(12) United States Patent
`Acheampong et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US8fi8i9MWB2
`*Apr. 1, 2014
`
`US008685930B2
`
`(54) METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`(71) Applicant: Allergan, Inc., Irvine, CA (US)
`
`(72)
`
`InVc11tors: Andrew Acheampong, Irvine, CA (US);
`Diane D. Tang-Liu, Las Vegas, NV
`(US); James N. Chang, Newport Beach,
`CA (US); David F. Power, Hubert, NC
`(US)
`
`Assignee: Allergan, Inc., Irvine, CA (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted 11nder 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`clairner.
`
`13/961,828
`
`Aug. 7, 2013
`
`Prior Publication Data
`
`US 2013/0338082 A1
`
`Dec. 19, 2013
`
`Related U.S. Application Data
`
`Continuation of application No. 11/897,177, filed on
`Aug. 28, 2007, now Pat. No. 8,618,064, and a
`continuation of application No. 10/927,857, filed on
`Aug. 27, 2004, now abandoned.
`
`Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(2006.01)
`
`Int. Cl.
`A61K 38/13
`U.S. Cl.
`USPC ....................................................... .. 514/20.5
`Field of Classification Search
`CPC .................................................... .. A6lK38/13
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,278,447
`4,388,229
`4,388,307
`4,614,736
`4,649,047
`4,764,503
`4,814,323
`4,839,342
`4,970,076
`4,990,337
`4,996,193
`5,047,396
`5,051,402
`5,053,000
`5,286,730
`5,286,731
`5,294,604
`5,296,158
`
`>>>>>>>>>>>>>>>>>>
`
`10/ 1966 McNich0las
`6/ 1983 Fu
`6/1983 Cavanak
`9/1986 Delevallee et al.
`3/1987 Kaswan
`8/1988 Wenger
`3/1989 Andrieu et al.
`6/ 1989 Kaswan
`1 1/1990 Horrobin
`2/ 1991 Kurihara et al.
`2/1991 Hewitt et al.
`9/ 1991 Orban et al.
`9/1991 Kurihara et al.
`10/1991 Booth et al,
`2/ 1994 Caufield et al.
`2/1994 Caufield et al.
`3/1994 Nussenblatt et al.
`3/1994 MacGilp et al.
`
`5,342,625
`5,368,854
`5,411,952
`5,424,078
`5,474,919
`5,474,979
`5,504,068
`5,540,931
`5,543,393
`5,589,455
`5,591,971
`5,614,491
`5,639,724
`5,652,212
`5,719,123
`5,739,105
`5,753,166
`5,766,629
`5,798,333
`5,807,820
`5,827,822
`5,827,862
`5,834,017
`5,843,452
`5,843,891
`5,858,401
`5,866,159
`5,891,846
`
`>>>>>>>>>>>>>>>>>>>>>>>>>>>>
`
`8/ 994 Hauer et al.
`,_ K.\
`994 Rennick
`995 Kaswan
`995 Dziabo
`995 Chartrain et al.
`995 Ding et al.
`996 Komiya et al.
`996 Hewitt et al,
`996 Kim et al.
`996 VVoo
`997 Shahar et al.
`997 VValch et al.
`997 Cavanak
`997 Cavanak et al.
`998 Morley et al.
`998 Kim et al.
`998 Dalton et al.
`998 Cho et al.
`998 Sherman
`998 Elias
`998 Floch’h et al.
`998 Yamamura
`998 Cho et al.
`998 VViedmann et al.
`998 Sherman
`999 Bhalani et al.
`999 Hauer et al.
`999 Ishida ct al.
`
`&e:§§E§§£@a&£2:@e:§@:£§§22
`
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`19810655
`0471293
`
`9/1999
`2/1992
`
`(Continued)
`OTHER PUBLICATIONS
`
`US. Appl. No. 90/009,944 and its entire prosecution history, filed
`Aug. 27, 2011.
`Abdulrazik, M. et al, Ocular Delivery of Cyclosporin A II. Effect of
`Submicron Emulsior1’s Surface Charge on Ocular Distribution of
`Topical Cyclosporin A, S.T.P. Pharma Sciences, Dec. 2001, 427-432,
`1 1(6).
`Acheampong, Andrew et al, Cyclosporine Distribution into The Con-
`junctiva, Cornea, Lacrimal Gland and Systemic Blood Following
`Topical Dosing of Cyclosporine to Rabbit, Dog and Human eyes,
`1996, 179.
`Acheampong, Andrew et al, Cyclosporine Distribution Into the Con-
`junctiva, Cornea, Lacrimal Gland, and Systemic Blood Following
`Topical Dosing of Cyclosporine to Rabbit, Dog, and Human Eyes,
`Adv. Exp. Med. Biol, 1998, 1001-1004, 438.
`
`(Continued)
`
`Primary Examiner — Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm—Laura L. Wine; Joel B.
