throbber
a4i=i%r:%!r/3‘
`PATENT OFFICE
`JAPANESE GOVERNMENT
`
`3|Jifi1ifi'.‘.f*J'7>§§HiiT§E7>tHl§§%%E7>B§7Fl:WEQ‘W:2:’5:’§EBFl‘1“Z.>.
`x
`This is to certify that the anne ed is a true copy of the following application as filed
`with this Office.
`
`
`
`1 9 8 7 55 8 H 2 0 E1 /
`513%” 5 Zilfififififi 2 O 7 2 2 4 4% /
`B K it $ I ¥ as at as $3:
`
`ii‘:
`
`55
`
`§ %
`
`gjatefifiofif/ippjlqicatlilon:
`Application Number:
`fpplicanfis):
`A
`
`1988 5% /0251
`
`3% 5%‘ E -E '3‘
`Commissioner,
`Patent Office
`
`7 B
`
`
`
`lama 6 3 — 4 9 o 0 9
`
`Mylan Exhibit 1004, Page 1
`
`Mylan Exhibit 1004, Page 1
`
`

`
`
`
`
`
`(14,000P3l)
`
`315%? Ma
`C07!) 215/00
`
`% %1@¢u %E%3b
`
`%me2$ ea @
`
`
`%%fiEE m m fl x w
`
`1.%%@z%
`4:2 II‘/§r2xm::‘/50 I~‘/3'33.
`
`z.%%%
`
`’
`
`am +$§m%mw#m722%m1
`
`B§m$I%fifi%&¢%%%fiW
`
`R2 w m a % '
`
`<a»4z>
`
`s.
`
`3.%%mmx
`
`Em ?m1%E%¥RmEWEfiW3TE7%fl1
`gm a%>agm$:¥&fi%a%
`V
`
`m§%
`
`m # fi x
`
`§%%§%%%oum%4uMfi)
`
`m mamx
`
`4.%H%fi®Efi
`
`m am:
`
`Mylan Exhibit 1004, Page 2
`
`
`
`
`
`
`
`Mylan Exhibit 1004, Page 2
`
`

`
`o u
`
`O o u
`
`o O o o o on
`
`5 . W%Mfl®%%%
`
`EW $$§m%mw#m722§m1
`
`BEm$I%$fi%&¢%H%%W
`
`fifi % X % f
`
`EW H
`
`Kg %
`
`L
`
`W
`
`%
`
`EW fi£fifi%£fiEfiWfi$EW1470
`
`EEW$I%%fi%fi&%W$fi%WW
`
`E% W T % W
`
`EW E
`
`L
`
`Efi % % E fl
`
`
`
`
`
`
`
`1m»:<»»«\‘~°
`
`s ‘I
`
`Mylan Exhibit 1004, Page 3
`
`
`
`Mylan Exhibit 1004, Page 3
`
`

`
`0
`
`on
`0
`9.
`O
`O
`son 0000
`
`o
`
`0 o
`
`0
`
`0
`
`II
`OD
`00
`
`3
`
`.0
`CC
`00
`
`
`
`.. ..
`
`.
`
`.
`I
`
`.0 0000
`. .
`C COO
`too
`
`no
`
`C
`
`593
`
`$81 %
`
`1.
`
`5:-.*H)ioJz¥¥I~
`
`*/UV%XNu/éflbyfi
`
`2.
`
`*f%§‘F%§‘3K03§'fi%
`
`—*¥T:%i"I(I)
`
`R“
`
`w
`
`R’
`
`W
`
`Y-Z
`
`<1 )
`
`N
`
`F
`
`[fi$\R‘,R2,R3$&UR‘m%h%h
`
`Z$:Z&:7}<§\ C,-.. 721/=t=2I/\ c,_3 7)1»:z$v\
`
`n—7F$9\i~7f$9\wc—7%$V\
`
`I"}7)l/7I‘I:1;€%)p\
`
`7):/;j-1:2‘ ant?!‘ 713%‘
`
`7m3W\71/$V§kM&V§W%*9&§
`
`‘}'fi“9"Za7J‘;
`
`R’ &R’ £6Z5!nLiR" &R‘ fa‘-—FHHC7:§-9?
`
`-CH=CH—CH=CH- éfilykz, ;.
`
`Yc;t-cH2-
`
`\
`
`"CHzCH2"\ —CH=CH-
`
`\
`
`-Cll2—CH=CH-
`
`Mylan Exhibit 1004, Page 4
`
`
`
`Mylan Exhibit 1004, Page 4
`
`

`
`:.~t;<:c;:-cH=cH—cHz- %£.%T‘E"<L;
`
`R11
`I
`
`ZL1 —(IIH-CHzf|3~CHz-C02R"" gm:
`
`OH
`
`OH
`
`(R"b;t7}<§Ef.:L;tC.-3 '7)u4‘~1v"c+3w3@‘
`
`R”m#§\R”(R”m$fl%Km#fi%L5
`
`57’/V‘Y'11/§’€*3>'>Z>.)E7‘.:LiM(MbiNH4
`
`i
`
`ku¥E$%Kfl%KfiE%fiT§é§E§L<
`
`u7$V-H?%éo)?%0\R”m‘#$E
`
`kmCh37w$w?&6.)éE%L;
`
`R5 mm?‘ c..., 71u$2x/\
`
`(33-6 ~‘/71:17)»
`
`-“f-11/§7‘.:&:t‘7;:.)I/-(CHz)m(mbil. 2$>»3b\
`
`u3fibé°)%E%?é.lK;@%b$né
`
`lbéw.
`
`3.%%®#fl£fi%
`
`fififiimflfififil
`
`
`
`Mylan Exhibit 1004, Page 5
`
`
`
`Mylan Exhibit 1004, Page 5
`
`

`
`
`
`$%%m\%fifl$/UVE§€?éxND/
`
`5arv%§%\%®%Em$;U%né%t%
`
`%$%m&%$;U%®%$fl\%w%U£§E
`
`mfi$;U7%u—Afi%WEmfifl&Lr®E
`
`mE$;U:n6%§%%&®tw®¢@%&%
`
`®¥fi&m%T5.
`
`'
`
`[fi%E%&%m%%fiJ
`
`%6fi®%%fi%E%\k&ifi:VNfl%V.
`
`m$M%XE/UV.%émm%hé®$§W%
`
`§%\éem§éfl%§%m:ux%n~w&é
`
`&®%fifi$?%5mmmAUia&—€
`0wwww)®E%Nf%éC£#fléhTh6.
`
`(A. Endo J. Med. Chem..
`
`28M) 401 (1985)) cs-
`
`514 ‘€32<_t“/
`
`‘J
`
`‘/L;tE2“;J¥I?I’~J6:%>7EJ‘}fi7Zi?%‘) «+1'§EI
`
`mfi%§m&fl@5é:&#iéno0%©\fi
`fifimEmfi§§\7%n—AfiflW@mfiK£
`
`®fifi\?%u€%?&é&%i6né°(Km
`
`Int. Symp. Drugs Affect. Lipid Metab., 1986,
`
`wmpm,w6)
`
`b#LKN5\M&%AUV75—€(mMm
`
`Mylan Exhibit 1004, Page 6
`
`
`
`Mylan Exhibit 1004, Page 6
`
`

`
`O I
`
`O
`
`O O O
`
`C
`
`00
`
`O I
`
`0
`
`I
`
`0000
`
`O I
`
`O
`
`OO OO
`
`C
`
`OQCOCIOC
`
`mm)®E%W®$%fl%§%\%KA?D§%
`
`$%mowzum6nkm#fléntw5®&?
`
`$95.,
`
`%%6u%%ménzmKw$/Uvfiéfiy
`
`éxwu/5obv%§%\%n6wflmTéV
`
`'$F'F1‘F“/7511/3*?‘/Ea*3ottJ~'%é’Lc‘o0)iF.1$¢J:EJ~'1
`
`2.5-n/b<E%o»Hnc-coA U 9’7 & —-+5
`
`(reductase)
`
`mm%%fi%fi?é:&%fi$L$%%é%mL
`kc
`
`‘
`
`7.l<%F9ic:F%§I'9”zaHnG—coA reductase I$E%“(§$i-‘lgé
`
`%0fifi®xNu/5a+v%§%mT%@—$
`
`213(1)
`
`R“
`
`R‘
`
`R2
`
`R‘
`
`Y-z
`
`(1)
`
`N
`
`R5
`
`
`
`Efi¢\R‘.R“.R“$&UR‘M%n%n
`
`3£¥!.:‘u:7J<$\ C1-4 711/$112‘ C1—3 721»:z=F~‘/\
`
`I1‘7'F$$h.i-7F‘¥9\sec-7'f$$m
`
`
`
`Mylan Exhibit 1004, Page 7
`
`
`
`Mylan Exhibit 1004, Page 7
`
`

