34550-718.305
`
`PATENT
`
`IN THE UNi'.i‘ED S'i”A'i‘ES PATEN_'1:,AND TRAl)EMAiR;K QFFZQE
`
`in re Application
`
`Inventor: Gregory I‘. Went, et al.
`
`Application No.1
`
`Filed:
`
`June 25, 203.2
`
`Title: Method for Administerizig an NMDA
`Receptor Antagonist to a Subject
`
`) Coiifiimation No;
`.3
`:3 Ari Unit: 1627
`)
`) Examiner: Kencira D. Carter
`3
`
`) Attorney Docket No. 345S0~7i 8.305
`3
`}
`}
`
`Declaration Under . 7 Cf.F.R.
`
`1.132
`
`‘f, Gregory ‘ll Weni, Pi1.D,, declare as foiiows:
`
`i.
`
`i’. am an imrentor ofthe pateni application identifieci above {“Applicaiion"}, and
`
`the subieci. matter described and claimed tlierein.
`
`2.
`
`I am Co-fomider, and am currently the Chief Executive Officer, of Adamas
`
`Phainiaceuticals, inc., the assignee ofihe Application.
`
`3.
`
`My curriculum vitae is attached as Appendix Av
`
`Memantine Property Background ~ Half Lifeand Side Effects
`
`4.
`
`Extended—release producis are usually ciesigned to prolong the absoifption of drugs
`
`with short liaifilives, thereby ailowing longer dosing intervals, wl1iie:mi.nimizing fluctuations in
`
`serum drug ievels. (Remixigtorfsz The Science and Piactlce of i3ha1'maey, 2i“ Eat, pp. 94445
`
`(2006)).
`
`Memantizie is a long haif—iife drug {about 60 hours), which is nearly completely
`
`bioavailable when given in immediate release form (Naziienda package insert {Z011}; and at the
`
`time the invention was made, was approved for dosing twice daily, This means that once
`
`immediate release memantine is given, its blood plasma eonceniratior: rises over a period of
`
`about 0-7 hours and then starts to siowly deceease. The blood piasma ooncemration has
`
`generally not decreased significantly be;E’o1'eil1enexi:<lose of memantine is given after l2 hours.
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`A person having ordinary skill in the art at the time of filing of the Appiicatior. wouid
`
`have iaoked motivation to prepare an extended reiease form of meniantine to extend its <;ioration
`
`of activity, as duration of activity is not reaiiy an issue with memsntine. Nor wouici that person
`
`have been motivated to tieveiop and administer memantine formuiations with a specific ioitiai
`
`rate of increase in concentration, with an expectation of success in significantiy reducing
`
`memantine"s CNS side effects to the point where it could be administered once per day, alone or
`
`with cionepezii.
`
`6}
`
`Extendeci~rei.ease formuiations may aiso be useful to reduce the peak piasma
`
`concentrations of drugs for which high peak plasma concentrations are associated with
`
`significant adverse effects in certain situations.
`
`i3~Iowever, the most significant side effects of
`
`immediate release mcmantine are aetuaiiy observed eariy in inetnantine dosing (Ambrozi,
`
`P.i1armaoopsyciiiat., 21(3): 144-146 (1938); Ditzier, Drug Res, 4101), Nr. 8: 7‘73.«780 (1991)),
`
`when plasma concentrations are a fraction of steady state peak plasma concentration. Thus, the
`
`person of orciinary skiii in the art wouid not have been motivated to prepare an extended reiease
`
`form of memantine to iower its peak plasma concentrations, as the most serious side effects of
`
`memantine appear before memantine has achieved high plasma concer1tratior.s,
`
`7“
`
`Immediate zrelease mematttine is not well toierated at doses higher than the iabeieci
`
`dose (i.e. above 20 mg/day) (Maier et. ai., i?ai.t1 103: 277-283 (2003); Swerdiow,
`
`Neuropsychopiiarm. 34118544364 (2009)). While reducing Cmax sometimes may be considered
`
`a I'€:8SOI1ai)i€
`
`basis for deveioping extended release formuiations of short haif-life drags, given
`
`the already relativeiy low iiuctuation of plasma memantiae eonceiitratiori observed with
`
`immediate reiease memantine at steady state {owing to the signiiicant accumulation of the drug
`
`at steady state due to its ioog haif iife), extendiiig the release of memantine would not have been
`
`expected to significantly reduce the Cmax at steady state. Thus, a person of ()1‘{iii1a1'ySi<iii in the
`
`art would not have expected that extending the reiease of memantine would improve its
`
`toierabiiity at doses higher than the iabei doses (21 e., greater than '20 mg per day.) A person
`
`having ordinary skill in the art at the time of the fiiing of the Application wouid therefore have
`
`lacked motivation to formoiate an extended release formulation of memantine, dosed once daily,
`
`at strengths greater than 20 mg/day (more speeificaiiy from 225 mg to 30 mg.) Without such
`motivation, the person of ordinary skiii in the art wouid not have found it obvious to formuiate a
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`onceoa-day extended release fermuiation of 22.5 mg to 30 mg of memantine,
`
`Exgerixnents Conducted
`
`§IR§, agd Mcmantine Extended Release gER'} Forms ALB and C
`
`8.
