POT/EP 0 5 / 5 0 1 ? 6
`
`Europ~iisches
`Patentamt
`
`European
`Patent Office
`
`Office europden
`des brevets
`
`1 6. 05. 2003
`
`Bescheinigung Certificate
`
`Attestation
`
`REC’D 2 1 JuL 2003
`
`WIPO
`
`PCT
`
`Die angehefteten Unterla-
`gen stimmen mit der
`urspr0nglich eingereichten
`Fassung der auf dem n~ch-
`sten Blatt bezeichneten
`europ&ischen Patentanmel-
`dung 0herein.
`
`The attached documents
`Les documents fix6s ~
`are exact copies of the
`cette attestation sont
`European patent application conformes & la version
`described on the following initialement d6pos6e de
`page, as originally filed, la demande de brevet
`europ6en sp6cifi6e & la
`page suivante.
`
`Patentanmeldung Nr. Patent application No. Demande de brevet n°
`
`02076929.5
`
`PRIORITY
`DOCUMENT
`
`SUBM[!TED OR TRANSMITTED IN
`COMPLIANCE WITH RULE 17.](a) OR (b)
`
`Der President des Europ~ischen Patentamts;
`Im Auftrag
`
`For the President of the European Patent Office
`
`Le Pr6sident de I’Office europ~en des brevets
`p.o.
`
`R C van Dijk
`
`EPA/EPO/OEB Form 1014.1 - 02.2000 7001014
`
`Lupin Ex. 1016 (Page 1 of 35)
`
`

`
`Europ&isches
`Patentamt
`
`European
`Patent Office
`
`Office europ~en
`des brevets
`
`Anmeldung
`Application no.: 02076929.5
`Demande no:
`
`Anmeldetag:
`Date of fjl~ng: 16.05.02
`Date de d~p6t:
`
`Anmelder/Applicant(s)/Demandeur(s):
`
`Tibot~c Pharmaceuticals Ltd.
`Unit 4, Block 4B, Blanchardstown Corporate
`Park
`Blanchardstown, Dublin 15
`IRLANDE
`
`Bezeichnung der Erfindung/Title of the ~nvention/Titre de l’invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, s~ehe Beschreibung.
`If no t~tle is shown please refer to the description.
`Si aucun t~tre B’est ~ndiqud se referer a la description.)
`
`Pseudopolymorphic forms of a HIV protease inhibitor
`
`In Anspruch genommene Prior~t(en) / Priority(~es) cla~med /Priori~(s)
`revend~qude(s)
`Staat/Tag/Ak~enze~chen/State/Date/File no./Pays/Date/Num~ro de d~p~t:
`
`Internationale Patentklassifikation/International Patent Classification/
`Classification internat~onale des brevets:
`
`C070493/00
`
`Am Anmeldetag benannte Vertragstaaten/Conteacting states designated at date of
`f~]~ng/Eta%s contractants d4s~gn~es lots du d4pOt:
`
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR
`
`02076929.5
`EPA/EPO/OEB Form 1014.2 - 01.2000
`
`7001014
`
`Lupin Ex. 1016 (Page 2 of 35)
`
`

`
`Lupin Ex. 1016 (Page 3 of 35)
`Lupin Ex. 1016 (Page 3 of 35)
`
`

`
`TIP-26-EPO-PRI
`
`009 16.05.2002 14:27:
`
`-I-
`
`PSEUDOPOLYMORPHIC FORM8 OF A HIV PROTEA8B INHIBITOR
`
`This ~vention ,~]~tP.,s to novel pseudopolymor!ohie formg of (3R,3a%baR)-hexahy~o-
`flaro [2,3-b] fum~-3~yl (IS,2R)-3-[[(4-aminoph¢ny~) sulfonyl] (~sobmyl)
`benzyl-2-hydroxvl~ropylc~rbmnate, a method for their 10r~sration as well as ~heir use
`as a medicament.
`
`2O
`
`The structure of (BR, B a~,6~)-h~xahydrofuro
`ph~yl) s~Ifo~yl] (i~obuWl) ~i~o]-l-b~yl-2-hy&ox~mpylc=b~a~ is sho~
`below:
`
`0
`
`°~~I~’A T ~H~
`OH ~ GH~
`0
`
`l~onnula
`
`Compound of formula (X) and processes ~or its preparation m’e disclosed in ~P 715613,
`WO 99/67417, US 6,248,775, and in B~i0orgaui_e_and Ohern~y Lett~r~, Vol. 8,
`pp. 687-690, 1998, "Potent liiy protease inhibi~ors ineorpora~ng high-affiniW P~.
`Hgmads mar (R)-(hydroxyethyl~m~o)sulfonamide isoz~re", all of which are
`incorporated heroin by reference.
`
`25
`
`3O
`
`Drugs utilized iu the pr~ratior~ ofphauuacsutical formulations must meet
`
`Lupin Ex. 1016 (Page 4 of 35)
`
`

