PTO/SB/OS (08-08)
`Approved for use through 06/30/2010. OMB 0651-0032
`U.S. Patent and Trademark Office. US. DEPARTMENT OF COMMERCE
`
`a”
`
`Under the Paperwork Reduction Act of 1995. no persons are recuired to respond to a collection of Information unless it diswlavs a v lid OMB control number
`UTILITY
`g"WWW 000th NO-
`
`21593210002/JMC/1VIRG/U-S
`
`First/nvenror
`
`MawtyesELUKASiIEV
`
`PATENT APPLICATION
`TRANSMITTAL
`
`(Only for new nonprovisional applications under 3? CFR 1. 53(b))
`
`APPLICATION ELEMENTS
`
`See MPEP chapter 600 concerning utility patent application contents............................................. ‘33“,3
`
`
`
`ADDRESS TO:
`
`Commissioner for Patents
`P.o. Box1450
`
`
`Alexandria VA 2231 3_1 4507777
`
`7777
`
`,
`
`1. E] Fee Transmittal Form (69., PTO/$811 7)
`2.
`A I‘ ant cl
`'
`ll
`‘
`.
`[:1 8:: g7 CFRartgsma entIty status
`Specification
`[Total Pages 3 8
`Both the claims and abstract must start on a new page
`(For Information on the preferred arrangement, see MPEP 60 01(a))
`
`.._i
`
`3.
`
`[Total Sheets
`4.-- Drawing(s) (35 U.S..C 113)
`[Total Sheets 2
`5. Oath or Declaration
`a. - Newly executed (original or copy)
`b.
`A copy from a préor application (37 CFR 1.63(d))
`for continuation/divisional with Box 18 completed)
`DELETION OF |NVENTOR(S)
`Signed statement attached deleting inventodsl
`name in the Prior application, see 37 CFR
`1-63id)(2) and 1-33ibi-
`
`i.
`
`‘3
`
`=
`
`ACCOMPANX!NGAEPLICAT'ON PARTS
`9. DAssignment Papers (cover sheet (PTO-1595) & document(s)’,
`Name Of ASSIgnee_BlptsgpldecMMA Inc‘
`
`___________________
`
`]
`
`‘ 10. E] 37 CFR 3.73(b) Statement
`(when there is an ass/ghee)
`
`CI ?ower of
`Attorney
`
`11. |:| English Translation Document (if applicable)
`
`12.
`
`Infowtion Disclosure Statement (PTO/SB/Os or PTO-1449)
`Copies of foreign patent documents,
`publications, & other information
`
`6.
`ApplicatIon Data Sheet. See 37 CFR 1.76
`7. E] CD-ROM or CD-R In dupIIcate, large table or
`pggzggfigrzmelgpggndix)
`8. Nucleotide and/or Amino Acid Sequence Submission
`(if applicable, items a. — c. are required)
`a. El Computer Readable Form (CRF)
`16. [:1 Nonpublication Request under 35 U.S.C. 122(b)(2)(B)(i).
`b.
`Specification Sequence Listing on:
`Applicant must attach form PTO/SB/35 or equivalent.
`17 - Other Authorization under 37 CFR 1.136(a)(3)
`27E ngROM or CD-R (2 COPIGSIO
`-mem
`er
`
`See 1 in Addendum
`c. D Statements verifying Identity of above copies
`18. If a CONTINUING APPLICATION, check appropriate box and supply the requisite information below andIn the first sentence of the
`I specification following the ti‘,tle or in an Application Data Sheet under 37 CFR 1 76:
`‘
`
`13_
`Preliminary Amendment
`14 :1 Return Receipt Postcard (MPEP 503)
`(Should be specifically itemized)
`
`15. D Certified Copy of Priority Document(s)
`(if foreign priorityIs claimed)
`
`5
`
`
`
`Continuation
`Prior application information:
`
`E] Divisional
`Examiner
`
`I: Continuation-in-part(ClP)
`JOhn D. ULM
`
`m
`
`12/526 296
`ofprior application No.: ..............9. ..................
`A” Unit'1649
`
`The address associated with Customer Number:
`
`77771779 CORRESPQNBENCE ASDRESS
`“mm“..................,
`53644
`;
`
`{
`
`OR El Correspondence address below
`
`,,;,,,JJAAAAE;
`.,,,,,,,,,,
`
`wStatew
`
`Marsha A. Rose
`
`This collection of information is required by 37 CFR 1.53(b). 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 1.11 and 1.14. This collection is estimated to take 12 minutes 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,
`US. Patent and Trademark Office, US. Department of Commerce, PO. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
`FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.0. Box 1450, Alexandria, VA 22313-1450.
