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 .
Summary
Receipt of Applicants Amendments, Arguments and Remarks filed on 06/09/2026 is acknowledged.
Claims 1-6, 11, 31, 36, 49, 56, 67, 69, 73, 78, 83-85 and 87-88 were pending prior to entry of the present Amendment.
Claims 5, 7-10, 12-30, 32-35, 37-48, 50-55, 57-66, 68, 70-72, 74-77, 79-82, 86 and 89 are cancelled.
Claims 69, 83-85, 87-88 are withdrawn from further consideration.
Claims 1, 67, 73, and 78 have been amended.
Claims 1-4, 6, 11, 31, 36, 49, 56, 67, 73 and 78 are pending and under examination in this application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/19/2026, 09/26/2025, and 07/31/2023 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
Claim Objections
Claim 6 is objected to under 37 CFR 1.75(c) as being in improper dependent form because claim 6, as pending, depends from claim 5, which has been cancelled by Applicant. See MPEP § 608.01(n). Notwithstanding this objection, claim 6 has been examined on the merits and is rejected under 35 U.S.C. § 103 as set forth in the Claim Rejections – 35 U.S.C. § 103 section below. See MPEP § 608.01(n) (examiner should reject on the merits any claim objected to for improper dependency). Applicant is required to cancel claim 6 or rewrite it in independent form or as a dependent claim referencing an existing pending claim. Appropriate correction is required.
The previous objection to claim 67 for the informality regarding "[[pH]]3.0 phthalate buffer" is withdrawn. Applicant has corrected the typographical error to read "pH 3.0 phthalate buffer." The correction is acceptable.
Claim Rejections – 35 U.S.C. § 112
The previous rejection of claims 73 and 78 under 35 U.S.C. § 112(b) for indefiniteness is hereby withdrawn. Applicant has amended claims 73 and 78 to delete the phrase "or the method," thereby removing the language that lacked antecedent basis in claim 1. As amended, claims 73 and 78 each recite "[t]he dosage form of claim 1," which is supported by the dosage form recited in claim 1. The § 112(b) rejection is therefore moot and is withdrawn.
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.
Claim 67 remains rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 67 recites: "The dosage form of claim 1, wherein about 40 wt%-60 wt% of deutetrabenazine is released within 7 hours, as measured in a USPII dissolution device, pH 3.0 phthalate buffer, 75 rpm." This limitation recites a dissolution release rate, which is a result or property of the dosage form, without specifying any additional structural feature, component, or compositional element that further limits the structure of the dosage form of claim 1.
Applicant argues, citing In re Stepan Co., 868 F.3d 1342, 1348 (Fed. Cir. 2017), that performance characteristics are given patentable weight and that claim 67 limits the scope of claim 1 by encompassing only those dosage forms possessing the recited release characteristic. This argument is not persuasive. Stepan addresses whether a functional claim limitation is given patentable weight in the context of § 103 obviousness—it does not hold that a result-only limitation in a dependent claim satisfies the structural further-limitation requirement of § 112(d). Under § 112(d), a dependent claim must specify a further limitation of the subject matter claimed, not merely characterize how the claimed composition performs. Claim 67 adds no structural element (e.g., no additional polymer, no specific polymer ratio, no coating weight, no specific excipient) that achieves or is responsible for the recited release rate. Any dosage form of claim 1—regardless of its specific structural makeup—could theoretically exhibit the recited release rate, and the claim provides no structural guidance as to how that result is achieved.
Applicant may overcome this rejection by: (1) canceling claim 67; (2) rewriting claim 67 in independent form; (3) adding to claim 67 at least one structural element that achieves the recited dissolution profile (e.g., a specific polymer, polymer ratio, coating weight, or excipient); or (4) providing a sufficient showing that the recited dissolution limitation structurally limits the dosage form of claim 1 in a manner consistent with § 112(d) and MPEP § 608.01(n).
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.
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 1-4, 6, 11, 31, 36, 49, 56, 67, 73, and 78 are rejected under 35 U.S.C. § 103 as being unpatentable over Austedo® (deutetrabenazine) tablets label (FDA; Year: 2017) ("Austedo®") in view of Gant (US 2010/0130480 A1) ("Gant"), Duffield (US 2012/0208773 A1) ("Duffield"), and further in view of Bosch (US 5,510,118) ("Bosch").
