June 18, 2007
`
`PRELIMINARY AMENDMENT
`Patent Application
`Docket No. SER-125
`
`IN THE UNITED STA TES PATENT AND TRADEMARK OFFICE
`
`Applicant
`
`Docket No.
`
`For
`
`Giampiero de Luca
`
`SER-125
`
`Cladribine Regimen for Treating Multiple Sclerosis
`
`Mail Stop PCT
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`PRELIMINARY AMENDMENT
`
`Sir:
`
`It is respectfully requested that the above-identified patent application be amended as
`follows:
`
`J :\SER\ 125\Amd-Resp\PreAmd.dodDNB/s1
`
`Hopewell EX1004
`
`1
`
`

`

`2
`
`Docket No. SER-125
`Patent Application
`
`In the Specification
`
`Please insert the following new paragraph after the Title of the invention on page 1, line 1:
`
`Cross-Reference to Related Application
`
`This application is the U.S. national stage application oflntemational Patent Application No.
`PCT/EP2005/056954, filed December 20, 2005, which claims the benefit of U.S. Provisional Patent
`Application No. 60/638,669, filed December 22, 2004, the disclosures of which are hereby
`incorporated by reference in their entireties, including all figures, tables and amino acid or nucleic
`acid sequences.
`
`After page 31: Please insert as new page 32 the attached Abstract of the Disclosure.
`
`J :\SER\125\Amd-Resp\PreAmd.dodDNB/sl
`
`2
`
`

`

`3
`
`In the Claims
`
`Docket No. SER-125
`Patent Application
`
`1-17 ( canceled).
`
`18 (new).
`
`A method of treating multiple sclerosis comprising the oral administration of a
`formulation comprising cladribine, wherein the formulation is to be orally administered following
`the sequential steps below:
`
`(i)
`
`(ii)
`
`(iii)
`
`an induction period wherein said cladribine formulation is administered and wherein
`the total dose of cladribine reached at the end of the induction period is from 1. 7
`mg/kg to 3.5 mg/kg;
`
`a cladribine-free period wherein no cladribine formulation is administered;
`
`a maintenance period wherein said cladribine formulation is administered and
`wherein the total dose of cladribine reached at the end of the maintenance period is
`lower than the total dose of cladribine reached at the end of the induction period (i);
`
`and
`
`(iv)
`
`a cladribine-free period wherein no cladribine formulation is administered.
`
`19 (new).
`
`The method according to claim 18, wherein the induction period lasts up to 4
`months, or up to 3 months, or up to 2 months.
`
`20 (new).
`
`The method according to claim 19, wherein the induction period lasts up to 2
`
`months.
`
`21 (new).
`
`The method according to claim 18, wherein the induction period lasts up to 2
`
`months.
`
`22 (new).
`
`The method according to claim 18, wherein the induction period lasts up to 4
`
`months.
`
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`
`3
`
`

`

`4
`
`Docket No. SER-125
`Patent Application
`
`23 (new).
`
`The method according to claim 19, wherein the induction period lasts up to 4
`
`months.
`
`24 (new).
`
`The method according to claim 18, wherein the total dose of cladribine
`reached at the end of the induction period is 1. 7 mg/kg.
`
`25 (new).
`
`The method according to claim 18, wherein the total dose of cladribine
`reached at the end of the induction period is 3.5 mg/kg.
`
`26 (new).
`
`The method according to claim 18, wherein the cladribine-free period lasts up
`to 10 months, or up to 9 months, or up to 8 months.
`
`27 (new).
`
`The method according to claim 18, wherein the cladribine-free (iv) period
`
`lasts up to 10 months.
`
`28 (new).
`
`The method according to claim 18, wherein the maintenance period lasts up to
`4 months, or up to 3 months or up to 2 months.
`
`29 (new).
`
`The method according to claim 18, wherein the total dose of cladribine
`reached at the end of the maintenance period is 1. 7 mg/kg.
`
`30 (new).
`
`The method according to claim 18, wherein the formulation is to be orally
`administered following the sequential steps below:
`
`(i)
`
`(ii)
`
`(iii)
`
`an induction period wherein said cladribine fommlation is orally administered and
`wherein the total dose of cladribine reached at the end of the induction period is from
`1. 7 mg/kg to 3. 5 mg/kg;
`
`a cladribine-free period wherein no cladribine formulation is administered;
`a maintenance period wherein said cladribine formulation is administered and
`wherein the total dose of cladribine reached at the end of the maintenance period is
`
`J :\SER\ 125\Amd-Resp\PreAmd.dodDNB/sl
`
`4
`
`

