8299539
`
`September 28, 2022
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`OF:
`
`APPLICATION NUMBER: 11/722,018
`FILING DATE: June 18, 2007
`PATENT NUMBER: 7713947
`ISSUE DATE: May 11, 2010
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 1 of 822
`
`

`

`June 18, 2007
`
`PRELIMINARY AMENDMENT
`Patent Application
`Docket No. SER-125
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant
`
`:
`
`Giampiero de Luca
`
`
`
`Docket No.—: SER-125
`
`For
`
`:
`
`Cladribine Regimen for Treating Multiple Sclerosis
`
`Mail Stop PCT
`Commissionerfor 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:
`
`JASER\125\Amd-Resp\PreAmd.doe/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 2 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 2 of 822
`
`

`

`2
`
`Docket No. SER-125
`Patent Application
`
`In the Specification
`
`Please insert the following new paragraphafter the Title of the invention on page 1, line 1:
`
`Cross-Reference to Related Application
`This application is the U.S. national stage applicationofInternational Patent Application No.
`
`PCT/EP2005/056954, filed December 20, 2005, which claimsthe 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, includingall figures, tables and amino acid or nucleic
`
`acid sequences.
`
`After page 31: Please insert as new page 32 the attached Abstract of the Disclosure.
`
`JASER\125\Amd-Resp\PreAmd.doo/DNB/si
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 3 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 3 of 822
`
`

`

`3
`
`In the Claims
`
`Docket No. SER-125
`Patent Application
`
`1-17 (canceled).
`
`18 (new).
`
`A methodoftreating 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)
`
`an induction period whereinsaid 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;
`
`(i1)
`
`(iii)
`
`a cladribine-free period wherein no cladribine formulation is administered;
`
`a maintenance period wherein said cladribine formulation is administered and
`
`whereinthetotal dose of cladribine reached at the end of the maintenanceperiod is
`
`lower thanthe total dose of cladribine reachedat the endof the inductionperiod(i);
`
`and
`
`(iv)|acladribine-free period wherein no cladribine formulation is administered.
`
`The methodaccording to claim 18, wherein the induction periodlasts up to 4
`19 (new).
`months, or up to 3 months, or up to 2 months.
`
`20 (new).
`months.
`
`21 (new).
`months.
`
`22 (new).
`months.
`
`The method accordingto claim 19, wherein the induction periodlasts up to 2
`
`The method accordingto claim 18, wherein the induction periodlasts up to 2
`
`The method accordingto claim 18, wherein the induction periodlasts up to 4
`
`JASER\I25\Amd-Resp\PreAmd.doce/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 4 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 4 of 822
`
`

`

`4
`
`Docket No. SER-125
`Patent Application
`
`23 (new).
`
`The method according to claim 19, whereinthe inductionperiod lasts up to 4
`
`months.
`
`24 (new).
`
`The method according to claim 18, wherein the total dose of cladribine
`
`reachedat 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.
`
`The method accordingto claim 18, wherein the cladribine-free periodlasts up
`26 (new).
`to 10 months, or up to 9 months, or up to 8 months.
`
`27 (new).
`lasts up to 10 months.
`
`The method according to claim 18, wherein the cladribine-free (iv) period
`
`The method accordingto claim 18, wherein the maintenanceperiodlasts up to
`28 (new).
`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
`
`reachedat the end of the maintenance period is 1.7 mg/kg.
`
`The method according to claim 18, wherein the formulationis to be orally
`30 (new).
`administered following the sequential steps below:
`
`(i)
`
`an induction period wherein said cladribine formulation is orally administered and
`wherein the total dose of cladribine reachedat the endofthe inductionperiodis from
`1.7 mg/kg to 3.5 mg/kg;
`
`accladribine-free period wherein no cladribine formulation is administered;
`(ii)
`(ili)|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
`
`JASER\125\Amd-Resp\PreAmd.doc/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 5 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 5 of 822
`
`

`

`5
`
`Docket No. SER-125
`Patent Application
`
`lower than the total dose of cladribine reached at the end of the induction period (1);
`
`and
`
`(iv)
`
`acladribine-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 (i1) lasts up to 10 months, or up to 8 months or up to 10 months; the
`
`maintenanceperiod(iii) lasts up to 2 months; the cladribine-free period (iv) lasts up to 10 months;
`
`the total dose of cladribine reached atthe end of the maintenance period is 1.7 mg/kgandsteps(iii)
`
`to (iv) are repeated performedone, twoorthree times.
`
`31 (new).
`
`The method according to claim 30, wherein the total dose of cladribine
`
`reachedat the end ofthe induction period is 3.5 mg/kg andthe total dose ofcladribine reached at the
`
`end of the maintenance period is 1.7 mg/kg.
`
`32 (new).
`
`The method according to claim 30, wherein the formulationis to be orally
`
`administered at a daily dose of 3 to 30 mgcladribine.
`
`33 (new).
`
`The method accordingto claim 32, wherein the pharmaceutical formulationis
`
`to be orally administered at a daily dose of 10 mg cladribine.
`
`34 (new).
`
`The method according to claim 18, wherein the pharmaceutical formulationis
`
`orally administered 1 to 7 days per month during the inductionperiod.
`
`The method accordingto claim 18, wherein thesteps(iii) to (iv) are repeated
`35 (new).
`at least one or two times.
`
`36 (new).
`
`The method according to claim 18, wherein said cladribine formulationis to
`
`be administered in combination with interferon-beta.
`
`JASER\125\Amd-Resp\PreAmd.dod¢/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 6 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 6 of 822
`
`

`

`6
`
`Docket No. SER-125
`Patent Application
`
`37 (new).
`
`The method according to claim 30, whereinsaid cladribine formulationis to
`
`be administered in combination with interferon-beta.
`
`JASER\125\Amd-Resp\PreAmd.doc/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 7 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 7 of 822
`
`

`

`7
`
`Remarks
`
`Docket No. SER-125
`Patent Application
`
`The Commissioner is hereby authorized to charge any fees under 37 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
`
`JASER\125\Amd-Resp\PreAmd,doc/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 8 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 8 of 822
`
`

`

`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 preparationis to
`
`5
`
`be orally administered and wherein re-treatments are possible.
`
`JASER\125\PTO-Misc\abstract.dac/DNB/s!
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 9 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 9 of 822
`
`

`

`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:
`
`Regular (National Stage)
`
`Utility
`
`None
`
`None
`
`None
`
`None
`
`None
`
`No
`
`No
`
`None
`
`CLADRIBINE REGIMEN FOR TREATING MULTIPLE
`SCLEROSIS
`
`Attorney Docket Number::
`
`SER-125
`
`Request for Early Publication::
`
`Request for Non-Publication::
`
`Suggested Drawing Figure::
`
`Total Drawing Sheets:
`
`Smali Entity?::
`
`Petition included?::
`
`Petition Type::
`
`Secrecy Order in Parent Appl.?::
`
`No
`
`No
`
`None
`
`None
`
`No
`
`No
`
`N/A
`
`No
`
`1/3
`
`iti
`
`Petitioner TWIP iarins., Inc.
`EX1003, Page 10 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 10 of 822
`
`

`

`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::
`
`Inventor
`
`Italy
`
`Unknown
`
`Giampiero
`
`DE LUCA
`
`Conches/Geneva
`
`Switzerland
`
`Street of Mailing Address::
`
`Chemin des Conches 15B
`
`City of Mailing Address::
`
`Conches/Geneva
`
`Country of Mailing Address::
`
`Switzerland
`
`Postal or Zip Code of Mailing Address::
`
`CH-1231
`
`Representative Information
`
`Representative Customer Number::
`
`000023557
`
`CorrespondenceInformation
`
`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
`.
`Petitioner TWi Pharms., Inc.
`EX1003, Page 11 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 11 of 822
`
`

`

`APPLICATION DATA SHEET
`
`Docket No. SER-125
`
`Domestic Priority Information
`
`Application::
`
`Continuity Type::
`
`Parent Application::
`
`Parent Filing Date::
`
`This application is a
`
`National Stage of
`
`PCT/EP2005/056954
`
`December20, 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::
`
`Laboratoires Serono S.A.
`
`Street of Mailing Address::
`
`Zone Industrielle de l’Ouriettaz
`
`City of Mailing Address::
`
`Country of Mailing Address::
`
`Aubonne
`
`Switzerland
`
`Postal or Zip Code of Mailing Address::
`
`CH-1170
`
`3/3
`
`Petitioner TW harms., Inc.
`EX1003, Page 12 of 822
`
`06/18/2007
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 12 of 822
`
`

`

`PCT/EP2005/056954
`
` Vill-4-1 |Declaration: Inventorship (only for
`
`the purposes of the designation of
`the United States of America)
`Declaration of Inventorship (Rules
`4.17(iv) and 51bis.1(a){iv)) for the
`purposesof the designation of the
`United States of America:
`
`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-
`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
`"Prior Applications", by application
`number, country or Member of the World
`Trade Organization, day, month, and year
`of filing, any application for a patent
`er inventor's certificate filed ina
`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.
`VIH-4-1-|Prior applications:
`60/638,669, US, 22 December 2004
`1
`(22.12.2004)
`;04106909.7, EP, 22
`
`December 2004 (22.12.2004)
`
`
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 13 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 13 of 822
`
`

`

`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.
`
`
`
`Vitl-4-1-
`
`Name (LAST, First)
`DE LUCA, Giampiero
`1-1
`
`2 ” (ayondeither US State,if applicable, Conches, Switzerland
`
`or country)
`
`Vill-4-1- {Mailing address:
`Chemin de Conches 15B 1231 Conches
`3
`Switzerland
`
`1-4
`VINI-4-1-
`|Citizenship:
`IT
`
` Vill-4-1-
`[Inventor's Signature:
`4-5
`(if not contained in the request, orif
`declaration is corrected or added under
`Rule 26ter afterthe filing of the
`international application. The signature
`mustbe thatof the inventor, not that of
`
`the agent)
`1-6 (of signature which is not contained in
`
`Vill-4-1-
`
`/Date:
`
`the request, or of the declaration thatis
`corrected or added under Rule 26ter
`after the filing of the international
`application)
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 14 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 14 of 822
`
`

`

`June 18, 2007
`
`INFORMATION DISCLOSURE
`STATEMENT
`Patent Application
`Docket No. SER-125
`
`IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`Applicant
`
`Filed
`
`For
`
`:
`
`:
`
`:
`
`Giampiero de Luca
`
`June 18, 2007
`
`Cladribine Regimen for Treating Multiple Sclerosis
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313
`
`INFORMATION DISCLOSURE STATEMENT
`UNDER37 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 copyof each cited referenceis 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 37 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.
`
`JASER\L25\PTO-Misc\lDS.doc/DNB/jps
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 15 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 15 of 822
`
`

`

`PTO/SB/08A (08-03)
`Approved for use through 07/31/2006. OMB 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 respondto a collection of information unless it contains a valid OMB
`control number.
`
`Substitute for form 1449A/PTO
`
`INFORMATION DISCLOSURE
`STATEMENTBY APPLICANT
`
`(use as many sheets as necessary)
`
`
`Complete if Known
`Application Number
`
`Piling Date
`June 18, 2007
`First Named Inventor
`Giampiero de Luca
`Art Unit
`
`Examiner Name
`
`
`Examiner
`initials*
`
`No
`
`Document Number
`Number- Kind Code’
`known
`
`(if
`
`U.S. PATENT DOCUMENTS
`Publication Date
`Nameof Patentee or Applicant
`MM-DD-YYYY
`of Cited Document
`
`Pages, Columns, Lines, Where
`Relevant Passages or Relevant
`Figures Appear
`
`Attorney Docket Number
`
`SER-125
`
`1 2
`
`|usjus
`Cc w
`
`4 5 6 7 8 9
`
`puss
`US:
`re
`U
`
`
`
`Pages, Columns, Lines
`Where Relevant Passages
`or Relevant Figures Appear
`
`A A
`
`WO 04/087101 A2
`
`10/14/2004
`
`EP 0 626 853 B1
`
`04/26/200
`
`The Scripps
`ResearchInstitute
`
`
`
`Examiner
`Signature
`
`Date
`Considered
`
`Initial if reference considered, whether or not citation is in conformance with MPEP 608. Drawline through citation if not in confarmance and not
`*EXAMINER:
`considered.
`include copy of this form with next communication to applicant. * Applicant's uniquecitation designation number(optional), ? See Kind Codes of
`USPTO Patent Documents at www.uspto.gov or MPEP901.04.
`* Enter Office that issued the document, by the two-letter cade (WIPO Standard 1.3).
`* For
`Japanese patent documents, the indication of the year of the reign of the Emperor must precede the serial number of the patent document.
`° Kind of document by
`the appropriate symbols as indicated on the document under WIPO Standard ST. 16 if possible.
`° Applicant is to place a check mark here if English language
`Transiation 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 public whichistofile (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 theindividual case. Any comments
`on the amountof 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:
`Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`if you need assistance in completing the form, call 1-800-PTO-9199 (1-800-786-9199) and selectoption 2.
`
`JASER\I25\PTO-Misc\[DS-form.doc/DNB/jps
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 16 of 822
`
` 1
`
`initiais*
`TPTETET|1|7m)7NFOFOrfe[oo[PS=
`
`Examiner
`
`Cite
`No!
`.
`
`FOREIGN PATENT DOCUMENTS
`
`Foreign Patent Document
`a
`Publication Date
`MM-DD-YYYY
`
`Country Goede?
`
`- Number ‘4 - Kind Gode'(if knawn
`
`Name of Patentee or
`Applicant of Cited Document
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 16 of 822
`
`

`

`Examiner
`Initials*
`
`Cite
`No. '
`
`(when appropriate), title of the
`Include nameof the author (in CAPITAL LETTERS), title of the article,
`item (book, magazine, journal, serial, symposium, catalog, etc.), date, page(s), volume-issue
`i
`i
`published.
`
`2
`
`Ro
`
`
`
`PTO/SB/08B (08-03)
`Approvedfor use through 07/31/2006. OMB 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 OMB
`control number.
`
`
`omplete if Known
`Substitute for form 1449B/PTO
`
`
`
`Application Number
`
`
`INFORMATION DISCLOSURE
`
`
`
`
`June 18, 2007
`Filing Date
`
`STATEMENT BY APPLICANT
`
`
`Giampiero de Luca
`First Named Inventor
`
`
`Group Art Unit
`
`(use as many sheets as necessary)
`Examiner Name
`
`Attorney Docket Number
`
`
`4
`
`
`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 a/. “Oral Cladribine for Multiple Sclerosis”, Neurology, March 1997,
`P03.070, pp. A174-A175, Vol, 48, No. 3, XP008047069.
`
`
`GRIEB, P. etal. “Effect of Repeated Treatments with Cladribine (2-Chlorodeoxyadenosine)
`
`on Blood Counts in Multiple Sclerosis Patients’, Archivum Immunologiae et Therapiae
`
`Experimentalis, 1995, pp. 323-327, Vol. 43, No. 5-6.
`
`KAZIMIERCZUK, Z. ef 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 impairmentin multiple sclerosis: An expanded disability
`
`status scale (EDSS)", Neurology, November 1983, pp. 1444-1452, Vol. 33.
`
`
`LANGTRY, H. et a/. “Cladribine: A Review of its Use in Multiple Sclerosis”, Biodrugs, May
`1998, pp. 419-433, Vol. 9, No. 3.
`
`
`LASSMANN, H. ef a/. “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 a/. “Defining the clinical course of multiple sclerosis: Results of an
`
`international survey”, Neurology, April 1996, pp. 907-911, Vol. 46.
`
`
`
`LUCCHINETTI, C. ef a/. “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.
`
`
`
` SER-125 NON PATENT LITERATURE DOCUMENTS
`
`awo
`
`aESE
`
`or)
`
`A~
`
`R10
`
`ys]
`
`=
`
`
`
`
`
`Date
`Examiner
`
`Considered
`Signature
`if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if net
`Initial
`*EXAMINER:
`in conformance
`and not considered. Include copyof this form with next communication to applicant.
`* Applicant's uniquecitation designation number (optional).
`* Applicantis to place a check mark hereif 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 whichis 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 theindividual 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, PO. Box 1450, Alexandria, VA 22313-1450.
`DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS.
`SEND TO:
`Commissionerfor Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`if you need assistance in completing the form, call 1-800-PTO-9199 (1-800-786-9199) and select option 2.
`Petitioner TWi Pharms., Inc.
`EX1003, Page 17 of 822
`
`J:\SER\125\PTO-Misc\IDS-form.doc/DNB/jps
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 17 of 822
`
`

`

`PTO/SB/08B (08-03)
`Approved for use through 07/31/2008. OMB 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 OMB
`control number
`
`Substitute for form 1449B/PTO
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`(use as many sheets as necessary)
`
`
`
`Application Number
`June 18, 2007
`Filing Date
`First Named Inventor
`Giampiero de Luca
`
`Group Art Unit
`Examiner Name
`
`
`
`
`
`
`
`
`eeeee
`
`Attorney Docket Number|SER-125
`
`NON PATENT LITERATURE DOCUMENTS
`
`(when appropriate), title of the
`Include nameof the author (in CAPITAL LETTERS), title of the article,
`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 a/. “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. ef a/. “Therapeutic advances in ALS”, Neurology, 1996, pp. S217, Vol. 47,
`Suppl. 4.
`
`
`
`
`
`
`
`Examiner
`Initials”
`
`Cite
`No. |
`
`2 3
`
`2 4
`
`2 a
`
`2 m
`
`2 5
`
`2 ©
`
`R.N oO
`
`2
`
`=
`
`NOSEWORTHY, J. ef a/. "Multiple Sclerosis”, The New England Journal of Medicine,
`September 28, 2000, pp. 938-952, Vol. 343, No. 13.
`
` POSER, C. et a/. “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 a/. “Cladribine and progressive MS: Clinical and MRI outcomes of a
`multicenter controlled trial’, Neurology, March 2000, pp. 1145-1155, Vol. 54.
`ROMINE, J. ef a/. “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 Evaiuation of Experimental Trials of Therapy in
`Multipie 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 Therapyin
`Progressive Multiple Sclerosis”, Can. J. Neurol. Sci., 1998, pp. 295-299, Vol. 25.
`
`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 a/. “A pilot trial of cladribine (2-chlorodeoxyadenosine) in remitting-
`
`relapsing multiple sclerosis’, Med. Sci Monit., 1998, pp. 4-8, Vol. 4, No. 1. a22
`z2 ao
`
`vy]23
`
`
`
`
`
`Date
`Examiner
`Considered
`Signature
`if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not
`Initial
`*EXAMINER:
`and not considered. Include copy of this form with next communication to applicant.
`* Applicant's unique citation designation number(optional).
`* Applicantis 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 whichisto 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
`amountof 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:
`Commissionerfor Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`if you need assistance in completing the form, call 1-800-PTO-9199 (1-800-786-9199) and select option 2.
`
`in conformance
`
`}\SERM25\PTO-Mise\IDS-form,doc/DNB/jps
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 18 of 822
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 18 of 822
`
`

