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
This office action is response to communication filed on 11/26/2025.
Election/Restrictions
Acknowledgement is made of Applicant's election without traverse filed on 11/26/2025 :
Group III invention ( claims 97, 98, 100, 102, 104, 107, 123-124, and 126-127): 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Claims 1, 2, 5, 13, 15, 27, 50, 60, 61, 64, 85, 86, 89, 92, 96, 131, 135, and 162 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention.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, 27, 50, 60-61, 64, 85-86, 89, 92, 96-98, 100, 102, 104, 107, 123-124, 126-127, 131, 135, and 162 are pending in the instant application.
Claims 1, 2, 5, 13, 15, 27, 50, 60, 61, 64, 85, 86, 89, 92, 96, 131, 135, and 162 are withdrawn.
Claims 97, 98, 100, 102, 104, 107, 123-124, and 126- 127 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 09/14/2023, 05/24/2024 and 11/26/2025 are in compliance with the provisions of 37 CFR1.97. Accordingly, the information disclosure statements is being considered by the examiner.
Claim Objections
Claims 123-124 are objected to because of the following informalities:
Claims 123-124 recite excipients in acronyms: PVP-VA, SLS, CSD that should be written in full names.
Drawings
The drawings are objected to because Figures 3, 4 and 6 are blurry and not clear. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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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Claim 107 recites limitation “wherein the suspension retains syringeability for at least 20 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.
Claim 127 recites “wherein the oral liquid suspension, when administered to a human subject in an amount equivalent to about 100 mg of Compound A, is sufficient to achieve in the subject a maximum observed blood plasma concentration (Cmax) of Compound A of at least about 100ng/mL”. The limitation “sufficient to achieve in the subject a maximum observed blood plasma concentration (Cmax) of Compound A of at least about 100ng/mL” is considered as the property of instant claimed oral liquid suspension or intended result of administering the oral liquid suspension which does not impart material characteristic structural limitation to the oral liquid suspension.
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 98, 100, 107, 123-124 and 126-127 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.
Claim 98 recites “The oral liquid suspension of claim 97, wherein Compound A or a pharmaceutically acceptable salt thereof is in a form of an amorphous solid dispersion”. Claims 100, 123-124 also recite limitation of “amorphous solid dispersion”. The form of amorphous solid dispersion is contradictory to liquid suspension and confusing. An ordinary skilled artisan would not know whether the dosage form is amorphous solid dispersion or liquid suspension, or how compound A and PVP-VA stay distributed within the amorphous solid dispersion after reconstitution into the liquid suspension as recited in claims 123-124. 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 100 recite limitation “wherein the amorphous solid dispersion comprises one or more polymers” . There is insufficient antecedent basis for this limitation in claim 100. Claims 100 depends on claim 97, but there is no recitation of “amorphous solid dispersion” in claim 97.
Claim 107 recites limitation “wherein the suspension retains syringeability for at least 20 minutes”. It’s not clear how the syringeability is evaluated/measured. Depending on different particle size and viscosity, oral suspension might not pass through different size of syringe. It’s not clear what’s the amount of compound A in combination with pharmaceutical excipient (s) would retain the cited syringeability for 20 mins.
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”. Claim 126 does not recite any dose amount of compound A for the oral liquid suspension and/or the tablet formulation comprising amorphous solid dispersion. Claim 126 does not recite any pharmaceutical excipients in the oral liquid suspension and/or the tablet formulation. It’s not clear what amount of compound A in combination with what pharmaceutically acceptable excipient(s) in the oral liquid suspension could be considered as bioequivalent to a tablet formulation of Compound A comprising any amount of Compound A in combination with any pharmaceutically acceptable excipient(s).
Claim 127 recites “wherein the oral liquid suspension, when administered to a human subject in an amount equivalent to about 100 mg of Compound A, is sufficient to achieve in the subject a maximum observed blood plasma concentration (Cmax) of Compound A of at least about 100ng/mL”. An ordinary skilled in the art would not be appraised the scope of claim 126 and 127 reciting intended result of administering instantly claimed oral liquid suspension.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 126 and 127 are rejected under 35 U.S.C. 112(d), as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 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”.
Claim 127 recites “wherein the oral liquid suspension, when administered to a human subject in an amount equivalent to about 100 mg of Compound A, is sufficient to achieve in the subject a maximum observed blood plasma concentration (Cmax) of Compound A of at least about 100ng/mL”.
