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`1 7 .. ..Jf•tf ~,·.,·411/(_~1I Prqd
`1 lt ( r ,,,lur \o.m-pan.r
`•1, ~. I ''·"'/' cl /;,,hmr
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`_.., .. ,, .. ,,,, J .J?rl1 ( •ti~itl'IY1
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`uo ,"'11",~•~ r,br,irf~ a.00
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`'" • O ..r.,h f,c:ro lind•r
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`tnll~c:ncc of Tonicily and pH ·on Lacrimation· ·and Ocular Drug
`Bioav~ilability•
`·
`
`J . M. CONRAD, W. :-A, RE'AY,
`R. E. P,OLCYN; ~nd
`J. R. ROBINS.ON
`
`Unhcrsit)' of\\'lsc'o.n.$i.o
`~bdisonl' \ Viscons.in
`
`,iBS•TTi.A_i::ti A r~ci,n/q11t i, p;,.w11_;d.
`,mpfo)'lng, com/lt.'1fl u~;,11hl miqosdntff
`,op~)' l_1Ji11g , ... ,~ iii ,,,,. TU_dlqprvoi, //,di
`ello~s lt1t~r.mi"ri,t:((a1J (lf;l,e -tUC/imntirm pq-(cid:173)
`,,n,_lal ufc/,;mict1/ a11d",,1,_.,,,1ra/ ag,111:,, Tht
`i)ositprr,eed_t1tt /IJl.!hk-es 111Dcen,r11i of Ike IW
`,lu!. rdtf(Oa(lfi.;e
`suhu.ancc:, tbg.tJ~h°Cr ·w11J1
`,;rlwet/,;,,,, in Or? o•• ti/ iJlh/110 r0Mi1Hmd
`mqn/1t/if11g :hi' ;;J,ni11axr ><·1th un -_,;er,mJ
`il_toh~. An inrti!u:J~ in tii~ drniua!:t r.at'° e1cm(cid:173)
`.sfl"'lJlgpalt faer(,n1,11itm. Tht tt:tht1fqu'i htu:
`be1n tl~Jfalofld lfJ .:xoml nf 11:e infb,2n~e. <;/
`~(Jlulit>iJ tnnii:fr)1::0ncl.pJI ~m-liltrinitt.rl,111,./1 is
`.1~0WIJ tlfo t ·solu tiara-.fao1,01:ie-•ot J;yp01omc
`i •lth rlsptct:.11)'U!J3.r~·do WJI imluf e lacrlmpho,:i
`but u: fin·cur incre:;,sr m the txltni cf lacri~
`ma.tic11 iJ:.•.obser.t•ttd for.. s.o/uJJ01,$ whh:h (I.rt
`h)'p·er1011k )\,fih ,ears. So/i1(i (}1£ JJ/1 w~i, also
`rested /r,r ,u lnfl.u-r1wf ()n lac-rfniatfr.m, No
`larrimat.!oTJ k 'il., n1JJtl'Ud w'/ip,·thc ,;,Juri'~'n
`pl/ ><:a., df)Sb 10 fhysiologftiII pH b111 ,m In•
`'""" war obs~-,.,..,/ ,l'iit!I siJ/111/t.rtt p(l di/•
`/r(<.U / rqm 1/i, 116/m,i/ 1(111" 1:o/11,li._ , 1/knllnr
`pH:~. /ndr,tt Jr~~1,.r lacrimaHo,,· ,ha11 (Jritf
`ttH.J./Jul [19th indure.grrmCr larrfo,iufnn tlum
`phy.tin/1,gic_.i/ pH. Th; bfi;,,1~aflnbllilJ' _vf
`:lye,;,;;, [,om fc,pitull;• ;,,m/1,11 JQl"l_h.>r.s·~j
`r.1/y/ng 1t/f a.tiiJ fo,rfrfty '-1'"·' .d.\.b de.urmfil1,d·
`oiu! t.£1..il.1.eJ t1~ thi--iurr:~rmlllmr pm;;,,iat ~J1h1:1
`- ------
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`• r.ra:~ _IUed--a1 1\\c ~l'!."tn!i M~t!O!..Pt ,h~..V~n:l\l~1al
`Dt'ug A~ocj1nllrn i,\ (.'.Jllog'.q. Ill,, {i;, Arr{H, l'>1-i
`Th·.::~ulMr-t ('Oni;;.d.--Rt.J)'_. ~n1t Rl,l:in~?n·an au~►
`_t.b!oQ whh 1h~SchV1ll er Pii.1tffntty. Untv,;,\it)' ·at
`\lii<.::on,Tn dni} ~r: .f'ole:~n ,-ilh I~ ~p,11t.i-1n:nl ,of
`Nuc~a., ·,-.,c-9,""<', ~:u:imlnt> ~c,l9n. ,trn:,•q.l,)'
`· H"6(hUI.I\, Mll.dJ~n._ \\' twi,111~;-.., ·s.:n~ 1n'ltt,h l¢
`>Nu!!~~ dn_e.t1 ~d ,11f0,. 1:t~bm.,an
`
`,,~u .fr,f~liori . Gip:ic,in leL:tih ln·1bt r-wne.u alld
`uqu_to·u·l h.1lltttJr,,LJs. a /t1nr1{011 of tim.e., Wo.:~
`dite.rmi,it:d rmd.used 10 a,upH . .bir}Ucaifa"Qllir)',
`it k'O_.sfound 1Aa11heblopz:oiff,•fiilhJ' efecrr~se~~
`1n"diu c1 ptop()rtlm~to.-lh• t.,1~1U<J.( lar1!mtt ·
`Uon tl,a, otcurre& F:Qr-so/ucfmt 1.onii:'1tiii ,._,,r.r
`fl>imJ th:tU blorwoJ/u~llirJi ~ .s le>~ jl>r hj• ..
