Document made available under
`Patent Cooperation Treaty (PCT)
`
`the
`
`International application number: PCT/EP2007/005597
`
`International filing date:
`
`25 June 2007 (25.06.2007)
`
`Document type:
`
`Certified copy of priority document
`
`Document details:
`
`Country/Office: GB
`0612721.1
`Number:
`Filing date:
`27 June 2006 (27.06.2006)
`
`Date of receipt at the International Bureau: 16 July 2007 (16.07.2007)
`
`Remark: Priority document submitted or transmitted to the International Bureau in
`compliance with Rule 17.1(a) or (b)
`
`m
`OMR!
`
`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
`Organisation Mondiale de la Propriete Intellectuelle (OMPI) - Geneve, Suisse
`
`TEVA EX. 1012
`Page 1
`
`

`

`Intellectual
`3 Property
`Qfiie ••••
`
`fot CrtiUvSy
`
`tntf (nnovallon
`
`ep&fNb^/ooss"?'^
`er.oe.o}
`
`Concept House
`Cardiff'Road
`Newport
`South Wales
`NP10 8QQ
`
`accordance
`in
`authorised
`duly
`I, the undersigned, being an officer
`
`certificates on behalf of
`issue
`of the Deregulation & Contracting Out Act 1994, to sign and
`
`the Comptroller-General, hereby
`certify
`that
`
`hereto annexed true copy of the documents is a
`
`
`as originally filed in connection with patent application GB0612721.1
`filed
`on June 2006.
`
`
`with
`
`Section
`
`74(1)
`
`27
`
`Rules Re-registration) 1982, if a company named
`
`(Companies
`In accordance with the Patents
`
`under
`in this certificate and any
`accompanying
`documents
`has
`
`re-registered the Companies
`registered
`Act 1980 with the same
`name
`as
`that
`with
`which
`it was
`substitution as, or inclusion as,
`the
`
`of last part the name of the words
`
`registration save
`for
`the
`"public limited company" or
`their equivalents in Welsh, references
`
`to
`
`the of the
`name
`company in this certificate
`and
`any
`
`
`
`
`accompanying shall be documents treated as references to
`the name with which it is so re-registered.
`
`immediately
`
`before
`
`In accordance with the
`pic, P.L.C. or PLC.
`
`rules,
`
`the
`
`words
`
`"public
`
`limited
`
`company"
`
`may
`
`be
`
`replaced
`
`by
`
`Act
`Re-registration under the Companies
`subjects the company to certain additional company
`
`does
`law
`
`
`
`a not constitute new legal entity but merely
`
`rules.
`
`(UM
`
`Signed
`
`Dated 17 April 2007
`
`UK Intellectual Property Office is an
`
`
`
`operating name of the Patent Office
`
`Idtt A DTI SERVICE
`
`TEVA EX. 1012
`Page 2
`
`

`

`Fonn 1/77
`Patents
`
`PattsttAd 1B7T
`(SidtlO
`
`Request for grant of a patent
`(Aa vrphvMtioy
`Ittikl m Aw to OH la (Mr lam f» tnlbUt
`tmm the hum
`OtBct)
`Application number GB
`1. Your reference:
`(opUonaQ
`
`% Office-?
`tx
`^ MC V
`2 7 JUN ZCSS
`
`iOMDOJi
`
`J206989/ COl 000245 POl/TTFK..
`28'7i.'W5 30.00
`flCCOUNT 0612721.1
`
`1/77
`
`Tbe Patent OIBtt
`
`CardHTRoad
`Newport
`South Wales
`NPI0 8QQ
`
`0612721.1
`
`2. Fufl name, address and postcode of the applicant
`Or of each applicant
`(underttne allsumama):
`
`Patents ADP number (Ifyou
`
`know
`
`ifc
`
`If the applicant is
`a corporate
`body, give
`country/state of its Incorporation:
`
`the
`
`3. Tide of the invention:
`
`4. Name of your agent (ifyou
`
`turn
`
`am/.
`
`'Address for service' In the United Kingdom
`to which all correspondence should be sent
`QnclutBng the pouatH)
`
`Patents ADP number (ifyou
`
`know
`
`11)'.
`
`5. Priority declaration: Are you claiming
`priority from one or more earlier-filed
`patent applications? If so,
`please give
`' details of the application(s):
`
`6. Dlvfetonals etc
`Is this
`application a divisional
`application, or being made
`fallowing resolution
`of an entitlement dispute about an earlier
`application? If so. please give the application
`number and filing date of the earlier application:
`
`50279P1
`
`Novartis ACS
`Lichtstrasse 35
`CH-4056 Basel
`Switzeriand
`
`Switzerland
`
`Organic Compounds
`
`Novartis Pharmaceuticals UK Limited
`Patents and Trademarks
`Wimblehurst Road
`Horsham, West Sussex
`RH12 SAB
`07181522002 <"
`Application number
`(Ifyou know Jd
`
`DateorflUng
`(day / month/ymar)
`
`Countiy
`
`Numberof eaiUer UK appllcaitoD
`
`DateorflUng
`(day /month /year)
`
`7. Inventorship: (Inventors must be Individuals not companies)
`
`(Please tick the appropriate boxes)
`
`Are all the applicants named
`
`also Inventors?
`above
`
`If yes, are there any other Inventors?
`
`8. Are you paying the application
`
`fee with this
`
`form?
`
`YES •
`
`YES •
`
`YES Q
`
`NO Q
`
`NO •
`
`NO •
`
`Patents Fonn 1/77
`
`TEVA EX. 1012
`Page 3
`
`

