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(12) STANDARD PATENT (11) Application No. AU 2015213681 B2 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2015213681 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2015213681 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Mast cell stabilizers for lung disease treatment (51) International Patent Classification(s) A61K 31/35 (2006.01) A61P 37/08 (2006.01) A61M 16/10 (2006.01) (21) Application No: 2015213681 (22) Date of Filing: 2015.02.09 (87) WIPO No: WO15/120392 (30) Priority Data (31) Number (32) Date (33) Country 62/105,453 2015.01.20 US 61/971,709 2014.03.28 US 61/937,928 2014.02.10 US 61/978,711 2014.04.11 US (43) Publication Date: 2015.08.13 (44) Accepted Journal Date: 2020.03.12 (71) Applicant(s) Respivant Sciences GmbH (72) Inventor(s) Gerhart, William;Keller, Manfred;Tutuncu, Ahmet;Soni, Pravin (74) Agent / Attorney Spruson & Ferguson, GPO Box 3898, Sydney, NSW, 2001, AU (56) Related Art WO 2010128111 A1 US 20070193577A1 LINDSTROM, M et al., "A simple pharmacokinetic method to evaluate the pulmonary dose in clinical practice - analyses of inhaled sodium cromoglycate.", Respiratory Medicine., (2004-01), vol. 98, no. 1, pages 9-16 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization lllllllllllllllllllllllllllllllllllllllllll^ International Bureau (10) International Publication Number (43) International Publication Date WO 2015/120392 Al 13 August 2015 (13.08.2015) WIPO I PCT (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/35 (2006.01) A61M16/10 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61P 37/08(2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2015/015033 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 9 February 2015 (09.02.2015) 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. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (30) Priority Data: 61/937,928 10 February 2014 (10.02.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 61/971,709 28 March 2014 (28.03.2014) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 61/978,711 11 April 2014 (11.04.2014) US DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 62/105,453 20 January 2015 (20.01.2015) US LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (71) Applicant: PATARA PHARMA, LLC [US/US]; 11455 GW, KM, ML, MR, NE, SN, TD, TG). El Camino Real, Suite 460, San Diego, CA 92130 (US). Declarations under Rule 4.17: (72) Inventors: GERHART, William; P.O. Box 1124, Del — as to applicant's entitlement to applyfor and be granted a IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIN Mar, CA 92014 (US). KELLER, Manfred; Neunkirchner- patent (Rule 4.17(H)) str. 60, 81379 Munich (DE). TUTUNCU, Ahmet; 1807 Seaview Avenue, Del Mar, CA 92014 (US). SONI, Prav- — as to the applicant's entitlement to claim the priority of the in; 1320 Bedford Avenue, Sunnyvale, CA 94087 (US). earlier application (Rule 4.17(iii)) (74) Agent: CAPPS, Kevin, J.; Wilson Sonsini Goodrich & Published: Rosati, 650 Page Mill Road, Palo Alto, CA 94304 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, IV 2 6 £ 0 n /sm OM (54) Title: MAST CELL STABILIZERS FOR LUNG DISEASE TREATMENT (57) Abstract: Methods for the treatment of lung diseases with mast cell stabilizers are provided. WO 2015/120392 PCT/US2015/015033 METHODS FOR THE TREATMENT OF LUNG DISEASES WITH MAST CELL STABILIZERS CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 61/937,928, filed February 10, 2014; U.S. Provisional Application No. 61/971,709, filed March 28, 2014; U.S. Provisional Application No. 61/978,711, filed April 11, 2014; andU.S. Provisional Application No. 62/105,453, filed January 20, 2015, all of which are incorporated by reference herein in their entireties. BACKGROUND OF THE INVENTION [0002] Mast cells play a key role in the inflammatory process. They are found in the perivascular spaces of most tissues and contain pro-inflammatory and vasoactive mediators, such as serine proteases, tryptase, histamine, serotonin, proteoglycans, thromboxane, prostaglandin D2, leukotriene C4, platelet-activating factor, and eosinophil chemotactic factor. When activated, mast cells rapidly release granules and various hormone mediators into the interstitium, a process referred to as degranulation. Degranulation of mast cells can be caused by physical or chemical injury, crosslinking of immunoglobulin G receptors, or by activated complement proteins. [0003] Mast cells are involved in the pathophysiology of