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 37-53 are pending and under examination on their merits.
Response to Arguments
Applicant’s arguments, see bottom paragraph on page 2, filed 3/2/2026, with respect to the rejection of claims 40-45 under 35 U.S.C. 112(d) have been fully considered and are persuasive. The rejection of claims 40-45 under 35 U.S.C. 112(d) has been withdrawn.
Applicant’s arguments, see paragraph 2 on page 2, filed 3/2/2026, with respect to the rejection of claims 47-48 under 35 U.S.C. 112(b) have been fully considered. The rejection of claim 48 is withdrawn. However, the rejection of claim 47 is maintained. There is a discrepancy between the sequences and the sequence identifiers in parentheses regarding the number of glycines at the N- and C-terminus of the sequence, thus the sequence identifier in parentheses leads to ambiguity in the claim scope because it differs from the recited sequence.
Applicant's remaining arguments filed 3/2/2026 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claims 37-39, 47-50 and 52-53 under 35 U.S.C. 103 over Ruegg in view of Leon on the grounds that Leon’s disclosure is not enabling because it is unclear whether Leon recites a total treatment dose range or the dose range within which each of the injected major muscles (Arguments, bottom paragraph on page 3).
Irrespective of the interpretation of Leon’s dosing, optimization of the total dose of botulinum toxin would have been routine for the person of ordinary skill in the art. Thus, the person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the dose of botulinum toxin administered to Leon’s muscle groups.
Applicant argues further against the rejection of claims 37-39, 47-50 and 52-53 under 35 U.S.C. 103 on the grounds that the improved response (as measured by Modified Ashworth Score) while maintaining high safety values at the highest dose group, 500 U, is an unexpected result (Arguments, paragraph 1 on page 4).
In response, this result is not unexpected. The prior art of Kirshblum et al. (PM&R 12.4 (2020): 349-355) teaches that high doses of up to 600 U of botulinum toxin are both safe and effective in the treatment of spasticity (Abstract Conclusions).
Applicant argues against the rejection of claim 40 under 35 U.S.C. 103 over Ruegg in view of Leon and Park on the grounds that the rejection does not establish why optimization of Ruegg's botulinum toxin A composition in the flexor digitorum profundus and the flexor digitorum superficialis for the treatment of upper limb spasticity comprising clenched fist would have been routine (Arguments, paragraph 1 on page 5).
In response, the rejection clearly states “The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.” Optimization for therapeutic effect is routine in the pharmaceutical sciences. For example, Park teaches that the injection doses for each muscle or muscle group are calculated based on body weight (page 592, right column, top paragraph after Table 2). Therefore, the person of ordinary skill in the art, such as a medical practitioner who injects botulinum toxin for therapeutic effect, would have clearly understood that optimization for therapeutic effect, using parameters such as body weight, is routine.
Applicant submits that the amendment overcomes the nonstatutory double patenting rejections of record and does not submit further arguments regarding the nonstatutory double patenting rejections (Arguments, page 6, Double Patenting Rejection).
In response, the amendment does not overcome the nonstatutory double patenting rejections of record because high doses of botulinum toxin for the treatment of spasticity are taught by the prior art of Kirshblum et al. (PM&R 12.4 (2020): 349-355), as discussed above.
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 37-53 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.
(New Rejection Necessitated by Amendment) Claim 37 recites a new limitation, wherein the individual presents with one or more types of upper limb spasticity comprising a flexed elbow, a flexed wrist and either a clenched fist or flexed fingers, in the last two lines. The limitation is subject to multiple reasonable interpretations, rendering the claim indefinite. Under one interpretation, the individual presents with one or more types of upper limb spasticity selected from a group. Under this interpretation, the claim is indefinite because the claim presents an open list of alternatives rather than a closed list of alternatives (“comprising” rather than “consisting of”). Under the second interpretation, the individual presents with upper limb spasticity comprising the three listed types (flexed elbow, flexed wrist, and clenched fist or flexed elbow, flexed wrist, and flexed fingers).
(New Rejection Necessitated by Amendment) Claim 38 recites: The method according to claim 37, wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm. The term “can” renders the claim indefinite because it is unclear whether the condition is required or not.
(New Rejection Necessitated by Amendment) Claim 39 recites: wherein the individual presents with the one or more types of upper limb spasticity consisting of a flexed elbow, a flexed wrist and either a clenched fist or flexed fingers. This limitation has multiple reasonable interpretations, rendering the claim indefinite. In one interpretation, the individual presents with one or more types of upper limb spasticity selected from the group consisting of a flexed elbow, a flexed wrist and a clenched fist; or with one or more types of upper limb spasticity selected from the group consisting of a flexed elbow, a flexed wrist, and flexed fingers. In a second interpretation, the individual presents with upper limb spasticity consisting of a flexed elbow, a flexed wrist, and a clenched fist; or the individual presents with upper limb spasticity consisting of a flexed elbow, a flexed wrist, and flexed fingers. Under the first interpretation, one or more types of upper limb spasticity are required, whereas under the second interpretation, three types of upper limb spasticity are required.
(Maintained Rejection) Claim 47 recites sequence identifiers (SEQ ID NO: 1, 2, or 3). The parentheses render the claim indefinite because it is unclear whether the sequence identifiers inside the parentheses are part of the claimed invention.
(New Rejection Necessitated by Amendment) Claims 38-53 are rejected for depending from a rejected base claim and not rectifying the sources of indefiniteness discussed above.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(New Rejection Necessitated by Amendment) Claims 39 and 49 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 39 fails to include all the limitations of the claim upon which it depends. Claim 39 limits the upper limb spasticity to flexed elbow, flexed wrist and either a clenched fist or a flexed finger. These types do not include the adducted and internally rotated shoulder recited in claim 38.
Claim 49 fails to include all the limitations of the claim upon which it depends because claim 49 requires a total treatment dose of 250 to 500 U, which is outside of the range recited in claim 1 (500 U to 700 U).
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
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.
The following rejections are necessitated by the amendment.
Claims 37-39 and 46-53 are rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355).
Ruegg teaches a method comprising administering by injection a dose of a sterile injectable composition into an area of the individual in need of treatment, wherein the composition comprises a botulinum toxin and a positively charged polylysine backbone having covalently attached thereto one or more positively charged efficiency groups ([0021]).
Ruegg teaches that the composition comprises botulinum toxin serotype A with molecular weight of 150 kDa ([0024]). Ruegg teaches that albumin may be omitted from the composition ([0039]). Ruegg teaches that the composition comprises a non-ionic surfactant ([0038]) and a pharmaceutically acceptable diluent such as phosphate buffered saline ([0054]), which is a diluent suitable for injection. Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]).
Ruegg teaches that the method achieves an extended duration therapeutic effect in an individual ([0021]). The extended duration effect is at least 6 months ([0068]), which overlaps with the claimed range of at least 16 weeks.
Ruegg teaches that the composition treats muscle spasms ([0018]). Ruegg exemplifies administering the composition to treat various spasms, including hemifacial spasm, adult onset spasmodic torticollis or neck spasms (Ruegg claim 18). Ruegg also teaches administering the botulinum to treat muscle spasms in the shoulders, palms, dorsa of the hands, or upper arms ([0064]). In summary, Ruegg teaches treating upper limb spasticity (e.g. muscle spasms in the upper arms).
Ruegg does not exemplify a specific total treatment dose for upper limb spasticity. Ruegg teaches a broad range of total treatment dose from 1 U to 400 U ([0066]). However, Ruegg exemplifies a total treatment dose of 40U for cosmetic treatment ([0140]), which is less than the claimed range of 500 U to 700 U.
Leon teaches injecting 50 to 300 units of botulinum toxin in the major muscles involved in severe closing of hand (“clenched fist”) and curling of wrist (“flexed wrist”) and curling of the forearm (“flexed elbow”). “Flexed wrist” is given its broadest reasonable interpretation in light of the specification as encompassing flexing the wrist in either direction. Therefore, a flexed wrist encompasses a curled wrist. See Figure 1 of the instant specification and specification [0016]. “Flexed elbow” encompasses curling of the forearm. See Figure 1 of the instant specification. See page 19, lines 8-11. Leon teaches that botulinum toxin type A is typically used to treat neuromuscular conditions (lines 10-11 on page 4).
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 Ruegg by increasing the total treatment dose per Leon’s teaching to specifically treat clenched fist, flexed wrist, and flexed elbow upper limb spasticity. The person of ordinary skill in the art would have had a reasonable expectation of success in modifying the dosage given that Leon also administers botulinum toxin serotype A.
The range of 50 to 300 units is less than the claimed range of 500 U to 700 U (claim 1).
Kirshblum teaches that higher doses than 400 units are efficacious and, at times, necessary to treat limb spasticity (bottom line bridging left and right columns on page 349). Kirshblum teaches that doses up to 600 units do not increase risk of adverse events (Abstract Conclusions).
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 total treatment dose of botulinum toxin within the range taught by Kirshblum (up to 600 units). The person of ordinary skill in the art would have been motivated to maximize the efficacy of treatment while minimizing adverse events. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the total botulinum toxin dose.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. Thus, claim 38 is also rejected here for the embodiment in which the upper limb spasticity does not comprise an adducted and internally rotated shoulder and/or pronated forearm.
Regarding claims 38-39, Leon exemplifies treating a patient suffering from spasticity resulting in clenched fist, flexed wrist, and flexed elbow or suffering from spasticity resulting in closed legs (page 19, lines 8-15). Thus, a patient presenting with upper limb spasticity consisting of clenched fist, flexed wrist, and flexed elbow is within the scope of Leon’s example.
Regarding claims 46 and 51, Kirshblum teaches that for high-dose botulinum injections used to treat spasticity, the risk of adverse events is 3.0% and the risk of unintended muscle weakness is 1.7% (Title and page 351, right column, bottom paragraph Adverse Events). Kirshblum tests three different levels of botulinum toxin doses: less than 400 units, 401-600 units, and greater than 600 units (Table 2). Only doses greater than 600 units result in greater risk (Table 2).
Regarding claims 47-48, Ruegg teaches that the positively charged carrier is a polylysine covalently attached to one or more positively charged efficiency groups that have an amino acid sequence selected from SEQ ID NO: 1-3 ([0023], pages 22-23). In one embodiment, the positively charged carrier is SEQ ID NO: 4 ([0023], page 23), which is SEQ ID NO: 3 covalently attached to both ends of a polylysine. SEQ ID NO: 1-4 are the same as the instant SEQ ID NO: 1-4. See OA Appendix A-D.