`

`Patents Form 1/77
`
`9. Accompanying documents: not counting
`duplicates, please enter
`the
`
`number of pages
`of each item accompanying this form:
`
`Continuation sheets of this form:
`
`Description:
`
`Claim ft:
`
`Abstract:
`
`Drawing (if.
`
`/
`16 / 1
`
`IF you are not filing a description, please
`give details of the previous application
`you are going to rely upon:
`
`Country
`
`Appfiadon Bumbcr
`
`DtxcofDUng
`(day / month /year)
`
`10. If you are also filing any of the foUowing,
`state how many against each item.
`Priority documents:
`
`Statement of Inventonhlp and right
`to grant of a patent (PKCMS Farm 7/77):
`
`Request for search (Pttenu form Mm):
`
`1
`
`Request for substantive examination
`(taeras
`Form 10/77);
`
`Any other documents:
`(plmu tpocUy)
`
`11. lAVe request the grant of a patent on
`
`the basis of this application.
`
`SlgnatureCs):
`
`Date:
`
`27/06/2006
`
`12. Name, email address,
`telephone,
`Fajt and/or mobile number, if any,
`of a contact point for the applicant:
`
`Mis S Schnerr
`
`phone: 01403 323 069
`lax : 01403 323 623
`
`Warning
`After an application for a patent has been filed, the Comptroller of the Patent Office win consider whether publication or
`
`22 of the Patents Art 1977. You wOl be Informed ff It
`communlc&Hon of the invention should be prohibited or restricted under section
`
`Is necessary to prohlbli or restrict your Invention In this way. Furtheimoie. If you are resident In the United Kingdom and your
`would safety of the
`
`
`appHcaaon contains bifoimatlon which
`relates
`to
`
`military technology, prejudicial to national security or or
`
`the
`public, section 23 of
`
`the Patents Act 1977 proUbtts you bam applying for a patent abroad without Oist getting written permission from
`the Patent OBlce unless an application has been Died at least 6 weeks beforehand tn the United Kingdom for e patent for the same
`invention and etther no
`direction
`prohibiting
`publication
`
`or been given, or any such direction has been communlcailan has
`
`
`(evoked.
`
`be
`
`Notes
`A leaflet on how to flli In this rorm b available from the Patent Office. Ifyou would like a copy of the leaflet It Is available on our
`website at http://www.patentgov.uk/patent/lnfo/ractOS.pdfor alternatively you could telephone 08459 500505 or send an email to
`
`enqulrles9paunt.gov.uk to request a copy.
`
`Patents Form 1/77
`
`TEVA EX. 1012
`Page 4
`
`

`

`Case 50279P1
`
`Oroanic Compounds
`
`The present
`invention relates
`prevention of neo-angiogenesis
`sclerosis.
`
`in the treatment or
`the to use of an S1P receptor modulator
`
`
`associated
`
`with a demyelinating disease,
`e.g.
`multiple
`
`S1 P receptor modulators are typically sphingosine analogues,
`
`as such 2-substituted 2-
`
`
`amino- propane-I.J-diol
`or
`
`2-amino-propanol derivatives, e. g. a compound comprising a
`group of formula X
`
`Sphingosine-1 phosphate (hereinafter "S1P*) is a natural serum lipid. Presently there are
`eight known S1P receptors, namely S1P1
`to
`S1P8.
`S1
`P
`
`receptor are typically
`sphingosine analogues, such as 2-substituted 2-amino- propane-1,3-diol or 2-amino-
`propanol derivatives, e. g. a compound comprising a group of formula X
`
`modulators
`
`z
`
`fw*
`
`CH2R12
`
`(X)
`
`substituted
`phenyl
`wherein Z is H, Ci^alkyl, Cj^alkenyl, Cj^alkynyl, phenyl,
`substituted by 1 to 3 substituents selected from the group consisting of halogen,
`Cj.
`scydoalkyl. phenyl and
`
`phenyl substituted by OH, or CHrR* wherein R* is OH, acyloxy or
`a residue of formula (a)
`
`by OH,
`
`Ci^alkyt
`
`OR*
`
`OR 6z
`
`'2'— B
`
`0
`
`(a)
`
`wherein Zi is a direct bond or O, preferably 0;
`
`each of R* and R*. independently,
`halogen atoms;
`
`
`
`is H, or Ci^alkyl optionally substituted or 3
`
`by 1,2
`
`Rn is OH. acyloxy or a residue of formula (a); and
`C^alkyl or acyl.
`
`
`
`each of R* and R*
`
`independently,
`
`is
`
`H,
`
`moiety which
`to a
`as attached a terminal group
`
`
`Group of formula X is a functional group
`may be hydrophilie or lipophilic and comprise one or more aliphatic, alicydic. aromatic
`
`and/or heterocyclic residues, to the extent that the resulting molecule wherein at least one
`
`TEVA EX. 1012
`Page 5
`
`

