S($ 10/97)
`ro
`ro
`
`03
`
`CO
`
`o
`03 ro
`-NI
`o
`-Pv !
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`Docket No: D-3111
`
`(Only for new nonprovisional applications under 37 CFR
`
`1.53(b))
`
`Total Pages in this Submission
`
`Transmitted herewith for
`invention entitled:
`
`-and invented by:
`
`TO THE U.S. PATENT AND TRADEMARK OFFICE
`PO BOX 1450
`ALEXANDRIA, VA 22313-1450
`
`filing under 35 U.S.C.
`
`
`
`
`
`and 111(a) 37 CFR 1.53(b) is a new utility patent application
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`ACHEAMPONG ET AL
`
`If a CONTINUATION APPLICATION,
`information:
`requisite
`check appropriate box an supply the
`[ ]Continuation [ JDivisional [ ]Continuation-in-part (CIP) of prior application No.:
`
`O
`LO
`tf- ^
`CO 00
`CM
`for an
`g?
`O)
`
`O r--
`CM
`eo
`o
`
`Enclosed are Application Elements:
`[X ]
`Filing Fee
`[X ]
`Specification having 34 page(s) and including the
`[X ]
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`[X ]
`Cross References to Related Applications
`[X ]
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`Brief Summary of the
`Invention
`[ ]
`Description of the Drawings
`[X ]
`Detailed Description
`[X ]
`Claim(s) as Classified Below
`[X ]
`Abstract of the Disclosure
`[ ] Informal
`_ Sheets of Drawings(s) (37 CFR 113) [ ] Formal
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`Oath or Declaration
`[X ] Executed
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`(37 CFR 1.63(d))
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`only)
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`
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`from Incorporation By Reference ~ The entire disclosure of the prior application which a copy of the oath or
`declaration is supplied under the above
`entry,
`is
`
`considered being part of the disclosure of as
`
`the
`accompanying
`application and
`is hereby
`incorporated by
`reference
`therein.
`Computer Program
`in Microfiche
`(Appendix)
`
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`
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`following:
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`(if applicable)
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`continuation/divisional
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`record
`to
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`there
`is an
`assignee)
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`(if applicable)
`
`[ ]
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`TEVA - EXHIBIT 1005 (PART 1 OF 3)
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`small
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`entity
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`
`SMALL ENTITY STATUS
`CFR1.9
`and
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`1.27)
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`TOTAL FILING FEE
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`[ ] A check in the amount of $ to cover the filing fee and the assignment fee is enclosed.
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`[X ] The Commissioner is hereby authorized to charge and/or credit Deposit Account Number 01-0885
`as described below.
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`phone: 949-450-1750
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`Respectfully Submitted,
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`Reg. No: 25,612
`
`page 2 of 2
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`0002
`
`

`
`D-3111 IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`PATENT
`In re application of:
`ACHEAMPONG ET AL.
`Serial No. N/A
`Dated: Submitted herewith
`Title:
`METHODS OF PROVIDING
`THERAPEUTIC EFFECTS USING
`CYCLOSPORIN COMPONENTS
`
`) Group Art Unit: N/A
`)
`) Examiner: N/A
`)
`)
`)
`)
`)
`)
`
`Express Mail Mailing Label
`No. EV 464416262 US
`Date of Deposit: AUGUST 27, 2004
`I hereby certify that the following documents as identified
`below are being deposited with the United States Postal Service
`"Express Mail Post Office to Addressee" service under 37 CFR
`on the date indicated above and are addressed to the Commissioner
`for Patents, PO Box
`
`1450, Alexandria, VA 22313-1450.
`Application Transmittal
`Application Data Sheet;
`Application;
`Declaration;
`Assignment and Recordation Sheet;
`Return receipt postcard.
`
`4
`6 >
`
`and
`
`1.10
`
`The 6 above-identified documents are
`
`enclosed
`
`herewith.
`
`Respectfully submitted.
`
`Janet E. McGhee, Office of
`Frank J. Uxa, Reg. No. 25,612
`Attorney for Applicant
`Reg. No. 36,331
`4 Venture, Suite 300
`Irvine, CA 92618
`(949) 450-1750
`Facsimile (949) 450-1764
`
`0003
`
`

