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
Claims 3, 7-11, 52-55 and 71-81 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 3, 7-11, 52-55, and 71-81, in the reply filed on 7/9/2026 is acknowledged.
Claims 3, 7-11, 52-55 and 71-81 are examined herein.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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.
Claim 3, 7-11, 52-55, and 71-81 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 3 recites the limitation "the affected muscle" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 72 recites the C-terminal amino acid residue of the BoNT/A translocation domain corresponds to N872 of SEQ ID NO: 2 and the N-terminal amino acid residue of the BoNT/B receptor binding domain corresponds to I860 in SEQ ID NO: 16. The claim has multiple reasonable interpretations, rendering the claim indefinite. In one interpretation, only the two amino acids N872 and I860 are required in the modified BoNT/A. In a second interpretation, the modified BoNT/A comprises the residues 1 to 872 of SEQ ID NO: 2 and the C-terminal residues of SEQ ID NO: 16 starting at I860.
Claim 78 recites the modified BoNT/A is produced by proteolytic cleavage of SEQ ID NO: 14 with an endoproteinase Lys-C. It is unclear whether the method further comprises an additional step of producing the BoNT/A or whether this is a product-by-process limitation further limiting the structure of the modified BoNT/A.
Claim 79 recites “wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s).” The parentheses render the claim indefinite because it is unclear whether one residue or more than one residue is required.
Claim 79 is further indefinite because the claim requires modifications at amino acid positions without a reference sequence.
Claims 7-11, 52-55 and 71-81 are rejected for depending from a rejected base claim and not rectifying the sources of indefiniteness discussed above.
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 80-81 are 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 80 fails to further limit the subject matter of the claim upon which it depends. Claim 80 depends from claim 79, which recites the modified BoNT/A comprises a modification at one or more amino acid residues that are specifically named in position (ASN 886, etc). However, claim 80 recites broader limitations of substitutions, insertions and deletions without reference to any specific position.
Claim 81 likewise fails to further limit the subject matter of claim 79 because the claim does not recite the specific residue where the modification occurs.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
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 79-81 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.
Claims 79-81 are drawn to a genus of modified BoNT/A comprising modifications at one or more amino acid residues selected from ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277. Claim 80 recites the modification is selected from substitution of an acidic surface exposed amino acid residue with a basic amino acid residue, substitution of an acidic surface exposed amino acid residue with an uncharged amino acid residue, substitution of an uncharged surface exposed amino acid residue with a basic amino acid residue, insertion of a basic amino acid residue, and deletion of an acidic surface exposed amino acid residue.
The person of ordinary skill in the art would not have recognized that the inventors, at the time the application was filed, had possession of the claimed genus of modified BoNT/A.
The specification discloses conservative amino acid residues and categorizes amino acids by basic, acidic, polar, hydrophobic, aromatic, and small.(page 77, Conservative amino acid substitutions). However, the specification never discloses which amino acid residues are surface exposed amino acid residues.
Liu (US 2019/0127427 A1) teaches a chimeric neurotoxin suitable for use in treating cervical dystonia ([0145]). Liu teaches the chimeric neurotoxin SEQ ID NO: 12 ([0125]), which is identical to the instant SEQ ID NO: 14 (OA Appendix A). SEQ ID NO: 12 is a modified BoNT/A (Table 3: see Chimera 3B; A1 is the BoNT/A fragment and B1 is the BoNT/B fragment). Liu teaches the amino acid substitution E1191M and S1199Y in the chimeric neurotoxin (Liu claim 8). Liu teaches that these mutations, among others (e.g. Y1183C, Y1183P), increase the binding affinity of BoNT/B neurotoxin for human synaptotagmin II (Syt II) as compared to the normal BoNT/B sequence ([0120] and [0122]). However, Liu does not teach which amino acid residues of the modified BoNT/A are surface exposed.
Given the lack of species of modified BoNT/A disclosed within the specification as well as the unpredictability in the state of the art with respect to what constitutes a surface-exposed amino acid residue, the person of ordinary skill in the art would not have recognized that the inventors had possession of the claimed genus of modified BoNT/A.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claims 3, 7-11, 52-55 and 71-78 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (US 2019/0127427 A1) in view of Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Regarding claims 3 and 55, Liu teaches a chimeric neurotoxin suitable for use in treating cervical dystonia ([0145]). Liu teaches the chimeric neurotoxin SEQ ID NO: 12 ([0125]), which is identical to the instant SEQ ID NO: 14 (OA Appendix A). SEQ ID NO: 12 is a modified BoNT/A (Table 3: see Chimera 3B; A1 is the BoNT/A fragment and B1 is the BoNT/B fragment). Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Regarding claim 3, Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
Regarding claim 7, Liu does not teach the total dose administered is between 5,250 pg and 170,000 pg.
Regarding claim 8, Liu does not teach that the unit dose administered contains from 1,000 pg to 16,000 pg modified BoNT/A.
Regarding claim 9, Liu does not teach the total dose administered is up to 160,000 pg of modified BoNT/A.
Regarding claim 10, Liu does not teach that the modified BoNT/A is administered to the affected neck muscle at a single injection site.
Regarding claim 52, Liu does not teach that a unit dose of the modified BoNT/A is administered per injection site at the affected neck muscle.
Regarding claim 53, Liu does not teach that at least a single unit dose of the modified BoNT/A is administered at multiple injection sites at the affected neck muscle.