`Ifyou need assistance in completing the form, call 1-800-PTO-9199 and select option 2.
`
`1482745
`Page 1 of 150
`
`Biogen Exhibit 2204
`Mylan v. Biogen
`IPR 2018-01403
`
`Biogen Exhibit 2204
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 150
`
`

`

`Addendum
`
`1. Authorization to Permit Access to Application by Participating Offices (PTO/SB/39);
`
`2.
`
`Certification and Request for Prioritized Examination Under 37 CFR. § 1.102(e);
`
`3. Request for Transfer of a Computer Readable Form Under 37 CFR 1.821(6);
`
`4. First Supplemental Information Disclosure Statement;
`
`5.
`
`Second Supplemental Information Disclosure Statement;
`
`6. Third Supplemental Information Disclosure Statement.
`
`Page 2 of 150
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`Page 2 of 150
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`

`

`Doc Code: TRACK1.REQ
`Document Description: TrackOne Request
`
`PTO/SB/424 (12-11)
`
`
`CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`
`
`
`.
`'
`N
`"
`IA I'
`'
`N
`"f
`
`
`-Matvey E. LUKASHEV WW ppm“ ”met"
`To be aSSIgned
`known):
`
`
`Treatment for Multiple Sclerosis (As Amended)
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`UNDER 37 CFR 1.102(e) (Page 1 of1)
`
` I
`
`3
`
`1. The processing fee set forth in 37 CFR 1.17ti), 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:
`
`if Or.iinal Au‘lication Track One - riiiei nder
`
`
`
` s1.102g§;m
`
`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. An executed oath or declaration under 37 CFR 1.63 is filed with the application.
`
`
`
`2
`Re :uest for Continued Examination - Prioritized Examination under
`
`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 1.102(e)(2).
`
`5
`
`'
`
`
`...._.\'......................
`\\\\\
` Sianature *
`‘\“"
`
`Name Marsha AR
`:Print/Twedt
`
`
`
`
`‘\
`“\“° “
`“
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`\
`3‘
`
`088..
`
`Date
`
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`<\\“ 3
`
`
`- \\\‘
`
`5
`
`E Practitioner
`RGQIS‘Fat'OnNumber58’403
`
`Note: Signatures of all the inventors or assignees of record of the entire interest or their representative(s) are required in accordance with
`37 CFR 1.33 and 11.18. Please see 37 CFR 1.4(d) for the form of the signature. If necessary, submit multiple forms for more than one
`si'nature, seebeIOW*
`
`
`*Total of“:
`
`forms are submitted.
`
`Page 3 of 150
`
`Page 3 of 150
`
`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of:
`
`LUKASHEV et al.
`
`1 Confirmation No.: To be assigned
`
`Art Unit: To be assigned
`
`Appl. No.: To be assigned
`
`Examiner: To be assigned
`
`(Continuation oprpl. No. 12/526,296; § 371(c)
`Date: January 13, 201])
`Filed: Herewith
`
`:
`
`For: Treatment for Multiple Sclerosis (As
`
`Amended)
`
`Atty. Docket: 2159.3210002/JMC/MRG/U-S
`
`Authorization to Treat a Reply as Incorporating an
`Extension of Time {Inder 37 C.F.R. § 1.136(a)(3)
`
`Commissioner for Patents
`
`PO Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`The US. Patent and Trademark Office is hereby authorized to treat any concurrent or future
`
`reply that requires a petition for an extension of time under this paragraph for its timely submission,
`
`as incorporating a petition for extension of time for the appropriate length of time. The US. Patent
`
`and Trademark Office is hereby authorized to charge all required extension of time fees to our
`
`Deposit Account No. 19-003 6, if such fees are not otherwise provided for in such reply.
`
`Respectfully submitted,
`
`STERNE, KESSLER, GOLDSTEIN & Fox P.L.L.C.
`
`
`
`Marsha A. Rose
`
`Attorney for Applicants
`Registration No. 58,403
`
`
`
`1100 New York Avenue, NW.
`Washington, DC. 20005-3934
`(202) 371-2600
`
`1474795__,_1.Docx
`
`Page 4 of 150
`
`Page 4 of 150
`
`

`

`7M
`
`APPLICATION DXTA SHEET
`
`M.
