MTon PHnnUACEUTICALS AND CIpm LTD.
`
`V.
`Apor¡x
`C.A. No. L4-cv-1453
`
`EXH
`urcrâ,
`
`IBITì+
`
`Maureen Donovan, Ph.D.
`
`DIRECT EXAMINATION DEMONSTRATIVES
`
`DDX 5.OO
`
`1
`
`CIP2177
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
`
`

`

`Maureen Donovan, Ph.D. - Background and Education
`
`Ëdr¡ojor¡:
`
`Unau.r¡Ay d llhn .ol¡ Coleeo d Ph¡¡m¡¿y
`U¡nar¡pof¡. fhne.of.
`A¡ctr¡5rdSd¡rp h Plt¡ñucü, tg&l
`Utvrrity of fficñi¡rr CoLe. oa Phüî.ct
`HcÞ H. R¡cttûrì SdìoGl ol Grú¡.¡ Sù¡d.r
`Ar¡n ArÈo., U¡.rüglfl
`Ph.D. (PhÍñalrb¡). lg89
`
`PROFE33þXAL ETFCNEXC€
`nl3tt*ttt
`
`n&nt3
`
`AOOSgnoolf
`
`¡rtorunt r¡r.óú.¡P¡oeræ
`^¡roc¡Llt
`CoLero,Phrym.úT
`th*nltttotlor.
`ldrCly. tA
`Dlvb¡oo lL.d
`t)þbirnolPftûrn cr¡tþú.nd Tr.n¡lúirn¡lTh.r.pG¡lh¡
`Urùv.r¡ny o, lor. GoLel. of Ptr¡ñn.cy
`lil.C¡¡I. lA
`Profr¡¡or
`Divb¡n ol Plrrnraúic¡ üd Trrrrl¡lÈl.l Th.r¡p.otar
`Univ.|t¡ty ol ¡ú¡ CoLga of Ph,rym.ct
`ldrCiV. L
`
`OlÍ..âddn 3:
`
`Edr¡c¡üon:
`
`Curioufr¡Vlr
`Ir¡lta¡ O. Doûova.r. Pll¡.
`
`Ur¡var¡¡lyol loua
`Cofe¡e detrmæy
`I t6 S. Grand Avr
`loe. C¡ty. A 5Zìa2
`mrnrn&rvrntluirn.rdu
`3rÈ3:t5{6e?
`
`Ur¡u.6¡ty of Uhn .of. ColLgl. o, Phm¡óT
`Uinna¡po¡¡, ilinaaof¡
`A.ch.lorolsd.nc. h Phrm.éy. lg8:l
`Udvcrsity of llkSi¡a Colbgr ol Phem¡ct
`HúH ll. R..{¡han Sdioololcr¿û¡.h Sù¡(g.j
`ArloArto., U¡dr¡g¡r
`Ph.D- (Phrnæsüc.). 1989
`
`PROFEISI'XAL ETP€REXGE
`2o13an*+ú ÈlæidrIr.ülorundcrff.dú¡¡ P¡oeræ
`ColLgrdPh.m¡¿
`UrúËrrtydlü¡
`ld.Ctt l,A
`Dårb¡oo ü.¡d
`O¡vÈin ot Phrñ¡dr¡lÈs rrd ln nC.lþnd lhsÐû¡li!
`UrúY.f3lty o, lorr Cofcgr d Ptrmacy
`lorrC¡V. lA
`
`2ü){'-.2t t3
`
`æ08*rrrrú
`
`PE¡.ta
`fltvbimol Phrrn¡o¡¡th¡ ¡ntTr|n lfüon¡l Tharapì¡tþ¡
`Un¡Y.lrlUo,ld. Gologn ol Ph¡rm¡cf
`loür Cily. lA
`
`flxtê¿008
`
`r98gr$t6
`
`1ln1
`
`t9€5.84
`
`Univü¡¡0ot lr. Co[.!o d Ph.m¡ct
`Divii'l ol Ph¡rrÞst¡cr
`¡il.City. L
`
`Urúnrr*, ot lo5¡ Cof.ge oa Ph,Ín.ct
`D¡vÈbn olPh.meutb3
`lqrCt.lA
`Yr¡¡line tdþlú
`SmiûK¡na Saadr¡m Pñ¡rrnåc.ltb¡l¡
`lúle ot Pru3¡i., PA
`ttlt Ptrr¡¡¡c¡¡i
`Clr* ftoab¡ior¡l e¡ym¡cy
`Yp¡l$ri. Ul
`
`DTX 293
`
`DDX 5.01
`
`2
`
`

`

`Sum ary of Opinions
`
`I I
`
`I A POSA formulator co-formulating a
`fl uticasone/azelastine nasal spray would have
`started working from the Flonase@ and Astelin@
`prod ucts.
`
`r The claimed combinations of fl uticaso ne/azelastine
`in a nasal spray are obvious.
`
`DDX 5.02
`
`3
`
`

`

`Framework for Analysis
`
`t Level of ordinary ski ll in the art.
`
`r Assess the scope of the pr¡or art.
`
`I Assess any differences between the pr¡or art and
`the claimed inventions.
`
`I Were the claims obvious in light of any differences
`from the prior art?
`
`DDX 5.03
`
`4
`
`

