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 27 February 2026 are acknowledged and have been fully considered. Claims 1-6, 8-13, 15-18, 20-24, 28, 30-32, 39, 45-46, and 48-49 are pending. Claims 1-6, 11-13, 15-18, 20-24, 30-32, 45-46, and 48-49 are under consideration in the instant office action. Claims 8-10, 28, 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking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. Claims 7, 14, 19, 25-29, 33-44, and 47 are cancelled.
Information Disclosure Statement
The information disclosure statement (IDSs) submitted on 23 June 2023 and 11 March 2024 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 attached.
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 “CHEMICAL COMPOSITION”. The title should be brief but technically accurate and descriptive and should contain fewer than 500 characters. The title does not describe the main purpose of the invention. It is generically applicable to making any coatings with any method which the instant invention is not drawn to. 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.
Election Restriction
Applicant’s election without traverse of Group I (1-6, 11-13, 15-18, 20-24, 30-32, 45-46, and 48-49) in the reply filed on 27 February 2026 is acknowledged. Additionally Applicant’s election without traverse combination of polyvinylpyrrolidone (PVP) and polyoxyethylene (20) sorbitan monooleate (Tween 80) as carriers in the reply filed on 27 February 2026 is also acknowledged.
Claim Objections
Claims 2-6, 12, 15, 17, 20-24, 31, 46, 48-49 are objected to because of the following informalities: Base claims start recitations with the articles “A or An” while dependent claims that depend from the base claims start recitations with the proposition “The”. 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.
Claim 30 is 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.
Claim 30 recites “optionally one or more additional (pharmaceutically acceptable) excipients.” It is unclear whether the recitation in parenthesis (pharmaceutically acceptable) is a required limitation or not. The metes and bounds of the recitation cannot be ascertained.
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.
Note: The claims are examiner with respect to the elected species of nanoparticles of atovaquone with combination of polyvinylpyrrolidone (PVP) and polyoxyethylene (20) sorbitan monooleate (Tween 80) as carriers. To clear the record claim 13 is interpreted to contain the elected carriers polyvinylpyrrolidone (PVP) and polyoxyethylene (20) sorbitan monooleate (Tween 80) as carriers.
Claims 1-6, 11-13, 15-18, 20-24, 30-32, 45-46, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Dearn (US Patent No. 6018080, IDS reference) in view of Muller et al. (US Patent No. 8202540), Sek et al. (Journal of Pharmacy and Pharmacology, 58, 809-820, 2006), and Tripathi et al. (US20060141024).
Applicants’ claims
Applicants claim an intramuscularly-injectable or subcutaneously-injectable formulation of nanoparticles of atovaquone.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Dearn teaches a process for the production of microfluidized particles of atovaquone having improved bioavailability (see abstract). A method for the preparation of microfluidized particles of atovaquone which comprises mixing atovaquone with a liquid vehicle to provide a mixture wherein the concentration of atovaquone is less than 450 mg/mL and subjecting said mixture to at least 3 passes through a Microfluidizer (see claim 1). A method for the preparation of microfluidized particles of atovaquone according to claim 1 wherein the microfluldized particles have a volume diameter in the range of 0.1-3 m (which the examiner notes this entails 100 nm to 3000 nm) (see claim 2). Dearn teaches in example 1 atovaquone was prepared by methods according to the prior art, e.g. U.S. Pat. No. 5,053,432 (incorporated herein by reference) 600 mL of a mixture consisting of 2.5% w/v atovaquone in 0.25% w/v aqueous Celacol M2500 was prepared and 100 mL were retained in a glass jar as a control. A laboratory scale model 120B Microfluidiser was connected to a 90 psi pneumatic supply and adjusted to produce a fluid pressure of 15000 psi. The machine base, interaction chamber and pipework of the Microfluidiser were immersed in a bath of cold water. 500 mL of the mixture were loaded into the Microfluidiser's bulk vessel and passed through the Microfluidiser interaction chamber before being returned to the top, and side, of the bulk chamber. The mixture was recirculated continuously through the interaction chamber, and samples were taken at 10, 20, 30, 45 and 60 minutes. The number of passes to which each of these samples had been subjected was calculated and is shown in Table 1 below.
