Docket No. 17618CON5B (AP)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant: Acheampong, et al.
`
`Examiner: TBA
`
`Serial No.: TBA
`
`Filed: Herewith
`
`For: METHODS OF PROVIDING
`THERAPEUTIC EFFECTS USING
`CYCLOSPORIN COMPONENTS
`
`Group Art Unit: TBA
`
`Confirmation No. TBA
`
`Customer No.: 51957
`
`PRELIMINARY AMENDMENT
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-14 50
`
`Dear Sir:
`
`Prior to examining the above-referenced application, please amend the specification as
`
`described on page 2 of this paper, and please amend the claims as described on pages 3-6 of this
`
`paper. Remarks follow on page 7.
`
`1
`
`APOTEX 1019, pg. 1924
`
`

`
`Docket No. 17618CON5B (AP)
`
`Amendments to the Specification
`
`Please replace page 1, lines 5-10 of the specification filed herewith with the following amended
`
`paragraph:
`
`This application is a continuation of copending U.S. Application Serial No. 13/961,818
`
`filed August 7, 2013, which is a continuation of copending U.S. Application Serial No.
`
`11/897,177, filed August 28, 2007, which is a continuation of U.S. Application Serial No.
`
`10/927,857, filed August 27, 2004, now abandoned, which claimed the benefit of U.S.
`
`Provisional Application No. 60/503,137 filed September 15, 2003, which-is are incorporated in
`
`its their entirety herein by reference.
`
`2
`
`APOTEX 1019, pg. 1925
`
`

`
`Docket No. 17618CON5B (AP)
`
`Amendments to the claims
`
`The following list of claims will replace all previous versions of claims presented in this
`
`application:
`
`1- 36. (Canceled)
`
`37.
`
`(New) A method of treating dry eye disease, the method compnsmg topically
`
`administering to the eye of the human an emulsion at a frequency of twice a day, wherein the
`
`emulsion comprises cyclosporin A 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 a tonicity agent
`
`or a 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 a 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 a 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.
`
`3
`
`APOTEX 1019, pg. 1926
`
`

`
`Docket No. 17618CON5B (AP)
`
`45.
`
`(New) The method of Claim 37, wherein the emulsion further comprises glycerine in an
`
`amount of about 2.2% by weight and a 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
`
`a human in an effective amount in treating dry eye syndrome, the blood of the human has
`
`substantially no detectable concentration of cyclosporin A.
`
`48.
`
`(New) The method of Claim 42, wherein the emulsion has a 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 A 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 A 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 a 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 a
`
`human, demonstrates a reduction in adverse events in the human, relative to an emulsion
`
`comprising cyclosporin A 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.
`
`4
`
`APOTEX 1019, pg. 1927
`
`

`
`Docket No. 17618CON5B (AP)
`
`54.
`
`(New) A method of reducing side effects in a human suffering from dry eye syndrome, the
`
`method comprising the step of topically administering to the eye of the human an emulsion at a
`
`frequency of twice a day, wherein the emulsion comprises:
`
`cyclosporin A 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;
`
`a tonicity component or a demulcent component in an amount of about 2.2% by weight;
`
`a 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
`
`a human in an effective amount in treating dry eye syndrome, the blood of the human has
`
`substantially no detectable concentration of the cyclosporin A.
`
`58.
`
`(New) The method of Claim 54, wherein the emulsion has a 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) A method of treating dry eye disease, the method comprising the step of topically
`
`administering to an eye of a human an emulsion, the emulsion comprising:
`
`cyclosporin A 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;
`
`5
`
`APOTEX 1019, pg. 1928
`
`

`
`Docket No. 17618CON5B (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 a pH in the range of about 7.2
`
`to about 7.6.
`
`6
`
`APOTEX 1019, pg. 1929
`
`