`
`
`
`O
`
`O
`
`I
`
`,
`o
`.
`
`..
`
`no
`
`....
`, .
`o coo
`,
`one
`
`.
`
`0
`
`o
`
`o
`
`no
`o
`g.
`0
`0
`9
`.
`000 coco
`
`00
`no
`0 c
`0
`° " "
`o
`o o
`00
`00
`
`0
`0
`
`F‘J7)U71'D2‘9“)I/\ 71Iz2‘z:z\ 9:213‘ 7'n:e\
`
`7;:-Ila 7_;/4‘--‘/if:6;t«\“‘/~‘/‘2v71*$~‘/éfi
`
`'5§“9"75iJ\;
`
`R’ 32R” 53%!/\&iR3 &R‘ /3‘*-‘§%¢Z72i-of
`
`.
`
`-CH=CH-CH=CH— éfiwkb;
`
`Y6i-CHz-
`
`\
`
`-CH2CH2-x -CH=CH-
`
`\ —CHz—CH=CH-
`
`¥7‘»:Li—CH=CH—CH2- éfilaab;
`
`R11
`I
`
`zzgt
`
`-(‘EH-CHz(’3—CHz-COZR”
`
`Efcbgt
`
`OH
`
`OH
`
`R”
`
`H0
`
`0
`
`0
`
`(R“b:t7}<§E7.:LiCz-:.~ 7)u=1‘—11/'c+53@\
`
`R”m#$\R”(R”mEE%Kmmfifi
`
`b557W*W§?%é.)$kuM(Mm
`
`NH4£km$fi$%afl%HEé%&?§
`
`6§E§L<m7SV»HT%%°)?%0\
`
`R”m\m§EkuCpa7w$w?&5,
`
`5
`
`Mylan Exhibit 1004, Page 8
`
`
`
`Mylan Exhibit 1004, Page 8
`
`

`
`
`
`not
`
`.
`
`0
`
`0
`.
`
`g
`
`'
`
`9
`
`°° ".
`9 0 ..
`
`5 0
`
`.
`
`)%.%‘i‘§EL/;
`
`R5 bwkix C,-¢, 7’)!/4‘)!/\
`
`(33.6 99:27
`
`112%”-JU§7:C;t7_r.:_)Ix-(CHz)m (mbil, 233%
`
`mm3T%%.)é§%?é°]K;@§bén
`
`Z>{E€r€"xJ'C<‘b%>.,
`
`*$fi(I)®E&§®E%KOmT\E¢%
`
`mWé$WzEmE%%m%%?é.
`
`R‘
`
`, R2, R“, R‘ #0.... 7;v$11/(+5;
`
`é%é®E%%EW&LTM\X%w\1%w\
`
`n—7°1:z1:°;u\
`
`i—7°ue.";1/x n-7'-3'-J1/\
`
`i—-
`
`7%w,wc-7%w&Ut—7+wfi$W6n\
`
`R‘
`
`, R’, R3, R‘
`
`13* C1-3 7’)Ix:1=$‘-“/’C'
`
`&6%§®E%%KWéLTu\Xb$9\Ib
`
`$9\n—7u£$9$&6i—7m£$vfi$
`
`wen%°
`
`R”#Cpa7w$wT%%%é®E%%E%
`
`&L'Cb;t\ 2‘?-Iv‘ 1&7-iv‘
`
`n—7D€W$&U
`
`i-7'1:1t"1WJ*%=W3“<’o7}’LZ>°
`
`R”#Ch37w$w?E%%é®E#%fiM
`aLzu‘x%w\1%w\n—7uaws;U
`
`
`
`6
`
`Mylan Exhibit 1004, Page 9
`
`
`
`Mylan Exhibit 1004, Page 9
`
`

`
`o
`o
`c
`
`,.
`
`on
`
`,...
`o
`,
`o con
`o
`00-
`
`.
`
`0
`
`u
`on
`on
`00
`..oooooo
`0
`0
`9
`'0
`0'
`.
`o
`0
`0 0
`0
`000 0000
`I0
`0'
`
`.
`0 Cu
`o
`
`OOO
`
`
`
`i"7U5W%$W6%é°
`
`R”0—)E{7$l34J7§i9'JrL'l/"C\ 2‘~)‘*)Iz\
`
`:1:a‘—)1/\
`
`n
`
`-7°Ut"ID\
`
`i-*7°I:1t°)D\ n-7‘.;r—;;,5c;U:i
`
`*7'9‘“1Wfi%S¢:“t’oé’LZ>..
`
`Mmfiflfiwmfifitfiéfiflfiaéfifimw
`
`3:1/'Cbi‘}*l*‘}'D.L~\ 7f7_’}'DJ.xiJ<z;g,3V,*0n\ it
`
`biC0zM0J{§IJcEL"c-co2NH..
`
`‘
`
`-CO-2Hv
`
`(1~3,!¢g2
`
`®ffi?¥&7Iv=FII«7$v@H:u:,H=1;<+;u7sy)
`
`fJ*‘$b;”'<’o:1'LZo.,
`
`R5#Ch67w$w?%5%§@g¢mgm
`
`<‘:L”Cb;t\ X31112‘
`
`:—7~2v\ n—7°ug,;,‘ 1-
`
`7”5W»n~7*w~i~7%»\mc~7%
`
`flu t‘_7’;“)I/\ n—’\°.‘/3‘)Iz:}’:>‘ckU‘°n—’\=}‘-~‘/
`
`wwéwenao
`
`R5#Cpb99u7w$»@%5%§@g¢
`
`Ff'~J7‘Jf§‘J&LTl:I\
`
`:‘/9t27°1:z 1:‘):/\ 9/au7'g—;;,\
`
`:‘/7D’\°:/‘3:‘)I’2£'D‘c}ZU:“/7IZ1’\=-Fyjl/f;{5=;}$Lj’¢5;{/L
`
`é°$kR5#7x;wmmm?%é%鮧
`
`Jiffr "7.1::.}I/7°I:1E_°)Iz;{)<;‘=_.}§(,j¢‘¢’9;n5°
`
`7
`
`Mylan Exhibit 1004, Page 10
`
`
`
`Mylan Exhibit 1004, Page 10
`
`

`
`o
`o
`no 0g
`o
`0 q
`o
`.
`g
`.
`
`0
`0
`0
`
`0‘
`
`on
`
`0000
`0 O
`0 one
`o
`one
`
`0
`
`0
`
`I
`
`O
`
`00
`0
`00
`0
`I
`0
`9
`000 0000
`
`0
`
`no
`0-
`O0
`0
`on
`
`O O
`o o
`
`on
`00
`on
`
`O
`0
`
`“flfi(I)?ibéh%xNu/5y}yg
`
`u\T%®Kmfiw%oZémén5.
`
`(WT\%B)
`
`
`
`
`
`Mylan Exhibit 1004, Page 11
`
`
`
`Mylan Exhibit 1004, Page 11
`
`

`
`I
`00 to
`0 0 q
`Q
`p
`
`O
`0
`I
`
`0‘
`
`on
`
`coco
`0 0
`0 000
`I
`000
`
`0
`
`O
`on
`
`O
`
`O
`
`CO
`
`O
`
`C
`
`6
`
`L
`
`1.
`
`25
`
`L.
`
`L.
`
`;
`
`Mylan Exhibit 1004, Page 12
`
`
`
`Mylan Exhibit 1004, Page 12
`
`
`

`
`.
`.
`pg c.
`g
`g g
`.
`.
`.
`.
`
`0
`9
`.
`
`..
`
`go
`
`....
`O I
`0 one
`.
`can
`
`Q
`
`0
`
`0
`
`0
`
`II
`0
`no
`0
`I
`I
`Q
`can 000:
`
`00
`00
`O O
`O
`' " "
`I
`O I
`09
`OI
`
`I
`O
`
`
`
`R1
`
`
`
`IO
`
`» Mylan Exhibit 1004, Page 13
`
`COZR‘2
`
`E
`
`R2
`
`
`
`Mylan Exhibit 1004, Page 13
`
`

`
`
`
`54-.10“'
`
`\
`
`no
`so
`00.
`0
`0000
`of‘
`I
`O
`Q
`I Q
`I
`0
`O
`O
`00
`0 I
`00 O.
`ooocooooo 0 once on
`I
`.
`0
`0
`0
`0
`an o
`0
`C
`O
`0
`no
`can
`000 0000
`00
`to
`
`O
`
`o
`
`m
`
`D:
`
`ZO :
`
`V‘
`
`v—-c
`
`:2:
`‘D
`
`v Q
`
`:
`
`to
`0:‘
`
`~
`CE
`
`2:
`
`"3
`
`
`
`77
`
`Mylan Exhibit 1004, Page 14
`
`
`
`Mylan Exhibit 1004, Page 14
`
`

`
`C
`
`.
`
`OOOOO
`
`000.0
`
`coo
`
`:*
`0. o :
`9
`coco I
`.
`.
`g
`000
`
`no
`
`0
`
`to
`0
`
`0
`
`0
`OI
`o
`0
`Q
`not 0000
`
`Ac
`
`'0
`
`‘
`O
`
`‘ '
`O 0
`-0
`
`00
`
`'
`
`EEfi¢\R‘,R‘,R“,R‘,R5,
`
`R”Mifi®~Mfi(I)®fi%&W§%T%@\
`
`R“¢1Cn—4 03{§§¥L'Z7JI/=T-‘)1/El3‘5\ 213-111‘ 1
`
`film n—7'r:I 611;‘
`
`i-7°t:z!:°11»\ n—7'a‘~)I/
`
`éibio
`
`IEAu1x%w®%~7w3—w«®Efifi
`
`m?&@%fi®@Em$m%\fiiL<d94v
`
`7%w7wS&bLtFUF%WhT\?F5t
`
`FU75V\Fw1VKE®%fi¢?—20T#
`
`62(VcfiiL,<m—1(Vc#é1.oraififm
`
`izamfééo
`
`IEBM%~7w3—w®7w¥tF«®fim
`
`Em?@0\%fifim%émw1\fim5:&#
`
`tB§EE>i)<\§l¥§'b<.b;t2<iFI/V9x:r')F‘EI3E")V
`
`:—v9Aamuau2<—I~>£HiwT0°Cb~Fo25°C
`
`?fiK5#&5mmx$WUwanUF—vx%
`
`wxw$$yF(wmn%m)%mwtfim5:
`
`&:7b\"C*é°Za.
`
`IECmhFU$VE;p1~%w®%mT%
`
`‘0‘:]"'?¢)cis-*1—ll~=i'-:‘/—2"(l*‘}~n
`
`1
`
`2
`
`Mylan Exhibit 1004, Page 15
`
`
`
`
`
`Mylan Exhibit 1004, Page 15
`
`

