111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US0088461 OOB2
`
`(12) United States Patent
`Shojaei et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,846,100 B2
`Sep.30, 20l 4
`
`(54) C O NTROLLED DOSE DRUG DEU VERY
`SYSTEM
`
`(75)
`
`Inventors: Amir S ho,jaei, Phoenixville, PA (US);
`Stephanie Read, Philadelphia, PA (US);
`Richa r d A. Conch, Bryn Mawr, PA
`(US); Pa ul Hodgkin s, Exton, PA (US)
`
`(73) Assignee: S hire LLC, Florence, KY (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1200 days.
`
`(21) Appl. No.: 11/383,066
`
`(22) Filed:
`
`May 12,2006
`
`(65)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Prior P ublication Data
`
`US 2007/0264323 A1
`
`Nov. 1 5, 2007
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Lnt. C l.
`A61K9116
`A61K 9148
`A61K 311137
`A61K9/50
`U.S. C l.
`CPC ............. A6IK914808 (2013.0 1); A6IX 311137
`(2013.01); A6I X 915078 (2013.01);
`A61K 911676 (2013.01)
`USPC ............................ 424/490: 424/463; 424/493
`F ield of C lassification Search
`USPC .................................. 424/489- 502, 464-483
`See application file for complete search history.
`
`Refcl'(mccs Cited
`
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`
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`2,881 ,113 A
`3,048,526 A
`3,066,075 A
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`
`FOREIGN PATENT DOCUMENTS
`
`AU
`EP
`JP
`JP
`JP
`JP
`JP
`JP
`WO
`wo
`WO
`WO
`wo
`wo
`wo
`
`109438
`0 640 337
`59-08231 I
`03-1482 15
`07-061922
`09-249557
`09-267035
`l0-081634
`W087/00441
`97/03673
`98/14168
`W099/03471
`W000/25752
`W000/35450
`2004028509 A1
`
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`6/1991
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`
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`
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`Shire Laboratories, Inc., Apr. 25, 2005.
`Answering E.xpert Report ofRobert Langer, Sc. D. Regarding United
`States Patent Nos. 6,322,819 and 6,605,300, expert Jor Shire Labo(cid:173)
`ratories Inc., dated Apr. 25, 2005.
`Barr Laboratories' Objections and Responses to PlaintiffShire Labo(cid:173)
`ratories Inc.'s Fitlh Set of Interrogatories (No. 17), dated Sep. 3,
`2004.
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`Counterclaims Shire LaboraJories, Inc. v. Barr l. aboratories. h1c.,
`Civil Action No. 03-CV-1219-PKC.
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`claims, dated Sep. 25, 2003.
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`tories Inc.'s Second Set of Interrogatories (Nos. 8-11), dated Feb. 18,
`2004.
`Barr Laboratories Inc.'s Objections and Responses to Shire Labora(cid:173)
`tories Inc.'s Fourth Set of Interrogatories (Nos. 15-16), dated Jul. 9,
`2004.
`
`(Continued)
`
`Primary Examiner - Nissa Westerber<J
`Assistant Examiner - Micah-Paul Young
`(74) Attorney, Agent, or Firm - McDermott Will & Emery
`LLP
`
`(57)
`
`ABSTRACT
`
`A multiple pulsed dose dmg delivery system for pharmaceu(cid:173)
`tically active amphetamine salts, comprising a pharmaceuti(cid:173)
`cally active amphetamine salt covered with an immediate(cid:173)
`release coating and a phanuaceutically active amphetamine
`salt covered with an entetic coating wherein the immediate
`release coating and the enteric coating provide for multiple
`pulsed dose delivery of the pharmaceutically active amphet(cid:173)
`amine salt. The product can be composed of either one or a
`muuber of beads in a dosage fonu, including either capsule,
`tablet, or sachet method for administering the beads.
`
`31 C laims, 10 Drawing Sh eets
`
`KVK-TECH EXHIBIT 1001
`
`

`

`US 8,846,100 B2
`Page2
`
`(56)
`
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`tiff Shire Laboratories loc.'s Third Set of loterrogatories (Nos.
`l2-l4)(Redacted), dated Aug. 27. 2004.
`to
`Barr
`laboratories.
`Inc.'s
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`U.S.C. §355(j)(2)(B)(ii) and 21 C.F.R. § 314.95).
`to
`laboratories,
`Inc.'s
`'819 Notification Pmsuant
`Barr
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`
`

