S$ 10/97
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`Docket No D-3111
`
`Only for new nonprovisional applications under 37 CFR 1.53b
`
`Total Pages in this Submission
`
`TO THE U.S PATENT AND TRADEMARK OFFICE
`POBOXI45O
`ALEXANDRIA VA 22313-1450
`
`Transmitted herewith for filing under 35 U.S.C 111a and 37 CFR 1.53b is
`invention entitled
`
`new utility patent application for an
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`-and invented by
`
`ACHEAMPONG ET AL
`
`If
`
`CONTINUATION APPLIcATIoN check appropriate box an supply the requisite information
`Continuation-in-part CIP of prior application No
`Divisional
`
`Enclosed are Application Elements
`Filing Fee
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`Specification having 34 pages and including the following
`
`Title of the Invention
`
`Cross References to Related Applications if applicable
`
`Background of the Invention
`
`Brief Summary of the Invention
`
`Description of the Drawings
`
`Detailed Description
`
`Claims as Classified Below
`
`Abstract of the Disclosure
`
`Sheets of Drawingss 37 CFR 113
`Oath or Declaration
`Executed
`Unexecuted
`Copy from prior application 37 CFR 1.63d for continuation/divisional
`Power of Attorney
`Executed
`Unexecuted
`from prior application 37 CFR .63d for continuation/divisional
`application only
`Incorporation By Reference -- The entire disclosure of the prior application from which
`copy of the oath or
`declaration is supplied under the above entry is considered as being part of the disclosure of the accompanying
`
`application only
`
`application and is hereby incorporated by reference therein
`
`Computer Program in Microfiche Appendix
`
`Accompanying Application Parts
`documentss
`Assignment Papers cover sheets
`The prior application is assigned of record to
`from prior application 37 CFR 1.63d for continuation/divisional
`37 CFR 3.73B Statement when there is an assignee
`English Translation Document
`
`if applicable
`
`application only
`
`pagelof
`
`FAMY CARE - EXHIBIT 1005-0001
`
`
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`Docket No D-3111
`
`Only for new nonprovisional applications under 37 CFR 1.53b
`
`Total Pages in this Submission
`
`TO THE U.S PATENT AND TRADEMARK OFFICE
`POBOXI45O
`ALEXANDRIA VA 22313-1450
`
`Transmitted herewith for filing under 35 U.S.C 111a and 37 CFR 1.53b is
`invention entitled
`
`new utility patent application for an
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`-and invented by
`
`ACHEAMPONG ET AL
`
`If
`
`CONTINUATION APPLIcATIoN check appropriate box an supply the requisite information
`Continuation-in-part CIP of prior application No
`Divisional
`
`Enclosed are Application Elements
`Filing Fee
`
`Specification having 34 pages and including the following
`
`Title of the Invention
`
`Cross References to Related Applications if applicable
`
`Background of the Invention
`
`Brief Summary of the Invention
`
`Description of the Drawings
`
`Detailed Description
`
`Claims as Classified Below
`
`Abstract of the Disclosure
`
`Sheets of Drawingss 37 CFR 113
`Oath or Declaration
`Executed
`Unexecuted
`Copy from prior application 37 CFR 1.63d for continuation/divisional
`Power of Attorney
`Executed
`Unexecuted
`from prior application 37 CFR .63d for continuation/divisional
`application only
`Incorporation By Reference -- The entire disclosure of the prior application from which
`copy of the oath or
`declaration is supplied under the above entry is considered as being part of the disclosure of the accompanying
`
`application only
`
`application and is hereby incorporated by reference therein
`
`Computer Program in Microfiche Appendix
`
`Accompanying Application Parts
`documentss
`Assignment Papers cover sheets
`The prior application is assigned of record to
`from prior application 37 CFR 1.63d for continuation/divisional
`37 CFR 3.73B Statement when there is an assignee
`English Translation Document
`
`if applicable
`
`application only
`
`pagelof
`
`FAMY CARE - EXHIBIT 1005-0001
`
`
`
`Information Disclosure Statement/PTO-1 449
`
`Copies of
`
`IDS Cited References
`
`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
`
`Total Claims
`
`36
`
`-20
`
`16
`
`Independent Claims
`
`Multiple Dependent Claims
`
