Docket No 176 18CON5B AP
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant Acheampong et at
`
`Examiner TBA
`
`Serial No TBA
`
`Filed Herewith
`
`For METHODS OF PROVIDNG
`THERAPEUTIC EFFECTS USING
`CYCLOSPORN COMPONENTS
`
`Group Art Unit TBA
`
`Confirmation No TBA
`
`Customer No 51957
`
`PRELIMINARY AMENDMENT
`
`Commissioner for Patents
`P.O Box 1450
`Alexandria VA 223 13-1450
`
`Dear Sir
`
`Prior to examining the above-referenced application please amend the specification as
`
`described on page
`
`of this paper and please amend the claims as described on pages 3-6 of this
`
`paper Remarks follow on page
`
`FAMY CARE - EXHIBIT 1004-0001
`
`

`

`Docket No 176 18CON5B AP
`
`Amendments to the Specification
`
`Please replace page
`
`lines 5-10 of the specification filed herewith with the following amended
`
`paragraph
`
`This application is
`
`filed August
`
`2013 which
`
`continuation of copending U.S Application Serial No 13/961818
`continuation of copending U.S Application Serial No
`
`is
`
`11/897177
`
`filed August 28 2007 which is
`
`continuation of U.S Application Serial No
`
`10/927857
`
`filed August 27 2004 now abandoned which
`Provisional Application No 60/503137 filed September 15 2003 whichis are incorporated in
`
`claimed the benefit of U.S
`
`its their entirety herein by reference
`
`FAMY CARE - EXHIBIT 1004-0002
`
`

`

`Docket No 176 18CON5B AP
`
`Amendments to the claims
`
`The following list of claims will replace all previous versions of claims presented in this
`
`application
`136 Canceled
`
`37
`
`method of
`
`New
`administering to the eye of the human an emulsion at
`
`treating
`
`dry eye disease
`
`the method
`
`comprising topically
`
`frequency of twice
`
`day wherein the
`
`emulsion comprises cyclosporin
`
`in an amount of about 0.05% by weight polysorbate 80
`
`Pemulen water and castor oil
`
`in an amount of about 1.25% by weight and
`
`wherein the topical ophthalmic emulsion is effective in treating dry eye disease
`
`38
`
`New The method of Claim 37 wherein the emulsion further comprises
`
`tonicity agent
`
`or
`
`demulcent component
`
`39
`
`New The method of Claim 38 wherein the tonicity agent or the demulcent component
`
`is
`
`glycerine
`
`40 New The method of Claim 37 wherein the emulsion further comprises
`
`buffer
`
`41 New The method of Claim 40 wherein the buffer is sodium hydroxide
`
`42
`
`New The method of Claim 37 wherein
`
`the topical ophthalmic
`
`emulsion further
`
`comprises glycerine and buffer
`
`43
`
`New The method of Claim 37 wherein the emulsion comprises polysorbate 80 in an
`
`amount of about 1.0% by weight
`
`44 New The method of Claim 37 wherein the emulsion comprises Pemulen in an amount of
`
`about 0.05% by weight
`
`FAMY CARE - EXHIBIT 1004-0003
`
`

`

`Docket No 176 18CON5B AP
`
`45
`
`New The method of Claim 37 wherein the emulsion further comprises glycerine in an
`
`amount of about 2.2% by weight and buffer
`
`46 New The method of Claim 45 wherein the buffer is sodium hydroxide
`
`47
`
`New The method of Claim 37 wherein when the emulsion is administered to an eye of
`human in an effective amount
`in treating dry eye syndrome the blood of the human has
`
`substantially no detectable concentration of cyclosporin
`
`48 New The method of Claim 42 wherein the emulsion has
`
`pH in the range of about 7.2
`
`to about 7.6
`
`49
`
`New The method of Claim 37 wherein the emulsion is as substantially therapeutically
`
`effective as an emulsion comprising cyclosporin
`
`in an amount of 0.1% by weight and castor
`
`oil
`
`in an amount of 1.25% by weight
`
`50
`
`New The method of Claim 37 wherein the emulsion achieves
`
`at
`
`least as much
`
`therapeutic effectiveness as an emulsion comprising cyclosporin
`
`in an amount of 0.1% by
`
`weight and castor oil
`
`in an amount of 1.25% by weight
`
`51
`
`New The method of Claim 37 wherein the emulsion breaks down more quickly in the
`
`eye of human once administered to the eye of the human thereby reducing vision distortion in
`the eye of the human as compared to an emulsion that contains only 50% as much castor oil
`
`52 New The method of Claim 37 wherein the emulsion when administered to the eye of
`
`human demonstrates
`
`reduction in adverse
`
`events
`
`in the human relative to an emulsion
`
`comprising cyclosporin
`
`in an amount of 0.1% by weight and castor oil
`
`in an amount of 1.25%
`
`by weight
`
`53 New The method of Claim 52 wherein the adverse events include side effects
`
`FAMY CARE - EXHIBIT 1004-0004
`
`