Regarding claim 54, Liu does not teach that a single unit dose of the modified BoNT/A is administered at the affected neck muscle.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin (“modified BoNT/A”) administered per injection site to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and claims 7-9, 11, and 52-54, it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Regarding claims 71-72, Liu teaches a chimeric BoNT/AB SEQ ID NO: 12 comprising 1-872 and 860-1291 fragments (Chimera 3B of Table 3 on page 11). Liu’s SEQ ID NO: 12 comprises the N-terminal fragment of the instant SEQ ID NO: 2 up to position N872 (OA Appendix C) and the C-terminal fragment of the instant SEQ ID NO: 16 starting at position I860 (OA Appendix B). Thus, Liu’s SEQ ID NO; 12 necessarily comprises a BoNT/A light-chain, a BoNT/A translocation domain, and a BoNT/B receptor binding domain.
Regarding claim 73, Liu teaches that the neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond ([0004]). Liu teaches that the di-chain form is the active form of the toxin ([0004]). Liu teaches the amino acid residues for the N- and C-terminal fragments of the di-chain (Chimera 3B in Table 3 on page 11). Therefore, the C-terminal amino acid residue of the BoNT/A translocation domain is necessarily covalently linked via the disulfide bond to the N-terminal amino acid residue of the BoNT/B receptor binding domain.
Regarding claim 74, Liu’s SEQ ID NO: 12 (Table 3 on page 11) aligns up to the C-terminus of the instant SEQ ID NO: 16 at position 1291 (OA Appendix B), thus Liu’s modified BoNT/A comprises the BoNT/B receptor binding domain corresponding to amino acids 860 to 1291 of SEQ ID NO: 16.
Regarding claims 75-77, Liu teaches the chimeric BoNT/AB comprises the substitutions E1191M and S1199Y (Chimera 1 of Table 3 on page 11). Therefore, the amino acid substitutions are necessarily in the BoNT/B receptor binding domain.
Regarding claim 78, Liu teaches producing the BoNT/AB chimeric molecules and proteolytically cleaving them with endoproteinase Lys-C to yield the active di-chain ([0177]). Liu teaches the chimeric neurotoxin SEQ ID NO: 12 ([0125]), which is identical to the instant SEQ ID NO: 14 (OA Appendix A).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3, 7-11, 52-55 and 71-78 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6 and 9-10 of U.S. Patent No. 11,434,265 (hereafter ‘265) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Claim 6 of ‘265 recites a chimeric neurotoxin comprising a LHN domain from a first neurotoxin covalently linked to a HC domain from a second neurotoxin. wherein the LHN domain corresponds to amino acid residues 1 to 872 of SEQ ID NO: 1 and the HC domain corresponds to amino acid residues 860 to 1291 of SEQ ID NO 2. SEQ ID NO: 1 of ‘265 is identical to the instant SEQ ID NO: 2, which is the BoNT/A translocation domain (see instant claim 72), thus the chimeric neurotoxin recited in claim 6 of ‘265 is a modified BoNT/A.
Claims 9-10 of ‘265 recite the HC domain co comprises the amino acid substitutions E1191M and S1199Y.
Claims 6 and 9-10 of ‘265 do not recite administering by intramuscular injection the chimeric neurotoxin to treat cervical dystonia in a subject in need thereof. Claims 6 and 9-10 of ‘265 do not recite the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Claims 6 and 9-10 of ‘265 do not recite that the total dose administered during the treatment is between 750 pg to 170,000 pg of the chimeric neurotoxin (“modified BoNT/A”).
Regarding instant claims 3 and 55, Liu teaches that the chimeric neurotoxin is suitable for use in treating cervical dystonia ([0145]). Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer by intramuscular injection the chimeric neurotoxin of claims 6 and 9-10 of ‘265 to a subject with cervical dystonia. The person of ordinary skill in the art would have been motivated by the teachings of Liu, who suggests administering a chimeric neurotoxin to treat cervical dystonia. The person of ordinary skill in the art would have had a reasonable expectation of success.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin of claims 6 and 9-10 of ‘265 administered to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and claims 7-9, 11, and 52-54, it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Instant claims 71-72 and 74 are obvious over claim 6 of ‘265 because SEQ ID NO: 1 of ‘265 is identical to the instant SEQ ID NO: 2 and SEQ ID NO: 2 of ‘265 is identical to the instant SEQ ID NO: 16.
Regarding instant claim 73, the C-terminus of the 1-872 fragment of SEQ ID NO: 1 of ‘265 is covalently linked to the N-terminus of the 860 to 1291 fragment of SEQ ID NO: 2 of ‘265. Claim 6 of ‘265 depends from claim 1 of ‘265, which explicitly recites the covalent linkage.
Regarding instant claims 75-77, claims 9-10 of ‘265 recite the amino acid substitutions E1191M and S1199Y.
Regarding instant claim 78, claims 6 and 9-10 of ‘265 do not recite producing the modified BoNT/A by proteolytic cleavage of SEQ ID NO; 14 with endoproteinase Lys-C.
