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 2, 4, 6-8, 32, and 34-36 are pending.
Claims 1, 3, 5, 9-31, 33, and 37 are cancelled.
Claim Objections
Claims 4, 7-8, and 36 are objected to because of the following informalities: levator palpebrae superiori should be levator palpebrae superioris. Appropriate correction is required.
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.
Claims 7 and 32 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 part (e) recites the broad recitation up to five doses, and the claim also recites preferably one dose in parenthesis, which is the narrower statement of the range. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claim 7 is further indefinite for (h) administering up to two unit doses (preferably one unit dose) and (j) administering up to two unit doses (preferably one unit dose) for the same reason.
In addition, claim 7 is indefinite because the claim recites the method further comprises administering one or more unit doses of the modified BoNT/A to one or more further muscles affected by the blepharospasm in accordance with the following dosage regiment: (a)-(m) (includes (a)-(c)). However, claim 7 depends from claim 2, which already recites steps a)-c). The use of both (a)-(c) and a)-c) leads to ambiguity in the claim scope as to whether the dosage regimen recited in claim 7 also includes the doses (a)-(c) recited in claim 2.
Claim 32 is similarly indefinite because the claim recites the method further comprises (a)-(c) but depends from claim 2, which recites a)-c).
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 2, 7, 32, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) in view of Liu et al. (US 2019/0127427 A1).
Regarding claims 2 and 7, Taylor teaches a method of treating blepharospasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the proceus and corrugator muscles on both sides at four to six sites (Fig. 1; page 134, left column, bottom two paragraphs). Based on Fig. 1, the injection points include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicular oculi muscle.
Taylor does not teach that the botulinum toxin is a modified BoNT/A comprising a BoNT/A light chain and translocation domain and a BoNT/B receptor binding domain.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC (heavy chain) domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace the BonT/A in the method of Taylor with the chimeric neurotoxin of Liu (“modified BoNT/A”). The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success in the substitution.
Taylor does not teach that the unit dose of the modified BoNT/A injected per muscle comprises at least 240 pg.
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]).
It would have been further 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 per muscle in the method of Taylor modified by Liu. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in the dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding claim 32¸ Taylor teaches bilateral injections for patients with blepharospasm (Fig. 1 and page 134, left column, bottom paragraph). Taylor’s injections include lateral upper orbicularis oculi, medial upper orbicularis oculi, and lateral lower orbicularis oculi muscles.
Regarding claim 34, Taylor teaches injecting between 2.5 and 5.0 MU of BonT/A at each site in all muscles except the ala nasi muscles and angular oris, which are injected 2.5 MU per injection (page 134, paragraph bridging left and right columns).
Taylor does not teach that a single unit dose is administered per injection site.
It would have been further 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 per injection site in each muscle. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding claim 35, Taylor teaches that the subjects are human (see the human face in Fig. 1).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) in view of Liu et al. (US 2019/0127427 A1), as applied to claims 2, 7, 32, and 34-35 above, further in view of Aramideh et al. (Movement disorders 9.4 (1994): 395-402).
The teachings of Taylor and Liu are incorporated into this rejection as well.
Taylor does not teach the method of treating blepharospasm further comprises injecting the levator palpebrae superioris muscle.
Aramideh teaches that some cases of blepharospasm further comprise dystonia (involuntary repetitive muscle contractions) in the levator palpebrae superioris muscle in addition to the orbicularis oris muscles (Abstract Summary, page 401, left column, bottom paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Taylor and Liu by injecting a unit dose of the chimeric BoNT/A (“modified BoNT/A”) of Liu into the levator palpebrae superioris muscle. The person of ordinary skill in the art would have been motivated by the teaching of Aramideh, who suggests that for s subset of patients with blepharospasm, muscle dysfunction is present in the levator palpebrae superioris. The person of ordinary skill in the art would have had a reasonable expectation of success in adding the additional injection site.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) in view of Liu et al. (US 2019/0127427 A1) as evidenced by Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
Taylor teaches a method of treating hemifacial spasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the procerus and corrugator muscles on the affected side at four to six sites and two or three injections of 2.5 MU in the angular oris and ala nasi muscles on the affected side of the face (Fig. 1; page 134, left column, bottom two paragraphs through right column, top paragraph). The ala nasi muscle is a subcomponent of the nasalis muscle.
