Trials@uspto.gov
`571-272-7822
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` Entered: April 14, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC,
`Petitioner,
`
`v.
`
`SHIRE LABORATORIES, INC.,1
`Patent Owner.
`
`
`Case IPR2017-00011
`Patent RE41,148 E
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`1 The Petition, as filed, identifies Shire Laboratories, Inc. as the Patent
`Owner. According to Patent Owner, “[t]he real parties-in-interest are Shire
`Laboratories, Inc. and Shire LLC.” Paper 4, 1. We note that Patent Owner
`has filed Papers 4 and 5 as “Shire Laboratories, Inc.,” but filed its
`Preliminary Response (Paper 6) as “Shire LLC.”
`
`
`571-272-7822
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` Paper 7
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` Entered: April 14, 2017
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC,
`Petitioner,
`
`v.
`
`SHIRE LABORATORIES, INC.,1
`Patent Owner.
`
`
`Case IPR2017-00011
`Patent RE41,148 E
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`1 The Petition, as filed, identifies Shire Laboratories, Inc. as the Patent
`Owner. According to Patent Owner, “[t]he real parties-in-interest are Shire
`Laboratories, Inc. and Shire LLC.” Paper 4, 1. We note that Patent Owner
`has filed Papers 4 and 5 as “Shire Laboratories, Inc.,” but filed its
`Preliminary Response (Paper 6) as “Shire LLC.”
`
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`IPR2017-00011
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`I. INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Mylan” or “Petitioner”) filed a Petition
`(Paper 1, “Pet.”) on October 4, 2016, requesting an inter partes review of
`claims 1–20 of U.S. Patent No. RE41,148 E (Ex. 1001, “the ’148 patent”).
`Shire LLC (“Shire” or “Patent Owner”) filed a Preliminary Response (Paper
`6, “Prelim. Resp.”) on January 17, 2017. We have statutory authority under
`35 U.S.C. § 314, which provides that an inter partes review may not be
`instituted “unless . . . there is a reasonable likelihood that the petitioner
`would prevail with respect to at least 1 of the claims challenged in the
`petition.”
`Upon consideration of the arguments and evidence presented in the
`Petition and the Preliminary Response, we are not persuaded that Petitioner
`has established a reasonable likelihood that it would prevail in its challenges
`to claims 1–20 of the ’148 patent. Accordingly, we do not institute an inter
`partes review of claims 1–20.
`
`A. Related Proceedings
`Petitioner informs us that “[t]he ’148 patent is currently the subject, as
`
`the parent patent[2] or current reissue form,” of the following proceedings:
`Shire LLC v. Amerigen Pharmaceuticals Ltd., No. 1:14-cv-06095-RMB-JS
`(D.N.J.); Shire LLC v. Abhai LLC, No. 1:15-cv-13909-WGY (D. Mass.);
`
`2 U.S. Patent No. 6,605,300, issued August 12, 2003 to Beth A. Burnside et
`al. (“the ’300 patent”).
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`Shire LLC v. Par Pharmaceutical, Inc., No. 1-14-cv-01454 (D.N.J.); Shire
`LLC v. CorePharma, LLC, No. 1-14-cv-05694 (D.N.J.); Shire LLC v. Neos
`Therapeutics, Inc., No. 3-13-cv-01452 (N.D. Tex.); Shire LLC v. Watson
`Pharmaceuticals, Inc., No. 1-11-cv-02340 (S.D.N.Y.). Patent Owner
`identifies, for the most part, the same related matters in its Mandatory
`Notices under 37 C.F.R. § 42.8(a)(2). Paper 4, 1.
`
`The parties further inform us that U.S. Patent RE42,096,3 a related
`patent, is currently the subject of IPR2016-01033—Mylan Pharmaceuticals,
`Inc. v. Shire Labs, Inc. Pet. 5; Paper 4, 2.
`Finally, Patent Owner represents that Petitioner “Mylan . . . has no
`litigation with Shire over [the ’148 and ’096] patents.” Prelim. Resp. 1.