Liu teaches that the chimeric neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by Lys-C proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond, which is the active di-chain ([0004] and [0177]). Liu teaches the amino acid residues for the N- and C-terminal fragments of the di-chain (Chimera 3B in Table 3 on page 11). SEQ ID NO: 12 is the single-chain polypeptide form of the di-chain (Table 3 on page 11). Liu’s SEQ ID NO: 12 is identical to the instant SEQ ID NO: 14.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to proteolytically cleave the chimeric neurotoxin of Liu’s SEQ ID NO: 12 in order to produce the active di-chain form of the chimeric neurotoxin of claim 6 of ‘265 in which the LHN domain is linked by a disulfide bond to the HC domain. The person of ordinary skill in the art would have had a reasonable expectation of success.
Claims 3, 7-11, 52-55 and 71-78 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 12, and 16 of U.S. Patent No. 12,421,284 (hereafter ‘284) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Claim 4 of ‘284 is drawn to a method for producing a chimeric neurotoxin comprising culturing a cell comprising a nucleotide sequence encoding a LHN domain from a first neurotoxin covalently linked to a HC domain from a second neurotoxin
Claim 12 of ‘284 recites the LHN domain comprises amino acid residues 1 to 872 of SEQ ID NO: 1 and the HC domain comprises amino acid residues 860 to 1291 of SEQ ID NO: 2. SEQ ID NO: 1 of ‘284 is identical to the instant SEQ ID NO: 2, which is the BoNT/A translocation domain (see instant claim 72), thus the chimeric neurotoxin recited in claim 12 of ‘284 is a modified BoNT/A.
Claim 16 of ‘284 requires the HC domain comprises two substitutions at E1191M and S1199Y.
Claims 4, 12, and 16 of ‘284 do not recite administering by intramuscular injection the chimeric neurotoxin to treat cervical dystonia in a subject in need thereof. Claims 4, 12, and 16 of ‘284 do not recite the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Claims 4, 12, and 16 of ‘284 do not recite that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
Regarding instant claims 3 and 55, Liu teaches that the chimeric neurotoxin is suitable for use in treating cervical dystonia ([0145]). Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to produce the chimeric neurotoxin of claims 4, 12, and 16 of ‘284 and then to administer the chimeric neurotoxin by intramuscular injection to a subject with cervical dystonia. The person of ordinary skill in the art would have been motivated by the teachings of Liu, who suggests administering a chimeric neurotoxin to treat cervical dystonia. The person of ordinary skill in the art would have had a reasonable expectation of success.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin administered per injection site to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and instant claims 7-9, 11, and 52-54 it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Instant claims 71-74 are obvious over claims 6 and 12 of ‘284 in view of Liu and Kessler. Instant SEQ IDNO: 2 is identical to SEQ ID NO: 1 of ‘284 and instant SEQ ID NO: 16 is identical to SEQ ID NO: 2 of ‘284.
Instant claims 75-77 are obvious over claim 16 of ‘284 in view of Liu and Kessler. Claim 16 of ‘284 recites the amino acid substitutions E1191M and S1199Y.
Regarding instant claim 78, claims 4, 12, and 16 of ‘284 do not recite proteolytic cleavage of the chimeric neurotoxin with endoproteinase Lys-C.
Liu teaches that the chimeric neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by Lys-C proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond, which is the active di-chain ([0004] and [0177]). Liu teaches the amino acid residues for the N- and C-terminal fragments of the di-chain (Chimera 3B in Table 3 on page 11). SEQ ID NO: 12 is the single-chain polypeptide form of the di-chain (Table 3 on page 11). Liu’s SEQ ID NO: 12 is identical to the instant SEQ ID NO: 14.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to proteolytically cleave the chimeric neurotoxin of Liu’s SEQ ID NO: 12 in order to produce the active di-chain form of the chimeric neurotoxin of claim 12 of ‘284 in which the LHN domain is linked by a disulfide bond to the HC domain. The person of ordinary skill in the art would have had a reasonable expectation of success.
Claims 3, 7-11, 52-55 and 71-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-27 of copending Application No. 19/309,183 (hereafter ‘183) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Claim 24 of ‘183 recites a nucleotide sequence encoding a chimeric neurotoxin comprising an amino acid sequence of SEQ ID NO: 12. Claim 25 of ‘183 is drawn to a vector comprising the nucleotide sequence. Claim 26 of ‘183 is drawn to a cell comprising the nucleotide sequence. Claim 27 of ‘183 is drawn to a cell comprising the vector. SEQ ID NO: 12 is identical to SEQ ID NO: 12 of Liu, which is a single polypeptide fusion of fragments of BoNT/A and BoNT/B (Table 3 on page 11), thus the chimeric neurotoxin recited in claims 24-27 of ‘183 is a modified BoNT/A.
Claims 24-27 of ‘183 do not recite administering by intramuscular injection the chimeric neurotoxin to treat cervical dystonia in a subject in need thereof. Claims 24-27 of ‘183 do not recite the dose administered to the affected neck muscle in the subject is 750 pg to 17,000 pg. Claims 24-27 of ‘183 do not recite that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
Regarding instant claims 3 and 55, Liu teaches that the chimeric neurotoxin is suitable for use in treating cervical dystonia ([0145]). Liu teaches the chimeric neurotoxin SEQ ID NO: 12 ([0125]), which is identical to SEQ ID NO: 12 of claim 24 of ‘183. Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to culture the host cell of claims 26-27 of ‘183 to produce the chimeric neurotoxin or to introduce the nucleic acid of claims 24-25 of ‘183 into a cell and then culture the cell to produce the chimeric neurotoxin. It would have been further obvious to administer the chimeric neurotoxin by intramuscular injection to a subject with cervical dystonia. The person of ordinary skill in the art would have been motivated by the teachings of Liu, who suggests administering the same chimeric neurotoxin to treat cervical dystonia. The person of ordinary skill in the art would have had a reasonable expectation of success.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin administered per injection site to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and instant claims 7-9, 11, and 52-54 it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Instant claims 71-74 are obvious over claims 24-27 of ‘183 in view of Liu and Kessler because SEQ ID NO; 12 of ‘183 is a fusion of the C-terminal amino acid residues 1 to 872 of instant SEQ ID NO: 2 and the N-terminal amino acid residues 860 to 1291 of instant SEQ ID NO: 16.
