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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to pharmaceutical compositions for oral administration comprising a therapeutically effective amount of mexiletine, in the reply filed on 04/13/2026 is acknowledged.
Applicant’s further election without traverse of the species of an ion exchange resin as a species of the release retarding agent in the reply filed on 04/13/2026 is acknowledged.
Claims 27-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/13/2026.
Claims 6 and 20 are cancelled.
Claim 36 is newly added.
Claims 1-5, 7-19, 21-26, and 36 are under current examination.
Priority
This application is a CIP of PCT/EP2022/065917, filed 06/10/2022. Foreign priority has been claimed to IN202131026198, filed 06/11/2021. The Examiner notes that an attempt by the Office to electronically retrieve the foreign application to which priority is claimed under the priority document exchange program has failed (please see communication from the Office mailed 02/15/2024).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/10/2023 and 05/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the Examiner.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 25 is objected to because of the following informalities: for readability of the claim, it is suggested that “at least most” in line 1 should read “most” or “more that 50%” (consistent with the language of instant claim 13). 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.
Claims 10-11, 17, and 21-23 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 10 recites “the plasma concentration of mexiletine in most human subjects after 16 hours administration is within at least about 33% of Cmax”. This is indefinite as “at least” requires a value of 33% or higher while “about” encompasses values less than 33%. The scope of values encompassed by “at least about” is therefore indefinite, and the metes and bounds of the claim uncertain.
Claim 11 similarly recites “a period of at least about 4 hours”. This is indefinite as “at least” requires a period of 4 hours or longer while “about” encompasses periods less than 4 hours. The scope of values encompassed by “at least about” is therefore indefinite, and the metes and bounds of the claim uncertain.
Claim 17 recites a ratio of mexiletine or pharmaceutically acceptable salt thereof to pharmaceutically acceptable ion exchange resin of about 1:0.5 to about 1:5. No units are associated with the recited ratio (i.e., weight, volume, etc.), which renders the metes and bounds of the claim uncertain. For purposes of examination and applying prior art, the Examiner interprets this as a weight: weight ratio.
Claim 21 recites the limitation “the composition exhibits (a) a median Tmax… after single-dose administration, and wherein each dose comprises about 100 – about 600 mg of mexiletine hydrochloride”. This is indefinite as it is unclear if the limitation “each dose comprises about 100 – about 600 mg of mexiletine hydrochloride” is intended to a) limit the pharmaceutical composition to a composition comprising about 100 – about 600 mg of mexiletine hydrochloride or b) limit the intended use “after single-dose administration” to administration of about 100 – about 600 mg of mexiletine hydrochloride. It is further unclear if “each dose” is intended to require that the pharmaceutical composition comprises multiple doses or not. For purposes of examination and applying prior art, the Examiner interprets that the pharmaceutical composition of claim 21 comprises about 100 – 600 mg of mexiletine hydrochloride.
Claims 22-23 are rejected under 35 U.S.C. 112(b) by virtue of their dependency on indefinite claim 21 and failure to cure the deficiency noted above.
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.
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 1-5, 7-19, 21-26, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Shan (CN 101032462A, published September 12th, 2007; included on IDS submitted 12/10/2023) in view of Mehta et al. (US 8,062,667 B2, published November 22, 2011), hereafter “Mehta”, and as evidenced by Statland et al. (“Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia”, JAMA 2012, 308(13), 1357-1365).
Herein, the Examiner relies on the translation of Shan submitted by Applicant on 12/10/2023.
Regarding instant claim 1, Shan teaches a slow release mexiletine hydrochloride preparation comprising mexiletine hydrochloride, a material with a slow releasing function, and other pharmaceutical adjuvants (see entire document, particularly abstract and claim 1). The material with a slow releasing function is taught as one or more of acrylic resin and various polymers including hydroxypropyl methylcellulose (claim 3). The composition is taught to be an oral medication (pg. 19, “Technical Field”).
Regarding instant claims 2-3, Shan exemplifies compositions comprising 200 mg of mexiletine hydrochloride (pg. 23, Embodiment 6).
Regarding instant claims 13-14, Shan exemplifies compositions wherein mexiletine hydrochloride is the only active pharmaceutical ingredient (see Embodiments).
Regarding instant claims 17, Shan teaches that mexiletine hydrochloride is present at 20-70% by weight and the material with a slow releasing function is present at 10-50% by weight (claim 1), suggesting a weight ratio of mexiletine hydrochloride to release retarding agent of 0.4:1 to 7:1, overlapping the claimed range. Per MPEP 2144.05 I., “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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)”.
Regarding instant claim 19, Shan teaches that the other pharmaceutical adjuvants can include diluents and binding agents (claim 4).
Regarding instant independent claim 21, as noted above, Shan teaches a slow release mexiletine hydrochloride preparation comprising mexiletine hydrochloride, a material with a slow releasing function, and other pharmaceutical adjuvants (see entire document, particularly abstract and claim 1). The material with a slow releasing function is taught as one or more of acrylic resin and various polymers including hydroxypropyl methylcellulose (claim 3). The composition is taught to be an oral medication (pg. 19, “Technical Field”). Shan exemplifies compositions comprising 200 mg of mexiletine hydrochloride (pg. 23, Embodiment 6).
Regarding instant claims 22-23, as noted above, Shan exemplifies compositions wherein mexiletine hydrochloride is the only active pharmaceutical ingredient (see Embodiments).
Regarding instant independent claim 24, as noted above, Shan teaches a slow release mexiletine hydrochloride preparation comprising mexiletine hydrochloride, a material with a slow releasing function, and other pharmaceutical adjuvants (see entire document, particularly abstract and claim 1). The material with a slow releasing function is taught as one or more of acrylic resin and various polymers including hydroxypropyl methylcellulose (claim 3). The composition is taught to be an oral medication (pg. 19, “Technical Field”). Shan exemplifies compositions comprising 200 mg of mexiletine hydrochloride (pg. 23, Embodiment 6).
Regarding instant claims 25-26, as noted above, Shan exemplifies compositions wherein mexiletine hydrochloride is the only active pharmaceutical ingredient (see Embodiments).
Shan does not teach the elected release retarding agent of an ion exchange resin (instant claims 1, 17-18, 21, 24, and 36) or that the composition is in a suitable liquid oral dosage form (instant claim 24). Shan does not teach the formation of a complex with a pharmaceutically acceptable ion exchange resin wherein the ion exchange resin comprises from about 30% to about 85% of the complex on a weight-to-weight basis (instant claim 18).
Mehta teaches pharmaceutical preparations having a drug ion-exchange resin complex that is treated to provide programmable release characteristics and a controllable modified release of active pharmaceuticals in the gastrointestinal tract for a duration of up to about 24 hours (see entire document, particularly column 1, lines 14-17 and column 2; lines 38-48). The drug-release pattern can be controlled by combining the drug and resin to form a complex matrix followed by application of a polymer barrier coating including polymers such as those based on ethyl cellulose, polyvinyl acetate, etc. (column 4, lines 6-61). Mehta teaches that cation-exchange resins, e.g., AMBERLITE IRP-69, are particularly well suited for use with drugs having a cationic functionality (column 7, lines 23-25). The amount of drug loaded onto the resin typically ranges from about 1% to about 75% by weight of the drug-ion exchange resin particles, with typical loadings of about 25% by weight being advantageously employed (column 10, lines 42-51), indicating that advantageously about 75% by weight of the complex is ion-exchange resin, and the weight ratio of drug to resin is about 1:3.
The drug release can be prolonged for up to 24 hours, providing the advantage that instead of taking multiple doses a day, one may take a once-a-day dose that would provide a more consistent supply of drug which is beneficial in patients who have difficulty swallowing larger solid dosage forms (column 4, line 62-column 5, line 6). The coated drug-ion exchange resins can be formulated in a liquid suspension that does not produce agglomeration and color migration, which may enhance compliance (column 5, lines 7-18). Compositions can be characterized by having a drug release where less than 50%, 60%, 70%, or 80% of the drug is released at about 12 hours from administration (column 5, lines 19-35).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the slow release mexiletine hydrochloride preparation of Shan with the programmable release treated drug ion-exchange resin complex of Mehta, with amounts and ratios of drug and ion-exchange resin consistent with the instant claims, and to formulate it as a liquid oral composition, as further suggested by Mehta. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to achieve a dosage form that can reduce the number of daily doses required to once a day and enhance patient compliance, as suggested by Mehta (column 4, lines 62-column 5, lines 18). There is a reasonable expectation of success as Shan similarly teaches slow release formulations with materials such as acrylic resins and polymers such as ethyl cellulose acting as release-slowing materials; Shan further teaches that mexiletine hydrochloride is rapidly absorbed following oral administration, the maintenance time within the therapeutically effective concentration range is short, and that it is desirable to develop sustained-release formulations which reduce the number of doses take and improve patient compliance (pg. 20, paragraphs 1-3). Mehta further teaches the advantageous use of cation exchange resins with drugs having cationic functionality; the mexiletine hydrochloride of Shan is illustrated to have such functionality (see structure on pg. 19).
The limitations of instant claim 1 “wherein the mexiletine or pharmaceutically acceptable salt thereof is released in a controlled release manner when the composition is administered to a human subject such that once-daily administration of the composition is effective for the treatment of myotonia”, of instant claim 21 “wherein the composition exhibits…after single-dose administration”, and of instant claim 24, “following administration of the composition to a human subject releases the mexiletine or pharmaceutically acceptable salt there in a controlled release manner such that once-daily administration of the composition is effective for the treatment of myotonia” are directed to future intended uses of the composition. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art is capable of performing the intended use, then it meets the claim.
As set forth above, the prior art combination of Shan and Mehta render obvious the structural components of the instant claim and arrives at a controlled-release formulation comprising mexiletine hydrochloride, a pharmaceutically acceptable ion-exchange resin, and one or more pharmaceutically acceptable excipients which can prolong drug release up to about 24 hours such that the compositions can be taken once a day. The combination further arrives at an amount of mexiletine hydrochloride and ratio of drug to ion-exchange resin consistent with the instant claims. As evidenced by Statland, mexiletine hydrochloride is an antiarrhythmic medication with a high affinity for muscle sodium channels, and is effective for reducing myotonia in patients with myotonic dystrophy type 1 (see paragraph bridging pgs. 1357-1358); further, the use of oral 200 mg doses of mexiletine improved patient-reported stiffness in patients with nondystrophic myotonias (see entire document, particularly “Context”, “Intervention”, and “Conclusion” on pg. 1357). Thus, the composition of the modified Shan is capable of performing the recited intended uses.
Regarding the Tmax, t1/2, Cmax, AUC, and dissolution properties recited in instant claims 4-5, 7-12, 15-16, and 21, absent evidence to the contrary, these properties will necessarily be present as the structural components of the claimed composition are rendered obvious by the teachings of the prior art. See also MPEP 2112.01 II. "A chemical composition and its properties are inseparable.”
Further, as noted above, Mehta teaches that controllable release formulations can be programmable to a pre-determined release profile and that a 24-hour release product can be modified to release have varying amounts of drug release at 12 hours from administration (see particularly column 5, lines 19-35). The combination of the prior art suggests the use of AMBERLITE IRP 69 ion exchange resin (see particularly Mehta column 7, lines 23-25) in combination with drugs at loading% and ratios which are consistent with compositions exemplified in Table 3 of the instant specification (see particularly Mehta, column 10, lines 42-51), demonstrated to have a dissolution profile consistent with the instant claims (see instant specification paragraphs [0445]-[0452]). Therefore, absent evidence to the contrary, the composition of the modified Shan is capable of providing the Tmax, t1/2, Cmax, AUC, and dissolution profile properties claimed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
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