The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroy!, thienyl, isothiazoly!, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinoly:, benzofuryl, isobenzofury!, benzothieny!, pyrazolyl, indoiyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazoly!, oxazolyl, benzthiazoly!

The presentinvention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting ofarthritis, osteoporosis, cancer, synergy with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with standard NSAID'S and analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic AQUESTIVE EXHIBIT 1004=page 1056 AQUESTIVE EXHIBIT 1004 page 1056

Solid compositions of a similar type may also be employedasfillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.

intravenous use) a sterile injectable solution of the active ingredient Salutions of a therapeutic compoundof the present invention in either sesame or peanutoil orin aqueous propylene glycol may be employed.

)propionicacid A solution of (2S)-2-hydroxy-3-(4-methoxybenzenesulfonyl)propionic acid benzyl ester (1.0 grams, 2.8 mmole) in methanol (70 mL) wastreated with 10% palladium on activated carbon (100 mg) and hydrogenated at 3 atmospheres pressure for 3 hours in a Parr shaker.

Al- though recent efforts in using chemical enhancers have fo- cused on substances categorized as generally recognized as safe (GRAS), early work included a wide range of materi- als.

Additives that en- hance skin delivery by altering solubility of the active ingredi- ent in the formulation (including supersaturation) or by opti- AQUESTIVE EXHIBIT 1024 page 0002

Penetration of Guinea Pig Skin by Acyclovir in Different Vehicles and Correlation with the Efficacy of Topical Therapy of Experimental Cutaneous Herpes Simplex Virus Infection.

Effect of Azone and Propylene Glycol on Penetration of Trifluorothymidine Through Skin and Efficacy of Different Topical Follnulations Against Cutaneous Herpes Simplex Virus Infections in Guinea Pigs.

Effect of Penetration Enhancers on the in vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Trans dermal Foi inulations .

Perceived Barriers to Diazepam Rectal Gel Administration in the School Perceived Barrier Number Privacy/setting Access/availability of nurse Legal/delegation issues Staff anxiety/fear Lack of training None Consent of ...

In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiaz- epoxide, clobazam, clonazepam, clorazepam, demox- azepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlor- diazepoxide, clobazam, clonazepam, clorazepam, demox- azepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlor- diazepoxide, clobazam, clonazepam, clorazepam, demox- azepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlor- diazepoxide, clobazam, clonazepam, clorazepam, demox- azepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlor- diazepoxide, clobazam, clonazepam, clorazepam, demox- azepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinationsthereof.

For compounds ofthe formula NRRoR3Ru™: (i) none of R ...

Priority under 35 U.S.C. § 119 12)L] Acknowledgmentis made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or(f). a)LJAll b)L ] Some*c)L] Noneof: 1.L] Certified copies of the priority documents have been received.

... teaching at column3, lines 65-67, none of the Examples taught by Sonne suggest nasal administration of a benzodiazepine drug formulation that contains only tocopherol or tocotrienol, a alcohol and optionally an alkylglcoside. And none ...

In some embodiments, the composition consists essentially of a benZodiaZepine drug that is fully dissolved in a solvent con sisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides Wherein the solution is at least substantially free of Water.

In some embodiments, the composition consists essentially of a benZodiaZepine drug that is fully dissolved in a solvent con sisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides.

In some embodiments, the composition con sists of a benZodiaZepine drug in a form including benZodi aZepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and Water.

[0049] In some embodiments, the composition contains a benZodiaZepine drug that at least partially in a particulate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol, one or more alcohols or glycols, and an alkyl glycoside.

In some embodiments, benzo diazepine comprises a member of the group consisting of alprazolam, diazepam, ?urazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benzodiazepine particles comprise at least one member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benzodiazepine particles comprise at least one member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the benzodiazepine drug comprises at least one member ofthe group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benzodiazepine particles comprise at least one member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benzodiazepine particles comprise at least one member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and 1 5 pharmaceutically acceptable salts and combinations thereof.