`perlOni.c~,oJr,tl,nu, wherf 1.J.i.~ /afri~tt1{ion wtlS'
`hi,gh, -rut:1 »•a.s· high for lri"i!ll.lOnir .w/uriottr
`'K.ficr.e. 1h1tla~rimalfrm ri ltt'.i!f.{g/titr. 1--'r,tr -su•
`lr,llon / l H fl k!n,tfbunil Jhui uiaxttnun, gl,i('(cid:173)
`e,rin lji.(.J(11:uiltJl/llll)' nallrrt.d ,iJ DJlpfQX1-
`'matrly i.Jh)'Sfol(Jgf_ciil ptl-. .,.,,nftJr W{1,Y u1i <Hh_t
`n~inim i'm . in . tlrt :ex-t~nl .</ ltic1i1hutfarf .. Al
`.p//',t awuy from ph;-,,/,)/(1,jfr,,I 1>H the oii.>·
`ai;_iiiltd/ifit)' d.rC'f,:.a,,i.! ~,•i1Jr n to,rn/f-Q'ndfhg
`lnfiT'!}~f~ l.n lcr TiNIDl_(an, JI (,r. alsO .ilfo-M•u f11ai
`fi{r J1on'it>t,i=_Qbli tl1'11J;f ,tuCh oJ· glyCerfn tht
`:~/oimuiluli7/irt d,I a J1111t1i()11 n{ so/1illon r,H
`".j:-OLt 1Jr14.111(h a mai-jmum. ro,rtsp(mdtng.1D
`phF°fli:,((>glea/ p/1, ud 1fr,l/ri,.,·nn·2fllrer sidf
`v[:liis pf/, Fi,r ionfc:abl.-d,,,gs: 1hr e.,unr pf
`drug. r1ibt,~rptio11 mus.( indUtie lactJmarlQfl
`e/Jfri., as-weil a;t.1lt,·(1.,,,o/ pf!-po.rr/1/,>5 , :r(cid:173)
`pb1nt1011. Tl,us. 1h, -pHsr.bS!)r/l,/()n pirJJNe
`JorpUotarpi11e eun-~n"· bt" r<r:plained .b.j in(cid:173)
`(1,bki'~ the,. lnr.rim&11011 "/fttl Of \\~flt as tf;t
`p.H-j:i,,1,t!c,n.~Jit:cl,
`I
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`Ot'ub-r drug:b1oa,•,mal;iilu,; frQl11 Ho dhiomil
`,,,phthnlnli'c dr~$ ,kri~·t-r) 1-...... ~·,~,1~ 15-gcrit.r.';!U)I
`c.uosid_cred )">.9T'. T1;~} lt du,c. ·in pa;,, 'tQ the
`hcm~m.lot,l.1'. p·hy~olog-fc:J1 <i6nS1rain·1~ impnscd
`·Dy 1he~}·c 1hi-0U,1rh·~;tt h facto(ia:s. t,etiF lur.n:
`Ql"tr \ I f,), in-<iflk<I fl~i•I dr,lno~c \ l-.6),
`
`Slayback Exhibit 1056, Page 1 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
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`d r_ug-t)rnk:rt ln1<:1,wion, t6--'l), 1hc rtlollvc
`fmp,:rmcab,Ji)y o(th~ l'()rn<>l ( I, ~;:1 '.I), , he
`subs.1n·nti11l ,r,urf.tte a rrn.oJ:-tllir cOnjll nc1 itY--S
`c~pa~cd 10 the come~ {Jl-l>); »_q u<0·u~
`humor turno•er- (I, 16), ·~nd lilc.rhm'tiPn.
`'F.qu~l!y fmi>mt~nl le the question of dr.~g
`bioii:vaHob,ility i-; the type of vcli;~1e·el)'iploycij
`(I, 17 20) ·and the-associa,cd drug Pnlj>'rl1c,
`( l , 18, 20.0 25): U-adcrlying lht vehicle eff~t<
`.is 1he~lanrxu·tan1 question or paticnl tom fort to
`.tXvlat:. J_1J vdut't.~. w.h1ut.· in lurn iS: ·lmimalt .1)'
`reJ~te-d 10 ibc.: lat;:rimn·t,ion mc.n:tloacd:carHcr.
`T ~e.-,on1p.;,1\bOily of pr:coorn·ca.l ~is~uc ~wirh
`,·chick c:ompone:rll's ·such as soJ,..tn,ts~ :pH.
`b\!iicr ('ompon~nls; s~ah c,oncen1 r,i1lon, p,tCS"'
`eNJltlves, dru(!t, mnJ oth~ f91muJ~~ing asents,
`~ 11 rn.nco from irrilaling, 10. lb~ Jxiiu~ or
`dama&(i, hl cou\J}!c.t.dy innQt;uou~ Tht:oughout
`thif ~pc.ctrum o.f ocular li$.$m: re:i~li9n t Q t.hc
`·jJK)~~lcnl 11ml ~,hcirUC~I n~ly1c. <,ir uphth.i lmiC'
`·~c.~i.ri8,'sisJcm~.-11 I~ eipc:c.11:d 1h~3t ~ffi a'.s~(cid:173)
`Med lncrinia lion will (iccut at1d.tliot 1hl$ ta(cid:173)
`c:r7n\:iiion win hb,•e: ru1 ttrlv.eri;:c effect pn ·ocut~
`dnl& bl&wailab:liiv, l'he ~;fl'ie or thi$ rcp,Jr!