Based on Fig. 1, the injection points include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicular oculi muscle.
Taylor’s method is generic to any hemifacial spasm, thus Taylor’s method is applicable to both atypical and typical hemifacial spasms, which differ only in the location of the onset and direction of progression. In atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles, as evidenced by Ryu (page 1173, left column, Summary, paragraph 1).
Taylor does not teach that the botulinum toxin is a modified BoNT/A comprising a BoNT/A light chain and translocation domain and a BoNT/B receptor binding domain.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace the BonT/A in the method of Taylor with the chimeric neurotoxin of Liu (“modified BoNT/A”). The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success in the substitution.
Taylor does not teach that the unit dose of the modified BoNT/A injected per muscle comprises at least 240 pg.
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]).
It would have been further 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 injected per muscle. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Claims 6 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) in view of Liu et al. (US 2019/0127427 A1) and Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
The teachings of Taylor and Liu, as applied to claim 4 above, are incorporated into this rejection as well.
Taylor does not teach administering the botulinum toxin into the orbicularis oris muscle.
Ryu teaches that in atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles (page 1173, left column, Summary, 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 modify the method of Taylor and Liu by injecting the chimeric BoNT/A of Liu (“modified BoNT/A”) into the orbicularis oris and buccinator muscles in order to further increase the efficacy of the method in treating atypical hemifacial spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in adding these additional injection sites.
Taylor does not teach that the unit dose of the modified BoNT/A injected per muscle comprises at least 240 pg.
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]).
It would have been further 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 dosage injected into the orbicularis oris and buccinator muscles. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
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 2, 7, 32, and 34-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of U.S. Patent No. 11,434,265 (hereafter ‘265) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138).
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 first neurotoxin is residues of 1-872 of SEQ ID NO: 1 (BoNT/A1) and the second neurotoxin is residues 860 to 1291 a SEQ ID NO: 2 (BoNT/B1).
Claim 6 of ‘265 does not recite intramuscularly administering a unit dose of the chimeric neurotoxin (“modified BoNT/A”) to the lateral upper orbicularis oculi, administering a unit dose of the chimeric neurotoxin to the medial upper orbicularis oculi, and administering a unit dose of the chimeric neurotoxin to the lateral lower orbicularis oculi of a subject to treat blepharospasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments (1-872 of BoNT/A1 and 860-1291 of BoNT/B1) as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively. In other words, Liu’s chimera 3B is the same as the chimeric neurotoxin recited in claim 6 of ‘265 and the chimeric neurotoxin of claim 6 of ‘265 necessarily comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating blepharospasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the proceus and corrugator muscles on both sides at four to six sites (Fig. 1; page 134, left column, bottom two paragraphs).
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Regarding instant claims 2 and 7, 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 (“modified BoNT/A”) of claim 6 of ‘265 in order to treat blepharospasm per method of Taylor. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
Claim 6 of ‘265 does not recite that the unit dose of the chimeric neurotoxin (“modified BoNT/A”) injected per muscle comprises at least 240 pg.
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]).
It would have been further 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 per muscle in the method of claim 6 of ‘265 modified by Liu and Taylor. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in the dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding instant claim 32¸ Taylor teaches bilateral injections for patients with blepharospasm (Fig. 1 and page 134, left column, bottom paragraph).
Regarding instant claim 34, Taylor teaches injecting between 2.5 and 5.0 MU of BonT/A at each site in all muscles except the ala nasi muscles and angular oris, which are injected 2.5 MU per injection (page 134, paragraph bridging left and right columns).
Taylor does not teach that a single unit dose is administered per injection site.
It would have been further 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 per injection site. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding instant claim 35, Taylor teaches that the subjects are human (see the human face in Fig. 1).
Claim 8 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of U.S. Patent No. 11,434,265 (hereafter ‘265) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138), as applied to claims 2, 7, 32, and 34-35 above, further in view of Aramideh et al. (Movement disorders 9.4 (1994): 395-402).
See discussion of claim 6 of ‘265, Liu, and Taylor above, which is incorporated into this rejection as well.
