,.
`
`......
`
`S($ 10/97)
`"'-=>
`"'-=>
`........
`-.,J
`c..:>
`
`<=:
`·0
`I~ ...._,
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`(Only for new nonprovisional applications under 37 CFR 1.53(b))
`
`Docket No: D-3111
`
`I
`
`I
`
`Total Pages in this Submission
`
`TO THE U.S. PATENT AND TRADEMARK OFFICE
`PO BOX 1450
`ALEXANDRIA, VA 22313-1450
`
`Transmitted herewith for filing under 35 U.S.C. 111 (a) and 37 CFR 1.53(b) is a new utility patent application for an
`invention entitled:
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`.,
`
`-and invented by:
`
`ACHEAMPONG ET AL
`
`If a CONTINUATION APPLICATION, check appropriate box an supply the requisite information:
`[]Continuation [ ]Divisional [ ]Continuation-in-part (CIP)
`of prior application No.:
`
`[]
`[X ]
`
`[X ]
`
`[X]
`
`Enclosed are Application Elements:
`[X ]
`Filing Fee
`Specification having 34 page(s) and including the following:
`[X]
`Title of the Invention
`[X ]
`[X 1
`Cross References to Related Applications (if applicable)
`[X]
`Background of the Invention
`Brief Summary of the Invention
`[X ]
`[ ]
`Description of the Drawings
`[X ]
`Detailed Description
`[X]
`Claim(s) as Classified Below
`Abstract of the Disclosure
`[X ]
`_Sheets of Drawings(s) (37 CFR 113) [ 1 Formal
`[ ] Informal
`[X 1 Executed
`[ 1 Unexecuted
`Oath or Declaration
`[]Copy from prior application (37 CFR 1.63(d)) (for continuation/divisional application only)
`[X ] Executed
`[ ] Unexecuted
`Power of Attorney
`[]Copy from prior application (37 CFR 1.63(d)) (for continuation/divisional application only)
`Incorporation By Reference -- The entire disclosure of the prior application from which a copy of the oath or
`declaration is supplied under the above entry, is considered as being part of the disclosure of the accompanying
`application and is hereby incorporated by reference therein.
`Computer Program in Microfiche (Appendix)
`
`[ 1
`
`Accompanying Application Parts
`[X 1
`Assignment Papers (cover sheets & documents(s))
`[ ] The prior application is assigned of record to
`[ 1 Copy from prior application (37 CFR 1.63(d)) (for continuation/divisional application only)
`37 CFR 3.73(B) Statement (when there is an assignee)
`English Translation Document (if applicable)
`
`[ ]
`[ ]
`
`page 1 of 2
`
`APOTEX 1019, pg. 517
`
`

`
`[]Copies of_ IDS Cited Reference(s)
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`[ ]
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`[X]
`[X]
`[X]
`[ ]
`
`Information Disclosure StatemenUPT0-1449
`Preliminary Amendment
`Acknowledgment postcard
`Certificate of Mailing by Express Mail
`APPLICATION DATA SHEET
`REQUEST FOR NON-PUBLICATION
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`Fee Calculation and Transmittal
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`* The filing fee is calculated on the basis of the claims existing in the prior application as amended by the
`accompanying preliminary amendment noted above.
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`CLAIMS AS FILED
`
`For
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`#Filed
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`#Allowed
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`·,
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`Total Claims
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`Independent Claims
`
`36
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`2
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`Multiple Dependent Claims
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`16
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`-20 =
`- 3=
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`X $18.00
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`X $86.00
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`OTHER FEE (specify purpose)
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`ASSIGNMENT
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`(Applicant has small entity status under 37 CFR 1.9 and 1.27)
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`TOTAL FILING FEE
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`Fee
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`$288.00
`
`$ 0.00
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`$ 0.00
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`$770.00
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`$ 40.00
`--
`$1,098.00
`
`[] A check in the amount of$_ 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
`fax:
`949-450-1764
`
`Respectfully Submitted,
`
`Attorney for Applicants
`Reg. No: 25,612
`
`page 2 of 2
`
`APOTEX 1019, pg. 518
`
`