`
`r7i:'_
`
`
`C
`
`O
`
`0
`g
`5
`A
`0
`
`0
`I
`O
`
`00
`
`CO
`
`0000
`0 0
`O 000
`I
`.00
`
`O
`
`O
`
`0
`
`n
`
`O0
`0
`to
`I
`I
`I
`C
`CDC OOIO
`
`0
`
`0
`O
`
`00
`CI
`CO
`
`0 n
`O I
`
`on
`00
`CO
`
`O
`I
`
`*7*WXP:w)1%uyw7+wU%oAé
`
`?F5tFn75y¢?MELz§&$&ku%
`
`WAmé%wmé%VéEmé%5:tu$@%
`é:&#?%é.
`
`EmfiE&LfM,—60~+78t@fifi§
`
`fiwézéflfiibwo
`
`IEDfi&m#fi%u&51+—w@§§?%
`
`@~@%&&bZfiEb<fiN§+w1vxw¢
`
`Vfi\fi%\fiEKEéfih%k5tpn75y\
`
`I7/—wKa&m&@fié%m¢?1o~25
`t?fiK5:&#?§é.IEc%%énk:F
`
`”*V5;WI—%wflfi%%fnfi%m$m¢
`
`%%+5-n—7+wxx%@$?5fiwfiIg
`DKEW?é:t$?%éo
`
`;~g:Fg§=_-,;x7~_,,/
`I$§E&;tJ:~}~——)v (1V).g;7.L,
`fi®¢7w7;%v&omé§mva@w:L<
`b;t1‘£€Z§_E&b’C3“I~'}'bLt:
`Ft} Fgn_7*g.,[,,)
`
`**‘5W“?*5tFD75v¢\—78t?
`fiH5:&m?§é._
`IfiFmxw£;w§@§fi§m?%@\$E
`
`1
`
`3
`
`Mylan Exhibit 1004, Page 16
`
`
`
`Mylan Exhibit 1004, Page 16
`
`

`
`7}<$4[’.%il¥EL,<bi7}<i{t>i<'§$+¥'}'D.A%%
`
`Wflfi/—w¢?—10tm525tfiEL<
`m—1otme5trfi5:a#f§5.
`
`IfiGmxx%w®m$fi%IE?%@~%%
`
`1U§f0JJ‘IiE\ Hi L ( L;t7}<E§fl:7!2 U '71.“ yxwt
`
`+bUbAémwz\x&/—w&§wm1y/
`
`—&&\m¢@fié%&¢?10tm&25t1
`?%K5:&#?§é°
`.
`
`::?%6nkfi%®&mfi%mfiEtfi%o
`
`<r’o’eEZ>Z.c‘:fJ<"Cé‘%’>.
`
`IEHmfi%®tFn$9%\I—2é%#E
`
`m$%5:aa;0xNu/5akv%&fié%
`
`é-IE“C*3‘>?9\
`
`’\‘I/“E1/%?a(«WZ3II‘)1x:I:I/'51-'1}Jl];?';
`
`§mLmm%$&?5mé%£?am\&awu
`
`EKfi§Kflmfl\k&iw%u+;5—v—7
`
`xK£émi5:&u;@fiK5:&#?§5°
`
`IEJMXND/5abV%&$/Uvfiég
`
`%?5:E%é@m%fim?%@\%fi§®N5
`
`VWL"fi§\uV0A~$§EfiWL\X5/
`
`"-)1/\ I57/~11/x '5“}‘5Yf—FC17‘3I/\ 7’~tzl‘
`
`
`
`/_:¢'/mw-'»*\‘-‘
`
`
`
`1 4
`
`Mylan Exhibit 1004, Page 17
`
`
`
`Mylan Exhibit 1004, Page 17
`
`

`
`
`
`5-
`
`I‘ ‘)1!/72i.J;’0J?§§¥‘3P\ 0~50°C§l¥EL/(611
`
`0~2 5°C’C‘fi‘72£“')C.’.&:iJ‘”C*§<Z:..
`
`%wwm%flénkmé%®flu\§1u$fi
`
`kit’ I
`
`-— 2 'C'§bé<é'Lé{E/é.\'«f%%7+<%¥9i0Jfi?2*;-c:
`
`$@%fiT%:t#?%%°
`
`‘£1
`
`
`
`
`
` ‘R’ R2 R3 R‘ R5
`
`
`
`
`
`
`
`7*-Me
`
`H
`
`6-0Me
`
`V H
`
`H
`
`H
`
`5*~Br
`
`H
`
`4*F
`
`6-C2
`
`8—°C.Q
`
`4—F
`
`6-Me
`
`8-Me
`
`4~F
`
`7-0He
`
`8*-0I'1e
`
`4-}?
`
`H
`
`H
`
`H
`
`H
`
`4-CH3
`
`4~C£
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`i-Pr
`
`i-Pr
`
`i—Pr
`
`i—Pr
`
`i-Pr
`
`i-Pr
`
`i—Pr
`
`i—Pr
`
`1
`
`5
`
`Mylan Exhibit 1004, Page 18
`
`
`
`Mylan Exhibit 1004, Page 18
`
`

`
`
`
`
`
` R‘ R’ R“ R‘ R5
`
`
`
`
`
`
`
`H
`
`6—Br
`
`6-02
`
`H
`
`H
`
`H
`
`H
`
`6.7
`
`
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`2-F
`
`2-!‘
`
`2-02
`
`4-0Me
`
`H
`
`H
`
`H
`
`H
`
`i-Pr
`
`i-‘Pr
`
`i-Pr
`
`i"'Pr
`
`3—Me
`
`5'~Me
`
`i-Pr
`
`3—l"le
`
`4'~F
`
`i-Pr
`
`4""0Ph
`
`4*}?
`
`4‘"F
`
`H
`
`H
`
`H
`
`i"'Pr
`
`i--Pr
`
`~<:>
`4
`
`4—Ph
`
`H
`
`i-—Pr
`
`4—PhCH2 H
`
`i-Pr
`
`4-F
`
`H
`
`Et
`
`
`
`
`
`§t:nemé%®¥fl$%mfi%KE\t&
`
`ifi+FUbAfi\é&m:x%wk&iw1%
`
`:.:..«'x««-W“
`
`‘
`
`‘:1
`
`
`
`_=.3:%“‘
`I
`I-1
`.;|fév
`'
`
`.~;r;"’/“
`
`1
`
`5
`
`Mylan Exhibit 1004, Page 19
`
`
`
`Mylan Exhibit 1004, Page 19
`
`

`
`
`
`w1X%W\X%wIX%wbHfiKLTé&T
`
`32>.
`$%%®mé%u\&m®fi%%%u;©fié
`
`nk$5K:VX&u~w$§fi®¢fi§$fi5
`
`éHM—%AU#a¢~€(mmuuw@%fi§
`
`%%KE%Té¢fi€%oT£©\fioT2vx
`
`%m—w®&é&ém%§tfififiTé:a#?
`
`gas.
`
`:a>:aia~«a%‘H§1In¢£\
`
`‘n%ur:—:§Ezmz~E;
`
`7%n—Afi%mEmfi®%fi¥&L1€%?%
`
`§°
`
`:@%fi&%u%®&5&%u;@fi~®fl®
`
`flflmfiflfiféé.
`
`$mé%mfi%@M®%?\%5wm&@$%
`
`wmmfi%L55.bo%§L5éxx&wgn
`
`u5abv@%?\&5wm%¥$%m%§L5
`
`éfi®%?&5?§:&#?%5°
`
`'
`
`$%%mfi5%$fl&%m\$%%mé%E%
`
`%éwufiE®¥fl%w%§$né%éfi(vm
`
`~y7°\ 7~“2I:“7:z‘L\\ 4:“-39°‘/\
`
`‘/1uz~_'.~, hp
`
`5fiVF\£UE;w€uUFygg)\fi%m
`
`1
`
`7
`
`Mylan Exhibit 1004, Page 20
`
`
`
`
`
`Mylan Exhibit 1004, Page 20
`
`

`
`(fl%\@fi\:—vx¢—%\Uy@»»ya
`
`A\7wHvf\7U9VK£)\%Wfl(X?
`
`7UV%7V$9fiA\9wfl\£UI%VVV
`
`U3—w\9Uhfl5)\fi%fl(U¢#Wb%
`
`%mz)tfiéb\%x\fifi\fiNiku»7
`
`&wflK£@%$E&é:&fiT%\fiD%K&
`
`%?5:a#¥§Lw.L#Lt#e\bB5m
`
`:nfiHKmE$M6%®?mK<\%fiDE5
`
`®fi%fi§%é.k&iK\w%£%\£U1%
`
`uyVU:~w\§/Uvxfififibuduta
`
`4F%®m%fi§Hémwt&fl&Lr®&5®
`
`fl%fib&é.
`
`'é6w$%wm;émé%u~flfi&¢%§L‘
`
`b#b§%%?&fl$mKm%fi®fi§%%4%
`
`y§&%%amaéb%é:&m?§é.
`
`mAé%fi?5%é@&5§u\~B§k0
`
`0.05~500mg\31?-'EL/<b:I:0.05~30mg?\
`
`~B1~3@&%én5#\$%\wE\fifit
`
`au;@&5§w@m¢a.
`
`fiH~W%fiT6fl%%u%fi?%©\k&i
`
`1
`
`8
`
`Mylan Exhibit 1004, Page 21
`
`
`
`
`
`Mylan Exhibit 1004, Page 21
`
`