`
`
`3 U.S. Patent RE42,096, reissued February 1, 2011 to Beth A. Burnside et
`al. (“the ’096 patent”).
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`B. The Asserted Ground of Unpatentability
`Petitioner asserts that claims 1–20 are unpatentable under 35 U.S.C.
`
`§ 103 as obvious over Mehta,4 PDR 1997,5 Brown,6 Amidon,7 and Slattum.8
`Pet. 8–58.
`
`Petitioner supports its challenges with the Declaration of David E.
`Auslander, Ph.D., executed September 17, 2016 (Ex. 1002, “Auslander
`Declaration”), and the Declaration of Anthony Palmieri, Ph.D., R.Ph.,
`executed August 26, 2016 (Ex. 1029, “Palmieri Declaration”). Patent
`Owner supports its position with the Declaration of Bernhardt L. Trout,
`Ph.D., executed January 10, 2017 (Ex. 2001, “Trout Declaration”).
`
`
`4 U.S. Patent No. 5,837,284, issued November 17, 1998, to Atul M. Mehta
`et al. (“Mehta”) (Ex. 1005).
`5 PHYSICIANS’ DESK REFERENCE 331, 2209–2211 (51st ed. 1997) (“PDR
`1997”) (Ex. 1009).
`6 Gerald L. Brown et al., Behavior and Motor Activity Response in
`Hyperactive Children and Plasma Amphetamine Levels Following a
`Sustained Release Preparation, 19 JOURNAL OF THE AMERICAN ACADEMY OF
`CHILD PSYCHIATRY 225–239 (1980) (“Brown”) (Ex. 1011).
`7 U.S. Patent 5,229,131, issued July 20, 1993, to Gordon L. Amidon et al.
`(“Amidon”) (Ex. 1004).
`8 Patricia W. Slattum et al., Comparison of Methods for the Assessment of
`Central Nervous System Stimulant Response after Dextroamphetamine
`Administration to Healthy Male Volunteers, 36 J. CLIN. PHARMACOL. 1039–
`1050 (1996) (“Slattum”) (Ex. 1031).
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`C. The ’148 Patent (Ex. 1001)
`The ’148 patent, titled “ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM,” is a reissue of U.S. Patent 6,605,300, and a continuation-in-part of
`U.S. Patent RE42,096 (“the ’096 patent”).9 Ex. 1001 (51), (63).
`The ’148 patent teaches that Adderall® “comprises a mixture of four
`amphetamine salts, dextroamphetamine sulfate, dextroamphetamine
`saccharate, amphetamine aspartate monohydrate and amphetamine sulfate,
`which in combination, are indicated for treatment of Attention Deficit[]
`Hyperactivity Disorder [ADHD] in children from 3–10 years if age.” Id. at
`3:16–21. According to the ’148 patent, ADHD in children conventionally is
`treated by administering two separate doses of medication, “one in the
`morning, and one approximately 4–6 hours later, commonly away from
`home under other than parental supervision.” Id. at 3:25–27. Administering
`two separate doses, however, “is time consuming, inconvenient, and may be
`problematic for those children having difficulties in swallowing tablet
`formulations.” Id. at 3:28–30.
`In order to avoid these disadvantages, the ’148 patent discloses a
`“pulsed dose delivery system for amphetamine salts and mixtures thereof”
`that includes: “one or more pharmaceutically active amphetamine salts that
`are covered with an immediate release coating,” and “one or more
`
`
`9 The ’096 patent is a reissue of U.S. Patent No. 6,322,819, issued
`November 7, 2001 to Beth A. Burnside et al. (“the ’819 patent”). Ex. 1001
`(63).
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`pharmaceutically active amphetamine salts that are covered with an enteric
`release coating.” Id. at 3:36–49. “The immediate release component
`releases the pharmaceutical agent in a pulsed dose upon oral administration
`of the delivery system” and “[t]he enteric release coating layer retards or
`delays of [a second dose] of the pharmaceutical active.” Id. at 4:4–7.
