Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-56 are pending in the application. Claims 1-56 are rejected. Claims 21, 29, 31, 32 and 34 are objected to.
Priority
This application is a 35 U.S.C. § 371 National Stage Filing of International Application No. PCT/US2022/073214, filed on June 28, 2022, which claims benefit of Provisional Application No. 63/298,291, filed on January 11, 2022, which claims benefit of Provisional Application No. 63/279,815, filed on November 16, 2021, which claims benefit of Provisional Application No. 63/216,877, filed on June 30, 2021.
Information Disclosure Statement
The Information Disclosure Statement(s) (IDS) filed on November 12, 2024 and October 16, 2025 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the Examiner has considered the IDS documents and signed copies of the 1449 forms are attached.
Claim Objections
Claim 21, 29, 31, 32 and 34 are objected to because of the following informalities:
Claim 21 should be amended to include the word -the- before the word “patient” in the second line of the claim for sake of consistency.
Claims 29, 31, 32 and 34 should each be amended to replace the word “weight” with the word -weighs- for sake of clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 5-8, 10, 12-27, 33, 38, 40, 47 and 53-56 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 5 recites the expression “an optimized dose” and is rejected as indefinite. Neither claim 5 nor the specification provides a clear definition regarding “an optimized dose.” Therefore, it is unclear how one of ordinary skill could reasonably determine the objective boundaries of the scope of the claim based on this recited expression. Dose optimization generally involves identifying a drug efficacy to drug toxicity ratio for a particular drug by considering the unique pharmacokinetic and pharmacodynamic properties associated with the drug. When administered to a patient, the “optimized dose” generally correlates to low or tolerable toxicity relative to the desired effect, pertaining to health or biological function, in the patient. Applicant, however, has not characterized, for instance, an efficacy-toxicity ratio required for a dose to be considered “optimized.” Therefore, in this situation it is unclear whether the recited “optimized dose” refers to a) a single optimum dose which maximizes the efficacy-toxicity ratio or b) an effective dose considered to be relatively safe. For example, it is not readily apparent whether a dose obtained from up-titrations past the claimed “period of no more than about six weeks” would result in a more effective dose tolerated by the patient and, if so, it is unclear whether a) both the increased and initial doses would be considered “an optimized dose” or b) only the increased dose would constitute “an optimized dose” while the initial dose would no longer be considered “an optimized dose.” For the purposes of examination, “an optimized dose” is being interpreted as any dose “optimized” and considered to be relatively safe and effective but not necessarily the optimum dose. Dependent claims 6-8, 12, 13, 17-19, 23 and 24 do not correct this issue of indefiniteness and are likewise rejected.
Claim 6 recites the limitation “for pediatric patients” and is rejected as indefinite. There is insufficient antecedent basis for this limitation in the claim as neither claim 6 nor parent claim 1 provides for patients (i.e., plural) let alone “pediatric patients.” It is also unclear whether “the patient” as recited in the fifth, sixth and seventh line of the claim is in reference to “a patient” (as recited in instant claim 1) or the aforementioned “pediatric patients” recited hitherto in the claim. As it is unclear whether or not the “for pediatric patients” is further limiting of “a patient” as recited in claim 1, for the purposes of examination, claim 6 is being interpreted as being drawn towards a patient population consistent with that of claim 1. Appropriate amendment(s) should be made to the claim to overcome this issue of indefiniteness.
Claim 17 recites the limitation “for patients having a body weight greater than or equal to 50 kg” and is rejected as indefinite. There is insufficient antecedent basis for this limitation in the claim as neither claim 17 nor its priority claims provide for patients (i.e., plural) let alone “patients having a body weight greater than or equal to 50 kg.” It is also unclear whether “the patient” as recited in the fifth, sixth and seventh line of the claim is in reference to “a patient” (as recited in instant claim 1) or the aforementioned “patients having a body weight greater than or equal to 50 kg” recited hitherto in the claim. As it is unclear whether or not the “for patients having a body weight greater than or equal to 50 kg” is further limiting of “a patient” as recited in claim 1, for the purposes of examination, claim 17 is being interpreted as being drawn towards a patient population consistent with that of claim 1. Appropriate amendment(s) should be made to the claim to overcome this issue of indefiniteness.
Claims 6, 10, 12, 15, 17, 21, 23 and 26 each recite the expression “satisfactory control” and are rejected as indefinite. The term “satisfactory” is both a relative and subjective term which renders the claim indefinite. The term “satisfactory” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how one of ordinary skill could reasonably determine the objective boundaries of the scope of the claim based on the term “satisfactory,” especially when considering that perception can vary among patients. A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. In re Musgrave, 431 F.2d 882, 893, 167 USPQ 280, 289 (CCPA 1970). For the purposes of examination, “satisfactory control” is being interpreted as correlating to reduced symptoms of dyskinesia due to cerebral palsy in a patient. Dependent claims 13, 14, 16, 18-20, 22, 24, 25, 27 and 53-56 do not correct this issue of indefiniteness and are likewise rejected.
