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 .
DETAILED ACTION
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on July 24, 2026, wherein claims 27, 61, 96, 127 are cancelled, new claims 173-184 are added, claims 1, 5, 50, 60, 64, 97, 100, 123, 124, 131, and 135 are amended.
Election/Restrictions
Applicant elected, without traverse, Group III invention and following species on 11/26/2025 :
Group III invention drawn to an oral liquid suspension comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl) pyridin-2-yl)thiazole-5-carboxamide (Compound A);
Species:
the polymer is polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA);
the flow-aid is colloidal silicon dioxide (CSD);
the surfactant is sodium lauryl sulfate (SLS);
and the filler is mannitol;
antifoam is simethicone.
Claims 1, 2, 5, 13, 15, 50, 60, 64, 85, 86, 89, 92, 131, 135, and 162 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention.
Status of Claims
Claims 1-2, 5, 13, 15, 50, 60, 64, 85-86, 89, 92, 97-98, 100, 102, 104, 107, 123-124, 126, 131, 135, 162, and 173-184 are pending in the instant application.
Claims 1, 2, 5, 13, 15, 50, 60, 64, 85, 86, 89, 92, 131, 135, and 162 remain withdrawn.
Claims 97, 98, 100, 102, 104, 107, 123-124, 126 and 173-184 are currently under examination.
Priority
The instant application 18/332,906 filed on 06/12/2023, is a continuation of PCT/US23/22430 filed on 05/16/2023 which claims benefit of US provisional application 63/342,533 filed on 05/16/2022.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 07/24/2026 is being considered by the examiner.
Claim Interpretation
As disclosed by instant specification (See [0002]), (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5- chloro-4-(trifluoromethyl) pyridin-2-yl) thiazole-5-carboxamide ("Compound A") (also known as tovorafenib, DAY101, DOT101, TAK-580, BIIB024 , or MLN 2480), having following structure, is a class II pan Raf kinase inhibitor useful for the treatment of Raf-mediated diseases such as cancer.
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Claims 97,107 and 173 recite limitation “wherein the suspension retains syringeability for at least” 15 minutes, 20 minutes or 30 minutes. The syringeability limitation is considered as the property of instant claimed oral liquid suspension which does not impart any material characteristic structural limitation to the oral liquid suspension. Once the oral suspension is formulated, the syringeability of the suspension could be evaluated through routine experiment.
Claim 126 recites limitation “wherein the oral liquid suspension is bioequivalent to a tablet formulation of Compound A, wherein the tablet composition comprises an amorphous solid dispersion comprising (i) about 40 wt.% of Compound A and (ii) about 60 wt.% of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate; and one or more pharmaceutically acceptable excipients”. The limitation “ wherein the oral liquid suspension is bioequivalent to a tablet formulation of Compound A” is considered as the property of instant claimed oral liquid suspension or intended result of administering the oral liquid suspension which does not impart any material characteristic structural limitation to the oral liquid suspension.
Action Summary
Applicant's remarks filed on 07/24/2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks .The text of those sections of 35 U.S. Code not included in this action can be found in a prior Office action.
Claim 97 is amended to recite weight percentage of the filler, surfactant, flow-aid and antifoam agent. The rejection of claim 97 anticipated by Chen et al. (US 9920048B2), rejection of claims 97 and 100 anticipated by Wright et al. (WO 2022099074 A1) under 35 USC§102 are withdrawn.
Please see Response to Arguments in the following reapplied rejections as necessitated by amendment under 35 USC § 112(b) and 103.
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 97, 98, 100, 107, 123-124 , 126 and 173-184 are rejected under 35 U.S.C. 112(b) 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(reapplied as necessitated by amendment).
Independent claim 97 is amended to recite an oral liquid suspension, comprising; Compound A or a pharmaceutically acceptable salt thereof,..., wherein each wt.% is based on the weight of the solids; and wherein the oral liquid suspension retains syringeability for at least 15 minutes. There is insufficient antecedent basis for “the solids” limitation in the claim. It’s not clear what components constitute “ the solids”. Is Compound A and the one or more polymer considered as a component of “the solids”? It’s unclear what total weight is to be used as the basis for determining the recited weight percentages. Claim 97 recites both concentration at mg/mL and amount at wt.% in the same formulation is confusing. The lack of clarity renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
Claims 98, 100, 102, 104, 107, 123-124, 126 and 173-184 are rejected due to dependency on claim 97.
