IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`
`Elliot Ehrich
`
`111083,167
`Application No.
`March 17, 2005
`Filed:
`Confirmation No. 8002
`For:
`Naltrexone Long Acting Formulations and Methods for Use
`
`Group No. 1617
`Examiner: Kendra D. Carter
`
`DECLARATION UNDER 37 CFR 1.132
`
`Dear Sir:
`
`I, Elliot Ehrich, am the inventor of the subject matter of the above-identified application.
`I am also employed by Alkermes, Inc, the assignee ofthe above-identified application.
`My curriculum vitae is attached hereto as Exhibit D.
`
`Background
`The present invention is directed to the unexpected discovery that a single injection of a
`naltrexone-containing long-acting formulation provides systemic exposure to naltrexone
`(AUC) which is at least 2 fold higher over a 28 day period than the AUC of an oral
`regimen of 50 mg per day over a 28 day period. The invention which is described in the
`above identified application resulted from a discovery made during clinical trial testing of
`Alkennes' MEDISORB® (injectable) Naltrexone (tradename VIVITREX®). Due to the
`size of the lengthy full Clinical Study Report only relevant portions of the Clinical Study
`Report# ALK21-005 (the "Report") finalized November 9, 2004 is attached hereto as
`Exhibits A and B. I will be referring to this Report throughout my declaration.
`
`Prior to obtaining the data discussed in the Report, it was believed that the doses of
`MEDISORB® Naltrexone suspension selected for the studies described in the Report (i.e.
`190 mg and 380 mg) would result in total systemic exposure (AUC) which was similar to
`the AUC of ari oral regimen of 50 mg per day naltrexone over a 28-day period. However,
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`Application No.: 11/083,167
`Declaration by Elliot Ehrich
`Page 2 of6
`
`as the data summarized in Table 8 of Exhibit A shows, the 380 mg dose has an AUC that
`is at least 3.3 times greater than the AUC of the per day dose of oral regimen of 50 mg
`per day naltrexone.
`
`Data Analysis
`Referring now to Table 8 of the Report shown in Exhibit A, note that the AUCo-t (AUC0_
`2sdays) for a single dose ofMEDISORB® Naltrexone 380 mg on a per day basis can be
`calculated for Cohort A by dividing the AU Co-t for Cohort A 120.6 by 28 days and for
`Cohort B, 137.8, by 28 days. For Cohort A, the per day 380 mg MEDISORB®
`Naltrexone AUCo-t is 4.307 which is about 3.3 times greater than the per day AUCo-t of
`oral Naltrexone 50 mg which is 1.278. For Cohort B, the per day 380 mg MEDISORB®
`Naltrexone AUCo-t is 4.921 which is about 3.3 times greater than the per day AUCo-t of
`oral Naltrexone 50 mg whichis 1.468. This result was unexpected.
`
`Based on the dose proportionality observed between 190 and 380 mg following a single
`dose, AUCo-2sdays for the 190 mg dose may reasonably be predicted to be approximately
`2-fold higher than AUC following oral dosing of 50 mg per day for 28 days. This is also
`evident from Cohort A data showing about a 2-fold higher AUC for MEDISORB®
`Naltrexone 190 mg. This result was also unexpected.
`
`Cited Reference US Pat No 6,306,425 ("Tice")
`I have read the rejections from the Examiner and I have reviewed Tice cited by the
`Examiner. The Examiner claims that the data found in the table in column 14 ofTice
`indicates that the F-1' naltrexone-containing injectable formula described also exhibits an
`AUC which is 3.3 times higher over a period of 32 days as compared to the oral dosing
`of 50 mg per day of naltrexone for 32 days. This is incorrect.
`
`Tice discloses an injectable formulation containing up to 350 mg of naltrexone.
`However, Tice does not disclose that the serum AUC of naltrexone is at least about 2 or
`3.3 times greater than that achieved by the equivalent 50 mg/day oral administration over
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`

`Application No.: 11/083,167
`Declaration by Elliot Ehrich
`Page 3 of6
`
`the same period of time. Given that the oral naltrexone is delivered in a daily dose, it is
`necessary to either extrapolate (or actually measure) the AU C derived from the daily oral
`dose over the time period in which the AUC of the injectable extended dose is ineasured,
`or it is necessary to divide the AUC ofthe injectable extended dose over the ,number of
`days that AUC measurements of the injected extended dose are taken in order to arrive at
`the daily AUC of the extended dose and thereafter compare that measurement to the daily
`AUC of the daily oral dose. Therefore what is actually disclosed Tice is that the
`extrapolated 32 day AUC after a single dose of a 50 mg tablet of oral naltrexone (column
`15, lines 62-65, 1600 mg naltrexone total dose) is similar to the AUCo-32 day after
`injection of the F-1' naltrexone formulation tested in Tice.
`
`The table in column 15 summarizes the data table in column 14 ofTice which compares
`the dose delivered in one day (with 50 mg) as compared to the delivery over 32 days.
`The mean dose is calculated by multiplying the mean daily dose over 32 days (to
`calculate the dose/day) is 27.8*32=889.6. The F-1' mean over32 days achieved a
`1051.6, which is less than twice the AUC. Looking at the data differently, the AUC over
`32 days is 1051.6. The dose per day is 32.8 (1051.6/32 = 32.8), which is not twice 27.8,
`the per day dose for the 50 mg oral.
`
`Comparison between Tice and the Present Application
`Referring now to the graphs of Exhibit C, AUC data for Tice are taken from the text and
`table in column 14. According to the table, a single oral dose of 50 mg naltrexone was
`administered, and a mean AUCo-24h value of27.8 ug h/L was obtained. This value is
`presented in the graph ofExhibit Cas the average daily AUC level for each of32 days. A
`second set of data indicates that a single 300 mg injection of naltrexone resulted in a
`mean AUC0_32d value of 1051.6 ug h!L. This value was divided by 32 days, and then
`graphed in Exhibit C as the average daily AUC value of 32.9 ug h!L.
`
`AUC data for MEDISORB® Naltrexone are taken from the text and table on page 6 of
`their clinical study report ALK21-005 (Exhibit B). According to the table on page 6 of
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`

