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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date (10) International Publication Number 12 February 2009 (12.02.2009) PCT WO 2009/018824 Al

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/165 (2006.01) C07C 317/28 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/4458 (2006.01) C07D 211/34 (2006.01) AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, A61P 25/28 (2006.01) CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (21) International Application Number: IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, PCT/DK2008/000249 LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (22) International Filing Date: 4 July 2008 (04.07.2008) RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW

(26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, PA 2007 0 116 3 August 2007 (03.08.2007) DK ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), PA 2007 01332 17 September 2007 (17.09.2007) DK European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, PA 2008 00182 11 February 2008 (11.02.2008) DK FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PA 2008 00625 2 May 2008 (02.05.2008) DK NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, PA 2008 00932 4 July 2008 (04.07.2008) DK CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

(71) Applicants and Published: (72) Inventors: TULLIN, Søren [DKTDK]; Karl Gjellerups — with international search report AlIe 18, DK-2860 Søborg (DK). OSLEN, Birger, Jan — before the expiration of the time limit for amending the [DKTDK]; Malmøgade 10 3.th, DK-2100 københavn 0 claims and to be republished in the eλ'ent of receipt of (DK). amendments

(54) Title: USE OF A COMPOSITION COMPRISING AT LEAST ONE BETA-BLOCKER FOR THE TREATMENT OF SLEEP DISORDERS

(57) Abstract: A composition comprising specific beta-blockers such as and for the treatment of insomnia and/or another sleep disorder. The composition should be given in such an amount that it causes a less than 40 % decrease in the amount of aMT6s in complete nocturnal urin. The composition can be a combination treatment comprising a specific beta-blocker in combination with another known drug e.g., melatonin with similar effect for treatment of insomnia. USE OF A COMPOSITION COMPRISING AT LEAST ONE BETA-BLOCKER FOR THE TREATMENT OF SLEEP DISORDERS

BACKGROUND OF THE INVENTION Current medical treatments for Insomnia (adapted from Wikipedia) Many insomniacs rely on sleeping tablets and other sedatives to get rest. All sedative drugs have the potential of causing psychological dependence where the individual cannot psychologically accept that they can sleep without drags. Certain classes of sedatives such as benzodiazepines and newer nonbenzodiazepine drugs can also cause physical dependence which manifests in withdrawal symptoms if the drug is not carefully titrated down. The most commonly used class of hypnotics prescribed for insomnia are the benzodiazepines. These medications can develop tolerance and dependence, especially after consistent usage over long periods of time. Nonbenzodiazepine prescription drugs, including the nonbenzodiazepines Zolpidem and zopiclone appear to cause both psychological dependence and physical dependence, and can also cause the same memory and cognitive disturbances as the benzodiazepines along with morning sedation. Some such as , and have a sedative effect, and are prescribed off label to treat insomnia. The major drawback of these drags is that they have antihistaminergic, anticholinergic and antiadrenergic properties which can lead to many side effects. Some also alter sleep architecture. Melatonin has proved effective for some insomniacs in regulating the sleep/waking cycle, but lacks definitive data regarding efficacy in the treatment of insomnia. Melatonin agonists, including Ramelteon (Rozerem), seem to lack the potential for abuse and dependence. This class of drugs has a relatively mild side effect profile and lower likelihood of causing morning sedation. The antihistamine diphenhydramine is widely used in nonprescription sleep aids. While it is available over the counter, the effectiveness of these agents may decrease over time and the incidence of next-day sedation is higher than for most of the newer prescription drags. Dependence does not seem to be an issue with this class of drags. Low doses of certain atypical antipsychotics such as (Seroquel) are also prescribed for their sedative effect but the danger of neurological and cognitive side effects make these drags a poor choice to treat insomnia. Some insomniacs use herbs such as valerian, chamomile, lavender, hops, and passion-flower. Valerian has undergone multiple studies and appears to be modestly effective. Cannabis has also been suggested as a treatment for insomnia. Though Alcohol may have sedative properties, the REM sleep suppressing effects of the drug prevent restful, quality sleep. Also, middle-of-the-night awakenings due to polyuria or other effects from alcohol consumption are common, and hangovers can also lead to morning grogginess.

