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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/061554 Al 21 April 2016 (21.04.2016) P O P C T

(51) International Patent Classification: (74) Agents: SKLAR, Steven, H. et al; Leydig, Voit & Mayer, A61K 31/335 (2006.01) A61K 31/437 (2006.01) Ltd., Two Prudential Plaza, Ste. 4900, 180 N. Stetson Av A61K 31/4174 (2006.01) C07D 233/58 (2006.01) enue, Chicago, Illinois 60601-6745 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 15/056096 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 16 October 2015 (16.10.201 5) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/064,500 16 October 20 14 ( 16.10.20 14) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: BIOXCEL CORPORATION [US/US]; 780 East Main Street, Branford, Connecticut 06405 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: NEGI, Harsh; B-2/44 Janakpuri, New Delhi GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 110058 (IN). SAINI, Deepa; F-l, Plot no.623, Ext-1, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Shalimar Garden, Shahibabad, Ghaziabad, Uttar Pradesh TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 201 105 (IN). SHARMA, Sameer; Bandla Tea Estate DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Palampur, Himachal Pradesh 17606 1 (IN). NANDABAL- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, AN, Krishnan; 228 Village Pond Road, Guilford, Con SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, necticut 06437 (US). YOCCA, Frank; 106 BarGate Trail, GW, KM, ML, MR, NE, SN, TD, TG). Killing-worth, Connecticut 06415 (US).

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(54) Title: SYNERGISTIC COMPOSITION OF KNOWN, SAFE PHARMACEUTICALS FOR USE IN AND A METHOD OF TREATMENT THEREOF (57) Abstract: A pharmaceutical composition of dexmedetomidine combined with for use in the treatment of disorder such as insomnia. The composition provides a healthy sleep pattern allowing the user to get seven or eight hours sleep. The invention also relates to a method of treating or enhancing sleep onset and maintenance of sleep, com prising identifying a patient in need of such enhancement, and administering the pharma ceutical composition.

Figure 1: Total sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity. o w o 2016/061554 Λ llll II II 11III III II II I III I I Hill II I II

Published: SYNERGISTIC COMPOSITION OF KNOWN, SAFE PHARMACEUTICALS FOR USE IN INSOMNIA AND A METHOD OF TREATMENT THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 62/064,500, filed October 16, 2014, which is incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention is the field of formulation development and relates to a synergistic combination composition of dexmedetomidine with doxepin and a method of treatment of insomnia and related conditions. More particularly, the invention relates to treatment of patients suffering from insomnia by the administering a combination composition having no residual side effects.

BACKGROUND OF THE INVENTION

[0003] A sleep disorder is a medical disorder of the sleep patterns of a person or animal. Disruptions in sleep can be caused by a variety of issues. Insomnia is a common sleep disorder that occurs when you have hard time initiating sleep, struggle to sleep maintenance, waking up frequently during night and you tend to wake up too early and are unable to go back to sleep. These symptoms of insomnia can be caused by a variety of biological, psychological and social factors. [0004] Until recently, medical literature has recognized four types of insomnia, including sleep onset insomnia; sleep maintenance insomnia, early morning awakening, and transient insomnia (e.g., new environment, first night in hotel syndrome). Sleep maintenance insomnia is when the person cannot sleep through the night, but wakes several times for indeterminate periods. Sleep maintenance insomnia is also called as trouble staying asleep. Sleep onset insomnia (initiating sleep) is trouble falling asleep. Particularly, those patients having problem in both sleep initiation as well as sleep maintenance, require treatment intervention that would quickly initiate sleep and can maintain it for at least 7 to 8 hours without leaving residual effects in the morning. Improved sleep can assist in keeping awake; keeping alert; keeping refreshed; and performing well the next day. While known sleeping pill compositions are effective for either treating sleep-onset insomnia, i.e. a subject's difficulty in falling asleep or treating sleep maintenance insomnia, i.e., maintaining a subject's sleep throughout a normal sleep period after falling asleep. However, there is no sleeping pill composition currently available which could treat both conditions simultaneously without residual side effect. [0005] Therefore, there is a need for improved pharmaceutical composition and method of treatment which could cater to both sleep initiation and sleep maintenance in a subject need of such treatment.