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116
310
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355
295
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163
308
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The above clearly teaches aqueous dispersions of nanoparticles of atovaquone in concentration overlapping with the claimed amount in claim 18.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Dearn do not specifically teach polyvinyl alcohol and Tween 80 as carriers. These deficiencies are cured by the teachings of Muller et al.
Muller et al. teach superfine microparticles and nanoparticles and a process for their gentle preparation with exclusion of water or minimization of water and/or exclusion of plasticizers and/or reduced temperature load, in which a matrix material is subjected to a high-pressure homogenization process in an anhydrous or water-poor medium and/or at low temperatures, preferably room temperature (20° C.) and in particular below the freezing point of water, which leads to a gentle particle reduction with minimization of the impairment of the chemical stability of the homogenized material (see abstract). Process for the gentle preparation of superfine micro- and nanoparticles having a particle size, as average diameter of the number distribution, of 5.6 μm or less, the method comprising: subjecting a matrix material comprising solid particles to a high-pressure homogenizing process in a piston-gap homogenizer in an anhydrous or water-reduced dispersion medium containing less than 50 wt. % of water in which the solid particles are suspended and at temperatures of 20° C. or less, which leads to a gentle particle size reduction with minimization of the impairment of the chemical stability of the homogenized material, to form superfine micro- and nanoparticles (see claim 1). Process according to claim 1, wherein the homogenized matrix material comprises at least one selected from the group consisting of drugs, pharmaceutical active ingredients, veterinary drugs, active ingredients, auxiliaries, additives for cosmetics, agricultural products, foodstuffs and preservatives (see claim 2). Process according to claim 1, wherein the homogenized matrix material comprises at least one selected from the group consisting of synthetic, semi-synthetic or natural polymers, and natural macromolecules (see claim 4). Process according to claim 4, wherein the homogenized matrix material comprises at least one selected from the group consisting of synthetic polymers, polylactide, polyglycolide, polylactide/-glycolide co-polymer, polyorthoester, polyhydroxybutyrate (PHB), polyhydroxyvaleriate (PHV), polyhydroxybutyrate/-valeriate co-polymer, polyacrylates, polymethacrylates, polyvinyl derivatives, block polymers of polyethylene glycol and polyesters, polyhydroxybutyric acid, polycyanoacrylates, polycarbonates and polycaprolactone (see claim 5). The substance to be converted into superfine microparticles or nanoparticles (e.g. active ingredients, polymers or active-ingredient-loaded polymers) is dispersed as powder accompanied by stirring in a liquid medium (dispersion medium) to prepare a pre-suspension. Dispersion can be carried out with mixers of various designs, e.g. propeller mixer, rotor-stator mixer (Ultra-Turrax), dissolver discs. Alternatively, the powdered substance can also be gradually wetted, e.g. with a mortar (mortar mill). Dispersion medium is progressively added to the substance in the mortar during mixing. All liquids apart from water with sufficiently low viscosity can be used as dispersion media, e.g. polyols such as e.g. glycerine, polyethylene glycols (PEGs) (e.g. PEG 400 and PEG 600), polyether and polyester polyols, glycols such as e.g. propylene glycol, ethylene glycol, oils such as e.g. medium chain triglycerides (MCT) (e.g. miglyols), long chain triglycerides (LCT) such as e.g. isopropyl myristate, vegetable oils such as avocado oil, cottonseed oil, safflower oil, peanut oil, jojoba oil, coconut oil, linseed oil, walnut oil, olive oil, palm-kernel oil, sesame oil, soybean oil, castor oil, wheat-germ oil, animal oils such as cod-liver