Unmet medical need As can be seen from this short review of the current medical treatments for insomnia, there is a huge unmet medical need for an efficacious treatment of insomnia (and other sleep disturbances) which does not cause psychological/physical dependence, morning sedation, neurological/cognitive side effects and/or many other side effects. The current invention addresses this unmet medical need by providing a novel safe and efficacious treatment for insomnia (and other sleep disturbances), without any of the side effects of the current treatments.

Beta-blockers and sleep disturbances Beta-blockers are notorious for causing sleep disturbances and nightmares, presumably because they inhibit the nocturnal Melatonin secretion ("Treatment with beta-adrenoceptor blockers reduces plasma melatonin concentration". PJ. Cowen et al., Br J Clin Pharmacol, Vol. 19 (2), 258- 260, 1985).. Analysis of the melatonin metabolite 6-sulfatoxy-melatonin (aMT6s) in urine from healthy volunteers, has e.g. shown that the beta-blockers S- (40 mg dose) and S- (50 mg dose) cause an impressive 80-90% decrease in the nocturnal aMT6s secretion 12 hours after taking the drug ("Influence of beta-blockers on melatonin release". K. Stoschitzky et al., Eur J Clin Pharmacol, Vol. 55, 111-115, 1999). Given that Melatonin plays a role in sleep induction and exerts various effects on circadian rhythm, it seems plausible that the sleep disturbances caused by beta-blockers are at least partly caused by their effects on the Melatonin levels. In contrast to the findings with S-Propranolol and S-Atenolol, a recent study has shown that the 3rd generation beta-blockers and Nebivolol have little if any effects on the nocturnal aMT6s urinary secretion in healthy volunteers ("Comparing Beta-Blocking Effects of Bisoprolol, Carvedilol and Nebivolol".K. Stoschitzky et al., Cardiology, Vol. 106, 199-206, 2006). Moreover, the same study shows that Carvedilol, Nebivolol and Bisoprolol have no negative effect on the quality of sleep in patients with hypertension. In contrast to this finding, a more recent publication suggests that Nebivolol can improve the quality of sleep in patients with hypertension ("Nebivolol is Different From Atenolol in Terms of Impact Onto Sleep". A. Erdem et al, The Anatolian Journal of Clinical Investigaton, Vol. 1(1), 25-29, 2007). The authors conclude that "the improvement of sleep quality in the Nebivolol group might well be due to simply blood pressure control and lack of central side effect of the drug". As support for this conclusion it is well known that hypertension is associated with poor quality of sleep (Prejbisz et al., Blood Pressure. Vol. 15, 213-219, 2006). Moreover, other anti-hypertensive drugs have also been shown to improve the quality of sleep in patients with hypertension. The ACE inhibitor Captopril has e.g. been shown to improve the quality of sleep in patients with hypertension ("Quality of Life and Antihypertensive Therapy in Men —A Comparison of Captopril with Enalapril". M.A. Testa et al., The New England Journal of Medicine Vol. 328, 907-913, 1993 ). The beneficial effect of the anti hypertensive 3rd generation beta-blocker Nebivolol on sleep quality in patients with hypertension (observed in Erdem' s paper but not in other publications) is accordingly most likely caused by the blood pressure reduction induced by the drug. The importance of in the regulation of sleep, has been studied in norepinephrine- deficient mice. The study suggests that norepinephrine is wake promoting after a mildly stressful event (" Norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine", M.S. Hunsley and R.D. Palmiter, Sleep, Vol. 26 (5), 521-526, 2003). In man it has been shown that poor sleep (in stressed elderly caregivers), is associated with an increased plasma norepinephrine concentration. ("Sleep Disturbance, Norepinephrine, and D-Dimer Are All Related in Elderly Caregivers of People With Alzheimer Disease",B. T. Mausbach et al, Sleep, Vol. 29(10), 1347-1352, 2006). DEFINITIONS It is believed that the present invention will be better understood from the following definitions.

As used herein aMT6s refers to the melatonin metabolite: 6-sulfatoxy-melatonin.