SUMMARY OF THE INVENTION

[0006] The present inventors are the first to realize the usefulness of low dose dexmedetomidine for sleep induction. Dexmedetomidine formulation useful for treating sleep disorders is not commercially available. Dexmedetomidine is only commercially available as an injectable formulation indicated for sedation, and it must be administered intravenously by a heath care professional. The commercially available injectable formulation is not suitable for use in insomnia that can be self-administered. [0007] On other hand, Doxepin is very effective at addressing sleep maintenance aspects of insomnia and at reducing early morning awakenings that can occur in some cases of insomnia. Though, doxepin has poor sleep onset latency problem. Doxepin binds with high specificity and affinity to the histamine HI receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises HI receptors, which is believed to promote maintenance of sleep. [0008] In one of the embodiments, the present invention describes a combination composition comprising dexmedetomidine and doxepin that is effective for providing sleep onset and sleep maintenance, as well as methods of using the combination compositions thereof. [0009] In one another embodiment, the invention provides a single sleeping pill comprising a combination of two pharmaceutical compounds, dexmedetomidine and doxepin, which have a synergistic effect when taken together than when taken alone. Preferably, the amount of each of the pharmaceutical compounds in the combination are lower than the amount of each individual compound that are required to consistently get seven to eight hours of sleep in night in comparison to pharmaceutical compounds are taken alone. [0010] In yet another embodiment, the invention provides a pill comprising a combination of a first compound and a second compound wherein, the first compound comprises dexmedetomidine and the second compound comprises doxepin. Preferably, the combination comprises from 0.0001 mg to 10 mg of the first compound combined with from 0.000 lmg to 10 mg of the second compound. [0011] In another aspect, the invention provides a method of promoting sleep in a human, the method comprises preparing a synergistic composition of first compound i.e. dexmedetomidine with second compound i.e. doxepin and administering the composition orally or parenterally to a human being prior to a sleep period. [0012] In yet another embodiment, the present invention relate to compounds, compositions and methods for treating sleep disorders using dexmedetomidine in combination with doxepin. [0013] In yet another embodiment, the present invention relate to a sublingual composition comprising of dexmedetomidine in combination with doxepin for treating sleep disorders. [0014] In particular, this combinations surprisingly and unexpectedly have the ability to provide improved sleep, with additional advantage of a reduced dose (e.g., reduced when compared to the normal dose when used alone) of one or both of dexmedetomidine and doxepin. The combination composition is very effective in treating sleep disorders without residual side effects. [0015] The combination is devoid of side effects seen with the therapeutically effective dose of the known and non- drugs when used alone or when an approved mono treatment dosage is used.

BRIEF DESCRIPTION OF FIGURES

[0016] Figure 1: Total sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity. [0017] Figure 2 : Percentage of total sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity. [0018] Figure 3 : Latency to sleep time of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity. [0019] Figure 4 : Number of sleep episodes of doxepin alone or in combination of dexmedetomidine with doxepin in comparison to the vehicle control in Wistar rats observed by video monitoring of home cage activity.