`Figure 1 of the ’148 patent is reproduced below.
`
`
`Figure 1 of the ’148 patent depicts the target plasma level profile of
`amphetamines produced by the immediate and delayed release components
`of the pulsed delivery system. Ex. 1001, 3:37–38.
`Both the ’148 and ’096 patents “are listed in the FDA’s ‘Orange
`Book’ of approved drug products for Adderall XR®,” an extended release
`formulation that uses two types of drug-containing beads designed to give a
`double-pulsed delivery of the same mixture amphetamine salts in
`Adderall®. Prelim. Resp. 1; Ex. 2001 (Trout Declaration) ¶ 29 (citing Ex.
`1001, 3:16–30; Ex. 2003 (Orange Book); Ex. 2004, 1; Ex. 2013, 4, 14; Ex.
`2019, 12).
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`D. Illustrative Claims
`Petitioner challenges claims 1–20 of the ’148 patent, of which claims
`1 and 12 are independent claims. Claims 1 and 12, reproduced below, are
`illustrative.
`1. A pharmaceutical formulation for delivery of a mixture of
`amphetamine base salts effective to treat ADHD in a human
`patient comprising:
`an immediate release dosage form that provides
`immediate release upon oral administration to said
`patient;
`a delayed enteric release dosage form that provides
`delayed release upon oral administration to said patient;
`and
`a pharmaceutically acceptable carrier;
`wherein said amphetamine base salts comprise
`dextroamphetamine sulfate, dextroamphetamine saccharate,
`amphetamine aspartate monohydrate and amphetamine sulfate;
`wherein said pharmaceutical formulation is sufficient to
`maintain an effective level of amphetamine base salts in the
`patient over the course of at least 8 hours without further
`administration of amphetamine base salt, and the peak plasma
`concentration of amphetamine base salts reached after release
`of said delayed enteric release dosage form exceeds the peak
`plasma concentration previously reached after release of said
`immediate release dosage form; and
`wherein said pharmaceutical formulation, when
`containing about a total dose of 20 mg, will produce in a human
`individual a plasma concentration versus time curve (ng/ml
`versus hours) having an area under the curve (AUC) of about
`467 to about 714 ng hr/ml.
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`Ex. 1001, 13:28–55.
`12. A pharmaceutical formulation for delivery of a mixture of
`amphetamine base salts effective to treat ADHD in a human
`patient comprising:
`an immediate release dosage form that provides
`immediate release upon oral administration to said
`patient;
`a delayed enteric release dosage form that provides
`delayed release upon oral administration to said patient,
`wherein said enteric release dosage form comprises a
`coating of a thickness of greater than 20 μm which
`comprises dried aqueous dispersion of an anionic
`copolymer based on methacrylic acid and acrylic acid
`ethyl ester, said coating being soluble at a pH of about
`5.5 upwards; and
`a pharmaceutically acceptable carrier;
`wherein said amphetamine base salts comprise
`dextroamphetamine sulfate, dextroamphetamine saccharate,
`amphetamine aspartate monohydrate and amphetamine sulfate;
`wherein said pharmaceutical formulation is sufficient to
`maintain an effective level of amphetamine base salts in the
`patient over the course of at least 8 hours without further
`administration of amphetamine base salt, and the peak plasma
`concentration of amphetamine base salts reached after release
`of said delayed enteric release dosage form exceeds the peak
`plasma concentration of said salts previously reached after
`release of said immediate release dosage form.
`Id. at 14:19–45.
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`II. ANALYSIS
`A. Claim Construction
`In an inter partes review, the claims of an unexpired patent are
`interpreted using the broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.200(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under
`that standard, claim terms are given their ordinary and customary meaning,
`as would be understood by one of ordinary skill in the art in the context of
`the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007).