`

`Original Paper
`spe
`Acta Haematol 1994;91:10-15
`
`
`
`Repeated Dosesof Cladribine
`
`Marrow Suppression Producedby
`
`Department of Molecular and
`Experimental Medicine,
`The Scripps ResearchInstitute,
`LaJolla, Calif., USA
`
`Key Words
`Aplastic anemia
`2-Chlorodeoxyadenosine
`Stem cell
`Thrombocytopenia
`Toxicity
`
`eae e cece chee cece cease pO REO Dees e ED ansneesHSEenSseHeussoesessossacrasassosasseseusesssenseeseseaees
`Abstract
`2-Chlorodeoxyadenosine (cladribine, Leustatin®) is being used extensively in .
`the treatment of hematologic malignancies, but relatively little is known re
`gardingits toxicity to the normal marrow. Long-term serial hematologic obser
`
`vations have been made on 29 patients with multiple sclerosis undergoing ex-
`perimental therapy with monthly courses of cladribine, each ofwhich consisted ::
`of 0.087-0.1 mg/kg per day for 7 days. The characteristic hematologic responses
`of the patients consisted of acute transient monocytopenia, prolonged, pro-
`found lymphopenia especially of CD4-positive cells, and modest lowering of %
`the granulocyte count and hemoglobin with development of long-lasting mac-
`rocytosis. Two patients developed severe aplastic anemia, requiring transfu- |
`sionboth ofred cells andplatelets. One of these had previously received exten- 2
`sive therapy with chlorambucil, while the other had received carbamazepine
`(Tegretol®) and was ingesting phenytoin (Dilantin®) at the time of cladribine e
`therapy. Both patients recoveredafter scveral months of marrow suppression.
`see ccercseencenesond
`
`
`
`
`
`mostof the patients given cladribine suffered from hema- =
`tologic malignancy with marrow involvement orhad previ-
`2-Chlorodeoxyadenosine (cladribine, Leustatin®) is a
`remarkably effective and, in most patients, relatively non-
`ously received extensive marrow-suppressive therapy, it
`toxic deoxyadenosine analogue that has recently been li-
`has always been difficult to ascertain whether marrow hy-=.
`censedfor the treatment of hairy cell leukemia. While pa-
`
`poplasia, whenit occurred, was due to the drug orto thes
`tients with hairy cell leukemia generally respondto a sin-
`basic disease andits prior treatment.
`gle course of treatment with cladribine, other lymphoid
`Wehave nowhadthe opportunity to study the effect of
`disorders such as low-grade lymphomaand chronic lym-
`
`the administrationof cladribine to 29 hematologically nor-
`phocytic leukemiaare also responsive to this drug, butsev-
`
`eral courses of therapy, typically given a month apart, are mal paticnts being treated experimentally for chronic pro-
`
`generally required to achieve remission[1].
`gressive multiple sclerosis in the course of a double-blind
`
`crossover study. Two patients developedsevere, long-last-
`The existence of stemcell toxicity giving rise to throm-
`
`bocytopenia, and to a lesser extent anemia and leukope-
`ing but reversible marrow hypoplasia, while 6 other pa-
`
`thrombocytopenia,
`nia, was recognized early in our investigations of this drug,
`tients developed moderate anemia,
`
`and neutropenia.
`and tended to occur in an idiosyncratic manner. Since
`
`.
` ¢
`d
`d
`P
`i.
`ci
`e
`Pp
`.
`>
`
`
`Lncst Beutler, MD
`Received:
`©19948, Karger AG, Basel
`November £1, 1993
`Department of Molecular and Experimental Medicine
`Accepted:
`The Scripps ResearchInstitute
`December 17, 1993
`Inc:
`seoeonposaisayPetitioner TWi Pharms.,
`
`
`|&
`E
`.
`
`
`
`Petitioner TWi Pharms., Inc.
`EX1003, Page 19 of 822
`
`

`

`
`
`
`
`
`
`
`
`Fig. t. The effect of the administration ofsix courses of cladribinc, each consisting of 7 days of 0.087 mg/kg/day, on
`the hemoglobin level, MCV ofthe red cells, platelet count, and absolute lymphocyte count ofpatients 14. These pa-
`tients were in the group in which there was 3-year follow-up. The bars represent one standard error.
`
`Treatment Protocol
`
`Methods and Results
`
`All patients were hematologically normal adults with chronic pro-
`vressive multiple sclerosis. Cladribine was administered by contin-
`uous infusion through « Portacath® (Bard Access Systems, MRIPort,
`Cranston, R.I., USA) for 7 days. Patients 1-4 received six cycles of
`drug, 1 month apart, each cycle consisting of 0.087 mg/kg/day for 7
`days. Patients 5 and 6 received3 cycles of 0.087 mg/kg/day for 7 days:
`Patient 7 wasgiven 0.1 mg/kg/dayin five 7-day cycles, 1 month apart,
`and patients 8-29 were placed ona protocol consisting of only 4 such
`cycles. Amongtheselatter 22 patients, drug therapy was stoppedin I
`case because ofafall in the platelet count after only two courses. A
`complete blood count and a chemistry panel were obtained on each
`patient before each infusion of drug. Age, sex, and diseasc severity-
`matched multiple sclerosis patients were matched to patients 7-29,
`and were givensaline placcbo. Hematologic values obtained on these
`patients servedas control values relative to patients 7-29.
`
`The effect of cladribine on the blood counts of-patients
`1-4, who received six coursesof drug, is shown in figures 1
`and 2. Monocyte counts were measured only during the
`first cycle of drug administration, since in subsequent cy-
`cles daily blood counts were not obtained. Relatively strik-
`ing macrocytosis, persisting in some cases for over 3 years
`