`German; Dcbra D. Condino
`
`(57)
`
`ABSTRACT
`
`Methods of treating an eye of a human or animal include
`administering to an eye of a human or animal a composition
`in the form of an emulsion including water, a hydrophobic
`component and a cyclo sporin component in a therapeutically
`effective amount of less than 0.1% by weight of the compo-
`sition. The weight ratio of the cyclosporin component to the
`hydrophobic component is less than 0.8.
`
`36 Claims, No Drawings
`
`FAMY CARE - EXHIBIT 1001-0001
`
`

`
`US 8,685,930 B2
`Page 2
`
`References Cited
`
`U.S. PATENT DOCUM:
`
`>>>>>>>>>>>>>>>>>>>
`
`5,916,589
`5,929,030
`5,951,971
`5,962,014
`5,962,017
`5,962,019
`5.977.066
`5,981,479
`5,981,607
`5,998,365
`6,004,566
`6,007,840
`6,008,191
`6,008,192
`6,022,852
`6,024,978
`6,046,163
`6,057,289
`6,159,933
`6,197,335
`6,254,860
`6,254,885
`6,267,985
`6,284,268
`6,294,192
`6,306,825
`6,323,204
`6,346,511
`6,350,442
`6,413,547
`6,420,355
`6,468,968
`6,475,519
`6,486,124
`6,544,953
`6,555,526
`6,562,873
`6,569,463
`6,582,718
`6,656,460
`6.872.705
`6,984,628
`7,202,209
`7,276,476
`7,288,520
`7,297,679
`7,501,393
`8,211,855
`8,288,348
`01/0003589
`01/0014665
`01/0036449
`02/0012680
`02/0013272
`02/0016290
`02/0016292
`02/0025927
`02/0045601
`02/0107183
`02/0119190
`02/0165134
`03/0021816
`03/0044452
`03/0055028
`03/0059470
`03/0060402
`03/0087813
`03/0104992
`03/0108626
`03/0109425
`03/0109426
`03/0133984
`03/0143250
`03/0147954
`03/0166517
`
`I\JI\)h)h)I\)I\)h)I\JI\JI\)I\JI\)I\)h)hJI\)hJI\JI\)I\>I\)hJI\)hJI\JI\J
`
`6/ 1999
`7/ 1999
`9/ 1999
`10/ 1999
`10/ 1999
`10/ 1999
`1 1/ 1999
`1 1/ 1999
`1 1/ 1999
`12/ 1999
`12/ 1999
`12/ 1999
`12/ 1999
`12/ 1999
`2/2000
`2/2000
`4/2000
`5/2000
`12/2000
`3/2001
`7/2001
`7/200 1
`7/200 1
`9/2001
`9/200 1
`10/2001
`1 1/ 200 l
`2/2002
`2/2002
`7/2002
`7/2002
`10/2002
`1 1/2002
`1 1/2002
`4/2003
`4/2003
`5/2003
`5/2003
`6/2003
`12/2003
`3/2005
`1/2006
`4/2007
`10/2007
`10/2007
`1 1/2007
`3/2009
`7/2012
`10/2012
`6/2001
`8/2001
`1 1/2001
`1/2002
`1/2002
`2/2002
`2/2002
`2/2002
`4/2002
`8/2002
`8/2002
`1 1/ 2002
`1/2003
`3/2003
`3/2003
`3/2003
`3/2003
`5/2003
`6/2003
`6/2003
`6/2003
`6/2003
`7/2003
`7/2003
`8/2003
`9/2003
`
`Hauer et a .
`I-Iamied et al.
`Kawashima et al.
`Hauer et a .
`Hauer et a .
`Cho et al.
`Cavanak
`Ko et al.
`Ding et al.
`Sherman
`Friedman et al.
`Hauer et al.
`Singh
`Al-Razzak et al.
`Klokkers et al.
`Hauer et al.
`Stuchlik ct al.
`Mulye
`Sherman
`Sherman
`Garst
`Cho et al.
`Chen et al.
`Mishra et al,
`Patel et al.
`Cavanak
`Burke
`Si11gl1 et al.
`Garst
`Bennett et al.
`Richter et al.
`Cavanak et al.
`Meinzer et al.
`Olbrich et al.
`Tsuzuki et al.
`Matsuo
`Olejnik et al.
`Patel et al.
`Kawashima
`Benita et al.
`Lyons
`Bakhit et al.
`Chang
`Chang et al.
`Chang et al.
`Chang
`Tien et al.
`Chang et al.
`Chang et al.
`Neuer et al.
`Fischcr ct al.
`Garst
`Patel et al.
`Cavanak et al
`Floc’h et al.
`Richter et al.
`Olbrich et al.
`Kawashima
`Petszulat et al.
`Meinzer et al.
`Richter et al.
`Ka11g et al,
`Ueno
`Stergiopoulos et al.
`Muller
`Cavanak et 31.
`Or et al.
`Or et al.
`Benita et al.
`Or et al.
`Or et al.
