DETAILED ACTION
Claims 1, 4-5, 8, 10, 12-15, 17, and 26-35 were pending; Applicant has amended claims 1, 12, 29, and 34 (the independent claims) per the reply of 3/10/2026.
Claims 1, 4-5, 8, 10, 12-15, 17, and 26-35 are pending.
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 .
Priority
19275631 filed 7/21/2025 is a Continuation of 19111178. 19111178 is a National Stage entry of PCT/US2023/074065, International Filing Date: 9/13/2023. 19111178 Claims Priority from Provisional Application 63407219, filed 9/16/2022.
Claim Rejections - 35 USC § 102
(Maintained)
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-5, 8, 10, and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fabiano et al. US 6,207,681 issued March 27, 2001.
Instant claim 1 is directed towards a pharmaceutical composition for treating a movement disorder in a subject in need thereof, by selectively targeting M1 and/or M4 muscarinic receptors in the subject, wherein the pharmaceutical composition comprises a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
This claim requires a pharmaceutical composition with enantiomerically enriched R-trihexyphenidyl (a known pharmaceutical active ingredient) and a pharmaceutically acceptable carrier. The recitation of the intended use and mode of action, “for treating a movement disorder in a subject in need thereof, by selectively targeting M1 and/or M4 muscarinic receptors in the subject,” does not change the requirements as the active ingredient has this property only when administered to a patient (the claim doesn’t require administration) and this property flows naturally from the composition’s properties. This is what the compound does. As such while the intended use and mode of action requires the composition be suitable for a pharmaceutical or exposure to a subject, the recitation does not require the subject, the administration, or the effect of administration.
Fabiano teaches pharmaceutical compositions for the treatment of urinary incontinence comprising enantiomerically enriched (R)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof, and an acceptable carrier are also disclosed. Fabiano states in claim 34, wherein said enantiomerically enriched (R)-trihexyphenidyl is present in an amount of about 1 mg to about 50 mg. This amount meets the limitation to “a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl” to treat a movement disorder in a subject in need thereof. Instant claim 1 is anticipated.
Instant claim 4 requires wherein said composition comprises an enantiomeric excess of at least about 95% of R-trihexyphenidyl.
Fabiano teaches in claim 38, (R)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof, substantially free of (S)-trihexyphenidyl. Fabiano states 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.
Instant claim 5 requires wherein said composition comprises an enantiomeric excess of at least about 99% of R-trihexyphenidyl.
Fabiano teaches in claim 22 and 24, a pharmaceutical composition, comprising (R)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof, substantially free of (S)-trihexyphenidyl, and a pharmaceutically acceptable carrier. 24, wherein (R)-trihexyphenidyl comprises at least 99% by weight of the total trihexyphenidyl in said pharmaceutical composition. This would therefore be at least 98% enantiomeric excess, however give the teaching one instantly envisages a higher excess and therefore instant claim 5 is anticipated.
Instant claim 8 requires wherein said the R-trihexyphenidyl is a pharmaceutically acceptable salt form selected from the group consisting of hydrochloride, hydrobromide, acetate, benzoate, carbonate, mesylate, and bitartrate.
Fabiano teaches “these salts can be prepared in situ during the final isolation and purification of the (R)-trihexyphenidyl. Representative salts include the bromide, chloride, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benxoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts and the like. (See, e.g., Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci., 66:1-19 (1977).)”
Instant claim 10 requires wherein said the dosage form is a tablet, capsule, or oral solution.
Fabiano teaches “in a preferred embodiment, the enantiomerically enriched trihexyphenidyl compositions of the present invention are provided in tablet or capsule form with, as inactive ingredients, dibasic calcium phosphate, lactose, magnesium stearate, providone and sodium starch glycolate. The capsules or tablets are preferably formulated with from about 0.25 mg to about 250 mg of (R)-trihexyphenidyl…”
Instant claims 1, 4-5, 8, and 10 are anticipated.
