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 .
Status of the Claims
The amendments and arguments filed on 12/17/2025 are acknowledged and have been fully considered. Claims 1-5, 19, 21-22, 24-28, and 30-36 are now pending. Claims 6-18, 20, 23, and 29 are canceled; claim 2 is amended; claims 32-36 are new.
Claims 1-5, 19, 21-22, 24-28, and 30-36 will be examined on the merits herein.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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, and constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 102
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 1, 4-5, 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Waard (2011).
Waard teaches a method of nano-crystallization comprising dissolving a drug (i.e., API) in a solvent (e.g., ethanol), then mixing with an anti-solvent (e.g., water), then removing the solvents by evaporation to form a dry nanocrystalline drug product (see Waard, page 1221, Bottom-up techniques, paragraph 3). While Waard does mention the use of a stabilizer, it is taught that it can be used and is not necessary (see Waard, page 1221, Bottom-up techniques, paragraph 3).
Response to Arguments
Applicant's arguments filed 12/17/2025 have been fully considered but they are not persuasive.
In regards to applicant’s arguments that the reading Waard is incorrect and not the natural way to read the passage, it is pointed out that the Waard clearly states that “To stabilize the nanocrystals, a carrier (e.g. gelatin) can be dissolved in the aqueous phase” (emphasis added) (see Waard, page 1221, Bottom-up techniques, paragraph 3). The use of “can be” would lead one with ordinary skill in the art to easily envisage a method that does not use a carrier (i.e., a stabilizer). Whether the reading of the art is the most natural or not, would be a matter of opinion and the rejection is based on the language of the prior art. If a carrier can be dissolved, it is also understood that can not be added as well. Further, the expression comprising of the claim’s language permits the presence of carrier, and other ingredient, active or inactive, even in major amounts.
Applicant further argues that List doesn’t teach examples of the method without a stabilizer and that Waard is summarizing the teachings of List, however the passage is not understood as a summary of List, rather a summary of the method (which can use a carrier or not) that was introduced in List originally in 1988. It would be within the understanding of one with ordinary skill in the art before the effective filing date of the instant application, that the original method of List may have been changed or improved on from the time of its publication to the time of Waard’s publication and as such would allow for a method without the use of a stabilizer.
In regards to applicant’s argument that the powder formed is in a nanostructured form, and that List and Waard do not teach this, first the rejection is made over Waard only in this case. While the teachings of List might be relevant, it is noted that Waard directly teaches a dry nanocrystalline drug product (see Waard, page 1221, Bottom-up techniques, paragraph 3).
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 1-5, 21, 24-28, and 30-36 are rejected under 35 U.S.C. 103 as being unpatentable over Waard (2011) in view of GB 2200048 A (List, 1988).
The teachings of Waard have been described supra.
Waard is silent on the API antisolvent to API solvent volume ratio, what the API is, the third mixture being a suspension, and the size of the nanocrystals.
List teaches a method of formulating solid particles of an active substance (see List, page 1, paragraph 4). The method comprises preparing a solution of the active agent in a solvent, such as alcohol like ethanol or isopropanol, and mixing the solution with water (i.e., an anti-solvent) (see List, page 10, final paragraph). The anti-solvent and solvent are then removed via evaporation in a rotary evaporator (see List, page 11, paragraphs 3-5).
In regard to claims 3 and 26, the active agent is taught to be cyclosporin A (i.e., cyclosporine) (see List, page 3, paragraph 5).
In regard to claims 2, 17, 25, 31, and 35, in Example 1, it is taught that the amount of ethanol used is 40 mL and the amount of water used is 200 mL (see List, page 13, example 1). The anti-solvent to solvent ratio is 200:40 or 5. “A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties.").” One with ordinary skill in the art would reasonably expect that a composition comprising an anti-solvent to solvent ratio of 5 would have the same properties as a composition comprising an anti-solvent to solvent ratio of 5.5.
In regard to claim 21, 32-34, and 36, the mixture of the solvent and water is taught to be a suspension (see List, page 11, paragraph 1). It is taught that the anti-solvent and solvent are then removed via evaporation in a rotary evaporator (see List, page 11, paragraphs 3-5). Further, it is taught that the size of the nanoparticles formed from the method are from about 1 nm to about 10000 nm (i.e., 10 µm) (see List, page 1, paragraph 2). Further in Example 1, it is taught that particle that were larger than 5µm were also formed (see page 13, example 1). MPEP 2144.05 states that "[i]n the case where the claimed ranges 'overlap or lie inside ranges disclosed by the prior art' a prima facie case of obviousness exists" quoting In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
In regards to claims 1-5, 21, 24-28, and 30-36, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to formulate a method as instantly claimed as the teaching of Waard and List have similar methods of formulating nanoparticles. It would be obvious to one with ordinary skill in the art to combine the teachings of List with Waard as the method of Waard does not include specific measurements of the solvent and anti-solvent and as such would look to the method of List for these to yield predictable results with a reasonable expectation of success. One with ordinary skill in the art would be motivated to combine prior art elements according to known methods to yield predictable results.
