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 1-2, 4-8, 19-24, 26-27, 29, 32, 39-41, 43-46, 48-49, and 52-54 are pending. Claims 3, 9-18, 25, 28, 30-31, 33-38, 42, 47, and 50-51 are cancelled. Claims 26-27, 29, 41, 45-46, and 48-49 are withdrawn.
Claims 1-2, 4-8, 19-24, 32, 39-40, 43-44, and 52-54 are under examination.
Claim 18 is cancelled rendering moot rejections of this claim.
The objection to the specification is withdrawn in view of the amendment to the specification filed on 09/10/2025.
In view of the claim amendment filed on 09/10/2025, the previous rejections under 35 U.S.C. 102(a)(1) are withdrawn; the previous rejection of claims 4-5 under 35 U.S.C. 112(d) is withdrawn; the nonstatutory double patenting rejection over claims 152-157 and 160-175 of copending Application No. 18/595,365 is withdrawn.
Copending U.S. Application No. 17/734,531 has been abandoned, so the provisional nonstatutory double patenting rejection over claims 1-2, 5, 9, 12, 19, 26, 40, 54, 71, 88, 95, 96, and 129-139 of ‘531 is withdrawn.
Response to Arguments
Applicant's arguments filed 9/10/2025 have been fully considered but they are not persuasive. Applicant traversed the rejection under 35 U.S.C. 103 and argued that Turkel’s teaching (that physicians are allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected were determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area) is too general to instruct a person of skill in the art to inject in electrode placement sites Fz, Pz, or Cz (Arguments, paragraph 1 on page 10).
In response, this argument is unpersuasive because in addition to Turkel’s teaching above regarding a patient-tailored approach determined by a physician, Turkel also teaches injection sites that directly neighbor Fz: Turkel’s fixed-site injection sites (Turkel Fig. 17) include F3 and F4, which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 4 on page 7).
With respect to the nonstatutory double patenting rejections of record, Applicant requests to hold the rejections over Application No. 18/244,279 in abeyance (Arguments, page 10, Double Patenting Rejection).
Per MPEP 804, part (I)(B)(1), only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.
Applicant also asserts that many of the applications cited in the rejections are not owned by Applicant and thus the nonstatutory double patenting rejections are improper (Arguments, page 10, Double Patenting Rejection).
However, all nonstatutory double patenting rejections made previously and in this action are over applications with common inventors and/or with a common assignee. Per MPEP 804, nonstatutory double patenting rejections over applications with a common inventor rather than a common assignee are also proper.
Claim Objections
Claims 22-24 are objected to because of the following informalities: the claim recites “Fz-and,” so there is either an extraneous hyphen or a missing space between “Fz” and “and.” 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.
(New Rejection Necessitated by Amendment) Claims 1-2, 4-8, 19-21, 32, 39-40, 43-44, and 52-54 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 1 recites injecting a botulinum toxin composition to at least 10 injection sites, wherein the at least 10 injection sites correspond to electrode placement sites selected from Cz, Pz, Fz, or any combination thereof, and to electrode placement sites selected from Fp1, Fp2, T3, T4, T5, T6, O1, O2, F3, F4, P3, P4, F7, F8, and Fpz. There are at least two different reasonable interpretations of this limitation, rendering claim 1 indefinite. In one interpretation, the at least 10 injection sites correspond to at least 10 electrode placement sites selected from Cz, Pz, Fz, Fp1, Fp2, T3, T4, T5, T6, O1, O2, F3, F4, P3, P4, F7, F8, and Fpz. In a second interpretation, the at least 10 injection sites require one or more electrode placement sites from Cz, Pz, and Fz and the remaining electrode placement sites are selected from Fp1, Fp2, T3, T4, T5, T6, O1, O2, F3, F4, P3, P4, F7, F8, and Fpz.
Claims 2, 4-8, 19-21, 32, 39-40, 43-44, and 52-54 are rejected for depending from a rejected base claim and not rectifying the source 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.