DETAILED DESCRIPTION

[0020] There is a demand for a pharmaceutical formulation for treatment of patients who are suffering from both sleep onset and sleep maintenance insomnia. [0021] In the treatment of insomnia, it is very important to consider the potential residual side effects of the medicament employed, including any associated drug dependency. The practitioner are aware of the potential undesirable absorption of drug taking place several hours after administration, which may give rise to decreased alertness and impaired psychomotor function during normal activity the following day. In this respect, wherever possible, it is important to expose patients only to short-term, or "on-demand", use of the lowest effective dose of any particular drug or combination of drug. [0022] Doxepin is a non DEA schedule IV drug approved for the treatment of insomnia characterized by difficulty with sleep maintenance. Though, doxepin has poor sleep onset latency problem and has been reported in clinical studies to increase sleep onset latency. Hence, if we take doxepin in regular dose then it might increase the sleep onset time especially in those patients which have difficulty in both sleep onset and sleep maintenance. To overcome, this major drawback of doxepin while retaining its good sleep maintenance property. The present inventor provided a solution wherein they reduced the dose of doxepin and combined it with sleep inducing drug in a low dose which has no reported residual side effect. [0023] Dexmedetomidine, the D-enantiomer of , is among the most potent sedative drugs known. Dexmedetomidine is reported to induce arousable sedation and has quick onset and short acting nature. Its sedative effects are mediated by subtype A of the a2 receptor, a G-protein-coupled receptor. Acting as an at this receptor, dexmedetomidine causes numerous intracellular changes that lead, generally speaking, to reduce neuronal excitability. Dexmedetomidine is impact on the locus ceruleus- and other awakening pathway activity to regulate the body wakefulness. Dexmedetomidine reduces the cerebral cortical hyper arousal level in patients with insomnia by changing the activity of locus ceruleus-noradrenergic system and other arousal pathways of ascending reticular activating system. It helps to restore the sleeping-awakening system and improve the symptoms of insomnia. Dexmedetomidine induces a qualitatively similar pattern of c-fos expression as seen during normal NREM sleep, a decrease in the locus ceruleus and tuberomammillary nucleus and an increase in the ventrolateral preoptic nucleus (VLPO). [0024] The present invention combined low dose dexmedetomidine with a non DEA schedule IV drug, with poor ability to decrease the sleep onset latency such as doxepin. The combination of dexmedetomidine with doxepin when compared to BZD and Z drug has no residual side effect such as dependence, rebound insomnia, post dose day residual sedation. [0025] In one another embodiment, the present invention discloses a synergistic pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with doxepin or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof. The synergistic composition help to lower down the dose of combined drugs with comparison to their individual dose amount for treatment of insomnia patient which in turn, helps in minimizing the residual side effects associated with such drugs when taken in full dose. Furthermore, composition according to the present invention is capable of providing levels of drug at an appropriate time after administration that do not give rise to the undesirable residual effects mentioned hereinbefore the following day. [0026] In one another embodiment of present invention, the synergistic combination composition could also be used in other related central nervous system conditions such as but not limited to snoring, sleep apnoea, sleep deprivation, and restless legs syndrome, central nervous system disorders and/or states are not limited to headache, pain, epilepsy, convulsions, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, ataxias, dystonia, movement disorders, memory disorders, depression, avoidant personality disorder, anxiety, panic disorder, obsessive-compulsive disorders, phobias, impulsive disorders, cognitive disorders, mood disorders, psychoses, schizophrenia, drug abuse, chemical dependencies, drugs tolerance or withdrawal, posttraumatic stress syndrome and eating disorders. [0027] The composition described herein may be administered to a subject in need of treatment by a variety of routes of administration, including orally and parenterally, (e.g., intravenously, subcutaneously or intramedullary), intranasally or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water, topically, intradermally, subcutaneously and/or administration via mucosal routes in liquid or solid form. The composition can be formulated into a variety of dosage forms, e.g., extract, pills, tablets, microparticles, capsules, oral liquid. [0028] There may also be included as part of the composition pharmaceutically or physiologically acceptable compatible binding agents, and/or adjuvant materials. In one embodiment, the mode of administration of the composition described herein is oral composition. Oral compositions generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. [0029] In one another embodiment, the present invention discloses an oral composition for the treatment of insomnia in a subject comprising dexmedetomidine or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof and doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof, wherein said insomnia treatment obtainable from the said combination exceeds the degree of insomnia treatment obtainable from doxepin alone or dexmedetomidine alone. Preferred route for delivery of pharmaceutical composition is an oral route. [0030] In yet another embodiment, an orally disintegrating synergistic pharmaceutical composition comprising doxepin or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative for shortening the time to sleep onset in a patient being treated for insomnia in combination with a sleep maintenance drug such as dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof. [0031] In yet another embodiment, the present invention discloses a pharmaceutical composition for treatment of sleep disorders comprising a pharmaceutically effective amount of a combination of (a) dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with (b) doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof, wherein the weight ratio of dexmedetomidine to doxepin is in a range of 120: 1 to 1:120. [0032] In the preferred embodiment, the present invention discloses a pharmaceutical composition for treatment of sleep disorders comprising a pharmaceutically effective amount of a combination of (a) dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with (b) doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof, wherein the weight ratio of dexmedetomidine to doxepin of about 1:60. [0033] In one of the another embodiment, the present invention discloses a pharmaceutical composition for inducing sleep comprising effective amount of a sleep onset shortening drug in combination of a sleep maintenance drug. [0034] In one another embodiment, the present invention discloses a composition comprising a first compound and a second compound, wherein: said first compound comprises dexmedetomidine and said second compound comprises doxepin; and wherein said composition comprises from 0.0001 mg to 10 mg of said dexmedetomidine combined with from 0.0001 mg to 10 mg of said doxepin. [0035] In yet another embodiment, the present invention discloses a sleeping pill of a composition comprising dexmedetomidine and doxepin as disclosed in description. The dexmedetomidine and doxepin in the composition are complementing each other for treatment of sleep disorder. Preferably sleep disorder is insomnia. [0036] Oral pharmaceutical composition of dexmedetomidine and doxepin could also be as liquid form preparations include solutions, suspensions and emulsions, for example, water or certain glycol solutions. For parenteral injections, liquid preparations can be formulated in solution in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, and stabilizing and thickening agents as desired. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. In another embodiment, the present invention discloses a mucoadhesive drug delivery system. [0037] In one another embodiment, the combination composition is delivered through controlled release drug delivery system. It has been further disclosed that mucoadhesive properties of a tablet has additional advantages, e.g. efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio, a much more intimate contact with the mucus layer. Mucoadhesive tablets can be tailored to adhere to any mucosal tissue including those found in stomach, thus offering the possibilities of localized as well as systemic controlled release of drugs. Mucoadhesive tablets are widely used because they release the drug for prolong period, reduce frequency of drug administration and improve the patient compliance. [0038] In one of the preferred embodiment, the pharmaceutical composition of the present invention is absorbed through oral mucosa. Drug delivery via the mucous membranes of the oral cavity has certain advantages, due to the properties of the oral mucosa itself. For example, the mucous membranes of the oral cavity are highly vascularized and well supplied with lymphatic drainage sites [0039] The composition according to the present invention is provided as a pharmaceutical composition, the pharmaceutical composition includes pharmaceutically acceptable carriers. [0040] The pharmaceutically acceptable carrier included in the pharmaceutical composition according to the present invention are those used generally in pharmaceutical formulation, and particular examples thereof include, but not limited to: lactose monohydrate, cellulose, crospovidone, magnesium stearate, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. [0041] In addition to the above, the pharmaceutical composition according to the present invention may further include a lubricant, wetting agent, sweetener, fragrance, emulsifier, suspending agent, preservative, or the like. Suitable pharmaceutically acceptable carriers and formulation thereof are described in detail in Remington's Pharmaceutical Sciences (19th edition, 1995). [0042] Adequate dose of the pharmaceutical composition of the present invention may be determined according to various factors, including methods of formulation, administration modes, ages, weights, sex, pathological conditions and diet of patients, administration periods, administration routes, excretion rates and reaction sensitivity. General dose of the pharmaceutical composition of the present invention is 0.01-1000 mg/kg weight in the case of adult patients. [0043] The pharmaceutical composition of the present invention may be formulated by using pharmaceutically acceptable carriers and/or excipients so that it may be provided as a unit dosage form or may be packed in a multi-dose container in a manner generally known to those skilled in the art. Such dosage forms include solutions or suspensions in oil or aqueous media, syrup, emulsion, elixir, powder, flour, granules, tablets, capsules, etc., and may further include a dispersant or stabilizer. When the dosage form is a chewing gum, the composition can comprise a carrier or excipient such as a gum base, a pH-adjusting agent or buffer system, and optionally a protecting agent. [0044] In yet another embodiment, the present invention discloses that the composition of present invention could be formulated as sublingual/or an oral tablet by a method like direct compression, wet granulation or dry granulation. In direct compression method, all materials including said drug substances are sifted in a specific sequence as per process optimized and then blended in V-blender or any other suitable blender sequentially to achieve uniform mixing of drug substances in the blend. The blend is then further compressed into tablets using appropriate tooling. [0045] In wet granulation method, the drug substance alone or with other excipients such as binder, sweetener and others are dissolved or dispersed into pharmaceutically acceptable solvents and granulated. The same are used to granulate the sifted blend of other ingredients. The granules are then dried and sized appropriately. The granules are then lubricated in a suitable blender and compressed into tablets of specific dimensions using appropriate tooling. For dry granulation method, the granules are prepared either by compaction (e.g. Roller compactor) or slugging or any other suitable technique and tablets are prepared in a similar manner to that of wet granulation technique. [0046] Other sublingual dosage forms such as films, buccal patches or spray formulations, will involve appropriate fabrication technology like usage of film casting equipment for preparing a film dosage form or usage of an impermeable or semi-permeable back liner for buccal patch dosage form or filling into canisters for spray dosage forms. [0047] Methods [0048] In one another embodiment, the synergistic composition of present invention is effective for the treatment of sleep disorder. Therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of doxepin or a pharmaceutically acceptable salt thereof is administrated to a patient for treatment of sleep disorders. More preferably, it is used for the treatment of insomnia. [0049] In further embodiment of carrying out the methods of the present invention for treating insomnia, the appropriate effective dosage to be administered to a subject can be evaluated in an appropriate patient population that has been selected based on factors such as age, weight, the number of hours of time in bed remaining. In certain embodiments, the composition of present invention can be administered in a quick-dissolving tablet or lozenge. [0050] In one another embodiment, the administration of the compositions of the present invention could be carried out via any of the accepted modes of administration to the mucous membranes of the oral cavity. [0051] In another embodiment of present invention, the synergistic composition is administered orally to human for the treatment of insomnia which comprises a combination formulation consisting essentially of 0.0001 to 10 mg of dexmedetomidme and 0.0001 to 10 mg of doxepin. [0052] Insomnia which could be treated using this method is not limited to sleep onset insomnia, sleep maintenance insomnia, early morning awakening insomnia, transient insomnia, middle-of-the-night insomnia, late night insomnia, prolonged awakening after sleep onset insomnia. [0053] In yet another embodiment, the present invention discloses a preferred oral dose of dexmedetomidme in range of 0.005 mg to 5 mg with doxepin and dose of doxepin in combination composition is preferably between about 0.01 mg and 6 mg. [0054] In yet another embodiment, a significant effect was observed with combination of 10 µg/kg of dexmedetomidme and 0.3 mg/kg of doxepin and combination of 10 µg/kg of dexmedetomidme and 0.6 mg/kg of doxepin. Further, the minimum latency to sleep (significant) was observed in combination of 10 µg/kg of dexmedetomidme and 0.6 mg/kg of doxepin. [0055] In some embodiments, the one or more drugs used in combination with doxepin, including those drugs of the listed categories can be utilized in a dosage that is the same as the approved dosage for the drug, the clinical or literature test dosage of the drug, or the dosage used for the drug as a monotherapy for a sleep disorder. In some aspects, both the doxepin and the one or more combination drugs can be used at a dosage that is same as or lower than the approved dosage for the drug, the clinical or literature test dosage or the dosage used for the drug as a monotherapy, preferably at a dosage that is lower than when used in their respective monotherapies [0056] In another embodiment, the dosage of dexmedetomidme is based on the serum concentration which induces sleep which is preferably 0.5 to 1.2ng/ml. The total dose required is estimated to be in a range of 0.005 to 5 mg. This dose is for a human having weight ranging from of 40 to 100 kg. [0057] In one of another embodiment, the present invention discloses a synergistic composition of therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with a therapeutically effective amount of doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof for treating sleep disorder in an obese patient. [0058] The term "synergistic pharmaceutical composition" means treatment of insomnia by combination of chemicals that is greater than