Instant claim 26 states the pharmaceutical composition of claim 1, wherein the movement disorder is selected from the group consisting of dystonia, Parkinson's Disease, cerebral palsy, and Angelman Syndrome. This intended use would only provide guidance to the scope of the dose range. Given Fabiano teaches “an amount of about 1 mg to about 50 mg,” this dose anticipates the effective dose required by instant claim 26.
Instant claim 26 is therefore anticipated.
Response to Applicant’s Arguments: Applicant’s arguments are misplaced, as Applicant argues the intended use and mode of action recited in the composition of matter claim is required for anticipation. This is not correct. This claim requires a pharmaceutical composition with enantiomerically enriched R-trihexyphenidyl (a known pharmaceutical active ingredient) and a pharmaceutically acceptable carrier. The recitation of the intended use and mode of action, “for treating a movement disorder in a subject in need thereof, by selectively targeting M1 and/or M4 muscarinic receptors in the subject,” does not change the requirements as the active ingredient has this property only when administered to a patient (the claim doesn’t require administration) and this property flows naturally from the composition’s properties. This is what the compound does. As such while the intended use and mode of action requires the composition be suitable for a pharmaceutical or exposure to a subject, the recitation does not require the subject, the administration, or the effect of administration. As such the claims are anticipated as the art teaches every element of the claim.
MPEP 2122 I. SOMETHING WHICH IS OLD DOES NOT BECOME PATENTABLE UPON THE DISCOVERY OF A NEW PROPERTY
"[T]he 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." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel."
Claim Rejections - 35 USC § 103
(Maintained)
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, 4-5, 8, 10, 12-15, 17, 26, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Jabbari et al. “Treatment of Movement Disorders with Trihexyphenidyl,” Movement Disorders Vol. 4, No. 3, 1989, pp. 202-212;
Ruben Vardanyan, Piperidine-Based Drug Discovery Chapter 2, 2017;
Adamson Donald Wallace GB-750156-A issued 6/13/1956;
Fabiano et al. US 6,207,681 issued March 27, 2001; and
Trihexyphenidyl hydrochloride tablet Insert (“Insert”) updated 11/2021.
Claims 1, 4-5, 8, 10, and 26 were anticipated above as being drawn to a pharmaceutical composition of enantiomerically enriched Trihexyphenidyl, specifically the (R) enantiomer.
The following 103 rejection will focus on claims 12-15, 17, 26, 27, 28 related to treating movement disorders with enantiomerically enriched Trihexyphenidyl in certain dose ranges, as the method would require the anticipated composition.
Claim 12 is generally directed towards a method of treating a movement disorder in a subject in need thereof by selectively targeting M1 and/or M4 muscarinic receptors in the subject comprising administering a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or pharmaceutically acceptable salt thereof to the subject.
Jabbari teaches that the racemic form of Trihexyphenidyl is used in the treatment of movement disorders.
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Jabbari doesn’t teach the use of the enantiomerically enriched composition.
Vardanyan states, “The absolute (R) configuration has been established for the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride [6].” Vardanyan highlights the following reference (Wallace), reference 6 in the chapter.
Wallace teaches the synthesis and isolation of the pure enantiomers of trihexyphenidyl. Wallace states, “It has now been found that the laevo-isomers of these compounds have properties which render them more valuable as therapeutic agents than the corresponding racemic forms.” Wallace also states, the other enantiomer is almost entirely inactive. Wallace then states the active isomer “was not more toxic” in IV injected mice, and the active enantiomer has a valuable and unexpected advantage over their racemic forms.
The Wallace reference provides a PHOSITA motivation to pursue enantiomerically enriched trihexyphenidyl.
This leads back to Fabiano, which teaches a composition of the single enantiomer of trihexyphenidyl in a carrier for use as a pharmaceutical.