`

`Person of Ordinary Sk¡ll in the Art: Formulation
`
`The relevant art: pharmaceutical formulations of
`topica I agents.
`
`I
`
`Level of ordinary skill in the art:
`o At least a bachelor's degree in chemistry, b¡ology, chemical
`engineering or pharmaceutical science;
`. 3-5 years of experience in formulation development of nasal dosage
`forms, ând the ability to operate independently on formulation
`a ctivities.
`Familiarity with pharmaceutical excipients and their uses.
`Could have advanced degree, with fewer years of experience
`
`o o D
`
`ate of invention: June 2002
`
`DDX 5.04
`
`5
`
`

`

`Scope of the Prior Art:
`Fluticasone Propionate (Flonase)
`
`Flonase Label (1998)
`
`FLOT{ASE'
`il¡d ¡9r¡t, lO ño¡
`Fa ll¡trr¡¡l U¡o O¡ly.
`
`rmtE llÍor¡¡lroaa
`
`8|r xEoEillLY
`¡EFOn8 U8è
`
`f¡¡I.tor o.Ûfiúr.. fr ft-
`Ílertóar or FLOta^t¡C llll E .r, ta a ryìlt{,r
`CtcitlþL:
`crlE¡|.lol sar ii. cffil
`rl'ta a, ûl¡¡clltrfil a.roaa¡rûtrFtttrút'ta¡{-ìtao.TÞ
`ttræErloçrñ..tr{ü}ttt{rùsrrþ.¡
`rt ì. Ebrre olnþJ rùrEtrr¡
`
`I II at ótI9
`
`t0
`¡¡
`
`t¡
`¡t
`ta
`rt
`tó
`It
`It
`It
`
`æ¡
`
`rúI
`
`tu¡
`
`t
`¡a
`
`nI
`
`t
`¡9
`l0
`ll
`t¡
`¡!
`ta
`¡5
`ta
`
`Art¡cr t *.ü.
`Fcüc.üyhÉ¡n¡h rt
`
`¡ ¡¡lt Þfft
`foït rtr.
`iüt-$rd
`&f. ¡ ¡
`r¡.'¡dr¡Ð h¿n ì!a ¡rú.rúóa|díûñtafG.rú
`
`-gltt
`ñ,(l{ 8C t3$at
`!O ie bì ¡ræ.! uFr-r C nraõl¡r lt¡lãl¡lÐbrt
`It
`ÞF¡r drrrt adrþ tr t-ûFËaD'ir!
`Ca tüt¡. aúrûr0 afir¡¡ll9. ¡LOiaA!Ë
`tirû.
`Ol.}¡trl!]d.¡rrì
`drút, ¡æ.a.ð,.tÉO¡t¡JrrùWìtr
`J.Cr.t. rld t¡. tt
`!t]r¡arú7.
`¡ a â¡a¡art þ lr¡rr Ga tr rÞ ¡.1ür ttl u¡ or af: a ¡¡it d tÞl.. lt ;xt c rær¡.
`A¡b Él r.ñìe C. r¡d¡6l
`rú! Ìù¡-n tItil æ no¡ d l¡aãr. ¡¡çna. ¡ t6 í|e
`tæ'türtú
`l-r ú d tf.O¡ !C t5d aFl Fd-
`oa biti¡hiú irq{ñ lb üJ t*.
`rF¡F A¡L. tA nñ gì!. fr ¡rn r
`Fracl-!nìay
`!l., l|t rñf -urÉ b tþt|(l
`rut ù. æ¡t
`Cf¡aE¡¡L ñ{ fl¡ÞOLOCl8 }'¡rh¡o,r. tÉCc.t ¡. l'ilìú!. il{..hd ærEo¡¡rüt rtÚl
`rt{f¡rÍtaE Êft
`¡|rüoôa rryr. d¡ùú
`¡c!ìaath|ìJr ü¡mr$dó tã3to.
`lìÈl*þ ùaîúe ailt !ü¡ ..rt -t dtürtaa ct¡ tç¡|ra r r ¡¡ .rt O,i7 rût
`Ëì
`ctgl'Í¡ü¡,'rq.aifaì. çfþrDrç!|-
`rll
`rbõ¡¡ü
`rEa-Éd ttl
`a¡¡]naalE taro õrl¡ O.¡ tn ¡ra t¡ld(rüa F.o.-+-r
`rth m dr ¡fta.t
`¡ËClFsllltÉrt-
`b frdrbl r¡-,fieãr¡ltaüaa
`. )tffi,
`ffi
`lr aæd l¡rka
`Plw¡r*.)
`a rü lú!'r.
`
`rtnladtqaaaûr.ll l.thÈt-rìb þ üÐ nrnl
`¡!- (n
`d ü- llúiet lr rúì b lr ¡r Ël|
`
`APTOIILAZ'L 00a0lt¡
`
`DTX 33, at 2
`
`DDX 5.05
`
`6
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mcA, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/mL per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02% w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`M icrocrystalline cellulose /
`Carboxymethyl cellulose sodiu m
`("MCC / CMC") (Avicel)
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.06
`
`7
`
`