`
`Docket No. 17618CON5B (AP)
`
`REMARKS
`
`The applicants have canceled Claims 1-36 and have added Claims 37-61. Support for the
`
`limitations recited in the new claims may be found throughout the specification, and at least at
`
`page 4, line 25- page 5, 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 a 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 Examiner's attention comments
`
`made in the Response filed on June 15, 2009 in U.S. Patent Application Serial No. 10/927,857
`
`(now abandoned) and comments made in the Amendment filed on June 15, 2009 in U.S. Patent
`
`Application Serial No. 11/897,177 (currently pending) regarding U.S. Patent No. 5,474,979 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 01-0885.
`
`Respectfully submitted,
`
`/Laura L. Wine/
`
`Laura L. Wine
`Attorney of Record
`Registration Number 68,681
`
`Date: August 14, 2013
`
`Please direct all inquiries and correspondence to:
`Laura L. Wine, Esq.
`Allergan, Inc.
`2525 Dupont Drive, T2-7H
`Irvine, California 92612
`Tel: (714) 246-6996 Fax: (714) 246-4249
`
`7
`
`APOTEX 1019, pg. 1930
`
`

`
`Doc Code: TRACK1.REQ
`Document Description: TrackOne Request
`
`PTO/AIA/424 (03-13)
`
`CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`UNDER 37 CFR 1.102(e) (Page 1 of 1)
`
`Andrew Acheampong
`
`I Nonprovisional Application Number (if I
`
`known):
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING CYCLOSPORIN COMPONENTS
`
`First Named
`Inventor:
`Title of
`Invention:
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`1. The processing fee set forth in 37 CFR 1.17(i)(1 ), the prioritized examination fee set forth in
`37 CFR 1.17(c), and if not already paid, the publication fee set forth in 37 CFR 1.18(d) 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.
`
`2. 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.
`
`3. The applicable box is checked below:
`0 Original Application (Track One)- Prioritized Examination under§ 1.102(e)(1)
`
`I.
`
`i.
`
`(a) The application is an original nonprovisional utility application filed under 35 U.S.C. 111 (a).
`This certification and request is being filed with the utility application via EFS-Web.
`---OR---
`( b) The application is an original nonprovisional plant application filed under 35 U.S.C. 111 (a).
`This certification and request is being filed with the plant application in paper.
`
`ii. The executed inventor's oath or declaration is filed with the application. (37 CFR 1.63 and 1.64)
`0 Request for Continued Examination - Prioritized Examination under§ 1.1 02(e)(2)
`
`II.
`
`i. A request for continued examination has been filed with, or prior to, this form.
`ii.
`If the application is a utility application, this certification and request is being filed via EFS-Web.
`iii. The application is an original nonprovisional utility application filed under 35 U.S.C. 111 (a), or is
`a national stage entry under 35 U.S.C. 371.
`iv. This certification and request is being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`v. No prior request for continued examination has been granted prioritized examination status
`under 37 CFR 1.1 02( e )(2).
`
`Siqnature/Laura L. Wine/
`~p~~~Typed) Laura L. Wine
`
`~~Augu~ 14,2013
`68681
`
`Practitioner
`Registration Number
`
`Note: This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4(d) for signature requirements and certifications.
`Submit multiple forms if more than one signature is required.*
`
`tJ *Total of
`
`1
`
`forms are submitted.
`
`APOTEX 1019, pg. 1931
`
`

