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 arguments in the reply filed on 17 March 2026 are acknowledged and have been fully considered. Claims 1-3, 11-15, 41-45, and 77-80 are pending. Claims 1-3, 11-15, and 77-80 are under consideration in the instant Office action. Claims 41-45 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claims. Claims 4-10, 16-40, 46-76 are canceled.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 1-3, 11-15, and 77-80 remain rejected under 35 U.S.C. 103 as being unpatentable over Hoppu et al. (WO 2014/044907, previously cited), Ek (US 2007/0003487, previously cited), and Toledano et al. (US20100016443, previously cited).
Applicant Claims
Applicant claims a pharmaceutical composition comprising separate individual particles.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Hoppu et al. teach a method of coating a pharmaceutical substrate, characterized by: providing a pharmaceutical substrate, which is a particle in a solid form; and depositing a coating layer over the pharmaceutical substrate by atomic layer deposition method (ALD method) (see claim 1). The method of claim 1, characterized in that the pharmaceutical substrate comprises at least one active pharmaceutical substance, pharmaceutical ingredient, or a blend of them (see claim 2). A method of claims 1 or 2, characterized in that the coating layer comprises of one or more different inorganic or organic materials or a combination of them (see claim 3). A method of claim 3, characterized in that the inorganic material comprises a metal oxide, preferably aluminum oxide (Al2O3) or titanium oxide ΤiΟ2 (see claim 4). The ingredients in the pharmaceutical formulation are mixed together using techniques well known in the art until the mixture is homogenous with respect to the drug. It is important that all ingredients are fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. The pharmaceutical particles may be reduced in a particle size using conventional milling techniques, such as air jet milling, ball milling, cad milling, multi milling and other suitable size reduction techniques (paragraph 0042). The thickness of the coating layer may be controlled by varying the number of molecule layers in the coating. The term thin layer means in this context a layer that may have any thickness between 1 nm and 500 μm, the thickness depends on the pharmaceutical agent, pharmaceutical ingredients and the desired final dosage form (see paragraph 0011). A coating layer in accordance with the present invention may have various thicknesses, depending upon the particular application. In the coating process usually a coating that is as thin as possible is desirable such that it will be sufficiently thick in order to have the desired properties. ALD layer thickness can also be used to control the release of pharmaceutical substance and consequently control the drug dissolution time. The layer thickness can be defined by ALD cycles. For example, one ALD cycle of TMA and water results 0.1 nm thick Al2O3 coating. In one embodiment of the present invention, wherein trimethyl aluminum (CH3)3Al is used as a precursor, the thickness of the coating is within the range of 1 nm to 500 nm, more preferably in the range of 1 of 100 nm, most preferably from 5 to 15 nm. However, the coating layer may have any thickness between 1 nm and 500 μm. The thickness of the coating layer depends on the pharmaceutical substance, pharmaceutical ingredients and the desired final dosage form (paragraph 0028). An advantage to the method of the invention is that difficult, moisture sensitive, electrically charged pharmaceutical substrates can be made more easily processable. The coating generated by the method is thin, dense and smooth; moreover the coating layers deposited by ALD are pinhole- free and very conformal (paragraph 0010). Pharmaceutical particles (as shown in Table 1 ) were coated by Beneq TFS 500 ALD tool, equipped with static particle bed reactor. This type of particle reactor is suitable for small amount of particles. The reactor is built up from five cells top of each other. Each cell is 200 mm of its diameter and 20 mm of its height. Paracetamol powder was loaded on the bottom of the reactor cells without any pretreatment and the reactor cells were then loaded into the reactor and pumped down to the operating pressure of around 2 mbar. Al2O3 and T1O2 were deposited on paracetamol particles with average particle size of approximately 50 μm at temperature of 100 to 140°C (paragraph 0050). A pharmaceutical substrate to be coated in the present invention may be any active pharmaceutical substance, pharmaceutical ingredient, or a blend of them which is in a solid form and capable of being deposited without changing structure and losing efficacy. The pharmaceutical substrate may contain one or more active pharmaceutical substances or pharmaceutical ingredients. The substrate may be, for example, a particle, granule, pellet, tablet or powder. Preferably it is a particle. A pharmaceutical formulation is a medicinal composition, including the active pharmaceutical substance, administered in a specific dosage form (paragraph 0016).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Hoppu et al. do not specifically teach the inclusion of polyamide based polymer layer in addition to the aluminum oxide layer on the drug particles. These deficiencies are cured by the teachings of Ek.