As used herein Quality of Sleep might be measured by employing the Pittsburgh Sleep Quality Index ("The Pittsburgh Sleep Quality Index: A New Instrument for Psychiatric Practice and Research", DJ. Buysse et al., Psychiatry Res Vol. 28, 193-213, 1989)

As used herein "Stress" refers to: An emotionally disruptive or upsetting condition occurring in response to adverse external influences and capable of affecting physical health which can be characterized by increased heart rate, a rise in blood pressure, muscular tension, irritability, insomnia and depression. Examples of stressful life events include, but are not limited to: Death of spouse, Divorce, Marital separation, Jail term or death of close family member, Personal injury or illness, Loss of job due to termination, Marital reconciliation or retirement, Pregnancy and Change in financial state (negative).

As used herein, "comprising" means that other steps and/or ingredients can be added.

As used herein beta-blocker refers to: Antagonists (full or partial) of beta- receptors. Some beta-blockers antagonize one specific subtype of beta-adrenergic receptors (e.g. a beta 1 selective beta-blocker which selectively antagonizes the beta-1 ), whereas other beta-blockers are non-selective. In context of this invention the term "beta-blocker" refers to all types of antagonists of beta- adrenergic receptors, regardless of whether the beta-blocker antagonize one, two or more beta- adrenergic receptors and regardless of whether they affect other processes. Examples of beta- blockers include, but are not limited to: , Atenolol, , Bisoprolol, Bucindolol, , Carvedilol, , Esmolol, , , , Nebivolol, , , Propranolol, . As used herein beta 1 selective beta-blocker refers to: Beta-blockers where the IC50 for inhibition of the effect of noradrenaline on the beta 1 adrenergic receptor in a functional assay (e.g. cellular cAMP production) is at least 5 times less than for any other adrenergic receptor.

As used herein complete nocturnal urine refers to: The total amount of urine that is produced during one night from the time an individual goes to bed until the individual wakes up in the morning.

As used herein complete daytime urine refers to: The total amount of urine that is produced during one day from the time an individual wakes up in the morning until the individual goes to bed.

As used herein patient refers to: A person suffering from insomnia or another sleep disorder.

As used herein: The term"elderly" is intended to mean humans from 65 years and above. The ternV'adults" is intended to mean humans from 18 to 64 years. The temTchildren" is intended to mean humans from 0 to 17 years.