Claim 6 of ‘265 does not recite and Liu and Taylor do not teach the method of treating blepharospasm further comprises injecting a unit dose of the chimeric neurotoxin (“modified BoNT/A”) into the levator palpebrae superioris muscle.
Aramideh teaches that some cases of blepharospasm further comprise dystonia (involuntary repetitive muscle contractions) in the levator palpebrae superioris muscle in addition to the orbicularis oris muscles (Abstract Summary, page 401, left column, bottom paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of claim 6 of ‘265, Liu and Taylor by injecting a unit dose of the chimeric neurotoxin (“modified BoNT/A”) of claim 6 of ‘265 into the levator palpebrae superioris muscle. The person of ordinary skill in the art would have been motivated by the teaching of Aramideh, who suggests that for s subset of patients with blepharospasm, muscle dysfunction is present in the levator palpebrae superioris. The person of ordinary skill in the art would have had a reasonable expectation of success in adding the additional injection site.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of U.S. Patent No. 11,434,265 (hereafter ‘265) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) as evidenced by Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See above for the recitation of claim 6 of ‘265, which is incorporated into this rejection as well.
Claim 6 of ‘265 does not recite intramuscularly administering a unit dose of the modified BoNT/A into the lateral upper orbicularis oculi, administering a unit dose of the modified BoNT/A into the medial upper orbicularis oculi, and administering a unit dose of the modified BoNT/A into the lateral lower orbicularis oculi of a subject to treat typical hemifacial spasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1 (“modified BoNT/A”). Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively. In other words, Liu’s chimera 3B is the same as the chimeric neurotoxin recited in claim 6 of ‘265 and the chimeric neurotoxin of claim 6 of ‘265 necessarily comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating hemifacial spasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the procerus and corrugator muscles on the affected side at four to six sites and two or three injections of 2.5 MU in the angular oris and ala nasi muscles on the affected side of the at the sites.(Fig. 1; page 134, left column, bottom two paragraphs through right column, top paragraph). The ala nasi muscle is a subcomponent of the nasalis muscle.
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Taylor’s method is generic to any hemifacial spasm, thus Taylor’s method is applicable to both atypical and typical hemifacial spasms, which differ only in the location of the onset and direction of progression. In atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles, as evidenced by Ryu (page 1173, left column, Summary, 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 administer the chimeric neurotoxin (“modified BoNT/A”) of claim 6 of ‘265 in the method of Taylor to treat typical hemifacial spasm. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric BoNT/AB (“modified BoNT/A”) neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
Claim 6 of ‘265 does not recite and Taylor does not teach that the unit dose of the chimeric neurotoxin (“modified BoNT/A”) administered per muscle comprises at least 240 pg.
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]).
It would have been further 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 dosage injected into the muscles taught by Taylor. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Claims 6 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of copending Application No. (reference application; hereafter ‘265) in view of Liu et al. (US 2019/0127427 A1), Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) and Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See discussion of claim 6 of ‘265, Liu, and Taylor as applied to claim 4 above, which is incorporated into this rejection as well.
Claim 6 of ‘265 does not recite and Taylor does not teach administering a unit dose of the chimeric neurotoxin into the orbicularis oris muscle.
Ryu teaches that in atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles (page 1173, left column, Summary, 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 further modify the method of claim 6 of ‘265, Liu and Taylor by injecting the chimeric neurotoxin (“modified BoNT/A“) of claim 6 of ‘265 into the orbicularis oris and buccinator muscles in order to further increase the efficacy of the method in treating atypical hemifacial spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in adding these additional injection sites.
Claim 6 of ‘265 does not recite and Taylor does not teach that the unit dose of the chimeric neurotoxin (“modified BoNT/A”) administered per muscle comprises at least 240 pg.
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]).
It would have been further 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 dosage injected into the orbicularis oris and buccinator muscles. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Claims 2, 4, 6-7, 32, 34, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4, 6, 8-10, 12, 24, 28, 31, 39-40, 45-46 and 52 of copending Application No. 19/665,322 (reference application; hereafter ‘322). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 2, 4, 6-7, 32, 34, and 36 are anticipated by claims 2-4, 6, 8-10, 12, 24, 28, 31, 39-40, 45-46 and 52 of ‘322.