`check if applicable
`
`OTHER FEE specify purpose
`
`Rate
`
`$18.00
`
`$86.00
`
`BASIC FEE
`
`ASSIGNMENT
`
`Fee
`
`$288.00
`
`0.00
`
`0.00
`
`770.00
`
`40.00
`
`Applicant has small entity status under 37 CFR 1.9 and 1.27
`
`SMALL ENTITY STATUS
`
`TOTAL FILING FEE
`
`$1098.00
`
`check
`
`in the amount of
`
`to cover the filing fee and the assignment
`fee is enclosed
`The Commissioner is hereby authorized to charge and/or credit Deposit Account Number 01-0885
`as described below
`Charge the amount of $1098.00 as filing fee
`
`Credit any overpayment
`filing fees required under 37 CFR .16 and 1.17
`
`Charge any additional
`
`VENTURE SUITE 300
`IRVINE CA 92618
`phone 949-450-1750
`fax
`949-450-1764
`
`Respectfully Submitted
`
`Attorney for Applicants
`Reg No 25612
`
`page
`
`of
`
`FAMY CARE - EXHIBIT 1005-0002
`
`
`
`D-31l1
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`PATENT
`
`In re application of
`ET AL
`ACHEANPONG
`
`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
`
`the following documents as identified
`hereby certify that
`below are being deposited with the United States Postal Service
`TExpress Mail Post Office to Addressee service under 37 CFR 1.10
`on the date indicated above
`and are addressed to the Commissioner
`for Patents P0 Box 1450 Alexandria VA 22313-1450
`
`Application Transmittal
`Application Data Sheet
`Application
`Declaration
`Assignment and Recordation Sheet
`Return receipt postcard
`
`and
`
`The
`
`above-identified documents are enclosed herewith
`
`Respectfully submitte
`
`McGhee Office of
`Janet
`Uxa Reg No 25612
`Frank
`Attorney for Applicant
`Reg No 36331
`Venture Suite 300
`Irvine CA
`92618
`949 4501750
`Facsimile 949 450-1764
`
`FAMY CARE - EXHIBIT 1005-0003
`
`
`
`DOCKET NO D-3111
`
`DOCKET NO.: D-3111
`
`ET AL IS
`THE ENCLOSED PATENT APPLICATION OF ACHEANPONG
`THE ENCLOSED PATENT APPLICATION OF ACHEAMPONG ET AL.
`IS
`BEING FILED IN ACCORDANCE WITH SECTION
`37 CFR 1.10 BY
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED
`FILING DATE
`EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`AUGUST 27 2004
`AUGUST 27, 2004
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`tlae
`
`FAMY CARE - EXHIBIT 1005-0004
`
`FAMY CARE - EXHIBIT 1005-0004
`
`
`
`S$ 10/97
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`
`Docket No D-3111
`
`Only for new nonprovisional applications under 37 CFR 1.53b
`
`Total Pages in this Submission
`
`TO THE U.S PATENT AND TRADEMARK OFFICE
`POBOXI45O
`ALEXANDRIA VA 22313-1450
`
`Transmitted herewith for filing under 35 U.S.C 111a and 37 CFR 1.53b is
`invention entitled
`
`new utility patent application for an
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`USING CYCLOSPORIN COMPONENTS
`
`-and invented by
`
`ACHEAMPONG ET AL
`
`If
`
`CONTINUATION APPLIcATIoN check appropriate box an supply the requisite information
`Continuation-in-part CIP of prior application No
`Divisional
`
`Enclosed are Application Elements
`Filing Fee
`
`Specification having 34 pages and including the following
`
`Title of the Invention
`
`Cross References to Related Applications if applicable
`
`Background of the Invention
`
`Brief Summary of the Invention
`
`Description of the Drawings
`
`Detailed Description
`
`Claims as Classified Below
`
`Abstract of the Disclosure
`
`Sheets of Drawingss 37 CFR 113
`Oath or Declaration
`Executed
`Unexecuted
`Copy from prior application 37 CFR 1.63d for continuation/divisional
`Power of Attorney
`Executed
`Unexecuted
`from prior application 37 CFR .63d for continuation/divisional
`application only
`Incorporation By Reference -- The entire disclosure of the prior application from which
`copy of the oath or
`declaration is supplied under the above entry is considered as being part of the disclosure of the accompanying
`
`application only
`
`application and is hereby incorporated by reference therein
`
`Computer Program in Microfiche Appendix
`
`Accompanying Application Parts
`documentss
`Assignment Papers cover sheets
`The prior application is assigned of record to
`from prior application 37 CFR 1.63d for continuation/divisional
`37 CFR 3.73B Statement when there is an assignee
`English Translation Document
`
`if applicable
`
`application only
`
`pagelof
`
`FAMY CARE - EXHIBIT 1005-0005
