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`PATENTU;;5;,Tg'CAT,ON
`
`TRANSNHTTAL
`(ONLYFOR NEW NONPROViS.'ONAt. AF‘Pt.tCA TtONS UNDER
`37 one 153(3))
`
`I’-ffomeii Docket No.
`
`20342i"1202Ei53-U88
`
`CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`Express Ma.-‘i Labeu‘ No.
`
`"""'-‘°A'”°” 5'-E'“E“T3
`See MPEP chapter 600 conceming utiiity patent apotication contents.
`Fee Transmittal Fom1 [e.g.. F'T0i5Bi1 T)
`(Sr.-hmui an origins: and a duplicate liar Fee processing}
`See 37 CFR 1.27.
`‘applicant “aims sma" anti” status‘
`Specification
`[Totai Pages
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`(For information on the preferred arrangement. see MPEP 603.01‘ {at}
`
`56
`
`X
`
`ADDRESS TO:
`
`E10:35 for Patents
`Alexandria VA 223134 450
`ACCOMPANYING APPLICATION PARTS
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`9. D Assignment Papers {cover sheet 8. dOcument(s)}
`Name of Assignee:
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`,0 E] 31 cm 3.730;) Stahernent
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`Copies of foreign patent documents,
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`18.
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`CI Continuation CI Divisional D Continuation-in-part {CIPJ
`Prior sppiication information: Examiner
`
`of prior application No.:
`Art Unit:
`
`______
`
`19. CORRESPONDENCE ADDRESS
`
`The address associated with Customer Number
`
`07278
`
`OR B C°”“35P°"‘j9"°e 355*“ bah“
`
`Joseph R. Robinson
`DARBY 8: DARBY P.C.
`
`P.O. BOX 5257
`
`New York
`
`| state
`Telephone
`
`286-2910
`
`Email Address
`
`10150-5257
`
`-L
`F
`Jeph R. Robinson
`
`.» 61*” , @333)
`
`Date
`Registration No.
`
`May 12, 2006
`
`Amerigen Ex. 1004, p. 1
`Amerigen Ex. 1004, p.
`1
`
`

`
`Application Data Sheet
`
`Application Information
`
`Application Type::
`
`Subject Matter::
`
`Suggested Group Art Unit::
`
`CD-ROM or CD-R?::
`
`Sequence submission?::
`
`Regular
`
`Utility
`
`1615
`
`None
`
`None
`
`Computer Readable Form (CRF)?::
`
`No
`
`Title::
`
`CONTROLLED DOSE DRUG DELIVERY
`
`Attorney Docket Number::
`
`20342/1202653—US8
`
`SYSTEM
`
`Request for Early Pub|ication?::
`
`Request for Non—Pub|ication?::
`
`Total Drawing Sheets:
`
`Small Entity?::
`
`Petition included?::
`
`Secrecy Order in Parent App|.?::
`
`No
`
`No
`
`10
`
`No
`
`No
`
`No
`
`Applicant Information
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country::
`
`US
`
`Status::
`
`Given Name::
`
`Family Name:
`
`Full Capacity
`
`Amir
`
`Shojael
`
`City of Residence::
`
`Phoenixville
`
`State or Province of Residence::
`
`Country of Residence::
`
`PA
`
`US
`
`Street of mailing address::
`
`241 Rivercrest Drive
`
`City of mailing address::
`
`Phoenixville
`
`Page # 1
`
`Initial 05/12/06
`
`Amerigen Ex. 1004, p. 2
`Amerigen Ex. 1004, p. 2
`
`

`
`State or Province of mailing address::
`
`Postal or Zip Code of mailing address::
`
`PA
`
`19460
`
`Correspondence Information
`
`Correspondence Customer Number::
`
`07278
`
`Representative Information
`
`Representative Customer Number::
`
`07278
`
`Domestic Priority Information
`
`Foreign Priority Information
`
`Assignee Information
`
`Assignee name::
`
`Street of mailing address::
`
`City of mailing address::
`
`State or Province of mailing address::
`
`Postal or Zip Code of mailing address::
`
`SHIRE LLC
`
`9200 Brookfield Court
`
`Florence
`
`KY
`
`41042
`
`Page # 2
`
`Initial 05/12/06
`
`Amerigen Ex. 1004, p. 3
`Amerigen Ex. 1004, p. 3
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`

