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`US008846100B2
`
`c12) United States Patent
`Shojaei et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,846,100 B2
`Sep.30,2014
`
`(54) CONTROLLED DOSE DRUG DELIVERY
`SYSTEM
`
`(75)
`
`Inventors: Amir Shojaei, Phoenixville, PA (US);
`Stephanie Read, Philadelphia, PA (US);
`Richard A. Couch, Bryn Mawr, PA
`(US); Paul Hodgkins, Exton, PA (US)
`
`(73) Assignee: Shire 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 Publication Data
`
`US 2007/0264323 Al
`
`Nov. 15, 2007
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K9/16
`A61K9/48
`A61K 311137
`A61K9/50
`U.S. Cl.
`CPC ............. A61K 914808 (2013.01); A61K 311137
`(2013.01); A61K 915078 (2013.01);
`A61K 911676 (2013.01)
`USPC ............................ 424/490; 424/463; 424/493
`Field of Classification Search
`USPC .................................. 424/489-502, 464-483
`See application file for complete search history.
`
`References Cited
`
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`
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`ratories Inc., dated Apr. 25, 2005.
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`tories Inc.'s Fourth Set of Interrogatories (Nos. 15-16), dated Jul. 9,
`2004.
`
`(Continued)
`
`Primary Examiner - Nissa Westerberg
`Assistant Examiner - Micah-Paul Young
`(74) Attorney, Agent, or Firm -McDermott Will & Emery
`LLP
`
`(57)
`
`ABSTRACT
`
`A multiple pulsed dose drug 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 pharmaceutically active amphetamine
`salt covered with an enteric 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
`number of beads in a dosage form, including either capsule,
`tablet, or sachet method for administering the beads.
`
`31Claims,10 Drawing Sheets
`
`Amerigen Ex. 1001, p. 1
`
`

`
`US 8,846,100 B2
`Page 2
`
`(56)
`
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`Mar. 2, 2006.
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`Reply to Counterclaims in Shire Laboratories Inc. v. Teva Pharma(cid:173)
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`(1-12) in Shire Laboratories Inc. v. Teva Pharmaceutical Industries
`Ltd., Case No. 2:06-cv-00952-SD dated Sep. 20, 2006.
`Defendants' Responses to Plaintiffs First Set of Request for the
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`00952-SD dated Oct. 4, 2006.
`
`Plaintiff's Response to Defendants' First Set of Interrogatories in
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`Plaintiffs Response to Defendants' First Set of Production Requests
`in Shire Laboratories Inc. v. Teva Pharmaceutical Industries Ltd.,
`Case No. 2:06-cv-00952-SD dated Oct. 11, 2006.
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`Inc. v. Teva Pharmaceutical Industries Ltd., Case No. 2:06-cv-
`00952-SD dated Nov. 8, 2006.
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`Effect of Physicochemical Properties, Drug Development and Indus(cid:173)
`trial Pharmacy, New York, NY, vol. 18, No. 19, Jan. 1, 1992, pp.
`2067-2079, XP009092848, ISSN: 0363-9045.
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`Enantiomers and pemoline in Attention-Deficit Hyperactivity Disor(cid:173)
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`which is related to the present application together with a letter from
`a foreign agent re. the Office Action in English.
`* cited by examiner
`
`Amerigen Ex. 1001, p. 4
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 1of10
`
`US 8,846,100 B2
`
`FIG. 1
`
`110 - - - - - ------ -- -- -- - --- ----- - -- - ----- - --- -- -- -- - -- - - - -- --- - -- - -- -- -- ------ -- - --- - --- ------ -- -- --- --- ---- -
`
`1 00 -- - - - -- --- -- - --- -- - - - - -- - -- -- - ---- -- -- --- - - - -- -- - -- --- --- ---- -- ------- - - -- - - ---- - - - -- --- - ----- ------- -
`
`90 -- - - - -- - --- -- -- - -- - -- --- -- - -
`-g 80
`.<:
`0 ::! 70
`c c 60
`G> ::
`G> 50
`D..