(New Rejection Necessitated by Amendment) Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 20 recites that the injection sites correspond to electrode placement sites selected from Cz, Pz, and Fz. However, claim 20, depends from claim 19, which depends from claim 1, which recites the at least 10 injection sites correspond to electrode placement sites selected from Cz, Pz, Fz, or any combination thereof and to electrode placement sites selected from Fp1, Fp2, T3, T4, T5, T6, O1, O1, F3, F4, P3, P4, F7, F8, and Fpz. Since Cz, Pz, and Fz, are listed separately from the remainder of the electrode placement sites, under one reasonable interpretation of the claim, they are already required, in which case claim 20 fails to further limit claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The following rejections are necessitated by Applicant’s amendment.
Claims 1-2, 4-8, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Turkel (EP 3 311 831 A1; cited in the Non-Final Action mailed on 3/10/2025) as evidenced by BitBrain (2018, website; cited in the Non-Final Action mailed on 3/10/2025) and Turkel2 (US 2017/0128552 A1; cited in the Non-Final Action mailed on 3/10/2025).
Claim 1 is interpreted as requiring that the at least 10 injection sites corresponding to Fpz. Claim 1 does not limit the depth of the injection. Therefore, claim 1 encompasses both intramuscular and extramuscular injection.
Regarding claim 1, Turkel teaches a method of treating headaches comprising injecting botulinum toxin into 31 fixed injection sites across seven head and neck muscles and optionally up to 8 additional injection sites into three specific muscles (Turkel claim 1 a)). Turkel Fig. 17 illustrates some of the injection sites (figure reproduced below). These injection sites include F3, F4, F7, F8 T3, T4, Fpz, Fp1, Fp2, O1, and O2 electrode placement sites (11 total sites) in the international 10-20 system, as evidenced by BitBrain (Fig. 3, panel B on page 5). See the red rectangles added by the examiner in the figures. Turkel specifies bilateral injection for the temporalis muscle (line 46 on page 10).
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Turkel Fig. 17. Red rectangles added by examiner outlining injection sites
corresponding to Fp1, Fpz, Fp2, F3, F4, F7, and F8 (leftmost panel), T3 and T4 (second panel from left), and O1 and O2 (third panel from left).
An EEG (electroencephalogram) detects electrical activity transmitted between neurons at locations of the brain’s cerebral cortex (i.e. “neuronal activity associated with EEG detectable brain cortical electrical activity”), as evidenced by Bitbrain: see page 2, Brain areas and function, bottom paragraph and page 4, “The 10-5, 10-10 and 10-20 EEG systems” paragraph 1). Electrode placement sites in the 10-20 system are named as Fp (fronto-polar), frontal (F), central (C), temporal (T), parietal (P), and occipital (O). Electrodes over the midline are labeled with the letter “z” (BitBrain, bullet points on page 6).
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BitBrain Fig. 3 on page 5 (red rectangles added by examiner).
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BitBrain Fig. 4 on page 7 (red rectangles added by examiner).
Turkel teaches that the botulinum toxin composition is administered with the diluent 0.9% sterile saline for injection ([0073]).
Turkel teaches that 155 U of toxin are administered at into 31-39 injection sites (Abstract on page 1, right column). 155 U is within the range of 100 U to 450 U. Per MPEP 2131.03(I), a specific example in the prior art which is within a claimed range anticipates the range.
Further regarding claims 1 and 20, Turkel does not teach the injection sites further correspond to electrode placement sites Cz, Pz, Fz, or any combination thereof, although Turkel’s fixed-site injection sites include F3 and F4, which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 3 on page 5 and Fig. 4 on page 7). Furthermore, Turkel teaches that physicians are allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected are determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area ([0074]). Therefore, in one embodiment, Turkel teaches additional injection sites tailored to the patient’s pain distribution pattern.
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 the method of Turkel by incorporating additional injection sites including the Fz injection site. This injection site is in the region of pain associated with migraine pain given that Turkel’s fixed-site injection sites include F3 and F4, which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 4 on page 7). The person of ordinary skill in the art would have had a reasonable expectation of success with additional injection sites, such as the neighboring Fz injection site, given that optimization based on patient pain distribution pattern is within the scope of Turkel’s disclosure.
Regarding claims 2 and 4-5, Turkel teaches the same injection protocol for the treatment of episodic headaches, chronic tension-type headaches, migraines with or without aura, and/or migrainous headaches ([0064]).
Regarding claim 6, Turkel teaches administering botulinum toxin to subjects who experience episodic migraines with a frequency of more than 16 headache days per month ([0064]). Therefore, Turkel teaches that the migraines are high-frequency episodic migraines.