Regarding claim 49, Kirshblum teaches a treatment dose for spasticity of less than 600 U, which overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, Ruegg teaches that the method achieves an extended duration therapeutic effect in an individual ([0021]). The extended duration effect is at least 6 months ([0068]), which overlaps with the claimed range of between 16 and 26 weeks.
Regarding claims 52-53, Ruegg teaches the composition further comprises a sugar such as trehalose, sucrose, or raffinose ([0058]). Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]). Ruegg teaches that the composition may contain a buffer such as citric acid, acetic acid, succinic acid, tartaric acid, maleic acid, or histidine in order to maintain the pH between 4.5 and 7.5 ([0060]).
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, and further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of Ruegg and Leon above, which is incorporated into this rejection as well.
Regarding claim 40, Ruegg or Leon does not teach injecting botulinum toxin A into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat upper limb spasticity comprising clenched fist.
Park teaches injecting botulinum toxin into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat clenched hand (“clenched fist’) in children with cerebral palsy (Title and page 590, right column, Muscle selection, 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 Ruegg by injecting the botulinum toxin A composition into the flexor digitorum profundus and flexor digitorum superficialis in order to treat upper limb spasticity comprising clenched fist per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of Ruegg’s botulinum toxin into the muscle groups taught by Park.
Park teaches that 200 U are injected into the flexor digitorum profundus (Table 3, “FDP,” on page 593). 200 U is above the presently claimed range. Park does not teach how many units of botulinum toxin are injected into the flexor digitorum superficialis.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the total treatment dose of Ruegg’s botulinum toxin A composition in the flexor digitorum profundus and the flexor digitorum superficialis for the treatment of upper limb spasticity comprising clenched fist. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, and further in view of Turkel et al. (US 9,078,892 B2) as evidenced by Lung et al. (StatPearl website, 2024).
See discussion of Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 41, Ruegg does not teach injecting the botulinum toxin A composition into the flexor carpi ulnaris muscles in order to treat upper limb spasticity comprising a flexed wrist.
Turkel teaches injecting 15 U to 60 U into the flexor carpi radialis muscle to treat upper limb spasticity ((6)(d) column 10).
Turkel teaches injecting 10 U to 40 U botulinum toxin into the flexor carpi ulnaris to treat upper limb spasticity ((6)(c) column 10). Turkel teaches injecting 15 U to 60 U of botulinum toxin into the flexor carpi radialis to treat upper limb spasticity (column 10 (6)(d)).
Spasticity in the flexor carpi ulnaris muscle necessarily flexes the wrist because “spasticity” is involuntary contraction of a muscle and contracting the flexor carpi ulnaris muscle flexes the hand (synonymous with flexing the wrist) as evidenced by Lung (Introduction lines 1-2).
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 Ruegg by injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris in order to treat upper limb spasticity per the teaching of Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of Ruegg’s botulinum toxin A into the flexor carpi radialis and flexor carpi ulnaris muscles taught by Turkel.
Turkel’s total treatment dose of 15 U to 60 U to the flexor carpi radialis and 10 U to 40 U to the flexor carpi ulnaris overlaps with the claimed range of 50 U to 100 U. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, and further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding clam 42, Ruegg does not teach injecting the botulinum toxin A composition into the biceps, brachioradialis, and brachialis muscles in order to treat upper limb spasticity comprising a flexed elbow.
Park teaches injecting botulinum toxin into the biceps, brachioradialis, and brachialis muscles to treat upper limb spasticity comprising flexed elbow (page 590, right column, Muscle selection, 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 Ruegg by injecting the botulinum toxin A composition into the biceps, brachioradialis, and brachialis muscles in order to treat upper limb spasticity comprising a flexed elbow per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of Ruegg’s botulinum toxin A into the muscle groups taught by Park.
Park teaches 20 U of botulinum toxin is injected into the biceps and 10 U into the brachioradialis (Table 3, “BR” is brachioradialis). 30 total U is less than the claimed range of 200 U to 300 U. However, Park does not teach how many units of botulinum toxin are injected into the brachialis muscle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of Ruegg’s botulinum A composition injected into the biceps, brachioradialis and brachialis muscles for the treatment of upper limb spasticity comprising a flexed elbow. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Claims 38 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, and further in view of Figus et al. (Journal of plastic, reconstructive & aesthetic surgery 62.7 (2009): 869-875) as evidenced by Peak Performance Fitness (2017, website).
See discussion of Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. This rejection applies to the embodiment in which the individual presents with upper limb spasticity further comprising an adducted and internally rotated shoulder and/or pronated forearm.
Ruegg does not teach injecting the composition into the pectoralis complex and latissimus dorsi muscle to treat spasms that result in internal shoulder rotation.
Figus teaches injecting botulinum toxin A into the latissimus dorsi (LD) muscle and pectoralis major (part of the pectoralis complex) in order to treat muscular twitching or contractions (page 870, left column, paragraph 6 and page 870, right column, last full paragraph). Each patient receives 100 U of botulinum toxin A (page 870, left column, first paragraph after Table 2). Figus also teaches injecting botulinum toxin into the pectoralis major (PM) muscle to treat myopasms (sudden involuntary contraction in the muscle; page 870, left column, paragraph 4).
Although Figus does not teach that the muscle spasms result in an adducted and internally rotated shoulder, contractions of the latissimus dorsi muscle necessarily result in adduction and internal shoulder rotation as evidenced by Peak Performance Fitness (page 2, paragraph 2). Therefore, Figus’s patients necessarily present this symptom because they suffer from latissimus dorsi muscle contractions.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to inject Ruegg’s botulinum toxin composition into the pectoralis complex and the latissimus dorsi muscles of patients in order to treat internal shoulder rotation resulting from the muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success given that Figus teaches that botulinum toxin A is useful in treating both pectoralis major and latissimus dorsi muscle spasms and Ruegg teaches injecting a botulinum toxin A composition to treat shoulder spasms [0064].
Figus teaches a treatment dose of 100 U (page 870, left column, first paragraph after Table 2), which is within the claimed range of 50 U to 100 U.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, and further in view of Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212) and Wong et al. (Journal of child neurology 17.2 (2002): 138-142).
See discussion of Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Ruegg does not teach injecting the botulinum toxin A composition into the pronator teres and pronator quadratus in order to treat spasticity resulting in a pronated forearm.
Yadav teaches injecting between 50 and 180 U of botulinum toxin A into the pronator teres in order to treat pronation posture and spasticity in cerebral palsy patients (Abstract Introduction, Abstract Results, page 210, left column, first full paragraph after Table 2). Pronation posture in cerebral palsy includes the pronation of the forearm (page 209, left column, 2.1 Methods, paragraph 3)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to inject Ruegg’s botulinum toxin A composition into the pronator teres of cerebral palsy patients suffering from pronated forearm associated with muscle spasms in the pronator teres. The person of ordinary skill in the art would have had a reasonable expectation of success given that Yadav teaches that injecting botulinum toxin A into the pronator teres treats pronation posture and spasticity in cerebral palsy patients.
Yadav does not teach injecting botulinum toxin into the pronator quadratus.
Wong teaches injecting 50 U of botulinum toxin into the pronator quadratus for the treatment of spasticity in children with cerebral palsy (Abstract, page 139, left column, top 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 include the additional injection site of the pronator quadratus taught by Wong in the method of Ruegg modified by Yadav. The person of ordinary skill in the art would have been motivated to further improve the method for the treatment of upper limb spasticity in patients with cerebral palsy. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of the pronator quadratus injection site.
The total treatment dose of the combination of Yadav’s 50 U to 180 U of botulinum toxin injected to the pronator teres with Wong’s 50 U to the pronator quadratus overlaps with the claimed range of 50 U to 100 U.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, and further in view of Tonkin et al. (The Journal of hand surgery, European volume 33.1 (2008): 77. Web) and Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212).
See discussion of Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Ruegg does not teach injecting the botulinum toxin A composition into the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles in order to treat upper limb spasticity comprising thumb-in-palm.
Tonkin teaches that patients with cerebral palsy often suffer from thumb deformity due to muscle imbalance (page 77, left column, lines 1-4). Tonkin teaches that the thumb-in-palm posture in cerebral palsy patients stems from muscle spasticity in the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles (page 78, left column, bottom paragraph). Tonkin also teaches injecting botulinum toxin as a non-operative treatment (paragraph bridging pages 78-79).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to inject Ruegg’s botulinum toxin A composition into the muscles taught by Tonkin (adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous) in order to treat upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the treatment given that Tonkin teaches the muscles involved in thumb-in-palm and suggests injecting botulinum toxin for treatment.
Tonkin does not teach how much botulinum toxin is injected.
Yadav teaches injecting botulinum toxin into the adductor pollicis muscle to treat thumb-in palm with a maximum of 50 U per injection site (page 209, right column)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the amount of botulinum toxin injected into the muscles taught by Tonkin for the treatment of upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the therapeutic dose.
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 the amendment.
Claims 37-39, 46-51, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-155, 160-161, 163, 169, 171, and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355).
Claim 152 of ‘365 is drawn to a method of administering botulinum toxin to achieve a therapeutic effect in an individual comprising administering by injection a treatment dose of a sterile injectable composition into an area of the individual in need thereof, wherein the composition comprises a pharmaceutically acceptable diluent suitable for injection, and a positively charged peptide carrier having an amino acid sequence SEQ ID NO: 4, wherein the treatment dose is about 10 U to about 100 U.
SEQ ID NO: 4 of ‘365 is identical to the instant SEQ ID NO: 4 and consists of a positively charged backbone (polylysine) covalently attached to a positively charged efficiency group with the amino acid sequence SEQ ID NO: 3.
Claim 152 of ‘365 does not recite that composition comprises albumin, so in one embodiment the composition is albumin-free.
Claim 153 of ‘365 recites that the treatment achieves an extended duration of effect for at least about 28 weeks. The range of at least about 28 weeks overlaps with the claimed range of at least 16 weeks.
Claim 154 of ‘365 recites that the composition comprises botulinum toxin of serotype A.
Claim 155 of ‘365 recites that the botulinum toxin of serotype A has a molecular weight of 150 kDa.