Claims 2-4, 6, 8-10, 24, 24, 28, 31, 39-40, 45-46 and 52 of ‘322 are drawn to a method comprising administering a unit dose of modified BoNT/A per injection site, wherein the injection sites are selected from the lateral upper orbicularis oculi muscle, the medial upper orbicularis oculi muscle and the lateral lower orbicularis oculi muscle, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain. Claims 2-4, 6, 24, 28, 31, 39-40, and 45-46 of ‘322 are drawn to a method of treating blepharospasm.
Claims 8-10 of ‘322 are drawn to a method of treating typical hemifacial spasm.
Claim 12 of ‘322 is drawn to a method of treating an atypical hemifacial spasm comprising administering the modified BoNT/A to the orbicularis oris muscles.
Instant claim 2 is anticipated by claims 2-4, 8, 24, 24, 28, 31, 39-40, 45-46 and 52 of ‘322.
Instant claim 4 is anticipated by claims 8-10 of ‘322.
Instant claim 6 is anticipated by claim 12 of ‘322.
Instant claim 7 is anticipated by claim 2 of ‘322 for the embodiment in which the further muscles are the procerus and corrugator muscles.
Instant claim 32 is anticipated by claim 4 of ‘322.
Instant claim 34 is anticipated by claim 52 of ‘322.
Instant claim 36 is anticipated by claim 12 of ‘322.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 19/665,322 (reference application; hereafter ‘322) in view of Aramideh et al. (Movement disorders 9.4 (1994): 395-402).
See above for the recitation of claim 2 of ‘322.
Claim 2 of ‘322 does not recite the method of treating blepharospasm further comprises injecting the levator palpebrae superioris muscle.
Aramideh teaches that some cases of blepharospasm further comprise dystonia (involuntary repetitive muscle contractions) in the levator palpebrae superioris muscle in addition to the orbicularis oris muscles (Abstract Summary, page 401, left column, bottom paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of claim 2 of ‘322 by injecting a unit dosage of the chimeric BoNT/A (“modified BoNT/A”) into the levator palpebrae superioris muscle. The person of ordinary skill in the art would have been motivated by the teaching of Aramideh, who suggests that for s subset of patients with blepharospasm, muscle dysfunction is present in the levator palpebrae superioris. The person of ordinary skill in the art would have had a reasonable expectation of success in adding the additional injection site.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 of copending Application No. 19/665,322 (reference application; hereafter ‘322) in view of Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138).
See above for the recitation of claim 2 of ‘322.
Claim 2 of ‘322 does not recite the subject is human.
Taylor teaches a method for treating blepharospasm in a human subject (Abstract and see the human face in Fig. 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 apply the method of claim 2 of ‘322 to a human subject in order to treat blepharospasm per the teaching of Taylor. The person of ordinary skill in the art would have had a reasonable expectation of success. Therefore, instant claim 35 is obvious over claim 2 of ‘322 in view of Taylor.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2, 4, 6-8, 32, 34, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 5, 9, 14, and 26 of copending Application No. 18/851,469 (reference application; hereafter ‘469). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 2, 4, 6-8, 32, 34, and 36 are anticipated by claims 2, 5, 9, 14, and 26 of ‘469.
Instant claim 2 is anticipated by claim 2 of ‘469.
Instant claim 4 is anticipated by claim 9 of ‘469.
Instant claim 6 is anticipated by claim 14 of ‘469.
Instant claim 7 is anticipated by claim 2 of’ 469 for the embodiment in which the further muscles affected by the blepharospasm are the procerus and/or the corrugator.
Instant claim 8 is anticipated by claim 26 of ‘469.
Instant claim 32 is anticipated by claim 5 of ‘469.
Instant claim 34 is anticipated by claim 2 of ‘469.
Instant claim 36 is anticipated by claim 14 of ‘469.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 35 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18/851,469 (reference application; hereafter ‘469) in view of Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138).
See above for the recitation of claim 2 of ‘469.
Regarding instant claim 35, claim 2 of ‘469 does not recite the subject is a human.