Claim 126 recites limitation “wherein the oral liquid suspension is bioequivalent to a tablet formulation of Compound A, wherein the tablet composition comprises an amorphous solid dispersion comprising (i) about 40 wt.% of Compound A and (ii) about 60 wt.% of copovidone, wherein the amorphous solid dispersion is a hot melt extrudate; and one or more pharmaceutically acceptable excipients”. The term “bioequivalent” is a relative term which renders the claim indefinite. Claim 126 does not recite any dose amount of compound A and any specific pharmaceutical excipients in the tablet formulation. The bioavailability of the tablet formulation recited in claim 126 is undetermined. Thus, it’s not clear how to determine the oral liquid suspension of claim 97 is bioequivalent to the tablet formulation recited in claim 126. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Response to Arguments
Applicant argues claim 126 recites a functional limitation of the oral liquid suspension and he skilled artisan would understand the scope of claim 126.
RESPONSE: As elaborated above, claim 126 does not recite the amount of compound A and any specific pharmaceutical excipient in the tablet formulation. The bioavailability of the tablet formulation recited in claim 126 is undetermined. One of ordinary skilled in the art would not know which bioavailability value of the tablet formulation is used to compare with bioavailability of the oral liquid suspension of claim 97.
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 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 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 97,100 and 126 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al. (WO 2022099074 A1, published on 05/12/2022, Applicant’s IDS dated 09/14/2023) (reapplied as necessitated by amendment).
Wright teaches compositions and methods for treating gliomas (e.g. pediatric low-grade glioma) comprises administering to a subject in need thereof, (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof (See abstract, [0047], claims 1-20 and 47).
Wright teaches Compound A or a pharmaceutically acceptable salt thereof is administered as oral liquid suspension (See [0009], [0094], claim 14). Wright teaches the dose/amount of Compound A, e.g. 10 to 50 mg... 150 to 250 mg, etc. (See [0005], [0044], claims, 1, 31 and 32).
Regarding the pharmaceutical acceptable excipient, Wright teaches pharmaceutical compositions comprise one or more fillers (e.g., mannitol, celluloses, starches, sugars(dextrose), or the like) in concentrations of at least about 10 wt. % by weight; a sweetener (e.g. sucralose, sorbitol, saccharin, fructose, aspartame, or a combination thereof) in a concentration of about 10% or less by weight; a disintegrant (e.g., croscarmellose sodium, sodium starch glycolate, or a combination thereof) in concentrations of about 10 wt. % or less by weight; optionally a wetting agent (e.g., sodium lauryl sulfate, SLS) in concentrations of about 10 wt. % or less by weight; a glidant (e.g., colloidal silicon dioxide, talc, or a combination thereof) in concentrations of about 2 wt. % or less by weight; and a lubricant (e.g., magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof) in concentrations of about 5 wt. % or less by weight of the composition(See [0042]).
Regarding claim 100, Wright teaches variety of pharmaceutical acceptable excipient, e.g. one or more of microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, vinylpyrrolidone-vinyl acetate copolymer (copovidone), sodium croscarmellose, etc. (See [0045]).
Regarding claim 126, Wright teaches Compound A is administered as an oral tablet or age-appropriate formulation (suspension or sprinkle) at 530 mg/m2 (not to exceed 800 mg). Patients who are able to swallow tablets will receive the tablet formulation and patients who are unable or unwilling to swallow tablets will receive the age-appropriate formulation (See [0094]). It would have been prima facie obvious and logical for a skilled artisan to administer oral suspension comprising compound A that’s bioequivalent to oral tablet for desired efficacy in treating pediatric gliomas (e.g. pediatric low-grade glioma) in the subject in need thereof.
Wright collectively teaches an oral liquid suspension comprising Compound A, one or more pharmaceutical excipients (e.g. vinylpyrrolidone-vinyl acetate copolymer (copovidone), mannitol, sodium lauryl sulfate , colloidal silica, etc. ) that read on instant claimed filler, surfactant, flow-aid, etc.