would be expected if the chemicals were used individually. [0059] Further, next-day residual sedative effect after administration of an over-the- counter or other sleeping aid is a major problem. It is very uncomfortable to patient do normal activities on next day. The present invention provides a method of treatment of insomnia which minimizes next day residual sedation caused by standard sleep therapy, comprising providing a pharmaceutical composition of dexmedetomidine or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof in combination with a doxepin or a pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof to a patient. The composition enhances onset of sleep as well as maintain 7 to 8 hour of uninterrupted sleep in individual in need of such enhancement. [0060] In yet another embodiment, the present invention discloses that the time range for sleep induction is less than 30 minutes, which is attributed to short acting nature of dexmedetomidine and it very effective when combined with doxepin, which is a poor in sleep induction and used only for sleep maintenance. The two drugs do not come under the DEA schedule IV list as well. [0061] While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. [0062] Definitions [0063] The term "sleep disorder" refers to a disruptive pattern of sleep arising from many causes including, without limitation, dysfunctional sleep mechanisms, abnormalities in physiological functions during sleep, abnormalities of the biological clock, and sleep disturbances that are induced by factors extrinsic to the sleep process. In particular, the term encompasses disorders associated with difficulties in staying asleep and/or falling asleep such as insomnia (e.g., transient, short-term, and chronic), delayed sleep phase syndrome, -dependent sleep disorder, and stimulant-dependent sleep disorder; disorders associated with difficulties in staying awake such as sleep apnoea, narcolepsy, restless leg syndrome, obstructive sleep apnoea, central sleep apnoea, idiopathic hypersomnia, respiratory muscle weakness-associated sleep disorder; disorders associated with difficulties in adhering to a regular sleep schedule such as sleep state misperception, shift work sleep disorder, chronic time zone change syndrome, and irregular sleep-wake syndrome; disorders associated with abnormal behaviours such as sleep terror disorder (i.e., parasomnia) and sleepwalking (i.e., somnambulism); and other disorders such as sleep bruxism, fibromyalgia, and nightmares. [0064] The term "insomnia" refers to a sleep disorder characterized by symptoms including, without limitation, difficulty in falling asleep, difficulty in staying asleep, intermittent wakefulness, and/or waking up too early. The term also encompasses daytime symptoms such as sleepiness, anxiety, impaired concentration, impaired memory, and irritability. [0065] The phrase "residual sedative effects" refers to a patient's subjective feeling of sedation upon awakening. The term "subject" or "patient" refers to humans. The term "pharmaceutically acceptable" includes those compounds, materials, compositions, dosage forms, and methods of use thereof that are within the scope of sound medical judgment and suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, while being commensurate with a reasonable benefit/risk ratio and eliciting a desired pharmacological response. [0066] Dexmedetomidme contains a basic nitrogen atom capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this respect refers to the relatively non-toxic, inorganic, and organic acid addition salts of dexmedetomidme. These salts may be prepared in situ during final isolation and purification of dexmedetomidme or by separately reacting purified dexmedetomidme in its free base form with a suitable organic or inorganic acid, and thereafter isolating the salt thus formed. Furthermore, the salt may be formed during a manufacturing process to produce formulation. The salts of dexmedetomidme comprises and are not limited to the hydrohalide (including hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethylsulfonate, and laurylsulphonate salts, and the like. [0067] Dexmedetomidine derivatives may include covalent modifications that create a pro-drug. Upon administration, the pro-drug derivative undergoes chemical modification by the mammal that yields dexmedetomidine. [0068] The formulation may be administered to mammals, including humans, as well as human companion animals (e.g., cats, dogs), agricultural livestock, and other animals in need thereof. [0069] The terms "combination composition of the invention", "pharmaceutical formulation", and equivalent expressions are meant to embrace compounds as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, the oxides, the solvates, e.g. hydrates, and inclusion complexes of that compound, where the context so permits, as well as a mixture of any such forms of that compound in any ratio. Inclusion complexes are described in Remington, The Science and Practice of Pharmacy, 19th Ed. 1:176-177 (1995), which is hereby incorporated by reference in its entirety. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims. Thus, in accordance with some embodiments of the invention, a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits. [0070] A "pharmaceutically acceptable" carrier or excipient, as used herein, means approved by a regulatory agency of the Federal or a state government, or as listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans. [0071] The term "pharmaceutical composition" as used in accordance with the present invention relates to compositions that can be formulated in any conventional manner using one or more pharmaceutically acceptable carriers or excipients. [0072] The term "solvate" refers to a composition of the present technology in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. [0073] The term "derivative" refers, for example, to crystal forms, polymorphs, or prodrugs of the compositions useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitter ionic forms, where possible, of the compositions of the invention. The term "prodrug" means compounds that are rapidly transformed in vivo to yield the parent compound, for example by hydrolysis in blood. Commonly, the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Compositions of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract. The composition may bear metabolically cleavable groups, which have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. [0074] Bundgaard, ed., Chapter 5; "Design and Applications of Prodrugs," p.113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgaard, 8, p.1-38 (1992); Journal of Pharmaceutical Sciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull, 32:692 (1984); Higuchi et al, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987), which are incorporated herein by reference in their entirety. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of amine functional groups in the compositions of the invention. [0075] As used herein, the term "human" or "patient," used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans. [0076] As used herein, the term "sedation" means depressed consciousness in which a patient or subject retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands. [0077] The term "dosage" is intended to encompass a formulation expressed in terms of µg/kg/hr, µg/kg/day, mg/kg/day, or mg/kg/hr. [0078] A "dose" is an amount of an agent administered to a patient in a unit volume or mass, e.g., an absolute unit dose expressed in mg of the agent. The dose depends on the concentration of the agent in the formulation, e.g., in moles per litre (M), mass per volume (m/v), or mass per mass (m/m). [0079] The term "drug addiction" means dependence on an illegal drug, controlled substance or a medication. When you're addicted, you may not be able to control your drug use and you may continue using the drug despite the harm it causes. Drug addiction can cause an intense craving for the drug. You may want to quit, but most people find they can't do it on their own. [0080] The term "method of treating" means amelioration or relief from the symptoms and/or effects associated with the disorders described herein. As used herein, reference to "treatment" of a patient is intended to include prophylaxis. [0081] The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples.