Taylor teaches a method of treating blepharospasm in a human subject (Abstract and see the human face in Fig. 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 apply the method of claim 2 of ‘469 to a human subject in order to treat blepharospasm per the teaching of Taylor. The person of ordinary skill in the art would have had a reasonable expectation of success. Therefore, instant claim 35 is obvious over claim 2 of ‘469 in view of Taylor.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2, 7, 32 and 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 52 of copending Application No. 18/851,566 (reference application; hereafter ‘566) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138).
Claim 52 of ‘566 recites a unit dosage form of chimeric botulinum neurotoxin BoNT/AB comprising greater than 17,000 pg of BoNT/AB, wherein the BoNT/AB comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
The range of greater than 17,000 pg overlaps with the presently claimed range of at least 240 pg.
Claim 52 of ‘566 does not recite intramuscularly administering a unit dose of the BoNT/AB to lateral upper orbicularis, administering a unit dose of the BoNT/AB to the medial upper orbicularis, and administering a unit dose of the BoNT/AB to the lateral lower orbicularis of a subject to treat blepharospasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating blepharospasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the proceus and corrugator muscles on both sides at four to six sites (Fig. 1; page 134, left column, bottom two paragraphs).
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicular oculi muscle.
Regarding instant claims 2 and 7, 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 BonT/AB of claim 52 of ‘566 in order to treat blepharospasm per the method of Taylor. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding instant claim 32¸ Taylor teaches bilateral injections for patients with blepharospasm (Fig. 1 and page 134, left column, bottom paragraph).
Regarding instant claim 34, Taylor teaches injecting between 2.5 and 5.0 MU of BoNT/A at each site in all muscles except the ala nasi muscles and angular oris, which are injected 2.5 MU per injection (page 134, paragraph bridging left and right columns).
Taylor does not teach that a single unit dose is administered per injection site.
It would have been further 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 per injection site. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding instant claim 35, Taylor teaches that the subjects are human (see the human face in Fig. 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 52 of copending Application No. 18/851,566 (reference application; hereafter ‘566) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138), as applied to claims 2, 7, 32, and 34-35 above, further in view of Aramideh et al. (Movement disorders 9.4 (1994): 395-402).
See discussion of claim 52 of ‘566, Liu, and Taylor above, which is incorporated into this rejection as well.
Claim 52 of ‘566 does not recite and Liu and Taylor do not teach the method of treating blepharospasm further comprises injecting a unit dose of the BoNT/AB into the levator palpebrae superioris muscle.
Aramideh teaches that some cases of blepharospasm further comprise dystonia (involuntary repetitive muscle contractions) in the levator palpebrae superioris muscle in addition to the orbicularis oris muscles (Abstract Summary, page 401, left column, bottom paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of claim 52 of ‘566, Liu and Taylor by injecting a unit dose of the chimeric BoNT/AB (“modified BoNT/A”) of claim 52 of ‘566 into the levator palpebrae superioris muscle. The person of ordinary skill in the art would have been motivated by the teaching of Aramideh, who suggests that for s subset of patients with blepharospasm, muscle dysfunction is present in the levator palpebrae superioris. The person of ordinary skill in the art would have had a reasonable expectation of success in adding the additional injection site.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 52 of copending Application No. 18/851,566 (reference application; hereafter ‘566) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) as evidenced by Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See above for the recitation of claim 52 of ‘566, which is incorporated into this rejection as well.
Claim 52 of ‘566 recites a unit dosage form of chimeric botulinum neurotoxin BoNT/AB comprising greater than 17,000 pg of BoNT/AB, wherein the BoNT/AB comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
The range of greater than 17,000 pg overlaps with the presently claimed range of at least 240 pg.
Claim 52 of ‘566 does not recite intramuscularly administering a unit dose of the BoNT/AB to lateral upper orbicularis oculi, administering a unit dose of the BoNT/AB to the medial upper orbicularis oculi, and administering a unit dose of the BoNT/AB to the lateral lower orbicularis oculi of a subject to treat typical hemifacial spasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating hemifacial spasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the procerus and corrugator muscles on the affected side at four to six sites and two or three injections of 2.5 MU in the angular oris and ala nasi muscles on the affected side of the at the sites.(Fig. 1; page 134, left column, bottom two paragraphs through right column, top paragraph). The ala nasi muscle is a subcomponent of the nasalis muscle.