`
`MW.
`
`W‘WWMW
`
`Stylesheet Version V14.1
`
`eMc
`
`Applicant Information
`
`Applicant Authority Type
`
`an
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`oo
`
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`4V.mmam.mmf\H.whhaNNMRo\Nn«I.mNeffWe»SN.\\m0”mennwootUmn.ueM.umnnmWe
`
`
`rCWetV.lBWau.0\\WM“\cwWkWV.1.1ait0h..“.\nMEWmCGMFCSCmy.mum.E\
`
`3
`
`Address-l 0f Mailing Address
`
`3 Address-2 of Mailing Address
`
`City of Mailing Address
`
`State of Mailing Address
`
`Postal Code of Mailing Address
`
`Country of Mailing Address
`
`Page 5 of 150
`
`\\§\\\{3r.kéi.riixiiiiiiitiéité‘é45xiii»it‘é.{xixééééxéééé<a);<>§§<>i¥éis$3.2»
`
`Inventor
`
`RU
`
`Matvey
`E.
`
`LUKASHEV
`
`Tewksbury
`MA
`
`US
`
`3 Louis Road
`
`Tewksbury
`MA
`
`01876
`
`rsmnI
`
`UG
`
`m0mSfl
`
`LmEN0
`
`Medford
`
`MA
`
`US
`
`17 Grove Street
`
`Medford
`
`MA
`
`Page 5 of 150
`
`
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`Postal Code of Mailing Address:
`
`Country of Mailing Address:
`Phone:
`
`Fax:
`
`E-mail:
`
`
`02155
`
`US
`
`3 Correspondence Information:
`Customer Number:
`
`53644
`
`*53644*
`
`Application Information:
`
`Title of Invention:
`
`Treatment for Multiple
`Sclerosis
`
`Application Type:
`
`regular, utility
`
`Attorney Docket Number: 2159.3210002/JMC/MRG/U-S
`
`Botanic Information:
`
`Publication Information:
`
`Suggested Figure for Publication -
`Suggested Classification -
`Suggested Technology Center -
`Total Number of Drawing Sheets - 4
`
`Representative Iifiornzation:
`
`Domestic Priority Information:
`
`This is a Continuation of US application number 12/526,296, having 21 § 371(c) date of 201 1-01-
`13, now pending.
`
`: US application number 12/526,296, having a § 371(c) date of2011-01-13, is the National Stage
`of international application number PCT/U82008/001602, filed 2008-02-07, which claims the
`benefit of US provisional application number 60/888,921, filed 2007-02—08.
`
`
`Foreign Priority Information:
`
`
`
`
`.9MmWWMWWWWWWWWWMM/wm<mmmvmWU/,,.........V.....,.,.,.V.,.V.V.,V.,:,,,,,,,,,,.,ataWtywwwwwwwwmv”awMN
`
`i
`
`Page 6 of 150
`
`Page 6 of 150
`
`

`

`
`
`i ASStgnee Informatlon:
`
`Assignee 1:
`
`Grganization Name:
`
`Biogen Idee MA Inc.
`
`Address-1 of Mailing Address:
`' Address-2 of Mailing Address:
`
`14 Cambridge Center
`
`City of Mailing Address:
`
`Cambridge
`
`3 State of Mailing Address:
`
`MA
`
`Postal Code of Maiiing Address: 02142
`
`Country of Mailing Address:
`Phone:
`
`US
`
`1 Fax:
`
`E-mali
`
`Respectfully submitted,
`
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
`’3
`...~\‘
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`
`
`
`Marsha A. Rose
`
`Attorney for Applicants
`Registration No. 58,403
`
`\3
`S w M § N,
`
`
`xv“:
`\fesfiv’ a W
`
`Date
`
`1100 New York Avenue, NW.
`Washington, DC. 20005-3934
`(202) 371—2600
`
`1474797___1.DOCX
`
`Page 7 of 150
`
`Page 7 of 150
`
`

`

`‘ "'i'thfib‘i‘fiifiififl"DECEKRLKTKQN‘EN?)"FG‘WER‘GF‘KXTCERNEY'
`
`"""'
`
`‘
`
`Attorney’s Docket Na:gm.132.;Q§§i§mg¢_;jgtg§
`
`As a. below named inventor, I hereby declare that:
`
`My residence, post office address and citizenship are as stated below next to my name.