EXAMPLE 1: Pre-clinical study for the combination of dexmedetomidine and doxepin

[0082] Combination of dexmedetomidine and doxepin was tested in Wistar rats for its ability to increase the amount of sleep or decrease sleep interruption or both without undesired effects. Test animals activity were continuously monitored by using a video camera overhead and data analysed for latency of sleep, total sleep time and number of sleep episodes by using the Noldus Ethovision-XT 11. [0083] Studies were conducted as follows: [0084] Animal Preparation: [0085] Male Wistar rats were approximately weighed of about 160g - 190g and age of about 5-7 weeks old. Animals were numbered and kept in acclimatization for a period of 5-7 days before the initiation of the experiment. All the experiments on animals were conducted in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India the Association for Assessment and Accreditation of Laboratory Animal Care international (AAALAC). [0086] Recording Environment: [0087] Animals were housed group wise (three animals per cage) within a microisolator cage modified with an inserted polycarbonate filter-top riser to allow more vertical headroom. Autoclaved corncob was used as bedding material. Animals were maintained on the normal rodent chow ad libitum and given free access to fresh autoclaved potable drinking water. Animals were kept in a controlled environmental condition with 22±3°C temperature, 50±20% humidity, a light dark cycle of 12 hours each and 15-20 fresh air changes per hour. [0088] Animal Groups: [0089] Winstar rats were randomly divided into different groups, each containing six animals. The study groups were divided as vehicle control group, test compound groups and combination of dexmedetomidine and doxepin groups. [0090] Drugs: [0091] Dexmedetomidine procured from M/s Neon labs, India and doxepin hydrochloride procured from M/s R.L. Fine Chem. India. [0092] Study Design and Dosing:

[0093] Animals were weight once at randomization and each day thereafter. On day 1, animals were dosed with vehicle control, test compound (doxepin) and combination of dexmedetomidine and doxepin and activity was recorded for 180 minutes using overhead video camera and analyzed the data with Noldus Ethovision-XT 11. Latency to sleep, total sleep time and number of sleep episodes were evaluated based on animal activity. On day 2 and day 3, all animals were trained to perform on the rotarod at a constant accelerating speed of 4-40 rpm for 300s. Three trials were performed each day, with an inter-trial interval of 15 minutes. On day 4, animals were administered with test compound (doxepin) and combination of dexmedetomidine and doxepin and motor coordination was tested on the rotarod at 3, 10, 17, 24 and 30 minutes post administration to establish a temporal scale of loss of motor activity and drowsiness. On day 7, animals were dosed with test compound (doxepin) and combination of dexmedetomidine and doxepin and respiratory parameters (tidal volume & frequency of respiration) and non-invasive measurement of heart rate and blood pressure was performed. A 10 minute baseline was recorded, test compound (doxepin) and combination of dexmedetomidine and doxepin was administered and the physiological parameters were recorded for up to 60 minutes after administration. On day 10, animals were dosed with test compounds and blood was collected at 30, 60 and 120 min post sublingual dosing to estimate plasma drug concentration of combination of dexmedetomidine and doxepin. Plasma was separated into a fresh tube (75-100µ1per time point) and stored at -80°C until analysis/ shipment of samples to client location. All the animals were euthanized by C0 2 inhalation on day 10. [0094] The vehicle control group received 0.9% saline water; test compound groups (doxepin dose (1) - O.lmg/kg, dose (2) - 0.3mg/kg and dose (3) - 0.6mg/kg), combination of dexmedetomidine and doxepin groups administered sublingually (dexmedetomidine dose (1) - 5µg/kg and dose (2) -10µg/kg); and doxepin dose (1) - 0.3mg/kg, dose (2) - 0.6mg/kg) were administered per oral in dose of 30 mg/kg. The treatment was given such that no rat receives the same treatment twice. Total sleep time, latency to sleep and number of sleep episodes was measured: [0095] After administration of each dose to an each group of animal the latency to sleep, total sleep time and number of sleep episodes were recorded. [0096] Results: [0097] A comparison of total sleep time, latency to sleep and number of sleep episodes for different groups: vehicle control, test compound group, combination of dexmedetomidine and doxepin groups at different doses has been tabulated in table 1 and table 2. [0098] Groups were compared for total sleep time, latency to sleep and number of sleep episodes using one-way ANOVA (analysis of variance) followed by Dunnett's Post-hoc test and the test was used to determine the significance between different groups. Table 1: 36 154 187.416332 26 1 Mean, SEM 145.50 177.07 23.33 1.67 37 Combination 152 184.982354 25 1 38 Treatment- 3 155 188.633321 20 1 Dexmedetomidme 39 (^g/kg) 148 180.1 14397 32 1 40 +Doxepin 138 167.944505 18 3 (0.3 mg/kg) 4 1 135 164.293538 37 2 42 146 177.680419 25 1 Mean, SEM 145.67 177.27 26.17 1.50 43 Combination 156 189.8503 1 13 4 44 Treatment-4 144 175.24644 29 2 Dexmedetomidme 45 (^g/kg) 141 171 .595473 20 2 46 +Doxepin 164 199.586224 13 2 (0.6 mg/kg) 47 155 188.633321 16 2 48 145 176.463429 35 1 Mean, SEM 150.83 183.56 18.00 2.17 * Outlier data.