`
`
`
`Information Disclosure Statement/PTO-1 449
`
`Copies of
`
`IDS Cited References
`
`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
`
`Total Claims
`
`36
`
`-20
`
`16
`
`Independent Claims
`
`Multiple Dependent Claims
`
`check if applicable
`
`OTHER FEE specify purpose
`
`Rate
`
`$18.00
`
`$86.00
`
`BASIC FEE
`
`ASSIGNMENT
`
`Fee
`
`$288.00
`
`0.00
`
`0.00
`
`770.00
`
`40.00
`
`Applicant has small entity status under 37 CFR 1.9 and 1.27
`
`SMALL ENTITY STATUS
`
`TOTAL FILING FEE
`
`$1098.00
`
`check
`
`in the amount of
`
`to cover the filing fee and the assignment
`fee is enclosed
`The Commissioner is hereby authorized to charge and/or credit Deposit Account Number 01-0885
`as described below
`Charge the amount of $1098.00 as filing fee
`
`Credit any overpayment
`filing fees required under 37 CFR .16 and 1.17
`
`Charge any additional
`
`VENTURE SUITE 300
`IRVINE CA 92618
`phone 949-450-1750
`fax
`949-450-1764
`
`Respectfully Submitted
`
`Attorney for Applicants
`Reg No 25612
`
`page
`
`of
`
`FAMY CARE - EXHIBIT 1005-0006
`
`
`
`D-31l1
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`PATENT
`
`In re application of
`ET AL
`ACHEANPONG
`
`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
`
`the following documents as identified
`hereby certify that
`below are being deposited with the United States Postal Service
`TExpress Mail Post Office to Addressee service under 37 CFR 1.10
`on the date indicated above
`and are addressed to the Commissioner
`for Patents P0 Box 1450 Alexandria VA 22313-1450
`
`Application Transmittal
`Application Data Sheet
`Application
`Declaration
`Assignment and Recordation Sheet
`Return receipt postcard
`
`and
`
`The
`
`above-identified documents are enclosed herewith
`
`Respectfully submitte
`
`McGhee Office of
`Janet
`Uxa Reg No 25612
`Frank
`Attorney for Applicant
`Reg No 36331
`Venture Suite 300
`Irvine CA
`92618
`949 4501750
`Facsimile 949 450-1764
`
`FAMY CARE - EXHIBIT 1005-0007
`
`
`
`DOCKET NO D-3111
`
`DOCKET NO.: D-3111
`
`ET AL IS
`THE ENCLOSED PATENT APPLICATION OF ACHEANPONG
`THE ENCLOSED PATENT APPLICATION OF ACHEAMPONG ET AL.
`IS
`BEING FILED IN ACCORDANCE WITH SECTION
`37 CFR 1.10 BY
`BEING FILED IN ACCORDANCE WITH SECTION 37 CFR 1.10 BY
`EXPRESS MAIL AND SHOULD BE ACCORDED
`FILING DATE
`EXPRESS MAIL AND SHOULD BE ACCORDED A FILING DATE
`
`AUGUST 27 2004
`AUGUST 27, 2004
`
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION
`SEE THE EXPRESS MAIL CERTIFICATE ATTACHED TO THE APPLICATION.
`
`tlae
`
`FAMY CARE - EXHIBIT 1005-0008
`
`FAMY CARE - EXHIBIT 1005-0008
`
`
`
`D-3111
`
`METHODS OF PROVIDING THERAPEUTIC
`
`EFFECTS
`
`USING CYCLOSPORIN COMPONENTS
`
`Related Application
`
`U.S
`benefit
`application
`This
`claims
`the
`of
`Provisional Application No 60/503137
`filed September 15
`2003 which
`is incorporated in its entirety herein by
`reference
`
`Background of
`
`the Invent ion
`
`invention relates to methods of providing
`The present
`desired therapeutic effects
`to humans or animals using
`More
`
`compositions
`
`including
`
`including
`
`cyclosporin
`components
`particularly the invention relates to methods
`human
`
`to
`
`an
`
`of
`
`or
`
`animal
`
`administering
`eye
`therapeutically effective amount of
`cyclosporin component
`desired therapeutic effect
`to provide
`preferably
`desired ophthalmic or ocular therapeutic effect
`The use of cyclosporin-A and cyclosporin
`derivatives
`to treat ophthalmic conditions has been the subject of
`for example Ding et al U.S Patent
`various patents
`5474979 Garst U.S Patent 6254860
`and Garst U.S
`6350442 this disclosure of each of which is incorporated
`entirely herein by
`reference
`in its
`In addition
`cyclosporin
`compositions
`conditions is the subject
`Such
`
`used
`
`of
`
`publications
`
`include
`
`in treating ophthalmic
`number of publications
`Blood
`for
`
`example
`during long-term treatment
`of cyclosporin
`with cyclosporin
`ophthalmic emulsions in patients with
`moderate to severe dry eye disease Small et al
`Ocul
`2002 Oct 185411-8 Distribution of
`Pharmacol Ther
`ocular
`tissues
`after
`in
`topical
`
`concentrations
`
`cyclosporin
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1005-0009
`
`
`
`D3111
`
`ophthalmic
`
`beagle dogs