`

`Case 50279P1
`
`residue
`of Z and Rn is or comprises a
`
`sphingosine-1-phosphate
`receptor.
`
`of formula
`
`(a),
`
`
`
`signals an agonist at as
`
`
`
`one
`
`of more
`
`are compounds which signal as agonists at one or more
`
`S1P receptor modulators
`receptors,
`
`
`
`a e.g. S1P1 to S1P8. Agonist binding to S1P receptor
`sphingosine-1 phosphate
`may e.g.
`result
`in dissociation
`of intracellular heterotrimeric
`G-proteins
`
`into and
`Gf3y-GTP, and/or
`increased
`
`of phosphorylation the agonist-occupied
`
`receptor
`and
`of downstream signaling pathways/kinases.
`
`Ga-GTP
`activation
`
`
`
`receptors may be
`
`by quantifying
`
`The binding affinity of S1P receptor modulators to individual human S1P
`determined in following assay:
`SIP receptor modulator activities of compounds are tested on the human S1P receptors
`SI Pi, SIP2, SIPj,
`and SIP5. Functional receptor
`activation
`is
`assessed
`SIP4
`compound induced GTP [y-^S] binding to membrane protein prepared from transfected
`CHO or RH7777 cells stably expressing the appropriate human S1P receptor. The assay
`technology used is SPA (scintillation proximity based assay). Briefly, DMSO dissolved
`compounds are serially diluted and added to SPA- bead (Amersham-Pharmacia)
`immobilised SIP
`receptor expressing membrane protein (10-20ng/well) in the presence of
`50 mM Hepes, 100 mM NaCI. 10 mM MgCfe, 10 pM GDP, 0.1% fat free BSA and 0.2 nM
`GTP ft-^Sl (1200 Ci/mmol). After incubation in 96 well microtiterplates at RT for 120 min,
`unbound GTP fr-^S] is separated by a centrifugation step. Luminescence of SPA beads
`triggered by membrane bound GTP
`is quantified with a TOPcount plate reader
`(Packard). EC30S are calculated using standard curve fitting software. In this assay, the
`S1P
`receptor modulators preferably have
`
`a
`
`
`
`
`
`affinity to binding receptor <50 nM.
`
`S1P
`
`their
`to
`are receptor modulators e.g. compounds which in addition
`
`
`Preferred S1P
`binding properties also
`
`
`have accelerating lymphocyte homing properties, e.g. compounds
`which elicit a lymphopenia resulting from a re-distribution, preferably reversible,
`of
`lymphocytes from circulation
`to secondary lymphatic tissue, without evoking a generalized
`immunosuppression. Naive
`
`
`cells are sequestered; CD4 and CD8 T-cells and B-cells from
`the blood are stimulated to migrate
`into lymph nodes
`(LN) and
`Peyer's
`
`S1P
`
`The lymphocyte homing property may be measured in following Blood Lymphocyte
`Depletion assay:
`
`patches
`
`(PP).
`
`TEVA EX. 1012
`Page 6
`
`

`

`Case 50279P1
`
`A SIP receptor modulator or the vehicle is administered orally by gavage
`to
`for hematological monitoring is
`obtained
`-1 to give the baseline
`on
`day
`individual values,
`and at 2,6,24,48 and 72 hours after application. In this assay, the S1P receptor agonist
`modulator depletes
`peripheral
`blood
`lymphocytes,
`e.g.
`by 50%,
`dose of e.g. < 20 mg/kg.
`
`rats.
`
`Tail blood
`
`or
`when
`
`administered
`
`Examples of appropriate S1P
`
`receptor
`
`for example:
`modulators
`
`are,
`
`- Compounds as disclosed
`
`in EP627406A1,
`
`e.g. a compound of formula I
`
`CHJOR,
`
`r5n—J—CHjQR,
`
`R4
`
`I
`
`R,
`
`wherein R1 is a
`straight-
`branched (C^^chain
`or
`• which may have
`in the
`chain
`a
`bond
`or
`a
`hetero
`bond, O, S, NRE, wherein Re is H, Ci^alkyl, aryl-Ci^alkyl, acyl or (C1^alkoxy)carbonyl, and
`carbonyl, and/or
`- which may have as
`substituent C^alkoxy, C^alkenyloxy,
`a
`Cz^alkynyloxy,
`arytCi^alkyl-oxy, acyl, CMalkylamino,
`CMalkylthio, acylamino,
`(Ci.
`4alkoxy)carbonyl, (Ci^alkoxy)-carbonylamino, acyloxy, (Ci^alkyQcarbamoyl,
`nitro, halogen, amino, hydroxyimino, hydroxy orcarboxy;
`or
`
`atom
`
`selected
`
`R1 is
`- a phenylalkyl wherein alkyl is a
`straight- or branched
`(C»3o)carbon chain;
`or
`• a phenylalkyl wherein alkyl is a straight- or branched (Ci^o)carbon chain wherein
`phenylalkyl is substituted
`by
`• a straight- or branched (Ce^carbon
`chain
`optionally substituted
`- a straight- or branched (Co4o)alkoxy chain
`optionally substitued
`by
`• a straight- or branched
`(CMo)alkenyloxy,
`• phenyl-Ci.walkoxy, halophenyl-Ci^alkoxy, phenyl-Ci.ualkoxy-C^.ualkyl, phenoxy-C,.
`^alkoxy or phenoxy-Ci^alkyl,
`• cydoalkylalkyl substituted
`by Cs-ztalkyl,
`- heteroarylalkyl substituted
`by Cs-zoalkyl,
`• heterocyclic Ce^alkyl or
`- heterocyclic alkyl substituted
`and wherein
`
`by Cj.joalkyl.
`
`said
`
`by
`halogen,
`halogen,
`
`TEVA EX. 1012
`Page 7
`
`

