U.S. PTO
`11/897177
`0812812007
`
`0
`~
`<0
`UTILITY
`c PATENT APPLICATION
`(n
`TRANSMITTAL
`,~.~~ new nonprovisionalapplications under 37 CFR 1.53(b))
`
`A
`
`Express M::~ill ::~h"'l No.
`
`APPLICATION ELEMENTS
`See MPEP chaoter 600 concerning utility patent application contents
`
`ADDRESS TO:
`
`i Du<.il\t:l •"vu. I 0-3111 CON
`First Inventor I A ... IICO III.JUIIY et al
`Title I Methods of P!oviding ;,~:rapeutic Effects Using
`us
`I EV51f-i
`Commissioner for Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`ACCOMPANYING APPLICATION PARTS
`
`1. ~ Fee Transmittal Form (e.g., PTO/SB/17)
`2. 0 Applicant claims small entity status.
`See 37 CFR 1.27
`3. ~ Specification
`(Total Pages
`Both the daims and abstract must start on a new page.
`(For information on the preferred arrangement, see MPEP 608.01(a))
`
`34
`
`(Total Sheets
`
`(Total Sheets
`
`2
`
`0
`Drawlng(s) {35 U.S. C. 113)
`4.
`5. ~ Oath or Declaration
`a. 0 Newly executed (original or copy)
`~ A copy from a prior application (37 CFR 1.63(d))
`i. 0
`
`b.
`
`(for continuation/divisional with Box 18 completecf)
`
`DELETION OF INVENTOR{S}
`Signed statement attached deleting inventor(s)
`name in the prior application. see 37 CFR
`1.63(d)(2) and 1.33(b)
`6. ~ Application Data Sheet. See 37 CFR 1.76
`7. 0
`CD-ROM or CD-R in duplicate. large table or
`Computer Program (Appendix)
`
`0 Landscape Table on CD
`
`8.
`
`Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a. -c. are requireci)
`
`b.
`
`Specification Sequence listing on:
`
`a. 0 Computer Readable Form (CRF)
`i. 0 CD-ROM or CD-R (2 copies); or
`ii. 0 Paper
`c. 0 Statements verifying identity of above copies
`
`I
`
`I
`
`I
`
`9. ~Assignment Papers (cover sheet & document(s))
`
`Name of Assignee Allergan, Inc.
`
`(when there is an assignee)
`
`10. 0 37 CFR 3.73(b) Statement 0 Power of Attorney
`11. 0 English Translation Document (if applicable)
`12. 0 Information Disclosure Statement (PTOISBI08 or PT0-1«9)
`0 Copies of citations attached
`0 Preliminary Amendment
`
`13.
`
`14. ~Return Receipt Postcard (MPEP 503)
`(Should be specifically 11ernizecf)
`0 Certified Copy of Priority Document(s)
`16. 0 Nonpublication Request under 35 U.S.C. 122(b)(2)(B)(i).
`
`15.
`
`(if foreign priority is claimecf)
`
`Applicant must attach form PTO/SB/35 or equivalent
`
`17. Oother
`
`18. If a CONTINU lNG APPLICATION, check appropriate box, and supply the requisite information below and in the first sentence of the specification
`following the title, or in an Application Data Sheet under 37 CFR 1.76:
`
`~ Continuation
`
`0 Divisional
`
`~ Continuation-in-part (CIP)
`
`of prior application No.: 10/927,857
`
`Prior application information:
`
`Examiner Cordero Garcia, Marcela
`
`Arl Unit 1654
`
`~ The address associated with Customer Number: I
`
`19. CORRESPONDENCE ADDRESS
`33197
`
`I
`
`Name
`
`Address
`
`City
`
`Country
`
`I State
`I Telephone
`I
`,,
`I Date
`J~~~1\!:~---t~<
`Signature
`I Registration No.
`Name (Print/Type) ~sA. Fisher
`
`(Attorney/Agent)
`
`OR 0 Correspondence address below
`
`Zip Code
`
`Fax
`
`Augus~. 2007
`
`36,510
`
`APOTEX 1019, pg. 2822
`
`