`
`Attorney Docket No. 203431202653-USS
`(PATENT)
`
`CONTROLLED DOSE DRUG DELIVERY SYSTEM
`
`BACKGROUND OF THE INVENTION
`
`Traditionally, drug delivery systems have focused on constant/sustained drug output with
`
`the objective of minimizing peaks and valleys of drug concentrations in the body to optimize
`
`drug efficacy and reduce adverse effects. Reduced dosing frequency and improved patient
`
`compliance can also be expected for constantfsustained release drug delivery systems, 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 I3-blockers, I3-estradiol, and salicylamide,
`
`undergo extensive first pass metabolism and require fast drug input to saturate metabolizing
`
`enzymes in order to minimize pre—systemic metabolism. Thus, a constantfsustained oral method
`
`of delivery would result in reduced oral bioavailability.
`
`Biological tolerance: Continuous release drug plasma profiles are often accompanied by a
`
`decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal
`
`nitroglycerin.
`
`Chronopharmacology and ci1'cadian rhythms: Circadian rhythms in certain physiological
`
`functions are well established. It has been recognized that a symptom or disease onset can occur
`
`during specific time periods of the 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 Gumey, HE Junginger, NA
`
`Peppeas, eds.) 1993; 11-24).
`
`Local therapeutic need: For the treatment of local disorders such as inflammatory bowel
`
`disease, the delivery of compounds to the site of inflammation with no loss due to absorption in
`
`the small intestine is highly desirable to achieve the therapeutic effect and to minimize side
`
`effects.
`
`Gastric irritation 01' drug instability in gastric fluid: For compounds with gastric irritation
`
`or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate
`
`gastric irritation and chemical instability in gastric fluid.
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 4
`Amerigen Ex. 1004, p. 4
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`

`
`Drug absorption differences in Various gastrointestinal segments: In general, drug
`
`absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining
`
`in the large intestine. Compensation for changing absorption characteristics in the
`
`gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery
`
`system to pump out the drug much faster when the system 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 a1'e capable of releasing the d1'ug after a predetermined time, have been 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 intake, stress, and illness; thus a single—unit pulsed—release system may exhibit
`
`higher variability compa1'ed to a multiple unit system. Additionally, drug laye1'ing or core making
`
`fo1' multiple unit systems is a time-consuming and hard-to-optimize process. Particularly
`
`challenging fo1' formulation scientists has been overcoming two conflicting hurdles for pulsatile
`
`formulation development, i.e., lag time and rapid release.
`
`Various enteric materials, e.g., cellulose acetate phthalate, hydroxypropyl
`
`methylcellulose phthalate, polyvinyl acetate phthalate, and the EUDRAGIT® acrylic polymers,
`
`have been used as gastroresistant, enterosoluble coatings for single drug pulse release in the
`
`intestine (Xu X and Lee P, Pharm Res. 1993; l0(8):l 144-] 152). The enteric materials, which are
`
`soluble at higher pH values, are frequently used fo1' colon-specific delivery systems. Due to their
`
`pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as
`
`well as inte1'- and intra-subject variability are major issues for using ente1'ic coated systems as a
`
`time-cont1'olled release of drugs.
`
`A retarding, swellable hydrophilic coating has been used for oral delayed release systems
`
`(Gazzaniga et al., Eur] Pharm Biopharm. 1994; 40(4):246—250; Gazzaniga et al., S.T.P. Pharma
`
`Sciences. 1996; 5(l):33—38). It was demonstrated that lag time was linearly correlated with
`
`coating weight gain and drug release was pH independent.
`
`Hydroxypropyl methylcellulose barriers with erodible andfor gellable cha1'acteristics
`
`fo1'med using press coating technology for tablet dosage forms have been described to achieve
`
`Attorney docket No. 20342!1202653—US8
`
`Amerigen Ex. 1004, p. 5
`Amerigen Ex. 1004, p. 5
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`

