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 .
This Office Action is in response to Applicant’s amendment filed May 27, 2026. Claims 36-45, 48-50 and 52-58 are pending in the application. Claims 46, 47, and 51 have been canceled. Claims 36 and 41 have been amended. Claims 56-58 are newly added. Claims 36-45, 48-50 and 52-58 will be examined.
Status of the Claims
The rejection of claims 36-50 and 52-55 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn due to Applicant’s amendment to claims 36 and 41.
The rejection of claims 36-47 and 52-55 under 35 U.S.C. 103 as being unpatentable over Beyerinck et al. (WO 2008/065506, pub. 06/05/2008) as evidenced by the Sodium Caseinate Publication (2025, Allinno.com) in view of Baumstuemmler et al. (US 2013/0012551, pub. 01/10/2013) is withdrawn due to Applicant’s amendment to independent claim 1 to add the limitation of “buffered acetate, phosphate, or citrate” aqueous solution”.
The rejection of claims 43, 48, 49, and 50 under 35 U.S.C. 103 as being unpatentable over Beyerinck et al. (WO 2008/065506, pub. 06/05/2008) as evidenced by the Sodium Caseinate Publication (2025, Allinno.com) in view of Baumstuemmler et al. (US 2013/0012551, pub. 01/10/2013) as applied to claims 36-47 and 52-55 above, and further in view of Lorenz (US 2020/0060976, filed 04/01/2019, equivalent to WO 2014/043208, cited on IDS) is withdrawn due to Applicant’s amendment to independent claim 1 to add the limitation of “buffered acetate, phosphate, or citrate” aqueous solution”.
Rejections not reiterated from the previous Office Action are hereby withdrawn. The following rejections are newly applied. They constitute the complete set of rejections presently being applied to the instant application.
New Rejections Necessitated by Amendment filed May 27, 2026
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 36-42, 44-45, 48-50, and 52-58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention.
While all of the factors have been considered, only those required for a prima facie case are set forth below.
The claims are drawn to: A method for producing nanoparticles comprising an active ingredient and hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein a volume of water is needed to dissolve 1 g of the active ingredient is at least 30 mL, the method comprising the steps of: a) providing an organic solution of the active ingredient and the HPMCAS in an organic solvent, wherein the organic solvent selected from the group consisting of acetone, tetrahydrofuran, ethanol, methanol, dichloromethane, and mixtures thereof; b) providing an aqueous solution having a pH of 5 to 8; and c) mixing the organic solution with a buffered acetate, phosphate, or citrate aqueous solution to precipitate the nanoparticles; wherein the organic solution is provided in the form of a first fluid stream, the aqueous solution is provided in the form of a second fluid stream, wherein the mixing includes directing the first and second fluid stream to contact one another; wherein each of the first and second stream is ejected from a nozzle, and wherein the fluid streams are directed to impinge on one another; wherein in step c) the ratio of the volume of the buffered acetate, phosphate, or citrate aqueous solution to the volume of the organic solution is at least 1.
Applicant does not have sufficient written description for every active ingredient wherein a volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claim indicates that these claims are drawn to a genus of active ingredients wherein a volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL.
The disclosure of a single disclosed species may provide an adequate written description of a genus when the species disclosed is representative of the genus. The present claim encompasses any and all active ingredients wherein a volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL. There is substantial variability among the species of every active ingredients wherein a volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL encompassed within the scope of the claims. Defining the active ingredient in functional terms would not suffice in the absence of a disclosure of structural features or elements of the basic substance that would have the stated function. Applicant is describing what the active ingredient does rather than what it is. Describing an active ingredient or compound by its functions will not substitute for written description of the structure of the compound. The invention should be explained in such a way as to describe what the invention is, not what the invention does. Describing the function of an active ingredient or compound fails to distinguish the compound from other molecules or agents that can perform the same functions.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). Consequently, the Examiner notes that the claimed invention which is drawn to a genus of active ingredients may be adequately described if there is a (1) sufficient description of a representative number of species, or (2) by disclosure of relevant, identifying characteristics sufficient to describe the claimed invention in such full, clear, concise and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. Here, the specification discloses that enzalutamide, itraconazole, aprepitant, or furosemide can be the active ingredient (page 16, examples 6 to 8 and page 17, Examples 9 to 13 and the specific active ingredients claimed in claim 43). Since the claimed genus encompasses active ingredients yet to be discovered, the disclosed structural features does not constitute a substantial portion of the claimed genus.