`

`Case 50279P1
`
`the alkyl moiety may have
`• in the carbon chain, a
`bond
`or
`a
`heteroatom
`S, sulfinyl, sutfonyl, or NRe, wherein Rg is as defined above,
`and
`•
`- as a substituent Ci^alkoxy, C^alkenyloxy, Cj^alkynyloxy, arylCi-talkyloxy, acyl,
`amino, Cmalkylthio, acylamino,
`(CMalkoxyJcartjonyl, (C1^alkoxy)carbonylamino,
`(Ci^alkyl)carbamoyl, nitro, halogen, amino, hydroxy or
`carboxy,
`and
`each of R2, Ra, R4 and Rs, independently,
`is H, Ci-« alkyl or acyl
`or a pharmaceutically acceptable
`or hydrate thereof;
`salt
`• Compounds as disclosed in EP1002792A1, e.g. a compound of formula II
`
`selected
`
`from a
`
`C^alkyl-
`acyloxy,
`
`O
`
`C
`
`(CH2)m-
`
`II
`
`CHjOR1,
`
`wherein m is 1 to 9 and each of R'z, R'a, R'4 and R's, independently, is H, Ci^alkyl or
`or a pharmaceutically acceptable salt or hydrate thereof;
`- Compounds as disclosed in EP0778263 A1, e.g.
`a compound of formula
`N R ' ^ R ' j
`
`III
`
`y
`
`acyl,
`
`W - C - Z j — 1
`
`1
`
`1
`
`
`
`CCH^-OR",
`
`wherein W is H; Ci^alkyl, Cj^alkenyl
`Cj^alkynyl; unsubstituted or by OH substituted
`or
`phenyl; R"40(CH2)n; or
`Ci^alkyl substituted
`to 3 substituents selected
`by 1
`from the
`consisting of halogen, CMcydoalkyl,
`phenyl and
`phenyl
`substituted
`by
`X is H or unsubstituted or substituted straight chain alkyl having a
`number p of carbon
`atoms or unsubstituted
`substituted straight chain alkoxy having
`or
`a number (p-1) of carbon
`atoms, e.g.
`substituted
`to 3 substitutents selected from the group consisting
`by 1
`of Ci.
`talkyl, OH, Ci^alkoxy, acyloxy, amino, Cualkylamino,
`acylamino,
`oxo,
`halogen, unsubstituted phenyl and phenyl substituted
`by 1
`substituents selected
`to
`3
`from
`the group consisting of Ci^alkyl, OH. Ci^alkoxy,
`acyl,
`acyloxy, amino,
`Ci^alkylamino,
`acylamino, haloCi«alkyl and
`halogen;
`Y is H, C^alkyl,
`acyloxy, amino.
`OH, C^alkoxy,
`acyl,
`
`group
`OH;
`
`haloCi^alkyt,
`
`TEVA EX. 1012
`Page 8
`
`

`

`Case 50279P1
`
`. 5 .
`
`
`
`halogen, Zj is a single bond or a straight chain
`
`integer to 20, with the proviso of 6<p+qf23,
`
`Cvealkylamino, acylamino, haloCi-ealkyl or
`alkylene having a
`
`number or carbon atoms of q,
`each of p and q, independently,
`is an
`of 1
`1,2 or 3, n is 2 or 3,
`C^atkyloracyl,
`isH,
`each of R"i, R'a. R"jand R"«, independently,
`or a pharmaceutically acceptable salt or hydrate thereof,
`- Compounds as disclosed in W002/18395,
`
`e.g. a compound of formula
`
`
`
`
`
`IVa or IVb
`
`•
`
`(RJJN-C-CHJ-XJ— P=0
`
`9^
`cn.
`
`%
`(RJa)2N.C.CH2-Xr- P=0
`I
`
`H,
`
`or
`
`CHj
`
`WCH,
`
`lVa
`
`V R4a
`
`IVb
`
`wherein Xe is O, S, NR1# or a group -(CHsW. which group is unsubstituted or substituted by
`
`
`
`or is H or (C^Jalkyl, which alkyl is unsubstituted substituted
`1 to 4 halogen; n, is 1 or 2, Rto
`by halogen; R1a is H, OH,
`(Ci^atkyl
`or
`
`0(Cm)alkyt wherein alkyl is unsubstituted or
`substituted by 1 to 3 halogen; R* is H, OH or (Ci^alkyl, wherein alkyl is unsubstituted
`substituted by halogen;
`
`each is independently selected from H or (Ci^alkyl, which alkyl R^
`
`is unsubstituted or substitued by halogen; R* is H, OH, halogen or 0(C^)alkyl
`wherein
`alkyl is unsubstituted or
`substituted
`by halogen;
`and
`Ra
`wherein alkyl is unsubstituted
`or
`substituted
`by hydroxy, or
`
`0(Ci)alkyl
`halogen; Ya is -CHr. -CtO)-, -CH(OH)-, -C(=NOH)-, 0 or S,
`unsubstituted or
`substituted
`by
`and R4a is
`or (C4.i4)alkenyl;
`
`(Chalky)
`or a pharmaceutically acceptable salt or hydrate thereof,
`- Compounds as disclosed in W002/06268AI, e.g.
`
`a
`
`
`
`compound of formula V
`
`or
`
`H, OH,
`is
`
`wherein
`-4
`
`m"
`
`is
`
`halogen,
`alkyl is
`
`TEVA EX. 1012
`Page 9
`
`

