DETAILED ACTION
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 .
Applicant’s response filed 4/2/2026 has been received and entered into the case.
Claims 5, 6, 9, 12-14, 16, 17, 20, 22-28 are pending and have been considered on the merits. All arguments and amendments have been considered.
Maintained rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 5, 6, 9, 12-14, 17, 20, 22-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/039244 (IDS) in view of WO2009/080313.
Regarding claims 14, 20, 24, 25, WO2015/039244 teaches a method for treating a tremor of an upper limb comprising administering a therapeutically effective amount of a botulinum neurotoxin to muscles of the forearm/wrist, elbow and shoulder, wherein the therapeutically effective amount of botulinum neurotoxin A, i.e., BoNT/A, for the forearm/wrist is between 5U-25U (especially 5-15U) and the specific muscles of the forearm/wrist taught to be treated include extensor carpi ulnaris (ECU), extensor carpi radialis (ECR), flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), pronator teres (PT), pronator quadratus (PQ), supinator (Sup), 10-50U (especially 20-40 or 10-30U) for the elbow muscles which includes triceps brachii, and 10-60U (especially 20-40 or 10-30U) for the shoulder muscle which includes pectoralis major, triceps, supraspinatus, infraspinatus (p. 6, lines 24-26, Table 5, Table 7, p. 10, lines 22-34, p. 25, Table 3, Ex. 1 and 2, p. 16-29, Table 5 p. 34-39). Thus, the reference teaches administering to at least four muscles of the forearm/wrist (teaching administering to 7 muscles of the forearm/wrist Table 3, 5, 6) and muscles of the shoulder and elbow (Table 3 and 5).
Additionally, Table 6 shows that to the ECU (4.1875 U), ECR (5.4875U), FCR (5.4875 U), FCU (4.1875 U), PT (3.195 U), PQ (3.195 U) and Sup (1.26 U) were administered; however, the reference teaches that “because BoNT A is available only in discrete unit sizes, 5 units is typically the minimum that would be injected into any one wrist muscle when an injection is indicated, and the results of the calculation should be rounded to the nearest 5 units. From Table 6, it is therefore apparent in light of the foregoing that each wrist muscle would receive 5 units of the BoNT A for a total of 35 units to the wrist joint.” (p. 36, lines 14-21). For muscles of the elbow, p. 39, Table 7 teaches each would receive 20U, and Shoulder muscles Pectoralis Major 20 U. Further and regarding claims 24 and 25, the reference teaches that ECR, ECU PQ and Sup each receive a dosage of 5U; however, increasing tremor severities would increase the total dosage, doubling the dosage to FCR 10 U, FCU 10U, ECR 10U, ECU 10U, PT 5U, PQ 5U and Sup 5U (p. 36, lines 10-p. 37, lines 1-2, Table 6). Thus, applicants claimed doses according to claims 14, 20, 24 and 25 fall within the disclosed ranges of WO’244. The claimed ranges “overlap or lie inside ranges” disclosed by the prior art of record See MPEP 2144.05. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."
Additionally, the reference teaches that doses are adjusted based upon amplitude of the tremors, and thus can be optimized (p. 10, lines 27-34, p. 23, lines 6-32, p. 42-45, Ex. 6) and reevaluated after first application of therapy for further optimization (p. 11, lines 5-p.12, Fig. 11C, D, E). WO244 teaches that the administered amounts are optimizable and are determined by accurately measuring (with kinematic sensors) which muscles are involved and their contribution to abnormal movement and thus one is able to more accurately determine concentrations and dose of drugs that each muscle requires for injection (p. 6, lines 31-p. 8, lines 1-27, p. 9, lines 6-p. 10, lines 1-21, p. 10-12, Ex. 1, ex. 4 p. 32-, Table 5).
