Table of Contents For Ex. 1014A
`File Wrapper of PCT Application No. PCT/US2008/001602
`
`Incoming ISA/202 – Notification of Receipt of Search Copy - page 2
`
`RO/102 – Notification Concerning Payment of Prescribed Fees
`
`and Annex ------------------------------------------------------------- pages 3 - 4
`
`RO/105 – Notification of the IA Number and of the International
`
`Filing Date ------------------------------------------------------------- page 5
`
`RO/101 – Annex (fee calculation sheet) --------------------------- page 6
`
`RO/101 - Request form for new IA – Conventional ------------- pages 7 – 10
`
`Specification ----------------------------------------------------------- pages 11 - 44
`
`Claims ------------------------------------------------------------------ pages 45 – 47
`
`Abstract ---------------------------------------------------------------- page 48
`
`Drawings --------------------------------------------------------------- pages 49 - 52
`
`Miscellaneous Internal Document ---------------------------------- page 53
`
`PCT Transmittal Letter ----------------------------------------------- page 54
`
`RO/102(b) - Chapter I Fee Recordation Sheet -------------------- page 55
`
`Placeholder sheet indicating presence of supplemental content
`
`in SCORE --------------------------------------------------------------- page 56
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 1 of 56
`
`

`
`PCT/US2008/00160221.07.2008
`PATENT COOPERATION TREATY
`1AP12 Rec'd PCTJPTO·!l JUL 2008
`peT
`
`From the INTERNATIONAL SEARCHING AUTHORITY
`
`To:
`
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER,. LLP
`Attn. Garrett, Arthur S.
`901 New Yprk Avenue, NW
`Washington, DC 20001-4413
`ETATS-UNIS D'AMERIQUE
`
`Applicant's or agent's file.reference
`
`8201.077-304
`International application No.
`
`PCT/US2008/001602
`
`Applicant
`
`BIOGEN IDEC MA INC.
`
`NOTIFICATION OF RECEIPT
`OF SEARCH COPY
`
`(PCT Rule 25.1 )
`
`Date of mailing
`(day/month/year)
`
`17/04/2008
`
`IMPORTANT NOTIFICATION
`
`International filing date(day/month/year)
`07/02/2008
`
`Priority date (day/month/year)
`08/02/2007
`
`1. Where the International Searching Authority and the receiving Office are not the same office:
`
`.The applicant is hereby notified thatthe search copy of the inter national application was received by this International Searching
`Authority on the date indicated below.
`
`Where the International Searching Authority and the receiving Office are the same o~ice:
`The applicant is hereby notified that the search copy of the international application was received on the date indicated below.
`
`__ ____ 3=-=1..!..../:....::0::....:3=--<-./.=2-=0'-0:....8-=--_---'-_ (date of receipt).
`
`2.
`
`o
`
`The search copy was accompanied by a nucleotide and/or amino acid sequence listing or tables related thereto in
`electronic form.
`
`3.
`
`D
`
`The search copy containec;t a nucleotide and/or amino acid sequence listing or tables related thereto in electronic form.
`
`4. Time limit for establishment of international search report and written opinion of the International Searching Authority
`The applicant is informed that the time limit for establishing the international se.arch report and the written opinion of the
`International Searching Authority is three months from the date of receipt indicated above or nine months from the priority date,
`whichever time limit expires later (Rules 42.1 and 43bis.l (a))
`
`5. A copy of this 'notification has been sent to the International Bureau and, where the first sentence of paragraph 1 applies,
`to the receiving Office.
`'
`'
`,
`
`Name and mailing address of the International Searching Authority
`
`a' NL-2280 HV Rijswijk
`J) European Patent Office. P.B. 5818 Patentlaan 2
`
`.~ Tel. (+31-70) 340-2040, Tx. 31 651 epo nl,
`Fax: (+31-70) 340-3016
`
`Authorized officer
`
`ISA/EP
`
`Form PCTIISAl202 CApnl 2005)
`
`**** COPY FOR RECEIVING OFFICE ****
`
`Page 2 of 56
`
`

`
`PATENT COOPERATION TREATY
`
`From the RECEIVING OFFICE
`
`To:
`
`ARTHUR S. GARRETT
`FINNEGAN, HENDERSON, FARABOW, GARRETT
`& DUNNER,
`L.L.P.