`A Cohen‘ c,’:‘64 subjects was randomized to one of four treatment arms of 16
`subjects each ~~ IR, A, B and C. Treatment arm IR received a single dose of20 mg of a
`cmnnxerciaily zwailable immediate release memantine (Naxnexxdag) Treatxnent arm A received
`
`22.5 mg of a first extended release memantine fennulation. Treatment amms B and C received
`
`22.5 mg of memantine in seccvnd and third
`
`formulations of memantxine, 1‘espective1y, Biood
`
`was drawn at T=0 and at 1, 2, 3, 4, 5, 6, '7, 8, 30, 12, 14, 16, 18, 20, 22, 24-, 36, 48,, 96, 144, and
`
`192 hours after oral adnministration of memantine foreacht1'eatment2u‘m, for the determination
`
`of memantine blood; plasma ‘ievei 21% each time point. Results of this study are depicted
`
`graphically in Figures 1a and lb, below. (Figure la depicts the Rue representing 50% IR dC/(ET
`
`over 0—Tmax; Figure 1b depicts the fine rep1‘ese11t§ng a dC/5'1‘ of 50% of memantine IR over 0-6
`
`hours.)
`
`Figure la. Results from ADS~])EM~C106 Plasma Memantine Concentratioxl Profile per
`
`Mg of Memantine {with the line for dC.’dT of 50% of memantine IR running from 0 t0
`
`Tmax)
`
`-+-5R (20 mg) «~45-A (22.5 mg)
`
`-~A-H (22.5 mg) ~+<-C(22.5 mg) w-~ dc/<IT cf 50% ofm
`
`; 3
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`Figure 1b. Results from ADS-DEM~C1()6 Plasma Mcmantine Concentration Pmfile per
`
`Mg of Memantine (with the line for dCfdT 01750“/8 of n1enm11tineIR running from 0-6
`
`hours)
`
`-6--ER-A, X mg£n=l§)
`~b3*ER‘C. .1 mginr-36}
`
`-6-ER-B, 3mg(rI=16§
`--up-!fl,in1g(n=1t3)
`
`_..fi.~._........_...........».-.,..M.~...._......_t.,,.._
`-
`....W
`
`_ _._
`
`E gag
`5,; M
`.5
`g 12 ;~—«~—«-—~»~—«~
`§
`:*.4~-~- _ -
`c:
`8 as ~§~ ~
`3
`‘
`U as
`
`—---—~
`
`
`
`7'3
`3 0.4 «~«— — —
`
`E 0.2
`E
`O
`
`’
`
`,.
`
`0
`
`7
`
`I.