`

`Scope of the Prior Art:
`Tonicity
`
`Science,
`
`T]ìe Årt,
`ond
`
`of
`
`lompounding
`
`Allen: The Art, Science and Technology of Pharmaceutical Compounding (1998)
`
`@
`The prefemed trgentc for adiusting the toniciff cf nasal solulions ore sodium
`chloride and dextrose. Severely hypertonf c solutir¡ns shcruld tn uvoided. Nq.rol fluitl
`has an isotoniclty volue similor trr c¡ 0.9oÁ stxllurn clloride solutltrn. Il't'he i.rotonic-
`ity ir beyon<l the proper rünge, the nasql ciliary movement nray slow or e¡'en stop.
`Tonicity ve¡lues nrnging fiu¡rt A.6Vo to 1.8o,ô sodium clrlrrricle equivoletrsy ûrÊ gener-
`ully occe¡rtuble, It't]re solution of the octive drug is hypotonic, it moy be necessary
`to add u suhstonce to ottoin the proper tonicity rûnge. So<liu¡u cttlclride, boric qcid,
`ilnd dextrose ûre commonly used for this purpot;e. A tunit:itv <lf 300 m0srn/I" is
`ideol, althouqh o range cf ?0O to 600 mOsm/l ls occerptoble.
`
`Lrydv.Âþ0,¡..
`Prûllcror rnd Ch.¡t
`Oaprrm¡nr ot
`¡nd
`Coll.c¿ ot
`Unlv¡r¡lty d
`C¡thhom. Clty.
`
`@ ^ffitoû
`
`,,'tt w¡hlngtoû. D.C,
`
`DTX 78, at L9
`
`DDX 5.07
`
`8
`
`

`

`Scope of The Prior Art
`
`Flonase@
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglml per spray)
`
`Astelin@
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02% w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.08
`
`9
`
`

`

`Scope of the Prior Art:
`Azelastine HCI (Astelin)
`
`Astelin Label (2000)
`
`ASTELIN'
`6zclrsriae hydrochloridc)
`Nrsel S¡nv- 13? ncc
`ni.izió¡.8
`For l¡rtr¡a¡s¡l Usc Onty
`
`DESCA¡F¡IO!¡
`A.nclia',le¡¡útr ùI¡r¡É¡¡oridÊ) N.¡rl SFry,
`l3t ¡¡sotrllr¡ (mcgl b û .üúû¡ÍbÊ
`¡sndldri u r oaard-rpaz¡r ¡l¡tlo¡ for
`i¡¡ru¡¡¡
`¡atn¡rlrlr¡ron
`Ard¡r¡B
`htttælüodda G¡ft a ¡ il¡¡rc, rlñor odorlã{
`Êrt¡¡¡¡lilE gorrtB eirb r b¡Blr'E¡s lt tr¡ r
`ælaler æig]|r of a¡&t?. lt ¡¡ rgrri¡t¡t $hÈlc
`¡tr FT|F, GúHot, ¡¡d FÞpt|!æ dxo¡ ad
`rti¡hüy slüÈlc iõ &!o¡t o(f¡qôù, üú a¡]rÉûr'û
`It ù¡s ¡ elt¡nr Fiáa oÍ úout zl5.c ril dÊ Èl
`ol ¿ r¡û¡¡lèd rôlüaioa ¡¡ ùcarÉËrr t.O ùd t a D¡
`chËf!¡e¡ ¡¡t
`ir (*)-l+¡Ð?t'Lr4n'c,r-l(a-
`cfiloro9ltratl) æùylÞ1<lr.¡¡ù),nG!-ælbyl-llf.
`urpin4-f'f>, nûîo¡ydrûct¡oûide, lB mld{ta-
`fomüL ¡¡ C¿H¡¡ÇO|¡OHCI viù û. ô¡lolint
`cìÊrn¡Él lnÉtE
`
`N¡$t 5¡n¡ cmuir o.l!&s¡l¡sti¡¡
`bldGblõ!& l,Á ú ¡qwûË þlu¡¡o! A Dll 6l t
`^dd¡nr
`OJ- ü ¡ls c¡[trlß tc¡ällor¡u cNô¡f6ê (¡rt
`trrct/ln4 cdcrtÊ.d¡s.d¡r¡Í\ lEdHvpr!¡t¡ ffitM
`Bll!¡Ga. c¡t¡lc rdd. d¡ü.¡¡6 æa$u gtsDñr¡c,
`odiun dùo¡ide ¡¡d püificd Etr.
`Âftcr grioûç; rrcL mlsld g¡y &l¡t rlr ¡
`O.¡3? nL E wllru ü¡b&ìú t3t E of
`(cqu¡r¡rcc þ 125
`of
`ul¡cím
`nÉlædglr!3'
`cI.rNtc¡lLÞa^nll cot¡Gv
`læl¡slùl... bfdrocù¡õ*lc, ¡
`tlûb¡¡tre"
`drriv¡ür¡Ê. qì¡úE
`lúgni¡c H¡4s¿lac
`úf'lea¡i 8¡vity itr irot¡¡d dsr¡
`!¡¡iËi!
`aodcl+ ¡¡d hEm ¡lclin'¡üre¡ Spr¡y b
`rdrn¡ßlLæd s a ænls nl¡¡s wlù o
`di8araoa b oà¡rütcolotlc rrllrtlt d!¿ b.rru
`tbc ffiloffi
`¿o ,r v¡ôro dr¡6ca Tùc.úlÞr
`
`DTX 22, at 6
`
`DDX 5.09
`
`APOTEX_AZFL 0059086
`
`DTX-O22.0006
`
`10
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglmL per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02o/o w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Polysorbate 80
`
`Thickening Agents
`
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.10
`
`11
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05o/o (w/w), or 0.5
`mg/mL per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02o/o w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.11
`
`12
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/mL per spray)
`
`Azelastine HCI (0.L% (w/w or w/v),
`0.137 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02%w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Water
`(1) Benzalkonium chloride (O.OL25%
`wlw);
`(2) EDTA disodium
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.L2
`
`13
`
`