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Taylor’s method is generic to any hemifacial spasm, thus Taylor’s method is applicable to both atypical and typical hemifacial spasms, which differ only in the location of the onset and direction of progression. In atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles, as evidenced by Ryu (page 1173, left column, Summary, 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 administer a unit dose of the BoNT/AB of claim 52 of ‘566 in the method of Taylor. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6 and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 52 of copending Application No. 18/851,566 (reference application; hereafter ‘566) in view of Liu et al. (US 2019/0127427 A1), Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) and Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See discussion of claim 52 of ‘566, Liu and Taylor as applied to claim 4 above, which is incorporated into this rejection as well.
Claim 52 of ‘566 does not recite and Taylor does not teach administering the botulinum toxin into the orbicularis oris muscle.
Ryu teaches that in atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles (page 1173, left column, Summary, 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 further modify the method of claim 52 of ‘566, Liu and Taylor by injecting a unit dose of the chimeric BoNT/A of Liu (“modified BoNT/A”) into the orbicularis oris and buccinator muscles in order to further increase the efficacy of the method in treating atypical hemifacial spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in adding these additional injection sites.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2, 7, 32 and 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 84 of copending Application No. 18/851,590 (reference application; hereafter ‘590) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138).
Claim 84 of ‘590 recites a unit dosage form of modified botulinum neurotoxin A comprising greater than 17,000 pg of modified BoNT/A and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
The range of greater than 17,000 pg overlaps with the presently claimed range of at least 240 pg.
Claim 84 of ‘590 does not recite intramuscularly administering a unit dose of the BoNT/AB to lateral upper orbicularis oculi, administering a unit dose of the BoNT/AB to the medial upper orbicularis oculi, and administering a unit dose of the BoNT/AB to the lateral lower orbicularis oculi of a subject to treat blepharospasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating blepharospasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the proceus and corrugator muscles on both sides at four to six sites (Fig. 1; page 134, left column, bottom two paragraphs).
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Regarding instant claims 2 and 7, 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 claim 84 of ‘590 in order to treat blepharospasm per method of Taylor. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding instant claim 32¸ Taylor teaches bilateral injections for patients with blepharospasm (Fig. 1 and page 134, left column, bottom paragraph).
Regarding instant claim 34, Taylor teaches injecting between 2.5 and 5.0 MU of BonT/A at each site in all muscles except the ala nasi muscles and angular oris, which are injected 2.5 MU per injection (page 134, paragraph bridging left and right columns).
Taylor does not teach that a single unit dose is administered per injection site.
It would have been further 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 per injection site. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding instant claim 35, Taylor teaches that the subjects are human (see the human face in Fig. 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 84 of copending Application No. 18/851,590 (reference application; hereafter ‘590) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138), as applied to claims 2, 7, 32, and 34-35 above, further in view of Aramideh et al. (Movement disorders 9.4 (1994): 395-402).
See discussion of claim 84 of ‘590, Liu, and Taylor above, which is incorporated into this rejection as well.
Claim 84 of ‘590 does not recite and Liu and Taylor do not teach the method of treating blepharospasm further comprises injecting a unit dose of the modified BoNT/A into the levator palpebrae superioris muscle.
Aramideh teaches that some cases of blepharospasm further comprise dystonia (involuntary repetitive muscle contractions) in the levator palpebrae superioris muscle in addition to the orbicularis oris muscles (Abstract Summary, page 401, left column, bottom paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of claim 84 of ‘590, Liu and Taylor by injecting a unit dose of the modified BoNT/A of claim 84 of ‘590 into the levator palpebrae superioris muscle. The person of ordinary skill in the art would have been motivated by the teaching of Aramideh, who suggests that for s subset of patients with blepharospasm, muscle dysfunction is present in the levator palpebrae superioris. The person of ordinary skill in the art would have had a reasonable expectation of success in adding the additional injection site.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 84 of copending Application No. 18/851,590 (reference application; hereafter ‘590) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) as evidenced by Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See above for the recitation of claim 84 of ‘590, which is incorporated into this rejection as well.
The range of greater than 17,000 pg overlaps with the presently claimed range of at least 240 pg.
