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`
`(12) United States Patent
`Shojaei et aL
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,846,100 B2
`Sep. 30, 2014
`
`CONTROLLED DOSE DRUG DELIVERY
`SYSTEM
`
`Inventors: Amir Shojaei, Phoeaixville, PA (US);
`Stephanie Read, Philadelphia, PA (US);
`Richard A. Couch, Bryn Mawr, PA
`(US); Paul Hodgkins, Exton. PA (US)
`
`Assignee: Shire LLC, Florence, KY (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1200 days.
`
`Appl. No.: 11/383,066
`
`(22)
`
`Filed:
`
`May 12, 2006
`
`(65)
`
`Prior Publication Data
`US 2007/0264323 Al
`Nov. 15. 2007
`
`(51)
`
`Int. Cl.
`A61K 9/16
`A61K 9/48
`A61K 31/137
`A61K 9/50
`(52) U.S. CI.
`CPC
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`461K 9/4808 (2013.01); 461K 31/137
`(2013.01); 461K 9/5078 (2013.01);
`A61K 9/1676 (2013.01)
`424/490; 424/463; 424/493
`USPC
`(58) Field of Classification Search
`424/489-502, 464-483
`USPC
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
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`
`FOREIGN PATENT DOCUMENTS
`
`109438
`0 640 337
`59-082311
`03448215
`07-061922
`09-249557
`09-267035
`10-081634
`W087/00441
`97/03673
`98114168
`W099/03471
`W000/25752
`W000/35450
`2004028509 Al
`
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`5/2000
`6/2000
`4/2004
`
`OTHER PUBLICATIONS
`
`EXHIBIT
`
`WIT:
`
`DATE:
`DEBRA STEVENS, RPR, CRR
`
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`Answering Expert Report o f Robert Langer, Sc. D. Regarding United
`States Patent Nos. 6.322,819 and 6,605,300, expert for Shire Labo-
`calories Inc.. dated Apr. 25, 2005.
`Barr Laboratories' Objections and Responses to Plaintiff Shire Labo-
`ratones Inc.'s Fifth Set of Interrogatories (No. 17). dated Sep. 3,
`2004.
`Barr Laboratories' Amended Answer, Affumative Defenses and
`Counterclaims Shire Laboratories, Inc. y. Barr Laboratories. inc.,
`Civil Action No. 03-CV-1219-PKC.
`Barr Laboratories' Answer, Affirmative Defenses. and Counter-
`claims, dated Sep. 25, 2003.
`Barr Laboratories Inc.'s Objections and Responses to Shire Labora-
`tories Inc.'s Second Set of Interrogatories (Nos. 8-11), dated Feb. 18,
`2004.
`Barr Laboratories Inc.'s Objections and Responses to Shire Labora-
`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
`
`ABSTRACT
`(57)
`A multiple pulsed dose drug delivery system for pharmaceu-
`tically active amphetamine salts, comprising a phamtaceuti-
`cally active amphetamine salt covered with an immediate-
`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-
`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.
`
`31 Claims, 10 Drawing Sheets
`
`KVK-TECH EXHIBIT 1001
`
`Page 1
`
`SHIRE EX. 2085
`KVK V. SHIRE
`IPR2018-00290
`
`

`

`US 8,846,100 B2
`Page 2
`
`(56)
`
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`Pursuant
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`§505(j)(2XBXii) of the Federal Food, Drug and Cosmetic Act (21
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`
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`

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`Defendants' Responses to Plaintiff Shire' s First Set of Interrogatories
`(1-12) in Shire Laboratories Inc. v. Teva Pharmaceutical Industries
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`No. 2:06-cv-00952-SD dated Oct. 11, 2006.
`Plaintiffs Response to Defendants' First Set of Production Requests
`in Shire Laboratories Inc. v. Teva Pharmaceutical Industries Ltd,
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`Defendants Responses to Plaintiffs Second Set of Requests for the
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`
`* cited by examiner
`
`Page 4
`
`