`
`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 a patent application or patent. Accordingly, pursuant to the requirements of
`the Act, please be advised that: (1) the general authority for the collection of this information is 35 U.S.C. 2(b)(2); (2)
`furnishing of the information solicited is voluntary; and (3) 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 a patent application or
`patent. If you do not furnish the requested information, the U.S. Patent and Trademark Office may not be able to
`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:
`
`1. The information on this form will be treated confidentially to the extent allowed under the Freedom of
`Information Act (5 U.S.C. 552) and the Privacy Act (5 U.S.C 552a). Records from this system of records may
`be disclosed to the Department of Justice to determine whether disclosure of these records is required by the
`Freedom of Information Act.
`2. A record from this system of records may be disclosed, as a routine use, in the course of presenting evidence
`to a court, magistrate, or administrative tribunal, including disclosures to opposing counsel in the course of
`settlement negotiations.
`3. A record in this system of records may be disclosed, as a routine use, to a Member of Congress submitting a
`request involving an individual, to whom the record pertains, when the individual has requested assistance from
`the Member with respect to the subject matter of the record.
`4. A record in this system of records may be disclosed, as a routine use, to a contractor of the Agency having
`need for the information in order to perform a contract. Recipients of information shall be required to comply
`with the requirements of the Privacy Act of 1974, as amended, pursuant to 5 U.S.C. 552a(m).
`5. A record related to an International Application filed under the Patent Cooperation Treaty in this system of
`records may be disclosed, as a routine use, to the International Bureau of the World Intellectual Property
`Organization, pursuant to the Patent Cooperation Treaty.
`6. A record in this system of records may be disclosed, as a 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.
`218(c)).
`7. A record from this system of records may be disclosed, as a routine use, to the Administrator, General
`Services, or his/her designee, during an inspection of records conducted by GSA as part of that agency's
`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
`inspection of records for this purpose, and any other relevant (i.e., GSA or Commerce) directive. Such
`disclosure shall not be used to make determinations about individuals.
`8. A record from this system of records may be disclosed, as a routine use, to the public after either publication of
`the application pursuant to 35 U .S.C. 122(b) or issuance of a patent pursuant to 35 U .S.C. 151. Further, a
`record may be disclosed, subject to the limitations of 37 CFR 1.14, as a 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
`application is referenced by either a published application, an application open to public inspection or an issued
`patent.
`9. A record from this system of records may be disclosed, as a routine use, to a Federal, State, or local law
`enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or regulation.
`
`Page 2
`
`APOTEX 1019, pg. 1932
`
`

`
`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of Invention:
`
`METHODS OF PROVIDING THERAPEUTIC EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`First Named Inventor/Applicant Name:
`
`Andrew Acheampong
`
`Filer:
`
`Laura Lee Wine/Lauren Barberena
`
`Attorney Docket Number:
`
`17618CONSB (AP)
`
`Filed as Large Entity
`
`Track I Prioritized Examination -Non provisional Application under 35 USC 111 (a) Filing Fees
`
`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USD($)
`
`Basic Filing:
`
`Pages:
`
`Claims:
`
`Utility application filing
`
`Utility Search Fee
`
`Utility Examination Fee
`
`Request for Prioritized Examination
`
`Claims in Excess of 20
`
`Independent claims in excess of 3
`
`1011
`
`1111
`
`1311
`
`1817
`
`1202
`
`1201
`
`1
`
`1
`
`1
`
`1
`
`5
`
`1
`
`280
`
`600
`
`720
`
`280
`
`600
`
`720
`
`4000
`
`4000
`
`80
`
`420
`
`400
`
`420
`
`APOTEX 1019, pg. 1933
`
`

`
`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USD($)
`
`Miscellaneous-Filing:
`
`Publ. Fee- Early, Voluntary, or Normal
`
`OTHER PUBLICATION PROCESSING FEE
`
`1504
`
`1808
`
`1
`
`1
`
`300
`
`130
`
`300
`
`130
`
`Petition:
`
`Patent-Appeals-and-Interference:
`
`Post-Allowance-and-Post-Issuance:
`
`Extension-of-Time:
`
`Miscellaneous:
`
`Total in USD ($)
`
`6850
`
`APOTEX 1019, pg. 1934
`
`

`
`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:
`
`17618CON5B (AP)
`
`Receipt Date:
`
`14-AUG-2013
`
`Filing Date:
`
`TimeStamp:
`
`18:49:39
`
`Application Type:
`
`Utility under 35 USC 111 (a)
`
`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)
`
`APOTEX 1019, pg. 1935
`
`