As used herein insomnia refers to: The perception or complaint of inadequate or poor-quality sleep because of one or more of the following: difficulty falling asleep; waking up frequently during the night with difficulty returning to sleep; waking up too early in the morning; or unrefreshing sleep. Insomnia is not defined by the number of hours of sleep a person gets or how long it takes to fall asleep. Individuals vary normally in their need for, and their satisfaction with, sleep. Insomnia may cause problems during the day, such as tiredness, a lack of energy, difficulty concentrating, and irritability. Types of Insomnia: Primary insomnia is associated with complaint in initiating, maintaining or non-restoratively sleep, not exclusively occurring due to another mental disorder, physiological effects of a substance or a general medical condition. Secondary insomnia is associated with complaint in initiating, maintaining or non-restoratively sleep, occurring due to another mental disorder, physiological effects of a substance or a general medical condition. Insomnia can be classified as transient (short term), intermittent (on and off), and chronic (constant). Insomnia lasting from a single night to a few weeks is referred to as transient. If episodes of transient insomnia occur from time to time, the insomnia is said to be intermittent. Insomnia is considered to be chronic if it occurs on most nights and lasts a month or more. Causes of Insomnia: Certain conditions seem to make individuals more likely to experience insomnia. Examples of these conditions include: advanced age (insomnia occurs more frequently in those over age 60); female gender; and a history of depression. If other conditions (such as stress, anxiety, a medical problem, or the use of certain medications) occur along with the above conditions, insomnia is more likely. There are many causes of insomnia. Transient and intermittent insomnia generally occur in people who are temporarily experiencing one or more of the following: stress, environmental noise, extreme temperatures, a change in the surrounding environment, sleep/wake schedule problems such as those due to jet lag, or medication side effects. Chronic insomnia is more complex and often results from a combination of factors, including underlying physical or mental disorders. One of the most common causes of chronic insomnia is depression. Other underlying causes include arthritis, kidney disease, , asthma, sleep apnea, narcolepsy, restless leg syndrome, Parkinson disease, and hyperthyroidism. However, chronic insomnia may also be due to behavioral factors, including the misuse of caffeine, alcohol, or other substances; disrupted sleep/wake cycles as may occur with shift work or other nighttime activity schedules; and chronic stress. Certain Behaviors: Behaviors that perpetuate insomnia in some people include: expecting to have difficulty sleeping and worrying about it, ingesting excessive amounts of caffeine, drinking alcohol or smoking cigarettes before bedtime, excessive napping in the afternoon or evening, and irregular or continually disrupted sleep/wake schedules. These behaviors may prolong existing insomnia, and they can also be responsible for causing the sleeping problem in the first place. Stopping these behaviors may eliminate the insomnia altogether. sed herein sleep disorder include: • Bruxism : The sufferer involuntarily grinds or clenches his or her teeth while sleeping. • Delayed sleep phase syndrome (DSPS): A sleep disorder of circadian rhythm, characterized by the inability to wake up and fall asleep at the desired times, but not by inability to stay asleep. • Hypopnea syndrome: Abnormally shallow breathing or slow respiratory rate while sleeping. • Narcolepsy : The condition of falling asleep spontaneously and unwillingly at inappropriate times. • Night terror or Pavor nocturnus or sleep terror disorder: abrupt awakening from sleep with behavior consistent with terror. • Parasomnias : Include a variety of disruptive sleep-related events. • Periodic limb movement disorder (PLMD): Sudden involuntary movement of arms and/or legs during sleep, for example kicking the legs. Also known as nocturnal myoclonus. See also Hypnic jerk, which is not a disorder. PLMD sufferers often do not also have RLS. • Rapid eye movement behavior disorder (RBD): Acting out violent or dramatic dreams while in REM sleep. • Hatzfeldt Syndrome or Systemic Neuro-Epiphysial Disorder (SNED) is a somnipathy mainly characterized by an irregular sleep pattern, as well as irregular behavior • Restless legs syndrome (RLS): An irresistible urge to move legs. RLS sufferers often also have PLMD. • Shift work sleep disorder (SWSD). • Sleep apnea: The obstruction of the airway during sleep, causing loud snoring and sudden awakenings when breathing stops. • Sleepwalking or somnambulism: Engaging in activities that are normally associated with wakefulness (such as eating or dressing), which may include walking, without the conscious knowledge of the subject. • Snoring: Loud breathing patterns while sleeping; sometimes this is a symptom of sleep apnea. • Dvsomnias - A broad category of sleep disorders characterized by either hypersomnolence or insomnia. The three major subcategories include intrinsic (i.e., arising from within the body), extrinsic (secondary to environmental conditions or various pathologic conditions), and disturbances of circadian rhythm. MeSH • Insomnia • Narcolepsy • Obstructive sleep apnea • Restless leg syndrome • Periodic limb movement disorder • Hypersomnia • Recurrent hypersomnia - including Kleine-Levin syndrome • Posttraumatic hypersomnia • "Healthy" hypersomnia • Circadian rhythm sleep disorders • Delayed sleep phase syndrome • Advanced sleep phase syndrome • Non-24-hour sleep-wake syndrome

As used herein Bruxism refers to: Grinding of the teeth, typically accompanied by clenching of the jaw. In most people, bruxism is mild enough not to be a health problem; however, some people suffer from significant bruxism that can become symptomatic. Bruxism often occurs during sleep and can even occur during short naps. Bruxism is one of the most common sleep disorders: 30 to 40 million Americans grind their teeth during sleep.