`

`5
`
`Docket No. SER-125
`Patent Application
`
`lower than the total dose of cladribine reached at the end of the induction period (i);
`and
`
`(iv)
`
`a cladribine-free period wherein no cladribine formulation is administered;
`wherein the induction period lasts up to 4 months, or up to 3 months or up to 2 months; the
`cladribine-free period (ii) lasts up to 10 months, or up to 8 months or up to 10 months; the
`maintenance period (iii) lasts up to 2 months; the cladribine-free period (iv) lasts up to 10 months;
`the total dose of cladribine reached at the end of the maintenance period is 1. 7 mg/kg and steps (iii)
`to (iv) are repeated performed one, two or three times.
`
`31 (new).
`
`The method according to claim 30, wherein the total dose of cladribine
`reached at the end of the induction period is 3 .5 mg/kg and the total dose of cladribine reached at the
`end of the maintenance period is 1. 7 mg/kg.
`
`32 (new).
`
`The method according to claim 30, wherein the formulation is to be orally
`administered at a daily dose of 3 to 30 mg cladribine.
`
`33 (new).
`
`The method according to claim 32, wherein the pharmaceutical formulation is
`to be orally administered at a daily dose of 10 mg cladribine.
`
`34 (new).
`
`The method according to claim 18, wherein the pharmaceutical formulation is
`orally administered 1 to 7 days per month during the induction period.
`
`35 (new).
`
`The method according to claim 18, wherein the steps (iii) to (iv) are repeated
`at least one or two times.
`
`36 (new).
`
`The method according to claim 18, wherein said cladribine formulation is to
`be administered in combination with interferon-beta.
`
`J :\SER\ 125\Amd-Rcsp\PreAmd. doo'DNB/sl
`
`5
`
`

`

`6
`
`Docket No. SER-125
`Patent Application
`
`37 (new).
`
`The method according to claim 30, wherein said cladribine formulation is to
`
`be administered in combination with interferon-beta.
`
`J :\SER\ 125\Amd-Resp\PreAmd.doo'DNB/sl
`
`6
`
`

`

`7
`
`Remarks
`
`Docket No. SER-125
`Patent Application
`
`The Commissioner is hereby authorized to charge any fees under 3 7 CFR § § 1.16, 1.17, and
`
`1.492 as required by this paper to Deposit Account No. 19-0065.
`
`Respectfully submitted,
`
`/FRANKCEISENSCHENK/
`
`Frank C. Eisenschenk, Ph.D.
`Patent Attorney
`Registration No. 45,332
`Phone No.:
`352-375-8100
`Fax No.:
`352-372-5800
`Address:
`P.O. Box 142950
`Gainesville, FL 32614-2950
`
`FCE/sl
`Attachment: Abstract of the Disclosure
`
`J:ISER\125\Amd-Resp\PreAmd.dodDNB/sl
`
`7
`
`

`

`32
`
`PCT/EP2005/056954
`
`Abstract of the Disclosure
`The present invention is related to the use of Cladribine for the preparation of a
`pharmaceutical formulation for the treatment of multiple sclerosis, especially relapsing-remitting
`multiple sclerosis or early secondary progressive multiple sclerosis, wherein the preparation is to
`be orally administered and wherein re-treatments are possible .
`
`5
`
`.J :\SER\ 125\PTO-Misc\abstract.doc/DNB/sl
`
`8
`
`