Claims 160-161 of ‘365 recite that the composition comprises an excipient selected from a group consisting of L-Histidine, L-Histidine hydrochloride, polysorbate 20, and trehalose. Claim 161 of ‘365 limits the excipient to trehalose.
Claims 163, 169, and 171 of ‘365 recite that the therapeutic effect is reduction of a symptom associated with cerebral palsy.
Claims 173-175 of ‘365 recite that the composition comprises a non-ionic surfactant and a buffer.
The treatment dose of about 10 U to about 100 U recited in claim 152 of ‘365 is less than the claimed range of between 500 U to 700 U.
Leon teaches injecting 50 to 300 units of botulinum toxin in the major muscles involved in severe closing of hand (“clenched fist”) and curling of wrist (“flexed wrist”) and curling of the forearm (“flexed elbow”). See page 19, lines 8-11. Leon teaches that botulinum toxin type A is typically used to treat neuromuscular conditions (lines 10-11 on page 4).
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 claims 152-155, 163, 169, 171, and 173-175 of ‘365 to inject the botulinum toxin A composition into muscles in order to treat upper limb spasticity. It would have been further obvious to increase the total treatment dose per Leon’s teaching to specifically treat upper limb spasticity in the form of clenched fist, flexed wrist, and flexed elbow. The person of ordinary skill in the art would have had a reasonable expectation of success in modifying the dosage given that Leon also administers botulinum toxin serotype A.
The range of 50 to 300 units is less than the claimed range of 500 U to 700 U.
Kirshblum teaches that higher doses than 400 units are efficacious and, at times, necessary to treat limb spasticity (bottom line bridging left and right columns on page 349). Kirshblum teaches that doses up to 600 units do not increase risk of adverse events (Abstract Conclusions).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dose of botulinum toxin within the range taught by Kirshblum (up to 600 units). The person of ordinary skill in the art would have been motivated to maximize the efficacy of treatment while minimizing adverse events. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the total botulinum toxin dose.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. Thus, claim 38 is also rejected here for the embodiment in which the upper limb spasticity does not further comprise an adducted and internally rotated shoulder and/or pronated forearm.
Regarding claims 38-39, Leon exemplifies treating a patient suffering from spasticity resulting in clenched fist, flexed wrist, and flexed elbow or suffering from spasticity resulting in closed legs (page 19, lines 8-15). Thus, a patient presenting with upper limb spasticity consisting of clenched fist, flexed wrist, and flexed elbow is within the scope of Leon’s example.
Regarding claims 46 and 51, Kirshblum teaches that for high-dose botulinum injections used to treat spasticity, the risk of adverse events is 3.0% and the risk of unintended muscle weakness is 1.7% (Title and page 351, right column, bottom paragraph Adverse Events). Kirshblum tests three different levels of botulinum toxin doses: less than 400 units, 401-600 units, and greater than 600 units (Table 2). Only doses greater than 600 units result in greater risk (Table 2)
Regarding claims 47-48, the composition recited in claims 152 of ‘365 comprises SEQ ID NO: 4. SEQ ID NO: 4 of ‘365 is identical to the instant SEQ ID NO: 4. SEQ ID NO: 4 consists of a positively charged backbone (polylysine) covalently attached to a positively charged efficiency group with the amino acid sequence SEQ ID NO: 3.
Regarding claim 49, Kirshblum teaches a treatment dose for spasticity of less than 600 U, which overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, claim 153 of ‘365 recites that the treatment achieves an extended duration of effect for at least about 28 weeks. The range of at least about 28 weeks is approaching the claimed range of between 16 and 26 weeks.
Claim 52 is obvious over claims 160-161 and 173-175 in view of Leon.
This is a provisional nonstatutory double patenting rejection.
Claim 53 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 160-161 and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1), Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39, 46-51, and 52 above, further in view of Ruegg (US 2018/0311333 A1).
See discussion of claims 160-161 and 173-175 of ‘365, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 53, claim 160-161 and 173-175 of ‘365 do not recite and Leon does not teach that the histidine is buffered to a pH between 4.5 and 6.8.
Ruegg teaches a method comprising administering by injection a dose of a sterile injectable composition into an area of the individual in need of treatment, wherein the composition comprises a botulinum toxin and a positively charged polylysine backbone having covalently attached thereto one or more positively charged efficiency groups ([0021]).
Ruegg teaches that the composition may contain a buffer such as citric acid, acetic acid, succinic acid, tartaric acid, maleic acid, or histidine in order to maintain the pH between 4.5 and 7.5 ([0060]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the composition within the pH range that Ruegg teaches. The person of ordinary skill in the art would have been motivated to apply the same pH range because Ruegg also teaches a composition comprising a botulinum toxin and a positively charged carrier. The person of ordinary skill in the art would have had a reasonable expectation of success in doing so.
This is a provisional nonstatutory double patenting rejection.
Claims 40 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-155, 160-161, 163, 169, 171, and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39, 46-51, and 52 above, further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 40, claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite injecting botulinum toxin A into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat upper limb spasticity comprising clenched fist.
Park teaches injecting botulinum toxin into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat clenched hand (“clenched fist’) in children with cerebral palsy (Title and page 590, right column, Muscle selection, 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 claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 modified by Leon and Kirshblum by additionally injecting the botulinum toxin A composition into the flexor digitorum profundus and the flexor digitorum superficialis in order to treat upper limb spasticity comprising clenched fist per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 into the muscle groups taught by Park.
Park teaches that 200 U are injected into the flexor digitorum profundus (Table 3, “FDP,” on page 593). 200 U is above the presently claimed range. Park does not teach how many units of botulinum toxin are injected into the flexor digitorum superficialis.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the total treatment dose of botulinum A composition in the method of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 for the treatment of muscle spasms in the flexor digitorum profundus and flexor digitorum superficialis to treat upper limb spasticity comprising clenched fist. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Regarding clam 42, claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite injecting the botulinum toxin A composition into biceps, brachioradialis and brachialis muscles in order to treat upper limb spasticity comprising a flexed elbow.
Park teaches injecting botulinum toxin into the biceps, brachioradialis, and brachialis muscles to treat upper limb spasticity comprising flexed elbow (page 590, right column, Muscle selection, 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 further modify the method of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 modified by Leon and Kirshblum by injecting the botulinum toxin A composition into the biceps, brachioradialis, and brachialis muscles in order to treat upper limb spasticity comprising flexed elbow per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of botulinum toxin into the muscle groups taught by Park.
Park teaches 20 U of botulinum toxin are injected into the biceps and 10 U are injected into the brachioradialis (Table 3, “BR” is brachioradialis). 30 total U is less than the claimed range of 200 U to 300 U. However, Park does not teach how many units of botulinum toxin are injected into the brachialis muscle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum A composition injected into the biceps, brachioradialis and brachialis muscles for the treatment of upper limb spasticity comprising flexed elbow. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
This is a provisional nonstatutory double patenting rejection.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-155, 160-161, 163, 169, 171, and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39, 46-51, and 52 above, further in view of Turkel et al. (US 9,078,892 B2) as evidenced by Lung et al. (StatPearl website, 2024).
See discussion of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 41, claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris muscles in order to treat upper limb spasticity comprising a flexed wrist.
Turkel teaches injecting 10 U to 40 U botulinum toxin into the flexor carpi ulnaris to treat upper limb spasticity ((6)(c) column 10).
Turkel teaches injecting 15 U to 60 U into the flexor carpi radialis muscle to treat upper limb spasticity ((6)(d) column 10).
Spasticity in the flexor carpi ulnaris muscle necessarily flexes the wrist because “spasticity” is involuntary contraction of a muscle and contracting the flexor carpi ulnaris muscle flexes the hand (synonymous with flexing the wrist) as evidenced by Lung (Introduction lines 1-2).
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 claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 modified by Leon and Kirshblum by injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris in order to treat upper limb spasticity comprising a flexed wrist per the teaching of Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of botulinum toxin into the flexor carpi ulnaris and flexor carpi radialis muscles taught by Turkel.
Turkel’s total treatment dose of 10 U to 40 U to the flexor carpi ulnaris and 15 U to 60 U to the flexor carpi radialis is within the claimed range of 50 U to 100 U.
This is a provisional nonstatutory double patenting rejection.
Claims 38 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-155, 160-161, 163, 169, 171, and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39, 46-51, and 52 above, further in view of Figus et al. (Journal of plastic, reconstructive & aesthetic surgery 62.7 (2009): 869-875) as evidenced by Peak Performance Fitness (2017, website).
See discussion of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. This rejection applies to the embodiment in which the individual presents with upper limb spasticity further comprising an adducted and internally rotated shoulder and/or pronated forearm.
Claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite injecting the composition into the pectoralis complex and latissimus dorsi muscles to treat spasms that result in internal shoulder rotation.
Figus teaches injecting botulinum toxin A into the latissimus dorsi (LD) muscle and pectoralis major (part of the pectoralis complex) in order to treat muscular twitching or contractions (page 870, left column, paragraph 6 and page 870, right column, last full paragraph). Each patient receives 100 U of botulinum toxin A (page 870, left column, first paragraph after Table 2). Figus also teaches injecting botulinum toxin into the pectoralis major (PM) muscle to treat myopasms (sudden involuntary contraction in the muscle; page 870, left column, paragraph 4).
Although Figus does not teach that the muscle spasms result in an adducted and internally rotated shoulder, contractions of the latissimus dorsi muscle necessarily result in adduction and internal shoulder rotation as evidenced by Peak Performance Fitness (page 2, paragraph 2). Therefore, Figus’s patients necessarily present this symptom because they suffer from latissimus dorsi muscle contractions.
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 claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 by injecting the botulinum toxin composition into the pectoralis complex and latissimus dorsi muscle of patients in order to treat internal shoulder rotation resulting from the muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success given that Figus teaches that botulinum toxin A is useful in treating both pectoralis major and latissimus dorsi muscle spasms.
Figus teaches a treatment dose of 100 U (page 870, left column, first paragraph after Table 2), which is within the claimed range of 50 U to 100 U.
This is a provisional nonstatutory double patenting rejection.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-155, 160-161, 163, 169, 171, and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39, 46-51, and 52 above, further in view of Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212) and Wong et al. (Journal of child neurology 17.2 (2002): 138-142).