Regarding instant claims 75-77, claims 24-27 of ‘183 do not recite the amino acid substitutions E1191M and S1199Y.
Liu teaches the amino acid substitution E1191M and S1199Y (Liu claim 8). Liu teaches that these mutations increase the binding affinity of BoNT/B neurotoxin for human synaptotagmin II (Syt II) as compared to the normal BoNT/B sequence ([0120] and [0122]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to introduce the E1191M and S1199Y amino acid substitutions into the chimeric neurotoxin of claims 24-27 of ‘183 in order to increase the binding affinity of the neurotoxin for human synaptotagmin II, as suggested by Liu. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding claim 78, claims 24-27 of ‘183 do not recite proteolytically cleaving the chimeric neurotoxin with endoproteinase Lys-C.
Liu teaches that producing the BoNT/AB chimeric molecules and proteolytically cleaving them with endoproteinase Lys-C to yield the active di-chain ([0177]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to proteolytically cleave the chimeric neurotoxin of claims 24-27 of ‘183 having SEQ ID NO: 12 (which is identical to the instant SEQ ID NO: 14) modified by Liu and Kessler per the teaching of Liu in order to yield the active di-chain. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 3, 7-11, 52-55 and 71-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5-6 of copending Application No. 19/423,511 (hereafter ‘511) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Claim 1 of ‘511 recites a di-chain chimeric neurotoxin comprising a HN domain from a first neurotoxin and a HC domain from a second neurotoxin, wherein the C-terminal amino acid residue of the HN domain is covalently linked to the N-terminal amino acid residue of the HC domain. Claim 5 of ‘511 is drawn to a pharmaceutical composition comprising the di-chain chimeric neurotoxin. Claim 6 of ‘511 is drawn to a kit comprising the pharmaceutical composition.
Claims 1 and 5-6 of ‘511 do not recite that the chimeric neurotoxin is a modified BoNT/A or administering by intramuscular injection the chimeric neurotoxin to treat cervical dystonia in a subject in need thereof. Claims 1 and 5-6 of ‘511 do not recite the dose administered to the affected neck muscle in the subject is 750 pg to 17,000 pg. Claims 1 and 5-6 of ‘511 do not recite that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
Regarding instant claims 3 and 55, Liu teaches that the chimeric neurotoxin is suitable for use in treating cervical dystonia ([0145]). Liu teaches the chimeric neurotoxin SEQ ID NO: 12 ([0125]), which is identical to the instant SEQ ID NO: 14 (OA Appendix A). SEQ ID NO: 12 is a modified BoNT/A (Table 3: see Chimera 3B; A1 is the BoNT/A fragment and B1 is the BoNT/B fragment). Liu teaches that the chimeric neurotoxin comprises a LHN domain from a first neurotoxin covalently linked to a HC domain from a second neurotoxin, wherein the first and second neurotoxins are different, wherein the C-terminal amino acid residue of the LHN domain corresponds to the first amino acid residue of the 310 helix separating the LHN and HC domains in the first neurotoxin, wherein the N-terminal amino acid residue of the HC domain corresponds to the second amino acid residue of the 310 helix separating the LHN and HC domains in the second neurotoxin ([0017]).
Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to specifically use a BoNT/A HN domain and a BoNT/B HC domain in the chimeric neurotoxin of claims 1 and 5-6 of ‘511 per the teaching of Liu. It would have been further obvious to administer the chimeric neurotoxin of claims 1 and 5-6 of ‘511 by intramuscular injection to a subject with cervical dystonia. The person of ordinary skill in the art would have been motivated by the teachings of Liu, who suggests administering a chimeric neurotoxin to treat cervical dystonia. The person of ordinary skill in the art would have had a reasonable expectation of success.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin administered per injection site to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and instant claims 7-9, 11, and 52-54 it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Regarding instant claims 71-72, claims 1 and 5-6 of ‘511 do not recite that the chimeric neurotoxin comprises a BoNT/A light-chain, a BoNT/A translocation domain, and a BoNT/B receptor binding domain (instant claim 71) or that the C-terminal amino acid residue of the BoNT/A translocation domain corresponds to N872 of SEQ ID NO: 2 and the N-terminal amino acid residue of the BoNT/B receptor binding domain corresponds to I860 of SEQ ID NO: 16 (instant claim 72).
Regarding instant claim 74, claims 1 and 5-6 of ‘511 do not recite that the BoNT/B receptor binding domain corresponds to amino acids 860 to 1291 of SEQ ID NO: 16.