`4
`Time (h)
`
`-------------~
`_
`»»»»»»».~
`*“’"°/V”
`
`.“?-54-?§?’”“°"“
`taro-shouts
`,4:
`53
`
`~~~~~-~-~~«
`"7"
`"'7
`8
`
`5
`
`9. Resuits of ADS—DEM~C1G6: As can be seen in Figures ‘la and lb, above:
`
`The IR memantine formulation achieved maximum blood plasma concemratitm in about
`
`7 hours, in agreement with the litetattu-e (Namenda Package insert) c0m'esponc1in.g ta 2:
`
`rate of change of mem2mt‘i11e blood plasma c0t1ce11tration (L6,, (EC/<3?) ef about 4
`
`nglmt/ht‘;
`
`ER. memantine for:m.ulation A achieved 80% of the IR dCfdT over 0-Timex; si.mi1a:*}y,
`
`fonnuiatien A achieved a dC/dT as measured between the peried of (}—6 hours ef the ER
`
`fe1‘t11uiat‘i.c-.n of about 73% efthe IR formuiamm (adjusted pmpettionally for strength);
`
`ER memamine formulation B achieved 40% ofthe IR dC/d.T over 0»Tmax; sitnitarly,
`
`formulation B achieved a dC/(IT as measured between the peried of 0-6 of the IR
`
`f{)1'mU§8fi0i} of about 34% ofthe 1R_{’0r1n'u1atio.11 (adjusted p1'op02't§ona1ly for strength.);
`
`BR,meman.t'1ue femutlation C achieved 30% 0fthe1R <iCfd’£‘ over 051‘max ; sintitariy,
`
`t°ormuiati0n C achieved a dC/dT as measured between the period of {}~6 hours ofthe IR
`
`formulation of about 27% of the IR f‘<3e1‘:11U-iation (adjusted ptioportionatly for strength) .
`
`Thus, whether measured over 0-6 hours or 0-Tmax, two ef the tested ER fomm1atic«ns{B and C)
`
`fall within the initial dC/dT1:equit'eme.11t specified in the appiication and the subject of the
`
`pending ctaims, whereas the ER and fortnulation A ER memantine formulations do not.
`
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`34550-7.3.8.395
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`20.
`
`In addie£io.n to the reiative dC/dT, the absolute rate of increase in memantine for
`
`fomudations B and C (faiiing within theins£ani'e§.ai111) were calculated from the mean plasma
`
`coxxcenncatioils from 2 to 4 hours. The values are reported in Table 1 beiow and are shown
`
`graphically in Figure 2. ForERme111antine f01‘mulatio_n. B, the c011eent1'ati011 increased steadii.y,
`
`after an initial lag 0152 hours, over 8 hours post dosing. The absolute rate of Emilia! increase in
`
`concentration within the first 4 hears of the profiie from 2 hours to about 4 hours post dust: is
`
`about £9 mg/tnL/hour. For BR meman‘tine for1n113ati011 C, the corxcentration increased steadily,
`
`after an iniiiai lag of 2 hours, over 8 hours posi dosing. The absolute rate of initial incxease in
`
`concentration within the first 4 hours ofthe pmfiie from hour 2 to about 4 hows post dose is
`
`about 1.2 ng/mL/hour. Thus, the ER profiles with an absoiute rate of increase in initial
`
`conlcentratiozx less than 2.1 mg,/mi./hr are wei1—tol;e1*ated.
`
`Figure 2. Results from ADS~DEM~C1fl6 Plasma Memantine Concexttmtiun Profile
`
`-«av-ERv822.S mg (m=1>S) ~a»ES’.~C 22.5 mg {M16}
`
`Memanfine-Concentrat§on(ngfmL}
`
`
` :1 ~42 hour
`. ._
`
`
`
`
`11.
`
`Reciuction in CNS Side Effects: The subjects in the study were evaluated for side
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`3455(}—718.30S
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`effects, especialiy these. side effects reiated to the centred nervous system (CNS), assocmied with
`
`memantine administration. The outcomes of these evaluations are summarized in Tabies 222 and
`
`21), below.
`
`Table 23: Number of Subjects with CNS Side Effects, Listed by Side Effect
`
`é
`
`
`
`______W
`
`
`
`
`
`
`
`Treatnzcizt B
`
`
`
`Headache *
`
`D§2.ziness*
`
`
`
`
`
`
`____._.«
`
`
`
`W.
`
`V‘
`
`F.--
`Fa(igue*
`§Somno1cn.cc*
`=—— ~-—~~——~
`
`Cognitive dis0rder*
`
`H30 in attention’?
`2!
` 0 %)
`Aggrc5s;itm*
`‘i
`»m6%
`{::[
`
`3 (
`,_....____
`
`3
`cum)
`owes)
`II
`..s.
`s——__
`
`O
`R
`
`
`
`
`
`Cou1‘usion*
`
`
`
`1
`
`Paraesthesia
`
`
`
`
`*Known CNS side effects oftnexnaminc
`
`Table 2}): Study Results ~ CNS Side Effects, dCfdT, Cmax/Cmean
`
`
`
`T1'eamusntIR
`(31:15)
`_
`‘
`5{3.§"/a)
`
`
`
`‘
`
`I
`2...