Additionally, regarding claim 20, drawn to a dose ratio in the range of 1:2 to 1:6 of wrist/forearm extensor and flexor muscles, WO’244 teaches that “One of the advantages of accurately determining the muscles involved in and their relative contributions to the abnormal movement is the ability to accurately determine the concentration and dose of a drug that each muscle requires to have injected therein. Thus, the drug may be administered to each muscle at a dosage based on the muscle group composition, the directional bias within each muscle group implicated in the abnormal movement and/or on the amplitude of the abnormal movement. In particular, the drug may be administered to each muscle at a dosage selected based on the amplitude of the abnormal movement. (p. 9, lines 6-13). The dosage of drug injected into each muscle may be determined by following a procedure whereby amplitude of an abnormal movement at each joint guides the maximum dose of the drug to be injected into the muscles involved with joint, the muscle composition of the abnormal movement guides how the maximum dosage is divided between muscle groups, and the directional bias within each muscle group guides how the dosage given to a muscle group is divided between individual muscles. The procedure may be followed manually by a clinician, or the procedure may be embodied in a computer program or software and the dosages for each individual muscle determined from calculations based on sensor data and pre-set or inputted parameters. For example, total dosage for a joint may be correlated to amplitude data for the abnormal movement at the joint, whereby the amplitude may be compared to a standard curve of amplitude vs. total dosage or to a standard dosage for a range of amplitudes. More severe abnormal movements would warrant a greater total dosage. Once the total dosage for a joint is determined, composition data showing the relative contribution of each muscle group (e.g. abductors/adductors, flexors/extensors, etc.) may permit dividing the total dosage for that joint between the various muscle groups on a pro-rated basis, for example if abductor muscles were found to contribute 40% to the abnormal movement at the joint then abductor muscles would receive 40% of the total dosage of drug for that joint. Once the division of total dose between muscle groups has been determined, the dosage for each individual muscle in the muscle group can be determined from the directional bias on a pro-rated basis, for example within the abductor/adductor muscle group if abductors are responsible for 80% of the abnormal movement caused by the abductor/adductor muscle group then the abductor muscles would receive 80% of the dosage and the adductor muscles would receive 20% (p. 9, lines 23-p. 10, lines 1-11)... Dosages of drugs will depend to a certain extent on the particular drug being used. For example, a dose range of: 10U-60U, especially 20U-40U or 10U-30U, of BoNT A can be used for each shoulder tremor contributing muscle; 10U-50U, especially 20U- 40U or 10U-30U, of BoNT A for every elbow tremor contributing muscle; and 5U-25U, especially 5U-15U, of BoNT A for every wrist tremor contributing muscle (e.g. forearm and wrist muscles). All dosages are adjusted based on amplitude of the tremor. Likewise, if the composition and directional bias in one patient shows that the tremor is predominantly flexor at the wrist, a physician can optimize dosage based on medical experience to inject a higher dose in the flexor carpi radialis and flexor carpi ulnaris, and give lower doses to the extensor carpi radialis and extensor carpi ulnaris muscles (p. 10, lines 26-31) and additionally if doses need to be decreased, i.e. removing 5 U for example, one should decrease dose allocated to the ECR and ECU muscles first to minimize risk of toxin spread (Fig. 11F, step 6.4). Thus, extensor muscles would receive lower doses.
Therefore, the administered amount of BoNT/A and to which muscle, it taken to be a result effective variable which is optimizable by the POSITA when practicing the method of WO’244.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). See MPEP 2144.05.
Regarding claim 5, the reference does not teach M. extensor digitorium communis, and thus, the BoNT/A is not taught to be administered to the M. extensor digitorium communis.
Regarding claim 6, the total dose to muscles of the forearm/wrist does not exceed 65 U, as the reference teaches 35 U (p. 39 Table 7).
Regarding claim 9, the total dose to muscles of the elbow does not exceed 40 U (p. 37, lines 27-28, Table 7).
Regarding claim 12, the total dose of BoNT/A administered does not exceed 60 U, as the reference teaches 40U (p. 39 Table 7).
Regarding claim 13, the recommended dosages can be adjusted based on severity of the tremors (p. 39-40, for example) and the total dose does not exceed 165 U (Table 7, teaching total dose of 125 U).
Regarding claim 17, the botulinum toxin includes BoNT/serotype A, or B (p. 8, lines 28-34).
Regarding claim 26, the tremor is an essential tremor (ET) (p. 16, lines 21-32, p. 20, line 10, Table 2, p. 33).
Regarding claim 27, the botulinum toxin is considered to be administered to a motor dominant upper limb as the motor dominant hand was considered for ET patients (p. 16, lines 31-32, for example).