Table 2 : s. Group Total Sleep Time % Total Sleep Latency to Sleep Number of Sleep No. (Mean and SEM) Time (Mean and SEM) Episodes (Mean and SEM) (Mean and SEM) 1 Vehicle Control 82.2 3.5 100 4 43.3 4.851498 3.3 0.5

2 Doxepin 139.5 5.6 170 7 27.8 4.232261 3.5 0.5 0.1 mg/kg

3 Doxepin 133.0 7.8 162 10 31.2 2.575706 2.7 0.3 0.3 mg/kg

4 Doxepin 147.7 3.8 180 5 30.7 3.396621 1.3 0.2 0.6 mg/kg

5 Dexmedetomidme 141 .3 2.8 172 3 27.2 5.046543 2.8 0.6 ^g/kg) +Doxepin (0.3 mg/kg)

6 Dexmedetomidme 145.5 2.7 177 3 23.3 2.256677 1.7 0.2 ^g/kg) +Doxepin (0.6 mg/kg) 7 Dexmedetomidme 145.7 2.9 177 4 26.2 2.681383 1.5 0.3 (^g/kg) +Doxepin (0.3 mg/kg) 8 Dexmedetomidme 150.8 3.3 184 4 18.2 2.674322 2.2 0.4 (^g/kg) +Doxepin (0.6 mg/kg)

[0100] Conclusion: [0101] Total sleep time (total duration of sleep in 180min): Total sleep time significantly increased at 0.1, 0.3 & 0.6 mg/kg (sublingual) for doxepin as compared to vehicle control. All the combinations tested for dexmedetomidme and doxepin also showed significant improvement in the total sleep time as compared to vehicle control with the maximum sleep time in combination of 10 µg/kg of dexmedetomidme and 0.6 mg/kg of doxepin. Similar data is also represented as percentage of total sleep time. [0102] Latency to sleep (time of sleep onset): Latency to sleep was reduced with doxepin (0.1, 0.3 & 0.6 mg/kg (sublingual)) as compared to the vehicle control. All the combinations tested for dexmedetomidme and doxepin also showed improvement in the latency to sleep as compared to vehicle control. A significant effect in combination was found with combination of 10 µg/kg of dexmedetomidme and 0.3 mg/kg of doxepin and combination of 10 µg/kg of dexmedetomidme and 0.6 mg/kg of doxepin. However, the minimum latency to sleep (significant) in combination of 10 µg/kg of dexmedetomidme and 0.6 mg/kg of doxepin was observed. Additionally, the combination of 10 µg/kg of dexmedetomidme and 0.6 mg/kg of doxepin; also showed significant effect (p<0.05) as compared to doxepin 0.6 mg/kg standalone. [0103] Number of sleep episodes: There was a trend towards improvement in the number of sleep episodes in combinations tested for dexmedetomidme and doxepin.

Example 2 :

[0104] The following examples is intended to be illustrative and not limiting: [0105] Composition for a tablet formulation used for sublingual or buccal delivery or an oral fast disintegrating purpose. Buccal delivery may require an additional back-liner if specified. Table 3 :

Example 3: Composition for a tablet formulation intended for oral administration (immediate release or extended release type.

Table 4 : Ingredients Per unit (% w/w) IR type ER type Dexmedetomidine 0.005% to 5% 0.005% to 5% Doxepin 0.01% to 10% 0.01% to 10% Povidone (and)/(or) Hypromellose (and)/(or) Hydroxy 1.0 - 20.0 % 1.0 - 70.0 % propyl cellulose (and)/(or) Methyl cellulose Crospovidone (and) / (or) Croscarmellose Sodium 0.1 to 20 % 0 to 5 % (and) / (or) Sodium starch glycollate Magnesium Stearate (and)/ (or) Silicon dioxide 0.1 - 1.0 % 0.1 - 1.0 % CLAIMS:

1. A synergistic pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with doxepin or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof.

2. A method for treating sleep disorder in a subject comprising: administering a therapeutically effective amount of pharmaceutical composition comprising of dexmedetomidine or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with a therapeutically effective amount of doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof.

3. A oral composition for the treatment of insomnia in a subject comprising dexmedetomidine or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof and doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof, wherein said insomnia treatment from the said combination composition exceeds the degree of insomnia treatment obtainable from doxepin alone.

4. A method of enhancing sleep onset and maintenance, comprising identifying a patient in need of such enhancement, and administering the pharmaceutical composition of claims 1to said patient.

5. An orally disintegrating synergistic pharmaceutical composition comprising doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof for shortening the time to sleep onset in a patient being treated for insomnia in combination with a sleep maintenance drug not limited to dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof.

