Document made available under
`Patent Cooperation Treaty (PCT)
`
`the
`
`International application number: PCT7US2005/043044
`
`International filing date:
`
`28 November 2005 (28.11.2005)
`
`Document type:
`
`Certified copy of priority document
`
`Document details:
`
`Country/Office: US
`60/631,483
`Number:
`29 November 2004 (29.11.2004)
`Filing date:
`
`Date of receipt at the International Bureau: 02 February 2006 (02.02.2006)
`
`Remark: Priority document submitted or transmitted to the International Bureau in
`compliance with Rule 17.1(a) or (b)
`
`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
`Organisation Mondiale de la Propriete Intellectuelle (OMPI) - Geneve, Suisse
`
`TEVA EX. 1015
`Page 1
`
`

`

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`UNITKI) Sl A^rES DEPARTMENT OP COMMERCE
`l iutoU Sfatcs Patent and Tradeinark Office
`
`January 30, 2006
`
`IS A TRUE
`THIS IS TO CERTIFY THAT ANNEXED HERETO
`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO
`
`BE GRANTED A
`FILING DATE.
`
`COPY
`
`APPLICATION NUMBER: 60/631,483
`FILING DATE: November 29, 2004
`RELATED PCT APPLICATION NUMBER: PCT/US05/43044
`
`THE COUNTRY CODE AND NUMBER OF YOUR PRIORITY
`APPLICATION, TO BE USED FOR FILING ABROAD UNDER THE PARIS
`CONVENTION, IS U360/631,483
`
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`TEVA EX. 1015
`Page 2
`
`

`

`ro
`CO
`4^
`
`no cr
`4^ ro
`
`c
`03-
`-II
`o
`
`Docket Number I TX/4-34053P1
`
`FILING BY
`
`"EXPRESS MAIL" UNDER
`
`37
`
`CFR
`
`1.10
`
`EV483667524US
`Express Mail Label Number
`
`November 29, 2004
`Date of Deposit
`
`tt-
`
`p
`CO
`oj'^r
`z>
`CO
`CO
`<0
`feSJlH
`o
`
`Commissioner for Patents
`PO Box 1450
`Alexandria. VA
`
`22313-1450
`
`PATENT COVER SHEET FOR PROVISIONAL APPLICATION
`Transmitted herewith for filing under 37 CFR §1.53(c) is the PROVISIONAL APPLICATION
`
`for patent of
`
`Given Name (first and middle pf any])
`
`INVENTOR(S)
`Family Name or Surname
`
`Residence (City and either State or Foreign Country)
`
`John M
`
`Kovarik
`
`Basel, Switzerland
`
`TITLE OF THE INVENTION
`(280 characters max)
`ORGANIC COMPOUNDS
`
`CORRESPONDENCE ADDRESS
`Direct all correspondence to the address associated with Customer No.
`001095,
`
`which is currently:
`
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`Corporate Intellectual Property
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`
`ENCLOSED APPLICATION PARTS
`
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`(check at! that apply)
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`
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`sheets
`E3 Other (specify): Application Data Sheet
`
`METHOD OF PAYMENT
`PROVISIONAL FILING FEE
`The Commissioner is hereby authorized to charge filing fee and any
`in the
`name
`additional fees required to Deposit Account Number: 19-0134
`of Novartis.
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`
`AMOUNT: 160
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`
`
`• U.S. Government agency and contract number:
`•r under a contract with an agency of the United States Government.)
`
`(if the invention was made by an agency of the United States Government
`
`Date: November 29, 2004
`
`Respectfully submitted,
`
`Thomas R. Savitsky
`Attorney for Applicant
`Reg. No. 31,661
`Tel. No. (862) 778-7909
`
`TEVA EX. 1015
`Page 3
`
`

`

`• Case TX/4-34053P1
`
`Organic Compounds
`
`relates
`The present invention
`the course of the
`treatment
`
`to
`of
`
`regimen
`dosage
`a
`transplant
`patients.
`
`of
`
`
`
`an particularly in
`
`S1P
`
`signal at one or more sphingosine-as agonists
`
`
`
`which
`compounds
`SI P receptor agonists are
`
`
`binding Agonist a S1P receptor may e.g. to
`
`S1P8.
`1 phosphate receptors, e.g. S1P1
`to
`G-proteins
`
`Ga-GTP into GPY-GTP,
`
`result in dissociation of
`intracellular
`heterotrimeric
`and/or increased phosphorylation
`of
`the
`agonist-occupied
`receptor
`and
`downstream signaling pathways/kinases.
`
`and
`
`of
`
`manufacture
`the
`for
`compounds
`valuable
`S1P receptor agonists are
`
`
`especially human beings. For example, S1P in
`mammals,
`treatment of various conditions
`in
`
`
`
`in used been the treatment of
`transplant patients,
`receptor agonists have successfully
`particularly prolonging allograft
`survival with
`great
`potency
`and
`excellent synergy with several
`immunosuppressants.
`This
`has
`been
`(skin, heart, liver, small bowel), dogs (kidney), and monkeys (kidney).
`Combination
`experiments with cyclosporin A
`showed
`
`synergy in skin and heart transplantation models
`rats and in monkey
`
`renal transplantation. SIP
`receptor
`agonists
`combined with everolimus
`
`Due
`prolong survival of cardiac
`(rat)
`and
`renal
`
`(monkey) to their immune-allografts.
`
`
`modulating potency, S1P
`receptor
`agonists
`are
`
`
`
`also the treatment of useful inflammatory for
`and autoimmune diseases. Further
`characteristics
`receptor
`of
`S1P
`the following publications:
`
`efficacy
`documented
`
`in
`
`agonists
`
`al
`et
`general
`
`FTY720
`(2001)
`immunosuppression.
`
`alters
`Transplant
`
`lymphocyte
`
`L,
`Brinkmann V, Chen S, Feng
`protects allografts without
`inducing
`33:530-531.
`lymphocyte
`L, Feng et al (2001) FTY720: altered
`
`
`Brinkmann V, Pinschewer D,
`(review).
`Transplantation;
`72:764-769.
`results in allograft protection
`
`Pinschewer DD, Ochsenbein AF, Odermatt B, et al (2000) FTY720
`immunosuppression
`impairs effector
`T-cell
`peripheral
`164:5761.
`induction, expansion, and memory.
`J
`Immunol;
`Yanagawa Y, Sugahara K,
`(1998)
`al
`Kataoka
`et
`H,
`mature
`circulating
`immunosuppressant,
`induces
`sequestration
`of
`acceleration of
`lymphocyte
`homing
`in
`allograft
`rats. II. FTY720 prolongs
`skin
`by decreasing T
`cell
`
`
`infiltration into grafts but not cytokine production in vivo. J
`Immunol.; 160(11):5493-9.
`dosage specific regimen, e.g. a loading dose,
`
`
`a
`that
`found
`It has now surprisingly been
`
`
`
`pIn provide further unexpected benefits. articular, the otherwise observed moderate
`and
`
`traffic
`
`homing
`
`without
`
`FTY720,
`lymphocytes
`survival
`
`will
`
`TEVA EX. 1015
`Page 4
`
`