`

`APPLICATION DATA SHEET
`
`Docket No. SER-125
`
`Application Information
`
`Application Type::
`
`Subject Matter::
`
`Suggested Classification::
`
`Suggested Group Art Unit::
`
`CD-ROM or CD-R?::
`
`Number of CD disks::
`
`Number of copies of CDs::
`
`Sequence submission?::
`
`Computer Readable Form?::
`
`Number of Copies of CRF::
`
`Title::
`
`Attorney Docket Number::
`
`Request for Early Publication::
`
`Request for Non-Publication::
`
`Suggested Drawing Figure::
`
`Total Drawing Sheets::
`
`Small Entity?::
`
`Petition included?::
`
`Petition Type::
`
`Secrecy Order in Parent Appl.?::
`
`Regular (National Stage)
`
`Utility
`
`None
`
`None
`
`None
`
`None
`
`None
`No
`No
`
`None
`
`CLADRIBINE REGIMEN FOR TREATING MULTIPLE
`SCLEROSIS
`SER-125
`No
`No
`
`None
`
`None
`No
`No
`
`N/A
`No
`
`1/3
`
`Initial 06/18/2007
`
`9
`
`

`

`APPLICATION DATA SHEET
`
`Docket No. SER-125
`
`Applicant Information
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`
`Status::
`
`Inventor One Given Name::
`
`Family Name::
`
`City of Residence::
`
`Country of Residence::
`
`Street of Mailing Address::
`
`City of Mailing Address::
`
`Inventor
`
`Italy
`
`Unknown
`
`Giampiero
`
`DE LUCA
`
`Conches/Geneva
`
`Switzerland
`
`Chemin des Conches 158
`
`Conches/Geneva
`
`Country of Mailing Address::
`
`Switzerland
`
`Postal or Zip Code of Mailing Address::
`
`CH-1231
`
`Representative Information
`
`Representative Customer Number::
`
`000023557
`
`Correspondence Information
`
`Correspondence Customer Number::
`
`000023557
`
`Telephone Number One::
`
`Telephone Number Two::
`
`Fax Number::
`
`Electronic Mail Address::
`
`(352) 375-8100
`
`(352) 372-5800
`
`fce@slspatents.com
`
`2/3
`
`Initial 06/18/2007
`
`10
`
`

`

`APPLICATION DATA SHEET
`
`Docket No. SER-125
`
`Domestic Priority Information
`
`Application::
`This application is a
`
`Continuity Type::
`
`National Stage of
`
`Parent Application::
`
`Parent Filing Date::
`
`PCT/EP2005/056954
`
`December 20, 2005
`
`PCT/EP2005/056954
`
`An application claiming
`the benefit under 35 USC
`119(e)of
`
`Foreign Priority Information
`
`60/638,669
`
`December 22, 2004
`
`Country::
`
`EP
`
`Application Number::
`
`Filing Date::
`
`Priority Claimed::
`
`04106909.7
`
`December 22, 2004
`
`Yes
`
`Assignee Information
`
`Assignee Name::
`
`Street of Mailing Address::
`
`City of Mailing Address::
`
`Country of Mailing Address::
`
`Laboratoires Serano S.A.
`
`Zone lndustrielle de l'Ouriettaz
`
`Aubonne
`
`Switzerland
`
`Postal or Zip Code of Mailing Address::
`
`CH-1170
`
`3/3
`
`Initial 06/18/2007
`
`11
`
`

`

`PCT /EP2005/056954
`
`I hereby declare that I believe I am the
`original, first and sole· (if only one
`inventor is listed below) or joint (if
`more than one inventor is listed below)
`inventor of the subject matter which is
`claimed and for which a patent is
`sought.
`This declaration is directed to
`international application PCT/
`EP2005/056954 (if furnishing declaration
`pursuant to Rule 26ter).
`I hereby declare that my residence,
`mailing address, and citizenship are as
`stated next to my name.
`I hereby state that I have reviewed and
`understand the contents of the above(cid:173)
`identified international application,
`including the claims of said
`application. I have identified in the
`request of said application, in
`compliance with PCT Rule 4.10, any claim
`to foreign priority, and I have
`identified below, under the heading
`11 Prior Applications 11
`, by application
`nwnber, country or Member of the World
`Trade Organization, day, month, and year
`of filing, any application for a patent
`or inventor's certificate filed in a
`country other than the United States of
`America, including any PCT international
`application designating at least one
`country other than the United States of
`America, having a filing date before
`that of the application on which foreign
`priority is claimed.
`60/638,669, US, 22 December 2004
`(22.12.2004) ;04106909.7, EP, 22
`December 2004 {22.12.2004)
`
`Vlll-4-1 Declaration: Jnventorship (only for
`the purposes of the designation of
`the United States of America)
`Declaration of lnventorship (Rules
`4.17(iv) and 51bis.1(a)(iv)) for the
`purposes of the designation of the
`United States of America:
`
`Vll\-4-1- Prior applications:
`1
`
`12
`
`