6. The method of any of the preceding claim wherein the sleep disorder is insomnia.

7. A method of minimizing next day residual sedation caused by standard sleep therapy, comprising providing a pharmaceutical composition of dexmedetomidine or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof to a patient.

8. A method for treating sleep disorder in an obese patient comprising administering to the patient a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with a therapeutically effective amount of doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof.

9. A pharmaceutical composition for treatment of sleep disorders comprising a pharmaceutically effective amount of a combination of (a) dexmedetomidine or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof in combination with (b) doxepin or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof, wherein the weight ratio of (a) to (b) is 120: 1 to 1:120

10. A pharmaceutical composition for inducing sleep comprising effective amount of a sleep onset shortening drug in combination of a sleep maintenance drug, wherein the weight ratio of the drugs is about 1:60.

11. The composition as claimed in claim 1, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof, solvate thereof, or derivative thereof is formulated for delivery through an oral route.

12. The composition as claimed in any of the preceding claims, wherein the therapeutically effective amount of dexmedetomidine is in a range of about 0.005 mg to about 5 mg.

13. The composition as claimed in any of the preceding claims, wherein the therapeutically effective amount of doxepin is in a range of about 0.1 mg to about 6 mg.

14. The method as claimed in any of the preceding claims, the wherein administering comprises applying to the oral mucosa, wherein the said synergistic pharmaceutical composition or pharmaceutically acceptable salt thereof, co-crystal thereof, or derivative thereof is absorbed through oral mucosa. 15. The method as claimed in any of the preceding claims, wherein the insomnia is sleep onset insomnia, sleep maintenance insomnia, early morning awakening insomnia, transient insomnia, middle-of-the-night insomnia, late night insomnia, prolonged awakening after sleep onset insomnia and sleep maintenance insomnia.

16. Use of synergistic pharmaceutical composition as claimed in claim 1 for the treatment of sleep disorders.

17. The use as claimed in claim 16, wherein the sleep disorder is insomnia.

18. A method of treating insomnia in a human in need of said treatment which comprises administering orally to said human a combination formulation consisting essentially of 0.005 to 5 milligrams of dexmedetomidine and 0.1 to 6 milligram of doxepin.

19. A pill comprising: a composition comprising a first compound and a second compound, wherein: said first compound comprises dexmedetomidine; said second compound comprises doxepin; and wherein said composition comprises from 0.005 mg to 5 mg of said dexmedetomidine combined with from 0.1 to 5 mg of said doxepin.

20. A pill comprising: a composition comprising dexmedetomidine and doxepin, said dexmedetomidine and said doxepin included in said composition are complementing each other for treatment of sleep disorder.

INTERNATIONAL SEARCH REPORT Internationa] application No. PCT/US 15/56096

A . CLASSIFICATION O F SUBJECT MATTER

IPC(8) - A61K 31/335, 31/41 74 , 31/437; C07D 233/58 (2015.01 ) CPC - A61K 31/335, 31/4174, 31/437; C07D 233/58 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC(8) Classification(s): A61 31/335, 31/4174, 31/437; C07D 233/58 (2015.01) CPC Classification(s): A61K 31/335, 31/4174, 31/437; C07D 233/58

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) PatSeer (US, EP, WO, JP, DE, GB, CN, FR, KR, ES, AU, IN, CA, INPADOC Data); Google Scholar; Google; ProQuest; EBSCO dexmedetomidine, doxepin, combination therapy, sleep disorder, insomnia

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

US 201 1/0077200 A 1 (JOCHELSON, P et al.) 3 1 March 201 1; paragraphs [0009]-[0010], 5, 6/5, 10 [0019], [0024], [0029], [0036], [0071], [0079]-[0081], [01 15]; claim 1 1-4, 6/1-4, 7-9, 11, 16-20

US 2010/0196286 A 1 (ARMER, TA et al.) 5 August 2010; paragraphs [0009]-[0010], [0017], 1-4, 6/1 -4, 7-9, 11, 16-20 [0019H0020], [0023], [0029], [0032], [0035], [0039]-[0040]; claims 2, 3 1

US 2008/0058408 A 1 (ROGOWSKI, RL et al.) 6 March 2008; entire document 1-5, 6/1-5, 7-1 1, 16-20

I Further documents are listed in the continuation of Box C. | | See patent family annex.

* Special categories of cited documents. "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than "&" document member of the same patent family the priority date claimed Date of the actual completion o f the international search Date of mailing of the international search report 23 November 2015 (23.1 1.2015) 0 6 JA N 2016

Name and mailing address of the ISA/ Authorized officer Mail Stop PCT, Attn: ISA/US, Commissioner for Patents Shane Thomas P.O. Box 1450, Alexandria, Virginia 22313-1450 Facsimile No. 571-273-8300 Form PCT/ISA/210 (second sheet) (January 20 5) INTERNATIONAL SEARCH REPORT International application No.

PCT/US1 5/56096

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

□ Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely:

Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:

3. Claims Nos.: 12-15 because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:

□ As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims.

□ As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of additional fees.

□ As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:

4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on Protest I I The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. I I The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. No protest accompanied the payment of additional search fees.

Form PCT/lSA/210 (continuation of first sheet (2)) (January 201 5)