`

`• Case TX/4-34053P1
`
`rate
`in heart
`transient decrease
`longer
`body is suppressed or
`no
`specific dosage
`regimen allows
`for
`decrease in heart rate.
`
`up-take
`the
`with
`associated
`of
`most
`the
`at
`after
`observed
`one
`
`
`of re-initiation the treatment after a hiatus
`avoiding
`
`week
`said
`
`SIP in the manufacture
`
`an of receptor agonist
`
`
`
`use
`the
`Accordingly it is provided
`of
`
`is
`
`in administered such a way that during
`
`medication, whereby said medication
`
`initial the 3 to
`6 days, preferably 4 or 5 days, most preferred 4 days, of treatment
`the
`dosage
`said
`of
`receptor agonist
`is
`raised
`so
`that
`in
`total
`the
`R-fold
`(R
`being
`is
`standard daily dosage of said SIP
`receptor
`agonist
`administered
`treatment is continued with
`the
`daily of said S1P receptor agonist. dosage
`
`
`
`standard
`
`a
`
`transplant patients providing prolonged
`
`for
`Preferred medications comprise medication
`survival rates, in particular prolonged allograft survival rates especially
`for
`
`renal or liver
`transplants, or for patients
`suffering
`from
`
`autoimmune multiple sclerosis. diseases,
`
`
`e.g.
`
`refers
`the the standard daily dosage medication,
`
`
`of
`taking
`In view of the normally prolonged
`steady-state
`necessary
`for
`a blood level of
`
`agonist
`to the dosage of an S1P
`receptor
`the medication or
`its active metabolite(s)
`providing
`effective
`
`treatment. is
`Said
`dependent on
`the accumulation factor
`(R).
`Steady-state
`
`trough levels may be
`blood
`assessed, for example, by
`averaging
`data
`
`
`
`
`at collected 3, and 6 of a months treatment with 2,
`a constant daily dosage,
`thereby
`allowing
`
`calculation Preferably R is approximately of R.
`
`
`from 3 to 12, preferably about 10.
`
`
`
`
`agonist to 6 days of treatment during the
`
`
`receptor
`S1P
`said
`Preferably, the dosage of
`of
`the
`preferred
`preferred dosage
`is increased stepwise. A particularly
`FTY720 is 5, 10, 15 and 20 mg, respectively, during
`
`the
`initial period of 4 days. Thereafter
`the treatment is continued with
`the maintenance
`therapy, a daily dosage of 5 mg. e.g.
`
`
`
`initial
`
`during agonist 3 to 6 days, preferably
`
`
`receptor
`Preferably, the dosage of said SIP
`incrementally
`up
`to
`
`4 or 5 days, most preferred
`
`days, 4 of treatment is increased
`
`particularly preferred up
`to
`4-fold, the standard daily dosage of
`said
`S1P
`receptor
`
`the
`
`3-
`agonist.
`
`typically
`SI P receptor agonists are
`propane-1,3-diol or 2-amino-propanol
`formula X
`
`2-amino-
`sphingosine analogues, such as 2-substituted
`
`derivatives,
`e.
`g.
`
`a a group of compound comprising
`
`
`TEVA EX. 1015
`Page 5
`
`