`

`US 8,846,100 B2
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`
`

`

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`
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`a foreign agent re. the Oltice Action in English.
`* cited by examiner
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 1 of 10
`
`US 8,846,100 B2
`
`FIG. 1
`
`120.--------------------------------------------------------------------.
`
`110 ------------------------------ ----------------.--------------------------------------------------••• ---
`
`1 00 -.. -- -------------.. ---------------- ------------------------------------------------------------------
`
`90 ----------------------------
`-g 80
`~
`0
`~ 70
`0
`t: 60
`4l
`!::!
`4l 50
`D..
`
`40
`
`30
`
`-+- PD0149-120 Initial, HFS+Opadry+Surefealie
`""*" PD0149-124 Initial, HIR+Surelease+FS
`
`20 ------------------- ----.---- ----------------------.--------------·-------•• ----------------·-. --•• ---
`
`10
`
`0 ._---=~~~~~------~----~------~------.-----~------~
`10
`12
`16
`14
`2
`6
`4
`8
`0
`Time (hours)
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 2 of 10
`
`US 8,846,100 B2
`
`FIG.2
`
`Protective coating
`
`Drug layered
`core
`
`Eudragit FS-300
`coating
`
`FIG. 3
`SPD465 Sustained Release Capsule
`
`Immediate-Release
`Bead (IR)
`
`Delayed-Release
`Bead 1 (DR1)
`
`Delayed Release
`Bead 2 (DR2)
`
`/
`33.3%
`
`Sustained-release
`polymer
`
`/
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 3 of 10
`
`US 8,846,100 B2
`
`FIG.4
`
`Dissolution Profile of SPD465 12.5mg Capsules Lot# A03552A
`
`80
`
`60
`
`g
`-g
`0 .. .l!!
`>
`0 c .. e 40
`.. Q.
`
`20
`
`Tlme(hr)
`
`FIG.S
`
`Dissolution Profile ofSP0465 25mg Capsules Lot#A03547A
`
`100~--------------------------------~~~---=~======~
`
`~ ~
`/
`~
`I
`~ 60+---------~~~--------------------------------------------
`~
`~
`l 40+--------+------------------------------------------------
`I
`,I
`
`.;
`
`20
`
`0
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`nme(hr)
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 4 of 10
`
`US 8,846,100 B2
`
`FIG.6
`
`Dissolution Profile of SP0465 37.5mg Capsules Lot# A03549B
`
`Time (hr)
`
`FIG. 7
`
`Dissolution Profile of SPD465 50mg Capsules Lot# A03536B
`
`"0
`d)
`>
`0
`0
`0
`
`60
`
`~ 0 - 80
`i5 .. 1:
`0 .. Cll 40
`
`d)
`
`Q.
`
`20
`
`0 ~------.-------~-------.------~------~~------~------,
`6
`8
`14
`2
`0
`10
`12
`4
`Time (hr)
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 5 of 10
`
`US 8,846,100 B2
`
`FIG.8
`
`A
`
`B
`
`100 -~
`- 80
`1
`0 60
`en
`en
`i5 40
`~
`Cl) e 20
`0
`
`Cl)
`Q.
`
`0 1 2 3 4 5 6 7
`Time (hr)
`
`8
`
`9 10 11 12 13 14 15 16
`
`FIG.9
`
`50
`
`--- SPD465 37.5 mg
`~ ADDERALL XRs 25 mg
`+ Mixed Amphetamine salts 12.5 mg
`
`40
`
`30
`
`"' E "' "'~
`o:-g
`"-<'00>
`CDC:
`:a;-c:
`c::=
`l~ 20
`-" Q)~
`.s::;c
`c.o
`~0
`
`CI>O
`
`"'C
`
`10
`
`0 .
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Tlme (hr)
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 6 of 10
`
`US 8,846,100 B2
`
`FIG. 10
`
`-+- ADDERALL XR* 25 mg
`+ Mixed Amphetamine salts 12.5 mg
`--- SPD465 37.5 mg
`
`18
`
`16
`
`12
`