`
`File Listing:
`
`Document
`Number
`
`Document Description
`
`File Name
`
`File Size( Bytes)/
`Message Digest
`
`Multi
`Part /.zip
`
`Pages
`(ifappl.)
`
`4360450
`
`1
`
`17618CON_SPEC.pdf
`
`yes
`
`34
`
`Multipart Description/PDF files in .zip description
`
`9b080e02f8cb41 c5b767d994b 15dca09f38
`dd180
`
`Document Description
`
`Start
`
`End
`
`Specification
`
`Claims
`
`Abstract
`
`Warnings:
`
`Information:
`
`28
`
`33
`
`34
`
`1
`
`29
`
`34
`
`1509913
`
`2
`
`Application Data Sheet
`
`17618CONSB_ADS.pdf
`
`no
`
`8
`
`Warnings:
`
`Information:
`
`f4175733ae4deae0cc2419f6f51 cf83740f4f3
`cS
`
`645090
`
`3
`
`Oath or Declaration filed
`
`17618CONSB_DECS.pdf
`
`no
`
`6
`
`1 cc2bbfb0fbf9a783362f088e6b 132ea37de
`5ba3
`
`Warnings:
`
`The page size in the PDF is too large. The pages should be 8.5 x 11 or A4. If this PDF is submitted, the pages will be resized upon entry into the
`Image File Wrapper and may affect subsequent processing
`
`Information:
`
`4
`
`Power of Attorney
`
`17618CONSB_POA.pdf
`
`no
`
`2
`
`1931210
`
`Obcb7a2e4 71 e5bfbe0f5c1769aa60a43fbca
`1109
`
`Warnings:
`
`Information:
`
`5
`
`17618CONSB_PRELIM_AMEND
`MENTS.pdf
`
`106465
`
`yes
`
`7
`
`c04b4e0a11bc2314b05581 c0329afa77487
`cbaed
`
`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Start
`
`End
`
`Preliminary Amendment
`
`Specification
`
`1
`
`2
`
`1
`
`2
`
`APOTEX 1019, pg. 1936
`
`

`
`Claims
`
`Applicant Arguments/Remarks Made in an Amendment
`
`3
`
`7
`
`6
`
`7
`
`Warnings:
`
`Information:
`
`6
`
`TrackOne Request
`
`17618CONSB_PRIORITIZED _EX
`AM. pdf
`
`153243
`
`e3999ce6355f3b02c50e19c9b45dd819e59
`01b53
`
`no
`
`2
`
`Warnings:
`
`Information:
`
`7
`
`Fee Worksheet (SB06)
`
`fee-info. pdf
`
`no
`
`2
`
`43444
`
`cl a3 bc365 ea64 53 9 580c4 3 dc2cc0c5 384 9d
`5ec9a
`
`Warnings:
`
`Information:
`
`Total Files Size (in bytes)
`
`8749815
`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New A~~lications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International A~~lication under 35 U.S.C. 371
`If a timely submission to enter the national stage of an international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/DO/E0/903 indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International A~~lication Filed with the USPTO as a Receiving Office
`If a new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 181 0), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/R0/1 OS) 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.
`
`APOTEX 1019, pg. 1937
`
`

`
`D-3111CON
`METHODS OF PROVIDING THERAPEUTIC EFFECTS
`
`USING CYCLOSPORIN COMPONENTS
`
`5 Related Application
`This application .ls a continuation of U.S. Applicat.ion
`Serial No. 10/927,857, filed August 27, 2004, ~-1hich claimed
`the benefit of U.S. Provisional Application No. 60/503,137
`filed September 15, 2003,
`\•lhich is incorporated in its
`entirety herein by reference,
`
`10
`
`15
`
`Bac.kg;round of the .Invention
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using
`compositions
`includin9 cyclosporin components.
`t<1ore
`particularly, the invention relates to methods including
`to an
`a
`human or animal
`administering
`eye of
`a
`therapeutically effective amount of a cyclosporin component
`to provide a desired therapeutic effect, prefe.r·ably 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
`5,474,919; 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,
`cyclospor:in A compositions used in treating ophthalmic
`conditions is the subject of a number of publications.
`publications
`for
`in.clude 1
`Such
`"Blood
`concentrations ot cyclosporin a during long-term treatment
`with cyclosporin a ophthalmic emulsions in patients with
`moderate to severe dry eye disease.u Small et al, J Ocul
`Pha.rmacol The.r, 2002 Oct,. 18(5):411-8; "Distribution of
`
`25
`
`30
`
`APOTEX 1019, pg. 1938
`
`

