`Page 2
`
`(56)
`
`References Cited
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`U.S. PATENT DOCUMENTS
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`5,951,971 A
`5,962,014 A
`5,962,017 A
`5,962,019 A
`5,977,066 A
`5,981,479 A
`5,981,607 A
`5,998,365 A
`6,004,566 A
`6,007,840 A
`6.008.191 A
`6.008.192 A
`6,022,852 A
`6,024,978 A
`6,046,163 A
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`6,197,335 B1
`6,254,860 B1
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`6,284,268 B1
`6,294,192 B1
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`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`0547229
`1/1993
`0760237
`3/1997
`95-31211
`11/1995
`00-00179
`1/2000
`01-32142
`5/2001
`01-41671
`6/2001
`02-09667
`2/2002
`02-49603
`6/2002
`03-030834
`4/2003
`03-053405
`7/2003
`OTHER PUBLICATIONS
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`Cyclosporin
`0.05%
`in Topical Steroid-Resistant Atopic
`Keratoconjunctivitis, Ophthalmology, 2004, 476-482, 111.
`Angelov, O. et al, Preclinical Safety 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, Xlth Congress of the European Soci
`ety of Ophthalmology, 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,
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`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 Chemotherapy, Apr. 1994, 817-823, 38(4).
`Brewster, Marcus et al, Intravenous and Oral Pharmacokinetic Evalu
`ation of a 2-Hydroxypropyl-|3-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-B-cyclodextrin Complexes of
`ywwwwvwwwwwwwo
`^ Pregnanolone^and Pregnenolone in Rat and Mouse, Journal of Phar-
`4mTimm^dences, Oct. 1995, 1154-1159, 84(10).
`Brinkmeier, Thomas et al, Pyodermatitis-Pyostomatitis 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 of Topical Cyclosporine
`A and Dissolvent on Corneal Epithelium Permeability of Fluores
`cein, Documenta Ophthalmologica, 1995, 49-55, 91.
`Cheeks, Lisa et al, Influence ofVehicle and Anterior Chamber Protein
`Concentration on Cyclosporine Penetration Through the Isolated
`Rabbit Cornea, Current Eye Research, 1992, 641-649, 11(7).
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`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
`(ii).
`Donnenfeld, Eric D., The Economics ofUsing Restasis, Ophthalmol
`ogy Management, Oct. 2003, 3 pages, US.
`Drosos, A. A. et al, Efficacy and Safety of Cyclosporine-A Therapy
`for Primary Sjogren's Syndrome, Ter. Arkh., 1998, 77-80, 60(4).
`
`514/20.8
`
`0503
`
` EXHIBIT 1024 (Part 4 of 4)
`
`
`
`US 8,629,111 B2
`Page 3
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`Pending US. Appl. No. 13/967,189, filed Aug. 14, 2013.
`Pending US. 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. 13/961,828, filed Aug. 7, 2013.
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`Re-Exam U.S. Appl. No. 90/009,944, filed Aug. 27, 2011.
`
`* cited by examiner
`
`0504
`
`
`
`US 8,629,111 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`RELATED APPLICATION
`
`2
`weight of cyclosporin A. With cyclosporin A concentrations
`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
`5 cyclosporin are employed, reduced amounts 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
`
`This application is a continuation of copending U.S. appli
`cation Ser. No. 13/961,828 filed Aug. 7, 2013, which is a
`continuation of copending U.S. application Ser. No. 11/897,
`177, filed Aug. 28, 2007, which is a continuation of U.S. 10
`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, which are
`incorporated in their entirety herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been dis-
`15 covered. Suchmethods 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. In particular, the
`The present invention relates to methods of providing
`present methods provide for reduced risks of side effects
`desired therapeutic effects to humans or animals using com-
`positions including cyclosporin components. More particu- 20 and/or drug interactions. Prescribing physicians advanta
`geously have increased flexibility in prescribing such meth
`larly, the invention relates to methods including administer
`ods and the compositions useful in such methods, for
`ing to an eye of a human or animal a therapeutically effective
`example, because of the reduced risks of harmful side effects
`amount of a cyclosporin component to provide a desired
`and/or drug interactions. The present methods can be easily
`therapeutic effect, preferably a desired ophthalmic or ocular
`25 practiced. In short, the present methods provide substantial
`therapeutic effect.