`

`PCT /EP2005/056954
`
`I hereby acknowledge the duty to
`disclose information that is known by me
`to be material to patentability as
`defined by 37 C.F.R. § 1.56, including
`for continuation-in-part applications,
`material information which became
`available between the filing date of the
`prior application and the PCT
`international filing date of the
`continuation-in-part application.
`I hereby declare that all statements
`made herein of my own knowledge are true
`and that all statements made on
`information and belief are believed to
`be true; and further that these
`statements were made with the knowledge
`that willful false statements and the
`like so made are punishable by fine or
`imprisonment, or both, under Section
`1001 of Title 18 of the United States
`Code and that such willful false
`statements may jeopardize the validity
`of the application or any patent issued
`thereon.
`DE LUCA, Giampiero
`Conches, Switzerland
`
`Chemin de Conches 15B 1231 Conches
`Switzerland
`IT
`
`Vlll-4-1- Name (LAST, First)
`1-1
`Vlll-4-1- Residence:
`(city and either US State, if applicable,
`1-2
`or country)
`Vlll-4-1- Mailing address:
`1-3
`
`VIIJ-4-1- Citizenship:
`1-4
`Vlll-4-1-
`1-5
`
`Inventor's Signature:
`(if not contained in the request, or if
`declaration is corrected or added under
`Rule 26ter after the filing of the
`international application. The signature
`must be that of the inventor, not that of
`the agent)
`Vlll-4-1- Date:
`(of signature which is not contained in
`1-6
`the request, or of the declaration that is
`corrected or added under Rule 26ter
`after the filing of the international
`application)
`
`13
`
`

`

`June 18, 2007
`
`INFORMATION DISCLOSURE
`STATEMENT
`Patent Application
`Docket No. SER-125
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant
`
`Giampiero de Luca
`
`Filed
`
`For
`
`June 18, 2007
`
`Cladribine Regimen for Treating Multiple Sclerosis
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313
`
`INFORMATION DISCLOSURE STATEMENT
`UNDER 37 CFR §§1.97 AND 1.98
`
`Sir:
`
`In accordance with 37 C.F.R. § 1.56, the references listed on the attached form PTO/SB/08
`
`are being brought to the attention of the Examiner for consideration in connection with the
`
`examination of the above-identified patent application. A copy of each cited reference is enclosed.
`
`It is respectfully requested that the references cited on the attached form PTO/SB/08 be
`
`considered in the examination of the subject application and that their consideration be made of
`
`record.
`
`Applicant respectfully asserts that the substantive provisions of 3 7 C.F .R. § § 1. 97 and 1. 98
`
`are met by the foregoing statement.
`
`Respectfully submitted,
`
`/FRANKCEISENSCHENK/
`
`Frank C. Eisenschenk, Ph.D.
`Patent Attorney
`Registration No. 45,332
`Phone No.:
`352-375-8100
`Fax No.:
`352-372-5800
`Address:
`P.O. Box 142950
`Gainesville, FL 32614-2950
`
`FCE/jps
`Attachments: Form PTO/SB/08; copies of references cited therein.
`
`J :\SER\ 125\PTO-Misc\IDS .dodDNB/j ps
`
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`

