(12) United States Patent
`Camden
`
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIDIIIII~ 1111111111111111111111111111
`USOO6I.77460Bl
`US 6,177,460 Bl
`"'.JillI. 23,2001
`
`(10) Patent No.:
`(4.<;) !lute of Putent:
`
`(54) Mt:THOn Of' TRf:"\TMfXr f'OR CANct:n
`OR VIRAL INn:CTIONS
`
`(75)
`
`[nvcntor
`
`Ja mes Ikrb,<,r CllIndcn, WcSl Chester,
`OH (US)
`
`(73) A~~igncc: The "roeter & Gflm hlc Compllny,
`Cincinal1i. 011 (US)
`
`( .) NOlice:
`
`Under 35 U.S.c. 154(b), the lenn of this
`patent shall be extended for () days.
`
`'Ibis patenl is subject 10 a terOlinal dis(cid:173)
`c lai mer.
`
`(21) Appl. No. : 09/408,664
`
`(22) Filed:
`
`Scpo 29, L999
`
`Reillted U.s. Application Ilata
`
`(60) ConliDuMioD·in-p.:.rt of applic~lion No. 09/364,021 , flied On
`JuJ. 30, IYW, wbic~ is a division of application No. {)8ft>76,
`7IJ5, fIled 00 Jun. 1(>, 1!I97, now )'al. No. 5,932,1>09, which
`is n division of application No. \J8J()I:!(),4<>8, fikd on Jut 15,
`1996, now Pat No. 5,932,60 .. 1, whi ch is a con linualion·in·
`part of aWl icalioo No. fW420,9 IJ, liled on AI". 12, 19'15,
`now I'al. No. 5.Ii29r 141.
`(60) P,ovi>.iVllal al'Vlic'aliOIl No 6O/IXl l,888, med orr Aug. 4,
`1995.
`
`A6lK 31/27
`Int. C I.7
`(51)
`5 14/48 5; 514J4tl8
`(52) U.S. C L.
`(58) Held of Search ................................. 514J485, 4H8
`
`(56)
`
`References C itl'ti
`
`U.s. PATENT DOCUMENTS
`
`2,695,225
`2,73 4,911
`2,10\,051
`3.799.758
`3,853,530
`3,903,297
`4,408,052
`4,542,219
`4.544. 5 12
`4,t>49,2lJ3
`4,775,758
`4,866,059
`5,1 14,<IS I
`5,254,715
`
`11 / 1954 Witm""
`71nJ4
`211956 Suai"
`.................................. 260/471
`W /471
`W IQ57 Bro<;kway
`...................................... 71 i86
`3/1974 fran?
`.................................... 71n~
`1211974 Fran?
`9/1975 Roben ............................... 4241305
`10/ 1983 Howmi ................................. 546/22
`W1QR5
`lIowmi
`541in2
`10/ 1985 HOllJmi el at
`3/19111 Nojima ................................ 54&'11 2
`10/198.8 Nojima ................................... 546!l2
`9/1989 Temple ............................... 5141248
`S/1Q92 King .................................... 51 41290
`10/ 1993 Picord ct at ........................ 560/13
`
`""'25
`
`5,..136.690
`5,629,:W 1
`5,656.615
`
`RlI 994 Picard ct 01. ......................... 514/5
`S{l997 Cllnr<icn
`514/41\5
`8/1997 Camden ............................. 5 14/76
`
`FOREIGN PATENT DOCUMENTS
`
`WO 96132103
`WO 96/32104
`
`10{1996 (WO) .
`10/1996 (WO).
`
`OTHER PUBLICATIONS
`
`NAS R. "CompUlcr A<;siSled SlruclUrc-Anticancer Activity"
`J. Phum. Sci., 74 (8) P 831-836 (Au!!, .. 1985.
`Zilkah, "Eflecl of Inh ibitors of Plant Cell Division on
`Mam malian Tumor CeiL'>," Cancer I{cscarrn, 41, 1879-1883
`(May, 198 1).
`Zilkah, el al. Proc. !\m. As.soc. CanL...,r Res., vol. 22, 270
`(1981 ).
`Merck Index, 11'h ed., Merck /( Co., Inc. (Kahway, NJ,
`1989) P 1232 (#7769).
`Browo, et aI., J. Cell BioI., vol 16, No.2, 5]4-536 (1974)
`Dialug, Els<:vitr Scictm: PulJlislll:rs AbSI. , No. 212600,
`XPOO20 11351 of Brown cot al.. 1. Cell. BioI., vol , 16, No.2.,
`514-536 ( 1974).
`n us et al. Arch. [mmuno). Ther. Exp., vol. 33, No. 219,
`325-329 (1985).
`Bandruina, et aI., ['harm. CbcmJ., vol. ] 2, No. I I, 35-37
`(Nov., 1978).
`Mochida. et al. Trop. Agrie. Res. Ser .. vol. 19. 195-208
`(1985).
`Wal1tuburg, "Inhibiturs uf Culon Cardnogcnt:sis" Caoc't:r
`40 (5 ) pp. 2432-2435 (Nov., 1977).
`,\lIdIlS, [[emicidcs, 2nd ed., vol. 2, pro 55-82, 385-387
`Academic I'rcss (J 976).
`Schuster "Effects of Herbicides of the Urea and Carbamate
`Type" Btr. [nst. Tabakrorschung Band 20 pp. 25-37 ( 1973)
`
`Primary Examiner-Jerome D. Goldberg
`(74) " /romey, IIgenl, or Firm-SlC"cn W. Mille r; Rose Ann
`Dabck
`
`(57)
`
`A BSTRACT
`
`Methods for the treatment of eanccr<; or viral infections in
`mammals are disclosed that include administration of an
`N ·ch loro p henylcarbamate,
`or
`a n
`N-chlorop henylthiocarbamatt:, or a salt Ihcreof. Such com·
`pounds may be llsed in combination wilh a chemot he rapeu·
`tic agent and/or a potentiator .