`We determine that no claim term requires express construction for the
`purpose of deciding whether to institute a review in this case. See, e.g.,
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`(“[C]laim terms need only be construed ‘to the extent necessary to resolve
`the controversy.’” (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200
`F.3d 795, 803 (Fed. Cir. 1999))).
`
`B. Asserted Obviousness of Claims 1–20
`Petitioner contends that the subject matter of claims 1–20 would have
`
`been obvious over the combined teachings of Mehta, PDR 1997, Brown,
`Amidon, and Slattum. Pet. 9–62. Patent Owner disagrees. Prelim. Resp.
`34–64. We begin our discussion with the teachings of the prior art.
`
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`1. Mehta (Ex. 1005)
`Mehta discloses that methylphenidate hydrochloride, “available
`
`commercially as, e.g., Ritalin®,” is commonly used to treat the symptoms of
`attention deficit disorder (ADD) and ADHD in children. Ex. 1005, 1:35–42.
`
`Mehta teaches that methylphenidate exists as four separate optical
`isomers—l-threo, d-threo, l-erythro, and d-erythro—and that “the threo pair
`of enantiomers of methylphenidate hydrochloride [the dl-threo racemate] is
`generally administered for the treatment of ADD and ADHD.” Id. at 1:48–
`65, 2:5–7. Mehta teaches that the dl-threo racemate “is a mild central
`nervous system stimulant with pharmacological activity qualitatively similar
`to that of amphetamines” (id. at 2:14–16), and “is a Schedule II controlled
`substance [that] produces a euphoric effect when administered through . . .
`ingestion, and thus carries a high potential for abuse.” Id. at 2:19–22.10
`Further according to Mehta:
`An additional problem is that children being treated with
`dl-threo methylphenidate must generally take one or more doses
`during the day. This creates a problem for school administrators
`who must store a controlled substance on school premises, with
`the associated risk that it may be stolen for illicit use.
`Furthermore, children may be traumatized by ridicule from peers
`when they must take medication at school.
`Id. at 2:34–41.
`
`
`10 Mehta also notes that the dl-threo racemate of methylphenidate is
`associated with “[u]ndesirable side effects . . . includ[ing] anorexia, weight
`loss, insomnia, dizziness and dysphoria.” Ex. 1005, 2:16–18.
`
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`Mehta notes that
`Sustained release formulations of dl-threo methylphenidate have
`been developed, which provide for slow release of the drug over
`the course of the day. However, it has been observed that peak
`plasma concentrations of the drug are lower when sustained
`release formulations are used. In some studies, sustained release
`formulations of methylphenidate have been shown to have lower
`efficacy than conventional dosage forms.
`Id. at 2:42–49.
`In order to “eliminate the risk of theft or loss of the second dose,
`while minimizing undesirable side effects and maximizing ease of
`administration” (id. at 2:56–58), Mehta proposes “administer[ing] only the
`active d-threo form of the drug” (id. at 2:29–32), in “a dosage form which
`provides, in one administration, an initial release followed, at a predictable
`delay, by a second release, of maximally effective methylphenidate” (id. at
`2:53–56).
`Mehta teaches that “[t]he release of the first dose preferably occurs
`substantially immediately; for example, within about 30 minutes following
`administration.” Id. at 5:31–33. Then, “[f]ollowing a period of little or
`substantially no drug release, the second dose is released.” Id. at 5: 33–35.
`The period of delay between the first and second doses is “from about
`2 hours to about 7 hours following ingestion before release of the second
`dose.” Id. at 3:18–19. According to Mehta, “the two releases can be
`referred to as ‘pulses’, and such a release profile can be referred to as
`‘pulsatile’.” Id. at 5:35–36. Moreover, Mehta distinguishes between
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`“sustained delivery . . . i.e., for the relatively constant administration of a
`drug,” and “pulsatile release of the drug, a very distinct phenomenon.” Id. at
`7:53–60.