`
`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 1.10
`on the date indicated above and are addressed to the Commissioner
`for Patents, PO Box 1450, Alexandria, VA 22313-1450.
`
`1. Application Transmittal
`2. Application Data Sheet;
`3. Application;
`4. Declaration;
`5.
`Assignment and Recordation Sheet; and
`6.
`Return receipt postcard.
`
`The 6 above-identified documents are enclosed herewith.
`
`Respectfully submi~t~,-
`
`.; d/Uu_j; --m~
`
`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
`
`APOTEX 1019, pg. 519
`
`

`
`DOCKET NO.: D-3111
`
`THE ENCLOSED PATENT APPLICATION OF ACHEAMPONG ET AL. IS
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`AUGUST 27, 2004
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`APOTEX 1019, pg. 520
`
`

`
`,.
`
`......
`
`S($ 10/97)
`"'-=>
`"'-=>
`........
`-.,J
`c..:>
`
`<=:
`·0
`I~ ...._,
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`(Only for new nonprovisional applications under 37 CFR 1.53(b))
`
`Docket No: D-3111
`
`I
`
`I
`
`Total Pages in this Submission
`
`TO THE U.S. PATENT AND TRADEMARK OFFICE
`PO BOX 1450
`ALEXANDRIA, VA 22313-1450
`
`Transmitted herewith for filing under 35 U.S.C. 111 (a) and 37 CFR 1.53(b) is a new utility patent application for an
`invention entitled:
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`.,
`
`-and invented by:
`
`ACHEAMPONG ET AL
`
`If a CONTINUATION APPLICATION, check appropriate box an supply the requisite information:
`[]Continuation [ ]Divisional [ ]Continuation-in-part (CIP)
`of prior application No.:
`
`[]
`[X ]
`
`[X ]
`
`[X]
`
`Enclosed are Application Elements:
`[X ]
`Filing Fee
`Specification having 34 page(s) and including the following:
`[X]
`Title of the Invention
`[X ]
`[X 1
`Cross References to Related Applications (if applicable)
`[X]
`Background of the Invention
`Brief Summary of the Invention
`[X ]
`[ ]
`Description of the Drawings
`[X ]
`Detailed Description
`[X]
`Claim(s) as Classified Below
`Abstract of the Disclosure
`[X ]
`_Sheets of Drawings(s) (37 CFR 113) [ 1 Formal
`[ ] Informal
`[X 1 Executed
`[ 1 Unexecuted
`Oath or Declaration
`[]Copy from prior application (37 CFR 1.63(d)) (for continuation/divisional application only)
`[X ] Executed
`[ ] Unexecuted
`Power of Attorney
`[]Copy from prior application (37 CFR 1.63(d)) (for continuation/divisional application only)
`Incorporation By Reference -- The entire disclosure of the prior application from which a copy of the oath or
`declaration is supplied under the above entry, is considered as being part of the disclosure of the accompanying
`application and is hereby incorporated by reference therein.
`Computer Program in Microfiche (Appendix)
`
`[ 1
`
`Accompanying Application Parts
`[X 1
`Assignment Papers (cover sheets & documents(s))
`[ ] The prior application is assigned of record to
`[ 1 Copy from prior application (37 CFR 1.63(d)) (for continuation/divisional application only)
`37 CFR 3.73(B) Statement (when there is an assignee)
`English Translation Document (if applicable)
`
`[ ]
`[ ]
`
`page 1 of 2
`
`APOTEX 1019, pg. 521
`
`

`
`[]Copies of_ IDS Cited Reference(s)
`
`[ ]
`[ ]
`[X]
`[X]
`[X]
`[ ]
`
`Information Disclosure StatemenUPT0-1449
`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 in the prior application as amended by the
`accompanying preliminary amendment noted above.
`
`CLAIMS AS FILED
`
`For
`
`#Filed
`
`#Allowed
`
`#Extra
`
`Rate
`
`·,
`
`Total Claims
`
`Independent Claims
`
`36
`
`2
`
`Multiple Dependent Claims
`
`16
`
`-20 =
`- 3=
`(check if applicable) [ ]
`
`X $18.00
`
`X $86.00
`
`OTHER FEE (specify purpose)
`
`BASIC FEE
`
`ASSIGNMENT
`
`(Applicant has small entity status under 37 CFR 1.9 and 1.27)
`
`SMALL ENTITY STATUS
`
`TOTAL FILING FEE
`
`Fee
`
`$288.00
`
`$ 0.00
`
`$ 0.00
`
`$770.00
`
`$ 40.00
`--
`$1,098.00
`
`[] A check in the amount of$_ 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
`fax:
`949-450-1764
`
`Respectfully Submitted,
`
`Attorney for Applicants
`Reg. No: 25,612
`
`page 2 of 2
`
`APOTEX 1019, pg. 522
`
`