Claim 33 recites the limitation “wherein the patient is 18 or older” and is rejected as indefinite. It is unclear what length of time the “18” is in reference to as the “18” could relate to years, months, days, etc. For the purposes of examination, claim 33 is being interpreted as being drawn towards patients 18 years of age or older. Applicant should amend claim 33 accordingly to overcome this issue of indefiniteness.
Claims 38, 40 and 47 recite the limitations “the UHDRS TMD score,” “the UHDRS functional assessment and functional capacity scores” and “the UHDRS TM,” respectively, and are rejected as indefinite. There is insufficient antecedent basis for these limitations in the claims as neither these claims nor parent claim 1 provide for a “UHDRS TMD score,” a “UHDRS functional assessment and functional capacity scores,” or a “UHDRS TM.” It is suggested Applicant amend claims 38, 40 and 47 to replace each instance of “the UHDRS” with -a UHDRS- to overcome the issues of indefiniteness.
Claim Rejections - 35 USC § 103
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.
Claims 1-56 are rejected under 35 U.S.C. § 103 as being unpatentable over Scalise et al. (Front Neurol. 2021, 12:612429) in view of McGee et al. (PCT Publication No. WO 2017/075340 A1; May 4, 2017) and O’Brien et al. (Mov Disord. 2015, 30:1681-1687) as evidenced by Cerebral Palsy Research Network (cprn.org/types-of-cerebral-palsy/; archived via Wayback Machine on June 18, 2021).
Determining the scope and contents of the prior art (See MPEP § 2141.01)
Scalise et al. teach the efficacy of tetrabenazine, “a selective and reversible depletor of monoamines from synaptic terminals” in children with dyskinetic cerebral palsy (otherwise dyskinesia due to cerebral palsy). See e.g., page 6.
Regarding instant claims 28-34, Scalise et al. teach the following with respect to twenty-three treated patients in Table 1:
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Therefore, the age range (i.e., 4.02-16.30 years) taught by Scalise et al. either overlaps or is near the instantly required patient age limitations as recited in instant claims 28, 30 and 33. Note that, as discussed above, instant claim 33 is being interpreted as being drawn towards patients 18 years of age or older. In addition, the weight range (12.00-62.00 kg) taught by Scalise et al. meets the patient weight requirements as recited in instant claims 29, 31, 32 and 34.
Regarding instant claim 35, Scalise et al. teach individuals diagnosed with dyskinetic cerebral palsy “according to the Surveillance of Cerebral Palsy in Europe criteria.” See e.g., page 2. Scalise et al. further teach individuals “classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy...[i.e.,] [a] five-level classification system [] used to define the subject (from I to V increasing severity)...based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.” See e.g., page 2. Scalise et al. further teach all levels of severity in a pool of 23 individuals with dyskinetic cerebral palsy, as seen in the following GMFCS data (see Table 1):
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Ascertainment of the differences between the prior art and the claims (See MPEP § 2141.02)
Regarding instant claims 1-4 and 37-52, Scalise et al. does not teach valbenazine for the treatment of dyskinesia due to cerebral palsy. However, McGee et al., in a similar field of endeavor, generally teach valbenazine [i.e., (S)-2-amino-3-methyl-butyric acid (2R,3R, 11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester] as a VMAT2 inhibitor for the “treatment of hyperkinetic movement disorders,” such as inter alia dyskinesias, cerebral palsy and tardive dyskinesia/dystonia. See e.g., paragraphs [0002] and [00270]. In addition, McGee et al. teach tetrabenazine as a VMAT2 inhibitor for “the treatment of various hyperkinetic movement disorders.” See e.g., paragraph [0004]. Furthermore, McGee et al. teach a therapeutically effective amount of “Valbenazine ditosylate Form I” or (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) for the inhibition of VMAT2, wherein “Form I” corresponds to the following XRPD: (see e.g., FIG. 1 and pages 19-20):
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According to paragraph [0044] of the instant specification, “polymorphic Form I,” as recited in instant claim 52, corresponds to the “polymorphic Form I as disclosed in U.S. Serial No. 15/338,214” which was issued into U.S. Patent No. 10,065,952 B2 (‘952) on September 4, 2018. The ‘952 patent discloses the following “crystalline Form I” (see e.g., column 12, lines 55-67) and corresponding XRPD (see e.g., FIG. 1), which is identical to the XRPD provided in FIG. 1 as disclosed by McGee et al:
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Also note that, regarding instant claims 2-4, dyskinetic cerebral palsy, as evidenced by the attached Cerebral Palsy Research Network reference, “is an umbrella term characterized by three different types of involuntary movements including dystonic, athetoid, and choreic...[and] [a] person with dyskinetic [cerebral palsy] may have one or more of these types of involuntary movements.” See e.g., page 2. In addition, note that the “wherein the treatment results in....” expression as recited in each of instant claims 37-47 is drawn towards characteristics that would necessarily be present from employing the method of instant claim 1 and is, therefore, considered to be non-limiting. “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. See MPEP § 2112.01(II).