`

`• Case TX/4-34053P1
`
`z
`
`R3ZR2ZN
`
`CH2R1Z
`
`(X)
`
`by
`phenyl substituted Ci^alkyl
`
`phenyl,
`C2-6alkenyl, C2^alkynyl,
`wherein Z is H, Ci^alkyl,
`halogen,
`consisting
`of
`group
`substituted by 1
`
`to 3 substituents selected
`from
`the
`8cycloalkyl, phenyl and phenyl
`
`substituted by OH, or CH2-R4Z wherein R42 is OH, acyloxy or a
`residue of formula
`(a)
`
`ORs,
`
`ORez
`
`z
`
`p
`O
`
`( a )
`
`wherein Z,
`
`
`
`is a direct bond preferably O; or O,
`
`
`
`
`
`each of R5Z and R6z, independently,
`halogen atoms;
`
`is H, or Ci^alkyl optionally
`
`
`
`
`
`by substituted 1, 2 or 3
`
`is OH, acyloxy or a
`R1z
`C^alkyl or acyl.
`
`residue
`
`of
`
`formula
`
`(a);
`
`and
`
`each
`
`and
`
`of
`
`Rsz
`
`group
`functional
`Group of formula X is a
`be hydrophilic or
`lipophilic and
`comprise
`heterocyclic residues,
`to
`the
`extent
`that
`R12 is or comprises a residue
`of
`formula
`sphingosine-1 -phosphate receptor.
`
`terminal
`a
`as
`attached
`aliphatic,
`more
`one
`or
`
`least one of and
`e wherein at
`molecul
`the
`resulting
`
`(a),
`
`signals one of more as
`an
`
`Z
`
`group
`alicyclic,
`
`agonist
`
`which their S1P binding in
`compounds addition to
`
`
`
`e.g.
`are
`Preferred S1P receptor agonists
`compounds
`homing
`properties,
`
`e.g. which
`properties also have accelerating lymphocyte
`re-distribution,
`preferably
`reversible,
`elicit a lymphopenia resulting
`from
`a
`from circulation to secondary lymphatic
`tissue, without
`evoking
`a
`generalized
`immunosuppression. Naive
`cells are
`sequestered;
`CD4
`and
`
`CDS T-cells the
`blood are stimulated
`to migrate
`into
`
`nodes lymph (LN) and Peyer's patches (PP).
`
`
`Examples of appropriate S1P
`
`receptor
`
`agonists
`
`are,
`
`for
`
`example:
`
`
`
`
`
`of
`
`formula
`
`I
`
`- Compounds as disclosed EP627406A1, e.g. a compound in
`9 H2O R3
`CH2OR2
`
`R4R5N
`
`R
`
`I
`
`TEVA EX. 1015
`Page 6
`
`

`

`• Case TX/4-34053P1
`
`_ /j _
`
`(C^^Jchain
`is a straight- or branched
`wherein R,
`- which may have in the chain a bond or a hetero atom selected from a double bond, a triple
`
`
`bond, O, S, NRe, wherein Re is
`H,
`alkyl,
`
`aralkyl, or alkoxycarbonyl, and acyl
`
`carbonyl,
`and/or
`- which may have as a substituent
`alkynyloxy,
`alkenyloxy,
`alkoxy,
`alkoxycarbonylamino,
`alkylamino, alkylthio, acylamino,
`alkoxycarbonyl,
`alkylcarbamoyl, nitro, halogen,
`amino,
`
`hydroxy hydroxyimino, or carboxy; or
`
`
`aralkyloxy,
`acyloxy,
`
`or
`a straight- or branched (C6.2o)carbon chain;
`
`
`a straight- branched (C^aojcarbon chain wherein or
`
`
`is
`
`by
`
`said
`
`halogen,
`
`or
`
`phenoxyalkyl,
`
`by
`
`C2-2oalkyl,
`
`Ri is
`- a phenylalkyl wherein alkyl is
`- a phenylalkyl wherein alkyl
`phenylalkyl is substituted by
`halogen,
`(C6-2o)carbon chain optionally substituted by
`
`- a straight- or branched
`(C6-2o)alkoxy chain
`optionally
`substitued
`- a straight- or branched
`- a straight- or branched (C6_2o)alkenyloxy,
`- phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy
`- cycloalkylalkyl substituted
`by Ce-^alkyl,
`- heteroarylalkyl substituted
`by Ce^oalkyl,
`- heterocyclic Ce-aoalM. or
`- heterocyclic alkyl substituted
`and wherein
`the alkyl moiety may have
`a
`from
`
`- in the carbon chain, a bond or a heteroatom selected
`and
`S, sulfinyl, sulfonyl, or NRe, wherein Re is as defined above,
`acyl, alkylthio,
`
`- as a substituent alkoxy,
`alkenyloxy,
`alkynyloxy,
`aralkyloxy,
`acylamino, alkoxycarbonyl, alkoxycarbonylamino,
`acyloxy,
`alkylcarbamoyl,
`amino, hydroxy or carboxy,
`and
`is H, alkyl or acyl
`each of R2, R3, R4 and R5, independently,
`thereof;
`or a pharmaceutically acceptable
`salt
`
`
`in - Compounds as disclosed EP 1002792A1, e.g. a compound of
`
`
`
`
`
`bond, double a triple bond, O,
`
`alkylamino,
`nitro,
`
`formula
`
`II
`
`CH.OR',
`I
`R'.R'sN-C-fCH^
`
`C H 20 R'2
`
`%
`
`//
`
`O
`
`C
`
`(C H 2)m
`
`y
`
`TEVA EX. 1015
`Page 7
`
`