HoWever, none of these documents describe aerosols of a nanoparticulate benZodiaZepine, such as loraZepam.

... compositions of nanoparticulate drugs include US. Pat. No. 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen,” and US. Pat. Nos. 5,399,363 and 5,494,683, both for “Surface Modi?ed Anticancer Nanoparticles.” None ...

For com pounds of the formula NR1R2R3R4(+): [0113] (i) none of R1-R4 are CH3 ...

Nonetheless, some patients and caretakers would prefer the transient discomfort of the present i.n. formulations to rectal administration of medica- tion in public settings.

Slovenia Slovakia Senegal Swaziland Chad Togo Tajikistan Turkmenistan Turkey Trinidad and Tobago Ukraine Uganda United States of America Uzbekistan Viet Nam Yugoslavia Zimbabwe

The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C,-C,)alkoxy, (C,-C, .

The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, suchas pyridyl, furyl, pyrroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryi, benzothienyl, pyrazolyl, indolyl, isoindoly!l, purinyi, carbazolyl, isoxazolyl, thiazolyi, oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C,- C,)alkoxy, (C,-C,,)aryloxy,trifluoromethoxy, difluoromethoxy and (C,-C,)alkyl.

The present invention also relates to a method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammai an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.

Although the surface area of the nose is not as large as that found in the lung, it does provide an effective site for the efficient systemic absorption of many conven- tional drugs, and particularly those compounds that are relatively water soluble but also lipophilic in nature (as shown by their partition- ing properties)1.

Indeed, recent studies performed in Japan and the United States would suggest that, almost invariably, the high bioavailabilities achieved with absorption enhancers for the delivery of polar compounds across mucosal membranes can be associated with tissue damage11.

It has been demonstrated that this chitosan ef- fect with various polypeptides, that include desmopressin, in- sulin, leuprolide, calcitonin, PTH, CCK-8, as well as with polar compounds for the treatment of migraine, such as alniditan, and analgesic agents such as morphine.These studies have been performed in an ovine model and in man4.

It would appear that inhalation systems – pulmonary or nasal – may soon be in development for cannabinoid delivery as part of a drive in the UK to establish whether these compounds could provide benefit in the treat- ment of pain and other conditions such as multiple sclerosis.

Update– latest news and views Adenosine receptors as potential therapeutic targets Sonya M. Kaiser and Ronald J. Quinn Antiplatelet therapies: from aspirin to GPIIb/IIIa-receptor antagonists and beyond Shaker A. Mousa Antisense oligonucleotides: a systematic high-throughput approach to target validation and gene function determination Margaret F. Taylor, Kristin Wiederholt and Fran Sverdrup Monitor– new bioactive molecules, combinatorial chemistry, invited profile In the December issue of Pharmaceutical Science & Technology Today… Update– latest news and views Synthesis and applications of novel highly efficient HPLC chiral stationary phases: a chiral dimension in drug research analysis G. Cancelliere, I. D’Acquarica, F. Gasparrini, D. Misti and C. Villani Aging processes in pharmaceutical polymers J-H. Guo Pegylated liposomal adriamycin: a review of current and future applications S. Stewart and C. Lewanski Monitor– drug delivery and analytical techniques AQUESTIVE EXHIBIT 1035 page 0007

Exemplary hydrophobic or lipophilic therapeutic agents which can be solubilized in accordance with the present invention include, but are in no way limited to, steroids such as Dexamethasone, 17-beta-Estradiol; benzodiazepenes such as Diazepam, alpraxolam, bromazepam, chlordiazepoxidem, clonazepam, estazolam, flunitrazepam, flurazepam, lorazepam, lormetazepam, mexazolam, nitrazepam, oxazepam, temazepam, and triazolam; Rapamycin and analogues; Taxol (paclitaxel) and analogues; Actinomycin D; Prostaglandins (PGEl); Vitamin A; Probucol; Batimastat; Statins (HMG-CoA Reductase Inhibitors; Trapidil (and other anti-proliferative Growth Factor Inhibitors); Cytochalasin B; and microtubule binding agents such as epothilones, elutherobin and discodermolide.