It would have been prima facie obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to further explore/ optimize oral suspension of Compound A based on Wright’s collective teaching and general knowledge of pharmaceutical formulation. One of ordinary skilled in the art would be motivated to do so with reasonably expectation that optimized oral suspension comprising compound A would facilitate administration to pediatric patients and provide flexible dosing with measurable liquid suspension.
Response to Arguments
Applicant argues Wright fails to recognize the need to improve the in-use stability during reconstitution, let alone suggesting or teaching a formulation with improved syringeability.
RESPONSE: Applicant’s argument is considered, but NOT persuasive. Instant claim 97 does not recite limitation of reconstitution. The absence of express teachings of “syringeability” does not necessarily distinguish instant claimed formulation since syringeability is an expected property of liquid suspension intended to be administered by syringe.
Claims 97, 98, 100, 102, 104, 107, 123-124, 126 and 173-181 are rejected under 35 U.S.C. 103 as being unpatentable over Brake et al. (WO 2015148828, hereafter “Brake ’828”, Applicant’s IDS dated 09/14/2023 ), in view of Strickley et al. (Journal Of Pharmaceutical Sciences, VOL. 97, NO. 5, MAY 2008 DOI 10.1002/jps.21101, Pediatric Drugs- A Review of Commercially Available Oral Formulations) (reapplied as necessitated by amendment).
Brake ’828 disclosed a pharmaceutical composition comprises: (1) a solid dispersion extrudate comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound 1, i.e. instant compound A) or its pharmaceutical salt and a vinylpyrrolidinone-vinyl acetate copolymer; and (2) pharmaceutical excipients, and method of treating BRAF associated-cancer (See abstract, [0004], [0008], Examples 1-7 , claims 1-20). Brake ’828 teaches solid dispersion extrudate comprising (1) about 40% w/w of Compound 1 or a pharmaceutically acceptable salt thereof and (2) about 60% w/w of a vinylpyrrolidinone-vinyl acetate copolymer (See [00136]).
Regarding claim 98, Brake ’828 teaches embodiments wherein the solid dispersion is amorphous (See [0054]-[0055], claim 5). Brake ’828 teaches dissolution property of Compound 1 can be improved by making amorphous solid dispersions prepared by hot melt extrusion (HME) (See [0019]) and further teachers formulations (e.g. tablet) of Compound 1 comprising solid dispersions extrudate (See Examples 1-7 ).
Regarding claim 100, Brake ’828 explicitly teaches vinylpyrrolidinone-vinyl acetate copolymer (See [0039]-[0053], [0066]-[0073], claims 1-3 and 8 ). Brake ’828 explicitly teaches vinylpyrrolidinone-vinyl acetate copolymer is copovidone at various amount (See [0066]-[0073], [00366], claims 3 and 18).
Brake ’828 teaches variety of embodiments comprising various amount of compound A and variety of pharmaceutical excipients (See [0088], [00234]- [00241],[00366], Embodiments 88, 177-185), e.g. 10-50 wt.% of a solid dispersion extrudate comprising (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide or its pharmaceutical salt and a vinylpyrrolidinone-vinyl acetate copolymer; and 50-90 wt.% of pharmaceutical excipients comprising filler, disintegrant, glidant and lubricant (See claim 2, [00240]).
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Brake ’828 teaches embodiments comprising glidant, wherein the glidant is colloidal silicon dioxide at various amount, e.g. 0.5-6 wt.% ( See [0083]-[0092], [0130]). Brake ’828 teaches embodiments comprising sodium lauryl sulfate (See [00366]). Brake ’828 teaches embodiments comprising filler, wherein the filler is microcrystalline cellulose at various amount, e.g. 46-81 wt.% See [0093]-[0106], [0130]).
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Brake ’828 collectively teaches a pharmaceutical composition comprising solid dispersion comprising about (R)-2-(1-(6-amino-5- chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin- 2-yl)thiazole-5-carboxamide (i.e. instant compound A), or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable excipients (vinylpyrrolidone-vinyl acetate copolymer, copovidone, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide, etc.) .
Brake ’828 is silent about solid dispersion reconstituted into oral liquid suspension. Brake ’828 is silent about simethicone and maltodextrin recited in claims 123-124.
