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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13 July 2026 has been entered.
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 13 July 2026 are acknowledged and have been fully considered due to the entered request for continued examination. Claims 1, 8-12, 14-23 and 37-39 are pending. Claims 1, 8-12, and 14-18 are under consideration in the instant office action. Claims 19-23 and 37-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claims.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 2-7, 13, 24-36 and 40-41 are canceled. Applicant’s claim amendments necessitated a new ground of rejections as set forth below.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Moot Arguments
Applicant’s arguments with respect to claim(s) 1, 8-12, and 14-18 have been considered but are moot because the new ground of rejections as set forth below.
New Objections/Rejections
Claim Objections
Claims 1 and 11-12 are objected to because of the following informalities: the term “Epinephrine” is capitalized in the middle of sentences. Appropriate correction is required.
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 of this title, 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 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 1, 10-12, and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over Schobel et al. (US2017/0290776, IDS reference) in view of Lim et al. (US 2020/0046637, newly cited, IDS reference 08/28/2024) and Surakitbanham et al. (WO2017/218918, newly cited).
Applicant Claims
Applicant claims “An oral solid dosage form comprising:
15-70 wt.% of an Epinephrine hormone or pharmaceutically acceptable salt or solvate thereof; 10-40 wt.% of a matrix former comprising gelatin, pullulan, starch, or combinations thereof; 10-40 wt.% of a structure former comprising mannitol, dextrose, lactose, galactose, cyclodextrin, or combinations thereof; 0.1-1 wt.% edetate disodium; 0.1-5 wt.% sodium metabisulfite; and a pH modifier.” Dependent claims thereof recite limitations further limiting different ingredients.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Schobel et al. teach a sublingual film with 46.4 wt% epinephrine bitartrate, 11.54 wt% HPMC, 27.92 wt% PVP, 0.12.wt% stabilizer, and 1.16 wt% artificial sweetener (example 19). Schobel et al. disclose a pharmaceutical composition, comprising: a polymeric matrix; a pharmaceutically active component in the polymeric matrix; and an adrenergic receptor interacter (see claim 1). The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a film further comprising a polymeric matrix, the pharmaceutically active component being contained in the polymeric matrix (see claim 6). The pharmaceutical composition according to claim 1, wherein the polymer matrix includes a polymer (see claim 20). The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is a chewable or gelatin based dosage form, spray, gum, gel, cream, tablet, liquid or film (see claim 23). The pharmaceutical composition according to claim 20, wherein the polymeric matrix comprises at least one polymer selected from the group of: pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, ethylene oxide, propylene oxide co-polymers, collagen, albumin, poly-amino acids, polyphosphazenes, polysaccharides, chitin, chitosan, and derivatives thereof (see claim 25). The pharmaceutical composition according to claim 1, further comprising a stabilizer (see claim 26). Additives may be included in the films. Examples of classes of additives include preservatives, antimicrobials, excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, anti-tacking agents, anti-static agents and mixtures thereof. These additives may be added with the pharmaceutically active component(s) (paragraph 0125). As used herein, the term “stabilizer” means an excipient capable of preventing aggregation or other physical degradation, as well as chemical degradation, of the active pharmaceutical ingredient, another excipient, or the combination thereof (paragraph 0126). Stabilizers may also be classified as antioxidants, sequestrants, pH modifiers, emulsifiers and/or surfactants, and UV stabilizers as discussed above and in more detail below (paragraph 0127). Antioxidants (i.e., pharmaceutically compatible compound(s) or composition(s) that decelerates, inhibits, interrupts and/or stops oxidation processes) include, in particular, the following substances: tocopherols and the esters thereof, sesamol of sesame oil, coniferyl benzoate of benzoin resin, nordihydroguaietic resin and nordihydroguaiaretic acid (NDGA), gallates (among others, methyl, ethyl, propyl, amyl, butyl, lauryl gallates), butylated hydroxyanisole (BHA/BHT, also butyl-p-cresol); ascorbic acid and salts and esters thereof (for example, acorbyl palmitate), erythorbinic acid (isoascorbinic acid) and salts and esters thereof, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT), propionic acid. Typical antioxidants are tocopherol