`
`DOCKET NO.: D-3111
`
`DOCKET NO.: D—3lll
`
`ACHEAMPONG
`THE ENCLOSED PATENT APPLICATION OF
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED
`A FILING
`
`IS
`THE ENCLOSED PATENT APPLICATION OF ACHEAMPONG ET AL.
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`ET
`
`DATE
`
`AL.
`
`AUGUST 27, 2004
`
`AUGUST 27, 2004
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`0004
`
`0004
`
`

`
`S($ 10/97)
`ro
`ro
`
`03
`
`CO
`
`o
`03 ro
`-NI
`o
`-Pv !
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`Docket No: D-3111
`
`(Only for new nonprovisional applications under 37 CFR
`
`1.53(b))
`
`Total Pages in this Submission
`
`Transmitted herewith for
`invention entitled:
`
`-and invented by:
`
`TO THE U.S. PATENT AND TRADEMARK OFFICE
`PO BOX 1450
`ALEXANDRIA, VA 22313-1450
`
`filing under 35 U.S.C.
`
`
`
`
`
`and 111(a) 37 CFR 1.53(b) is a new utility patent application
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`ACHEAMPONG ET AL
`
`If a CONTINUATION APPLICATION,
`information:
`requisite
`check appropriate box an supply the
`[ ]Continuation [ JDivisional [ ]Continuation-in-part (CIP) of prior application No.:
`
`O
`LO
`tf- ^
`CO 00
`CM
`for an
`g?
`O)
`
`O r--
`CM
`eo
`o
`
`Enclosed are Application Elements:
`[X ]
`Filing Fee
`[X ]
`Specification having 34 page(s) and including the
`[X ]
`Title of the Invention
`[X ]
`Cross References to Related Applications
`[X ]
`Background of the Invention
`[X ]
`Brief Summary of the
`Invention
`[ ]
`Description of the Drawings
`[X ]
`Detailed Description
`[X ]
`Claim(s) as Classified Below
`[X ]
`Abstract of the Disclosure
`[ ] Informal
`_ Sheets of Drawings(s) (37 CFR 113) [ ] Formal
`
`Oath or Declaration
`[X ] Executed
`[ ] Unexecuted
`[ ] Copy from prior application
`(37 CFR 1.63(d))
`Power of Attorney [X ] Executed
`[ ] Unexecuted
`[ ] Copy from prior application (37 CFR 1.63(d)) (for
`only)
`application
`continuation/divisional
`
`
`from Incorporation By Reference ~ The entire disclosure of the prior application which a copy of the oath or
`declaration is supplied under the above
`entry,
`is
`
`considered being part of the disclosure of as
`
`the
`accompanying
`application and
`is hereby
`incorporated by
`reference
`therein.
`Computer Program
`in Microfiche
`(Appendix)
`
`[ ]
`[X ]
`
`[X ]
`
`[X ]
`
`[ ]
`
`following:
`
`(if applicable)
`
`(for
`
`continuation/divisional
`
`application
`
`only)
`
`Accompanying Application Parts
`documents(s))
`[X ]
`Assignment Papers (cover sheets &
`record
`to
`[ ] The prior application is assigned of
`[ ] Copy from prior application (37 CFR 1.63(d)) (for
`37 CFR 3.73(B) Statement (when
`there
`is an
`assignee)
`English Translation Document
`(if applicable)
`
`[ ]
`[ ]
`
`page 1 of 2
`
`continuation/divisional
`
`application
`
`only)
`
`0005
`
`