`
`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 1.10
`on the date indicated above and are addressed to the Commissioner
`for Patents, PO Box 1450, Alexandria, VA 22313-1450.
`
`1. Application Transmittal
`2. Application Data Sheet;
`3. Application;
`4. Declaration;
`5.
`Assignment and Recordation Sheet; and
`6.
`Return receipt postcard.
`
`The 6 above-identified documents are enclosed herewith.
`
`Respectfully submi~t~,-
`
`.; d/Uu_j; --m~
`
`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
`
`APOTEX 1019, pg. 523
`
`

`
`DOCKET NO.: D-3111
`
`THE ENCLOSED PATENT APPLICATION OF ACHEAMPONG ET AL. IS
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`AUGUST 27, 2004
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`APOTEX 1019, pg. 524
`
`

`
`D-3111
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`
`USING CYCLOSPORIN COMPONENTS
`
`5
`
`10
`
`15
`
`2 0
`
`25
`
`30
`
`Related Application
`the benefit of U.S.
`claims
`This
`application
`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 eye disease," Small et al, J Ocul
`Pharmacol Ther, 2002 Oct, 18 (5) :411-8; "Distribution of
`cyclosporin A
`in
`ocular
`tissues
`after
`topical
`
`APOTEX 1019, pg. 525
`
`

`
`D-3111
`
`2
`
`rabbits and beagle dogs,"
`to albino
`administration
`Acheampong et al, Curr Eye Res, 1999 Feb, 18(2):91-103b;
`"Cyclosporine distribution into the coniunctiva, cornea,
`lacrimal gland, and systemic blood following topical dosing
`of cyclosporine to rabbit, dog, and human eyes," Acheampong
`et al, Adv Exp Med Biol, 1998, 438:1001-4; "Preclinical
`safety studies of cyclosporine ophthalmic emulsion,"
`Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`"Cyclosporin & Emulsion
`& Eye," Stevenson et al,
`and
`"Two
`Ophthalmology,
`2000 May,
`107(5} :967-74;
`multicenter, randomized studies of the efficacy and safety
`of cyclosporine ophthalmic emulsion in moderate to severe
`dry eye disease. CsA Phase 3 Study Group," Sall 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(cid:173)
`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 of emulsions in which the
`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
`The Ding et al patent placed no
`weight castor oil.
`significance in Composition B relative to Compositions A,
`C and D of Example 1.
`Over time, it has become apparent that cyclosporin A
`emulsions for ophthalmic use preferably have less than 0. 2%
`by weight of cyclosporin A.
`With cyclosporin A
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 526
`
`

`
`.-
`
`D-3111
`
`3
`
`the amount of castor oil
`concentrations less than 0.2%,
`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.
`
`Summary of the Xnvention
`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
`addition, other important benefits are obtained employing
`the present methods.
`For example, patient safety is
`enhanced.
`In particular, the present methods provide for
`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, 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
`advantages, such as increased safety and/or flexibility.
`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
`
`5
`
`10
`
`15
`
`2 0
`
`25
`
`30
`
`APOTEX 1019, pg. 527
`
`

`
`D-3111
`
`4
`
`the
`The weight ratio of
`the composition.
`weight of
`cyclosporin component to the hydrophobic component is less
`than 0.08.
`the relatively increased
`that
`found
`It has been
`amounts of hydrophobic component together with relatively
`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 disease, is
`substantially equal to an identical 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 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.
`treating any
`in
`The present methods are useful
`sui table 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
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 528
`
`

`
`D-3111
`
`5
`
`conjunctivitis, atopic kerapoconjunctivitis, corneal graft
`rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`Employing
`reduced concentrations of cyclosporin
`component, 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, 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(cid:173)
`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.
`cyclic
`group of nonpolar
`Cyclosporins
`are
`a
`oligopeptides with
`immunosuppressant activity.
`known
`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 eleven
`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
`
`3 0
`
`APOTEX 1019, pg. 529
`
`

`
`D-3111
`
`6
`
`individual cyclosporins and
`
`two or more
`mixtures of
`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
`may be present in an amount of up to about 1.0% by weight
`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 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
`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,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 530
`
`