Weighing all the factors, the breadth of the claims reading on basic substances yet to be discovered, the lack of correlation between structure and function of the basic substances, level of knowledge and skill in the art, one of ordinary skill in the art would not recognize from the disclosure that the applicant was in possession of the genus of active ingredients wherein a volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL.
The written description requirement is not satisfied.
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.
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.
Claims 36-45, 48-50, and 52-58 are rejected under 35 U.S.C. 103 as being unpatentable over Beyerinck et al. (WO 2008/065506, pub. 06/05/2008) as evidenced by the Sodium Caseinate Publication (2025, Allinno.com) in view of Lorenz (US 2020/0060976, filed 04/01/2019, equivalent to WO 2014/043208, cited on IDS) and Baumstuemmler et al. (US 2013/0012551, pub. 01/10/2013). Beyerinck et al. cited by Applicant on the IDS dated 11/16/2021.
Applicant’s Invention
A method for producing nanoparticles comprising an active ingredient and hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein a volume of water is needed to dissolve 1 g of the active ingredient is at least 30 mL, the method comprising the steps of: a) providing an organic solution of the active ingredient and the HPMCAS in an organic solvent, wherein the organic solvent selected from the group consisting of acetone, tetrahydrofuran, ethanol, methanol, dichloromethane, and mixtures thereof; b) providing an aqueous solution having a pH of 5 to 8; and c) mixing the organic solution with a buffered acetate, phosphate, or citrate aqueous solution to precipitate the nanoparticles; wherein the organic solution is provided in the form of a first fluid stream, the aqueous solution is provided in the form of a second fluid stream, wherein the mixing includes directing the first and second fluid stream to contact one another; wherein each of the first and second stream is ejected from a nozzle, and wherein the fluid streams are directed to impinge on one another; wherein in step c) the ratio of the volume of the buffered acetate, phosphate, or citrate aqueous solution to the volume of the organic solution is at least 1.
Determination of the scope of the content of the prior art
(MPEP 2141.01)
Regarding claim 36, Beyerinck et al. teach a process for forming nanoparticles, comprising a) forming an organic solution comprising the compound (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (Compound A) and an enteric polymer dissolved in a solvent; (b) forming an aqueous solution; (c) mixing said organic solution with said aqueous solution to form a first mixture; (d) removing said solvent from said first mixture to form a suspension comprising said nanoparticles and said aqueous solution (pg. 1, line 26; pg. 18, claim 15).
Regarding claim 36, Beyerinck et al. teach that once the organic solution is formed, it is then mixed with the aqueous solution and homogenized to form an emulsion of fine droplets of the water immiscible solvent distributed throughout the aqueous phase. The volume ratio of organic solvent to aqueous solvent used in the process will generally range from 1:100 (organic solvent:aqueous solution) to 2:3 (organic solvent: aqueous solution). Preferably, the organic solvent:aqueous solution volume ratio ranges from 1:9 to 1:2 (organic solvent:aqueous solution)(pg. 7, lines 39-41-pg. 8, lines 1-3; pg. 9, lines 3-9).
Regarding claim 38, the solution was further emulsified using a Microfluidizer (Microfluidics) (pg. 11, lines 33-41).
Regarding claim 40, Beyerinck et al. teach compound A is present in the nanoparticles in non-crystalline form, wherein another term form non-crystalline form of a material is the “amorphous” form (page 4, lines 3-10).
Regarding claim 41, Beyerinck et al. teach the average size of the nanoparticles is less than 400 nm…most preferably less than 200 nm (page 2, lines 36-37).