`901 NEW YORK AVENUE, NW
`WASHINGTON, DISTRICT OF COLUMBIA
`0001-4413
`
`Applicant's or agent's file reference
`8201 .077-304
`
`peT
`
`NOTIFICATION CONCERNING PAYMENT
`OF PRESCRIBED FEES
`
`(PCT Rules 14, 15 and 16 and Administrative
`Instructions, Sections 1 02bis( c), 304,
`323(b), 707(b) and 803)
`
`Date of mailing
`(day/month/vear)
`
`PAYMENT DUE
`
`28 Mar 2008
`
`see item 3 for time limits
`
`International application No.
`PCT/US200S/001602
`
`International filing datelDate of receipt
`(day/month/year)
`
`07 Feb 2008
`
`Priority date (day/month/year)
`08 Feb 2007
`
`Applicant
`BIOGEN IDEC MA INC.
`
`1. The applicant is hereby notified that this receiving Office has received:
`
`the payment of all the prescribed fees, and D an overpayment, which will be refunded in due course.
`
`no or insufficient payment of the prescribed fees and the applicant is hereby invited to pay the balance due, as
`summarized under item 2, within the time limit(s) indicated under item 3.
`
`2. Fees and payment calculation:
`
`3,976.00
`Total fees payable
`
`D The details of the calculation are given in the Annex.
`
`3,976.00
`Amount paid
`
`0.00
`
`Balance
`
`3. Time limit(s) for payment and amount(s) payable (Rules 14.1, 15.4 and 16.1(f)):
`
`D within ONE MONTH from the date of receipt of the international application (for the transmittal fee (if any), the search
`
`fee and the international filing fee). The amount payable for each fee is the amount applicable on the date of receipt of the
`international application.
`
`D within 16 MONTHS from the priority date (only for the fee for priority document). The applicant's attention is drawn to the
`
`fact that the request made by the applicant under Rule 17.1 (b) will be considered not to have been made unless the fee is paid
`within that time limit.
`
`4. Additional observations (ifnecessary):
`
`D The search copy will not be transmitted to the International Searching Authority until the search fee is paid (therefore the
`
`start of the international search will be delayed) (Rule 23.1(a) and (b)).
`
`Name and mailing address of the receiving Office
`
`Mail Stop PCT, Commissioner for Patents
`P.O. Box 1450, Alexandria, VA 223l3-1450
`
`Facsimile No. 571-273-3201
`
`Form PCT/RO/I02 (January 2004)
`
`Authorized officer
`Larry Hammond
`
`Telephone No. 703-308-9290 EX 101
`
`Page 3 of 56
`
`

`
`ANNEX TO FORM PCTIRO/102
`CALCULATION OF THE PRESCRIBED FEES
`
`International application No.
`
`PCTlUS2008/001602
`
`lTI TransmittalFee
`Prescribed amount:
`
`Amount paid:
`
`.
`
`.
`
`Balance: . . . . . . . . . . . . . . . . . . . . . . . . . . =
`
`m Search Fee
`
`Prescribed amount:
`
`Amount paid:
`
`.
`
`.
`
`Balance: . . . . . . . . . . . . . . . . . . . . . . . . . . =
`
`OJ International Filing Fee
`
`Fixed amount for first 30 sheets:
`16 x ___ ----'1--=3c:...0::...c0'-
`Number of sheets
`Fee per sheet
`in excess of 30
`
`1 ,194.00 [II]
`
`208.00 [2]
`
`Additional
`component:.
`
`.
`
`. 400 x
`
`0.00
`Fee per sheet
`
`0.00 [3l
`
`Reduction where the international application is filed
`(See PCT Applicant's Guide, Volume I, General Part,
`for details on the availability of this reduction):
`using the PCT-EASY software:.
`.
`.
`.
`or
`in electronic form where the text of the
`description, claims and abstract is not in
`character coded format:.
`.
`.
`.
`.
`.
`.
`.
`.
`or
`in electronic form where the text of the
`description, claims and abstract is in character
`coded format:.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`0.00 [1J
`
`0.00 [1J
`
`0.00 [1J
`
`Sub-total:
`
`.
`
`.
`
`.
`
`.
`
`.