`Application No.: 111083,167
`Declaration by Elliot Ehrich
`Page 4 of6
`
`the Report, a single oral dose of 50 mg naltrexone was administered, and a mean AUCo-oo
`value of30.5 ug h/L (1.270 ng days/mL) was obtained. This value is presented in the
`graph ofExhibit Cas the average daily AUC level for each of32 days. A second set of
`data indicates that a single 190 mg injection ofnaltrexone resulted in a mean AUCo-oo
`value of 1722 ug h/L (71.75 ng days/mL). This value was divided by 32 days, and then
`graphed in Exhibit C as the average daily AUC value of 53.8 ug h!L. A third set of data
`indicates that a single 380 mg injection ofnaltrexone resulted in a mean AUCo-oo value of
`3444 ug h/L (143.5 ng days/mL). This value was divided by 32 days, and then graphed in
`Exhibit Cas the average daily AUC value of 107.6 ug h!L.
`
`Comparisons between the graphed data from column 14 ofTice and the data from Exhibit
`Bas shown in Exhibit C indicate that the 50 mg oral doses ofTice and Exhibit Band the
`single injectable dose of300 mg ofTice result in similar average daily AUC values of
`28-33 ug h!L. On the other hand, a single injectable dose of MEDISORB® Naltrexone
`190 mg or MEDISORB® Naltrexone 380 mg (Alkennes) result in average daily AUC
`values that are, respectively, 1.6x (53.8 ug h/L) and 3.3x (107.6 ug h/L) greater than the
`average daily AUC value of 32.9 ug h/L, obtained from a single injectable dose of 300
`mg in accordance with Tice.
`
`Conclusion
`Therefore, Tice does not disclose an injectable naltrexone formulation that has the
`presently claimed AUC of at least 3.3 times greater than that of 50 mg oral Naltrexone.
`In addition, based on what was known in the prior art including Tice, it was unexpected
`that an injectable naltrexone formulation such as the MEDISORB® Naltrexone
`fonnulation would have an AUC of at least 3.3 times greater than that of 50 mg oral
`Naltrexone."
`
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`

`

`Application No.: 111083,167
`Declaration by Elliot Ehrich
`Page 5 of6
`
`I hereby declare that all statements made herein of my own knowledge are true and that
`all statements made on information and belief are believed to 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 imprisonment, 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.
`
`Elliot Ehrich
`
`Attachments: Exhibits A, B, C and D
`
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`

