DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-19 are pending.
Priority
This application is filed 11/11/2024, and claims the benefit of domestic priority as below:
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Information Disclosure Statements
One IDS(s) received on 11/11/2024 has been considered unless marked with a strikethrough.
Specification
The use of the terms including "Eudragit L100-55", "Peceol" and "Maisine CC", which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 5, 10, 13, 14 and 17 are objected to because of the following informalities:
Claim 1 are objected to because the abbreviation “HLB” should be “hydrophile-lipophile balance (HLB)”.
Claims 5 and 10 are objected to because the phrase “further comprises” should be “further comprising”.
Claim 13 is objected to because the phrase “a drug, which N-(3-{3-Cyclopropyl…” should be “a drug, which is N-(3-{3-Cyclopropyl…”.
Claim 14 is objected to because it has different formatting from the other claims. It should be amended consistency. See MPEP 608
Claim 17 is objected to because the phrase “according to Claim 13:” should be “according to Claim 13,”.
Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6 and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, 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.
Claims 6 and 16 contain the trademark/trade name "Soluplus". Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and, accordingly, the identification/description is indefinite. Soluplus is a specific commercial product having a defined composition of polyethylene glycol, vinyl caprolactam, and vinyl acetate. Thus, it is unclear whether the claim encompasses the recited graft polymer generally or is limited to the specific Soluplus product.
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 nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 8-14, and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (US 2015/0328320 A1, pub'd 11/19/2015), in view of Peresypkin et al. (US 2007/0298099 A1, pub'd 12/27/2007).
With respect to independent claim 1, the claim recites that a liquid pharmaceutical composition comprising: (a) a drug, which is N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4, 7-trioxo-3,4,6, 7-tetrahydropyrido[ 4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide ("compound") or a pharmaceutically acceptable salt or solvate thereof, and (b) pharmaceutically acceptable solubilizers with relative amount of an oil, a water-insoluble surfactant having an HLB below 11, a water-soluble surfactant having an HLB of 11 or greater, and a hydrophilic cosolvent.
Campbell teaches 1) pharmaceutical formulations containing N-{3-[3-cyclopropy 1-5-(2-fluoro-4-iodo-pheny !amino )-6,8-dimethyl-2,4, 7-trioxo-3,4,6, 7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1 yl]phenyl}acetamide (trametinib) dimethyl sulfoxide solvate, methods of using the compositions in therapy and processes for preparing the same (abstract); 2) pharmaceutically acceptable excipients including a prepared aqueous formulation and a stable oral pharmaceutical formation comprising trametinib mixed with an aqueous vehicle (claims 6-9, and paragraph [0011]); 3) the initial trametinib concentration was 1 mg/mL and after five days trametinib concentration is reduced to about 7-10% of the initial concentration (paragraph [0128]); the starting concentration of trametinib (i.e., free or unsalted and unsolvated compound form) is about 0.05 mg/mL no significant amount of the drug will precipitate out of solution (paragraph [0029], and [0128]); and the presence of HPMC in a cavitron solution increases the stability of trametinib solution by inhibiting the precipitation of the trametinib out of the solution (paragraph 0129)). Thus, Campbell teaches a low concentration liquid trametinib formulation and further teaches that trametinib’s concentration, solubilization, and precipitation are formulation variables affecting solution stability.
Campbell fails to teach a trametinib liquid composition comprising the claimed combination and relative amounts of an oil, a water-insoluble surfactant having an HLB below 11 (hereinafter “low-HLB surfactant”), a water-soluble surfactant having an HLB of 11 or greater (hereinafter “high-HLB surfactant”), and a hydrophilic cosolvent.
Peresypkin teaches 1) self-emulsifying or self-micro emulsifying composition comprising 1) taranabant, a surfactant having an HLB of 1 to 8, a surfactant having an HLB of over 8 to 20 and optionally, a digestible oil and/or cosolvent and/or antioxidant or preservative (abstract); 2) liquid and semi solid pharmaceutical formulations for oral administration of a poorly water-soluble drug using the same classes of solubilizing excipients recited in claim 1 including sorbitan fatty acid ester as SPAN 80 for the low-HLB surfactant, and polyoxyl sorbitan fatty acid ester as Polysorbate 80 for the high-HLB surfactant (paragraph [0006], [0021] and [0022], and claim 21); 3) hydrophilic surfactants having an HLB of 8-20, preferably greater than 10, and lipophilic surfactants having an HLB below 8 (paragraph [0021] and [0022]; and 4) broad quantitative ranges for the high-HLB surfactant, low-HLB surfactant, digestible oil, and cosolvent and states that the ratio of the drug, surfactants, digestible oils, and/or cosolvents depends upon the efficiency of emulsification and solubility (paragraph [0046]).