`
`FEE TRANSMITTAL
`for FY 2005
`
`Patent tees are subjeCt to annual revision.
`
`0 Application claims small entity status. See 37 CFR 1.27
`I ($) 1400.00
`METHOD OF PAYMENT (check all that apply)
`
`TOTAL AMOUNT OF PAYMENT
`
`Complete if Known
`Not yet known
`Aj)Qiication Number
`Filing Date
`Herewith
`First Named Inventor
`Acheampong et al.
`N/A
`
`Examiner Name
`
`Art Unit
`
`N/A
`
`Attorney Docket No.
`
`D-3111 CON
`
`Deposit Account Number
`
`01-0885
`
`Deposit Account Name
`
`Allernan
`
`0 Check 0 Credit Card 0 Money Order 0 None 0 Other (please identify): __
`[gl Deposit Account
`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`0 Charge fee(s) indicated below, except for the filing fee
`[gl Charge fee(s) indicated below
`[gl Charge any additional fee(s) associated with this
`[g) Credit any overpayments
`communication
`WARNING: Information on this form may become public. Credit card information should not be included on this form. Provide credit card information and
`authorization on PT0-2038.
`FEE CALCULATION
`
`1. BASIC FILING SEARCH AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Enti!X
`Small Enti!X
`En.W
`En.W
`150
`250
`
`En.W
`500
`100
`300
`
`500
`
`0
`
`100
`100
`
`150
`100
`
`50
`150
`
`250
`
`0
`
`EXAMINATION FEES
`Small Entl!X
`En.W
`100
`65
`80
`
`En.W
`200
`130
`160
`
`600
`
`0
`
`300
`
`0
`
`Fees Paid Ill
`1000
`
`Aeelicatlon T~ee
`Utility
`Design
`Plant
`
`En.W
`300
`200
`200
`
`Reissue
`Provisional
`
`300
`200
`
`2. EXCESS CLAIM FEES
`
`Fee Oescrtotion
`
`Subtotal (11
`
`--
`
`Small Entity
`Fee 1$1
`Feel$1
`50
`25
`200
`100
`360
`180
`MuHiele Deeendent Claims
`~ Fee Paid Ill
`-- --
`
`Each claim over 20 or, for Reissues, each claim over 20 and more than In the original patent
`Each Independent claim over 3 or, for Reissues, each Independent claim more than in the original patent
`Multiple Dependent Claims
`Extra Claims ~ Fee Paid Ill
`Total Claims
`-20 orHP =
`4
`24
`50
`200
`X
`[HP = highest number of total claims paid for, if greater than 20
`En.W
`Extra Claims
`lndee. Claims
`-3orHP=
`4
`X
`1
`200
`HP = highest number of independent claims paid for, if greater than 3
`
`Fee Paid Ill
`200
`
`3. APPLICATION SIZE FEE
`r the specification and drawings exceed 100 sheets of paper, the application size fee due Is $250 ($125 for small entity) for each additional 50 sheets or fraction
`hereof. See 35 U.S.C. 41(a){1)(G) and 37 CFR 1.16{s).
`Extra
`Sheets
`
`Tota I S!Jeets
`
`Number of each additional 50 or fraction thereof
`
`~ Fee Paid Ill
`
`Subtotal (21
`
`400
`
`~
`Fee Paid Ill
`
`35
`
`-100 =
`
`0
`
`/50= ___ (round up to a whole number)
`
`X
`
`=
`
`Subtotal(31
`
`4. OTHER FEElSl
`0 Surcharge- Late filing fee or oath/declaration: $130 fee ($65 small entity discount)
`0 Non-English Specification: $130 fee (no small entity discount)
`0 1-monlh extension of time: $120 fee ($60 small entity discount)
`0 2-monlh extension of lime: $450 fee ($225 small entity discount)
`0 3-month extension oflime: $1020 fee ($51 0 small entity discount)
`0 4-month extension of time: $1590 fee ($795 small entity discount)
`0 5-month extension of lime: $2160 fee ($1080 small entity discount)
`0
`Information Disclosure Statement Fee: $180 fee (no small entity discount)
`0 Notice of Appeal: $500 fee ($250 small entity discount)
`0 Filing a Brief in Support of Appeal: $500 fee ($250 small entity discount)
`0 Request for Oral Hearing: $1000 fee ($500 small entity discount)
`0 Utility Issue Fee: $1400 fee ($700 small entity discount)
`0 Recording each patent assignment per property (times number of properties): $40 fee (no small entity fee discount)
`0 Request for Continued Examination: $790 fee ($395 small entity discount)
`0 Other. - -
`
`SUBMITTED BY
`Name
`1Print!Tvoe)
`
`Signature
`
`I Registration No.
`( ~lo~~ ~,~_<
`\...__-
`
`/ \ Carlos A. Fisher
`
`• (Attomev/Aqent)
`
`~
`
`I 36,510
`
`Subtotall4l
`
`0
`
`Telephone
`
`949-450-1750
`
`Date
`
`August~. 2007
`
`APOTEX 1019, pg. 2823
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application No.
`Applicant
`Filed
`Title
`
`To be assigned
`Acheampong et al.
`Herewith
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING
`CYCLOSPORIN COMPONENTS
`
`Confirmation No.
`
`TC/A.U.
`Examiner
`
`NA
`NA
`
`Docket No.
`Customer No.
`
`D-3111 CON
`33197
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`EXPRESS MAIL CERTIFICATE
`
`EXPRESS MAIL MAILING LABEL NO.
`
`Date of Deposit:
`
`EV 516292203 US
`
`August 28, 2007
`
`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, P.O. Box 1450, Alexandria, VA 22313-1450:
`
`~ Utility Patent Application Transmittal
`
`~ Assignment; 37 CFR 3.73(b) Statement
`(Copy)
`D Information Disclosure Statement
`~Fee Transmittal
`D Cited References
`~Application Data Sheet (~ page(s))
`D Preliminary Amendment
`~Specification/Abstract (34 page(s))
`D Drawings (
`D Non-publication Request
`sheet(s))
`~Declaration (f. page(s)) (Copy)
`~ Stamped, self-addressed postcard
`D Other: __
`D Power of Attorney
`Each of the I above-identified documents are enclosed herewith.
`
`Respectfully submitted,
`
`Date: _....:...A=u=g=us=t,__2_t_,.-=2=0=0..:....7_
`
`~/W~
`
`Shawnna Waddell
`Assistant to Carlos A. Fisher
`Stout, Uxa, Buyan & Mullins, LLP
`4 Venture, Suite 300
`Irvine, California 92618
`Telephone: 949-450-1750
`
`·
`
`APOTEX 1019, pg. 2824
`
`

`
`U.S. PTO
`11/897177
`0812812007
`
`0
`~
`<0
`UTILITY
`c PATENT APPLICATION
`(n
`TRANSMITTAL
`,~.~~ new nonprovisionalapplications under 37 CFR 1.53(b))
`
`A
`
`Express M::~ill ::~h"'l No.
`
`APPLICATION ELEMENTS
`See MPEP chaoter 600 concerning utility patent application contents
`
`ADDRESS TO:
`
`i Du<.il\t:l •"vu. I 0-3111 CON
`First Inventor I A ... IICO III.JUIIY et al
`Title I Methods of P!oviding ;,~:rapeutic Effects Using
`us
`I EV51f-i
`Commissioner for Patents
`P.O. Box 1450
`Alexandria VA 22313-1450
`ACCOMPANYING APPLICATION PARTS
`
`1. ~ Fee Transmittal Form (e.g., PTO/SB/17)
`2. 0 Applicant claims small entity status.
`See 37 CFR 1.27
`3. ~ Specification
`(Total Pages
`Both the daims and abstract must start on a new page.
`(For information on the preferred arrangement, see MPEP 608.01(a))
`
`34
`
`(Total Sheets
`
`(Total Sheets
`
`2
`
`0
`Drawlng(s) {35 U.S. C. 113)
`4.
`5. ~ Oath or Declaration
`a. 0 Newly executed (original or copy)
`~ A copy from a prior application (37 CFR 1.63(d))
`i. 0
`
`b.
`
`(for continuation/divisional with Box 18 completecf)
`
`DELETION OF INVENTOR{S}
`Signed statement attached deleting inventor(s)
`name in the prior application. see 37 CFR
`1.63(d)(2) and 1.33(b)
`6. ~ Application Data Sheet. See 37 CFR 1.76
`7. 0
`CD-ROM or CD-R in duplicate. large table or
`Computer Program (Appendix)
`
`0 Landscape Table on CD
`
`8.
`
`Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a. -c. are requireci)
`
`b.
`
`Specification Sequence listing on:
`
`a. 0 Computer Readable Form (CRF)
`i. 0 CD-ROM or CD-R (2 copies); or
`ii. 0 Paper
`c. 0 Statements verifying identity of above copies
`
`I
`
`I
`
`I
`
`9. ~Assignment Papers (cover sheet & document(s))
`
`Name of Assignee Allergan, Inc.
`
`(when there is an assignee)
`
`10. 0 37 CFR 3.73(b) Statement 0 Power of Attorney
`11. 0 English Translation Document (if applicable)
`12. 0 Information Disclosure Statement (PTOISBI08 or PT0-1«9)
`0 Copies of citations attached
`0 Preliminary Amendment
`
`13.
`
`14. ~Return Receipt Postcard (MPEP 503)
`(Should be specifically 11ernizecf)
`0 Certified Copy of Priority Document(s)
`16. 0 Nonpublication Request under 35 U.S.C. 122(b)(2)(B)(i).
`
`15.
`
`(if foreign priority is claimecf)
`
`Applicant must attach form PTO/SB/35 or equivalent
`
`17. Oother
`
`18. If a CONTINU lNG APPLICATION, check appropriate box, and supply the requisite information below and in the first sentence of the specification
`following the title, or in an Application Data Sheet under 37 CFR 1.76:
`
`~ Continuation
`
`0 Divisional
`
`~ Continuation-in-part (CIP)
`
`of prior application No.: 10/927,857
`
`Prior application information:
`
`Examiner Cordero Garcia, Marcela
`
`Arl Unit 1654
`
`~ The address associated with Customer Number: I
`
`19. CORRESPONDENCE ADDRESS
`33197
`
`I
`
`Name
`
`Address
`
`City
`
`Country
`
`I State
`I Telephone
`I
`,,
`I Date
`J~~~1\!:~---t~<
`Signature
`I Registration No.
`Name (Print/Type) ~sA. Fisher
`
`(Attorney/Agent)
`
`OR 0 Correspondence address below
`
`Zip Code
`
`Fax
`
`Augus~. 2007
`
`36,510
`
`APOTEX 1019, pg. 2825
`
`

`
`FEE TRANSMITTAL
`for FY 2005
`
`Patent tees are subjeCt to annual revision.
`
`0 Application claims small entity status. See 37 CFR 1.27
`I ($) 1400.00
`METHOD OF PAYMENT (check all that apply)
`
`TOTAL AMOUNT OF PAYMENT
`
`Complete if Known
`Not yet known
`Aj)Qiication Number
`Filing Date
`Herewith
`First Named Inventor
`Acheampong et al.
`N/A
`
`Examiner Name
`
`Art Unit
`
`N/A
`
`Attorney Docket No.
`
`D-3111 CON
`
`Deposit Account Number
`
`01-0885
`
`Deposit Account Name
`
`Allernan
`
`0 Check 0 Credit Card 0 Money Order 0 None 0 Other (please identify): __
`[gl Deposit Account
`For the above-identified deposit account, the Director is hereby authorized to: (check all that apply)
`0 Charge fee(s) indicated below, except for the filing fee
`[gl Charge fee(s) indicated below
`[gl Charge any additional fee(s) associated with this
`[g) Credit any overpayments
`communication
`WARNING: Information on this form may become public. Credit card information should not be included on this form. Provide credit card information and
`authorization on PT0-2038.
`FEE CALCULATION
`
`1. BASIC FILING SEARCH AND EXAMINATION FEES
`FILING FEES
`SEARCH FEES
`Small Enti!X
`Small Enti!X
`En.W
`En.W
`150
`250
`
`En.W
`500
`100
`300
`
`500
`
`0
`
`100
`100
`
`150
`100
`
`50
`150
`
`250
`
`0
`
`EXAMINATION FEES
`Small Entl!X
`En.W
`100
`65
`80
`
`En.W
`200
`130
`160
`
`600
`
`0
`
`300
`
`0
`
`Fees Paid Ill
`1000
`
`Aeelicatlon T~ee
`Utility
`Design
`Plant
`
`En.W
`300
`200
`200
`
`Reissue
`Provisional
`
`300
`200
`
`2. EXCESS CLAIM FEES
`
`Fee Oescrtotion
`
`Subtotal (11
`
`--
`
`Small Entity
`Fee 1$1
`Feel$1
`50
`25
`200
`100
`360
`180
`MuHiele Deeendent Claims
`~ Fee Paid Ill
`-- --
`
`Each claim over 20 or, for Reissues, each claim over 20 and more than In the original patent
`Each Independent claim over 3 or, for Reissues, each Independent claim more than in the original patent
`Multiple Dependent Claims
`Extra Claims ~ Fee Paid Ill
`Total Claims
`-20 orHP =
`4
`24
`50
`200
`X
`[HP = highest number of total claims paid for, if greater than 20
`En.W
`Extra Claims
`lndee. Claims
`-3orHP=
`4
`X
`1
`200
`HP = highest number of independent claims paid for, if greater than 3
`
`Fee Paid Ill
`200
`
`3. APPLICATION SIZE FEE
`r the specification and drawings exceed 100 sheets of paper, the application size fee due Is $250 ($125 for small entity) for each additional 50 sheets or fraction
`hereof. See 35 U.S.C. 41(a){1)(G) and 37 CFR 1.16{s).
`Extra
`Sheets
`
`Tota I S!Jeets
`
`Number of each additional 50 or fraction thereof
`
`~ Fee Paid Ill
`
`Subtotal (21
`
`400
`
`~
`Fee Paid Ill
`
`35
`
`-100 =
`
`0
`
`/50= ___ (round up to a whole number)
`
`X
`
`=
`
`Subtotal(31
`
`4. OTHER FEElSl
`0 Surcharge- Late filing fee or oath/declaration: $130 fee ($65 small entity discount)
`0 Non-English Specification: $130 fee (no small entity discount)
`0 1-monlh extension of time: $120 fee ($60 small entity discount)
`0 2-monlh extension of lime: $450 fee ($225 small entity discount)
`0 3-month extension oflime: $1020 fee ($51 0 small entity discount)
`0 4-month extension of time: $1590 fee ($795 small entity discount)
`0 5-month extension of lime: $2160 fee ($1080 small entity discount)
`0
`Information Disclosure Statement Fee: $180 fee (no small entity discount)
`0 Notice of Appeal: $500 fee ($250 small entity discount)
`0 Filing a Brief in Support of Appeal: $500 fee ($250 small entity discount)
`0 Request for Oral Hearing: $1000 fee ($500 small entity discount)
`0 Utility Issue Fee: $1400 fee ($700 small entity discount)
`0 Recording each patent assignment per property (times number of properties): $40 fee (no small entity fee discount)
`0 Request for Continued Examination: $790 fee ($395 small entity discount)
`0 Other. - -
`
`SUBMITTED BY
`Name
`1Print!Tvoe)
`
`Signature
`
`I Registration No.
`( ~lo~~ ~,~_<
`\...__-
`
`/ \ Carlos A. Fisher
`
`• (Attomev/Aqent)
`
`~
`
`I 36,510
`
`Subtotall4l
`
`0
`
`Telephone
`
`949-450-1750
`
`Date
`
`August~. 2007
`
`APOTEX 1019, pg. 2826
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application No.
`Applicant
`Filed
`Title
`
`To be assigned
`Acheampong et al.
`Herewith
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING
`CYCLOSPORIN COMPONENTS
`
`Confirmation No.
`
`TC/A.U.
`Examiner
`
`NA
`NA
`
`Docket No.
`Customer No.
`
`D-3111 CON
`33197
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`EXPRESS MAIL CERTIFICATE
`
`EXPRESS MAIL MAILING LABEL NO.
`
`Date of Deposit:
`
`EV 516292203 US
`
`August 28, 2007
`
`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, P.O. Box 1450, Alexandria, VA 22313-1450:
`
`~ Utility Patent Application Transmittal
`
`~ Assignment; 37 CFR 3.73(b) Statement
`(Copy)
`D Information Disclosure Statement
`~Fee Transmittal
`D Cited References
`~Application Data Sheet (~ page(s))
`D Preliminary Amendment
`~Specification/Abstract (34 page(s))
`D Drawings (
`D Non-publication Request
`sheet(s))
`~Declaration (f. page(s)) (Copy)
`~ Stamped, self-addressed postcard
`D Other: __
`D Power of Attorney
`Each of the I above-identified documents are enclosed herewith.
`
`Respectfully submitted,
`
`Date: _....:...A=u=g=us=t,__2_t_,.-=2=0=0..:....7_
`
`~/W~
`
`Shawnna Waddell
`Assistant to Carlos A. Fisher
`Stout, Uxa, Buyan & Mullins, LLP
`4 Venture, Suite 300
`Irvine, California 92618
`Telephone: 949-450-1750
`
`·
`
`APOTEX 1019, pg. 2827
`
`

`
`D-3111CON
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`
`USING CYCLOSPORIN COMPONENTS
`
`5 Re1ated App1ication
`
`This application is a continuation of U.S. Application
`Serial No. 10/927,857, filed August 27, 2004, which claimed
`the benefit of U.S. Provisional Application No. 60/503,137
`filed September 15, 2003, which is incorporated in its
`
`10 entirety herein by reference.
`
`Background of the Invention
`
`15
`
`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
`20 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
`Pharmacal Ther, 2002 Oct, 18(5) :411-8; "Distribution of
`
`25
`
`30
`
`APOTEX 1019, pg. 2828
`
`

`
`D-3111CON
`
`2
`
`5
`
`10
`
`topical
`after
`tissues
`ocular
`in
`cyclosporin A
`to albino
`rabbits
`and beagle dogs,"
`administration
`Acheampong et al, Curr Eye Res, 1999 Feb, 18(2):91-lOJb;
`"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, 438:1001-4; "Preclinical
`safety studies of cyclosporine ophthalmic emulsion,"
`Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;
`al,
`"...;;.C..,d;y....;c;_;l_o.;_s..;;_p.........,;.o_r....;.i_n _ __;,&_.......;::.E.;_m....;.u:..=l;....;s;_;l=-· o=-n:...:...._____;&;;:____;;;E;..~y--=-e , " Stevenson
`e t
`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,
`15 Ophthalmology, 2000 Apr, 107 (4): 631-9.
`Each of these
`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
`weight castor oil.
`The Ding et al patent placed no
`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%
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 2829
`
`

`
`D-3111CON
`
`3
`
`by weight of cyclosporin A.
`cyclosporin A ·
`With
`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.
`
`5
`
`10
`
`Summary of the Invention
`
`20
`
`New methods of treating a human or animal using
`cyclosporin
`component-containing
`emulsions have been
`15 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
`30 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
`
`25
`
`APOTEX 1019, pg. 2830
`
`

`
`D-3111CON
`
`4
`
`in a therapeutically effective amount of less than 0.1% by
`weight of the composition.
`The weight ratio of
`the
`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
`suitable condition which is therapeutically sensitive to or
`treatable with cyclosporin components.
`Such conditions
`preferably are ophthalmic or ocular conditions, that is
`relating to or having to do with one or more parts of an
`eye of a human or animal.
`Included among such conditions
`are,
`without
`limitation,
`dry
`eye
`syndrome,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 2831
`
`

`
`D-3111CON
`
`5
`
`uveitis,
`endophthalmitis,
`phacoanaphylactic
`vernal
`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
`immunosuppressant activity.
`oligopeptides with
`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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 2832
`
`

`
`D-3111CON
`
`6
`
`10
`
`cyclosporin group and derivatives thereof, as well as
`mixtures of
`two or more
`individual cyclosporins and
`derivatives thereof.
`Particularly preferred cyclosporin components include,
`5 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,
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 2833
`
`

`
`D-3111CON
`
`7
`
`components,
`surfactant
`components,
`polyelectrolyte
`viscosity inducing components, acids and/or bases to adjust
`
`5
`
`10
`
`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
`15 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
`20 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
`30 presently useful compositions to the eye or eyes of a human
`or animal.
`Each and every feature described herein, and each and
`
`25
`
`APOTEX 1019, pg. 2834
`
`

`
`D-3111CON
`
`8
`
`every combination of two or more of such features, is
`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.
`The present methods have been
`
`to be very
`
`found
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 2835
`
`

`
`D-3111CON
`
`9
`
`effective in providing the desired therapeutic effect or
`effects while, at the same time, substantially reducing, or
`even substantially eliminating, side effects which may
`result from the presence of the cyclosporin component in
`the blood of the human or animal being treated, and eye
`irritation which,
`in the past, has been caused by the
`presence of certain components in prior art cyclosporin(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
`
`Such conditions
`treatable with cyclosporin components.
`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 vari