`
`I believel am the original, first and sole inventor (if only one name is listed below) or an original, first and
`joint inventor (if plural names are listed belowlof the subject matter which is claimed and for which a patent is
`sought on the invention entitled I{ggtfiggng‘gggMulti’ggle Sclerosis has amended}, the specification of which:
`
`{3
`
`is attached. hereto,
`
`___________ .
`as Application No.
`was filed on
`l}
`
`is}. was filed as PCT International Application No. PCT/ 33038104) 1.602, filed on February 7, 2008, and
`as amended: herewith in US. Apelication as E‘s/526,296, which is the national stage entry of
`PC’FIUSEOGS/Wl 602 and having a§ 31’!(<:}tiate ofjanuary l3, 20l
`
`I hereby state that l have reviewed and understand the contents oi" the above—identified specification,
`including the claims, as amended by any amendment referred to above.
`
`I acknowledge the duty to disclose all information I know to be material to patentability in accordance with
`Title 37, Code of Federal Regulations, §l.56.
`
`I hereby claim the benefit under Title 35, United States Code, §l l 9(e)(1) of any United States provisional
`applicafi0n(s) listed below:
`
`’-.S- SantamlNea...
`’
`“shown
`
`”Expired
`
`
`
`Status
`
`I hereby claim the benefit under Title 35, United States Code, §120 of any United States application(s)
`listed below and, insofar as the subject matter of each of the claims of this application is not disclosed in the prior
`United States application in the manner'provided by the first paragraph of Title 35, United States Code, §112, I
`acknowledge the duty to disclose all information I know to be material to patentability as defined in Title 37, Code
`of Federal. Regulations, §l.56(a) which became available between the filing date ofthe prior application and the
`national or PCT international filing date of this application:
`
`
`
`he“
`
`.‘c‘m‘auu
`Filmsbate
`
`Status.
`
`I hereby claim foreign priority-benefits under Title 35, United States Code, §l 1'9 of any foreign
`application(s), for patent or inventor.’s certificate or of any PCT international application(s) designating at least one
`country other than the United States of America listed below and have also identified below any foreign application
`for patent or inventor’s certificate or any PCT international application(s) designating at least one country other than
`the United States of America filed by me on the same subject matter having a filing date before that of the
`applicationCs) of which priority is claimed:-
`
`Counter
`
`teammate
`1M-~~~‘ ngvnvrv----.-----A--
`"
`"
`'
`
`Priori Claimed
`[]Yes
`[]N‘o
`
`Page 8 of 150
`
`Page 8 of 150
`
`

`

`Attorney’s Docket No.1 32:I_§2_3§;Z9I_QQQIQMQM+R/U-S
`
`
`Combined fieeisrsfion and. flower oi’Attemey
`Page 2 of 2 Pages
`
`I hereby appoint the following attorneys and/or agents to prosecute this application and to transact all
`business in the Patent and Trademark Office connected therewith:
`
`AI] Attorneys and Agents associated with
`
`53544
`PTO Customer Notiiiéer
`
`Direct 2111 mic-phone 135111510 John M. Covert at teiephone number (202), 77218-673.
`
`{Erect sii terrespundence to the foiiewéng:
`
`53644
`PTO Customer Number
`
`E For Assigned Inventions: I understand that the purpose of making this appointment is to permit
`prosecution ofpatent applications for the above-identified invention for the benefit of my assignee, and that this
`appointment does not create a personal attorney-client relationship between me and these appointees.
`
`1 herein}! dedsreithat 1111 stamnwn‘ts made herein of my @1111 knowiedge are true. 111111111211 5:1 snatements made
`on information and beiiiei are beiieved to be true; and further that these statements were made with the knowiesige
`:1111 15111111 false statements and the hike so made are punishabie by tzne or imprisonment or both under Seetion
`1801 9*” 11th: 1% ofthe United States Code and that suit11 wiiifui faise statements mnyjeopardize the 1:111:11 ty of the
`appiieation or any pawns issued thereon
`
`Full Name of Inventor: Matvey E. LUI‘CA“sglut
`
`usetts
`
`Inventor’s Signature:
`Residence Address :~
`Citizenship:
`Post Office Address:
`
`‘Hv“Wu““w.
`
`«.1...
`‘ Tewksb‘ury,”
`Russian Federation
`3 Louis Road, Tewksbury, MA 01876
`
`Full Name of'Inventor:
`Inventor’s Signature:
`
`Residence Address:
`Citizenship:
`Post Office Address:
`
`0111131115SWNFW
`.33
`"
`§:[’\A—
`
`..1w.15“...me- ....M... m..m~“.wm...WW............