`
`D-3111CON
`
`2
`
`II;
`
`-
`
`•
`
`,,.
`
`,
`
`after
`ocular
`in
`A
`topical
`tissues
`to albino
`rabbits
`and beagle dogs,"
`administration
`Ach~~ampong et al, Curr Eye Res,. 1999 E'eb, 18(2):91-103b;
`"Cyclosporine distribution into the conjunctiva, cornea,
`lacrimal gland, and systemic blood following topical dosing
`of cyclosporine to rabbit, dog, and human e'i_es,'"' Acheampong
`et al, Adv Exp Med Biol, 1998~ 438:1001-4;
`''Preclinical
`safety studies of cyclosporine ophthalmic emulsion,u
`Angelov et al 1
`Adv Exp Med Bioil
`1998,
`438:991-5;
`"_C,..j.y_·c'-J_. o;.....s_·f._J_o_r_i_n __ & __ E_"m__;_u.;.;.l..;.;s..;.;i_o_;...n.;.__--'-& __ E;_:~y..;.;..e 1 N
`S t.even son
`e t~
`a 1,
`2000 May,
`1 ny (5) ~ 96"'1- ·74 •
`and
`Ophthalmology,
`''Two
`.J. v
`multicenter~ rt.mdomized studies of the effic~cy and safety
`of cyclospprine ophthalmic emulsion in .moderate to severe
`dry eye disease. CsA Phase .3 Study Group,'' Sal.l et al,
`Each of these
`15 Ophthalmology, 2000 A.px, 107 (4): 631-9.
`publications is incorporated in its entirety herein by
`reference.
`In addition, cyclosporin A-containing oil-in-
`water emulsions have been clinically
`tested, under
`conditions of confidentiality, since the mid 1990's in
`order to obtain U.S. Food and Drug Administration {FDA)
`regulatory approval.
`Examples of useful cyclospor:in A-containing emulsions
`are set out in Ding et al U.S. Patent 5,474 1 979. 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,
`included 0. 2% by weight. cyclosporin A and 5% by
`which
`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 ophthal.m.ic use preferably have less than 0. 2%
`
`5
`
`10
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 1939
`
`

`
`D-3111CON
`
`3
`
`With cyclosporin A
`by weight of
`cyclosporin A.
`concentrations less than 0. 2%,
`the amount of castor oil
`employed has been reduced since one of the functions of the
`castor oil is to solubilize the cyclosporin A. Thus, if
`reduced amounts of cyclc>sporin are employed,
`reduced
`amounts of castor oil are needed to provide effective
`solubilization of cyclosporin A.
`There cont.inues to be a need for providing enhanced
`methods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`5
`
`10
`
`15
`
`Summary of the Invention
`Ne\v methods of treating a human or animal using
`component-containing emulsions
`have
`cyclosporin
`be-en
`Such methods provide substantial overall
`discovered.
`efficacy in providing desired therapeutic effects.
`In
`addition, other important benefits are obtained employing
`the present methods.
`For exanlple, patient safety _is
`In particular~ the present methods provide for
`enhanced,
`reduced risks of side effects and/or dr1Jg interactions.
`Prescribing physicians
`advantageously have
`increased
`such methods
`the
`flexibility
`in
`prescribing
`and
`compositions useful in such methods, for example 1 because
`of the reduced risks of harmful side effects and/or drug
`interactions. The present methods can be easily practiced.
`the present methods provide substantial and
`In short,
`acceptable
`efficacy,
`overall
`together with
`othe.t'
`advantages, such as increased safety and/or flexibility.
`Tn one aspect of the present inventiont the present
`30 methods comprise administering to an eye of a human or
`animal a composition in the for:m of an emulsion comprising
`'water, a hydrophobic component and a cyclosporin component
`
`20
`
`25
`
`APOTEX 1019, pg. 1940
`
`