`administration to
`rabbits
`albino
`and
`Acheampong et al Curr Eye Res 1999 Feb 18291-103b
`Cyclosporine distribution into the conjunctiva
`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
`4381001-4 Preclinical
`emulsion
`safety
`cyclosporine
`studies
`of
`438991-5
`et al
`
`Angelov
`
`et al
`Cyclosporin
`
`Adv
`
`Exp Med Biol
`1998
`Eye Stevenson
`Emulsion
`1075967-74
`May
`Ophthalmology
`randomized studies of
`the efficacy and safety
`ophthalmic emulsion in moderate to severe
`of cyclosporine
`Study Group Sall et al
`dry eye disease CsA Phase
`2000 Apr 1074631-9
`Each of
`these
`in its entirety herein by
`is incorporated
`In addition cyclosporin A-containing oil-in-
`emulsions
`have
`been
`under
`tested
`clinically
`conditions of confidentiality since the mid 1990s
`in
`order to obtain U.S Food and Drug Administration FDA
`regulatory approval
`
`10
`
`15
`
`20
`
`25
`
`30
`
`2000
`
`and
`
`multicenter
`
`Ophthalmology
`
`publications
`
`reference
`
`water
`
`are set out
`
`of
`
`Examples of useful cyclosporin A-containing emulsions
`in Ding et al U.S Patent 5474979
`Example
`series of emulsions in which the
`this patent
`shows
`ratio of cyclosporin
`
`to castor oil
`
`in each of
`
`these
`
`compositions was 0.08 or greater except
`which
`included
`0.2% by weight cyclosporin
`weight castor oil
`
`The Ding et al patent
`placed
`relative to Compositions
`significance in Composition
`
`for Composition
`and 5% by
`
`no
`
`and
`
`Over
`
`of Example
`time it
`has become apparent
`that cyclosporin
`emulsions for ophthalmic use preferably have less than 0.2%
`With
`of
`
`by weight
`
`cyclosporin
`
`cyclosporin
`
`FAMY CARE - EXHIBIT 1005-0010
`
`
`
`D-3111
`
`concentrations
`
`the
`
`less than 0.2% the amount of castor oil
`the functions of
`employed has been reduced since one of
`castor oil
`is to solubilize the cyclosporin
`amounts
`of
`
`reduced
`
`cyclosporin
`amounts of castor oil are needed
`solubilization of cyclosporin
`There continues to be
`
`if
`
`Thus
`reduced
`
`are employed
`to provide effective
`
`methods of
`
`need for providing enhanced
`treating ophthalmic or ocular conditions with
`
`cyclosporin-containing
`
`emulsions
`
`10
`
`Suitunary of
`
`the Invention
`
`New methods of
`
`treating
`
`component-containing
`
`cyclosporin
`
`discovered
`
`efficacy
`
`human or animal using
`have
`emulsions
`been
`Such methods
`substantial overall
`provide
`in providing desired therapeutic effects
`In
`addition other important benefits are obtained employing
`the present methods
`For example patient safety is
`enhanced
`the present methods provide for
`In particular
`reduced risks of side effects and/or
`drug interactions
`have
`increased
`
`Prescribing
`
`physicians
`
`advantageously
`
`15
`
`20
`
`25
`
`30
`
`in
`
`such
`
`the
`
`of
`
`provide
`
`methods
`and
`flexibility
`prescribing
`compositions useful
`in such methods for example because
`the reduced risks of harmful side effects and/or drug
`interactions The present methods can be easily practiced
`In short
`the present methods
`substantial
`and
`overall
`
`with
`
`other
`
`acceptable
`
`advantages
`
`water
`
`in
`
`together
`efficacy
`such as increased safety and/or
`flexibility
`In one aspect of
`invention the present
`the present
`methods comprise administering to an eye of
`human or
`composition in the form of an emulsion comprising
`animal
`component and
`hydrophobic
`cyclosporin component
`therapeutically effective amount of
`less than 0.1% by
`
`FAMY CARE - EXHIBIT 1005-0011
`
`
`
`D-3111
`
`weight of
`
`cyclosporin component
`than 0.08
`
`the composition
`
`The weight
`to the hydrophobic
`
`ratio of
`
`the
`
`component
`
`is less
`
`It
`
`has
`
`been
`
`found
`
`that
`
`amounts of hydrophobic
`
`component
`
`the
`
`relatively increased
`together with relatively
`effective
`amounts
`
`of
`
`reduced
`
`yet
`
`therapeutically
`cyclosporin component provide substantial and advantageous
`benefits For example the overall efficacy of
`the present
`compositions for example in treating dry eye disease is
`to an identical
`substantially equal
`composition in which
`in an amount of 0.1%
`
`10
`
`15
`
`20
`
`25
`
`30
`
`the cyclosporin component
`is present
`by weight
`Further
`relatively high concentration
`is believed