`
`1 ,402.00 Ii 1 +i2+i3-rI
`
`Prescribed total amount (The amount to be entered at I is the sub-total
`entered at (il+i2+i3-r), except where the applicant is (or all applicants
`are) entitled to a reduction of 75%, in which case the amount to be
`entered at I is 25% of the sub-total (il+i2+i3-r); certain applicantsfrom
`certain States are entitled to a reduction of 75% of the international
`filing fee; see Notes to the Fee Calculation Sheet as annexed to the
`Request Form, PCTIROI10l,fordetails): ..
`
`Amount paid:
`
`.
`
`Balance:.
`
`.
`
`.
`
`.
`
`[f] Fee for Priority Document
`Prescribed amount: .
`
`Amount paid:
`
`Balance: . .
`
`Form PCTIRO/102 (Annex) (January 2004)
`
`300.00 [T]
`300.00
`0.00
`
`2,274.00 [SJ
`2.274.00
`0.00
`
`~ correct amount
`D overpayment
`D balance due
`
`IVI
`L::::::I correct amount
`D overpayment
`D balance due
`
`1,402.00 m
`1,402.00
`0.00
`
`Igj correct amount
`D overpayment
`D balance due
`
`0.00 [PJ
`0.00
`0.00
`
`[gJ correct amount
`D overpayment
`D balance due
`
`Page 4 of 56
`
`

`
`PATENT COOPERATION TREATY
`
`From the RECEIVING OFFICE
`
`To:
`ARTHUR S. GARRETT
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER,
`L.L.P.
`901 NEW YORK AVENUE, NW
`WASHINGTON, DISTRICT OF COLUMBIA
`0001-4413
`
`Confirmation No: 5377
`
`Applicant's or agent's file reference
`8201 .077-304
`
`International application No.
`PCT/US2008/001602
`
`Applicant
`BIOGEN IDEC MA INC.
`
`peT
`
`NOTIFICATION OF THE INTERNATIONAL
`APPLICATION NUMBER AND OF THE
`INTERNATIONAL FILING DATE
`
`(PCT Rule 20.2(c))
`
`Date of mailing
`(day/month/year)
`
`28 Mar 2008
`
`IMPORTANT NOTIFICATION
`
`International filing date (day/month/year)
`
`07 Feb 2008
`
`Priority date (day/month/year)
`08 Feb 2007
`
`Title of the invention
`NRF2 SCREENING ASSAYS AND RELATED METHODS AND COMPOSITIONS
`
`1.
`
`The applicant is hereby notified that the international application has been accorded the international application nwnber and the
`international filing date indicated above.
`
`2.
`
`The applicant is further notified that the record copy of the international application:
`28 Mar 2008
`
`was transmitted to the International Bureau on
`
`has not yet been transmitted to the International Bureau for the reason indicated below and a copy of this notification
`has been sent to the International Bureau *:
`
`D because the necessary national security clearance has not yet been obtained.
`D because (reasontobespecijied):
`
`* The International Bureau monitors the transmittal ofthe record copy by the receiving Office and will notifY the applicant (with
`Form PCT IIB/30 1) of its receipt. Should the record copy not have been recei ved by the expiration of 14 months from the priority
`date, the International Bureau will notifY the applicant (Rule 22.1 (c)).
`
`3.
`
`FOREIGN TRANSMITTAL LICENSE INFORMATION
`
`Completed by: _L_H _______ _
`
`the equivalent U. S. national application. Refer to that license for information concerning its scope.
`
`D Additional license for foreign transmittal not required. This subject matter is covered by a license already granted or
`D License for foreign transmittal not required. 37 CFR. 5.1 1 (e)(1) or 37 CFR 5.11(e)(2). However, a license may be
`[xl Foreign transmittal license granted. 35 U.S.C. 184; 37 CFR 5.11 on
`D 37 CFR 5.15(a)
`
`required for additional subject matter. See 37 CFR 5.15(b).
`
`IVl
`Ill.I
`
`37 CFR 5.15(b)
`
`24 Mar 2008
`
`(date)
`
`Name and mailing address of the receiving Office
`Mail Stop PCT, Commissioner for Patents
`P.O. Box 1450, Alexandria, VA 22313-1450
`
`Authorized officer
`LaITY Hammond
`
`Facsimile No. 571-273-3201
`Form PCT/ROn05 (April 2007)
`
`Telephone No. 703-308-9290 EX 101
`
`Page 5 of 56
`
`

`
`This sheet is not part of and does not count as a sheet of the international application.