`and acceptable overall efficacy, together with other advan
`The use of cyclosporin-A and cyclosporin A derivatives to
`tages, such as increased safety and/or flexibility.
`treat ophthalmic conditions has been the subject of various
`In one aspect of the present invention, the present methods
`patents, for example Ding etal U.S. Pat. No. 5,474,979; Garst
`U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442,
`comprise administering to an eye of a human or animal a
`this disclosure of each of which is incorporated in its entirely 30 composition in the form of an emulsion comprising water, a
`herein by reference. In addition, cyclosporin A compositions
`hydrophobic component and a cyclosporin component in a
`used in treating ophthalmic conditions is the subject of a
`therapeutically effective amount of less than 0.1% by weight
`number of publications. Such publications include, for
`of the composition. The weight ratio of the cyclosporin com-
`example, "Blood concentrations of |cyclosporin a|during
`ponent to the hydrophobic component is less than 0.08.
`long-term treatment with§cycTospom™~|5pfiWaImicv emul- 35
`It has been found that the relatively increased amounts of
`sions in patients with moterat&""T0"SE^ji^''dry eye disease,"
`hydrophobic component together with relatively reduced, yet
`Small et al, JOcul Pharmacol Ther, 2002 October, 18(5):411 -
`therapeutically effective, amounts of cyclosporin component
`8; "Distribution of cyclosporin A in ocular tissues after topi-
`provide substantial and advantageous benefits. For example,
`cal administration to albino rabbits and beagle dogs,"
`the overall efficacy of the present compositions, for example
`Acheampong et al, Curr Eye Res, 1999 February, 18(2):91- 40 in treating dry eye disease, is substantially equal to an iden-
`103b; "Cyclosporine distribution into the conjunctiva, cor-
`tical composition in which the cyclosporin component is
`nea, lacrimal gland, and systemic blood following topical
`present in an amount of 0.1% by weight. Further, a relatively
`dosing of cyclosporine to rabbit, dog, and human eyes,"
`high concentration of hydrophobic component is believed to
`Acheampong et al, Adv Exp Med Biol, 1998, 438:1001-4;
`provide for a more quick or rapid breaking down or resolving
`"Preclinical safety studies of cyclosporine ophthalmic emul- 45 of the emulsion in the eye, which reduces vision distortion
`sion," Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`which may be caused by the presence of the emulsion in the
`"Cyclosporin & Emulsion & Eye," Stevenson et al, Ophthal-
`eye and/or facilitates the therapeutic effectiveness ofthecom-
`mology, 2000 May, 107(5):967-74; and "Two multicenter,
`position. Additionally, and importantly, using reduced
`randomized studies of the efficacy and safety of cyclosporine
`amounts of the active cyclosporin component mitigates
`ophthalmic emulsion in moderate to severe dry eye disease. 50 against undesirable side effects and/or potential drug interac-
`CsA Phase 3 Study Group," Sail et al, Ophthalmology, 2000
`tions.
`April, 107(4):631-9. Each of these publications is incorpo
`In short, the present invention provides at least one advan
`rated in its entirety herein by reference. In addition,
`tageous benefit, and preferably a plurality of advantageous
`cyclosporin A-containing oil-in-water emulsions have been
`benefits.
`clinically tested, under conditions of confidentiality, since the 55
`The present methods are useful in treating any suitable
`mid 1990's in order to obtain U.S. Food and Drug Adminis
`condition which is therapeutically sensitive to or treatable
`tration (FDA) regulatory approval.