`

`Scope of the Prior Art:
`Preservative Concentration 0.002% to 0.05%
`
`Uniteð Stetes P¡tent rr¡¡
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`¡avrc lrrl
`ABm¡Cr
`R¡ltrd cft¡¡
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`Srhich
`
`^ Éth¡ 5 Éiw htrld¡ñr .2rldil d ¡ DIF¡ô¡oûi.
`U.S. PA'ENT DOCUMENTS
`e¡lt rqt.ÞL.dt.
`lrllg ¡/t!?t
`t,lriß ür9.¡¡
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`¡z Cb¡E no Drrlt
`
`tról
`
`t ttu
`2UY
`2r2tÐa
`
`Astelin Patent (L992)
`
`contain
`
`The solutions or formulatiol¡s
`servabves
`and their
`tGtrâ-tc€tic ¡cid
`-
`i s¡lts such as-@,
`sah, c¡lcium ¡8lt calcium'sodium s¡l¡)' lower alkyl
`ptryaroxybenzoates, chlorohe¡ídine (for exarnple in the
`forrn of thc rcctrte or gluconete), Phenyl mercury bo'
`rate. Furthetmorg it is poesible, for eremple' to use
`rodiurn{2- ethylmerct¡rithio)'bcnzoatc gcncrally
`known as 'Ihimc¡osal" wbich rnay be prcscnt in an
`e¡¡ount of O.(Fl to 0.05, prderably from 0.m5 rc O.02"
`for example O.0l7o (wdthy'volrmre in liquid formule-
`tions, otherwisc weighVwcight). Othcr ¡uitrblc PnÊsÊr-
`vatives are: pharrr¡æutically ttscful gustelîary ünmr>
`nium coütpoundq fior eranple cetylpyridinium chlo-
`ridc, taradecyltriraahyl arnrronium bromide' gcncrally
`known as'tetrimide", bcnzyldirrethyl'[2'[2'tP{ t, 1,3,}
`tetramcthyl- butyl)þtreoorylethoryJ-rnrnonium chlo-
`ride, generally known es "bcnzetboaiusr chloride" ¡nd
`myrisr yl-:-picolinium chloridc. E ch
`lna
`
`O.(I)2 to O.O5
`
`tions, otherwi¡e
`
`DTX 16, at 2 col.2:46-68
`
`DDX 5.13
`
`14
`
`

`

`Scope of The Prior Art
`
`Flonase@
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglmL per spray)
`
`Astelin@
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02%w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Water
`
`(1-) Benzalkonium chloride (0.0L25%
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations al 0.002o/o to 0.05%
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.14
`
`15
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propionate (50 mca, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglmL per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(1) Benzalkonimum chloride
`(0.02%w/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Surfactants
`
`Polysorbate 80
`
`Thickening Agents
`
`MCC / CMC
`
`Water
`(L) Benzalkonium chloride (0.0L25%
`w/w);
`
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.15
`
`16
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mca, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglml per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02% w/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`
`(1-) Benzal konium chloride (0.0L25o/o
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002% to 0.05%
`None needed
`
`HPMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.16
`
`17
`
`