See discussion of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite injecting the botulinum toxin A composition into the pronator teres or the pronator quadratus in order to treat spasticity resulting in a pronated forearm.
Yadav teaches injecting between 50 and 180 U of botulinum toxin A into the pronator teres in order to treat pronation posture and spasticity in cerebral palsy patients (Abstract Introduction, Abstract Results, page 210, left column, first full paragraph after Table 2). Pronation posture in cerebral palsy includes the pronation of the forearm (page 209, left column, 2.1 Methods, paragraph 3)
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 claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 by injecting the botulinum toxin A composition into the pronator teres of cerebral palsy patients suffering from pronated forearm associated with muscle spasms in the pronator teres. The person of ordinary skill in the art would have had a reasonable expectation of success given that Yadav teaches that injecting botulinum toxin A into the pronator teres treats pronation posture and spasticity in cerebral palsy patients.
Yadav does not teach injecting botulinum toxin into the pronator quadratus.
Wong teaches injecting 50 U of botulinum toxin A into the pronator quadratus for the treatment of spasticity in children with cerebral palsy (Abstract, page 139, left column, top 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 include the additional injection site of the pronator quadratus taught by Wong in the method of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 modified by Yadav. The person of ordinary skill in the art would have been motivated to further improve the method for the treatment of upper limb spasticity in patients with cerebral palsy. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of the pronator quadratus injection site.
The total treatment dose of the combination of Yadav’s 50 U to 180 U of botulinum toxin injected to the pronator teres with Wong’s 50 U to the pronator quadratus overlaps with the claimed range of 50 U to 100 U.
This is a provisional nonstatutory double patenting rejection.
Claim 45 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 152-155, 160-161, 163, 169, 171, and 173-175 of copending Application No. 18/595,365 (hereafter ‘365) in view of Leon (AU 2005200251 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39, 46-51, and 52 above, further in view of Tonkin et al. (The Journal of hand surgery, European volume 33.1 (2008): 77. Web) and Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212).
See discussion of claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365, Leon and Kirshblum above, which is incorporated into this rejection as well.
Claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite injecting the botulinum toxin A composition into the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles in order to treat upper limb spasticity comprising thumb-in-palm.
Tonkin teaches that patients with cerebral palsy often suffer from thumb deformity due to muscle imbalance (page 77, left column, lines 1-4). Tonkin teaches that the thumb-in-palm posture in cerebral palsy patients stems from muscle spasticity in the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles (page 78, left column, bottom paragraph). Tonkin also teaches injecting botulinum toxin as a non-operative treatment (paragraph bridging pages 78-79).
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 claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 by injecting the botulinum toxin A composition into the muscles taught by Tonkin (adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous) in order to treat upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the treatment given that Tonkin teaches the muscles involved in thumb-in-palm.
Claims 152-155, 160-161, 163, 169, 171, and 173-175 of ‘365 do not recite and Tonkin does not teach how much botulinum toxin is injected.
Yadav teaches injecting botulinum toxin into the adductor pollicis muscle to treat thumb-in palm with a maximum of 50 U per injection site (page 209, right column)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the amount of botulinum toxin injected into the muscles taught by Tonkin for the treatment of upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the therapeutic dose.
This is a provisional nonstatutory double patenting rejection.
Claims 37-39 and 46-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 21-25 and 30 of copending Application No. 18/031,861 (hereafter ‘861) in view of Leon (AU 2005200251 A1), Ruegg (US 2018/0311333 A1) and Kirshblum et al. (PM&R 12.4 (2020): 349-355).
Claims 1 and 5 of ‘861 are drawn to a method of treating cervical dystonia (involuntary muscle contractions that cause the head to twist in a variety of directions) in an individual comprising administering by injection a treatment dose of a sterile injectable composition to one or more muscles causing cervical dystonia, wherein the composition comprises a pharmaceutically acceptable diluent suitable for injection and a botulinum toxin of serotype A and 150 kD, wherein the total treatment dose of botulinum toxin component administered to the individual is 125 U or 250 U, wherein the composition comprises a positively charged carrier, wherein the therapeutic effect is associated with a risk of moderate to severe adverse events or risk of muscle weakness below 10%.
Claims 1 and 5 of ‘861 do not recite that the composition comprises albumin, so in one embodiment the composition in albumin-free.
250 U is below the claimed range of 500 U to 700 U.
Claim 12 of ‘861 recites the positively charged carrier has the amino acid sequence SEQ ID NO: 4, which is identical to the instant SEQ ID NO: 4.
Claims 21-25 of ‘861 limit the duration of treatment effect to: at least 16 weeks (claim 21), at least 20 weeks (claim 22), at least 22 weeks (claim 23), at least 24 weeks (claim 24), and at least 26 weeks (claim 25). All of the ranges overlap with the presently claimed range of at least 16 weeks.
Claim 30 of ‘861 recites that the risk of muscular weakness is less than 7%, 5% or 3%.
Claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite treating upper limb spasticity comprising a flexed elbow, a flexed wrist, and clenched fist because cervical dystonia is a spasm of the head rather than the arm, forearm, or hands.
Leon teaches injecting 50 to 300 units of botulinum toxin in the major muscles involved in severe closing of hand (“clenched fist”), curling of wrist (“flexed wrist”), and curling of the forearm (“flexed elbow”). See page 19, lines 8-11. Leon teaches that botulinum toxin type A is typically used to treat neuromuscular conditions (lines 10-11 on page 4).
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 claims 1, 5, 12, 21-25 and 30 of ‘861 to specifically treat upper limb spasticity comprising clenched fist, flexed wrist, and flexed elbow. The person of ordinary skill in the art would have been motivated to treat additional conditions with the composition and upper limb spasticity, like cervical dystonia, involves involuntary muscle contractions. The person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method given that Leon also administers botulinum toxin serotype A, which is the same active ingredient.
The range of 50 to 300 units is less than the claimed range of 500 U to 700 U.
Kirshblum teaches that higher doses than 400 units are efficacious and, at times, necessary to treat limb spasticity (bottom line bridging left and right columns on page 349). Kirshblum teaches that doses up to 600 units do not increase risk of adverse events (Abstract Conclusions).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dose of botulinum toxin within the range taught by Kirshblum (up to 600 units). The person of ordinary skill in the art would have been motivated to maximize the efficacy of treatment while minimizing adverse events. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the total botulinum toxin dose.
Claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite that the composition further comprises a non-ionic surfactant.
Ruegg teaches a method comprising administering by injection a dose of a sterile injectable composition into an area of the individual in need of treatment, wherein the composition comprises a botulinum toxin and a positively charged polylysine backbone having covalently attached thereto one or more positively charged efficiency groups ([0021]).
Ruegg teaches the composition further comprises a sugar such as trehalose, sucrose, or raffinose ([0058]). Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]). Ruegg teaches that the composition may contain a buffer such as citric acid, acetic acid, succinic acid, tartaric acid, maleic acid, or histidine in order to maintain the pH between 4.5 and 7.5 ([0060]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include the same excipients, such as trehalose and polysorbate 20, in the composition of the method of claims 1, 5, 12, 21-25 and 30 of ‘861 per the teaching of Ruegg. The person of ordinary skill in the art would have been motivated to apply Ruegg’s teachings because Ruegg teaches the same positively charged carrier. It would have been further obvious to buffer the composition with histidine to within the pH range that Ruegg teaches. The person of ordinary skill in the art would have been motivated to apply the same pH range because Ruegg also teaches a composition comprising a botulinum toxin and the same positively charged carrier. The person of ordinary skill in the art would have had a reasonable expectation of success in these modifications.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. Thus, claim 38 is rejected here for the embodiment in which the upper limb spasticity does not further comprise an adducted and internally rotated shoulder and/or pronated forearm.
Regarding claims 38-39, Leon exemplifies treating a patient suffering from spasticity resulting in clenched fist, flexed wrist, and flexed elbow or suffering from spasticity resulting in closed legs (page 19, lines 8-15). Thus, a patient presenting with upper limb spasticity consisting of clenched fist, flexed wrist, and flexed elbow is within the scope of Leon’s example.
Regarding claims 46 and 51, claim 1 of ‘861 recites that the therapeutic effect is associated with a risk of moderate to severe adverse events or risk of muscle weakness below 10%, which overlaps with the claimed range of below 5%.
Regarding claims 47-48, SEQ ID NO: 3 of claim 1 of ‘861 is the same as the instant SEQ ID NO: 3. SEQ ID NO: 4 of claim 12 of ‘861 is the same as the instant SEQ ID NO: 4. Claim 12 of ‘861 recites the positively charged carrier has the amino acid sequence SEQ ID NO: 4, which is identical to the instant SEQ ID NO: 4. SEQ ID NO: 4 consists of the positively charged efficiency group SEQ ID NO: 3 covalently attached to both ends of polylysine.
Regarding claim 49, Kirshblum teaches a treatment dose for spasticity of less than 600 U, which overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, the durations of therapeutic effect recited in claims 21-25 of ‘861 overlaps with the claimed range.
Regarding claims 52-53, Ruegg teaches the composition further comprises a sugar such as trehalose, sucrose, or raffinose ([0058]). Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]). Ruegg teaches that the composition may contain a buffer such as citric acid, acetic acid, succinic acid, tartaric acid, maleic acid, or histidine in order to maintain the pH between 4.5 and 7.5 ([0060]).
This is a provisional nonstatutory double patenting rejection.
Claims 40 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 21-25 and 30 of copending Application No. 18/031,861 (hereafter ‘861) in view of Leon (AU 2005200251 A1), Ruegg (US 2018/0311333 A1), and Kirshblum et al. (PM&R 12.4 (2020): 349-355), as applied to claims 37-39 and 46-53 above, further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of claims 1, 5, 12, 21-25 and 30 of ‘861, Leon, Ruegg, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 40, claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite injecting botulinum toxin A into the flexor digitorum profundus and flexor digitorum superficialis muscles to treating upper limb spasticity comprising clenched fist.
Park teaches injecting botulinum toxin into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat clenched hand (“clenched fist’) in children with cerebral palsy (Title and page 590, right column, Muscle selection, 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 further modify the method of claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, and Kirshblum by injecting the botulinum toxin A composition into the flexor digitorum profundus and flexor digitorum superficialis in order to treat upper limb spasticity per the teaching of Park. The person of ordinary skill in the art would have been motivated to expand the utility of the composition in treating muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition into the muscle groups taught by Park.