Regarding claim 7, the botulinum toxin is serotype A ([0016]).
Regarding claim 8, the molecular weight of all seven serotypes of botulinum toxin is 150 kDa, as evidenced by Turkel2 ([0039]). Therefore, Turkel’s botulinum toxin of serotype A has a molecular weight of 150 kDa.
Regarding claim 19, Turkel’s injection sites further comprise the trapezius muscles (see Figure 17, injection sites labeled G) and the masseter muscle ([0072], [0112]).
Regarding claim 21, Turkel teaches a minimum of 31 injection sites at 0.1 mL of 5U Botulinum Toxin A for a fixed-site, fixed-dose injection (see Table 23, line 48 on page 31), which is slightly above the claimed range of 10-25 injection sites. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Claims 1, 20, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Turkel (EP 3 311 831 A1) as evidenced by BitBrain (2018, website) and Turkel2 (US 2017/0128552 A1), as applied to claims 1-2, 4-8, and 19-21 above, and further in view of Binder (U.S. Patent No. 10,401,297).
See discussion of Turkel and evidentiary references BitBrain and Turkel2 above, which is incorporated into this rejection as well.
Regarding claim 1, Turkel does not teach the injection sites further comprise C3, C4, Cz, P3, P4, and Pz.
Regarding claim 20, Turkel does not teach the injection sites further comprise Cz and Pz.
Regarding claim 32, Turkel does not teach that the injection volume is 100 to 400 µL per injection site.
However, Turkel teaches that physicians are allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected are determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area ([0074]). Therefore, in one embodiment, Turkel teaches additional injection sites tailored to the patient’s pain distribution pattern.
Binder teaches a method of treating a patient with a migraine headache comprising administering a therapeutically effective amount of botulinum toxin (Binder claim 1). Binder teaches several botulinum toxin injection sites (positions 10 and 20 in Fig. 1, lines 32-34 in column 3) that are in the vicinity of the frontal, central, and parietal electrode placement regions (BitBrain Figure 4 on page 7 and bullet 1 on page 6). Binder also teaches injecting botulinum toxin into the temporal area of the head for the treatment of migraine (lines 60-62, column 13).
Regarding claims 1 and 20, 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 the method of Turkel by administering at additional injection sites taught by Binder, which include injection sites in the vicinity of C3, Cz, C4, P3, Pz, P4, T5, and T6. It would have been further obvious to optimize the method by administering at additional injection sites based on the patient pain distribution, as suggested by Turkel.
Regarding claim 32, Binder teaches an injection volume of between 100 µL (0.1 cc) and 200 µL (0.2 cc). See Binder lines 57-59 on column 13. Binder’s range overlaps with the instantly claimed range of 100 to 400 µL. It would have been obvious to apply Binder’s guidance regarding injection volume to the method of Turkel, given Turkel’s silence on injection volume. The person of ordinary skill in the art would have had a reasonable expectation of success given that Binder’s method is in the same field of treating migraines by injecting a botulinum toxin.
Claims 39-40 and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Turkel (EP 3 311 831 A1) as evidenced by BitBrain (2018, website) and Turkel2 (US 2017/0128552 A1), as applied to claims 1-2, 4-8, and 19-21 above, and further in view of Reuter et al. (Headache: The Journal of Head and Face Pain 58 (2018): 48-59).
See discussion of Turkel and evidentiary references BitBrain and Turkel2 above, which is incorporated into this rejection as well.
Regarding claims 39-40 and 43, Turkel does not teach that the method further comprises administering the anti-CGRP antibody erenumab sequentially with the botulinum toxin composition.
Reuter teaches a human monoclonal antibody erenumab that significantly reduces episodic migraine headache frequency (page 50, right column, Role of novel targeted treatments in meeting goals of preventative therapy, first paragraph, page 51, left column, first paragraph). Reuter teaches that the calcitonin gene-related peptide (CGRP) pathway has been shown to have a pivotal role in migraine pathophysiology (page 50, right column, Role of novel targeted treatments in meeting goals of preventative therapy, first paragraph). Reuter teaches that erenumab is designed to target the calcitonin gene-related peptide (CGRP) receptor (page 50, right column, Role of novel targeted treatments in meeting goals of preventative therapy, first 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 combine the administration of erenumab with the administration of botulinum toxin taught by Turkel in order to increase the efficacy of treatment by targeting both pain signals and the CGRP receptor. The person of ordinary skill in the art would have had a reasonable expectation of success in the combination of two treatments each individually known to be effective in the treatment of headaches by different mechanisms. Furthermore, it would have been obvious to administer the erenumab sequentially with the botulinum toxin composition such that the patient would have experienced both pain relief and a reduction in frequency of headaches but would not have suffered injections at the same time.