`

`Case 50279P1
`
`• 6 -
`
`NR1dR
`20 R«U-A7i
`—Y«—Rsa
`Hj)n^^rXd'
`
`R4«
`
`v
`
`wherein each
`of RM
`RM is hydrogen, a
`
`is independently, H or an amino-protecting group;
`
`RWt
`and
`
`
`hydroxy-protecting group or a residue of formula
`OR*
`— P< OR*
`o
`
`R* is Ci^alkyl;
`6;
`to
`nd is an integer of 1
`a having - D-CHr (wherein D is
`group
`a
`Xa is ethylene, vinylene, ethynylene,
`
`
`carbonyl, - CH(OH)-, O. S or N), aryl or aryl substituted by up
`
`
`to substitutents three
`selected from group a
`as
`defined
`hereinafter,
`
`Yi is single bond, Cuoalkylene,
`
`Ci.ioalkylene which is substituted up to three by
`substitutents selected
`from groups
`
`a Ci.ioalkylene having O and b,
`
`
`
`or S In the middle or end
`of the carbon chain,
`or
`
`Ci.ioalkylene having 0 or S in the middle or end of the carbon chain
`which is substituted
`
`by up to three substituents selected from groups a and b;
`by up
`RM is hydrogen, C»ecycloalkyl, aryl, heterocyclic group, C»cycloalkyl substituted
`
`three substituents selected from groups
`
`a and b, aryl substituted by up
`
`to substituents three
`selected from groups a and b, or heterocyclic group substituted by up to three substituents
`selected from groups a and b;
`is H or a substituent selected from group a;
`each of Red and RTO, independently,
`each of Ran and RM, independently,
`is H orCi^alkyl optionally substituted
`by halogen;
`<group a > is halogen,
`lower aDcyl, halogeno lower alkyl, lower alkoxy, lower alkylthk),
`carboxyl, lower alkoxycarbonyl, hydroxy,
`lower aliphatic
`acyl,
`amino,
`mono-lower
`alkylamino, di-Ci^alkylamino, acylamino,
`cyano
`or
`nitro; and
`<group b > is CMcydoalkyl, aryl or
`
`heterocyclic group, each being optionally substituted
`up to three substituents
`selected
`
`from group a;
`
`with the proviso that when is hydrogen,
`is a either a single bond or
`RM
`alkylene, or a pharmacologically acceptable salt, ester or hydrate thereof;
`
`linear C
`1-10
`
`by
`
`•Compounds as disclosed in JP-14316985
`
`
`
`(JP2002316985), e.g. a compound of formula VI
`
`formula
`
`to
`
`TEVA EX. 1012
`Page 10
`
`

`

`Case 5Q279P1
`
`R6e
`NR1eRa,
`<CHs)n,
`
`.Xe-V-R5.
`%
`s
`
`V I
`
`*3.0^
`wherein Ri«,R20.R3«.R46.Rs#,Rs#,R?#, ru. X* and Y. are as disclosed in JP-14316985:
`or a pharmacologically acceptable salt, ester or hydrate thereof;
`
`*7.'
`
`•Compounds as disclosed in WO03/062252A1, e.g.
`fc.
`•A/""'"
`l«Uu
`
`(CH,!.,
`A/
`
`a
`
`RI/
`
`VII
`
`wherein
`
`
`
`
`
`compound formula VII of
`
`
`
`Ar is phenyl or
`naphthyl; each of rig and ng independently is 0 or 1; A is selected from
`COOH, POsH*. POjH. SO3H PO(Cijalkyl)OH and 1H-tetrazol-5-yl; each
`of Ri9and
`independently is
`
`H, halogen, OH, COOH or optionally substituted by halogen; CMalkyl
`
`Rjg
`is H orCi^alkyl optionally substituted
`by halogen
`
`OH; or each R^ independently is halogen,
`
`or optionally halogen substituted Ci^alkyl or Ci^alkoxy; and
`each of Rj and M has one of
`
`the significances as indicated for B and C, respectively, in WO03/062252A1;
`or a pharmacologically acceptable salt, solvate or hydrate thereof;
`
`Rj,
`
`-Compounds as disclosed in WO 03/062248A2, e.g. a compound of formula VIII
`
`%
`
`A
`
`R5-M
`
`VIII
`
`wherein Ar is phenyl or naphthyl; n is 2,3 or 4; A is COOH, 1H-tetrazol-5-yl, PQsHs, PO2H2, •
`SO3H or PO(Rsh)OH wherein Rsb is selected from Ci^alkyl, hydroxyCi^alkyl, phenyl,
`-CO-Ci.
`jalkoxy and -CH(OH)-phenyl wherein said
`phenyl or
`phenyl moiety is
`optionally
`each of Rm and Ra
`
`
`is Independently H, halogen, OH, COOH, or
`optionally halogeno
`
`H is substituted Ci^alkyl or phenyl; Ru or C^alkyl optionally substituted by halogen
`
`
`OH; each R^
`
`is independently halogeno, OH, COOH, Ct^alkyl, S(0)o.i wsCioalkyl, C1.
`
`salkoxy, CMcycloalkoxy, aryl or aralkoxy, wherein the
`alkyl portions may
`optionally be
`
`and/
`
`substituted;
`
`TEVA EX. 1012
`Page 11
`
`