Park teaches that 200 U are injected into the flexor digitorum profundus (Table 3, “FDP,” on page 593). 200 U is above the presently claimed range. Park does not teach how many units of botulinum toxin are injected into the flexor digitorum superficialis.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the total treatment dose of botulinum A composition for the treatment of muscle spasms in the flexor digitorum profundus and flexor digitorum superficialis to treat upper limb spasticity comprising clenched fist. The person of ordinary skill in the art would have been motivated to expand the utility of the composition in treating muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Regarding clam 42, claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite injecting the botulinum toxin A composition into biceps muscle in order to treat upper limb spasticity comprising a flexed elbow.
Park teaches injecting botulinum toxin into the biceps, brachioradialis, and brachialis muscles to treat upper limb spasticity comprising flexed elbow (page 590, right column, Muscle selection, 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 claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, and Kirshblum by injecting the botulinum toxin A composition into the biceps, brachioradialis, and brachialis muscles in order to treat upper limb spasticity per the teaching of Park. The person of ordinary skill in the art would have been motivated to expand the utility of the composition in treating muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition into the muscle groups taught by Park.
Park teaches 20 U of botulinum toxin are injected into the biceps and 10 U are injected into the brachioradialis (Table 3, “BR” is brachioradialis). 30 total U is less than the claimed range of 200 U to 300 U. However, Park does not teach how many units of botulinum toxin are injected into the brachialis muscle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum A composition injected into the biceps, brachioradialis and brachialis muscles for the treatment of upper limb spasticity comprising flexed elbow. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
This is a provisional nonstatutory double patenting rejection.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 21-25 and 30 of copending Application No. 18/031,861 (hereafter ‘861) in view of Leon, Ruegg, and Kirshblum, as applied to claims 37-39 and 46-53 above, further in view of Turkel et al. (US 9,078,892 B2) as evidenced by Lung et al. (StatPearl website, 2024).
See discussion of claims 1, 5, 12, 21-25 and 30 of ‘861, Leon, Ruegg, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 41, claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite injecting the botulinum toxin A composition into the flexor carpi radialis and the flexor carpi ulnaris muscles in order to treat upper limb spasticity comprising a flexed wrist.
Turkel teaches injecting 15 U to 60 U into the flexor carpi radialis muscle to treat upper limb spasticity ((6)(d) column 10).
Turkel teaches injecting 10 U to 40 U botulinum toxin into the flexor carpi ulnaris to treat upper limb spasticity ((6)(c) column 10).
Spasticity in the flexor carpi ulnaris muscle necessarily flexes the wrist because “spasticity” is involuntary contraction of a muscle and contracting the flexor carpi ulnaris muscle flexes the hand (synonymous with flexing the wrist) as evidenced by Lung (Introduction lines 1-2).
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 claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, and Kirshblum by injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris in order to treat upper limb spasticity comprising a flexed wrist per the teaching of Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition of claims 1, 5, 12, 21-25 and 30 of ‘861 into the flexor carpi radialis and flexor carpi ulnaris muscles taught by Turkel.
Turkel’s total treatment dose of 15 U to 60 U to the flexor carpi radialis and 10 U to 40 U to the flexor carpi ulnaris overlaps with the claimed range 50 U to 100 U.
This is a provisional nonstatutory double patenting rejection.
Claims 38 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 21-25 and 30 of copending Application No. 18/031,861 (hereafter ‘861) in view of Leon, Ruegg, and Kirshblum, as applied to claims 37-39 and 46-53 above, further in view of Figus et al. (Journal of plastic, reconstructive & aesthetic surgery 62.7 (2009): 869-875) as evidenced by Peak Performance Fitness (2017, website).
See discussion of claims 1, 5, 12, 21-25 and 30 of ‘861, Leon, Ruegg, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. This rejection applies to the embodiment in which the individual presents with upper limb spasticity further comprising an adducted and internally rotated shoulder and/or pronated forearm.
Claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite injecting the composition into the latissimus dorsi muscle to treat spasms that result in internal shoulder rotation.
Figus teaches injecting botulinum toxin A into the latissimus dorsi (LD) muscle and pectoralis major (part of the pectoralis complex) in order to treat muscular twitching or contractions (page 870, left column, paragraph 6 and page 870, right column, last full paragraph). Each patient receives 100 U of botulinum toxin A (page 870, left column, first paragraph after Table 2). Figus also teaches injecting botulinum toxin into the pectoralis major (PM) muscle to treat myopasms (sudden involuntary contraction in the muscle; page 870, left column, paragraph 4).
Although Figus does not teach that the muscle spasms result in an adducted and internally rotated shoulder, contractions of the latissimus dorsi muscle necessarily result in adduction and internal shoulder rotation as evidenced by Peak Performance Fitness (page 2, paragraph 2). Therefore, Figus’s patients necessarily present this symptom because they suffer from latissimus dorsi muscle contractions.
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 claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, and Kirshblum by injecting botulinum toxin composition into the pectoralis complex and the latissimus dorsi muscles of patients in order to treat internal shoulder rotation resulting from the muscle spasms. The person of ordinary skill in the art would have been motivated to expand the utility of the composition in treating muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success given that Figus teaches that botulinum toxin A is useful in treating both pectoralis major and latissimus dorsi muscle spasms.
Figus teaches a treatment dose of 100 U (page 870, left column, first paragraph after Table 2), which is within the claimed range of 50 U to 100 U.
This is a provisional nonstatutory double patenting rejection.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 21-25 and 30 of copending Application No. 18/031,861 (hereafter ‘861) in view of Leon, Ruegg, and Kirshblum, as applied to claims 37-39 and 46-53 above, further in view of Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212) and Wong et al. (Journal of child neurology 17.2 (2002): 138-142).
See discussion of claims 1, 5, 12, 21-25 and 30 of ‘861, Leon, Ruegg, and Kirshblum above, which is incorporated into this rejection as well.
Claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite injecting the botulinum toxin A composition into the pronator teres and pronator quadratus in order to treat spasticity resulting in a pronated forearm.
Yadav teaches injecting between 50 and 180 U of botulinum toxin A into the pronator teres in order to treat pronation posture and spasticity in cerebral palsy patients (Abstract Introduction, Abstract Results, page 210, left column, first full paragraph after Table 2). Pronation posture in cerebral palsy includes the pronation of the forearm (page 209, left column, 2.1 Methods, paragraph 3)
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 claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, and Kirshblum by injecting the botulinum toxin A composition into the pronator teres of cerebral palsy patients suffering from pronated forearm associated with muscle spasms in the pronator teres. The person of ordinary skill in the art would have been motivated to expand the utility of the composition in treating muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success given that Yadav teaches that injecting botulinum toxin A into the pronator teres treats pronation posture and spasticity in cerebral palsy patients.
Yadav does not teach injecting botulinum toxin into the pronator quadratus.
Wong teaches injecting 50 U of botulinum toxin A into the pronator quadratus for the treatment of spasticity in children with cerebral palsy (Abstract, page 139, left column, top 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 include the additional injection site of the pronator quadratus taught by Wong in the method of claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, Kirshblum, and Yadav. The person of ordinary skill in the art would have been motivated to further improve the method for the treatment of upper limb spasticity in patients with cerebral palsy. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of the pronator quadratus injection site.
The total treatment dose of the combination of Yadav’s 50 U to 180 U of botulinum toxin injected to the pronator teres with Wong’s 50 U to the pronator quadratus overlaps with the claimed range of 50 U to 100 U.
This is a provisional nonstatutory double patenting rejection.
Claim 45 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 12, 21-25 and 30 of copending Application No. 18/031,861 (hereafter ‘861) in view of Leon, Ruegg, and Kirshblum, as applied to claims 37-39 and 46-53 above, further in view of Tonkin et al. (The Journal of hand surgery, European volume 33.1 (2008): 77. Web) and Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212).
See discussion of claims 1, 5, 12, 21-25 and 30 of ‘861, Leon, Ruegg, and Kirshblum above, which is incorporated into this rejection as well.
Claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite injecting the botulinum toxin A composition into the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles in order to treat upper limb spasticity comprising thumb-in-palm.
Tonkin teaches that patients with cerebral palsy often suffer from thumb deformity due to muscle imbalance (page 77, left column, lines 1-4). Tonkin teaches that the thumb-in-palm posture in cerebral palsy patients stems from muscle spasticity in the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles (page 78, left column, bottom paragraph). Tonkin also teaches injecting botulinum toxin as a non-operative treatment (paragraph bridging pages 78-79).
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 claims 1, 5, 12, 21-25 and 30 of ‘861 modified by Leon, Ruegg, and Kirshblum by injecting the botulinum toxin A composition into the muscles taught by Tonkin (adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous) in order to treat upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the treatment given that Tonkin teaches the muscles involved in thumb-in-palm.
Claims 1, 5, 12, 21-25 and 30 of ‘861 do not recite and Tonkin does not teach how much botulinum toxin is injected.
Yadav teaches injecting botulinum toxin into the adductor pollicis muscle to treat thumb-in palm with a maximum of 50 U per injection site (page 209, right column)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the amount of botulinum toxin injected into the muscles taught by Tonkin for the treatment of upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the therapeutic dose.
This is a provisional nonstatutory double patenting rejection.
Claims 37-39, 46-47, 49-51, and 52-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,092,788 (‘788) in view of Ruegg (US 2018/0311333 A1), Leon (AU 2005200251 A1), and Kirshblum et al. (PM&R 12.4 (2020): 349-355).
Claim 1 of ‘788 is drawn to a composition comprising a biologically active protein and a positively charged carrier comprising a positively charged polymeric backbone having attached thereto amino acid sequences selected from the group consisting of SEQ ID NO: 2-4.
SEQ ID NO: 2-4 of ‘788 are identical to the instant SEQ ID NO: 1-3.
Claim 1 of ‘788 does not recite administering by injection the positively charged carrier in a composition together with a botulinum toxin of serotype A having a molecular weight of 150 kDa, a diluent and a non-ionic surfactant in order to treat upper limb spasticity.