such as, for example, α-tocopherol and the esters thereof, butylated hydroxytoluene and butylated hydroxyanisole. The terms “tocopherol” also includes esters of tocopherol. A known tocopherol is α-tocopherol. The term “α-tocopherol” includes esters of α-tocopherol (for example, α-tocopherol acetate) (paragraph 0128). pH modifiers include acids (e.g., tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, ascorbic acid, acetic acid, succininc acid, adipic acid and maleic acid), acidic amino acids (e.g., glutamic acid, aspartic acid, etc.), inorganic salts (alkali metal salt, alkaline earth metal salt, ammonium salt, etc.) of such acidic substances, a salt of such acidic substance with an organic base (e.g., basic amino acid such as lysine, arginine and the like, meglumine and the like), and a solvate (e.g., hydrate) thereof. Other examples of pH modifiers include silicified microcrystalline cellulose, magnesium aluminometasilicate, calcium salts of phosphoric acid (e.g., calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate and calcium lactate or mixtures thereof), sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g., croscarmellose sodium and/or calcium), polacrilin potassium, sodium and or/calcium alginate, docusate sodium, magnesium calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, sodium stearyl fumarate, and combinations thereof (see paragraph 0130). In other embodiments, stabilizers include ascorbyl palmitate, ascorbic acid, alpha tocopherol, butylated hydroxytoluene, buthylated hydroxyanisole, cysteine HCl, citric acid, ethylenediamine tetra acetic acid (EDTA), methionine, sodium citrate, sodium ascorbate, sodium thiosulfate, sodium metabisulfite, sodium bisulfite, etc., “Metal chelators” include, but are not limited to, EDTA, EGTA, o-phenanthroline, and citrate. “Detergents” include, but are not limited to, SDS and sodium lauroyl sarcosyl. “Chaotropes” include, but are not limited to guandinium hydrochloride, isothiocyanate, urea, and formamide. As discussed herein, stabilizers can be present in 0.0001%-50% by weight, including greater than 0.0001%, greater than 0.001%, greater than 0.01%, greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 1%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% by weight (see paragraph 0133). The examiner notes that these amounts cover the amounts of antioxidants and chelating agents. Useful additives can include, for example, gelatin, vegetable proteins such as sunflower protein, soybean proteins, cotton seed proteins, peanut proteins, grape seed proteins, whey proteins, whey protein isolates, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragancanth), pectin, water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC), carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids and polyacrylic acid esters, polymethacrylic acids and polymethacrylic acid esters, polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP), polyvinylpyrrolidone (PVP), PVA/vinyl acetate copolymer, or polycrotonic acids; also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates possessing, for example, a tertiary or quaternary amino group, such as the diethylaminoethyl group, which may be quaternized if desired; or other similar polymers (paragraph 0134). Other ingredients can include binders which contribute to the ease of formation and general quality of the films. Non-limiting examples of binders include starches, natural gums, pregelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, or polyvinylalcohols (paragraph 0136). Further potential additives include solubility enhancing agents, such as substances that form inclusion compounds with active components. Such agents may be useful in improving the properties of very insoluble and/or unstable actives. In general, these substances are doughnut-shaped molecules with hydrophobic internal cavities and hydrophilic exteriors. Insoluble and/or instable pharmaceutically active components may fit within the hydrophobic cavity, thereby producing an inclusion complex, which is soluble in water. Accordingly, the formation of the inclusion complex permits very insoluble and/or unstable pharmaceutically active components to be dissolved in water. A particularly desirable example of such agents are cyclodextrins, which are cyclic carbohydrates derived from starch. Other similar substances, however, are considered well within the scope of the present invention (paragraph 0137). The additional components can range up to about 80%, desirably about 0.005% to 50% and more desirably within the range of 1% to 20% based on the weight of all composition components, including greater than 1%, greater than 5%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, about 80%, greater than 80%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, about 3%, or less than 1% (paragraph 0135). Schobel et al. teach the sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof, saccharin and its various salts such as the sodium salt; dipeptide