`
`010 16.05.2002 14:27:~
`
`Conference on H~on~ation). Such st~d~ds ~clude
`~comp~s aheterog~eous ~d ~de range of physicS, eh~ic~ ~d ph~aoeutie~
`
`V~ete~. It is ~s v~eW ofp~et~s to ~nsidor, which m~e ph~aceufi~
`regulations a compbx tec~ic~ ~seip~e.
`
`lZor ~ustaUCeo and as example, ~ drag utilized fo~ ~e ptep~ation ofp~utic~
`fo~agons shoed meet ~ accep~ble p~ty. ~e~o ~e e~tablished ~idel~e~ ~t
`de~e ~s l~i~ ~d ~ficafion of ~p~t/es in new ~g sub~o~ produced by
`eh~caI ~esis, i.e. a~l ~d pot~fi~ imp~ties most l~¢ely to ~so d~g ~¢
`s~esis, g~fi~fion> ~d s~omge of~o new d~g ~bst~c¢. Ouideli~s ~e insfi~ted
`for the ~o~ of allowed ~fion products of ~0 ~g subsl~, o~ r~ofio~
`pmdu~s of ~e d~g sub~mc~ ~th ~ oxcipt~t ~d/or i~ediato co~¢~olos~e
`syst~.
`
`Stability i~ also a parameter considered
`opdm~ stabilit] ~11 ~sm’¢ ~a~ ~o d~¢d o~o~ ~¢~W of drag ~b~ce~ is
`m~t~ned d~ag
`over w~oh ~ product o~ be relied ~pon m ret~ hs q~iW eh~acte~stics wh~
`~(cid:128)
`stored ~d~ ~p¢ctefl or d~eo~ed storage conditions. D~g ~is p~od ~e ~g may
`he a~i~stered w~ li~le or no risk, as ~e presence ofpoteafi~ly d~g~o~
`de~afioa prodRcts does ~ot pose ~y projudici~ ¢ons~u~e~ to ~¢ h¢~ of~e
`r~odver, nor the low~ content
`
`Diffe~en~ factors, such as light radiation, temporat~e, oxygen, humidity, pI~
`in so!~ions, nmy play t negative role for st~biliw mud m~y bdng difficulties to drags in
`maintaining a determinvd shelf life.
`
`Phygco-ohen~ical factors ~nd the pharmaco~technica~ fen,an[utica can h~w a g~eat
`repe~cussba h~ the bioavatlability ofth~ drag. As such, severn! propo~ies of the drug
`such as diszociatioa conspire% dissolution ~ate, solubility, polymorphio form, p~icle
`size, play a crucial role in bioavo;Llability.
`
`I0
`
`15
`
`~0
`
`25
`
`3O
`
`3~
`
`Lupin Ex. 1016 (Page 5 of 35)
`
`

`
`011 16.05.2002 14:27:
`
`-3-
`
`It is also rebvant to establish tbt~ the sele~ed pharmaceutical formulation is capable of
`mamffactm:e, more s~tably, of large-scale m~ufactare,
`
`Therefor:e, pharmaeeutica~ formdations of the drag with, for example, improved
`stabiliV], optimal bio~vailability, which, for instance, can be raanufaetured in suffblent
`high purity to be aeeeptabl~ for phamaceutieal use is a desirable goal.
`
`I0
`
`In view of the various and many technical requirements, mid it~ irdlueneing p~ameters,
`it is not obvious to fores~ whie.h ~h~rmac~utbal formulations willbe aeceptabl~. As
`such. it was vnexpeet~dly found that modifications of the solid sta~e of compound of
`formul~ (X) resulted in pharmae~xttioal formulations that meet certain industry
`
`In a finrt a~peet, the presem inv~tton provides pseudopol3a’norphs of
`25 hex~ro~o [2.3-b] ~-3-yl (lS,2R)-3~[[(4-~oph~yl) sulfonyl3 (isob~W1)
`~izo]- 1 -b ~l-2-h~drox~ropyl ~b~ato,
`Ps~dopol~o~s prodded in~udo alcoholics, more in p~c~, C!-C4
`al~holates; hy~tes; ~a solvates, more ~ p~i~l~, ~1-C4 alk~e solvat~;
`k~onates; e~er solvat~s; eyeloe~ $olvates ~d ~t~ solutes of~e ~po~d of
`fo~i~ (X), Pr~e=~ pseudopol~o~hs ~e ph~aee~ly aee~table solvat~,
`such ~ hy~t~s ~d ~hauolate.
`
`30
`
`P~¢~pse~dopol~o~hs ~e Fo~ A (e~olate), Poma B
`(men.late), Po~ D (aee~ne solvate), Yo~ ~ (di~omme~e solva%e),
`(e~yla~ate solvate), Yo~ G (1-me~oxy-2-propmd solvate), ~o~ H (anisole
`solv~te), Fo~ [ (te~y~o~e solvate), ~o~ J 0soprop~ola~e) of temporal of
`~ta (X).
`
`In a second aspee% present invention relates to proeess~ for prepmSnZ
`pseudopolymorphs. Pseudopolymorphs of compound offormvlla (X) are prepared by
`
`Lupin Ex. 1016 (Page 6 of 35)
`
`

`
`012 16.05.2002 14:28:
`
`-4-
`
`5 ~ a third ~p~ct, the inven~on r~latos ~o the use of the
`~e m~ufae~e of ph~aceufieal regulations for i~biting ~V prot~s¢ a~iviW
`m~m~s. In relation m ~e ~rap~ufi¢ field, a pref~ed ~mbod~ of
`r~Iat~s to $o use ofph~a¢~fie~ly a~coptabl¢
`compo~d of ferule ~) for ~he ~o~=~t of=HW ~r~
`ne~ ~(cid:128)of, w~eh m~od ¢om~se$ a~inist~g to s~d
`~o~t of a ph~ae~Iy acceptable ps~dopol~o~e fo~ of ¢ompo~d of
`festa (~,
`
`10
`
`The following drawings p~ovid~ ~dit~onal information on the oharactexist~cs of the
`pseudopolymorphs according to present inwntiom
`
`15
`
`Brief Des~t’iptioa of the Drawings
`FIOUKB 1, ~IO~ 2 ~d FIG~ 3 ~o ~e powd~ X-ray ~f~action pa~s
`Yo~ A of compo~d of festa ~) (1:1),
`20 FIGU~ 4 dcpio~ Fo~ A (~ :1) ~ ~ dim~sio~ wi~ tho ato~ identical.
`
`~ ~o~ho~ fo~ of compo~d of fo~ul~ ~ ~d ~ ~bonyl s~etc~ng re,on
`ell 800dO0 ~l ~d ~o re, on 330~2000
`FIGU~ 6 is a comp~son of~ ~p~d~d K~ sputa of Yo~ ~ B, D, ~, F, H,
`
`25
`
`.(~ :~) =d ~ ~hous fo~ of compo=fi of ferule (X) m~ ~ e~boayl.
`
`~IGU~ 7 is a comp~son ofSa ~xp~ded ~ sp~ o~Fo~
`(1:1) ~d ~ ~o~hoas fo~ of compo~d of festa (~ ~d ~ c~bonyl
`s~atc~ng ra$oa of ! 400-800 ~l.
`30 FIG~E ~ is ~ Diff~r¢~ Sang C~o~etdc (DSC) ~o~aph ofFo~ A of
`compo~d of festa (X) (1 ’.I),
`
`35
`
`The term "polymoxphlsm" refers to the e~paei~y era ch~raieal structure to oco~ in
`different forms and is known to o¢ou~ in many o~gmiic ¢ompom~ds including drugs, As
`m~, ’59olymorphb forms" include drug substances Lh~t appear in amorphous form, in
`~rysmlli=o form, in mahydrous ~brm, at vmio~ls degrees of hydration or solvation, with
`emtrap~d ~olvent molecules, as well as substances vmTing in o.~ystal hm:dness, shape
`and size, The d~ff~tt polymorptm vaxy in physical p~op~rdes such as solubility,
`
`Lupin Ex. 1016 (Page 7 of 35)
`
`

`
`013 16.05.2002 14:28:
`
`dissolution, solid-state s,ability as well as processlng b,haviour in terms of powder
`flow and compaction during tabletting.
`
`The term "amorphous form" is d,fmed as a form in which a throe dimensional long-.
`range order does not exist. In the amorphous form the position of the molecules
`relative *o on, another are essentially random, i.e. Without regular arrangement of the
`molecules ca a lattice structure.
`
`The term "crystalline" is de~med as a ~?orm in which filo position of the molecules
`relative to one a~otker is orgards~d according to a throe-dimensional lattice structure.
`
`I0
`
`The term "anhydrous form" refers to a 1)articular form essentially ~¢¢ ofw~r.
`"Hydration" mJ:brs to th~ process o~ adding water molecules ~o a substanc~ that occuzs
`
`in a pm-ficular Zorm and "hyckates" ate substances that ar~ formed by adding water
`1~ molecules. "Solvating" refers to the process o~incorpomthlg molecules of a solvent
`imo a substauc~ occurring in a a-ystallino form. Therefore, the term "selvage" is
`defined as a crystal form that contains ¢ither stoichiomctric or non-stoichiometrio
`amounts o~ solvent. Since water is a solvent, solvzttes also include hydrates. The term
`"pseudopolymo~h" is applied to polymorphio m-ysta!liae forms that h~vo solvent
`20 moleoMes incorporated ia thdr letttce structures. Th~ t~rm pseudopolymorphism is
`used frequently to designate solver,s (Bym, Pfeiffer, Stowell, (1999) 8olM-ata~e
`Chemistry of Drgga, 2rid Ed.., published by $$CI, Ino).
`
`The present inv~tion provides pseudopolyraozphs of(3R,3aS,6aR.)~hexahydrofuro
`
`25 .
`
`[2o3-b] ~r~-3,yl (1S,2R)-3-[[(4-~ophony!) sulfonyl] (isobu~) ~no]-
`hy~ox~zopylo~b~te.
`
`In one embodiment pseudopolymorphs ate alcoholate% more in pmCicular, CI ~4
`aleoholat~s; hydrates; ~muo solvates, more in particular, CI-C4 alkano soIvatcs;
`ketone solver, s; ethe~ solvate, s; cyclo~ther solvates or ester solvates of fixo compound of
`formula (X). The te~m "C1-C4 alcoholate" d~fin~s straight and!or branohed chained
`saturated or unsatmated hydrocarbons with at bast a hydroxyl group having from 1 to 4
`carbon atoms, suck as, for exampb, methanol, ethanol, pmpanol, butataol, 2-mothyl-
`propanol, and the like. Th~ term "C1-C4 allr~ve solvate" defines straigh~ and/or
`branched chained saturated or unsaR~rate~t hydro~azbons having from 1 to 4 carbon
`atoms aud optionally substimt~ with halogen, such as, for example, dichloromethane.
`The term ’qtatone solv~o" define2 straight and/or branched chained saturated,
`unsaturated or partially unsaturated hydxocarbons with at least a carbonyl group, such
`a~ P~-C(O)-R’. The term "~thor solvates" defines straight and/or branched chained
`
`35
`
`Lupin Ex. 1016 (Page 8 of 35)
`
`

`
`014 16.05.2002 14:29:
`
`saturated, unsaturated o~" pa~rdal!y ~msaV~ated hydrocarbons with at least an o~.y group,
`such ~s R-O-P,’. Th~ term "cycloether solvates" defines (i) divalent cyclic or
`polycyclio s~mrated, ~n~aturated or partiatly unsaturated hydrocarbons; or (ii) aromatic
`cazbocyclic groups with one or multiple condensed tings in which at least one ring is
`aromatic; both including at least an oxy group. The term "ester solwttes"
`straight and!or branched chained saturated, unsaturated or partialIy unsaturated
`hydroc~bons with at least a carboxyl goup, such as R-C(O)O-R’. P,. md R’ can
`ind~p~nflently from one another be hydrogen; a straigh% branched ch~nefl saturated,
`parga!ly uus~turat~d, or ~.msaturated hydrocarbon having 1 to 8 ~arbon atoms; halogen;
`
`a cyclb saturated, partially unsaturated or unsaturated hydrocarbon having 3 m 7
`carboa atoms.
`
`Pseudopolymorphs of the present invention, which are ph~a’maeeut~oaIly acceptable, for
`instance hydrates, alcoholates, such as, ethanolat~, ~ pmf~wed forms.
`
`15
`
`2O
`
`Ps~dopolymorphs are described in this application and incl~¢~o Form A (~hm’~olato),
`Form B (hydrate), Form C (methanoIate), Yorra D (accton~ ~olvato), Form E
`(diohloromethane ~olvat~)0 Form 1~ (othylac~:ato solvate), Form G (1-mcf.hoxy-2-
`propanol selvage), Form I¢ (anise1 solwto), Form I (tgtrahydrofurane solvato), or Form
`J (isopropmolato), of compound of formuIa (X~).
`
`Solva*os can occur in different ratioa of solvation. Solwnt enmoat of fire crystal may
`vary in different ratios depending on th~ conditions applied. Solvate crystal forms o1
`compound of formula (X) may comprise ~p to 5 mol~cules of solvent per molecub of
`compound of formula (X), appearing in.different solvated states including, amongst
`others, hemisolvat~, monosolvate, dlsolvate0 tri~olvate crystals, intermediate solvatcs
`crystals, and mixtures thereof. Thus, the ratio of compound of formula (X) to the
`solvent may range betweea (5:1) and (I :5). In particular, th~ ra~[o may tango from
`about 0.2 to about 3 moleot~les of sotv~nt per 1 molcoul~ of compound of formula (X),
`~0 mor~ in particular, tho ratio may rang~ from abou~ I m about 2 molecules of solvent per
`1 mo!~oul~ of compound of formula CA), preferably the rat~o is 1 molecule of solvea~
`p~r 1 molecul~ of compound of fommla (X). Consequently, the terra "Form" wilI b~
`used h~r~in to refer to el! the solvato o~ystal forms of compound of formula (X)
`comprising from about 0.2 ~o about 5 molecules of solvent p~r 1 moI~oule of compound
`of fon’aula (X), i~tarm~diato senates crystals, and mixtures thereof.
`
`35
`
`Solvatcs may also occur at diffewertt levels ofhydraGon. As such, solvate crystal re,was
`of compound of formula (X) may in addition comprise ~mder certain circumstances,
`water molecules parCi~lly or folly in the crystal structures. Lfkewise, the term "Porto’°
`
`Lupin Ex. 1016 (Page 9 of 35)
`
`

`
`015 16.05.2002 14:29:
`
`-7-
`
`The X-ray powder diffraction is a technique to charactedso polymorphic forms
`including pseudopoIymorphs of compound of formula (X) and to dlffer~fiate solVate
`crystal forms from oth~r c~]stal and non-crystal fo~z of compound of formula (X).
`
`As suc~h, X-ray powder diffraction spectra were coll~tod on ~ Phillips PW 1
`powder difffactomet~, model Bmgg-Br~ntaao. Powdars of Form A, afeared 200 mg
`each sample, w~m packed in 0.5 ram glass capillary tubes and were analysed according
`to a standard method in the art. The X-ray generator was op~rat~xt at 4~ Kv and 32
`mA, n~{ng the copper Ka line ~ the radiation soarce. There was no rotation of the
`samplo along tho clg axis and data was colloct~ boBv~ort 4 and 60° 2-th~ta step size.
`Form A of ¢ompoand of formula (X) co~prising about 1 molecule of ethanol p~r
`~ole~..flo of compound of formula (X) has th~ characteristic two-theCa angle positions
`of peaks as shown in FIG. 1~ 2 aud 3 at: 7,04° ~: 0,5% 9,24° ± 0,5% 9,96~’
`:~ 0,5% 11~30" ~- 0,~% 12,82~ ¯ 0,5% 13,80¢ ± 0°5% I4,56~ ± 0,5°, 16,65°
`¯ 0~5% !8,28~ * 0,5% 19,10° ¯ 0,5% 20,00° * 0°5% 20,50° ~ 0.5% 21,22~ :~ 0,5% 22,68~
`e 0,5% 23,08(cid:128) ¯ Off% 2~,66~ ~ Off% 25,08° ¯ 0,5e, 25~58° ¯ 0~5(cid:128), 26,28~ ¯ 0,5% 27,18~
`¯ 0,5% 28,22~ ¯ 0,5% 30,20~ e 0.5% 31,34~ ¯ 0~5", 32,68~ ¯ 0,5% 33,82~ ¯ 0,5% 39,18~
`~ 0,5% 4!,20" ¯ 0,5% 42,06° ¯ 0,5% md 48,74~ ¯ 0,5%
`
`In anoth~" s~ of analytical ~xp~4meat% X-ray single diffra~ion was applied to Form A
`of c’om o d (X) (cid:128)omprising about I mole vle of hanol per mo! cul of
`compo~md of formula (X), which r~s~lted in tho following crystal configuratior~ listed
`in TABLE ! below:
`
`10
`
`15
`
`20
`
`25
`
`. Crystal Data
`
`.o~al dim~bns
`
`Prism
`0,56 x 0,3S x 0.24 mm
`Colorless
`P 2t 2~ 2t orthorhombie
`
`Lupin Ex. 1016 (Page 10 of 35)
`
`