As used herein hypertension refers to: "High blood pressure",HTN or HPN, a medical condition in which the blood pressure is chronically elevated. It was previously referred to as arterial hypertension, but in current usage, the word "hypertension" without a qualifier normally refers to arterial hypertension. Hypertension can be classified as either essential (primary) or secondary. Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition. Secondary hypertension indicates that the high blood pressure is a result of (i.e. secondary to) another condition, such as kidney disease or certain tumors (especially of the adrenal gland). As used herein hypertension is considered to be present when the seated systolic blood pressure >140 mrnHg and the seated diastolic blood pressure >90 mmHg. As used herein an individual is considered non-hypertensive when the seated systolic blood pressure <140 mrnHg or the seated diastolic blood pressure <90 mrnHg. In another embodiment hypertension is considered to be present when the seated systolic blood pressure >140 mrnHg and/or the seated diastolic blood pressure >80 mmHg. According to this embodiment an individual is considered non-hypertensive when the seated systolic blood pressure <140 mmHg and the seated diastolic blood pressure <80 mmHg. EXAMPLES

Example 1) 6 non-hypertensive stressed individuals with transient insomnia (5 males and 1 female) were treated with 1,25 mg Hypoloc (Nebivolol) 2 hours before bedtime. All individuals reported a significant improvement in sleep quality.

Example 2) 1,25 mg Bisoprolol is given 2 hours before bedtime to stressed individuals suffering from insomnia.

Example 3) A composition comprising 1,25 mg Hypoloc (Nebivolol) and 1 mg Melatonin is given 1 hour before bedtime to individuals above 55 years of age, who are suffering from insomnia.

Example 4) 10 mg Propal (Propranolol) is given in the morning to individuals suffering from insomnia that is associated with stress. CLAIMS What is claimed is: 1. A composition comprising beta-blocker in an amount that cause a less than 40 % decrease in the amount of aMT6s in complete nocturnal urine for the treatment of insomnia and/or another sleep disorder. 2. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of Bruxism. 3. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of insomnia. 4. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of primary insomnia. 5. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of secondary insomnia. 6. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of sleep disorders due to occasional stress. 7. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of transient, intermittent and/or chronic insomnia. 8. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of insomnia in individuals suffering from stress, anxiety or depression. 9. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of insomnia in adults, elderly and/or children. 10. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol for the treatment of insomnia wherein the composition is taken or inhaled at bedtime, after bedtime, when an insomnia episode is experienced or less than 6 hours before bedtime. 11. A composition comprising an amount of Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol, which is less than 51% of the lowest amount that is normally used for chronic treatment of hypertension, for the treatment of insomnia 12. A composition comprising an amount of Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol, which is less than 26% of the lowest amount that is normally used for chronic treatment of hypertension, for the treatment of insomnia 13. A composition comprising Bisoprolol, Nebivolol, Carvedilol, Acebutolol, Betaxolol, Bucindolol, Carteolol, Celiprolol, Esmolol, Labetalol, Metoprolol, Penbutolol, Pindolol or Timolol plus at least one compound or extract taken from the following list - Melatonin, any Melatonin receptor agonist, Valerian (Valeriana officinalis) extract, Doxylamine, Diazepam (Stesolid), Oxazepam (Sobril), Lorazepam (Temesta), Alprazolam (Xanor), Hydroxizin (Atarax), Buspiron (Buspar), Zopiclone (Imovane), Zolpidem (Ambien), Zaleplon (Sonata), Ramelteon (Rozeram), Eszopiclone (Lunesta), Diphenhydramine (Benadryl), (Atarax), Flurazepam (Dalmane), Quazepam (Doral), Triazolam (Halcion), Estazolam (ProSom), Temazepam (Restoril), Nitrazepam, Lormetazepam, Tylenol - for the treatment of insomnia. 14. A composition according to any of claims 1 to 13 for the treatment according to any of claims 1 to 13, wherein the treated individual or patient is non-hypertensive. INTERNATIONAL SEARCH REPORT International application No PCT/DK2008/000249 A CLASSIFICATION OF SUBJECT MATTER A61K31/165, A61K31/4458, A61P25/28, C07C317/28, C07D21 1/34

According to International Patent Classification (IPC) or to both national classification and IPC FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K, A61P

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

hlectronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPODOC, WPI, REGISTRY, HCAPLUS

C. DOCUMENTS CONSIDERED TO BE RELEVANT

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

(D1) US 2005143378 A 1 (YUN ANTHONY J et al.) June 30, 2005 1, 3-5, 7-14 See claims 1, 21, 42.

