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 .
Formal Matters
Applicant’s response in the reply filed on October 23, 2025 is acknowledged and has been fully considered. Claims 13-36 are pending. Claims 13-26 are under consideration in the instant office action. Claims 27-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on December 05, 2022 and December 08, 20205 are noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. Signed copies are herein attached.
Election/Restriction
Applicant's election of Group I (claims 13-26) in the reply filed on October 23, 2025 is acknowledged. Additionally, Applicant's election of species as set forth below in the reply filed on October 23, 2025 is also acknowledged:
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Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Objection to the title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The title of the instant application is “NANOPARTICULATE COMPOSITION”. The title should be brief but technically accurate and descriptive and should contain fewer than 500 characters. The title does not reflect the main inventive concept of Applicant’s invention and the major components of the “NANOPARTICULATE COMPOSITION”. The title is generic and can be applicable to any “NANOPARTICULATE COMPOSITION”. The examiner advises Applicant to consider including major components of the composition (e.g., the recited active agent and the main inactive ingredients) in the title to precisely reflect the inventive concept. Inasmuch as the words "new," "improved," "improvement of," and "improvement in" are not considered as part of the title of an invention, these words should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues. Similarly, the articles "a," "an," and "the" should not be included as the first words of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues.
Claim Objections
Claim 16 is objected to because of the following informalities: Claim 16 recites the phrase “the at least surface stabilizer”. The phrase should be written as “the at least one surface stabilizer”. Appropriate correction is required.
Claim 23 is objected to because of the following informalities: Claim 23 recites the phrase “wherein the poloxamer is poloxamer 407(also known as Pluronic F-127) or poloxamer 188 (also known as Pluronic F68).”. Applicant used hyphen when reciting PluronicF-127 but not when reciting Pluronic F68. For consistency purpose, Applicant should consider reciting the terms in the same manner. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13-15 and 20-23 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.
Instant claim 13 recites the phrase “by weight (volume based)”. The phrase is internally inconsistent and unclear because it simultaneously invokes two distinct and mutually exclusive measurement bases or parameters—weight and volume. The claim therefore fails to inform, with reasonable certainty, a person of ordinary skill in the art whether the recited proportion is intended to be: a weight bases measurement (e.g., wt%); a volume based measurement (e.g., vol%); or some hybrid or conversion between weight and volume. Because the specification does not provide a special definition resolving the conflict, one of ordinary skill in the art would be unable to determine the proper basis for measurement or how to interpret the claimed limitation. As such, the scope of the claim is ambiguous or unclear. Furthermore, it is unclear whether the phrase in parenthesis is a required limitation or not.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 14 recites the broad recitation “wherein the effective average particle size is in the range from about 90 nm to about 210 nm”, and the claim also recites “more preferably in the range from about 100 nm to about 200 nm.” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 15 recites the broad recitation “wherein the at least one active ingredient is present in an amount in the range from about 99.5% by weight to about 0.001% by weight”, and the claim also recites “preferably in the range from about 95% by weight to about 0.1% by weight, and more preferably in the range from about 90% by weight to about 0.5% by weight ” which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 20 contains the trademark/trade names “tween”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe nonionic surfactants which are conventionally known with brand names of Polysorbates and, accordingly, the identification/description is indefinite.
Claim 21 recites the limitation "the poloxamer block" in claim 20. There is insufficient antecedent basis for this limitation in the claim.
Claims 22-23 contains the trademark/trade names Pluronic, Pluronic F-127, and Pluronic F-68. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names Pluronic F-127 and Pluronic F-68 are used to identify/describe the surfactants poloxamer 407 and poloxamer 188 respectively and, accordingly, the identification/description is indefinite.
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.
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 13-26 are rejected under 35 U.S.C. 103 as being unpatentable over Avelar et al. (EP 1 708 694, previously provided to Applicant in the previous office action of 09/02/25) in view of Dodd et al. (US 2016/0022637) and Khopade et a. (WO2009/087678).