`
`D-3111
`
`7
`
`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 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 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.
`an
`for
`The present methods preferably provide
`administering step comprising topically administering the
`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
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`D-3111
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`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 is
`less than 0.08.
`the present administering step
`As noted above,
`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.
`to be very
`found
`The present methods have been
`effective in providing the desired therapeutic effect or
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`D-3111
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`effects while, at the same time, subs.tantially 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(cid:173)
`containing emulsions.
`Also,
`the use of
`the present
`compositions which
`include
`reduced
`amounts of
`the
`cyclosporin
`components
`allow
`for more
`frequent
`administration of the present compositions to achieve the
`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 syndrome.
`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
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`for
`administration may occur on an as needed basis,
`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.
`the present
`One of
`the
`important advantages of
`invention is the reduced concentration of the cyclosporin
`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(cid:173)
`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.
`The LC-MS/MS test is advantageously run as follows.
`One ml of blood is acidified with 0.2 ml of 0.1 N HCl
`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 with
`a
`turbo-ionspray source
`(PE-Sciex, Concord, Ontario,
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`the
`Canada). Molecular reaction monitoring enhances
`sensitivity and selectivity of this assay.
`Protonated
`molecules for the analyte and an internal standard are
`collisionally dissociated and product ions at m/z 425 are
`monitored for the analyte and the internal standard. Under
`these conditions, cyclosporin A and the internal standard
`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
`represented by Formula 1
`
`cyclosporin A
`
`is
`
`for
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`Formula :I
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`As used herein the term "derivatives" of a cyclosporin
`refer to compounds having structures sufficiently similar
`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 useful
`cyclosporin A derivatives are those selected from
`( (R)(cid:173)
`methylthio-Sar) 3 - (4' -hydroxy-MeLeu) cyclosporin A,
`( (R)-
`(Cyclo)alkylthio-Sar) 3-(4'-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:
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`0
`
`Me
`
`}
`
`~~'?
`
`0
`
`0
`
`0
`
`Me
`
`Formula I I I
`
`(DI)
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`Formula IV
`
`(l)
`
`o=:N-m'--r-N-.,...,._.N-+--n-0 ~
`
`Me
`
`Me
`
`is 2-6C alkylene or 3-
`is methyl; Alk
`wherein Me
`6C cycloalkylene; R is OH, COOH, alkoxycarbonyl, -NR1R2 or
`is H,
`alkyl,
`3-6C
`N(R3 )-(CH2 )-NR1R2 ; wherein R1 ,R2
`cycloalkyl, phenyl (optionally substituted by halo, alkoxy,
`alkoxycarbonyl, amino, alkylamine or dialkylamino), benzyl
`or saturated or unsaturated heterocyclyl having 5 or 6
`members and 1-3 heteroatoms; or NR1R2 is a 5 or 6 membered
`further N,
`heterocycle which may contain a
`0 or S
`heteroatom and may be alkylated; R3 is H or alkyl and n is
`2-4; and the alkyl moieties contain 1-4C.
`is
`In one embodiment,
`the cyclosporin component
`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
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`The advantages of
`weight of the cyclosporin component.
`such low-concentrations of cyclosporin components have been
`discussed
`in
`some detail
`elsewhere herein.
`Low
`concentrations of cyclosporin component,
`together with
`concentrations of the hydrophobic component such that the
`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 be
`considered as comprising a discontinuous phase in the
`presently
`useful
`cyclosporin
`component-containing
`emulsions, with the water or aqueous phase being considered
`the continuous phase in such emulsion.
`The hydrophobic
`component is preferably selected so as to solubilize the
`cyclosporin
`component, which
`is often substantially
`insoluble in the aqueous phase.
`Thus, with a sui table
`hydrophobic component included in the presently useful
`emulsions,
`the
`cyclosporin
`component
`is preferably
`solubilized in the emulsions.
`the hydrophobic
`In one very useful embodiment,
`in particular, a
`component comprises an oily material,
`material which is substantially not miscible in water.
`Examples of useful oily materials
`include, without
`limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils, and the like and mixtures thereof. Thus,
`the present hydrophilic components may comprise naturally
`occurring oils,
`including, without
`limitation refined
`naturally occurring oils, or naturally occurring oils which
`have been processed to alter their chemical structures to
`some extent or oils which are substantially entirely
`synthetic. One ve