`
`hydrophobic component
`to provide for
`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
`effectiveness
`the
`therapeutic
`of
`the
`composition Additionally and importantly using reduced
`amounts
`the active cyclosporin component mitigates
`of
`against undesirable side effects
`and/or potential
`interactions
`
`of
`
`more
`
`drug
`
`In short
`
`the present
`
`invention provides at
`
`least one
`
`and preferably
`
`plurality of
`
`The
`
`advantageous
`benefit
`advantageous benefits
`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
`human or animal
`Included among such conditions
`eye of
`are
`limitation
`
`without
`
`dry
`
`phacoanaphylactic
`
`endophthalmitis
`
`eye
`uveitis
`
`syndrome
`
`vernal
`
`FAMY CARE - EXHIBIT 1005-0012
`
`
`
`D3111
`
`conjunctivitis atopic kerapoconjunctivitis
`rejection and the like conditions
`
`corneal graft
`invention
`The present
`is particularly effective in treating dry eye syndrome
`concentrations
`reduced
`Employing
`
`of
`
`cyclosporin
`component
`invention is advantageously
`as in the present
`effective to provide the blood of
`the human or animal under
`treatment with
`reduced
`
`component preferably with substantially
`concentration
`cyclosporin
`of
`the
`
`no detectable
`
`component
`
`The
`
`10
`
`cyclosporin
`
`component
`
`concentration
`
`of
`
`blood
`
`can
`
`be
`
`concentrations
`
`of
`
`cyclosporin
`
`of clyclosporin
`
`group
`
`of
`
`nonpolar
`
`cyclic
`
`known
`
`have
`
`measured
`advantageously
`validated
`liquid
`using
`chromatography/mass spectrometry-mass spectrometry VLC/MS
`MS analytical method such as described elsewhere herein
`in the present methods the blood of
`In one embodiment
`the human or animal has concentrations
`less
`component of 0.1 ng/ml or
`Any suitable cyclosporin component effective in the
`present methods may be used
`Cyclosporins
`are
`oligopeptides with
`immunosuppressant activity
`along with several other minor metabolites
`been
`identified
`through
`In
`addition
`nuinber of synthetic analogs have been prepared
`In general commercially available cyclosporins may
`contain mixture of several
`individual cyclosporins which
`cyclic peptide structure consisting of eleven
`amino acid residues with
`total molecular weight of about
`1200 but with different substituents or configurations of
`the amino acids
`some of
`The term cyclosporin component
`intended
`include
`individual
`to
`
`15
`
`20
`
`25
`
`30
`
`Cyclosporin
`
`cyclosporin
`
`all share
`
`cyclosporin group
`
`any
`and derivatives
`
`as used herein is
`
`member
`
`of
`
`the
`
`thereof
`
`as well
`
`as
`
`FAMY CARE - EXHIBIT 1005-0013
`
`
`
`D31l1
`
`mixtures of
`
`derivatives
`
`or more
`two
`thereof
`
`individual
`
`cyclosporins
`
`and
`
`Particularly preferred cyclosporin components include
`without
`limitation
`derivatives
`
`cyclosporin
`
`of
`
`cyclosporin
`
`and
`
`the
`
`like
`
`and mixtures
`
`thereof
`
`Cyclosporin
`
`is
`
`an
`
`especially
`
`useful
`
`cyclosporin
`
`component may be employed in
`
`component
`Any suitable hydrophobic
`invention
`the present
`the cyclosporin
`Advantageously
`is solubilized in the hydrophobic component
`component may be considered as comprising
`phase in the presently useful cyclosporin
`component-containing emulsions
`The hydrophobic
`component preferably is present
`emulsion compositions
`in an amount greater
`0.625% by weight
`For example the hydrophobic
`component
`in an amount of up to about 1.0% by weight
`may be present
`or about 1.5% by weight or more of
`the composition
`
`component
`
`hydrophobic
`
`discontinuous
`
`The
`
`in the
`
`than about
`
`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
`very useful embodiment
`comprises
`or more
`
`In
`
`component
`
`one
`
`the hydrophobic
`acid
`higher
`
`fatty
`
`the
`
`results are obtained when
`Excellent
`glycerides
`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
`
`of
`
`such
`
`other
`
`Examples
`components
`limitation emulsifier components
`tonicity components
`polyelectrolyte
`surfactant
`
`components
`
`components
`
`the compositions
`include without
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1005-0014
`
`
`
`D-3111
`
`viscosity inducing components acids and/or bases to adjust
