Trials@uspto.gov
`571.272.7822
`
`
`
`
`
`
` Paper No. 56
`
` Entered: July 3, 2019
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`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`KVK-TECH, INC.,
`Petitioner,
`
`v.
`
`SHIRE PLC,
`Patent Owner.
`____________
`
`
`
`
`
`Case IPR2018-00293
`Patent 9,173,857 B2
`____________
`
`
`
`Before RAMA G. ELLURU, SHERIDAN K. SNEDDEN, and
`DEVON ZASTROW NEWMAN, Administrative Patent Judges.
`
`NEWMAN, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a); 37 C.F.R. § 42.73
`
`
`
`
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`IPR2018-00293
`Patent 9,173,857 B2
`
`
`
`
` INTRODUCTION
`This is a Final Written Decision in an inter partes review challenging
`the patentability of claims 1–29 of U.S. Patent No. 9,173,857 B2 (Ex. 1001,
`“the ’857 patent”). We have jurisdiction under 35 U.S.C. § 6. The
`evidentiary standard is a preponderance of the evidence. See 35 U.S.C.
`§ 316(e); 37 C.F.R. § 42.1(d). We issue this Final Written Decision
`pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`Having reviewed the arguments of the parties and the supporting
`evidence, we determine that Petitioner has not demonstrated by a
`preponderance of the evidence that the challenged claims are unpatentable.
`
`A. Procedural History
`KVK-Tech, Inc. (“Petitioner”) filed a Corrected Petition requesting an
`inter partes review of claims 1–29 of the ’857 patent. Paper 7 (“Pet.”).
`Shire PLC (“Patent Owner”) filed a Preliminary Response to the Petition.
`Paper 91 (“Prelim. Resp.”). We instituted an inter partes review of all
`challenged claims on all grounds, pursuant to 35 U.S.C. § 314. Paper 13
`(“Inst. Dec.”), 35.
`Patent Owner filed a Response (Paper 19, “PO Resp.”). Petitioner
`filed a Reply (Paper 31, “Reply”). With our permission (see Paper 36,
`authorizing additional briefing), Patent Owner filed a Sur-Reply (Paper 40,
`“PO Sur-Reply”), and Petitioner filed a Response to Patent Owner’s Sur-
`Reply. (Paper 46, “Pet. Resp. to PO Sur-Reply”).
`
`
`1 Patent Owner first filed a confidential version of the Patent Owner’s
`Preliminary Response. Paper 8. We refer to the public version of the
`Preliminary Response.
`
`2
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`IPR2018-00293
`Patent 9,173,857 B2
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`
`Petitioner and Patent Owner both filed Motions to Exclude Evidence.
`Papers 41 and 44, respectively. Petitioner and Patent Owner both filed
`respective Oppositions to Motions to Exclude Evidence. Papers 45 and 47,
`respectively. Petitioner and Patent Owner both filed Replies in Support of
`the Motion to Exclude Evidence. Papers 50 and 49, respectively.
`An oral hearing was held on April 4, 2019, and a transcript of the
`hearing is included in the record. Paper 53 (“Tr.”).
`
`B. Related Proceedings
`Petitioner states that another petitioner previously petitioned for inter
`partes review of claims 1–31 of U.S. Patent No. 8,846,100 (the “’100
`patent”), the application of which is the parent to the ’857 patent (Case
`IPR2017-00665), but withdrew its Petition prior to the deadline for Patent
`Owner’s Preliminary Response. Pet. 3; Paper 3, 1. Petitioner also identifies
`a concurrently filed petition for inter partes review of the ’100 patent, which
`was instituted as case IPR2018-00290. Pet. 3. Patent Owner asserts that the
`’857 patent is being asserted in Shire Development LLC et al v. Teva
`Pharmaceuticals USA, Inc., 1:17-cv-01696-RGA (D. Del). Paper 3.