`

`Case 50279P1
`
`substituted by 1-3 halogens; and each
`Rh and M has one of the significances
`of
`indicated for B and C,
`respectively,
`in WO03/062248A2
`or a pharmacologically acceptable
`salt,
`or hydrate thereof.
`solvate
`
`as
`
`- Compounds as disclosed in WO 04/103306A. WO
`05/000833, WO 05/103309 or WO
`05/113330, e.g.
`compounds
`of formula IXa or
`IXb
`
`*1
`
`V^P..
`
`'•nr-NH
`
`Xo-w/R"
`
`"V"
`
`IXa
`
`IXb
`
`IH-tetrazol-S-yl,
`Rsk being H
`
`wherein
`At, is COORsk, OPO(ORsi<)2, PO(ORa)2t SOjORsk, PORaORsk or
`orCi^alkyl;
`Wk is a bond, Ci^alkyiene or
`C^alkenylene;
`Vk is Cfrioaryl or C^sheteroaryl, optionally substituted
`to 3 radicals selected
`by 1
`from
`halogene, OH, NOz, Ci^alkyl, Ci^alkoxy; halo-substituted Ci^alkyl
`halo-substituted
`and
`Ci^alkoxy;
`Zk is a heterocyclic group
`indicated in WO 04/103306A. e.g. azetidine;
`as
`Rik is Ce-ioaryl or C^heteroaryl,
`optionally substituted
`by Ci^alkyl, Ce-ioaryl, Cs-^rylC,.
`4alkyll CMheteroaryl, Cj-sheteroarylCi^alkyl, CMCycloalkyl,
`CucycloalkylCi^alkyl,
`Cuheterocydoalkyl or CuheterocycloaikylC^alkyl; wherein any
`aryl,
`heteroaryl,
`or heterocycloalkyl of Rik may be substituted by 1
`groups selected
`to
`5
`from halogen, Ci.
`salkyl, Ci^alkoxy and
`halo
`substituted-C^alkyl
`or
`-Ci^alkoxy;
`Rjk is H, Ci^alkyl, halo substituted Ci^alkyl, Cj-salkenyl or Cj^alkynyl: and
`each of Rak or Ru,
`independently,
`is H,
`halogen, OH, C^alkyl, Ci^alkoxy
`Ci-ealkyl or Ci^alkoxy;
`and the N-oxide derivatives
`thereof or prodrugs
`thereof,
`or a pharmacologically acceptable salt, solvate or hydrate thereof.
`
`substituted
`or
`halo
`
`cycloalky!
`
`The compounds of formulae
`I to IXb may exist
`in free or salt form. Examples of
`'
`pharmaceutically acceptable
`salts
`of the compounds of the formulae I
`to VI include salts
`with inorganic acids,
`such
`hydrochloride, hydrobromide and
`as
`sulfate,
`salts with organic
`acids, such as acetate, fumarate, maleate,
`benzoate,
`citrate, malate,
`methanesulfonate
`benzenesulfonate
`salts,
`when appropriate, salts with metals such as
`or,
`sodium, potassium,
`
`and
`
`TEVA EX. 1012
`Page 12
`
`