`
`Mehta further specifies that:
`“Immediate release” . . . means release within about a half
`hour following ingestion, preferably about 15 minutes, and more
`preferably within about 5 minutes following ingestion. “Delayed
`release” . . . refers to a drug release profile which includes a
`period during which no more than about 10 percent of the drug
`in a particular dosage form is released, followed by a period of
`from about 0.5 hour to about 2.5 hours, preferably about 1.5
`hours, more preferably about 1 hour, in which no less than about
`70 percent, preferably no less than about 80 percent, and more
`preferably no less than about 90 percent, of the drug is released.
`Id. at 6:5–16.
`Mehta discloses preparation of layered pellets containing d-threo-
`methylphenidate (d-MPD) cores, coated with a sealant comprising
`hydroxypropyl methylcellulose, and further coated with varying amounts
`and ratios of ammoniomethacrylate polymers (Eudragit® RS30D and
`Eudragit® RL30D) in Examples 1–3, or with Eudragit® NE30D in Example
`4. Ex. 1005, 12:50–14:10. The results of the dissolution measurements are
`presented in Table 1, reproduced below.
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`Ex. 1005, 14:21–45. Table 1 presents results of dissolution measurements
`for the various types of layered and coated pellets produced in Mehta’s
`Examples 1–3. Trial 1 is the pellet of Example 4—in which “no delay was
`observed; substantially all of the drug was released within approximately
`one hour.” Id. at 14:8–10. Trials 2–21 are delayed release formulations.
`According to Mehta, “[t]he results indicate that the amount of drug released
`is influenced by: amount of coating, ratio of the two polymers, amount of
`talc, and curing time.” Id. at 13:58–60.
`
`Finally, Mehta teaches that particles (pellets) providing substantially
`immediate release and particles providing delayed release can be combined
`in a capsule, or the two groups of particles can be compressed into a tablet.
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`Id. at 11:55–60. Alternatively, Mehta discloses a layered dosage form
`comprising “a single group of particles providing both a substantially
`immediate dose of a methylphenidate drug, and a delayed dose.” Id. at
`11:66–12:10, 15:57–16:9.
`
`2. PDR 1997 (Ex. 1009)
`PDR 1997 discloses Adderall® tablets containing, in combination, the
`
`neutral sulfate salts of dextroamphetamine and amphetamine, as well as the
`dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate
`(i.e., dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine
`saccharate, and amphetamine aspartate monohydrate)—for a total of 10 or
`20 mg of mixed amphetamine salts per tablet. Ex. 1009, 2209-2210.
`The recommended dosage and administration for treatment of ADHD
`is as follows:
`In children from 1 to 5 years of age, start with 2.5 mg daily; daily
`dosage may be raised in increments of 2.5 mg at weekly intervals
`until optimal response is obtained.
`In children 6 years of age and older, start with 5 mg once
`or twice daily; daily dosage may be raised in increments of 5 mg
`at weekly intervals until optimal response is obtained. Only in
`rare cases will it be necessary to exceed a total of 40 mg per day.
`Give first dose on awakening; additional doses (1 or 2) at
`intervals of 4 to 6 hours.
`Id. at 2210.
`
`Adderall tablets carry a black box label warning of the potential for
`abuse of the drug. Id. at 2209.
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`In addition, PDR 1997 teaches that urinary acidifying agents, such as
`ammonium chloride, sodium acid phosphate, etc., “[i]ncrease the
`concentration of the ionized species of the amphetamine molecule, thereby
`increasing urinary excretion” and “lower[ing] blood levels and efficacy of
`amphetamines.” Id. at 2210.
`
`3. Brown (Ex. 1011)
`Brown describes the results of a study “undertaken to review
`pharmacokinetic differences between tablets and sustained-release
`d-amphetamine following single-dose administration” to hyperactive
`children. Ex. 1011, 226. According to Brown, sustained-release
`d-amphetamine, “like earlier single-dose amphetamine studies in
`hyperactive children, shows significant behavior and motor activity
`responses to the medication only during the absorption phase, and these
`responses are not correlated with specific plasma levels of d-amphetamine.”