`

`PTO/SB/OBA
`(08-03)
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`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid 0MB
`control number
`
`r Substitute for form 1449A/PTO
`INFORMATION DISCLOSURE
`ST A TEMENT BY APPLICANT
`
`(use as many sheets as necessary)
`
`\..
`
`Sheet
`
`I
`
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`
`I of I
`
`Complete if Known
`
`June 18, 2007
`Giampiero de Luca
`
`Application Number
`
`Filing Date
`
`First Named Inventor
`
`Art Unit
`
`Examiner Name
`
`3
`
`Attorney Docket Number SER-125
`
`"
`
`~
`
`Examiner
`Initials*
`
`Cite
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`US-
`US-
`US-
`US-
`
`U1
`U2
`U3
`U4
`U5
`U6
`U7
`U8
`U9
`
`Cite
`No. 1
`
`F1
`
`F2
`F3
`F4
`F5
`F6
`F?
`
`Examiner
`Initials*
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`[ Examiner
`Signature
`
`Ivax Corporation
`The Scripps
`Research Institute
`
`All
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`All
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`]
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`T'
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`Country Code 3
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`- Kind Code5 (if known)
`WO 04/087101 A2
`
`10/14/2004
`
`EP O 626 853 B1
`
`04/26/200
`
`*EXAMINER:
`Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance and not
`considered. Include copy of this form with next communication to applicant. 1 Applicant's unique citation designation number (optional). 2 See Kind Codes of
`3 Enter Office that issued the document, by the two-letter code (WIPO Standard T.3).
`4 For
`USPTO Patent Documents at www.uspto.gov or MPEP901.04.
`Japanese patent documents, the indication of the year of the reign of the Emperor must precede the serial number of the patent document. 5 Kind of document by
`the appropriate symbols as indicated on the document under WIPO Standard ST. 16 if possible. 6 Applicant is to place a check mark here if English language
`Translation is attached.
`This collection of information is required by 37 CFR 1.97 and 1.98. The information is required to obtain or retain a benefit by the publ,c which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 2 hours to complete,
`including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the individual case. Any comments
`on the amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent
`and Trademark Office, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO:
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`If you need assistance in completing the form, ca/11-800-PTO-9199 (1-800-786-9199) and select option 2 .
`
`.J:\SER\125\PTO-Misc\lDS-form.doc/DNB/jps
`
`15
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`