As discussed above, the specific muscles taught to be treated include flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), extensor carpi radialis (ECR), extensor carpi ulnaris (ECU), pronator teres (PT), pronator quadratus (PQ), supinator (Sup), pectoralis major, triceps, supraspinatus, infraspinatus (p. 6, lines 24-26, Table 5, Table 7), pronator teres (PT), triceps brachii (p. 25, Table 3, Ex. 1 and 2, p. 16-29, Table 5 p. 34-39). Of particular interest are joints and muscle groups of the upper body, particularly especially the upper limbs (p. 6, lines 24-26).
However, the reference differs from the claimed invention in that it does not teach all of the 2 elbow muscles and 4 shoulder muscles, specifically the reference does not teach M. brachialis and M. latissimus dorsi of claims 14 and 20, as well as claims 20 and 28 drawn to specific muscles not injected.
WO’313 teaches a method of treating a motor disorder, i.e., spasticity, comprising administering a botulinum neurotoxin free of complexing proteins of the botulinum toxin complex (p. 4, lines 15-21) to muscles of the upper limb including those of the shoulder. The muscles that are most commonly treated are in the upper limb and include M. pectoralis complex, latissimus dorsi, brachialis, pronator quadratus, pronator teres, flexor carpi radialis, flexor carpi ulnaris. As used herein, the term "upper limb" refers to the arm comprising the shoulder and, thus, may involve muscles such as for example (a) shoulder: pectoralis complex, latissimus dorsi, teres major and subscapularis, (b) elbow: brachioradialis, biceps, brachialis, (c) forearm: pronator quadratus, pronator teres, (d) wrist: flexor carpi radialis, flexor carpi ulnaris (p. 12, lines 29-p. 13, lines 1-3, p. 17, lines 29-p. 18, lines 1). Thus, M. brachialis and M. latissimus dorsi are known muscles of the elbow and shoulder, respectively.
WO’244’s method and determination of muscles for injection is based upon a subject’s own amplitude of tremors based upon kinetic data (kinematic analysis) collected using a sensor system to study wrist, elbow and shoulder movement, directional bias of joint movement, amplitude and muscle contributions to the total tremor (see Examples of WO’244). WO’244 teaches muscles to which the BoNT/A can be administered including those of claims 14 and 20 and specifically teach that abnormal movements of upper limbs of greatest importance include those of one or more of lateral shift/tilt related muscles, sagittal shift/tilt related muscles, flexion-extensor (F/E) muscles, ulnar-radial (U/R) muscles, pronation-supination (P/S) muscles and abduction-adduction (A/A) muscles. Specifically, the reference teaches that the method provides advantages which better assess the tremor by obtaining and analyzing data for overall joint motion from a plurality of joints by applying kinematic sensors to the body, measuring overall joint movement with sufficient degrees of freedom to be deconstructed into multiple degrees of freedom for each individual joint, analysis of the amplitude of movement and contributions from and directional bias for each muscle group, wherein a personalized treatment regimen may be determined from amplitude and relative contribution of each muscle group to the movements caused by the movement disorder/tremor. Because one can determine the relative contributions of each muscle group, one is able to administer and determine the dosage needed to each muscle and muscle group implicated in the movement. (p. 3, lines 10-p. 7, p. 9, lines 6-22). The amplitudes of tremors are determined based postural tasks, and abnormal movements of upper limbs are of greatest importance including those of one or more of lateral shift/tilt related muscles, sagittal shift/tilt related muscles, flexion-extensor (F/E) muscles, ulnar-radial (U/R) muscles, pronation-supination (P/S) muscles and abduction-adduction (A/A) muscles (see Ex. 5, Fig. 11A-J).
Further, regarding claims 20, 22, 23, 28 using the above kinematic analysis, it is the examiners position that it would have been within the purview of one of ordinary skill in the art to determine which muscles are contributing to the tremor for injection as well as the number of injection points for each muscle.
Therefore, it is the Examiners position that it would have been obvious and well within the purview of a POSITA practicing the method of WO’244 to determine which of the known lateral shift/tilt related muscles, sagittal shift/tilt related muscles, flexion-extensor (F/E) muscles, ulnar-radial (U/R) muscles, pronation-supination (P/S) muscles and abduction-adduction (A/A) muscles of the shoulders, elbow and wrists of claims 14 and 20 (taught by WO’244 and WO’313) to inject (and not inject according to claim 28) and at what injection sites (and how many) with the BoNT/A based upon the subject’s need and kinematic analysis disclosed by the prior art references of record.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/039244 (IDS) in view of WO2009/080313 as applied to claims 5, 6, 9, 12-14, 17, 20, 22-28 above, and further in view of each of WO2006/005910 (IDS) and US8398998 (IDS).
The teachings of WO’244 in view of WO’313 are found above.
While WO’244 teaches BoNT/A, which is known in the art to include BOTOX®, DYSPORT®, PURTOX® AND XEOMIN® (a complex-free Bot toxA prep), for example, the reference is silent as to whether the neurotoxin is devoid of any other protein components of the neurotoxin complex.
WO910 teaches a neurotoxic component of a botulinum neurotoxin complex devoid of any other protein component of the C. botulinum neurotoxin complex (p. 2, lines 25-p. 3, whole page) which is intended to treat spasms, dystonia’s, writer’s cramp, hand dystonia, occupational cramps, tremors (p. 10, lines 23-p. 11, lines 1-11, p. 14, lines 29-p. 15).
US998 teaches a botulinum neurotoxin which is free of the complexing proteins which naturally form the botulinum neurotoxin complexes together with the neurotoxins for treating dystonic or spastic muscles (abstract, col. 1, lines 1-28, 62-67). The advantage of a free neurotoxin is that it does not induce neutralizing antibodies in the patient and can be administered over long periods without losing effect (col. 1, lines 19-23, col. 2, lines 50-67, col. 3, lines 17-26).
Therefore, before the effective filing date of the claimed invention, neurotoxic component of a botulinum neurotoxin complex devoid of any other protein component of the C. botulinum neurotoxin complex were known and used for treating tremors, and a POSITA would have been motivated by the teachings of the advantages when using said neurotoxin to treat tremors of the upper limb, given the combined teachings of the prior art references of record.
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 5, 6, 9, 12-14, 17, 20, 24, 25, 26, 27, 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 13 of U.S. Patent No. 10231665 in view of WO2015/039244 (IDS) in view of WO2009/080313.
The claimed inventions are drawn to methods of treating tremors in muscles comprising administering Botulinum toxin. US’665 does not specifically claim particular muscle groups or muscles within the groups or amounts to be administered; however,
WO2015/039244 teaches a method for treating a tremor of an upper limb comprising administering a therapeutically effective amount of a botulinum neurotoxin to muscles of the forearm/wrist, elbow and shoulder, wherein the therapeutically effective amount of botulinum neurotoxin A, i.e., BoNT/A, for the forearm/wrist is between 5U-25U (especially 5-15U) and the specific muscles of the forearm/wrist taught to be treated include extensor carpi ulnaris (ECU), extensor carpi radialis (ECR), flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), pronator teres (PT), pronator quadratus (PQ), supinator (Sup), 10-50U (especially 20-40 or 10-30U) for the elbow muscles which includes triceps brachii, and 10-60U (especially 20-40 or 10-30U) for the shoulder muscle which includes pectoralis major, triceps, supraspinatus, infraspinatus (p. 6, lines 24-26, Table 5, Table 7, p. 10, lines 22-34, p. 25, Table 3, Ex. 1 and 2, p. 16-29, Table 5 p. 34-39). Thus, the reference teaches administering to at least four muscles of the forearm/wrist (teaching administering to 7 muscles of the forearm/wrist Table 3, 5, 6) and muscles of the shoulder and elbow (Table 3 and 5).
Additionally, Table 6 shows that to the ECU (4.1875 U), ECR (5.4875U), FCR (5.4875 U), FCU (4.1875 U), PT (3.195 U), PQ (3.195 U) and Sup (1.26 U) were administered; however, the reference teaches that “because BoNT A is available only in discrete unit sizes, 5 units is typically the minimum that would be injected into any one wrist muscle when an injection is indicated, and the results of the calculation should be rounded to the nearest 5 units. From Table 6, it is therefore apparent in light of the foregoing that each wrist muscle would receive 5 units of the BoNT A for a total of 35 units to the wrist joint.” (p. 36, lines 14-21). For muscles of the elbow, p. 39, Table 7 teaches each would receive 20U, and Shoulder muscles Pectoralis Major 20 U. Further and regarding claims 24 and 25, the reference teaches that ECR, ECU PQ and Sup each receive a dosage of 5U; however, increasing tremor severities would increase the total dosage, doubling the dosage to FCR 10 U, FCU 10U, ECR 10U, ECU 10U, PT 5U, PQ 5U and Sup 5U (p. 36, lines 10-p. 37, lines 1-2, Table 6). Thus, applicants claimed doses according to claims 14, 20, 24 and 25 fall within the disclosed ranges of WO’244. The claimed ranges “overlap or lie inside ranges” disclosed by the prior art of record See MPEP 2144.05. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."