`i, to de~eriOe " te~'hnfq~c to m6~W:e d~l(cid:173)
`ci!li)' ,od phy,iclill)' ,nduci!~ Jn.~rin101 i~n. lo
`aS<css I.he cffoc1 e((onieity a:nd pH \>n )3cri·
`--rn!ltion and, fior. ll\' 1 10 Qvii:Ju9.(c the .i-nfl uence
`or lacr-imatioa on~ ocul ar dtug: bio3va.,la.b'ili•
`Ly.
`I,hc·cyc is an ciqu1,ltcly:scnsiti-Vc-organ to
`rhy,,ka l aod thcniical ln,ults..,;<1 maJnr p,o,
`tc.nh·c aspect of. d1e:prc"-o.rnc.al a..r-ea· js la.eel~
`.nution,_a ptoc~ whkh a11~mpts.todilutc·a:od
`rcrnovc .s-_gcnts t:hal a-re insuhJT\g tO.pr,e+Om.cal
`thsu~, The druln1':£.c ~,ppa rat-u~ of h.un1a-ns-;
`r~b\'ltJ, ~nd Qthcr onimnls ,, e4u1ppcd t,o
`•himdlt..,in incr.c!,ii~~ lff ~,c;rimoUluIO s~n,c lte:in
`~a, tornmoct:,tc i ubSlarrth1I \'Q1IHJ1C::> of nuiiJ
`"\\:i1hou-1 s p11l!>t C-..61U lu: ibr;ck :rnii ,, it~ol ,rt~
`p11tlcni. bc1TI.z in~::frc ·th.u.an -in~~!.S.c h;15 CX:'.'
`currod, For i~amp!e. M j;l,im, ,t 11/ \ l5) ,;,
`port that the 1u11h)\'t~r rtUC' of tea rs.· c:rn in-.
`:c<taSt from l6'Ji./ minu« lo 10~/minule in
`J 111mans·a-nd thc:~:ubjccts were un:i\\ .ar~ \h.1 1
`:,1t:lner~!l':e h;id oca;urrc-d. lt.thvuld beob-\'iou.r,
`f r9m t~i, d~rlp1ion:1h:n1 J31JbJ«l~\·e -ar1lr.tti~ul
`o(bcrim111iim i, ,e,Hffi-cult a11d proce.d.u:rcs':rue
`0\.);'d.cd to 1µ_c;n,urc_;i11d q-uu:rnlry 1h, c;Hcltl of
`
`I SO
`
`1•:Crimali.on, h is 111,;o ar;,i1r.cnt 1h~1 CfTlpl~),ng
`pa1icnt a.ct1:r.1a11Cti 3$ a ~rii~rla fnr j·~Iec tion
`of~ j\iiriicula; •chitlo mighl he q~cstioiiab!e
`Ir 9ptimu111 d, ug ~.,,i v;iilo.blllty ·i1 sough,;-
`Th·e Use-of technetium and r~dio~Clmlgr,a.
`phy LO mo111tof ic.lir lurnov~f !\rrd .~ol~Ji~:)
`,fr',iiru,ge In <:xJ:X:tfmentill ,mi-nlMs ~ncJ h~m!~
`ha~ bccq repo,1ed t26-33), • • h:rv, clinitai
`::51 udic.a on tht pa:-tcJ1c~· or the: :d rain~g.; ::_pPa,
`r'atu< (~6, 27, 30, 12) and to dctccl llb1><>iin1I
`1;.::ar lurnv\ Cf. (27--...29, :t'J), ~ ' ili, -s.ui.t~blc
`mo.d.i'f'ic-a.tfoox tht~e ('foccdU,es can bt ,c~
`plo.):cd.to mcasurc. l:acrfo1atloa :::md·to lm.·cs.U~
`gate .the lnnuco~:otphy~kat and chemiC3}
`;.gent); 011 lti~r.hp:3.don.
`The th.crp lurc COl)lain~ .. no-mero.01 siatc•
`m~r,ti;Jha1:. pa.nku lar pl l. tt.mk Hy, o:r. buffer
`comPQ~.tion l.;;_appf:Qfir:hl te. for, h.e. eye. Row.
`c.\·,cr, lh~s.ci ta l<imen.Ls. a.re.-gcncrnUy b~r~ed OB
`JQmc-~ub[«tivc.c.omfo,t lnowi w11~ minimal
`,u.ppgrtin~ ,,iihmcnr.i I 'd41~, Indeed th.r~-t,
`O~•r<p,.,rl~tl mei hQ{! t-0 l11low ~u~n).i1Mion ol
`1:lcrfnia.tJon. (\ notab1c:c.xct'.:p1to,i b: the v-vrk
`by ~fou.riccf3~) l''ho _u,ei(, n~_nr,;~cej~ di:~-
`1fon toi:1inlquc lO l»immc the inn~.once or
`t(>rtidty 011 [l0!l,n1 ~omfoil. He ~oncluddi [hat
`~ohitton, wllh ii tg-~i<iiy ~!Jillvalenl ~n~ iii,
`alum chlorit!e Qr_-r.rC:stcr "'◊uld be lrril>.tl~t
`and cause le.crfrn.atlon. The iludy, hQ\\·cvcr,
`w,s limit ca in , c'lipc .. Studic5' J)n ,P.H ,r~a la:·
`c,imatlo1, have bcco r, w p~~,15) but thm:is
`,llc.ncral asrccmc·nt tha-t cXl rc·mc·5 in pH 1"\\1Y
`r.,om phf~i-OIQgledT pH ~ u~.s laorirruuion 2-r;d,
`In 1h~eitreme. \:cr.y acid ic and bj.sic $1.llotion~:·
`cra.u:S.c dam~~c to Pi:ecornerl fr,:\u¢.. .Spc~:fic
`buffer ctfedr un lnc;r.1maHDn ha.i;ie bc-;.n ,~1~
`cus-s~d an4 r:ccommt11l.d.;111ons ·m,dc. (l l:l-5,
`JS) but Ilic~, wer.c.- P,rc,u,nmbly .ba.scd on
`hurry_an .accC_pt.:incc 0£ 1~¢ ~pcoifi~ bu.ff-or~
`! lla,i~d. Ther~ hav,c·bc.c"n no rcpom; Q.,1c.-rhPt•
`f~·g 10 r(fat~ .lii¢f"L,r1a.tkin 10 J r~~ biv;;-.•j ll•
`a~lnty,
`.