` “*‘1
`N
`3-99%
`ix
`5
`(190%)
`g-———-—~—~
`§
`1,11
`
`3
`
`Trentmentfi
`(:1=16)
`
`l
`%
`_._._
`
`2(13°/o)
`
`.
`34°/3
`(40%
`1.94
`
`}
`
`"‘
`
`27%
`
`(30%)
`.- -~——~—
`-2:03
`
`3
`
`
`TreainneutB
`
`(317-=16)
`
`
`F__......._......._______...x
`'
`I
`(i{f}%)
`=
`
`Ts-eai:uentA
`(n=I6)
`
`
`
`4(25%)
`
`
`i
`I ‘Number cfsubjects with at least one kumvn CNS
`E
`siée effect of Mem:miim=. other than headache
`“"1
`! ’‘‘'‘'‘
`”""""'”"“"""“"“““‘*""""
`73%
`‘
`dC/dT relative to same quantity M311 memamtine
`
`
`(30%)
`5
`over the period 0-6 hams (0-Tmax)
`
`
` % —* L—————__——.——§
`3 Cm‘ax/Cmcan over the time period offl to 3 hour::l¥ ~
`
`
`
`
`
`
`‘ In accordance with convcmimml znethodelogy, in the snnmsaliuu oflhe uumbcx‘ ofsxxbjccis mponing side eiTe<-ts‘ each individual subjccx is counted on}; cncc,
`no maitct how many side effects they xeported. Accordingly, Hm number ofshie effects in the table may not be aqua} to the number of subjects reporting sid-: effects.
`Ln this declaration, headache has been excluded from the sxznznxaiion bemuse since it is a common adversa event ohserwd in phascl smdiss and the reasons for it can
`be many, inciuding resxriclioxx of‘c.'si}‘cinc inmku-, confinnnem, lack ofsfcep DI‘ distuxbed sleep duc to many bleed samples during the night.
`
`60?"?
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`12,
`
`Evaluation 0t‘Memantine~Re}ated CNS Side Effects. The treatment emergent
`
`incidence of memantine related CNS side effects were analyzed and are st1mn1arizedinTab1e ib.
`
`Headache was excluded from the analysis summarized in Table 1b, since it is a con1mcne<iverse
`
`event observed in phase I studies and the reasons for it can be many, ineludingrestrictio11 of
`
`catteine intake, confinement, tack cf sleep or disturbed sleep due to many btood sempies during
`
`the night.
`
`13.
`
`S'u1'p1:isingiy, as can be seen in Tabie lb, fewer subjects receiving Treatments 3
`
`and C had incidences ct’memantine~t‘elated CNS side effects than these administered Treatment
`
`A or IR. As can be seen in Table 1b, five of 16 (31%) of patients in the fii'R1ne2nax1tine arm, and
`
`4 of 16 (25%) of subjects who w'e1‘ead1niniste1‘ed formulation A had at least one known CNS
`
`side effect of memantine other than headache.
`
`in contrast, zero ef 16 (0%) subjects administered
`
`fo1*muiationB and two of 16 (13%) of subjects administered ferinuiation C respectively,
`
`experienced any memantine-related side effect other than headache. Thus, there is a cieariy
`
`d.iscer.r1ibie, significant and unexpected trend toward decrease in mema11tine~reiateci side effects
`
`in the ERmen1antine study arms in which the patients were administered ER memantine having
`
`dC/dT Values less than 50% of the memantine dC/dT 0f1R_ memantine {p=fl.0433 2~sitted
`
`Fisher’s exact test).
`
`ME-i igggmfiteady State ggmgnistaration of 20 tnggiggggggggtigejggygegjgtegeieasg(10 mg IR
`
`memantine administeltxi twice a dew) anti;/35 mg extended release 1ne111an,ti§ie fo.r.rt;u.iation B
`
`§§fl1ii1i§L<31:Qd_<>£Q§,flE3_i§i..CQ33l
`
`14.