`with cyclosporin components. Such conditions preferably are
`Examples of useful cyclosporin A-containing emulsions
`ophthalmic or ocular conditions, that is relating to or having
`are set out in Ding etal U.S. Pat. No. 5,474,979. Example 1 of
`to do with one or more parts of an eye of a human or animal.
`this patent shows a series of emulsions in which the ratio of 60 Included among such conditions are, without limitation, dry
`cyclosporin A to castor oil in each of these compositions was
`eye syndrome, phacoanaphylactic endophthalmitis, uveitis,
`0.08 or greater, except for Composition B, which included
`vernal conjunctivitis, atopic^ kerapoconjunctivitis J corneal
`0.2% by weight cyclosporin A and 5% by weight castor oil.
`graft rejection and the like coh^fB^n^TE^^re^senfmvention
`The Ding et al patent placed no significance in Composition
`is particularly effective in treating dry eye syndrome.
`B relative to Compositions A, C and D of Example 1.
`65 Cyclosporin has been found as effective in treating immune
`Over time, it has become apparent that cyclosporin A emul-
`mediated keratoconjunctivitis sicca (KCS or dry eve disease)
`sions for ophthalmic use preferably have less than 0.2% by
`in a patient suffering therefrom. The activity of|cyclosporine§
`
`0505
`
`
`
`US 8,629,111 B2
`
`4
`3
`of such other components include, without limitation, emul-
`| is as^n immunosuppressant and in the enhancement or restor
`ing of lacrimal gland tearing. Other conditions that can be
`sifier components, tonicity components, polyelectrolyte
`treated with cyclosporin components include an absolute or
`components, surfactant components, viscosity inducing com
`partial deficiency in aqueous tear production (keratoconjunc
`ponents, acids and/or bases to adjust the pH of the composi-
`tion, buffer components, preservative components and the
`tivitis sicca, or KCS). Topical administration to a patient's 5
`tear deficient eye can increase tear production in the eye. The
`like. Components may be employed which are effective to
`treatment can further serve to correct corneal and conjuncti
`perform two or more functions in the presently useful com
`val disorders exacerbated by tear deficiency and KCS, such as
`positions. For example, components which are effective as
`corneal scarring, corneal ulceration, inflammation of the cor-
`both emulsifiers and surfactants may be employed, and/or
`*W^"'
`^KOKOLOKOKOKOK
`nea or conjunctiva, filamentary^keratisis,^mucopurulent
`dis- 10 components which are effective as both polyelectrolyte com-
`charge and vascularization of tHeTBIBEStr*
`ponents and viscosity
`inducing components may be
`Employing reduced concentrations of cyclosporin compo-
`employed. The specific composition chosen for use in the
`nent, as in the present invention, is advantageously effective
`present invention advantageously is selected taking into
`to provide the blood of the human or animal under treatment
`account various factors present in the specific application at
`with reduced concentrations of cyclosporin component, pref- 15 hand, for example, the desired therapeutic effect to be
`erably with substantially no detectable concentration of the
`achieved, the desired properties of the compositions to be
`cyclosporin component. The cyclosporin component concen
`employed, the sensitivities of the human or animal to whom
`tration of blood can be advantageously measured using a
`the composition is to be administered, and the like factors.
`validated liquid chromatography/mass spectrometry-mass
`The presently useful compositions advantageously are
`spectrometry (VLC/MS-MS) analytical method, such as 20 ophthalmically acceptable. A composition, component or
`described elsewhere herein.
`material is ophthalmically acceptable when it is compatible
`In one embodiment, in the present methods the blood of the
`with ocular tissue, that is, it does not cause significant or
`human or animal has concentrations of^clyclosporin^compo-
`undue detrimental effects when brought into contact with
`nent of 0.1 ng/ml or less.
`ocular tissues.
`Any suitable cyclosporin component effective in the 25
`Such compositions have pH's within the physiological
`present methods may be used.
`range of about 6 to about 10, preferably in a range of about 7.0
`Cyclosporins are a group of nonpolar cyclic oligopeptides
`to about 8.0 and more preferably in a range of about 7.2 to
`with known immunosuppressant activity. Cyclosporin A,
`about 7.6.
