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 in the reply filed on 5/19/2026 is acknowledged. The election of R-trihexyphenidyl as species is also acknowledged. Claims 96, 217-220, 222-225, 229-231, 244-254 are pending, of which claims 231 and 254 are withdrawn. Claims 96, 217-220, 222-225, 229-230, 244-253 encompass the elected invention and species and are examined herein on the merits for patentability.
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.
Claim(s) 96, 217-219, 222-225, 229-230, 244-248, and 250-253 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung et al. (J. Pharm. Sci., 1988, 77, p. 748-50) in view of Yeleswaram et al. (US 2020/0253879), Nelson et al. (US 11,938,224) and Hinova Pharmaceuticals (CN 113559074).
Cheung teaches that twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCI (a-cyclohexyl-a-phenyl-l- piperidinepropanol HCI). The dosage regimens were a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 h later, and two 5-mg sustained-release (SR) capsule formulations given daily. The number of adverse experiences following the SR formulation were -50% of those for the IR formulation, the peak concentration (Cmax) An ideal SR or CR formulation will maintain constant plasma concentrations after Cmax has been reached. Therefore, an optimal way of characterizing the performance of a SR or CR formulation would be to determine the time duration over which the plasma concentrations are sustained above a certain percentage of the Cmax after the SR formulation was significantly lower (p < 0.05) than that after the first dose of the IR formulation, and the time to reach Cmax was significantly longer after the SR formulation (p < 0.05). The SR Cmax formulation maintained serum concentrations above 50,60, and 70% of values for average time periods of 11.7,9.4, and 5.9 h, respectively, compared with values of 1.8, 1.2, and 0.9 h after the IR formulation; the differences were all significant (p < 0.05). The mean elimination half- life was similar (p > 0.05) after the SR (10.1 h) and IR (8.7 h) formulations. The statistical power of the study was 98.1% to detect a 20% difference in the area under the curve from time zero to time infinity (AUC) between formulations. Although the AUC, after the SR formulation was statistically smaller (p < 0.05) than after the IR tablet, the difference was <20%. Therefore, the SR formulation was bioequivalent to the IR tablet formulation of trihexyphenidyl.
Evaluation of the performance of a SR formulation of trihexyphenidyl hydro- chloride (a-cyclohexyl-a-phenyl-1-piperidinepropanol HC1) relative to that of an immediate-release formulation is taught. Trihexyphenidyl is a synthetic antispasmodic drug that is widely used in the treatment of patients with all forms of parkinsonism, including primary or idiopathic Parkinson’s disease, as well as those with secondary symptomatic parkinsonism (postencephalitic, arteriosclerotic, infection-induced, tumor- induced, trauma-induced, and drug-induced). The method of analysis used achieves two objectives: It allows an evaluation of the performance of CR or SR formulations independent of T and it takes into account the shape of the concentration-time profile (page 748).
In summary, the SR formulation of trihexyphenidyl had good SR characteristics and was bioequivalent to the conventional IR tablet formulation of the drug. The results also showed that there were no differences between the disposition kinetics of trihexyphenidyl given as either formulation. Furthermore, the use of the SR formulation of the drug resulted in a substantial reduction in reported adverse effects, attributable to a reduction in the Cmax observed. The new method described herein for the evaluation of a SR formulation of trihexyphenidyl should have general applicability to the evaluation of SR formulations for other drugs and illustrates how SR formulations can potentially improve the safe utilization of drugs, especially those that can produce adverse effects related to the central nervous system (page 750).
Cheung does not specifically recite wherein the sustained release formulation comprises the claimed amount of trihexyphenidyl, HPMC, microcrystalline cellulose, lactose, dicalcium phosphate and magnesium stearate.
Yeleswaram teaches a sustained release dosage form comprising {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, and doses and methods related thereto (paragraph 0002).