Regarding claim 41,Beyerinck et al. teach the polydispersity of the nanoparticles is less than 0.5…more preferably less than about 0.3 (page 3, lines 1-4).
Regarding claim 42, Beyerinck et al. teach the nanoparticles are small particles of Compound A and the polymer, with each particle containing Compound A and the enteric polymer (page 2, lines 31-32).
Regarding claims 36 and 43, Beyerinck et al. teach in Example 1 the nanoparticles were made containing Compound A, hydroxypropyl methylcellulose acetate succinate and sodium caseinate as a surface stabilizer. First, Compound A and HPMCAS was dissolved in ethyl acetate:methylene chloride to form an organic solvent. Next sodium caseinate was added to deionized water to form an aqueous solution. Sodium caseinate has a neutral pH of approximately 7.0, as evidenced by the Sodium Caseinate Publication (pg. 1, PH section). The organic solution was then poured into the aqueous solution and emulsified using a Kinematica Polytron rotor/stator.
Regarding claims 44 and 45, Beyerinck et al. teach the composition of the invention comprises nanoparticles, wherein the nanoparticles comprise at least 20 wt.% Compound A, at least 45 wt.% of the enteric polymer, and at least 20 wt.% sodium caseinate, wherein the enteric polymer is hydroxypropyl methylcellulose acetate succinate (pg. 10, lines 21-24).
Regarding claim 46, Beyerinck et al. teach exemplary solvents include acetone, tetrahydrofuran, ethanol, and methanol (page 8, lines 27-29).
Beyerinck et al. teach the aqueous solution is preferably water (pg. 8, lines 33-34).
Regarding claim 50, Beyerinck et al. teach that non-ionic surfactants can be surface stabilizers (pg. 7, lines 1-11). Beyerinck et al. teach polyoxyethylene sorbitan fatty acid esters (polysorbates) as a surface stabilizer (pg. 7, line 19; claims 11-12).
Regarding claim 52, the nanoparticle suspension of Example 1 was spray-dried (pg. 12, lines 17-33).
Regarding claim 52, Beyerinck et al. teach the precipitation process result in the formation of a suspension of the nanoparticles in the aqueous solution. Exemplary processes for removing at least a portion of the liquids include spray drying (pg. 9, lines 26-29).
Beyerinck et al. teach the solvent solution and aqueous solution are combined under conditions that cause solids to precipitate as nanoparticles. The mixing can be by addition of a stream of organic solvent to a container of stirred aqueous solution. Alternatively, a stream or jet of organic solvent can be mixed with a moving stream of aqueous solution. In either case, the precipitation results in the formation of a suspension of nanoparticles in the aqueous solution (pg. 8, lines 35-39).
Beyerinck et al. teach in Example 4, nanoparticles containing Compound A were prepared using a precipitation method as follows. First , a water-miscible organic solvent was formed using Compound A, HPMCAS-L and methanol. The methanol solution was pumped through a tube. The tube was located inside another tube through which was fed purified water. This resulted in the formation of a suspension of nanoparticles in the water/methanol liquid. An aqueous solution containing sodium caseinate was added to this suspension to form a Compound A/polymer/sodium caseinate nanoparticle suspension. The pH of the suspension was adjusted to a pH of 7 with an aqueous solution containing sodium hydroxide (pg. 14, lines 28-28-pg. 15, lines 1-2)
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
Beyerinck et al. do not specifically disclose a buffered acetate, phosphate, or citrate aqueous solution; the aqueous solution having a pH of 5 to 8, as claimed in claim 36; the method steps of claim 36 c), claims 38, 39, 53, 54, and 55; the elected active ingredient species, enzalutamide; or the buffered aqueous solution comprises acetate buffer, as claimed in claim 48 and dependent claims 49 and 50. It is for this reason Baumstuemmler et al., the Sodium Caseinate Publication, and Lorenz are added as secondary references.