`Ambuhl et al.
`Hauer et al.
`Yang et al.
`Frickcr ct al.
`
`............... .. 514/20.8
`
`2005/0014691 A1
`2005/0059583 A1
`2007/0015691 A1
`2007/0027072 A1
`2007/0087962 A1
`2007/0149447 A1
`2007/0299004 A1
`2008/0039378 A1
`2008/0070834 A1
`2008/0146497 A1
`2008/0207495 A1
`2009/0131307 A1
`2010/0279951 A1
`2011/0009339 A1
`2011/0294744 A1
`2012/0270805 A1
`2013/0059796 A1
`
`1/2005 Bakhit et al.
`3/2005 Acheampong
`l/2007 Chang
`2/2007 Tien et al.
`4/2007 Tien et al.
`6/2007 Chang et al.
`12/2007 Acheampong et al,
`2/2008 Graham et al.
`3/2008 Chang et al.
`6/2008 Graham et al.
`8/2008 Graham ct al.
`5/2009 Tien et al.
`11/2010 Morgan et al.
`1/2011 Schiffman
`12/2011 Morgan et al.
`10/2012 Chang et al.
`3/2013 Chang et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`VVO
`VVO
`VVO
`VVO
`W0
`VVO
`VVO
`VVO
`
`0547229
`0760237
`95-31211
`00-00179
`01-32142
`01-41671
`02-09667
`02-49603
`03 -030834
`03-053405
`
`1/1993
`3/1997
`11/1995
`1/2000
`5/2001
`6/2001
`2/2002
`6/2002
`4/2003
`7/2003
`
`OTHER PUBLICATIONS
`Acheampong, Andrew et al, Distribution ofCyclosporin A in Ocular
`Tissues After Topical Administration to Albino Rabbits and Beagle
`Dogs, Current Eye Research, 1999, 91-103, 18(2).
`Akpek. Esen Karamursel et al. A Randomized Trial of Topical
`Cyclosporin
`0.05% in
`Topical
`Steroid-Resistant Atopic
`Keratoconjunctivitis, Ophthalmology, 2004, 476-482, 111.
`Arigelov, O. et al, Preclinical Safely Studies of Cyclosporine
`Ophthalmic Emulsion, Adv Exp Med Biol, 1998, 991-995, 438.
`Angelov, O. et al, Safety Assessment of Cyclosporine Ophthalmic
`Emulsion in Rabbits and Dogs, XIth Congress of the European Soci-
`ety ofOphthalmology, 1997, 25-28, 1-5, Soc. Ophthalmol Eur., HU.
`Ardizzone, Sandro et al, A Practical Guide to the Management of
`Distal Ulcerative Colitis, Drugs, 1998, 519-542, 55(4).
`Banic, Marko et al, Effect of Cyclosporine in a Murine Model of
`Experimental Colitis, Digestive Diseases and Sciences, Jun. 2002,
`1362-1368, 47(6).
`Bonini, S. et al, Vernal Keratoconjunctivitis, Eye, 2004, 345-351, 18.
`Brewster. Marcus et al, Enhanced Delivery of Ganciclovir to the
`Brain Through the Use of Redox Targeting, Antimicrobial Agents
`and Cllemotherapy. Apr. 1994, 817-823, 38(4).
`Brewster, Marcus et al, Intravenous and Oral Pharmacokinetic Evalu-
`ation of a 2-Hydroxypropyl-[5-cyclodextrin-Based Formulation of
`Carbamazepine in the Dog: Comparison with Commercially Avail-
`able Tablets and Suspensions, Journal of Pharmaceutical Sciences,
`Mar. 1997, 335-339, 86(3).
`Brewster. Marcus et al, Preparation, Characterization, and Anesthetic
`Properties of 2-Hydroxypropyl-[5-cyclodextrin Complexes of
`Pregnanolone and Pregnenolone in Rat and Mouse, Journal of Phar-
`maceutical Sciences, Oct. 1995, 1154-1159, 84(10).
`Brinkmeier, Thomas et al. Pyodermatitis-Pyo stomatitis Vegetans: A
`Clinical Course of Two Decades with Response to Cyclosporine and
`Low—Dose Prednisolone, Acta Derm Venereol, 2001, 134-136, 81.
`Castillo, Jose M. Benitez Del et al, Influence ofTopical Cyclosporine
`A and Dissolvent on Corneal Epithelium Permeability of Fluores-
`ccin, Documcnta Ophthalmologica, 1995, 49-55, 91.
`Cheeks, Lisa et al, Influence ofVehicle andAnterior Chamber Protein
`Concentration on Cyclosporine Penetration Through the Isolated
`Rabbit Cornea, Current Eye Research, 1992, 641-649. 11(7).
`Database VVPI Week 200044, Derwent Pub. Ltd., London, GB; An
`2000-492678 & JP2000/143542, 2000, 2 Pages.