`Id. at 237. Brown further explains, compared to immediate-release tablets,
`“the peak plasma level occurs later and lasts longer with sustained-release
`(up to h 8), though this later occurrence and more plateau-like peak plasma
`level is not accompanied by a longer period of significant response to the
`medication (in fact, the significant response appears to be shorter).” Id. at
`234. That is, “there is no evidence that a prolonged clinical response results
`from the use of the sustained-release preparation.” Id. at 237.
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`4. Amidon (Ex. 1004)
`Amidon discloses a drug delivery system “which delivers pulsed
`doses at predetermined time intervals to achieve a bioavailability which is
`equivalent to immediate release dosage forms administered in divided
`doses.” Ex. 1004, 1:15–20. According to Amidon:
`The drug delivery system, or dosage form . . . has one or
`more . . . individual drug-containing units (also referred to herein
`as “subunits”) in a unitary drug depot which dissolve at different
`sites and/or times in the gastrointestinal tract to release “pulse
`doses.” The drug delivery system . . . is an extended interval
`dosage form as compared to a conventional sustained release
`dosage form which provides a slow, steady release of drug over
`a long period of time. The term pulse dose is used herein to
`describe the rapid delivery of a dose of drug (F1, F2, . . . , Fn) at
`specific respective times (T1, T2, . . . , Tn) into the portal system
`which is analogous to the rate of release from an immediate
`release dosage form administered according to an appropriate
`dosing schedule.
`Id. at 6:59–7:6.
`
`Further according to Amidon:
`This drug delivery system has significant advantages for
`the oral administration of first-pass metabolized drugs which
`exhibit a non-linear relationship between input rate of the drug
`into the portal system and bioavailability. By devising a drug
`dosage delivery form which will release pulsed doses at rates
`comparable to immediate release forms, bioavailability will not
`be compromised by a decreased release rate as has been observed
`in conventional sustained release dosage forms for these drugs
`(e.g., INDERAL-LA).
`Id. at 7:7–16.
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`Amidon teaches that means of controlling dissolution include “(1) pH-
`sensitive enteric coatings which are eroded in response to the pH of the
`aqueous environment in the gastrointestinal tract and (2) permeability-
`controlled systems which are subject to disruption in response to absorption
`of water from the environment which creates a pressure as the core contents
`expand.” Id. at 7: 19–25. “Variation of process variables and coating and
`core compositions . . . enables precise tailoring of the dissolution, or pulse,
`time of the individual unit cores . . . [which] are combined into a unitary
`depot which may be single tablet or a gelatin capsule or any other form
`known in the art. Id. at 7:25–31.
`Amidon provides an extensive list of formulation and process
`variables “which must be taken into consideration in the successful design of
`a permeability-controlled drug delivery system.” Id. at 11:31–33; see id. at
`11:35–12:10. For example, formulation variables include “the choice of
`polymer and plasticizer as well as their initial and final concentration in the
`polymer coat” and representative polymers include cellulose acetate, ethyl
`acetate latexes, ethyl cellulose and . . . Eudragit RS and Eudragit E 30 D.”
`Id. at 11:60–62. “[P]rocess variables for the coating include spray rate,
`spray distance, atomization pressure, drying temperature and rate, and pan
`rotation speed.” Id. at 12:6–8. Amidon further proposes a theoretical model
`for permeability-controlled embodiments which incorporates variables such
`as film thickness (see id. at 11:35–12:10, 19:30–22:22; see also id. at 20:27).
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`Amidon exemplifies a polymer coated dosage form comprising a
`tablet core containing propranolol HCl and citric acid. Id. at 22:26–62. In
`vitro and in vivo “dissolution testing was performed to demonstrate that the
`coating would withstand transit through the acidic pH environment of the
`stomach.” Id. at 22:66–68.
`Finally, according to Amidon, although the examples involve
`propranolol, “the principles of the invention are applicable to any other
`drug” and the disclosed formulation and process variables “will enable one
`of ordinary skill in the art to fabricate a pulsatile drug delivery system for
`any given drug and dosing schedule or combination of drugs and dosing
`schedules.” Id. at 25:6–13.