`

`Docket No 176 18CON5B AP
`
`54
`
`New
`method comprising the step of topically administering to the eye of the human an emulsion at
`
`method of reducing side effects in human suffering from dry eye syndrome the
`
`frequency of twice
`
`day wherein the emulsion comprises
`
`cyclosporin
`
`in an amount of about 0.05% by weight
`
`castor oil
`
`in an amount of about 1.25% by weight
`
`polysorbate 80 in an amount of about 1.0% by weight
`
`Pemulen in an amount of about 0.05% by weight
`
`tonicity component or
`
`demulcent component
`
`in an amount of about 2.2% by weight
`
`buffer and
`
`water
`
`55 New The method of Claim 54 wherein the buffer is sodium hydroxide
`
`56
`
`New The method of Claim 54 wherein the tonicity component or the demulcent
`
`component
`
`is glycerine
`
`57
`
`New The method of Claim 54 wherein when the emulsion is administered to the eye of
`human in an effective amount
`in treating dry eye syndrome the blood of the human has
`
`substantially no detectable concentration of the cyclosporin
`
`58 New The method of Claim 54 wherein the emulsion has
`
`pH in the range of about 7.2
`
`to about 7.6
`
`59
`
`New The method of Claim 54 wherein the emulsion is effective in treating dry eye
`
`disease
`
`60
`
`New
`
`method of treating dry eye disease the method comprising the step of topically
`
`administering to an eye of
`
`human an emulsion the emulsion comprising
`
`cyclosporin
`
`in an amount of about 0.05% by weight
`
`castor oil
`
`in an amount of about 1.25% by weight
`
`polysorbate 80 in an amount of about 1.0% by weight
`
`FAMY CARE - EXHIBIT 1004-0005
`
`

`

`Docket No 176 18CON5B AP
`
`Pemulen in an amount of about 0.05% by weight
`
`glycerine in an amount of about 2.2% by weight
`
`sodium hydroxide and
`
`water
`
`wherein the emulsion is effective in treating dry eye disease
`
`61 New The method of Claim 60 wherein the emulsion has
`
`pH in the range of about 7.2
`
`to about 7.6
`
`FAMY CARE - EXHIBIT 1004-0006
`
`

`

`Docket No 176 18CON5B AP
`
`REMARKS
`
`The applicants have canceled Claims 1-36 and have added Claims 37-6
`
`Support
`
`for the
`
`limitations recited in the new claims may be found throughout
`
`the specification and at least at
`
`page
`
`line 25
`
`page
`
`line 14 page 10 lines 1-7 page 26 lines 5-19 and page 27 lines 4-31
`
`of the application specification filed herewith No new matter has been added
`
`The claims of the present application may vary in scope from the claims pursued in the
`
`parent applications To the extent any prior amendments or characterizations of the scope of any
`
`claim or the specification or referenced art could be construed as
`
`disclaimer of any subject
`
`matter supported by the present disclosure the Applicants
`
`hereby rescind and retract such
`
`disclaimer
`
`Specifically the Applicants would like to bring to the Examiners attention comments
`made in the Response filed on June 15 2009 in U.S Patent Application Serial No 10/927857
`
`now abandoned and comments made in the Amendment
`filed on June 15 2009 in U.S Patent
`Application Serial No 11/897177 currently pending regarding U.S Patent No 5474979 and
`
`the present application specification Since these comments have been filed the Applicants have
`
`collected evidence that supports the patentability of the pending claims
`
`The Commissioner is hereby authorized to charge any fees required or necessary for the
`
`filing processing or entering of this paper or any of the enclosed papers and to refund any
`
`overpayment to deposit account
`
`1-0885
`
`Respectfully submitted
`
`/Laura
`
`Wine/
`
`______________________
`Laura Wine
`Attorney of Record
`Registration Number 68681
`
`Date August 14 2013
`
`inquiries and correspondence to
`Please direct all
`Laura Wine Esq
`Allergan Inc
`2525 Dupont Drive T2-7H
`Irvine California 92612
`Tel 714 246-6996 Fax 714 246-4249
`
`FAMY CARE - EXHIBIT 1004-0007
`
`