`the composition buffer components preservative
`the pH of
`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
`and
`
`polyelectrolyte
`
`components
`
`viscosity
`
`inducing
`
`The
`
`to be achieved
`
`components may be employed
`composition
`specific
`chosen for use in the present
`invention advantageously
`selected taking into account various factors present
`specific application at hand
`for example the desired
`the desired properties
`therapeutic effect
`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
`ophthalmically
`acceptable
`composition component or
`material is ophthalmically acceptable when it
`is compatible
`is it does not cause significant
`with ocular tissue that
`or undue detrimental effects when brought
`into contact with
`tissues
`ocular
`Such compositions have pHs within the physiological
`to about 10 preferably in
`range of about
`range of
`about 7.0 to about 8.0 and more preferably in
`about 7.2 to about 7.6
`
`is
`
`in the
`
`are
`
`range of
`
`The
`
`present methods
`
`for
`
`preferably
`provide
`an
`administering step comprising topically administering the
`presently useful compositions to the eye or eyes of
`human
`or animal
`Each and every feature described herein and each and
`combination of
`two or more of
`features
`such
`
`every
`
`is
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1005-0015
`
`
`
`D-3111
`
`invention provided
`included within the scope of
`the present
`the features included in such
`combination are not
`that
`
`mutually inconsistent
`These and other aspects and advantages of
`invention
`
`the
`
`following
`
`apparent
`are
`in
`description example and claims
`
`the present
`detailed
`
`Detailed Description
`
`of
`
`The present methods are effective for treating an eye
`human or animal
`Such methods in general
`comprise
`administering preferably topically administering to an
`human or animal
`eye of
`
`emulsion
`
`pure water
`
`hydrophobic
`
`component
`
`in
`
`cyclosporin component-containing
`for example U.S
`The emulsion contains water
`and
`component
`cyclosporin
`therapeutically effective amount of
`the emulsion
`than
`0.1% by weight
`In addition
`of
`beneficial results have been found when the weight ratio of
`the cyclosporin component
`to the hydrophobic
`less than 0.08
`
`less
`
`component
`
`is
`
`above
`noted
`As
`the
`present
`administering
`step
`preferably includes topically administering the emulsion to
`or animal
`human
`the
`patient
`of
`of
`eye
`Such
`
`administering may
`useful compositions or
`
`involve
`
`single use of
`
`the presently
`repeated or periodic use of such
`compositions
`for example
`achieve the therapeutic effect
`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
`
`as
`
`required or desired to
`
`to be obtained
`
`The topical
`
`have
`been
`The present methods
`found
`to be
`very
`effective in providing the desired therapeutic effect or
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1005-0016
`
`
`
`D-3111
`
`in prior art cyclosporin
`
`effects while at
`the same time substantially reducing or
`even substantially eliminating side effects which may
`the cyclosporin component
`in
`result from the presence of
`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
`Also
`emulsions
`include
`
`containing
`
`compositions
`
`which
`
`the
`
`use
`
`reduced
`
`of
`
`the present
`amounts
`
`of
`
`the
`
`cyclosporin
`
`allow
`
`for
`
`more
`
`components
`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
`are useful
`The present methods
`in treating any
`condition
`which
`sensitive to
`
`is
`
`therapeutically
`treatable with cyclosporin components
`preferably are ophthalmic or ocular conditions that
`relating to or having to do with one or more parts of an
`human or animal
`Included among such conditions
`eye of
`without
`are
`limitation
`syndrome
`dry
`
`or
`
`Such conditions
`
`is
`
`eye
`
`10
`
`15
`
`25
`
`30
`
`20
`
`phacoanaphylactic
`
`endophthalmitis
`
`uveitis
`
`vernal
`
`conjunctivitis atopic kerapoconjunctivitis
`rejection and the like conditions
`
`corneal graft
`invention
`The present
`is particularly effective in treating dry eye syndrome
`The frequency of administration and the amount of
`useful
`
`the
`
`presently
`composition
`use
`during
`to
`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