`
`[ ] Copies of _ IDS Cited Reference(s)
`
`[ ]
`[ ]
`[X ]
`[X ]
`[X]
`[ ]
`
`Information Disclosure Statement/PTO-1449
`Preliminary Amendment
`Acknowledgment postcard
`Certificate of Mailing by Express Mail
`APPLICATION DATA SHEET
`REQUEST FOR NON-PUBLICATION
`
`Fee Calculation and Transmittal
`
`* The filing fee is calculated on the basis of the claims existing
`accompanying preliminary amendment noted
`above.
`
`in
`
`the
`
`prior
`
`application
`
`as
`
`amended
`
`CLAIMS AS FILED
`
`For
`
`Total Claims
`
`Independent Claims
`
`#Filed
`
`36
`
`2
`
`#Allowed
`-20 =
`3 =
`
`#Extra
`
`16
`
`Rate
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`X $18.00
`
`X $86.00
`
`Multiple Dependent Claims
`
`(check if applicable) [
`
`]
`
`OTHER FEE (specify purpose)
`
`BASIC FEE
`
`ASSIGNMENT
`
`Fee
`
`$288.00
`$ 0.00
`$ 0.00
`$ 770.00
`
`$ 40.00
`
`(Applicant has
`
`small
`
`entity
`
`status
`
`under
`
`37
`
`SMALL ENTITY STATUS
`CFR1.9
`and
`
`1.27)
`
`TOTAL FILING FEE
`
`$1,098.00
`
`[ ] A check in the amount of $ to cover the filing fee and the assignment fee is enclosed.
`
`[X ] The Commissioner is hereby authorized to charge and/or credit Deposit Account Number 01-0885
`as described below.
`[X ]
`Charge the amount of $1,098.00 as filing fee.
`[X ]
`Credit any overpayment.
`[X ]
`Charge any additional filing
`
`
`
`fees required under 37 CFR 1.16 and 1.17.
`
`4 VENTURE, SUITE 300
`IRVINE, CA 92618
`phone: 949-450-1750
`949-450-1764
`fax:
`
`Respectfully Submitted,
`
`FRANK J. UXA
`Attorney for Applicants
`Reg. No: 25,612
`
`page 2 of 2
`
`0006
`
`

`
`D-3111 IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`PATENT
`In re application of:
`ACHEAMPONG ET AL.
`Serial No. N/A
`Dated: Submitted herewith
`Title:
`METHODS OF PROVIDING
`THERAPEUTIC EFFECTS USING
`CYCLOSPORIN COMPONENTS
`
`) Group Art Unit: N/A
`)
`) Examiner: N/A
`)
`)
`)
`)
`)
`)
`
`Express Mail Mailing Label
`No. EV 464416262 US
`Date of Deposit: AUGUST 27, 2004
`I hereby certify that the following documents as identified
`below are being deposited with the United States Postal Service
`"Express Mail Post Office to Addressee" service under 37 CFR
`on the date indicated above and are addressed to the Commissioner
`for Patents, PO Box
`
`1450, Alexandria, VA 22313-1450.
`Application Transmittal
`Application Data Sheet;
`Application;
`Declaration;
`Assignment and Recordation Sheet;
`Return receipt postcard.
`
`4
`6 >
`
`and
`
`1.10
`
`The 6 above-identified documents are
`
`enclosed
`
`herewith.
`
`Respectfully submitted.
`
`Janet E. McGhee, Office of
`Frank J. Uxa, Reg. No. 25,612
`Attorney for Applicant
`Reg. No. 36,331
`4 Venture, Suite 300
`Irvine, CA 92618
`(949) 450-1750
`Facsimile (949) 450-1764
`
`0007
`
`

`
`DOCKET NO.: D-3111
`
`DOCKET NO.: D—3lll
`
`ACHEAMPONG
`THE ENCLOSED PATENT APPLICATION OF
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED
`A FILING
`
`IS
`THE ENCLOSED PATENT APPLICATION OF ACHEAMPONG ET AL.
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`ET
`
`DATE
`
`AL.
`
`AUGUST 27, 2004
`
`AUGUST 27, 2004
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`0008
`
`0008
`
`

`
`D-3111
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`Related Application
`This application claims the benefit of U.S.
`Provisional Application No. 60/503,137 filed September 15,
`2003, which is incorporated in its entirety herein by
`reference.
`
`Background of the Invention
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using
`compositions including cyclosporin components,
`More
`particularly, the invention relates to methods including
`administering to an eye of a human or animal a
`therapeutically effective 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 cyclosporin A derivatives
`to treat ophthalmic conditions has been the subject of
`various patents, for example Ding et al U.S. Patent
`5,474,979; Garst U.S. Patent 6,254,860; and Garst U.S.
`6,350,442, this disclosure of each of which is incorporated
`in its entirely herein by reference.
`In addition,
`cyclosporin A compositions used in treating ophthalmic
`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 emulsions in patients with
`moderate to severe dry eve
`
`disease." et al, J Ocul Small
`
`Pharmacol Ther, 2002 Oct, 18(5):411-8; "Distribution of
`cyclosporin A in ocular tissues after topical
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`0009
`
`