`

`Case 50279P1
`
`calcium and'aluminium, salts with amines, such as
`amino adds, such as
`lysine. The compounds and salts of the
`invention encompass
`hydrate
`and
`
`solvate forms.
`
`triethylamine and with dibasic
`
`combination of the
`
`salts
`present
`
`Acyl as
`residue is Ci^alkyl, CMCydoalkyl,
`
`R^-CO* wherein
`a
`be
`may
`above
`indicated
`phenyl or phenyl-C^alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may
`be
`straight or branched.
`
`Ry
`
`Aryl may be phenyl or naphthyl, preferably phenyl.
`
`substituted,
`Ri is
`of formula I the carbon chain as
`
`When in the compounds
`
`nitro, amino,
`hydroxy or
`carboxy. When the carbon
`chain
`substituted by halogen,
`interrupted by an
`optionally substituted
`phenylene,
`the
`carbon
`unsubstituted. When the phenylene moiety is
`substituted,
`preferably
`halogen, nitro, amino, methoxy, hydroxy or carboxy.
`
`
`
`it is
`
`
`
`it is
`
`preferably
`
`is
`
`chain
`substituted
`
`is
`
`preferably
`
`by
`
`optionally substituted
`of formula I are those wherein R1 is Ciuoalkyl,
`Preferred compounds
`by nitro, halogen, amino, hydroxy or
`carboxy,
`and,
`more preferably wherein Rt is
`
`those
`
`phenylalkyl substituted
`
`by Ctiralkyl chain optionally substituted
`by halogen and
`the
`alkyl
`moiety is a
`Ci^aDcyl optionally substituted
`by hydroxy. More preferably,
`R,
`substituted on the phenyl by a
`straight or
`branched,
`
`straight, preferably Ce-ualkyl chain. The
`
`
`Ce-ualkyl chain may be in ortho, meta or para,
`preferably
`in para.
`
`is
`
`Preferably each
`
`
`
`of R2 to is H.
`
`R$
`
`group" represents a 5- to 7 membered heterocydic
`
`In the above formula of V "heterocydic
`group having 1 to 3 heteroatoms selected from S, O and N. Examples of such
`heterocyclic
`groups indude
`the
`heteroaryl
`
`groups indicated above, and
`
`heterocydic compounds
`
`corresponding to
`partially or
`completely hydrogenated
`
`groups, heteroaryl furyl, thienyl,
`pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl. 1,2>
`oxadiazolyl, triazolyl, tetrazolyl,
`thiadiazolyl, pyranyl, pyridyl, pyridazinyl.
`pyrimidinyl,
`pyrazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl,
`imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,
`thiazolidinyl
`and
`groups
`or pyrazolidinyl Preferred
`heterocydic
`
`groups are 5-or6-membered heteroaryl
`the most preferred heteocydic
`group
`is
`a
`morpholinyl, thiomorpholinyl or
`
`e.g.
`
`A preferred compound of formula I is 2>amino-2-tetradecyl-1l3-propanediol. A particularly
`preferred SIP
`
`receptor agonist of formula I is FTY720, Le. 2-amino-2-[2-(4-octylphenyl)
`
`phenyl-C14alkyl
`
`piperidinyl group.
`
`TEVA EX. 1012
`Page 13
`
`

`

`Case 50279P1
`
`- 1 0 -
`
`form or
`in free
`et)iy0propane-1,3-diol
`hereinafter as Compound A), e.g.
`the
`
`in a
`hydrochloride, as
`
`acceptable pharmaceutically salt form (referred to
`
`
`
`
`shown:
`
`HO—1 OH
`K,N
`
`• HCI
`
`of R'j to R's is H and m is 4, i.e.
`A preferred compound of formula II is the one wherein each
`2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyt]ethyl}propane-1,3-diol,
`
`in free
`form
`pharmaceutically acceptable
`salt
`form (referred
`to
`hereinafter
`as
`Compound B), e.g
`the
`hydrochloride.
`
`or
`
`in
`
`CHj, each of R"i to R' s is H, Zj
`
`A preferred compound of formula III is the one wherein W is
`is ethylene, X is heptyloxy and
`Y is
`H, i.e.
`
`2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol1
`form (referred to hereinafter
`as
`in free form or
`in pharmaceutically
`acceptable
`salt
`Compound C), e.g.
`the
`
`hydrochloride. The R-enantiomer is particularly preferred.
`
`
`the
`IVa is
`of formula
`A preferred compound
`FTY720-phosphate is OH, Xe is O,
`(Rz,
`A preferred compound of formula IVb is the Compound C-phosphate
`R1a and Rib are
`OH).
`
`(R* is H. Rjb is OH. X. is 0, Ri. and Rib are OH. Ya is 0 and R,.
`is heptyl). A preferred
`compound of formula V is Compound B-phosphate.
`
`is
`
`H,
`
`of formula VI is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-
`A preferred compound
`benzo[b]thien-6-yl]-2-methylbutarv1-ol.
`
`A preferred compound
`1-{4-t1-(4-cyclohexyl-3-trifluoromethyl«
`of formula IXa is e.g.
`benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic add, or a prodrug thereof.
`
`properties
`known as having immunosuppressive
`
`S1P receptor agonists or modulators are
`
`anti-angiogenic properties
`in the
`
`of treatment tumors, e.g. as disclosed in EP627406A1,
`WO 04/103306, WO 05/000833, WO 05/103309,
`WO
`05/113330
`
`or
`
`or
`
`nervous with
`
`central
`of the
`an immune-mediated disease
`
`(MS) is
`Multiple sclerosis
`chronic inflammatory demyelination
`sensory
`
`leading to progressive decline of motor and
`functions and permanent
`
`disability. The therapy of multiple sclerosis
`is only partially
`effective, and
`in most cases
`
`only offers a short delay in disease
`progression despite anti­
`inflammatory and
`immunosuppressive
`treatment.
`
`Accordingly, there is a need for agents
`which are effective in the inhibition or treatment
`of demyelinating diseases,
`e.g.
`
`WO
`
`03/097028.
`
`system
`
`multiple
`
`TEVA EX. 1012
`Page 14
`
`