`C. The ’857 Patent
`The ’857 patent relates to a “method for treating attention deficit
`hyperactivity disorder (ADHD)” comprising administering a “long-acting
`amphetamine pharmaceutical composition, which includes an immediate
`release component, a delayed pulsed2 release component and a sustained
`
`
`2 U.S. Patent No. 6,555,136 (Apr. 29, 2003) (Ex. 1018, “Midha”) at 1:30–35
`explains that “[f]or some types of drugs, it is preferred to release the drug in
`‘pulses,’ wherein a single dosage form provides for an initial dose of drug
`followed by a release-free interval, after which a second dose of drug is
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`release component, to meet the therapeutic needs for [Attention Deficit
`Hyperactivity Disorder “ADHD”] patients with longer-day demands.” Ex.
`1001, 3:61–65, claim 1. “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.” Id. at 3:65–4:3.
`Adderall is the immediate release (“IR”) formulation of a mixture of
`four amphetamine salts indicated for the treatment of ADHD in children. Id.
`at 3:13–19. According to the ’857 patent, one disadvantage of IR-only
`treatments for children is that two separate doses are required to be
`administered, one in the morning and one approximately 4–6 hours later. Id.
`at 3:20–27. “ADDERALL XR® met the need for a dosage form, which can
`be administered once, in place of the two oral doses which are needed using
`the conventional drug delivery formulations of the prior art.” Id. at 3:27–30.
`Adderall XR is designed to provide a duration effect up to 12 hours. Id. at
`3:39–42.
`The ’857 patent indicates that some patients, however, require
`additional treatment with a short-acting stimulant to extend the daily
`therapeutic effect. Id. at 3:34–37. “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 [of Adderall
`XR], typically at 8-10 hours post-dose, with a dose of the same immediate-
`release (IR) medication.” Id. at 3:45–49. Thus, the ’857 patent recognizes
`
`
`released, followed by one or more additional release-free intervals and drug
`release ‘pulses.’”
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`that “a need exists for a once-daily, long-acting oral composition that
`provides effective treatment of ADHD, without supplementation, for
`patients with longer day demands (e.g., 14-16 awake hours).” Id. at 3:54–
`57.
`D. Illustrative Claim
`Petitioner challenges claims 1–29 of the ’857 patent, of which
`claim 1 is the only independent claim. Claim 1 is representative and
`is reproduced below:
`1. A method for treating attention deficit hyperactivity disorder
`(ADHD) which comprises:
`administering to a patient in need thereof, a pharmaceutical
`composition comprising:
`(a) an immediate release bead comprising at least one amphetamine
`salt;
`(b) a first delayed release bead comprising at least one
`amphetamine salt; and
`(c) a second delayed release bead comprising at least one
`amphetamine salt; wherein the first delayed release bead
`provides pulsed release of the at least one amphetamine salt and
`the second delayed release bead provides sustained release of
`the at least one amphetamine salt;
`wherein the second delayed release bead comprises at least one
`amphetamine salt layered onto or incorporated into a core; a
`delayed release coating layered onto the amphetamine core; and
`a sustained release coating layered onto the delayed release
`coating,
`wherein the sustained release coating is pH-independent;
`and wherein the first delayed release bead and the second
`delayed release bead comprise an enteric coating.
`Ex. 1001, 31:56–32:36.
`
`Dependent claims 2–29 recite additional, or more restricted,
`limitations with respect to those in claim 1, including specifying
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`IPR2018-00293
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`coating characteristics or components (claims 2–4, 13–16, and 29),
`pharmaceutical parameters (claims 5–12), amphetamine salts and
`amounts in the composition (claims 17, 18, and 20–28). Id. at 32:39–
`34:24. Claim 19 recites that “the composition does not include a food
`effect. Id. at 34:1–2.
`
`E. Challenged Claims and Reviewed Grounds of Unpatentability
`We instituted a trial to consider Petitioner’s challenges to the
`patentability of claims 1–29 of the ’857 patent on the following grounds
`(Ins. Dec. 34):
`
`Reference(s)
`Burnside3
`Burnside
`Adderall XR4,5 and Burnside
`
`Basis
`§ 102(a)
`§ 103
`§ 103
`
`Claims challenged
`1–19, 29
`1–29
`1–29
`
`Petitioner relies on the Declarations of Dr. Diane Burgess (Ex. 1004,
`“Burgess Decl.”), Dr. William Jusko (Ex. 1006, “Jusko Decl.”), and Dr.