`
`2
`D-3111
`administration to albino rabbits and beagle dogs."
`Acheampong et al, Curr Eye Res, 1999 Feb, 18 (2):91-103b;
`"Cvclosporine distribution into the con-junctiva. cornea,
`lacrimal gland, and systemic blood following topical dosing
`of cvclosporine to rabbit, dog, and human eves. " Acheampong
`et al, Adv Exp Med Biol, 1998, 438:1001-4; "Preclinical
`safety studies of cvclosporine ophthalmic emulsion."
`Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`"Cyclosporin & Emulsion & Eve." Stevenson et al,
`Ophthalmology, 2000 May, 107 (5) : 967-74; and "Two
`multicenter. randomized studies of the efficacy and safety
`of cvclosporine ophthalmic emulsion
`in
`moderate
`dry eve disease. CsA Phase 3 Study Group." Sail et al,
`Each of these
`Ophthalmology, 2000 Apr, 107(4):631-9.
`publications is incorporated in its entirety herein by-
`reference. In addition, cyclosporin A-containing oil-in-
`water emulsions have been clinically tested, under
`conditions of confidentiality, since the mid 1990's in
`order to obtain U.S. Food and Drug Administration (FDA)
`regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are set out in Ding et al U.S. Patent 5,474,979. Example
`
`1 of this patent shows a series emulsions in which the of
`
`ratio of cyclosporin A to castor oil in each of these
`compositions was 0.08 or greater, except for Composition B,
`which 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 Compositions A, to
`
`C and D of Example 1.
`Over time, it has become apparent that cyclosporin
`emulsions for ophthalmic use preferably have less than 0.2%
`by weight of cyclosporin A.
`With cyclosporin A
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`to
`
`severe
`
`A
`
`0010
`
`

`
`D-3111
`3
`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 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
`methods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`5
`
`10
`
`20
`
`25
`
`30
`
`Summary of the Invention
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been
`discovered.
`Such methods provide substantial overall
`efficacy in providing desired therapeutic effects. In
`15 . addition, other important benefits
`are
`obtained
`the present methods.
`For example, patient safety is
`enhanced. In particular, the present methods
`provide
`reduced risks of side effects and/or drug interactions.
`Prescribing physicians advantageously have increased
`flexibility in prescribing such methods and the
`compositions useful in such
`methods,
`for
`example,
`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
`advantages, such as increased safety
`and/or
`In one aspect of the present invention, the present
`methods comprise administering to an eye of a human or
`animal a composition in the form of an emulsion comprising
`water, a hydrophobic component and a cyclosporin component
`in a therapeutically effective amount of less than 0.1% by
`
`employing
`
`for
`
`flexibility.
`
`0011
`
`

`
`relatively
`
`disease,
`
`the
`
`4
`D-3111
`The weight ratio of the
`weight of the composition,
`cyclosporin component to the hydrophobic component is less
`than 0.08.
`It has been found that the relatively increased
`amounts of hydrophobic component
`together
`with
`reduced, yet therapeutically effective, amounts of
`cyclosporin component provide substantial and advantageous
`benefits. For example, the overall efficacy of the present
`compositions, for example in treating
`dry
`
`eye is
`substantially equal to an identical composition in which
`the cyclosporin component is present
`
`an in 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
`in the eye, which reduces vision distortion which may be
`caused by the presence of the emulsion in the eye and/or
`facilitates the therapeutic effectiveness of the
`composition. Additionally, and importantly, using reduced
`amounts of the active cyclosporin component mitigates
`against undesirable side effects and/or potential drug
`interactions.
`In short, the present invention provides at least one
`advantageous 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 cyclosporin 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
`
`5
`
`10
`
`15
`
`2 0
`
`25
`
`30
`
`0012
`
`