`
`20 C laims, Nu J)rawings
`
`Apotex v. Abraxis - IPR201 8-00151 , Ex. 1028, p.O I of 14
`
`

`

`us 6, 177,460 B I
`
`M.ETHOI) 01- TRt:ATMENT FOR CANCI-:R
`O R VIRAL INn :CTIONS
`
`'(be prescol application is a conlinualion.in-par1 of U.s
`Ser. No. 091364,02 1, filed JuL 30. 1999 which is a divisional
`of 08/876,705 ftled J UII. 16, 1997. now U.S. 5,932,609
`whidl is a d;";S;()/lal..,f U.S. Ser. Nt). 08/680,468 filed on
`JuL 15, 1')96 now U.s. Pat. No_ 5,932,604. U.s Su No
`08/6M,46R is a oonlinuation-in-parl application of U.S. Scr.
`No. Q8J420,91J ftJcd Apr. 12. 1995, now U.S. 1'31. No.
`5.629,)41, U.S. Ser. No. 08/680,468 also claims priority to
`U.S. Ser. No. 60/00] ,888 likd Aug. 4, 1995. 11Ie patem and
`palent applica tions are incorpo ra ted by reference herein.
`
`TECHNICAL FJELD
`
`'Ibe present invemion relates to methods for Ihe treatmen t
`of cancer or a viral infcclino in mammals, particularly in
`h.uman and warm blooded animals, using a composition
`conta i n ing
`N - ch lorophc nylca rb a mate.
`N-chlorophenylthiocarbamate or salt thereef. The methods 20
`may use such a compound in C(lmbination with a potentia tor
`or a chemotherapeutic agent.
`
`2
`lIuclear phagocytic lill .... age. illcluding blood m .... n<.><;yles.
`tissue macrophages. Langerhans cells of the skin and den(cid:173)
`dritic reticulum cells wilhin lym ph nodc-;.
`I're<,;un;or cells in the 000<: marrow an: re leased inlH the
`blood in an immature circulating fonn known as monocytes
`Monocyte~ usc the blood .~lrictly a", " lransport med ium
`Once Ihey arrive where they're going to be usc(l. the)' le3vc
`the blood and complete differentiation inte macrophages
`Cells of tbe monocy1c/ma<.:rophage lineagc an: a major targ" t
`10 popul1l1ion for infection wit h illY in the body and are
`thought to provide reservoir;; of virlL~ for disseminating
`infection throughout the body. HlY is also neurotropic.
`<.:apablc of infecting monO<.:ytes and ma .... rophages in tilt:
`eelltral nervous system can$ing severe neurologic d amage
`15 They can interact and fusc with CD4-bcaring T cells, cans(cid:173)
`ing T cell depletion and thus contribllling 10 the pathogenesis
`of AIDS.
`Progression from III V infection to AIDS is primarily
`determined hy the effeel~ o[ HlY on the cells that it infects,
`including CD4+ T lymp hocytes and macrop hages. In tum.
`cdl activation. dilTen:ntiati()n and prolife ratio n regulate III V
`infection a,Kl replication in those cells. Hl Y and olher
`lentiviruscs can proliferate in nonproliferating, termin~lly
`25 differentiated maerophagcs and growth-arrested T lympho(cid:173)
`cytes. This ability of lentiviruses. including IIIV. to replicate
`in lIo"proliferating cells, partH:ularly in 11I a~·r .... phages, is
`believed to be nnique among retroviruses
`Due to the above-mentioned problems in the art. the
`.W prt~ n! invtn!or has sou!,:ht improvcmt n ~ an d provilJes
`such improvements herein.
`
`BACKGROUND OF TIlE INVEN"IlON
`Cancers arc the leading cause of death in animals and
`humans. 'Illc exact cause of cancer is not known, but links
`betwccn certain activities such a.~ smoking or expesure to
`carcinogens and the inci,kncc of certain types of cancers
`and tumors ha.~ becn .~hown by a num!;>"r of TC.')Can::hers.
`Many ty pes of chemotherapeutic agents have Ixen shown
`to he effective aga in"'t cancers anti tumor cell~. hut not all
`types of cancers an d IIImors respond to these agents.
`Unfortunately. many of these agems also destroy normal
`"dIs. 11"" ex,...·t med,:..niSIl) fm the aClion of these d""mo_ 35
`the rapeu tic agents arc not always known.
`Despit<: adva",.:cs in the field of canwr treatment th~
`leading therapies to date arc surgery. radiation and chemo·
`the rapy. Chemotherapeutic approaches arc said to fight
`cancers that arc metastasized or ones that are particularly 40
`aggressive. Such cytocidal or cytestatic agents work best on
`<.:an~"Crs with large growth [a<.:ton;, i.e., ()nQ; whoSt: cells arc
`rapidly dividing. '10 date, hormoncs, in particular estrogen,
`progesterone and tcstno;terone. and some antihioties pro·
`duced by a variety of microbes. alkylating agcnts, and ~5
`an timetabolit~s form tbe bulk of tb~rapies available 10
`oncologists. Ideally cytotoxic agents that haw specificity for
`canccr and tumor cells while not affecting normal cells
`would be extremcly desirable. Unfortunatcly. none have
`been found and instead agents lh311argct especially rapidly su
`dividing ~"Clls (both tu mor and normal) have lJ<,en us.: d.
`Oearly. tbe devc lopme nt of materials that would targct
`cancer cells due to some unique specificity for them would
`be a breakthrougb. Al1ematively, materials that were cyto(cid:173)
`toxic to cancer cells whiJc exerting mild effects on normal
`cells would be desirable.
`Ilum an Immunodeficiency Virus (l ll V), the etiological
`agent for A]])S (acquired immune deficiency syndrome). is
`a m.::mber of the lenti\'iruscs. a subfamily of retro\'iru.~cs.
