Nonetheless. for ophthalmic uses, the previously described polymer concentration ranges are preferred.

Although many attempts have been made to safely and efficiently administer insulin, heparin and other macromolecular drugs by non- injectable routes, none have proved successful, and it has become apparent that the success of such ...

None of the six volunteers had local irritation of the nostrils 30 minutes after application, see table 2.

Edward T. Maggio 16870 W. Bernardo Drive Suite 390 San Diego, CA 92127 (hereinafter “Inventor(s)),” have invented certain new and useful improvements in Multimodal Particulate Formulations X for which Application No. 12/1 16 842 was filed on May 7, 2008 in the United States Patent Office; WHEREAS, Aegis Therapeutics, LLC, a limited liability company of the State of California, having a place of business at 16870 W. Bernardo Drive Suite 390, San Diego, CA 92127, (hereinafter “Assignee”), is desirous of acquiring the entire right, title and interest in and to said Application(s) and the inventions disclosed therein, and in and to all embodiments of the inventions, heretofore conceived, made or discovered, whether jointly or severally, by said lnventor(s) (hereinafter collectively referred to as “Inventions”), and in and to any and all patents, inventor's certificates and other forms of protection (hereinafter “Patent(s)”) thereon granted in the United States, foreign countries, or under any international convention, agreement, protocol, or treaty.

NOW, THEREFORE, in consideration of good and valuable consideration acknowledged by said lnventor(s) to have been received in full from said Assignee: Said lnventor(s) do hereby sell, assign, transfer and convey unto said Assignee the entire right, title and interest (a) in

fullest extent the right, title and interest herein conveyed in the United States, foreign countries, or under any international convention, agreement, protocol, or treaty.

Such cooperation by said lnventor(s) shall include prompt production of pertinent facts and documents, giving of testimony, execution of petitions, oaths, specifications, declarations or other papers, and other assistance all to the extent deemed necessary or desirable by said Assignee (a) for perfecting in said Assignee the right, title and interest herein conveyed; (b) for prosecuting any applications covering said Inventions; (c) for filing and prosecuting substitute, divisional, continuing or additional applications covering said Inventions; (d) for filing and prosecuting applications for reissuance of any said Patent(s); (e) for interference or other priority proceedings involving said Inventions; and (f) for legal proceedings involving said Inventions and any applications therefor and any Patent(s) granted thereon, including without limitation reissues and reexaminations, opposition proceedings, cancellation proceedings, priority contests, public use proceedings, infringement actions and court actions; provided, however, that the expense incurred by said lnventor(s) in providing such cooperation shall be paid for by said Assignee.

‘ Docket Number 35401-714201 IN WITNESS WHEREOF said Inventor(s) have executed and delivered this instrument to said Assignee as of the dates written Bygflb'; (fir; _'

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 ...

Furthermore, due to the nature of seizures and muscle spasms, it can be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drug orally and care-givers may be reluctant to place their hands in patients’ mouths.

[011] - Some embodiments described herein provide a method oftreating a patient with a disorder which may be treatable with a benzodiazepine drug, comprising: administering to one or more nasal mucosal membranes of a patient a pharmaceutical solution for nasal administration consisting of a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w); and an alkyl glycoside.

[054] In some embodiments, the composition contains a benzodiazepine drug that at least partially in a paniculate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol and one or more alcohols or glycols.

[055] 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, benzodiazepine comprises a member of the group consisting of alprazolam, diazepam, flurazepam, loracham, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.

Journal of Controlled Release, 2 0 1992 Elsevier Science Publishers B.V. All rights reserved 01%3659/92/$05.00 165 COREL 00753 Microspheres as a nasal delivery system for peptide drugs P. EdmanaTb, E. Bjiirka>b and L. RydCnb “Kabi Pharmacia Therapeutics, Uppsala, Sweden bCrppsala University, Department of Pharma~~t~cs, BMC, Uppsa~a, Sweden (Received 7 July 199 1; accepted in revised form 9 March 1992 ) Microspheres of starch and dextran, cross-linked with epichlorohydrine, function as an enhancer system for the absorption of insulin in rats.