`
`D-311.1CON
`
`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 h.ydrophobic component is less
`than 0.08,
`the relatively increased
`that
`found
`It has been
`amounts of hydrophobic component toget.her with relatively
`therapeutically effective 1
`reduced,
`yet
`am<mnts 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, v.:hich reduces vision distortion which may be
`caused by the presence of the emulsion in the eye and/or
`facilitates
`effectiveness
`the
`the
`therapeutic
`of
`composit.ion. Additionally, and importantly, using reduced
`amounts of
`the active cyclosporin component mitigates
`against undesixable side effects and/or potential drug
`interactions.
`In short. the present invention provides at least one
`advantageous benefit,
`and preferably
`a plurality of
`advantageous bene£ its.
`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
`Included among such conditions
`eye of a human or animal.
`are,
`without
`limitation,
`dry
`eye
`syndrome,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 1941
`
`

`
`D-3111CON
`
`5
`
`vernal
`endophthalmi t .i.s,
`phacoanaphylactic
`uve.i.t:is,
`conjunctivitis~ atopic kerapoconjunctivitis, corneal graft
`rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`reduced concentrat.ions of cyclosporin
`Employing
`component, as in the present invention, is advantageously
`effective to provide the blood of the human or animal under
`treatment
`\'lith
`reduced concentrations of cyclosporin
`component, preferably tvi th substantially no detectable
`cyclosporin
`component,
`concentration of
`the
`The
`cyclosporin com-ponent concentration of blood can be
`liquid
`advantageously meas.ured
`using
`a
`validated
`chromatography/mass spectrometry-mass spectrometry (VLC/NS(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 o:r less.
`Any suitable cyclosporin component effective in the
`present methods may be used.
`nonpolar
`of
`are
`a
`Cyclospo.rins
`cyclic
`group
`immunosuppressant activity.
`known
`oligopeptides Hith
`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, cornn1ercially available cyclosporins rnay
`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 substituent! or configurations of
`some of the amino acids.
`The term "cyclosporin component" as used herein is
`.i.ntended
`any
`individual member of
`the
`to
`include
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 1942
`
`

`
`D-3111CON
`
`6
`
`10
`
`15
`
`cyclospori.n 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
`an especially useful
`is
`cyclosporin
`component.
`Any sui·table hydrophobic component may be employed in
`the p:cesent invention. Advant:aqeously,
`the cyclosporin
`component is solubili.zed in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`discontinucms 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 wei9ht. For example, the hydrophobic component
`may be present in ~n amount of up to about 1.0% by weight
`or about 1.5% by weight or more of the composition.
`Preferably, the hydrt)phobic component comprises one or
`more oily materials.
`Examples of useful oil materials
`include, t.vithout 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
`obtained 1.-1hen
`the
`glycerides.
`Excellent results are
`hydrophobic component comprises castor oiL
`The presently useful compositions may include one or
`more other components in amounts effective to facilitate
`the compositions.
`the usefulness and effectiveness of
`include, without
`components
`suc.h other
`Examples of
`limitation, emulsifier components,
`tonicity components,
`
`20
`
`25
`
`30
`
`APOTEX 1019, pg. 1943
`
`

`
`D-3111CON
`
`7
`
`5
`
`10
`
`components,
`surfactant
`components,
`polyelectrolyte
`viscosity inducing components, acids and/or bases to adjust
`the pH of the composition, buffer components 1 preservative
`components and the like. Compon~?nts may be employed which
`are effective to perform two or more fu.nctions in the
`presently useful compositions.
`For example, cornponents
`which are effective as both emulsifiers and su.rfactants may
`be employed, and/or components ~,rhich 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
`the desired
`specific application at hand, for example 1
`therapeutic effect to be achieved, the desired properties
`1