oil, halibut-liver oil, neat's foot oil, liquid hydrocarbons such as e.g. liquid paraffin, viscous paraffin and hexane,alcohols such as methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2-butanol, pentanol, hexanol, octanol, decanol, allyl alcohol, propargyl alcohol. If desirable for the final product, a proportion of water can be added to the dispersion medium (e.g. addition of water to PEG 400 with a view to a later packing in soft gelatine capsules). As a rule, the water proportions lie in the range from 1 to 10%, but higher proportions can also be used. A limiting factor in this case is the chemical stability of the substance to be homogenized. Although higher proportions of water have no or little effect on the average diameter of the prepared particle dispersion, the proportion of larger particles is additionally minimized. As a rule, the 95% diameter decreases slightly. For many products, this is of no relevance. It is useful however in the preparation of nanoparticle dispersions for intravenous injection. If too many particles larger than 5 μm remain in the product, this can lead to capillary blockage (column 5, lines 7-49). Substances such as HPMC, PEG 6000 or Aerosil can also be dissolved in the water if this is desirable for the sought final formulation to which the micro- and nanoparticle dispersions are to be processed. These are important in particular with regard to the manufacture of tablets, e.g. calcium phosphates, lactose, starch and its derivates such as starch hydrolysates, celluloses, cellulose derivatives, polyethylene glycols, polyvinylpyrrolidone (PVP), hexites, glucose; with regard to the manufacture of ointments, substances such as bentonite, Aerosil, cellulose ethers, cellulose esters, alginates, pectinates, tragacanth, polyvinyl alcohol, polyethylene glycols, gum arabic, polyacrylates, paraffin, polymethacrylates, petrolatum, plastibases, can be considered; and with regard to the processing into capsules, e.g. polyethylene glycols, paraffin, liquid triglycerides (vegetable or animal) are important (column 5, lines 50-64). To stabilize the suspension and the micro- and nanoparticles prepared from it, stabilizing substances can be added to the dispersion medium. Examples of this are: 1. sterically stabilizing substances such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene block copolymers), ethoxylated sorbitan fatty acid esters, in particular polysorbates (e.g. Polysorbate 80 or Tween 80®), ethoxylated mono- and diglycerides, ethoxylated lipids, ethoxylated fatty alcohols or fatty acids, and esters and ethers of sugars or of sugar alcohols with fatty acids or fatty alcohols (e.g. saccharose stearate, saccharose distearate, saccharose laurate, saccharose octanoate, saccharose palmitate, saccharose myristate). 2. charged ionic stabilizers such as diacetyl phosphates, phosphatidylglycerol, lecithins of various origins (e.g. egg lecithin or soybean lecithin), chemically modified lecithins (e.g. hydrogenated lecithins), as well as phospholipids and sphingolipids, mixture of lecithins with phospholipids, sterols (e.g. cholesterol and cholesterol derivatives as well as stigmasterol) and likewise charged and uncharged fatty acids, sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate or their mixtures, etc.,(column 5, lines 65-67 and column 6, lines 1-31). Active ingredients can also already be incorporated into the polymers before the homogenization, e.g. from the above-named therapeutic groups and/or chemical groups. The active ingredients can be e.g. dissolved, dispersed, solubilized or otherwise incorporated into the polymers. The pre-suspension is then further processed, e.g. in one of the following dispersion systems: high-pressure homogenizers of the piston-gap homogenizer type (APV Gaulin Systeme, French press, Avestin), jet-stream homogenizers (e.g. Microfluidizer), rotor-stator systems (Ultra-Turrax, Silverson homogenizers), ultrasound bath, ultrasound rod and ultrasound homogenizers (column 10, lines 33-44).
Dearn do not specifically teach the atovaquone nanoparticles being dispersed in oily medium. These deficiencies are cured by the teachings of Sek et al.
