DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Summary
Receipt of Applicant’s Remarks and Amendments filed on 12/06/2023 is acknowledged. Claims 1 and 4-22 are pending.
Claims 2-3 have been have been cancelled.
Claims 1 and 4-22 are pending and under examination in this application.
Priority
The current application filed on 12/06/2023 is a 371 of PCT/EP2022/065542 filed 06/08/2022, which in turn claims priority to patent application PCT/EP2022/065542 filed on 06/09/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/18/2025, 11/06/2025, 10/03/2025, 10/29/2024, 08/20/2024, 06/25/2024 and 12/06/2023 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements have been considered by the examiner. Signed copies have been attached to this office action.
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.
Claims 1, 4-12 are rejected under 35 U.S.C. 103 as being unpatentable over Curatolo (US 20120288542 A1) in view of Beyerinck (US 20050031692 A1), Warashina (EP 3023110 A1) and further in view of Solubility enhancement, solvent effect and thermodynamic analysis of pazopanib in co-solvent mixtures (hereinafter the reference is referred as Shi).
Curatolo Spray drying processes are used to form pharmaceutical
compositions comprising a Solid amorphous dispersion of a drug and a polymer (Abstract). Moreover, Curatolo discloses a process for preparing spray dried amorphous solid dispersions (ASDs) of poorly water soluble drugs (¶ 0027) using dispersion polymers, directly addressing and enhancing bioavailability of poorly soluble drugs through spray drying (¶s 0012-0028), analogous to the subject matter of instant application.
Regarding claims 1, 6, 9, 10, 11, 17, 20-22, Curatolo teaches a process for making a spray dried solid dispersion comprising: A) forming a solution comprising (i) a polymer, (ii) a sparingly water-soluble drug, and (iii) a solvent in which both (i) and (ii) are soluble; and wherein (B) is a spray drying solution (¶ 0012-¶ 0023). Curatolo explicitly teaches spray dried amorphous solid dispersions (ASDs) solution (¶ 0016-¶ 0017), a sparingly water-soluble drug corresponding to an active drug (¶ 0012), and hydroxy propyl methyl cellulose acetate succinate (HPMCAS) (¶ 0012), and further discloses amorphous dispersions of drug and conventional matrix materials PVP, HPC, or HPMC can be formed and then triturated with HPMCAS (¶ 0050). Curatolo further discloses solvents suitable for spray-drying can be any organic compound in which the drug and HPMCAS are mutually soluble, and solvents include methanol, ethanol, ethyl acetate and various other solvents (¶0059).
Regarding claim 5, Curatolo broadly teaches that the spray solvent forms the bulk of the spray solution by weight, as total solids content is typically less than 25 wt% and often less than 15 wt% (¶ 0016). Thus, a solvent content of at least 50 wt% necessarily follows from these solids content ranges and is therefore obvious.
Regarding claim 6, Curatolo teaches biologically active compounds (¶ 0028-¶ 0037).
Regarding claim 7, Curatolo teaches In a preferred embodiment the concentration of drug in the solvent is less than 20 g/100 g of solvent with a total solids content less than 25 weight%, preferably less than 15 weight % (¶ 0016). Thus, a concentration of at least 0.5 wt% is the low end of a broadly known and routinely optimized parameter and is therefore obvious.
Regarding claim 14, Curatolo teaches mixtures of solvents can also be used, as can mixtures with water as long as the polymer and HPMCAS are sufficiently soluble to make the spray-drying process practical (¶ 0059).
While Curatolo discloses the general class of solvents including methanol, ethanol, and ethyl acetate individually and as potential mixtures, Curatolo does not specifically claim or exemplify a binary mixed solvent system of the specific ester plus alcohol combinations recited in claim 1 (methyl acetate, methyl formate, ethyl acetate, or ethyl formate paired with methanol or ethanol) in a defined 10:90 to 90:10 (w:w) ratio. Moreover, Curatolo does not specifically enumerate methyl acetate or methyl formate as preferred solvents.