`
`PCT/US2008/001602
`
`e For receiving Office use only
`~CT/US 081 01
`602
`I Date stamp of the receiving Office
`
`i
`International Application No.
`
`07-02-2008
`
`peT
`
`FEE CALCULATION SHEET
`Annex to the Request
`
`Applicant's or agent's
`file reference
`
`8201.077-304
`
`Applicant
`BIOGEN IDEC MA INC. et al.
`
`CALCULATION OF PRESCRIBED FEES
`
`I. TRANSMITTAL FEE
`
`2. SEARCH FEE
`EP
`International search to be carried out by
`(If two or more international Searching Authorities are competent to carry out the
`international search, indicate the name of the Authority which is chosen to carry out
`the international search.)
`
`I
`I
`
`300 ITl
`2274 rsl
`
`3.
`
`INTERNATIONAL FILING FEE
`Where items (b) and/or (c) of Box No. IX apply, enter Sub-total number of sheets } 46
`Where items (b) and (c) of Box No. IX do not apply, enter Total number of sheets
`I
`
`[IT] first 30 sheets
`
`1194 [IT]
`
`[ill
`
`16
`number of sheets
`in excess of 30
`
`x
`
`13
`fee per sheet
`
`= I
`
`2081i2\
`
`[ill additional component (only if a sequence listing and/or tables
`related thereto are filed in electronic form under Section 801 (a)(i),
`or both in that form and on paper, under Section 801 (a)(ii»:
`
`400 x
`
`0
`fee per sheet
`
`=1
`
`Add amounts entered at iI, i2 and i3 and enter total at I
`
`1
`(Applicants from certain States are entitled to a reduction of 75% of the
`international filing fee. Where the applicant is (or al/ applicants are) so
`entitled, the total to be entered at J is 25% of the international filing fee.)
`
`0!i3l
`
`1402 m
`
`4. FEE FOR PRIORITY DOCUMENT (if applicable)
`
`5. TOTAL FEES PAYABLE.
`Add amounts entered at T, S, I and P,and enter total in the TOTAL box
`
`. .
`
`I
`I
`
`0 IPl
`
`TOTAL
`
`3976 I
`
`MODE OF PAYMENT (Not all modes of payment may be available at all receiving Office~)
`181 authorization to char~e
`D postal money order D cash
`deposit account (see. elow)
`D revenue stamps
`D bank draft
`IX) cheque
`AUTHORIZATION TO CHARGE (OR CREDIT) DEPOSIT ACCOUNT
`(This mode of payment may not be available at all receiving Offices)
`
`D coupons
`D other (specifY):
`
`0 Authorization to charge the total fees indicated above.
`KI (This check-box may be marked only if the conditionsfor deposit accounts
`of the receiving Office so pennil) Authorization to charge any deficiency
`or credit any overpayment in the total fees indicated above.
`0 Authorization to charge the fee for priority document.
`Form pel/RO/IOl (Annex) (Apnl2007)
`
`Receiving Office: RO/ US
`06-0916
`Deposit Account No.:
`F eg.r6aJy 7. 2008
`.. /
`Name: 1)1 ~r~J Jt (;~
`/ fI}///tItrIf //ItA///ti
`. /
`Ij
`
`Date:
`
`Signat ... _
`
`• V17
`
`See Notes 10 the fee calculatIOn sheet
`
`Page 6 of 56
`
`

`
`peT IUS2008/00 1602
`
`For receiving 0
`
`
`
`Ice use only ffi
`
`International APpRGT.lUS 08/ 01602
`
`peT
`
`REQUEST
`
`The undersigned requests that the present
`international application be processed
`according to the Patent Cooperation Treaty.
`
`International Filing Date
`
`07-02-2008
`
`ROIUS
`
`Name of receiving Office and "PCT International Application"
`
`Applicant's or agent's file reference
`(if desired) (J 2 characters maximum) 8201 .077 -304
`
`Box No.1
`
`TITLE OF INVENTION
`
`Nrf2 SCREENING ASSAYS AND RELATED METHODS AND COMPOSITIONS
`
`Box No. II
`
`APPLICANT
`
`~ This person is also inventor
`
`Name and address: (Family namefollowed by given name; for a legal entity.foll official designation. Telephone No.
`The address must include postal code and name of country. The country of the address indicated in this
`Box is the applicant's State (that is. country) of residence if no State of residence is indicated below.)