`

`Doc Code TRACKI.REQ
`Document Description TrackOne Request
`
`PTO/A1N424 03-13
`
`CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`UNDER 37 CFR 1.102e Page
`
`of
`
`Andrew Acheampong
`
`onFDrvisional
`
`Application Number
`
`if
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING CYCLOSPORIN COMPONENTS
`
`ron
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION
`
`The processing fee set forth in 37 CFR 1.1 7i1 the prioritized examination fee set forth in
`37 CFR 1.17c and if not already paid the publication fee set forth in 37 CFR 1.18d have
`been filed with the request The basic filing fee search fee examination fee and any required
`excess claims and application size fees are filed with the request or have been already been
`paid
`
`The application contains or is amended to contain no more than four independent claims and no
`more than thirty total claims and no multiple dependent claims
`
`The applicable box is checked below
`
`El Original Application Track One Prioritized Examination under 1.102e1
`
`utility application filed under 35 U.S.C iii
`The application is an original nonprovisional
`is being filed with the utility application via EF5-Web
`This certification and request
`---0 R--
`The application is an original nonprovisional plant application filed under 35 U.S.C iii
`This certification and request
`is being filed with the plant application in paper
`
`ii
`
`The executed inventors oath or declaration is filed with the application 37 CFR .63 and
`
`.64
`
`II
`
`LII Request for Continued Examination Prioritized Examination under 1.102e2
`
`ii
`
`iii
`
`request for continued examination has been filed with or prior to this form
`is being filed via EF5-Web
`this certification and request
`If the application is
`utility application
`The application is an original nonprovisional
`utility application filed under 35 U.S.C iii
`or is
`national stage entry under 35 u.s.c 371
`iv This certification and request
`is being filed prior to the mailing of
`to the request for continued examination
`No prior request for continued examination has been granted prioritized examination status
`under 37 CFR 1.102e2
`
`first Office action responsive
`
`signature/Laura
`
`Wine
`
`Laura Wine
`
`Print/Typed
`
`Date August 14 2013
`
`Number 68681
`
`This form must be signed in accordance with 37 CFR 1.33 See 37 CFR 1.4d for signature
`Note
`Submit multiple forms if more than one signature is required
`
`requirements and certifications
`
`Total of _________
`
`forms are submitted
`
`FAMY CARE - EXHIBIT 1004-0008
`
`

`

`Privacy Act Statement
`
`The Privacy Act of 1974 P.L 93-579 requires that you be given certain information in connection with your
`submission of the attached form related to
`patent application or patent Accordingly pursuant to the requirements of
`of this information is 35 U.S.C 2b2
`the Act please be advised that
`the general authority for the collection
`furnishing of the information solicited is voluntary and
`the principal purpose for which the information is used by the
`U.S Patent and Trademark Office is to process and/or examine your submission related to
`patent application or
`information the U.S Patent and Trademark Office may not be able to
`If you do not furnish the requested
`patent
`process and/or examine your submission which may result in termination of proceedings
`or abandonment of the
`application or expiration of the patent
`
`The information provided by you in this form will be subject to the following routine uses
`
`to
`
`The information on this form will be treated confidentially to the extent allowed under the Freedom of
`u.S.C 552a Records from this system of records may
`U.S.C 552 and the Privacy Act
`Information Act
`be disclosed to the Department of Justice to determine whether disclosure of these records is required by the
`Freedom of Information Act
`routine use in the course of presenting evidence
`record from this system of records may be disclosed as
`including disclosures to opposing counsel
`in the course of
`court magistrate or administrative tribunal
`settlement negotiations
`routine use to Member of congress submitting
`record in this system of records may be disclosed as
`to whom the record pertains when the individual has requested assistance from
`request involving an individual
`the Member with respect
`to the subject matter of the record
`record in this system of records may be disclosed as
`contractor of the Agency having
`routine use to
`need for the information in order to perform contract Recipients of information shall be required to comply
`u.s.c 552am
`with the requirements of the Privacy Act of 1974 as amended pursuant to
`record related to an International Application filed under the Patent cooperation Treaty in this system of
`routine use to the International Bureau of the World Intellectual Property
`records may be disclosed as
`Organization pursuant to the Patent cooperation Treaty
`record in this system of records may be disclosed as
`routine use to another federal agency for purposes
`of National Security review 35 U.S.C 181 and for review pursuant to the Atomic Energy Act 42 U.S.C
`218c
`routine use to the Administrator General
`record from this system of records may be disclosed as
`by GSA as part of that agencys
`Services or his/her designee during an inspection of records conducted
`responsibility to recommend improvements in records management practices and programs under authority of
`44 U.S.C 2904 and 2906 Such disclosure shall be made in accordance with the GSA regulations governing
`i.e GSA or Commerce directive Such
`of records for this purpose and any other relevant
`inspection
`disclosure shall not be used to make determinations about individuals
`record from this system of records may be disclosed as
`routine use to the public after either publication of
`patent pursuant to 35 U.S.C 51 Further
`the application pursuant to 35 U.S.C 122b or issuance of
`record may be disclosed subject to the limitations of 37 CFR 1.14 as
`routine use to the public if
`the record
`was filed in an application which became abandoned or in which the proceedings were terminated and which
`published application an application open to public inspection or an issued
`application is referenced
`by either
`
`patent
`record from this system of records may be disclosed as
`Federal State or local
`routine use to
`the USPTO becomes aware of
`enforcement agency if
`violation or potential violation of law or regulation
`
`law
`
`Page
`
`FAMY CARE - EXHIBIT 1004-0009
`
`