`Medford, Massachusetts
`USA
`17 Grove Street, Medford, MA 02155
`
`-
`
`ft.
`Date: 9&- 2} 201-;
`
`14049451 .DOC
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`Page 9 of 150
`
`Page 9 of 150
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization .
`International Bureau
`5
`
`(43) International Publication Date
`14 August 2008 (14.08.2008)
`
`(51) International Patent Classification:
`G01N 33/50 (2006.01)
`
`
`
`
`
` llllllllllll||Illllilllll||l|||l|||||il||||||Elllllllllllllllllllll:
`
`
`
`lllllllllllllllllllllll
`
`(10) International Publication Number
`
`WO 2008/097596 A2
`
`(21) International Application Number:
`PCT/U82008/001602
`
`(22) International Filing Date: 7 February 2008 (07.02.2008)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/888,921
`
`8 February 2007 (08.02.2007)
`
`US
`
`(71) Applicant (for all designated States except US): BIOGEN
`[DEC MA INC. [US/US]; 14 Cambridge Center, Cam-
`bridge, MA 02142 (US).
`
`(72) Inventor; and
`LUKASHEV,
`(for US only):
`(75) Inventor/Applicant
`Matvey, E. [US/US]; 3 Louis Road, Tewksbury, MA
`01876 (US).
`
`(3'4) Agent; GARRETT, Arthur, 5:; Finnegan, Henderson,
`Farahow, Garrett & Dunner L138, 90‘: New York Avenue,
`NW, Washington, DC 000L441} (US),
`
`
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
`C31, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN,
`MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`
`SY, TJ, TM, TN, TR,
`,, TZ, UA, UG, US, UZ, VC, VN,
`ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL,
`NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published;
`
`without international search report and to be republished
`upon receipt of'tlzaz report
`
`
`
`(54) Title: NRF2 SCREENING ASSAYS AND RELATED METHODS AND COMPOSITIONS
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`90
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`N (57) Abstract: Provided are certain methods of screening, identifying, and evaluating neuroprotective compounds useful for treat-
`F‘ ment of neurological diseases, such as, e.g., multiple sclerosis (MS). The compounds described upregulate the cellular cytoprotective
`pathway regulated by Ner. Also provided are certain methods of utilizing such compounds in therapy for neurological disease, par—
`ticularly, for slowing or reducing demyelination, axonal loss, or neuronal and oligodendrocyte death.
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`WO 2008/097596
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`PCT/US2008/001602
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`5?er SCREENING ASSAYS
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`AND RELATED METHODS AND COEFOSITIONS
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`[0001]
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`Provided are certain compounds for treating neurological diseases,
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`including demyelinating neurological diseases, such as, e.g., multiple sclerosis.
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`[0002]
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`Multiple sclerosis (MS) is an autoimmune disease with the autoimmune
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`activity directed against central nervous system (CNS) antigens. The disease is
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`characterized by inflammation in parts of the CNS, leading to the loss of the myelin
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`sheathing around neuronal axons (demyelination), loss of axons, and the eventual
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`death of neurons, oligodenrocytes and glial cells.
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`[0003] An estimated 2,500,000 people in the world suffer from MS.
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`it is one of
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`the most common diseases of the CNS in young adults. MS is a chronic, progressing,
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`disabling disease, which generally strikes its victims some time after adolescence, with
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`diagnosis generally made between 20 and 40 years of age, although onset may occur
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`eariier. The disease is not directly hereditary, although genetic susceptibility plays a
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`part in its development. Relapsing-remitting MS presents in the form of recurrent
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`attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and
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`recur, seemingly randomly over many years. Remission is often incomplete and as
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`one attack follows another, a stepwise downward progression ensues with increasing
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`permanent neurological deficit.
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`[0004] Although various immunotherapeutic drugs can provide relief in
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`patients with MS, none is capable of reversing disease progression, and some can
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`cause serious adverse effects. Most current therapies for MS are aimed at the
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`reduction of inflammation and suppression or modulation of the immune system. As of
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`2006, the available treatments for MS reduce inflammation and the number of new
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`episodes but not all have an effect on disease progression. A number of clinical trials
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`have shown that the suppression of inflammation in chronic MS rarely significantly
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`timits the accumuiatinn at disabitity tnrnugn sustained disease prngressicn, suggesting
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`that neurnnai damage and inflammatidn are independent patneingies. Promoting CNS
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`remyelinaticn as a repair mechanism and ctherwise preventing axonal loss and
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`‘WQ ease/{mess
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`PCTIUSEtiiiéE/{itfltifiz
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`neuronal death are some of the important goals for the treatment of MS. For a
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`comprehensive review of MS and its current therapies, see, e.g., McAIpine’s Multiple
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`Sclerosis, by Alastair Compston et al., 4th edition, Churchill Livingstone Elsevier,
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`2006.
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`[0005]
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`“Phase 2 enzymes" serve as a protection mechanism in mammalian
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`cells against oxygen/nitrogen species (ROS/RNS), electrophiles and xenobiotics.
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`These enzymes are not normally expressed at their maximal levels and, their
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`expression can be induced by a variety of natural and synthetic agents. Nuclear factor
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`E2-related factor 2 (Nrf2) is a transcription factor responsible for the induction of a
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`variety of important antioxidant and detoxification enzymes that coordinate a protective
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`cellular response to metabolic and toxic stress.
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`[0006] ROS/RNS are most damaging in the brain and neuronal tissue, where
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`they attack post-mitotic (i.e., non-dividing) cells such as glial cells, oligodendocytes,
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`and neurons, which are particularly sensitive to free radicals. This process leads to
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`neuronal damage. Oxidative stress has been implicated in the pathogenesis of a
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`variety of neurodegenerative diseases, including ALS, Alzheimer's disease (AD), and
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`Parkinson's disease (PD). For review, see, e.g., van Muiswinkel et al., Curr. Drug
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`Targets CNS--Neurol. Disord., 2005, 42267-281. An anti-oxidative enzyme under
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`control of Nrf2, NQO‘E (NAD(P)H dehydrogenase, quinone (1), was recently reported
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`to be substantially upregulated in the brain tissues of AD and PD subjects (Muiswinkel
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`et al., Neurobiol. Aging, 2004, 25: 1253). Similarly, increased expression of NQO1
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`was reported in the ALS subjects’ spinal cord (Muiswinkel et al., Curr. Drug
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`Targets--CNS. Neurol. Disord., 2005, 4267-281) and in active and chronic lesions in
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`the brains of patients suffering from MS (van Horssen et al., Free Radical Biol. & Med.,
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`2008, «it 311011;; These absewatiens indicate that the Ne? pathway may be
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`activated in neeradegeaerative and aeureintiammatery aiseasas as an endogenous
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`pretee‘tive mechanism.
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`indeed, mes-t resentiy, it has beer; reported that teamed
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`activation at Nrt2~depeettent genes by certain cycioeenanenebased campaunds
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`{NEPF} counters the taxis attests at metabeiis iahibitiea and RQSIRNS pradestien it:
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`‘WQ 200810537596
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`PCT/{JSEGGSISMGOZ
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`the brain and protects neurons from death in vitro and in vivo (see Satoh et al., PNAS,
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`2006, 103(3):768—773).
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`[0007] Additionally, many publications have reported neuroprotective effects of
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`compounds in natural plant-derived compounds (“phytochemicals”), including
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`o-tocopherol (vitamin E), lycopene (tomatoes), resveratrol (red grapes), sulforaphane
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`(broccoli), EGCG (green tea), etc. For review, see Mattson and Cheng, Trends in
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`§\leurosci., 2006, 29(11):632-639. Originally, the action of these compounds was
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`attributed to their anti-oxidant properties. However, while most anti-oxidants are
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`effective only at high concentrations, at least some of these compounds appear to
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`exert neuroprotective effects at much lower doses. Emerging evidence suggests that
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`these compounds may exert their neuroprotective effects by activating cellular
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`stress-response pathways, including the Ner pathway, resulting in the upregulation of
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`neuroprotective genes. However, the exact mechanism of action of these compounds
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`remains poorly understood.
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`[0008] To date, more than 10 different chemical classes of inducers of Ner
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`pathway have been identified including isothiocyanates and their thiol addition
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`products, dithiocarbamates, as well as 1,2-dithioIe-3-thiones, trivalent arsenic
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`derivatives (e.g., phenyl arsenoxide), heavy metals, certain conjugated cyclic and
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`acyclic polyenes (including porphyrins, chlorophyllins. and chlorophyll), and vicinal
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`dimercaptans. These inducers have few structural similarities. They are mostly
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`electrophiles, and all can react chemically with thiol groups by alkylation, oxidation, or
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`reduction, suggesting that the intracellular sensor for inducers is likely to contain very
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`highly reactive (cysteine) thiols. The inducers can neodify thiol greups by a variety of
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`mechanisms including: alkylation (Michael addition acceptors, isothiocyanates,
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`quinones); oxidation (e.g., peroxides and hydroperoxides); and direct reaction with
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`thiol/disulfide linkages (e.g., vicinal dithiols such as 1,2-dimercaptopropanol, lipoic
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`acid). These diverse response mechanisms provide plasticity for cellular responses to
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`a variety of electrophilic and oxidant stressors.
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`[0009] Provided are methods that comprise at least one of the following
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`methods:
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`Wt} 2998119975§6
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`FCT/ESZGGSIGGE 682
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`t} metheee ef screening fer et teeet {me new eenttidete cemeeued fer
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`treetthg e neuretegieet eteeeee:
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`2) methette et evetuetihg neureereteettve ereeerttee et at teeet ene drug
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`eeetttctete ter treetthg e heeretegteei eieeeee;
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`3} methette ef eerneertng (veg, ter hieeeutvetehee} et teeet hive
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`ehermeceetteet eeeteeetttehe which eemhriee temerte eettt eettvetivee;
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`4t} metheee et treettng e heuretegteet eteeeee by administering te the subject
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`in heett thereet et teeet ehe eemeeued that is eertéetty etreeturetty eimtier te
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`DMF er Nth/ER end
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`5) metheee et treettrtg e heeretegieei eieeeee hy e eemhinetieh therapy that
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`eemeneee ectnttntetretien et at teeet ene tiret eemeeenct thet neregutetee
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`the htrtB eethwey and et teeet ehe eeeend eemheehe that deee het
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`uereguiete the htrt2 eethwey.
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`mete}
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`ht eeme emhedtmehte, the neuretegteet dieeeee is e neerectegehetettve
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`eieeeee eeeh es, fer exempte, ALS, Perktneeh’e eteeeee, Atzhetmer’e dieeeee, ene
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`Heettngten‘e ttieeeee.
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`th eeme emhetttmente the neuretegteet eteeeee ts MS er
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`enether {temyetthetthg heeretegieet eteeeee.
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`{Gm t}
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`in eerne ernhetttrnente, the metheee t~3 further eemertee:
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`e} eenteettng e eeti with the teet eemheehe, entt
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`h) determining whether the htrtz pathway 3e eeregutetee in the eett.
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`th eeme emhettirhehte, the methette they further eemeriee:
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`e) eetermthtrtg whether the test eemeeentt stews er prevehte demyettnetien,
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`exehet tees, endler heerehet death, end/er
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`it) eeteettng the test eemeeentt as e eentttctete fer treating neerectegeheretten
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`th e heuretegteet ttteeeee it t) the Nrt2 eethwey 3e epregetetert and 3)
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`demyetthettehg exehet teee, eheier neumeet {teeth ereiie prevented er
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`stewed.
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`teem}
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`th eerne ernhettintehte, the methette his eemertee eehteettng e cett with
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`at Eeeet erte teet eemeeene and determining whether the Mt? pathway is epregutetee
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`th the eett.
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`th eeeh methede, eh upregutetten et the tee eethwey eheve e threehetd
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`‘WG ZGbSiQWSSNS
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`E’CTIUSZGOSI’GGMGZ
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`(ag, by at taaat 30% (Net a bahtmt) thdtbataa that tha at taaat aha cambbmd has at
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`taaat aha bibtbgtcat ptbbatty bahatibiat tn treating a habrbtbgtbat ataaaaa tag,
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`haurbbrataattva btabatttaa},
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`in same ambbatmahta, tha abragutattah bf tha m2
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`bathway is; assessed (in viva ahdlat Eh vita); by at taaat we at the tbitbwihg:
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`t} axbraasiba tavats bf ahttbgahbusty brattacatt ahdibt exagahauaty
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`thtrbducad Ntt2;
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`ti) aabcatttziar tbcattzattbh ahdibr aactaar tranatbcatibh at Nth;
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`tit) axbrasstbh iavata ahaiar activity at me at mare gahaa uhdar cantmt at
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`Mt? tag, abdagahbus NQO’E) at an Nrt2~tagatatact rabattar gaha Eh an
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`atttfibtat repartar cahatmat;
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`iv)
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`tavats at Nat? bihdthg ta thb Nt‘fR-xbtt‘tdtt‘tg {DNA atamant ARE;
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`v) stabtttty 0t NttEfKaabt bambtaxas; and
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`vi) maaihcattah (6.9, atkytattbh} Eavats at Keaht aadibr at Beast baa bthar
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`NaziKaapt asserstatatt QF‘QEQEF‘ESI
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`{($13}
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`tn abma ambbaimahta at mathbds “b3, the Cambbtmds that are being
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`acraahact, avatbatad, at cambatad bambrtsa at Eaaat baa mambar at at taast me at the
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`tattbwihg btaasas 0t campaunda: mttd atkytatthg agents, httchaat adattiaa aacap‘tbra,
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`and camabahds that ata matabattzaa apart admthiatratibh tb Mtcbaat addtttbh
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`acbabtars. Eh Sasha ambaatmahta, the Michaat actcttttah abbabtbr has the Structure at
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`Farmuta t? it, tit, at W sat faith baiaw.