Regarding claim 44, Turkel does not explicitly teach that the individual to which the botulinum toxin composition and erenumab are administered is a non-responder or insufficient responder to one or more triptan drugs.
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 Turkel by administering the botulinum toxin composition and erenumab to non-responder or insufficient responders to triptan drugs, given that non-responders or insufficient responders to triptans would have been in need of alternative migraine treatments. The person of ordinary skill in the art would have had a reasonable expectation of success because the mechanism of headache treatment by triptans (small molecule drugs) is different than both botulinum toxin and erenumab, as evidenced by Turkel2 ([0024]).
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.
The following rejections are necessitated by Applicant’s amendment.
Claims 1-2, 4-8, 19-24, 32, 39-40, 43-44, and 52-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 15-22 and 24-27 of copending Application No. 18/244,279 (reference application; hereafter ‘279) in view of Turkel (EP 3 311 831 A1; cited in the Non-Final Action mailed on 3/10/2025) as evidenced by BitBrain (2018, website).
Claim 1 is interpreted as requiring that the at least 10 injection sites corresponding to electrode sites are as follows: at least one electrode placement site is selected from Cz, Pz, and Fz and the remaining electrode placement sites are selected from Fp1, Fp2, T3, T4, T5, T6, O1, O2, F3, F4, P3, P4, F7, F8, and Fpz.
Claims 1-7, 15-17, 19-22 and 24-27 of ‘279 do not recite the total treatment dose of botulinum toxin. However, claim 18 of ‘279 recites that the treatment dose is 100 U to 450 U. Claims 2-7, 15-22 and 24-27 of ‘279 all depend from claim 1 and are all methods of treating or reducing frequency of headaches in an individual, thus 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 administer the treatment dose of 100 U to 450 U in the method of claims 1-7, 15-17, 19-22 and 24-27 of ‘279 as well.
Regarding claims 1 and 20, claims 1-7, 15-17, 19-22 and 24-27 of ‘279 do not recite the injection sites further correspond to electrode placement sites Cz, Pz, Fz, or any combination thereof,
Turkel teaches a method of treating headaches comprising injecting botulinum toxin into 31 fixed injection sites across seven head and neck muscles and optionally up to 8 additional injection sites into three specific muscles (Turkel claim 1 a)). Turkel Fig. 17 illustrates some of the injection sites (figure reproduced below). These injection sites include F3, F4, F7, F8 T3, T4, Fpz, Fp1, Fp2, O1, and O2 electrode placement sites (11 total sites) in the international 10-20 system, as evidenced by BitBrain (Fig. 3, panel B on page 5). Turkel specifies bilateral injection for the temporalis muscle (line 46 on page 10).
Turkel’s fixed-site injection sites included F3 and F4, which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 3 on page 5 and Fig. 4 on page 7). Furthermore, Turkel teaches that physicians are allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected are determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area ([0074]). Therefore, in one embodiment, Turkel teaches additional injection sites tailored to the patient’s pain distribution pattern.
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 the method of claims 1-7, 15-17, 19-22 and 24-27 of ‘279 by incorporating additional injection sites including the Fz injection site, which is in the region of pain associated with migraine pain given that Turkel’s fixed-site injection sites include F3 and F4 which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 3 on page 5 and Fig. 4 on page 7). The person of ordinary skill in the art would have had a reasonable expectation of success in including additional injection sites, such as the neighboring Fz injection site, given that optimization based on patient pain distribution pattern is within the scope of Turkel’s disclosure, which teaches many of the same injection sites as claims 1-7, 15-17, 19-22 and 24-27 of ‘279.
Claim 2 is unpatentable over claim 2 of ‘279 in view of Turkel because the claims both recite post-traumatic headache, a post-craniotomy headache, tension-type headache, cluster headache, and medication-overuse headache.
Claim 4 is unpatentable over claim 3 of ‘279 in view of Turkel.