`
`D-3111
`5
`conjunctivitis, atopic kerapoconjunctivitis, corneal graft
`rejection and the like conditions. The present invention
`is particularly effective in
`treating
`dry
`eye
`Employing reduced concentrations of cyclosporin
`component, as in the
`present
`invention,
`is
`effective to provide the blood of the human or animal under
`treatment with reduced concentrations of cyclosporin
`component, preferably with substantially no detectable
`concentration of the cyclosporin component,
`The
`cyclosporin component concentration of blood can be
`advantageously measured using a validated liquid
`chromatography/mass spectrometry-mass spectrometry (VLC/MS-
`MS) analytical method, such as described elsewhere herein.
`In one embodiment, in the present methods the blood of
`the human or animal has concentrations of clyclosporin
`component of 0.1 ng/ml
`or less.
`Any suitable cyclosporin component effective in the
`present methods may be used.
`Cyclosporins are a group of nonpolar cyclic
`oligopeptides with known immunosuppressant activity.
`Cyclosporin A, along with several other minor metabolites,
`cyclosporin B through I, have been identified,
`In
`addition, a number of synthetic analogs have been prepared.
`In general, commercially available cyclosporins may
`contain a mixture of several individual cyclosporins which
`all share a cyclic peptide structure consisting
`of
`amino acid residues with a total molecular weight of about
`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 of the
`cyclosporin group and derivatives thereof, as well as
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`syndrome.
`
`advantageously
`
`eleven
`
`0013
`
`

`
`6
`D-3111
`mixtures of two or more 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 useful cyclosporin
`component.
`Any suitable hydrophobic component may be employed in
`the present invention. Advantageously, the cyclosporin
`component is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`discontinuous phase in the presently useful cyclosporin
`component-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
`1.0%
`may be present in an amount of up
`to
`about
`or about 1.5% by weight or
`more
`of
`the
`composition.
`Preferably, the hydrophobic component comprises one or
`more oily materials. Examples of useful oil materials
`include, without limitation, vegetable
`oils,
`animal
`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.
`include or
`The presently useful compositions
`may
`
`more other components in amounts effective to facilitate
`the usefulness and effectiveness of the compositions.
`Examples of such other components include, without
`limitation, emulsifier components, tonicity components,
`polyelectrolyte
`components,
`surfactant
`components.
`
`one
`
`oils,
`
`5
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`0014
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`

`
`7
`D-3111
`viscosity inducing components, acids and/or bases to adjust
`the pH of the composition, buffer components, preservative
`components and the like. Components may be employed which
`are effective to perform two or more functions in the
`presently useful compositions. For example, components
`which are effective as both emulsifiers and surfactants may
`be employed, and/or components which are effective as both
`polyelectrolyte components and viscosity inducing
`components may be employed. The specific composition
`chosen for use in the present invention
`advantageously
`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.
`advantageously
`The presently useful compositions
`ophthalmically acceptable. A composition, component or
`material is ophthalmically acceptable when 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 have pH's within the physiological
`range of about 6 to about 10, preferably in a range of
`about 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
`administering step comprising topically
`administering
`presently useful 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
`
`the
`
`are
`
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`
`8
`D-3111
`included within the scope of the present invention provided
`that the features included in such a combination are not
`mutually inconsistent.
`These and 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
`administering, preferably topically administering, to an
`eye of a human or animal a cyclosporin component-containing
`emulsion. The emulsion contains water, for example U.S.
`pure water, a hydrophobic component and a cyclosporin
`component in a therapeutically effective amount of less
`than 0.1% by weight of the emulsion,
`In addition.
`beneficial results have been found when the weight ratio of
`the cyclosporin component to the hydrophobic
`component
`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
`
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`0016
`
`

