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
Claims 1-2, 7-9, 15-19, 21-23, 26, and 29 are pending in this office action. Claims 3-6, 10-14, 24-25, 27-28, and 30 are cancelled. Claims 36-48 have been withdrawn from consideration. Applicant is encouraged to amend the withdrawn claims to be in alignment with the pending claims to expedite rejoinder. All pending claims are under examination in this application.
Priority
The current application filed on November 29, 2021 is a 371 of PCT/US2020/035413 filed May 29, 2020, which in turn claims domestic priority to provisional patent application 62/855,740 filed on May 31, 2019.
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 non-obviousness.
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 1-2, 7-9, 15-19, 21-23, 26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Baker-Glenn et al. (US8815882B2) in view of Vilkov et al. (US2006/0039975A1), and Zhang et al. (WO2010/093944A2).
[The Examiner is going to introduce each reference, and then combine them where appropriate to reject the instant claims.]
1. Baker-Glenn et al.
Baker-Glenn et al. is regarded as being the prior art closest to the subject-matter of the present application as it teaches pyrazole aminopyrimidine derivatives as LRRK2 modulators (see title). Furthermore, Baker-Glenn et al. disclose Compounds of the formula I:
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or pharmaceutically acceptable salts thereof,
wherein X, R1, R2, R3, R4 and R5 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease (see abstract).
2. Vilkov et al.
Vilkov et al. teach paroxetine formulations (see title). Additionally, Vilkov et al. disclose paroxetine is a drug used to treat psychiatric problems such as depression. Controlled release dosage forms comprising release-retarding materials other than hydroxypropyl methylcellulose are described. Also described are methods of wet granulating controlled release paroxetine dosage forms (see abstract).
3. Zhang et al.
Zhang et al. teach delayed release, oral dosage compositions that contain amorphous CDDO-ME (see title). Further, Zhang et al. disclose pharmaceutical formulations exhibit a desirably low Cmax, among other properties, that contain particles of amorphous bardoxolone methyl, either in pure form or in the form of a solid dispersion, admixed with particles of a hydrophilic binding agent. Such formulations possess the advantage of higher oral bioavailability, relative to formulations based on the crystalline form of bardoxolone methyl (see abstract).
Combination of Baker-Glenn et al., Vilkov et al., and Zhang et al.
Regarding instant claim 1, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach a modified release formulation comprising a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and at least one release-modifying agent. The necessary citations within Baker-Glenn et al., Vilkov et al., and Zhang et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 1
Baker-Glenn et al., Vilkov et al., and Zhang et al. Citations
A modified release formulation comprising
Baker-Glenn et al. disclose a modified release formulation (see column 33, lines 3-12). Furthermore, Vilkov et al. disclose the use of controlled-release formulations (see paragraphs [0010-0011] within Vilkov et al.). Thus, the controlled-release techniques within Vilkov et al. can be applied to the Baker-Glenn et al. reference by a skilled artisan.
a therapeutically effective amount of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and at least one release-modifying agent,
a therapeutically effective amount of 2-methyl-2-(3-methyl- 4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1 H-pyrazol-1-yl)propanenitrile (see column 248, lines 1-5, and 40-50)
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and at least one release-modifying agent (see column 35, lines 3-5 within Baker-Glenn et al.).
(i) the release modifying agent is polyvinyl acetate, wherein the release-modifying agent comprises from 3% to 10% by weight of the formulation ; (ii) the release modifying agent is HPMC or polyvinyl alcohol (PVA) polymer, wherein the release-modifying agent comprises 20-30% by weight of the formulation; or (iii) the release modifying agent is poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonium ethyl methacrylate chloride), wherein the release-modifying agent comprises from 3-20% by weight of the formulation.
Baker-Glenn et al. does not disclose specific release modifying agents. However, Vilkov et al. disclose the use of a variety of hydrophilic and hydrophobic polymers such as polyvinylalcohol (PVA) as a release-retarding agent (see paragraphs [0075] and [0080] within Vilkov et al.). A Markush Group [as written in (i)] is an alternative embodiment. The Examiner is relying on one member, polyvinylalcohol (PVA) to reject the claim. Furthermore, Vilkov et al. disclose that the release retarding materials can be hydrophilic and/or hydrophobic polymers. The oral dosage form can contain about 1 wt% to about 80 wt% (see paragraph [0080] within Vilkov et al.).