`14 -..J
`E -0)
`c: -c: 10
`.Q -~ c:
`~
`6 8
`c:
`
`8
`
`4
`
`2
`
`0
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Time (hr)
`
`FIG. 11
`
`25~----------------------------------------~
`
`_..__ Single Dose (Day 1)
`-m- Multiple Dose (Day 7)
`
`20
`
`ca
`E
`{/) ca.--..
`-...I
`a..E
`<I>-(cid:173)
`ce>
`·- c E-
`.$§
`~:0::::
`a.~ Ec
`4=8
`
`'t)C
`0
`~(.)
`(()
`::2
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 7 of 10
`
`US 8,846,100 B2
`
`{f)
`
`Q) --
`c::;Ol
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`co
`E
`co..--.
`-...J o.E
`·- c:: E-roc: -o Q)·-
`..c::-
`0.~ Ec
`1~ 40
`"t)C::
`c::o
`roO
`Q)
`:::;:!
`
`FIG. 12
`
`---.- 12.5 mg (Day 7)
`-ID- 25 mg (Day 7)
`-+- 50 mg (Day 7)
`---"'?-- 75 mg (Day 7)
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`FIG.13
`
`0
`
`Individual Values
`
`- Mean
`
`......... Power Model Regression line
`
`........
`..
`
`0
`§
`.40.·
`
`0
`0
`
`0
`
`..
`~ .. .
`.,. , ....
`
`"
`
`, .....
`~-/ ..
`
`0
`
`0
`
`..
`_, .. -" .......
`.. · ..
`
`··t
`
`.•
`
`0
`
`0
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`0
`
`0
`
`250
`
`200
`
`150
`
`100
`
`50
`
`....-.
`...J
`E
`.._
`Ol .s
`X
`"'
`E
`()
`Q)
`c::
`.E
`ro
`4>
`..c::
`0.
`E
`<(
`-6
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 8 of 10
`
`US 8,846,100 B2
`
`FIG. 14
`
`5000
`
`:::J
`E 4000
`---tn
`c: • ....
`.c:
`~ .., 3000
`"! e.
`0
`::::>
`<{
`<!)
`. E
`c:
`2
`<!)
`.c:
`0. 1000
`E
`<{ -o
`
`2000
`
`0
`
`0
`
`0
`
`Individual Values
`Mean
`
`....... Power Model Regression Line
`
`..........
`
`~ .. ----9- .
`..
`
`§
`.--- ~
`8
`
`0
`
`0
`
`0
`8
`---------------~
`--·
`...
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`FIG. 15
`10 .--------------------------------------------.
`
`---- Single Dose (Day 1)
`-ffi- Multiple Dose (Day 7)
`
`8
`
`co
`E
`Ill J!!::J
`CL E
`<1)--
`.E g> 6
`E(cid:173)
`co c:
`(ii .Q
`.g_'§
`E c
`<f~
`-
`c:
`c: 0
`ljlO
`:::;:::
`
`4
`
`2
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr}
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 9 of 10
`
`US 8,846,100 B2
`
`FIG. 16
`
`60~------------------------------------------~
`
`50
`
`(/)
`
`~ 12.5 mg (Day7)
`-Iii- 25 mg (Day 7)
`~ 50 mg (Day7)
`~ 75 mg (Day?)
`
`m
`E
`£ :::::1
`(!) .§
`r: Ol
`.E .s
`J~ r:
`Q)~
`-3_~
`E c
`<f ~ 20
`-
`r:
`r: 0
`m <.>
`(!)
`2
`
`40
`
`30
`
`10
`
`0
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`FIG. 17
`
`o
`Individual Values
`• Mean
`Power Model Regression Line
`
`0
`
`0
`
`.. ----~
`~
`..... 1·················
`.·· . .. -·
`
`0
`0
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`

`

`U.S. Patent
`
`Sep.30,2014
`
`Sheet 10 of 10
`
`US 8,846,100 B2
`
`FIG. 18
`
`1800
`
`0
`
`Individual Values
`
`- Mean
`
`· ·k· Power Model Regression Line
`
`0
`
`~ ... ·· ...
`........
`... ·· g•
`..............
`0
`0
`
`s-
`~ ... ······
`..
`
`... ...
`..
`.......
`
`0
`
`8
`.. -·····r
`
`0
`
`0
`
`_ .....
`
`ue. 1000
`::>
`<
`<!)
`c
`.E
`«!
`<!)
`.c
`a..
`E
`<
`-L
`
`........ 1600
`....1
`E
`.._
`0> 1400
`c
`·~ .c
`.._.,
`~
`<)I
`
`1200
`
`-
`
`800
`
`600
`
`400
`
`200
`
`0
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`