Beyerinck teaches spray drying processes are used to form pharmaceutical compositions comprising a solid amorphous dispersion of a drug and a polymer (abstract).
Regarding claims 1, 4, 9-12, 20-22, Beyerinck teaches solid amorphous dispersion (¶ 0029-¶ 0036) by spray drying processes, drug and polymer, comprising the polymer hydroxy propyl methyl cellulose acetate (HPMCAS) (¶ 0061), exemplary cellulosic polymers listed in (¶ 0148) includes (HPMCAS), HPMCP, CAP, carboxy- methyl ethyl cellulose or CMEC), and solvents suitable for spray-drying can be any compound in which the drug and polymer are mutually soluble, and preferred solvents include alcohols such as methanol, ethanol, ethyl acetate and various other solvents, wherein mixtures of solvents, for examples 50 % methanol and 50 % acetone, can also be used, as can mixtures with water as long as the polymer and drug are sufficiently soluble to make the spray-drying process practicable. In some cases it may be desired to add a small amount of water to aid solubility of the polymer in the spray solution (¶ 0062). Regarding the 10:90 to 90:10 (w:w) solvent ratio recited in claim 1 encompasses the 50:50 ratio exemplified by Beyerinck, and the solvent 1:solvent 2 (20:80 to 80:20) subrange, it is obvious for a PHOSITA to perform routine optimization of ratios. Optimizing solvent ratios to achieve full dissolution of both drug and polymer is standard practice described in the art. A PHOSITA would routinely screen solvent compositions across this entire range as a matter of course. The selection of a specific numeric range does not impart patentability when the range is within the range taught by the prior art or is the result of routine optimization. Therefore the limitations of a mixture of solvents are taught and it would have been obvious for a PHOSITA to use ethyl acetate + methanol as a combination.
Regarding claim 5, Beyerinck teaches to form a spray solution having a 5 wt % dissolved solids content and which results in a solid amorphous dispersion having a 25 wt % drug loading, the spray solution would comprise 1.25 wt % drug, 3.75 wt % polymer and 95 wt % solvent. The drug may be dissolved in the spray solution up to the solubility limit; however, the amount dissolved is usually less than 80% of the solubility of drug in the solution at the temperature of the solution prior to atomization. The dissolved solids content may range from 0.2 wt % to 30 wt % depending on the
solubility of the drug and polymer in the solvent. For drugs having good solubility in the solvent, the spray solution preferably has a solids content of at least 3 wt %, more preferably at least 5 wt %, and even more preferably at least 10 wt %. However, the dissolved solids content should not be too high, or else the spray solution may be too viscous to atomize efficiently into small droplets (¶ 0056). Thus, a solvent content of at least 50 wt% necessarily follows from these solids content ranges and is therefore obvious.
Regarding claim 6, Beyerinck teaches biologically active agents (¶ 0134-¶ 0137).
Regarding claim 7, Beyerinck teaches in order to reduce the amount of inactive material to be dosed, it is usually desired that the drug is present in the solid amorphous dispersion in an amount that is as great as possible while still achieving a dispersion that performs well (e.g., enhances dissolved drug concentration in a use environment and bioavailability when dosed to an animal, such as a mammal). The amount of drug relative to the amount of polymer present in the solid amorphous dispersions of the present invention depends on the drug and polymer. Often, the amount of drug present is greater than the solubility of the drug in the polymer. The present invention allows the drug to be present in the solid amorphous dispersion at a level greater than its solubility in the polymer while still being homogeneously dispersed. The amount of drug may vary widely from a drug-to-polymer weight ratio of from 0.01 to about 49 (e.g., 1 wt% drug to
98 wt% drug). However, in most cases it is preferred that the drug-to-polymer ratio is at least about 0.05 ( 4.8 wt% drug), more preferably at least 0.10 (9 wt % drug), and even more preferably at least about 0.25 (20 wt % drug). Higher ratios may be possible depending on the choice of drug and polymer, such as at least 0.67 (40 wt% drug). However, in some cases, the degree of concentration-enhancement decreases at high drug loadings, and thus the drug-to polymer ratio may for some dispersions be less than about 2.5 (71 wt% drug), and may even be less than about 1.5 (60 wt% drug) (¶ 0038). Furthermore, Beyerinck discloses in order to achieve dispersions that are almost
completely amorphous and substantially homogeneous, the solvent yields a spray solution in which the polymer and drug are both soluble and preferably highly soluble. The drug and polymer should preferably be fully dissolved in the solvent in the spray solution prior to atomization. This allows intimate mixing of the polymer, drug and solvent at the molecular level. Preferably, the drug has a solubility in the solvent at 25° C. of at least 0.5 wt %, preferably at least 2.0 wt % and more preferably at least 5.0 wt % (¶ 0060).