`in treating various
`flexibility
`ocular
`conditions
`to
`the desired therapeutic effect or effects with
`reduced risk of side effects and/or
`eye irritation
`
`achieve
`
`Such
`
`FAMY CARE - EXHIBIT 1005-0017
`
`
`
`D3111
`
`10
`
`on
`
`an
`
`as
`
`administration may occur
`needed basis
`example in treating or managing dry eye syndrome on
`time basis or on
`repeated or periodic basis once
`twice
`thrice or more times daily depending on the needs of
`human or animal being treated and other
`factors involved in
`the application at hand
`
`for
`
`one
`
`the
`
`One
`
`of
`
`important
`the
`advantages
`invention is the reduced concentration
`
`of
`
`the present
`
`component
`
`in the blood of
`
`result
`
`of administering
`herein
`
`One
`
`step
`
`provides
`
`10
`
`15
`
`20
`
`25
`
`30
`
`the cyclosporin
`of
`the human or animal as
`as described
`the present
`very useful
`
`composition
`
`embodiment
`
`of
`
`the present
`no substantial detectable
`
`administering
`concentration
`in the blood of
`of cyclosporin component
`human or animal Cyclosporin component
`blood
`determined
`is
`preferably
`
`concentration
`
`the
`
`in
`
`using
`liquid
`spec troscopy LC
`spectroscopy-mass
`chromatography-mass
`MS/MS which test has
`cyclosporin component detection
`limit of 0.1 ng/ml Cyclosporin component concentrations
`below or
`0.1 ng/ml are therefore considered
`less than
`substantially undetectable
`The LC-MS/MS test
`
`run asfollows
`is advantageously
`One ml of blood is acidified with 0.2 ml of 0.1
`
`HC1
`solution then extracted with ml of methyl t-butyl ether
`After separation from the acidified aqueous
`layer
`is neutralized with
`NaOH
`phase
`ml of 0.1
`organic
`reconstituted
`water/acetonitrile-based
`evaporated
`in
`50 mm 3/2m pore size
`mobil phase and injected onto
`reverse phase high pressure
`C-8
`liquid chromatography
`HPLC
`column
`PA
`Keystone Scientific Bellefonte
`Compounds are gradient-eluted at 0.2 mL/min and detected
`using an API
`
`the
`
`2.1
`
`III
`
`turbo-ionspray
`
`triple quadrupole mass spectrometer with
`PE-Sciex
`Concord Ontario
`source
`
`FAMY CARE - EXHIBIT 1005-0018
`
`
`
`D311l
`
`11
`
`Molecular
`
`which
`
`10
`
`15
`
`Canada
`reaction monitoring enhances
`sensitivity and selectivity of
`Protonated
`this assay
`molecules for the analyte
`and an
`internal
`collisionally dissociated and product
`ions at m/z
`monitored for the analyte and the internal standard
`these conditions cyclosporin
`and the internal standard
`elute with retention times of about
`cyclosporin
`3.8
`minutes
`The lower limit of quantitation is 0.1 ng/mL at
`concentration
`the coefficient
`of variation and
`is 15%
`deviation from nominal concentration
`noted
`suitable
`As
`previously
`cyclosporin
`any
`component effective in the present methods may be employed
`Very useful
`cyclosporin
`include without
`components
`limitation cyclosporin
`derivatives of cyclosporin
`the like and mixtures thereof
`
`the
`
`standard are
`
`425 are
`
`Under
`
`and
`
`The
`
`chemical
`
`structure
`
`for
`
`cyclosporin
`
`is
`
`represented by Formula
`
`Formula
`
`FAMY CARE - EXHIBIT 1005-0019
`
`
`
`D3111
`
`12
`
`to
`
`the
`
`manner
`
`to the
`
`As used herein the term derivatives of
`cyclosporin
`refer to compounds
`having structures sufficiently similar
`cyclosporin
`function
`so
`as
`to
`in
`substantially similar to or substantially identical
`cyclosporin for example cyclosporin
`in the present
`methods
`Included without
`limitation within the useful
`are those selected from
`
`cyclosporin
`
`derivatives
`
`10
`
`methylthio-Sar3--
`
`-hydroxy-MeLeu
`cyclosporin
`Cycloalkylthio-Sar3-4-hydroxy-MeLeu4-cyclosporin
`and R-Cycloalkylthio-Sar3-cyclosporin
`described below
`These cyclosporin derivatives are represented by the
`II
`III
`IV
`following
`general
`and
`formulas
`
`derivatives
`
`respectively
`
`FAMY CARE - EXHIBIT 1005-0020
`
`
`
`D3111
`
`13
`
`Formula II
`
`II
`
`Me
`
`Mc
`
`OMe
`
`e/
`
`Me
`
`Me
`
`Mc
`
`Mc7\
`OHMe
`
`Formula III
`
`IU
`
`Me tMe
`Me
`
`FAMY CARE - EXHIBIT 1005-0021
`
`
`
`D3111
`
`14
`
`Formula IV
`
`Ill
`Me Me
`Me\
`ORMe
`
`Me_/
`
`Me
`
`MC_izM6
`Mel
`
`wherein Me
`
`is methyl Alk
`2-6C alkylene
`is
`is OH COOH alkoxycarbonyl
`6C cycloalkylene