Strickley teaches oral formulation ( e.g. oral suspension) for pediatric drugs (See whole article, Tables 1-3, page 1759-, Suspensions). Strickley teaches reconstitution of solid (e.g. powder or granules or tablet) to oral suspension is one of the most common practice for pediatric oral drugs, wherein the solid phase is manufactured and packaged for long-term storage/ transportation, subsequently constituted to a suspension for the patient in-use phase and most solids are constituted with water, e.g. Amoxicillin/Amoxil for Oral Suspension, reconstituted from powder with water (See Table 3; page 1766, right column, last para; page 1767, left column, first para). Strickley teaches the ability to
accurately administer the suspension is critical and syringe is used for accurate dosing of suspension (See page 1767, right column).
Regarding claim 104, Strickley teaches various amount/concentration of active ingredients in oral suspension, e.g. 25-75 mg/mL in Cefaclor/Ceclor® suspension reconstituted with water, etc. (See Table 3). Where 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. MPEP 2144.05.
Regarding claim 174, Strickley teaches active ingredient reconstituted in water buffered at different pH, e.g. 3.2-3.8 (See Table 2; page 1771, left column, 1st para).
Strickley teaches variety of pharmaceutical excipients/inactive ingredient in pediatric formulation/reconstituted oral suspensions, e.g. Benazepril HCl/Lotensin®, Deferasirox/Exjade® (See Table 1-3,), e. g. bulk diluter/filler (e.g. mannitol, microcrystalline cellulose), suspending /dispersing agents (povidone, crospovidone, etc.), surfactant (e.g. sodium lauryl sulfate) , glidant (e.g. silicon dioxide), antifoam ( simethicone, dimethicone), maltodextrin, etc. (which read on the excipients recited in claims 123 and 124). Strickley teaches a solid formulation have favorable flow properties for manufacturing and packaging which might require the addition of a glidant such as silicon dioxide. The physical stability of a suspension includes foaming wherein foaming can be minimized by the addition of simethicone in the form of a powder (See page 1767, right column, first para).
Liquid oral dosage forms such as aqueous solutions and suspensions are often preferred for pediatric or geriatric patients that find it difficult to swallow tablets. It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to reconstitute amorphous solid dispersion taught by Brake ’828 into aqueous suspension for pediatric use or patients who are unable or unwilling to swallow tablets as taught by Strickley, together with further experimentation/ optimization based on general knowledge of pharmaceutical formulation. Brake ’828 collectively teaches a pharmaceutical composition comprising solid dispersion comprising instant compound A and pharmaceutically acceptable excipients (vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose, colloidal silicon dioxide, etc.) at various amount. Strickley further teaches surfactant (e.g. sodium lauryl sulfate), antifoam ( simethicone, dimethicone) and maltodextrin that could be used in aqueous oral suspension. One of ordinary skilled in the art would be motivated to do so with reasonably expectation that resulting oral suspension comprising compound A would facilitate administration to pediatric patients and provide flexible dosing with measurable liquid suspension.
Regarding new claims 175-181, Brake ’828 already teaches various amount of Compound A and pharmaceutically acceptable excipients (e.g. filler, surfactant, flow-aid etc.) in the solid dispersion. A skilled artisan would have known to further explore/optimize concentration of these ingredients in the oral suspension for desired property of oral suspension, e.g. stability, syringebility, etc. Where 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. MPEP 2144.05.
A skilled artisan would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and exploration/optimization based on general knowledge of pharmaceutical formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues The skilled artisan would have had no reasonable expectation of success in arriving at the claimed oral liquid suspension which retains syringeability for at least 15 minutes... oral liquid suspensions comprising Compound A (as claimed) tend to agglomerate and/or form viscous gels immediately after reconstitution,..., Neither Brake nor Strickley acknowledge this particular problem with formulating Compound A as an oral liquid suspension, nor do they suggest any solutions to overcome this problem...(Remarks, page 15-16).
RESPONSE: Applicant’s arguments is considered, but NOT persuasive. Strickley teaches variety of pediatric formulation/reconstituted oral suspensions comprising various pharmaceutical excipients that are administered by syringe. The absence of express teachings of “syringeability” does not necessarily distinguish instant claimed formulation since syringeability is an expected property of liquid suspension intended to be administered by syringe. A skilled artisan reformulating the solid dispersion of Compound A into oral liquid suspension would have considered the factors/properties such as viscosity, particle size, stability, syringeability, etc. and optimize the pharmaceutical excipients in combination with Compound A accordingly to achieve the desired properties of the oral suspension, particularly the prior art already teach the relevant ingredients in the solid dispersion.