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`time—programmed release of drugs (Conte et al., Biomaterials. 1993; l4(l3):l0l7—l023). Barrier
`
`formulation variables (such as grade of hydroxypropyl methylcellulose, water—soluble and water-
`
`insoluble excipients) significantly altered the lag time and the release rate from the center cores.
`
`Special grades of hydroxypropyl methylcellulose, e.g., METOLOSE® 60SH, 90SH
`
`(Shin-Etsu Ltd., Japan), and METHOCEL® F4M (Dow Chemical Company, USA) have been
`
`used as a hydrophilic matrix material to achieve bimodal drug release for several drugs, i.e.,
`
`aspirin, ibuprofen, and adinazolam (WO 87300044). Bimodal release is characterized by a rapid
`
`initial release, followed by a period of constant release, and then by a second rapid drug release.
`
`Tablets or capsules coated with a hydrophobic wax—surfactant layer, made from an
`
`aqueous dispersion of carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and
`
`hydroxypropyl methylcellulose have been used for rapid drug release after a predetermined lag
`
`time. However, even though a two—hour lag time was achieved for the model drug theophylline
`
`at a higher coating level (60%), three hours were required for a complete release of theophylline
`
`afte1' the lag time. (Wa1ia et al., Pharm Dev Tech. 1998; 3(l):l03-113)
`
`A sustained-release d1'ug delivery system is described in U.S. Pat. No. 4,871,549. When
`
`this system is placed into dissolution medium or the gastrointestinal tract, wate1' influx and the
`
`volume expansion of the swelling agent cause the explosion of the water permeable membrane.
`
`The drug thus releases after a predetermined time period.
`
`The OROS® push—pull system (Alza Company) has been developed for pulsatile delivery
`
`of water—soluble and water—insoluble drugs (Theeuwes, Drug Dev lnd Pharm. 1983; 9(7): I 331-
`
`1357; Theeuwes F, Novel Drug Delivery and Its Therapeutic Application (LF Prescott and WS
`
`Nimmos eds.) 1989; 323-340), e.g. the OROS-CT® system and is based on the swelling
`
`properties of an osmotic core compartment which provides a pH-independent, time-controlled
`
`drug release.
`
`The PULSlNCAP® dosage form releases its drug content at either a predetermined time
`
`or at a specific site (e.g., colon) in the gastrointestinal tract (WO 90709168). The drug
`
`formulation is contained within a water—insoluble capsule body and is sealed with a hydrogel
`
`plug. Upon oral administration, the capsule cap dissolves in the gastric juice and the hydrogel
`
`plug swells. At a controlled and predetermined time point, the swollen plug is ejected from the
`
`PULSINCAP® dosage form and the encapsulated drug is released. A pulsatile capsule system
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 6
`Amerigen Ex. 1004, p. 6
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`

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`containing captopril with release after a nominal 5—hr period was found to perform, reproducible
`
`in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no
`
`measurable amounts of the drug were observed in the blood, possibly due to instability of the
`
`drug in the distal intestine. (Wilding et al., Pharm Res. l992;9(5):6S4—657)
`
`ADDERALL® is an immediate release composition, which includes a mixture of four
`
`amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine
`
`aspartate monohydrate and amphetamine sulfate. This combination of amphetamines is
`
`indicated fo1' the treatment of Attention Deficit Hyperactivity Disorder in children f1'om 3-10
`
`years of age.
`
`One disadvantage of immediate release—only treatments for children is that two separate
`
`doses are administered, one in the morning and one approximately 4-6 hours later, commonly
`
`away from home under other than parental supervision. This requires a second treatment, which
`
`is time-consuming, inconvenient and may be problematic for those child1'en having difficulties in
`
`swallowing tablet formulations. ADDERALL XR® met the need for a dosage form, which can
`
`be administered once, in place of the two oral doses which a1'e needed using the conventional
`
`drug delivery formulations of the prior art. See U.S. Patent Nos. 6,322,819 and 6,605,300; co-
`
`pending Reissue Application Nos. 1l:"09l,010 and l l/091,0] 1.
`
`There a1'e currently two medications (ADDERALL XR® and STRATTERATM) approved
`
`by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD in adults.
`
`ADDERALL XR® is a mixed amphetamine salts medication. STRATTERA‘”"' is an
`
`atomoxetine (a norepinephrine reuptake inhibitor) medication. Long acting stimulant
`
`preparations, such as ADDERALL XR® and CONCERTA® (methylphenidate), are designed to
`
`provide a duration of effect up to 12 hours. However, clinicians have noted that a proportion of
`
`patients treated with these formulations require additional treatment with a short-actin g stimulant
`
`to extend the daily therapeutic effect. For patients taking long—acting stimulant formulations who
`
`require duration of clinical benefit beyond 10-12 hours, clinicians have augmented the morning
`
`long—acting formulation, typically at 8-10 hours post-dose, with a dose of the same immediate-
`
`release (]R) medication. Typically, the dose of the IR medication is smaller than the long—acting
`
`dose. This augmentation strategy is most relevant to the “longer day demands” of adult and
`
`adolescents, rather than school age, pediatric patients.
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 7
`Amerigen Ex. 1004, p. 7
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`