`

`Scope of the Prior Art
`CMC Is Compatible W¡th Azelasti e HCI
`
`I
`
`United St¡tes P¡tent rr¡t
`llrncl!
`
`Ir{l rzf,tlst¡NEd)NTÀ¡Nt¡(G
`tlEIc¡¡t¡Éx¡t
`liEfror: lLlÍtlüâqDlÉñbch,H.
`F
`LFdoCNr)
`fñ!
`OCúw
`^ß¡tËÈ ^Êh¡rcFd.ßsof
`fiit ^F - M, Ër¡..
`l::l t¡¡¡c¡rr it¡l rA ltto
`
`dk.þ.20t¿ !*rï.i ¡t!lù.
`Í631 bffi
`f 30¡
`lonlat Atd¡¡dù Frldlr D¡a¡
`xôv lr¡m ÞEl H.lo dk'....-læ¡
`tûo., --..-.--,---.-. trrf 9/1.û Aatx !l/5
`f!¡l
`U6. C! .,,,,..",.,..,,...,..-.,,,....,.... ølQt $atar.
`lr¡¡
`lld4\aúlgi t2uûti tnmz
`Dhld ot ¡B¡ ., .-,,.,,,..,.,.. 4¡4l{1,4ôd 4lt. rt.
`frsl
`121/4, Stanû, ztuttlì l.!/l+ ¡ttâo&
`¡4l/t(l
`f!6,
`tufusü Ctd
`U,S. PA'E5IþCUM TS
`ltl!g Llttt br-....,---.--..-........-..¡avt
`... ,......,,..,... Ðg
`t.lrqß urglt ¡tøt
`¡.lhm lvt9!¡ llùÈÉh...-.-...--.....-.,. ¡¡¿lB
`
`ilrsml[$ilrllilrmmmulllllü
`flrt l¡d$rNu¡rbæ
`trlf¡1,194
`Fq DúcolDrrü¡
`l{r.ú,1Ð,
`ll¿r.C AD .,--.-..,*--.-....,-.., 2a{/10¡
`¡¡t¿û¡1
`USI
`8m
`2,9tJd
`l¿fa V{dq ---.-.,..-. #D!
`¡tr3g
`^tu--.---,.--..,-.-,
`¡n¡t Ê{d d ú ..,,,..,,....,..,.-. ,l¡/¡U
`+4,Ð
`tÁr bdd...-.-*-.tl@J
`F(NE¡GN'ATEI¡I DOCI'I'GNTS
`2W 1ltnl rdtO.oloffiry -- rylll
`,'ø! Uü tu¡Þ.oftu!.-.
`t¡a^¡¡
`¡¡U¡ mn ruIiËb.
`('lHEn P¡r¡LtcaltoNs
`lÈfw. Oæb-ctd¡¡lr Dnt¡ rd ñ.h 6Þ
`ry,8¡-U,(l9l?p.rH9.
`EB.F! âF¡rS læ¡-
`O¡¡-Gño dm ¡nC rlçlr FñE
`rd, nL No.
`rt6 (194t|
`rgH.íF t97¿-t9!5, Þ tro md 9J9
`^æb!!sl
`(19Ð.
`âri.? A¿rþFl¡E
`ß. !.¡.
`&¡WbItaIt
`¡*y
`AffiM Ar6t e Fñ-<vhm, D.rby & C¡r¡ú¡
`tttl
`^Btt¡cr
`ñùêamr f¡a ¡s¡ s d þr s li tll. Or rìich
`æü¡¡ú ¡ FlÈ h|frdd¡ aEl5d¡.6 ¡ Dltdólott-
`^
`clly *st.trL rir,
`It C¡¡E No DñdE
`
`Astelin Patent (L992)
`
`þ{srçsven, it is postihle ao ndd thick¡nuim.n rÊËnls tü
`rolutisn@of
`to Freuunr ühe
`sÐlütiurls
`quickly r¡rd tu
`¡l*e tl¡e solutton ¡ vfueo¡ity
`türe ngçe tgo
`of ¡bsut 1.5 to 3, prcføahtry 2 urPr;s. Surh thic&,mine
`t*:: ,caltulffiE dËrivetiúelTffil
`for c¡,fl¡n
`t¡
`ÈL
`s frsË
`h tl¡c celluloÉË-hyd¡ory
`gûo¡rp6 nr'e punidly ethæiÍld n¡inh lpwrr uru¡tr¡¡lrcd
`aliphatie ded¡ons end./Er lower urffirtnrËfrd nliphsrùe
`oxynleohoh ffor cr¡rnpïc rmsrhyü çctluluron
`lstc
`ï
`
`(wrter
`t
`tmgas
`eonlËh binding ffid thhkrning sgËûts am the bülç of
`ethyl cellulosr), elglnic ¡sid, polyvinyl ¡hohol, polf
`aenylic *cid, p*cuin nnd equivdcnl. lgËüts. $hsr¡¡d thËEÊ
`subnances contnin rsid grq¡po, uhe curr*pürrding
`ph¡ninlogieelly nceept*tr.e qTtr rrùry al¡a hs usËd.
`
`I
`
`DTX 16, at 3 col. 4:51-66
`
`DDX 5.L7
`
`DTX.oí6_OfÐ1
`
`18
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propíonate (50 mca, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/ml per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02o/o w/w);
`(2) Phenyl ethyl alcohol (025%
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`
`(1-) Benzalkonium chloride (0.0L25%
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`Astelin patent others, including
`cMc
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`DDX 5.18
`
`19
`
`

`

`Scope of The Prior Art
`
`Active Ingredient Fluticasone propionate (50 mcA, or
`0.05 mg, or 0.05o/o (w/w), or 0.5
`mglml per spray)
`
`Azelastine HCI (0.1% (w/w or Wv),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02o/ow/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`(1-) Benzalkonium chloride (0.0L25%
`w/w);
`
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002% to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`NaCI
`
`pH
`
`5to7
`
`DDX 5.19
`
`20
`
`

`

`Scope of the Prior Art
`Tonicity Adjusters
`
`Uniteû St¡tcs P¡tent rre¡
`lI4tid¡.
`
`¡!{ AlzE¡lsfll¡E(IÍtftllll¡¡G
`Mrc^IqElt'¡
`pi¡ ¡n*Bor: l¡ht ||tdr Dldñboh, F.d.
`fßF oloøü'
`Ftl ron¡e
`¡¿!¡ ¡¡et. t¡o, rr¡¡r¡
`
`tLdUAAaú.dthb
`lúg¡ entffi dtu.htot?¿ &.1 |tll,.ò...
`fæhr frE ¡üÒ Fdcfirl¡.a.
`tlol
`ìôv. lI tS ÞË¡ HIF dtur-...-
`lnl r¡ß o. -.--,*.*-,-. ü¡¡
`l¡! Cl.r
`llll
`
`tru¡
`
`f!ó¡
`
`+1',/ll*, taølaUUt9.l
`Li@s Clraa
`U.s. PArNf IDCUMEI.IIS
`ttf,lg vlnt
`t,ltts ú/tg¡l
`¡.t3fh :v¡9!t
`
`ugþlt6.l9lÀ
`tút ll¡r.ot Nurbæ t,lú{19,1
`g¡¡ Dlc of Frúdrit Nw. l?, 1Ð92
`&tt?,tH ll4rtl ñr .,"..-.....---.,,--.-,.,..., ¿all10¡
`¡.9tJ8 r/[rt &tu
`-....."-...-.....-,-. ryro¿
`t¡rü
`r¡n vqdq...--...-.-..-,.,*¡¡t
`lUIt fu¡l d d --.-....,."--, ,lø1,
`+ü¡t
`.,7úX VIW lbqd,,---.-.
`tlø.t
`FOREIGN ?ATEI{Í D(E1'}GNTA
`ztffit Vln F.d- ið. olodrry --. Jaøl!!
`lJøl Mü HlÞ.ottut--t¡a2ll
`arut lÃm truXLIb.
`oÎ}lÊn n SucA¡roNS
`[hrür Ed îr¡ Ët!.
`
`I, l¡45,
`
`Nqw.
`
`Astelin Patent (1992)
`In the case of dosage forms containing \ryater, it is
`optionally possible to use additional isotonization
`rEents. Isotonization agents which rräy, for exarnple, be
`used are: saccharose, glucose, glvcerine. sorbitol, 1,2-
`propylene glycol, NaCl.
`
`APOIEXJTZFL 0054t80
`
`DTX-or6.0001
`
`DTX 16, at 3 col. 4:31-35
`
`DDX 5.20
`
`21
`
`

`

`Scope of The Prior Art
`
`Flonase@
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/mL per spray)
`
`Astelin@
`
`Azelastine HCI (0.1-% (w/w or w/v),
`0.1-37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02o/ow/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`Water
`
`(1-) Benzalkonium chloride (0.0L25%
`Ww);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`NaCl
`Astelin patent saccharose, glucose,
`glycerin, sorbitol, 1,2-propylene
`glycol
`
`DDX 5.2L
`
`22
`
`

`

`Scope of The Prior Art
`
`Flonase@
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05o/o (w/w), or 0.5
`mglml per spray)
`
`Astelin@
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(1) Benzalkonimum chloride
`(0.02o/o w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`
`(1-) Benzalkoniu m chloride (0.0L25o/o
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, 1-,2-propylene glycol
`6.8 +l- 0.3
`(6.5 to 7.1) (buffered with citric acid
`and dibasic sodium phosphate)
`
`DDX 5.22
`
`23
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Flutícasone propionate (50 mcg, or
`0.05 mg, or 0.05o/o (w/w), or 0.5
`mg/ml per spray)
`
`Azelastine HCI (0.1-% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02% w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Sudactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`(L) Benzalkonium chloride (0.0L25o/o
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`Astelin patent: others, including CMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose.
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- 9.3
`(6.5 to 7.L) (buffered with citric acid
`and dibasic sodium phosphate)
`
`Obvious Combination
`Formulation
`Fluticasone propionate (50 mcg,
`or 0.05 mg, or O.O5o/o (wlw), or 0.5
`mglmL per spray)
`Azelastine HC¡ (0.1% (w/w) or
`(Vv),0.137 mg per spray)
`
`DDX 5.23
`
`24
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mcA, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/ml per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02o/o w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`pH
`
`5to7
`
`Water
`(L) Benzalkoniu m chloride (0.0L25o/o
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`NaCl
`Astelin patent saccharose, glucose,
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- 0.3
`(6.5 to 7.L) (buffered with citric acid
`and dibasic sodium phosphate)
`
`Obvious Combination
`Formulation
`Fluticasone propionate (50 mca, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglml per spray)
`Azelastine HCI (0.L% (w/w) or (w/v),
`0.L37 mg per spray)
`
`"microfine" (< 10 microns)
`
`DDX 5.24
`
`25
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propionate (50 mcA, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglml per spray)
`
`Azelastine HCI (0.1-% (w/w or w/v),
`0.137 mg per spray)
`
`Obvious Combination
`Formulation
`Fluticasone propionate (50 mcA, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/mL per spray)
`Azelastine HCI (0.1% (w/w) or (w/v),
`0.137 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`"microfine" (< 10 microns)
`
`Water
`
`Water
`
`Water
`
`(1-) Benzalkonium chloride (0.01.25%
`w/w);
`
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002% to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Vehicle
`
`Preservatives
`
`(1-) Benzalkonimum chloride
`(0.02%w/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- 9.3
`(6.5 to 7.1) (buffered with citric acid
`and dibasic sodium phosphate)
`
`DDX 5.25
`
`26
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/ml per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.137 mg per spray)
`
`Obvious Combination
`Form u lation
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/ml per spray)
`Azelastine HCI (0.1-% (w/w) or (w/v),
`0.137 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`"microfine" (< 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02o/o w/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`(L) Benzalkonium chloride (0.0L25o/o
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Water
`(1) Benzalkonimum chloride
`(0.0L25% or O.O2o/" w lw);
`(2) Phenyl ethyl alcohol
`(0.25o/o w/w)
`(3) EDTA disodium (0.002% -
`0.0s%)
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- 0.3
`(6.5 to 7.1-) (buffered with citric acid
`and dibasic sodium phosphate)
`
`DDX 5.26
`
`27
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propionate (50 mca, or
`0.05 mg, or 0.05% (Ww), or 0.5
`mg/mL per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02% w/w);
`(2) Phenyl ethyl alcohol (0.25"/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`(1) Benzalkonium chloride (0.01,25%
`w/w);
`
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- 0.3
`(6.5 to 7.1-) (buffered with citric acid
`and dibasic sodium phosphate)
`
`Obvious Combination
`Formulation
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/mL per spray)
`Azelastine HCI (0.1-% (w/w) or (w/v),
`0.137 mg per spray)
`"microfine" (. 10 microns)
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.0L25o/o or 0.02% w/w);
`(2) Phenyl ethyl alcohol
`(0.25%ow/w)
`(3) EDTA disodium (0.002o/o - 0.05%)
`
`Polysorbate 80
`
`DDX 5.27
`
`28
`
`