Claim 84 of ‘590 does not recite intramuscularly administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi, administering a unit dose of the BoNT/AB to the medial upper orbicularis oculi, and administering a unit dose of the BoNT/AB to the lateral lower orbicularis oculi of a subject to treat typical hemifacial spasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating hemifacial spasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the procerus and corrugator muscles on the affected side at four to six sites and two or three injections of 2.5 MU in the angular oris and ala nasi muscles on the affected side of the at the sites.(Fig. 1; page 134, left column, bottom two paragraphs through right column, top paragraph). The ala nasi muscle is a subcomponent of the nasalis muscle.
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Taylor’s method is generic to any hemifacial spasm, thus Taylor’s method is applicable to both atypical and typical hemifacial spasms, which differ only in the location of the onset and direction of progression. In atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles, as evidenced by Ryu (page 1173, left column, Summary, 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 administer the modified BoNT/A of claim 84 of ‘590 in the method of Taylor to treat typical hemifacial spasms. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6 and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 84 of copending Application No. 18/851,590 (reference application; hereafter ‘590) in view of Liu et al. (US 2019/0127427 A1), Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) and Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See discussion of claim 84 of ‘590, Liu, and Taylor as applied to claim 4 above, which is incorporated into this rejection as well.
Claim 84 of ‘590 does not recite and Taylor does not teach administering the botulinum toxin into the orbicularis oris muscle.
Ryu teaches that in atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles (page 1173, left column, Summary, 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 further modify the method of claim 84 of ‘590, Liu and Taylor by injecting a unit dose of the modified BoNT/A of claim 84 of ‘590 into the orbicularis oris and buccinator muscles in order to further increase the efficacy of the method in treating atypical hemifacial spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in adding these additional injection sites.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2, 7, 32 and 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 137 of copending Application No. 19/351,105 (reference application; hereafter ‘105) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138).
Claim 137 of ‘105 recites a unit dosage form of modified BoNT/A comprising 750 pg to 17,000 pg of BoNT/AB, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain.
The range of 750 pg to17,000 pg overlaps with the presently claimed range of at least 240 pg.
Claim 137 of ‘105 does not recite intramuscularly administering a unit dose of the modified BoNT/A to lateral upper orbicularis oculi, administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi, and administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi of a subject to treat blepharospasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1. Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating blepharospasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the proceus and corrugator muscles on both sides at four to six sites (Fig. 1; page 134, left column, bottom two paragraphs).
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Regarding instant claims 2 and 7, 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 claim 137 of ‘105 in order to treat blepharospasm per method of Taylor. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
Regarding instant claim 32¸ Taylor teaches bilateral injections for patients with blepharospasm (Fig. 1 and page 134, left column, bottom paragraph).
Regarding instant claim 34, Taylor teaches injecting between 2.5 and 5.0 MU of BonT/A at each site in all muscles except the ala nasi muscles and angular oris, which are injected 2.5 MU per injection (page 134, paragraph bridging left and right columns).
Taylor does not teach that a single unit dose is administered per injection site.
It would have been further 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 per injection site. The person of ordinary skill in the art would have had a reasonable expectation of success based on Liu’s teaching that variations in these dosage levels can be adjusted using standard empirical routines for optimization ([0152]).
Regarding instant claim 35, Taylor teaches that the subjects are human (see the human face in Fig. 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 137 of copending Application No. 19/351,105 (reference application; hereafter ‘105) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138), as applied to claims 2, 7, 32, and 34-35 above, further in view of Aramideh et al. (Movement disorders 9.4 (1994): 395-402).
See discussion of claim 137 of ‘105, Liu, and Taylor above, which is incorporated into this rejection as well.
Claim 137 of ‘105 does not recite and Liu and Taylor do not teach the method of treating blepharospasm further comprises injecting a unit dose of the modified BoNT/A the levator palpebrae superioris muscle.
Aramideh teaches that some cases of blepharospasm further comprise dystonia (involuntary repetitive muscle contractions) in the levator palpebrae superioris muscle in addition to the orbicularis oris muscles (Abstract Summary, page 401, left column, bottom paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of claim 137 of ‘105, Liu and Taylor by injecting a unit dose of the modified BoNT/A of claim 137 of ‘105 into the levator palpebrae superioris muscle. The person of ordinary skill in the art would have been motivated by the teaching of Aramideh, who suggests that for s subset of patients with blepharospasm, muscle dysfunction is present in the levator palpebrae superioris. The person of ordinary skill in the art would have had a reasonable expectation of success in adding the additional injection site.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 137 of copending Application No. 19/351,105 (reference application; hereafter ‘105) in view of Liu et al. (US 2019/0127427 A1) and Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) as evidenced by Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See above for the recitation of claim 137 of ‘105, which is incorporated into this rejection as well.