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`f./nltrio/s
`l-.f11lc; ;.l\:i'nu ro bbh:t, t.S:~ Z.4 KS~ "" c,c uw:1
`in:a11.s1udicsL I .lrhtfnt!"ancJ t1udio s1J;muli \\·tre-
`
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`t•he:~nl11
`til;fl_"-',ln
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`3 (tc( " i
`UJ\l il • 1
`3110'- fo
`>oh.Uicin
`1~1\ (rnr
`All o
`~n?IJJ;1
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`SMu
`U"!,((
`p!'!re fr
`e:x·~rh
`·, ,-(all~
`~~~ 2S
`i 10;1i
`!lo1u1lo
`1-ttg. ··c
`&ohnio
`IOl co
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`cft:ect
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`'JsirrgJ
`lii<fruJ
`Oibasi;
`S:Q). 1
`,\ lkla·
`•iQ}u.d~
`PcllO!
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`def.ire;:
`tc$1 5fi
`~n.o.x
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`'•"''"'l11f 11t...i'tJ.,,.,.+n1I U, .. f .\"-"'"" 11-.ea
`
`Slayback Exhibit 1056, Page 2 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
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`P.•epafed by-:iddition of the U'li,glyccr~n sr>(cid:173)
`lution. to Y:trious coocentratlon.s of NaCl ~0-.
`1·ution, Jr1 lerms··of 1onlcUy a, t. i% glycerin
`s.(JhHi(l11 rs approxiu,;;ttcly :on~-half h,oloni~.
`Tcchnc~ltiJn ~olmlont• were.· PJ~.~t~ by
`ad~ition or V'mTcp,~ I Q so ulion,.lo , nryii]g
`pM • nd 1onlci1y, Sp«:iriqlly. -40- ~0 rnCI of
`iw,wto .as pcrt~hnc-ta\~ ion wn.." drawn off tJ,'e .
`go.ncr~uorl,1!;12-n,t of i-.(llooic .s;!.ifo~~ Thii wa~
`lidded io-a 50-ml ~,,rotor) fun,ltblrmg \\Ith
`1·:r ml of S.5 N J',:aOH an,1 0 11< ~rop-of'.lOi\
`'H,<1, lo inJu(C oomplcie•fo'rma!i,,11 of-lho
`p::r1ah-11e1atC ion, Art~ 1h·a.J.:h1g, l h~ ni-i.iJure(cid:173)
`w,,~_nllowcd t~ cq,Jflbr~lc for I$ minute~ allll
`1ben 15 ml ,.,r [t~•h1y d••lilt<d nicthyl ethyl
`,ketone '(MEK) W:»,l1MJ:11. The mjj,l\1'C 11',U
`.sh:ak~n ·~nd :t,~a(lttoo~~ µh.afo:di~artlcd, Tl}e
`M 6K,.,;01ttainf1}& l lie f>Crt~f~frnerntc. iOn' W:\S
`l.r~ n,forrcd lo .8 clean l:>ca~cr :u,d lhc M F.-K
`rn1R6(a'.{clb-)' ~ ~;~ful warming or the ~~f:K
`Wiuiio~ whlie l'as;-1i,lg ll stream ·or l'illcrc-0 :1-ir
`o·i.er tile bcakcf, The r_bidool per,cchnct~ ie
`·1ni\ was'. then ,ec.orisiitul~ wilh 2-ml of tho
`nj)pru.i)tial~ p·R bltffer or 1Cnicity ,olu~lon end
`lr~iTJ;(e,r,_d 10:·t St~dlc c,atu:,,H:d ,ial ro, USt
`in lh~Jacrlmation ~auJics. lt u:.as·dc1(:rmlt1c.d
`thro'u.gh osmomc.lry tha:l:,;·~mic:0.- did m) t·
`npprcdably ,rffe~t 1onlc11yof 1he.spJu1i9nS. /\l
`thC conclusion or \h:,S.t\)dy the Uf1U·S~ •.S.Olu 4
`1lon~ "''ct~•.altowed to dc.C-'5'1 to Qilc,kg_r,,u nd
`,adla1lon level,, 72~96 hou;,,,~nd 11\en tolu-
`110.11 pl-! and (onicily rech<c}.cd_.