`
`BIOGEN IDEC MA INC.
`14 Cambridge Center
`Cambridge, MA 02142
`United States of America
`
`Facsimile No.
`
`Applicant's registration No. with the Office
`
`State (that is, country) of nationality:
`US
`This person is applicant
`for the purposes of:
`
`o all designated
`
`States
`
`.1 SUS (that is, country) of residence:
`the United States of America o the United States
`00 all designated States except
`
`of America only
`
`D
`
`the States indicated in
`the Supplemental Box
`
`Box No. III
`
`FURTHER APPLlCANT(S) AND/OR (FURTHER) INVENTOR(S)
`
`~ Further applicants andlor (further) inventors are indicated on a continuation sheet.
`Box No. IV AGENT OR COMMON REPRESENTATIVE; OR ADDRESS FOR CORRESPONDENCE
`lR] agent
`Name and address: (Family namefollowed bygiven name;fora legal entityJull oJJicial designation. Telephone No.
`The address must include postal code and name of country.)
`Carol Marshall 1202.408.4181
`
`The person identified below is herebylhas been appointed to act on behalf
`of the applicant(s) before the competent International Authorities as:
`
`Dcommon
`representative
`
`GARRETT, Arthur S.
`Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.
`901 New York Avenue, NW
`Washington, DC 0001-4413
`United States of America
`
`Facsimile No.
`
`202.408.4400
`
`Agent's registration No. with the Office
`
`20,338
`
`0 Address for correspondence: Mark this check-box where no a~ent or common representative is/has been appointed and the
`
`space above is used instead to indicate a special address to whic correspondence should be sent.
`
`Form PCT/ROIIOI (first sheet) (April 2007)
`
`See Notes to the request/arm
`
`Page 7 of 56
`
`

`
`PCT/US2008/001602
`Sheet No . . . z ...
`
`Box No. III
`
`FURTHER APPLICANT(S) ANDIOR (FURTHER) INVENTOR(S)
`
`l/none a/the/allowing sub-boxes is used, this sheet should not be included in the request.
`
`Name and address: (Family namefollowed by given name; for a legal entity.foll official designation. This person is:
`The address must include postal code and name of country. The country of the address indicated in this
`0 applicant only
`Box is the applicant's State (that is. country) of residence if no State of residence is indicated below.)
`[i] applicant and inventor
`0 inventor only (If this check-box
`
`is marked, do not jilt in below.)
`
`LUKASHEV, Matvey E.
`3 Louis Road
`Tewksbury, MA 01876
`United States of America
`
`Applicant's registration No. with the Office
`
`Slate (that is, country) of nationality:
`
`I SUS (that is, country) of residence:
`This person is applicant o all designated o all designated States except
`[KJ the United States 0 the States indicated in
`
`for the purposes of:
`
`Stales
`
`the United Stales of America
`
`of America only
`
`the Supplemental Box
`
`Name and address: (Family namefollowed by given name; for a legal entity,full official designation. This person is:
`The address must include postal code and name of country. The country of the address indicated in this
`0 applicant only
`Box is the applicant's State (that is. country) of residence if no State of residence is indicated below.)
`0 applicant and inventor
`0 inventor only (If this check-box
`
`is marked, do not jill in below.)
`
`App~icant's registration No. with the Office
`
`State (that is. country) of nationality:
`
`I State (that is, country) of residence:
`This person is applicant o all designated o all designated States except o the United States 0 the States indicated in
`The address must include postal code and name of country. The country of the address indicated in this 0
`D applicant and inventor
`0 inventor only (Ifthi:; check-box
`
`for the purposes of:
`
`States
`
`the United States of America
`
`of America only
`
`the Supplemental Box
`
`N arne and address: (Family name followed by given name; for a legal entity,full official designation. This person is:
`Box is the applicant's State (that is, country) of residence if no State of residence is indicated below.)
`
`applicant only
`
`is marked, do not jill in below.)
`
`•
`
`Applicant's registration No. with the Office
`
`State (that is, country) of nationality:
`
`I State (that is, country) of residence:
`This person is applicant o all designated o all designated States except D the United States D the States indicated in
`
`for the purposes of:
`
`States
`
`the United States of America
`
`of America only
`
`the Supplemental Box
`
`Name and address: (Family name/allowed by given name; for a legal el1lity,full o/ficial designation. This person is:
`The address must include postal code and name of country. The country oIthe address indicated in this
`0 applicant only
`Box is the applicant's State (that is, COUl1lry) of residence if no State of residence is indicated below.)
