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 37-54 are pending and under examination on their merits.
Claim Objections
Claims 40 and 47 are objected to because of the following informalities:
Claim 40 recites “a flexed fingers” (line 2) instead of flexed fingers or a flexed finger, and the word “fist” is missing after “clenched” in line 3.
Claim 47 recites “gly” residue, rather than conforming to the standard nomenclature “G” for the amino acid residue, as used in other positions in the same sequence. The sequences should be (G)p-RGRDDRRQRRR-(G)q, (G)p-YGRKKRRQRRR-(G)q, and (G)p-RKKRRQRRR-(Q)q.
Appropriate correction is required.
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Claim 48 recites an amino acid sequence that is not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). The amino acid sequence should be accompanied with a sequence identifier adjacent to the sequence. In addition, with respect to claim 47, the recited amino acid sequences do not match the sequences of the SEQ ID NO:’s in parentheses.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 37-54 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 37 recites the limitation "the sterile injectable composition" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 39 recites one or more types of upper limb spasticity selected from a group consisting of (i) flexed elbow, flexed wrist, and a clenched fist or (ii) flexed elbow, flexed wrist, and flexed fingers. There are at least two different reasonable interpretations of the claim, rendering it indefinite. In one interpretation, there are two alternative groups (i) and (ii) and the one or more types of upper limb spasticity are selected from either group. Under this interpretation, combinations such as flexed elbow and clenched fist would be permissible. In a second interpretation, the one or more types of upper limb spasticity are flexed elbow, flexed wrist, and a clenched fist or flexed elbow, flexed wrist, and flexed fingers (i.e. selected from the group consisting of (i) and (ii)). Under this interpretation, the combination of flexed elbow and clenched fist would not be permissible because this group does not include flexed wrist. Thus, the source of indefiniteness is whether the “one or more types of upper limb spasticity” are the groups (i) and (ii) or the individual types of upper limb spasticity within (i) and (ii).
Claim 45 recites flexor pollicis brevis/opponens. The flexor pollicis brevis and opponens pollicis are separate muscles. The combination of two different muscles separated by a slash renders claim 45 indefinite because it is unclear which muscle is within the scope of the claim or whether both muscles are within the scope of the claim.
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.
Claim 48 is likewise indefinite because the sequence identifier SEQ ID NO: 4 is in parenthesis, thus it is unclear whether the sequence identifier inside the parenthesis are part of the claimed invention.
Claim 50 recites “greater than 16 weeks to 26 weeks,” which is indefinite because it is unclear whether the claimed range is greater than 16 weeks, greater than 26 weeks, or from 16 to 26 weeks (i.e. between 16 and 26 weeks).
Claim 52 recites the composition comprises a physiologically compatible buffer for maintaining the pH between 4.5 and 6.8. There are at least two different reasonable interpretations of the claim rendering it indefinite. In one interpretation, “for maintaining the pH between 4.5 and 6.8” is purely the intended use of the buffer and does not further limit the method other than the inclusion of a buffer. In a second interpretation, the pH of the composition is required to be between 4.5 and 6.8.
Claims 38-54 are rejected for depending from a rejected base claim and not rectifying the sources of indefiniteness discussed above.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 39-45, 48, and 54 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.
Claims 40-45 each recite a treatment dose for a specific type of upper limb spasticity, which is less than the amount recited in claim 37 (250 U to 1000 U). Claims 39-45 each depend from claim 38, which depends from claim 37. Claim 38 recites wherein one or more types of upper limb spasticity are treated. This rejection applies to the embodiment in which only a single type of upper limb spasticity is treated. Claims 39-45 fail to include all the limitations of the claim upon which it depends because in the embodiment in which only a single type of upper limb spasticity is treated, the total treatment dose is less than the amount required in claim 37.
Claim 45 recites wherein the individual presents with upper limb spasticity comprising a thumb in palm.” However, thumb-in-palm is not one of the types of upper limb spasticity recited in claim 38. Therefore, claim 45 fails to include all of the limitations of the claim upon which it depends.