`
`016 16.0S.2002 14:29:
`
`-8-
`
`1.248
`
`Siemens P4
`
`ambient
`138.14°
`
`Tot~; 3912
`
`~to~ct~rc Solution and P~efinement
`
`I Numb~ of Observations
`
`Residm~l
`
`The resulting thrs~dimer~ional ~cmee of Form A (1:1) is depleted in 1~I(], 4.
`
`TABLE 2 shows the a~mic coordinates (x 10(cid:128)) and equivalent iso~ropi¢ displaoement
`.par~ra~tcrs (A? x I0~) for Fo~ A (~ :i). The x, y. =d z ~ac~onA ~ord~ates ~dicato
`~e posi~on of atoms rda~ve to ~e ofi~ of the ~it ~. U(~) is defined ~ on~
`of~e ~ace of~ o~ogonallz~ ~tensor.
`
`X
`7778(3)
`7171(4)
`68310)
`
`7527(4)
`
`SSO~(3)
`
`5533(2)
`
`2944(2)
`35~3(2)
`3046(2)
`¯ 24! i(2)
`1533(2)
`1241(2)
`1642(2)
`24,16(2)
`2702(1)
`2656(1)
`
`9946(1)
`9487(9.)
`8823(2)
`879:3(2)
`8708(2)
`9457(2)
`9809(!)
`9534(2)
`8945(1)
`7768(1)
`
`V(~q),,,
`700)
`
`70(1)
`
`62(1)
`51(i)
`~(t)
`
`O1
`C2
`C3
`C3A
`C4
`C5
`05
`
`07
`08
`
`Lupin Ex. 1016 (Page 11 of 35)
`
`

`
`017 16.05.2002 i~:~0:
`
`-9-
`
`Y
`
`Z
`
`2256(1)
`19!6(2)
`
`~o~(~.)
`
`-200(2)
`
`-413(3)
`
`2464(2)
`2112(I)
`~o7(~)
`
`4247(3)
`4414(1)
`38600)
`
`9o3s(~)
`9111(3)
`
`7881(3)
`78~0(2)
`7976(2)
`7502(1)
`7740(2)
`7721(1)
`7048(2)
`6473(2)
`
`5779(2)
`84400)
`9015(I)
`
`5080(2)
`
`8509(2)
`
`6341(2)
`61~3(2)
`
`4~69(2)
`
`8564(2)
`g909(2)
`
`223~(7)
`~9o(6)
`
`5258(4)
`5564(4)
`
`C9
`NI0
`
`C17
`
`09.o
`¢21
`
`0~
`029
`
`X
`4791(3)
`3590(2)
`2638(3)
`2223(3)
`
`3937(4)
`
`5494(5)
`
`3926(5)
`
`494(2)
`1829(3)
`699(3)
`
`-6~(~)
`-1453(5)
`-47(7)
`
`-693(2)
`
`~S030).
`
`4033(4)
`4063(4)
`299S(4)
`
`o~
`
`,,!768(4)
`
`TABLI~ 3 shows the anisotropio displacement parameters (A~ x 10~) for Fo~ A (1 :t ).
`~ ~iso~opio ~splac~t f~tor exponent ~es
`
`Lupin Ex. 1016 (Page 12 of 35)
`
`

`
`018 16,05.2002 14:301
`
`5~(2)
`
`37(2)
`61(2)
`72(3)
`78(2)
`47(~.)
`
`~(~)
`~0(2)
`~a(2)
`
`s9(3)
`30(2)
`
`S6(~)
`
`79(3)
`
`4~(~)
`5o(2)
`
`sT(~)
`
`V~2
`89(2)
`68(2)
`
`7s(2)
`74(2)
`67(2)
`80(2)
`so(~.)
`69(1)
`68(1)
`410)
`~o(t)
`
`42(I)
`
`72(2)
`6o(2)
`~(~)
`
`~(~)
`~?(~)
`
`s~(2)
`aS(2)
`
`~7(~)
`
`46(!)
`48(0
`
`63(2)
`
`s5(1)
`
`49(1)
`6i(2)
`71(2)
`7o(i)
`
`50(0
`
`49(1)
`49(i)
`57(1)
`87(2)
`78(2)
`
`~4~(+)
`
`~(~)
`
`~(~)
`~(~)
`6~(z)
`~o~(~)
`6s(2)
`
`9~(~)
`
`~4(~)
`
`~(~)
`
`Ol
`c2
`cs
`
`c4
`c5
`o6
`C6A
`O7
`08
`C9
`NI0
`CII
`C12
`C13
`C14
`C15
`
`C19
`020
`
`N22
`C23
`C24
`
`C26
`S27
`028
`O29
`C30
`
`¢32
`C33
`C34
`C35
`
`~r13
`-19.(0
`
`-6(2)
`
`-6(2)
`-!(1)
`
`o(!)
`2(2)
`
`7(2)
`
`32(3)
`10(2)
`
`o(i)
`-s(~)
`-I~(~)
`
`6(1)
`1(0
`-4(2)
`2(~)
`
`.i~(2)
`4(9.)
`
`-s(~)
`-1
`-i2(I)
`-s(z)
`
`-7(~)
`4(2)
`-7(2)
`-9(1)
`-12(1)
`~(~)
`-2(t)
`-2(1)
`-4(I)
`o(!)
`9(2)
`iz(2)
`2s{~_)
`38(s)
`
`-6(i)
`~(~)
`3(~)
`~(a)
`
`-6(3)
`10)
`-7(1)
`~o(i)
`~(~)
`~(~)
`
`-3(2)
`-2(2)
`
`Lupin Ex. 1016 (Page 13 of 35)
`
`