Baumstuemmler et al. teach a method for producing microparticles or nanoparticles of water-soluble and water-insoluble substances by controlled precipitation, co-precipitation and self-organization processes in microjet reactors, a solvent, which contains at least one target molecule, and a nonsolvent being mixed as jets that collide with each other in a microjet reactor at defined pressures and flow rates to effect very rapid precipitation, co-precipitation or a chemical reaction, during the course of which microparticles or nanoparticles are formed (abstract, pg. 1, paragraph [0001], pg. 5, claim 1).
Regarding claim 36, element claim c) and claim 38, Baumstuemmler et al. teach a device for producing microparticles or nanoparticles of water-soluble and water-insoluble substances, said device having at least two nozzles each of which has its own pump and feed line for injecting one liquid medium in each case into a reactor chamber enclosed in a reactor housing and on to a shared collision point, the reactor housing being provided with a first opening through which a gas can be introduced so as to maintain the gaseous atmosphere within the reactor, notably at the collision point of the two impinging liquid jets, and to cool the resulting products, and a further opening for removing the resulting products and excess gas out of the reactor housing (pg. 1, paragraph [0002], pg. 2, paragraphs [0030-0032]).
Regarding claim 39, Baumstuemmler et al. teach the term “precipitation reactor” or “microjet reactor” include all of geometries of EP1165224 (pg. 3, paragraph [0039]). Baumstuemmler et al. teach a microjet reactor of this kind has at least two nozzles each of which has its own pump and feed line for injecting one liquid medium in each case into a reactor chamber enclosed in a reactor housing and on to a shared collision point, the reactor housing being provided with a first opening through which a gas, an evaporating liquid, a cooling liquid or a cooling gas can be introduced so as to maintain the gaseous atmosphere within the reactor, notably at the collision point of the two liquid jets, and to cool the resulting products, and a further opening for removing the resulting products and excess gas out of the reactor housing...with excess gas are removed from the reactor housing through an opening by positive pressure on the gas input side or negative pressure on the product and gas discharge side (pg. 1, paragraph [0018]; pg. 6, claim 6).
Regarding claims 41 and 58, Baumstuemmler et al. teach auxiliary agents or surface modifiers, the resulting particles with polydisperse indices generally below 2.0, preferably below 1.0 and most preferably below 0.4 (pg. 4, paragraph [0064]). Baumstuemmler provides examples where the PDI ranges from 0.100 to 0.182 (see Fig. 3).
Regarding claim 46, Baumstuemmler et al. teach suitable organic solvents include, readily water-miscible substances such as ethanol, methanol, tetrahydrofuran (pg. 4, paragraph [0071]).
Regarding claim 53, Baumstuemmler teaches that solvent and nonsolvent streams with flow rates exceeding 0.1 mL/min collide as impinging jets at a speed preferably greater than 1 m/s, more preferably greater than 50 m/s, and a Reynolds number of more than 100, preferably more than 500 (pg. 3, paragraph [0059]).
Regarding claim 54, Baumstuemmler et al. teach solvent and nonsolvent are formed in nozzles to jets which are preferably smaller than 1,000 µm, more preferably smaller than 500 µm and best of all smaller than 300 µm and have pressures generally of 1 bar, preferably in excess of 10 bar and even more preferably in excess of 50 bar, the pressure being controlled in this method by a pressure regulator (pg. 3, paragraph [0059]).
Regarding claim 55, Baumstuemmler et al. teach that in the disc-edge area, very rapid mixing occurs at mixing speeds generally below 1 millisecond, frequently below 0.5 ms and mostly below 0.1 ms ( pg. 4, paragraph [0060]).
Lorenz et al. teach formulations of enzalutamide and their use for treating hyperproliferative disorders (abstract). Lorenz discloses a solid dispersion having the properties such as improvement solubility and absorption of enzalutamide, and a pharmaceutical composition containing the solid dispersion which has dissolution stability (pg. 2, paragraph [0016], pg. 28, claims 83 and 92). Lorenz et al. teach that the amorphous (i.e., in a non-crystalline state) enzalutamide may be prepared by any known means, including spray-drying, hot melt extrusion, and precipitation from solution on addition of a non-solvent (pg. 2, paragraphs [0020-0022], [0030], pg. 3, paragraph [0032]). Lorenz teaches enzalutamide amorphous enzalutamide particles (pg. 3, paragraph [0034]). Lorenz et al. provide examples with 2-fluid spray nozzle feeds with HPMCAS (pg. 16, [0181], Table 2.1).