`HIY in tc~ates its gCI",tic inf .... rmation inlo lhe genoule of lhe
`host. Most importantly, Ill Y infects and invades cells of th e
`immune ~ystem; it breaks down the body' s immu nc ~ystem
`and renders the patient susceptible to <:lpportunistic infec(cid:173)
`tions ami n" oplasms. II IV-!
`is .... ytopathi ....
`f .... r T4
`lymp hocytes, cells of the immune system that express the 65
`c"l1 .<;lIrfa<.:c d ifferentiation .ntigen C04. In additirmtn r: 0 4 ..
`T cells. the host range of HlY indudes cells of the mono-
`
`SUMMARY OF TIlE INYEN"n ON
`Methods for trealment of mammals, and io particular,
`warm hloodcd animals and humans th at nrC affected h)'
`cancer or viral infection comprising administering a thera(cid:173)
`p~uti<.:ally eiftctive amount of an N-chlorophcnykarbamate.
`an N-oehlorophenylthiocarbamale, or a salt thereof, arc pro·
`vided
`hy
`the
`pr esen t
`in " ent ion
`An
`N- ch loro ph enylcarbamat e .
`or
`an
`N-oehloro phe ny lthiocaroamate has the formula
`
`where;n n is from ! ((l 3, X is oxygen or sulfur, and I{ is
`selected from the group con~sting of hydrogen. lower alkyl.
`lower alkeny!. cyclohexyl, phcnalkyl of u)) to 8 camon
`atoms, and phenyl.
`'Jbes.: compositiolls arc effectivc in killing or slowing the
`growth nf cancers. yet arc safer than adria myein On no rmal.
`55 healthy cells. The compositions arc also particularly effec(cid:173)
`tive against cells of monocytic lineage infected with Hl Y.
`
`DETAILED ])ESCRlP"1l0N OF THE
`INVENnON
`
`60 A. ])EI~l NITIONS:
`A As used herein, "a therapeutically dfcctive amou nl."
`means the concentration or quantity o r level of the com·
`pound of the present inven tion Ihat can attain a particular
`medical end, such as .. :untrol .... r destruction of <.:allWr cells.
`virally-infected cells, or viruses without producing unac(cid:173)
`ecptank toxic symplOm!>. Th" term "!;;Ife and e ffcclive
`amount" refers to the quantity of a component which is
`
`Apotex v. Abraxis - IPR201 8-00151 , Ex. 1028, p.02 of 14
`
`

`

`us 6, 177,460 81
`
`JO
`
`3
`loUmt:K:m to yicW a o.ksircd Ihc<1Ipt:ulic rcspooso;: wit hout
`undue ad\'c~ side clfcCl.~ (such as toxicity, irritalion, or
`allergic response) commensurate wilh a reasonable benefil/
`ri5k raTio when used in lilt: manne r of Ihis inv"'ntion. 'Inc
`specific ··!i.lfc ~ nd ,,[ cclive amount" will vary wilh such
`fao;lo~ u the p~rl icu lar cnodil io n being tr<:al«i, [be ph~iClll
`condition of the pa lien!, the type o f mammal being lreale(!.
`ItIt duration uf Itt..: trealment. lilt nalure o f '-Ol1CurrcUl
`l!\crap y (if any), and the specific fomlllla lioru; employed and
`the structure of the compounds or it!; saliS.
`As used here;", a "subject in need lhcrcof,~ is a mamlllal
`h ~v ing ca~r or hl"jog a viral infection. As used herein.
`'·<,!3.rl<,:l;r~ rden; to ~l! Iypt=S of calK--.:rs. or nwplasms or
`be ni gn or ma ligna nt tu mors. In one embodiment, lOOse
`c~ nccrs that Mtac k no rmal hcal1hy hlood cells or ho ne
`marrow are co nt em plated by the present invention. Preferred 15
`ca nce rs for treatmen t us ing methods provided herein iJIClud c
`,.,~r,.,illuill a. By ··,.,ucilluma" is mcant a l>t:nign or IIlalignalll
`epilhelial h ,mor U1d illC ludes, bUI is DOl limi ted to, breast
`ca rcinoma, prosta te carcinoma, no n-sma ll cell lung
`c~rcinoma, colo n cucinom~. CNS carcinoma, mela noma 10
`carcil1Oll1a, uvuilrl ,.,~n;ioom~, or reo~1 c arciooma. A Pl"(_
`fcrr-ed hosl is I humi~ IKlst.
`A~ L'!lCd herein. 'a cell of monocylic li ncage" mea ns , cell
`having a bone marrow precursor cell an d lbal di ITereotiales
`into a macrophage cell, and includes monocylcs and mac·
`ruphlg." •.
`A5 used here in, -viruses~ inclurks vi ruses Ihal (3u>!;t
`di.'lCL'iC in warm blooded anim als including rcl rO\· iru~ .. such
`u III V Of" I rn.v, in fl uenu., rh inO\'ilU$Cs, herpes, or lhe li kc .
`As LL!><;d herein , aD N-chlorupheoylcarbamalt:. Of" aD
`N·cbloropheuyithiocuballla te. Of" sail !bereof are 'COIII(cid:173)
`pound .. o f Ihe prc.'<Cnt invcntion." Such compounds are
`furtller set forth iu Section B infra.
`As used herein. ··potentiators' are materials that affect lhe
`imillune systtm ur euh.1.Il<."e tht eITecti"encss uf the drug!>
`and are furlbc:r sc t fort h io sec tion E hereio
`A~ UKd herein, "clM;:molherapc utic agents" includes
`DNA-in teractive :!gems, ~ntim e t~boILles. tub ulio-interactive
`'\,lents . hormonal agents 3nd others. such as asparagioase or
`hydroxyul\!3 and arc IS further se t forth in Section D infra.