`
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`T·Jic ~AP:dmC!tlaj 1.~Cflniqu_c.11 1.11 iU1.t4 in th~
`a'.qu_t;()US ri·umor ·dru}t bi,<l,W!iibbility ; Lutlic.5
`&,Yi~"cri r<'fl<lrl~d r•r.<l'rnusly W S, 18). IJn(cid:173)
`:incsJfu:1 f.,.ed anlti.rnfa wCrcu~cd in-tttJ St udies~
`A ts:jd do~ \\'3-S Cfl_lpltiYcJI a1 ~II I iu1cs-nnd
`;;,mples 11i1hdr.1wn af 5, IO', 20. JO. 45. ond:60
`rnlnu1 cs· pos:1 dosin~. The-allerrr:rLl! .. cye.sam~
`pli n$ ·prt,ocder< tle;cribcd .:or.lie, (I.~) was
`U~t:"d ror the ·$ .md lO m¼n·,1.c polr.ts•wh1lc:a!I
`9.thcr,~rn~q,c:,Jnt ~"ltupki. " 'ere qbt,;i.l o_et:I ,,~ine
`bo.1h c:}·c, for l hc .s;,mc tbot,point: ,\licini\Cc
`left-right nod d~hl•ltft cy~ dosing wa~ fol.
`IQ.~:od In oll.co«i (16),
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`Cl"'~'~inc'd co_n,1'nl 1>n :• L~-110_uf 11~,;~ ·~nd
`11,earirmalsJc,d • rcgul:11 die! wnh nO·rci tri~
`li..ln~ Qn (000 or W\H.er jf\~a.Kc .
`1•C-Gl)'(c,ol' ~lcrire • 440011< <<i)utlcn,
`,oecir.o ""liviiy 16.0 ;,Cl/Ing, \(,is o$cd no
`i'~~lf':_{LTC~hnclium \\f)lution,s \\·c!c prep:i rc;:d
`,.flt! "ffiilkhrg'' a · molybdenum gC.1l.et;1t6t>
`~r.1il i Ociirec:f Jewel or 3ctivJty Wi!"s .. rcached to
`,-ltO'-'' foe. lo&ll'.es-111 t_hc cxtrlctlon-prOC:c:".ses.. A 11
`. _iillu.iiOllS u~tdb':id ?~n:Tc- pf:e,~n, as·11mTcel~(cid:173)
`. ~ 11 h b Jn-rodlum p:ct1c1;,;hncta.te·,
`· All 0 1 lier eh¢mi\:":lls wcre<lth.cr-'r~.ge.n-1 or
`•~•ly1kal trade,.
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`Solution P.:reparµ/l()n~A:s1oc.k. sQ:lu1fon o(
`1.J%'.(O.J ,l M) glyccr.olwa~cmployed 1.0 pre,
`p;rc frc$'h dosin!. glyccr.ol Jo!u1ion$ for.~
`,:<J1Crlment, A lypici,I j9lu1fon ,~o.s prcwrqi
`,; follows: Tc pr~paro 3() dose,,, "!'£h 9f" ~fi:h
`,-as 2'5 µI . 30 µ]·of "C-ll,l~c•rol we,, n_dd~d'1,:,
`ilO pl of' '<g!d" gly~cro1 $lock 1iiluifon ~i IQ .
`~huibri~.Q( ~1Jt)1in& pH a:ri.d ·b~.nlc:ff>' ~~1n1'ail'\-(cid:173)
`iot. " c-014'' ,gl)'S''i" - Tiiu,, 1h'c ffn~I tluiiqS
`~tul fon 1la0 an··;idlivity or•1\p_prhxim3teJy 3 ) <
`IQ~•cgunl•/ii\ln• t,Yl'.1. 'J'k ad~lli<in at r<t;(cid:173)
`·1.lt mol 19111r; "colt!' ' &,ly_cuolfsolution lied "o
`tffi::c't <tit lhe. fin:11 solution tonicityt ··
`Th_e varidusburfer Solnt-i(),)S'. ~•ere p:rcparal
`u;ing ~yrlr<ichloric A
`d \pH ~ I ), potassium
`hJ4roe<n 1ihthala1e \pH.= 4), on,! mono':snd
`dibasic-sodi1rm phosphate (pl I = i.251 J_O,,.,nd
`8,0). The pl I F 9 .O.~oL.nion•.\\'OSl)rcpa-rcd with
`/\1kb,s-l'an1in h.ttffcr ( 46),Tbc fir.al pH or ~II
`•~ 1wlons·wa5:·cbc.~kcd wlth·a pl-I m t:H.Cf~ and,
`pcrlod,c·all\•, wilh sensfth·c indicalor stic.h::1
`h.otonicit):'tli.,~ maint:?iuc:~ . u . .nk.s~ o,~·crwrs'.t
`.d~sltcJ, by iiddhkrr-i of .sodiumchlorid~ to th'c.
`lc11_so!u_ifon5,, Tonis,Ily ""•<ehe~k~d_by· "-'• of
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`Slayback Exhibit 1056, Page 3 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Cf);n"tll lirug Cun~t lJliatla.n. Ve(sus Timr
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`Prafi.lt1'
`ThC c:xperlm.cntal 1echolquc.s lJl itiz.e.~ lnLhe
`cOTTJiat l>iwv~ il.rbllit.Y.itudles h-~ \ '¢ bqcn de•
`s~llhcJ pte.;iou, lj,_ ($), '(;9rm:al .am i>l~n verc
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`In wooden fC:S.lr3)n ing ; bo'!:c.:s in tt,t: o-orm:ll
`Ujmgh1 ~~l·~;e.\Jtr4n~hctizcd t1oimals were:
`cmplQyc<j ·in ~JI i1 uJios.