(D2) WO9731629 A 1 (LILLY & CO ELI) September 4, 1997 1, 3-5, 7-14 See abstract; page 1-2; and Claim 1.

X1A (D3) US 5496560 A (LIEDTKE RAINER K) March 5, 1996 X: 1, A: 3-5, 7-14 See column 4 lines 47-63; and claims 3, 7.

X1A (D4) US 2005021092 A 1 (YUN ANTHONY et al.) January 27, 2005 X: 1, A: 3-5, 7-14 See pages 14-15, (paragraphs [0163] - [0177]).

X A (D5) US 6638963 B 1 (LEWY et al.) 28. Oktober 2003 X: 1, A: 3-5, 7-14 See abstract; column 19 line 56 - column 20 line 2 1; and column 22 line 58 - column 23 line 14).

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

• Special categories of cited documents ' "]~" 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 Io be ot particular relevance the piinciple or theory underlying the invention "E" earlier application or patem but published on or after ihe international '"X" document of particular relevance, lhe claimed invention cannot be filing date considered novel or cannot he considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when che document is taken alone cited to establish the publication date ot another citation or other "Y" document of particular lelevance. the claimed invention cannot be special re son (as specified) considered to involve an inventive step when the document is O" document referring to an oral disclosure, use, exhibition or oilier 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 lhc priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 09/12/2008 08/12/2008 Name and mailing address of the ISA/ Authorised officer Nordic Patent Institute Helgeshøj AIIe 8 1, 2630 Taastrup, Denmark Marianne Vind Sørensen Facsimile No. Telephone No. Form PCT/1SA/2I0 (second sheet) (July 2008) INTERNATIONAL SEARCH REPORT International application No. PCT/DK2008/000249

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:

1. J I 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. I I Claims Nos.: 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:

Inventions 1: A composition comprising specific beta-blockers for the treatment of bruxism (claim 1 (partly), claim 2, and claim 14 (partly)). Invention 2: A composition comprising specific beta-blockers for the treament of insomnia (claim 1 (partly), claims 3-5, 7-13 and claim 14 (partly)). Invention 3: A composition comprising specific beta-blockers for the treament of a sleep disorder due to stress (claim 1 (partly), claim 7, and claim 15 (partly)).

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

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

3. I I 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.: 1(partly), 3-5, 7-13, 14(partly), second invention as agreed upon with applicant.

Remark on Protest | | The additional search fees were accompanied by the applicant's protest and. where applicable, the payment of a protest fee. 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. D No protest accompanied the payment of additional search fees. Form PCT/ISA/2 10 (continuation of first sheet (2)) (July 2008) INTERNATIONAL SEARCH REPORT International application No. Information on patent family members PCT/DK2008/000249

US2005143378 A 1 20050630 NON

WO9731629 A 1 19970904 CA2245871 A 1 19970904 AU2058697 A 1997091 6

EP0792649 A 1 19970903

CA2245871 A 1 19970904 AU2058697 A 19970916 EP0792649 A 1 19970903

US5496560 A 19960305 EP0649652 A 1 19950426 EP0649652 B 1 19990602 DK649652T T3 199911 15 AT180667T T 19990615 DE4334919 A 1 19950420

US2005021092 A 1 20050127 US2005240241 A 1 20051027

US7363076 B2 20080422 WO20041 10551 A2 20041223 WO20041 10551 A3 20050512 US2004249416 A 1 20041209 US7149574 B2 20061212

US6638963 B 1 20031028 US20061 65786 A 1 20060727

US2004044064 A 1 20040304 US2003008912 A 1 20030109 US6794407 B2 20040921 US6423738 B 1 20020723 WO9848796 A 1 19981 105 CA2289093 A 1 19981 105 AU7265798 A 19981124 US6069164 A 20000530 US5707652 A 199801 13 US5716978 A 19980210 WO9505819 A 1 19950302 AU7603094 A 19950321 US5591768 A 19970107 US5420152 A 19950530 US5242941 A 19930907

Form PCT'ISA'2 10 (patent family annex) (July 2008)