As stated in MPEP 716.02(d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. Instant claim 97 is drawn to a broad scope of oral liquid suspension comprising genus of filler, surfactant, flow-aid, anti-foam agent at broad range. The working examples as disclosed by instant Spec (Example 7- 9, Table 17, 18 and 25) comprise specific combination of excipients (e.g. mannitol, SLS, CSD) and do not sufficiently support the genus of filler, surfactant, flow-aid, anti-foam. Further, no working example is syringable after 60 minutes (See Table 25). In other words, instantly disclosed syringeability of oral liquid suspension does not commensurate with the broad scope of claim 97 comprising the genus of filler, surfactant, flow-aid, antifoam, etc.
Claims 97, 98, 100, 102, 104, 107, 123-124, 126 and 173-184 are rejected under 35 U.S.C. 103 as being unpatentable over Brake et al. (WO 2015148828, “Brake ’828”, Applicant’s IDS dated 09/14/2023 ), in view of Murphy et al. ( WO2005123076A2, Applicant’s IDS dated 09/14/2023)(reapplied as necessitated by amendment) (reapplied as necessitated by amendment).
The collective teachings of Brake ’828 are elaborated in preceding 103 rejection and applied as before. Brake ’828 collectively teaches a pharmaceutical composition comprising solid dispersion comprising about (R)-2-(1-(6-amino-5- chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin- 2-yl)thiazole-5-carboxamide (i.e. instant compound A), or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable excipients (vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose, colloidal silicon dioxide, etc.) .
Brake ’828 is silent about solid dispersion reconstituted into oral liquid suspension.
Murphy teaches pharmaceutical composition comprising liquid/aqueous suspension or amorphous solid dispersion of water-insoluble active ingredient (VX-950), at least one polymer (e.g. polyvinylpyrrolidone) and one or more solubility enhancing surfactant (See abstract, page 4, last paragraph; claims 1-61) . Murphy teaches liquid vehicle comprising variety of polymer(e.g. PVP-VA (polyvinylpyrollidone-vinyl acetate, polyvinyl alcohols (PVA); etc.) at various amount (See page 18, last para and page 19) and surfactant (e.g. sodium lauryl sulfate SLS) at about 0% to about 20% by weight (See page 22, last para; page 23) . Murphy teaches embodiments wherein the surfactant is SLS from about 0.25% to about 5% by weight, preferably about 1% by weight and simethicone to reduce foaming (preferably in an amount of about 0.002% by weight) (See page 26, first para; Examples 11; claim 51-52). Murphy teaches embodiments administered in a syringe mixed with water (See page 42, Example 12).
It’s common practice in pharmaceutical industry to explore different dosage form for active drug, wherein liquid suspension is widely-used formulation that’s alternative for solid dosage form, especially for patient in need of easy and flexible dosing. It would have been prima facie obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to reconstitute amorphous solid dispersion taught by Brake ’828 into aqueous suspension, with further experimentation/ optimization of inactive ingredients based on Murphy’s teaching and general knowledge of pharmaceutical formulation. Brake ’828 collectively teaches a pharmaceutical composition comprising solid dispersion comprising instant compound A and pharmaceutically acceptable excipients (vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose, colloidal silicon dioxide, etc.) at various amount. Murphy teaches liquid/aqueous suspension and amorphous solid dispersion comprising various amount of surfactant (e.g. sodium lauryl sulfate), antifoam ( simethicone ) that could be used in aqueous oral suspension/solid dispersion. One of ordinary skilled in the art would be motivated to combine the teachings of prior art with reasonably expectation that alternative oral suspension comprising compound A would provide a flexible dosing for patient in need thereof with measurable liquid suspension and comparable bioavailability.
Regarding new claims 175-184, Brake ’828 and Murphy already teach various amount of Compound A and pharmaceutically acceptable excipients in the solid dispersion and liquid suspension. A skilled artisan would have known to further explore/optimize the concentration of these ingredients in the oral suspension for desired property of oral suspension, e.g. stability, syringebility, etc. Where 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. MPEP 2144.05.