`D applicant and inventor
`0 inventor only (If/his check-box
`
`is marked, do not jill in below.)
`
`Applicant's registration No. with the Office
`
`State (that is, country) of nationality:
`
`I State (that is, country) of residence:
`
`for the purposes of:
`
`States
`
`the United States of America
`
`of America only
`
`the Supplemental Box
`
`This person is applicant 0 all designated D all designated States except o the United States 0 the States indicated in
`D Further applicants and/or (further) inventors are indicated on another continuation sheet.
`
`Form peTIROIIOI (continuation sheet) (April 2007)
`
`See Notes to the request/arm
`
`Page 8 of 56
`
`

`
`PCT/US2008/001602
`
`. Sheet No
`
`... 3 .. .
`
`Box No. V
`
`DESIGNATIONS
`
`The filing of this request constitutes under Rule 4.9(a), the designation of all Contracting States bound by the PCT on the international
`filing date, for the grant of every kind of protection available and, where applicable, for the grant of both regional and national patents.
`However,
`D DE Germany is not designated for any kind of national protection
`D JP Japan is not designated for any kind of national protection
`D KR Republic of Korea is not designated for any kind of national protection
`D RU Russian Federation is not designated for any kind of national protection
`(The check-boxes above may only be used to exclude (irrevocably) the designations concerned if. at the time offiling or subsequently under
`Rule 26bis. i, the international application contains in Box No. VI a priority claim to an earlier national applicationfiled in the particular
`State concerned. in order to avoid the ceasing of the effect. under the national law. of this earlier national application.)
`
`Box No. VI
`
`PRIORITY CLAIM
`
`The priority of the following earlier application(s) is hereby claimed:
`
`Filing date
`of earlier application
`(day/month/year)
`
`Number
`of earlier application
`
`Where earlier application is:
`national ap~cation:
`ember regional application:
`country or
`regional Office
`ofWTO
`
`international application:
`receiving Office
`
`08/02/2007
`
`60/888,921
`
`US
`
`item (I)
`
`item (2)
`
`item (3)
`
`D Further priority claims are indicated in the Supplemental Box.
`Transmit certified copy: the receiving Office is requested to prepare and transmit to the International Bureau a certified copy of the
`earlier application(s) (only if the earlier application was filed with the Office which for the purposes of this international application
`is the receiving Office) identified above as:
`D item (3) D other, see Supplemental Box
`D item (2)
`D all items
`(KJ item (I)
`Restore the right of priority: the receiving Office is requested to restore the right of priority for the earlier application(s) identified
`above or in the Supplemental Box as item(s) (
`). (See also the Notes to Box No. Vi; fimher
`information mllst be provided to support a request to restore the right of priority.)
`Incorporation by reference: where an element of the international application referred to in Article II (l)(iii)(d) or (e) or a part of
`the description, claims or drawings referred to in Rule 20.5(a) is not otherwise contained in this international application but is
`completely contained in an earlier application whose priority is claimed on the date on which one or more elements referred to in
`Article II (I )(iii) were first received by the receiving Office, that element or part is, subject to confirmation under Rule 20.6,
`incorporated by reference in this international application for the purposes of Rule 20.6.
`
`Box No. VII
`
`INTERNATIONAL SEARCHING AUTHORITY
`
`Choice of International Searching Authority (ISA) (if two or more international Searching Authorities are competent to carry out the
`international search. indicate the Authority chosen; the two-letter code may be used):
`ISA / .E;P .................... , ........ , .......... , ..... , ............ , .... , .... , .........................