Unexpected Results:
Zhang et al. disclose Eudragit formulations [(iii)] that exhibit lower Cmax values while maintaining the overall oral bioavailablity (see abstract within Zhang et al.). Zhang et al. does not disclose formulations comprising [(ii) PVA and HPMC].
Therefore, a skilled artisan (POSITA; person having ordinary skill in the art) would combine the teachings of Baker-Glenn et al., Vilkov et al., and Zhang et al. to meet all the claim limitations of instant claim 1.
[The remainder of the instant claims presented within this 35 U.S.C. 103 Section are dependent directly or indirectly on instant claim 1, and are taught in full by the combination of Baker-Glenn et al., Vilkov et al., and Zhang et al.]
Regarding instant claims 2 and 22, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach pellets containing 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and coated with the at least one release-modifying agent. Vilkov et al. disclose the use of pellets in their formulation (see paragraph [0089] within Vilkov et al.). Baker-Glenn et al. disclose the use of tablets, capsules, or powders (see column 35, line 24 within Baker-Glenn et al.) containing 2- methyl-2-(3-methy1-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (see column 248, line 1-5 and 40-50 within Baker-Glenn et al.) and coated with the at least one release-modifying agent (see column 35, lines 3-5 within Baker-Glenn et al.). Therefore, a skilled artisan (POSITA) could transfer this formulation teaching from Vilkov et al. into the Baker-Glenn et al. disclosure.
Regarding instant claim 7, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the modified release formulation comprises 10% to 50% by weight of 2-methyl-2-(3- methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1 H-pyrazol- 1- yl)propanenitrile. Baker-Glenn et al. disclose that in tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound (see column 33, lines 26-31 within Baker-Glenn et al.).
Regarding instant claim 8, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is crystalline. Baker-Glenn et al. disclose the recrystallization of the synthetic material (see column 250, line 22 within Baker-Glenn et al.) indicating a crystalline product. Furthermore, the synthetic product can be converted with the aid of an acid for formulation purposes, to a "pharmaceutically acceptable salt" of the compound. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt (see column 8, lines 56-63; also see claim 20; both within Baker-Glenn et al.). Therefore, the salt form can be crystalline similar to the free base.
Regarding instant claim 9, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein crystalline 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile is milled or micronized. Baker-Glenn et al. disclose that the compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained
by means known in the art, for example by micronization (see column 34, lines 49-54 within Baker-Glenn et al.). Other means known in the art would include milling.
Regarding instant claim 15, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein release of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)-1H-pyrazol-1-yl)propanenitrile is less than 60% at two hours and greater than 60% at 8 hours when tested using USP Type-II Apparatus at 50-75 rpm and 37°C in pH 3 Mcllvaine buffer, wherein the formulation is a tablet. Baker-Glenn et al. disclose the wherein the formulation is a tablet (see column 35, line 24 within Baker-Glenn et al.), but does not disclose, wherein release of 2-methyl-2-(3-methy1-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-yl)propanenitrile is less than 60% at two hours and greater than 60% at 8 hours when tested using USP Type-II Apparatus at 50-75 rpm and 37 °C in pH 3 Mcilvaine buffer. However, it would have been obvious to one with skill in the art (skilled artisan; POSITA) to utilize the formulations disclosed wherein release of the active compound is tested utilizing routine dissolution tests at conditions similar to consumption of said tablet; wherein the coating is modified to allow for release at a desired biological target, through routine experimentation.
Regarding instant claims 16-18, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the tablet comprises 10 to 500 mg of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H- pyrazol-1-yl)propanenitrile. Baker-Glenn et al. disclose that formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms (see column 33, lines 9-12 within Baker-Glenn et al.).
Regarding instant claim 19, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the release-modifying agent is HPMC. Vilkov et al. disclose the use of HPMC as a release-modifying agent (see paragraph [0134-0135] within Vilkov et al.).