`NR3CH2NR1R2
`wherein
`alkyl
`3-6C
`R11R2
`cycloalkyl phenyl optionally substituted by halo alkoxy
`alkoxycarbonyl amino alkylamino or dialkylamino benzyl
`or saturated or unsaturated heterocyclyl
`having
`members and 1-3 heteroatoms or NR1R2
`which may
`contain
`heterocycle
`heteroatom and may be alkylated R3
`or alkyl and
`is
`2-4 and the alkyl moieties contain 1-4C
`embodiment
`the
`In one
`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
`
`or
`
`3-
`
`-NR1R2 or
`
`is
`
`or
`
`is
`
`or
`
`membered
`
`further
`
`or
`
`is
`
`One important feature of
`
`invention is that
`the present
`the presently useful compositions contain less than 0.1% by
`
`10
`
`15
`
`20
`
`FAMY CARE - EXHIBIT 1005-0022
`
`
`
`D3111
`
`weight of
`
`discussed
`
`such low-concentrations
`
`15
`
`the cyclosporin component
`The advantages of
`of cyclosporin components have been
`herein
`elsewhere
`Low
`some detail
`
`in
`
`concentrations
`
`of cyclosporin component
`
`together with
`
`concentrations
`
`of
`
`the hydrophobic
`
`component
`
`such that
`
`the
`
`weight
`
`ratio of
`
`to hydrophobic
`
`phase
`
`in the
`
`cyclosporin
`component
`than 0.08
`one or more
`is greater
`provides
`component
`substantial advantages in the present methods
`Any suitable hydrophobic
`component may be employed in
`invention
`Such hydrophobic component may be
`the present
`considered as comprising
`discontinuous
`useful
`presently
`cyclosporin
`component-containing
`emulsions with the water or aqueous phase being considered
`the continuous phase in such emulsion
`The hydrophobic
`is preferably selected so as to solubilize the
`which
`cyclosporin
`often
`component
`insoluble in the aqueous phase
`included
`hydrophobic
`
`component
`
`is
`
`substantially
`Thus with
`
`suitable
`
`component
`
`in the presently useful
`
`emulsions
`cyclosporin
`solubilized in the emulsions
`
`the
`
`component
`
`is
`
`preferably
`
`In
`
`one
`
`embodiment
`very useful
`hydrophobic
`an oily material
`component
`comprises
`in particular
`material which is substantially not miscible in water
`useful oily materials
`include without
`of
`Examples
`limitation vegetable oils animal oils mineral oils
`synthetic oils and the like and mixtures thereof
`Thus
`
`the
`
`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
`One very useful hydrophobic
`synthetic
`
`includes
`
`component
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1005-0023
`
`
`
`D3111
`
`16
`
`higher
`
`fatty acid glycerides
`
`Examples of useful hydrophobic
`components
`include
`without
`limitation olive oil
`arachis oil
`castor oil
`mineral oil
`silicone fluid and the
`like and mixtures
`
`thereof
`
`fatty acid glycerides such as olive oil
`Higher
`peanut oil castor oil
`and the like and mixtures thereof
`
`useful
`
`in
`
`the
`
`present
`
`invention
`
`are particularly
`Excellent
`results are
`obtained
`using
`hydrophobic
`component comprising castor oil Without wishing to limit
`the invention to any particular theory of operation it
`believed
`includes
`that
`castor oil
`relatively high
`concentration of ricinoleic acid which itself may be useful
`in benefitting ocular
`tissue and/or
`in providing one or
`more therapeutic effects when administered to an eye
`The hydrophobic component
`is preferably present
`in the
`presently useful cyclosporin component-containing emulsion
`compositions
`than about
`in an amount greater
`
`is
`
`0.625% by
`
`weight
`
`present
`
`For example the hydrophobic
`component may be
`in an amount up to about 0.75% by weight or about
`1.0% by weight or about
`
`the
`
`1.5% by weight or more of
`presently useful emulsion compositions
`The presently useful compositions may include one or
`more other
`in amounts effective to facilitate
`components
`and effectiveness of
`
`the usefulness
`
`the present methods
`the presently useful compositions
`Examples of such
`include without
`
`and/or
`
`other
`
`components
`
`limitation emulsifier
`
`surfactant
`components
`tonicity components
`components
`poiy electrolyte components emulsion stability components
`viscosity inducing components demulcent
`components acid
`and/or bases to adjust
`the composition buffer
`and the like
`
`the pH of
`
`com
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