The range of 750 pg to 17,000 pg overlaps with the presently claimed range of at least 240 pg.
Claim 137 of ‘105 does not recite intramuscularly administering a unit dose of the modified BoNT/A to lateral upper orbicularis oculi, administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi, and administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi of a subject to treat typical hemifacial spasm.
Liu teaches a modified BoNT/A comprising the light chain and translocation domain of BoNT/A and the heavy chain of BoNT/B (Table 2, Table 3, [0004], [0032]). The HC domain comprises a C-terminal targeting component ([0004]) or receptor binding domain. The LHN domain consists of an endopeptidase domain (light chain) and the domain responsible for translocation of the endopeptidase into the cytoplasm ([0032]). Chimera 3B of Table 3 includes residues 1-872 of BoNT/A1 and 860-1291 of BoNT/B1 (“modified BoNT/A”). Table 2 identifies these fragments as LHN (comprising the light chain and translocation domains) and HC (heavy chain comprising the targeting component or “receptor binding domain”), respectively.
Liu teaches that the chimeric neurotoxin with enhanced properties is suitable for use in treating various spasmodic conditions including blepharospasm and hemifacial spasm (Abstract and [0145]). Liu teaches that chimera 3B displayed greater potency than recombinant BoNT/A1 in cleaving SNAP 25 ([0199]).
Taylor teaches a method of treating hemifacial spasm in a human subject comprising injecting BoNT/A into the pretarsal preseptal muscles, the pretarsal orbicularis muscles, the procerus and corrugator muscles on the affected side at four to six sites and two or three injections of 2.5 MU in the angular oris and ala nasi muscles on the affected side of the at the sites.(Fig. 1; page 134, left column, bottom two paragraphs through right column, top paragraph). The ala nasi muscle is a subcomponent of the nasalis muscle.
Based on Fig. 1, the injection points into the pretarsal preseptal muscles and the pretarsal orbicularis muscles include the lateral (farther away from the middle line of the body) upper orbicularis oculi muscle, the medial (towards the midline of the body) upper orbicularis oculi muscle, and the lateral lower orbicularis oculi muscle.
Taylor’s method is generic to any hemifacial spasm, thus Taylor’s method is applicable to both atypical and typical hemifacial spasms, which differ only in the location of the onset and direction of progression. In atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles, as evidenced by Ryu (page 1173, left column, Summary, 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 administer the modified BoNT/A of claim 137 of ‘105 in the method of Taylor. The person of ordinary skill in the art would have been motivated by the teaching of Liu, who suggests that the chimeric BoNT/AB (“modified BoNT/A”) neurotoxins display greater potency than recombinant BoNT/A. The person of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6 and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 137 of copending Application No. 19/351,105 (reference application; hereafter ‘105) in view of Liu et al. (US 2019/0127427 A1), Taylor et al. (Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 26.3 (1991): 133-138) and Ryu et al. (Acta neurochirurgica 140.11 (1998): 1173-1176).
See discussion of claim 137 of ‘105, Liu, and Taylor as applied to claim 4 above, which is incorporated into this rejection as well.
Claim 137 of ‘105 does not recite and Taylor does not teach administering the botulinum toxin into the orbicularis oris muscle.
Ryu teaches that in atypical hemifacial spasms, the spasms first affect the orbicularis oris and buccinator muscles and then spread to the orbicularis oculi, whereas in typical hemifacial spasms, the spasms first affect the orbicularis oculi and then spread to the orbicularis oris and buccinator muscles (page 1173, left column, Summary, 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 further modify the method of claim 137 of ‘105, Liu and Taylor by injecting a unit dose of the modified BoNT/A of claim 137 of ‘105 into the orbicularis oris and buccinator muscles in order to further increase the efficacy of the method in treating atypical hemifacial spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in adding these additional injection sites.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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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