`Request to use results of earlier search; reference to that search (if an earlier search has been carried out by or requested ji'om the
`International Searching Authority):
`Date (day/month/year)
`
`Country (or regional Office)
`
`Number
`
`Box No. VIII DECLARATIONS
`
`The following declarations are contained in Boxes Nos. VlIl (i) to (v) (mark the applicable
`check-boxes below and indicate in the right column the number of each type of declaration):
`D Box No. VIlI (i)
`Declaration as to the identity of the inventor
`D Box No. VIII (ii)
`Declaration as to the applicant's entitlement, as at the international filing
`date, to apply for and be granted a patent
`D Box No. VllI (iii)
`Declaration as to the applicant's entitlement, as at the international filing
`date, to claim the priority of the earlier application
`D Box No. VlII (iv)
`Declaration of inventors hip (only for the purposes of the designation of the
`United States of America)
`D Box No. VIII (v)
`Declaration as to non-prejudicial disclosures or exceptions to lack of novelty
`Fonn PCT/RO/lOl (second sheet) (April 2007)
`
`Number of
`declarations
`
`:
`
`:
`:
`
`See Notes to the request form
`
`Page 9 of 56
`
`

`
`PCT/US2008/001602
`Sheet No. ..:4 ....
`Box No. IX CHECK LIST; LANGUAGE OF FILING
`
`Number
`ofitems
`
`This international application is accompanied by the following
`item(s) (mark the applicable check-boxes below and indicate in
`right column the number of each item):
`I. kJ fee calculation sheet
`2. 0 original separate power of attorney
`3. 0 original general power of attorney
`4. 0
`copy of general power of attorney; reference number,
`ifany: ........ " ................................. .
`statement explaining lack of signature
`it~~rlZ ~~~~~e~:(~~ ~~~n.t~~~~ ~n B.OX. ~o: ~I .as ........... .
`translation of international application into
`(language): ....................................... .
`separate indications concerning deposited microorganism
`or other biological material
`sequence listing in electronic form
`(indicate type and number of carriers)
`
`5. 0
`6. 0
`
`7. 0
`
`8. 0
`
`Rule 13ter only (and not as part of the international application) :
`
`9. 0
`(i) o copy submitted for the purposes of international search under
`o (only where check-box (b)(i) or (c)(i) is marked in left column)
`
`additional copies including, where applicable, the copy for the
`purposes of international search under Rule 13ter
`
`46
`
`(ii)
`
`This international application contains:
`(a) on paper, the following number of
`sheets:
`request (including
`declaration and
`supplemental sheets)
`description (excluding
`sequence listing and/or
`tables related thereto)
`claims
`abstract
`drawings
`
`Sub-total number ofsheets
`sequence listing
`tables related thereto
`(for both, actual number
`of sheets if filed on paper.
`whether or not also
`filed in electronicform;
`see (c) below)
`
`4
`
`34
`3
`1
`4
`46
`o
`o
`
`Total number of sheets
`(b) 0 only in electronic form
`(Section 801 (a)(i»
`(i) 0 sequence listing
`(ii) 0 tables related thereto
`(c) 0 also in electronic form
`(Section 80 I (a)(ii»
`(i) 0 sequence listing
`(ii) 0 tables related thereto
`Type and number of carriers (diskette,
`CD-ROM, CD-R or other) on which are
`contained the
`
`o sequence listing: ............... .
`o tables related thereto: ......... .
`
`(additional copies to be indicated under
`items 9(iO and/or lO(iO, in right column)
`
`(iii)
`
`10. 0
`
`(i)
`
`(ii)
`
`(iii)
`
`II. 0
`
`o together with relevant statement as to the identity of the copy or
`
`copies with the sequence listing mentioned in left column
`tables in electronic form related to sequence listing
`(indicate type and number of carriers)
`
`o copy submitted for the purposes of international search under
`o (only where check-box (b)(ii) or (c)(ii) is marked in left column)
`o together with relevant statement as to the identity of the copy or
`
`Section 802(b-quater) only (and not as part of the international
`application)
`
`additional copies including, where applicable, the copy for the
`purposes of international search under Section 802(b-quater)
`
`copies with the tables mentioned in left column
`other (specify): ......................................... .
`
`Language of filing of the
`Figure of the drawings which
`international application:
`should accompany the abstract:
`Box No. X
`SIGNATURE OF APPLICANT, AGENT OR COMMON REPRESENTATIVE
`Next to each signature. indicate the name of the p
`n 'gning and the capacity in which the person signs (if such capacity is not obvious from reading the request).
