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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/08/2026, has been entered.
Claim Rejections - 35 USC § 102-Withdrawn
The rejection of claims 1-19 under 35 U.S.C. 103 as being unpatentable over Ketner of record (WO2008047201A2), as evidenced by Salvatore of record (World J. Chemical Education, 2015), is overcome by the Applicants’ arguments, and is therefore, withdrawn. Specifically, the arguments argue on the grounds that although Ketner discloses that amines (which encompass ammonia), can be used as a base, Ketner fails to suggest or teach, wherein as ammonia is removed, the ammonium salt of the active agent is converted back to its free acid form in the solid dispersion (see page 6 of Remarks). Applicants’ arguments have been fully considered and are found to be persuasive.
Status of the Claims
Claims 1-19 are pending.
Applicants’ arguments, filed on 04/08/2026, have been fully considered. Rejections and/or objections not reiterated from previous Office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claims 1-19 are subject of the Office action below.
Claim Rejections - 35 USC § 103
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.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Ketner of record (WO2008047201A2), as evidenced by Salvatore of record (World J. Chemical Education, 2015), and in view of Takeuchi et al (hereinafter “Takeuchi”, Chem. Pharm. Bull., 1987, 35(9), 3800-3806).
By way of a background, Applicants’ invention is directed to a method of using ammonia as a processing aid in the formation of a sprayed solid dispersion of poorly soluble ionizable drugs (see, e.g., page 1, lines 13-14 of the specification). Ammonia is used to form cationic species (ammonium salt) of the weak-acid active agent, thus, enhancing solubility of the active (see, e.g., page 3, lines 3-7 and page 5, lines 38-40 of the specification).
Under the broadest reasonable interpretation (BRI), consistent with the specification, independent claim 1 is being interpreted as a method for preparing a sprayed solid dispersion comprising:
a) combining:
i) an active agent (in a free acid form, has a pKa ≤ 7 and a solubility ≤ 40 mg/mL in a solvent);
ii) a dispersion polymer (e.g., PVP or HPMC);
iii) an amount of ammonia (sufficient to solubilize the active agent in the solvent); and
iv) a solvent (solvent comprises a C1-C3 alkanol, i.e., methanol, ethanol, propanol),
to form a spray solution;
b) spraying the spray solution to form a sprayed solid dispersion comprising the active agent, the dispersion polymer, and ammonia; and
c) removing residual ammonia from the sprayed solid dispersion to form a product comprising a solid dispersion of the active agent, the dispersion polymer, and ≤500 ppm ammonia.
Note: adding ammonia solves the solubility problem of the poorly soluble ionizable active agent by forming cationic species (ammonium salt) of the active agent.
Similar to the Applicants’ invention, Ketner (see reference claim 14), teaches a process for forming a solid dispersion, comprising:
(a) forming a spray solution comprising a poorly water-soluble ionizable drug, a dispersion polymer, a base, and a solvent;
(b) the neutral form of said drug having:
(i) a solubility of < 1 mg/mL in aqueous solution at a pH of between 6 and 7,
(ii) a solubility of < 20 mg/mL in a volatile organic solvent, and
(iii) an acidic pKa of > 5;
(c) evaporating said solvent to form said solid dispersion, said solid dispersion comprising said drug, a cationic species, and said dispersion polymer;
(d) at least 90 wt% of said drug in said solid dispersion being non-crystalline form; and
(e) said drug, said cationic species and said dispersion polymer constitute at least 80 wt% of said solid dispersion.
Regarding the requirement that the neutral form of active agent, has a pKa of ≤ 7 and a solubility of ≤ 40 mg/mL in a solvent, Ketner discloses pKa of > 5 and a solubility of < 20 mg/mL in a solvent, for the neutral form of the active agent (see discussions above).
A prima facie case of obviousness exists in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" (see MPEP § 2144.05).
In the instant case, because the claimed pKa of ≤ 7 and a solubility of ≤ 40 mg/mL, overlaps or lies inside ranges disclosed by the prior art (see discussions above), a prima facie case of obviousness exists.
Regarding the inventive solid dispersion, Ketner (see pages 10-11), states:
“As described above, drugs suitable for use in this invention are poorly water soluble. Because of this, it is desirable to formulate the drugs ·into solid dispersions to improve solubility and bioavailability. However, because the drugs are poorly soluble in volatile organic solvents, processing the drugs into a solid dispersion by solvent processing can be impractical.
The inventors have found that when a drug of the present invention is present in a pharmaceutically acceptable ionized form, its solubility in volatile organic solvents is significantly increased relative to the neutral form of the drug. This higher solubility leads to improved manufacturability and processing of the compound into an efficacious formulation.” Emphasis added.
Suitable volatile organic solvents include methanol (a C1-alkanol), ethanol (a C2-alkanol), propanol (a C3-alkanol), acetone, mixtures of any of these with water and mixtures thereof (see page 20, lines 5-21).