`

`• Case TX/4-34053P1
`
`- 5 -
`
`wherein m is 1 to 9 and each of R'2, R'3, R'4 and R's, independently,
`or a pharmaceutically acceptable
`salt
`thereof;
`
`
`in - Compounds as disclosed EP0778263 A1, e.g. a
`N R". R".
`I
`1
`2
`W-C-Z2
`I
`(CH2)m.OR " 3
`
`Y
`
`X
`
`III
`
`is
`
`
`
`alkyl H, or acyl,
`
`
`
`compound
`
`of
`
`formula
`
`III
`
`or
`
`
`by
`
`of
`
`(p-1)
`C^
`
`
`
`6<p+q<23,
`
`m'
`
`chain
`
`unsubstituted
`C2^alkynyl;
`wherein W is H; C^ealkyl, C2-6alkenyl or
`phenyl; R"40(CH2)n; or Ci^alkyl
`
`substituted by 1 to 3 substituents selected
`
`from group the
`consisting of halogen, Cs-acycloalkyl, phenyl
`and
`
`
`substituted phenyl by OH;
`p
`X is H or unsubstituted or substituted straight chain
`alkyl
`having
`a number
`number
`or unsubstituted or substituted
`straight
`chain
`alkoxy
`having
`a
`of
`
`e.g. substituted by 1 3 substitutents selected to
`
`from
`the
`group
`
`consisting alkyl, OH,
`
`Ci^alkoxy, acyloxy, amino, C^alkylamino, acylamino, oxo, haloC^alkyl, halogen,
`substituents 3 the group
`
`unsubstituted phenyl and phenyl
`substituted
`by
`1
`
`to selected from
`
`consisting of C^alkyl,
`
`
`OH, C^alkoxy, acyl, acyloxy, amino, C^alkylamino, acylamino,
`haloC^alkyl and halogen; Y is H, C^alkyl, OH, C^alkoxy,
`
`acyl, acyloxy, amino, Ci.
`
`or Z2 is a single bond or halogen,
`
`6alkylamino, acylamino, haloC^alkyl
`a straight
`alkylene having a number or
`carbon
`atoms
`of
`q,
`
`each of p and q, independently, is an
`
`
`1 of integer to 20, with the proviso of
`1, 2 or 3, n is 2 or 3,
`is H,
`independently,
`each of R"i, R'z, R's and R"4,
`or a pharmaceutically acceptable
`salt
`thereof,
`- Compounds as disclosed in WO02/18395,
`
`e.g. a compound of
`
`Ci^alkyl
`
`or
`
`acyl,
`
`formula
`
`IVa
`
`or
`
`IVb
`
`?H2R3a
`I
`(R2a)2N-C-CH2-XT
`
`CH2
`CH2
`
`P =0
`
`Rib
`
`or
`
`?H2R3b
`I
`(R 2 a)2N-C-CH2-X-
`
`CH2
`
`CH2
`
`Ria
`I
`P = 0
`
`Rib
`
`(CH2)7CH3
`
`IVa
`
`VRo
`
`IVb
`
`TEVA EX. 1015
`Page 8
`
`

`

`. Case TX/4-34053P1
`
`a or -(CHaJna-. which group
`S, NR1s
`
`
`is O,
`wherein Xa
`substituted by
`group is unsubstituted or
`
`
`1 to 4 halogen; na is
`1 or 2, R1s
`
`H is which alkyl is unsubstituted or substituted or (C^Jalkyl,
`
`
`
`is H, OH, (Ci^)alkyl or 0(Ci^)alkyl wherein alkyl is unsubstituted or
`by halogen;
`substituted by 1 to 3 halogen; R^ is H, OH or (C^alkyl, wherein alkyl
`or
`is unsubstituted
`from which alkyl H
`
`or
`substituted by halogen; each R2a
`is
`independently
`selected
`
`is unsubstituted or substitued by halogen; Raa is H, OH, halogen
`or
`
`©(C^alkyl alkyl
`
`OH, H, halogen, (C^Jalkyl
`
`is unsubstituted or substituted by halogen; and
`Rab is
`wherein
`
`alkyl is unsubstituted or substituted by hydroxy, or 0(Ci^)alkyl wherein alkyl is unsubstituted
`-CHa-,
`-CH(OH)-, O or S, and Rja is
`or substituted by halogen; Ya
`
`-C(=NOH)-l
`is
`-0(0)-,
`(C4.
`i4)alkyl or (C4 .i
`4)alkenyl;
`thereof;
`hydrate
`or a pharmaceutically acceptable
`salt
`or
`
`- Compounds as disclosed in WO 02/076995, e.g. a compound of
`formula V
`
`^40^30^
`
`R1c
`
`Rc
`
`(CH2)mc-XcR2c V
`
`wherein
`mc
`is 1, 2 or 3;
`is O or a direct bond;
`Xc
`is H; C^ alkyl optionally substituted by OH, acyl, halogen, Ca-iocycloalkyl, phenyl or
`
`R1c
`
`hydroxy-phenylene; Ca^alkenyl; Cz^alkynyl; phenyl optionally substituted by OH; or
`
`is
`
`Rzc
`
`OR*
`— p<
`ORsc
`
`o
`optionally
`wherein Rsc is H or C^alkyl
`is H or C^alkyl optionally substituted by
`halogen;
`each of Rsc and R4C, independently,
`is
`H, C^alkyl
`
`and
`Rc
`
`is C13_2oalkyl which may optionally have in the chain an oxygen atom and which may
`
`optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of
`formula (a)
`
`
`
`substituted optionally halogen, or acyl,
`
`
`
`
`
`substituted or 3 halogen atoms, and Rec by 1,
`
`
`
`
`
`2
`
`TEVA EX. 1015
`Page 9
`
`