A skilled artisan would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and optimization based on general knowledge of pharmaceutical formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments are similar as Brake ’828 in view of Strickley, and argues Murphy fails to cure the deficiencies of Brake.
RESPONSE: As elaborated hereinabove, Brake ’828 already teach relevant ingredients in the solid dispersion of Compound A. Murphy further teaches excipients (e.g. polymer, surfactant, antifoam) in oral liquid suspension dosed in a syringe. A skilled artisan reformulating the solid dispersion of Compound A into oral liquid suspension would have known to optimize the ingredients accordingly to achieve the desired properties of the oral suspension, e.g. syringeability. More importantly, instantly disclosed syringeability of oral liquid suspension does not commensurate with the broad scope of claim 97 comprising the genus of filler, surfactant, flow-aid, antifoam, etc.
Claims 97, 98, 100, 102, 104, 107, 123-124, 126 and 173-181 are rejected under 35 U.S.C. 103 as being unpatentable over Kodono et al. ( WO 2021/108616 A1, hereafter “Kodono ’616”, Applicant’s IDS dated 09/14/2023 ), in view of Strickley et al. (Journal Of Pharmaceutical Sciences, VOL. 97, NO. 5, MAY 2008 DOI 10.1002/jps.21101, Pediatric Drugs- A Review of Commercially Available Oral Formulations) (reapplied as necessitated by amendment).
Kodono ’616 disclosed a pharmaceutical composition comprising solid dispersion comprising about 10 % w/w to about 70 % w/w of (R)-2-(1-(6-amino-5- chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin- 2-yl)thiazole-5-carboxamide (i.e. instant compound A), or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients (e.g. polymer suitable for hot melt extrusion, vinylpyrrolidone-vinyl acetate copolymer) for treating BRAF-mediated disease/disorder (e.g. cancer) (See abstract, [0007]-[0016]; Examples 1-7; claims 1-48).
Regarding claim 98, Kodono ’616 teaches solid dispersion refers to an amorphous dispersion comprising Compound 1(i.e. instant compound A/ tovorafenib) and a vinylpyrrolidone-vinyl acetate copolymer in a solid state that is prepared by hot melt extrusion(See [0009],[0075],[0099], claim 30-34).
Regarding claim 100, Kodono ’616 teaches the solid dispersion comprises a polymer used in hot melt extrusion (HME). Exemplary commonly used polymers and co-polymers for HME is a high molecular weight hydrophilic polymer, where the high molecular weight hydrophilic polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer (e.g. copovidone), cross linked polyvinyl N-pyrrolidone, polyvinyl alcohol (PVA), polysaccharide, hydroxypropyl methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyethylene oxides (PEOs), hydroxypropyl-β -cyclodextrin (HP-β -CD), sulfobutylether-β -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS-HF), polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVAc-PVCap-PEG), poly(lactide-co-glycolide) (PLGA), cellulose-esters, cellulose-acrylates, poly (ethylene-co-vinyl acetate), poly-methacrylate derivatives, poloxamers, polylactic acid (PLA) and/or poly(glycolide) (PGA) (See [0015], [0053], claim 4, 11, 17). Kodono ’616 further teaches the polymer is vinylpyrrolidone- vinyl acetate copolymer, e.g. copovidone (See claim 2, 17)(which reads on instant elected polymer species). Kodono ’616 explicitly teaches solid dispersion comprises: (a) about 10 % w/w to about 70 % w/w of (R)-2-(1-(6-amino-5-chloropyrimidine-4-arboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof; and (b) about 30 % w/w to about 90 % w/w of a vinylpyrrolidone-vinyl acetate copolymer(See abstract, [0007]-[0011], [0053], [0066], claim 1)
Regarding the amount/concentration limitation recited in claims 123-124, Kodono ’616 explicitly teaches solid dispersion consists of about 60 % w/w of Compound 1 and about 40 % w/w of vinylpyrrolidone-vinyl acetate copolymer (See [0065], Examples).
Kodono ’616 teaches pharmaceutical excipients. e.g. adjuvants, anti-adherents, binders, carriers, disintegrants, fillers, flavors, colors, diluents, lubricants, glidants, preservatives, sorbents, solvents, surfactants, and sweeteners (See [0146]; claims 23-29). Kodono ’616 teaches pharmaceutical composition comprising about 50 % w/w to about 80 % w/w of one or more pharmaceutically acceptable excipients, e.g. a disintegrant, a glidant, a lubricant, or a combination thereof.