Additionally, the reference teaches that doses are adjusted based upon amplitude of the tremors, and thus can be optimized (p. 10, lines 27-34, p. 23, lines 6-32, p. 42-45, Ex. 6) and reevaluated after first application of therapy for further optimization (p. 11, lines 5-p.12). WO244 teaches that the administered amounts are optimizable and are determined by accurately measuring (with kinematic sensors) which muscles are involved and their contribution to abnormal movement and thus one is able to more accurately determine concentrations and dose of drugs that each muscle requires for injection (p. 6, lines 31-p. 8, lines 1-27, p. 9, lines 6-p. 10, lines 1-21, p. 10-12, Ex. 1, ex. 4 p. 32-, Table 5). Therefore, the administered amount of BoNT/A, it taken to be a result effective variable which is optimizable by the POSITA when practicing the method of WO’244.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). See MPEP 2144.05.
Regarding claim 5, the reference does not teach M. extensor digitorium communis, and thus, the BoNT/A is not taught to be administered to the M. extensor digitorium communis.
Regarding claim 6, the total dose to muscles of the forearm/wrist does not exceed 65 U, as the reference teaches 35 U (p. 39 Table 7).
Regarding claim 9, the total dose to muscles of the elbow does not exceed 40 U (p. 37, lines 27-28, Table 7).
Regarding claim 12, the total dose of BoNT/A administered does not exceed 60 U, as the reference teaches 40U (p. 39 Table 7).
Regarding claim 13, the recommended dosages can be adjusted based on severity of the tremors (p. 39-40, for example) and the total dose does not exceed 165 U (Table 7, teaching total dose of 125 U).
Regarding claim 17, the botulinum toxin includes BoNT/serotype A, or B (p. 8, lines 28-34).
Regarding claim 26, the tremor is an essential tremor (ET) (p. 16, lines 21-32, p. 20, line 10, Table 2, p. 33).
Regarding claim 27, the botulinum toxin is considered to be administered to a motor dominant upper limb as the motor dominant hand was considered for ET patients (p. 16, lines 31-32, for example).
As discussed above, the specific muscles taught to be treated include flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), extensor carpi radialis (ECR), extensor carpi ulnaris (ECU), pronator teres (PT), pronator quadratus (PQ), supinator (Sup), pectoralis major, triceps, supraspinatus, infraspinatus (p. 6, lines 24-26, Table 5, Table 7), pronator teres (PT), triceps brachii (p. 25, Table 3, Ex. 1 and 2, p. 16-29, Table 5 p. 34-39). Of particular interest are joints and muscle groups of the upper body, particularly especially the upper limbs (p. 6, lines 24-26).
However, the reference differs from the claimed invention in that it does not teach all of the 2 elbow muscles and 4 shoulder muscles, specifically the reference does not teach M. brachialis and M. latissimus dorsi of claims 14 and 20.
WO’313 teaches a method of treating a motor disorder, i.e., spasticity, comprising administering a botulinum neurotoxin free of complexing proteins of the botulinum toxin complex (p. 4, lines 15-21) to muscles of the upper limb including those of the shoulder. The muscles that are most commonly treated are in the upper limb and include M. pectoralis complex, latissimus dorsi, brachialis, pronator quadratus, pronator teres, flexor carpi radialis, flexor carpi ulnaris. As used herein, the term "upper limb" refers to the arm comprising the shoulder and, thus, may involve muscles such as for example (a) shoulder: pectoralis complex, latissimus dorsi, teres major and subscapularis, (b) elbow: brachioradialis, biceps, brachialis, (c) forearm: pronator quadratus, pronator teres, (d) wrist: flexor carpi radialis, flexor carpi ulnaris (p. 12, lines 29-p. 13, lines 1-3, p. 17, lines 29-p. 18, lines 1). Thus, M. brachialis and M. latissimus dorsi are known muscles of the elbow and shoulder, respectively.