Specifically, Peresypkin explains that the proportions of compound I (taranabant), surfactant, digestible oil, and/or co-solvent vary depending on emulsification efficiency and solubility, with solubility determined by the target dosage per capsule. Generally, the content ranges (based on wt%) for the components of the compound I formulation are as follows: Compound I 0.01–50%, co-solvent 0–99.99%, high-HLB surfactant 0–99.99%, low-HLB surfactant 0–99.99%, and digestible oil 0–99.99% (paragraph [0046]). In Claim 18, one of Peresypkin’s formulations comprises, based on the total weight of the composition, 0.01–25% of the drug (or a pharmaceutically acceptable salt or solvate thereof), 0–70% of digestible oil, 0–50% of high-HLB surfactant, and 0–70% of low-HLB surfactant. Therefore, the scope of Peresypkin’s formulations overlaps with the scope of the present claim.
It would have been obvious to a PHOSITA to formulate Campbell’s low concentration liquid trametinib composition using Peresypkin’s oil/surfactant, cosolvent solubilization system. A PHOSITA would have been motivated to make such a combination because Campbell identifies solubility and precipitation as formulation concerns for liquid trametinib, while Peresypkin teaches that its oil, surfactant, cosolvents system provides the advantages of increased drug solubility, improved emulsification, maintain poorly soluble drug in dissolved form, and improved oral bioavailability. A PHOSITA would have had a reasonable expectation of successfully making the combination because Campbell shows that trametinib can be formulated as a low concentration liquid pharmaceutical composition, and Peresypkin teaches as established liquid oral formulation system for solubilizing poorly water-soluble drugs using the same classes of oil, low-HLB surfactant, high-HLB surfactant, and hydrophilic cosolvent recited in claim 1.
The combination of Campbell and Peresypkin does not disclose the specific combination of all claimed component ranges and trametinib concentrations. However, the claimed component ratios and trametinib content would have been subject to routine optimization regarding variables known to affect the outcome. While Peresypkin discloses that the relative amounts of formulation components affect emulsification and solubility and that trametinib concentration affects precipitation and solution stability, Campbell discloses that trametinib concentration affects precipitation and solution stability (see Campbell, paragraph [0128], and Peresypkin, paragraph [0046]). Thus, the combination of Campbell and Peresypkin recognizes the relationship between the variables being adjusted and the formulation properties sought to be optimized (see in re Antonie, 559 F.2d 618 (CCPA 1977), In re Aller, 220 F.2d 454 (CCPA 1955), and MPEP 2144.05). In the absence of evidence establishing criticality or unexpected results different in kind, such selection would have constituted routine optimization of recognized results effective variables.
With respect to claims 2-4, the claims recite a list of the oil, the water-insoluble surfactant, and the water-soluble surfactant.
Peresypkin teaches glyceryl monooleate as the digestible oil, as required in claim 2; SPAN 80 and CRILL 4 as sorbitan monooleate for the low-HLB surfactant, as required in claim 3; and CREMOPHOR EL and ETOCAS 30 as polyoxyl 35 castor oil for the high-HLB surfactant, as required in claim 4 (claim 4). Accordingly, claims 2-4 would have been obvious for the same reasons discussed with respect to claim 1.
With respect to claim 5, the claims recite the pharmaceutical composition according to Claim 1, further comprises one or more precipitation inhibitors selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl methylcellulose acetate succinate (HPMCAS).
Campbell teaches a solubilizer prevents recrystallization and precipitation of the dissolved drug out of solution, and further teaches suitable solubilizers include, but are not limited to, Hypromellose (HPMC), polyvinylpyrrolidone, sulfobutylether B-cyclodextrin (Captisol) and hydroxypropyl B-cyclodextrin (Cavitron) (paragraph [0120]). Accordingly, claim 5 would have been obvious for the same reasons discussed with respect to claim 1.
With respect to claims 8-9, the claims recite further narrow the formulation of claim 1 by claimed particular proportions of the oil, water-soluble surfactants, and cosolvent, with further reciting a specific combination of 5 weight % of glyceryl monooleate, 35 weight% of polyethylene glycol 400 (PEG400), 20 weight% of caprylocaproyl polyoxylglyceride, and 40 weight% of lauroyl polyoxylglyceride, and the drug’s combination ranges.