`
`ME} it} was 2. two period, two treatment crossover study without a washout
`
`between treatments in 24 healthy subjects. In period 1, haif the subjects were randomized to
`
`receive 10 mg twic.e—e~day IR treatment and the other bait‘ was ranck.-niized to receive the 25 mg
`
`0nce—dai1y ER t1'ealn1entfi)r 14 days. (Since IR m.emantine is typicaliy dt3se~tit1*ated over 4 weeks
`
`using a three-step regiment, a one week run-in period of 5 mg twice~a~day IR preceded the IR
`
`treatment; and a one week run in period with piacebo preceded the ER treatment.) In period 2,
`
`which began immediately after end of dosing in period i without a washout, the subjects were
`
`crossed over to receive the aiteinate treatment fer 14 days. Blood samples to measure
`
`inemantine concentration were taken on the 14”‘ day 0ft:‘eatment in both periods at pr-edcse and
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`1, 2, 4, 6, 7, 8, 10, 12, 13, 34, 16, 18, 19, 20, 22, 24 houre post dose on the 34”’ day‘ The
`
`immediate release (IR) formulation was the cen1n1e1'eia13y avaitable immediate reiease
`
`memantine marketed under the trade name Name:nda® dosed at the maximum rec0.mmenc1ed dose
`
`of20 mg/day (administered 10 mg twice daily). The extended release memantine was 25 mg of
`
`the previoush/~desc3‘ibed formu.§ati.0n B, which has an absolute rate ef initial increase in
`
`concentration within the first 4 hours of approximately 2.} ng/natfhr, administered once daiiy.
`
`Results ofthe study are suzmnarized in Figure 3, below.
`
`Figure 3. ‘\/Iemantine plasma comsentmtion in a steady state PK study
`
`M5110 Steady State Ptasma Concentration Profiles
`
`
`
`-e~tR{10 mg 830}
`
`“~_tE~ER (25 mg)
`
`
`
`0.00
`
`8am
`
`12pm
`
`4pm
`
`8pm
`
`Ttme {h}
`
`15,
`
`In Figure 3, above, the stead state blood elasma. concentration of mexmmtine for
`
`25 mg/day extended release (ER) memantine is ‘represented by the upper curve (boxes) and the
`
`blood plasma concentration for the 20 mg/day 1R memantine is ‘represented by the lower curve
`
`(diamonds). As can be seen, 25 mg ER mem amine .t.‘o1‘mui-atimt achieved overalt higher biood
`
`plasma concentrations and memantine exposure than 2(} mg,/day IR memantine ~~ with a Cmax
`
`that was 20% higher than the average Cmax of the IR fommlation and an AUCQ4 that was 15%
`
`higher than the average AUC24 ofiR1nemantine.
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` MemantinePiasma"c3£c’§;EE£%'£E.T£{Z£Z£}"£:."Ii""”'”””“
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`3-455l}—'7l8.305
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`36.
`
`Despite having been administered. at a dose higher than the maxlmum
`
`recommended dose of memamine (20 mgfday, see Namenda®Pacl<age insert), surprisilxgly, the
`once a day 25 mg ER formulation. was wellaelerated w.i%hnoinclclel1ce ofmemamine-1‘elaled
`
`CNS side effects (0 out of 24 sub} ecfs). It was pa2'tlcula1'ly sm‘prls.ing to see no incidence of
`
`memantinemrelated CNS side effects with 25 mg memantine, despite having reaclzeel higher
`memanllne plasma ceneetztratien and AIEC than that ofthe maximum recommended dose of IR
`
`memantine, and despite having been administered once dallyrall1erlhan the 1'ecorm.nemled twice
`
`daily for lhe immediate release.
`
`17.
`
`l hereby declare that all statements made herein of my awn knowledge are true
`
`and that all st'aten1ents macle on information and belief are believed 10 be true; and further that
`
`these statements were made with the knowledge that willful false statements and the like so
`
`made are punishable by fine or lmgoriso11n1en.t, or both, under Section 1001 of Title 18 of the
`
`United States Code. and that such willful false statements may jeopardize the validity of the
`
`application or any patent issued thereon.
`>
`
`By: _._
`
`Date: 3?‘ 3’*~‘I§:_l;€t:..j“’l..:'~’-
`
`M Gregory T. Went Pl.1.D.,
`DeolarantfD eponent
`Country of Citizenship: {Jailed Slates ofAmerlca
`Residence: 257 Buene Vista, Mi.ll Valley, CA 949434204
`Post Office Address: Same
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