Ruegg teaches a method comprising administering by injection a dose of a sterile injectable composition into an area of the individual in need of treatment, wherein the composition comprises a botulinum toxin and a positively charged polylysine backbone having covalently attached thereto one or more positively charged efficiency groups ([0021]).
Ruegg teaches that the composition comprises botulinum toxin serotype A with molecular weight of 150 kDa ([0024]). Ruegg teaches that albumin may be omitted from the composition ([0039]). Ruegg teaches that the composition comprises a non-ionic surfactant ([0038]) and a pharmaceutically acceptable diluent such as phosphate buffered saline ([0054]), which is a diluent suitable for injection. Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]).
Ruegg teaches that the method achieves an extended duration therapeutic effect in an individual ([0021]). The extended duration effect is at least 6 months ([0068]), which overlaps with the claimed range of at least 16 weeks.
Ruegg teaches that the composition treats muscle spasms ([0018]). Ruegg exemplifies administering the composition to treat various spasms, including hemifacial spasm, adult onset spasmodic torticollis or neck spasms (Ruegg claim 18). Ruegg also teaches administering the botulinum to treat muscle spasms in the shoulders, palms, dorsa of the hands, or upper arms ([0064]). In summary, Ruegg teaches treating upper limb spasticity (e.g. muscle spasms in the upper arms).
Ruegg teaches a broad range of total treatment dose from 1 U to 400 U ([0066]). However, Ruegg’s exemplifies a total treatment does of 40U for cosmetic treatment ([0140]), which is less than the claimed range of between 500 U and 700 U. Ruegg does not exemplify a specific total treatment dose for upper limb spasticity.
Leon teaches injecting 50 to 300 units of botulinum toxin in the major muscles involved in severe closing of hand (“clenched fist”) and curling of wrist (“flexed wrist”) and curling of the forearm (“flexed elbow”). See page 19, lines 8-11. Leon teaches that botulinum toxin type A is typically used to treat neuromuscular conditions (lines 10-11 on page 4).
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 include a botulinum toxin of serotype A with a molecular weight of 150 kDa as the biologically active protein in the composition of claim 1 of ‘788 and to administer the composition by injection to treat upper limb spasticity per the teachings of Ruegg. It would have been further obvious to include the same excipients taught by Ruegg (such as the non-ionic surfactant and the diluent) in the composition of claim 1 of ‘788. The person of ordinary skill in the art would have had a reasonable expectation of success in these modifications.
The range of 50 to 300 units is less than the claimed range of 500 U to 700 U.
Kirshblum teaches that higher doses than 400 units are efficacious and, at times, necessary to treat limb spasticity (bottom line bridging left and right columns on page 349). Kirshblum teaches that doses up to 600 units do not increase risk of adverse events (Abstract Conclusions).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dose of botulinum toxin within the range taught by Kirshblum (up to 600 units). The person of ordinary skill in the art would have been motivated to maximize the efficacy of treatment while minimizing adverse events. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the total botulinum toxin dose.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. Thus, claim 38 is also rejected here for the embodiment in which the upper limb spasticity does not comprise an adducted and internally rotated shoulder and/or pronated forearm.
Regarding claims 38-39, Leon exemplifies treating a patient suffering from spasticity resulting in clenched fist, flexed wrist, and flexed elbow or suffering from spasticity resulting in closed legs (page 19, lines 8-15). Thus, a patient presenting with upper limb spasticity consisting of clenched fist, flexed wrist, and flexed elbow is within the scope of Leon’s example.
Regarding claims 46 and 51, claim 1 of 788 does not recite and Ruegg and Leon do not teach that the risk of adverse events is less than 5% (claim 46) or that the risk of muscle weakness is less than 5% (claim 51).
Kirshblum teaches that for high-dose botulinum injections used to treat spasticity, the risk of adverse events is 3.0% and the risk of unintended muscle weakness is 1.7% (Title and page 351, right column, bottom paragraph Adverse Events). Kirshblum tests three different levels of botulinum toxin doses: less than 400 units, 401-600 units, and greater than 600 units (Table 2). Doses greater than 600 units result in greater risk of adverse events (Table 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dose of botulinum toxin in the method of claim 1 of ‘788 modified by Ruegg and Leon in order to minimize the risk of adverse events such as muscle weakness. The person of ordinary skill in the art would have had a reasonable expectation of success given that doses less than 600 units generally have less than 5% risk for adverse events such as muscle weakness.
Regarding claim 47, SEQ ID NO: 1-3 of the instant application are exactly the same as SEQ ID NO: 2-4 of ‘788.
Regarding claim 49, Kirshblum teaches a treatment dose for spasticity of less than 600 U, which overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, Ruegg teaches that the method achieves an extended duration therapeutic effect in an individual ([0021]). The extended duration effect is at least 6 months ([0068]), which overlaps with the claimed range of between 16 and 26 weeks.
Regarding claims 52-53, Ruegg teaches the composition further comprises a sugar such as trehalose, sucrose, or raffinose ([0058]). Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]). Ruegg teaches that the composition may contain a buffer such as citric acid, acetic acid, succinic acid, tartaric acid, maleic acid, or histidine in order to maintain the pH between 4.5 and 7.5 ([0060]).
Claims 40 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,092,788 (‘788) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 46-47, 49-51, and 52-53 above, further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of claim 1 of ‘788, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 40, claim 1 of ‘788 does not recite that the upper limb spasticity comprises clenched fist or injecting botulinum toxin A into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat upper limb spasticity comprising clenched fist.
Park teaches injecting botulinum toxin into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat clenched hand (“clenched fist’) in children with cerebral palsy (Title and page 590, right column, Muscle selection, 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 administer the composition of claim 1 of ‘788 modified by Ruegg into the flexor digitorum profundus and the flexor digitorum superficialis in order to treat upper limb spasticity per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition into the muscle groups taught by Park.
Park teaches that 200 U are injected into the flexor digitorum profundus (Table 3, “FDP,” on page 593). 200 U is above the presently claimed range. Park does not teach how many units of botulinum toxin are injected into the flexor digitorum superficialis.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the total treatment dose of the botulinum A composition of claim 1 of ‘788 modified by Ruegg for the treatment of muscle spasms in the flexor digitorum profundus and the flexor digitorum superficialis to treat upper limb spasticity comprising clenched fist. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Regarding clam 42, claim 1 of ‘788 does not recite and Ruegg does not teach injecting the botulinum toxin A composition into biceps, brachioradialis, and brachialis muscles muscle in order to treat upper limb spasticity comprising a flexed elbow.
Park teaches injecting botulinum toxin into the biceps, brachioradialis, and brachialis muscles to treat upper limb spasticity comprising flexed elbow (page 590, right column, Muscle selection, 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 1 of ‘788 modified by Ruegg by injecting the botulinum toxin A composition into the biceps, brachioradialis, and brachialis muscles in order to treat upper limb spasticity per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition into the muscle groups taught by Park.
Park teaches 20 U of botulinum toxin are injected into the biceps and 10 U are injected into the brachioradialis (Table 3, “BR” is brachioradialis). 30 total U is less than the claimed range of 200 U to 300 U. However, Park does not teach how many units of botulinum toxin are injected into the brachialis muscle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum A composition injected into the biceps, brachioradialis and brachialis muscles for the treatment of upper limb spasticity comprising flexed elbow. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,092,788 (‘788) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 46-47, 49-51, and 52-53 above, further in view of Turkel et al. (US 9,078,892 B2) as evidenced by Lung et al. (StatPearl website, 2024).
See discussion of claim 1 of ‘788, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 41, claim 1 of ‘788 does not recite and Ruegg does not teach injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris muscles in order to treat upper limb spasticity comprising a flexed wrist.
Turkel teaches injecting 15 U to 60 U into the flexor carpi radialis muscle to treat upper limb spasticity ((6)(d) column 10).
Turkel teaches injecting 10 U to 40 U botulinum toxin into the flexor carpi ulnaris to treat upper limb spasticity ((6)(c) column 10).
Spasticity in the flexor carpi ulnaris muscle necessarily flexes the wrist because “spasticity” is involuntary contraction of a muscle and contracting the flexor carpi ulnaris muscle flexes the hand (synonymous with flexing the wrist) as evidenced by Lung (Introduction lines 1-2).
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 1 of ‘788 modified by Ruegg by injecting the botulinum toxin A composition into the flexor carpi ulnaris and flexor carpi radialis in order to treat upper limb spasticity per the teaching of Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the composition of claim 1 of ‘788 modified by Ruegg into the flexor carpi ulnaris and flexor carpi radialis muscles taught by Turkel.
Turkel’s treatment dose of 15 U to 60 U to the flexor carpi radialis and 10 U to 40 U to the flexor carpi ulnaris overlaps with the claimed range 50 U to 100 U.
Claims 38 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,092,788 (‘788) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 46-47, 49-51, and 52-53 above, further in view of Figus et al. (Journal of plastic, reconstructive & aesthetic surgery 62.7 (2009): 869-875) as evidenced by Peak Performance Fitness (2017, website).
See discussion of claim 1 of ‘788, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Claim 1 of ‘788 does not recite and Ruegg does not teach injecting the composition into the pectoralis complex and latissimus dorsi muscles to treat spasms that result in internal shoulder rotation.
Figus teaches injecting botulinum toxin A into the latissimus dorsi (LD) muscle and pectoralis major (part of the pectoralis complex) in order to treat muscular twitching or contractions (page 870, left column, paragraph 6 and page 870, right column, last full paragraph). Each patient receives 100 U of botulinum toxin A (page 870, left column, first paragraph after Table 2). Figus also teaches injecting botulinum toxin into the pectoralis major (PM) muscle to treat myopasms (sudden involuntary contraction in the muscle; page 870, left column, paragraph 4).
Although Figus does not teach that the muscle spasms result in an adducted and internally rotated shoulder, contractions of the latissimus dorsi muscle necessarily result in adduction and internal shoulder rotation as evidenced by Peak Performance Fitness (page 2, paragraph 2). Therefore, Figus’s patients necessarily present this symptom because they suffer from latissimus dorsi muscle contractions.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to inject the botulinum toxin composition of claim 1 of ‘788 modified by Ruegg, Leon, and Kirshblum into the pectoralis complex and latissimus dorsi muscles of patients in order to treat internal shoulder rotation resulting from the muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success given that Figus teaches that botulinum toxin A is useful in treating pectoralis major and latissimus dorsi muscle spasms and Ruegg teaches injecting a botulinum toxin A composition to treat shoulder spasms [0064].