`EXHIBIT A
`
`Page 53 of 1308
`
`Source:Append1>c }(..~'. T:1bl,: g
`' Presented as median (range): :o: !'..;••27: ''' N~ 13: ldi Cm": :c: t,""· ill AUC,.,
`SD ~ Standard deviation: %Fluet= Pcrcc!lt fluctuation. calculated as (C,m, , .. -C,,, ,c,).i C"' « * l 00: R = /\ccumulatinn mtio. calculated as AUC:-:<J". Do" •. ,/AUC .. zx,""· no":
`
`!~:hi .. '[(). T;il_-..k !2 Lihk·1-i. andTJt.,!c 16
`
`1'
`
`.
`
`~-~:~~lC~L ... __ ...... _2:~~------_-:----r=-~ --1~=~~:-~j~~~::~~J
`:j_ s 7t2io:s6r>J--~~~
`~J
`i (ng*clays/mL)
`~\UC"~-~=-:~
`(ng*days/mL)
`r
`~uc
`(days)
`tma,_.,r•J
`(ng/mL)
`Cmox.S>
`(days)
`---i·~~;--------
`(ng*days/mL)
`~\uco.~
`(ng*days/mL)
`
`I
`l
`~---------r7o:8--(2<f6j __________ l
`,
`I
`~I
`·
`
`. ~
`159 9 (24 !)
`
`.
`
`-
`
`2.00 (1.75--3.00)
`
`1
`
`~~~8(C'916'
`
`I
`
`I
`
`1
`
`1
`
`4.732(1.333)
`
`I
`
`~=-~t~·--25.'o'3'('1I'69)f<rr--=~-=-~-27.96(12.17)
`
`!
`1
`
`---= ~-
`
`:
`
`; ---
`
`__________________________ l'T ___________________________________________ '______
`
`1
`
`---------------~ :.;--7---8---C--24 4)[11
`
`.
`
`.
`
`.l
`
`2.00 (l.75-24.o.tJ
`
`i
`
`00"")61.(010T"')
`
`~168(0940)
`
`0.1683(0.0687)c
`
`(
`
`iii/2,ss
`
`1.ss9 (0.971 )[cJ
`1 468 co 940)
`
`•
`
`•
`
`Cl.035 (0.020-0.170)
`
`13.70(10.63)
`
`i
`i
`1
`
`j
`
`"0-t. "
`
`..
`
`-
`
`..
`
`-
`
`--1--~----------------------------ll
`
`143.5(29.3)
`
`I
`
`7!.75(9.06)
`
`1.270(0.591)i61
`
`4.948(1.255)
`
`7.363(3.036)
`
`o:l61l(o.lo6sr
`
`DOSE 4 of 4
`
`N = 10
`
`2.00 (1.50--2.00)
`
`DOSE 1 of 4
`
`-----ll.90 (4.67)
`
`N"" 12
`
`I
`
`!
`........... 10.20 (6.6"7) ''""··'=''m-~~'-
`
`N = 12
`
`I
`i
`~-~-~---61-A9-(1-4-.'7'8)" _________ -------l-2C-l.6-(T9.6) _______ __
`
`NALT~l~~~~ER~90 MG ~~~;~~~~~6~(~li~~~~=-~:-~-=-··-~m~~~~;~:;~~~8(~~:~='-=11
`
`(SD)J
`Doses (Cohmi B) of Oral Naltrcxone (50 mg) and Medisorb Naltrexone (190 and 380 mg) ~[Arithmetic Mean
`Pham1acokinetic Parameters by Treatment for Naltrexone Following a Single Dose (Cohort A) and Repeat
`
`Table 8
`
`AL.K21-005
`Alkem1es, Inc.
`
`CONFIDENTIAL
`
`Clinical Study R~p01i
`FINAL
`
`! AlJC0
`--t,~;~}"T' _____________________ T __________ (i:(i4--(i:i'.-62~-o_-6-8') ___________ --------2.00 ( 1.75--24.0)
`~~;~nL)
`
`1.278 (0.589)
`
`i
`
`.
`
`_
`
`(davs)
`
`1
`
`I
`I COHORT I PARAMETEI~ N == 14 (Cohort B)
`N = 28 (Cohort A)
`
`--r-----
`.. l .......... !0.64 (6.92)·-----
`NAl/i'H~~;;E 50 MG
`
`(Multiple
`
`Dose)
`
`B
`
`1
`
`Dose)
`(Si~gle
`
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`

`

`CLINICAL STUDY REPORT
`
`1.0 TITLE PAGE
`
`Tide:
`
`An Evaluation of the Steady-State and Single-Dose
`Pharmacokinetics ofMedisorbl!v Naltrexone in Healthy Subjects
`
`Study Number:
`
`ALK21-005
`
`Study Sponsor
`
`Alkermes, Inc.
`88 Sidney Street
`Cambridge, Massachusetts 02139 United States
`
`Date of Report:
`
`Final: 09 November 2004
`
`CONFIDENTIAL
`
`Information and data in this document contain trade secrets and privileged or confidential
`information which is the property of Alkermes, Inc. No person is authorized to make it
`public \vitbout vvritten permission from Alkcrmes, Inc.
`
`EXHIBIT B
`
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`