`PTO/SB/088 (08-03)
`Approved for use through 07131/2006. 0MB 0651-0031
`U S. Patent and Trademark Office: U S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it contains a valid 0MB
`control number
`r
`
`<,;omp1ete 11 Known
`
`Substitute for form 14498/PTO
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`
`"
`
`~
`
`T2
`
`Application Number
`Filing Date
`First Named Inventor
`Group Art Unit
`Examiner Name
`Attorney Docket Number SER-125
`
`June 18, 2007
`Giampiero de Luca
`
`\,_
`
`Sheet
`
`I
`
`2
`
`3
`
`Examiner Cite
`No. 1
`Initials*
`
`R1
`
`R2
`
`R3
`
`R4
`
`R5
`
`R6
`
`R7
`
`R8
`
`R9
`
`R10
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`R11
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`R12
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`(use as many sheets as necessary)
`I ot I
`NON PATENT LITERATURE DOCUMENTS
`Include name of the author (in CAPITAL LETTERS), title of the article, (when appropriate), title of the
`item (book, magazine, journal, serial, symposium, catalog, etc.}, date, page(s), volume-issue
`number(s), publisher, city and/or country where published.
`BEUTLER, E. et al. "Marrow Suppression Produced by Repeated Doses of Cladribine",
`Acta Haematol, 1994, pp. 10-15, Vol. 91.
`BEUTLER, E. et al. "Treatment of Multiple Sclerosis and Other Autoimmune Diseases With
`Cladribine", Seminars in Hematology, January 1, 1996, pp. 45-52, Vol. 33, No. 1,
`Supplement 1.
`BEUTLER, E. et al. "The treatment of chronic progressive multiple sclerosis with
`cladribine", Proc. Natl. Acad. Sci. USA, February 1996, pp. 1716-1720, Vol. 93.
`ELLISON, G. et al. "Oral Cladribine for Multiple Sclerosis", Neurology, March 1997,
`P03.070, pp. A174-A175, Vol. 48, No. 3, XP008047069.
`GRIEB, P. et al. "Effect of Repeated Treatments with Cladribine (2-Chlorodeoxyadenosine)
`on Blood Counts in Multiple Sclerosis Patients", Archivum lmmunologiae et Therapiae
`Experimentalis, 1995, pp. 323-327, Vol. 43, No. 5-6.
`KAZIMIERCZUK, Z. et al. "Synthesis of 2'-Deoxytubercidin, 2'-Deoxyadenosine, and
`Related 2'-Deoxynucleosides via a Novel Direct Stereospecific Sodium Salt Glycosylation
`Procedure", J. Am. Chem. Soc., 1984, pp. 6379-6382, Vol. 106, No. 21.
`KURTZKE, J. "Rating neurologic impairment in multiple sclerosis: An expanded disability
`status scale (EDSS)", Neurology, November 1983, pp. 1444-1452, Vol. 33.
`LANGTRY, H. et al. "Cladribine: A Review of its Use in Multiple Sclerosis", Biodrugs, May
`1998, pp. 419-433, Vol. 9, No. 3.
`LASSMANN, H. et al. "Heterogeneity of multiple sclerosis pathogenesis: implications for
`diagnosis and therapy", TRENDS in Molecular Medicine, March 2001, pp. 115-121, Vol. 7,
`No. 3.
`LUBLIN, F. et al. "Defining the clinical course of multiple sclerosis: Results of an
`international survey", Neurology, April 1996, pp. 907-911, Vol. 46.
`LUCCHINETTI, C. et al. "Multiple sclerosis: recent developments in neuropathology,
`pathogenesis, magnetic resonance imaging studies and treatment", Current Opinion in
`Neurology, 2001, pp. 259-269, Vol. 14.
`MATTSON, D. "Update on the diagnosis of multiple sclerosis", Expert Review of
`Neurotherapeutics, May 2002, pp. 319-327, Vol. 2, No. 3.
`
`[ ~~g~~~~~~
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`I
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`I g~~8
`sidered I
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`]
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`*EXAMINER:
`Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance
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`J :\SER \ 125\PTO-Misc\IDS-form .doc/DNB/jps
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`16
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`Substitute for form 1449B/PTO
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
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`(use as many sheets as necessary)
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`\._
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`3
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`Complete It Known
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`Application Number
`Filing Date
`First Named Inventor
`Group Art Unit
`Examiner Name
`Attorney Docket Number SER-125
`
`June 18, 2007
`Giampiero de Luca
`
`"
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`~
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`T2
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`PTO/SB/08B (08-03)
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`U.S. Patent and Trademark Office U.S. DEPARTMENT OF COMMERCE
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`control number
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`Examiner Cite
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`Initials*
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`NON PATENT LITERATURE DOCUMENTS
`Include name of the author (in CAPITAL LETTERS), title of the article, (when appropriate), title of the
`item (book, magazine, journal, serial, symposium, catalog, etc.), date, page(s), volume-issue
`number(s), publisher, city and/or country where published.
`MCDONALD, W. et al. "Recommended Diagnostic Criteria for Multiple Sclerosis: Guidlines