`

`• Case TX/4-34053P1
`
`-(CH2)2^--
`
`R7C
`
`(a)
`
`Rec
`
`Ci.2oalkanoyl,
`substituted
`is H, Chalky! or Ci^alkoxy, and Rgc is
`
`wherein R/c
`phenylC^^alkyl wherein
`
`the C^alkyl is optionally substituted by halogen
`or OH,
`cycloalkylCi-ualkoxy or
`phenylC^Malkoxy
`wherein
`the
`
`cycloalkyl is
`or
`optionally substituted by
`
`halogen, C^alkyl and/or C^alkoxy, phenylC^alkoxy-
`Ci.^alkyl, phenoxyCi.^alkoxy
`or
`phenoxyCi.ualkyl,
`being also a residue of
`formula
`(a)
`wherein
`Ca^alkenyl or Ca^alkynyl,
`or a compound of
`formula VI
`
`Rsc is
`
`Ci.^alkoxy
`
`Rc
`
`R4XR3XN
`
`R1x
`
`(CH2)n-
`CH2-OR2X
`
`Rsx
`
`VI
`
`Rex
`
`Rex
`
`
`
`C^alkyl optionally substituted by
`
`halogen
`
`or
`
`wherein
`nx
`is 2, 3 or 4
`is H; C^alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or
`
`R1x
`hydroxy-phenylene; Cz-ealkenyl; C2-6alkynyl; or
`phenyl
`optionally
`
`substituted OH;
`is H, C^alkyl or acyl
`R2X
`is H,
`each of Rsx and R4X, independently
`and
`is H, Ci^alkyl or C^alkoxy,
`Rsx
`cyloalkylC^ualkoxy the cycloalkyl wherein
`
`
`cycloalkyl;
`by
`is C^oalkanoyl
`substituted
`
`halogen,
`C^alkyl and/or C^alkoxy;
`phenylCv^alkoxy
`by
`ring is optionally substituted
`wherein the phenyl ring is optionally substituted by halogen,
`
`C^alkyl and/or C^alkoxy,
`Rex being also C^alkoxy
`
`when is C2-4alkyl substituted by OH,
`or
`pentyloxy
`R1x
`when Ru
`is C^akyl,
`provided that Rex is other
`
`than phenyl-butylenoxy when either
`or a pharmaceutically acceptable
`salt
`thereof;
`
`
`- Compounds as disclosed in W002/06268AI, e.g. a compound of
`
`by
`
`acyl,
`
`or
`
`hexyloxy
`
`is H or R1x is methyl,
`Rsx
`
`formula VII
`
`TEVA EX. 1015
`Page 10
`
`

`

`• Case TX/4-34053P1
`
`R6d, ^7d
`NR1dR2d
`(CH2)nff
`
`— Yd—R5d
`
`V I I
`
`R4d
`
`R 3d 0
`
`an wherein each of and R2d, independently, is H or amino-protecting group;
`
`
`Rad is hydrogen, a hydroxy-protecting
`
`group or a residue of
`formula
`OR,,
`— P<
`OR 8d
`
`o
`
`R4d is lower alkyl;
`to 6;
`nd is an integer of 1
`formula is
`a D -CH2-
`
`
`having
`a group
`Xd is ethylene, vinylene, ethynylene,
`
`carbonyl, - CH(OH)-, O, S or N), aryl or aryl substituted by to three substitutents selected up
`
`from group a as defined
`hereinafter;
`substituted three substitutents
`
`is
`which
`Yd is single bond, C^oalkylene,
`Ci.ioalkylene
`
`
`in middle or end of the he carbon t
`
`b,
`selected from groups a and
`C^^alkylene having O or S
`
`
`the
`chain, or Ci.^alkylene
`
`S or having O in the middle or end of
`
`
`carbon
`is
`chain
`substituted by up
`to
`three
`substituents
`selected
`
`from and b;
`groups
`a
`Rsd is hydrogen, cycloalkyl, aryl,
`heterocycle,
`cycloalkyl
`substituted
`by
`substituents selected
`from
`groups
`a and
`b,
`substituted aryl up to three substituents
`
`
`
`and selected from groups a b, or heterocycle substituted by
`
`up
`to
`three
`from groups a and b;
`group
`from
`each of Red and R/d, independently, is H or a substituent selected
`
`each of R8d and Rgd, independently, is H or C^alkyl
`
`optionally substituted by halogen;
`<group a >
`is halogen,
`lower alkyl,
`
`lower halogeno alkyl, lower alkoxy,
`
`lower alkylthio,
`carboxyl, lower alkoxycarbonyl,
`hydroxy,
`
`
`lower aliphatic acyl, amino, mono-lower alkylamino,
`di-lower alkylamino,
`lower aliphatic
`acylamino,
`cyano
`or
`nitro;
`and
`<group b > is cycloalkyl, aryl, heterocycle,
`
`each being optionally substituted
`
`by up to three
`substituents selected
`from
`group
`a;
`with the proviso
`that when Rsd is
`hydrogen,
`alkylene, or a pharmacologically
`acceptable
`
`-Compounds as disclosed
`
`in
`
`JP-14316985
`
`(JP2002316985),
`
`e.g.
`
`a
`
`Yd
`salt
`
`is a
`or
`
`ester
`
`1-10
`
`either
`thereof;
`
`a
`
`by
`
`—
`
`which
`
`up
`
`by
`substituents
`
`a;
`
`TEVA EX. 1015
`Page 11
`
`