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`Thus, a need exists for a once—daily, long—acting oral composition that provides effective
`
`treatment of ADH D, without supplementation, for patients with longer day demands (e.g., 14-16
`
`awake hours).
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a long-acting amphetamine pharmaceutical composition,
`
`which includes an immediate release component, a delayed pulsed release component and a
`
`sustained release component, to meet the therapeutic needs for ADHD patients with longe1'-day
`
`demands. The present invention fills the need for once-daily longer-day treatment of ADHD by
`
`providing an amphetamine pharmaceutical composition that is bioequivalent to an equal dosage
`
`of ADDERALL XR® followed by an IR amphetamine composition 8 hours later.
`
`The addition of a second delayed pulsed release formulation, having a lag time of about 8
`
`hours, to ADDERALL XR® cannot, as one might expect, meet the recognized need for a once-
`
`daily long-acting amphetamine composition that meets a patient’s longe1' day requirements (i.e.,
`
`a once-daily amphetamine composition that is bioequivalent to ADDERALL XR® plus an
`
`immediate release amphetamine composition administered 8 hours later). A delayed pulsed
`
`formulation having a lag time of about 8 hours would be unsuitable because it would release the
`
`active agent in the distal gastrointestinal tract (the colon), resulting in decreased absorption of the
`
`active agent.
`
`Unexpectedly, it has been discovered that a sustained release formulation administered in
`
`combination with immediate release and delayed pulsed release components similar to those
`
`present in ADDERALL XR® can mimic the bioavailability of an equivalent total amphetamine
`
`dosage provided by ADDERALL XR® followed by an immediate release amphetamine
`
`composition 8 hours late1'. However, the “usual” or “typical” construction for a sustained release
`
`formulation is not suitable. Typically, a sustained release formulation is constructed with a
`
`delayed release coating overlaying a sustained release coating. Such a usual or typical sustained
`
`release construction results in a Tmax that is too early afte1' administration to a patient to result in
`
`a composition that meets the longer—day requirements for the treatment of ADHD. For example,
`
`the dissolution profiles for a typical sustained release formulation (PDUl49~l24) and a sustained
`
`release formulation of the present invention (PDO149-120) a1'e illustrated in FIG. 1. PD0149-
`
`l24 has a typical sustained release formulation construction, wherein the immediate release bead
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 8
`Amerigen Ex. 1004, p. 8
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`

`
`of Example I (see Examples 1 and 2, infra) is coated with a sustained release coating
`
`(SURELEASE®), the sustained release coating is coated with a delayed release coating
`
`(EUDRAGIT® FSSU D), and the delayed release coating is coated with a protective laye1'
`
`(OPADRY®). PD0l49—l20 is an embodiment ofa sustained release formulation of the present
`
`invention. PDOI49-120 has a construction wherein the immediate release bead of Example 1 is
`
`coated with a delayed release coating (EUDRAGIT® FS 30 D), the delayed release coating is
`
`coated with a protective coating (OPADRY®), and the protective coating is coated with a
`
`sustained release coating (SURELEASE®). As illustrated in FIG. 1, PDOl49-120 provides a
`
`later Tmax relative to a typically—const1'ucted sustained release formulation, PD0l49— l 24.
`
`According to the present invention, an atypical, counter—intuitiVe construction for a
`
`sustained release amphetamine formulation, when administered in combination with an
`
`immediate release formulation and a delayed pulsed release formulation, is bioequivalent to
`
`ADDERALL XR® followed by an immediate release amphetamine formulation administered 8
`
`hours later. A sustained release formulation of the present invention comprises at least one
`
`amphetamine salt layered onto, or incorporated into, a core; a delayed release coatin g layered
`
`onto the amphetamine core; a sustained release coating layered onto the delayed release coating;
`
`and, optionally, a protective coating. See FIG. 2.
`
`In a preferred embodiment, the delayed release
`
`component is pH dependent.
`
`A sustained release pharmaceutical formulation of the present invention can comprise
`
`about 10% to about 150% of the amphetamine dosage of the immediate release mixed
`
`amphetamine salt composition andfor an extended release mixed amphetamine salt composition.
`
`For example, the sustained release formulation can be administered, in the same or different
`
`dosage forms, with the IR and delayed pulsed release components of ADDERALL XR® in an
`
`amphetamine dosage ratio of 1:l:l (e.g., 10 mg immediate release amphetamine, 10 mg delayed
`
`pulsed release amphetamine, 10 mg sustained release amphetamine). Thus, in this example, the
`
`sustained release composition comprises about 33% of the total amphetamine dose.
`
`In another
`
`example, a patient with ADHD and insomnia can be administered a reduced amount of the
`
`sustained release composition, e.g., 10 mg immediate release amphetamine, 10 mg delayed
`
`pulsed release amphetamine, and 5 mg sustained release amphetamine (the sustained release
`
`composition comprises 20% of the total amphetamine close). Thus, according to the present
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 9
`Amerigen Ex. 1004, p. 9
`
`