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`{(3914}
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`in aama ambbdimahta mathatfi t cathbriaaa:
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`a) bahtacttng a bait with a bturattty at teat bambbtzhda,
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`b) datam‘tiathg whether the Nth? pathway is upragutatad in the bait, and
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`a) aatacttfig tram tha bturattty at bbmabbhtta at taaat aha abhtbburtd that
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`abragutataa tha Nth? pathway,
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`whataih an uptagutatibh at the Nrtz hathway by the satabtact at taast aha cambaubd
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`indicataa that the aatabtatt at taast aha abmbbuha may be: asatttt tar treating a
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`hauratagtcat ataaaaa, The bittraitty at bambbumta may be rabrasabtad, a.g., by a
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`bambthatbttat chbmibat tibrary; amt the mathatt may ha fiefim‘meti ag, by
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`highwthrbughbbt acraahthg.
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`‘WO 2968/997596
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`PCT/'1}SZtitiS/‘titi‘ttétifi
`
`[0015]
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`in some embodiments method 2 comprises:
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`a) contacting a cell with the at least one drug or drug candidate. and
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`b) determining whether the Nrf2 pathway is upregulated in the cell,
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`wherein an upregulation of the Nrf2 pathway by the at least one drug or drug
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`candidate indicates that the at least one drug or drug candidate is useful for
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`neuroprotection in treating a human having a neurological disease.
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`[0016]
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`In some embodiments method 3 comprises:
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`a) contacting a cell with a first composition comprising at least one test
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`compound, and
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`t3) comparing the ievei of Nrf2 pathway upregniation in the oeii by the at teast
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`one test compound to the corresponding ievei of the Nrf2 pathway
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`npregniation in a oontroi ceit treated with a second composition comprising
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`at least one of DMF and MMF.
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`[0017]
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`in some embodiments of method 3, the test compound is fumaric acid,
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`a salt thereof, or a fumaric acid derivative.
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`In some embodiments, the first
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`composition comprises DMF, MMF, or both.
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`In some embodiments, the dose and/or
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`the formulation of the first composition differs from the dose and/or the formulation of
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`the second composition.
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`[0018]
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`In some embodiments, method 3 further comprises:
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`c) comparing at least one pharmacokinetic parameter (e.g., serum-haIf-life) of
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`the first and the second compositions.
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`[0019]
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`In some embodiments method 4 comprises administering to the
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`mammal a therapeutically effective amount of at least one neuroprotective compound
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`having Formula I, ll, ill, or IV, e.g., a fumaric acid derivative (e.g., DMF or MMF).
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`[0020]
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`In some embodiments method 4 provides a method of slowing or
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`preventing neurodegeneration in a patient in need thereof, by administering the
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`compound in an amount and for a period of time sufficient to slow or prevent
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`demyelination, axonal loss, and/or neuronal death, e.g., by at least 30% relative to a
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`control.
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`{0021]
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`in some embodiments method S comprises:
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`W9 2008/997596
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`E’iifT/ETSZGG8/{iti1602
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`a} administering ta the manarnai a iherapeatiaaiiy effective amenni at at Beast
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`ane first cemeannd that anregniates the Nit? pathway, and
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`b) administering a therapeutically effective amount of at least one second
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`compound that does not upregulate the Ner pathway.
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`[0022]
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`In some embodiments of method 5, the at least one first compound,
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`used in step (a), is a compound of Formula I, II, III, or IV,