Liu teaches a chimeric BoNT/AB SEQ ID NO: 12 comprising 1-872 and 860-1291 (Chimera 3B of Table 3 on page 11). Liu’s SEQ ID NO: 12 comprises the N-terminal fragment of the instant SEQ ID NO: 2 up to position N872 (OA Appendix C) and the C-terminal fragment of the instant SEQ ID NO: 16 starting at position I860 (OA Appendix B). Thus, Liu’s SEQ IDN O; 12 necessarily comprises a BoNT/A light-chain, a BoNT/A translocation domain, and a BoNT/B receptor binding domain. Liu’s SEQ ID NO: 12 (Table 3 on page 11) aligns up to the C-terminus of the instant SEQ ID NO: 16 at position 1291 (OA Appendix B), thus Liu’s modified BoNT/A comprises the BoNT/B receptor binding domain corresponding to amino acids 860 to 1291 of SEQ ID NO: 16.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply the teachings of Liu regarding the amino acid sequence of the chimeric neurotoxin to the generic chimeric neurotoxin of claims 1 and 5-6 of ‘511. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu’s chimeric neurotoxin is a species of the chimeric neurotoxin recited in claims 1 and 5-6 of ‘511.
Regarding claims 75-77, claims 1 and 5-6 of ‘511 do not recite amino acid substitutions E1191M and S1199Y.
Liu teaches the chimeric BoNT/AB comprises the substitutions E1191M and S1199Y (Chimera 1 of Table 3 on page 11). Therefore, the amino acid substitutions are necessarily in the BoNT/B receptor binding domain. Liu teaches that these mutations increase the binding affinity of BoNT/B neurotoxin for human synaptotagmin II (Syt II) as compared to the normal BoNT/B sequence ([0120] and [0122]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to introduce the E1191M and S1199Y into the chimeric neurotoxin of claims 1 and 5-6 of ‘511 in order to increase the binding affinity of the neurotoxin for human synaptotagmin II, as suggested by Liu. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding claims 73 and 78, claims 1 and 5-6 of ‘511 do not recite proteolytically cleaving the chimeric neurotoxin with endoproteinase Lys-C or that the C-terminal amino acid residue of the BoNT/A translocation domain is covalently linked to the N-terminal amino acid residue of the BoNT/B receptor binding domain in the chimeric neurotoxin.
Liu teaches that the chimeric neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by Lys-C proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond, which is the active di-chain ([0004] and [0177]). Liu teaches the amino acid residues for the N- and C-terminal fragments of the di-chain (Chimera 3B in Table 3 on page 11). SEQ ID NO: 12 is the single-chain polypeptide form of the di-chain (Table 3 on page 11). Liu’s SEQ ID NO: 12 is identical to the instant SEQ ID NO: 14.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to proteolytically cleave the chimeric neurotoxin of Liu’s SEQ ID NO: 12 in order to produce the active di-chain form of the chimeric neurotoxin of claims 1 and 5-6 of ‘511 in which the C-terminal amino acid residue of the BoNT/A translocation domain is linked by a disulfide bond (covalent linkage) to the N-terminal amino acid residue of the BoNT/B receptor binding domain. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 3, 7-11, 52-55 and 71-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 19/341,888 (hereafter ‘888) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Claim 1 of ‘888 recites a di-chain chimeric neurotoxin comprising a LHN domain from a BoNT/A1 and a HC domain from a BoNT/B1, wherein the C-terminal amino acid residue of the LHN domain is directly linked to the N-terminal amino acid residue of the HC domain, wherein the C-terminal amino acid residue of the LHN domain corresponds to N872 in SEQ IDN O: 1 and the N-terminal amino acid residue of the HC domain corresponds to I860 in SEQ ID NO: 2. SEQ ID NO: 1 of claim 1 of ‘888 is identical to the instant SEQ ID NO: 2, so the chimeric neurotoxin of claim 1 of ‘888 is a modified BoNT/A (see instant claim 72).
Claim 2 of ‘888 recites the HC domain corresponds to amino acids 860 to 1291 of SEQ ID NO 2. Claim 3 of ‘888 recites the HC domain comprises the amino acid substitution E1191M or S1199Y. Claims 4-5 of ‘888 require the HC domain comprises the two amino acid substitutions E1199M and S1199Y. Claim 6 of ‘888 is drawn to a pharmaceutical composition comprising the di-chain. Claim 7 of ‘888 is drawn to a kit comprising the pharmaceutical composition. Claim 8 is drawn to a di-chain chimeric neurotoxin produced by proteolytic cleavage of SEQ ID NO; 12 with endoproteinase Lys-C. Claim 9 of ‘888 is drawn to a pharmaceutical composition comprising the chimeric neurotoxin of claim 8. Claim 10 of ‘8888 is drawn to a kit comprising the pharmaceutical composition of claim 9.
Claims 1-10 of ‘888 do not recite administering by intramuscular injection the chimeric neurotoxin to treat cervical dystonia in a subject in need thereof. Claims 1-10 of ‘888 do not recite the dose administered to the affected neck muscle in the subject is 750 pg to 17,000 pg. Claims 1-10 of ‘888 do not recite that the total dose administered during the treatment is between 750 pg to 170,000 pg of the chimeric neurotoxin ("modified BoNT/A”).