`from the International Panel on the Diagnosis of Multiple Sclerosis", Annals of Neurology,
`July 2001, pp. 121-127, Vol. 50, No. 1.
`MILLER, R. et al. "Therapeutic advances in ALS", Neurology, 1996, pp. S217, Vol. 47,
`Suppl. 4.
`
`NOSEWORTHY, J. et al. "Multiple Sclerosis", The New England Journal of Medicine,
`September 28, 2000, pp. 938-952, Vol. 343, No. 13.
`
`POSER, C. et al. "New Diagnostic Criteria for Multiple Sclerosis: Guidelines for Research
`Protocols", Annals of Neurology, March 1983, pp. 227-231, Vol. 13, No. 3.
`
`RICE, G. et al. "Cladribine and progressive MS: Clinical and MRI outcomes of a
`R17 multicenter controlled trial", Neurology, March 2000, pp. 1145-1155, Vol. 54.
`ROMINE, J. et al. "A Double-Blind, Placebo-Controlled, Randomized Trial of Cladribine in
`Relapsing-Remitting Multiple Sclerosis", Proceedings of the Association of American
`Physicians, January/February 1999, pp. 35-44, Vol. 111, No. 1.
`SCHUMACHER, G. et al. "Problems of Experimental Trials of Therapy in Multiple
`Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in
`Multiple Sclerosis", Annals New York Academy of Sciences, March 31, 1965, pp. 552-568,
`Vol. 122.
`SELBY, R. et al. "Safety and Tolerability of Subcutaneous Cladribine Therapy in
`Progressive Multiple Sclerosis", Can. J. Neural. Sci., 1998, pp. 295-299, Vol. 25.
`
`R18
`
`R19
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`R20
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`SIPE, J. et al. "A neurologic rating scale (NRS) for use in multiple sclerosis", Neurology,
`October 1984, pp. 1368-1372, Vol. 34.
`
`STELMASIAK, Z. et al. "A pilot trial of cladribine (2-chlorodeoxyadenosine) in remitting-
`relapsing multiple sclerosis", Med. Sci Monit., 1998, pp. 4-8, Vol. 4, No. 1.
`
`R21
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`R22
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`R23
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`R24
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`Examiner
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`Considered
`Signature
`Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance
`*EXAMINER:
`and not considered. Include copy of this form with next communication to applicant.
`1 Applicant's unique citation designation number (optional). 2 Applicant is to place a check mark here if English language Translation is attached.
`This collection of information is required by 37 CFR 1.98. The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO
`to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 2 hours to complete, including
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`amount of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and
`Trademark Office, PO. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS.
`SEND TO:
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`If you need assistance in completing the form, call 1-800-PTO-9199 (1-800-786-9199) and select option 2.
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`I Date
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`J: \SER I 125\PTO-Misc\lDS-form. doc/DNB/jps
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`(19) J) Europaisches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`I IIIIIII IIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll llllll llll llll llll
`EP O 626 853 B1
`
`(11)
`
`(12)
`
`EUROPEAN PATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`26.04.2000 Bulletin 2000/17
`
`(21) Application number: 93906071.1
`
`(22) Date of filing: 18.02.1993
`
`(51) Int. Cl.7: A61 K 31/70
`
`(86) International application number:
`PCT/US93/01467
`
`(87) International publication number:
`WO 93/16706 (02.09.1993 Gazette 1993/21)
`
`(54) USE OF SUBSTITUTED ADENINE DERIVATIVES FOR TREATING MULTIPLE SCLEROSIS
`
`Verwendung van substituierten Adeninderivaten zur Behandlung van MultipleSklerose
`UTILISATION DE DERIVES D'ADENINE SUBSTITUEE POUR LE TRAITEMENT DE LA SCLEROSE
`EN PLAQUES
`
`(84) Designated Contracting States:
`AT BE DE DK ES FR GB GR IE IT LU MC NL PT
`SE
`
`(30) Priority: 19.02.1992 US 838546
`
`(43) Date of publication of application:
`07.12.1994 Bulletin 1994/49
`
`(73) Proprietor:
`THE SCRIPPS RESEARCH INSTITUTE
`La Jolla, CA 92037 (US)
`
`(72) Inventor: BEUTLER, Ernest
`La Jolla, CA 92037 (US)
`
`(74) Representative:
`Hedley, Nicholas James Matthew
`Stephenson Harwood
`One, St. Paul's Churchyard
`London EC4M SSH (GB)
`
`(56) References cited:
`EP-A- 0 379 145
`
`• J. CUN. INVEST. vol. 86, no. 5, November 1990,
`pages 1480 - 1488 C.J. CARRERA ET AL 'Potent
`toxicity of 2-chlorodeoxyadenosine toward
`human monocytes in vitro and in vivo.'
`• Science, vol. 154, 1966, p.1044-1046
`• Adv. Exp. Med. Biol., vol. 237, 1988, p.839-42
`• Acta Neurol. Scand., vol. 75, 1987, p.352-355
`• J. Exp. Med., vol. 160, 1984, p.310-316
`• Nervenarzt, vol. 66, 1995, p.299-303
`
`,....
`CD
`M
`LO co
`co
`C\I co
`0
`a.
`w
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
`notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
`a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
`99(1) European Patent Convention).
`
`Printed by Xerox (UK) Business Services
`2.16.7 (HRS)i3.6
`
`18
`
`