Applicant Claims
Applicant claims a nanoparticulate composition comprising laflunimus (the drug recited in claim 13 as evidenced by Applicant’s specification paragraph 0010) and sodium starch glycolate and/or poloxamer 407.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Avelar et al. teach the present invention provides the claimed compositions, for use in devices and methods for the treatment of contracture, and in particular, for use in human and animal patients. The compositions described herein may be used after an injury in order to prevent or minimize contracture formation. In the case of established contracture, the compositions of the invention can be used to complement a release procedure (e.g., forced manipulation, open release, arthroscopic release, or debulking of scar) to prevent the recurrence of scarred and abnormal tissue which can lead to a contracture. The administration may be intra-articular in cases where the contracture is caused by an intra-articular scar, or may used peri-articularly where the contracture is caused by not only scarring within the joints, but also by scar tissue outside the joint. An example of the latter would include interphalangeal contractures, not only is the scar within the joint, the outside volar plate is also involved. The use or administration of the instant compositions provides for an efficacious treatment which is reasonably safe and well tolerated and may further provide other related advantages. The drug contained in the compositions of the invention may be selected from a variety of therapeutically active compounds which will provide symptomatic, disease modifying or prophylaxis effect in conditions associated with contracture. The method of use of such compositions may also vary, but includes all routes of administration, doses, and dosing frequencies which will provide such a benefit (paragraph 0008). In another embodiment, the pharmacologically active compound is a hydroorotate dehydrogenase inhibitor (e.g., leflunomide (4-isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-), laflunimus (2-propenamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4(trifluoromethyl)phenyl)-, (Z)-), or atovaquone (1,4-naphthalenedione, 2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-, trans-, or an analogue or derivative thereof) (paragraph 0199). Therapeutic agents may be incorporated into the compositions and devices of the invention by various methods, such as being contained (e.g., dispersed) in a polymeric matrix (e.g., a polymeric carrier), bound by covalent linkages (e.g., to a solid or semi-solid substrate), encapsulated in microcapsules, encapsulated in microspheres or nanospheres, or included as a component in a coating. Within certain preferred embodiments of the invention, therapeutic compositions are provided in non-capsular formulations such as microspheres (ranging from nanometers to micrometers in size), pastes, threads of various size, films and sprays (paragraph 0286). In certain embodiments of the invention, a drug or drugs are contained within a carrier that is a solution or a suspension. A solution consists of molecularly dispersed or colloidally dispersed material in a liquid phase, typically an aqueous phase such as normal or buffered saline. Colloidal dispersions include micellar solutions, liposomes and microemulsions. Solutions within the scope of the invention are clear and have in them a homogeneously dispersed, therapeutically effective amount of a drug or drugs. Solutions may also contain excipients (discussed in detail below). Solutions may be made viscous by the addition of viscosity builders, such as polymers or sugar. These systems may be gels or even hydrogels, which are discussed in detail below (paragraph 0289). Other disperse systems include emulsions, in which the first phase is a liquid dispersed within a second liquid phase. Characteristically, the two phases are largely immiscible and the dispersion is stabilized by the addition of a surfactant. Acceptable surfactants for use in the instant compositions include ionic or non-ionic surfactants and polymeric stabilizers, examples of which are well known in the art. In an emulsion, the therapeutic agent may be contained in either phase. In yet other dispersed systems within the scope of the invention, the formulation may include a liposome or a liquid crystal or precursors thereto (paragraph 0291). The therapeutic composition may be a disperse system that includes a carrier formed as a microparticle. "Microparticle" as used herein refers to spheres or irregularly shaped particles having a size of less than 1 mm in diameter. Typically, the mean diameter of a microparticle may be in the range of 1-500 µm, but it may be lower, for example, in the range of 200 - 1000 nm, or lower, for example, 10 - 250 nm. Microparticles may be microspheres, which are essentially spherical and have a size in the micron range, e.g., a mean diameter between about 1-1000 µm. Microparticles may contain a therapeutically active amount of a drug and excipients used to form the microparticle. Microparticles may be formed with polymeric excipients, as discussed above, but may be formed with non-polymeric excipients, such as waxes, or hydrocarbon alcohols (e.g., cetyl alcohol and stearyl alcohol). Microparticles may be formed by techniques known to those skilled in the art, including for example, spray drying, solvent evaporation or removal, hot melt microencapsulation, or ionic gelation techniques. The microspheres can be in a non-porous or a porous form (paragraph 0292). In addition to a therapeutic agent, compositions may further include one or more excipients, including but not limited to, polymeric or non-polymeric materials, phospholipids, viscosity increasing agents, pharmaceutically or veterinarilly acceptable vehicles, diluents, preservatives, stabilizers, colorants, antioxidants, binders, pore formers, density, tonicity, pH, or osmotic pressure adjusting materials, degradation accelerants, radioopaque or echogenic materials, and magnetic resonance imaging responsive materials (paragraph 0322). In some embodiments, the excipient may include a synthetic polymer, such as homopolymers, copolymers or cross-linked polymers. Polymeric excipients may be polyethers, such as polyethylene glycol, polyesters such as