`Followiog long-st an ding patent I.w oonvcntinn, th e Ic rm.~
`.. ~" and 'an" me an "one o r more" whe n used in this
`applicalion. includi ng Ihe claims.
`B . N·C HL O ROPHENYLCARBAMATE OR
`N·CHLORQI'HENYI;111l0 CARBAMATE
`an
`nr
`An
`N·ch lor o p h e n y lcarham a l c
`N-chlorophcn)'llh iocarbamale has the following structure
`
`is a ll
`
`4
`i n ve n t io ,, "
`cumpound of t h e " r ese ll t
`o r
`N· ch loro p h e n ylcilrbamate,
`N<h lo rophc nyllhioclrbama tc, Of D sal! lhereof.
`Ph3fmaceu tically acceptable add it io n sa lt s of
`N -ch loruphenylcarbamatc .
`or
`aD
`N<hloropheuyJth"xlroamat~, are cousiden:d wilhio lhe
`IICOJlC of oompound'l of lhe pn:.o;cnt in"cll tion and are ~ It.~
`wilh an organic Of" inorganic acid. Preferred acid additioo
`" Its are chlorides. bro mid..::s. sulfates. ni trates. phosphates.
`~u lrona tes, fur rl1 ates. tarlrates. maica tes, malalcs, cilrates,
`be nzoates, salicylalcs, ilSCOroales,or the like. Suc h sailS may
`he synthesized from tIM;: com pound. or derivative 1hereof. nr
`the prese nt in,"ention lhat cQ nlaius a basic or acidic moie t)·
`by co nvcntional chemical mcChods. Generally. such salls
`!IIay be pre pared b y re acting a free ac id or base fonn of the
`cn mpn und, Dr d c r iv ~tive thereof, with ~ s1oichiome1ric
`amount of th e appropriate OOSC or acid in wal er or io an
`OrGa ni c !IOlvcnt, or in a mixlurc o f lhe two; gef)Crally.
`like
`,., tlle r, e th yl aL"C tate, ~ lhl nol.
`nonal.]ueous meLli,
`isopropanol, or acetooitriJc are pre ferred. Further suit able
`sal1.~ may be fnund in Nell/iilg/otl: H,e .'icience and Practice
`of Plltlmracy, ]9th ed ., ~h ck Pub lishing Com pany, Easton.
`I' a., 1995. p. 1457.
`Pharml[.:cutica lly ICl."eptable salts of tlte compounds of
`15 the pre'\C nt inve ntio n inc lude conventional non-toxic sailS or
`!be qUI te mary am monium sailS of the compounds or deriva(cid:173)
`tives for med. for exa mple. from non-toxic inorganic or
`oq:allic lICids. For eump le, such conyc nlional OOI\-lOXIc
`salts include lhose derived from inorganic acids such as
`.}() hydrochloric. hydrobromic. sulfuric. sulfamic, phosphoric,
`oitrie. or tIM;: like; and sailS p repared from organic acids such
`as acc lic. propionic. 5Llccinic, glycolic, stearic. Lactic, malic,
`tartar ic. ci tric, asc o rb ic, male ic. h yd roxy maleic.
`phe ny lacetic, g lutamic. ben1.Oic, sa licylic, s ulfani lic.
`35 2-acetOllybenzo i c, fumaric. IOlue n esulfo ni c .
`methaDCsulfo nic, etliane disu lfooic. oxalic. isethionic. or lhe
`like . Prcf~rrttl ac id addition salts ar~ dtlorido:s. bromidts.
`sulfates, nitra tes, ph05phales, sulfonates, fomlates,tarlrates,
`m alcate~, ma l al e.~, c itrate.', henzn al c.~, sal ic yla les,
`<10 ascorhmes. Of" the like.
`Further. included withi n the scope of 1he compoun d. o r
`salts thereof. usdul for the: presen t invention are prod rugs .
`As used herein. ~ "prodnrg" is a elmg covalen tly bonded to
`a curier wherein re lel.'\C nf thc drug occurs iu viv o when thc
`. s prod rug is adm inistered to a mam malian subject. l'rod rugs
`of the COllll)()uutls of lhe p f\:SCnl invention are prepa n:d by
`modifying fu nc1ional groups preSCOI in the co mpounds in
`such /I way lhal Ille mod ilica1ioll'< are cleavcd , e ithcr in
`rootine manipulation or io vi,'o, 10 yield Ihe desired com·
`50 pound . Prodrugs include compourxls whe rein hydroxy.
`~lIlilLe, ur sulfl,yd ryl \,lruulJS if'"' bonded to any \,ltoUp Ihlt,
`when administered 10 I mam malian SUbjec1, is cleaved to
`form a fr« hydro~yl. ami flO. or solfhydryl grou p. rc.~pcc·
`lively. Ellampies o f prodrugs ioclude. bot are 1IOt li mited 10.
`ss acetatc. fOffllate, Of tJ,;: nloa t ~ lkri"a tivcsuf alco hol or amint:
`functional groups in the compoondsof the prese nt in\"ention;
`ptno;phale e:llcrl'o. dimCl h)'lglycinc c.'<1cn;., Iminoa ll.:ylhcnzyl
`estcrs. amiooalky l esters or carboxyalky l eslers of alcohol or
`phenol functional groups in the compou nds of Ihe prest nl
`60 in ... ~nt iun; or the like-.
`Co m pounds of the pre5Cnt invenlion are !mown fOf" lheir
`herbicidal act"·ilies. They are systemic herbicides used to
`prevcn t and eradica1e certa io planlS Of" weoos. Systemic
`h~ ,bi ... id<:" ~re d i rrer"nl i~I'"'tl fll.>L1l ul!tC I hcrbi"idts by Iheir
`65 abi lil y to be absorbed by Ihe plant and to move Ihrough lhe
`pl~nl . ·Ilii.' systemic Hllili ty i., not 3 neces.~uy requiremc nt nf
`the (.'Ompounds o f th is invt:nt iou.