Regarding instant claims 3 and 55, Liu teaches that the chimeric neurotoxin is suitable for use in treating cervical dystonia ([0145]). Liu teaches that producing the BoNT/AB chimeric molecules and proteolytically cleaving them with endoproteinase Lys-C to yield the active di-chain ([0177]). Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer the chimeric neurotoxin of claims 1-10 of ‘888 by intramuscular injection to a subject with cervical dystonia. The person of ordinary skill in the art would have been motivated by the teachings of Liu, who suggests administering a chimeric neurotoxin to treat cervical dystonia. The person of ordinary skill in the art would have had a reasonable expectation of success.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin administered per injection site to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and instant claims 7-9, 11, and 52-54 it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Instant claims 71-72 are obvious over claim 1 of ‘888. Instant SEQ ID NO: 2 is identical to SEQ ID NO: 1 of ‘888 and instant SEQ ID NO: 16 is identical to SEQ ID NO: 2 of ‘888.
Regarding instant claim 73, claim 1 of ‘888 recites that the C-terminal amino acid residue of the LHN domain is directly linked to the N-terminal amino acid residue of the HC domain. However, claim 1 of ‘888 does not recite that the linkage is a covalent linkage.
Liu teaches that the chimeric neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by Lys-C proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond, which is the active di-chain ([0004] and [0177]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to produce the chimeric di-chain of claim 1 of ‘888 per the teaching of Liu in order to introduce a disulfide bond (covalent linkage) between the C-terminal amino acid residue of the LHN domain comprising the BoNT/A translocation domain and the N-terminal amino acid residue of the HC domain comprising the BoNT/B receptor binding domain. The person of ordinary skill in the art would have had a reasonable expectation of success.
Instant claim 74 is obvious over claim 2 of ‘888 in view of Liu and Kessler.
Instant claims 75-77 are obvious over claims 3-5 of ‘888 in view of Liu and Kessler because claims 3-5 of ‘888 recite the amino acid substitutions E1191M and S1199Y.
Instant claim 78 is obvious over claim 8 of ‘888 in view of Liu and Kessler because SEQ ID NO: 12 of ‘888 is identical to the instant SEQ ID NO: 14.
This is a provisional nonstatutory double patenting rejection.
Claim 3, 7-9, 54, and 71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 48 of copending Application No. 18/851,566 (hereafter ‘566). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 3 and 7-9 are obvious over claim 2 of ‘566 and instant claim 54 is obvious over claim 48 of ‘566.
Claim 2 of ‘566 recites a method for treating cervical dystonia comprising administering a chimeric botulinum neurotoxin (BoNT/AB) by intramuscular injection to tan affected neck muscle of a subject, wherein the BoNT/AB is administered by way of a unit dose of greater than 17,000 pg, wherein at least a single unit dose is administered to the affected neck muscle, wherein the total dose administered during the treatment is up to 400,000 pg and wherein the BoNT/AB comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
Claim 48 of ‘566 recites the BoNT/AB is administered by a unit dose per injection site at an affected neck muscle.
A chimeric BoNT/AB is a type of modified BoNT/A. The unit dose of greater than 17,000 pg is approaching the presently claimed range of 750 pg to 17,000 pg. The total dose administered up to 400,000 pg overlaps with the presently claimed range of between 750 pg and 170,000 pg. Instant claim 3 is thus obvious over claim 2 of ‘566.
Instant claims 7-9 are obvious over claim 2 of ‘566.
Regarding instant claim 7, the total dose administered up to 400,000 pg overlaps with the presently claimed range of between 5,250 pg and 170,000 pg.
Regarding instant claim 8, the unit dose of greater than 17,000 pg is approaching the presently claimed range of from 1,000 pg to 16,000 pg.
Regarding instant claim 9, the total dose administered up to 400,000 pg overlaps with the presently claimed range of up to 160,000 pg.
Instant claim 54 is obvious over claim 48 of ‘566.
Instant claim 71 is obvious over claim 2 of ‘566.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10-11, 52-53, 55 and 72-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 48 of copending Application No. 18/851,566 (hereafter ‘566) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
See discussion of claims 2 and 48 of ‘566 above, which is incorporated into this rejection as well.
Regarding instant claim 10, claim 2 of ‘566 does not recite that the modified BoNT/A is administered to the affected neck muscle at a single injection site.
Regarding instant claim 11, claim 48 of ‘566 recites the BoNT/AB is administered by way of less than a unit dose per injection site. Claim 2 of 566 recites the unit dose is up to 400,000 pg. However, claim 48 of ‘566 does not recite that the modified BoNT/A is administered by way of a unit dose of from 750 pg to 4,000 pg per injection site.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12). Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin per injection site administered to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and instant claims 11 and 52-53, it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Regarding instant claim 55, claim 2 of ‘566 does not recite that the subject is a human being.
Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to specifically administered the chimeric neurotoxin of claim 3 of ‘566 do a human being to treat cervical dystonia per the teaching of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding claims 72 and 74, claim 2 of ‘566 does not recite that the C-terminal amino acid residue of the BoNT/A translocation domain corresponds to N872 of SEQ ID NO: 2 and the N-terminal amino acid residue of the BoNT/B receptor binding domain corresponds to I860 in SEQ ID NO: 16 (instant claim 72) or that the BoNT/B receptor binding domain corresponds to amino acids 860 to 1291 of SEQ ID NO: 16 (instant claim 74).