`
`-+-PD0149-120 Initial, HFS+Opadry+Surelease
`"""*-PD0149-124 Initial, HIR+Surelease+FS
`
`40 -- - - - - --- - - - --- - --- -- -- ---- - - - --- - ---- - -- --- --- - - --- --- - -- -- - - -- ---- -- - -- - - - - -- -- -- - - --- --- --- ------ -
`
`30 - -- - - - - --- - - - -- - - --- -- - -- - -- - -
`
`- -- -- - ---- - --- - - - -- --- -- - --- - -- --- --- ---- - - - -- - - - -- - -- -- - - --- --- --~---
`
`20 --- - -- - ---- -- -- ---- - --- ---- - ------ - -- -- -- - - ----- --- --- - - - - ---- -- -- - --- -- - --- -- -- -- - ----- -- - -- - - -- --- -
`
`o*-~~~~'--~~~-,--~~~~.--~~~-,--~~~~..---~~~-.-~~~~.-~~~----1
`2
`16
`4
`14
`10
`12
`0
`8
`6
`Time (hours)
`
`Amerigen Ex. 1001, p. 5
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 2of10
`
`US 8,846,100 B2
`
`FIG.2
`
`Protective coating
`
`_--111----t- 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)
`
`Drug layer
`
`Overcoating
`
`Drug layer
`
`Overcoating
`
`l
`
`33.3%
`
`/
`
`/ Sustained-release
`
`polymer
`
`33.3%
`
`QD (morning)-+ SPD465 Capsule -+TIO dosing profile
`
`Amerigen Ex. 1001, p. 6
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 3of10
`
`US 8,846,100 B2
`
`FIG.4
`
`Dissolution Profile of SPD465 12.Smg Capsules Lot# A03552A
`
`80
`
`g
`1J
`GI 60
`>
`Ci
`VI
`.!!! c
`c GI
`l::!
`GI c..
`
`40
`
`20
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`Tlme(hr)
`
`FIG.5
`
`Dissolution Profile of SPD465 25mg Capsules Lot# A03547A
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`Time (hr)
`
`Amerigen Ex. 1001, p. 7
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 4of10
`
`US 8,846,100 B2
`
`FIG.6
`
`Dissolution Profile of SPD465 37.Smg Capsules Lot# A035498
`
`80
`c
`'tl
`G) >
`0 60
`i5 .... c
`
`U)
`U)
`
`G)
`
`I:?
`G) 40
`D.
`
`o.--~~~---,-~~~~.-~~~---.~~~~..--~~~-r-~~~~.---~~~~
`0
`2
`4
`6
`8
`10
`12
`14
`
`Time (hr)
`
`FIG. 7
`
`Dissolution Profile of SPD465 50mg Capsules Lot# A035368
`
`~ c
`'tl
`G) >
`0
`i5 .... c
`0 .. G)
`
`U)
`U)
`
`G)
`
`D.
`
`80
`
`60
`
`40
`
`20
`
`0
`
`2
`
`4
`
`6
`
`8
`Time (hr)
`
`10
`
`12
`
`14
`
`Amerigen Ex. 1001, p. 8
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 5of10
`
`US 8,846,100 B2
`
`FIG.8
`
`A
`
`B
`
`100 -~
`- 80
`l 0 en 60
`en
`Q 40
`1: Cl) e 20
`Cl> a.
`
`0
`
`0 1 2
`
`3 4 5 6 7
`Time (hr)
`
`8
`
`9 10 11 12 13 14 15 16
`
`FIG.9
`
`_..._ SPD465 37.5 mg
`-4>- ADDERALL XR® 25 mg
`+Mixed Amphetamine salts 12.5 mg
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Time (hr)
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0 .
`
`0
`
`(I]
`
`!:
`<ll
`a:-g
`"'~
`"-"'Ol
`Q) c:
`::;;:~
`c:
`Q) 0
`c::;:::;
`·~g
`~ c:
`Q) 8
`.c: c:
`c..o
`~o
`
`"C
`
`Amerigen Ex. 1001, p. 9
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 6of10
`
`US 8,846,100 B2
`
`18
`
`16
`
`FIG. 10
`
`__.__ ADDERALL XR® 25 mg
`+Mixed Amphetamine salts 12.5 mg
`_.._ SPD465 37 .5 mg
`
`14 -....J
`E 12 -0) c: -c: 10
`....
`.Q
`(!! c Q) u
`
`8
`
`6
`
`c:
`0
`(.)
`
`4
`
`2
`
`0
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Time (hr)
`
`FIG.11
`
`--- Single Dose (Day 1)
`-ID- Multiple Dose (Day 7)
`
`20
`
`Ctl
`E
`en
`ro(cid:173)
`-.....1
`o.. E
`c Cl
`Cl) -(cid:173)
`
`·- c E-ro c -o
`1? :o::l
`0. ~ Ee
`~~
`"Cl c
`0
`~ (.)
`Cl)
`~
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`Amerigen Ex. 1001, p. 10
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 7of10
`
`US 8,846,100 B2
`
`FIG. 12
`
`--- 12.5 mg (Day 7)
`-ID- 25 mg (Day 7)
`---+- 50 mg (Day 7)
`--v- 75 mg (Day 7)
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`(lj
`
`E
`(/)
`ro-
`-_J
`o... E
`c: Ol
`0) ---
`·- c: E-
`(lj c:
`..... 0
`O)·-
`..c: .....
`c.~ Ee
`
`<( 0)
`I
`()
`1:J c:
`c: 0
`(lj (.)
`0)
`::'2
`
`0
`
`0
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`0
`
`::::?
`E
`
`---Ol .s
`x
`"' E
`(.)
`0)
`c:
`.E
`m
`Q)
`.r:
`c.
`E
`<(
`-6
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`FIG.13
`
`0
`
`0
`
`-·~
`/@
`
`...... .,. ...........
`
`..
`
`0
`
`Individual Values
`
`- Mean
`
`··•--· Power Model Regression Line
`
`0
`§
`.-4.m·
`.............
`
`0
`0
`
`..
`
`0
`
`...
`__ ;. .. --...
`~ ...... -··
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`Amerigen Ex. 1001, p. 11
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 8of10
`
`US 8,846,100 B2
`
`FIG.14
`
`0
`
`.......
`
`Individual Values
`Mean
`Power Model Regression Line
`
`...
`
`§
`----~
`
`0
`0
`
`0
`
`-~----··
`~ .. -····
`.. •
`
`0
`
`0
`8
`__ ... ----~
`... ... ............
`
`5000
`
`:::J'
`E 4000
`
`°' i:::
`~ ....
`£
`~ 3000
`~
`0
`::::i
`<(
`Q)
`i::: . E
`2
`Q)
`..c:
`0. 1000
`E
`<(
`-0
`
`2000
`
`0
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`FIG. 15
`
`---- Single Dose (Day 1)
`-ffi- Multiple Dose (Day 7)
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`Amerigen Ex. 1001, p. 12
`
`

`
`U.S. Patent
`
`Sep.30,2014
`
`Sheet 9of10
`
`US 8,846,100 B2
`
`FIG.16
`
`------ 12.5 mg (Day7)
`-ID- 25 mg (Day 7)
`-+- 50 mg (Day7)
`-t- 75 mg (Day7)
`
`0
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`50
`
`(/)
`
`Cll
`E
`£ :::::J'
`tll _§
`.E .s
`c Ol
`lll c
`Qi 2
`.g_ ~
`E c
`<f ~ 20
`c
`c
`0
`Cll ()
`tll
`2
`
`40
`
`30
`
`10
`
`100
`
`80
`
`60
`
`40
`
`20
`
`----....J
`E
`Oi c::
`.._.
`~
`E u
`tll c .E
`Cll
`Qi
`..c
`a.
`E
`<(
`-!..
`
`FIG.17
`
`Individual Values
`O
`• Mean
`Power Model Regression Line
`
`.. .··
`...
`..
`~ ... ·····~······
`8 ...
`
`0
`
`0
`
`.... ~ ..... ···················l
`
`.. ~
`
`0
`0
`0
`
`0-1----,-~..-----,---,,----,......--,.~...,....----,-~,