Sek et al. teach in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). Inclusion of Cremophor EL, a surfactant with a high hydrophilic–lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products andco-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB(0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavailability benefits beyond that achievable using simple lipid solutions (see abstract). Stirring of the LC-CREL and LC-PF68 formulations for30 min in either water or 0.1M HCl yielded completely orpartly-emulsified dispersions, respectively. Particle size determinations by PCS showed that the LC-CREL formulation dispersed to form small particles with mean particle sizes of 196.6 ±1.9 nm and 149.0 ± 1.5 nm (Z-avemean ± s.d., n ¼ 3) in water and 0.1M HCl, respectively. Dispersion of the LC-PF68 formulation yielded larger particles with diameters of 439.1 ± 4.0 nm and424.2 ± 3.0 nm (Z-ave mean ± s.d., n ¼ 3) in water and0.1M HCl, respectively. The particle size determinations were in agreement with visual observations. The remaining four surfactant-containing formulations did not show improved dispersion properties over the surfactant-free lipid formulation, which phase separated into grossly dispersed lipid droplets. Particle size determinations were not possible for these poorly dispersed systems (see results page 813).
Dearn do not specifically teach a kit with instructions as recited in claims 45-46 and 48 for its injectable composition. These deficiencies are cured by the teachings of Tripathi et al.
Tripathi et al. teach a method for preparation of synergistic combination kits of α,β-arteether, sulfadoxin and pyrimethamine for the treatment of severe/multi-drug resistant cerebral malaria (abstract). A combination kit for the treatment of malaria caused by P. falciparum for a period of two to five days schedule, the kit comprising: a. individual dose of anti-malarial agents sulfadoxine and pyrimethamine; and b. individual dose of anti-malarial agent α,β arteether; c. instruction manual for the administration of the three antimalarial drugs (see claim 1). A kit as claimed in claim 1 wherein the α,β arteether is taken in ground nut oil filled in a injection vial or soft gelatin capsule or in the form of capsules or tablets (see claim 3). Sulfadoxin and pyrimethamine capsules/tablets and α,β arteether injections or capsules/tablets are obtained commercially or prepared by conventional methods. For instance, injection containing α,β-arteether can be prepared by first dissolving α,β-arteether in neutralized and sterilized arachis oil (75 g/L), filling the solution in injection vial and sealing the injection (see paragraph 0082).
Finding of Prima Facie Obviousness Rational 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 application to modify the teachings of Dearn by utilizing polyvinyl alcohol and Tween 80 as carriers because Muller et al. teach superfine microparticles and nanoparticles and a process for their gentle preparation with exclusion of water or minimization of water and/or exclusion of plasticizers and/or reduced temperature load, in which a matrix material is subjected to a high-pressure homogenization process in an anhydrous or water-poor medium and/or at low temperatures, preferably room temperature (20° C.) and in particular below the freezing point of water, which leads to a gentle particle reduction with minimization of the impairment of the chemical stability of the homogenized material (see abstract). Process for the gentle preparation of superfine micro- and nanoparticles having a particle size, as average diameter of the number distribution, of 5.6 μm or less, the method comprising: subjecting a matrix material comprising solid particles to a high-pressure homogenizing process in a piston-gap homogenizer in an anhydrous or water-reduced dispersion medium containing less than 50 wt. % of water in which the solid particles are suspended and at temperatures of 20° C. or less, which leads to a gentle particle size reduction with minimization of the impairment of the chemical stability of the homogenized material, to form superfine micro- and nanoparticles (see claim 1). Process according to claim 1, wherein the homogenized matrix material comprises at least one selected from the group consisting of drugs, pharmaceutical active ingredients, veterinary drugs, active ingredients, auxiliaries, additives for cosmetics, agricultural products, foodstuffs and preservatives (see claim 2). Process according to claim 1, wherein the homogenized matrix material comprises at least one