Regarding instant claim 21, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the release-modifying agent comprises 20-30% w/w of the formulation. Vilkov et al. disclose the use of 2 wt% to about 30 wt% of a release-modifying agent (see paragraph [0093] within Vilkov et al.).
Regarding instant claim 23, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the capsule is a multi-unit particulate combination of immediate release pellets and modified release pellets contained in the capsule. Please see the discussion and citations within instant claims 2 and 22. Vilkov et al. disclose the combination of multi-unit particulates for immediate release and modified release (see paragraph [0261] within Vilkov et al.).
Regarding instant claim 26, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the modified release formulation is selected from a delayed-release pellet formulation, a controlled-release pellet formulation, an extended-release pellet formulation, and a pulsatile-release pellet formulation. Please see the discussion and citations within instant claim 23. Furthermore, Baker-Glenn et al. disclose sustained release formulations for the pharmaceutical compositions (see column 33, lines 3-9 within Baker-Glenn et al.). Vilkov et al. disclose the use of pulsed-release (see paragraph [0014] within Vilkov et al.), extended-release (see paragraph [0033] within Vilkov et al.), controlled-release (see paragraph [0026] within Vilkov et al.), and delayed-release (see paragraph [0032] within Vilkov et al.) formulations.
Regarding instant claim 29, Baker-Glenn et al., Vilkov et al., and Zhang et al. teach wherein the coating agent comprises a specific amount of EUDRAGIT, EUDRAGIT RS 30 D, or EUDRAGIT NM 30 D by weight of the formulation. Vilkov et al. disclose the coating agent comprises about 20 wt% to about 85 wt% of the water-insoluble polymer (see paragraph [0102] within Vilkov et al.).
Analogous Art
The Baker-Glenn et al., Vilkov et al., and Zhang et al. references are directly applicable to the instant application, due to their application within the release modified drug delivery area of research and development. Each citation is directed to the endeavor of the instant application.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and release modifying agent disclosed by Baker-Glenn et al., using the teachings of both Vilkov et al. and Zhang et al. to incorporate the necessary claim limitations. Starting with Baker-Glenn et al., the skilled person only had to try the use the necessary claim limitations taught by both Vilkov et al. and Zhang et al. The combination of Baker-Glenn et al., Vilkov et al., and Zhang et al. would allow one to arrive at the present application without employing inventive skill. This combination of the 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and release modifying agent taught by Baker-Glenn et al. along with the use of the necessary claim limitations disclosed by both Vilkov et al. and Zhang et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and release modifying agent disclosed by Baker-Glenn et al. with the use of the necessary claim limitations disclosed by both Vilkov et al. and Zhang et al. This combined modification would have led to an enhanced 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile and release modifying agent that would be beneficial for patients/consumers.
Allowable Subject Matter
Claims 20 and 31-35 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 20 and 31-35 are allowable subject matter because the prior art does not address the unexpected results encompassing a reduction in Cmax while maintaining oral bioavailability. Motivation is lacking to add this unexpected series of results to the closest reference of record, Baker-Glenn et al. (US881588B2).
Response to Arguments
Applicant's arguments filed February 6, 2026 have been fully considered but they are not persuasive.
The claim amendments addressed all the 35 U.S.C. §112(b) rejections and the claim objections. They are therefore withdrawn from the record.
The Applicant’s claim amendments did prompt the Examiner to necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the unexpected results encompassing a reduction in Cmax while maintaining oral bioavailability should allow all claims over the prior art.
Examiner’s Rebuttal: The Examiner respectfully disagrees. The formulations involving both Kollicoat® and Parteck® were allowable subject matter, and do not exist within the prior art. However, formulations comprising Eudragit® were rejected based on the Zhang et al. citation, which concluded the same “unexpected finding.”
Additionally, despite the PVA and HPMC formulation being allowable subject matter, the claim limitation clause comprising the Eudragit® formulation is within instant claim 1. This inclusion rejects instant claim 1.
Therefore, the 35 U.S.C. 103 rejection is maintained for instant claims 1-2, 7-9, 15-19, 21-23, 26, and 29.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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