Claim 5 is unpatentable over claim 4 of ‘279 in view of Turkel.
Claim 6 is unpatentable over claim 5 of ‘279 in view of Turkel.
Claim 7 is unpatentable over claim 6 of ‘279 in view of Turkel.
Claim 8 is unpatentable over claim 7 of ‘279 in view of Turkel.
Claim 19 is unpatentable over claims 16-17 of ‘279 in view of Turkel.
Claim 20 is unpatentable over claims 15-17 of ‘279 in view of Turkel.
Claim 21 is unpatentable over claims 1 and 15-17 of ‘279 in view of Turkel because claims 1 and 15-17 of ‘279 recite administering by injection an injectable botulinum toxin composition to a plurality of injection sites consisting of a list of electrode placement sites that includes a total number of sites between 2 and 17. The range of between 10 and 25 overlaps with between 2 and 17.
Claim 22 is unpatentable over claims 1 and 15-17 of ‘279 in view of Turkel.
Claims 23-24 are unpatentable over claims 16-17 of ‘279 in view of Turkel.
Claim 32 is unpatentable over claim 19 of ‘279 in view of Turkel.
Claim 39 is unpatentable over claims 20-22 and 24-27 of ‘279 in view of Turkel.
Claim 40 is unpatentable over claim 22 of ‘279 in view of Turkel.
Claim 43 is unpatentable over claim 27 of ’279 in view of Turkel.
Claim 44 is unpatentable over claim 25 of ‘279 in view of Turkel.
Claims 52-54 are unpatentable over claims 1 and 15-18 of ‘279 in view of Turkel because 200 to 300 U is within the range of 100 to 450 U. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 20, and 22-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-17 of copending Application No. 18/244,279 (reference application; hereafter ‘279) in view of Turkel (EP 3 311 831 A1; cited in the Non-Final Action mailed on 3/10/2025) as evidenced by BitBrain (2018, website) and Binder (U.S. Patent No. 10,401,297).
See discussion of claims 15-17 of ‘279 and Turkel above, which is incorporated into this rejection as well.
Regarding claims 1, 20, and 22-24, claims 15-17 of ‘279 do not recite and Turkel does not teach the injection sites further correspond to electrode placement site Cz and Pz.
However, Turkel teaches that physicians are allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected are determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area ([0074]). Therefore, in one embodiment, Turkel teaches additional injection sites tailored to the patient’s pain distribution pattern.
Binder teaches a method of treating a patient with a migraine headache comprising administering a therapeutically effective amount of botulinum toxin (Binder claim 1). Binder teaches several botulinum toxin injection sites (positions 10 and 20 in Fig. 1, lines 32-34 in column 3) that are in the vicinity of the frontal, central, and parietal electrode placement regions (BitBrain Figure 4 and bullet 1 on page 6). Binder also teaches injecting botulinum toxin into the temporal area of the head for the treatment of migraine (lines 60-62, column 13).
Regarding claims 1, 20, and 22-24, 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 the method of claims 15-17 of ‘279 modified by Turkel by incorporating additional injection sites taught by Binder, which include injection sites in the vicinity of C3, Cz, C4, P3, Pz, P4, T5, and T6. It would have been further obvious to optimize the method by incorporating additional injection sites based on the patient pain distribution, as suggested by Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the method to include additional injection sites, which was already suggested by Turkel.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 4-8, and 19-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 5-8, 10-12, 15-18, and 22-26 of copending Application No. 17/850,383 (hereafter ‘383) in view of Turkel as evidenced by BitBrain and Turkel2.
Claim 1 is interpreted as requiring that the at least 10 injection sites corresponding to electrode placement sites are as follows: at least one electrode placement site is selected from Cz, Pz, and Fz and the remaining electrode placement sites are selected from Fp1, Fp2, T3, T4, T5, T6, O1, O2, F3, F4, P3, P4, F7, F8, and Fpz.
Claim 2 of ‘383 is drawn to a method for treating, alleviating or reducing the intensity or frequency of occurrence of a migraine comprising administering a CGRP antagonist in combination with a clostridial derivative to a peripheral nerve, a cranial nerve, or combinations thereof, thereby treating alleviating or reducing the intensity or frequency of occurrence of the migraine, wherein the CGRP antagonist is an antibody to CGRP. Claims 5-8 and 10 of ‘383 further limit the method of claim 1.