selected from the group consisting of synthetic, semi-synthetic or natural polymers, and natural macromolecules (see claim 4). Process according to claim 4, wherein the homogenized matrix material comprises at least one selected from the group consisting of synthetic polymers, polylactide, polyglycolide, polylactide/-glycolide co-polymer, polyorthoester, polyhydroxybutyrate (PHB), polyhydroxyvaleriate (PHV), polyhydroxybutyrate/-valeriate co-polymer, polyacrylates, polymethacrylates, polyvinyl derivatives, block polymers of polyethylene glycol and polyesters, polyhydroxybutyric acid, polycyanoacrylates, polycarbonates and polycaprolactone (see claim 5). The substance to be converted into superfine microparticles or nanoparticles (e.g. active ingredients, polymers or active-ingredient-loaded polymers) is dispersed as powder accompanied by stirring in a liquid medium (dispersion medium) to prepare a pre-suspension. Dispersion can be carried out with mixers of various designs, e.g. propeller mixer, rotor-stator mixer (Ultra-Turrax), dissolver discs. Alternatively, the powdered substance can also be gradually wetted, e.g. with a mortar (mortar mill). Dispersion medium is progressively added to the substance in the mortar during mixing. All liquids apart from water with sufficiently low viscosity can be used as dispersion media, e.g. polyols such as e.g. glycerine, polyethylene glycols (PEGs) (e.g. PEG 400 and PEG 600), polyether and polyester polyols, glycols such as e.g. propylene glycol, ethylene glycol, oils such as e.g. medium chain triglycerides (MCT) (e.g. miglyols), long chain triglycerides (LCT) such as e.g. isopropyl myristate, vegetable oils such as avocado oil, cottonseed oil, safflower oil, peanut oil, jojoba oil, coconut oil, linseed oil, walnut oil, olive oil, palm-kernel oil, sesame oil, soybean oil, castor oil, wheat-germ oil, animal oils such as cod-liver oil, halibut-liver oil, neat's foot oil, liquid hydrocarbons such as e.g. liquid paraffin, viscous paraffin and hexane,alcohols such as methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2-butanol, pentanol, hexanol, octanol, decanol, allyl alcohol, propargyl alcohol. If desirable for the final product, a proportion of water can be added to the dispersion medium (e.g. addition of water to PEG 400 with a view to a later packing in soft gelatine capsules). As a rule, the water proportions lie in the range from 1 to 10%, but higher proportions can also be used. A limiting factor in this case is the chemical stability of the substance to be homogenized. Although higher proportions of water have no or little effect on the average diameter of the prepared particle dispersion, the proportion of larger particles is additionally minimized. As a rule, the 95% diameter decreases slightly. For many products, this is of no relevance. It is useful however in the preparation of nanoparticle dispersions for intravenous injection. If too many particles larger than 5 μm remain in the product, this can lead to capillary blockage (column 5, lines 7-49). Substances such as HPMC, PEG 6000 or Aerosil can also be dissolved in the water if this is desirable for the sought final formulation to which the micro- and nanoparticle dispersions are to be processed. These are important in particular with regard to the manufacture of tablets, e.g. calcium phosphates, lactose, starch and its derivates such as starch hydrolysates, celluloses, cellulose derivatives, polyethylene glycols, polyvinylpyrrolidone (PVP), hexites, glucose; with regard to the manufacture of ointments, substances such as bentonite, Aerosil, cellulose ethers, cellulose esters, alginates, pectinates, tragacanth, polyvinyl alcohol, polyethylene glycols, gum arabic, polyacrylates, paraffin, polymethacrylates, petrolatum, plastibases, can be considered; and with regard to the processing into capsules, e.g. polyethylene glycols, paraffin, liquid triglycerides (vegetable or animal) are important (column 5, lines 50-64). To stabilize the suspension and the micro- and nanoparticles prepared from it, stabilizing substances can be added to the dispersion medium. Examples of this are: 1. sterically stabilizing substances such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene block copolymers), ethoxylated sorbitan fatty acid esters, in particular polysorbates (e.g. Polysorbate 80 or Tween 80®), ethoxylated mono- and diglycerides, ethoxylated lipids, ethoxylated fatty alcohols or fatty acids, and esters and ethers of sugars or of sugar alcohols with fatty acids or fatty alcohols (e.g. saccharose stearate, saccharose distearate, saccharose laurate, saccharose octanoate, saccharose palmitate, saccharose myristate). 