Lorenz et al. teach HPMCAS as an exemplary cellulosic polymer that is at least partially ionized at physiologically relevant pH(s) (pg. 6, paragraph [0064]). Lorenz et al. focus on HPMCAS as one out of three hydrophobic polymers showing the best performance in vitro dissolution values (pg. 7, paragraphs [0067-0068], [0071-0072]). Lorenz et al. teach that dispersions comprise greater than 20wt % and less than 75wt % enzalutamide (pg. 2, paragraph [0031]).
Regarding claim 45 (i.e., active in the organic solution does not exceed HPMCAS), Lorenz et al. teach spray solution was prepared by dissolving 1 wt.% enzalutamide and 3 wt.% HPMCAS-M in acetone (pg. 16, paragraph [0180] Example 2).
Regarding claim 46, Lorenz et al. teach acetone (page 16, paragraph [0180] Example 2).
Regarding claim 48, Lorenz et al. teach sodium acetate as an additional pH modifier to enhance the rate of dissolution (pg. 12, paragraph [0122]). Lorenz et al. teach polysorbate as a surfactant (pg. 12, paragraph [0133]).
Regarding claims 49 and 50, Lorenz et al. teach suitable surfactants include polysorbate-80 and polysorbate-20 and phospholipids (pg. 11, paragraph [0121]).
Finding a prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to combine the teachings of Beyerinck et al., as evidenced by the Sodium Caseinate Publication, Baumstuemmler et al. and Lorenz et al. and use a buffered acetate, phosphate or citrate in the compositions. One of ordinary skill in the art would have been motivated to use acetate buffer as the buffered aqueous solution in the compositions taught by Beyerinck et al, as modified by the Sodium Caseinate Publication. Beyerinck et al. teach a process for forming nanoparticles, comprising a) forming an organic solution comprising the Compound A and an enteric polymer dissolved in a solvent; (b) forming an aqueous solution; (c) mixing said organic solution with said aqueous solution to form a first mixture; (d) removing said solvent from said first mixture to form a suspension comprising said nanoparticles and said aqueous solution. Beyerinck et al. teach various methods of producing the nanoparticles with different aqueous solutions including an aqueous solution containing sodium caseinate which was added to this suspension to form a Compound A/polymer/sodium caseinate nanoparticle suspension. The pH of the suspension was adjusted to a pH of 7 with an aqueous solution containing sodium hydroxide. It would have been obvious to one of ordinary skill to substitute a known pH modifiers in the compositions, such as sodium acetate to enhance the dissolution of the composition, with a reasonable expectation of success.