`

`U.S Patent
`
`Sep. 30, 2014
`
`Sheet I of 1.0
`
`US 8,846 00 B2
`
`FIG. 1
`
`120
`
`110
`
`100
`
`90
`
`P0G149-120 ?NW, HFS+Opadry+Stirelease
`-N--PD0149-124 Initial, HIR+Surelease+FS
`
`6
`
`8
`Time (hours)
`
`10
`
`12
`
`14
`
`16
`
`Page 5
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 2 of 10
`
`US 8,846,100 B2
`
`FIG.2
`
`Protective coating
`
`Surelease coating
`
`Drug layered
`core
`
`Eudragit FS -30D
`coating
`
`FIG.3
`SPD465 Sustained Release Capsule
`
`Immediate -Release
`Bead (IR)
`
`Delayed -Release
`Bead 1 (DR1)
`
`Drug layer
`
`Overcoat!
`
`Drug layer
`Overcoating
`
`Delayed- release
`polymer
`
`Overcoating
`
`Delayed Release
`Bead 2 (DR2)
`
`Delayed- release
`polymer
`
`33.3%
`
`33.3%
`
`Sustained- release
`polymer
`
`QD (morning)--0.
`
`SPD4b`5 Capsule
`
`--Po-TM dosing profile
`
`Page 6
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 3 of 10
`
`US 8,846,100 132
`
`FIG.4
`
`lasso!
`
`on Profile ofSPD45512.5mg Capsules Lot#A03552A
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`Time (hr)
`
`FIG,5
`
`Dissolution Profile of SPD466 25mg Capsules Lot# A03647A
`
`o
`
`8
`
`10
`
`12
`
`14
`
`Time (fir)
`
`Page 7
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 4 of 10
`
`US 8,846,100 B2
`
`FIG.6
`
`Dissolution Profile of SPD46S 37.5mg Capsules Lot# A035498
`
`100
`
`60
`
`20
`
`100
`
`80
`
`60
`
`40
`
`20
`
`6
`
`Time (hr)
`
`10
`
`12
`
`14
`
`F1G.7
`Dissolution Profile of SPD465 60mg Capsules Lot# A03636B
`
`14
`
`Page 8
`
`

`

`U.S. Pa ent
`
`Sep. 30, 2014
`
`Sheet 5 of 10
`
`US 8,84ó,100 B2
`
`FIG
`
`2
`
`4
`
`5
`
`6
`
`7
`8
`Time (hr)
`
`9
`
`10 11 12 13 14 15 16
`
`--- SPD4t35 37.5 mg
`-4-- AapERALTr XR 25 mg
`+ mixed Amphetamine salts 12.5 mg
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`so
`
`Time (hr)
`
`Page 9
`
`

`

`U.S. Patent
`
`Sep, 30, 2014
`
`Sheet 6 of 10
`
`US 8,846,100 B2
`
`FIG. 10
`
`Time (hr)
`
`FIG. 1 1
`
`0
`
`4
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`Page 10
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 7 of 10
`
`US 8,846,100 B2
`
`F G.12
`
`-AI- 12.5 mg (Day 7)
`25 mg (Day 7)
`-4- 50 mg (Day 7)
`-v- 75 mg (Day 7)
`
`160
`
`140 -
`
`120
`
`80 -
`
`60 -
`
`40
`
`20 -
`
`E c
`
`o
`
`E
`2.5
`o c0o
`
`Eo
`
`8
`1:1 coc o
`
`o
`
`4
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`FIG 13
`
`o o
`
`o
`Individual Values
`mg Mean
`*-- Power Model Regression Line
`
`o
`
`o
`
`250
`
`200
`
`150
`
`100
`
`50
`
`E
`
`0o
`
`.c
`E
`co
`
`o.
`E<
`-6
`
`o
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`Page 11
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 8 of 10
`
`US 8,846,100 B2
`
`FIG 14
`
`Individual Values
`O
`.0 Mean
`Power Model Regression Line
`
`5000
`
`4000 -
`
`3000 -
`
`2000 -
`
`1000 -
`
`If»
`4L.
`
`F,
`
`.6o
`
`e
`
`a)
`
`0
`
`0
`
`,
`
`-
`
`10
`
`20
`
`I
`30
`
`f
`40
`
`Dose (mg)
`
`FIG 15
`
`O
`
`O
`
`8
`
`-r
`50
`
`60
`
`70
`
`80
`
`-ID- Single Dose (Day 1)
`-CH Multiple Dose (Day 7)
`
`:
`
`o
`
`D
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`10
`
`Ec
`
`o)
`
`6
`
`4 -
`
`2 -
`
`o
`
`o
`
`"1- Ea) --
`
`C»
`
`E c
`
`o F.,
`
`to
`
`4 a.
`
`2))- aCOco oo
`
`Page 12
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 9 of 10
`
`US 8,846,100 B2
`
`FIG.16
`
`-0- 12.5 mg (Day7)
`-fill- 26 mg pay 7)
`60 mg (Day7)
`-6-- 75 mg (Day7)
`
`4
`
`8
`
`12
`Time (hr)
`
`16
`
`20
`
`24
`
`o o
`
`**
`
`oo
`
`F1G.17
`
`Individual Values
`O
`NIB Mean
`
`Power Model Regression Line
`
`o
`
`0
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`60
`
`50 -
`
`3 -
`0
`
`2 0 -
`
`o
`
`o
`
`E c
`
`o
`
`---
`co
`.c
`E c
`03 C
`V, o
`
`c8
`
`cc 0
`co oo2
`
`Page 13
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 10 of 10
`
`US 8,846,100 B2
`
`FIG 18
`
`0
`individual Values
`mil Mean
`-A- Power Model Regression Une
`
`o
`
`o
`
`o
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`Dose (mg)
`
`1800
`
`1600
`EIs 1400
`
`1200
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`o
`0-
`
`CES
`
`I
`
`E
`
`o
`
`o
`
`Page 14
`
`