`
`wbc:rci n u is from I to 3, X is oxygen or sulfur, and R is
`l'(:1e<:tcd from the group con.";stingof hydrogen. lowcr ! ll.:yl,
`lower I ll.:e nyl. cyclohexyl. phenalkyl of up to 8 carbon
`atoms and phen)'!.
`l'rcf~rn:d ~'<lI Ii PU Ll [1lh; an: those in wioid , R is ~lky l with 1
`to 4 carboll5, preferably, io;opropyJ; X is oxygen; n isi ; and
`the chlom grou p is in Ihe 3 pct"ition 0 0 the phenyl group.
`N-3chk>ropheny lcarbamate is a most pre ferred compou nd.
`·n",:;.; .. :ompuunJs au; prcJla[ ~ d a .. :\. ... " diojl. 10 the Ill<:thoo:]
`descrilxd in U.S. Pal. No. 2,695,225 issued 10 Wil mao
`( 1954) and U.s. !'al. No. 2.734.91 1 i!lsucd tn Strain ( 1956).
`incorpor31oo by reference herein. As used hereio, a ~a
`
`Apotex v. Abraxis - IPR201 8-001 5 1, Ex. 1028, p.03 of 14
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`us 6, 177,460 B I
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`s
`
`C. SCREENING ASSAYS
`Screening a~ys for determin ing those cancers suscep(cid:173)
`ti ble to lrcalment ll~ing rompou nds of the prescnt invention
`include incubaling cell line models represe nting specific
`can~"'rs as set forth, fo r example, by the Na tio nal Cam:cr
`Institu te, in the presence and absem.-e o f such compounds.
`Via bility of ccll~ may he determined by the MIT as.'<II y
`(Promega Corp .. Madison. Wis. 53711). or the SRB
`(sulforbodamine 11) assay (Skehan, e1 aL.JNCI, 82: 13.1 107.
`1990). Susu:plil>ility 10 sailll'OJIl)}(Juuus exists wlJ<:!l viab il- 10
`ity in the presence of a compou nd of the pre.sent invention
`is less th an v iability in Ihc absence of such compound.
`Exe mplary cell line models representing specific cancers
`indude, bul an:: no l limi ted 10. the following:
`No n -.~m3 11 cell
`lung cancer N C 11123, NC 11 1324,
`NC1H522, A549//I,I CC, A549(ASC), CALU I, EKYX,
`NCl II 125 M, NC IH 226, N C IH 520, S KMESI.
`NCl H322 M, NC!H 358M, NCl H460, N CIH2 92,
`1101'62, 1I01' 1H, lI01'19, 110 1' 92, LXI' L 529,
`SWI573. IXFS 6501., MI,I OI9, MIJ076, MI.I045, or 20
`UAllLG22;
`Small ccll lung canccr: NCI 1l6Q, NC111 146, NCl1I82,
`NC1H524, DMS 114, OMS 273, HQI'27, 5 111'77, or
`RHOS:
`CAlIon canccr: 111'29, HC':C2998, He n Hi, LOYO, SW
`111 6, SW620, COLO 205, DLDI , W[l)R, COLO
`320DM, He rt5, CXF 280, KM12, KM20L2, COLO
`74 [, CXF 264L, COLO 746, UAllC02, MU059,
`CACU2, IIT291l'M, 1IT29/MDRl , vr NI34;
`Breasl e am:tr: MCF7, MCF7/ADRRES. ZR751. ZR7530,
`MI)AM H231 /ATCC, HS 578'1; UISOBCAI , MCI'7/
`AILC, SKilR3, MDAMB435, MDAN, 11'1'549. '1'470,
`MDAMIl231. MAX F 401. BT474, or M DAMB488;
`Ov ar i ~n C ~n ce r OVCAID, OVC An 4, OVCA R5,
`OVCARS. A2780, IGROYI, SKOY3, OYXF 899,
`A1336, or ES2:
`Lcu kemia: 1'388, I'38M/AD R, CC r~ FCEM , CCRFSB,
`K562, MOlT 4, Lill O, HL60(TH), RI'MI8226, SR, or
`K562/ADR;
`Fibrohlas! IMR90, or CC DI 9LU;
`Re nal ca ncer: U031, SN12C, SNI2SI, SNI2 KI,
`SNI2L1, SN12A1. M98, A704, CAK II , RXF 393,
`RXF83I, 7860, SW156. TK1 64, 7691', SS78, ACHN,
`T KlO, RX F 4864 U0K57, or U0K57LN;
`Melanoma: LO X IM YI. MA LM E3 M, 1~ I >MI19SI ,
`SKMEL2, S KMELS, SKME L2S, S KMELJI . UCSD
`242L, UCS D 354L. M14. MI 9M EL. UACC82 .
`UACC257, MEX F 5144 or UABMEL3;
`Pr(l;lale cancer PC3, PC3M, DU145. LNCAP, IO I3L.
`UMSCP1, WIS, JE. RE R. MRM, DHM, AG, Ril. RVP,
`I'C, WAE, DU/SMC. JCAI, ND I , WM .... TSUPRI,
`mrA, GOP, 1'10, WilW, RV I'I, r.r WI,I ,;
`CNS cancer SNU7, SNBl9. SNB4, SNB56. SNB75,
`SNU7H, U251, '1'1.:671, $ 1'26$, SF2\l5, $1'539, XF 498,
`SW 1088, SW 1783. U87 MG.SF767, SF763,AI72. or
`SMSKCNY:.
`ilone/muscle: A204/ATIT., OilS, TE8 S, A673, 01A.";9,
`MHM 25, lUI 18, RH30, or RD; and
`Lymp homa: AS283, liT, KIJ488, PA6H2, SUUIlL7, RL,
`OB, SUOllt!. SUDIIL4. SUDln.10, NUDULl, or
`HUT 102.