based sweeteners such as aspartame, neotame, advantame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. The examiner notes that dextrose and mannitol are designated as structure former in the instant application (see specification paragraph 0101 and claim 10). Emulsifiers typically used in the water-based emulsions described above are, preferably, either obtained in situ if selected from the linoleic, palmitic, myristoleic, lauric, stearic, cetoleic or oleic acids and sodium or potassium hydroxide, or selected from the laurate, palmitate, as stearate, or oleate esters of sorbitol and sorbitol anhydrides, polyoxyethylene derivatives including monooleate, monostearate, monopalmitate, monolaurate, fatty alcohols, alkyl phenols, allyl ethers, alkyl aryl ethers, sorbitan monostearate, sorbitan monooleate and/or sorbitan monopalrnitate (paragraph 0148). The amount of pharmaceutically active component to be used depends on the desired treatment strength and the composition of the layers, although preferably, the pharmaceutical component comprises from about 0.001% to about 99%, more preferably from about 0.003 to about 75%, and most preferably from about 0.005% to about 50% by weight of the composition, including, more than 0.005%, more than 0.05%, more than 0.5%, more than 1%, more than 5%, more than 10%, more than 15%, more than 20%, more than 30%, about 50%, more than 50%, less than 50%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, or less than 0.005%. The amounts of other components may vary depending on the drug or other components but typically these components comprise no more than 50%, preferably no more than 30%, and most preferably no more than 15% by total weight of the composition (paragraph 0149).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Schobel et al. do not specifically teach a freeze-dried oral solid dosage form and the incorporation of edetate disodium. These deficiencies are cured by the teachings of Lim et al. and Surakitbanham et al.
Lim et al. teach a solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form includes at least one biologically active material, and at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. A method of producing the same and a kit including the same are also provided (see abstract). A solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises:
a) at least one biologically active material, and
b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity and wherein the biologically active material is chosen from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, an active material that binds to one or more adrenergic receptors, and an N-methyl-D-aspartate receptor antagonist (see claim 1). The solid dosage form of claim 1 wherein the active material that binds to one or more adrenergic receptors is adrenaline (epinephrine), or an adrenaline salt (see claim 4). There is an unmet need in the medical field for dosage forms, which have a rapid dissolution rate in the oral cavity. The previous attempts to overcome the problems associated with solid dosages forms include effervescent tablets, films, chewable tablets, disintegrants and wicking agents. These dosage forms are particularly useful for patients who have difficulty in swallowing e.g. children and elderly people. There are several technologies used for preparing such dosage forms, including freeze-drying, spray-drying, tablet moulding and tablet compression (paragraph 0004). According to another aspect of the present invention there is provided a method to produce the solid dosage form of the present invention comprising the steps of:
(a) combining at least one matrix forming agent with a biologically active material to form a homogeneous mixture; and
(b) freeze drying the mixture to prepare the solid dosage form of the present invention (see paragraph 0021). In a preferred embodiment of the present invention, the mixture comprising the matrix forming agent and the biologically active material is measured (by weight or volume) into a preformed plastic or aluminium blister mould (individual dose). The blister mould is placed into a freeze dryer for 24 hours and the resultant fast dissolving solid dosage form is then sealed with aluminium or plastics foil to prevent moisture absorption. Preferably, the freeze drying technique is used to remove the solvent from the blister mould. Sealing the solid dosage form into the plastic or aluminium foil prevents or reduces moisture absorption (paragraph 0328).
Surakitbanham et al. teach in claim 1 a pharmaceutical composition comprising:
epinephrine;
one or more antioxidant, the antioxidant being present in the composition in an amount of about 0.07 wt. % or less (e.g., about 0.05 wt. % or less, about 0.04 wt. % or less, about 0.035 wt. % or less, or the like, such a down to about 0.005 wt. % or down to about 0.01 wt. %) (e.g., on a free base basis);
one or more pH buffering agent;
one or more chelating agent;
one or more tonicity modifier; and
an aqueous medium.