`

`Clinical Study Report
`CONFlDENTlAL
`-----------------------------------
`St~tistk~i MeHwds:
`PK parameters were calculated fl·om pla>ma concentration of naltrcxone and 6i.\-nal1rexo! using
`noncompartm.:ntai techniques. Descriptive statistics of PK parameters arc summarized in
`~t.:ctiun 9.7.~2 ·:~.
`
`Alkermes, Inc.
`ALK2l-005
`
`!\nalysis of variance (/\NOV!\) models including treatment or analyk as !!xed effects and subject
`as a random cllCct were fit to the data and the result was reported for the total population.
`
`Data from subjects who received Medisorb Naltrexonc 190 mg and 38() mg in Cohort /\were used
`to assess dose proportionality (AUC: and Cm,J lor naltrexone and 6f.\-naltrexoi. To assess the time
`invariam:c of naltrexone and 6f3-nall rexol PK tbllowing Medisorb Naitn::xone administration, iog-
`transl(lrmed AUC and t1,2 were compared I(JJlowing single and multiple doses. /\ccumui<Jtion of
`naltrcxone and 6f.l-naltrexol tclllov.-·ing Medisorb Naltrexone ad:11inistra<ion was assessed by
`comparing AUC,.,_ Dose .t with AUCo.t. Do;e 1 l]·om subjects in Cohort B using a repeated rneasure
`/\NOV A. Steady state \vas Jssessed by examination of the 90% conildence interval (Cl) t(x the
`slope of the linear regression oflog-transl()rmed trough levels versus time. !n addition, the
`theoretical time to steady state (by using the terminal elimination t!/2 following a singic dose} was
`also considered. The ratio of 61.\-naltrexoi AUC0 .. , to naltrexonc AUC1_,, foliowing oral naltrexone
`ar:J Mcdisorb Naltrexone doses was analyzed using a repeated rnea<;ure ANOV A modcl.
`
`Descriptive statistics were provided EJr the appropriate safety parameters. i:Kiuding iaboratory
`ilSScs:;mcnts and \·ital signs. by study group.
`
`;\secondary post-hoc analysis was perll>rmcd to explore gender difkrcnces in the PK pill"amctcrs
`i\l iC,_, _ _, 8 and C," ov..:rali in all subjects administered a single Mcdisorb Naltn:xone dose. An
`,\NOV/\ model including gender was used to determine stutistical difkrcnces in the overall PK
`paramekrs i\LiC. 2, and Cmax bc:tween genders.
`i\ cnmpkte description of sutistical methods for this study is presented in'),_:;:; :u:; 'J. 7.
`-----------··-----····------·---------·-----·--·----····----------···---·-··--
`RESULTS
`
`----------·-----···----·····------
`PK parameters f(Jr naltrexonc and 6[3-naltrexo! ti:Jllowing a single dose of oral na!trcxone and
`r
`Medisorb Na!trexone l{Jr subjects in Cohort A arc presented in the table below:
`MEDI-SORB~ll
`r-MEDISORB
`I NALTREXONI<:
`NALTREXONE
`i
`i!' ANA.LYTE 1. PARAMETER I OR."'.L 50 MG
`380 MG
`190 MG
`N=l2
`N=i2
`N=Z8
`-·---·· ----··-------...jt
`:
`I
`, .
`·-·-----·-·-
`: Al;C. •. ~
`1· 1
` Naltrexone
`71 75 t9 ()('))
`!43.5 (29.3)
`l./.7() lf,',_5()j\,"
`'
`,.
`1j
`·
`·
`_ ··----------
`\ng*daysl!_llL)
`- ·
`\ ·
`!2.90 (-t67)
`Cmax (ng/mL)
`10.64 (6.92)
`-----
`·-
`-
`-
`
`I
`i'---·
`1
`····---~rcr·
`-· 2.00 ( 1.?0-2.00)
`l 111,cx_(days) c
`0.0.'.~JQ:02-0.08l_-+---
`•
`328.5 (80.2) ~~
`ii 6!3-mJltrexol AliCl).~
`!
`35.71 (7.62)
`175A- (26.7lli•1
`.
`·
`(ng*days/mL)
`!i
`14.08 (7.s4rl-·--~i3(6.35) ·j:l
`c:,nJ!O __ (ngJ~ll~""") __ '-__ -+--fo"8.6(35~6)
`il
`~~=~-~20,,, __ (~~E,)'
`I OTJ4"(0.02-0~_3.Q_Q.~4."5)!-· 3.00 (2.0_0-21.0)
`.'
`Data arc Dresen ted as arithmetic mean ( SD).
`Ia! N···27: 'tt'i n·JO
`lot Prcscrncd HS median !rang~).
`PK parameters ior naltrexonc and 6H-naltrexo! loilowing multiple doses of" oral naltrcxonc and
`Mcciisorb Naitrexonc j()r subjccts in Cohort Bare presented :n the tabk below:
`
`.
`
`!,.
`
`tl
`
`:
`
`1:
`
`11
`
`Page 6 of 1308
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`