`Aft~r prcf~ rntfou v( 1he v~rious ~9111Tc p l I
`buffer or sah Sfl!111ion,~ tu~ ~.scd lu the P~·
`lieu la, slu.dy, c-ich 25·,µ.I ~.uso· 1o·bc ~dmi.nis,
`1ered "'" chec~cd (p'.r·,~~;~,2,fvil.)o,_~•11P!.oyp1g
`:rte• .C'.>pnltet Do,,; c 211Ufr_a tof.7 Arter da sing
`!be eye-wit Ii• mi~roii1ersyring~• 1J,c.1cs1 an•
`Ima! was~· immcdi~td ); J,P\1i1~ne.lf whh th.e
`punqum or cha 11~s'Ollicf+111.aJ (jlJ~·t 1.:~ t m
`a\\·ay fr9m t'llc openlni :or lh~ r inli~l.c t olli(cid:173)
`matqr atrn.d 1.ed to lhe g~ritma ~m·c;ra/ A
`~ fTip,ill~r lin<10·10 lhc tnmmo cimier., s~or~.,
`the r<idioot 1ivlly=1lmc d!ita fOr ltit-cr rc1riCva1 ..
`At, eom.?Ut-cr l•J.O,Br,itm11 :e Uow.s 1>ie 01~~ra1or· ,·o
`v.bsfi·fvc 1he di_s.ttibu•iion of ra'(iioaciivfty (>ti a.
`ca , h·ode-, ,:y Iii be and lo Qwlinc regions of iii•
`t~r c:~1 Llµ-Ou_gl'i use of· q "Joy-s11ck" ah311-ge(cid:173)
`-rntJH, Aftcriatuji~1g-on r.egltJni or interC:s;', a
`cornp.u1c.fprl1,10ut of th·c..cou.rn$:pcE>Cnt In 1bc
`,cg,ori, as• rcfrc1,q11 of discrcle lime periods,
`tn n be' ◊bralue-d. ·
`ThC. pti11:t l!..l _i;fat ~ W~J COnvcr:11:-ri to a.
`~counu f mihul~ bl'i5is ~1\11 pJnttcd _on.s.emiiog•
`-ar i, hmic.pape, , S iOirc '!r:2irr.ii e.of an m~-1i!lcd
`:-:solu1ion <x...,.tufs d uri'flg itit fi~ fevr' mmu1«
`ros11n, 1illa1ioQ, only 1f,._ri~~t f<II( 11ri nu101 or
`~ach run v.'a:s' cmpl~y~ti toC)bJalri tht 4r:a!na.gc
`rat~ c.ons~ nt.
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`All. 1mimah ~'l?r..c ut cd only· on€.c. in cJrt:h
`s_tuay ~.nd l>uiJ,.eycs or coch·a'~i,;;111 Wtrc·c'm-
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`l Modd t:li'C~••n .... ~."-~lie~, l1K,, ffi°l l.!bm gh. Pk.
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`II l'.QP 1140 n~~d Gimm& 11 P,tir-u.'m, .Plt-tU.f
`F(1utpn1cn1 t;ti,p,. Ma,y11.u,d, Mass.. ·
`
`·ploy.ed,'Tb_e:rc w:u ~sicntiq,Uy no t ifrr)'ove.r o!
`!he pr~•fo.o•I~ ~~sed. er.~ In tbe fina l ·d,~
`p, in1ou1 ~iJlCC 1·ltc :plrihttk <◊llim.aJor cffcc(cid:173)
`,th/e·ly i cr.t~.ris o.ul :ill~ut U1C immcd-b 1-e"area·
`II is focu,c,I Qn.
`Jn t he cvC1)1 1ba_1 a;, frrii.m;,J J-;$1,d par1fal or
`oo,qplcte ~IIJ!'.k~_g:q o.f lh~ ~r.iin~g~ a ppara1U!;
`whk h ~;~uld.:1:>_e Qbv1Qw. from 1ho fo·IJ off io
`ra dida( t[vh\l, 1hr:-~hlmal was clirni na led from
`1hc~Stutly .
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`\';irying co,h;c nrrali.Oc.i .t1( s6d(uT1, chl.Oildt
`wore:c•xrunincd for thClt racrfma.iioq ro1e n1i.a:I
`In thc:rabbli er<- ·Figure-I di, pJaj,~· tlic, results
`o( tbii·SJuJy. As:c:~:Pct t cd, an in,;rt;:(~~ m ~
`huJpo l-Qniclty bcyonri the. is'otoniC v3!u~ of
`Q.9% kacf$. to .a conslderii ble incte;)S-9 l11 fa(cid:173)
`i rimafion. For :sah so!mto·ns. less 1lmn iiotOnfc:
`.~.e., ·hyf1'Ho~l:C'· ~ot·ution-s,, no ,t~.tf~dtaU_.;,' rig:
`nf.ftt')nt C-ll1tng~s. in .t h~ tacd 1)1a.don rate· c()n,
`t •~TI·t ~ou1a· ~ r.ored, IJudoubiedl)', Lin; hr,(cid:173)
`pcuonic- .s.ol11tiOn docs· !11tluc.e ~.omc di:gr« of
`b ctiinl1, ion but the mo·n1tor"ing,. H:stert1 cm-·
`pteye~d in' lh~-1mCt~$Cl~ttg.raphy w.tts·-appar-(cid:173)
`cm-lrnc}t ·~ l!itiVe.cnoug,h t~ pt~k up vcry.s.-mall
`chhflg~ in 1:,a.in1a·1fon, ~vt}Tch Would be ovi ..