In a specific embodiment, a composition herein formulated into pharmaceutical dosage forms of a solid or gel dosage form, such as a fast dissolving composition, e.g., an orally disintegrating or dissolving tablet or other dosage form. In specific embodiments, a solid dosage form optionally comprises a lyophilized formulation (e.g., lyophilized from an aqueous formulation, such as described herein) (paragraph 045). In certain embodiments, a composition provided herein comprises edetate (e.g., as a chelating agent). In some embodiments, the composition comprises about 0.01 wt. % of edetate or less (e.g., about 0.001 wt. % to about 0.01 wt. %) (paragraph 030). Any suitable chelating agent is optionally utilized. In specific embodiments, the chelating agent is, by way of non-limiting example, edetate. In various embodiments, edetate is ethylenediaminetetraacetic acid, or an anion (e.g., -1, -2, -3, or -4 anion), solvate, or salt thereof, such as a compound represented by the formula: (ROOCCH2)2NCH2CH2N(CH2COOR)2, wherein each R is independently H or a negative charge (which negative charge may be in association with a cationic species, such as Na+, Ca2+, ]¾0+, or the like). In various embodiments herein, compositions comprising edetate are formulating using ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, such as, by way of non-limiting example, calcium disodium, edetate disodium, edetate disodium anhydrous, edetate sodium, edetate disodium dehydrate, edetate tetrasodium, and/or a combination thereof. In some embodiments, chelating agent (e.g., edetate) is utilized in an amount of about 0.001 wt % to about 1 wt. %. In specific embodiments, edetate disodium is utilized to formulation a composition herein. In further or alternative embodiments, chelating agent (e.g., edetate, such as formulated with edetate disodium) is utilized in an amount of about 0.001 wt. % to about 0.05 wt. % (e.g., about 0.005 wt. % to about 0.05 wt. %, about 0.005 wt. % to about 0.01 wt. %, or the like). In some embodiments, the weight ratio of chelating agent (e.g. edetate - e.g., using edetate disodium in formulating) to epinephrine is about 1 :20 to about 1 :2 (paragraph 079).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Schobel et al. by preparing the oral solid dosage form in a freeze-dried form because Lim et al. teach a solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form includes at least one biologically active material, and at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. A method of producing the same and a kit including the same are also provided (see abstract). A solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises:
a) at least one biologically active material, and
b) at least one matrix forming agent,
wherein the dosage form substantially dissolves in the oral cavity and wherein the biologically active material is chosen from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, an active material that binds to one or more adrenergic receptors, and an N-methyl-D-aspartate receptor antagonist (see claim 1). The solid dosage form of claim 1 wherein the active material that binds to one or more adrenergic receptors is adrenaline (epinephrine), or an adrenaline salt (see claim 4). There is an unmet need in the medical field for dosage forms, which have a rapid dissolution rate in the oral cavity. The previous attempts to overcome the problems associated with solid dosages forms include effervescent tablets, films, chewable tablets, disintegrants and wicking agents. These dosage forms are particularly useful for patients who have difficulty in swallowing e.g. children and elderly people. One of ordinary skill in the art would have been motivated to do so because Lim et al. teach that there are several technologies used for preparing such dosage forms, including freeze-drying, spray-drying, tablet moulding and tablet compression (paragraph 0004). According to another aspect of the present invention there is provided a method to produce the solid dosage form of the present invention comprising the steps of:
(a) combining at least one matrix forming agent with a biologically active material to form a homogeneous mixture; and