poly(DL-lactide), poly(glycolide), poly(glycolide-co-lactide), poly(L-lactide), poly(ε-caprolactone), or poly(δ or γ-valerolactone), polymers of acrylic acid and derivatives thereof, such as polyacrylic acid or polymethylmethacrylate, polyurethanes, polyethylene, polystyrene, ethylene vinyl acetate, poloxamers, silicones, polystyrene, polypropylene, crosslinked divinyl benzene, vinyls such as polyvinyl chloride, polyvinyl acetate, or polyvinyl alcohol, polythioesters, polyanhydrides, polyamides, and polyorthoesters (paragraph 0324). As noted above, therapeutic agents, therapeutic compositions, or pharmaceutical compositions provided herein may be prepared for administration by a variety of different routes, including for example, periarticular injections or intraarticularly to a joint (e.g., direct injection with a needle or catheter, under fluoroscopy, through a portal in a arthroscope) or transdermally). Other representative routes of administration include spraying soft tissue after an open or closed procedure or administration of the therapeutic composition into the affected area through a directed route such as a needle, or leaving a therapeutic composition releasing the therapeutic agent in the area. Systemic administration of an agent may also be used (paragraph 0378).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Avelar et al. do not teach the incorporation of the elected poloxamer-407 in the composition. This deficiency is cured by the teachings of Dodd et al.
Dodd et al. teach poor bioavailability is a significant problem encountered in the development of compositions in the therapeutic, cosmetic, agricultural and food industries, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH. An active material's bioavailability is the degree to which the active material becomes available to the target tissue in the body or other medium after systemic administration through, for example, oral or intravenous means. Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material (see paragraph 0003). In one aspect the present invention is directed to the unexpected finding that particles of a biologically active material can be produced by dry milling processes at commercial scale. In one surprising aspect the particle size produced by the process is equal to or less than 2000 nm. In another surprising aspect the particle size produced by the process is equal to or less than 1000 nm. In another surprising aspect the crystallinity of the active material is unchanged or not substantially changed. In a preferred embodiment the present invention is directed to the unexpected finding that particles of indomethacin can be produced by dry milling processes at commercial scale (paragraph 0019). Thus in a first aspect the invention comprises a method producing a composition, comprising the steps of dry milling a solid biologically active material and a millable grinding matrix in a mill comprising a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material (see paragraph 0020). In one preferred embodiment, the average particle size, determined on a particle number basis, is equal to or less than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm (paragraph 0021). In another preferred embodiment, the particles have a median particle size, determined on a particle volume basis, equal or less than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the median particle size is equal to or greater than 25 nm. Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 2000 nm (%<2000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 1000 nm (%<1000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500 nm (%<500 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 300 nm (%<300 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 200 nm (%<200 nm). Preferably, the Dx of the particle size distribution, as measured on a particle volume basis, is selected from the group consisting of less than or equal to 10,000 nm, 5000 nm, 3000 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm; wherein x is greater than or equal to 90 (paragraph 0022). In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline. More preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subjected to the method as described herein (paragraph 0023). In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous. Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein (paragraph 0024). In another preferred embodiment, the grinding matrix is a single material or is a mixture of two or more materials in any proportion. Preferably, the single material or a mixture of two or more materials is selected from the group consisting of poloxamer 188, poloxamer 407, etc., (paragraph 0028). Preferably, the grinding matrix is selected from the group consisting of in sections (a)-(k): Poloxamer 407, Poloxamer 338, Poloxamer 188, etc., (paragraph 0029). In another preferred embodiment, a milling aid or combination of milling aids is used. Preferably, the milling aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, a stearic acid and derivatives thereof. Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, etc., (paragraph 0042). Dodd et al. teach for example in another preferred embodiment, Indomethacin is milled with lactose monohydrate, alkyl sulfates and another surfactant or polymers. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and polyether sulfates. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and polyethylene glycol 40 stearate. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and polyethylene glycol 100 stearate. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and a poloxamer. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and poloxamer 407 (paragraph 0043). Another highly preferred aspect of the method is the inclusion of a suitable milling aid in the matrix to improve milling performance. Improvements to milling performance would be things such as, but not limited to, a reduction in caking or higher recovery of powder from the mill. Examples of suitable milling aids include surfactants, polymers and inorganics such as silica (including colloidal silica), aluminium silicates and clays (paragraph 0135). Poloxamer 407 is listed as surfactants to be suitable as milling aids (paragraph 0136). Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w (paragraph 0137).