Further, in regards to the use of a stabilizer in List, it is pointed out that while List does teach the use of a stabilizer, it is taught that it is “preferably added” to prevent the size of larger particles and is not a mandatory component of the method (see List, page 7, paragraph 4).
Claims 1-5, 21, 24-28, and 30-36 are rejected under 35 U.S.C. 103 as being unpatentable over Waard (2011) in view of GB 2200048 A (List, 1988) and Chen (2017).
While it is the examiner’s position that the rejection of claims 1-5, 21, 24-28, and 30-36 over Waard in view of List, this rejection is included in the interest in compact prosecution.
The teachings of Waard have been described supra.
Waard is silent on the API antisolvent to API solvent volume ratio, what the API is, the third mixture being a suspension, and the size of the nanocrystals.
The teachings of List have been described supra.
Chen teaches a method of antisolvent crystallization using ethanol as the solvent for an active pharmaceutical ingredient (API) and water as an anti-solvent and 0 g of PEG4000 (i.e., a stabilizer) (see Chen, page 225, preparation of samples by anti-solvent crystallization). The ratio of water to ethanol is 40:6, which is 6.6 (see Chen, page 225, preparation of samples by anti-solvent crystallization). This anti-solvent to solvent ratio overlaps with the instant claims. MPEP 2144.05 states that "[i]n the case where the claimed ranges 'overlap or lie inside ranges disclosed by the prior art' a prima facie case of obviousness exists" quoting In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
In regards to claims 32-34 and 36, it is noted as the size of the nanocrystals is known to affect the final composition’s properties such as solubility (i.e., having a better dissolution rate and better bioavailability (see Chen, page 224, introduction, paragraph 2)) (see Chen, introduction, paragraph 1), the solubility, dissolution rate and bioavailability are variables that can be modified, among others, by adjusting the size of the nanocrystals, solubility increasing as size is decreased, the size of the nanocrystals would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed size of the nanocrystals cannot be considered critical. Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, the size of the nanocrystals in Chen to obtain the desired balance between the solubility as taught by Chen (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223). “[W]here 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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
In regards to claims 1-5, 21, 24-28, and 30-36, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to formulate a method as instantly claimed as the teaching of Waard, List, and Chen have similar methods of formulating nanocrystals of APIs. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would be obvious to one with ordinary skill in the art to combine the teachings of List and Chen with Waard as the method of Waard does not include specific measurements of the solvent and anti-solvent and as such would look to the methods of List and Chen for these to yield predictable results with a reasonable expectation of success. One with ordinary skill in the art would be motivated to combine prior art elements according to known methods to yield predictable results.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Waard (2011) in view of GB 2200048 A (List, 1988) and Chen (2017) as applied to claims 1-5, 21, 24-28, and 30-36 above, and further in view of “Etoposide” (Sigma, 1996; as submitted on PTO-892 of 02/01/2024).
The teachings of Waard, List, and Chen have been described supra.
The teachings of Waard, List, and Chen are silent on the API being etoposide.
Sigma teaches that etoposide is known to have poor solubility but is soluble in organic solvents such as ethanol and methanol (see Sigma, solubility).
In regards to claim 19, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to formulate a method as instantly claimed using etoposide as the method of Waard, List, and Chen is used with active agents that have poor water solubility (see List, pages 2-3). As etoposide is also known for having poor solubility, it would be obvious to one with ordinary skill in the art to modify the teachings of Waard, List, and Chen with Sigma (i.e., substituting simvastatin with etoposide) in order to increase the bioavailability and dissolution rate of the etoposide. It would have been prima facie obvious to one with ordinary skill in the art to combine the teachings of Sigma with Waard, List, and Chen according to the method of Waard, List, and Chen to yield predictable results with a reasonable expectation of success. One with ordinary skill in the art would be motivated to combine prior art elements according to known methods to yield predictable results.
Claims 22 is are rejected under 35 U.S.C. 103 as being unpatentable over Waard (2011) in view of GB 2200048 A (List, 1988) and Chen (2017) as applied to claims 1-5, 21, 24-28, and 30-36 above, and further in view of Joye (2013).