`

`Scope of the Prior Art
`g Agent Concentration: MCC/CMC
`Thicke I
`
`I
`
`I
`
`Handbook of
`PHÁ.RMÄ
`EX
`
`Seconil
`
`Edi,ted bt
`Ainley Wade and Panl
`
`Àil{rh¡ft Sì¡nn¡aê0th¡rl lrÉoilrths
`Wr¡Ë6gtoû
`
`t99¿
`
`DTX 62, at L3
`
`Handbook of Pharmaceutical Excipients
`
`Þ'lic¡t¡r:r-VsË rn EE Ë et e *reË lufuisiþ' $tr¡#: rarþû xs¡¡t e Éf f gl*€E Ën ËrneÊ e{idj uiT¡
`Æf-iål,f ; ."i rrr{rel ÆLi.5$,1; ¡J y¡r:ell
`il i
`b Ie, c+I]$lqr$ç,.
`"u.g.ler:,+r
`*¿ll¡¡r*r!* **l *rtæ$s itu¿{ t*Ìx:l;çlssr hSrgrttr+eopic:
`
`"dvi¿red
`.d,rp* qr''trr¡ c:a i rru',h ile
`por+,rt*t:.
`F.å¿TtrI1,üeirticrp*Trr*: B::= JXln and {JËFhlF.
`."4. *, irii I^y / r* litri Ërlr rt3l:
`T:rÏ'[ . -= #-fl'' l.-trr ¿t 1 ,?l/ç roriv tu¡urtlçn ilispcrs[ftn.
`
`ut¡¡lliÊ'r* csllulose nnd rsr[r*r-
`#r¡r¡ï1ff*n nç; mi n Í,tr.i'ü.$ +l' ltri¿:r
`I il,F*
`yffiq{}sy[ç{î{
`p*r$r
`'ll$Íi s
`¡ÉÌ r4rfitÊf ü
`Trnr¡ r
`pnttdu*e thixqrtr+pic g+lç ilr* "srlilahh *r¡
`*$ ¡fr
`t¡s'h
`¡
`ttlt:rlff
`nf
`pfus r rrrä.u*Ë tåti*t¡Ë ll*rr:r ul;r
`TË l{r¡rfiunf. ¿¡ Ëtl
`ecilurl.:¡Ë $)ff$Ênt fir'{l lfÈrT h*tne+n
`fi.f - [ñ..t{u.ro w¡r+ d*p**+lilrg
`rÃFi]rt {-hr. gru*r1* ¿r,[' rTff*rl:riíx.J-
`
`DDX 5.28
`
`29
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient
`
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglml per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`Obvious Combination
`Forrnulation
`Fluticasone propionate (50 mca, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglmL per spray)
`Azelastine HCI (0.1-% (w/w) or (w/v),
`0.1-37 mg per spray)
`"microfine" (. 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`(1) Benzalkonimum chloride
`(0.02o/ow/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Sudactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`
`Water
`
`(1-) Benzalkonium chloride (0.0125o/o
`w/w);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002o/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`(1-) Benzalkonimum chloride
`(0.0L25% or 0.02o/o w /w);
`(2) Phenyl ethyl alcohol
`(0.25%w/w)
`(3) EDTA disodium (0.002% - 0.05%)
`
`Polysorbate 80
`
`MCC/CM C (Avicel) (1.2o/o),
`HPMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, 1-,2-propylene glycol
`6.8 +/- Q.3
`(6.5 to 7.1) (buffered with citric acid
`and dibasic sodium phosphate)
`
`DDX 5.29
`
`30
`
`