`along with several other minor metabolites, cyclosporin B
`The present methods preferably provide for an administer-
`through I, have been identified. In addition, a number of 30 ing step comprising topically administering the presently use
`synthetic analogs have been prepared.
`ful compositions to the eye or eyes of a human or animal.
`In general, commercially available cyclosporins may con
`Each and every feature described herein, and each and
`tain a mixture of several individual cyclosporins which all
`every combination of two or more of such features, is
`share a cyclic peptide structure consisting of eleven amino
`included within the scope of the present invention provided
`acid residues with a total molecular weight of about 1,200, but 35 that the features included in such a combination are not mutu-
`with different substituents or configurations of some of the
`ally inconsistent.
`amino acids.
`These and other aspects and advantages of the present
`The term "cyclosporin component" as used herein is
`invention are apparent in the following detailed description,
`intended to include any individual member of the cyclosporin
`example and claims.
`group and derivatives thereof, as well as mixtures of two or 40
`more individual cyclosporins and derivatives thereof.
`Particularly preferred cyclosporin components include,
`The present methods are effective for treating an eye of a
`without limitation, cyclosporin A, derivatives of cyclosporin
`A and the like and mixtures thereof. Cyclosporin A is an
`human or animal. Such methods, in general, comprise admin-
`45 istering, preferably topically administering, to an eye of a
`especially useful cyclosporin component.
`human or animal a cyclosporin component-containing emul
`Any suitable hydrophobic component may be employed in
`sion. The emulsion contains water, for example U.S. pure
`the present invention. Advantageously, the cyclosporin com
`water, a hydrophobic component and a cyclosporin compo
`ponent is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`nent in a therapeutically effective amount of less than 0.1 % by
`discontinuous phase in the presently useful cyclosporin com- 50 weight of the emulsion. In addition, beneficial results have
`been found when the weight ratio of the cyclosporin compo
`ponent-containing emulsions.
`The hydrophobic component preferably is present in the
`nent to the hydrophobic component is less than 0.08.
`emulsion compositions in an amount greater than about
`As noted above, the present administering step preferably
`0.625% by weight. For example, the hydrophobic component
`includes topically administering the emulsion to the eye of a
`may be present in an amount of up to about 1.0% by weight or 55 patient of a human or animal. Such administering may
`about 1.5% by weight or more of the composition.
`involve a single use of the presently useful compositions, or
`repeated or periodic use of such compositions, for example,
`Preferably, the hydrophobic component comprises one or
`more oily materials. Examples of useful oil materials include,
`as required or desired to achieve the therapeutic effect to be
`obtained. The topical administration of the presently useful
`without limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils and the like and mixtures thereof. In a very 60 composition may involve providing the composition in the
`useful embodiment, the hydrophobic component comprises
`form of eye drops or similar form or other form so as to
`one or more higher fatty acid glycerides. Excellent results are
`facilitate such topical administration.
`obtained when the hydrophobic component comprises castor
`The present methods have been found to be very effective
`oil.
`in providing the desired therapeutic effect or effects while, at
`The presently useful compositions may include one or 65 the same time, substantially reducing, or even substantially
`more other components in amounts effective to facilitate the
`eliminating, side effects which may result from the presence
`of the cyclosporin component in the blood of the human or
`usefulness and effectiveness of the compositions. Examples
`
`DETAILED DESCRIPTION
`
`0506
`
`
`
`US 8,629,111 B2
`
`6
`5
`copy (LC-MS/MS), which test has a cyclosporin component
`animal being treated, and eye irritation which, in the past, has
`detection limit of 0.1 ng/ml. Cyclosporin component concen
`been caused by the presence of certain components in prior art
`trations below or less than 0.1 ng/ml are therefore considered
`cyclosporin-containing emulsions. Also, the use of the
`substantially undetectable.
`present compositions which include reduced amounts of the
`The LC-MS/MS test is advantageously run as follows.