`
`019 16.05.2002 14:31~
`
`-11-
`
`4(2)
`6g(7)
`
`67(8)
`
`r2o(lo)
`
`-1~_(2)
`
`N36
`!237
`(738
`O39
`
`Ramaa @~etro~copy h~s beer widely used to elueid~ molecular structures,
`etTz~l~,~{ty and polyraorphism. The low-frequency Ram~ mode~ ar~ pm-tieut~ly
`~eful in distinguishing different molec~- packings in cry~al. As such, Ramma
`5 ~eol~a were recorded on a B~ker FT-Rama~ RFS100 spectrometer equipped with a
`photomultipliex robe and optical mal~ichz.nnel cletectom. Samples placed in qu~trtz
`capillary tubes were ~xeited by an m’gon ion la~er. The laser power ~tt the samples was
`adjusted to about 100 mW and the spectral resolution was about 2 emq. It wzs fomad
`that pseudopolytaorphic Forms A, B, D, E, F, and H, (1:1) and the amoq0ho~ form of
`I0 oompotmd o£ formala (X) have the Raman spectra which appear in FI~S. 5, 6, and 7.
`
`15
`
`Thermomieroscopy is another ~npo~aut technique in ~e study of solid-state kinetics,
`The ldnefies of nucleation processes f~om solutions or melts, including the ~y~is of
`the nucleation speed, can be quantified. The simplest ~d mos~ widely used method {s
`the melting point det~a’ninatien. As such, a Metrler model FP 82 eon~roller wi~
`heating stage w~s used on a L~itz mietoscol~e, A f~w partioIe~ of Foma A wer~ placed
`on a glass slido and obs~c’ved while heating at 10°¢ p~ minute, The melting ~ang~ for
`Ferns A (I:I) was fouad to bebetw~ 90~ and 110~ C,
`
`2O On anocher memos of eharact~ation, ~e solubilRy of Forra A, comprising:about 1
`mole~OIe of ethanol per molecule of compourtd of formul~ (X) was also a matte~
`s~tbj~t to study. Its solt~billtyin different solvems at approximate 23°C was
`determined to be as ~’ollows:
`
`25 TABLE 4: Approximate solubility for Form A
`of compound of formula (X) (1;l), ~a
`mg/ml,
`
`Solvent
`
`Approximate solubflity
`~orm A (mg/ml)
`
`106 - 211
`105 - 209
`160 - 213
`102 - 204
`71 - I07
`
`Lupin Ex. 1016 (Page 14 of 35)
`
`

`
`020 16.05.2002 14:31:,
`
`-12-
`
`A!~proxima~e solubility
`
`< 3.4
`< 3°4
`< 3.5
`< 3.4
`> 200
`<3.4
`< 3.4
`102 - 203
`<3.5 _
`
`In a second aspect, the present invention ~dates to processes for preparing
`9seudopolymo~hs. Pseudopolymorphs of compound of formula (X) ~re prepared by
`combining compound of formula (X) with aa orgartie solvent, water, or mid:lures of
`water aud water misdble orgavde solvents, applying may suitable technique to induce
`crystallization, ~d isolating the desired l~sendOl~olymowhs.
`
`By teclmiqu~ for inducing crystallization a~e to be understood those 9roeesse~ for
`production of ~st~s, w~eh inelud~ ~ongst o~ers, ~sml~ng or ~sing
`compo~d of ~uh (X) ~ a solver med~, bfin~g ~ solution ~ ~sp~sion of
`~mpound of ferule (X) ~d ~e solver(s) to a desked conc~n~on, brining ~
`s~d $olu~og or ~sp~ion to ~ desked ~p~re, eff~ng ~y suitable pre~re,
`r~o~ng m~or s~=a~g my ~desh’ed mat~ or imp~fies, d~ng ~e fo~
`" c~s to obt~ ~ pseafl0pol~o~hs ~ a solid state, if ~eh sta~ is desired, .-
`
`Bringing the solution o~ dispersion of eompotmd of formula CA) and solvents to n
`de~ffed concentration does not necessarily imply aa increase in the eoneexttration of
`~ompound of formula (X), ~ eert~ eases, a de,tease or no ehang~ frt ooneentration
`could be preferable, By bxing~g th~ said solu~on or dispersion to a desired
`tempemOare, one will understand the acts of heating, cooling oi" lezving at ambient
`temperature.
`
`The techniques used for obt~i~ng ~t desired eozcentrafion ~ ~os~ ~o~on in ~ ~
`for in~t~, ~aporafion by a~o~h~e dtsfillatio~ vaeum di~fillafio~ ~a~ion~
`~s~l~{on, ~eo~opie dis~llafion, film evapora~on, oflt~ teo~qu~ wen ~o~ in ~e
`~ ~fl comb~ation~ ~eof. ~ optio~ process for obta~ing ~ desired ~oncen~afion
`~uld a~ well involw ~e saturation of ~e solution of eompo~d of festa ~ ~d
`
`I0
`
`15
`
`20
`
`25
`
`Lupin Ex. 1016 (Page 15 of 35)
`
`

`
`021 16.05.2002 14:31 :
`
`-13-
`
`solve% for example, by adding ~ sufficient volume of a t~on-soIvent to ~he solution to
`zeaoh the salvration point. Other s~itabb t~chrgques fo~: saturating the solution include,
`by way of examples the introduction of ~Iditional compound of formula (X) to the
`solution end/or evaporation o{ a poRion.of the solvent from the solution. As referred ~o
`heroin, saturated solution encompasses solutions at thei~ samratlon points or exceeding
`their saturation points, i.e. supo~sax’ua’a~ed.
`
`R~moving ~d]or separating any und~imd mater~ai or impurities may be performed by
`purification, filtexing, washing, precipitation or similar t~c~iqu~s. Separation, for
`example, can be conducted by known solid-liquid scparationt~chniques. ~iltering
`procedures known to those skill~d in the ar~ can as well be used ia the present process.
`Th~ filtrations can b~ p~rform~, amongst other m~thods, by eon~fiagation, or v~ing
`Budmex style filter, Rosenmund fil~or or plates, or fram~ press. Preferably, in.line
`filtration or safety filtration may b~ advantageously intercalated in ~he p~oc~ssos
`dls~lo~ed above, in order to increase the purity of the r~sulting pSe~dopolymorphic
`fern. Additionall~, filt#r~ng agents such as silica gel, A~:bocol®, dioalit~ diatomit~, o$
`the like, may also be employed to septets impurities from th~ crystals ofintzr~st.
`
`2O
`
`Crystals obtained may be a~so dried, and such drying process may optionally
`the diff0~ent crystallization passages, if more than one crystallization passag~ is
`applied. Drying procedures include all tee]aniqRes known to thOSe skilled in the art,
`such as heating, applying vacuum, circulating ai~ or gas, addkxg a desiccant,
`drying, spray-drying, evaporating, or the like, or may combination thereof.
`
`3O
`
`Processes-for crystallization of pseudopo!ymorphs of compound of f0_r~..ula-(X)
`embmc~ multipl~ combinations oft~hniques and variations thereof. As sucl~ and~" "
`
`way of example, c~ystallization of pseudopolymorphs of compound of ~rmula (X) may
`be executed by dissolving or dispersing compound of formula (X) at a suitab!e
`temperature in ~dae solwnt whereby poffdon of the said ~olvent ~vaporams increasing the
`concentration of the compound o~ formula (X) in the said solution oz disp~sion,
`cooling the said mixtur,, and optionally washing and/or filtering and d~ns resulting
`solvat~ ca-ystals of compound of formula (X). Optionally, pseudopobrmorphs of
`compound of formula (X) may be prepared by solving or dispersing compound of
`~orm~a (X) in a solwnt medium, cooling said solution or dispersion and subsequently
`iiltering and drying the obt~d pseudopolyaxorph. Another ~xaml~l~ of preparation of
`solver,s of compound of formula (X) ~0u]d b~ by saturating compound of formula (X)
`in the solvcn~ medium, and optionally filtering, washing and dz~ng obtained crystals.
`
`Lupin Ex. 1016 (Page 16 of 35)
`
`

`
`022 16.05.2002 14:32:
`
`-14-
`
`By dissolving or dispersit~g compound of formula (X) in the organic solvent, wa[er or R
`mixture of water and water miscible organic solvents, one may obtain d~f~erem degrees
`of dispersion, such as suspensions, emulsions, slurries or mixtt~es; or preferably obtain
`homogeneous one-phase solutions.
`
`15
`
`Optionally, the solvent medium may contain additives, fo~ example one or more
`
`dispersing agents, surfa~tants or other additives, or mixtm:e~ thereof ot~the ty13e
`
`2O
`
`normally wed ht the preparation of crystalline suspensions and wlfich are well
`
`documc-ated in*he literature. The additives may be advantageously used in modifying
`the shape of crystal by increasing the leniency and decreasing the surt~aee ~ea.
`
`25
`
`~0
`
`The solvent medium containing the solution may optionally be stirred for a csrtain
`period o~time, or vigorously agitateA using, for example, a high shear mixer.or
`homogeniser or a combination ofth~s~, to g~nerate the desired droplet size for the
`orgaaai~ compotm&
`
`Examples of organic solvents usefffl for the present invention include C1.C4 alcohols
`such as meth~mol: ethanol 2-prop~ol, ~d ~e Hke; C1-C4 Mk~es such as di~hlom-
`me~e; ketches sudx ~ ~etone; o~ such as 1-m~oxy-2-prop~ol, ~isole, ~d
`Se l~e; eyeloe$~s such ~ te~y&o~< est~ such as ~y]acetats; ~d ~e like.
`
`35
`
`Examples ofmlxtures of water mad water miscible org~ic solvents include, mixtures of
`wmer with all organic solvents listed above provided they ~re miscible ~a water,
`ethanol/Water (50/50
`
`Preferred solvents are those phm’maeeutieally aec~t~tble solv~t~. However,
`pharmaceutically nort-aec~ptable solvor~t~ may also find their ~e in the pzep~a’ation
`
`Lupin Ex. 1016 (Page 17 of 35)
`
`

`
`023 16.05.2002 14:32:
`
`In a preferred method, the solwnt is a pharmacoutbally acceptable solvent elude.it
`results in a pharmaceutically acceptable pseudopolymorph, In a more preferred
`method, the solvent is ethanol.
`
`In a particular embodiment, pharmaceutically acceptable ps~udopolymorphs of
`compound of formula (X) can be prepared sta~ing from pseudopolymorph£e forms of
`compound of formula (X), whidx may not he ne~esmrily pharmaceutically acc~l~table.
`For instance~ Form A may be prepa~eai sfA~ing from l~orm J isol~mpanolate.
`Pseudopolymorphs may also be prepared starting from the amo~hous form.
`
`In the mix~-ures of w~,er and water miscible organio solvents, the amount of water can
`vary from about 5% by volum~ to about 9~% by volume, preferably from abou~ 2~% to
`abo~ 75% by volume, more preferably ~om about 40% to about 60% by volume,
`
`It should also be noted that the quality of selected organic solvent (absolute,
`donaturated, or other) also imquences the resulting quality of the pseudopolymorph.
`
`10
`
`I5
`
`20 Control of precipitation temperatare mad seeding may be ~dNflonNly used tO ~Nove
`~e reproduoibfli~ of~e ~t~l~fion process, ~e p~clo size ~s~udon ~d fo~
`of~ product. As ~h, the ~st~afion cmb~ effect~ ~ou~ s~ng ~
`~s~Ms of ~e ~mpo~d of ~e ferule ~) or pmf~ly in ~e pres~ of ~stals of
`¯ e ~mpo~d of~e fo~ ~), which ~(cid:128) ~l~oduccd in~ ~e solution by seeding.
`25 . S~ding cm ~so bs (cid:128)ffect~d sev~ ~es at v~ous t~p~a~es. The ~o~t of th~
`Seed mat~ dep~s on ~ ~o~tof ~ solufioR md cm r¢a~y be det~ned by a" ¯ ¯
`p~son s~ed in ~e ~.
`
`The time for erystallizalion in each crystallization step will depend on th~ conditions
`applied, the ~chnique.s employed and/or solvemts used.
`
`3O
`
`BreI~king up the lszge particles or aggregates of pro-titles after c~stN conv~sion may
`addifion~y be p~o~ed in ord~ to obt~ a do~ed ~d homog~eous p~cle ~e.
`Ac~rd~#y, ~(cid:128) sol~te c~tal ~ of compo~d of festa (X) ~ op~an~ly
`~I!~ ~or~rgo~g ¢onv~ion. Milling or ~n~g ref~ to physieNly bre~g
`up ~o l~ge p~le~ or a~egatos of p~eles using m~ods ~d apD~ams well
`~o~ in the ~ for p~le siz~ re~fion of powd~. ResNfing parole sizes may
`~ge from mfll~eters to n~omet~s, ~eld~ i.e. nmo~st~s, mi~o~s~Is.
`
`Lupin Ex. 1016 (Page 18 of 35)
`
`

`
`02zJ Z5.05.2002 lz~ :33:0
`
`-16-
`
`The yield oft he pzepara6on p[ocess o~the pseudopoly~orphs o~ compouad of form~
`
`(X) may be 10% or more, a more p~eferred yield wo£1d vsfy from 40% to 100%.
`Interestingly, the yield varies b~vee~ 70% and 100%.
`
`Suitably, psev, dopolymo~phs of~h~ present invention have a purify greater thox~ 90
`percent, More saitably, the present pseudopolymorphs have a purity greater than 95
`percextt. Even mor~ suitably, the present pseudopolymorphs have a purity greater than
`99 percent,
`
`I0
`
`15
`
`20
`
`¯ 25
`
`3O
`
`35
`
`In a third a~eet, the preset iaven~don relates to a pharmaceutical form~ation
`comprising an effective amount of a pseudopolymorph of compound of formula (X),
`and a pharmac,ufieally a~eeptable carrier or diluem tlaereof,
`
`one embodiment, present invention r~l~tes ~o the ~e ofph~aeeufiegly aee~table
`pseudopol~hb fo~s of compo~d of fo~ula (X), ~mfembly Form A of
`~po~d of festa (X), in ~e mm~ae~ era me~e~t for ~eafing ~seases
`oaused by re~o~ms~, such ~ HW infections, for ~x~ple, heq~ed ~e
`Deficiency S~om¢ (A~S) ~ ~.elate~ ~mpl~ (~C),
`
`In another embodiment, present ktveation provides a method for the ~reatment of a viral
`irdection, for exm’aple a~ HIV infection, in a mamm~I ~uch ~s u human~ which
`eomprise$ administering to the mammal in need thereof an effective antiv~ral amount of
`a phan’naceuttcally acceptable pseudopolymorphi~ form of compound of fon~ula (X),
`preferably ~orm A of compound of formula (X).
`Present iavomion also relates to a method in.which th~ treaime~lt of a HIV~ xdral_
`infeotion comprises the reduction of HIV load. Present invention a~o relates to ~ "
`method in which the tr~tmont of said HIV viral infection comprises the increase of
`CD4+ cell comnt, Pres¢nt inwntion ~¢lates as woR ~o a me$od ~a which the ~r~atmcnt
`of so.td H1V viral infe~ion comprises inhibiting HIV pretense activity in a mmaamal,
`
`Pharm~eutieally acceptable pseudopolymorphl= forms of compound of formula (X),
`preferably Feint A of compound of formula (X), also ~efc~red to herein as the active
`
`phmanace~tical ingredients, may be adm{rfiste~ed by ~ny route approFga~¢ to ~he
`
`condition to b~ tre~te~ preferably orally. It will b~ ~ppreciatcd how~v~, that the
`prefer~M mine may vary wi~h, for axample, ths comtifion of the r~oipient,
`
`For each of the above-indicated aRiliiSes mad ~ndications th~ amotmt requLr~d of the
`active ingredi~t will depend upon a number of factors including the sevar~ty of the
`oonditioa to be treated aud the id~tity of~k¢ reoipiem and will dtknat¢ly bc at the
`
`Lupin Ex. 1016 (Page 19 of 35)
`
`

`
`025 16.05.2002
`
`-1%
`
`discr~ion of ffm at-toadant physician or veterinarian. Tl’m desired dose preferably may
`be presente£1 as one, two, three or four or more subdosss administered at ~pp~opriat~
`imervals throughout the day.
`
`For an oral administration form, pseudopolymorphs of~e pmsem inventioa are mixed
`with saitabb additives, sueh as excipioats, stabilizers or inert diluen~s, sad brought by
`moans of the oustomvry metlmds into the suitable administration forms, such as tablets,
`coated tablets, hard capsules, aqueous, alcohol{c