`Ding, Shulin et al, Cyclosporine Ophthalmic O/W’ emulsion: Formu-
`lation and Emulsion Characterization, Pharm Res, 1997, 1 page, 14
`(1 l).
`Donnenfeld, Eric D., The Economics ofUsing Restasis, Ophthalmol-
`ogy Managcmcnt, Oct. 2003, 3 pages, US.
`
`FAMY CARE - EXHIBIT 1001-0002
`
`

`
`US 8,685,930 B2
`Page 3
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Drosos, A. A. et al, Efficacy and Safety of Cyclosporine-A Therapy
`for Primary Sjogren’s Syndrome, Ter. Arkh.. 1998, 77-80, 60(4).
`Drosos, A.A. et al, Cyclosporin A Therapy in Patients with Primary
`Sjogren’s Syndrome: Results at One Year, Scand J Rheumatology,
`1986, 246-249, 61.
`Eisen, Drore et al, Topical Cyclosporine for Oral Mucosal Disorders,
`JAmAcad Dermatol, Dec. 1990, 1259-1264, 23.
`Epstein, Joel et al, Topical Cyclosporine in a Bioadhesive for Treat-
`ment of Oral Lichenoid Muscosal Reactions. Oral Surg Oral Med
`Oral Pathol Oral, 1996, 532-536. 82.
`Erdmarm.
`S.
`ct
`al, Pcmphigus Vulgaris Dcr Mund—Und
`Kehlkopfschleirnhaut Pemphigus Vulgaris of the Oral Mucosa and
`the Larynx, I-I+G 7,eitschrift Fuer Hautkrankheiten, 1997, 283-286,
`72(4).
`FDA Concludes Restasis (Cyclosporine) Not Effective for Dry Eye
`(Jun. 18, 1999). Accessed onlinc at http://www.drycycinfo.org/
`Restasis_Cyclosporine.htm on Aug. 14, 2009. 1 Page.
`Gaeta, GM. et al, Cyclosporin Bioadhesive Gel in the Topical Treat-
`ment of Erosive Oral Lichen Planus,
`International Journal of
`Irnmunopathology and Pharmacology, 1994. 125-132, 7(2).
`Gipson, Ilene et al, Character of Ocular Surface Mucins and Their
`Alteration in Dry Eye Disease, The Ocular Surface, Apr. 2004, 131-
`148, 2(2).
`Gremse, David et al, Ulcerative Colitis in Children, Pediatr Drugs,
`2002, 807-815, 4(12).
`al, Topical Cyclosporin Treatment of
`Gunduz, Kaan
`et
`Keratoconjunctivitis Sicca in Secondary Sj ogren’s Syndrome, Acta
`Ophthalmologica, 1994, 438-442, 72.
`http://web.archive.org/web/2001030625323/http://WWW. surfactant.
`co.kr/surfactants/pegester.html. 2001, 6 Pages, retrieved 011 Jul. 5,
`2008.
`Hunter, PA. et al, Cyclosporin A Applied Topically to the Recipient
`Eye Inhibits Corneal Graft Rejection, Clin Exp Immunol, 1981,
`173-177, 45.
`Jurnaa, Muhannad et al, Physicochemical Properties and IIemolytic
`Effect of Different Lipid Emulsion Formulations Using a Mixture of
`Emulsifiers, Pharmaceutica Acta Helvetiae, 1999, 293-301, 73.
`Kanai, A. et al, The Effect on the Cornea of Alpha Cyclodextrin
`Vehicle for Eye Drops, Transplantation Proceedings, Feb. 1989,
`3150-3152. vol. 21.
`Kanpolat. Ayfer et al, Penetration of Cyclosporin A into the Rabbit
`Cornea and Aqueous Humor after Topical Drop and Collagen Shield
`Administration, Cornea/External Disease, Apr. 1994, 119-122,
`20(2).
`Kaur, Rabinder et al, Solid Dispersions of Drugs in Polyocyethylene
`40 Stearate: Dissolution Rates and Physico-Chemical Interactions,
`Journal of Pharmacy and Pharmacology, Dec. 1979, 48P.
`Kuwano, Mitsualci et al, Cyclosporine A Formulation Affects Its
`Ocular Distribution in Rabbits, Pharmaceutical Research, Jan. 2002,
`108-111,19(1).
`for
`Lambert Technologies Corp. Material Safety Data Sheet
`LIIMULSETM POE-40 MS KP, last revision Aug. 22, 2003. 3 pages.
`Leibovitz, Z. et al., Our Experience in Processing Maize (Corn) Germ
`Oil, Journal ofThe American Oil Chemists Society, Feb. 1983, 395-
`399, 80 (2), US.
`I_ixin, Xie et al, Effect ofCyclo sporine A Delivery System in Corneal
`Transplantation, Chinese Medical Journal, 2002, 110-113, 115 (1),
`US.
`I_opatin, D.E., Chemical Compositions and Functions of Saliva, Aug.
`24, 2001, 31 Pages.