`

`. Case TX/4-34053P1
`
`R4e
`
`• 9 "
`
`X - V — R5 e
`
`N R 16^28
`
`R
`6e
`
`(CH2)ne-4}
`
`Rze
`
`S
`
`VIII
`
`RaeO
`Ye are
`
`wherein Rie.Rae.Rae^e.Rse.Ree.Rye, ne, Xe
`as
`and
`thereof;
`or a pharmacologically acceptable salt or
`ester
`-Compounds as disclosed in WO 03/29184 and WO 03/29205, e.g. compounds of formula
`IX
`
`disclosed
`
`in
`
`JP-14316985;
`
`RH
`
`R2f
`
`x,
`
`Rsr
`
`NH2
`
`•<CHA)NF
`
`CH2OR4F
`CH20R5(
`
`I X
`
`wherein Xf is O or S, and RK, R2f, Raf and nf are as disclosed in WO
`
`03/29205, each of R^and
`Rsf, independently
`
`H
`is
`or
`
`03/29184
`and
`a
`residue
`
`WO
`of
`
`ORsr
`P<
`OR9f
`
`o
`
`
`is C^alkyl optionally substituted by or
`
`wherein each of Ref and Rgf, independently,
`H
`halogen; e.g. 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diol or
`2-amino-2-[4-(ben2yloxyphenylthio)-2-
`chlorophenyl]propyl-1,3-propane-diol,
`or
`pharmacological salt
`thereof;
`
`a
`
`-Compounds as disclosed
`
`
`
`
`
`e.g. in WO03/062252A1, a compound of
`
`formula X
`
`("40)0.4
`N
`Ar-_
`I
`(CH2)MFL
`
`R — M
`
`(C
`A /
`
`Ri.
`
`X
`
`wherein
`
`Ar is phenyl or naphthyl; each
`independently selected from
`
`rrig and
`of
`ng
`
`POtC^alkylJOH and 1H-tetrazol-5-yl; each of R^ and R2g
`COOH, PO3H2, PO2H SO3H,
`independently is H, halogen, OH, COOH or Ci^alkyl optionally substituted by halogen;
`
`H or C^alkyl optionally substituted by halogen
`or
`OH;
`each
`R4g
`
`optionally halogen substituted C^alkyl or C^alkoxy; and each of Rg and M has one of the
`significances as indicated
`
`for and C, respectively, in WO03/062252A1; B
`
`
`is
`
`0
`
`Rag is
`
`TEVA EX. 1015
`Page 12
`
`

`

`• Case TX/4-34053P1
`
`- 1 0 -
`
`
`
`-Compounds as disclosed in WO 03/062248A2, e.g. a compound of
`
`formula XI
`
`A
`
`R1h
`
`Jn H
`R2h
`
`C4h)o-4
`
`R-M
`
`XI
`
`wherein Ar is phenyl or naphthyl; n is 2,3 or 4; A is COOH, 1H-tetrazol-5-yl, PO3H2, PO2H2,
`
`
`-
`
`)OH wherein Rsh is selected
`hydroxyCi^alkyl,
`SO3H or PO(R5h
`
`from
`
`C^alkyl, phenyl, -CO-Ci.
`
`aalkoxy and -CH(OH)-phenyl
`wherein
`said
`
`phenyl moiety is opitonally substituted; or phenyl
`
`each of
`and R2h independently is H,
`halogen, OH, COOH, or optionally halogeno
`
`
`or Rah or phenyl; is H C^alkyl optionally substituted
`
`substituted C^alkyl
`
`by
`halogen
`OH; each R4h independently is halogeno, OH,
`COOH,
`
`C^alkyl, otfC^alkyl, C^
`S(0)o,i
`salkoxy, Cs^cycloalkoxy, aryl
`or
`aralkoxy,
`
`wherein portions may optionally be the alkyl
`
`
`substituted by 1-3
`halogens;
`and
`each
`of
`Rg and
`M
`
`for B and C, respectively, in W003/062248A2.
`
`and/
`
`has
`
`for use in the
`
`invention, the a S1P receptor agonist
`
`
`of
`According to a further embodiment
`receptor, e.g. a compound which possesses a
`invention may also be a selective S1P1
`selectivity for
`
`the S1P1 receptor over
`the SI P3 receptor of at least 20 fold, e.g. 100, 500,
`1000 or 2000 fold, as measured by the ratio of EC50 for
`the EC50
`
`the S1P1 receptor to
`for
`S1P3 receptor as evaluated in a 35S-GTPYS binding assay,
`
`said compound having an
`for binding to the S1P1 receptor of 100 nM or less as evaluated by
`
`the 35S-GTPyS binding
`assay. Representative S1P1
`receptor
`
`
`agonists are e.g. the compounds listed in WO
`03/061567, the contents of which being incorporated herein by reference,
`for instance a
`compound of
`formula
`
`the
`EC50
`
`CF,'
`
`_J
`
`NH
`
`0
`
`XII
`
`OH
`
`or
`
`i
`
`CHj-fCH,),-
`
`XIII
`
`OH
`
`OH
`
`/ rr~oH
`
`o
`
`When the compounds of
`have
`XIII
`I
`formulae
`as
`understood
`be
`to
`molecule, the present
`invention
`is
`are
`isomers, as well as
`
`racemates, diastereoisomers and mixtures
`thereof
`Compounds of
`formula
`III
`or
`IVb,
`
`the when atom bearing
`
`carbon the amino group
`
`asymmetric, have preferably
`the
`
`R-configuration at this carbon atom.
`
`to
`
`one
`
`or
`embracing the
`embraced.
`is
`
`more
`
`TEVA EX. 1015
`Page 13
`
`