`

`EP O 626 853 B1
`
`Description
`
`Technical Field
`
`5
`
`[0001]
`This invention relates to the use of substituted adenine derivatives for the manufacture of a medicament for
`treating multiple sclerosis.
`
`Background of the Invention
`
`10
`
`15
`
`[0002]
`Multiple sclerosis (MS) is the result of demyelination in the brain and spinal cord (central nervous system).
`Symptoms resulting from this demyelination include weakness, visual impairment, incoordination, and paresthesia
`(abnormal tingling). The course of the disease is largely unpredictable, but often progresses through a cycle of exacer(cid:173)
`bation of symptoms followed by remission.
`[0003]
`Conventional treatments presently employ therapy with ACTH or corticosteroids such as prednisone. Con-
`trolled studies suggest that such treatments induce more rapid clearing of acute symptoms and signs but leave the
`long-term outcome of the disease unaffected. Long-term maintenance therapy with ACTH or corticosteroids is contrain(cid:173)
`dicated. Evidence indicates that immunosuppressant agents have no long-term benefit. (Cecil Textbook of Medicine,
`Beeson et al., eds., 15th ed., W.B. Saunders Company, Philadelphia, (1979) page 847)
`[0004]
`The etiology of multiple sclerosis is unknown but is linked to a variety of genetic and environmental factors.
`20 Both cell-mediated and humoral immune responses, triggered by extraneous or autoantigens may contribute to the
`pathogenesis of multiple sclerosis. Certain immune response genes may be associated with an increased susceptibility
`to the disease. The disease may be mediated by T cells that recognize an as yet unidentified autoantigen. For example,
`experimental allergic encephalomyelitis (EAE), an animal model of demyelinating diseases such as multiple sclerosis,
`can be induced by immunizing mice with whole myelin or specific myelin components such as myelin basic protein.
`[0005]
`In humans with multiple sclerosis, exacerbations are correlated with high levels of neopterin in blood and
`cerebrospinal fluid. Neopterin is a factor released from monocytes and macrophages in the presence of activated T(cid:173)
`cells, thereby implicating these cells as being involved in multiple sclerosis exacerbations. (Fredrickson et al. (1987),
`Acta Neurol. Scand., 75:352-355; Huber et al. (1984), J. Exp. Med., 160:310-316). At the microscopic level, monocytes,
`microglial cells (macrophages of the central nervous system) and activated T-cells are found within the demyelinated
`regions of the nerve cells during multiple sclerosis exacerbations. (Cecil Textbook of Medicine (1979), Beeson et al.
`(eds.), W.B. Saunders Co., Philadelphia, PA).
`[0006]
`Various conventional treatment methodologies have been employed to ameliorate the symptoms of multiple
`sclerosis. Many of these are directed to use of palliative, anti-inflammatory agents. No treatment to date has had any
`consistent positive effect on the course of the disease.
`[0007]
`Recently, the art has described the use of specific deoxyribosides as anti-inflammatory agents. For instance,
`U.S. Patent No. 4,481,197 (Rideout et al.) relates to the use of unsubstituted 3-deaza-2'-deoxyadenosine derivatives in
`the treatment of inflammation. U.S. Patent No. 4,381,344 (Rideout et al.) relates to a process for the synthesis of deox(cid:173)
`yribosides that utilizes a bacterial phosphorylase.
`[0008]
`A deoxyriboside derivative, 2-chloro-2'-deoxyadenosine (CdA), has been found to be an effective agent for
`the treatment of chronic lymphocytic leukemia and some T cell malignancies. (Carson et al. (1984) Proc. Natl. Acad.
`Sci. U.S.A., fil.:2232-2236; Piro et al. (1988), Blood 72:1069-1073) The pharmacokinetics of orally and subcutaneously
`administered 2-chloro-2'-deoxyadenosine in the treatment of chronic lymphocytic leukemia have been described and
`compared. (Liliemark et al. (1992) Journal of Clinical Oncology, 1Q, (10): 1514-1518; Juliusson et al. (1992) Blood, 80
`(Suppl. 1): 1427) Chronic lymphocytic leukemia is a malignancy of B lymphocytes that bear the Leu-I surface antigen.
`[0009]
`The Leu