`Lyons, R.T. et al, Influence of Three Emulsion Formulation Param-
`eters on the Ocular Bioavailability of Cyclosporine A in Albino
`Rabbits, Am Assoc Pharm Sci, 2000, 1 Page, 2(4).
`Pedersen, Anne Marie et al, Primary Sjogren’s Syndrome: Oral
`Aspects on Pathogenesis, Diagnostic Criteria, Clinical Features and
`Approaches for Therapy, Expert Opin Pharma, 2001, 1415-1436,
`2(9).
`
`Phillips. Thomas et al, Cyclosporine Has a Direct Effect on the
`Differentiation of a Mucin-Secreting Cell Line, Journal of Cellular
`Physiology, 2000, 400-408, 184.
`Present, D.H. et al, Cyclosporine and Other Immunosuppressive
`Agents: Current and Future Role in the Treatment of Inflammatory
`Bowel Disease, American Journal of Gastroenterology, 1993, 627-
`630, 88(5).
`Restasis® Product Information Sheet, Allergan. Inc.. 2009, 5 Pages.
`Restasis® Increasing Tear Production, Retrieved on Aug. 14, 2009,
`http://vWWv.restasisprofessional.com/_clinical/clinical_increasing.
`htm 3 pages.
`Robinson, N.A. et al, Desquamative Gingivitis: A Sign of
`Mucocutaneous Disorders—a Review, Australian Dental Journal,
`2003, 205-211, 48(4).
`Rudinger, J., Characteristics of the Amino Acids as Components of a
`Peptide Hormone Sequence, Peptide Hormones, 1976, 1-7.
`Sall. Kenneth et al, Two Multicenter, Randomized Studies of the
`Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Mod-
`erate to Severe Dry Eye Disease, Ophthalmology, 2000, 631-639,
`107.
`Sandborn, VVilliam et al, A Placebo -Controlled Trial of Cyclo sporine
`Enemas for Mildly to Moderately Active Left-Sided Ulcerative
`Colitis, Gastroerlterology, 1994, 1429-1435, 106.
`Sandborn, VVilliam et al, Cyclosporine Enemas for Treatrnent-Resis-
`tant, Mildly to Moderately Active. Left-Sided Ulcerative Colitis,
`American Journal of Gastroenterology, 1993, 640-645, 88(5).
`Schwab, Matthias et al. Pharmacokinetic Considerations in the Treat-
`ment of Inflammatory Bowel Disease, Clin Pharm, 2001, 723-751,
`60(10).
`Secchi, Antonio et al, Topical Use of Cyclosporine in the Treatment
`ofVernal Keratoconjunctivitis, American Journal of Ophthalmology,
`Dec. 1990, 641-645, 110.
`Small, Dave et al, The Ocular Pharmacokinetics of Cyclosporine in
`Albino Rabbits and Beagle Dogs, Ocular Drug Delivery and Metabo-
`lism, 1999. 54.
`Small, David et al, Blood Concentrations of Cyclosporin A During
`Long-Term Treatment With Cyclo sporin A ophthalmic Emulsions in
`Patients with Moderate to Severe Dry Eye Disease, Journal of Ocular
`Pharmacology and Therapeutics, 2002, 411-418, 18(5).
`Smilek, Dawn et al, A Single Amino Acid Change in a Myelin Basic
`Protein Peptide Confers the Capacity to Prevent Rather Than Induce
`Experimental Autoimmune Encephalomyelitis, Proc. Natl. Acad.
`Sci.. Nov. 1991. 9633-9637, 88.
`Stephenson, Michelle, The Latest Uses of Restasis, Review of Oph-
`thalmology, Dec. 30, 2005, 7 Pages, US.
`Stevenson, Dara et al. Elficacy and Safety of Cyclosporin A
`ophthalmic Emulsion in the Treatment of Moderate—to-Severe Dry
`Eye Disease, Ophthalmology, 2000. 967-974, 107.
`Tesavibul, N. et al, Topical Cyclosporine A (CsA) for Ocular Surface
`Abnormalities
`in Graft Versus Host Disease Patients,
`Invest
`OphthalmolVis Sci, Feb. 1996, S1026, 37(3).
`The Online Medical Dictionary. Derivative, Analog, Analogue,
`Xerostomia, accessed Jul. 7, 2005 and Jul. 13, 2005, 6 Pages.
`Tibell, A. et al., Cyclosporin A in Fat Emulsion Carriers: Experimen-
`tal Studies on Pharmacokinetics and Tissue Distribution, Pharmacol-
`ogy & Toxicology, 1995, 115-121, 76, US.
`Tsubota, Kazuo et al, Use of Topical Cyclosporin A in a Primary
`Sj ogren’s Syndrome Mouse Model, Invest Ophthalmol Vis Sci, Aug.
`1998, 1551-1559. 39(9).
`Van Der Reijden, Willy et al, Treatment of Oral Dryness Related
`Complaints (Xerostomia) in Sjogren’s Syndrome, Ann Rheum Dis,
`1999, 465-473, 58.