`
`
`
`C O
`
`O I O
`
`I C I O O II
`
`%é=a>t;om: mediumc:i?i%;*&L,_i%%é%li$~:L,%c. FBS
`
`émmuE§&i5:&m;@mflW:ux%D
`
`~W&éfl%fl~%L4%Ei§?éC&€fi%
`
`bTM5o24fiE%§%\mMw%%§\fik
`
`oz 5 %LpDS’E’%L‘DME medium (1. 5 m2) ’§37JIl:?.\
`
`%¥m%&muwmw%%Lkfifi%15n2%
`
`%mun.afi$%m&o%m<B—1&>a5
`
`mu4fi%%(B—2&)m($”cJ%&+r
`
`UbAm5um)é%mLEu4fifi%§é%fi
`
`L/75° 1fJ::‘§:’E5§7?'£medium%%2‘Eb\ $353754 "C61
`
`%wbkUv@§@&Efifimwm)?3@%@
`
`Lk&\mWé5N—£Uxvv?fi%%KEW
`
`Lk.%6nkmm«vvbu200u2@u5
`
`NmHémi37tr~%mfiLmfl%%fiLk
`
`1% :w—E§%15%mwmmM'?&vmLk.
`
`ix‘-?u’o>I’Lfc7F’r ‘/fl:.HE§7‘J\ 5:» 3 :9 —Hydroxysterol
`
`éSperry4E>0)77‘?i‘:
`
`; J. Biol Chem., 187.
`
`97
`
`u%m\m$Uz9¥b;v%flEu;@fimL
`
`%®fl%%émELn.$k\flw%fifio%@
`
`m~E§#é§E§€mEL‘mm§E1m%t
`
`2
`
`1
`
`Mylan Exhibit 1004, Page 22
`
`
`
`Mylan Exhibit 1004, Page 22
`
`

`
`0®RM%%éMT:ux%D~wEéfi%&L
`
`k°E%fifim\3VEm—wK£H§V¥P$
`
`FAWfl§hk&M%%§50%E%Té%E
`
`(IC5o) “GEL/7:0
`
`O
`
`2<%H)ao:onz)4t:{a\4znc:owc, J:%a0)7i‘?£>£fE
`
`fibTHM—%AvY9§—€Kfl?éM%%fi
`
`éwibzfizmfiififlfifiemh.
`
`$2 fi%Am£H5$%%mé%@m%%fi
`
`434%
`
`I950 cmwarm
`
`I-"51
`
`1.O><10‘8
`
`I-52
`
`I-53
`
`7.1><10‘°
`
`1.9X10"’
`
`I-13
`
`1.25X10"7
`
`(mam)
`XE/‘)7
`
`L4xJ.0”
`
`CS-514
`
`9.0X10'°
`
`cm?‘ am)
`
`
`
`
`
`IJf¢X‘§<‘{"..§<«?\\\\'.u
`
`
`
`2
`
`2
`
`Mylan Exhibit1004, Page 23
`
`
`
`Mylan Exhibit 1004, Page 23
`
`

`
`o O
`
`g o on
`
`
`
`$3 fifiBK$H5$%%flé%®m%fifi
`
`(B —1?33)
`
`
`____‘£f=fl’______._
`1*51
`1x10”
`(idflfiisfi)
`3.5><1o~'*
`cs—514
`
`
`2 3
`
`Mylan Exhibit 1004, Page 24
`
`
`
`Mylan Exhibit 1004, Page 24
`
`

`
`
`
`)l\I\\9.':..\Vu\
`I.:L:l4
`
`$%%mé%ufifiAw$wrm%%%?%5
`
`cs—514 zbzaowcztx 2:/*1‘/aL:Li'E]%a)~2%1‘§§
`
`%L\fi%Bu£mzum—m4;@Enkfifi
`
`éfibk.
`
`gmul
`
`I%W(E)—&5—VtFm$V~7—[4’
`
`— (4”-—7)Dx:27;n;1v)-2’ — (1” —
`
`x%wI?w)—$/UV—3’~4w]«7+
`
`—6—uL/1—r Hbéwl-11) VF%®
`
`($235901—a)0J7\5-«y7°io~<5!I%:‘?sb'Z\
`
`(ifififill
`
`1—®i?®X%v7éfiTé&Lk°)
`
`(%m@w1—a)
`
`1%nw—4—(4’-—7w%
`
`D7x:Ju)—2-(1’-f}¥vu1%na —$
`/uv—3—4w—ww£#yu—+(mé%w
`~1>
`5
`
`Sim (J. Org. Chem., 2899 (1966)) czéafiog
`
`fifimfihéfibk.
`
`2-73/-4’ —7)1x71“x:z«\“‘/‘/'7:a/3/
`
`&45g(Q03¥w);;+w4v7%Uw7
`
`*\‘
`vlziééx“-* I‘ 5.5 3 g
`
`(0.035 ‘Ell/)
`
`\ %%6}}§fi§0,1m£
`
`
`
`2 4
`
`Mylan Exhibit 1004, Page 25
`
`
`
`
`
`Mylan Exhibit 1004, Page 25
`
`

`
`
`
`%./ ‘
`3%.
`g
`Ra I:
`HQ
`2
`
`n
`.
`
`v
`
`y
`0
`
`. o
`
`0
`
`. o 9:
`o
`
`0
`to
`~
`0C ‘ C C O U.
`
`o
`
`o
`
`«A
`
`§30m£®%fi@K&#L\100TT%1O
`
`5%?-a‘I}JB¥.'&L,f.:o 2-73/-4’ ~71xz71~t:2«<y
`
`V7;/V#fifi%kLt®%fiE7n?r75
`
`74—vm%&\&mmé§&:r%wu\x%
`
`.
`
`L/7:45 m20J%%7‘/=r::_7‘7J<&:7k120 m.€03
`
`fiéfimwfiaumikofifibzétmfiwm
`
`@fiE¢w~&ME?5:&m;@@mLn°;
`
`®@%%w§®1&/—w;©E%&L\a@fi
`
`$&47g(55%)%%k.m.68—7Q5
`
`we
`
`(%J3Ef§1J1—b)
`
`4- (4’ *"7)L/2“1f1‘7_y_;:
`
`1v)—3——tFu4m>x%n-2—(1'-1;
`
`Ivlawv) -$/ 0 v (’ll:.é"1‘?JVI—1)
`
`‘O
`
`§$§@%T?mé%w-1@a4g(mm6
`
`¥w)%fimbwxyu&#L\%%¢?0Tm
`
`%wLk.:®%mu16(E§)%V4v7+
`
`1:x71u$:«*§At Fr)
`
`}~“—I~)1xJ:‘/~}§;~‘:~2{§4 omggfigj
`
`TL\%®&Em0t?2fifi%#Lk.mé%
`
`W—1#%ém%%bt:a%EEanv+¢5
`
`74~?%%LT#é\0t?%mEm7v%;
`
`2 5
`
`Mylan Exhibit 1004, Page 26
`
`
`
`Mylan Exhibit 1004, Page 26
`
`

`
`bL%fiémiz§m%%¢$%k°&mE%%
`
`mx~%wémi1\€%Eéfi%Lk.¥wfi
`
`%a»t47—Fm%fiémit%%$&~%k
`
`m:~%w?m&Lk;x~¢wm$%&é%r
`
`fi#fi&?V%vbAT%fi\fi@b\fifi%%
`
`$Lk.§%x4wmflETé&%%mLk°%
`
`&I+»-n—«$&y;@fi%%LzE%%%
`
`&3sé%koW$70%~m.136-137
`
`.m
`
`(%3$5{§IJ1—-c)
`
`4~ (4’ —711z7ru7;:.
`
`w)~2—(1’~X?w1?W)*$/Uvf
`
`3-4»-%w£$y7w?tF(mé%V—
`
`1) EUV;bAflnn9nx~bz0g(&
`
`I
`3ZU%w)t&4g®fiK%@V*F%fimV
`
`§na}fiV10m£¢K%%$%\Z®fi§fi
`
`'thc:1I:€.~*»‘bJv1~ 1031 g
`
`(3.4 s U=r:2v) éfizk
`
`yauuxyylomzufifiéfikfifiéifi
`
`??b%#Kmikof%fi%%Lk&~I-%
`
`»100m2émi;<#§§%ko§mfié%
`
`%vvbHw®E%fiL1&m%EL~fifiéw
`
`
`
`/s«.'7.m<:..\"-\
`
`
`
`2 6
`
`Mylan Exhibit 1004, Page 27
`
`
`
`Mylan Exhibit 1004, Page 27
`
`