Kodono ’616 teaches embodiments wherein the one or more pharmaceutically acceptable excipients comprise a filler, a disintegrant, a glidant (e.g. silica), and/or a lubricant etc. wherein the filler is microcrystalline cellulose, mannitol, sodium dodecyl sulfate, etc. (See [0069]- [0074], claim 20-21). Kodono ’616 teaches the filler (e.g. microcrystalline cellulose, mannitol) be present in the composition at about 30 % w/w to about 80 % w/w, at about 40 % w/w to about 70 % w/w (See [0070]) (which reads on instant claim 123(b), 124(b) and (c)) . Kodono ’616 teaches the glidant (e.g. colloidal silicon dioxide, etc.) be present in the composition at about 0.1 % w/w to about 5% w/w, 0.2 % w/w to about 3 % w/w (See [0072])(which reads on instant claim 123(d) and 24(e)) .
Regarding claim 126, Kodono ’616 teaches dissolution profile of hot melt extrusion (HME) and loaded tablets comprising compound 1 (100mg) made with different particle sizes of HME (40% HME in tablet) (See [0019]-[0028], Fig 1-14).
Kodono ’616 collectively teaches a pharmaceutical composition comprising solid dispersion comprising about 10 % w/w to about 70 % w/w of (R)-2-(1-(6-amino-5- chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin- 2-yl)thiazole-5-carboxamide (i.e. instant compound A), or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients (vinylpyrrolidone-vinyl acetate copolymer).
Kodono ’616 is silent about amorphous solid dispersion reconstituted into liquid suspension as recited in instant claim 102. Kodono ’616 is silent about sodium lauryl sulfate, simethicone and maltodextrin recited in claims 123-124.
The collective teachings of Strickley is elaborated in preceding 103 rejections and applied as before. Strickley teaches reconstitution of solid (e.g. powder or granules or tablet) to oral suspension with variety of pharmaceutical excipients/inactive ingredient e. g. mannitol, microcrystalline cellulose, surfactant (e.g. sodium lauryl sulfate) , glidant (e.g. silicon dioxide), antifoam ( simethicone, dimethicone), maltodextrin, etc. (which read on the excipients recited in claims 123 and 124).
It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instantly claimed invention to reconstitute amorphous solid dispersion taught by Kodono ’616 into aqueous suspension for pediatric use as taught by Strickley, together with further experimentation/ optimization based on general knowledge of pharmaceutical formulation. Kodono ’616 collectively teaches a pharmaceutical composition comprising solid dispersion comprising instant compound A and pharmaceutically acceptable excipients (vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose, mannitol, colloidal silicon dioxide, etc.) at various amount. Strickley further teaches surfactant (e.g. sodium lauryl sulfate), antifoam ( simethicone, dimethicone) and Maltodextrin that could be used in aqueous oral suspension. One of ordinary skilled in the art would be motivated to do so with reasonably expectation that resulting oral suspension comprising compound A would facilitate administration to pediatric patients and provide flexible dosing with measurable liquid suspension.
Regarding new claims 175-181, Kodono ’616 already teaches various amount of Compound A and pharmaceutically acceptable excipients in the solid dispersion. A skilled artisan would have known to further explore/optimize the concentration of these ingredients in the oral suspension for desired property of oral suspension, e.g. stability, syringebility, etc. Where 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. MPEP 2144.05.
A skilled artisan would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and optimization based on general knowledge of pharmaceutical formulation. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments are similar as Brake ’828 in view of Strickley and argues Kodono fails to cure this deficiency.
RESPONSE: As elaborated hereinabove, Kodono ’616 already teach relevant ingredients in the solid dispersion of Compound A. Strickley further teaches excipients in oral liquid suspension that could be administered by syringe. A skilled artisan reformulating the solid dispersion of Compound A into oral liquid suspension would have known to optimize the ingredients accordingly to achieve the desired properties of the oral suspension, e.g. syringeability. More importantly, instantly disclosed syringeability of oral liquid suspension does not commensurate with the broad scope of claim 97 comprising the genus of filler, surfactant, flow-aid, antifoam, etc.
Conclusion
No claim is 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.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