`

`FINAL
`C!inicai Study Report
`
`CONFIDENTIAL
`
`A!kermes, lnc.
`ALK2l-005
`
`I
`
`' · ' ( '
`
`MEDiSORB
`M~:DISORB
`NALTREXONE
`NALTREXONE
`380 MG
`38!l MG
`Dose 4 of 4
`PARAMETER
`Dose l of 4
`ORAL 50 MG
`_________ N_=_i 4------+--'-N'-=.:.l2'----+--
`lr-:--:------+-~---·
`--·-
`N= 10
`L
`. NailrL'~·l)l1'' 1
`!70.8(29.6)
`l.559(0.97l)l<>l
`·' ~ 1"'U n-~s;
`J!:l_g*_· davs;ml.)_______
`__
`'I
`27.9fi_(.i2.l~
`:~~-
`I --:l-::3-:.7::-(;,...' (-l(-).·6--cJ·,-)-+-,-2·S.03 ( l2.69)1cr···l
`'(:,:,, (ng/mL)
`-c:-.......,,----,..+t·"''"-'» "(days}15:_
`1 0.035 rri~12"o-o. 1 70; }.Oo ( l.75-~~.:2i~-_Q{jTl-:7s=I"uo)·=
`'
`:r·.,.
`I
`:: 6P-nal!rt:xol AUC:o~-."
`1
`' ... ····'~.·, .. ···'1
`~~~days/mL) - ---1
`..... 1 !
`i --
`i 27.46 ( ll.78) 1
`~- (ng/mL)
`"======~~~~"'"""""''3-~ (ctaysJr,1__ T o.o4 (O.o2:o:17)13~oo (_3.oo-2"'~oir,"':14J--3=-.o.:.co:::.(2.oo-3.oo)
`Dati: arc presented as arithmetic mean (SDl.
`!a} NcJ3
`ibJ Prcs<:ntcd as median (range).
`lei Cm:~x. fJj l,cx
`
`. .
`
`,
`
`47.20 (14.08)
`i 38.7 (36.0)
`
`i
`
`l
`1
`
`'
`
`-----
`
`318.3 (80.5}
`34.2:1 __ ( l2. 92) _
`
`Dos\<:J~rQRortionalitv: Ratios and 90% Cls t(Jr the assessment of dose-proportionality ofnaltrexonc
`and 613-naltrexol PK parameters following a single dose of Mcdisorb Naltrcxone (Cohort A) arc
`presented below.
`
`GEO!\IETRlC LS MEANS __ J
`
`I :___________________
`
`i
`MEDISORB
`MED!SORB
`!
`!
`NALTREXONE NALTREXONE!
`,!
`iiANALYn:l
`iRAT!01":!
`190 MG
`90% C!
`380 MG
`PAR"'-METER
`--:-
`.. .... -
`----------
`.
`----
`. ......
`'
`r--
`.
`· - - -
`I
`1.756, 2.222
`7i.3
`l 9"5
`i! Na!trcxonc iAUC,,_~(ng*daysnnL)
`'..11
`l :4~5
`_-----~--=----
`!em," (ng!mL) ---
`lj
`0.99L 2.!35
`8.34
`I l.843
`I! 6f.l-n;1;rcxol k'll~:_<!:::c(ng~days/mL)_
`l.590, 2. i 37
`320
`!74
`l8.4=TIJ65-- ~:--2~279
`i[ ___________ _Ls~-""J~q.:inL)
`ll.8
`r
`--rill~at;~)-oTgeomclric LS means between the two doses.
`
`t'
`
`Naltrexone and 61.\-naltre:.;ol A UCo.·~ and Cmax were dose-proportional across the 190 and 380 mg.
`dose range as the 90%, Cls h1r all 4 pararnc!ers included the value of 2.
`
`:rJ.r!1.Ltnvariancc: Assessment of time in variance of naltrexone and 6G-nattrexol PK parameters
`foilov .. ing Medisorb Nu!trexonc 380 mg is presented below.
`
`61:\-naltrexoi
`
`GEOMETRIC LS MEANS !
`== ,== - - ~-
`'PARAMETER- COHORT A i COHOR(B] RATI01_"_1-----! __ 9 ...... o_~_;._, G
`AJ"iALY]_~~;-
`!
`i\UC1" 1
`141
`I
`Naltrexon.:
`158
`Ll24
`0.982, 1.287
`i
`4.56-:-----+I---::0-.9_5::-:l---+---,-o..,_.7n Ll72
`4.79---
`l;,2
`I
`I
`320
`287
`0.896
`0.754_, !.065
`t\UCibJ
`_l
`cl.7s5, !.092
`!
`5.52
`s.o2
`0,908
`t:.·
`=
`Cohort A: Single dose; Cohort B: Multip!e dose
`fol Ratio of geometric LS means between cohorts
`f:OJ Caiculat~:d as 1\UCoy, (Cohort ;\)/.A1.JC:c, 1 Dose'' (Cohort B}.
`Naltrexunc and 615-naltrcxol f\UC and 1112 did not change with time as the 90% Cis lor all 4
`parameters included the value of!.
`
`li
`I'
`
`!.\.~c\CiJITlUlation: Asscssm<:nt of accumulation ot' naltrexone and 613-naltrc:xol k1llowing multiple
`dust:s oi'i'vkdisorb Naitrexone 380 mg (Cohort 6) is pr:::sented below.
`
`---------------------------
`
`Page 7 of J 308
`
`_______ .. ________ _
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 9 of 18
`
`