2. charged ionic stabilizers such as diacetyl phosphates, phosphatidylglycerol, lecithins of various origins (e.g. egg lecithin or soybean lecithin), chemically modified lecithins (e.g. hydrogenated lecithins), as well as phospholipids and sphingolipids, mixture of lecithins with phospholipids, sterols (e.g. cholesterol and cholesterol derivatives as well as stigmasterol) and likewise charged and uncharged fatty acids, sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate or their mixtures, etc.,(column 5, lines 65-67 and column 6, lines 1-31). Active ingredients can also already be incorporated into the polymers before the homogenization, e.g. from the above-named therapeutic groups and/or chemical groups. The active ingredients can be e.g. dissolved, dispersed, solubilized or otherwise incorporated into the polymers. The pre-suspension is then further processed, e.g. in one of the following dispersion systems: high-pressure homogenizers of the piston-gap homogenizer type (APV Gaulin Systeme, French press, Avestin), jet-stream homogenizers (e.g. Microfluidizer), rotor-stator systems (Ultra-Turrax, Silverson homogenizers), ultrasound bath, ultrasound rod and ultrasound homogenizers (column 10, lines 33-44). One of ordinary skill in the art would have been motivated to incorporate PVA because Muller et al. teach that substances such as HPMC, PEG 6000 or Aerosil can also be dissolved in the water if this is desirable for the sought final formulation to which the micro- and nanoparticle dispersions are to be processed. These are important in particular with regard to the manufacture of tablets, e.g. calcium phosphates, lactose, starch and its derivates such as starch hydrolysates, celluloses, cellulose derivatives, polyethylene glycols, polyvinylpyrrolidone (PVP), hexites, glucose; with regard to the manufacture of ointments, substances such as bentonite, Aerosil, cellulose ethers, cellulose esters, alginates, pectinates, tragacanth, polyvinyl alcohol, polyethylene glycols, gum arabic, polyacrylates, paraffin, polymethacrylates, petrolatum, plastibases, can be considered; and with regard to the processing into capsules, e.g. polyethylene glycols, paraffin, liquid triglycerides (vegetable or animal) are important (column 5, lines 50-64). One of ordinary skill in the art would have been motivated to incorporate Tween 80 because Muller et al. teach that to stabilize the suspension and the micro- and nanoparticles prepared from it, stabilizing substances can be added to the dispersion medium. Examples of this are: 1. sterically stabilizing substances such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene block copolymers), ethoxylated sorbitan fatty acid esters, in particular polysorbates (e.g. Polysorbate 80 or Tween 80®), ethoxylated mono- and diglycerides, ethoxylated lipids, ethoxylated fatty alcohols or fatty acids, and esters and ethers of sugars or of sugar alcohols with fatty acids or fatty alcohols (e.g. saccharose stearate, saccharose distearate, saccharose laurate, saccharose octanoate, saccharose palmitate, saccharose myristate). 2. charged ionic stabilizers such as diacetyl phosphates, phosphatidylglycerol, lecithins of various origins (e.g. egg lecithin or soybean lecithin), chemically modified lecithins (e.g. hydrogenated lecithins), as well as phospholipids and sphingolipids, mixture of lecithins with phospholipids, sterols (e.g. cholesterol and cholesterol derivatives as well as stigmasterol) and likewise charged and uncharged fatty acids, sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate or their mixtures, etc.,(column 5, lines 65-67 and column 6, lines 1-31). Active ingredients can also already be incorporated into the polymers before the homogenization, e.g. from the above-named therapeutic groups and/or chemical groups. The active ingredients can be e.g. dissolved, dispersed, solubilized or otherwise incorporated into the polymers. The pre-suspension is then further processed, e.g. in one of the following dispersion systems: high-pressure homogenizers of the piston-gap homogenizer type (APV Gaulin Systeme, French press, Avestin), jet-stream homogenizers (e.g. Microfluidizer), rotor-stator systems (Ultra-Turrax, Silverson homogenizers), ultrasound bath, ultrasound rod and ultrasound homogenizers (column 10, lines 33-44). The selection of a known material 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). Furthermore, in the case where the amount of ingredients, concentrations and particle sizes "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). 