Peresypkin teaches the same general formulation component classes and further teaches glyceryl monooleate as an oil, PEG400 as a cosolvent, caprylocaproyl polyoxylglyceride (i.e., Labrasol ALF), and lauroyl polyoxylglyceride (i.e., GELUCIRE 44/14) as water-soluble surfactants (claim 8).
Although Campbell and Peresypkin fail to teach claimed ranges in claim 8 or the precise 5/35/20/40 weight% in claim 9, these limitations further narrow the formulation variables addressed above with respect to claim 1. Accordingly, the additional limitations of claims 8 and 9 would have been obvious for the reasons discussed above with respect to claim 1.
With respect to claim 10, the claim recites that the pharmaceutical composition according to Claim 9, further comprises one or more precipitation inhibitors.
Campbell teaches that HPMC inhibits precipitation of trametinib and increases solution stability (paragraph [0120]). Accordingly, claim 10 would have been obvious for the same reason discussed with respect to claim 1.
With respect to claim 11, the claim recites the pharmaceutical composition further comprising one or more antioxidants.
Peresypkin teaches the antioxidants for use according to the invention include BHA (butylated hydroxyanisole), BHT (t-butylhydroxytoluene), tocopherol, propyl gallate, etc.) and other preservatives (paragraph [0048] and claim 12). Accordingly, claim 11 would have been obvious for the same reason discussed with respect to claim 1.
With respect to claim 12, the claim recites the pharmaceutical composition wherein the composition is for oral administration.
Campbell teaches an oral trametinib solution (claim 6). Accordingly, claim 12 would have been obvious for the same reason discussed with respect to claim 1.
With respect to claim 13, the claim recites a liquid pharmaceutical composition comprising:
(a) a drug, which N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4, 7-trioxo-3,4,6, 7-tetrahydropyrido[ 4,3-d]pyrimidin-l (2H)-yl }phenyl)acetamide ("compound") or a pharmaceutically acceptable salt or solvate thereof, (b) pharmaceutically acceptable solubilizers, and (c) one or more precipitation inhibitors, wherein the solubilizers consist of, based on the total weight of the solubilizers, weight% of one or more water-soluble surfactants having an HLB of 11 or greater, and 97 weight% of one or more hydrophilic cosolvents; the drug is included at the compound content of 0.01 weight% to 0.3 weight%, 0.01 weight% to 0.2 weight%, or 0.05 weight% to 0.15 weight%, based on the total weight of the composition; the water-soluble surfactant is polyoxyl castor oil, polyoxyl hydrogenated castor oil, polyoxyl sorbitan fatty acid ester, polyoxyl tocopherol ester derivatives, or polyoxylglyceride; the hydrophilic cosolvent is diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol, or alcohol; and the precipitation inhibitor is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).
As discussed above with claims 1, the combination of Campbell and Peresypkin teaches the liquid trametinib formulation, solubility considerations, and use of high-HLB/low-HLB surfactants and hydrophilic cosolvents substantially as discussed above with respect to claim 1.
Claim 13 further requires one or more precipitation inhibitors and specifies that the pharmaceutically acceptable solubilizers consist of 3 weight% of one or more water-soluble surfactants having an HLB of 11 or greater, and 97 weight% of one or more hydrophilic cosolvents, together with the claimed trametinib concentration ranges.
Campbell additionally teaches that trametinib is susceptible to precipitation from aqueous solution and that HPMC inhibits precipitation of trametinib and improves solution stability (paragraph [0127]-[0129] and [0120], and Figs 2-4). Thus, Campbell teaches the precipitation inhibitor required by claim 13 and provides a reason to employ such an inhibitor in a liquid trametinib formulation.
The combination of Campbell and Peresypkin fails to teach the claimed solubilizers consist of 3 weight% of one or more water-soluble surfactants having an HLB of 11 or greater, and 97 weight% of one or more hydrophilic cosolvents. However, as discussed above with respect to claim 1, Peresypkin teaches that relative amounts of surfactants and cosolvents depend upon, emulsification efficiency and drug solubility, and discloses broad quantitative ranges encompassing mixtures of high-HLB surfactants and hydrophilic cosolvents (paragraph [0046]). Therefore, Peresypkin establishes the relative amount of these carrier components as formulation variables affecting solubilization performance.
Accordingly, it would have been obvious to a PHOSITA to optimize the relative amounts of Peresypkin’s known high-HLB surfactants and hydrophilic co-solvents when applying them to Campbell’s trametinib formulation to ensure adequate trametinib solubilization and solution stability, and the claimed 3/97 weight % ratio represents selection of values of the result-effective formulation variables through routine optimization.