`
`...........-.nu’.
`
`
`
`E%ELk,§§éV477uEw1—%wK%
`
`%L\$%%EfiWbk.fifié§UWE%Eb\
`
`fiE§V477nEw1~%w#6E%fiL\W
`
`§@7UXAfi%%Q7g(W$70%)§%ko
`
`m.124~126T.
`
`MR6wm(mm23¢)
`
`L1U,bmL3m LNM,hWL6m
`
`3.7 (m,
`
`1H)
`
`3.7 (q,
`
`J=7Hz.
`
`2H)
`
`Lfiu,hmL1m anmlm &%m,m)
`
`7.05~«8.2 (m,
`
`8H)
`
`(%%W1—d)3?(3’~1f$9—1’-
`
`tFD$9—2’—7u&;w)~4—(4’—
`
`711/7I‘D’7:.:—)I/) -2- (1’ -zla‘-1v:z:~tF
`
`w)$/Uv (mé%N—1)
`
`cis~1—1F$9~2~(FU-n—7?
`
`wX§;W)l%VVL13g(&133U¥
`
`1I»)>.$.‘»8 m20).:i.Ei7}<~?r=2I: FD7-3vo:<37h~L,\
`
`§$fimT? ~78tu%mLk°:m%mu
`
`'15(Eé)%n~7;wv+aA—n—«$&
`
`VfiW2mE
`
`(&2EU¥w)éfiTb\45
`
`2 7
`
`Mylan Exhibit 1004, Page 28
`
`
`
`Mylan Exhibit 1004, Page 28
`
`

`
`fiE%%Lk&\mé%V-1®Q75g(26
`
`S'}»*;-2:/)%,:if:.7k5~b5~t.F‘t175‘/1‘0 m26Z
`
`@#LkfiW%fiTbk°fimfié%%-78$
`
`?2%fi%fiLk&\fiflfifi7v%;bL@m
`
`2m£%miT\&m€%i$%k.91%wi
`
`—%w?€%Eém$L§x~awmm%§@m
`
`fifim?%@b\fi%W&7V$vfiL?%&L
`
`7.20
`
`‘?$i1¥é“@§F_E—F6:’%’?&L/\ §§‘?§én-’\$*d*‘/
`
`c‘:7”eF-=I~‘}II»Fa‘I6:é:‘EEé:‘~lz\
`
`'?~x‘zl*5-l*‘})Iz
`
`§%WETKfifi%%Lk°%6nkmfi%%9
`
`Ufi¥wfl5L7U7FV574—K#HT(%
`%K25%X§f~w—ann$wL)fi%mm
`
`fi®E%%&91gé%k.
`
`(iflwfll-e) (E)-3—[4’ —(4” —
`
`7WfiW37x:JV)—2’ —(1” —x§vv1%
`
`w)—$/UV-3’~4w]Tu«y7w¥t
`
`F’Hbé%m—1)
`
`mé%N—1®a91g%%katFu75y
`
`2 0 m£6:?$fi¥$‘a-\ 7R5 ;m2&p— M1/1‘/1
`
`w¢v@1oom§mz\§mr24fi@%#L
`
`
`
`2 8
`
`Mylan Exhibit 1004, Page 29
`
`
`
`
`
`
`
`[a~.;‘_5-19.»)-65;;;,\\a.\x
`
`
`
`Mylan Exhibit 1004, Page 29
`
`

`
`
`
`
`
`7:.»
`
`iiFL"3‘?$‘??§&:Vi?-)v1—5-)v>§37}u;2_*(%z[§j;g3
`
`mL\wm§mmv%@\%mm&vr2vaA
`
`T%fi%\%&€WETK%$Lk,fi§§yu
`
`fi¥ww5Lau7r7a74—mmHz(@m
`
`Q
`
`W=7UD*wA)E%%%Eé7UxL§gL
`
`Tfifiu a4g (50%)
`
`mm 127-128
`
`‘Co
`
`(%23WIJ1—r)
`
`I%)1«(E) —7— [4' —
`
`(4” ‘-711/73‘EI‘7.:.:'—}I/) -2’ - (1" ._,z
`
`5‘-11/3:-7-)v)~—::-/x}~/—3' _4,1,]_.5_E,_
`
`FU$V—3—%$7~7b—6—I/l—r
`
`({l:{3‘%H—1)
`
`60%*)‘l“}‘D.1.\I:I~“’} F5 0mg%%7‘-9'§X:7:7E:r:
`
`‘.
`
`—%wfi%@L\§$fi%TT%§Lk%\fim
`
`%F5tFD75V5m£¢K%%$%k.§$
`
`%E%"c*——15°c:‘(%HJL,\ 7%: FE;=‘§§1=;'-11»
`
`120%(Q923Ufw)§fiTL\15fifi
`
`%Wbk.WWT15fE§)%n~7%wU+
`
`fiL—n—~$fiV@fiQ6m£(Q92$U¥
`
`w)émTLz30%%%#L‘%umé%m—
`
`2 9
`
`Mylan Exhibit 1004, Page 30
`
`
`
`Mylan Exhibit 1004, Page 30
`
`

`
`1®160m(&5sU%w)§mm;+;tF
`
`u75vu@%é%k%fié%T\1fi@%fiL
`
`k.fimE%%a—15t?%mfim7y%;a
`
`.L\7k‘?3§'?3i1m£€7JH7?.\
`
`~‘/“J:a‘-1v1——5-11/"c3[1EJ
`
`.
`
`%&Lk°I~%w%W%%Wfifim?%#~%
`
`mfi@7¢$v0A?%fiLt%\wETm%E
`
`Lk.%§EV477uEw1—ffiW6§%fl
`
`L\E@%%130m(W$59%)E%k.
`
`m.99—101to
`
`(¥ZE9’1J1—g)
`
`:I:~3‘*Jl/ (E) -3.5 —-~‘/'l:FD
`
`=t=~‘/—7- E4’ — (4” "'7)l/j‘D7.:::—)lz)
`
`—-2' — (1" ——x%;v1J*11/) —=l"—/U‘/-—3
`'-4w)—«7W-6—i/I-b(mé%I
`
`~.'
`
`-11)
`
`%$§E%T?mé%H~1®110m(mM
`
`5 S‘)=&;v) >215’/~21»5 mE€Z‘?§§Zi="5‘¥.3_'\
`
`0
`
`twfiELk&\#fiw$0§+bUbA10m
`
`(0.263 S ')=E;v) >E7JI17l\
`
`-*3€°f'z§1?%?$L7‘c.
`
`10%fi&m1m2%mi\I—%w?3Em$
`
`Lk.:—%w%m€fiflfifi#T%fi\fimm
`
`
`
`3 o
`
`Mylan Exhibit 1004, Page 31
`
`
`
`Mylan Exhibit 1004, Page 31
`
`

`
`
`
`E£*?fl‘7‘~~‘/r§L.’C*%i:';":f&.
`
`‘2fi52Jj”:‘F’C‘$ZEiL,7.:.,
`
`5%
`
`%’7!“/I’)v%£/’)iJ’J"11»75-§.L.au7}~7’57,;—-
`
`c:ot”)¥§§¥L (?$§E‘?i§5%x57/—;u—&u1:zrk
`
`11/L) $=‘E'¥<’H.<EI=’1’~J%é.3fi.£é0J;'/E1Jl3i’1*Z.’J& L”C?'+§‘=f.:.
`
`7 Omg (IDZ$6 4 %)
`
`NMR
`
`( 6ppm CD023 E13)
`
`1.30 (t,
`
`J=8Hz.
`
`3H)
`
`1.39 (d,
`
`J=8Hz,
`
`6H)
`
`1.4 ~1.8 (m,
`
`2H)
`
`2.42 (d,
`
`J=7Hz,
`
`2H)
`
`3.0 ~3.8 (m,
`
`2H)
`
`3.50 (m,
`
`1H)
`
`3.9~ 4.6
`
`(m,
`
`2H)
`
`4.20 (q.
`
`J=8Hz,
`
`2H)
`
`5.35 (m,
`
`1H)
`
`6.59 (m,
`
`1H)
`
`7.10~8.18 (m,
`
`8H)
`
`.%fi’1i_-?{§IJ2
`
`(E)-&5—VtFD#V—7—[4’~
`
`(4” —721»;rn7;:.2.1»)_~2’
`
`-— (1" —;<
`
`9‘-Jul-'1-11/)—=%‘-/U‘/-3’ -/{II/J -’\7°l~
`
`-6-I‘/fi§d*b')*7J»if.*=§({l:’.a‘*¥?JI-51)
`
`fl:é%I~110J6 Omg (0.133 39°C-)1/)
`
`7.53
`
`Smewla/—wu@mé%.a5N»t4v
`
`-57‘7}<?$‘2&0.2 6 m.eé‘?r%iTL/7:. §?n‘?1'C*2-Sr’oo:
`
`153FFa7§§é.‘¥‘¥3L7‘:?&\ ?1&FETo::n5v/——2wE%’§L,.
`
`
`
`3
`
`1
`
`Mylan Exhibit 1004, Page 32
`
`
`
`Mylan Exhibit 1004, Page 32
`
`

`
`'9
`'9
`CO to
`»'q_
`1 .
`O
`U
`5
`0
`
`0
`U
`0
`
`60
`
`DC
`
`soon
`‘o 0
`Q '9.
`0
`--on
`
`'
`
`‘o
`
`'0
`
`no
`
`o
`
`'0
`'01
`'0
`I
`'0
`0
`000 coop
`
`-9
`
`v
`Q
`
`'00
`
`its
`'9’:
`
`o o
`-a 4
`
`'00
`
`to
`‘co
`
`-o
`0
`
`m5m2§mz\x—%wémmLt.mE§m
`
`%%@L\&fifiE@fi$40m(67%)%%
`
`7‘.:., mp. 207—-209“C (§3‘§$),
`
`(MT\%E)
`
`
`
`3 2
`
`Mylar-1 Exhibit 1004, Page 33
`
`
`
`Mylan Exhibit 1004, Page 33
`
`