`cyclosporin components allow for more frequent administra- 5
`One ml of blood is acidified with 0.2 ml of 0.1 N HC1
`tion of the present compositions to achieve the desired thera
`peutic effect or effects without substantially increasing the
`solution, then extracted with 5 ml of methyl t-butyl ether.
`risk of side effects and/or eye irritation.
`After separation from the acidified aqueous layer, the organic
`phase is neutralized with 2 ml of 0.1 N NaOH, evaporated,
`The present methods are useful in treating any condition
`reconstituted in a water/acetonitrile-based jmobil fihase, and
`which is therapeutically sensitive to or treatable with
`injected onto a 2.1 x50 mm, 3 (im pore size C-8 reverse phase
`cyclosporin components. Such conditions preferably are oph-
`high pressure liquid chromatography (HPLC) column (Key-
`thalmic or ocular conditions, that is relating to or having to do
`with one or more parts of an eye of a human or animal.
`stone Scientific, Bellefonte, Pa.). Compounds are gradient-
`Included among such conditions are, without limitation, dry 15 eluted at 0.2 mL/min and detected using an API III triple
`eye syndrome, phacoaiiaphylacticjegdogb^almiti_s, uveitis,
`quadrupole mass spectrometer with a turbo-ionspray source
`vernal conjunctivitis, atopic I kerapoconTun^
`corneal
`(PE-Sciex, Concord, Ontario, Canada). Molecular reaction
`graft rejection and the like conditions. Tne present invention
`monitoring enhances the sensitivity and selectivity of this
`is particularly effective in treating dry eye syndrome.
`assay. Protonated molecules for the analyte and an internal
`The frequency of administration and the amount of the 20 standard are collisionally dissociated and product ions at m/z
`presently useful composition to use during each administra
`425 are monitored for the analyte and the internal standard.
`Under these conditions, cyclosporin A and the internal stan
`tion varies depending upon the therapeutic effect to be
`obtained, the severity of the condition being treated and the
`dard cyclosporin G elute with retention times of about 3.8
`like factors. The presently useful compositions are designed
`minutes. The lower limit of quantitation is 0.1 ng/mL, at
`in 25 which concentration the coefficient of variation and deviation
`to allow the prescribing physician substantial flexibility
`treating various ocular conditions to achieve the desired
`from nominal concentration is <15%.
`therapeutic effect or effects with reduced risk of side effects
`As noted previously, any suitable cyclosporin component
`and/or eye irritation. Such administration may occur on an as
`effective in the present methods may be employed. Very use-
`needed basis, for example, in treating or managing dry eye
`ful cyclosporin components include, without limitation,
`syndrome, on a one time basis or on a repeated or periodic 30 cyclosporin A, derivatives of cyclosporin A and the like and
`mixtures thereof.
`basis once, twice, thrice or more times daily depending on the
`The chemical structure for cyclosporin A is represented by
`needs of the human or animal being treated and other factors
`Formula 1
`involved in the application at hand.
`
`H3C.
`
`HO,,
`'1,,
`
`O
`
`N
`I
`CH3
`'CH3
`
`CH3
`
`H3C'
`H
`N
`
`CH3
`
`H3C'
`
`H3C.
`
`N
`
`CH3
`I
`N
`
`O
`H3C
`
`H3C.
`
`•CHj
`
`P
`
`CH3
`
`O
`
`• N.
`
`H3C
`
`N
`H
`
`O
`
`CH3
`
`O
`
`Formula 1
`
`.CH3
`
`N'
`
`•p
`
`rCH3
`
`O
`
`.NH
`
`o
`
`O
`
`'N'
`I
`CH3
`H3C
`
`'CHj
`
`H
`N
`
`O
`•CH3
`
`N—CH3
`
`CH3
`
`'CH3
`
`As used herein the term "derivatives" of a cyclosporin refer
`One of the important advantages of the present invention is
`the reduced concentration of the cyclosporin component in 60 to compounds having st