In some embodiments, the sustained-release dosage forms of the invention may include a sustained-release matrix former. Example sustained-release matrix formers include cellulosic ethers such as hydroxypropyl methylcellulose (HPMC, hypromellose) which is a high viscosity polymer, and methyl celluloses. Example hydroxypropyl methylcelluloses include Methocel™ K15M, Methocel™ K4M, Methocel™ K100LV, Methocel™ E3, Methocel™ E5, Methocel™ E6, Methocel™ E15, Methocel™ E50, Methocel™ E10M, Methocel™ E4M, and Methocel™ E10M. In some embodiments, the sustained release dosage form comprises one or more hypromelloses. In some embodiments, the sustained release dosage form comprises a first hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of about 80 cP to about 120 cP and a second hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of about 3000 cP to about 5600 cP. In some embodiments, the sustained release dosage form comprises about 8% to about 20% by weight of one or more hypromelloses. In some embodiments, the sustained release dosage form comprises about 10% to about 15% by weight of one or more hypromelloses.
In some embodiments, the sustained-release dosage forms of the invention can further include one or more fillers, glidants, disintegrants, binders, or lubricants as inactive ingredients. In some embodiments, the filler comprises microcrystalline cellulose, lactose monohydrate, or both. In some embodiments, the sustained release dosage form comprises about 16% to about 22% by weight of microcrystalline cellulose. In some embodiments, the sustained release dosage form comprises about 45% to about 55% by weight of lactose monohydrate (paragraph 0066).
In some embodiments, lubricants can be present in the dosage forms of the invention in an amount of 0 to about 5% by weight. Non-limiting examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate. In some embodiments, the formulations include magnesium stearate, stearic acid, or both. In some embodiments, the sustained release dosage form comprises about 0.3% to about 0.7% by weight of magnesium stearate (paragraph 0067).
In Protocol A: Individually screen the adipic acid salt of the compound of Formula I, microcrystalline cellulose, hypromelloses (Methocel K100 LV and Methocel K4M), and lactose monohydrate.
25 mg SR: Composition of 25 mg Sustained Release Tablets are taught in paragrpah 0229+.
Weight
Composition
Component
Function
(mg/tablet)
(wt %)
Adipic acid salt of the
Active
31.6 a
12.6
compound of Formula
I a
Microcrystalline
Filler
105.0
42.0
Cellulose
Hypromellose,
Release Control
25.0
10.0
(Methocel K100LV)
Hypromellose,
Release Control
25.0
10.0
(Methocel K4M)
Lactose Monohydrate
Filler
62.15
24.9
Magnesium Stearate b
Lubricant
1.25
0.5
Purified Water c
Granulating
q.s.
—
Liquid
Total
250
100.0
a Conversion factor for adipate salt to free base is 0.7911
Nelson teaches a 12-hour anti-tussive modified release solid tablet or tablet-in-capsule is described which comprises a benzonatate-silicon dioxide adsorbate powder in a hydrophilic matrix to provide a 12-hour modified release profile to the benzonatate, wherein there is substantially no benzonatate release from the tablet or capsule in the buccal cavity and no more than about 1% release of the benzonatate within half an hour as determined in an in vitro dissolution assay (abstract).
A variety of food grade and pharmaceutical grade hydrophilic polymers are commercially available. For example, METHOCEL™ K-type Food Grade HPMCs, including, e.g., K100M, K15M, F4M, K4M, K100LV, K3, E15LV, E5 and E3. For purposes of illustration only, these may have average viscosities of about 4000 mPa-s (K4M), about 15,000 mPa-s (K15M), or about 100,000 mPa-S. One hydroxypropyl cellulose is characterized by a molecular weight of 95,000 and a viscosity of 75-150 mPa-S. Another illustrative HPC is characterized by a viscosity of 300 to 600 mPa-s and a molecular weight of about 80 kDa. Combinations of hydrophilic polymers may be utilized, including a combination of two or more hydrophilic polymers within the same class, but having different viscosities or molecular weights (e.g., two HPMCs), or two or more hydrophilic polymers of different classes (e.g., an HPC and an HPMC).
Typically, a benzonatate composition as provided herein may contain a filler or a mixture of fillers in the range of about 10% w/w to about 50% w/w, about 20% w/w to about 40% w/w, or about 30% w/w of the total tablet or capsule weight. As used herein, the term “filler” and “bulking agent” are used interchangeably. Suitable fillers may include, e.g., mannitol, lactose, maltose, fructose, sucrose, xylitol, maltitol, microcrystalline cellulose, dicalcium phosphate, guar gum, xantham gum, tragacanth gum, pre-gelatinized starch, compressible sugar, calcium carbonate, magnesium carbonate, calcium sulfate, dextrates, maltodextrin.
In one embodiment, a benzonatate tablet contains a blend of microcrystalline cellulose and lactose monohydrate. In certain embodiments, the bulking agent is selected from isomalt or microcrystalline cellulose, hypromellose, or another cellulose derivative, or combinations thereof. However, other suitable bulking agents are known and may be selected. The bulking agent may be present in the core in an amount of about 20% by weight to about 50% by weight. In certain embodiments, the binder is copovidone. Such binder(s) are generally present in an amount of about 30% to about 50% by weight of the tablet core.
Hinova Pharmaceuticals teaches a quinoline compound sustained-release tablet, which comprises the following raw and auxiliary materials in proportion by weight: 1-40 parts of a quinoline compound, 100-300 parts of a filler, 50-200 parts of a sustained-release material and a lubricant dose 0.5 to 4 servings. The fillers include but are not limited to mannitol, microcrystalline cellulose, lactose, starch, corn starch, dibasic calcium phosphate hydrate, magnesium carbonate, calcium carbonate, purified sucrose and/or glucose; the sustained release materials include but are not Limited to hypromellose, hypromellose and povidones, glyceryl behenate and/or long chain fatty acids; the lubricants include but are not limited to magnesium stearate, calcium stearate, sucrose Fatty acid esters, sodium stearyl fumarate, polyethylene glycol, talc, glyceryl behenate and/or stearic acid.
The sustained release preparation is developed to effectively reduce the blood concentration after the medicine is taken and reduce the in vivo bioavailability of the medicine from Cmax, potential toxic and side effects.
Further, the lactose includes, but is not limited to lactose monohydrate, anhydrous lactose, and/or lactose of different particle sizes, the microcrystalline cellulose includes, but is not limited to, microcrystalline cellulose PH101, PH102, PH301, and/or PH302, the hypromellose includes, but is not limited to, hypromellose K4M, K100LV, and/or K750, and the lubricant is magnesium stearate.
In Example 4, preparation of sustained-release tablets of quinolines is taught comprising 2- [4- (6-bromoquinolinyl) -thio ]-2-ethylbutanoic acid, crystalline form 15g, lactose monohydrate 226.1g, microcrystalline cellulose PH 10130 g, hypromellose K4M (HPMC K4M), 57g, hypromellose K100LV (HPMC K100LV), 60g, magnesium stearate 1.9 g.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a sustained release formulation of trihexyphenidyl comprising HPMC 100SR and HPMC 15,000SR, microcrystalline cellulose, dicalcium phosphate, lactose and magnesium stearate when the teaching of Cheung is taken in view of Yeleswaram, Nelson and Hinova. One would have been motivated to do so because Cheung teaches that a sustained release of trihexyphenidyl may be bioequivalent to immediate release formulation, and provides advantages including reduced Cmax, maintained serum concentrations over longer time period and reduced side effects compared to an immediate release formulation of the drug. It is noted that a racemic form of trihexyphenidyl comprises R-trihexyphenidyl. It would have been obvious to optimize the amount of active agent, sustained release polymer, filler, binder, lubricant as a matter of routine optimization in preparation of a composition providing optimal sustained release of the trihexyphenidyl by selection from among known ranges of active agent, sustained release polymer, filler, binder, lubricant as known in the prior art for preparation of a sustained release formulation. See also MPEP 2144.05 directed to obviousness of similar and overlapping ranges, amounts, and proportions. 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 reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range). Regarding claim 253 the claimed amounts correspond to the claimed percentages of claim 96.
With regard to claims 217-219, 248 and 250-253, it is noted that the claims are directed to a pharmaceutical composition, not a method of administration. It is submitted that the methods of administration and administration of a composition to a patient having a disorder does not distinguish the composition itself.
With regard to claims 222-225 and 244, directed to plasma concentration and/or AUC, it is submitted that the claims are directed to a pharmaceutical composition itself, a composition and it’s properties are inseparable. The physical components of the composition have been addressed by Cheung in view of Yeleswaram, Nelson and Hinova. Further claimed parameters such including plasma concentration can be dependent on size of patient, fed/fasting state, etc. As such the recited functional do not distinguish over in Cheung in view of Yeleswaram, Nelson and Hinova. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
Further, with regard to the amounts of active agent, sustained release polymer, fillers, lubricant, differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim(s) 96, 217-220, 222-225, 229-230, 244-248, and 250-253 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung et al. (J. Pharm. Sci., 1988, 77, p. 748-50) in view of Yeleswaram et al. (US 2020/0253879), Nelson et al. (US 11,938,224) and Hinova Pharmaceuticals (CN 113559074), in further view of Edgren et al. (US 5,221,536).
The rejection over Cheung in view of Yeleswaram, Nelson and Hinova is applied as above.
With regard to claim 220, a bilayer tablet is not specifically recited.
Edgren teaches a pharmaceutically acceptable composition comprising a drug pair indicated for treating Parkinson's disease, and which pharmaceutically acceptable composition can be delivered from a dosage form manufactured as a drug delivery device (column 1-2). Edgren further teaches a treatment for Parkinson's disease at a controlled rate in a constant dose per unit time over a prolonged period of time.
First and second compositions are arranged into bilayer cores.
An anti-Parkinson drug is present in the bilayer core as an anti-Parkinson drug pair, said pair comprising (e) a member selected from the group consisting of bromocriptine, lisuride, pergolide, mesulergine, levodopa, carbidopa, levodopa-carbidopa, amantadine, deprenyl, trihexyphenidyl, benztropine, biperiden, ethopropazine, procyclidine, and a (a) different member selected from the group consisting of bromocriptine, lisuride, pergolide, mesulergine, levodopa, levodopa-carbidopa, amantadine, deprenyl, trihexyphenidyl, biperiden, ethopropazine, and procyclidine (claim 5).
It would have been obvious to one of ordinary skill in the art to provide the trihexyphenidyl in the form of a bilayer tablet when the teachings of Cheung in view of Yeleswaram, Nelson and Hinova are taken in view of Edgren. One would have been motivated to do so, with a reasonable expectation of success, because Edgren teaches that a dosage formulation, including for treatment of Parkinson's disease at a controlled rate in a constant dose per unit time over a prolonged period of time, wherein a dosage form comprises an anti-Parkinson pair, one of which may be trihexyphenidyl, in the form of a bilayer tablet.
Claim(s) 96, 217-219, 222-225, 229-230 and 244-253 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung et al. (J. Pharm. Sci., 1988, 77, p. 748-50) in view of Yeleswaram et al. (US 2020/0253879), Nelson et al. (US 11,938,224) and Hinova Pharmaceuticals (CN 113559074), in further view of Fabiano (US 6207681).
The rejection over Cheung in view of Yeleswaram, Nelson and Hinova is applied as above.
With regard to claim 249, a 95% enantiomeric excess is not specifically recited.
Fabiano teaches trihexyphenidyl, 3-(1-piperidyl)-1-cyclohexyl-1-propanol, a synthetic antispasmotic drug, is described as being useful in treating parkinsonism, and has been used in muscarinic receptor binding studies. Similar adverse effects to those for anticholinergic drugs may result with the use of trihexyphenidyl.
Methods of treating urinary incontinence by administration to a subject in need thereof a therapeutically effective amount of enantiomerically enriched (R)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof are taught. In a preferred embodiment of this method, the enantiomerically enriched (R)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof, is substantially free of (S)-trihexyphenidyl (column 1-2).
The term “substantially free of (S)-trihexyphenidyl” will be understood to have similar purity ranges., ie., at least 85% by weight of the (R)-trihexyphenidyl enantiomer relative to the (S)-trihexyphenidyl enantiomer, more preferably at least 90% by weight, and even more preferably at least 95% by weight (column 4).
It would have been obvious to one of ordinary skill in the art at the time of the invention to probide R-trihexyphenidyl in greater than 95% enantiomeric excess when the teachings of Cheung in view of Yeleswaram, Nelson and Hinova are taken in further view of Fabiano. One would have been motivated to do so, with a reasonable expectation of success, because Fabiano teaches that use of the (R)-trihexyphenidyl enantiomer, free of the (S) enantiomer, including at least 95% excess, allows for treatment of urinary incontinence with fewer side effects.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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