`
`
`
`imws
`
`(E)-&5—VtFn$9—7—[4’?
`
`(4”~7w%n7;;»)—2’—(1”—x
`
`%1I/3:5‘-11») ——=i‘—/
`
`'1‘/~—3'
`
`-411») —’\7°l~
`
`—6~IVfi(mé%I—21)
`
`fl:’e}%I—110)110mg(0.244 su=e;u)
`
`é1om2mx&/—»u%fié%a5NwtX
`
`V—¢m%fi&[9m£€fiTLk°§fi?é6
`
`K1fi@%%Lt&\WETm1§/~wé%§
`
`u.m1omeémz\;—;»r%mLn°m
`
`E%%Efim?%%fi&b(M4)\l—%w?
`
`3@%$E<@fiLk.1w%wE€~%KLT
`m@?7ZvvA?%fiL\%fi€WETw%%
`
`LT\&fi%Mfi%90m%%ko
`
`NMR
`
`( once 3 ¢0 appm
`
`1.36 (d,
`
`J=7Hz, an)
`
`2.4 (m,
`
`2H)
`
`3.5(m,1H)
`
`3.45 (m,
`
`1H)
`
`3.8 ~«4.6 (m,
`
`2H)
`
`5.40 (dd.
`
`J;e19Hz,
`
`J2=8Hz,
`
`1H)
`
`6.55 (a,
`
`J=19Hz,1H)
`
`Lo~&3m,m>
`
`’
`
`%Bifif§IJ4
`
`3 3
`
`Mylan Exhibit 1004, Page 34
`
`
`
`Mylan Exhibit 1004, Page 34
`
`

`
`(E)~6—[4’-(4”—7w%u7;;
`
`w)~2’—(1”—x%w1%w)—$/my
`
`-3’ —4’}lx3:ET‘:—)U]4——l:F1:I:}=y——3,4,5,
`
`6-5~E\’Jl=F’I3—2H—t”‘2‘/-2-7I*V (fté
`
`%I—3 1)
`
`{l:{:a‘¥9JI—2 10J90mg%3;‘~¥1.f\7}<I~1t»1‘/10 m
`
`2K&#b\3W@V—V—X9*7%E(%m
`
`Smm)EOHTm%EfiLk°rw:yémE
`
`%$L\%¥@%%V4v7nHwI—%w#é
`
`E%%bT~fié7UXL&40m€%koM.
`
`182-184'Co
`
`VvUwVwfiE9uvr7574~m;@&&
`
`%m97x%u#v—m5&d<fi%Lt29m
`
`&Wx£vb%5ik°(E%@fi3%x§/—
`
`)1z——§1:2urJ=)Ix.L)
`
`%w%1—a&flfi®fi&u$0mé%W—2
`
`~W—6éé&Lk°:mé®m%%®%fiE%
`
`fi4w%Lt°(E¢®w,R=,R3,w,
`
`w,R~umé%wm§mau%m¢a°>
`
`
`
`3 4
`
`Mylan Exhibit 1004, Page 35
`
`
`
`Mylan Exhibit 1004, Page 35
`
`

`
`
`
`0
`I
`00 In
`0
`0
`g
`0
`Q
`C
`Q
`
`I
`I
`0
`
`O
`
`I 0
`0 tau
`O
`001
`
`0
`
`0
`
`I
`
`no
`0
`0
`'0
`J
`Dino able
`
`9-
`
`O O
`0 9
`
`O
`I
`
`00
`on
`
`no
`I
`
`
`
`R5 R“
`R‘
`R“
`R’
`R‘
`412*:->%
`
`
`P-F H
`
`CH3 C2H5
`
`121-122
`
`VH_2
`
`V11” 3
`
`V11“-4
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`V11-5
`
`6-CEH H
`
`V1I—6
`
`6-619,
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CH3 C2115
`
`102-102.5
`
`i—Pr CzHs
`
`85—85.5
`
`cH'3czH5
`
`1oo.5—1o1.5
`
`i—Pr C2115
`
`105.5-106.5
`
`%)3MIJ1— b £:]§]*%0.)fi‘?£(':.ck0\
`
`fl:’.sWJVI—
`
`2~V—6%é&Lk°(§¢®M,R2,R%
`
`r, Wumé%w&vmE&§wfim?é.)
`
`$5
`
`'
`
`{haw
`
`R‘
`
`R’
`
`R“
`
`R‘
`
`R5
`
`.§i{,x§(°c).
`
`
`
`VI—2
`
`VI— 3
`
`VI— 4
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`VI— 5
`
`(3-02 H
`
`V— 6
`
`6-C2 H
`
`p-FH
`
`CH3‘
`
`—.——
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CH3
`
`149-151
`
`i-Pr
`
`130-130.5
`
`CH3
`
`139-141
`
`i-Pr
`
`168-169
`
`%73EH1J1— c &FB'J1§0)75?£-b:J:30{E€:*%V—-
`
`2
`
`‘:T<‘-:. ’/Z‘c\‘\
`
`
`3 5
`
`Mylan Exhibit 1004, Page 36
`
`
`
`Mylan Exhibit 1004, Page 36
`
`

`
`
`
`~V—6ééfibk.(i¢mm,H2.H%
`
`w, wumé%V®§mEufim?5.)
`
`$6
`
`
`wé%%% W W W W P
`flfi(t)
`
`p—F H
`
`CH3
`
`125-128
`
`v'— 2
`
`v'— 3
`
`v'— 4
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CH3
`
`143-146
`
`i-Pr
`
`92493
`
`cm
`
`zmam
`
`V-5 &c2H H
`
`V-— 6 140-140.5 6—C£ Ii 11 H i—Pr
`
`
`
`
`
`
`
`
`
`
`
`
`
`%m%1—d&fi%®fi&m;bmé%N—2
`
`~N~6%é&Lk.(§¢®w,R2,R%
`
`W, wumé%wo§maafimra.>
`
`$7
`
`
`mé%%% W W W W W‘
`fl§(t)
`
`Iv-— 2
`
`N—3
`
`HV— 4
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`IV- 5
`
`6-0.2 H
`
`4—F H
`
`CH3
`
`177-179
`
`H
`
`H
`
`H
`
`H W3
`
`Ii
`
`H
`
`i—Pr
`
`CH3
`
`—
`
`-
`
`-
`
`
`IV——6
`6-C2 H
`H
`71
`i-Pr
`-
`
`
`
`
`
`3 5
`
`Mylan Exhibit 1004, Page 37
`
`
`
`Mylan Exhibit 1004, Page 37
`
`

`
`
`
`%HM1—e&@%®fiEu;0wé%m—2
`
`~m—6éé&Lk.(§¢®w,H=,H%
`
`W, wHmé%mm§&§uwmr5.>
`
`is
`
`
`
`mé%%% W W W w W a é(T)
`
`III-2
`
`III-3
`
`III-4
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`III-5
`
`6~C£‘H
`
`III-6
`
`6—CQ H
`
`4—F H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CH3
`
`CH3
`
`194-196
`
`170—171.5
`
`i—Pr
`
`107—108.5
`
`CH3
`
`192-194
`
`i—Pr
`
`125.5-127
`
`%m%1—taH%@fi&m;0mé%H—2
`
`~H—6éé&Lk°(%¢®m,H2,H%
`
`W, Fuméwflmfififimfimié.)
`
`E9
`4b%%§%-H1 W R3R‘ W R”
`
`_
`fl Hi(t)
`
`H-2
`
`H
`
`3
`
`H — 4
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`5
`
`5-c.e H
`
`p-F H
`
`CH3 CzH5
`
`‘éfiwlii’-EM
`
`H
`
`H
`
`H
`
`H
`
`H—
`
`H
`
`CH3 Czfls
`
`105-106
`
`i—Pr C2Hs
`
`88.5-90.5
`
`CH3 C2Hs
`
`77-82
`
`3 7
`
`Mylan Exhibit 1004, Page 38
`
`
`
`Mylan Exhibit 1004, Page 38
`
`

`
`11-6. 6-02 H
`
`H
`
`H
`
`i-Pr CzHs
`
`96-98
`
`”£23MIJ1—ga:rfl$§%oJ7‘5?12c:;©1té*%I-12
`
`~I-16%%&Lk.
`
`£10
`
`
`
`00212”
`
`it/.s>%%% R‘
`
`R’
`
`R“
`
`R‘
`
`R‘ R“
`
`(°c)
`r':"J§1.'.5T£
`vxxxarn
`
`1—12
`
`I-13
`
`I—14
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`I-15 6-012 H
`
`I-16 6-0.0.
`
`H
`
`4—FH
`
`?EHiHi5@J
`CH3 C2145
`M/e 423,292.
`264,249
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CH3CzH5
`
`92-105
`
`i—Pr CZHS
`
`97-100
`
`CH3 C2115
`
`?fB3Hi’-1?)
`
`i-Pr CZHS
`
`HMHWJ
`
`(BUR £513)
`
`
`
`I
`...
`/.1;
`
`3 8
`
`Mylan Exhibit 1004, Page 39
`
`
`
`Mylan Exhibit 1004, Page 39
`
`

`
`
`
`¥)3E{§lJ2 c‘:F-?1$§0)7:‘?.£-c:J:0H:’é‘.%I — 51~
`
`I~55§%&bko
`
`E11
`
`
`
`Hcé.MbJ%% R’
`
`R2
`
`R3
`
`R‘
`
`R5 R” r‘?H1,'%1
`
`(°C)
`
`I-52
`
`I *'53
`
`I
`
`-—54
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`4-F H
`-
`
`CH3 Na
`
`H
`
`H
`
`H
`
`H
`
`CH3 Na
`
`1-Pr Na
`
`138-142
`(6J‘H$)
`
`130-132
`U3‘
`i’)
`
`l96~197
`(5? 1?)
`
`I ‘-55
`
`6-0.2 H
`
`I “-56
`
`6-02 H
`
`211-215
`(3%?)
`195-198
`(53‘fi=’r’)
`
`
`H
`
`H
`
`H
`
`H
`
`CH3 Na
`
`1—Pr Na
`
`(l>l"F\
`
`3'I%EI)
`
`3
`
`9
`
`Mylan Exhibit 1004, Page 40
`
`
`
`Mylan Exhibit 1004, Page 40
`
`