Figus teaches a treatment dose of 100 U (page 870, left column, first paragraph after Table 2), which is within the claimed range of 50 U to 100 U.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,092,788 (‘788) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 46-47, 49-51, and 52-53 above, further in view of Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212), and Wong et al. (Journal of child neurology 17.2 (2002): 138-142).
See discussion of claim 1 of ‘788, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Claim 1 of ‘788 does not recite and Ruegg, Leon, and Kirshblum do not teach injecting the botulinum toxin A composition into the pronator teres and pronator quadratus in order to treat spasticity resulting in a pronated forearm.
Yadav teaches injecting between 50 and 180 U of botulinum toxin A into the pronator teres in order to treat pronation posture and spasticity in cerebral palsy patients (Abstract Introduction, Abstract Results, page 210, left column, first full paragraph after Table 2). Pronation posture in cerebral palsy includes the pronation of the forearm (page 209, left column, 2.1 Methods, paragraph 3)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to inject the botulinum toxin A composition of claim 1 of ‘788 modified by Ruegg, Leon, and Kirshblum into the pronator teres of cerebral palsy patients suffering from pronated forearm associated with muscle spasms in the pronator teres. The person of ordinary skill in the art would have had a reasonable expectation of success given that Yadav teaches that injecting botulinum toxin A into the pronator teres treats pronation posture and spasticity in cerebral palsy patients.
Yadav does not teach injecting botulinum toxin into the pronator quadratus.
Wong teaches injecting 50 U of botulinum toxin A into the pronator quadratus for the treatment of spasticity in children with cerebral palsy (Abstract, page 139, left column, top 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 include the additional injection site of the pronator quadratus taught by Wong in the method of claim 1 of ‘788 modified Ruegg, Leon, Kirshblum and Yadav. The person of ordinary skill in the art would have been motivated to further improve the method for the treatment of upper limb spasticity in patients with cerebral palsy. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of the pronator quadratus injection site.
The total treatment dose of the combination of Yadav’s 50 U to 180 U of botulinum toxin injected to the pronator teres with Wong’s 50 U to the pronator quadratus overlaps with the claimed range of 50 U to 100 U.
Claim 45 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,092,788 (‘788) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 46-47, 49-51, and 52-53 above, further in view of Tonkin et al. (The Journal of hand surgery, European volume 33.1 (2008): 77. Web) and Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212).
See discussion of claim 1 of ‘788, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Claim 1 of ‘788 does not recite and Ruegg, Leon, and Kirshblum do not teach injecting the botulinum toxin A composition into the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles in order to treat upper limb spasticity comprising thumb-in-palm.
Tonkin teaches that patients with cerebral palsy often suffer from thumb deformity due to muscle imbalance (page 77, left column, lines 1-4). Tonkin teaches that the thumb-in-palm posture in cerebral palsy patients stems from muscle spasticity in the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles (page 78, left column, bottom paragraph). Tonkin also teaches injecting botulinum toxin as a non-operative treatment (paragraph bridging pages 78-79).
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 1 of ‘788 modified by Ruegg, Leon, and Kirshblum by injecting the botulinum toxin A composition into the muscles taught by Tonkin (adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous) in order to treat upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the treatment given that Tonkin teaches the muscles involved in thumb-in-palm.
Claim 1 of ‘788 does not recite and Tonkin does not teach how much botulinum toxin is injected.
Yadav teaches injecting botulinum toxin into the adductor pollicis muscle to treat thumb-in palm with a maximum of 50 U per injection site (page 209, right column)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum toxin injected into the muscles taught by Tonkin for the treatment of upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the therapeutic dose.
Claims 37-39, 47, 49-50, and 52-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of U.S. Patent No. 9,211,248 (‘248) in view of Ruegg (US 2018/0311333 A1), Leon (AU 2005200251 A1), and Kirshblum et al. (PM&R 12.4 (2020): 349-355).
Claims 1-76 of ‘248 are drawn to a method of topically administering a pharmaceutically acceptable composition comprising an effective amount of botulinum toxin and an effective amount of a positively charged carrier comprising a positively charged polymeric backbone having covalently attached a positively charged efficiency groups, thereby treating muscle-spasm pain.
Claim 52 recites that the botulinum toxin serotype includes serotype A.
Claim 53 recites that the molecular weight of the botulinum toxin is 150 kDa.
Claims 1-76 of ‘248 do not recite that the composition further comprises a pharmaceutically acceptable diluent or a non-ionic surfactant.
Claims 1-76 of ‘248 do not recite that the composition is sterile or that the composition is administered by injection.
Claims 1-76 of ‘248 do not recite the duration of treatment effect is at least 16 weeks.
Ruegg teaches a method comprising administering by injection a dose of a sterile injectable composition into an area of the individual in need of treatment, wherein the composition comprises a botulinum toxin and a positively charged polylysine backbone having covalently attached thereto one or more positively charged efficiency groups ([0021]).
Ruegg teaches that the composition comprises botulinum toxin serotype A with molecular weight of 150 kDa ([0024]). Ruegg teaches that albumin may be omitted from the composition ([0039]). Ruegg teaches that the composition comprises a non-ionic surfactant ([0038]) and a pharmaceutically acceptable diluent such as phosphate buffered saline ([0054]), which is a diluent suitable for injection. Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]).
Ruegg teaches that the method achieves an extended duration therapeutic effect in an individual ([0021]). The extended duration effect is at least 6 months ([0068]), which overlaps with the claimed range of at least 16 weeks.
Ruegg teaches that the composition treats muscle spasms ([0018]). Ruegg exemplifies administering the composition to treat various spasms, including hemifacial spasm, adult onset spasmodic torticollis or neck spasms (Ruegg claim 18). Ruegg also teaches administering the botulinum to treat muscle spasms in the shoulders, palms, dorsa of the hands, or upper arms ([0064]). In summary, Ruegg teaches treating upper limb spasticity (e.g. muscle spasms in the upper arms).
Ruegg teaches a broad range of total treatment dose from 1 U to 400 U ([0066]). However, Ruegg’s exemplifies a total treatment does of 40U for cosmetic treatment ([0140]), which is less than the claimed range of 500 U to 700 U.
Ruegg does not exemplify a specific total treatment dose for upper limb spasticity.
Leon teaches injecting 50 to 300 units of botulinum toxin in the major muscles involved in severe closing of hand (“clenched fist”) and curling of wrist (“flexed wrist”) and curling of the forearm (“flexed elbow”). See page 19, lines 8-11. Leon teaches that botulinum toxin type A is typically used to treat neuromuscular conditions (lines 10-11 on page 4).
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 claims 1-76 of ‘248 by formulating the composition for injection per the teachings of Ruegg by including a pharmaceutically acceptable diluent and a non-ionic surfactant in the composition. It would have been further obvious to administer the composition by injection in order to treat muscle spasms. The person of ordinary skill in the art would have been motivated by Ruegg’s teaching that botulinum toxin administered by injection treats muscle spasms. Regarding the duration of therapeutic effect, Ruegg teaches a botulinum toxin composition comprising the same positively charged carrier and that the duration of treatment effect is at least 6 months ([0068]), which overlaps with the claimed range of at least 16 weeks, thus the person of ordinary skill in the art would have had a reasonable expectation of success in the duration of treatment effect lasting at least 16 weeks.
Claims 1-76 of ‘248 do not recite the total botulinum toxin treatment dose of 500 U to 700 U.
Kirshblum teaches that higher doses than 400 units are efficacious and, at times, necessary to treat limb spasticity (bottom line bridging left and right columns on page 349). Kirshblum teaches that doses up to 600 units do not increase risk of adverse events (Abstract Conclusions).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dose of botulinum toxin within the range taught by Kirshblum (up to 600 units). The person of ordinary skill in the art would have been motivated to maximize the efficacy of treatment while minimizing adverse events. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the total botulinum toxin dose.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. Thus, claim 38 is rejected here for the embodiment in which the upper limb spasticity does not further comprise an adducted and internally rotated shoulder and/or pronated forearm.
Regarding claims 38-39, Leon exemplifies treating a patient suffering from spasticity resulting in clenched fist, flexed wrist, and flexed elbow or suffering from spasticity resulting in closed legs (page 19, lines 8-15). Thus, a patient presenting with upper limb spasticity consisting of clenched fist, flexed wrist, and flexed elbow is within the scope of Leon’s example.
Regarding claims 46 and 51, Kirshblum teaches that for high-dose botulinum injections used to treat spasticity, the risk of adverse events is 3.0% and the risk of unintended muscle weakness is 1.7% (Title and page 351, right column, bottom paragraph Adverse Events). Kirshblum tests three different levels of botulinum toxin doses: less than 400 units, 401-600 units, and greater than 600 units (Table 2). Only doses greater than 600 units result in greater risk (Table 2).
Regarding claim 47, claim 71 of ‘248 recites a positively charged polymeric backbone that is a polylysine having covalently attached thereto one or more positively charged efficiency groups having the amino acid sequence SEQ ID NO: 4, which is the same sequence depicted as SEQ ID NO: 3 of the instant application in claim 47. Claim 71 of ‘248 recites that the number of glycines at the N- and C-terminus is an integer from 0 to 20, which overlaps with the presently claimed range of 0 to 8.
Regarding claim 49, Kirshblum teaches a treatment dose for spasticity of less than 600 U, which overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, Ruegg teaches that the method achieves an extended duration therapeutic effect in an individual ([0021]). The extended duration effect is at least 6 months ([0068]), which overlaps with the claimed range of between 16 and 26 weeks.
Regarding claims 52-53, Ruegg teaches the composition further comprises a sugar such as trehalose, sucrose, or raffinose ([0058]). Ruegg teaches that the composition comprises a non-ionic surfactant such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or sorbitan ester ([0059]). Ruegg teaches that the composition may contain a buffer such as citric acid, acetic acid, succinic acid, tartaric acid, maleic acid, or histidine in order to maintain the pH between 4.5 and 7.5 ([0060]).
Claims 40 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of U.S. Patent No. 9,211,248 (‘248) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 47, 49-50, and 52-53 above, further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of claims 1-76 of ‘248, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 40, Ruegg does not teach injecting botulinum toxin A into the flexor digitorum profundus and the flexor digitorum superficialis muscles to treat upper limb spasticity comprising clenched fist.
