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 Remarks and Restriction/Elections filed on 12/22/2025 is acknowledged.
Claims 1-6, 11, 31, 36, 49, 56, 67, 69, 73, 78, 83-85 and 87- 88 are pending.
Claims 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Claims 69, 83-85, 87-88 are withdrawn.
Election/Restrictions
Applicant elects Group I without traverse, claims 1-6,11, 31, 36, 49, 56, 67, 73, and 78.
Claims 25-27, 33-34, 40-43, 48-57, 69, 83-85 and 87-88 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The election is made FINAL.
Claims 1-6, 11, 31, 36, 49, 56, 67, 73, and 78 are pending and under examination in this application.
Priority
The current application filed on 03/16/2023 is a 371 of PCT/US2021/050785 filed 09/28/2021, which in turn claims priority to U.S. provisional application 63/091,064 filed on 10/13/2020, which in turn has U.S. provisional application 63/079,786 filed on 09/17/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 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 67 is objected to because of the following informalities: claim 67 recites “pH PH3.0 phthalate buffer” in lines 2-3. It should only say pH 3.0 phthalate buffer” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 73 and 78 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.
Claims 73 and 78 recites the limitation "the dosage form or the method of claim 1" in line 1. However, there is only a dosage form in claim 1, not a method. The Specification, (e.g., page 21) describes methods of treatment, but the claim language lacks antecedent basis for “the method”, creating ambiguity about the scope. A PHOSITA could not reasonably determine if the pharmacokinetic profiles apply to the product or an undefined method. There is insufficient antecedent basis for this limitation in the claim.
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 is 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”. However, these are merely characteristics of the composition and does not further limit the structure of claim 1. Stated another way, the claim recites a result with no structure specified to achieve that result. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 1-6, 11, 31, 36, 49, 56, 67, 73, and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Austedo® (deutetrabenazine) Label in view of Gant (US 2010/0130480 A1), Duffield (US 2012/0208773 A1), and further in view of Bosch (US 5,510,118).
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 claims 5 and 6, Bosch teaches reducing poorly soluble drugs having extremely small effective average particle size can be prepared by milling in a microfluidizer in conjunction with a surface modifier, and that such particles are stable and do not appreciably flocculate or agglomerated into pharmaceutical compositions exhibiting unexpectedly high bioavailability (column 4, lines 31-67), and the surface modifier is adsorbed on the surface of the drug substance in an amount sufficient to maintain an effective average particle size of less than about 400 nm (0.4 µm) (column 6, lines 29-31). Moreover, Bosch disclose particle size refers to a number average particle size of less than about 400 nm as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By "effective average particle size of less than about 400 nm" it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques. In preferred embodiments of the invention, the effective average particle size is less than about 250 nm. In some embodiments of the invention, an effective average particle size of less than about 100 nm has been achieved. With reference to the effective average particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In particularly preferred embodiments, essentially all of the particles have a size less than 400 nm (column 6, lines 37-54). Bosch suggests that reducing insoluble drugs (like tetrabenazine) to extremely small size, such as particle size of less than about 400 nm, it would be reasonable to expect improve solubility and dispersion. Therefore, it would have been obvious to a PHOSITA to modify deutetrabenazine, which is considered a poorly water soluble drug, like tetrabenazine, and reduce the particle size in the claimed ranges of 0.02 to 2.0 micron to enhance dissolution and improve bioavailability in a controlled release composition.
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 involved 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.
Conclusion
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