`
`invention, a clinician can adjust the sustained release formulation dosage to meet the needs of an
`
`individual patient suffering from ADHD.
`
`The pharmaceutical composition of the present invention, comprising an immediate
`
`release amphetamine component, a delayed pulsed release amphetamine component and a
`
`sustained release amphetamine component, delivers, in a single dose, mixed amphetamine salts
`
`to a patient with a pharmacokinetic profile similar to a 2-dose treatment with a currently
`
`available commercial extended release composition (i.e., ADDERALL XR®) plus an immediate
`
`release composition administered about eight hours after the ADDERALL XR®. See, for
`
`example, FIG. 9. This similarity in bioequivalence is surprising because it would be expected
`
`that some part of the drug delivered by the delayed release components of compositions of the
`
`present invention (i.e., the delayed pulsed release and/or the sustained release components)
`
`would be lost (i.e., not absorbed) in the colon. The FDA package insert and labeling for
`
`ADDERALL XR® (Shire US, Inc.) a1'e hereby incorporated by reference in their entirety.
`
`Preferred amphetamine salts are those in ADDERALL XR®, i.e., dext1'oamphetamine
`
`sulfate, dextroamphetamine saccharate, amphetamine aspartate monohyd1'ate and amphetamine
`
`sulfate. However, the invention is not limited to these salts. Other amphetamines and
`
`amphetamine salts can be used in the pharmaceutical compositions of the present invention
`
`including, for example, amphetamine base, chemical and chiral derivatives thereof; other
`
`amphetamine salts; and mixtures of the foregoing.
`
`The three components comprising the extended release amphetamine composition of the
`
`invention release doses of the active ingredients at varying, pre-determined times to provide for
`
`full day treatment (i.e., about 14 hours to about 16 hours) of conditions such as ADHD. A
`
`treatment fo1' ADHD, which can be delivered in a single dosage is especially beneficial to
`
`adolescents and adults who typically have longe1' daily waking hours compared to children.
`
`The compositions of the present invention comprise an immediate release component, a
`
`delayed pulsed release component, and a sustained release component.
`
`In embodiments of the
`
`invention, delayed pulsed release and.r"or sustained release can be provided by an enteric coating.
`
`ln a particular embodiment, the immediate release component, delayed pulsed release
`
`component and sustained release component each contain equal amounts of active ingredient.
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 10
`Amerigen Ex. 1004, p. 10
`
`