`

`Scope of the Prior Art
`Tonicity Adjusters
`
`Handbook of
`PHARMACEUTICAT"
`EXCTPTENTS
`
`Seconil Edition
`
`Edited by
`Ainley ìVade and Paul J lVeller
`
`Handbook of Pharmaceutical Excipients
`
`Glycerin
`,4u timicr+hiHl Fr+s,*rui{titn; ernnllicnt: hunrutarrl ; ¡:htsiirr¡¿l';
`s+llui:nl.; r¡lur'¿=tf,.ning rr¡runtl t*niË'iIy ugrlnl.
`
`Osmolqrit¡,: a 2.6% viv nqueo$$ rulution is iro-osmotic witb
`SfiUNL
`I-
`
`Wrslirgro¡
`
`'r99¿
`
`Ifu fh¡üû¡ß*üü'rÊl Pl{És
`I^qdqr
`
`DTX 62, at22
`
`DDX 5.30
`
`31
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mg/ml per spray)
`
`Azelastine HCI (0.1% (w/w or w/v),
`0.L37 mg per spray)
`
`Obvious Combination
`Formulation
`Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglmL per spray)
`Azelastine HCI (0.1% (w/w) or (w/v),
`0.137 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`"microfine" (< 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.02% w/w);
`(2) Phenyl ethyl alcohol (0.25%
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`(L) Benzalkonium chloride (0.0L25o/o
`Ww);
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002% to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Water
`
`(L) Benzalkonimum chloride
`(0.0125% or 0.02% w/w);
`(2) Phenyl ethyl alcohol
`(0.25%ow/w)
`(3) EDTA disodium (0.002o/o - 0.05%)
`
`Polysorbate 80
`
`MCC/CMC (Avicel): L.2%
`HPMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- Q.3
`(6.5 to 7.1-) (buffered with citric acid
`and dibasic sodium phosphate)
`
`Dextrose, NaCl, saccharose,
`sorbitol, 1,2-propylene glycol,
`glucose, glycerin (<2.60/")
`
`DDX 5.31
`
`32
`
`

`

`Scope of the Prior Art:
`Compatible pH Range
`
`i:r,ìi;trilijtt¡!¡jlm
`
`Ik Art,
`ond
`
`Science,
`Iechnology
`HrormoceuTi
`
`of
`col Compunding
`
`Allen: The Art, Science and Technology of Pharmaceutical Compounding (1998)
`
`¡ll'l CInd Betf$'el'ing
`
`nre E]üd!ilürily brlffcred qrT thelFi{ of m$xi}num gt{rbillt: fcrr'
`. Th*'butfers are intlucl¡iil to minimiz:e any ch$nge Ín þH
`tlre
`e-Ìr colr
`thc.t-ryûl orct¡r durinü tåle ,rlor*g¡gr tife *f th* ,fnl$, Thlu r:hnng¡e itt'¡rfd <nn aff*c{ t}re
`so-Iuï:îlity <ttrd steibÍltt,v nf:rlrugr; c*rr"1ec¡ue¡ttþ it is il'irportss¡t'tp miniini¿e suqh flr¡s-
`Lurltiorrs. The, ['ruÊÌ'er rystenr should be ctesigned to nrr¡imt'lin the pfÏ ttrror¡ghotlt the
`F{ in
`exfiected shelf Ëife of tlrê prøduct. hut with u lorç buffer ca
`üi'enernll
`of /¡ tCI fi is cstrsilered
`nnrl
`urn.
`rhe
`
`tqdV. Ai.n,.lr- ÞfD
`Pmfær rnd Chr¡t
`Oer.tmart ot M.dlcin.l
`¡nd Phstmulþl
`Col¡âOe ot Phtfm¡cY
`Univarßlry ol Old¡lrom.
`Ollâhornr C¡ty,
`
`@ttL
`
`^rðrlGaî
`wxhlogroñ. D.C,
`
`DTX 78, at 19
`
`DDX 5.32
`
`33
`
`

`

`Scope of The Prior Art
`
`Flonase@
`
`Astelin@
`
`Active Ingredient Fluticasone propionate (50 mcg, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglml per spray)
`
`Azelastine HCI (0.1-% (w/w or w/v),
`0.L37 mg per spray)
`
`Obvious Combination
`Formulation
`Fluticasone propionate (50 mcA, or
`0.05 mg, or 0.05% (w/w), or 0.5
`mglmL per spray)
`Azelastine HCI (0.1% (w/w) or (w/v),
`0.L37 mg per spray)
`
`Particle Size
`
`"microfine" (< 10 microns)
`
`Dissolved in solution
`
`"microfine" (< 10 microns)
`
`Vehicle
`
`Preservatives
`
`Water
`(L) Benzalkonimum chloride
`(0.02o/"w/w);
`(2) Phenyl ethyl alcohol (0.25o/o
`w/w)
`
`Surfactants
`
`Thickening Agents
`
`Polysorbate 80
`MCC / CMC
`
`Water
`(1) Benzalkonium chloride (0.0125%
`w/w);
`
`(2) EDTA disodium
`Astelin patent: other preservatives;
`concentrations at 0.002"/o to 0.05%
`None needed
`
`HPMC
`
`Astelin patent: others, including CMC
`
`Water
`
`(1-) Benzalkonimum chloride
`(0.01,25o/o or 0.02% w/w);
`(2) Phenyl ethyl alcohol
`(0.25%w/w)
`(3) EDTA disodium (0.002o/o - 0.05%)
`
`Polysorbate 80
`
`MCC/CMC (Avicel): 1.2%
`HPMC
`
`Tonicity Adjuster Dextrose
`
`NaCl
`
`pH
`
`5to7
`
`Astelin patent: saccharose, glucose,
`glycerin, sorbitol, L,2-propylene glycol
`6.8 +/- 9.3
`(6.5 to 7.L) (buffered wit