Ek teaches a pharmaceutical composition, constituting a spray suspension includes at least one liquid excipient and at least one solid excipient substantially insoluble in the liquid excipient, and at least one pharmaceutical active ingredient. A method of preparing porous suspension particles includes: a) wet-milling or dry-milling the solid excipient(s) or a mixture of at least one active ingredient and a solid excipient(s) in a milling equipment inducing essentially compression and shear forces, resulting in fine particulate quality, where more than 90% by weight is smaller than 5 m; b) drying and aggregating the product of step a) alone or with the addition of at least one active ingredient, in fine particulate form, which will produce essentially isodiametrical aggregate particles. A suspension particles obtainable by the method pharmaceutical preparation, utilizing the composition or porous suspension particles and a method for treatment of disorders using the preparation are disclosed (see abstract). According to a further preferred embodiment of the first aspect of the present invention there is provided a pharmaceutical composition wherein the composition also contains at least one additional solid excipient which is capable of forming an outer membrane layer around the suspension particles, where the membrane layer retards the drug release and where the membrane layer is composed of non-polymeric- or polymeric materials such as calcium phosphate, ethyl cellulose, methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate (paragraph 0061). According to a further preferred embodiment of the second aspect of the present invention there is provided a method of preparing porous suspension particles (comprising an active ingredient), according to the first aspect of the present invention wherein it comprises the steps of; [0065] a. porous excipient particles, excluding any active ingredient, (thus not including any active ingredient) are prepared in accordance with the method of the second aspect of the present invention; and [0066] b. at least one active ingredient is added to the product of step a. whereby the active ingredient is essentially positioned within the pore structure of the product of step a. According to a further preferred embodiment of the second aspect of the present invention there is provided a method of preparing non-porous suspension particles (including an active ingredient) wherein the active ingredient is applied, by e.g. a coating process, as an outer layer on solid, non-porous, excipient particles (paragraph 0067). According to a further preferred embodiment of the second aspect of the present invention there is provided a method of applying a drug release retarding outer membrane layer to the suspension particles as set out above and where the membrane layer is composed of non-polymeric- or polymeric materials such as calcium phosphate, ethyl cellulose, methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate (paragraph 0068). A pharmaceutical composition, constituting a spray suspension comprising at least one liquid excipient and at least one solid excipient which essentially is insoluble in the liquid excipient, and at least one pharmaceutical active ingredient (claim 1). A pharmaceutical composition in accordance with claim 1, characterised in that the excipient particles together with the active ingredient forms a plurality of larger individual particles (suspension particles) (see claim 11). A pharmaceutical composition in accordance with claim 11, characterised in that the composition also contains at least one additional solid excipient which is capable of forming an outer membrane layer around the suspension particles, where the membrane layer retards the drug release and where the membrane layer is composed of non-polymeric- or polymeric materials such as calcium phosphate, ethyl cellulose, methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate (see claim 14).
Hoppu et al. do not specifically teach the core has a median particle size on a volume average basis between 0.1mm and 10 mm. These deficiencies are cured by the teachings of Toledano et al.