Avelar et al. and Dodd et al. do not teach the incorporation of the elected sodium glycocholate in the composition. This deficiency is cured by the teachings of Khopade et al.
Khopade et al. teach a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a water miscible solvent and water, said nanoparticles comprising one or more taxane derivative, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts (see asbrtract). The present invention also provides a solution comprising one or more taxane derivative, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts in a water miscible solvent, which upon dilution with an aqueous liquid vehicle gives nanodispersion. The present invention also provides nanoparticles having a mean particle size less than 300 nms comprising one or more taxane derivative, surfactant comprising a mixture of sterol or its derivatives or its salts and fatty acid or its salts and a polymer (see page 4). According to preferred embodiment, the surfactant used is selected from the group consisting of caprylic acid and sodium glycocholate or ursodeoxycholic acid and/or mixtures thereof (see page 12). Example 16 shows the use of sodium glycocholate. The term nanoparticle as used herein means any particle having controlled dimensions of the order of nanometers. The nanoparticles as claimed in the present invention can be a polymeric nanoparticle (matrix of polymer entrapping the drug) and/or a polymeric nanovesicle (polymer stabilized nano sized vesicle encapsulating the drug.) and/or a polymeric, nanocapsule (polymeric membrane surrounding drug in core) and/or nano sized particles of the drug stabilized by surfactants, and the like having mean size less than 300 nm (see page 7).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify Avelar et al. by incorporating poloxamer-407 in the composition because Dodd et al. teach poor bioavailability is a significant problem encountered in the development of compositions in the therapeutic, cosmetic, agricultural and food industries, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH. An active material's bioavailability is the degree to which the active material becomes available to the target tissue in the body or other medium after systemic administration through, for example, oral or intravenous means. Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material (see paragraph 0003). In one aspect the present invention is directed to the unexpected finding that particles of a biologically active material can be produced by dry milling processes at commercial scale. In one surprising aspect the particle size produced by the process is equal to or less than 2000 nm. In another surprising aspect the particle size produced by the process is equal to or less than 1000 nm. In another surprising aspect the crystallinity of the active material is unchanged or not substantially changed. In a preferred embodiment the present invention is directed to the unexpected finding that particles of indomethacin can be produced by dry milling processes at commercial scale (paragraph 0019). Thus in a first aspect the invention comprises a method producing a composition, comprising the steps of dry milling a solid biologically active material and a millable grinding matrix in a mill comprising a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material (see paragraph 0020). In one preferred embodiment, the average particle size, determined on a particle number basis, is equal to or less than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the average particle size is equal to or greater than 25 nm (paragraph 0021). In another preferred embodiment, the particles have a median particle size, determined on a particle volume basis, equal or less than a size selected from the group 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. Preferably, the median particle size is equal to or greater than 25 nm. Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 2000 nm (%<2000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 1000 nm (%<1000 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500 nm (%<500 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 300 nm (%<300 nm). Preferably, the percentage of particles, on a particle volume basis, is selected from the group consisting of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 200 nm (%<200 nm). Preferably, the Dx of the particle size distribution, as measured on a particle volume basis, is selected from the group consisting of less than or equal to 10,000 nm, 5000 nm, 3000 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, and 100 nm; wherein x is greater than or equal to 90 (paragraph 0022). In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline. More preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subjected to the method as described herein (paragraph 0023). In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous. Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein (paragraph 0024). In another preferred embodiment of the invention, a facilitating agent is used or combination of facilitating agents is used. Preferably, the facilitating agent is selected from the group consisting of: surfactants, polymers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, agents that may form part of a medicament, including a solid dosage form or a dry powder inhalation formulation and other material required for specific drug delivery. Preferably, the facilitating agent is added during dry milling. Preferably, the facilitating agent is added to the dry milling at a time selected from the group consisting of: with 1-5% of the total milling time remaining, with 1-10% of the total milling time remaining, with 1-20% of the total milling time remaining, with 1-30% of the total milling time remaining, with 2-5% of the total milling time remaining, with 2-10% of the total milling time remaining, with 5-20% of the total milling time remaining and with 5-20% of the total milling time remaining. Preferably, the facilitating agent is added to the milled biologically active material and grinding matrix and further processed in a mechanofusion process. Mechanofusion milling causes mechanical energy to be applied to powders or mixtures of particles in the micrometer and nanometer range (paragraph 0045). One of ordinary skill in the art would have been motivated to incorporate or utilize poloxamer 407 in the composition of Avelar et al. because Dodd et al. teach in another preferred embodiment, the grinding matrix is a single material or is a mixture of two or more materials in any proportion. Preferably, the single material or a mixture of two or more materials is selected from the group consisting of poloxamer 188, poloxamer 407, etc., (paragraph 0028). Preferably, the grinding matrix is selected from the group consisting of in sections (a)-(k): Poloxamer 407, Poloxamer 338, Poloxamer 188, etc., (paragraph 0029). In another preferred embodiment, a milling aid or combination of milling aids is used. Preferably, the milling aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, a stearic acid and derivatives thereof. Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, etc., (paragraph 0042). Dodd et al. teach for example in another preferred embodiment, Indomethacin is milled with lactose monohydrate, alkyl sulfates and another surfactant or polymers. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and polyether sulfates. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and polyethylene glycol 40 stearate. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and polyethylene glycol 100 stearate. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and a poloxamer. Preferably indomethacin is milled with lactose monohydrate, sodium lauryl sulfate and poloxamer 407 (paragraph 0043). Even furthermore, one of ordinary skill in the art would have been motivated to do so because Dodd et al. teach that another highly preferred aspect of the method is the inclusion of a suitable milling aid in the matrix to improve milling performance. Improvements to milling performance would be things such as, but not limited to, a reduction in caking or higher recovery of powder from the mill. Examples of suitable milling aids include surfactants, polymers and inorganics such as silica (including colloidal silica), aluminium silicates and clays (paragraph 0135). Poloxamer 407 is listed as surfactants to be suitable as milling aids (paragraph 0136). Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w (paragraph 0137). The selection of a known material and its amounts based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) Furthermore, in the case where the claimed ranges for amounts of ingredients and actives “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus, an ordinary skilled artisan would have had a reasonable expectation of success upon combination of the Avelar et al. and Dodd et al. because both references teach nanoparticles based compositions comprising active agents.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify Avelar et al. and Dodd et al. by utilizing sodium glycocholate as a surfactant because Khopade et al. teach a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a water miscible solvent and water, said nanoparticles comprising one or more taxane derivative, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts (see asbrtract). The present invention also provides a solution comprising one or more taxane derivative, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts in a water miscible solvent, which upon dilution with an aqueous liquid vehicle gives nanodispersion. The present invention also provides nanoparticles having a mean particle size less than 300 nms comprising one or more taxane derivative, surfactant comprising a mixture of sterol or its derivatives or its salts and fatty acid or its salts and a polymer (see page 4). One of ordinary skill in the art would have been motivated to do so because Khopade et al. teach that the term nanoparticle as used herein means any particle having controlled dimensions of the order of nanometers. The nanoparticles as claimed in the present invention can be a polymeric nanoparticle (matrix of polymer entrapping the drug) and/or a polymeric nanovesicle (polymer stabilized nano sized vesicle encapsulating the drug.) and/or a polymeric, nanocapsule (polymeric membrane surrounding drug in core) and/or nano sized particles of the drug stabilized by surfactants, and the like having mean size less than 300 nm (see page 7). According to preferred embodiment, the surfactant used is selected from the group consisting of caprylic acid and sodium glycocholate or ursodeoxycholic acid and/or mixtures thereof (see page 12). Example 16 shows the use of sodium glycocholate. The selection of a known material and its amounts based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) Furthermore, in the case where the claimed ranges for amounts of ingredients and actives “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus, an ordinary skilled artisan would have had a reasonable expectation of success upon combination of the Avelar et al., Dodd et al, and Khopade et al. et al. because all of the references teach nanoparticles based compositions comprising active agents.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619