Lastly, brought in is the Trihexyphenidyl hydrochloride tablet Insert (“Insert 2021”) which teaches that the racemic drug is used for the treatment of parkinsonism (a movement disorder) and discusses the dosing of the drug. The following is taught:
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Claim 12 is obvious because at the time of filing one knew that the absolute (R) configuration has been established as the “more active” and “more valuable” as a therapeutic agent. The drug is known to treat movement disorders, and given the above fact it would be obvious to use the more valuable enantiomer for the treatment of movement disorders as this would limit toxic effects of administration of a large amount of non-active non-productive chemical compound to the patient, thereby being more efficient. The practitioner would simply take the known composition of Fabiano and use it for movement disorders to predictable treat the disorder with less side effects. One would also look to dose the compound in a similar fashion, that is knowing the dosage “should be individualized” and one would know that the weight of a racemic compound containing roughly 50% by weight a “almost entirely inactive” form, one would understand the need to dose the material in half by weight of the “active” agent. Therefore claim 12 was obvious at the time of filing.
Instant claims 13-15 mimic the instant composition claims of 4, 5, and 10 of the composition and are taught by Fabio and are therefore obvious.
Instant claim 17 requires the subject exhibits a reduction in the number, frequency, or severity of uncontrolled movements, spasms, or exhibits an improvement in measurements in gross or fine motor function tasks, after administration. The positive recitation of the desired outcome is not given patentable weight. See MPEP 2111.04. The court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Instant claim 27 requires wherein the movement disorder is selected from the group consisting of dystonia, Parkinson's Disease, cerebral palsy, and Angelman Syndrome. The Insert states the use of the drug for parkinsonism. As such this indication is known and obvious to use the improved composition.
Instant claim 28 requires wherein the therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or pharmaceutically acceptable salt thereof is a dosage of from 3 mg per day to 30 mg per day. This amount is taught in the Insert, with the caveat that one would understand to reduce the amount by half.
Response to Applicant’s Arguments: Applicant’s 1st argument is that the art does not recognize (is silent on) the chemical property of enantiomerically enriched R-trihexyphenidyl to selectively targeting M1 and/or M4 muscarinic receptors in the subject. This recitation simply recites the result of the process step, the administration of enantiomerically enriched R-trihexyphenidyl selectively targets M1 and/or M4 muscarinic receptors in the subject inherently by the chemical structure of the drug interacting with the muscarinic receptors, this flows naturally. The court has noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). As noted above, this interaction with the muscarinic receptors is the intended result of administration. Therefore while the art doesn’t discuss the mode of action, the mode is inherent to the chemical property of the enantiomerically enriched compound.
Applicant’s 2nd argument is the skilled artisan would have no reason to combine the art of record. This is incorrect as Wallace teaches the synthesis and isolation of the pure enantiomers of trihexyphenidyl. Wallace states, “It has now been found that the laevo-isomers of these compounds have properties which render them more valuable as therapeutic agents than the corresponding racemic forms.” Wallace also states, the other enantiomer is almost entirely inactive. Wallace then states the active isomer “was not more toxic” in IV injected mice, and the active enantiomer has a valuable and unexpected advantage over their racemic forms. One would clearly look to avoid the more toxic compound for the active drug.
Applicant argues the Vardanyan individually. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Simply pointing out the discussion of Vardanyan and the reference noting other druga and their properties doesn’t detract from the teaching of Vardanyan that states, “The absolute (R) configuration has been established for the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride [6].”
Applicant argues the Fabino reference is not directed to a movement disorder, and that Fabino doesn’t note any adverse effects of the (S) enantiomer. Therefore this is counter to the other art of record. The problem is that Fabino simply is used to teach that a pharmaceutical composition of either enantiomer can be made. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. The Fabiono reference is not used to provide motivation, and therefore this attack is not persuasive.
Lastly, Applicant argues that the skilled artisan would not have arrived at the instant invention based on Applicant’s own inventive path. That is the selectively targeting M1 and/or M4 muscarinic receptors in the subject. The obviousness rejection is not based on Applicant’s path, it is based on using a known drug (trihexyphenidyl) for it’s known indication (a movement disorder) in a safer form (enantiomerically enriched trihexyphenidyl). While Applicant has discovered a different rationale, Applicant has not discovered a non-obvious method as instantly claimed.