(b) freeze drying the mixture to prepare the solid dosage form of the present invention (see paragraph 0021). In a preferred embodiment of the present invention, the mixture comprising the matrix forming agent and the biologically active material is measured (by weight or volume) into a preformed plastic or aluminium blister mould (individual dose). The blister mould is placed into a freeze dryer for 24 hours and the resultant fast dissolving solid dosage form is then sealed with aluminium or plastics foil to prevent moisture absorption. Preferably, the freeze drying technique is used to remove the solvent from the blister mould. Sealing the solid dosage form into the plastic or aluminium foil prevents or reduces moisture absorption (paragraph 0328).The examiner reminds Applicant that 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). Stabilizers such as antioxidants and metal chelators, pH modifiers, and other pharmaceutical ingredients are conventional pharmaceutical ingredients known to perform a known function. Selection of such ingredients based on their known intended use is prima facie obvious even if the list is long. Furthermore, in the case where the claimed concentration or amount of the active agent and other ingredients "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). One of ordinary skill in the art would have had a reasonable expectation of success in producing the Schobel et al. and Lim et al. because both references solid dosage form oral compositions containing epinephrine and other substantially similar ingredients.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Schobel et al. and Lim et al. by utilizing edetate disodium as a chelating agent in the composition because Surakitbanham et al. teach in claim 1 a pharmaceutical composition comprising:
epinephrine;
one or more antioxidant, the antioxidant being present in the composition in an amount of about 0.07 wt. % or less (e.g., about 0.05 wt. % or less, about 0.04 wt. % or less, about 0.035 wt. % or less, or the like, such a down to about 0.005 wt. % or down to about 0.01 wt. %) (e.g., on a free base basis);
one or more pH buffering agent;
one or more chelating agent;
one or more tonicity modifier; and
an aqueous medium.
One of ordinary skill in the art would have been motivated to do so because Surakitbanham et al. teach that in a specific embodiment, a composition herein formulated into pharmaceutical dosage forms of a solid or gel dosage form, such as a fast dissolving composition, e.g., an orally disintegrating or dissolving tablet or other dosage form. In specific embodiments, a solid dosage form optionally comprises a lyophilized formulation (e.g., lyophilized from an aqueous formulation, such as described herein) (paragraph 045). In certain embodiments, a composition provided herein comprises edetate (e.g., as a chelating agent). In some embodiments, the composition comprises about 0.01 wt. % of edetate or less (e.g., about 0.001 wt. % to about 0.01 wt. %) (paragraph 030). Any suitable chelating agent is optionally utilized. In specific embodiments, the chelating agent is, by way of non-limiting example, edetate. In various embodiments, edetate is ethylenediaminetetraacetic acid, or an anion (e.g., -1, -2, -3, or -4 anion), solvate, or salt thereof, such as a compound represented by the formula: (ROOCCH2)2NCH2CH2N(CH2COOR)2, wherein each R is independently H or a negative charge (which negative charge may be in association with a cationic species, such as Na+, Ca2+, ]¾0+, or the like). In various embodiments herein, compositions comprising edetate are formulating using ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, such as, by way of non-limiting example, calcium disodium, edetate disodium, edetate disodium anhydrous, edetate sodium, edetate disodium dehydrate, edetate tetrasodium, and/or a combination thereof. In some embodiments, chelating agent (e.g., edetate) is utilized in an amount of about 0.001 wt % to about 1 wt. %. In specific embodiments, edetate disodium is utilized to formulation a composition herein. In further or alternative embodiments, chelating agent (e.g., edetate, such as formulated with edetate disodium) is utilized in an amount of about 0.001 wt. % to about 0.05 wt. % (e.g., about 0.005 wt. % to about 0.05 wt. %, about 0.005 wt. % to about 0.01 wt. %, or the like). In some embodiments, the weight ratio of chelating agent (e.g. edetate - e.g., using edetate disodium in formulating) to epinephrine is about 1 :20 to about 1 :2 (paragraph 079). It would have been prima facie obvious to substitute the chelating agents of Schobel et al. with the edetate disodium because the chelating agents are functionally equivalent. The examiner reminds Applicant that 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). Stabilizers such as antioxidants and metal chelators (edetate disodium), pH modifiers, and other pharmaceutical ingredients are conventional pharmaceutical ingredients known to perform a known function. Selection of such ingredients based on their known intended use is prima facie obvious even if the list is long. Furthermore, in the case where the claimed concentration or amount of the active agent and other ingredients "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). One of ordinary skill in the art would have had a reasonable expectation of success in producing the Schobel et al., Lim et al., and Surakitbanham et al. because all of the references teach solid dosage form oral compositions containing epinephrine and other substantially similar ingredients.