A wide range of bases may be used to form the ionized form of the drug in a volatile organic solvent and generally, the base should have a pKa of > about 6, more preferably > about 7, and most preferably > about 8 (see page 11, lines 12-18). Suitable bases include but not limited to amines (which encompass ammonia), hydroxides, bicarbonates and oxides (see page 11, lines 19 through page 12, line 2). Suitable cationic species include but not limited to ammonium (see page 12, lines 3-13).
“The amount of base required to be co-dissolved with the drug in the solvent to convert the drug to the ionized form will depend on the properties of the base selected, and in particular with the pKa of the base. Generally, for a strong base (with a pKa of about 9 or greater), one mole of base will convert one mole of the drug to the ionized form. For example, to form a solution in which essentially all of the drug was in the ionized form, equal moles of the drug and a strong base would be co-dissolved in the solvent. In one embodiment, an excess of base is added to the solvent to ensure essentially all of the drug is in the ionized form.” See Ketner at page 21, lines 3-10 (emphasis added).
Suitable polymers include but not limited to polyvinyl pyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) and mixtures thereof (see page 14, line 30 through page 15, line 14).
The removal of, for example, excess ammonia and drying of the spray solution, is a result effective variable that would have been routinely determined and optimized in the art by a person skilled in the art through test series following the requisite guidelines set forth in the prior art disclosure. For example, Ketner (see page 22), states:
“The spray solution can be delivered to the spray nozzle or nozzles at a wide range of temperatures and flow rates. Generally, the spray solution temperature can range anywhere from just above the solvent's freezing point to about 20°C above its ambient pressure boiling point (by pressurizing the solution) and in some cases even higher. Spray solution flow rates to the spray nozzle can vary over a wide range depending on the type of nozzle, spray-dryer size and spray-dry conditions such as the inlet temperature and flow rate of the drying gas. Generally, the energy for evaporation of solvent from the spray solution in a spray-drying process comes primarily from the drying gas.
The drying gas can, in principle, be essentially any gas, but for safety reasons and to minimize undesirable oxidation of the drug or other materials in the solid dispersion, an inert gas such as nitrogen, nitrogen-enriched air or argon is utilized. The drying gas is typically introduced into the drying chamber at a temperature between about 60° and about 300°C and preferably between about 80° and about 240°C.” Emphasis added.
Although Ketner discloses that amines (which encompass ammonia), can be used as a base, and generally, the base should have a pKa of > about 8 (see discussions above), Ketner is not explicit in disclosing an exemplary embodiment of using ammonia as a base.
However, the claimed invention would have been obvious over Ketner, because at the time of the instant invention, it was known in the art that: i) the pKa of ammonia is > about 8; and ii) ammonia can be used in formulation of solid dispersion of poorly water-soluble drugs. For example:
i) Salvatore teaches pKa of ammonia as 9.25 (see page 105); and
ii) Similar to Ketner (see discussions above), Takeuchi teaches a method for using ammonia in the preparation of solid dispersion of poorly water-soluble drug, in order to improve the solubility of the poorly water-soluble drug (see, e.g., abstract, pages 3800-3803 and Figures 1-5). Similar to the Applicants’ invention (see discussions above), Takeuchi teaches that the ammonium salts formed, reverted to their original forms during the spray drying process (see page 3802).
Accordingly, at the time of the instant invention, one skilled in the art would have readily envisaged a process for forming a solid dispersion, comprising:
(a) forming a spray solution comprising a poorly water-soluble ionizable drug, a dispersion polymer, a base (e.g., ammonia), and a solvent (e.g., methanol);
(b) the neutral form of said drug having:
(i) a solubility of < 1 mg/mL in aqueous solution at a pH of between 6 and 7,
(ii) a solubility of < 20 mg/mL in a volatile organic solvent, and
(iii) an acidic pKa of > 5 (e.g., a pKa of ≤ 7);
(c) evaporating said solvent to form said solid dispersion, said solid dispersion comprising said drug, a cationic species that revert to their original forms during the spray drying process, and said dispersion polymer;
(d) at least 90 wt% of said drug in said solid dispersion being non-crystalline form; and
(e) said drug, said cationic species and said dispersion polymer constitute at least 80 wt% of said solid dispersion,
in the Ketner, Salvatore and Takeuchi disclosures.
One skilled in the art would have had a reasonable expectation that: i) the addition of a base (e.g., ammonia), would significantly increase the solubility of the active agent in a volatile organic solvent (e.g., methanol), which would lead to improved manufacturability and processing of the compound into an efficacious formulation; and ii) the ammonium salts form would revert to their original forms during the spray drying process.
Obviousness requires only a reasonable expectation of success, not complete confidence in a given outcome; "at least some degree of predictability" is all that is required. M.P.E.P. § 2143.02.
The prior art can be modified or combined to reject claims as prima facie obvious as long as there is a reasonable expectation of success. See In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (see MPEP § 2143.02).
Therefore, claim 1 is obvious over Ketner, Salvatore and Takeuchi.