Claim Rejections - 35 USC § 103
Claims 1, 4-5, 8, 10, 12-15, 17, 26, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Jabbari et al. “Treatment of Movement Disorders with Trihexyphenidyl,” Movement Disorders Vol. 4, No. 3, 1989, pp. 202-212; Ruben Vardanyan, Piperidine-Based Drug Discovery Chapter 2, 2017; Adamson Donald Wallace GB-750156-A issued 6/13/1956; Fabiano et al. US 6,207,681 issued March 27, 2001; and Trihexyphenidyl hydrochloride tablet Insert (“Insert”) updated 11/2021, as applied to claims 1, 4-5, 8, 10, 12-15, 17, 26, 27, and 28 above in further view of Donato et al. “Strategies and Molecular Probes to Investigate the Role of Cytochrome P450 in Drug Metabolism,” Clin. Pharmacokinet. 2003; 42 (2): 153-178; and Gaedigk et al. “The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype,” CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 2, FEBRUARY 2008 235.
In regards to claims 29-35 related to cytochrome P450 metabolism and dose and the need to obtain the subject's genotype for cytochrome P450 enzymes comprising at least CYP2D6 and to adjust the dose accordingly.
Claim 29 is generally directed towards a method for treating a movement disorder in a subject in need thereof, wherein the subject is a poor CYP2D6, CYP3A4/CYP3A5, or CYP2C19 metabolizer, and wherein the method comprises administering a therapeutically effective amount of enantiomerically enriched R-trihexyphenidyl or a pharmaceutically acceptable salt thereof to the subject.
Claims 1, 4-5, 8, 10, 12-15, 17, 26, 27, and 28 were rendered obvious as shown above, those references are incorporated here. They do not teach giving the drug to a poor metabolizer.
Donato teaches us the basic understanding in the art about drug research and understanding the metabolism of the drug relative to Cytochrome P450. Donato states drug metabolism is the major determinant of drug clearance and, because of polymorphic or inducible expression of drug-metabolizing cytochrome P450s (CYPs), is the factor most frequently responsible for interindividual differences in pharmacokinetics. A number of well characterized CYP substrates and inhibitors have been identified that allow precise measurements of individual CYP isoforms. Their use, alone or in combination, facilitates the phenotype characterization
of hepatocytes in vitro and in vivo.
Given the Insert already noted the need to individualize treatment dosing with Trihexyphenidyl, one would find it obvious to use the known techniques of pharmacokinetics which include CYP profiling on the drug, Trihexyphenidyl, in order to better understand how to give this drug on an individual basis based on the individuals CYP genotype/phenotype in coordination with the drugs metabolic clearance pathway. One can see from the Donato reference the CYPs to be profiled include CYP2D6 and the others required by the instant claims, see Figure 1.
Donato doesn’t discuss “poor metabolizers” in reference to the specific CYP enzymes.
Gaedigk teaches a simplified method of genotype interpretation and improve phenotype prediction, they evaluated the utility of an ‘‘activity score’’ (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Gaedigk teaches there are fully functional alleles, reduced function alleles, and non-functional
alleles, which convey a wide range of activity from ultrarapid to no metabolism. Consequently, poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) metabolizer phenotypes are observed when a population is challenged with a probe substrate. There is also considerable variability in the allele distribution among ethnic groups giving rise to variable percentages of UM, EM, IM, and PM subjects within a given population.
A person of ordinary skill in the art would recognize that a patient would benefit from personalized medicine in order to avoid overdose and subsequent toxicity in patients that have are poor metabolizers in CYPs responsible for metabolism of trihexyphenidyl. Preforming the known methods, CYP metabolic profile of the drug, genotyping the patient for CYP profile, and combining this knowledge would allow a skilled artisan to know when to adjust the dose of trihexyphenidyl for the individual. Moreover, this drug is specifically dosed to the individual at present, as such dosing with more knowledge using newer known methods would be obvious. Therefore, instant claims 29-35 capture the known techniques of personalized medicine. Adjusting dose to the individual is obvious in view of the prior art.
Response to Applicant’s Arguments: Applicant states the second 103 should be withdrawn for the reasons discussed in the rejection above. See the response there.
Conclusion
No claims 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 MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached M-F 8-6 MidDay Flex.
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/MICHAEL J SCHMITT/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629