Specifically, pharmaceutical compositions of the present invention can be administered by any of the following nonlimiting exemplary routes, intraabdominal, intraarterial, intraarticular, intracapsular, intracervical, intracranial, intraductal, intradural, intralesional, intralocular, intralumbar, intramural, intranasal, intraocular, intraoperative, intraparietal, intraperitoneal, intrapleural, intrapulmonary, intraspinal, intrathoracic, intratracheal, intratympanic, intrauterine, and intraventricular.

In addition, the instant pharmaceutical solution can be formulated into sustained-release preparations and devices including, but not limited to, those relying on osmotic pressures to obtain a desired release profile.

Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.

Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6) :318 ( 1986)) and typically take the form of an optionally AQUESTIVE EXHIBIT 1014 page 0012

[0003] Ethanol constitutes a good solubilizing agent for perfuming ingredients, and additionally has the advantage of being inexpensive and of alloWing the formulation of trans parent compositions.

[0005] A ?rst route consists in replacing ethanol With aqueous compositions containing hydrophilic solubilizing agents such as polyethoxylated hydrogenated castor oils.

Moreover, the presence of Water in a large quantity is capable of causing degradation of the perfuming ingredients over time and therefore of adversely affecting the olfactory characteristics of the product.

[0006] Another solution further consisted in providing perfume compositions in Which the ethanol is at least partially replaced by one or more volatile silicones Which are lineariof the polydimethylsiloxane type4or cyclic.

[0007] HoWever, the applicant has noW discovered, sur prisingly, that by choosing a particular combination of silicone compounds not described in the prior art, it Was possible to obtain a perfume composition Whose rate of evaporation is close to that of ethanol and possessing a ?ash point greater than or equal to 00 C., preferably greater than or equal to 10° C. [0008] The subject of the present invention is therefore a perfume composition comprising a mixture of fragrant mate rials in a physiologically acceptable carrier comprising a mixture of polydimethylsiloxanes, characterized in that the said mixture of polydimethylsiloxanes consists of hexam ethyldisiloxane and octamethyltrisiloxane in a hexamethyl disiloxane to octamethyltrisiloxane Weight ratio ranging from 30:70 to 70:30.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, brotiZolam, chlordiaZepoxide, clobaZam, clon aZepam, cloraZepam, demoxaZepam, ?umaZenil, ?uraZepam, halaZepam, midaZolam, nordaZepam, medaZepam, diaZ AQUESTIVE EXHIBIT 1015 page 0006

In some embodiments, the nanoparticulate benZodi aZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, midaZolam, temaZepam and phar maceutically acceptable salts and combinations thereof.

In some embodiments, the benZodiaZepine particles comprise at least one member of the group consist ing of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, midaZolam, temaZepam and phar maceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, mida Zolam, temaZepam and pharmaceutically acceptable salts and combinations thereof.

In some embodiments, the nanoparticulate benZodiaZepine particles comprise at least one member of the group consisting of alpraZolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mexaZolam, mida Zolam, temaZepam and pharmaceutically acceptable salts and combinations thereof.

... citations and explanations supporting such statement Statement Novelty (N) Inventive step (1S) Industrial applicability (IA) Claims Claims 9-12, 32-35 1-8, 13-31, 36-62 Claims Claims Claims Claims NONE 1-62 1-62 NONE ...

Nonetheless, social objections by older children and adults and legal concerns about rectal adminis- tration havelimited its use.

... (hours) Figure 2 Mean (+standard deviation) plasma concentration—timeprofiles of diazepam after intravenous and intranasal adminis- tration in twenty-four subjects (semi-logarithmic scale). criteria of a serious adverse event, and none ...