`

`FINAL
`Clinical Study Report
`- - - · · · - - - - ·
`
`CONFIDENTIAL
`
`Alkermes. Inc.
`ALK2!-005
`·····---·--·---------
`
`GEOMETRIC LS MEANS
`~
`.; ANA~~:nE !PARAMET~r-Q.Q_SE 1
`_1 DOSE4
`11 Naltrexone
`jAUC0_,
`/
`L_
`j(l"_~g*days/ml~)
`i
`I
`!i 6B-na!trcxoi
`.J\UC0_,
`ii
`( ng~ days/!!]~;,:;2=. Li~ ===2=5 .=5 ==d.· ===2=84==:=h==l=. "l~ 1=4~~="'==1 =· 0=4=3=, =! =· l=9=l.dl
`'"1 Ratio of geometric l.S means. culcuiated as AUC0.,_ Do>e~/<.UC0., Dose 1 (Cohort B).
`Naltrexone and 613-naltrexol accumulation ( 13 and l J %, respectively) was not considered
`clinically relevant.
`
`_,__ __
`
`1.048. 1.226
`
`I
`!54=1' -··· l.l34. __
`
`. T
`
`1
`
`... l36
`
`11
`
`~:.)tate: Assessmen1 of steady state of na\trcxone and 65-na!trexol following muitiple doses of
`Medisorb Naltrexone 3&0 mg (Cohort B) is presented below.
`
`SLOP£1"1
`-0.001
`
`-0.0110
`
`I
`9{)% C!
`----r··----~:004. () 0~~-,2---·-
`I
`
`0 IW4. O.OIIJ
`
`il
`
`.......... ANALYTE
`l
`~ __________ __J_____
`1 ~"_,:':~:::::,
`I
`
`J
`
`!ol Slope was determined based on the LS mean of log trough levels folhJ\ving doses l ··· 4 in
`Cohort B
`Based on rcsu!!s of the linear regression analy;is. both naltrexone and 613-na!trc:>-oi concentrations
`reached skady stale at the end of the dosing interval t(JJiowing the first dose.
`fvletaboiite:narcnt AUC JSJ!ll9_; Assessment ofmetabolite:parent AUC ratios following oral
`na!trexone 50 mg and Mcdisorb Naltrexcme I 90 mg and 380 mg. arc prt!Sentcd beiO\v.
`~-===-~~-~-================r~A=L~l~C=G~E=O=~=I~~=:T=·=R====I=C=.I=~=S~~=f=E=A=N=,S=.=!r=============~·==r
`l'-----,--------+----'"(_ng ... *_ · a,_'a~)'-'s_lm_, _L...:.}----+~---=,...,-------ll
`i!COHORT~ DOSE GROUP
`I NALTEXONE 66-NALTREXOL j Ratioial l
`90% Cl:
`A
`3~.-!~ ____ l._ 30.253 _125.969, 35.244
`Oral (50 mg)
`l.J6
`jj
`i
`r:~·~,iisc,rb N.::ltr~xone i
`i
`!
`1:
`I 2:_~?-~:.. 2.626
`l9(~ _ _mg
`I 73
`2.4)2
`_ '.'
`jj
`: ~
`···--r---·
`Medisorb Naltrcxone
`.. l,l
`2.274 I 2.117.2.442
`320
`141
`380mg
`1'----+--.,.-'-:'....-.,':'=---+---:-:-'-:----+-----:'=::----t--:-::--:':::.,-+:-~":-:-'-::..:~::c:-11
`Oral (50 mQ)
`!.24
`34.7
`28.074
`':20.752. 37.979!
`!!
`li
`----"·-------
`:'
`" -
`1-:--c·
`I
`<
`!Mcdisorb Naltn::-.:onc
`:1
`.L
`L,~-'="~~--j"=='=380mg
`1.598,2._0~~-J
`1.8!3
`287
`158
`1"1 /\UC0.". <:nd AUC0_, were used to c<Jlculatc the ratio and 90% Cl following single :md multiple!
`doses. respectively.
`The mctabolite:parent AUC ratio Jollowing oral naltrexone administration was approximately
`30, whereas, the ratio lollowing Mcdisorb Naltrcxonc administration was approximately 2.
`CendGLDit1erences: Assessment of gender differences of naltrexone and 6~-naltrexol
`following a single dose of Medisorb Naitrexone is presented below.
`-------------·
`---·--------
`------····-----
`
`II
`
`:
`
`7 L3
`
`Page 8 of 1 308
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 10 of 18
`
`

`

`FlNAL
`Clinical Study Report
`
`CONFIDENTIAL
`
`Alkermes, Inc.
`ALK21-005
`
`---···------·---------------------------------- ---------------------
`
`fa; The ratio was obtained by exponentiating the difference in the LS means of the naturallog-
`transf()rmed parameters. Presented as Female/Malt:
`lbJ 90% Cls for the ratio of Females to Males.
`Naitrexont and 6B-naltrcxol C:max were lower in ft:males compared with males. Naltrexone and 6L\-
`naitrcx<Ji AUCo.:>s were similw· between females and males following a single dose ofMcdisorb
`Na!trcxon.c.
`--····-----------------·---------- -------------------------------------
`Safety alld
`No :;erious adverse events (SAEs) occurred. All AEs were mild in severity. with the e:--:ception of
`To!i!ra!Ji!ity:
`1 event or moderate inknsity: no subject experienced a severe AE during the study in any study
`group.
`
`Orijl Naltrcxone
`Four of the 28 subjects enrolled in Cohort A and 6 of the !4 subjects enrolled in Cohort B reported
`at least one 1\E following oral administration. All AEs reported during the ora! period were mild in
`severity and classified as possibly related to study drug by the lnv:::stigator. The most common AE
`in Cohort A was dizziness. In Cohort B, nausea and somnolence were the most common AEs.
`
`Medisorb Ni~)trexonc ··· Cobm:t A
`Two of l 2 subjccLs administered Medisorb Naltrexone 190 rng and I of 12 sui:Jjects administered
`Medisorb Naltrexone 380 mg reported at least one AE. Ail AEs reported ior Cohort A were mild in
`severity and classilicd as possibly related to study drug by the lnvestigator. No AEs wen: reported
`by subjects administered placebo.
`
`Fuur of l2 subjects administered Medisorb Naltrexone 380 mg reporkd at lea<>t one AE. All AEs
`reported !(Jr Cohort B were mild in severity with the exception of i subject who reported diarrhea of
`moderate severity. The most common i\Es in Cohort B were vomiting and dizziness. No AEs were
`reported by subjt.:cts administered placebo.
`Three subjects reported injection site reactions ( ISRs) following iM administration ofrvlcdisorb
`Naltrc:--:one 380 mg. t\li ISRs were reported f(JJlowing single dose administration in Cohort A or
`fo!lov.;ing Dose 1 in Cohort B. Subject 205-02 i reported induration and tenderness; Subject
`?.05-l 02 reported induration. l-inch eeehy;-notic area. tenderness. and redness; and Subject
`205-103 reported induration and tenderness. Ali reported !SRs resolved without sequelae.
`
`"i here were no trends or ci inicaily meaningli.d changes trom baseline observed in mea.'1 or median
`clinical laboratory values or vital signs ior any of the study groups.
`There were no trends or clinically rneaningli.Ii changes observed in ECG values !or subjects in this
`study. QTcB and QlcF interval data wue comparable f()r all dose groups. There was no evidence
`of an effect on cardiac conduction as detailed by the 12-lead ECG intervais duration.
`-------- --~- -~--------
`No efticacy parameters were evaluated during this clinical trial.
`----- ~-----·-------···-----
`
`Page 9 of !308
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 11 of 18
`
`