`
`0
`0
`on no
`O A
`n
`C
`O
`0
`0
`
`0
`O
`I
`
`on
`
`.900
`9 0
`O 000
`I
`to can
`
`I
`
`I
`
`to
`
`0
`
`O
`on
`0
`O
`I
`I
`one coco
`
`u
`
`C
`
`0
`O
`
`to
`
`O0
`on
`
`A o
`O O
`
`on
`
`00
`no
`
`0
`O
`
`%)5’tEf§lJ3 cEI3]¥§$0)7i‘?£b:J:@4|$’r}?ibJI—2 2~
`
`I-2 6é’r§lfl'C§Z>o
`
`$12
`
`r3:'I1,€.(°C)
`R5
`R‘
`R“
`H2
`R‘
`4t{a\%%v'%'-
`.2xz&7bn
`
`I -22
`
`I-23
`
`I -24
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`1-25 6-C2 H
`
`I-26 6—C'2
`
`H
`
`4—F H
`
`CH3
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`CH3
`
`i—Pr
`
`CH3
`
`i-Pr
`
`
`
`4 0
`
`Mylan Exhibit 1004, Pagé 41
`
`
`
`Mylan Exhibit 1004, Page 41
`
`

`
`
`
`%%W4&fl%@fi&m;@mé%I¥32~
`
`I—36%éfi?%é.
`
`$13
`
`
`
`R1
`
`R2
`
`4k.é}%>§~‘%‘~
`
`R‘
`
`R2
`
`R3
`
`R‘
`
`I-32
`
`I--33
`
`I-34
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`I—35
`
`6-012 H
`
`I -36 6-Cfl
`
`H
`
`4—F H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`H
`
`(BUR $13)
`
`4
`
`1
`
`Mylan Exhibit 1004, Page 42
`
`
`
`Mylan Exhibit 1004, Page 42
`
`

`
`O
`
`0
`0
`I0 00
`0 I 0
`O
`O
`0
`I
`
`I
`O
`0
`
`O0
`
`0'‘ vote
`0 0
`0 I90
`I
`
`000
`
`0
`
`I
`
`0
`
`O
`
`I
`or
`00
`O
`I
`0
`I
`009 000:
`
`O
`
`Go
`I
`no
`
`so
`IO
`on
`
`Q
`
`0
`
`0 Q
`
`I 9
`
`O
`
`3
`.’
`I
`
`&K$%Ww%%é%fi?5fl%®m§%¢°
`- mwu1=a:~z
`asu
`fifi(100fi)
`
`E
`K
`E E
`
`
`{bé%I-51
`
`LS«bfJ*b‘{>7fi§-Vi}
`
`>’a)Iz3<“=F~‘/2!?-1wlz11»1:z——x
`
`1(g)
`
`20
`
`2
`
`1,5
`fr”}I:’:.11/7)v:2—21x
`Q5
`x%7Uv&vy$y§L
`
`
`25
`
`i%&fifi§§%@\Vflfié%KAh\%*
`
`Kfiébkoimfiéfiféfififlfififfiflé
`
`L750 "“3i%H00DE§&i2 5 Omgféiofc.
`¥%W2:&wTtwfi
`
`fifi(100w7tw)
`
`E E
`
`m
`m
`
`
`fl3{Ez‘%I—51
`
`1(g)
`
`7i")-—-7'93!
`19
`
`
`ifi&fifi§é%@\fi~Kfi§b\200m"
`
`.
`
`20
`
`‘
`‘
`
`‘
`
`a
`
`I
`
`
`
`4 2
`
`Mylan Exhibit 1004, Page 43
`
`
`
`
`
`
`
`Mylan Exhibit 1004, Page 43
`
`

`
`5.
`
`.2 .“.-2"’
`
`:'E ‘. ' II? '
`.
`
`_
`
`fvflwftwmfifixfifibk.
`%%W3:%fifi
`
`&fi(100@)
`
`.2 .".
`
`.". .".
`
`.5. .:Z. ’ -22- -22-
`
`an
`
`552
`
`
`
`E E
`
`{bé%I—-51
`
`mm&4&
`
`$3 3% «h )1» :2 — :4
`
`fl E
`
`1 (g)'
`
`3
`
`9
`
`6
`
`Xf7UV&7VX9bL
`1
`
`
`20
`
`i%fl%fi§§%@\fi~Kfi%Lk%\%fi
`
`ébx -"E’=’§”) 2 O 0mg&7‘.§ZaJ:'36::63":=I1.L7‘.:.
`
`fimlféllzg
`
`fill
`
`&fi(1o0m)
`
`m
`K
`E E
`
`
`’”$’€s‘%I“'51
`
`A
`
`1 (g)
`
`wmifl
`79
`
`
`80
`
`ifi&fifiE%fi©\38T?fi~Kflfié%\
`
`$w@#wfiwL1$wk&m%@«&m%.$
`
`4 3
`
`Mylan Exhibit 1004, Page 44
`
`A
`
`;
`.’
`
`
`'
`I
`
`II
`
`i i I
`
`
`
`Mylan Exhibit 1004, Page 44
`
`

`
`§’J1flEH:’i7C390)E§HI0.8 8'C%o7‘co
`
`*?#%‘l‘tBIi§A
`
`EIEfl:.$I%fi:’c§’z'W’i
`
`
`
`4 4
`
`Mylan Exhibit 1004, Page 45
`
`
`
`Mylan Exhibit 1004, Page 45
`
`

`
`
`
`:
`
`;‘
`ta"
`
`GROUP ART UNIT}
`
`129;
`
`IN RE APPLICATION OE:
`
`YOSHIHIRO FUJIKAWA ET AL ‘
`>sEn1AL'No;:<»d7/d7/233)752»
`
`.
`
`FILED:
`
`AUGUST l9;.l988
`
`.ao
`
`EXAMINER:
`
`SPRINGER
`
`FOR:
`—
`
`QUINOKINE TYPE MEVA-
`LONOLACTONES'
`
`» '
`...‘;.H?'I.-
`.
`<
`DECLARATION
`‘-Rix_
`
`I
`
`‘HONORABLE COMMISSIONER OF PATENTS & TRADEMARKS
`
`WASHINGTON, D.C.
`
`20231
`
`SIR:
`
`'
`Now comes MIDORIKO MATSUDA who deposes and saysi
`That my name is MIDORIKO MATSUDA;
`That my aqoress is'll~3,_Eamiosaki 2—Ghome,..
`Shinagawa-ku, Tokyo, Japan;_
`A.
`That I know well both the English and Japanese
`
`languages;
`
`A
`
`the_attacfied English language translation is
`_That
`true and correct translation of Japanese Patent»
`'Application'No. 207224/1987 filed on August 20, 1987 to
`
`the best of my knowledge and belief;
`
`.
`
`7
`
`
`
`
`
`Mylan Exhibit _1_OO4, Page 46
`
`
`
`Mylan Exhibit 1004, Page 46
`
`

`
`
`
`
`
`I here5Y oeclare-further_that all statementsfmade
`herein of my own knowledge are true enfi that all
`‘statements made on information and belief are believed to
`be true; and further_that these statements were made with@
`Athe knowledge-that willful fielee statements andԤhe liker
`so made are puhishehle by fine b£=imp£1sohment or both,’
`
`under Section 1001 of Title 13 of the United States Code"
`
`and that such willful false statements may'jeopardize the _-
`_Validity of this application or any pateht issuing”
`
`thereon.
`
`FURTHER DEPGNENT SAITH NOT.
`
`
`
`..My|an ‘Exhibit 1004, Page 47 *
`
`
`
`Mylan Exhibit 1004, Page 47
`
`

`
`
`
`
`
`PATENT OFEICE
`—JAPANESE.GOVERNMENT
`.Tfiis is to cerfiifiy.that the annexed is a tfifie copy pf
`theVVfo1?1‘owi~r§g'Appiiiicagi-an"as fiuied‘ with this office.-
`
`‘ Date of Application;
`
`1
`
`‘Ve‘August 20, 1987
`
`Application Numbef:
`
`Patent Application No. 207224/1987
`
`Applicant:
`
`.,
`
`'
`
`Nissan Chemical Industries Ltd.“
`
`Octeber 7, 1988
`
`pFumitake:Yoshida
`Director—General, Patent Office
`
`_
`
`Mylan Exhibit 1004, Page 48
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mylan Exhibit 1004, Page 48
`
`