`D. CI IEMOTHERAPEUTI C AG ENTS
`Cbtmotherapeutic agents are gtnerally grouped as DNA(cid:173)
`intc racti\'c agc nt,., antimctaholitcs,
`luh ulin_intcractive
`agenls. hormonal a,gems, Olher agents such as asparaginasc
`
`6
`or hyd rox yurea, a ,Ki agcut" a~ SCI forth in Table L Each o f
`th e groups of c hemolhe ra pe ulic age nts can be further
`div i(tc<l by lype of acrivily or oom pouoo. C1lcmOlhe raPCUlie
`agenls
`used
`in
`combinalion wilh
`an
`N_ eh [orop hen y lcarbamat e ,
`or
`a n
`N-chlorop heny lthiocarbamalc. or s alls thtrcof u f lhe preselll
`invention may he scloctcd from any of thcse grou ps hut arc
`nollimiled therelo. For a detailed disuJssion of lhe chemo-
`lherapeutic agenLS and lheir melhod o f adminislratio n. see
`Dorr. d al. CI/Ilcer ClwlIlolfl ertljJ)' fllilldbook, 2d edition,
`pages 15-34, App[elo n & La nge (Connecticut, 1994) herein
`incorporated hy refcrence.
`DNA,interactive agents include alky la!ing agenlS, e.g
`cisp[a1in, ~'yclophosp ha midc, all rctam inc; DNA s lrand·
`15 breakage agents, such as bleomycin; iu!ercalating lopo i(cid:173)
`wmcrasc 11 in hih ito rs, e.g .• dact inomycin and doxoruhici n);
`nonint ercala ling lopoisomcrase II inhibilor:> such as, elopo(cid:173)
`side and lcniposide; and lhc DNA minor groo\'e bi nder
`pican'yci n, for e.umplc.
`The alkylaling agents (orm covalent chemical add ucts
`with ccllular DNA, I~ NA, or protci n molecules, or Wilh
`smaller am ino acids. glu lalhione, or similar chemicals
`Gencrall y, alky[atin~ agents rca"t with a nUl.lcoph ilie alom in
`a cell ul ar conslituenl. such as an amino, carboxyl.
`25 phosph ale, or suUhydryl group in nucleic acids, pro teins,
`am ino acids, or in g[utalhione. The mechanism and lhe role
`of lhesc a[kyl:ning agents in cancer therapy is nOI wel l
`unde rslood.
`Typical aLky[aling agenls include. but are no t limited 10,
`] 0 nitr og en mus ta rds, suc h as chloramhucil,
`cyclophosphamide, isofamide. mec hloret ha mi ne ,
`melphalan, uracil mustard; aziridine s uch as IhiolCpa; mClb(cid:173)
`arJCsulpho nate ester:> such as busulfan; ni troso ureas, such as
`carmustine, lom~stinc, Slrcpt ozo.cin; plali num complexes,
`35 such as cisplatin. carboplalin; bioreductive alkylator. such as
`mitomycin . aud procarbazine, dacarbazine and allrelamine
`DNA slrand breaking age nls include bkomycin. [or
`example.
`DNA lopoiwmerasc II in hihitors include the following
`40 inlercalalors . such as amsac r ine. da CI in om ycin.
`dauno rubici n, dOl«)rubici n (adriamycin), idarub iein, and
`miloxantront; nonintercalalors, such as etoposide and
`teniposide, for example
`A DNA minor groove binder is p[icamycin, fo r example
`Antimelabolites interfere with the production of nucleic
`acids by OllC of lwo major mechanisms. Certain Jru~ in hibit
`prod uClion of deoxyrioonucleoside trip hosphatcs lhal arc the
`immediate precursors for DNA synlhcsi", thus inhihiting
`DNA replication. CeMain of the compounrls arc analogues o f
`su purines or pyrimidines and are incorporated in anabolic
`nucleolide palhways. TIICS t analogucs an: lhell subsliluted
`into l)NA or RNA instead of tt.cir no rmal counterparts
`AntimelaoolileS uf;C fu [ herein include, hut arc nOlli miled
`to. fo [ale anlagonists such as mel holrexale and IIimelrexale;
`55 pyrimidine anlagonisls . such as fluo rourac il,
`lIuorodeox),uridinc. e Il3?1?, alacilidine, cytarabi ne, and
`floxuridinc; purine antag<lni,<;ls include merca ptopurine,
`6lhioguanine, f1udarabine. pentostatin; sugar modified ana(cid:173)
`logs indude cycltabine, Hudarabine; and ribonu clOOlide
`60 reducta~c iuhibilors iucludc hydroxyu rea.
`Tubulin interaclive agenlS acl by binding to specitic sites
`on lubu[i n, a protein lhal polymeri?.cs 10 form cellular
`microtubu[es. Micrombu[es are crilical cell Slrucmre un ilS
`When lile inlera ~1i"e ~ge nts bind the p rolein. lhe wll .:an not
`65 form micrombules. Tubu li n interactive agents include vin(cid:173)
`cristin.;: and \'innl as!inc, hol h alkaloids and pacliln cl, for
`example.
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1028, p.04 of 14
`
`

`

`us 6,177,460 B I
`
`7
`trcalrm:lIl of
`Hunnollai agcoLS art: ai!;() u>;<.: ru\ in the
`c ancers arK! t\lmors. '\bey are used in hormonally susceptible
`tumors and arc lL~lIaJJy derived from nalUral sources. Hor(cid:173)
`mo nal agents include. but arc nOl limited 10. estrogens,
`conjugated ~S lrog tns and cth inyl es tradiol and
`dicthylstilb<:ste roJ, chlortriani5ell and idelleslrol; progestins
`as
`hy drn xyprn gcs l cro nc
`ca pr oa te ,
`~lIc h
`mcdroxyp rogcsleronc, and megestrol; amI androgens such
`as testoste rone. testosterone prop ionate; fiuoxymeSierone.