Claims 12 and 22 of ‘383 are drawn to a method for treating, alleviating or reducing the intensity of frequency of occurrence of migraine comprising administering a CGRP antagonist in combination with a clostridial derivative, wherein the CGRP antagonist is a combination of an antibody to CGRP and a small molecule CGRP antagonist. Claims 15-18 of ‘583 further limit the method of claim 11 of ‘583. Claims 23-26 of ‘383 further limit the method of claim 21 of ‘383.
Claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 do not recite administering by injection a dose of an injectable botulinum toxin composition using an injection paradigm that provides botulinum toxin at one or more locations of neuronal activity associated with EEG detectable brain cortical electrical activity in the individual to achieve the therapeutic effect following treatment with the botulinum toxin composition; wherein the botulinum toxin composition comprises a botulinum toxin component and pharmaceutically acceptable diluent suitable for injection; and wherein the total treatment dose of botulinum toxin component administered to the individual is 100 U to 450 U which is administered in one or more injections sites.
Turkel teaches a method of treating headaches comprising injecting botulinum toxin into 31 fixed injection sites across seven head and neck muscles and optionally up to 8 additional injection sites into three specific muscles (Turkel claim 1 a)). Turkel Fig. 17 illustrates some of the injection sites (figure reproduced below). These injection sites include F3, F4, F7, F8 T3, T4, Fpz, Fp1, Fp2, O1, and O2 electrode placement sites in the international 10-20 system, as evidenced by BitBrain (Fig. 3, panel B on page 5). See the red rectangles added by the examiner in the figures.
An EEG (electroencephalogram) detects electrical activity transmitted between neurons at locations of the brain’s cerebral cortex (i.e. “neuronal activity associated with EEG detectable brain cortical electrical activity”), as evidenced by Bitbrain: see page 2, Brain areas and function, bottom paragraph and page 4, “The 10-5, 10-10 and 10-20 EEG systems” paragraph 1). Electrode placement sites in the 10-20 system are named as Fp (fronto-polar), frontal (F), central (C), temporal (T), parietal (P), and occipital (O). Electrodes over the midline are labeled with the letter “z” (BitBrain, bullet points on page 6).
Turkel teaches that the botulinum toxin composition is administered with the diluent 0.9% sterile saline for injection ([0073]).
Turkel teaches administering 155 total units of botulinum toxin (Table 23), which is within the claimed range of 100 to 450 U. See MPEP 2131.03(I).
Regarding claim 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 combine the method of claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 with the method of Turkel in order to treat headaches. The person of ordinary skill in the art would have had a reasonable expectation of success in the combination of two different treatments (botulinum toxin and CGRP antagonist) for the same purpose (headache treatment) that each relied on different mechanisms for treatment.
Further regarding claims 1 and 20, Turkel does not teach the injection sites further correspond to electrode placement sites Cz, Pz, Fz, or any combination thereof, although Turkel’s fixed-site injection sites include F3 and F4 which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 3 on page 5 and Fig. 4 on page 7). Furthermore, Turkel teaches that physicians are allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected were determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area ([0074]). Therefore, in one embodiment, Turkel teaches additional injection sites tailored to the patient’s pain distribution pattern.
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 the method of claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 modified by Turkel by incorporating additional injection sites including the Fz injection site. This injection site is in the region of pain associated with migraine pain given that Turkel’s fixed-site injection sites includes F3 and F4 which neighbor the Fz electrode placement site, as evidenced by BitBrain (Fig. 3 on page 5 and Fig. 4 on page 7). The person of ordinary skill in the art would have had a reasonable expectation of success with additional injection sites, such as the neighboring Fz injection site, given that Turkel teaches optimization based on patient pain distribution pattern.
Regarding claims 2 and 4-5, Turkel teaches the same injection protocol for the treatment of episodic headaches, chronic tension-type headaches, migraines with or without aura, and/or migrainous headaches ([0064]).
Regarding claim 6, Turkel teaches administering botulinum toxin to subjects who experience episodic migraines with a frequency of more than 16 headache days per month. Therefore, Turkel teaches that the migraines are high-frequency episodic migraines ([0064]).
Regarding claim7, the botulinum toxin is serotype A (Turkel [0016]).