`
`
`
`
`
`
`
`
`
`International Patent_Classification
`C07D
`215/00
`
`PETITIONZFOR PATENT APPLICATION
`fig; 1§&7_-
`.
`August
`To: Director—Genera1, Patent Office:
`Kunio Ogawa
`
`1. Title of the Ifivention:
`
`QUINOLTNE TYPE MEVALON_OEACTON'E-S
`
`2.
`
`Inventor(s):
`
`Name:
`
`Yoshihiro_Fujikawa
`
`(and four others)
`
`.Address:
`
`' Nissan Chemical Industries Ltd;
`Chuo Kenkyusho, 722e1, Tsuboi—cho,
`Funabashi—shi,_Chiba—ken
`
`3.“ Patent Agplicant:
`
`Name:
`
`_
`
`(398) Nisgaa Chemical Industries Ltd.
`
`Representative: Takeo;§kai
`
`‘
`
`‘Address:
`
`7-1} 3~éhSEé,_Kanaa~Nishiki—cho,
`Chiyoda—ku, Tokyo
`101
`
`Please contact:
`
`TEL. 0474-6541111
`
`.4. List of Attached-Documents:
`(1) Specification
`(2) Duplicate of Petition
`
`A
`
`'
`
`1 copy
`1 copy
`
`Mylan Exhibit 1004, Page 49 1
`
`
`
`Mylan Exhibit 1004, Page 49
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`Inventors excegt above—mentioned:
`
`Name:
`
`Mikio Suzuki
`
`’Address:
`
`Nissan Chemical Industries Ltd»
`Chuo Kenkyusho, 722—l, Tsuboi—cho,
`Funabashi~shi, Chiba—ken
`
`-Name:v
`
`Address:
`Name:
`
`-
`
`_
`
`fflinoshi Iwasaki
`
`Vsame as abeve
`Mitsuaki Sakashita
`
`_Address:
`
`I
`
`Nissan Chemicai Industries Ltd.
`Seibutsukagaku Kenkyusho, 1470,
`-Oaza—shiraoka, shiraokaemachi,
`Minamisaitama—gun, Saitama—ken
`
`Name:
`
`_ Masaki Kitahara
`
`Address:
`
`same as above
`
`.. g _-
`
`
`
`Mylan Exhibit 1004, Page 50
`
`
`
`Mylan Exhibit 1004, Page 50
`
`

`
`
`
`
`
`
`
`NC-115 1/3 m/h
`(1573/1589)
`'
`
`....
`
`_
`
`SPECIFICATION
`
`lrTITLE of THE INVENTION:
`
`QUINOLINE TYPE MEVALONOLACTONES
`
`;2-scoPE OF ma: CLAIM:
`l.
`‘A oompoond of the formula:
`
`(1)
`
`3
`
`l
`2
`and R4 are independently hydrogen, Cl_4
`wherein R ,’R , R
`H alkyl, Cl_3 alkoxy, n~buto;;,
`i—butoxy,.sec—butoXy,
`trifluofomethyl, fluoro, Qgibfo, bromo; phenyl, phenoxy or
`5benzyloxy§ or when lobated it the ortho position to each
`other, R1 and,R?, or R3 and R4 together form
`
`-CH=CH—CH¥CH-; Y is -CH2-, +CH2CH2—,
`or--cH=cH—cH2—; and_z is
`
`-CH=CH—,
`R
`
`-CH2—CH=CH-
`
`.
`
`'
`
`°r
`
`1
`
`-CH-CHzfi'CH2‘C02RJ2
`
`I 0
`
`3
`
`OH
`
`
`
`ll
`is hydrogen,
`wherein_R ‘is hydrogen or C1_3 alkyl, R
`R14 (wherein R14 is physioiogically hydrolyzable alkyl or
`
`12
`
`Mylan Exhibit 1004, Page 51
`
`
`
`Mylan Exhibit 1004, Page 51
`
`

`
`
`
`
`
`
`
`
`
`_
`
`2
`
`_
`
`M (wherein M is NH4, a metal capable of forming a salt
`which is pharmaceutically acceptable, or an amine'H) and
`l3
`5
`
`is hydrogen or Cl_3 alkyl) and R
`R
`alkyl,.C3_6 cycloalkyl, phenyl—(CH2)m-
`ar 3).
`_
`3lDETAILED DESCRIPTION OF THE_INVENTION:
`
`is hydr09€n/ Cl_6
`(wherein m is_l,
`H
`
`2
`
`[Industrial Field of Utilizationlt
`“The present invention relates to novel
`
`mevalonolactones having a quinoline ring, proeesses far
`their production, pharmaceutical compositions containing.
`them and their pharmaceutical uses particularly as
`.
`hypolipoproteinemig and anti-atherosclerotic agents,
`and intermediates useful for their production and processes
`for the production of such éptermediates.
`_ [Prior Art and its Problem] -
`:*
`--us.-.._
`-
`Some fermentation metabolic products such as
`._compactine, CS—5l4, Mevinofifiy or semi-synthetic
`derivatives or fully synthetic derivatives thereof are
`
`known to be inhibitors against HMG-CoA reductase which is
`
`a rate limiting enzyme for cholesterol biosynthesis.
`Endo.J. Med.’Chem., 23(4)’ 401 (1985))
`
`(A.
`
`CS—5l4 and Mevinolin have been clinically proved to be
`
`potentially useful anti—hyperlipoproteinemic agents, and
`
`they are considered to beférfective for curing or
`preventing diseases of cordgary artery sclerosis or”’
`atherosclerosis.
`(IXth In€:'Symp. Drugs Affect. Lipid
`Metab.,
`l9.86, p30, p31,
`p6't'.3:--)-
`
`Mylaln Exhibit 1004, Page 52
`
`
`
`Mylan Exhibit 1004, Page 52
`
`

`
`
`
`
`
`
`
`-3-
`
`However; with respect to fully synthetic derivatives,
`
`particulerly'hd3mmydfli derivatives of inhihitors
`against HMG..c'oA ,_-’e‘_du¢ta5e#‘
`the-re hasgbeen disclosed
`1‘imited’..in-formation.
`«
`_
`-
`The present inventors have found that mevalonolactone.
`
`the corresponding
`derivatives having a quinoiine ring,
`dihydroxy carboxylic acids_and salts and esters thereof,
`have high inhibitory activities againstfflW3‘C°A reductase.
`
`The present invention has-been accomplished on the basis of
`
`‘this discovery.
`
`Th
`
`1
`..
`-
`3
`.
`-
`.
`e nove mevalonolactone derivatives of the;present
`invention having high inhibitory activities against
`HMG—CoA reductase are represented by the fdllowing formnla‘
`
`-I:
`
`__ -
`
`R“
`
`R2»
`
`wherein R1, R2, R3 and R4 are independently hydrogen, Cl_4»
`
`i-butoxy,'sec-butoxy,
`elkyl, Cl_3 alkoxy, n~buto§y,
`.trifluoromethyl, fluoro,:cé%oro, bromo) phenyl, phenoxy or
`benzyloxy, or when located:fit.the ortho position to
`hint
`-
`.
`E
`o
`eac
`her,
`2’
`3
`R1 and R , or_R ;and R4 together form —CH:CH—CH=CH-; Y is -CH2-,
`
`Mylan Exhibit 1004, Page 53
`
`
`
`Mylan Exhibit 1004, Page 53
`
`

`
`
`
`
`
`
`
`-CH CH2 2-,
`
`-CH=CI-I-, _-CH2—CH=CI_-i- or '-CI-I=CH_-CH2-; and. z 15
`
`HI!
`I
`
`-CH-CH2E*CH2-C0zR‘z
`'
`"on
`on
`
`or
`
`l
`
`R13.
`
`0
`
`H0~
`
`0
`
`wherein R11 is hydrogen or-C143 alkyl; R
`4
`.
`14 .
`.1
`-
`Rl (wherein R
`is phygamgmgny hydrolyzable alkyl) or
`M (wherein M is NH4, a metal capable of forming a salt_
`
`is hydrogen,
`
`12
`
`which is pharmaceutically acceptable or an amine.H) and
`R13 is hydrogen or Cl_3 alkyl; and,R5 is hydrogen, Cl_6
`-alkyl, C3_6 cycloalkyl or Efienyl-(cH2)m— (wherein m is
`l,
`2 or 3),
`'
`_:;E‘
`J
`' Variofis substituents'ifi*the formula I will bé
`
`described in detail with reference to specific examples.
`
`‘$1-4 alkyl for R1 R2
`I
`
`I
`
`R3 and. R4includes;_for
`
`2 I
`
`i-propyl, n—butyl,
`?XamPle, methyl, ethyl, n-propyl,
`i-butyl, sec—butyl and t—butylf Cl_3 alkoxy for R1, R
`and
`R
`lnCl'UdeS, for example, methoxy
`ethoxy
`_
`4
`
`’
`
`I
`
`.
`'
`n‘P1'-'0POXy and j.f‘pr'QpO‘XY.
`11 .T 2
`inckfifies, for eXample"methyl
`_
`.
`ethyl, n-propyl and i_propi1;_ N
`'
`13 .
`»:
`Cl_3.alkYl for R"
`lncfhdes, for.examp1e,_methYl
`ethyl I n—Pr°PYl and i"pI.‘QpY_']_
`I
`-
`Alkyl for R14 -. 1 d
`-
`inc u es, for example, methyl, ethyl’
`i-propyl, n—butyl and i;butYl
`
`Cl_3 alkyl for R
`
`.
`
`.1
`
`n~propyl,
`
`Mylan Exhibit -1004, Page 54
`
`
`
`Mylan Exhibit 1004, Page 54
`
`

`
`
`
`
`
`‘.A metal capable of forming a pharmaceutically H
`
`acceptable salt for M‘
`
`includes, for example, sodium and
`
`potassium.
`
`.H_
`..CQ2M includes, for example, —CO2NH4 and 7902
`'JP£imafiy tcftertiary'lower alkfilamine such aé*
`
`trimethylamine),
`
`'Cl_6 alkyl for R5 includes, for example, methyl,
`ethY1, n-prqpyl,
`iepropyl,'n+putyl,
`i—butYl, sec-Eutyl,
`t~butyl, n—pentyl and n—hexyl.
`I
`l
`5
`-in

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket