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` Entered: April 18, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMERIGEN PHARMACEUTICALS LIMITED,
`Petitioner,
`
`v.
`
`SHIRE LLC,
`Patent Owner.
`
`
`Case IPR2015-02009
`Patent RE42,096 E
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`I. INTRODUCTION
`Amerigen Pharmaceuticals Limited ( “Petitioner”) filed a Petition
`(Paper 1, “Pet.”) on October 1, 2015, requesting an inter partes review of
`claims 1–3, 5, 8, 9, 11, 18–21, 23, and 25 of U.S. Patent No. RE42,096 E
`(Ex. 1001, “the ’096 patent”). Shire LLC (“Shire” or “Patent Owner”) filed
`a Preliminary Response (Paper 7, “Prelim. Resp.”) on January 19, 2016. We
`have jurisdiction 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 information presented in the Petition and
`the Preliminary Response, we are persuaded that Petitioner has established a
`reasonable likelihood that it would prevail in its challenges to claims 18–21,
`23, and 25 of the ’096 patent. Accordingly, we institute an inter partes
`review of those claims.
`
`A. Related Proceedings
`Petitioner informs us of the following related judicial matters: Shire
`
`LLC v. Amerigen Pharms. Ltd., 14-cv-6095 (D.N.J. Oct. 1, 2014); Shire LLC
`v. Corepharma LLC, 14-05694 (D.N.J. Sept. 12, 2014); Shire LLC v. Par
`Pharm. Inc., 15-cv-01454 (D.N.J. Feb. 26, 2015). Pet. 1. Patent Owner
`
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`identifies the same related matters in its Mandatory Notices under 37 C.F.R.
`§ 42.8(a)(2).1 Paper 6, 1.
`
`B. The Asserted Grounds of Unpatentability
`Petitioner asserts the challenged claims are unpatentable on the
`
`following grounds. Pet. 4–8, 17–60.2
`
`References
`
`Mehta3
`
`Mehta and Adderall PDR4
`Mehta, Adderall PDR, and
`Rosen5
`
`Basis
`
`Claims Challenged
`
`§ 102(e)
`
`§ 103(a)
`
`§ 103(a)
`
`1–3, 5, 8, 9, 11, 18–
`21, 23, and 25
`1–3, 5, 18–21, 23,
`and 25
`8, 9, and 11
`
`
`1 Patent Owner informs us of a number of additional related judicial and
`administrative matters. Prelim. Resp. 2–7. We are not persuaded that
`Petitioner’s failure to include those matters in its mandatory notices warrants
`dismissal of the Petition, and decline to do so on that basis.
`2 Petitioner supports its challenges with the Declaration of Edmund J. Elder,
`Jr., Ph.D., R.Ph., executed September 30, 2015 (“Elder Declaration”)
`(Ex. 1006).
`3 U.S. Patent No. 5,837,284, issued November 17, 1998, to Mehta et al.
`(“Mehta”) (Ex. 1003).
`4 PHYSICIANS’ DESK REFERENCE 331, 2209–11 (51st ed. 1997) (“Adderall
`PDR”) (Ex. 1004).
`5 Earl Rosen et al., Absorption and Excretion of Radioactively Tagged
`Dextroamphetamine Sulfate from a Sustained-Release Preparation, 194
`JAMA 145–147 (1965). (“Rosen”) (Ex. 1015).
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`C. The ’096 Patent (Ex. 1001)
`The ’096 patent, titled “ORAL PULSED DOSE DRUG DELIVERY
`SYSTEM,” is a reissue of U.S. Patent 6,322,819,6 and “is listed in the FDA’s
`‘Orange Book’ of approved drug products for Adderall XR®, which is
`indicated for Attention Deficit Hyperactivity Disorder (ADHD).” Prelim.
`Resp. 1.
`The ’096 patent teaches that 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.” Ex. 1001, 3:20–13.
`Administering two separate doses, however, “is time consuming,
`inconvenient, and may be problematic for those children having difficulties
`in swallowing tablet formulations.” Id. at 3:14–17.
`The ’096 patent, thus, discloses a pharmaceutical composition
`comprising “an oral multiple pulsed dose delivery system for amphetamine
`salts and mixtures thereof” (id. at 3:22–24), “in which there is immediate
`release of drug and enteric release of drug wherein the enteric release is a
`pulsed release and wherein the drug includes one or more amphetamine salts
`and mixtures thereof” (id. at 3:53–57). In other words, “[t]he immediate
`release component releases the pharmaceutical agent in a pulsed dose upon
`oral administration of the delivery system” (id. at 3:58–60), while “[t]he
`
`
`6 U.S. Patent No. 6,322,819, issued November 7, 2001 to Burnside et al.
`(“the ’819 patent”) (Ex. 1017).
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`enteric release coating layer retards or delays the release of the
`pharmaceutical active or drug for a specified time period (“lag time”) until a
`predetermined time, at which time the release of the drug is rapid and
`complete” (id. at 3:61–64).
`In accordance with a preferred embodiment . . . there is
`provided a pharmaceutical composition for delivering one or
`more pharmaceutically active amphetamine salts that includes:
`(a) one or more pharmaceutically active amphetamine
`salts that are covered with an immediate release coating,
`and
`(b) one or more pharmaceutically active amphetamine
`salts that are covered with an enteric release coating
`wherein (1) the enteric release coating has a defined
`minimum thickness and/or (2) there is a protective layer
`between
`the at
`least one pharmaceutically active
`amphetamine salt and the enteric release coating and/or (3)
`there is a protective layer over the enteric release coating.
`Id. at 3:28–42.
`According to the ’096 patent, plasma levels of the pharmaceutically
`active amphetamine salts “will reach a peak fairly rapidly after about 2
`hours, and after about 4 hours a second pulse dose is released, wherein a
`second fairly rapid additive increase of plasma drug levels occurs which
`slowly decreases over the course of the next 12 hours.” Id. at 10:4–9. Thus,
`“the multiple dosage form of the . . . invention can deliver rapid and
`complete dosages of pharmaceutically active amphetamine salts to achieve
`the desired levels of the drug in a recipient over the course of about 8 hours
`with a single oral administration.” Id. at 9:66–10:3.
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`Finally, the ’096 patent teaches that
`Pharmaceutical active amphetamine salts contemplated to be
`within the scope of the present invention include amphetamine
`base, all chemical and chiral derivatives and salts thereof;
`methylphenidate, all chemical and chiral derivatives and salts
`thereof; phenylpropanolamine and its salts; and all other
`compounds indicated for the treatment of attention deficit
`hyperactivity disorder (ADHD).
`Id. at 7:50–57.
`
`D. Illustrative Claims
`Petitioner challenges claims 1–3, 5, 8, 9, 11, 18–21, 23, and 25 of the
`’096 patent, of which claims 1, 2, 5, 8, 11, and 18 are independent claims.
`Claims 1 and 18, reproduced below, are illustrative.
`1. A pharmaceutical composition for delivery of one or more
`pharmaceutically active amphetamine salts, comprising:
`(a) one or more pharmaceutically active amphetamine
`salts covered with an immediate release coating;
`(b) one or more pharmaceutically active amphetamine
`salts that are covered with an enteric release coating that
`provides for delayed pulsed enteric release,
`wherein said enteric release coating releases essentially
`all of said one or more pharmaceutically active amphetamine
`salts coated with said enteric coating within about 60 minutes
`after initiation of said delayed pulsed enteric release;
`wherein the pharmaceutically active amphetamine salts
`in (a) and (b) comprise mixed amphetamine salts.
`Ex. 1001, 12:53–67.
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`18. A pharmaceutical composition for delivery of one or more
`pharmaceutically active amphetamine salts comprising:
`(a) one or more pharmaceutically active amphetamine
`salts covered with an immediate release coating;
`(b) one or more pharmaceutically active amphetamine
`salts that are covered with an enteric release coating that
`provides for delayed pulsed enteric release, wherein said
`enteric release coating releases said one or more
`pharmaceutically active amphetamine salts coated with
`said enteric coating within about 60 minutes after
`initiation of said delayed pulsed enteric release; and
`(c) a protective layer between the at least one
`pharmaceutically active amphetamine salt and the enteric
`release coating.
`Ex. 1001, 14:63–15:11.
`
`II. ANALYSIS
`
`A. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are given
`their broadest reasonable interpretation in light of the specification of the
`patent in which they appear. 37 C.F.R. § 42.100(b). Under this standard, we
`presume that a claim term carries its “ordinary and customary meaning,”
`which “is the meaning the term would have to a person of ordinary skill in
`the art in question” at the time of the invention. In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007). See also Trivascular, Inc. v. Samuels,
`812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under a broadest reasonable
`interpretation, words of the claim must be given their plain meaning, unless
`such meaning is inconsistent with the specification and prosecution
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`history.”). Any special definition for a claim term must be set forth in the
`specification with reasonable clarity, deliberateness, and precision. In re
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Finally, only terms which are
`in controversy need to be construed, and then only to the extent necessary to
`resolve the controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g. Inc., 200
`F.3d 795, 803 (Fed. Cir. 1999).
`For purposes of this Decision, and on this record, only the following
`terms require explicit construction.
`1. “pharmaceutically active amphetamine salts,”
`“amphetamine salt,” and “mixed amphetamine salts”
`The parties agree that the term “pharmaceutically active amphetamine
`salts” is explicitly defined in the ’096 patent, at column 7, lines 51–58. Pet.
`9–10; Prelim. Resp. 18–19. That explicit definition is as follows:
`Pharmaceutical[ly] active amphetamine salts contemplated to be
`within the scope of the present invention include amphetamine
`base, all chemical and chiral derivatives and salts thereof;
`methylphenidate, all chemical and chiral derivatives and salts
`thereof; phenylpropanolamine and its salts; and all other
`compounds indicated for the treatment of attention deficit
`hyperactivity disorder (ADHD).
`Ex. 1001, 7:50–57.
`
`Given the specification’s explicit definition, we agree with the parties
`that the term “pharmaceutically active amphetamine salts” includes non-
`salts, such as “amphetamine base” and “methylphenidate,” as well as salts of
`amphetamine base and methylphenidate.
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`The term “amphetamine salt(s)” appears in several places in the
`
`specification of the ’096 patent, without the adjacent language
`“pharmaceutically active,” but is not separately defined. See e.g., id. at 1:9,
`10, 4:17–18, 22–23, 51. In at least one instance, the term “amphetamine
`salts” is closely followed by the term “pharmaceutically active amphetamine
`salts”:
`
`in view of a need for successfully
`Accordingly,
`administering a multiple pulsed dose of amphetamine salts and
`mixtures thereof, the present invention provides an oral multiple
`pulsed dose delivery system for amphetamine salts and mixtures
`thereof. FIG. 1 illustrates the desired target plasma level profile
`of the pharmaceutical active contained within the delivery
`system.
`In accordance with a preferred embodiment of the present
`invention, there is provided a pharmaceutical composition for
`delivering one or more pharmaceutically active amphetamine
`salts that includes:
`(a) one or more pharmaceutically active
`amphetamine salts that are covered with an immediate
`release coating, and
`(b) one or more pharmaceutically active
`amphetamine salts that are covered with an enteric release
`coating . . .
`Id. at 3:20–36 (emphases added).
`Having consulted the specification, we find little guidance as to the
`difference in scope, if any, between “pharmaceutically active amphetamine
`salts” and “amphetamine salts.” We next look to evidence of how a person
`of ordinary skill in the art would understand the relationship between these
`terms. Petitioner’s witness, Dr. Elder, testifies that one of ordinary skill in
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`the art “would construe amphetamine salt to mean pharmaceutically active
`amphetamine salt” because “the ’096 patent uses ‘amphetamine base’ to
`describe the compound commonly referred to as amphetamine; on [sic] the
`way the terms are used in describing the features of the disclosure relative to
`how they appear in the claims” (Pet. 9–10 (citing Ex. 1005 ¶¶ 108–135));
`and because “the term ‘amphetamine salt(s)’ refers back to the term
`‘pharmaceutically active amphetamine salts’ as an antecedent” in claims 8,
`11, and 20 of the ’096 patent. Pet. 9 (citing Ex. 1026, 9 n.5); see, e.g., Ex.
`1001, 13:45–63, 15:15–17. Alternatively, Dr. Elder testifies that one of
`ordinary skill in the art would have understood that “amphetamine salts is
`used more broadly than pharmaceutically active amphetamine salts in
`several locations.” Pet. 11 (citing Ex. 1001, 3:20–25; Ex. 1005 ¶ 122).
`For purposes of this decision, we need not determine whether
`“amphetamine salts” is broader than “pharmaceutically active amphetamine
`salts,” or whether the two terms are coextensive. Rather, for purposes of this
`decision, it is enough that we are persuaded by Dr. Elder’s testimony that the
`ordinary artisan would not have understood “amphetamine salts” to be
`narrower than “pharmaceutically active amphetamine salts.” Thus, we also
`are persuaded that the ordinary artisan would have understood the term
`“amphetamine salts,” like the term “pharmaceutically active amphetamine
`salts,” to include “amphetamine base” and “methylphenidate,” as well as
`salts of amphetamine base and methylphenidate.
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`The term “mixed amphetamine salts” also is not separately defined in
`
`the specification of the ’096 patent, and apart from the claims, appears only
`in Examples 1 and 2, with no further elaboration (Ex. 1001, 10:21, 32, 43–
`44). However, the term “amphetamine salts” appears several times without
`the adjacent language “pharmaceutically active,” but followed immediately
`by the words “and mixtures thereof.” See, e.g., id. at 3:21, 23, 56–57.
`Petitioner contends that we “should find mixed amphetamine salts to
`
`mean ‘made up of pharmaceutically active amphetamine salts of more than
`one kind.’” Pet. 12.
`Patent Owner argues that “‘[m]ixed amphetamine salts” means a
`combination of two or more salts of α-methylphenethylamine” (Prelim.
`Resp. 20), and Petitioner’s proposal “is unreasonably broad” (id. at 21).
`Patent Owner contends that “[t]he separate set of ‘pharmaceutically active
`amphetamine salts’ comprising . . . methylphenidate, is not imported into the
`narrower set of ‘mixed amphetamine salts.’” Id. at 20–21. Patent Owner
`contends that unlike the term “pharmaceutically active amphetamine salts,”
`the terms “amphetamine” and “mixed” were “not redefined . . . to include
`methylphenidate” (id.), and should be given their ordinary meaning—that is
`to say that “‘Amphetamine’ has its ordinary meaning: one or both
`enantiomers of α-methylphenethylamine” (id. at 20), and two salts “are
`‘mixed,’ when one or both of the acid and base components of the salt are
`different” (id.).
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`Patent Owner is correct in that a patentee, to act as a lexicographer
`“must clearly set forth a definition of the disputed term other than its plain
`and ordinary meaning,” or in other words, “must clearly express an intent to
`redefine the term.” Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324,
`1330 (Fed. Cir. 2012).
`
`Moreover, we agree that nothing in the specification sets forth a
`special definition for the naked term “amphetamine salts” or “mixed
`amphetamine salts.” The problem is that the Applicants of the ’096 patent,
`having set out a definition of “pharmaceutically active amphetamine salts”
`in the specification that included, among other things, amphetamine base
`and salts thereof and methylphenidate and salts thereof, did not then make it
`clear that modifying the term “amphetamine salts” with the word “mixed”
`instead of “pharmaceutically active” meant that methylphenidate salts were
`excluded. Dr. Elder testifies to that effect. Ex. 1005 ¶¶ 106–115, 122,
`154–161. We agree with Dr. Elder that one of ordinary skill in the art,
`reading the specification, would have understood the term “amphetamine
`salt” to be at least as broad as “pharmaceutically active amphetamine salts,”
`and to include both amphetamine base and methylphenidate (as well as their
`salts). Logically, then, we are persuaded that one of ordinary skill in the art
`would have understood the term “amphetamine salts and mixtures thereof”
`to include pharmaceutically active amphetamine salts and mixtures thereof,
`and “mixed amphetamine salts” to be a simple rearrangement of the term
`“amphetamine salts and mixtures thereof.”
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`That, in and of itself, does not settle the matter. We still must
`consider Patent Owner’s contention that its construction is supported by the
`prosecution history. DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`469 F.3d 1005, 1014 (Fed. Cir. 2006) (“In determining the meaning of the
`disputed claim limitation, we look principally to the intrinsic evidence of
`record, examining the claim language itself, the written description, and the
`prosecution history, if in evidence.”); Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292, 1298 (Fed. Cir. 2015) (instructing the PTO to consider
`prosecution history in inter partes review).
`Patent Owner directs us to two statements in the prosecution history
`of the ’096 patent. The first is a statement accompanying an amendment
`dated May 18, 2007 and a Supplemental Reissue Declaration, and identifies
`an amendment to original independent claim 1 as the basis for reissue. The
`first statement is as follows: “This amendment narrows claim 1 by the added
`limitation: ‘wherein the pharmaceutically active amphetamine salts comprise
`mixed amphetamine salts (MASL).’ . . . This is an error correctable by
`reissue because original claim 1 may be too broad, and the amendment
`accordingly narrows the claim.” Ex. 2012, 134. The second is a statement
`in support of nearly identical amendment to claim 1 dated March 6, 2008:
`“Further, ‘mixed amphetamine salts’ is a subgroup of drugs falling within
`‘pharmaceutically active amphetamine salts.” Ex. 2012, 217.
`We agree that these amendments narrowed the claims, but are not
`persuaded that either of these statements unambiguously supports Patent
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`Owner’s proposed construction. The clause “wherein the pharmaceutically
`active amphetamine salts in (a) and (b) comprise mixed amphetamine salts”
`refers back to “one or more pharmaceutically active amphetamine salts.”
`The “one or more” requirement can be satisfied by a single pharmaceutically
`active amphetamine salt, or by more than one. “Mixed amphetamine salts”
`can be interpreted as requiring more than a single pharmaceutically active
`amphetamine salt.
`
`Thus, at this stage of the proceeding, we are not persuaded that
`Petitioner’s proposed construction is unreasonably broad. Accordingly, for
`purposes of this decision, we construe “mixed amphetamine salts” to mean
`made up of pharmaceutically active amphetamine salts of more than one
`kind.
`
`2. enteric release coating
`Petitioner contends that “[t]he broadest reasonable construction of
`enteric coating, based on the ordinary and customary meaning of this term,
`is ‘a layer of material that protects medication in the stomach and releases
`medicine in the intestines.’” Pet. 13.
`Patent Owner proposes a similar construction:
`A drug release is “enteric” when the release happens after
`a delay, when the drug has passed through the stomach.
`“Covered with an enteric coating” means covered with a coating
`that is intended to delay release of drug until the drug has passed
`through the stomach.”
`The ordinary meaning of ‘enteric’ is: ‘of, referring to, or
`being within the intestines . . . which in context means a
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`composition designed to pass through the stomach and reach the
`intestines.
`Prelim. Resp. 24 (citing Ex. 1012, 4; Ex. 1008, 19–20).
`Apart from Patent Owner’s use of the words “intended” or
`“designed,” the constructions are essentially the same. For our purposes, we
`need not resolve the nuances of the two constructions, it is enough that we
`are persuaded that “enteric release coating” refers to a coating that will delay
`release of a drug until the drug has passed through the stomach and reached
`the intestines.