`deul by.au in~rc;1s.c in Otc, draITl~g,t: r.at~CO.n•
`stant. f:urthef reJTllcrh_cB.U·iri 1t1e.cX'JY.!r.imcn:caJ
`ti?~hniqLre- l'n:iy k~d.t" wTficfom ~truiHvity t9
`mca'SUFC thCsC·srn;,11 diffcrc11( e~
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`~./lri-r bf S9!J11itm•p ll 011,LJlb.lmC1foi,
`Soluliorl$ C/fpll 1-:0,-4a(). 7.0aM 9.0wcre
`Pr0--p_a(e~~. u~ tJc>9Jbcd CM,ife:r. a.nd ~•x.:irnined
`-for th:iirl:rcrlmatiQn potential 1.binJ! the saine
`tracer m_cf-h8d :ul~ rnicK""Sdn.1l~ra-phy ~.ppa •
`falu-s'uited Jii i·~e tonlcit) Jlrnlfon of th~ ~,·ork.
`The rc<ul<s or tlid t ~dyMc 4l<J\l• t ed.in Fli;urc
`2. As 1s.t Yldcm froni this h_giir.( I~ more add
`Qr;il kallnc 111<: ius1illcd ~'<)lu.Jf1;ln ihc.Efl;:l t~r fht
`la,r1matiori. P.erhap* n-ol $urpr~'i"O~J_r 111c- eye
`is -n1rJrc tQlcran1 of ~eidk th:i:n nlknlinc..1-0)1,1.
`1fo·ni ;i~ i!Vidt oce.d bv the ~uli~t a mia l l,icr~tis't
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`1n l:,H.'Tim:11jon raie c1111M~n1 w~cn CQ111p!srin8-(cid:173)
`PH 7 l<l pl I 9,0 nnd ehcJcs,ror 01111~!'" th:u <)J!(cid:173)
`l\ilr5 whcn;SQfng (rom ~H 7,0 to pH 4.0. T ~il
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`data is, ·prt..>~r:le
`·ordct err ~Cl o f
`j!i-\iinB,Jhi:: t rC-.41i
`s.e;)111 iOn; or' fo.u,
`the ·lo"~M. As r(cid:173)
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`Slayback Exhibit 1056, Page 4 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
`

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`'iiJ,c, ojs,,/ur/o,r T~nlriiy (Jn Ql_\',·cr./n
`11roa1,•(lf/.:Jb1li1y
`11·1e lnnucncc- or tudiCJty f)n 1hc Gio:iyiil~
`~bilit)' or gly«fin ·w•} ~uifi;ifby m9nliorin&
`1:hc drug,. l~vflt fn fhC funu;,a an·d nque·o.u$
`hum()r a~~ fatu;ti!)Titlf•fimc r(>r i quc0us·~p(cid:173)
`h,i11~ns Of vnyifl~ t(>11i~i1)•, eoriic.1l_"~rug fovd
`dat• i, ()l_e<ecnted In rig11r~·3, f'J(llc I he ro o~
`ocder e[fcct or tonit ity With dii,tillcd wutcr
`~ivlng.l he-~'rca1<>t)>ilID;ailabiliir omt th< l.(,-i.
`'M:l\1;J!iDri. or·,f(Jun imt.., lsolel'lie Solution, &\virit♦
`tlre lowest. A.s mcntiOac'd ·tarliCr 1 he dk illlc-d
`w·al~r valucrtally t orti?Sponds td a'0.45\\l'snll
`~olut\on Cir onc-: halr i·so.tonic ~Jnce a L3%
`glyc-trin solution contrih't1t~.th:u mu-:h- of a
`S'!h ci.1ui\'":.l1cnl.
`iheelirln•oak,dcuj! llme> m 1hc ""'""" _is
`·(l.)11,sl~rcol wTih'cor.J\t:tf drug d!5po.s1rn,n:s.1odfcs
`fa, Qther drus~such ·~~-pffoc~r.plnc arul rTun(cid:173)
`romctl,olonc ( IR,,20). Tht dcd, nc in,c.,rneol
`drug c·onC<'ntration occ;:uT.,·_du~ h'i dn.~g_·-p_cnc:
`lrJtiug 1(> t he .i_tjlJC:o uS hu-rTIQ'r,
`Siblttllicnl tm~lp,ii; or 1h~· .~iffotcn·cc~ b'!=·
`twt.cn 1h+C: [our i n1ut1Ml~ iA·a! rh'll a.ttc:mp1eO bui
`-illip(\L--rl't- (n'tm ,•t<u:.11 irup.:.c-11~,tll h~i the il~(cid:173)
`tilled_ w;_:11ct :-ululinn b, g,e:Jtcr·'a t p\osl time
`:point .. fro m 1hC .rmn11inin~ :<olu)fons .ind tti::il
`
`Figu'r1 , --Laain,1,I f!,ai.lJ,:1sr ;;,,, 1;,1!.i1onl P> O·
`/unnlut1 ol irutlllfd .col11.1tw+ JIil. A mjnimum q/ 10
`f->'t-1 '1\1ne,,.,n;d /tJr ,a.ck Jnl uilM pl(.
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`d1ffer~ncc~ bclw~en tht;-:rcm;rl11Htg. $ofptiiiri!
`.alsQ eilSl,
`Aqu~ous hurovr Mut ley~! "~""' lime
`Jtri}fih:.1., ni'CA~ryicwh·a1 ml)~~ dis:~rimim11ing In
`distlnp,.ishill/l 11"' tout te>t snlu1_;ons. The5c
`d;u:, :1 r~p,.e:.,i:.ntc::l_fifl fi.2,Ui t 4. Thesa:me nm"
`(\f ~; r 6:is.t~ iO tl1e~q__u_e~uShurnc.\f a:mt·as"cx•.