`
`In one embodiment, the immediate release, delayed pulsed release and sustained release
`
`components of the composition are present on the same core. In another embodiment, the
`
`immediate release and delayed pulsed release components are present on different cores.
`
`In a
`
`further embodiment, the delayed pulsed release and sustained release components are present on
`
`different co1'es.
`
`In a p1'eferred embodiment, the immediate release, delayed pulsed release and
`
`sustained release components are present on different cores. See FIG. 3.
`
`In yet another embodiment, the amphetamine salt is coated onto a co1'e.
`
`In a furthe1'
`
`embodiment, the amphetamine salt is incorporated into a co1'e.
`
`lt is contemplated that compositions of the present invention can include a combination
`
`of the hereinabove referred to cores (one or more cores that include three components on the
`
`same core, one or more cores that include two of the three components on the core, and one or
`
`more cores that include one of the three components on the core).
`
`In an embodiment of the present invention, a pharmaceutical composition is provided in
`
`which there is immediate release of drug, a delayed pulsed release of drug, and a sustained
`
`release of drug, and wherein the drug includes one or more amphetamine salts and mixtures
`
`thereof. In a preferred embodiment, the delayed pulsed release of d1'ug begins about one hour
`
`after oral administration of the composition to a patient in the fasted state and the sustained
`
`release of drug begins about four hours to about six hours after oral administration to a patient in
`
`the fasted state.
`
`Surprisingly, amphetamine salt pharmaceutical compositions of the present invention
`
`deliver about bioequivalent drug levels to a patient in either a fasted state or fed state. Thus, an
`
`amphetamine salt composition according to the present invention does not exhibit a food effect.
`
`This is surprising because it would be expected that some of the drug delivered by delayed
`
`release would be released earlier in the presence of food (especially fatty food) due to the
`
`increase in gastric pH that accompanies the ingestion of food.
`
`A pharmaceutical composition according to the present invention includes:
`
`(a)
`
`(b)
`
`(C)
`
`an immediate release bead comprising an amphetamine salt;
`
`a first delayed release bead comprising an amphetamine salt; and
`
`a second delayed release bead comprising an amphetamine salt;
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 11
`Amerigen Ex. 1004, p. 11
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`

`
`wherein the first delayed release bead provides pulsed release of the mixed amphetamine salt and
`
`the second delayed release bead provides sustained release of the mixed amphetamine salt.
`
`A pharmaceutical composition of the present invention provides a patient with at least
`
`about 14 hours to about 16 hours of effective therapy for Attention Deficit Hyperactivity
`
`Disorder (ADHD).
`
`In an embodiment of the invention, the d-amphetamine Cm,“ after administ1'ation of a 37.5
`
`mg amphetamine pharmaceutical composition to a human patient is about 50 ng/ml.
`
`In another embodiment, the d-amphetamine area under the cu1've from time 0 to the last
`
`measured time (AUCO—last) after administration of a 37.5 mg amphetamine pharmaceutical
`
`composition to a human patient is about 1058 ng-hr/ml.
`
`Further, according to an embodiment of the present invention, the d—amphetamine area
`
`under the curve from time 0 to time infinity (AUCO-inf) after administration of a 37.5 mg
`
`amphetamine pharmaceutical composition to a human patient is about 1085 ng-hrfml.
`
`In an embodiment, the present invention provides a pharmaceutical composition, wherein
`
`the d-amphetamine T.,,,,,,
`
`is about 8.2 hours after administ1'ation of a 37.5 mg amphetamine
`
`pharmaceutical composition to a human patient.
`
`In a particular embodiment, the {—amphetamine Cm“ after administration of a 37.5 mg
`
`amphetamine pharmaceutical composition to a human patient is about l5 ngfml.
`
`In a further embodiment, the .’—amphetamine area under the curve from time 0 to the last
`
`measured time (AUCo_[a5,) after administration of a 37.5 mg amphetamine pharmaceutical
`
`composition to a human patient is about 354 ng-hrfml.
`
`In another embodiment, the I-amphetamine area under the curve from time 0 to time
`
`infinity (AUCo_;,,.c) after administration of a 37.5 mg amphetamine pharmaceutical composition to
`
`a human patient is about 373 ng-hrfml.
`
`Further, in an embodiment of the present invention, the Lamphetamine Tm“ is about 8.4
`
`hours after administration of a 37.5 mg amphetamine pharmaceutical composition to a human
`
`patient.
`
`In a further embodiment, a protective layer is provided over at least one enteric coating.
`
`In another embodiment, a protective layer is provided between the amphetamine salt and at least
`
`Attorney docket No. 20342/1202653—US8
`
`Amerigen Ex. 1004, p. 12
`Amerigen Ex. 1004, p. 12
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`