Regarding claim 8, the molecular weight of all seven serotypes of botulinum toxin is 150 kDa, as evidenced by Turkel2 ([0039]). Therefore, Turkel’s botulinum toxin has a molecular weight of 150 kDa.
Regarding claim 19, Turkel’s injection sites further comprise the trapezius muscles (see Figure 17, injection sites labeled G) and the masseter muscle ([0112]).
Regarding claim 21, Turkel teaches a total of at least 31 injection sites (see Table 23, line 48 on page 31), which is slightly above the claimed range of 10-25 injection sites. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 39-40 and 43-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 5-8, and 10-12 of copending Application No. 17/850,383 (hereafter ‘383) in view of Turkel (EP 3 311 831 A1) as evidenced by BitBrain (2018, website) and Turkel2, as applied to claims 1-2, 4-8, and 19-21 above, further in view of Reuter et al. (Headache: The Journal of Head and Face Pain 58 (2018): 48-59).
See discussion of claims 2, 5-8, and 10-12 of ‘383, Turkel, and BitBrain above, which is incorporated into this rejection as well.
Regarding the instant claims 39-40 and 43, claims 2, 5-8, and 10-12 of ‘383 do not recite that the anti-CGRP antibody erenumab is administered sequentially with the botulinum toxin composition.
Reuter teaches a human monoclonal antibody erenumab that significantly reduces episodic migraine headache frequency (page 50, right column, “Role of novel targeted treatments in meeting goals of preventative therapy, first paragraph, page 51, left column, first paragraph). Reuter teaches that the calcitonin gene-related peptide (CGRP) pathway has been shown to have a pivotal role in migraine pathophysiology (page 50, right column, “Role of novel targeted treatments in meeting goals of preventative therapy,” first paragraph). Reuter teaches that erenumab is designed to target the calcitonin gene-related peptide (CGRP) receptor (page 50, right column, “Role of novel targeted treatments in meeting goals of preventative therapy, first 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 use erenumab as the CGRP antagonist antibody in the method of claims 2, 5-8, and 10-12 of ‘383. It would have been further obvious to combine the method of claims 2, 5-8, and 10-12 of ‘383 modified by Reuter with the administration of botulinum toxin taught by Turkel in order to increase the efficacy of treatment by targeting both pain signals and CGRP release. The person of ordinary skill in the art would have had a reasonable expectation of success in the combination of two treatments each individually known to be effective in the treatment of headaches by different mechanisms. Furthermore, it would have been obvious to administer erenumab sequentially with the botulinum toxin composition such that the patient would have experienced both pain relief and a reduction in frequency of headaches but would not have suffered injections at the same time.
Regarding claim 44, claims 2, 5-8, and 10-12 of ‘383 do not recite and Turkel does not explicitly teach that the individual to which the botulinum toxin composition is administered is a non-responder or insufficient responder to one or more triptan drugs.
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 Turkel’s botulinum toxin composition with the CGRP antagonist of claims 2, 5-8, and 10-12 of ‘383 to a non-responder or insufficient responder to triptans given that non-responders or insufficient responders would have been in need of an alternative treatment besides triptans. The person of ordinary skill in the art would have had a reasonable expectation of success because the mechanism of headache treatment by triptans (small molecule drugs) is different than both botulinum toxin and erenumab, as evidenced by Turkel2 ([0024]).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 20, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 5-8, 10-12, 15-18, and 22-26 of copending Application No. 17/850,383 (hereafter ‘383) in view of Turkel (EP 3 311 831 A1) as evidenced by BitBrain (2018, website) and Turkel2, as applied to claims 1-2, 4-8, and 19-21 above, further in view of Binder (U.S. Patent No. 10,401,297).
See discussion of claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383, Turkel, and BitBrain above, which is incorporated into this rejection as well.
Regarding claim 1, claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 do not recite and Turkel does not teach the injection sites further comprise C3, C4, P3, and P4.
Regarding claim 20, claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 do not recite and Turkel does not teach the injection sites further correspond to electrode placement site Cz and Pz.
Regarding claim 32, claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 do not recite and Turkel does not teach that the injection volume is 100 to 400 µL per injection.
However, Turkel teaches that physicians were allowed to use a more individualized or patient-tailored treatment approach and that the number of injection sites within each specified muscle area and dose injected were determined by the physician based on the patient’s usual pain distribution pattern and the severity of pain in the particular muscle area ([0074]). Therefore, in one embodiment, Turkel teaches additional injection sites tailored to the patient’s pain distribution pattern.
