The International Bureau of WIPO 34, chemin des Colombettes 1211 Geneva 20, Switzerland Date of issuance of this report 25 March 2014 (25.03.2014) AnthOHZEd officer ... Llngfel Bal Facsimile No. +41 22 338 82 70 Form PCT/IB/373 (January 2004) e-mail: pt02.pct@wipo.int

Regarding claim 36, Cartt teaches wherein the pharmaceutical solution comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w) (para[0015]).

Regarding claim 37, Cartt teaches wherein the pharmaceutical solution comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about75% (w/w) (para[0015]).

Regarding claim 44, Cartt teaches wherein the administration of the pharmaceutical solution comprises spraying at least a portion of the therapeutically effective amount of the benzodiazepine into at least one nostril (para[0029]).

Regarding claim 45, Cartt teaches wherein the administration of the pharmaceutical solution comprises spraying at least a portion of the therapeutically effective amount of the benzodiazepine into each nostril (para[0029]).

A concise explanation of the relevance of each patent, publication or other information providedthat is not in Englishis as follows: Pursuant to 37 CFR §1.98(a)(3)(i), a copy of a translation, or a portion thereof, of the non-English language reference(s) is provided herewith.

lt would have been obvious to one of ordinary skill in the art formulating the composition of Sonne to incorporate the alkyl glycosidase of Meezan in orderto increase nasal absorption, and thus the bioavailability, of the active ingredient.

Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE Under the Paperwork Reduction Act of 1995, no persons required to respond to a collection of information unless it contains a valid OMB control number.

(Currently Amended) The pharmaceutical solution of elat#2 claim 1, wherein the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam,nitrazepam, oxazepam,lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

(Withdrawn) The methodof claim 23, wherein the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,diazepam,flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

Representative examples of useful surface stabilizers include but are not limited to Low viscosity hydroxypropyl cellulose (HPC or HPC-SL); hydroxypropyl methyl cellulose (HPMC); hydroxymethy] cellulose (HMC); ethycellulose; povidone; Pluronics; sodium deoxycholate; PEG-Phospholipids; Tyloxapol and other approved tritons, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor o1] derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens” suchas ¢.g., Tween 20° and Tween 80° (ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550" and 934® (Union Carbide)), polyoxyethylenestearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodtum, methylcellulose, hydroxyethylcellulose, hydroxypropyimethylcellulose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl aleohol (PVA), 4-(1,1,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e¢.g., Pluronics F68® and F108°, which are block copolymers of ethylene oxide and propylene oxide); poloxamines(e.g., Tetronic 908°, also known as Poloxamine 908°, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508° (T-1508) (BASF Wyandotte Corporation), AQUESTIVE EXHIBIT 1004 page 1765

dimethylaminoethyl methacrylate dimethyl sulfate, 1,2 Dipalmitoyl-sn-Glycero- 3~Phosphoethanolamine-N-[Amino(Polyethylene Glycof)2000] (sodiumsalt) (also known as DPPE-PEG(2000)-Amine Na) (Avanti Polar Lipids, Alabaster, Al), Poly(2-methacryloxyethyl trimethylammonium bromide) (Polysciences,Inc., Warrington, PA) (also known as $1001), poloxamines such as Tetronic 908°, also known as Poloxamine 908°, whichis a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.), lysozyme, long-chain polymers suchas alginic acid, carrageenan (FMC Corp.), and POLYOX (Dow, Midland, MI).

Such ranges tend to afford an optimal balance betweenefficient particle size reduction and media erosion but are in no waylimiting Theattrition time can vary widely and depends primarily upon the particular mechanical means and processing conditions selected.

In general, suitable polymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding.

Amethod of making an injectable nanoparticulate olanzapine composition that produces an intramuscular depot upon administration comprising: contacting particles of olanzapineorasalt thereof with at least one surface stabilizer for a time and under conditions sufficient to provide a AQUESTIVE EXHIBIT 1004 page 1796

Canada Central African Republic Congo Swiwerland Céte dIvoire Cameroon Czechoslovakia Germany Denmark Madagascar Mali Mongolia Mauritania Malawi Netherlands Norway Poland Romania Sudan Swedea Senegal Sovict Union Chad Togo

Thus, the preferred exemplary embodiments exhibit significant increases in viscosity in response to substantially simultaneous upshifts in both temperature and pH to those conditions encountered in the ocular milieu those skilled or at typical injectable drug delivery sites.

Thus, an exemplary composition of the present invention comprises a homogeneous association complex of a macromolecular mixture of methylcellulose, a polysaccharide available from Dow Chemical under the trade name Methocel, and a cross-linked polyacrylic acid such as Carbopol 940, a hydrophilic acrylic polymer available from the B. F. Goodrich Company.

such as cefoxitin, n~formamidoyl-thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, cefazolin, cephalori- dine, chibrorifamycin, gramicidin, bacitracin, sulfonamides: amino— glycoside antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin; nalidixic acid and analogs such as norfloxacin and the antimicrobial combination of flucalanine/pentizidone: nitrofurazones, and the like;

anti-inflammatorics such as cortisone, hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone, dexamethasone sodium phosphate, prednisone, methylpredinisolone, medrysone, fluoro-— metholone, fluocortolone, prednisolone, prednisolone sodium phosphate, triamcinolone, indomethacin, sulindac, its salts and its corresponding sulfide, and the like; (4) miotics as_echothiophate,and anticholinergics such pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, epinephrine, dipivolyl epinephraine, neostigmine, echothiophate iodide, demecarium bromide, carbachol, methacholine, bethanechol, and the like; (5) mydriatics such as atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium, eucatropine, and the like; and other medicaments used in the treatment of eye conditions or diseases such as

The publisher makes no representation, express or ot accept any legal responsibility or implied, with regard to the accuracy of the information contained in this book and canu liability for any errors or omissions that may be made.

Applications in Pharmaceutical Formulation or Technology Alpha tocopherol is primarily recognized as a source of vi— tamin E and the commercially available materials and speci- fications reflect this purpose.

Comments: «tocopherois excipient is described in the USP as a vegetable oil solution containing not less than 50.0% of total tocopherois, of which not less than 80.0% consists of varying amounts of beta, delta, and gamma tocopherols.

(5] However, a 2% v/v aqueous solution in a polyethylene cone tainer, stored at 20°C, may lose up to 15% of its benzyl alu coho] content in 13 weeksml Losses to polyvinyl chloride and polypropylene containers under similar conditions are usually 13.

Regulatory Status Included in the FDA Inactive Ingredients Guide (injections, oral capsules, solutions and tablets, topical, and vaginal prep- arations).