page 17; and entire document); Fonfria et al., also discloses the molecular mechanisms, biochemical properties, mode of action and physiological effects of clostridial toxins including BonT/A and provide evidence that peripherally injected BonT/A triggers distal changes at various levels (¶ 4.1, page 9; ¶ 2, page 10).
Regarding claim 7, Meyer-Frießem et al., (Curr. Med. Res. Opinion., 2019, Vol. 35(10): 1793-1803) teach methods such as Numerical rating scale (NRS) to assess pain relief/reduction following BonT/A administration (Abstract; Methods, col. 2 ¶ 2, page 1794; Fig. 2-3, page 1797; Table 2, page 1798; Table 3, page 1799; and entire document).
Regarding claims 36-41, Dong et al., (US 11,104,891 B2; priority 06/08/2017) disclose wherein the clostridial neurotoxin comprises a L domain corresponding to amino acid residues 1-448 of SEQ ID NO: 1… wherein the clostridial neurotoxin comprises a Hc domain corresponding to amino acid residues 860-1291 of SEQ ID NO: 2… wherein the Hc domain comprises an amino acid substitution selected from the group consisting of: V1118M; Y1183M; E1191M; E1191I; E1191Q; E1191T; S1199Y; S1199F; S1199L; S1201V; E1191C; E1191V, E1191L; E1191Y; S1199W; S1199E; S1199H; W1178Y; W1178Q; W1178A (see provided sequence alignments; Abstract; Fig. 1-2; Cols. 3, 39-40, reproduced below; and entire document).
US 11,104,891 Dong et al.,
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Therefore, using the indications of Bresnahan R., Fonfria et al., Meyer-Frießem et al., and Dong et al., as references, it would have been easy for a person skilled in the art to utilize use of clostridial toxins including BonT/A and chimeric toxins pre-emptively/prior to surgery to mitigate post-surgical pain in the claimed method and modify the teachings of Hunt TJ., and a skilled artisan would realize, as said modification is advantageous for use of clostridial toxins including BonT/A and chimeric toxin pre-emptively/prior to surgery to mitigate post-surgical pain. As such, disclosures of Hunt TJ., Bresnahan R., Fonfria et al., Meyer-Frießem et al., and Dong et al., provide the structural and functional elements in the claimed method for utilizing clostridial toxins including BonT/A and chimeric toxins pre-emptively/prior to surgery to mitigate post-surgical pain and as claimed in the instant invention. One of ordinary skill in the art would have a reasonable expectation of success and predictable results, since basic strategy for to utilize use of clostridial toxins including BonT/A and chimeric toxins pre-emptively/prior to surgery to mitigate post-surgical pain and for experimentally measuring the effects of said treatment are taught by the references of Hunt TJ., Bresnahan R., Fonfria et al., Meyer-Frießem et al., and Dong et al. Therefore, the above references renders claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 prima facie obvious to one of ordinary skill in the art.
Therefore, claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hunt TJ., (US 2008/0113051 A1; Published: 05/15/2008; Effectively Filed: 11/13/2006) and further in view of Bresnahan R., (Ph.D., Thesis, Univ. of Sheffield, UK, 2018, pages 1-211), Fonfria et al., (Toxins, 2018, Vol. 28, pages 1-27), Meyer-Frießem et al., (Curr. Med. Res. Opinion., 2019, Vol. 35(10): 1793-1803) and Dong et al., (US 11,104,891 B2; priority 06/08/2017).
Summary of Pending Issues
The following is a summary of issues pending in the instant application.
Claims 38-41 is rejected under 35 U.S.C. 112(d).
Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are rejected under 35 U.S.C. 112(a) for written-description and enablement.
Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are rejected under 35 U.S.C. 103(a) as being unpatentable over Hunt TJ., (US 2008/0113051 A1; Published: 05/15/2008; Effectively Filed: 11/13/2006) and further in view of Bresnahan R., (Ph.D., Thesis, Univ. of Sheffield, UK, 2018, pages 1-211), Fonfria et al., (Toxins, 2018, Vol. 28, pages 1-27), Meyer-Frießem et al., (Curr. Med. Res. Opinion., 2019, Vol. 35(10): 1793-1803) and Dong et al., (US 11,104,891 B2; priority 06/08/2017).
Conclusion
None of the claims are allowable. Claims 2-3, 7, 13, 16-17, 19, 22, 25 and 30-41 are rejected for the reasons identified in the Rejections and Summary sections of this Office Action. Applicants must respond to the rejections in each of the sections in this Office Action to be fully responsive for prosecution.
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/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652
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