`
`achieve
`
`9
`D-3111
`effects while, at the same time, substantially reducing, or
`even 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 which, in the past, has been caused by the
`presence of certain components in prior art cyclosporin-
`Also, the use of the present
`containing emulsions.
`compositions which include reduced amounts of the
`cyclosporin
`frequent
`for
`components
`allow
`more
`administration of the present compositions
`to
`desired therapeutic 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 cyclosporin 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
`The frequency of administration and the amount of the
`presently useful composition to use during each
`administration varies depending upon the therapeutic effect
`to be obtained, the severity of the condition being treated
`and the like factors. The presently useful compositions
`are designed to allow the prescribing physician substantial
`flexibility in treating various ocular conditions to
`achieve the desired therapeutic effect or effects with
`reduced risk of side effects and/or
`eye
`irritation. Such
`
`
`syndrome.
`
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`
`

`
`10
`D-3111
`administration may occur on an as needed basis, for
`example, in treating or managing dry eye syndrome, on a one
`time basis or on a repeated or periodic basis once, twice,
`thrice or more times daily depending on the needs of the
`human or animal being treated and other factors involved in
`the application at hand.
`One of the important advantages of the present
`invention is the reduced concentration
`of the
`component in the blood of
`
`the human or animal as a result
`of administering the present composition as described
`herein.
`One very useful embodiment of the present
`administering step provides no substantial detectable
`concentration of cyclosporin component in the blood of the
`human or animal. Cyclosporin component concentration in
`blood preferably is determined using a liquid
`chromatography-mass spectroscopy-mass spectroscopy (LC-
`MS/MS) , which test has a cyclosporin component detection
`limit of 0.1 ng/ml. Cyclosporin component concentrations
`below or less than 0.1 ng/ml are therefore considered
`substantially undetectable.
`run follows.
`as
`
`The LC-MS/MS test is advantageously
`One ml of blood is acidified with 0.2 ml of 0.1 N HC1
`solution, then extracted with 5 ml of methyl t-butyl ether.
`After separation from the acidified aqueous layer, the
`organic phase is neutralized with 2 ml of 0.1 N NaOH,
`evaporated, reconstituted in a water/acetonitrile-based
`mobil phase, and injected onto a 2.1 x 50 mm, 3//m pore size
`C-8 reverse phase high pressure liquid chromatography
`(HPLC) column (Keystone Scientific, Bellefonte, PA).
`Compounds are gradient-eluted at 0.2 mL/min and detected
`using an API III triple quadrupole mass
`spectrometer
`a turbo-ionspray source (PE-Sciex, Concord, Ontario,
`
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`
`cyclosporin
`
`with
`
`0018
`
`

`
`11
`D-3111
`Molecular reaction monitoring enhances the
`Canada).
`sensitivity and selectivity of this assay. Protonated
`molecules for the analyte and an internal standard are
`collisionally dissociated and product
`ions
`at
`m/z
`monitored for the analyte and the internal standard. Under
`these conditions, cyclosporin
`A and
`the
`internal
`cyclosporin G elute with retention times of about 3.8
`minutes. The lower limit of quantitation is 0.1 ng/mL, at
`which concentration the coefficient of variation and
`deviation from nominal concentration
`is
`<15%.
`As noted previously, any suitable cyclosporin
`component effective in the present methods may be employed.
`Very useful cyclosporin components include, without
`limitation, cyclosporin A, derivatives of cyclosporin A and
`the like and mixtures thereof.
`The chemical structure for cyclosporin A is
`represented by Formula 1
`
`5
`
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`
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`
`425
`
`standard
`
`Formula I
`
`H3C.
`
`'H3
`
`H3C'
`
`H>CV
`
`o
`CH3 O
`H3<r ^CH3
`
`SH3
`H
`
`H3C'
`
`CHa O
`
`H3C
`
`.0
`
`•CH3
`
`N-CH3
`
`?H3
`'CH3
`
`N
`i
`
`CHg
`
`O
`
`HaC"
`
`'CH,
`
`0019
`
`

`
`12
`D-3111
`As used herein the term "derivatives" of a cyclosporin
`refer to compounds having structures
`sufficiently
`to the cyclosporin so as to function in a manner
`substantially similar to or substantially identical to the
`cyclosporin, for example, cyclosporin A, in the present
`methods. Included, without limitation,
`within
`the
`cyclosporin A derivatives are those selected from ((R)-
`methylthio-Sar)3-(4 '-hydroxy-MeLeu) cyclosporin A, ((R)-
`(Cyclo) alkylthio-Sar)3- (4 1 -hydroxy-MeLeu) 4-cyclosporin A,
`and ( (R) - (Cyclo) alkylthio-Sar) 3-cyclosporin A derivatives
`described below.
`These cyclosporin derivatives are represented by the
`
`following general formulas (II), (III), and (IV)
`respectively:
`
`5
`
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`similar
`
`useful
`
`0020
`
`