The limitation “wherein the oral liquid suspension is bioequivalent to a tablet formulation of Compound A” and “is sufficient to achieve in the subject a maximum observed blood plasma concentration (Cmax) of Compound A of at least about 100ng/mL” are considered as intended result of administering the oral liquid suspension which do not impart any further physical or otherwise material characteristic structural limitation to the oral liquid suspension of claim 97 upon which they depend. As such, these limitation fail to further limit the subject matter of the claim upon which they depend.
In order to overcome this ground of rejection, Applicant may wish to (a) cancel the claims, rewrite claim to incorporate the subject matter of claims or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 97 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Chen et al. (US 9920048B2, hereafter “Chen’048”, Applicant’s IDS dated 09/14/2023 ).
Chen’048 disclosed compound of Formula I as Raf kinase inhibitor and pharmaceutical composition thereof for a method of treating Raf-mediated disease/disorder (e.g. cancer) (See abstract, Col.3, lines 1-16; claims 1-13). Chen’048 explicitly disclosed instant compound A (See claim 13).
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Chen’048 teaches pharmaceutically acceptable compositions comprise active compound and pharmaceutically acceptable carrier, adjuvant, or vehicle, including solvents diluents , or other liquid vehicle , dispersion or suspension aids, binders, lubricant (e.g. sodium lauryl sulfate), colloidal silica, polyvinylpyrrolidone, etc. (See Col. 33, lines 14-63). Chen’048 teaches liquid dosage forms for oral administration, e.g. solutions , suspensions , syrups and elixirs, etc. wherein the liquid dosage form contain active compound and inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers, suspending agents, sweetening, flavoring agent , etc. (See Col. 35. lines 26-40).
Chen’048 collectively teaches an oral liquid suspension comprising active compound ( e.g. compound A), one or more pharmaceutical excipients (e.g. sodium lauryl sulfate , colloidal silica, polyvinylpyrrolidone, etc. ) and water. As such, Chen’048 anticipates instant claimed invention.
Claims 97 and 100 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wright et al. (WO 2022099074 A1, published on 2022-05-12, Applicant’s IDS dated 09/14/2023).
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).
Regarding claim 100, Wright teaches 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 the pharmaceutical excipients, 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]).
Wright collectively teaches an oral liquid suspension comprising Compound A, one or more pharmaceutical excipients (e.g. vinylpyrrolidone-vinyl acetate copolymer/copovidone, sodium lauryl sulfate , colloidal silica, etc. ). As such, Wright anticipates instant claimed invention.
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, 126-127 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).
The collective teachings of Wright are elaborated in preceding 102 rejection and applied as before. Wright collectively teaches an oral liquid suspension comprising Compound A, one or more pharmaceutical excipients (e.g. vinylpyrrolidone-vinyl acetate copolymer (copovidone), sodium lauryl sulfate , colloidal silica, etc. ).
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 gliomas (e.g. pediatric low grade glioma) in the subject in need thereof.
Regarding claim 127, Wright teaches various dose amount for Compound A or a pharmaceutically acceptable salt thereof from 10 mg to 200 mg per tablet (See [0044], [0052]-[0054]), wherein the administered amount is sufficient to achieve in the subject a observed Cmax of Compound A of 2000 ng/mL to 8000 ng/mL (See [0006], [0078]). It would have been prima facie obvious to a skilled artisan to evaluate the observed Cmax of oral suspension and reasonably expect the reconstituted oral suspension comprising Compound A would achieve the Cmax for at least about 100ng/mL in the subject in need thereof, in the absence of evidence to the contrary.
Claims 97, 98, 100, 102, 104, 107, 123-124 and 126-127 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).
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], 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], 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 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, microcrystalline cellulose, colloidal silicon dioxide, etc.) .
Brake ’828 is silent about solid dispersion reconstituted into oral liquid suspension. Brake ’828 is silent about sodium lauryl sulfate, 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.
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. 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. 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.
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.
Claims 97, 98, 100, 102, 104 107, 123-124 and 126-127 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 Murphy et al. ( WO2005123076A2, Applicant’s IDS dated 09/14/2023).
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).
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. 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. One of ordinary skilled in the art would be motivated to combine the teachings of prior art with reasonably expectation that resulting alternative oral suspension comprising compound A would provide a flexible dosing for patient in need thereof with measurable liquid suspension and comparable bioavailability.
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.
Claims 97, 98, 100, 102, 104, 107, 123-124, and 126-127 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).
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 is 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. 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. 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.
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.
Conclusion
No claim is allowed.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628