Binder teaches a method of treating a patient with a migraine headache comprising administering a therapeutically effective amount of botulinum toxin (Binder claim 1). Binder teaches several botulinum toxin injection sites (positions 10 and 20 in Fig. 1, lines 32-34 in column 3) that are in the vicinity of the frontal, central, and parietal electrode placement regions (BitBrain Figure 4 and bullet 1 on page 6). Binder also teaches injecting botulinum toxin into the temporal area of the head for the treatment of migraine (lines 60-62, column 13).
Regarding claims 1 and 20, 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 the method of claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 modified by Turkel by incorporating additional injection sites taught by Binder, which include injection sites in the vicinity of C3, Cz, C4, P3, Pz, P4, T5, and T6. It would have been further obvious to optimize the method by incorporating additional injection sites based on the patient pain distribution, as suggested by Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the method to include additional injection sites, which was already suggested by Turkel.
Regarding claim 32, Binder teaches an injection volume of between 100 µL (0.1 cc) and 200 µL (0.2 cc). See Binder lines 57-59 on column 13. Binder’s range overlaps with the instantly claimed range of 100 to 400 µL. It would have been obvious to apply Binder’s guidance regarding injection volume to the method of claims 2, 5-8, 10-12, 15-18, and 22-26 of ‘383 modified by Turkel, given Turkel’s silence on injection volume. The person of ordinary skill in the art would have had a reasonable expectation of success given that Binder’s method was highly similar (a method of treating migraines by injecting a botulinum toxin into the head).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 4-8, and 19-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,819,541 (‘541) in view of Turkel (EP 3 311 831 A1) as evidenced by BitBrain (2018, website) and by Turkel2 (US 2017/0128552 A1; cited on the IDS filed on12/12/2023).
Claim 1 is interpreted as requiring that the at least 10 injection sites corresponding to electrode placement sites are as follows: at least one electrode placement site is selected from Cz, Pz, and Fz and the remaining electrode placement sites are selected from Fp1, Fp2, T3, T4, T5, T6, O1, O2, F3, F4, P3, P4, F7, F8, and Fpz.
Claim 1 of ‘541 recites a method for the prophylaxis of headache in a patient with migraine comprising administering to the patient by intramuscular injection a composition comprising about 155 units of botulinum neurotoxin type A to a total of 31 injection sites across seven head and neck muscles, thereby reducing the frequency of occurrence of headache in the patient. Claims 2-11 further limit the method of claim 1 of ‘541. Claim 3 of ‘541 recites that the headache is a chronic migraine. Claim 4 of ‘541 recites that the headache is an episodic migraine. Claim 7 of ‘541 recites that the powdered BoNT/A pharmaceutical composition consists of the BoNT/A complex, human albumin, and sodium chloride (i.e. pharmaceutically acceptable diluents). Claim 12 of ‘541 is a similar method to claim 1 of ‘541 and claims 13-19 of ‘541 further limit the method of claim 12 of ‘541.
Claims 1 and 12 of ‘541 recite administering 155 total units of botulinum toxin (Table 23), which is within the claimed range of 100 to 450 U. See MPEP 2131.03(I) regarding obviousness of overlapping ranges.
However, claims 1-19 of ‘541 do not recite administering by injection a dose of an injectable botulinum toxin composition using an injection paradigm that provides botulinum toxin at one or more locations of neuronal activity associated with EEG detectable brain cortical electrical activity in the individual to achieve the therapeutic effect following treatment with the botulinum toxin composition; wherein the botulinum toxin composition comprises a botulinum toxin component and pharmaceutically acceptable diluent suitable for injection.
Turkel teaches a method of treating headaches comprising injecting botulinum toxin into 31 fixed injection sites across seven head and neck muscles and optionally up to 8 additional injection sites into three specific muscles (Turkel claim 1 a)). Turkel Fig. 17 illustrates some of the injection sites (figure reproduced below). These injection sites include F3, F4, F7, F8 T3, T4, Fpz, Fp1, Fp2, O1, and O2 electrode placement sites in the international 10-20 system, as evidenced by BitBrain (Fig. 3, panel B on page 5). See the red rectan