`We further note that the specification of the ’096 patent teaches that
`the enteric coating may comprise pH-dependent polymers, which will not
`dissolve “in the acidic stomach environment of approximately below pH 4.5,
`but [are] not limited to this value.” Ex. 1001, 8:12–19. According to the
`specification, “[t]he pharmaceutical active should become available when
`the pH-sensitive layer dissolves at the greater pH, after a certain delayed
`time, or after the unit passes through the stomach” and “[t]he preferred delay
`time is in the range of two to six hours.” Id. at 8:20–24. In addition, the
`specification teaches “[i]n a preferred embodiment, the lag time period is
`only time-dependent, i.e., pH independent” and “[t]he lag time is preferably
`within 4 to 6 hours after oral administration of the delivery system.” Id. at
`3:61–4:8. Finally, the ’096 patent discloses and claims a composition
`“wherein said enteric release coating is a non-pH dependent enteric release
`coating.” Id. at 13:43–44.
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`3. “essentially all”
`The term “essentially all” is not defined in the ’096 patent. Petitioner
`and Patent Owner agree that “essentially all” means “less than 100%, and
`not less than 80%.” Pet. 17 (citing Ex. 1026, 21; Ex. 1010, 7); Prelim. Resp.
`28 (citing Ex. 2030, 6, 8, 12 (describing dissolution testing “until either 80%
`of the drug from the drug product is released or an asymptote is reached.”).7
`At this stage of the proceeding, we see nothing in the specification or
`prosecution history of the ’096 patent inconsistent with this construction,
`and are persuaded, for purposes of this decision, that one of ordinary skill in
`the art would understand “essentially all” to mean “less than 100%, and not
`less than 80%.”
`
`B. Patent Owner’s Argument under § 325(d)
`Patent Owner argues that we should decline to institute an inter partes
`review pursuant to 35 U.S.C. § 325(d), which gives the Board authority to
`reject a petition that presents the same or substantially the same prior art or
`arguments as were previously presented to the Office. See Prelim. Resp. 7–
`12.
`
`Patent Owner contends that Mehta, the Adderall PDR, and Rosen
`(Exs. 1003, 1004, and 1015) appear on the face of the ‘096 patent, and the
`Examiner acknowledged them. Prelim. Resp. 8 (citing Ex. 1001 [56]; Ex.
`
`
`7 The preliminary Response incorrectly cites Exhibit 2032 for this
`parenthetical. The correct exhibit is Exhibit 2032—SUPAC-MR: Modified
`Release Solid Oral Dosage Forms (1997) (“1997 FDA Guidance).
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`2012, 81, 82). Patent Owner further contends that Mehta was a principal
`reference, and was overcome, during prosecution of the original ’819 patent
`and the ’096 patent upon reissue. Id. Patent Owner contends that the
`Petition depends on arguments about Mehta that already were considered in
`the original prosecution and upon reissue. Id. at 1.
`Under § 325(d), “the Director may take into account whether, and
`reject the petition . . . because, the same or substantially the same prior art or
`arguments previously were presented to the Office.” The permissive
`language in the statute signals that we are not required to reject a petition
`simply because it relies on art that was cited to the Office previously, and we
`decline to do so in this case, at least in part because our preliminary claim
`constructions differ in certain respects from those advanced during
`prosecution.
`
`C. Claims 1–3, 5, 8, 9, 11, 18–21, 23, and 25—
`Asserted Anticipation by Mehta
`1. Mehta (Ex. 1003)
`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. 1003, 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–
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`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 2:19–22.8
`
`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.
`
`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.
`
`
`8 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. 1003, 2:16–18.
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`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). Though Mehta emphasizes the advantages of administering a
`composition comprising only the d-threo isomer of methylphenidate
`hydrochloride, the administration of the dl-threo racemate is also disclosed.
`See e.g., Ex. 1003, 15:5–10, 16:10–11.
`
`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
`“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.
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`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. 1003, 12:50–14:10. The results of the dissolution measurements are
`presented in Table 1, reproduced below.
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`Ex. 1003, 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 re