`and md hyh"SIOS(" WIl<'.
`Adrenal c:ortiCQ:Sleroicb are deriv~d from natu ral adrenal
`cortisol or hydrocortisone. They arc us.cd ncc3lL<;e of their
`anti· jnflammalQry benefits as well as Ihe ability of some to
`in hibit milOtic lIiv~ions and 10 haft DNA synthesis. These
`COlllpou nds ir>eludc , but arc nol limited 10, predniso ne, 15
`dexam.::lhasone, methylprcclnisolone, and prednisolone.
`Leulinizi ng ho rmo ne re leasing hormone agenls or
`gonadotropin-releasing hormone antagonists are used pri-
`
`indudc !cu.
`IIlarily Ihe Irealll)clII of proslal" cauc"r. 111~
`prolidc acelate and goserclin acctale They
`prevent lhe
`biosynthesis of steroids in the testes.
`Amihonno nal antigen.s include. for example. anlieslro(cid:173)
`genic .:Igems suc h ~s tamoxifen, anli~ ndrogen agenlS such as
`Ilutam ide; and antiadrenal agents such as mi totane and
`aminoglutethimide.
`Further agents include the following: hydro xyurea
`10 appears 10 act primarily Ih rough inh ibition of Ihe ~ m:yme
`ribonucleotide reductase, and asparaginase is an enzyme
`whic h converts asparagine to nonfunctional aspartic acid
`and Ihus blocks protein synlhesis in Ihe tu mor
`Tax()l (pa clit~xe l ) i.~ a preferred c hemothera peulic age nt
`A listing of currently available chemotherapeutic agen ts
`accordin g 10 class. and including diseases for which lhe
`agents arc indicated. is provided as Table I.
`
`TABLE I
`
`to."eopt..,ic 0;.. .... ' for which Exemp la,y OO.m"d .... peut;c .~n .....
`roo·cate<!
`
`a_
`Name
`'1;'1'" of "lie ...
`Alkyllting '>.s''''' Nitroj;<n M,~ .. ruo M,d,kJI<thmi ••
`(lL"J
`CYClopbo<pMOl>:le
`lfoofa ... >:I.
`
`M':pml""
`
`O lo,".,b",U
`
`F)o)"t'.'",;n ... od
`M<th)·Im<lo.",in ..
`"'k~1 Sullo, ..... ,
`"it"""'u ....
`
`E.tra m .... ;ne
`I ruomah)· I"",lam;n.
`·lbi<:«p.
`l:S<>;uJl ••
`ll>rm.:";"
`
`L.:> ... ' lir.<
`
`$emu";",,
`
`St .. p",rocm
`
`,\ otin .. ",""1 it""
`
`Trior.c".
`
`flac" b."i ..
`P""","',,;nc
`A7j ~dj""
`Fol ic "6d ,\ o"og' M<th""u ...
`Tri ..... ,... ...
`
`lfu.",'
`
`Ho<It;li.·, di><."". 00.·
`Ho<Isk-i .. ·• lympborn ..
`Aout< and cbrOilic 1~D\pbc:<;ylic
`"'o.ok<mias, lIodgkin·. di ..... ,
`"" •. lIodS)'.in·.'p"pho.,u.
`mullip'" Ol~"CI"m ••
`...,robl ... """ •• """". "'.,Hl·,
`IUD/!. Wilm'· t"Olor, «,,"ix,
`.. "is,.oft ti ........ rcom ..
`~tukipl. ",)"'1"",", h ... ",
`",·orr
`Oronic lyrr,,:boc)1;C leukemi>.,
`prim .. ,)" m""",slob"'i .. ,,, .. ,
`H<>dgki .. ·• di>< ... , !\O ••
`H<>dgki,,· . lympborn ..
`rro.tate
`.",."
`Blodde,. b ... II . ","DI)·
`I.."lororuc \lmnUIOC)1ic I.uk.ma
`1I000gkio·. di ...... !\olI"
`1I000gkin·, Iympbom ••. priOl'ry
`brain IUrTOOT1. ttml';ple
`m)"ol""",. ""lill""nt
`"",1o,.,.",.
`Il<>dgki .. ·• di>l: ... , !\O ••
`Ilo<lgkin·, Iympbom ... priOl'ry
`brain tu"",,, • • ",.1I·c:<;11 lu<S
`I'rimOC)· b,.in tumor<.
`'IOm.ch, colo ..
`~Illi",".' pane",atic
`insuli.orna. mIOlipa.'
`carcinoid
`~bl ill"".' .",I, .on ...
`lIodgki.·, di ..... , .on I; .....
`.. reon.."
`"rute IY.'l'hoq1;c I.uk •• , ,,-,
`c""rioearcio...,.,., myc".;'
`fu",oides, breast, bead .od
`oed:.. hmj;. ", .. o~. ;c
`
`--
`
`F}·, ;", ;J;""
`Aoalogs
`
`Puri .. /\.r:alop
`.0<1 Relorod
`Inh ibitors
`
`I'l"'''",''''cil
`~10r0.:,idir.c
`
`Mer""F"'puri"
`
`Il" .. ', <>'~' •• , ,,,n,,ch,
`pa""' .... o'''''y, ""ad ood
`ned, ",ir:ary bl.Jcler,
`prormJii" •• t . kin l .. ions
`(topical)
`C}t .... bi .. A""ir id in. Ac"" !!",nulOi,;)tic ...... ""''''
`lymphoc}1;' I.o.ok<o;""
`1\out. lympbo<:}1ic, .0'"1t
`lI"'nUIOC}1ic. 000 chronic
`""""Ioc}·t;c l<u1«n' "",
`
`Apotex v. Abraxis - IPR20 18-00 ISI , Ex. 1028, p.OS of 14
`
`

`

`us 6,177,460 B I
`
`1lJ
`
`9
`
`TABLE I-continued
`
`NeoploSlic IX. ...... ' for w hich ElIOmplor}" OI<aloth<ro.pou,", "leots ....