Toledano et al. teach a process for coating a solid, water-insoluble particulate matter, with a metal oxide comprising: (a) contacting the solid, water-insoluble particulate matter with an ionic additive and an aqueous medium to obtain a dispersion of said particulate matter having positive charges on its surface; (b) subjecting the particulate matter to a coating procedure comprising precipitating a metal oxide salt onto the surface of the particulate matter to form a metal oxide layer thereon to thereby obtain particulate matter coated by a metal oxide coating layer; (c) repeating step (b) at least 4 more times; and (d) aging said coating layer. The invention further relates to particles comprising a particulate matter coated by a metal oxide layer, to a use of the particles for topical administration, and to a method for preventing, reducing, or eliminating pests at a locus, using the particles (see abstract). The present invention is based on the finding of a manner of obtaining a thick and dense coating of metal oxide on a solid water-insoluble particulate matter. The formation of the metal oxide layer by the new method is irreversible, i.e. it does not erode or disintegrate upon dispersion in water. The new method further enables to obtain a more dense layer and is capable of fine tuning of the width of the metal oxide layer, thus allowing better control of the release of the active ingredient from the microparticles upon application on a surface (such as skin or mucosal membrane, or pest-infested surface) (paragraph 0022). Further provided by the invention are particles comprising a core composed of a solid, water insoluble particulate matter; said core is coated by a metal oxide layer; wherein said metal oxide layer is substantially not in an amorphous and/or not in a crystalline form (paragraph 0035). The “solid, water-insoluble particulate matter” constitutes the “core” of the particles obtained by the process. The solid, water-insoluble particulate matter, is preferably in such a state of subdivision that it can be suspended in water, e.g. in the form of a finely-divided powder having a D90 (see definition below), preferably in the range of 0.3-50 micron. Such a particulate matter can readily be suspended in an aqueous systems by stirring, with or without the aid of a surfactant. The “solid, water-insoluble particulate matter” may be comprised of the active ingredient per se or may be comprised of the active ingredient and excipients (e.g. solid carrier) (paragraph 0044). The core (i.e. solid, water insoluble particulate matter) may be of any shape for example rod-like, plate-like, ellipsoidal, cubic, or spherical shape (paragraph 0049). Referring to size of particles will be through their D90 meaning that 90% of the particles have the stated dimension or less (measured by volume). Thus, for examples, for spherical particles stated to have a diameter of 10 micrometer (“microns”), this means that the particles have a D90 of 10 microns. The D90 may be measured by laser diffraction. For particles having a shape other than spheres, the D90 refers to the mean average of the diameter of a plurality of particles (paragraph 0050). In the case of cores having a spherical shape, the diameter (D90) may be in the range of 0.3 to 90 microns, preferably 0.3 to 50 microns, more preferably 1 to 50, even more preferably 5 to 30 microns (paragraph 0051). By the term “D90 may be in the range of 0.3 to 90 microns” is meant that 90% by volume of the particles (in this case the particle's core) may be less than or equal to a value in the range of 0.3 to 90 microns (paragraph 0052). For generally cubic-shaped cores or cores having a shape resembling that of a cube, the mean size of a side may be in the range 0.3 to 80 microns, preferably 0.3 to 40 microns, more preferably 0.8 to 40, even more preferably 4 to 15 microns (paragraph 0053). For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, the largest dimension (that of the longest axis) is typically in the range 10 to 100 microns, preferably 15 to 50 microns; and the smallest dimension is typically in the range 0.5 to 20 microns, and more preferably 2 to 11 microns (paragraph 0054). According to a preferred embodiment of the present invention the particles (coated particulate matter) have a diameter of 0.5-100 micron. More preferably the diameter of the particles is in the range 1-50 micron and most preferably in the range 2-30 micron (paragraph 0178). Preferably the solid, water insoluble particulate matter is a dermatological active agent (paragraph 0124). Preferably the dermatological active agent is selected from antifungal agents, antibacterial agents, anti-inflammatory agents, antipuritic agents, anti psoriatic agent, and anti acne agents. The dermatological agent may also be combinations of any of the above agents (paragraph 0125). The dermatological active agent may be for example antifungal agents such as ketoconazole, bacteriostatic drugs such as metronidazole or erythromycin, bactericidal drugs such as bacitracin, corticosteroids such as mometasone furoate, methylprednisolone aceponate, prednicarbate, triamcinolone acetonide, fluocinonide, desoximetasone, bethasone valerate or mometasone furoate, antipruritic agent such as doxepin hydrochloride, and anti acne agents such as benzoyl peroxide, azelaic acid, retinoids such as tretinoin (all trans retinoic acid), tazarotene, iso-tretinoin or adapalene (paragraph 0127).