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 at before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schobel et al. (US2017/0290776, IDS reference) in view of Lim et al. (US 2020/0046637, newly cited, IDS reference 08/28/2024) and Surakitbanham et al. (WO2017/218918, newly cited) as applied to claims 1, 10-12, and 14-18 above, and further in view of Wong et al. (US Patent No. 7972621, Previously cited).
Applicant Claims
Applicant claims an oral solid dosage form comprising the ingredients as recited. Instant claims 8-9 recite different types of gelatin as the matrix material.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of Schobel et al., Lim et al., and Surakitbanham et al. are described above in detail and are incorporated herein by reference. Additionally, Schobel et al. teach mucosal surfaces, such as the oral mucosa, are a convenient route for delivering drugs to the body due to the fact that they are highly vascularized and permeable, providing increased bioavailability and rapid onset of action because it does not pass through the digestive system and thereby avoids first pass metabolism. In particular, the buccal and sublingual tissues offer advantageous sites for drug delivery because they are highly permeable regions of the oral mucosa, allowing drugs diffusing from the oral mucosa to have direct access to systemic circulation. This also offers increased convenience and therefore increased compliance in patients. For certain drugs, or pharmaceutically active components, a permeation enhancer can help to overcome the mucosal barrier and improve permeability. Permeation enhancers reversibly modulate the penetrability of the barrier layer in favor of drug absorption. Permeation enhancers facilitate transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and modulated by a variety of parameters, such as but not limited to film size, drug loading, enhancer type/loading, polymer matrix release rate and mucosal residence time.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Schobel et al., Lim et al., and Surakitbanham et al. do not specifically teach the different types of gelatin recited in claim 8 and the high molecular weight fish gelatin recited in claim 9. These deficiencies are cured by the teachings of Wong et al.
Wong et al. teach a pharmaceutical composition comprising a carrier and an active ingredient, wherein the carrier is at least one fish gelatin predetermined on the basis of the molecular weight profile of the gelatin. In some embodiments, particularly when the concentration of carrier comprises a relatively lower percentage of the total composition, the carrier may be exclusively a high molecular weight fish gelatin, or may be comprised of a mixture with standard molecular weight gelatin in which high molecular weight gelatin comprises a predominant portion. In those embodiments where the concentration of carrier comprises a relatively larger percentage of the total composition, the carrier may be an exclusively standard molecular weight fish gelatin, or may be comprised of a mixture in which standard molecular weight gelatin comprises a predominant portion. Thus, compositions may be designed to optimize performance for various required gelatin concentration formulations (see abstract). In some embodiments, the at least one fish gelatin carrier further comprises a first gelatin further comprising a high molecular weight gelatin in which more than 50%, preferably more than 60% and most preferably more than 70% of the molecular weight distribution of the gelatin is greater than 30,000 daltons. In other embodiments, the at least one fish gelatin carrier further comprises a second gelatin further comprising a standard molecular weight gelatin in which more than substantially 50%, preferably more than 60% and most preferably more than 70% of the molecular weight distribution of the gelatin is below than 30,000 daltons (column 4, lines 7-17). The fast dispersing dosage forms containing a single grade of fish gelatin, or combinations of fish gelatins differing in molecular weight profiles, of the instant invention enables a significant advance in the state of the art. The preferred embodiments of the dosage forms accomplish this by new and novel combinations of elements that demonstrate previously unavailable but preferred and desirable capabilities (column 4, lines 40-46). Particularly for pharmaceutical formulations, an advantageous alternative to the use of mammalian derived gelatin is the use of fish gelatin, especially non-gelling fish gelatin. Non-gelling fish gelatin is preferably obtained from cold water fish and has a sol-gel transition temperature, that is, the temperature at which a given solution of gelatin in water, transitions between a liquid and a gel state, that is lower than that of most mammalian derived gelatins. There appears to be a relationship between the temperature at which the animal or fish metabolizes food and the properties of the skin and resultant extracted gelatins (column 2, lines 47-57).