`
`5. Slattum
`Slattum discloses the results of a study to evaluate a series of potential
`pharmacodynamic measures of central nervous system stimulation after
`dextroamphetamine administration to healthy male volunteers. Ex. 1031,
`Abstract. Subjects received 5 mg, 10 mg, or 20 mg of dextroamphetamine
`or placebo orally and underwent a series of tests—including quantitative
`electroencephalography (EEG) and neuroendocrine, mood, and psychomotor
`performance measures—in addition to blood collection for determination of
`various pharmacokinetic parameters. Id. at 1044–1055. Mean values for the
`pharmacokinetic parameters are presented in Table II, reproduced below:
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` Table II presents mean values for pharmacokinetic parameters,
`including AUC0–∞ (area under the concentration-time curve extrapolated to
`infinity). Ex. 1031, 1044, Table II.
`Slattum further discloses that “[u]rine pH was maintained between 4.5
`and 6.5 by administering doses of ammonium chloride . . . throughout the
`study period . . . to acidify the urine and thus enhance the excretion of
`dextroamphetamine and decrease the pharmacokinetic variability among
`participants.” Id. at 1042.
`
`6. Analysis
`Independent Claim 1 & Dependent Claims 2–11, 15–20
`
`Independent claim 1 is directed to a pharmaceutical formulation
`effective to treat ADHD in a human patient comprising an immediate dosage
`form that provides immediate release of four specific amphetamine base
`salts upon oral administration to a patient, and a delayed enteric release form
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`that provides delayed release of the same mixture of salts, sufficient to
`maintain an effective level of the amphetamine base salts over the course of
`at least eight hours, where the peak plasma concentration of amphetamine
`base salts reached after release of the delayed enteric dose exceeds the peak
`plasma concentration reached after the release of the immediate release dose,
`and where the pharmaceutical formulation, when containing a total dose of
`20 mg produces a plasma concentration versus time curve (ng/ml versus
`hours) having an area under the curve (AUC) of about 467 to about 714 ng
`hr/ml.
`Petitioner contends that claim 1 would have been obvious over the
`combined teachings of Mehta, PDR 1997, Brown, Amidon, and Slattum.
`Pet. 16–30.
`Specifically, Petitioner cites Mehta as disclosing “methylphenidate, ‘a
`mild central nervous system stimulant with pharmacological activity
`qualitatively similar to that of amphetamines,’” used to treat ADHD, in
`“a formulation comprising immediate release and delayed release enteric
`dosage forms” which “eliminates the need for a patient . . . to carry a second
`dose for ingestion several hours after ingestion of a first dose.” Pet. 11
`(citing Ex. 1005, 1:26–46, 2:5–16, 33–7, 5:18–21).
`
`Petitioner cites PDR 1997 as evidence that Adderall® IR, an instant
`release dosage form containing the same mixture of four specific
`amphetamine base salts required by claim 1, “was a known pharmaceutical
`composition used for the treatment of ADHD,” “administered in a twice
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`daily dose, with a starting dose followed by a second dose that is
`administered 4 to 6 hours after the first.” Pet. 1 (citing Ex. 1009 at 2210), 19
`(citing Ex. 1001, 3:16–21; Ex. 1002 (Auslander Declaration) ¶¶ 42–43), 20
`(citing Ex. 1009, 2209–2210; Ex. 1002 ¶ 99).