`
`D-3111
`
`13
`Formula II
`
`Me
`
`(10
`
`le
`
`Me
`o-ifro
`
`Me"\ N^Me
`
`f
`Me>. Mt 01
`Alk
`MeV
`I
`Me
`\
`I I
`Me S
`•N»T
`N-fr
`r\ 0
`N
`-N-
`0
`0 Me
`0
`4
`7 i i i " " 1 1 v ' 'i
`•NH-
`o Me
`0
`0 / Me X
`Me
`M
`e—|
`1
`Me'
`Me
`OH Me
`
`Me
`
`0
`
`0
`Me
`
`0 Me
`
`Me
`
`Formula III
`
`Me
`
`m
`
`[e
`
`Mev
`
`.Me 01
`
`-N-
`
`Me
`
`Me
`
`0 Me
`
`0
`
`Me
`~\ N=Me
`Me
`
`0 Me
`
`R /
`fY -N-fr
`Alk
`Me
`l—t)
`I
`I
`I
`•NHT
`0=N-TO
`0
`0
`/H'
`0 Me 11 ¥ vn
`7 i | i
`tw
`0 / Me A o 1
`_J -
`J
`Me Me
`Mc
`I
`M57
`Me
`Me
`
`0
`N-Me
`
`0021
`
`

`
`D-3111
`
`14
`Formula IV
`
`(0
`
`Me
`
`Me
`
`0=11 1111
`
`II H ll
`
`Me
`
`Me
`
`MeO Vt
`Me n N»7
`/t.
`Me" \ i rT
`II
`0 Me n A j • rn
`
`Me
`
`Me
`
`8
`
`0 Me
`
`O
`*• H 1 <
`4
`•NH*
`r—NH
`O / Me A 0
`_J
`0 Me
`Me Me
`Me
`~|
`Me
`OH Me
`Me
`
`Me
`
`-NR^
`
`wherein Me is methyl; Alk is 2-6C alkylene or 3-
`6C cycloalkylene; R is OH, COOH,
`
`alkoxycarbonyl, or
`N(R3)-(CH2)-NR1R2; wherein RI,R2 is H, alkyl, 3-6C
`cycloalkyl, phenyl (optionally substituted by halo, alkoxy,
`alkoxycarbonyl, amino, alkylamino or dialkylamino), benzyl
`or saturated or unsaturated heterocyclyl having 5 or 6
`members and 1-3 heteroatoms;
`or NR^ is a 5 or 6 membered
`heterocycle which may contain a further N, 0 or S
`heteroatom and may be alkylated; Rj is H or alkyl and n is
`2-4; and the alkyl moieties
`contain
`1-4C.
`In one embodiment, the cyclosporin component is
`effective as an immunosuppressant. Without wishing to be
`limited to any particular theory of operation, it is
`believed that, in certain embodiments of the present
`invention, the cyclosporin component acts to enhance or
`restore lacrimal gland tearing in providing the desired
`therapeutic effect.
`One important feature of the present invention is that
`the presently useful compositions contain less than 0.1% by
`
`5
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`20
`
`0022
`
`

`
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`
`that
`
`be
`
`15
`D-3111
`weight of the cyclosporin component. The advantages of
`such low-concentrations of cyclosporin components have been
`Low
`discussed in some detail elsewhere herein,
`concentrations of cyclosporin component, together with
`concentrations of the hydrophobic
`component
`such
`weight ratio of cyclosporin component to hydrophobic
`component is greater than 0.08, provides one or more
`substantial advantages in the
`present
`methods.
`Any suitable hydrophobic component may be employed in
`the present invention. Such hydrophobic component
`may
`considered as comprising a discontinuous phase in the
`presently
`useful
`cyclosporin
`component-containing
`emulsions, with the water or aqueous phase being c