`
`English
`
`r---------------------- For receiving Office use only _______ ............ oIoloi ... ..,. __ ___ __ _ ...,
`IAP07R . ~d peT 0 7 FEB ZOO
`eo
`I. Date of actual receipt of the purported
`2. DraWi~gs:
`0 received:
`international application:
`o not received:
`
`3. Corrected date of actual receipt due to later but
`timely received papers or drawings completing
`the purported international application:
`
`4. Date of timely receipt of the required
`corrections under peT Article r 1(2):
`
`5. International Searching Authority
`(if two or more are competent):
`
`ISA /
`
`EP
`
`Transmittal of search copy delayed
`until search fee is paid
`
`For International Bureau use only ____________________ .,
`
`Date of receipt of the record copy
`by the International Bureau:
`
`Form PCT/ROII 0 I (last sheet) (April 2007)
`
`See Notes to the request form
`
`Page 10 of 56
`
`

`
`Agent Ref. 08201.0077-00304
`
`PCT/US2008/001602
`
`Nrf2 SCREENING ASSAYS
`AND RELATED METHODS AND COMPOSITIONS
`
`[0001]
`
`Provided are certain compounds for treating neurological diseases,
`
`including demyelinating neurological diseases, such as, e.g., multiple sclerosis.
`[0002]
`Multiple sclerosis (MS) is an autoimmune disease with the autoimmune
`
`activity directed against central nervous system (eNS) antigens. The disease is
`characterized by inflammation in parts of the eNS, leading to the loss of the myelin
`
`sheathing around neuronal axons (demyelination), loss ofaxons, and the eventual
`death of neurons, oligodenrocytes and glial cells.
`[0003] An estimated 2,500,000 people in the world suffer from MS. It is one of
`the most common diseases of the eNS in young adults. MS is a chronic, progressing,
`disabling disease, which generally strikes its victims some time after adolescence, with
`diagnosis generally made between 20 and 40 years of age, although onset may occur
`earlier. The disease is not directly hereditary, although genetic susceptibility plays a
`part in its development. Relapsing-remitting MS presents in the form of recurrent
`
`attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and
`recur, seemingly randomly over many years. Remission is often incomplete and as
`one attack follows another, a stepwise downward progression ensues with increasing
`permanent neurological deficit.
`
`[0004] Although various immunotherapeutic drugs can provide relief in
`patients with MS, none is capable of reversing disease progression, and some can
`
`cause serious adverse effects. Most current therapies for MS are aimed at the
`reduction of inflammation and suppression or modulation of the immune system. As of
`
`2006, the available treatments for MS reduce inflammation and the number of new
`episodes but not all have an effect on disease progression. A number of clinical trials
`
`have shown that the suppression of inflammation in chronic MS rarely significantly
`limits the accumulation of disability through sustained disease progression, suggesting
`
`that neuronal damage and inflammation are independent pathologies. Promoting eNS
`remyelination as a repair mechanism and otherwise preventing axonal loss and
`
`- 1 -
`
`Page 11 of 56
`
`

`
`Agent Ref. 08201.0077-00304
`
`PCT/US2008/001602
`
`neuronal death are some of the important goals for the treatment of MS. For a
`
`comprehensive review of MS and its current therapies, see, e.g., McAlpine's Multiple
`
`Sclerosis, by Alastair Compston et aI., 4th edition, Churchill Livingstone Elsevier,
`
`2006.
`
`[0005]
`
`"Phase 2 enzymes" serve as a protection mechanism in mammalian
`
`cells against oxygen/nitrogen species (ROS/RNS), electrophiles and xenobiotics.
`
`These enzymes are not normally expressed at their maximal levels and, their
`expression can be induced by a variety of natural and synthetic agents. Nuclear factor
`
`E2-related factor 2 (Nrf2) is a transcription factor responsible for the induction of a
`
`variety of important antioxidant and detoxification enzymes that coordinate a protective
`
`cellular response to metabolic and toxic stress.
`
`[0006] ROS/RNS are most damaging in the brain and neuronal tissue, where
`
`they attack post-mitotic (Le., non-dividing) cells such as glial cells, oligodendocytes,
`
`and neurons, which are particularly sensitive to free radicals. This process leads to
`
`neuronal damage. Oxidative stress has been implicated in the pathogenesis of a
`
`variety of neurodegenerative diseases, including ALS, Alzheimer's disease (AD), and
`
`Parkinson's disease (PO). For review, see, e.g., van Muiswinkel et aI., Curr. Drug
`
`Targets CNS--Neurol. Disord., 2005,4:267-281. An anti-oxidative enzyme under
`
`control of Nrf2, N001 (NAD(P)H dehydrogenase, quinone (1), was recently reported
`
`to be sub