In addition, one of ordinary skill in the art would have been motivated to use a combination of an acetate buffer and the claimed surfactants in claims 49 and 50 in the nanoparticles. Beyerinck et al. teach polyoxyethylene sorbitan fatty acid esters (polysorbates) as a surface stabilizer. Lorenz et al. teach the same surfactants, polysorbates, are used in the composition. As such, it would have been obvious to one of ordinary skill in the art to use known surfactants in the nanoparticle compositions.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to combine the teachings of Beyerinck et al., as evidenced by the Sodium Caseinate Publication, Baumstuemmler et al. and Lorenz et al. and know that the pH of the aqueous solution has a pH of 5 to 8, as claimed in claim 36. Beyerinck et al. teach in Example 1 the nanoparticles were made containing Compound A, hydroxypropyl methylcellulose acetate succinate and sodium caseinate as a surface stabilizer. First, Compound A and HPMCAS was dissolved in ethyl acetate:methylene chloride to form an organic solvent. Next sodium caseinate was added to deionized water to form an aqueous solution. Sodium caseinate has a neutral pH of approximately 7.0, as evidenced by the Sodium Caseinate Publication. Therefore, it would have been obvious to one of ordinary skill in that art that the sodium caseinate in an aqueous solution has a pH of 7, which falls within the pH range of claim 36.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to combine the teachings of Beyerinck et al., as evidenced by the Sodium Caseinate Publication, Baumstuemmler et al. and Lorenz et al. and use the method steps of claim 36 c), claims 38, 39, 53, 54, and 55. Beyerinck et al. teach a process for forming nanoparticles, comprising a) forming an organic solution comprising the compound (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (Compound A) and an enteric polymer dissolved in a solvent; (b) forming an aqueous solution; (c) mixing said organic solution with said aqueous solution to form a first mixture; (d) removing said solvent from said first mixture to form a suspension comprising said nanoparticles and said aqueous solution. Beyerinck et al. teach that HPMCAS is the preferred enteric polymer, as taught in the examples. Beyerinck et al. teach the precipitation process result in the formation of a suspension of the nanoparticles in the aqueous solution. Beyerinck et al. teach the solvent solution and aqueous solution are combined under conditions that cause solids to precipitate as nanoparticles. Baumstuemmler et al. teach a device for producing microparticles or nanoparticles of water-soluble and water-insoluble substances, said device having at least two nozzles each of which has its own pump and feed line for injecting one liquid medium in each case into a reactor chamber enclosed in a reactor housing and on to a shared collision point, the reactor housing being provided with a first opening through which a gas can be introduced so as to maintain the gaseous atmosphere within the reactor, notably at the collision point of the two impinging liquid jets, and to cool the resulting products, and a further opening for removing the resulting products and excess gas out of the reactor housing. Since Beyerinck et al. teach that a stream or jet of organic solvent can be mixed with a moving stream of aqueous solution and that the precipitation results in the formation of a suspension of nanoparticles in the aqueous solution, one of ordinary skill in the art would have been motivated to use the precipitation process taught by Baumstuemmler et al. to form the nanoparticles taught in Beyerinck et al., with a reasonable expectation of success, as a person with ordinary skill has good reason to pursue known options within his or technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex lnc. 82 USPQ 2d 1385 (Supreme Court 2007).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to combine the teachings of Beyerinck et al., as evidenced by the Sodium Caseinate Publication, Baumstuemmler et al., and Lorenz et al. and formulate a composition comprising enzalutamide as the active ingredient. Beyerinck et al. teach a process for forming nanoparticles, comprising a) forming an organic solution comprising the Compound A and an enteric polymer dissolved in a solvent; (b) forming an aqueous solution; (c) mixing said organic solution with said aqueous solution to form a first mixture; (d) removing said solvent from said first mixture to form a suspension comprising said nanoparticles and said aqueous solution. Beyerinck et al. teach that HPMCAS is the preferred enteric polymer, as taught in the examples. One of ordinary skill in the art would have been motivated to try a different pharmaceutical active in the methods taught by Beyerinck et al., as modified by the Sodium Caseinate Publication and Baumstuemmler et al. Lorenz et al. teach that enzalutamide is a sparingly soluble compound. Lorenz et al. further teach preparing compositions comprising enzalutamide with the same enteric polymer used in the formulations of Beyerinck et al., HPMCAS, in an organic acid that has dissolution stability. As such, one of ordinary skill in the art would have motivated to use a different sparingly soluble compound in the methods taught by Beyerinck et al. and Baumstuemmler et al. to form nanoparticles of enzalutamide with a reasonable expectation of success.
Regarding the limitation of wherein a volume of water is needed to dissolve 1 g of the active ingredient is at least 30 mL, Beyerinck et al. teach the compound, torcetrapib, is a poorly water soluble lipophilic compound. Based on this teaching one of ordinary skill in the art would have found it obvious that torcetrapib would have the property claimed. In addition, regarding the elected species of enzalutamide, by Applicant’s own admission, it has the properties currently claimed.
Therefore, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made because every element of the invention has been fairly suggested by the cited references.