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 application to modify the teachings of Hoppu et al. by including a polyamide layer because Ek teaches a pharmaceutical composition, constituting a spray suspension includes at least one liquid excipient and at least one solid excipient substantially insoluble in the liquid excipient, and at least one pharmaceutical active ingredient. A method of preparing porous suspension particles includes: a) wet-milling or dry-milling the solid excipient(s) or a mixture of at least one active ingredient and a solid excipient(s) in a milling equipment inducing essentially compression and shear forces, resulting in fine particulate quality, where more than 90% by weight is smaller than 5 m; b) drying and aggregating the product of step a) alone or with the addition of at least one active ingredient, in fine particulate form, which will produce essentially isodiametrical aggregate particles. A suspension particles obtainable by the method pharmaceutical preparation, utilizing the composition or porous suspension particles and a method for treatment of disorders using the preparation are disclosed (see abstract) One of ordinary skill in the art would have been motivated to do so because Ek teaches that according to a further preferred embodiment of the first aspect of the present invention there is provided a pharmaceutical composition wherein the composition also contains at least one additional solid excipient which is capable of forming an outer membrane layer around the suspension particles, where the membrane layer retards the drug release and where the membrane layer is composed of non-polymeric- or polymeric materials such as calcium phosphate, ethyl cellulose, methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate (paragraph 0061). According to a further preferred embodiment of the second aspect of the present invention there is provided a method of preparing porous suspension particles (comprising an active ingredient), according to the first aspect of the present invention wherein it comprises the steps of; [0065] a. porous excipient particles, excluding any active ingredient, (thus not including any active ingredient) are prepared in accordance with the method of the second aspect of the present invention; and [0066] b. at least one active ingredient is added to the product of step a. whereby the active ingredient is essentially positioned within the pore structure of the product of step a. According to a further preferred embodiment of the second aspect of the present invention there is provided a method of preparing non-porous suspension particles (including an active ingredient) wherein the active ingredient is applied, by e.g. a coating process, as an outer layer on solid, non-porous, excipient particles (paragraph 0067). According to a further preferred embodiment of the second aspect of the present invention there is provided a method of applying a drug release retarding outer membrane layer to the suspension particles as set out above and where the membrane layer is composed of non-polymeric- or polymeric materials such as calcium phosphate, ethyl cellulose, methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate (paragraph 0068). A pharmaceutical composition, constituting a spray suspension comprising at least one liquid excipient and at least one solid excipient which essentially is insoluble in the liquid excipient, and at least one pharmaceutical active ingredient (claim 1). A pharmaceutical composition in accordance with claim 1, characterised in that the excipient particles together with the active ingredient forms a plurality of larger individual particles (suspension particles) (see claim 11). A pharmaceutical composition in accordance with claim 11, characterised in that the composition also contains at least one additional solid excipient which is capable of forming an outer membrane layer around the suspension particles, where the membrane layer retards the drug release and where the membrane layer is composed of non-polymeric- or polymeric materials such as calcium phosphate, ethyl cellulose, methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate (see claim 14). It should be noticed that Hoppu et al. teach that an advantage to the method of the invention is that difficult, moisture sensitive, electrically charged pharmaceutical substrates can be made more easily processable. The coating generated by the method is thin, dense and smooth; moreover the coating layers deposited by ALD are pinhole- free and very conformal. The pharmaceutical formulations obtained by the methods of the present invention are uniform in the content, which ensures that the same active pharmaceutical ingredient dose is delivered within each dosage form. In addition, the pharmaceutical formulations of the present invention have good protection against moisture, oxygen and light. Furthermore, poor drug solubility may be overcome with an individually tailored coating to allow for modified or sustained release in a specific environment (see paragraph 0010). A coating layer in accordance with the present invention may have various thicknesses, depending upon the particular application. In the coating process usually a coating that is as thin as possible is desirable such that it will be sufficiently thick in order to have the desired properties. ALD layer thickness can also be used to control the release of pharmaceutical substance and consequently control the drug dissolution time. The layer thickness can be defined by ALD cycles. For example, one ALD cycle of TMA and water results 0,1 nm thick AI2O3 coating. In one embodiment of the present invention, wherein trimethyl aluminum (CH3)3AI is used as a precursor, the thickness of the coating is within the range of 1 nm to 500 nm, more preferably in the range of 1 of 100 nm, most preferably from 5 to 15 nm. However, the coating layer may have any thickness between 1 nm and 500 μιτι. The thickness of the coating layer depends on the pharmaceutical substance, pharmaceutical ingredients and the desired final dosage form (paragraph 0028, Hoppu et al.). different coating layers may be used to produce different pharmaceutical dosage forms, such as immediate release, controlled release, and/or combinations of both immediate and controlled release dosage forms. Controlled release dosage forms, may include particles or beads containing a drug or active agent, where the particles or beads are coated with a release- controlling polymer. Controlled release beads may comprise an inert core, coated with an inner drug-containing layer and an outer membrane layer controlling drug release from the inner layer. The inert core may be a sphere or bead of sugar, a hydrophilic cellulosic polymer, or a crosslinked hydrophilic synthetic polymer (paragraph 0032, Hoppu et al.). In the case where the claimed ranges for the amounts of ingredients 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). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). It is within the purview of the skilled artisan to optimize the amounts of ingredients and particle sizes. An ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Hoppu et al. and Ek because both references teach controlled, sustained, or modified release pharmaceutical compositions. With regard to the limitations claims 11-15 they are written in product-by-process format and "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). See also Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). However, in the context of an infringement analysis, a product-by-process claim is only infringed by a product made by the process recited in the claim. Id. at 1370 ( "a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim" ).
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 the teachings of Hoppu et al. and Ek by making the core with a median particle size on a volume average basis between 0.1mm and 10 mm because Toledano et al. teach a process for coating a solid, water-insoluble particulate matter, with a metal oxide comprising: (a) contacting the solid, water-insoluble particulate matter with an ionic additive and an aqueous medium to obtain a dispersion of said particulate matter having positive charges on its surface; (b) subjecting the particulate matter to a coating procedure comprising precipitating a metal oxide salt onto the surface of the particulate matter to form a metal oxide layer thereon to thereby obtain particulate matter coated by a metal oxide coating layer; (c) repeating step (b) at least 4 more times; and (d) aging said coating layer. The invention further relates to particles comprising a particulate matter coated by a metal oxide layer, to a use of the particles for topical administration, and to a method for preventing, reducing, or eliminating pests at a locus, using the particles (see abstract) The present invention is based on the finding of a manner of obtaining a thick and dense coating of metal oxide on a solid water-insoluble particulate matter. The formation of the metal oxide layer by the new method is irreversible, i.e. it does not erode or disintegrate upon dispersion in water. The new method further enables to obtain a more dense layer and is capable of fine tuning of the width of the metal oxide layer, thus allowing better control of the release of the active ingredient from the microparticles upon application on a surface (such as skin or mucosal membrane, or pest-infested surface) (paragraph 0022). Further provided by the invention are particles comprising a core composed of a solid, water insoluble particulate matter; said core is coated by a metal oxide layer; wherein said metal oxide layer is substantially not in an amorphous and/or not in a crystalline form (paragraph 0035). The “solid, water-insoluble particulate matter” constitutes the “core” of the particles obtained by the process. The solid, water-insoluble particulate matter, is preferably in such a state of subdivision that it can be suspended in water, e.g. in the form of a finely-divided powder having a D90 (see definition below), preferably in the range of 0.3-50 micron. Such a particulate matter can readily be suspended in an aqueous systems by stirring, with or without the aid of a surfactant. The “solid, water-insoluble particulate matter” may be comprised of the active ingredient per se or may be comprised of the active ingredient and excipients (e.g. solid carrier) (paragraph 0044). The core (i.e. solid, water insoluble particulate matter) may be of any shape for example rod-like, plate-like, ellipsoidal, cubic, or spherical shape (paragraph 0049). Referring to size of particles will be through their D90 meaning that 90% of the particles have the stated dimension or less (measured by volume). Thus, for examples, for spherical particles stated to have a diameter of 10 micrometer (“microns”), this means that the particles have a D90 of 10 microns. The D90 may be measured by laser diffraction. For particles having a shape other than spheres, the D90 refers to the mean average of the diameter of a plurality of particles (paragraph 0050). In the case of cores having a spherical shape, the diameter (D90) may be in the range of 0.3 to 90 microns, preferably 0.3 to 50 microns, more preferably 1 to 50, even more preferably 5 to 30 microns (paragraph 0051). By the term “D90 may be in the range of 0.3 to 90 microns” is meant that 90% by volume of the particles (in this case the particle's core) may be less than or equal to a value in the range of 0.3 to 90 microns (paragraph 0052). For generally cubic-shaped cores or cores having a shape resembling that of a cube, the mean size of a side may be in the range 0.3 to 80 microns, preferably 0.3 to 40 microns, more preferably 0.8 to 40, even more preferably 4 to 15 microns (paragraph 0053). For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, the largest dimension (that of the longest axis) is typically in the range 10 to 100 microns, preferably 15 to 50 microns; and the smallest dimension is typically in the range 0.5 to 20 microns, and more preferably 2 to 11 microns (paragraph 0054). According to a preferred embodiment of the present invention the particles (coated particulate matter) have a diameter of 0.5-100 micron. More preferably the diameter of the particles is in the range 1-50 micron and most preferably in the range 2-30 micron (paragraph 0178). Preferably the solid, water insoluble particulate matter is a dermatological active agent (paragraph 0124). Preferably the dermatological active agent is selected from antifungal agents, antibacterial agents, anti-inflammatory agents, antipuritic agents, anti psoriatic agent, and anti acne agents. The dermatological agent may also be combinations of any of the above agents (paragraph 0125). The dermatological active agent may be for example antifungal agents such as ketoconazole, bacteriostatic drugs such as metronidazole or erythromycin, bactericidal drugs such as bacitracin, corticosteroids such as mometasone furoate, methylprednisolone aceponate, prednicarbate, triamcinolone acetonide, fluocinonide, desoximetasone, bethasone valerate or mometasone furoate, antipruritic agent such as doxepin hydrochloride, and anti acne agents such as benzoyl peroxide, azelaic acid, retinoids such as tretinoin (all trans retinoic acid), tazarotene, iso-tretinoin or adapalene (paragraph 0127). In the case where the claimed ranges for thickness “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 and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration or particle size will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). It is within the purview of the skilled artisan to optimize the amounts of ingredients and particle sizes. An ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Hoppu et al., Ek, and Toledano et al. because all of the references teach controlled, sustained or modified release pharmaceutical compositions. With regard to the limitations claims 11-15 they are written in product-by-process format and "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). See also Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). However, in the context of an infringement analysis, a product-by-process claim is only infringed by a product made by the process recited in the claim. Id. at 1370 ( "a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim"
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 was 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.
Response to Arguments
Applicant's arguments filed 17 March 2026 have been fully considered but they are not persuasive.
Applicant argues Hoppu and Ek are directed at very different goals-while Hoppu aims to produce separate individual particles via a dry process, Ek aims to create a spray formulation via a solution-based process. The examiner's analysis is based on hindsight as it starts from the claimed invention to look for motivations to fill the gap between the prior art and the claimed invention (why an additional polymer layer may be needed). Section 103 expressly requires considering the claimed invention as a whole. Focusing the Section 103 inquiry on a particular aspect of the invention that differs from the prior art improperly disregards the "as a whole" statutory mandate. MPEP § 2141.02. See Jones V. Hardy, 727 F.2d 1524, 1530 (Fed. Cir. 1984); Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1275 (Fed. Cir. 2004). ("This form of hindsight reasoning, using the invention as a roadmap to find its prior art components, would discount the value of combining various existing features or principles in a new way to achieve a new result-often the very definition of invention."); Princeton Biochemicals, Inc. V. Coulter, Inc., 411 F.3d 1332, 1337 (Fed. Cir. 2005); Allergan, Inc. V. Apotex, Inc., 754 F.3d 952 (Fed. Cir. 2014). The claimed invention as a whole requires coating separate drug particles with both an inner metal oxide layer and an outer polymer layer. Before the current application, there was no suggestion that a combination of an inner metal oxide and an outer polymer coating is beneficial to a drug formulation.
The above assertions are not found persuasive because first in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Second, the combination does not rely on hindsight. To make the record clear the examiner started from the explicit teachings of Hoppu et al. (individual pharmaceutical particles with thin conformal aluminum oxide coatings via dry ALD), identified the known desirability of outer polymer coatings for further release control and barrier properties (Ek’s polyamide coatings or membranes) and looked to Toledano for the established techniques and results of producing pin-hole-free, conforming metal oxide layers on pharmaceutical particles that can incorporate polymeric components. These motivations and teachings are present in the prior art itself and in the knowledge of one of ordinary skill in the art working in pharmaceutical particle coating. Applicant’s characterization that the analysis “starts from the claimed invention to look for motivations to fill the gap” misstates the proper inquiry under KSR Int’l Co. V.. Teleflex Inc., 550 U.S. 398 (2007), and MPEP 2141-2145. The prior art provided both the elements and the reason to combine them for the predictable result of multi-layer coated pharmaceutical particles having the recited size, thickness, conformality, and pin-hole-free attributes.
Applicant then argues as Dr. Wang explained in her declaration submitted on October 2, 2025 ("Wang Declaration"), it is very difficult to apply a conformal and pin-hole free polymer coating to individual small particles with a particle size of between 0.1 µm and 20 µm, because small particles tend to agglomerate during the coating process, leading to pin-holes. Wang Declaration, T 3. Hoppu also discloses "the processing of nanoparticles has been extremely laborious due to electricity, physical interactions and their natural tendency for aggregation." Hoppu, [0013]. Ek's teachings regarding a release retarding membrane are not directed at nanoparticles with the claimed size (between 0.1 µm and 20 µm). Indeed, Ek only discloses applying a release retarding membrane when "the solid excipient is in the form of relatively large, pre-formed, non-porous particles." Ek, [0022]. Example 7 explains "relatively large" particles can refer to particles of 45-106 µm. More importantly, avoiding agglomeration of nanoparticles to create a pin-hole free coating is not an issue in Ek because Ek aims to create a spray formulation via a solution-based process. Further, while Ek discloses that a release retarding membrane can be applied to suspension particles by "a coating process" (Ek, [0022], [0046]), Ek does not disclose any coating process at all and never tested any such coating process in its examples. Ek, Examples 1-8. As such, a POSITA would not have had a reasonable expectation of success in combining Hoppu and Ek to create separate individual coated particles with a conformal and pin-hole free polymer coating. Nothing suggests Ek's release retarding membrane can be applied to create separate individual particles with a particle size of 0.1-20 micron, much less to create "separate individual particles. wherein the outer polymer coating layer conforms to the inner metal oxide coating layer and is substantially pin-hole free."