`\Vinte1', T.A. et al, Cyclosporin A Retention E11e111as i11 Refractory
`Distal Ulcerative Colitis and ‘Pouchitis’, Scand J Gastroenterol,
`1993, 701-704, 28.
`Pending U.S. Appl. No. 13/967,189, filed Aug. 14,2013.
`Pending U.S. Appl. No. 13/976,179, filed Aug. 14,2013.
`Pending U.S. Appl. No. 13/961,818, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,835, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,808, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/967,163, filed Aug. 14,2013.
`Pending U.S. Appl. No. 13/967,168, filed Aug. 14,2013.
`
`* cited by examiner
`
`FAMY CARE - EXHIBIT 1001-0003
`
`

`
`US 8,685,930 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COIVIPONENTS
`
`RELATED APPLICATION
`
`This application is a continuation of copendi11g U.S. appli-
`cation Ser. No. 11/897,177, filed Aug. 28, 2007, which is a
`continuation of US. application Ser. No. 10/927,857, filed
`Aug. 27, 2004, now abandoned, which claimed the benefit of
`U.S. Provisional Application No. 60/503,137 filed Sep. 15,
`2003, wl1icl1 are incorporated in their entirety herein by ref-
`erence.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using com-
`positions including cyclosporin components. More particu-
`larly, the invention relates to methods including administer-
`ing to an cyc of a human or animal a therapeutically cffcctivc
`amount of a cyclosporin component to provide a desired
`therapeutic effect, preferably a desired ophthalmic or ocular
`therapeutic effect.
`The use of cyclosporin-A and cyclosporinA derivatives to
`treat ophthalmic conditions has been the subject of various
`patents, for example Ding et al U.S. Pat. No. 5,474,979; Garst
`U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442,
`this disclosure of each of which is incorporated i11 its entirely
`herein by rcfcrcncc. In addition, cyclosporin A compositions
`used in treating ophthahnic conditions is the subject of a
`number of publications. Such publications include,
`for
`example, “Blood concentrations of cyclosporin a during
`long-term treatment with cyclosporin a ophthalmic emul-
`sions in patients with moderate to severe dry eye disease,”
`Small et al, J Ocul Pharmacol Ther, 2002 October, 18(5):41 1-
`8; “Distribution ofcyclosporin A in ocular tissues after topi-
`cal administration to albino rabbits and beagle dogs,”
`Acheampong et al, Curr Eye Res, 1999 February, l8(2):9l-
`l03b; “Cyclosporine distribution into the conjunctiva, cor-
`nea, lacrimal gland, and systemic bloodfollowing topical
`dosing of cyclosporine to rabbit, dog, and human eyes,”
`Acheampong et al, Adv Exp rlled Biol, 1998, 43821001-4;
`“Preclinical safety studies ofcyclosporine ophthalmic emul-
`sion,” Angelov et al, Adv Exp Med Biol, 1998, 4382991-5;
`"Cyclosporin & Emulsion & Eye,” Stevenson et al, Ophthal-
`mology, 2000 May,
`07(5):967-74; and “Two multicenter,
`randomized studies ofthe eficacy and safety ofcyclosporine
`ophthalmic emulsion in moderate to severe dry eye disease.
`CsA Phase 3 Study Group,” Sall et al, Ophthalmology, 2000
`April, 107(4):63l-9. Each of these publications is incorpo-
`rated in its entirety herein by reference.
`In addition,
`cyclosporin A-containing oil-in-water emulsions have been
`clinically tested. unde * conditions of confidentiality, since the
`mid 1990’s in order to obtain U.S. Food a11d Drug Adminis-
`tration (FDA) regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are set out in Ding et al U.S. Pat. No. 5,474,979. Example 1 of
`this patent shows a series of emulsions in which the ratio of
`cyclosporin A to castor oil in each ofthese compositions was
`0.08 or greater, except for Composition B, wl1ich included
`0.2% by weight cyclosporin A and 5% by weight castor oil.
`The Ding et al patent placed no significance in Composition
`B relative to Compositions A, C and D of Example 1.
`Over time, it l1as become apparent that cyclosporinA emul-
`sions for ophthalmic use preferably have ess than 0.2% by
`weight of cyclosporin A. With cyclosporin A concentrations
`
`2
`less than 0.2%, the amount of castor oil employed has been
`reduced since one of the functions of the castor oil is to
`
`solubilize the cyclosporin A. Thus, if reduced amounts of
`cyclosporin are employed, reduced amotmts of castor oil are
`needed to provide effective solubilization of cyclosporin A.
`There continues to be a need for providing enhanced meth-
`ods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`SUMMARY OF THE INVENTION
`
`New methods of treating a human or animal using
`cyclosporin component—containing emulsions have been dis-
`covered. Such methods provide substantial overall efficacy in
`providing desired therapeutic effects.
`In addition, other
`important benefits are obtained employing the present meth-
`ods. For example, patient safety is enhanced. Inparticular, the
`present methods provide for reduced risks of side effects
`and’or drug interactions. Prescribing physicians advanta-
`geously have increased flexibility in prescribing such meth-
`ods and thc compositions uscful
`in such methods,
`for
`example, because of the reduced risks of harmful side effects
`and/or drug interactions. The present methods can be easily
`practiced. In short, the present methods provide substantial
`and acceptable overall efficacy, together with other advan-
`tages, such as increased safety and/or flexibility.
`In one aspect ofthe present invention, the present methods
`comprise administering to ar1 eye of a human or animal a
`composition in the fonn of an emulsion comprising water, a
`hydrophobic component and a cyclosporin component in a
`therapeutically effective amount of less than 0.1% by weight
`of tlie composition. The weight ratio of the cyclosporin com-
`ponent to the hydrophobic component is less than 0.08.
`It has been found that the relatively increased amounts of
`hydrophobic component together with relatively reduced, yet
`therapeutically effective, amotmts of cyclosporin component
`provide substantial and advantageous benefits. For example,
`the overall efficacy of the present compositions, for example
`in treating dry eye disease, is substantially equal to an iden-
`tical composition in which the cyclosporin component is
`present in an amount of 0.1% by weight. Further, a relatively
`high concentration of hydrophobic component is believed to
`provide for a more quick or rapid breaking down or resolving
`of the emulsion in the eye, which reduces vision distortion
`which may be caused by the presence of the emulsion in tlie
`eye and/or facilitates the therapeutic effectiveness of the com-
`position. Additionally,
`and importantly, using reduced
`amounts of the active cyclosporin component mitigates
`against undesirable side effects and/or potential drug interac-
`tions.
`
`In short, the present invention provides at least one advan-
`tageous benefit, and preferably a plurality of advantageous
`benefits.
`The present methods are useful in treating any suitable
`condition which is therapeutically sensitive to or treatable
`with cyclo sporin components. Such conditions preferably are
`ophthalmic or ocular conditions, that is relating to or having
`to do with one or more parts of an eye of a human or animal.
`Included among such conditions are, without limitation, dry
`eye syndrome, phacoanaphylactic endophthalmitis, uveitis,
`vernal conjunctivitis, atopic kerapoconjunctivitis, corneal
`graft rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`Cyclosporin has been found as effective in treating immune
`mediated keratoconjunctivitis sicca (KCS or dry eye disease)
`in a patient suffering therefrom. The activity of cyclosporine
`is as an imn1unosuppressa11t and in the enhancement or restor-
`
`FAMY CARE - EXHIBIT 1001-0004
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`

`
`US 8,685,930 B2
`
`3
`ing of lacrir11al glar1d tearing. Other cor1ditior1s that car1 be
`treated witl1 cyclosporin con1pone11ts include an absolute or
`partial deficiency in aqueous tear production (keratoconjunc-
`tivitis sicca, or KCS). Topical adn1inistratio11 to a patient’s
`tear deficient eye can increase tear production in the eye. The
`treatment can further serve to correct corneal and conjuncti-
`val disorders exacerbated by tear deficiency and KCS, such as
`corneal scarring, corneal ulceration, inflammation of the cor-
`nea or conjunctiva, filamentary keratisis, mucopurulent dis-
`charge and vascularization of the cornea.
`Employing reduced concentrations of cyclospori11 compo-
`nent, as in the present invention, is advantageously effective
`to provide the blood of the human or animal under treatment
`with reduced concentrations of cyclosporin component, pref-
`erably with substantially no detectable concentration of the
`cyclo sporin cor11por1ent. The cyclo sporin cor11por1er1t cor1cen-
`tration of blood can be advantageously measured using a
`validated liquid chromatography/mass spectrometry-mass
`spectrometry (VI C/MS-MS) analytical method, such as
`described elsewhere herein.
`In one embodiment, in the present methods the blood ofthe
`human or animal has concentrations of clyclosporin compo-
`nent of 0.1 ng/ml or less.
`Any suitable cyclosporin con1poner1t effective ir1 the
`present methods may be used.
`Cyclosporins are a group ofnonpolar cyclic oligopeptides
`with known irnmunosuppressant activity. Cyclosporin A,
`along Witl1 several other minor metabolites, cyclospori11 B
`through I, have been identified. In addition, a number of
`synthetic analogs have been prepared.
`In general, commercially available cyclosporins may con-
`tain a mixture of several individual cyclosporins which all
`share a cyclic peptide structure consisting of eleven amino
`acidresidues with a total molecular weight ofabout 1,200, but
`with different substituents or configurations of some of the
`amino acids.
`The term “cyclosporin component” as used herein is
`intended to include any individual member ofthe cyclosporin
`group and derivatives thereof, as well as mixtures of two or
`n1ore individual cyclosporins and derivatives thereof.