A conceivable hypothesis with regard to the mech- anism of action of DSM can be that the epithelial mucosa is dehydrated, with a reversible “shrinkage” of the cells, thus giving a physical separation of the intercellular junctions.

This finding indicates that the mode of action of DSM on the epitheiial cell barrier, giving in- creased permeability of hydrophiIic compounds, is a temporary widening of the tight junctions, AQUESTIVE EXHIBIT 1032 page 0006

Even though a lot of informa- tion has been gathered about DSM, there are several questions which have to be answered be- fore the microspheres can be considered as a re- 171 alistic alternative for the nasal formulation of peptide drugs.

K. Morimoto, H. Yamaguchi, Y. Iwakura, K. Morisaka, Y. Ohashi and Y. Nakai, Effects of viscous hyaluronate- sodium solution on the nasal absorption of vasopressin and an analogue, Pharm. Res.

Oxidation products include tocopheroxide, tocopherylquinone, and tocopherylhydroqui(cid:173) none, a well as dimers and trimers.

None of these infants had a five- minute Apgar score exceeding 5 (Table).

... Gwozdz, Jim Thorpe, PA; Andrew Loxley, Residence Not Provided; Mark Mitchnick, East Hampton, NY; David Hale, San Diego, CA; Edward T. Maggio, San Diego, CA; Hale Biopharma Ventures, Encinitas, CA Power of Attorney: None ...

) - None.

... Gwozdz, Jim Thorpe, PA; Andrew Loxley, Residence Not Provided; Mark Mitchnick, East Hampton, NY; David Hale, San Diego, CA; Edward T. Maggio, San Diego, CA; Hale Biopharma Ventures, Encinitas, CA; Power of Attorney: 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, 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.

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

Certified copies: a)I:l All b)|:l Some” c)I:l None of the: 1.I:I Certified copies of the priority documents have been received.

) - None.

Certified copies: a) [I A” b) D Some *c) I] None of the: 1. I] Certified copies of the priority documents have been received.

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 tetrazolyl, pyrazinyl, imidazolyl, benzimidazolyl, isothiazolyl, thienyl, furyl, pyroyl, pyridyl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, pyrimidyl, quinolyl, isoquinoly., benzofuryl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl.

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

28 -2-H drox -3- 4-metho hen Isulfan l ro ionic acid benz lester Example 1 A solution of 1 M ethylmagnesium bromide in diethyl ether (16.6 mL, 16.7 mmole) was diluted with tetrahydrofuran (32 mL) and cooled in an ice bath.

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

then any of the carbon atoms of said ring, capable of forming an additional bond, may be optionally substituted by a substituent independently selected from the group consisting of fluoro, chloro, bromo, (C1-C6)alkyl.

The present invention pro vides a significant improvement over the type of com positions disclosed in the aforementioned patent by reducing the amount of inhibited phenol required to produce the same ameliorative effect.

Some are a con sequence of a local effect (such as a laceration, or cut) while others may reflect underlying constitutional dis orders (such as the yellowing of skin that may occur in liver diseases).

The objectionable external appear ance caused by these disorders may be minimized or corrected in a non-surgical fashion by the application of a composition, such as that disclosed herein, which is not harmful to one's health and which produces two fundamental and simultaneous reactions, one in the epidermis and another in the dermis.

These responses, in turn, are manifest by a peeling of the outermost skin layer and the consequent removal of surface irregularities, blem ishes and discolorations, and by a strengthening of the underlying dermis which results from an increase in the numbers of connective tissue cells which surround and support the hair follicles, glands and vessels.

Moreover, this same response may cause the obliteration or collapse of certain poorly formed blood vessels in the dermis and result in the disappearance or fading of certain types of birth marks.

Nonetheless, it is an interesting and perhaps an important finding.