Liu teaches a chimeric BoNT/AB SEQ ID NO: 12 comprising fragments 1-872 and 860-1291 (Chimera 3B of Table 3 on page 11). Liu’s SEQ ID NO: 12 comprises the N-terminal fragment of the instant SEQ ID NO: 2 up to position N872 (OA Appendix C) and the C-terminal fragment of the instant SEQ ID NO: 16 starting at position I860 (OA Appendix B). Thus, Liu’s SEQ IDN O; 12 necessarily comprises a BoNT/A light-chain, a BoNT/A translocation domain, and a BoNT/B receptor binding domain. Liu’s SEQ ID NO: 12 (Table 3 on page 11) aligns up to the C-terminus of the instant SEQ ID NO: 16 at position 1291 (OA Appendix B), thus Liu’s chimeric neurotoxin comprises the BoNT/B receptor binding domain corresponding to amino acids 860 to 1291 of SEQ ID NO: 16.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply the teachings of Liu regarding the amino acid sequence of the chimeric neurotoxin to the generic chimeric neurotoxin of claim 2 of ‘566. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu’s chimeric neurotoxin is a species of the chimeric neurotoxin recited in claim 2 of ‘566.
Regarding claims 75-77, claim 2 of ‘566 does not recite that the chimeric neurotoxin comprises amino acid substitutions E1191M and S1199Y.
Liu teaches the chimeric BoNT/AB comprises the substitutions E1191M and S1199Y (Chimera 1 of Table 3 on page 11). Therefore, the amino acid substitutions are necessarily in the BoNT/B receptor binding domain. Liu teaches that these mutations increase the binding affinity of BoNT/B neurotoxin for human synaptotagmin II (Syt II) as compared to the normal BoNT/B sequence ([0120] and [0122]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to introduce the E1191M and S1199Y into the chimeric neurotoxin of claim 2 of ‘566 modified by Liu and Kessler in order to increase the binding affinity of the neurotoxin for human synaptotagmin II, as suggested by Liu. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding claims 73 and 78, claim 2 of ‘566 does not recite proteolytically cleaving the chimeric neurotoxin with endoproteinase Lys-C or that the C-terminal amino acid residue of the BoNT/A translocation domain is covalently linked to the N-terminal amino acid residue of the BoNT/B receptor binding domain in the chimeric neurotoxin.
Liu teaches that the chimeric neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by Lys-C proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond, which is the active di-chain ([0004] and [0177]). Liu teaches the amino acid residues for the N- and C-terminal fragments of the di-chain (Chimera 3B in Table 3 on page 11). SEQ ID NO: 12 is the single-chain polypeptide form of the di-chain (Table 3 on page 11). Liu’s SEQ ID NO: 12 is identical to the instant SEQ ID NO: 14.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to proteolytically cleave the chimeric neurotoxin of Liu’s SEQ ID NO: 12 in order to produce the active di-chain form of the chimeric neurotoxin of claim 2 of ‘566 in which the C-terminal amino acid residue of the BoNT/A translocation domain is linked by a disulfide bond (covalent linkage) to the N-terminal amino acid residue of the BoNT/B receptor binding domain. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 3, 7-11, 52-55 and 71-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-73 of copending Application No. 19/665,308 (hereafter ‘308) in view of Liu (US 2019/0127427 A1) and Kessler et al. (Journal of neurology 246.4 (1999): 265-274).
Claims 1-66 of ‘308 are drawn to a modified BoNT/A comprising a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain. Claim 66 of ‘308 recites the modified BoNT/A comprises a polypeptide sequence having a least 70% identity to SEQ ID NO: 6. Claims 67 of ‘308 is drawn to a unit dosage form of modified BoNT/A comprising greater than 8000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain. Claims 70-72 of ‘308 further limit the unit dosage form. Claim 73 of ‘308 is drawn to a kit comprising the unit dosage form.
Claims 1-73 of ‘308 do not recite administering by intramuscular injection the modified BoNT/A to treat cervical dystonia in a subject in need thereof. Claims 1-73 of ‘308 do not recite the dose administered to the affected neck muscle in the subject is 750 pg to 17,000 pg. Claims 1-73 of ‘308 do not recite that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
Regarding instant claims 3 and 55, Liu teaches a chimeric neurotoxin suitable for use in treating cervical dystonia ([0145]). Liu teaches the chimeric neurotoxin SEQ ID NO: 12 ([0125]), which is identical to the instant SEQ ID NO: 14 (OA Appendix A). SEQ ID NO: 12 is a modified BoNT/A (Table 3: see Chimera 3B; A1 is the BoNT/A fragment and B1 is the BoNT/B fragment). Liu teaches a method for treating a subject comprising administering an effective amount of a chimeric neurotoxin to a human being ([0144]). By “effective amount,” it is meant that the chimeric neurotoxin or pharmaceutical composition is administered in a quantity sufficient to provide the effect for which it is indicated ([0144]). Liu teaches a preferred route of administration is intramuscular injection ([0152]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer the modified BoNT/A of claims 1-73 of ‘308 by intramuscular injection to a subject with cervical dystonia. The person of ordinary skill in the art would have been motivated by the teachings of Liu, who suggests administering a chimeric neurotoxin to treat cervical dystonia. The person of ordinary skill in the art would have had a reasonable expectation of success.
Liu quantifies the dose of chimeric neurotoxin that leads to DAS 4 (digit abduction score), which is an assessment of muscle weakening ([0165]). The DAS4 dose for chimera 2 was >300 pg/mouse (Table 5 on page 12).