Regarding claims 14-16, Beyerinck expressly teaches that “mixtures with water” can be used “as long as the polymer and drug are sufficiently soluble” (¶ 0062). Thus, the addition of water to the mixed solvent system is therefore explicitly taught.
Regarding claim 15, Beyerinck teaches mixtures of solvents, as can mixtures with water can also be used, as long as the polymer and drug are sufficiently soluble to make the spry-drying process practicable, and in some cases it may be desired to add a small amount of water to aid solubility of the polymer in the spray solution (¶ 0062). Moreover, Beyerinck discloses that up to 40% of the solvent may comprise a lower-volatility component (¶ 0064) and teaches limiting water content to maintain solubility. Thus, ≤ 30 % water is within the ranges taught.
Warashina teaches any solvent capable of dissolving both a drug and a polymer is used for production of a solid dispersion comprising a drug, HPMCAS dissolved therein is filtered for removal of undissolved matter before coating or spray drying (¶ 0010-¶ 0014).
Regarding claims 13, 18 and 19, Warashina teaches a solvent for the solution for spray drying is an arbitrary solvent capable of dissolving both the drug and the HPMCAS therein. Examples of the solvent preferably include water, acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran, and di-chloro-methane. The solvent may be used singly or in combination of two or more. When the solution for spray drying contains a water-miscible solvent, water may be added to the solution (¶ 0044, claim 4). Moreover, Warashina discloses A solution for spray drying was prepared by dissolving 1 g of ketoconazole as a poorly water-soluble drug, and 1 g of each HPMCAS in a mixed solution of dichloromethane and ethanol at the weight ratio of 1:1 (¶ 0064). Therefore, Warashina teaches binary ester/alcohol solvent system with or without water can be utilized, and without water is the most basic embodiment of the mixed solvent concept, and a combined ester/alcohol content of at least 70 % of the mixed solvent is routine optimization.
Shi teaches Co-solvency or solvent mixing, as a powerful drug solubilizing technique, is the most common and easy-to-use method and widely used in pharmaceutical sciences for practical and increasing of the drug solubility and in order to improve the pazopanib (drug) solubility, co-solvency is an effective method, the solubility of pazopanib in (ethyl acetate + ethanol) and (ethyl acetate + 2-propanol) binary solvents at temperatures ranging from 288.15 K to 328.15 K; evaluate the effect of solvent properties of solvent mixtures on solubility of pazopanib by KAT-LSER method; correlate the solubility data by using Jouyban-Acree model and Apelblat-Jouyban-Acree model and calculate the thermodynamic properties of the dissolution process of pazopanib in two solvent mixtures (page 2, left column, 1st ¶).