Regarding claims 2 and 19, Ketner states:
“The amount of base required to be co-dissolved with the drug in the solvent to convert the drug to the ionized form will depend on the properties of the base selected, and in particular with the pKa of the base. Generally, for a strong base (with a pKa of about 9 or greater), one mole of base will convert one mole of the drug to the ionized form. For example, to form a solution in which essentially all of the drug was in the ionized form, equal moles of the drug and a strong base would be co-dissolved in the solvent. In one embodiment, an excess of base is added to the solvent to ensure essentially all of the drug is in the ionized form.” See Ketner at page 21, lines 3-10 (emphasis added).
Regarding claim 3, Ketner discloses, wherein at 90 wt% of the active agent in the product is in the free acid form (see discussions above) and Takeuchi teaches that the ammonium salts formed, reverted to their original forms during the spray drying process (see discussions above).
Regarding claims 4-5, Ketner discloses solvent selected from the group consisting of the list that include methanol, acetone, ethyl acetate THF and mixtures thereof (see page 20, lines 11-21).
Regarding claim 6, the amount of water and C1-C3 alkanol (e.g., methanol), is a result effective variable that would have been routinely determined and optimized in the art by a person skilled in the art through test series following the requisite guidelines set forth in the prior art disclosure. For example, Ketner discloses that mixtures of solvents can be used, as can mixtures with water, so long as the polymer and the drug are sufficiently soluble to make the spray-drying process practicable (see page 20, lines17-18).
Regarding claim 7, Ketner discloses that addition of a base significantly increases solubility of the active agent relative to the neutral form of the drug (see discussions above). Takeuchi discloses that the dissolution rate from the solid dispersions was markedly improved compared with that from the original or spray-dried drug powder (see abstract).
Regarding claims 8-9, Ketner (see page 18), states:
“The amount of dispersion polymer relative to the amount of drug present in the dispersion of the present invention depends on the characteristics of the polymer and may vary widely from a drug-to-polymer weight ratio of from 0.01 (1 part drug to100 parts polymer) to about 3 (i.e., from 1 wt% drug to 75 wt% drug). Preferably, the drug-to-polymer weight ratio ranges from 0.01 to 2 (from 1 wt% drug to 66 wt% drug), and more preferably from 0.05 to 1 (from 5 wt% drug to 50 wt% drug).” Page 18, lines 17-22 (emphasis added).
“In one embodiment, the solid dispersion comprises at least about 1 wt% drug, or a pharmaceutically acceptable form thereof. In another aspect, the solid dispersion comprises at least about 5 wt%, at least about 1 0 wt%, at least about 15 wt%, at least about 20 wt%, at least about 25 wt%, at least about 30 wt%, at least about 35 wt%, at least about 40 wt%, or at least about 45 wt% drug, or a pharmaceutically acceptable form thereof.” Page 18, lines 23-28 (emphasis added).
Regarding claims 10-15, the removal of, for example, excess ammonia and drying of the spray solution, is a result effective variable that would have been routinely determined and optimized in the art by a person skilled in the art through test series following the requisite guidelines set forth in the prior art disclosure. For example:
i) Ketner (see page 22), states:
“The spray solution can be delivered to the spray nozzle or nozzles at a wide range of temperatures and flow rates. Generally, the spray solution temperature can range anywhere from just above the solvent's freezing point to about 20°C above its ambient pressure boiling point (by pressurizing the solution) and in some cases even higher. Spray solution flow rates to the spray nozzle can vary over a wide range depending on the type of nozzle, spray-dryer size and spray-dry conditions such as the inlet temperature and flow rate of the drying gas. Generally, the energy for evaporation of solvent from the spray solution in a spray-drying process comes primarily from the drying gas.
The drying gas can, in principle, be essentially any gas, but for safety reasons and to minimize undesirable oxidation of the drug or other materials in the solid dispersion, an inert gas such as nitrogen, nitrogen-enriched air or argon is utilized. The drying gas is typically introduced into the drying chamber at a temperature between about 60° and about 300°C and preferably between about 80° and about 240°C.” Emphasis added.
ii) Takeuchi teaches spray drying technique, wherein the ammonium salts formed, reverted to their original forms (see discussions above).
Regarding claims 16-17, Ketner discloses HPMC (see discussions above) and Takeuchi teaches HPMCP (see page 3800).
Regarding claim 18, Ketner discloses that spray solution can include water (see discussions above).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Thus, the claims fail to patentably distinguish over the state of the art as represented by the cited references.
Conclusions
No claim is allowable.
If Applicants should amend the claims, a complete and responsive reply will clearly identify where support can be found in the disclosure for each amendment. Applicants should point to the page and line numbers of the application corresponding to each amendment, and provide any statements that might help to identify support for the claimed invention (e.g., if the amendment is not supported in ipsis verbis, clarification on the record may be helpful). Should the Applicants present new claims, Applicants should clearly identify where support can be found in the disclosure.
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Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IBRAHIM D BORI whose telephone number is (571)270-7020. The examiner can normally be reached on Monday through Friday 8:00AM-5:00PM(EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S LUNDGREN can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IBRAHIM D BORI/
Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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