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`' 11
`
`Slayback Exhibit 1056, Page 5 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
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`E.:1Apllt111 ,,,,,~ultl.s a--.ntinirmi_m-Ofl·S e.p[S1
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`e:har,:ict~rJstics of glycerin in lhc .ttqu.eou~
`humor; c:g .. p<:al< (frug:J~v~l at _20 :ro minutes,
`~ppa.rcnt (>1i"t _c(l111pnttmcn\ dlsroiilion,-et~,.
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`llic.fnOucni:l; or p~fM'glyccriri \,ioovail,
`-a'biii!J W:t!i ~amir\¢ by moril1C1~1l!s tl1e cornc~
`,;n.G1tqucb1,.1i{ lmmor dfug levels, Cs:a tunctiot1
`or 6mc, ftlr-s~lutlons oFvar·j·int p1 I. Fi~,ute:5
`di!.j'tlay'S the cUrneal d'rug. re·~eli•as·a fu.~cl ion
`• of rime for <il<h hi ,he pH 1•olucs ,11,dic<l. Not~(cid:173)
`that lb~ bp1>:1ten1 bi<1a.vanabilil)' of ~Jycerin
`fro,11-pH I.0 is.1imil•ttn pH 7,0and: th'a.t 9f
`lhc;,11 4,0·soluuon ls·s.frnil«r.10 •h~ pl-l-9-.Ci"
`~J'obtio·n.
`:A ll or lhe.gly~crin s;tmtic.s.,":c~c c;onducted
`for only 69 minut~ b(-,c:n,~¢ T'fcH,;,in;,,ry r:~.
`~rmcnls b ·:!d \:~frificd-1·h·a.t .t l\·t1;-1in d irniria •
`tiar1 fo1t~w5 ·apj)arcnt .Urst-~·r·d·ar kln~,r~.(cid:173)
`Thfoe µniplcs ol I imci k» I h.i11 S 111fnut!iJ
`"·aC ho1 nl>.Ut.ifi,td.d\Jt"J.Q ,:he timt cOOStrflinl.S
`of d~sing ~nJ , u,g~(i.
`Aq_o:cO~,.· .hunior c:lru-& d o t_,;, yield 1!imilai'
`r€!Wts a's shown jn Figure 6. There i1, .£,-;1.t-n•
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`~•ith pr-~
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`liall.)'. lh< $Orne-rank order afiho pH tolu1iq111
`cxa·in•".lf{I Howt.vc.t. u.nlil;~ \he. ( Qrue.a lhctf
`lfa ·d,stln~I r•n~ or<lctr.;,nllc rH ~.o. 7.0, .and
`9.0 ,ohnl9111: Tl><; pfi 1.0 :.olutlon o,'Cflap:.; the
`i,H i.o·..,11,fion ~ I somo of the ti,;.,c l)Olnts: An
`upfa~a'ii~II or.the <iala "'ill l11e prllS<nlcd in tho
`tUscussion se·~tior1.
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`Corr,laiib,r a/ To,!lcily lndu(ed
`1:oc..•ri.J-m:H{on.mul G1yctrln Biom:n-Jl.abllit>:
`-Oni:.·can wmpar_c ,gly,::~rln bioavo.ifa~ility
`for ,·a-ripus· lor-khY~~!utfoflj by.,11~dm~fog:
`the. dra.inagt ta.{t? c.cmst<tn\ i:fata wiih~ 1bc
`glyterTTl bio.~.Yailabm.ty ,lat a. as~ rS- shown rn
`Flgur.c 7. l'Ql_ tho glyc.ccin bfoo.1-;i\lnbilil y ifot:L
`the• 20-rniuutc drug lc,·cl .point was u~C'(I .Sfn\X.
`giyccrTn (li,ro!liiloo fi9~ thc~e_ ~~utfoi:is ~s.
`idcnlit;il anftlu.drug ~•*l. dcicrmlncd LO be
`p~~,icly_.~~~;1:?.(ti. 11 j\·:rp.prriprlll_lf! to tJ:<~ l~~~
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`n:13ttd.10. the. in, ,cc~!,;ed l:lC',-un:uion produccc,l
`
`134
`
`Slayback Exhibit 1056, Page 6 of 13
`Slayback v. Eye Therapies - IPR2022-00142
`
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`a) c1nr CUI, racek-ul,:u1y~inl"C' lher,: 1-. no a_p.
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`trairu1,: c cxpe,imr11t.a l tech niq ue i, surncie111ly
`ins~11sith·c to ,liow th e coo1irt11ed decrc,1scin
`!i1ctinu.\JOn :&I Joy, s.:,h le,-dt. An all cr nale.
`,,.pbn>,ion ls 1ha1 t!)'Ccriri ITTU\'crncrtl imo 1bc
`,OIPCb iJ< foci lhal<O by sol vent nux in to tl,c
`C(!mea r,otn i hyl'()lonle.s()lutiop. /\ hJ 1»1ooic
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`on 1m:rc.uc in wate.rpc:netrtttlon into lhc cor•
`ou . v r « n ,,,d Green (49) h,v c •hown th&•
`th t rc Occ1fon C<>trrfcitn\ for tlie:-corncal cpl ..
`thcUurn h I ~ than O"fte sn th-?t nonckcW~1es
`hkc gl>·':Crin couJd p('ncu.1.1c 1hc cphh.dium
`frwi sal vcn1 dr~g .
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`soluti1 l (L \ thc.dl.\ta In n ~ . 7 Joe. iHw:S\f.tlt~ th ;d
`• ~ , c a ! i n i ; ~ h COf>CCOlt3lion q d t l<>intt=«!
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