`

`• Case TX/4-34053P1
`
`- 1 1 -
`
`The compounds of
`formulae
`I
`may exist in
`to
`XIII
`free or salt form. Examples of
`pharmaceutically acceptable
`salts
`compounds of the
`of
`the
`formulae
`I
`to
`XIII
`with inorganic acids, such
`as
`hydrochloride,
`hydrobromide and sulfate,
`salts
`organic
`with
`acids, such as acetate, fumarate, maleate,
`benzoate,
`malate, methanesulfonate and
`citrate,
`benzenesulfonate salts, or, when
`appropriate,
`metals such as sodium, potassium,
`salts
`with
`calcium and aluminium,
`salts with
`amines,
`such
`as
`triethylamine
`dibasic amino
`and
`acids, such as
`lysine. The
`compounds
`and salts of the combination
`of
`the
`present
`encompass hydrate and
`solvate
`forms.
`
`include
`
`invention
`
`Cs^cycloalkyl,
`
`Acyl as indicated above may be a residue Ry-CO- wherein Ry
`C^alkyl,
`is
`phenyl or phenyl-C^alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be
`straight or branched.
`
`When in the compounds of
`formula
`the carbon chain as Ri
`I
`is
`substituted,
`is preferably
`substituted by halogen, nitro,
`amino,
`carboxy. When the carbon chain
`hydroxy
`or
`is
`interrupted by an optionally
`substituted
`phenylene, the carbon chain
`is
`preferably
`unsubstituted. When the phenylene moiety
`is substituted,
`is preferably substituted by
`it
`halogen, nitro, amino, methoxy,
`hydroxy
`or carboxy.
`
`it
`
`Preferred compounds of
`formula
`are those wherein RT is Ci3-2oalkyl, optionally substituted
`I
`by nitro, halogen, amino, hydroxy or carboxy, and, more
`preferably
`those
`RT is
`wherein
`phenylalkyl substituted by C6_i4-alkyl
`chain optionally substituted by
`halogen
`alkyl
`and the
`moiety is a C^alkyl optionally substituted by
`Ri is phenyl-Ci^alkyl
`hydroxy. More
`preferably,
`or branched, preferably straight, Ce-^alkyl
`substituted on
`the phenyl by
`a
`straight
`chain.
`Ce-^alkyl chain may be
`ortho, meta or para, preferably
`in
`para.
`in
`
`The
`
`Preferably each of R2
`
`to
`
`R5
`
`is
`
`H.
`
`Preferred S1P receptor agonists
`preferably 7 to 10 days.
`
`are
`
`those having
`
`a
`
`half-life
`
`of
`
`approximately
`
`A preferred compound of
`formula
`I is 2-amino-2-tetradecyl-1,3-propanediol. A particularly
`preferred S1P receptor agonist
`of
`formula
`is
`I
`in free form or in a pharmaceutically acceptable
`ethyl]propane-1,3-diol
`form
`hereinafter as Compound A),
`e.g.
`the
`hydrochloride,
`shown:
`
`salt
`as
`
`FTY720,
`(referred
`
`2-amino-2-[2-(4-octylphenyl)
`
`HO—1 OH
`H2N
`
`HCI
`
`TEVA EX. 1015
`Page 14
`
`

`

`• Case TXy4-34053P1
`
`- 12 -
`
`A preferred compound of
`formula
`is the one wherein each of
`II
`to R 's
`2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol,
`pharmaceutically acceptable
`salt
`form
`(referred
`to
`hydrochloride.
`
`and m is 4, i.e.
`is H
`in
`free
`hereinafter
`
`as
`
`form
`Compound
`
`A preferred compound of
`formula
`is the one wherein W
`III
`is CH3,
`H, Z2
`is ethylene, X is heptyloxy and
`Y
`is
`H,
`i.e.
`2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol,
`in free form or
`in pharmaceutically acceptable
`salt
`form
`(referred
`to
`hereinafter
`Compound C), e.g.
`the hydrochloride.
`The R-enantiomer
`is particularly
`preferred.
`
`A preferred compound of
`formula
`IVa
`is
`the
`FTY720-phosphate
`Ria and R1b are OH). A preferred compound
`of
`IVb is the Compound C-phosphate
`formula
`(R2a is H, Rab is OH, Xa is O, R-ia and R1b are OH, Ya is O and R4a
`is heptyl). A preferred
`compound of formula V is Compound B-phosphate.
`
`(R2a
`
`A preferred compound of
`pentyloxy-phenyl)-butyl]ester.
`
`formula
`
`V
`
`is
`
`phosphoric
`
`acid
`
`mono-[(R)-2-amino-2-methyl-4-(4-
`
`A preferred compound of
`formula
`benzo[b]thien-6-yl]-2-methylbutan-1-ol.
`
`VIII
`
`is
`
`(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-
`
`Binding affinity of S1P receptor agonists to individual human S1P receptors may be
`determined in
`following assays:
`
`Transient transfection of
`human
`S1P
`receptors
`HEK293 cells
`into
`EDG receptors and Gi proteins are cloned, and equal
`of 4 cDNAs for
`amounts
`the EDG
`receptor, Gi-ct, GrP
`and Gry
`are mixed
`used to transfect monolayers of HEK293 cells
`and
`using the calcium phosphate precipitate method (M. Wigler et
`al..
`Cell.
`and DS.
`1977;11;223
`Im et al., Mol. Pharmacol. 2000;57;753).
`Briefly,
`a
`DNA
`pg of DNA and
`mixture
`containing
`0.25 M CaCI is added
`HEPES-buffered 2 mM Na2HP04. Subconfluent monolayers
`to
`of
`HEK293 cells are poisoned with
`25 mM
`chloroquine,
`DNA precipitate
`and
`is then applied
`the
`to the cells. After 4 h,
`the monolayers are washed with
`phosphate-buffered
`saline
`media (90% 1:1 Dulbecco's modified
`essential
`media (DMEM):F-12 + 10% fetal bovine
`serum). The cells are harvested
`h after addition of the DNA by scraping
`48-72
`HME buffer
`in
`(in mM: 20 HEPES, 5 MgCl2, 1 EDTA, pH 7.4) containing 10%
`sucrose
`on
`ice', and
`using a Dounce homogenizer. After
`centrifugation
`the supernatant
`at
`800xg,
`is diluted with
`HME without sucrose and
`centrifuged
`at
`for 1h. The resulting pellet is
`100,000xg
`
`and refed
`
`disrupted
`
`TEVA EX. 1015
`Page 15
`
`