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Schobel et al., Lim et al., and Surakitbanham et al. by utilizing high molecular weight fish gelatin because Wong et al. teach a pharmaceutical composition comprising a carrier and an active ingredient, wherein the carrier is at least one fish gelatin predetermined on the basis of the molecular weight profile of the gelatin. In some embodiments, particularly when the concentration of carrier comprises a relatively lower percentage of the total composition, the carrier may be exclusively a high molecular weight fish gelatin, or may be comprised of a mixture with standard molecular weight gelatin in which high molecular weight gelatin comprises a predominant portion. In those embodiments where the concentration of carrier comprises a relatively larger percentage of the total composition, the carrier may be an exclusively standard molecular weight fish gelatin, or may be comprised of a mixture in which standard molecular weight gelatin comprises a predominant portion. Thus, compositions may be designed to optimize performance for various required gelatin concentration formulations (see abstract). In some embodiments, the at least one fish gelatin carrier further comprises a first gelatin further comprising a high molecular weight gelatin in which more than 50%, preferably more than 60% and most preferably more than 70% of the molecular weight distribution of the gelatin is greater than 30,000 daltons. In other embodiments, the at least one fish gelatin carrier further comprises a second gelatin further comprising a standard molecular weight gelatin in which more than substantially 50%, preferably more than 60% and most preferably more than 70% of the molecular weight distribution of the gelatin is below than 30,000 daltons (column 4, lines 7-17). One of ordinary skill in the art would have been motivated to utilize high molecular weight fish gelatin because Wong et al. teach that the fast dispersing dosage forms containing a single grade of fish gelatin, or combinations of fish gelatins differing in molecular weight profiles, of the instant invention enables a significant advance in the state of the art. The preferred embodiments of the dosage forms accomplish this by new and novel combinations of elements that demonstrate previously unavailable but preferred and desirable capabilities (column 4, lines 40-46). Particularly for pharmaceutical formulations, an advantageous alternative to the use of mammalian derived gelatin is the use of fish gelatin, especially non-gelling fish gelatin. Non-gelling fish gelatin is preferably obtained from cold water fish and has a sol-gel transition temperature, that is, the temperature at which a given solution of gelatin in water, transitions between a liquid and a gel state, that is lower than that of most mammalian derived gelatins. There appears to be a relationship between the temperature at which the animal or fish metabolizes food and the properties of the skin and resultant extracted gelatins (column 2, lines 47-57). It should be also noticed that Schobel et al. teach mucosal surfaces, such as the oral mucosa, are a convenient route for delivering drugs to the body due to the fact that they are highly vascularized and permeable, providing increased bioavailability and rapid onset of action because it does not pass through the digestive system and thereby avoids first pass metabolism. In particular, the buccal and sublingual tissues offer advantageous sites for drug delivery because they are highly permeable regions of the oral mucosa, allowing drugs diffusing from the oral mucosa to have direct access to systemic circulation. This also offers increased convenience and therefore increased compliance in patients. For certain drugs, or pharmaceutically active components, a permeation enhancer can help to overcome the mucosal barrier and improve permeability. Permeation enhancers reversibly modulate the penetrability of the barrier layer in favor of drug absorption. Permeation enhancers facilitate transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and modulated by a variety of parameters, such as but not limited to film size, drug loading, enhancer type/loading, polymer matrix release rate and mucosal residence time. Furthermore, the examiner reminds Applicant that 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) (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.) The skilled artisan would have had a reasonable expectation of success in combining the teachings of Schobel et al., Lim et al., and Surakitbanham et al. and Wong et al. because all of the references are drawn to an oral solid dosage form for rapid release of active agent to the buccal or sublingual route.
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 at 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 claim is allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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