Park teaches injecting botulinum toxin into the flexor digitorum profundus and flexor digitorum superficialis muscles to treat clenched hand (“clenched fist’) in children with cerebral palsy (Title and page 590, right column, Muscle selection, 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 claims 1-76 of ‘248 modified by Ruegg, Leon, and Kirshblum by injecting the botulinum toxin A composition into the flexor digitorum profundus and flexor digitorum superficialis in order to treat upper limb spasticity per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition of claims 1-76 of ‘248 modified by Ruegg into the muscle groups taught by Park.
Park teaches that 200 U are injected into the flexor digitorum profundus (Table 3, “FDP,” on page 593). 200 U is above the presently claimed range. Park does not teach how many units of botulinum toxin are injected into the flexor digitorum superficialis.
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 total treatment dose of botulinum toxin A in the method of claims 1-76 of ‘248 modified by Ruegg, Leon, and Kirshblum for the treatment of muscle spasms in the flexor digitorum profundus and flexor digitorum superficialis. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Regarding clam 42, claims 1-76 of ‘248 do not recite and Ruegg does not teach injecting the botulinum toxin A composition into biceps, brachioradialis, and brachialis muscles muscle in order to treat upper limb spasticity comprising a flexed elbow.
Park teaches injecting botulinum toxin into the biceps, brachioradialis, and brachialis muscles to treat upper limb spasticity comprising flexed elbow (page 590, right column, Muscle selection, 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 claims 1-76 of ‘248 modified by Ruegg, Leon, and Kirshblum by injecting the botulinum toxin A composition into the biceps, brachioradialis, and brachialis muscles in order to treat upper limb spasticity comprising flexed elbow per the teaching of Park. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition into the muscle groups taught by Park.
Park teaches 20 U of botulinum toxin are injected into the biceps and 10 U are injected into the brachioradialis (Table 3, “BR” is brachioradialis). 30 total U is less than the claimed range of 200 U to 300 U. However, Park does not teach how many units of botulinum toxin are injected into the brachialis muscle.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum toxin A injected into the biceps, brachioradialis and brachialis muscles for the treatment of upper limb spasticity comprising flexed elbow. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dose for therapeutic effect.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of U.S. Patent No. 9,211,248 (‘248) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 47, 49-50, and 52-53 above, further in view of Turkel et al. (US 9,078,892 B2) as evidenced by Lung et al. (StatPearl website, 2024).
See discussion of claims 1-76 of ‘248, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 41, claims 1-76 of ‘248 do not recite and Ruegg, Leon, and Kirshblum do not teach injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris muscles in order to treat upper limb spasticity comprising a flexed wrist.
Turkel teaches injecting 15 U to 60 U into the flexor carpi radialis muscle to treat upper limb spasticity ((6)(d) column 10).
Turkel teaches injecting 10 U to 40 U botulinum toxin into the flexor carpi ulnaris to treat upper limb spasticity ((6)(c) column 10).
Spasticity in the flexor carpi ulnaris muscle necessarily flexes the wrist because “spasticity” is involuntary contraction of a muscle and contracting the flexor carpi ulnaris muscle flexes the hand (synonymous with flexing the wrist) as evidenced by Lung (Introduction lines 1-2).
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 claims 1-76 of ‘248 modified by Ruegg, Leon, and Kirshblum by injecting the botulinum toxin A composition into the flexor carpi radialis and flexor carpi ulnaris in order to treat upper limb spasticity per the teaching of Turkel. The person of ordinary skill in the art would have had a reasonable expectation of success in injecting the botulinum toxin composition into the flexor carpi radialis and flexor carpi ulnaris muscle taught by Turkel.
Turkel’s total treatment dose of 15 U to 60 U to the flexor carpi radialis and 10 U to 40 U to the flexor carpi ulnaris muscles overlaps with the claimed range 50 U to 100 U.
Claims 38 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of U.S. Patent No. 9,211,248 (‘248) in view of Ruegg, Leon and Kirshblum, as applied to claims 37-39, 47, 49-50, and 52-53 above, further in view of Figus et al. (Journal of plastic, reconstructive & aesthetic surgery 62.7 (2009): 869-875) as evidenced by Peak Performance Fitness (2017, website).
See discussion of claims 1-76 of ‘248, Ruegg, Leon and Kirshblum above, which is incorporated into this rejection as well.
Regarding claim 38, the limitation “wherein the one or more types of upper limb spasticity can further comprise an adducted and internally rotated shoulder and/or pronated forearm” is interpreted as an optional limitation. This rejection applies to the embodiment in which the individual presents with upper limb spasticity further comprising an adducted and internally rotated shoulder and/or pronated forearm.
Claims 1-76 of ‘248 do not recite and Ruegg does not teach injecting the composition into the pectoralis complex and latissimus dorsi muscles to treat spasms that result in internal shoulder rotation.
Figus teaches injecting botulinum toxin A into the latissimus dorsi (LD) muscle and pectoralis major (part of the pectoralis complex) in order to treat muscular twitching or contractions (page 870, left column, paragraph 6 and page 870, right column, last full paragraph). Each patient receives 100 U of botulinum toxin A (page 870, left column, first paragraph after Table 2). Figus also teaches injecting botulinum toxin into the pectoralis major (PM) muscle to treat myopasms (sudden involuntary contraction in the muscle; page 870, left column, paragraph 4).
Although Figus does not teach that the muscle spasms result in an adducted and internally rotated shoulder, contractions of the latissimus dorsi muscle necessarily result in adduction and internal shoulder rotation as evidenced by Peak Performance Fitness (page 2, paragraph 2). Therefore, Figus’s patients necessarily present this symptom because they suffer from latissimus dorsi muscle contractions.
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 claims 1-76 of ‘248 modified by Ruegg, Leon and Kirshblum by injecting the botulinum toxin composition into the pectoralis complex and latissimus dorsi muscles of patients in order to treat internal shoulder rotation resulting from the muscle spasms. The person of ordinary skill in the art would have had a reasonable expectation of success given that Figus teaches that botulinum toxin A is useful in treating pectoralis major and latissimus dorsi muscle spasms and Ruegg teaches injecting a botulinum toxin A composition to treat shoulder spasms [0064].
Figus teaches a treatment dose of 100 U (page 870, left column, first paragraph after Table 2), which is within the claimed range of 50 U to 100 U.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of U.S. Patent No. 9,211,248 (‘248) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 47, 49-50, and 52-53 above, further in view of Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212) and Wong et al. (Journal of child neurology 17.2 (2002): 138-142).
See discussion of claims 1-76 of ‘248, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Claims 1-76 of ‘248 do not recite and Ruegg does not teach injecting the botulinum toxin A composition into the pronator teres and pronator quadratus in order to treat spasticity resulting in a pronated forearm.
Yadav teaches injecting between 50 and 180 U of botulinum toxin A into the pronator teres in order to treat pronation posture and spasticity in cerebral palsy patients (Abstract Introduction, Abstract Results, page 210, left column, first full paragraph after Table 2). Pronation posture in cerebral palsy includes the pronation of the forearm (page 209, left column, 2.1 Methods, paragraph 3)
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 claims 1-76 of ‘248 modified by Ruegg, Leon, and Kirshblum by injecting the botulinum toxin A composition into the pronator teres of cerebral palsy patients suffering from pronated forearm associated with muscle spasms in the pronator teres. The person of ordinary skill in the art would have had a reasonable expectation of success given that Yadav teaches that injecting botulinum toxin A into the pronator teres treats pronation posture and spasticity in cerebral palsy patients.
Yadav does not teach injecting botulinum toxin into the pronator quadratus.
Wong teaches injecting 50 U of botulinum toxin A into the pronator quadratus for the treatment of spasticity in children with cerebral palsy (Abstract, page 139, left column, top 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 include the additional injection site of the pronator quadratus taught by Wong in the method of claims 1-76 of ‘248 modified by Ruegg, Leon, Kirshblum and Yadav. The person of ordinary skill in the art would have been motivated to further improve the method for the treatment of upper limb spasticity in patients with cerebral palsy. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of the pronator quadratus injection site.
The total treatment dose of the combination of Yadav’s 50 U to 180 U of botulinum toxin injected to the pronator teres with Wong’s 50 U to the pronator quadratus overlaps with the claimed range of 50 U to 100 U.
Claim 45 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-76 of U.S. Patent No. 9,211,248 (‘248) in view of Ruegg, Leon, and Kirshblum, as applied to claims 37-39, 47, 49-50, and 52-53 above, further in view of Tonkin et al. (The Journal of hand surgery, European volume 33.1 (2008): 77. Web) and Yadav et al. (Journal of clinical orthopaedics and trauma 11.2 (2020): 208-212).
See discussion of claims 1-76 of ‘248, Ruegg, Leon, and Kirshblum above, which is incorporated into this rejection as well.
Claims 1-76 of ‘248 do not recite and Ruegg, Leon, and Kirshblum do not teach injecting the botulinum toxin A composition into the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles in order to treat upper limb spasticity comprising thumb-in-palm.
Tonkin teaches that patients with cerebral palsy often suffer from thumb deformity due to muscle imbalance (page 77, left column, lines 1-4). Tonkin teaches that the thumb-in-palm posture in cerebral palsy patients stems from muscle spasticity in the adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous muscles (page 78, left column, bottom paragraph). Tonkin also teaches injecting botulinum toxin as a non-operative treatment (paragraph bridging pages 78-79).
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 claims 1-76 of ‘248 modified by Ruegg, Leon, and Kirshblum by injecting the botulinum toxin A composition into the muscles taught by Tonkin (adductor pollicis, flexor pollicis brevis, flexor pollicis longus, and first interosseous) in order to treat upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the treatment given that Tonkin teaches the muscles involved in thumb-in-palm.
Claims 1-76 of ‘248 do not recite and Tonkin does not teach how much botulinum toxin is injected.
Yadav teaches injecting botulinum toxin into the adductor pollicis muscle to treat thumb-in palm with a maximum of 50 U per injection site (page 209, right column).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum toxin injected into the muscles taught by Tonkin for the treatment of upper limb spasticity comprising thumb-in-palm. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the therapeutic dose.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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