`

`Electronic Patent Application Fee Transmittal
`
`Application Number
`
`Filing Date
`
`Title of Invention
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING CYCLOSPORIN
`COMPON ENTS
`
`First Named Inventor/Applicant Name
`
`Andrew Acheampong
`
`Filer
`
`Laura Lee Wine/Lauren
`
`Barberena
`
`Attorney Docket Number
`
`1761 8CON5B AP
`
`Filed as Large Entity
`
`Track Prioritized Examination Nonprovisional Application under 35 usc 111
`
`Filing Fees
`
`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total
`USD$
`
`in
`
`Basic Filing
`
`Pages
`
`Claims
`
`Utility application filing
`
`UtilitySearchFee
`
`Utility Examination Fee
`
`Request
`
`for Prioritized Examination
`
`Claims in Excess of 20
`
`Independent claims in excess of
`
`101
`
`1111
`
`1311
`
`1817
`
`1202
`
`1201
`
`280
`
`600
`
`720
`
`280
`
`600
`
`720
`
`4000
`
`4000
`
`80
`
`420
`
`400
`
`420
`
`FAMY CARE - EXHIBIT 1004-0010
`
`

`

`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total
`USD$
`
`in
`
`Miscellaneous-Filing
`
`Pubi Fee- Early Voluntary or Normal
`
`OTHER PUBLICATION PROCESSING
`
`FEE
`
`1504
`
`1808
`
`300
`
`130
`
`300
`
`130
`
`Petition
`
`Patent-Appeals-and-Interference
`
`Post-Allowance-and-Post-Issuance
`
`Extension-of-Time
`
`Miscellaneous
`
`Total
`
`in USD
`
`6850
`
`FAMY CARE - EXHIBIT 1004-0011
`
`

`

`Electronic Acknowledgement Receipt
`
`EFSID
`
`Application Number
`
`16593100
`
`13967179
`
`International Application Number
`
`Confirmation Number
`
`8654
`
`Title of Invention
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`First Named Inventor/Applicant Name
`
`Andrew Acheampong
`
`Customer Number
`
`51957
`
`Filer
`
`Laura Lee Wine/Lauren
`
`Barberena
`
`Filer Authorized By
`
`Laura Lee Wine
`
`Attorney Docket Number
`
`1761 8CON5B AP
`
`Receipt Date
`
`Filing Date
`
`Time Stamp
`
`14-AUG-2013
`
`184939
`
`Application Type
`
`Utility under 35 USC 11
`
`Payment information
`
`Submitted with Payment
`
`Payment Type
`
`Payment was successfully received in RAM
`
`RAM confirmation Number
`
`Deposit Account
`
`Authorized User
`
`yes
`
`Deposit Account
`
`$6850
`
`6223
`
`010885
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows
`
`Charge any Additional Fees required under 37 C.F.R Section 1.17 Patent application and reexamination processing
`
`fees
`
`Charge any Additional Fees required under 37 C.F.R Section 1.21 Miscellaneous fees and charges
`
`FAMY CARE - EXHIBIT 1004-0012
`
`