`
`one enteric coating. A protective layer can also be provided over the sustained release coating
`
`according to the present invention.
`
`In a particular embodiment, the amphetamine salt is selected from the group consisting of
`
`dextroamphetamine
`
`sulfate,
`
`dextroamphetamine
`
`saccharate,
`
`amphetamine
`
`aspartate
`
`monohydrate, amphetamine sulfate, and mixtures thereof.
`
`In
`
`a more
`
`particula1'
`
`embodiment,
`
`the
`
`amphetamine
`
`salt
`
`is
`
`a mixture of
`
`dextroamphetamine
`
`sulfate,
`
`dextroamphetamine
`
`saccharate,
`
`amphetamine
`
`aspa1'tate
`
`monohydrate, and amphetamine sulfate.
`
`In an aspect of the present invention, the pharmaceutical composition does not exhibit a
`
`food effect.
`
`The present
`
`invention encompasses methods for treating ADHD, which comprise
`
`administering the amphetamine salt pharmaceutical composition of the present invention to a
`
`patient suffering from ADHD.
`
`The delayed pulsed release and sustained release components retard or delay the release
`
`of the pharmaceutically active ingredient(s) fo1' a specified time period ("lag time") until a
`
`predetermined time. For example, a delayed pulsed release component having an enteric coating
`
`layer retards or delays the release of the pharmaceutical active or drug for a lag time, then
`
`releases the drug rapidly and completely, i.e., a pulsed release.
`
`In one embodiment of a delayed
`
`pulsed release, the entire dose is released within about 30-60 minutes following a lag time afte1'
`
`administration of the composition.
`
`In another example, a sustained release component having an
`
`enteric release coating retards or delays the release of the pharmaceutical active or drug for a lag
`
`time and then the release of the drug is sustained (i.e., release of the entire dose takes greater
`
`than about 60 minutes).
`
`The delay 01' lag time will take into conside1'ation factors such as transit times, food
`
`effects, inflammatory bowel disease, use of antacids or other medicaments, which can alter the
`
`pH of the GI tract.
`
`According to the present invention, the lag time for the delayed pulsed release component
`
`can be pH dependent or pH independent.
`
`In an embodiment of the invention, the lag time for the
`
`delayed pulsed release component is only time-dependent, i.e., pH independent.
`
`In a preferred
`
`embodiment, the lag time is pH dependent.
`
`1 0
`
`Attorney docket N0. 20342f1202653—US8
`
`Amerigen Ex. 1004, p. 13
`Amerigen Ex. 1004, p. 13
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`

`
`According to the present invention, a lag time can be about 1 hour to about 14 hours.
`
`Multiple dose formulations can have more than one lag time.
`
`In a preferred embodiment, the
`
`delayed pulsed release component has a lag time of about 60 minutes and the sustained release
`
`component has a lag time of about 4 to about 6 hours.
`
`In one aspect, the present invention is directed to a composition that provides for enteric
`
`release of at least one pha1'maceuticall y active amphetamine salt, including at least one
`
`pharmaceutically active amphetamine salt that is coated with an enteric coating wherein (1) the
`
`enteric release coating has a defined minimum thickness andfor (2) there is a protective layer
`
`between the at least one pharmaceutically active amphetamine salt and the enteric release coating
`
`andfor (3) there is a protective layer over the enteric release coating.
`
`In attempting to provide for delayed pulsed release of an amphetamine salt, applicants
`
`found that use of an enteric release coating as generally practiced in the art did not provide the
`
`desired release profile. Using the typical amount of enteric coating (10 to 15 wt %) fo1' the
`
`delayed pulsed release component resulted in undesired premature leakage of the drug from the
`
`delivery system into the upper gastrointestinal tract, and drug delivery at the desired, more distal
`
`location in the gastrointestinal tract was reduced. Thus, this coating did not meet the
`
`requirements for a drug release profile, which provides full beneficial therapeutic activity at the
`
`desired time.
`
`Applicants found that using a thicker application of enteric coating on the delayed pulsed
`
`release component allowed for the delayed release pulsed dose to be released only, and
`
`completely, at the appropriate time in the desired predetermined area of the gastrointestinal tract,
`
`i.e., in the intestine.
`
`This was surprising because an increase in ente1'ic coating thickness above a minimum
`
`thickness of about 5 to 10 wt % typically does not have a significant effect on release of drug
`
`from within such coatings. Typically, application ofa thicker coating (greater than 15 wt %) will
`
`only marginally increase the time