Liu does not teach the dose to the affected neck muscle in the subject is 750 pg to 17,000 pg. Liu does not teach that the total dose administered during the treatment is between 750 pg to 170,000 pg of the modified BoNT/A.
However, Liu teaches that the dosage range required depends on the precise nature of the chimeric neurotoxin, the route of administration, the nature of the formulation, the age of the patient, the nature, extent, or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician ([0152]). Variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Kessler teaches a BoNT/A injection technique to treat cervical dystonia with BoNT/A (Abstract and page 266, right column, Toxin preparation and injection technique, paragraph 1). The toxin is diluted to 1.6 ng (1,600 pg) pure toxin per milliliter and injections are carried out with a 2 mL syringe (page 266, right column, Toxin preparation and injection technique, paragraph 1). The sternocleidomastoid muscle is injected at one or two sites, the splenius capitis muscle at three to six separate sites depending on muscle mass and neck diameter and the trapezius and lateral neck muscles (scalenii or levator scapulae) generally at two or three sites (page 266, right column, Toxin preparation and injection technique, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the unit dose of chimeric neurotoxin administered per injection site to the subject based on the teachings of Liu. The person of ordinary skill in the art would have had a reasonable expectation of success given that Liu already teaches guidelines for the amount of chimeric BoNT/AB administered to a mouse model and furthermore, Liu teaches that optimizing the dose is routine.
Regarding the total dose and instant claims 7-9, 11, and 52-54 it would have been further obvious to optimize by routine experimentation the total number of injection sites and consequently the total dose administered. The person of ordinary skill in the art would have had a reasonable expectation of success in the optimization of the number of injection sites and hence the total dose administered given that Kessler teaches guidelines regarding the number of injection sites per muscle and also teaches that the amount of botulinum toxin administered depends on the muscle mass.
Regarding instant claim 10, Kessler teaches that for some muscles (e.g. the sternocleidomastoid muscle), injecting a single injection site is sufficient (page 266, right column, Toxin preparation and injection technique, paragraph 1).
Instant claims 71-74 are obvious over claim 66 of ‘308 in view of Liu and Kessler.
Regarding instant claims 71-72, SEQ ID NO: 6 of ‘308 is identical to SEQ IDN O: 12 of Liu. Liu teaches a chimeric BoNT/AB having SEQ ID NO: 12 comprising fragments 1-872 and 860-1291 (Chimera 3B of Table 3 on page 11). Liu’s SEQ ID NO: 12 comprises the N-terminal fragment of the instant SEQ ID NO: 2 up to position N872 (OA Appendix C) and the C-terminal fragment of the instant SEQ ID NO: 16 starting at position I860 (OA Appendix B). Thus, Liu’s SEQ IDN O; 12 necessarily comprises a BoNT/A light-chain, a BoNT/A translocation domain, and a BoNT/B receptor binding domain.
Regarding claim 74, Liu’s SEQ ID NO: 12 (Table 3 on page 11) aligns up to the C-terminus of the instant SEQ ID NO: 16 at position 1291 (OA Appendix B), thus Liu’s modified BoNT/A comprises the BoNT/B receptor binding domain corresponding to amino acids 860 to 1291 of SEQ ID NO: 16.
Regarding claims 75-77, claims 1-73 of ‘308 do not recite that the modified BoNT/A comprises the amino acid substitutions E1191M and S1199Y.
Liu teaches the chimeric BoNT/AB comprises the substitutions E1191M and S1199Y (Chimera 1 of Table 3 on page 11). Therefore, the amino acid substitutions are necessarily in the BoNT/B receptor binding domain. Liu teaches that these mutations increase the binding affinity of BoNT/B neurotoxin for human synaptotagmin II (Syt II) as compared to the normal BoNT/B sequence ([0120] and [0122]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to introduce the E1191M and S1199Y into the modified BoNT/A of claims 1-73 of ‘308 in order to increase the binding affinity of the neurotoxin for human synaptotagmin II, as suggested by Liu. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding claims 73 and 78, claims 1-73 of ‘308 do not recite proteolytically cleaving the chimeric neurotoxin with endoproteinase Lys-C or that the C-terminal amino acid residue of the BoNT/A translocation domain is covalently linked to the N-terminal amino acid residue of the BoNT/B receptor binding domain in the chimeric neurotoxin.
Liu teaches that the chimeric neurotoxins are synthesized as a single-chain polypeptide that is modified post-translationally by Lys-C proteolytic cleavage to form two polypeptide chains joined together by a disulfide bond, which is the active di-chain ([0004] and [0177]). Liu teaches the amino acid residues for the N- and C-terminal fragments of the di-chain (Chimera 3B in Table 3 on page 11). SEQ ID NO: 12 is the single-chain polypeptide form of the di-chain (Table 3 on page 11). Liu’s SEQ ID NO: 12 is identical to the instant SEQ ID NO: 14.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to proteolytically cleave the chimeric neurotoxin of Liu’s SEQ ID NO: 12 in order to produce the active di-chain form of the modified BoNT/A of claims 1-73 of ‘308 in which the C-terminal amino acid residue of the BoNT/A translocation domain is linked by a disulfide bond (covalent linkage) to the N-terminal amino acid residue of the BoNT/B receptor binding domain. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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