The above assertions are not found persuasive because one of ordinary skill in the art would have been motivated to produce multilayer coated pharmaceutical particles 9thin inner aluminum oxide layer plus outer polyamide polymer layer) for improved stability, processability of individual particles, and controlled release would combine Hoppu’s ALD aluminum oxide coatings on discrete small/nano-scale pharmaceutical particles with Ek’s polyamide membrane teachings and Toledano’s guidance on achieving dense, pin-hole free, conforming coatings. The claimed particle size range , layer thickness, conformality, and substantially pin-hole free character are all within the capabilities and teachings of the combined references as described above in detail. Applicant’s emphasis on agglomeration difficulties and process differences (dry versus solution-based) confuses process limitations with product obviousness. The claim is directed to a composition of separate individual coated particles having the recited structural and dimensional features, not a specific method of manufacture. Even if one of ordinary skill in the art elected to apply the outer polyamide layer via a technique adapted from Ek or Toledano after Hoppu’s dry ALD step, the expected result would be the claimed multilayer particles. Known challenges or nanoparticles handling are precisely the problems the cited art addresses with conformal ALD and controlled coating methods; they do not render the combination non-obvious or the claimed product unattainable. Applicant has not shown that the prior art teaces away from coating particles in the 0.1 to 20 micron range with an outer polyamide layer over aluminum oxide underlayer while maintain separate individual particles and a substantially pin-hole free conformal outer coating. Furthermore, the examiner reminds Applicant that the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). The arguments therefore fail to rebut the prima facie case of obviousness.
Applicant also argues as the only teaching about a polymer coating comes from Ek, the combined teachings of the references cited in the Office Action would not have led one of ordinary skill in the art to arrive at a pharmaceutical composition comprising separate individual nanoparticles (particle size of 0.1-20 micron) comprising a drug-containing core enclosed by a thin polymer coating layer (thickness of 0.1 nm to 400 nm) that is conformal and substantially pin-hole free, with a reasonable expectation of success.
The above assertions are not found persuasive because first Hoppu is not limited to inorganic metal oxide coatings. It expressly teaches the use of Atomic Layer Deposition (ALD) and Molecular Layer Deposition (MLD) techniques to deposit organic polymers or hybrid organic-inorganic layers onto pharmaceutical particles or substrates. Hoppu teaches that such organic or hybrid coatings (including via MLD or organic materials such as sugars/sweeteners) can be applied as thin, conformal layers, lone or in combination with metal oxide layers to form multilayer or nanolaminate structures that provide controlled release, taste masking or other functional benefits while maintaining individual, discrete particles. Hoppu therefore supplies an independent teaching of polymer (organic) coatings on the same class of pharmaceutical particles that receive aluminum oxide coatings, including the ability to create sequential layers. Ek specifically identifies polyamide among suitable polymers for outer membrane coating layers that retard or control release in pharmaceutical particle formulations. Ek’s teaching supplies a particular, well known polymer (polyamide) that one of ordinary skill in the art would select when seeking an outer organic polymer layer for additional barrier or release control functions. One of ordinary skill in the art starting from Hoppu’s individual pharmaceutical particles coated with a thin conformal aluminum oxide layer via ALD would have been motivated to apply an additional outer polymer coating to further modulate release, improve barrier properties, or enhance processability as described above-precisely the multilayer approach of Hoppu itself contemplates through sequential ALD/MLD depositions or hybrid layers. Ek’s teaching supplies a particular, well known polymer (polyamide) that one of ordinary skill in the art would select when seeking an outer organic polymer layer for additional barrier or release control functions. Even further, Toledano confirms that polymers can be successfully integrated into (or applied with) metal oxide coatings on such particles to achieve dense, conforming, pin-hole free coverage. The combination therefore provides both the motivation and a reasonable expectation of success in arriving at the claimed product with the claimed dimensional ranges. No unpredictable result or technical barrier is present that would have undermined the expectation of success. Applicant’s premise that polymer coating teachings originate solely from Ek is incorrect. Even if Ek were the sole source of the polyamide identification, the remaining references, supply the foundational particle-coating platform, multi-layer capability, and techniques for achieving conformal pin-hole-free coverage, rendering the addition of a polyamide outer layer an obvious and predictable refinement. The argument therefore fails to rebut the prima facie case of obviousness under 35 USC 103. The rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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