Response to Arguments
Applicant argues that Beyerinck, the Sodium Caseinate Publication, and Baumstuemmler does not disclose or suggest all of the limitations of the presently amended claims, specifically the limitations 1) “wherein the volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL”; and 2) “wherein in step c) the ratio of the volume of the buffered acetate, phosphate, or citrate aqueous solution to the volume of the organic solution is at least 1”. In response to Applicant’s argument, Beyerinck et al. teach the compound, torcetrapib, is a poorly water soluble lipophilic compound. Based on this teaching one of ordinary skill in the art would have found it obvious that torcetrapib would have the property claimed, as poorly water soluble lipophilic compounds have the claimed property. In addition, regarding the elected species of enzalutamide, by Applicant’s own admission, it has the properties a volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL.
Regarding Applicant’s argument of “wherein in step c) the ratio of the volume of the buffered acetate, phosphate, or citrate aqueous solution to the volume of the organic solution is at least 1”, Beyerinck et al. teach that once the organic solution is formed, it is then mixed with the aqueous solution and homogenized to form an emulsion of fine droplets of the water immiscible solvent distributed throughout the aqueous phase. The volume ratio of organic solvent to aqueous solvent used in the process will generally range from 1:100 (organic solvent:aqueous solution) to 2:3 (organic solvent: aqueous solution). Preferably, the organic solvent:aqueous solution volume ratio ranges from 1:9 to 1:2 (organic solvent:aqueous solution), which falls within the range of at least 1, 2 to 20 and 3 to 10. It would have been obvious to one of ordinary skill to substitute a known pH modifiers in the compositions, such as sodium acetate, to enhance the dissolution of the composition, with a reasonable expectation of success. Likewise, one of ordinary skill in the art would have been motivated to use experimentation and optimization to determine the amount of buffered acetate to use to form the nanoparticles.
Applicant argues that the case is rebutted by unexpected results. In response to Applicant’s argument, the data in Examples 1 to 5 contain no active ingredients. Examples 6 to 8 comprise enzalutamide dissolved in acetone and HPMCAS. The data is not commensurate in scope with the claimed invention. Applicant claims a method for producing nanoparticles comprising an active ingredient and hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein a volume of water is needed to dissolve 1 g of the active ingredient is at least 30 mL, the method comprising the steps of: a) providing an organic solution of the active ingredient and the HPMCAS in an organic solvent, wherein the organic solvent selected from the group consisting of acetone, tetrahydrofuran, ethanol, methanol, dichloromethane, and mixtures thereof; b) providing an aqueous solution having a pH of 5 to 8; and c) mixing the organic solution with a buffered acetate, phosphate, or citrate aqueous solution to precipitate the nanoparticles; wherein the organic solution is provided in the form of a first fluid stream, the aqueous solution is provided in the form of a second fluid stream, wherein the mixing includes directing the first and second fluid stream to contact one another; wherein each of the first and second stream is ejected from a nozzle, and wherein the fluid streams are directed to impinge on one another; wherein in step c) the ratio of the volume of the buffered acetate, phosphate, or citrate aqueous solution to the volume of the organic solution is at least 1.
The process used to formulate the nanoparticles in Examples 1 to 8 is not the same as the process currently claimed. Examples 7 and 8 indicate the compositions with a pH of 6 and 7 have a particle size of 423nm and 582nm, respectively. In addition the PDI is 0.244 and 0.557, respectively. However, only one active ingredient and one organic solvent are used in the compositions. In addition, only one buffered aqueous solution was used. It cannot be determined if any active ingredient wherein the volume of water needed to dissolve 1 g of the active ingredient is at least 30 mL, will provide the same results as enzalutamide and acetone mixed with HPMCAS when mixed with acetic acid and/or acetate in water. Evidence of nonobviousness must be commensurate in scope with that of the claimed subject matter. Applicant has not established nonobvious evidence that is commensurate in scope with that of the claimed subject matter.
Conclusion
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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/ANDRIAE M HOLT/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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