`

`FINAL
`Clinicai Study Report
`CONFIDENTIAL
`·---------·---·--------·-------
`Condusiolls:
`Naltr.:xon<: and 6l3-naltrcxol AUC0 .. , and Cma' were dose-proportional !ollo;ving single
`administration of Mcdisorb Nahrexone across the !90 to 380 mg close range.
`
`Alkermes, Inc.
`ALK2l-005
`
`Bas~ed on time invariance analysis of AUC: and! 112, the PK of naltrexone and 6f.\-naltrexol was
`similar between single and multiple doses of Mcdisorb Nallrexon<: 380 mg.
`
`Accumulation of n:1ltrexonc and 6!3-naltrcxol was l3 and ll %,, respectively. fol!owing
`multiple doses ofMedisorb Naltrcxone.
`
`~
`
`Steady state was reached for naltrexonc and 613-naltrexol at the end of the dosing interv3i
`!()]lowing the lirst dose ofMcdisorb Naltrexone 380 mg.
`
`The n:etabo!ite:parent AUC ratios i(JIIowing l'v1edisorb Naltrexone and oral administration
`were approximately 2 and 30, respectively. OveralL naltrexone exposure Jollowing Medi~orb
`Naltrexone was higher and 6£\-naltrcxol exposure was lower following Medisorb Naltrexonc
`380 mg administration compared with the oral naltrexone 50 mg administration.
`
`~
`
`Nailrcxone Cma' was approximately l /3 lower in females compared with males. how<:ver,
`uverall exposure (AUC} was similar between males and females.
`
`Single and multiple doses ofMedisorb Naltrexone were well tolerated based on the number
`and severity of reported AEs. There were no trends or ciiniea!ly meaningful chang~.:s from
`baseline observed in mean or median clinical laboratory values or vita! sign Jindings for any of
`the stt:dy groups.
`
`There were no trends or clinically meaningfUl changes observed in ECG values l(Jr subjects in
`1his study. There was no evidence of an effect on cardiac conduction ilS detailed hy the
`J 2-lc3c! f·:CG intervals duration
`
`--·-·--·--·--·----·-----
`Good Clinical Pmctice (GCP) is an international cthic<Jl and scicntii]c quality standard klr
`designing, conducting., recording and reporting trials that involve the participation of human
`subjects. The Aikcrmes commitment is compliance with this stanc!ard to provide assurance that the
`rights, sakty, and well-being of trial subjects will be protected, consistent with the principles that
`have their origin in the Declaration of Helsinki.
`
`Date of the Repnrt:
`Final: 09 November 2004
`· - - - - ·---~- ----------~ --------·----- · - - - - - · - - - -
`
`Page I() of J 308
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 12 of 18
`
`

`

`AUC ug h/L
`Oral
`50mg
`DAY Tice et al
`27.8
`1
`2
`27.8
`27.8
`3
`4
`27.8
`27.8
`5
`27.8
`6
`7
`27.8
`27.8
`8
`27.8
`9
`10
`27.8
`27.8
`11
`12
`27.8
`13
`27.8
`14
`27.8
`15
`27.8
`16
`27.8
`17
`27.8
`18
`27.8
`19
`27.8
`20
`27.8
`21
`27.8
`22
`27.8
`23
`27.8
`24
`27.8
`25
`27.8
`26
`27.8
`27
`27.8
`28
`27.8
`29
`27.8
`27.8
`30
`31
`27.8
`32
`27.8
`
`Injectable
`300mg
`50mg
`ALK21-005 Tice et al
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`30.5
`32.9
`
`380mg
`190mg
`ALK21-005 ALK21-005
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`53.8
`107.6
`
`EXHIBIT C
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 13 of 18
`
`

`

`Naltrexone Average Daily AUC Levels
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`:3'
`........
`..r:::
`Ill)
`2.
`u
`::::>
`<C
`
`~""'""'Oral, single SO mg dose: extrapolated
`(Tice et al.)
`
`~""'""'Oral, single SO mg dose: extrapolated
`(ALK21-00S)
`
`.·.·.·.·.·.·.·.·.·.·.·Injectable, single 300 mg dose:
`averaged over 32 days (Tice et al.)
`
`averaged over 32 days (ALK21-00S)
`
`0
`
`.;....
`,.......
`.···.···
`. , :: : : ,
`. .
`, , , : : :: ,........
`. ..... ".'" ,"'."~Injectable, single 380 mg dose:
`averaged over 32 days (ALK21-00S)
`1 3 s 7 9 11 13 1S 17 19 21 23 2S 27 29 31
`
`DAY
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 14 of 18
`
`