WO’244’s method and determination of muscles for injection is based upon a subject’s own amplitude of tremors based upon kinetic data (kinematic analysis) collected using a sensor system to study wrist, elbow and shoulder movement, directional bias of joint movement, amplitude and muscle contributions to the total tremor (see Examples of WO’244). WO’244 teaches muscles to which the BoNT/A can be administered including those of claims 14 and 20 and specifically teach that abnormal movements of upper limbs of greatest importance include those of one or more of lateral shift/tilt related muscles, sagittal shift/tilt related muscles, flexion-extensor (F/E) muscles, ulnar-radial (U/R) muscles, pronation-supination (P/S) muscles and abduction-adduction (A/A) muscles. Specifically, the reference teaches that the method provides advantages which better assess the tremor by obtaining and analyzing data for overall joint motion from a plurality of joints by applying kinematic sensors to the body, measuring overall joint movement with sufficient degrees of freedom to be deconstructed into multiple degrees of freedom for each individual joint, analysis of the amplitude of movement and contributions from and directional bias for each muscle group, wherein a personalized treatment regimen may be determined from amplitude and relative contribution of each muscle group to the movements caused by the movement disorder/tremor. Because one can determine the relative contributions of each muscle group, one is able to administer and determine the dosage needed to each muscle and muscle group implicated in the movement. (p. 3, lines 10-p. 7, p. 9, lines 6-22). The amplitudes of tremors are determined based postural tasks, and abnormal movements of upper limbs are of greatest importance including those of one or more of lateral shift/tilt related muscles, sagittal shift/tilt related muscles, flexion-extensor (F/E) muscles, ulnar-radial (U/R) muscles, pronation-supination (P/S) muscles and abduction-adduction (A/A) muscles (see Ex. 5, Fig. 11A-J). Further, regarding claims 21-23, using the above kinematic analysis, it is the examiners position that it would have been within the purview of one of ordinary skill in the art to determine which muscles are contributing to the tremor for injection as well as the injection points for each muscle.
Therefore, it is the Examiners position that it would have been obvious and well within the purview of a POSITA practicing the method of WO’244 to determine which of the known lateral shift/tilt related muscles, sagittal shift/tilt related muscles, flexion-extensor (F/E) muscles, ulnar-radial (U/R) muscles, pronation-supination (P/S) muscles and abduction-adduction (A/A) muscles of the shoulders, elbow and wrists of claims 14 and 20 (taught by WO’244 and WO’313) to inject (and not inject) and at what injection sites (and how many) with the BoNT/A based upon the subject’s need and kinematic analysis disclosed by the prior art references of record.
Thus, the examined claims would have been obvious in view of US’665 in view of WO’244 and WO’313.
Response to Arguments
Applicant's arguments filed 4/2/2026 have been fully considered but they are not persuasive.
Applicants argue the amendment to claim 20, drawn to “one injection point”. Applicants argue that Rahimi (WO244) does not teach or suggest injection sites and that Jost (WO313) teaches away from injection wrist/forearm muscles at one injection point for each muscle, as the reference teaches two injection points for FCR and FCU muscles.
It should be noted that WO313 does teach one injection site for PT and PQ, for example, however, this reference was not relied upon to meet the injection site limitations, only to demonstrate common muscles of the upper limb to which BoNTA may be administered. The claim limitations of claims 21-23 were rejected over Rahimi’s method and their teaching of the kinematic analysis, which when determining injection sites would have been within the purview of one of ordinary skill in the art to determine which muscles are contributing to the tremor for injection as well as the injection points for each muscle when practicing the method of Rahimi (see page 11 of Non-final Rejection mailed 01/14/2026). Rahimi’s method allows the accurate determination of muscles involved in and their contributions to the tremor movements and contribution to the movement of each joint, as well as the ability to accurately determine concentration and dose that each muscle requires to have injected. The kinematic analysis allows the injections to be tailored based upon measured data.