Regarding instant claims 5-27 and 53-56, Scalise et al. does not teach the instantly claimed “optimized dose” and “up-titration over a period of no more than about six weeks.” Note that, as discussed above, an “optimized dose,” as recited for instance in instant claim 5, is being interpreted as being any dose considered to be relatively safe and effective. However, Scalise et al. does teach a gradual up-titration “10 days after each dose increasing” to adjust the dose of tetrabenazine to identify a customized “dose level that clinically reduced movement disorders and was well tolerated” (up to “a maximum of 50 mg/day”) for each individual (i.e., wherein satisfactory control of abnormal involuntary movements is achieved). See e.g., pages 5 and 6. In addition, O’Brien et al., in the same field of endeavor, teach a “6-week, double-blind, parallel-group, placebo-controlled, multi-center dose-titration study to evaluate the safety, tolerability, and efficacy of NBI-98854” (i.e., valbenazine). See e.g., page 1682. O’Brien et al. further teach a “once-daily starting dose of NBI-98854 [of] 25 mg, which could be escalated in increments of 25 mg every 2 weeks to a maximum of 75 mg.” See e.g., page 1682.
Regarding instant claim 36, Scalise et al. does not teach the patient has a Clinical Global Impression of Severity (CGI-S) score of at least 4. However, Scalise et al. emphasizes the importance of “a standardized outcome measure...to detect changes in an objective way” in children with dyskinetic cerebral palsy. See e.g., page 6. For example, Scalise et al. teach MD-CRS as “a standardized clinical outcome measure in the evaluation and follow-up of children with [dyskinetic cerebral palsy].” See e.g., page 3. Similarly, O’Brien et al., in the same field of endeavor, teach the “seven-point Clinical Global Impression of Change-TD scale (CGI-TD; 1 = very much improved, 7 = very much worse)” to assess valbenazine treatment efficacy. See e.g., page 1683.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1-4 and 37-52, it would, therefore, have been obvious to a person of ordinary skill in the art to modify the teachings of Scalise et al. in view of the teachings of McGee et al. to arrive at the instantly claimed methods. Considering that McGee et al. teach both tetrabenazine and “Valbenazine ditosylate Form I” as VMAT2 inhibitors (see e.g., paragraphs [0004] and [00265]), a person of ordinary skill would reasonably expect to obtain predictable results (e.g., VMAT2 inhibition) when substituting the VMAT2 inhibitor taught by Scalise et al. (i.e., tetrabenazine) with another VMAT2 inhibitor, such as the “Valbenazine ditosylate Form I” taught by McGee et al. MPEP § 2143(I) states:
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Therefore, considering that McGee et al. teach “improved pharmacokinetic and tolerability profiles” for valbenazine relative to tetrabenazine, a person of ordinary skill would have been motivated to make the aforementioned substitution at least in the interest of obtaining “a distinctive improvement in the treatment of hyperkinetic movement disorders.” See e.g., paragraph [0006].
Regarding instant claims 5-27 and 53-56, it would have been obvious to a person of ordinary skill in the art to arrive at the instantly claimed up-titration dosing requirements and optimized dose based on the teachings of the Scalise et al. in view of O’Brien et al. The optimization of result-effective variables, i.e., variables that achieve a recognized result, such as dosages and dosing schemes are considered to be within the ability of the skilled artisan. “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.” In re Williams, 36 F.2d 436, 438 (CCPA 1929). Based on the collective prior art teachings described above, a skilled artisan would be motivated to optimize the prior art dosages/dosing schemes as part of a general routine optimization process and would be reasonably expected to arrive at the instantly claimed methods. “[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).
Regarding instant claim 36, it would have been obvious to a person of ordinary skill in the art to apply the Clinical Global Impression of Severity (CGI-S) criteria to patients prior to treatment for dyskinetic cerebral palsy. It is considered within the ability of a skilled artisan to utilize standardized measurement techniques (e.g., CGI-S, MD-CRS, CGI-TD, etc.) to determine and characterize the severity of a disease in patients within a patient population. At least in the interest of utilizing a standardized measurement to detect changes (e.g., reduced abnormal involuntary movements) in an objective way, a skilled artisan would have been motivated to employ the instantly claimed method.
Conclusion
No claims are allowed.
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/D.M.S./Examiner, Art Unit 1626
/REBECCA L ANDERSON/Primary Examiner, Art Unit 1626
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