`Particularly preferred cyclosporin components include,
`without limitation, cyclosporin A, derivatives of cyclosporin
`A and the like and mixtures thereof. Cyclosporin A is an
`especially uscfiil cyclosporin component.
`Any suitable hydrophobic component may be employed in
`the present invention. Advantageously, the cyclosporin com-
`ponent is solubilized ir1 the hydrophobic cor11por1er1t. The
`hydrophobic component may be considered as comprising a
`discontinuous phase i11 the presently useful cyclosporin com-
`ponent-containing emulsions.
`The hydrophobic component preferably is present in the
`emulsion compositions in an amount greater than about
`0.625% by weight. For example, the hydrophobic component
`may be present in an amount ofup to about 1 .0% by weight or
`about 1.5% by Weight or more of the composition.
`Preferably, the hydrophobic component comprises one or
`n1ore oily materials. Examples ofu seful oil materials include,
`without limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils and the like and mixtures thereof. In a very
`useful embodiment, the hydrophobic component comprises
`one or more higher fatty acid glycerides. Excellent results are
`obtained when the hydrophobic component comprises castor
`oil.
`The presently useful compositions may include one or
`n1ore other components in amounts effective to facilitate the
`usefulness ar1d effectiveness of the cor11positior1s. Examples
`of such other components include, without limitation, emul-
`sifier components,
`tonicity components, polyelectrolyte
`components, surfactant components, viscosity inducing com-
`ponents, acids and/or bases to adjust the pH of the composi-
`tion, buffer components, preservative components and the
`
`4
`like. Components may be employed wl1icl1 are effective to
`perform two or more functions in the presently useful com-
`positions. For example, components which are effective as
`both emulsifiers and surfactants may be employed, a11d/or
`components which are effective as both polyelectrolyte com-
`ponents and viscosity inducing components may be
`employed. The specific composition chosen for use in the
`present
`invention advantageously is selected taking into
`account various factors present in the specific application at
`hand, for example,
`the desired therapeutic effect
`to be
`achieved, the desired properties of the compositions to be
`employed, the sensitivities of the human or animal to whom
`the composition is to be administered, and the like factors.
`The presently useful compositions advantageously are
`ophthalmically acceptable. A composition, component or
`material is ophthalmically acceptable wl1er1 it is compatible
`with ocular tissue, that is, it does not cause significant or
`undue detrimental effects when brought into contact with
`ocular tissues.
`Such compositions l1ave pH’s witl1i11 the physiological
`range ofabout 6 to about 10, preferably in a range ofabout 7.0
`to about 8.0 and more preferably in a range of about 7.2 to
`about 7.6.
`The present methods preferably provide for an administer-
`ing step comprising topically administering the presently use-
`ful compositions to the eye or eyes of a human or animal.
`Each and every feature described herein, and each and
`every combination of two or more of such features,
`is
`included within the scope of the present invention provided
`that the features included in such a combination are not mutu-
`ally inconsistent.
`These a11d other aspects and advantages of the present
`invention are apparent in the following detailed description,
`example and claims.
`
`DETAILED DESCRIPTION
`
`The present methods are effective for treating an eye of a
`human or animal. Such methods, in general, comprise admin-
`istering, preferably topically administering, to ar1 eye of a
`human or animal a cyclosporin con1ponent—containing emul-
`sion. The emulsion contains water, for example U.S. pure
`water, a hydrophobic component and a cyclosporin compo-
`nent i11 a therapeutically effective amount ofless than 0.1% by
`weight of the emulsion. In addition, beneficial results have
`been found when the weight ratio of the cyclosporin compo-
`nent to the hydrophobic component is less than 0.08.
`As noted above, the present administering step preferably
`includes topically administering the emulsion to the eye of a
`patient of a human or animal. Such administering may
`involve a single use of the presently useful compositions, or
`repeated or periodic use of such compositions, for example,
`as required or desired to achieve the therapeutic effect to be
`obtained. The topical administration of the presently useful
`composition may involve providing the composition in the
`form of eye drops or similar form or other form so as to
`facilitate such topical administration.
`The present methods have been found to be very effective
`in providing the desired therapeutic effect or effects while, at
`the same time, substantially reducing, or cvcn substantially
`eliminating, side effects which may result from the presence
`of the cyclosporin component in the blood of the human or
`animal being treated, and eye irritation Wl1icl1, ir1 the past, l1as
`been caused by the presence ofcertain components in prior art
`cyclosporin-containing emulsions. Also,
`the use of the
`present compositions which include reduced amounts of the
`cyclospori11 components allow for n1ore frequent admini stra-
`tion of the present compositions to achieve the desired thera-
`peutic effect or effects Without substantially increasing the
`risk of side effects and/or eye irritation.
`The present methods are useful in treating any condition
`which is therapeutically sensitive to or treatable with
`
`FAMY CARE - EXHIBIT 1001-0005
`
`

`
`US 8,685,930 B2
`
`6
`standard are collisionally dissociated and product i