Applicants argue that WO’244 (Rahimi) teaches administering equal doses to the flexor and extensor muscles in the forearm/wrist unlike the limitation of administering to wrist/forearm extensor and flexor muscles in a dose ratio in range of 1:2 to 1:6, and the results of the calculation should be rounded to the nearest 5 unites, thus guiding a posita to administer in multiples of 5 units, even in cases where calculated amounts are less than 5 U.
First, it should be noted that claim 20 is not limited to a dose of less than 5, but rather is drwn to “about 2.5 to 5 units” and thus includes dosages of 5 Units (to the extensor muscles) and about 5 to 15 U (to the flexor muscles). Further, as previously presented, it is the Examiners position that WO’244 suggests that “… if the composition and directional bias in one patient shows that the tremor is predominantly flexor at the wrist, a physician can optimize dosage based on medical experience to inject a higher dose in the flexor carpi radialis and flexor carpi ulnaris, and give lower doses to the extensor carpi radialis and extensor carpi ulnaris muscles (p. 10, lines 26-31) and additionally if doses need to be decreased, i.e. removing 5 U for example, one should decrease dose allocated to the ECR and ECU muscles first to minimize risk of toxin spread (Fig. 11F, step 6.4), thus suggesting the extensor muscles to receive lower doses first when calculated dose per muscle. One of the advantages of accurately determining the muscles involved in and their relative contributions to the abnormal movement is the ability to accurately determine the concentration and dose of a drug that each muscle requires to have injected therein. Thus, the drug may be administered to each muscle at a dosage based on the muscle group composition, the directional bias within each muscle group implicated in the abnormal movement and/or on the amplitude of the abnormal movement. In particular, the drug may be administered to each muscle at a dosage selected based on the amplitude of the abnormal movement. (p. 9, lines 6-13). The dosage of drug injected into each muscle may be determined by following a procedure whereby amplitude of an abnormal movement at each joint guides the maximum dose of the drug to be injected into the muscles involved with joint, the muscle composition of the abnormal movement guides how the maximum dosage is divided between muscle groups, and the directional bias within each muscle group guides how the dosage given to a muscle group is divided between individual muscles. The procedure may be followed manually by a clinician, or the procedure may be embodied in a computer program or software and the dosages for each individual muscle determined from calculations based on sensor data and pre-set or inputted parameters. For example, total dosage for a joint may be correlated to amplitude data for the abnormal movement at the joint, whereby the amplitude may be compared to a standard curve of amplitude vs. total dosage or to a standard dosage for a range of amplitudes. More severe abnormal movements would warrant a greater total dosage. Once the total dosage for a joint is determined, composition data showing the relative contribution of each muscle group (e.g. abductors/adductors, flexors/extensors, etc.) may permit dividing the total dosage for that joint between the various muscle groups on a pro-rated basis, for example if abductor muscles were found to contribute 40% to the abnormal movement at the joint then abductor muscles would receive 40% of the total dosage of drug for that joint. Once the division of total dose between muscle groups has been determined, the dosage for each individual muscle in the muscle group can be determined from the directional bias on a pro-rated basis, for example within the abductor/adductor muscle group if abductors are responsible for 80% of the abnormal movement caused by the abductor/adductor muscle group then the abductor muscles would receive 80% of the dosage and the adductor muscles would receive 20% (p. 9, lines 23-p. 10, lines 1-11).
Therefore, one or ordinary skill in the art would have been capable of applying the known method of WO’244 to determine which muscles contribute to the tremor and the proper dosage to administer. The art suggests that if the tremor is predominantly at the flexor muscles, then those muscles would receive a higher dose.
Applicants argue that Jost is directed to treating spasticity, not tremor. Rahimi teaches that the method can be used to treat movement disorders including tremors and spasticity, for example (p. 6, lines 4-10). Therefore, one would have a reasonable expectation is treating movement disorders including both tremors and spasticity when administering BoNT-A to muscles involved in the disorders given the teachings of Rahimi and Jost.
The ODP rejection is maintained for reasons applied to the prior art rejection over WO’244 and WO’313.
Conclusion
THIS ACTION IS MADE FINAL. 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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/TIFFANY M GOUGH/ Examiner, Art Unit 1651
/MELENIE L GORDON/ Supervisory Patent Examiner, Art Unit 1651
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