`

`US 8,846,100 B2
`
`1
`CONTROLLED DOSE DRUG DELIVERY
`SYSTEM
`
`BACKGROUND OF THE INVENTION
`
`30
`
`20
`
`Traditionally. drug delivery systems have focused on con-
`stant/sustained drug output with the objective of minimizing
`peaks and valleys of drug concentrations in the body to opti-
`mize drug efficacy and reduce adverse effects. Reduced dos -
`ing frequency and improved patient compliance can also be 10
`expected for constantlsustained release drug delivery sys-
`tems, compared to immediate release preparations. However,
`for certain drugs, sustained release delivery is not suitable and
`is affected by the following factors
`First pass metabolism: Some drugs, such as p- blockers,
`p- estradiol, and salicylamide, undergo extensive first pass
`metabolism and require fast drug input to saturate metaboliz-
`ing enzymes in order to minimize pre -systemic metabolism.
`Thus, a constant/sustained oral method of delivery would
`result in reduced oral bioavailability.
`Biological tolerance: Continuous release drug plasma pro-
`files are often accompanied by a decline in the pharmaco-
`therapeutic effect of the drug, e.g., biological tolerance of
`transdermial nitroglycerin.
`Chronopharmacology and circadian rhythms: Circadian 25
`rhythms in certain physiological functions are well estab-
`lished. It has been recognized that a symptom or disease onset
`can occur
`specific time periods of
`24 hour day, e.g.,
`asthma and angina pectoris attacks are most frequently in the
`morning hours (Lemmer, B. J Controlled Release. 1991
`16:63 -74; Lemmer B. Pulsatile Drug Delivery: Current
`Applications and Future Trends (R Gurney, H E Junginger, N
`A Peppeas, eds.) 1993; 11 -24).
`Local therapeutic need: For the treatment of local disorders
`such as inflammatory bowel disease, the delivery of com- 35
`pounds to the site of inflammation with no loss due to absorp-
`tion in the small intestine is highly desirable to achieve the
`therapeutic effect and to minimize side effects.
`Gastric irritation or drug instability in gastric fluid: For
`compounds with gastric irritation or chemical instability in 40
`gastric fluid, the use of a sustained release preparation may
`exacerbate gastric irritation and chemical instability in gastric
`fluid.
`Drug absorption differences in various gastrointestinal
`segments: In general. drug absorption is moderately slow in 45
`the stomach, rapid in the small intestine, and sharply declin-
`ing in the large intestine. Compensation for changing absorp-
`tion characteristics inthe gastrointestinal tract may be impor-
`tant for some drugs. For example, it is rational for a delivery
`system to pump out the drug much faster when the system 50
`reaches the distal segment of the intestine, to avoid the
`entombment of the drug in the feces.
`Pulsed dose delivery systems, prepared as either single unit
`or multiple unit formulations. and which are capable of
`releasing the drug after a predetermined time, have been ss
`studied to address the aforementioned problematic areas for
`sustained release preparations. These same factors are also
`problematic in pulsed dose formulation development. For
`example, gastrointestinal transit times vary not only from
`patient to patient but also within patients as a result of food 60
`intake, stress, and illness; thus a single -unit pulsed -release
`system may exhibit higher variability compared to a multiple
`unit system. Additionally, drug layering or core making for
`multiple unit systems is a time- consuming and hard-to-opti-
`mize process. Particularly challenging for formulation s