`

`Case 50279P1
`
`- 1 1 -
`
`sclerosis or Guillain-Barr6 syndrome, including reduction of, alleviation of,
`relief from the symptoms which affect the organism.
`
`
`
`stabilization or
`
`of
`
`Characteristic pathological features of demyelinating diseases include inflammation,
`demyelination and axonal and oligodendrocyte loss. In addition lesions can also have a
`significant vascular component. A firm link has recently been established between chronic
`inflammation and angiogenesis and neovascularization seems to have a significant role in
`the progression of disease.
`
`found
`It has now been
`angiogenesis associated
`
`an
`that receptor modulators have S1P
`
`
`with demyelinating
`
`diseases, e.g. MS.
`
`inhibitory effect
`
`on
`
`neo-
`
`present invention provides:
`
`the
`specific or alternative embodiments,
`In a series of further
`neo-angiogenesis
`1.1
`A method for preventing,
`inhibiting or
`treating
`thereof,
`comprising
`demyelinating disease,
`
`
`MS, e.g. in a subject
`in need
`administering to
`said
`
`subject a therapeutically effective amount of an S1P receptor
`modulator, e.g.
`
`a compound of formulae
`I to IXb.
`
`associated
`
`with a
`
`1.2
`
`demyelinating
`of the symptoms of a
`A method for alleviating or delaying progression
`disease, e.g. multiple sclerosis or Guillain-Barrg syndrome,
`in a subject in need
`thereof, in which method
`neo-angiogenesis
`
`associated disease is with said
`
`prevented or
`inhibited, comprising administering
`to said subject a
`therapeutically
`effective amount
`of an
`S1P
`receptor
`modulator, compound of formulae I to e.g.
`
`
`a
`IXb.
`
`1.3 A method for reducing or preventing or alleviating relapses
`demyelinating
`in a
`in a subject in need
`disease, e.g. multiple sclerosis or Guillain-Barrd syndrome,
`thereof, in which method
`neo-angiogenesis
`associated
`
`with said is
`prevented or
`inhibited, comprising administering
`to
`said subject
`effective amount
`of an
`
`S1P receptor modulator, e.g.
`a
`
`compound to
`IXb.
`
`a
`
`of formulae
`
`disease
`therapeutically
`
`I
`
`1.4
`
`A method for slowing progression
`
`of a demyelinating disease, e.g.
`subject
`being
`in
`a
`or Guillain-Barrd syndrome,
`in a
`disease,
`in which method neo-angiogenesis associated with said disease is
`prevented or inhibited, comprising administering
`
`to said subject a
`therapeutically
`effective amount of an
`
`S1P receptor modulator, e.g.
`a
`compound
`of formulae to
`
`Xlb.
`
`multiple sclerosis
`
`
`relapsing-remitting the
`
`I
`
`phase
`
`TEVA EX. 1012
`Page 15
`
`

`

`Case 50279P1
`
`- 1 2 -
`
`the 1.5 A method as indicated above, wherein Si P receptor modulator
`
`
`
`
`intermittently.
`
`is administered
`
`For example,
`
`
`the
`2ni or 3rt day or once a week.
`
`S1P receptor modulator may be administered to
`
`the
`
`subject
`
`eveiy
`
`of the to 1.5,
`
`
`in any
`use
`for
`A pharmaceutical composition
`
`a
`I to IXb as
`comprising an S1P
`receptor modulator,
`e.g.
`defined hereinabove,
`together
`with one
`or more phaimaceutically acceptable
`
`diluents or carriers therefor.
`
`one
`
`methods
`compound
`of formulae
`
`
`
`1.1
`
`a
`receptor modulator, e.g
`An S1P
`
`
`
`
`to above, for use in any one of the methods 1.1 1.5.
`
`
`
`of compound to IXb as defined herein formula
`
`
`
`
`
`I
`
`4
`
`An S1P
`receptor modulator, e.g. compound of formulae I to IXb as a
`
`
`above, for use in the preparation of a medicament for use
`in any
`1.1 to 1.5.
`
`defined herein
`one
`
`of the
`
`methods
`
`patterns:
`four having MS into types of disease
`
`
`patients
`Clinicians usually categorize
`• Relapsing-remitting (RR-MS): Discrete motor, sensory, cerebellar or visual attacks that
`occur over 1-2 weeks and often resolve over 1-2 months. Some
`
`patients accrue disability
`with each episode, yet remain clinically stable between relapses. About 65% of patients
`initially experience the RR form of MS, but within 10 years about half will develop the
`secondaiy progressive form.
`• Secondary-progressive
`(SP-MS): Initially RR followed by gradually increasing disability,
`with or without relapses. Major irreversible disabilities appear most often during SP.
`• Primary-progressive (PP-MS): Progression disease course from onset without any
`relapses or
`remissions,
`
`affecting about 15% of MS patients.
`• Progressive-relapsing
`(PR-MS): Progressive disease from onset with clear acute
`relapses; periods between
`relapses
`characterized
`by continuing
`
`progression.
`
`comprising a group
`
`the e.g. S1P receptor modulators
`
`
`receptor modulators,
`Utility of the S1P
`of formula X, in preventing or treating neo-angiogenesis associated with a demyelinating
`disease as
`hereinabove
`specified, may
`
`be animal test methods demonstrated as
`
`
`in clinic, for example
`in accordance
`with the
`
`
`methods described. hereinafter
`
`in
`
`well as
`
`In vivo: Relaosino Experimental Autoimmune Encephelomvelltis
`
`(EAE)
`
`TEVA EX. 1012
`Page 16
`
`

`

`Case 50279P1
`
`•13-
`
`Disease is induced in female Lewis rats by immunization with guinea pig spinal cord tissue
`emulsified in complete Freund's adjuvant. This results in an acute disease within 11 days,
`followed by an almost complete remission around day 16 and a relapse at around days
`On day 26 rats are
`thoracectomized
`after
`having been
`deeply anesthetized with
`Isofiurane
`<3%, 20 L / min) and perfused through the left ventric