`
`Petitioner further cites Brown’s study of the pharmacokinetics of
`single-dose administration of sustained-release d-amphetamine capsules in
`hyperactive children. Pet. 14 (citing Ex. 1011, 225, 227). Petitioner notes,
`in particular, Brown’s observation that “significant behavior and motor
`activity responses to the medication [occur] only during the absorption
`phase, and these responses are not correlated with specific plasma levels of
`d-amphetamine.” Id. (citing Ex. 1011, 233, 237). Moreover, Petitioner
`notes that Brown teaches that “[c]ompared to the immediate-release tablet,
`the peak plasma level of the sustained release dosage form occurs later and
`lasts longer, though this later occurrence and more plateau-like peak plasma
`level is not accompanied by a longer period of significant response to the
`medication.” Id. at 20 (citing Ex. 1011, 234). According to Petitioner’s
`declarant, Dr. Auslander,
`[p]ut another way, the data in Brown would have indicated to a
`POSA [person of ordinary skill in the art] that sustained-release
`d-amphetamine would not have led to a prolonged clinical
`response, i.e. that making a sustained release dosage form would
`not have led to longer period of significant response to the
`medication. Therefore, the POSA would have had to look for an
`alternative solution if they were seeking to develop a once-a-day
`Adderall® formulation (and would not have looked to available
`sustained release formulations).
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`Ex. 1002 ¶ 101.
`Petitioner contends, therefore, that a person of ordinary skill in the art,
`“seeking to develop a once-a-day Adderall® formulation” in order to
`provide “reduced abuse potential, improved convenience of administration,
`and better patient compliance,” “would have been motivated to look at a
`pulsed delivery because such a formulation would have had the same release
`profile as taking Adderall® immediate-release formulation two times a day.”
`Pet. 20 (citing Ex. 1002 ¶¶ 101, 102), 21 (citing Ex. 1002 ¶ 105; Ex. 1005,
`1:26-29). Essentially, Petitioner contends that one of ordinary skill in the art
`would have “look[ed] to other art in the field of attention deficit disorders to
`find an approach that provided for an immediate dosage and a delayed
`second dosage, whereby, the second dosage is released in a rapid manner
`(i.e., pulsed)” (id. at 21 (citing Ex. 1002 ¶ 102)), and “[t]he fact that [Mehta]
`focuses on using methylphenidate, rather than amphetamines, would not
`have detracted the POSA from the teachings of [Mehta] because . . .
`methylphenidate is ‘a mild central nervous system stimulant with
`pharmacological activity qualitatively similar to that of amphetamines’” (id.
`(citing Ex. 1005, 2:5-16)).
`With respect to claim 1’s requirement for an immediate release dosage
`form and a delayed enteric release dosage form, Petitioner notes that:
`The release of the first dose [from Mehta’s formulation]
`preferably occurs substantially immediately; for example, within
`about 30 minutes following administration. Following a period
`of little or substantially no drug release, the second dose is
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`released. The two releases can be referred to as “pulses,” and
`such a release profile can be referred to as “pulsatile.”
`Pet 21 (quoting Ex. 1005, 5:31-36). “The second, delayed release” occurs
`“from about 0.5 hour to about 2.5 hours, preferably about 1.5 hours, more
`preferably about 1 hour” after the first release (id. at 22 (citing Ex. 1005,
`6:10-17; Ex. 1002 ¶ 112)), but “by varying the parameters, release profiles
`for up to 10 hours were obtained” (id. (citing Ex. 1002 ¶ 112; Ex. 1005,
`Table 1, 13:57-60)).11 According to Petitioner, Mehta teaches that “dosage
`amounts of the immediate release and delayed release dosages” and “delay
`times” can be adjusted “based on the amount of coating, ratio of two
`polymers, amount of talc, and curing time.” Id. at 22–23 (citing Ex. 1002
`¶ 112; Ex. 1005, 6:55–61, 13:57–60).
`Petitioner contends that “it would have been obvious to ‘maintain an
`effective level of amphetamine base salts in the patient over the course of at
`least 8 hours without further administration of amphetamine base salt,” as
`required by claim 1, given Mehta’s teachings. Pet. 22 (citing Ex. 1002
`¶ 112; Ex. 1005, 6:55–61). Petitioner also contends that Mehta “provid[es]
`
`
`11 Mehta does not use the word “enteric,” or otherwise disclose expressly an
`intent to deliver the delayed dosage to the intestines, rather
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