Regarding claim 8, Shi teaches the co-solvency phenomenon was occurred in the dissolution process of pazopanib in two mixed solvents. The maximum solubility value appeared at w = 0.60 (the mass fraction of ethyl acetate in mixed solvents systems). At 288.15 K, solubility was increased by 4.37 and 3.94 times. Moreover, Shi discloses The thermodynamic models can all correlate the solubility behavior of pazopanib in pure and mixed solvents mixtures well. In addition, from the solvent effect results, nonspecific dipolarity/polarizability interactions are favorable to dissolution, and the nonspecific dipolarity/polarizability interactions had a great contribution to dissolution. Moreover, apparent thermodynamic quantities of pazopanib dissolution process in the ethyl acetate + ethanol/2-propanol mixtures, and The results of apparent dissolution properties are all positive which indicate the dissolution of pazopanib in two mixed solvents is an endothermic and entropy-increasing process and the enthalpy is the main contributor to standard Gibbs energy of solution process in all compositions. The discovery of co-solvency phenomenon is important to optimize the purification and improve bioavailability of pazopanib, and the solvent mixing is a common, easy-to-use and effective method to improve the solubility of pazopanib (abstract). Therefore, this supersaturation benefit of mixed solvents is well understood by a PHOSITA and is explicitly the motivation for using binary solvent systems, and achieving a drug concentration at least 1.1-fold above a single-solvent solubility is the predictable result of mixing co-solvents.
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to arrive at the method for spray drying an ASD using a binary mixed solvent of a short-chain ester (methyl/ethyl acetate or formate) and a short-chain alcohol (methanol or ethanol), with standard dispersion polymers. The claimed invention at is core, aims on improving drug solubility through ASD formation by spray drying, and using a binary ester/alcohol solvent to dissolve both the drug and the dispersion polymer, both are well recognized and is a straightforward application of co-solvency principles universally applied in pharmaceutical processing. Therefore, every element of this combination was known in the pharmaceutical spray drying art of record before the effective filing date. Curatolo established the ASD spray drying paradigm with HPMCAS and an open solvent genus. Beyerinck provided the rationale and guidance for selecting and mixing esters and alcohols specifically for spray drying ASDs, exemplifying 50:50 solvent mixtures. Warashina specifically identified methyl acetate and ethyl acetate as suitable solvents for HPMCAS spray drying in combination with methanol and ethanol. Shi expressly teaches the co-solvency phenomenon comprising ethyl acetate + ethanol/2-propanol mixtures. Together, these references render the claimed method obvious to a PHOSITA, who would have had a reasonable expectation of success in that selecting any ester/alcohol binary combination from Warashina's and Shi enumerated list in a standard ratio would produce a high-quality ASD. One of ordinary skill in the art would have been motivated to combine the teachings of Curatolo, Beyerinck, Warashina and Shi because all the references are drawn to methods for addressing (1) the identical technical problem of improving bioavailability of poorly-soluble drugs by spray drying to form ASDs. A PHOSITA would naturally look to Beyerinck's comprehensive solvent selection framework and Warashina's HPMCAS-specific solvent guidance when implementing or optimizing the Curatolo spray drying process. The motivation to combine is directly related in the shared problem and solution domain. Beyerinck explicitly teaches that both esters (ethyl acetate) and alcohols (methanol, ethanol) are preferred spray drying solvents, and that solvent mixtures are used routinely. The skilled practitioner knows that combining an ester solvent with an alcohol co-solvent is a standard technique for adjusting the solvation power of the spray solution to dissolve both the drug and the polymer, which is a principle well established in the spray drying art. Warashina specifically identifies methyl acetate and ethyl acetate as suitable solvents for HPMCAS-based spray drying and explicitly authorizes their use in combination with methanol and ethanol. The Warashina reference therefore bridges any gap between the Curatolo/Beyerinck teachings and the specific solvent 1 candidates recited in claim 1. There is a direct reason to select methyl acetate or ethyl acetate as a co-solvent when working with HPMCAS, as Warashina and Shi expressly endorses these combinations. Therefore, each element of the combination was known to perform its intended function in the ASD context. The combination of Curatolo's process framework, Beyerinck's solvent guidance, and Warashina's and Shi’s specific solvent list for HPMCAS/HPMC systems yields only predictable results, a spray dried ASD of good quality.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615