`

`• Case TX/4-34053P1
`
`- 1 3 -
`
`rehomogenized and centrifuged
`a
`second
`hour
`at
`100,000xg.
`membrane pellet
`resuspended in HME with
`sucrose, aliquoted,
`and
`by immersion in liquid
`snap-frozen
`nitrogen. The membranes are
`stored
`70oC. Protein concentration
`at
`is
`determined
`spectroscopically by Bradford
`protein
`assay.
`
`is
`
`This
`
`GTPYS binding assay using SIP
`
`receptor/HEK293
`membrane preparations
`
`GTPyS binding experiments are performed
`as
`described
`by
`DS.
`2000; 57:753. Ligand-mediated GTPyS
`binding
`to G-proteins
`is
`NaCI, 10 MgC^, pH 7.5) using 25 |jg of a membrane
`buffer (in mM: 50 HEPES,
`100
`preparation from
`transiently
`transfected
`HEK293 cells. Ligand
`is added to membranes
`the
`in
`presence of 10 pM GDP
`0.1 nM [35S]GTPyS (1200 Ci/mmol) and
`and
`incubated at 30oC
`for
`30 min. Bound GTPyS
`is
`separated
`from
`using the Brandel harvester
`unbound
`(Gaithersburg, MD) and
`counted
`with
`a
`liquid
`scintillation
`
`counter.
`
`Im
`measured
`
`further
`
`specific
`
`or
`
`alternative
`
`In a series of
`provides:
`The use of a SIP
`receptor
`agonist,
`in the manufacture of a medication,
`e.g.
`FTY720,
`1.1
`whereby said medication
`is administered
`such a way to a subject that a steady-
`in
`state of the S1P
`receptor agonist
`blood
`levels
`in less than a week.
`is
`attained
`
`embodiments,
`
`the
`
`present
`
`invention
`
`is
`
`is
`
`The steady-state attained
`is
`such
`that
`the
`subject
`sufficiently
`e.g. it shows no
`signs
`or symptoms of acute graft
`rejection
`or
`relapse
`or
`the autoimmune disease. During
`initial 3 to 6 days, preferably 4 or 5 days, most
`the
`preferred 4 days, of treatment
`the
`daily
`dosage
`of
`the
`agonist is raised
`S1P
`stepwise up to 3-
`to
`6-fold
`standard daily dosage of
`the
`said SI
`P receptor agonist
`and thereafter
`the
`treatment
`is
`continued
`with
`the
`standard
`receptor agonist. The S1P
`receptor
`agonist
`preferably
`life of from 5
`to 10 days.
`1.2. The use of FTY720
`in
`manufacture of a medication, whereby
`the
`said medication
`is
`administered in
`such a
`way that during the
`initial 4
`days
`of
`treatment
`the
`FTY720 is 5, 10, 15
`and 20 mg,
`respectively, and thereafter
`the
`treatment
`is
`continued with
`the standard
`daily
`dosage
`of
`FTY720,
`e.g.
`1.3. The use of an S1P
`receptor
`agonist,
`e.g.
`in the manufacture of
`FTY720,
`a
`medication, whereby said medication
`administered in
`is
`such a way
`that
`during
`initial 3 to 6 days, preferably
`4 or
`most preferred 4 days,
`5
`days,
`of
`treatment
`the
`dosage of said S1P
`receptor
`agonist
`is
`raised
`total the R-fold standard daily
`so
`that
`in
`
`receptor
`
`daily
`compound
`
`a
`
`5
`
`the
`
`TEVA EX. 1015
`Page 16
`
`

`

`• Case TX/4-34053P1
`
`- 14-
`
`thereafter
`is administered and
`dosage of said SI P receptor agonist
`
`continued with
`the standard
`daily
`dosage
`
`said of receptor agonist.
`
`the
`SIP
`
`treatment
`
`is
`
`an treating autoimmune disease in a subject
`
`
`rejection or
`inhibiting graft
`A method for
`to
`
`the P receptor agonist, e.g. subject a
`
`
`in need thereof, comprising administering
`
`FTY720, in such a pharmaceutically effective amount
`that
`a
`steady-state
`receptor agonist blood
`levels
`is
`
`attained in the subject in
`less
`
`a than week. Thereafter
`
`the treatment is continued with
`the
`standard daily dosage of said S1P
`
`receptor
`agonist. Preferably
`
`the SIP receptor agonist
`is a
`compound
`having
`a
`5 to 10 days.
`
`SI
`of
`
`half-life
`
`initial
`
`5
`
`days,
`
`dosage
`
`the
`
`2.1
`
`2.2
`
`2.3
`
`3.
`
`in
`levels a
`
`of steady-state P receptor agonist blood SI
`
`
`
`A method f