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). An ordinary skilled artisan would have had a reasonable chance of success in combining the teachings of Dearn and Muller et al. because both references teach preparation of nanoparticles of poorly soluble drugs using microfludizers. With regard to the limitations “intramuscularly-injectable or subcutaneously-injectable”, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Since the cited prior art references render obvious the same atovaquone containing nanoparticle/nanocapsule comprising the same polyvinyl alcohol and Tween 80 carrier, the examiner concludes the composition of the references is “intramuscularly-injectable or subcutaneously-injectable”.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Dearn by dispersing the atovaquone nanoparticles in oily medium because Sek et al. teach in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). One of ordinary skill in the art would have been motivated to disperse atovaquone nanoparticles in oily medium because Sek et al. teach inclusion of Cremophor EL, a surfactant with a high hydrophilic–lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products andco-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB(0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavailability benefits beyond that achievable using simple lipid solutions (see abstract). Stirring of the LC-CREL and LC-PF68 formulations for30 min in either water or 0.1M HCl yielded completely or partly-emulsified dispersions, respectively. Particle size determinations by PCS showed that the LC-CREL formulation dispersed to form small particles with mean particle sizes of 196.6 ±1.9 nm and 149.0 ± 1.5 nm (Z-avemean ± s.d., n ¼ 3) in water and 0.1M HCl, respectively. Dispersion of the LC-PF68 formulation yielded larger particles with diameters of 439.1 ± 4.0 nm and424.2 ± 3.0 nm (Z-ave mean ± s.d., n ¼ 3) in water and0.1M HCl, respectively. The particle size determinations were in agreement with visual observations. The remaining four surfactant-containing formulations did not show improved dispersion properties over the surfactant-free lipid formulation, which phase separated into grossly dispersed lipid droplets. Particle size determinations were not possible for these poorly dispersed systems (see results page 813). An ordinary skill in the art would have had a reasonable chance of success in combining the references because both references teach atovaquone nanoparticles.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Dearn by including a kit comprising containers wherein the active is in solid form in one container and a diluent in another container to make solution of the active ready for injection because Tripathi et al. teach a method for preparation of synergistic combination kits of α,β-arteether, sulfadoxin and pyrimethamine for the treatment of severe/multi-drug resistant cerebral malaria (abstract). A combination kit for the treatment of malaria caused by P. falciparum for a period of two to five days schedule, the kit comprising: a. individual dose of anti-malarial agents sulfadoxine and pyrimethamine; and b. individual dose of anti-malarial agent α,β arteether; c. instruction manual for the administration of the three antimalarial drugs (see claim 1). A kit as claimed in claim 1 wherein the α,β arteether is taken in ground nut oil filled in a injection vial or soft gelatin capsule or in the form of capsules or tablets (see claim 3). Sulfadoxin and pyrimethamine capsules/tablets and α,β arteether injections or capsules/tablets are obtained commercially or prepared by conventional methods. For instance, injection containing α,β-arteether can be prepared by first dissolving α,β-arteether in neutralized and sterilized arachis oil (75 g/L), filling the solution in injection vial and sealing the injection (see paragraph 0082). One of ordinary skill in the art would have been motivated to utilize the kit with instructions and vials for efficient administration antimalaria drugs such as atovaquone as demonstrated by Tripathi for other anti-malaria drugs. One of ordinary skill in the art would have had a reasonable chance of expectation of success in combining the teachings of Dearn and Tripathi et al. because both references teach anti-malaria active containing injectable formulations.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, 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
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