Claim 48 recites the sequence RRRQRRKKRG-(K)15-GRRRQRRKKR, which fails to further limit the sequences recited in claim 47, from which claim 48 depends.
Claim 53 recites wherein the composition comprises a 150 kD botulinum toxin of serotype A, the positively charge carrier, a non-reducing disaccharide or a non-reducing trisaccharide selected from trehalose, polysorbate 20, and histidine buffered to pH between 4.5 and 6.8. Claim 53 is indefinite because polysorbate 20 and histidine are not non-reducing disaccharides or trisaccharides. It is unclear whether the composition comprises trehalose, polysorbate 20, and histidine or whether the composition comprises a diluent selected from the group consisting of trehalose, polysorbate 20, and histidine.
Claim 54 recites the total treatment dose of botulinum toxin is administered to the individual in an amount of 175 U to 350 U. However, claim 54 depends from claim 37, which requires that the total treatment dose of botulinum toxin administered to the individual is between 250 U and 1000 U. Therefore, claim 54 fails to include all of the limitations of the claim upon which it depends because the lower bound for the dose recited in claim 54 (175 U) is less than the lower bound for the dose recited in claim 1 (250 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.
Claims 37-39, 47-50, and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1).
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 250 U to 1000 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). The range of 50 to 300 units overlaps with the claimed range of 250 U to 1000 U.
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.
Regarding claim 38, “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.
Claim 39 is interpreted as requiring one or more types of upper limb spasticity selected from group (i) or one or more types selected from group (ii).
Regarding claims 38-39, Leon teaches treating clenched fist, flexed wrist, and flexed elbow (page 19, lines 8-11).
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, Leon’s range of 50 to 300 units (page 19, lines 8-11) overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, “greater than 16 to 26 weeks” is interpreted as between 16 and 26 weeks. 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]).
Regarding claim 54, Leon’s 50 to 300 units (lines 10-11 on page 4) overlaps with the claimed range of 175 U to 350 U.
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) as applied to claims 37-38 above, and further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
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) as applied to claims 37-38 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 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) as applied to claims 37-38 above, and further in view of Park et al. (Yonsei medical journal 47.5 (2006): 589).
See discussion of Ruegg 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 75 U to 150 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.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1) as applied to claims 37-38 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 above, which is incorporated into this rejection as well.
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) as applied to claims 37-38 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 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) as applied to claims 37-38 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 above, which is incorporated into this rejection as well.
Claim 45 is interpreted as requiring injection into either the flexor pollicis brevis or the flexor pollicis opponens,
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.
Claims 46 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Ruegg (US 2018/0311333 A1) in view of Leon (AU 2005200251 A1), as applied to claims 37-39, 47-50, and 52-53 above, further in view of Kirshblum et al. (PM&R 12.4 (2020): 349-355).
See discussion of Ruegg and Leon above, which is incorporated into this rejection as well.
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 (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 Ruegg modified by 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 37-39, 47-50, 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).
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 250 U to 1000 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).
The range of 50 to 300 units overlaps with the claimed range of 250 U to 1000 U.
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.
Regarding claim 38, “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 and [0016] of the instant specification. “Flexed elbow” encompasses curling of the forearm. See Figure 1 of the instant specification.
Regarding claims 38-39, Leon teaches treating clenched fist, flexed wrist, and flexed elbow (page 19, lines 8-11).
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, Leon’s range of 50 to 300 units (page 19, lines 8-11) overlaps with the claimed range of 250 U to 500 U.
Regarding claim 50, “greater than 16 to 26 weeks” is interpreted as between 16 and 26 weeks. 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.
Regarding claim 54, Leon’s 50 to 300 units (lines 10-11 on page 4) overlaps with the claimed range of 175 U to 350 U.
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) and Ruegg (US 2018/0311333 A1).
See discussion of claims 160-161 and 173-175 of ‘365 and Leon 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.
Claim 40 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 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 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 by 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.
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 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 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 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 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.
Claim 42 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 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 above, which is incorporated into this rejection as well.
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 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 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). 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 43 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