`

`Elliot W. Ehrich, MD
`
`-1-
`
`Elliot W. Ehrich, MD
`
`Senior Vice President, Research and Development
`Chief Medical Officer
`Alkermes, Inc.
`
`Work:
`88 Sidney Street
`Cambridge MA, 02139
`Phone 617 583 6190
`elliot.ehrich@alkermes.corn
`www.alkermes.com
`
`Home:
`2 Oak Meadow Rd.
`Lincoln, MA 01773
`781 259 4470
`
`•
`•
`•
`•
`
`Senior Vice President
`Research and Development, Chief Medical Officer
`Executive Officer
`Vice President, Science and Development, Chief Medical Officer
`Vice President, Medical Affairs
`
`2007 -Present
`2006-Present
`2003-2007
`2000-2003
`
`PRIOR EMPLOYMENT
`Merck & Co., Inc.
`
`• Senior Director, Clinical Research, Pulmonary-Immunology
`• Director, Clinical Research, Pulmonary-Immunology
`• Associate Director, Clinical Pharmacology
`
`EDUCATION
`
`SCHOOL
`
`MAJOR
`
`DEGREE
`
`1993-2000
`
`1998-2000
`1995- 1998
`1993-1995
`
`Princeton University 1977- 1981 Biochemistry
`Princeton, NJ
`
`B.A., Magna cum Laude,
`Phi Beta Kappa
`
`Columbia University 1982- 1986 Medicine
`College of Physicians and Surgeons, New York, NY
`
`M.D.
`
`EXHIBIT D
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 15 of 18
`
`

`

`Elliot W. Ehrich, MD
`
`-2-
`
`POSTGRADUATE TRAINING
`
`Stanford University, Stanford, CA
`
`1986- 1993
`
`Internship and Residency, Department of Medicine
`Clinical Fellowship, Rheumatology, Division of Immunology and Rheumatology
`Cancer Research lnstitute/FW. Kirby Foundation Postdoctoral Fellowship 1990-1993,
`Laboratory of Dr. Mark Davis, HHMI, Department of Microbiology and Immunology
`
`1981, 1985
`European Molecular Biology Laboratory (EMBL)
`Heidelberg, Germany, Research Associate, Laboratory Dr. Hans Lehrach
`
`ACADEMIC APPOINTMENT
`
`Clinical Assistant Professor of Medicine
`Robert Wood Johnson Medical School
`
`PROFESSIONAL HONORS
`
`1997 -Present
`
`Fellow, American College of Rheumatology 1993 - Present
`American College of Rheumatology Senior Rheumatology Scholar Award
`Board Certification, Rheumatology, American Board of Internal Medicine 1993-2003
`Board Certification, Internal Medicine, American Board of Internal Medicine 1989-
`Present
`Board Certification, National Board of Medical Examiners 1986-Present
`
`PUBLICATIONS
`
`A Poustka, T Pohl, D Barlow, G Zehetner, A Craig, F Michiels, E Ehrich, A-M Frischauf, and H
`Lehrach (1986): Molecular Approaches to Mammalian Genetics, Cold Spring Harbor Symposium
`on Quantitative Biology, 51 : 131-139.
`
`Ehrich, Elliot, Alister Craig, Annemarie Poustka, Anna-Maria Frischauf and Hans Lehrach (1987):
`A Family of Cosmid Vectors with the Multi-Copy R6K Replication Origin, Gene, 57:229-237.
`
`Ehrich, Elliot W., James L. McGuire, Hugh 0. McDevitt (1990): A Late Relapse of Wegener
`Granulomatosis (Letter), Annals of Internal Medicine, 112: 965.
`
`Ehrich, Elliot W., R. Elaine Lambert, James L. McGuire: Therapy of Immune Mediated
`Rheumatic Disease. In Melmon, K, H. Morelli, B Hoffman and D. Nierenberg (eds): Clinical
`Pharmacology, Basic Principles in Therapeutics, Third Edition (1991 ), J.D. Lippincott, New York.
`
`AMN1003
`IPR of Patent No. 7,919,499
`
`Page 16 of 18
`
`

`

`Elliot W. Ehrich, MD
`
`-3-
`
`PUBLICATIONS Cont.
`
`Ehrich, Elliot W., James L. McGuire, Youn H. Kim (1992): Association of Granuloma Annulare
`with Sarcoidosis. Archives of Dermatology: 128:855-6.
`
`Jorgensen, Jeffery L., Phillip A. Reay, Elliot Ehrich, and Mark M. Davis (1992): Molecular
`Components ofT Cell Recognition, Annual Review oflmmunology, 10: 835-73.
`
`Ehrich, Elliot W., Brigitte Devaux, Jeffery L. Jorgensen, Y.S. Chien and Mark M. Davis (1993): T
`Cell Receptor Recognition of Peptide/MHC and superantigen/MHC Complexes are dominated by
`antigen. J. Exp. Med., 178: 713-722.
`
`Hansjorg Schild, Nassim Mavaddat, Christ