`indic.,ed
`
`CI ...
`
`I),..,. or """.1
`
`A<;tJl< g,..nuloc)1k, a<:U<O
`l)"!l1p boc"",, ond chronic
`sranuloc).ic leukemia.
`Jla ir)'ccI11eukemio, m)"",;'
`fu.g:>~ •• chronic lymph"")";'
`letll:<mi.
`Chr"Dic 1)"'p/lOC)1ic le nk< ... ia,
`Hodgkin"' . nd "" •• Hodgkin" ,
`lymph" ..... , "')'cos;'
`fil'SOkle.
`Hodgkin', dioe .... non_
`lIodgkill'. l)'.,pho.,"" breast.
`
`-,
`
`"""l< Iy.'p~c)'lic leukemia.
`n.umbl".to",.. Wil.".· tumo.,
`r~ .. bdomyo."'""m.:t. Itodgk in' ,
`dise .... Il<1n' J!odgkin',
`l)'rnpholrOl$, $1;11111-<:<11 lu.g
`VonCO' '''''''''"t """t<
`lymphOC)1i< leukem;". ch,,,,,i<;
`myeloq1ic leukem ia.
`md.DO",., Iymphom ... brc ...
`T • .,;, •• mol[.cc ll lunS ~od
`"'her lunil- b"""t. I!odgki.·,
`dis .... , Il<1n'I1od~n's
`1)"rt'1phoow, acul< gr ...... 1oc)1ic
`leukemi • . K>.pooi', ,&rCO"'"
`C'bo,ioc.rc""""', Wilms'
`tUIIlQI, rMbdo"'y<»aICOmO,
`'<>fi,. ""'I>o,i', • .,e"",,,
`Acut< s"nulocytic .nd !leut<
`1)"rt'1pho<;)1i<; Ieu •• mi.,
`Soft ti ...... , "'leOsenil:, ,00
`<lIher •• J<XIO.,,; lloog\; oo'"
`di, .. "", no,,'T lo<lg~ i ,,"
`1)''''1'''''"_, ""'''' Ie.,""",;",,,
`b,OI", geni'"",i.",),. 'h ymw.
`lung. ""'lOcb. o<urobla",,,,,,,,
`T • .,;", ... d and .. ck, «kin,
`.",ph'g.., luog,'oJ
`genitouriMI)' ,,,,:"t, H<>CISl:i. "
`dise ... , ""n,Tladgk;n',
`1)"rt'1pho ....
`Te.,is, m.lis.,..,
`h)'jXlcal<;<mUi
`Stomach, CO"'"", ""Jo', b, .... ,
`ponere •• , bladd<" head •• d
`.«
`Acul< lyD'p~c)'lic leukemia
`B' ..... O\~,;."
`
`Tut;'. o' ''''y. bl.ddt,. bood
`. od ,,",ck. lu.g. 'hymi<!. ct"i •.
`.n<lno,." i""" ".",,,,1.1,, •• ,,,,,,,,
`""l<ogeoic .. u;oma
`"""l< granuioc)'li<: " ukemi.\,
`b" ",
`Olo"ic S","uloc)" ic I<ul«o:;",
`po lyc)"hemis ,' ... , ... ~"' ;.I
`,h",ot1>oc)"o,is, maligna . t
`"",10'0"'"
`Hodgkin'. d"" ...
`
`Il.:!ir)'<:< 111eukomio, Kap""i',
`sa,<:o",o, ",et •• om ••
`carcinoid, "oal cell, "var)'.
`bladder, non.lio~k iD·'
`lymph" ..... , m)'C<>'Ii.
`fu. I"~ •. mullipl. myelo .....
`chronic Il,"Dul<xytic I<uk",;'
`1\1"", Necm,i. F.etor l ov."iS",io .. l
`Thm",·lnli lt,..t;'g
`10v.";g" .,001
`l ymphoc)1es
`U.pl.tin
`C.,bopl.tin
`
`Epip<;<loph)ilo",.;". El<>pCI!Iidc
`Too ,p",idc
`
`[}aunorubicin
`
`[>Ox"",bicin
`4'.o.ox)"'loxorm id n
`
`I.'"Aspa ,as;i""'"
`l>OC<taxel
`r.cli ..... 1
`["'e,fe"'n Ai r.
`
`EM)'''''''
`1>""n ..
`n ,."ido
`JlloloS'''''
`Respo_
`).1<><1if .. "
`
`Plot;o"m
`Coo<di .. ,i<>.
`0:;""'1'1««
`
`).1«byl 11)"<1"",;«
`Dcri,'lI!;'"
`
`PfQCO.,bez;r.e
`
`Apotex v. Abraxis - IPR20 18-00 15 1, Ex. 1028 , p.06 of 14
`
`

`

`us 6,177,460 B I
`
`12
`
`11
`
`TABLE I-continued
`
`NeoplaSlic IX. ...... ' for w hich ElIOmplor}" OI<aloth<ro.pou,", .l<ots ....
`indic.,ed
`
`CI ...
`
`110"""." or.d
`A"lagon41S
`
`I),..,. o( """.1
`Adruocorti",t
`Supple .....
`Ad'<oocortj·
`CO<t~ !'(lid.
`
`P'QS~"i ..
`
`&llOgo[15
`
`A nti ... ,~ ••
`And «>~ ..
`
`AnliDndrogcn
`Gona<lotrop; ••
`rel""";"i hormo ..
`. .. IOll
`
`No=
`
`Vi>cas<'
`
`Mit"'"