The prior art rejection of claim 1 is maintained and is strengthened by Applicant's amendment adding the particle size limitation. As set forth in the Non-Final Office Action mailed January 30, 2026, (hereinafter "NFOA"), the combination of Austedo®, Gant, and Duffield renders obvious a controlled release oral dosage form for once-daily administration of deutetrabenazine comprising sustained release beads having a core comprising deutetrabenazine and a pharmaceutically acceptable excipient, and a pH-independent and/or pH-dependent polymer coat. That mapping is incorporated herein by reference. The full prior art mapping for the base structural limitations of claim 1 (sustained release beads, core comprising deutetrabenazine and excipient, pH-independent and/or pH-dependent polymer coat, once-daily oral dosage form) is set forth in the NFOA and relies on Austedo® (excipients, dose, API identity), Gant (¶¶ [0011]-[0022], [0054]-[0067]; deutetrabenazine, modified release motivation), and Duffield (¶¶ [0009]-[0013], [0123]-[0145], [0166], [0301]-[0302], [0392]; sustained release multiparticulate beads, pH-independent ethylcellulose coat, pH-dependent Eudragit® coat, once-daily CR platform).
Applicant has added to claim 1 the limitation that the deutetrabenazine has a median particle size of one of the following: 0.02 to 2.0 micron, or 0.02 to 0.9 micron, or 0.05 to 0.5 micron, or 0.1 to 2.0 micron, or 0.1 to 1.6 micron, or 0.2 to 1.6 micron, or 0.15 to 1.2 micron, or 0.15 to 1.0 micron (the "particle size limitation"). This limitation is presented as a Markush-type alternative; the claim is anticipated or rendered obvious if any one of the enumerated size ranges is taught or suggested by the prior art. See Ex parte Markush; MPEP § 2173.05(h).
Bosch (US 5,510,118) is already of record and expressly teaches the preparation of nanoparticulate drug substances by milling poorly soluble drugs with a surface modifier to yield particles having an effective average particle size of less than about 400 nm (0.4 µm) (col. 6, ll. 29-54). Bosch further teaches that, in preferred embodiments, the effective average particle size is less than about 250 nm, and that sizes less than 100 nm have been achieved (col. 6, ll. 37-54). These teachings directly and squarely fall within at least the following alternatively claimed particle size ranges of amended claim 1: (i) 0.02 to 2.0 micron; (ii) 0.02 to 0.9 micron; and (iii) 0.05 to 0.5 micron.
It would have been obvious to a person of ordinary skill in the art (PHOSITA) before the effective filing date to prepare deutetrabenazine particles in the size ranges taught by Bosch and incorporate them into the sustained-release bead formulation taught by Austedo®/Gant/Duffield. The motivation to do so is expressly supplied by the art: Bosch states that reducing poorly soluble drugs to nanoparticulate size improves solubility, dispersion, and bioavailability, and that such preparations exhibit "unexpectedly high bioavailability" (col. 4, ll. 31-40). Deutetrabenazine is a poorly water-soluble drug, as acknowledged by Applicant and confirmed by the Duffield reference (Duffield ¶ [0010], noting tetrabenazine is "practically insoluble" at pH 3-12). A PHOSITA would have been motivated to apply Bosch's well-established particle size reduction technique to deutetrabenazine to improve the dissolution rate and bioavailability of the sustained-release formulation taught by the combination of Austedo®, Gant, and Duffield, with a reasonable expectation of success.
Furthermore, the claimed particle size ranges (0.02-2.0 micron at their broadest) overlap with or are encompassed by Bosch's disclosed particle sizes (<0.4 micron preferred; <0.25 micron more preferred; <0.1 micron achieved). Under In re Aller, 220 F.2d 454, 456 (CCPA 1955), and MPEP § 2144.05, overlapping ranges create a prima facie case of obviousness.
Austedo® is an FDA-approved drug known as deutetrabenazine (API) and the label discloses oral dosage formulation, with known dose ranges (6-48 mg) in once a day, twice a day and disclosed inactive ingredients: ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide,
polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide (page 12, 1st ¶).
Regarding claims 1, 11 and 49, as noted above, Austedo® label discloses deutetrabenazine (API) in oral administration, and known dosage range overlaps with instant dose range of 6 mg -72 mg, and many of the inactive substances are known pharmaceutically acceptable excipient comprises an antioxidant (butylated hydroxyanisole, butylated hydroxytoluene); a binder (Povidone (Polyvinylpyrrolidone/PVP): a binder commonly used in wet granulation), Polyvinyl Alcohol (PVA): commonly used as a binder and coating agent; a filler, mannitol, microcrystalline cellulose; a surfactant, polysorbate 80 (known to help with defoaming), polyethylene glycol (PEG) known to be used as foam control in some formulations. Moreover, Austedo® label discloses short half-life metabolites (page 13, ¶ Elimination), known safety issues of pharmacodynamics and pharmacokinetics tied to peak exposure (page 12, ¶ 12.2 and ¶ 12.3) and patients with hepatic impairment issues (¶ 8.6 and page 14).
Austedo® fails to specifically disclose extended-release formulation, sustained release beads, and pH-independent polymer coat, and pH-dependent polymer coat to further improve a composition comprising deutetrabenazine (API).
Gant teaches new benzoquinoline compounds, pharmaceutical compositions made thereof, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject are also provided for, for the treatment of chronic hyperkinetic movement disorders (¶ 0002), and tetrabenazine (Nitoman, Xenazine, Ro 1-9569), 1,3,4,6,7,11 b-Hexahydro-9,1 0-dimethoxy-3-(2-methylpropyl)-2H-benzo[ a ]quinoline, is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine is commonly prescribed for the treatment of Huntington's disease (¶ 0003). Moreover, Gant discloses Deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been demonstrated previously with some classes of drugs (¶ 0011), and tetrabenazine is a VMAT2 inhibitor. The carbon hydrogen bonds of tetrabenazine contain a naturally occurring distribution of hydrogen isotopes, namely 1 Hor protium (about 99.9844%), 2H or deuterium (about 0.0156%), and 3H or tritium (in the range between about 0.5 and 67 tritium atoms per 1018 protium atoms). Increased levels of deuterium incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could affect the pharmacokinetic, pharmacologic and/ortoxicologic profiles of tetrabenazine in comparison with tetrabenazine having naturally occurring levels of deuterium (¶ 0012), and in certain embodiments, the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half-life (T 112), lowering the maximum plasma concentration (Cmax) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions (¶ 0022). Therefore, Gant explicitly teaches deutetrabenazine and the benefits thereof.
Regarding claims 1-4, 11 and 49, as noted above, Gant teaches the deutetrabenazine formulations (tablets, capsules, excipients, binders, fillers, antioxidants and dose in the range of 6-72 mg) and suggests controlled release, PK for metabolites (¶ 0045 - ¶ 0048, and ¶ 0054 - ¶0067), formulations comprising the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-,
accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (¶ 0054), wherein the capsules, tablets, granules binders, inert diluents, surface active or dispersing agents, and the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein (¶ 0057).
Gant fails to specifically teach beads and pH-independent and pH-dependent coat coating of the core.
Duffield teaches a pharmaceutical composition that includes tetrabenazine and a release-retarding agent; and a method of treating a hyperkinetic movement disorder (e.g., Huntington's disease, chorea associated with Huntington's disease, hemiballismus, senile chorea, tic disorders, tardive dyskinesia, myoclonus, dystonia and/or Tourette's syndrome). The method includes administering an effective amount of the pharmaceutical composition, for a period of time effective to treat the hyperkinetic movement disorder (abstract).
Regarding claims 1-4, 11, 31, 36, 49, 56, Duffield teaches commercially available tetrabenazine (¶ 0005-¶ 0008 and specifically in ¶ 0016, ¶ 0019), and formulations as controlled-release can sometimes reduce the side effect, smoothing out the Cmax value and can also provide simplified once-a-day administration (¶ 0009), and Comparative Example 1 illustrates that tetrabenazine is practically insoluble in the pH range of 3-12 and slightly soluble at pH 2 (as found in the stomach) Immediate-release formulation tablets including tetrabenazine which are currently available are designed to disintegrate in the stomach leading to dissolution and absorption of tetrabenazine in the stomach (¶ 0010), and Immediate-release formulations require that a drug is administered in a high dose at a given time only to have to repeat that dose several hours or days later. This is inconvenient to the patient and can result in damaging side effects. In contrast, controlled-release formulations enable drugs to be delivered to the patient continually for prolonged time periods and in a controlled fashion (¶ 0011). Duffield further teaches that pH levels in GI tract affects tetrabenazine in practically to insoluble form (¶ 0012). Therefore, it would be expected that by formulating tetrabenazine as a controlled-release formulation, so preventing the drug from being released in the stomach and delaying release until the drug reaches regions of the GI tract where it is less soluble, the bioavailability of tetrabenazine would be significantly reduced (¶ 0013), and the pharmaceutical compositions described herein can be provided in a variety of dosage forms. For example, pharmaceutical compositions described herein can be a tablet, powder, capsule, sachet, troche or lozenge (¶ 0020). Furthermore, Duffield discloses The percentage of tetrabenazine included in the pharmaceutical compositions described herein can vary, for example, the tetrabenazine can be present in amounts varying from about 5% (w/w) to about 20% (w/w) of the composition (¶ 0022), and in certain compositions, tetrabenazine is from about 5 mg to about 50 mg (¶ 0160), and the pharmaceutical compositions described herein can be a modified-release dosage unit form, a controlled release dosage unit form, an extended release dosage unit form, a prolonged-release dosage unit form, a delayed release dosage unit form, an enhanced absorption dosage unit form, a pulsatile release dosage unit form, a gastro-retention unit dosage form, or a sustained-release dosage unit form (¶ 0025). Moreover, Duffield teaches modified release dosage forms comprising coated beads granules, pellets, microparticles, with drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional immediate release dosage forms. The rate of release of the active drug from a modified release dosage form is controlled by features of the dosage form and/or in combination with physiologic or environmental conditions rather than by physiologic or environmental conditions alone. The modified release dosage forms of certain embodiments can be contrasted with conventional immediate release dosage forms which typically produce large maximum/minimum plasma drug concentrations (Cmax/Cmin) due to rapid absorption of the drug into the body (i.e., in-vivo, relative to the drug's therapeutic index; i.e., the ratio of the maximum drug concentration needed to produce and maintain a desirable pharmacological response) (¶ 0123).
Notably, Duffield discloses the design of conventional immediate release dosage
forms is generally based on getting the fastest possible rate of drug release, and therefore absorbed, often at the risk of creating undesirable dose related side effects. The modified release dosage forms of certain embodiments of the invention, on the other hand, improve the therapeutic value of the active drug by reducing the ratio of the maximum/minimum plasma drug concentration (Cmax/Cmin) while maintaining drug plasma levels within the therapeutic window. The modified release dosage forms of certain embodiments attempt to deliver therapeutically effective amounts of tetrabenazine as a once-daily dose so that the ratio Cmax/Cmin in the plasma at
steady state is less than the therapeutic index, and to maintain drug levels at constant effective levels to provide a therapeutic benefit over a period of time ( e.g. 24-hour period). The modified release dosage forms of certain embodiments of the invention, therefore, avoid large peak-to-trough fluctuations normally seen with conventional or immediate release dosage forms and can provide a substantially flat serum concentration curve throughout the therapeutic period. Modified-release dosage forms can be designed to provide a quick increase in the plasma concentration of the tetrabenazine which remains substantially constant within the therapeutic range of tetrabenazine for a period of time (e.g. 24-hour period). Alternatively, modified-release dosage forms can be designed to provide a quick increase in the plasma concentration
of the drug, which although may not remain constant, declines at a rate such that the plasma concentration remains within the therapeutic range for a period of time ( e.g. 24-hour period). The modified release dosage forms of certain embodiments of the invention can be constructed in many forms known to one of ordinary skill in the drug delivery arts and described in the prior art. The USP considers that the terms controlled release, prolonged release and sustained release are interchangeable. Accordingly, the terms "modified- release", controlled-release", "control-releasing", "rate controlled release", "extended release", "prolonged-release", and "sustained-release" are used interchangeably herein. For the discussion herein, the definition of the term "modified release" encompasses the scope of the definitions for the terms "extended release", "enhanced-absorption", "controlled release", "sustained release" and "delayed release" (¶ 0123). Additionally, Duffield discloses multiparticulates, granules, beads and pellets
refers to a drug formulation in discrete particulate form, and the terms are interchangeable (¶ 0129) and tablets (¶ 0130), controlled release coat, modified release polymers include pH independent polymers, pH dependent polymers (such as for example enteric or reverse enteric types), soluble polymers, insoluble polymers, lipids, lipidic materials, and mixtures thereof (¶ 0138), enteric polymer (¶ 0138-¶ - ¶ 0141) and functional coat (¶ 0142), non-functional coat (¶ 0143), and pH independent polymer coats (ethylcellulose) (¶ 0392), pH dependent polymer coats (EUDRAGIT® RS and RL) (¶ 0166). Duffield further discloses the term "core" as used herein is defined to mean a solid vehicle in which at least one active drug is uniformly or non-uniformly dispersed. The core can be formed by methods and materials well known in the art, such as for example by compressing, fusing, or extruding the active drug together with at least one pharmaceutically acceptable excipient. The core can be manufactured into, for example, a homogenous or non-homogenous unitary core, a multiparticle, or a plurality of microparticles compressed into a unitary core (¶ 0144), and explanation of modified release matrix core (¶ 0145). Duffield further teaches pharmaceutically acceptable carriers, excipients and/or diluents (¶ 0051), and conventional excipients in extended release (XR) tablets, XR core, a binder, (¶ 0175 - ¶ 0177). In certain embodiments of the present invention, a multi particulate system is provided which contains multiple microparticles each containing an effective amount of tetrabenazine and at least one pharmaceutically acceptable excipient. The multiparticulates can be contained within a capsule or can be compressed into a matrix or tablet, that upon ingestion disintegrate into multiple units ( e.g. pellets), wherein the sub-units or pellets possess the desired controlled release properties of the dosage form. The multiparticulates or the multiple unit dosage forms can be surrounded by one or more coatings. Examples of such coatings include polymeric controlled release coatings, delayed release coatings, enteric coatings, immediate release coatings, taste masking coatings, extended release coatings, and non-functional coatings (¶ 0301). The tetrabenazine in the microparticles of certain embodiments can be present in an effective amount of from about 0.1 % to about 99% by weight of the microparticles and In certain embodiments wherein the microparticles are manufactured using a drug layering on bead process, the tetrabenazine can be present in the microparticles in an amount of from about 0.1 % to about 60%; in other such embodiments from about 5% to about 50%; and in still other such embodiments from about 10% to about 40% by weight of the microparticle. In at least one embodiment wherein the microparticles are manufactured using a drug layering on bead process, the tetrabenazine is present in the microparticle in an amount of about 25% by weight of the microparticle (¶ 0302).
Regarding claim 67, Duffield teaches the amount of the tetrabenazine present in the controlled release matrix can vary in an amount of from about 40% to about 90%
by weight of the matrix tablet dry weight (¶ 0212) and the skilled artisan will appreciate that controlling the permeability can control the release of the tetrabenazine and/or the amount of coating applied to the tablet cores and the permeability of the XR controlled release coat can be altered by varying the ratio of the water-insoluble, water-permeable film-forming polymer: plasticizer: water-soluble polymer and/or the quantity of coating applied to the tablet core. A more extended release can be obtained with a higher amount of water-insoluble, water-permeable film forming polymer. The addition of other excipients to the tablet core can also alter the permeability of the controlled release coat (¶ 0208). Moreover, Duffield discloses the XR tablet of certain embodiments of the invention provides an extended release of the tetrabenazine and in at least one embodiment no pore forming agent is present in the XR coating formulation. An extended release tetrabenazine formulation is provided in certain embodiments such that after about 2 hours, not more than about 20% of the tetrabenazine content is released. For example, in certain embodiments, from about 2% to about 18%, from about 4% to about 8%, or about 5% of the tetrabenazine content is released after
about 2 hours. After about 4 hours, from about 15% to about 45% of the tetrabenazine content is released. For example, in certain embodiments from about 21% to about 37%, from about 28% to about 34%, or about 32% of the tetrabenazine content is released after about 4 hours. After about 8 hours, about 40% to about 90% of the tetrabenazine content is released. For example, in certain embodiments from about
60% to about 85%, from about 68% to about 74%, or about 74% of the tetrabenazine content is released after about 8 hours. After about 16 hours not less than about 80% of the tetrabenazine content is released. For example, in certain embodiments not less than about 93%, not less than about 96%, or not less than about 99% of the tetrabenazine content is released after about 16 hours (¶ 0210) and also, extended release tablets are provided in certain embodiments wherein after about 2 hours not more than about 40% (e.g., about 33%) of the tetrabenazine is released; after about 4 hours from about 40 to about 75% of the tetrabenazine is released ( e.g., about 59% ); after about 8 hours at least about 75% of the tetrabenazine is released (e.g., about
91 % ); and after about 16 hours at least about 85% of the tetrabenazine is released ( e.g., about 97% ). In all instances herein when actual or prophetic dissolution profiles are provided this means that the medicament possesses such a profile in at least one dissolution medium under prescribed conditions such as are identified herein and are well known to those skilled in the art. Such dissolution media, dissolution conditions
and apparatus for use therein are disclosed in the United States Pharmacopoeia (USP) and European and Japanese counterparts thereof (¶ 0211).
Regarding claims 73 and 78, Duffield discloses pharmacokinetic and statistical analyses were carried out on plasma tetrabenazine, α-dihydrotetrabenazine (α-DHTBZ) and β-dihydrotetrabenazine (β-DHTBZ) from 7 subjects, and mean pharmacokinetic parameters for each analyte are shown in Table 1, Summary statistics are presented in
Table 2. A listing of the α-DHTBZ /β-DHTBZ ratios for each treatment is presented in Table 3 (¶ 0596-¶ 0695). The recitation of the pharmacokinetic profile and characteristics of the oral dosage form comprising the known administration of the various amount of deutetrabenazine, and measurements of the α-DHTBZ and β-DHTBZ in vivo plasma profile to include AUC and Cmax are explicitly taught. These pharmacokinetics/pharmacodynamics outcomes are the intended result of a controlled release formulation and it would have been obvious to a PHOSITA to tune and/or optimize to achieve percentage release, peak plasma release, AUC in order to have a desirable effective bioavailable formulation. The characteristics are obvious and non-limiting.
Duffield fails to specifically teach deutetrabenazine particle size of less than 2.0 micron.
Bosch teaches a process of preparing nanoparticulate drug substances comprising the steps of: preparing a premix of the drug substance and a surface modifier, and subjecting the premix to mechanical means to reduce the particle size of the drug substance, the mechanical means producing shear, impact, cavitation and attrition (abstract). Furthermore, Bosch discloses the invention can be practiced with a wide variety of drug substances. The drug substance preferably is present in an essentially pure form. The drug substance must be poorly soluble and dispersible in at least one liquid medium. By "poorly soluble" it is meant that the drug substance has a solubility in the liquid dispersion medium, e.g. water, of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. A preferred liquid dispersion medium is water. However, the invention can be practiced with other liquid media in which a drug substance is poorly soluble and dispersible including, for example, aqueous salt solutions, safflower oil and solvents such as ethanol, t-butanol, hexane and glycol. The pH of the aqueous dispersion media can be adjusted by techniques known in the art (column 4, lines 54-67).
Regarding claim 6 (rejected on the merits notwithstanding the objection for improper dependency noted above): Claim 6 depends from cancelled claim 5 and recites that the deutetrabenazine has a particle size distribution characterized by a D90 of about 0.8 to about 1.6 micron. Claim 6 is rejected under 35 U.S.C. § 103 as being unpatentable over Austedo® in view of Gant, Duffield, and Bosch, for the same reasons set forth above with respect to claim 1. The recited D90 of about 0.8 to about 1.6 micron falls squarely within Bosch’s disclosed particle size distributions: Bosch teaches that at least 90% of particles (i.e., D90) have a weight average particle size of less than about 400 nm (0.4 µm) (col. 6, ll. 37–41), and in preferred embodiments less than about 250 nm. The claimed D90 range of 0.8 to 1.6 micron is broader than Bosch’s preferred range and represents the higher end of particle sizes for milled drug substance; however, a PHOSITA would have understood that milling conditions can be tuned to achieve any particle size within or above Bosch’s preferred range as a matter of routine optimization. Under In re Aller, 220 F.2d 454 (CCPA 1955), and MPEP § 2144.05, the overlap between the broadly claimed D90 range and Bosch’s taught particle size distribution establishes a prima facie case of obviousness.
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to formulate deutetrabenazine into a once-daily oral controlled-release dosage form comprising sustained-release beads having a polymeric coating, as taught by Gant and Duffield, in view of the known pharmacokinetic limitations of immediate-release deutetrabenazine as disclosed in the Austedo® labeling. Furthermore, it would have been obvious to employ pH-dependent and/or pH-independent polymer coatings, as taught by Duffield in order to modulate release throughout the gastrointestinal tract. The inclusion of immediate-release beads in combination with sustained-release beads represents a predictable variation taught by Duffield to tailor onset and duration. Optimization of particle size via milling in a microfluidizer in conjunction with a surface modifier and adjustment of dissolution and pharmacokinetic parameters would involve routine experimentation using known techniques, yielding predictable and expected results as taught by Bosch in view of Duffield and Gant. The Austedo® labeling establishes deutetrabenazine oral dosing with known amounts and identifies PK limitations, requiring improvements. Gant teaches the rational and obvious to use deuteration of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles of tetrabenazine. Duffield teaches multi-particulate sustained-release beads using polymer coatings, selection of pH-dependent and pH-independent polymers to control GI release. A PHOSITA would have been motivated to combine these teachings to achieve a once-daily dosing with reasonable and predictable success.
Response to Applicant's Arguments
Applicant's arguments have been fully considered and are not found to be persuasive for the reasons set forth below.
Argument 1: The Prior Art Does Not Teach or Suggest a Dosage Form Comprising Sustained Release Beads with Deutetrabenazine Having the Claimed Particle Sizes.
Applicant argues that the cited references do not disclose or suggest a dosage form comprising sustained release beads containing particulate deutetrabenazine having the particle sizes required by claim 1, and that the Office has not identified evidence that a PHOSITA would have had a reasonable expectation that nanonized or micronized deutetrabenazine could successfully be used in an Austedo®-type dosage form configured for once-daily administration.
This argument is not persuasive. Applicant conflates two distinct concepts: (1) whether the prior art teaches nanonized/micronized deutetrabenazine in a sustained-release bead formulation for once-daily use, and (2) whether a PHOSITA would have been motivated to combine the relevant teachings with a reasonable expectation of success. The examiner does not contend that any single reference discloses the precise combination. Rather, the rejection is based on the combination of the four cited references under KSR. The following points are determinative:
First, Bosch explicitly teaches particle size reduction for "poorly soluble" drugs, defines a preferred particle size of <400 nm (0.4 µm) by milling in a microfluidizer with a surface modifier, and states that such preparations exhibit improved solubility and "unexpectedly high bioavailability" (col. 4, ll. 31-40; col. 6, ll. 29-54). Deutetrabenazine is poorly soluble (Duffield ¶ [0010]). A PHOSITA reading Bosch would immediately recognize the applicability of Bosch's technique to deutetrabenazine.
Second, Duffield teaches once-daily controlled-release multi-particulate formulations of tetrabenazine—an analog of deutetrabenazine—using pH-independent and pH-dependent polymer coatings on beads (Duffield ¶¶ [0123]-[0145], [0301]-[0302]). Duffield expressly recognizes that the purpose of controlled-release bead formulations is to enable once-daily dosing with a controlled PK profile (Duffield ¶¶ [0009]-[0013], [0123]).
Third, Gant teaches deutetrabenazine specifically and provides motivation to formulate deutetrabenazine as a modified release dosage form to improve PK, PD, and tolerability (Gant ¶¶ [0011]-[0022], [0054]-[0067]).
The combination of these three teachings with the Austedo® label—which identifies the known pharmacokinetic limitations of the immediate-release twice-daily formulation—provides ample motivation and a clear path for a PHOSITA to formulate a once-daily sustained-release deutetrabenazine bead product with nanonized/micronized drug substance. This is a textbook application of KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007): combining known elements using known methods to yield predictable results.
Argument 2: No Reasonable Expectation of Success That Nanonized Deutetrabenazine Would Produce the Required Once-Daily Release Profile.
Applicant argues that Bosch addresses "bioavailability" in general and provides no relevant teaching concerning the effect of nanonized/micronized deutetrabenazine on the release profile needed for once-daily administration, and that Applicant has "surprisingly discovered" that nanonized deutetrabenazine provides better dissolution profiles than unmilled drug. Applicant additionally argues that the combination of nanonized deutetrabenazine with the sustained-release bead platform required for once-daily dosing of a VMAT2 inhibitor would not have been within the reasonable expectation of a PHOSITA.
This argument is not persuasive for the following reasons:
(a) Particle size reduction and dissolution improvement are well-established. Bosch expressly teaches that reducing poorly soluble drug particles to the nanometer range improves dissolution and bioavailability (col. 4, ll. 31-40). This is a foundational principle of pharmaceutical science. The improvement in dissolution upon milling is not surprising—it is the expected and intended result of particle size reduction, well recognized in the art and described in pharmaceutical textbooks. A PHOSITA formulating a sustained-release product from a poorly soluble drug would routinely consider particle size reduction as a standard tool to improve dissolution kinetics.
(b) Applicant's particle size limitation does not define a specific release mechanism. The particle size limitation added to claim 1 specifies a range for the deutetrabenazine API within the core of the sustained release beads. The release profile of the overall dosage form, however, is primarily controlled by the pH-independent and/or pH-dependent polymer coat—not solely by the API particle size within the core. Duffield explicitly teaches how to tune the polymer coating composition and weight to achieve desired dissolution rates (Duffield ¶¶ [0208]-[0212]). A PHOSITA would understand that once a nanonized drug substance is incorporated into the core, the release profile is modulated by the outer polymer coat, for which Duffield provides extensive guidance. The combination of Bosch's particle size reduction with Duffield's polymer coating optimization provides a complete and reasonable roadmap for achieving the claimed formulation.
(c) Applicant's "surprising results" are not supported by comparative evidence sufficient to rebut prima facie obviousness. Applicant references Figure 3 of the application as showing that nano-milled deutetrabenazine produces a better dissolution profile than micro-milled or unmilled drug. However, the mere showing that nanonization improves dissolution over larger particle sizes does not constitute evidence of unexpected results—this is precisely what Bosch and the prior art predict. To overcome a prima facie case of obviousness based on overlapping ranges, Applicant must show that the claimed ranges produce results that differ in kind, not merely in degree, from the prior art. See In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). A better dissolution profile from a smaller particle size is an expected result, not an unexpected one. Moreover, Applicant has not provided a § 1.132 Declaration from a qualified expert or comparator establishing unexpected results vis-à-vis the closest prior art combination.
Argument 3: The Austedo® Label Does Not Teach a Once-Daily Formulation with Nanonized Deutetrabenazine.
Applicant argues that Austedo® is approved for twice-daily administration and that the Office has not established that a PHOSITA would have had a reasonable expectation of successfully converting the Austedo® twice-daily regimen into a once-daily formulation using nanonized deutetrabenazine.
This argument is misplaced. The rejection does not rely on Austedo® to teach once-daily dosing with nanonized drug. Austedo® is cited for: (1) establishing deutetrabenazine as a known drug with known doses and known inactive excipients; and (2) identifying the PK limitations of the immediate-release twice-daily formulation (short half-life metabolites, Cmax-related side effects, hepatic impairment considerations) that would motivate a PHOSITA to develop a controlled-release once-daily alternative. The motivation for once-daily dosing is supplied by Duffield ¶¶ [0009]-[0013] and [0123], and the motivation for nanonization is supplied by Bosch. Austedo® does not need to teach once-daily nanonized dosing—it is the starting point, not the solution.
Argument 4: Claim 67 – Performance Characteristic Under In re Stepan.
Applicant argues that claim 67's dissolution release rate is a performance characteristic that limits the scope of claim 1 under In re Stepan Co., 868 F.3d 1342 (Fed. Cir. 2017), and therefore that the § 112(d) rejection should be withdrawn. As discussed under the § 112(d) section above, this argument does not overcome the § 112(d) rejection. However, Applicant's reliance on Stepan is noted in the context of § 103. To the extent the dissolution profile of claim 67 is accorded patentable weight under § 103, it does not distinguish the claim from the prior art, because Duffield expressly teaches dissolution profiles within the recited range and teaches routine adjustment of coating parameters to achieve a desired release profile (Duffield ¶¶ [0208]-[0212]), as discussed above.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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