`

`File Listing
`
`Document
`Number
`
`Document Description
`
`File Name
`
`File SizeBytesI
`Message Digest
`
`Multi
`
`Part I.zip
`
`Pages
`if appl
`
`4360450
`
`17618C0N_SPEC.pdf
`
`yes
`
`34
`
`9b080e0218cb41c5b767d994b1
`
`5dca09138
`
`ddl8O
`
`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Start
`
`End
`
`Specification
`
`Claims
`
`Abstract
`
`28
`
`33
`
`34
`
`29
`
`34
`
`Warnings
`
`Information
`
`Warnings
`
`Information
`
`Warnings
`
`Application Data Sheet
`
`761 8CON5B_ADS.pdf
`
`Oath or Declaration
`
`filed
`
`1761 8CON5B_DECS.pdf
`
`1509913
`
`141 75733ae4deae0cc241916151c1837401413
`
`645090
`
`1cc2bbth0fb19a7833621088e6b1
`
`32ea3Jde
`
`Sba3
`
`no
`
`no
`
`The page size in the PDF is too large The pages should be 8.5
`Image File Wrapper and may affect subsequent processing
`
`11 or A4 If this PDF is submitted the pages will be resized upon entry into the
`
`Information
`
`Warnings
`
`Information
`
`PowerofAttorney
`
`17618C0N5B_POA.pdf
`
`1931210
`
`ObcbJa2e4JleSbfbeOIScl
`
`769aa60a43thca
`
`1109
`
`17618C0N5B
`
`PRELIM AMEND
`
`MENTS.pdf
`
`106465
`
`cO4b4eOal 1bc2314b05581c0329a1a77487
`
`cbaed
`
`Multipart Description/PDF files in .zip description
`
`no
`
`yes
`
`Document Description
`
`Start
`
`End
`
`Preliminary Amendment
`
`Specification
`
`FAMY CARE - EXHIBIT 1004-0013
`
`

`

`Claims
`
`Applicant Arguments/Remarks Made in an Amendment
`
`TrackOne Request
`
`17618C0N5B
`
`PRIORITIZED
`
`EX
`
`AM.pdf
`
`153243
`
`e3999ce635513b02c50e1
`
`9c9b45dd81 9e59
`
`01b53
`
`Fee Worksheet SBO6
`
`fee-info.pdf
`
`43444
`
`ci 3bc365e6453958Oc43dc2ccOc53849d
`
`5ec9
`
`no
`
`no
`
`Warnings
`
`Information
`
`Warnings
`
`Information
`
`Warnings
`
`Information
`
`Total Files Size in bytes
`
`8749815
`
`Receipt evidences receipt on the noted date by the USPTO of the indicated documents
`This Acknowledgement
`characterized by the applicant and including page counts where applicable It serves as evidence of receipt similarto
`Post Card as described in MPEP 503
`
`If
`
`New Applications Under 35 U.S.C 111
`filing date see 37 CFR
`new application is being filed and the application includes the necessary components for
`.53b-d and MPEP 506 Filing Receipt 37 CFR 1.54 will be issued in due course and the date shown on this
`Receipt will establish the filing date of the application
`Acknowledgement
`
`If
`
`National Stage of an International Application under 35 U.S.C 371
`timely submission to enter the national stage of an international application is compliant with the conditions of 35
`Form PCTIDOIEOI9O3
`U.S.C 371 and other applicable requirements
`indicating acceptance of the application as
`national stage submission under 35 U.S.C 371 will be issued in addition to the Filing Receipt
`in due course
`
`If
`
`New International Application Filed with the USPTO as Receiving Office
`new international application is being filed and the international application includes the necessary components for
`filing date see PCT Article 11 and MPEP 1810 Notification of the International Application Number
`an international
`and of the International Filing Date Form PCT/RO/1 05 will be issued in due course subject
`to prescriptions concerning
`national security and the date shown on this Acknowledgement
`Receipt will establish the international
`filing date of
`the application
`
`FAMY CARE - EXHIBIT 1004-0014
`
`

`

`0-311 ICON
`
`METHODS OF PROVIDING THERAPEUTIC
`
`EFFECTS
`
`USING CYCLOSPORIN COMPONENTS
`
`Related Application
`
`continuation of U.S Application
`This application is
`Serial No 10/927 857 filed August 27 2004 which claimed
`the nenefit of
`ProvratoraI oplicatron No
`60/503137
`15 2003 whIch
`is incorporated in its
`entirety herein by reference
`
`filed September
`
`Background of
`
`the Invention
`
`More
`
`Including
`
`invention relates to methods of providing
`The present
`des red therapeutic effects
`to humans or animals using
`cyclosporin
`components
`compc.sitions
`including
`particularly the invention relates to methods
`human
`
`of
`
`cr
`
`animal
`
`administerinq
`
`to
`
`an
`
`eye
`therapeutica ly effective amount of
`cyclosporin component
`destred therapeut Ic effect
`to ptovide
`preferably
`therapeutic effect
`desired ophttalmc or ocular
`The use of oclosporinA and cyclosporin
`derivatives
`to treat ophthalmic conditions has
`the subject of
`been
`et al U.S Patent
`patents
`various
`example
`Ding
`for
`5474979 Garst U.S Patent 6254860
`and Carat U.S
`350 442 this disclosure of each of which is Incorporated
`in adda Lion
`reference
`
`in its
`
`entirely herein
`
`by
`
`cyc .ospo.nn
`conditions
`
`comoosa Lions
`
`used
`
`is the subject
`
`of
`
`Such
`
`publications
`
`include
`
`in
`
`rca t.ing
`
`ophtha lmic
`numoer of puolacataons
`Blood
`example
`
`for
`
`concentrations
`
`during lonqLerm treatment
`of cyclosporin
`with cyclosporin
`ophthaLmic emulsions in patients with
`et al
`moderate to severe dry eve__disease
`Small
`Ocul
`2Q02 Oct
`411 -5 Distribution of
`Pharmacol Ther
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1004-0015
`
`

`

`D3I1ICON
`
`in
`
`ocular
`
`tissues
`
`after
`
`safety
`
`multicenter
`
`2000
`
`publications
`reference
`
`cyclosporin
`topical
`dogs
`albino
`administration
`to
`rabbits
`and
`beagle
`et al Curr Eye Res 1999 Feb 18291-103b
`Acheampong
`çyylosporine distribution into the conj unctiva cornea
`lacrimal gland and systemic blood following typical dosing
`of cyclosporine to rabbit dog and human eyes Acheampong
`at al Adv Exp Med BIol 1998 4381001-4 Preclinical
`emulsion
`studies
`of
`ophthalmic
`cyclosporine
`et al Mv
`438991-5
`Exp Med Biol
`1998
`Angelov
`Eye Stevenson
`çyposporin
`at al
`Emulsion
`1075 96774
`Two
`May
`and
`Ophthalmology
`randomized studies of
`the efficacy and safety
`of cyclosporine ophthalmic emulsion in moderate to severe
`Study Group Sail et al
`dry eye disease OsA Phase
`2000 Apr 1074631-9
`Each of
`these
`15 Ophthalmology
`is incorporated in its entirety herein by
`In addition cyclosporin Acontaining oiL-in
`tested
`emulsions
`been
`under
`water
`clinically
`have
`conditions of confidentiality since the mid 1990s
`in
`and Drug Administration FDA
`order to obtain U.S Food
`
`10
`
`20
`
`25
`
`30
`
`regulatory approval
`
`are set out
`
`of
`
`shows
`
`weight
`
`Example
`
`to castor oil
`
`in each of
`
`these
`
`and
`
`5% by
`
`Examples of useful cyclosporin A-containing emulsions
`in Ding et al US Patent 5474979
`series of emulsions in which the
`this patent
`ratio of cyclosporin
`compositions was 0.08 or greater except
`for Composition
`which
`included
`0.2% by weight cyclosporin
`castor oil
`
`The Ding et al patent
`placed
`relative to Compositions
`
`no
`
`significance in Composition
`
`and
`
`of Example
`time it has become apparent
`that cyclosporin
`emulsions for ophthalmic use preferably have less than 0.2%
`
`Over
`
`FAMY CARE - EXHIBIT 1004-0016
`
`

`

`D3iilC0N
`
`by weight
`concentrations
`
`of
`
`cyclosporin
`cyclosporin
`less than 0.2% the amount of castor oil
`
`With
`
`employed has been reduced since one of
`castor oil
`is to solubilize the cyclosporin
`employed
`amounts
`to provide effective
`
`the functions of
`
`the
`
`Thus if
`
`reduced
`
`reduced
`
`of
`
`cyclosporin
`
`are
`
`amounts of castor oil
`
`are needed
`
`solubilization of cyclosporin
`
`There continues to be
`
`need
`
`methods of
`
`cyclosporin-containing
`
`for providing enhanced
`treating ophthalmic or ocular conditions with
`emulsions
`
`Summary of the Invention
`New methods
`
`of
`
`treating
`
`cyclosporin
`
`componentcontaining
`
`human or animal using
`been
`emulsions
`have
`
`discovered
`Such methods
`substantial overall
`provide
`efficacy in providing desired therapeutic effects
`addition other important benefits are obtained employing
`the present methods
`For example patient
`safety is
`enh.anced
`the present methods provide for
`reduced risks of side effects
`drug interactions
`
`In particular
`
`and/or
`
`In
`
`Prescribing
`
`physicians
`
`advantageously
`
`have
`
`increased
`
`in
`
`such
`
`methods
`
`and
`
`the
`
`flexibility
`prescribing
`in such methods for example because
`compositions useful
`the reduced risks of harmful side effects and/or drug
`of
`interactions
`The present methods can be easily practiced
`provide substantial
`the present methods
`with
`efficacy
`overall
`together
`such as increased safety and/or
`
`In short
`
`acceptable
`
`advantages
`
`and
`
`other
`
`flexibility
`
`10
`
`15
`
`20
`
`25
`
`invention the present
`the present
`In one aspect of
`human or
`30 methods comprise administering to an eye of
`animal
`composition in the form of an emulsion comprising
`component and
`
`water
`
`hydrophobic
`
`cyclosporin component
`
`FAMY CARE - EXHIBIT 1004-0017
`
`

`

`D311ICON
`
`in
`
`less than 01% by
`therapeutically effective amount of
`weight of
`the composition
`ratio of
`the
`The weight
`
`cyclosporin component
`than 0.08
`
`to the hydrophobic
`
`component
`
`is less
`
`It
`
`has
`
`been
`
`found
`
`that
`
`the
`
`relatively increased
`together with relatively
`amounts
`of
`
`amounts of hydrophobic component
`reduced
`therapeutically
`effective
`yet
`cyclosporin component provide substantial and advantageous
`For example the overall efficacy of the present
`benefits
`compositions for example in treating dry eye disease is
`to an identical composition in which
`substantially equal
`the cyclosporin component
`by weight
`Further
`
`in an amount of 0.1%
`
`is present
`relatively high concentration of
`is believed to provide for
`hydrophobic component
`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
`therapeutic
`of
`the
`composition Additionally and importantly using reduced
`amounts of
`the active cyclosporin
`component mitigates
`against undesirable side effects and/or potential drug
`interactions
`
`more
`
`the
`
`least one
`
`plurality of
`
`In short the present
`invention provides at
`benefit
`and preferably
`advantageous
`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
`human or animal
`eye of
`Included among such conditions
`are
`without
`syndrome
`limitation
`dry
`eye
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1004-0018
`
`

`

`D3111C0N
`
`phacoanaphylactic
`
`endophthalmitis
`
`uveitis
`
`vernal
`
`corneal graft
`conjunctivitis
`atopic kerapoconjunctivitis
`rejection and the like conditions
`invention
`The present
`is particularly effective in treating dry eye syndrome
`concentrations
`of
`nploying reduced
`cyclosporin
`as in the present
`component
`invention is advantageously
`the human or animal under
`effective to provide the blood of
`treatment with
`reduced
`concentrations
`
`cyclosporin
`
`of
`
`preferably with substantially
`component
`concentration
`
`of
`
`the
`
`cyclosporin
`
`cyclosporin
`
`component
`
`concentration
`
`no detectable
`
`component1
`blood
`
`of
`
`The
`
`can
`
`be
`
`validated
`measured
`liquid
`using
`advantageously
`chromatography/mass epectromet ry-mase 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
`of clyclosporin
`component of 0.1 ng/ml or less
`Any suitable cycloeporin component effective in the
`present methods may be used
`are
`Cyclosporins
`
`group
`
`of
`
`nonpolar
`
`cyclic
`
`oligopeptides
`
`Cycloeporin
`
`cyclosporin
`
`with
`
`known
`
`activity
`1.mmunosuppressant
`along with several other minor metabolites
`identified
`have
`been
`In
`
`through
`number of synthetic analogs have been prepared
`addition
`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
`
`all share
`
`The term cyclosporin component
`intended
`to
`include
`individual member of
`
`any
`
`as used herein is
`
`the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1004-0019
`
`

`

`D3111CON
`
`and derivatives thereof
`cyclosporin group
`mixtures of
`two or more individual
`derivatives thereof
`
`as well as
`
`cyclosporins
`
`and
`
`Particularly preferred cyclosporin components include
`without
`derivatives
`
`limitation
`
`cyclosporin
`
`and
`
`cyclosporin
`the
`and mixtures
`
`like
`
`of
`
`thereof
`
`is
`
`an
`
`especially
`
`useful
`
`cyclosporin
`
`component may be employed in
`the cyclosporin
`
`Advantageously
`
`The
`
`in the
`
`of
`
`Cyclosporin
`component
`Any suitable hydrophobic
`invention
`the present
`is solubilized in the hydrophobic
`component
`component
`hydrophobic component may be considered as comprising
`discontinuous phase in the presently useful cyclosporin
`component-containing emulsions
`The hydrophobic
`component preferably is present
`than about
`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 15% by weight or more of
`the composition
`Preferably the hydrophobic
`component comprises one or
`wore oily materials
`Examples of useful oil materials
`limitation vegetable oils animal oils
`include without
`mineral oils synthetic oils and the like and mixtures
`thereof
`In
`the hydrophobic
`very useful embodiment
`or more
`fatty acid
`one
`comprises
`higher
`component
`Excellent
`results are obtained
`when
`glycerides
`the
`hydrophobic component comprises castor oil
`The presently useful compositions may include one or
`in amounts effective to facilitate
`more other components
`and effectiveness
`the compositions
`the usefulness
`include
`without
`
`such
`other
`components
`Examples
`limitation emulsifier components
`
`of
`
`tonicity components
`
`10
`
`15
`
`20
`
`25
`
`30
`
`FAMY CARE - EXHIBIT 1004-0020
`
`

`

`D3lllCON
`
`polyelectrolyte
`
`components
`
`surfactant
`
`components
`
`viscosity inducing components acids and/or bases to adjust
`
`the pH of
`
`the composition buffer components preservative
`and the like Components may be employed which
`components
`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
`components which are effective as both
`and/or
`be employed
`
`polyelectrolyte
`
`components
`
`and
`
`viscosity
`
`inducing
`
`The specific composition
`invention advantageously is
`
`may be employed
`components
`chosen for use in the present
`selected taking into account various factors present
`at hand
`for example
`specific application
`the desired properties
`therapeutic effect
`the compositions to be employed the sensitivities of
`the human or animal
`to whom the composition
`administered and the like factors
`
`of
`
`to be achieved
`
`in the
`
`the desired
`
`is to be
`
`The presently useful compositions advantageously
`
`are
`
`acceptable
`
`composition component or
`
`10
`
`15
`
`25
`
`30
`
`ophthalmically
`20 material
`
`is ophthalmicaily acceptable when
`is compatible
`it
`is it does not cause significant
`into contact with
`or undue detrimental effects when brought
`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 72 to about 7.6
`present methods
`The
`
`with ocular
`
`tissue that
`
`range of
`
`preferably
`
`provide
`
`for
`
`an
`
`administering step comprising topically administering the
`presently useful compositions to the eye or eyes of
`or animal
`Each and every feature described herein and each and
`
`human
`
`FAMY CARE - EXHIBIT 1004-0021
`
`

`

`eye of
`emulsion
`pure water
`in
`component
`0.1% by weight
`
`cyclosporin componentcontaining
`for example U.S
`The emulsion contains water
`and
`
`cyclosporin
`component
`hydrophobic
`therapeutically effective amount of
`In addition
`emulsion
`
`of
`
`the
`
`less
`
`D3lllCON
`
`that
`
`every combination of
`the present
`included within the scope of
`the features included in such
`combination are not
`
`two or more of
`
`such
`
`features
`
`is
`
`invention provided
`
`mutually inconsistent
`and other aspects and advantages of
`
`These
`
`invention
`are
`apparent
`description example and claims
`
`in
`
`the
`
`following
`
`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
`
`than
`
`beneficial
`
`results have been found when
`
`the weight
`
`ratio of
`
`to the hydrophobic component
`
`is
`
`the cyclosporin component
`less than 008
`As
`noted
`
`above
`
`the
`
`present
`
`administering
`
`step
`
`preferably includes topically administering the emulsion to
`human or animal
`of
`Such
`
`the
`
`eye of
`
`patient
`
`involve
`
`single use of
`
`the presently
`
`administering may
`useful compositions or
`repeated or periodic use of such
`for example
`required or desired