The teachings of Waard, List, and Chen have been described supra.
The teachings of Waard, List, and Chen are silent on the API being concentration being between 1mg/mL and 3mg/mL in the first solution.
Joye discusses various factors that can affect the production of nanoparticles using liquid anti-solvent precipitation (see Joye, abstract; page 116, important parameters). Joye teaches that the compound concentration in the initial solution has been found to be important in the formation of particles (see page 116, Compound concentration). It is taught that a higher solution concentration leads to the formation of more and smaller nuclei but also the nuclei growth will be promoted, while also increasing viscosity leading to non-uniform supersaturation, slower nucleation rates, and increased particle agglomeration (see Joy, page 116, Compound Concentration).
In regard to claim 22, the viscosity and particle size of the nanoparticles are variables that can be modified and have an effect on the final product, among others, by adjusting the concentration of the compound, viscosity and particle size of the nanoparticles changing as concentration of the compound is changed, the concentration of the compound would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed concentration of the compound cannot be considered critical. Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, concentration of the compound in Waard, List, and Chen to obtain the desired balance between the viscosity and particle size of the nanoparticles as taught by Joye (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223). “[W]here 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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
Response to Arguments
Applicant's arguments filed 12/17/2026 have been fully considered but they are not persuasive in view of the new grounds of rejection as necessitated by amendment.
In regards to applicant’s arguments against the references Waard and List, most of the arguments have been addressed above and as such, only the points that have not been addressed yet will be rebutted below.
Applicant argues that a carrier (i.e., a stabilizer) is used when a dry structure is obtained in List, however the rejection is made in view of Waard and List. As discussed above, the teachings of Waard do not require a carrier and as such one with ordinary skill in the art would be able to envisage a method as instantly claimed using the teachings of Waard and List. Further applicant mentions that List teaches that a carrier is used when drying, however Waard teaches that the carrier is optional when used to produce a dry nanocrystalline drug product (see Waard, page 1221, Bottom-up techniques, paragraph 3). The expression comprising of the claim’s language permits the presence of carrier, and other ingredient, active or inactive, even in major amounts.
Further, the teachings of Chen have been described and detailed above as a similar method of anti-solvent precipitation of nanocrystals without the use of a stabilizer clearly. This addresses the applicant’s notes that List and Waard fail to provide any alternative to achieve stabilization of they particles as Chen shows that a stabilizer is not needed for the method to produce stable nanocrystals.
In regards to applicant’s arguments that Waard and List fail to teach method of drying a mixture to obtain a nanostructured powder that includes nanocrystalline agglomerates, it is pointed out that Waard teaches that the method comprises a step of removing the solvents by evaporation or lyophilization to formulate small particles (i.e., a powder) of dry nanocrystalline drug product (see Waard, page 1221, Bottom-up techniques, paragraph 3).
In regards to applicant’s arguments that the particle size is not taught in Waard or List, it is pointed out that the List teaches that the size of the nanoparticles formed from the method are from about 1 nm to about 10000 nm (i.e., 10 µm) (see List, page 1, paragraph 2). Further with the teachings of Chen, it is noted as the size of the nanocrystals is known to affect the final composition’s properties such as solubility (i.e., having a better dissolution rate and better bioavailability (see Chen, page 224, introduction, paragraph 2)) (see Chen, introduction, paragraph 1), the solubility, dissolution rate and bioavailability are variables that can be modified, among others, by adjusting the size of the nanocrystals, solubility increasing as size is decreased, the size of the nanocrystals would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed size of the nanocrystals cannot be considered critical. Accordingly, one of ordinary skill in the art before the effective filing date of the invention would have optimized, by routine experimentation, the size of the nanocrystals in Chen to obtain the desired balance between the solubility as taught by Chen (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223). “[W]here 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.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
In regards to applicant’s argument that the art does not teach the instant antisolvent to solvent ratio, Chen teaches that ethanol is the solvent and water is the anti-solvent (see Chen, page 225, preparation of samples by anti-solvent crystallization). The ratio of water to ethanol is 40:6, which is 6.6 (see Chen, page 225, preparation of samples by anti-solvent crystallization). This anti-solvent to solvent ratio overlaps with the instant claims. MPEP 2144.05 states that "[i]n the case where the claimed ranges 'overlap or lie inside ranges disclosed by the prior art' a prima facie case of obviousness exists" quoting In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Isis A Ghali/Primary Examiner, Art Unit 1611
/A.A.A./ Examiner, Art Unit 1611
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