a number of lung diseases and conditions. Sustained release of pro-inflammatory and vasoactive mediators from mast cells in lung tissues can result in diseases and conditions such as asthma, fibrotic lung disease, interstitial lung disease, and chronic obstructive pulmonary disease. Another lung condition in which mast cells play a role in the pathophysiology is chronic cough. Mast cells have been found in the airway smooth muscle bundles of patients with chronic cough. Moreover, chronic cough also has neurological components. Afferent vagal activity of unmyelinated C-fibers, myelinated Αδ-fibers, and stimulation of prostaglandin-sensitive nerve endings have been implicated in the pathophysiology of certain forms of cough. Some lung diseases and conditions have been treated by the local delivery of active pharmaceutical agents, including mast cell stabilizers, to the lungs. However, a need exists for improved methods of treating lung diseases and conditions mediated by mast cells. SUMMARY OF THE INVENTION [0004] The foregoing and further needs are satisfied by embodiments of the methods disclosed herein. Specifically, disclosed herein are methods of treating lung diseases and conditions by delivering both a systemically effective amount of a mast cell stabilizer and/or a locally effective amount of a mast cell stabilizer to a patient with an inhalation device. In some embodiments of the methods disclosed herein, administration of a mast cell stabilizer with an inhalation device 1 WO 2015/120392 PCT/US2015/015033 produces a systemically effective amount of the mast cell stabilizer and a high deposited lung dose of the mast cell stabilizer in the patient. In certain embodiments, a lung disease or condition treatable by the methods disclosed herein is selected from the group consisting of idiopathic pulmonary fibrosis, chronic idiopathic cough, pulmonary fibrosis, bronchopulmonary fibrosis, pulmonary artery hypertension, exercise-induced bronchoconstriction, hyperactive airway disorder, respiratory infections, respiratory syncytial virus infection, bronchiolitis obliterans, sarcoidosis, lung fibrosis, cystic fibrosis, chronic cough, steroid resistant pediatric asthma, bronchiectasis, radiation fibrosis, radiation pneumonitis, fibrosing mediastinitis, Birt-Hogg-Dube syndrome, lymphangioleiomyomatosis, neurofibromatosis type I, alpha-1 antitrypsin deficiency, elastin mutations, salla disease, familial pulmonary arterial hypertension, pulmonary alveolar proteinosis, pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, hereditary hemorrhagic telangiectasia, pulmonary alveolar microlithiasis, Kartagener syndrome, primary ciliary dyskinesia, central alveolar hypoventilation, narcolepsy, Marfan syndrome, Ehler-Danlos syndrome, ABCA3- related lung disease, SP-A-related lung disease, SP-B-related lung disease, SP-C-related lung disease, Hermansky-Pudlak syndrome, Gaucher disease, Neiman Pick C, Wegener’s granulomatosis, Goodpasture syndrome, microscopic polyangiitis, polyarteritis nodosa, Churg- Strauss syndrome, cystic adenomatoid malformation, pulmonary sequestration, neuroendocrine cell hyperplasia, amyotrophic lateral sclerosis, myasthenia gravis, dermatomyositis, polymyositis, sarcoidosis, Langerhans cell histiocytosis, idiopathic pulmonary hemosiderosis, sickle cell anemia, lymphangiomatosis, and refractory chronic cough. In some embodiments of the methods disclosed herein, the lung disease or condition is not chronic obstructive pulmonary disease, allergic asthma, non-allergic asthma, wheezing, epistaxis, laryngotracheobronchitis, bronchitis, diffuse bronchiolitis, bronchiolitis obliterans, bronchiectasis, alveolitis, community acquired pneumonia, hospital acquired pneumonia, ventilator associated pneumonia, healthcare associated pneumonia, aspiration pneumonia, lipid pneumonia, eosinophilic pneumonia, chemical pneumonia, atypic pneumonia, severe acute respiratory system disease, pulmonary infection, emphysema, sarcoidosis, tuberculosis, nontuberculous mycobacterial pulmonary diseases, cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, interstitial lung disease, pertussis, or graft rejection after lung transplantation. In some embodiments, the mast cell stabilizer is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, magnesium cromoglycate, dihydropyridines such as nicardipine and nifedipine, lodoxamide, nedocromil, bamidipine, YC- 114, elgodipine, niguldipine,
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