With respect to claim 14, the claim recites the pharmaceutical composition, wherein the water-soluble surfactant is at least one selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate, tocopherol polyethylene glycol succinate, lauroyl polyoxylglyceride, and caprylocaproyl polyoxylglyceride.
Peresypkin teaches the same general formulation component classes, and further teaches caprylocaproyl polyoxylglyceride (i.e., Labrasol ALF), and lauroyl polyoxylglyceride (i.e., GELUCIRE 44/14) as water-soluble surfactants (claim 8). Accordingly, claim 14 would have been obvious for the same reason discussed with respect to claim 13.
With respect to claim 17, the claim recites that the pharmaceutical composition according to Claim 13: wherein the solubilizers consist of, based on the total weight of the solubilizers, 77 weight% of PEG400, 20 weight% of diethylene glycol monoethyl ether, and 3 weight% of Polysorbate 80, and the drug is included at the compound content of 0.01 weight% to 0.3 weight%, 0.01 weight% to 0.2 weight%, or 0.05 weight% to 0.15 weight%, based on the total weight of the composition.
Peresypkin teaches PEG400 and diethylene glycol monoethyl ether (i.e., TRANSCUTOL) as suitable cosolvents and Polysorbate 80 as a high-HLB surfactant and further teaches mixtures of these types or carrier components (claim 8 and paragraph [0012]).
The combination of Campbell and Peresypkin fails to teach the claimed 77/20/3 weight% limitation. However, the distribution further narrows the formulation variables addressed above with respect to claim 13. Accordingly, the additional limitations of claim 17 would have been obvious for the result-effective formulation variables through routine optimization reasons discussed above with respect to claim 1 and 13.
With respect to claim 18, the claim recites that the pharmaceutical composition, according to Claim 13, further comprising one or more antioxidants.
Peresypkin teaches the antioxidants for use according to the invention include BHA (butylated hydroxyanisole), BHT (t-butylhydroxytoluene), tocopherol, propyl gallate, etc.) and other preservatives (paragraph [0048] and claim 12). Accordingly, claim 18 would have been obvious for the same reason discussed with respect to claim 13.
With respect to claim 19, the claim recites that the pharmaceutical composition according to Claim 13, wherein the composition is for oral administration.
Campbell teaches an oral trametinib solution (claim 6). Accordingly, claim 19 would have been obvious for the same reason discussed with respect to claim 3.
Claim(s) 6, 7, 15 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (US 2015/0328320 A1, pub'd 11/19/2015), and Peresypkin et al. (US 2007/0298099 A1, pub'd 12/27/2007) as applied to claims 1 and 13 above, and further in view of Leutner et al. (US 2017/0014414 A1, pub'd 01/19/2017, made of record in the IDS).
With respect to claims 6 and 16, the claims further limit the precipitation inhibitor to polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).
The combination of Campbell and Peresypkin fails to teach the specific precipitation inhibitor as Soluplus.
Leutner teaches that 1) a pharmaceutical composition comprising trametinib or a pharmaceutically acceptable salt thereof as active ingredient and a carrier (claim 1); 2) a pharmaceutical composition comprising a pharmaceutically acceptable carriers including HPMC, HPMCAS, PVP, copovidone, and Soluplus (paragraph [0024], and [0030]-[0031]); 3) the trametinib formulation having adequate dissolution properties, and improved storage stability and shelf-life (paragraph [0009]).
For the same reasons previously discussed regarding claims 1 and 13, the use of Leutner’s Soluplus as the polymeric component in the trametinib formulations of Campbell and Peresypkin would have been obvious to a PHOSITA. Leutner suggests that Soluplus is a suitable carrier for trametinib, while Campbell proposes the use of polymeric excipients to inhibit trametinib precipitation and improve solution stability. Therefore, a PHOSITA would have had a reasonable expectation that Soluplus could be successfully employed as the claimed polymeric precipitation inhibitor.
With respect to claims 7 and 15, the claims recite that the weight ratio of the compound to the precipitation inhibitor is in the range of 1:1 to 1:10, 1:4 to 1:9, or 1:4.
The combination of Campbell and Peresypkin fails to teach the specific weight ratio of the compound to the precipitation inhibitor.
Leutner teaches that the weight ratio of active ingredients to carriers is in the range of 1:1 to 1:150 that falls in the claimed ranges (claim 13). Accordingly, claims 7 and 15 would have been obvious for the same reason discussed above with respect to claims 6 and 16.
Conclusion
Claims 1-19 are rejected.
Claims 1, 5, 10, 13, 14 and 17 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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