`James McCracken (Ex. 1045, “McCracken Decl.”).
`
`
`3 Burnside, Beth A. et al., US 6,605,300 B1, issued August 12, 2003
`(“Burnside,” Ex. 1002).
`4 PHYSICIAN’S DESK REFERENCE, entry for Adderall XR, 3144–3146 (58th
`ed. 2004) (“Adderall XR,” Ex. 1003).
`5 FDA Adderall XR Label, 2004 (published August 2004) (“Adderall XR,”
`Ex. 1031).
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`
`Patent Owner relies on the Declarations of Dr. Bernhardt Trout
`(Ex. 2001, “Trout Decl.”), Dr. Sara Rosenbaum (Ex. 2002,
`“Rosenbaum Decl.”), and Dr. James Polli (Ex. 2060, “Polli Decl.”).
`
`II. ANALYSIS
`A. Level of Ordinary Skill in the Art
`In determining the level of ordinary skill in the art, various factors
`may be considered, including the “type of problems encountered in the art;
`prior art solutions to those problems; rapidity with which innovations are
`made; sophistication of the technology; and educational level of active
`workers in the field.” In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995)
`(internal quotation and citation omitted). In addition, the prior art itself
`demonstrates the level of skill in the art at the time of the invention. See
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that
`specific findings regarding ordinary skill level are not required where
`“the prior art itself reflects an appropriate level and a need for testimony is
`not shown”) (quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755
`F.2d 158, 163 (Fed. Cir. 1985)).
`Petitioner proposes that the person of ordinary skill would have had
`“at least a Bachelor of Science Degree in Pharmacy, Chemistry, or Chemical
`Engineering, or similar field, and experience in the field of pharmaceutics
`(including pharmaceutical formulation or pharmacokinetics or a similar
`technical field of study).” Pet. 16 (emphasis added); Ex. 1004 ¶ 21.
`Petitioner further asserts that a person of ordinary skill in the art would have
`had “access to and may consult with a pharmacologist with experience in
`pharmacokinetics and/or an M.D. with experience with ADHD and
`pharmacological treatments for ADHD.” Pet. 16; see also Tr. 67:11–68:8.
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`
`Patent Owner proposes that a person of ordinary skill in the art at the
`time of the invention would have had “a Bachelor of Science Degree in
`Pharmacy, Chemistry, or Chemical Engineering, or similar field, and three
`years of experience in the field of pharmaceutics (including pharmaceutical
`formulation or pharmacokinetics or a similar technical field of study).” PO
`Resp. 17 (emphasis omitted). Patent Owner notes that Petitioner proposes
`“at least” a certain identified skill level, whereas Patent Owner proposes
`“three years” of experience. Id. at 15. According to Patent Owner, “[i]f
`Petitioner’s ‘at least’ imputes a higher skill, as by osmosis from others on a
`team, Okajima’s reasoning could ‘bridge over gaps’ in Petitioner’s case, and
`disfavor Patent Owner via hindsight.” Id. at 16.
`To the extent Petitioner’s proposed “at least” interjects ambiguity in
`the level of ordinary skill, we do not adopt that part of Petitioner’s proposed
`definition. Otherwise, we find it is not necessary to resolve any perceived
`differences in the parties’ definitions of the level of ordinary skill in the art
`for purposes of this Final Written Decision. With the deletion of the “at
`least” in Petitioner’s proposed definition of the level of ordinary skill, our
`determination regarding the patentability of the challenged claims does not
`turn on any remaining differences between the parties’ definitions; our
`conclusions would be the same under either assessment.
`
`B. Claim Interpretation
`In an inter partes review filed before November 13, 2018, the Board
`interprets claim terms in an unexpired patent according to the broadest
`reasonable construction in light of the specification of the patent in which
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`they appear.6 37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136
`S. Ct. 2131, 2142 (2016) (affirming applicability of broadest reasonable
`construction standard to inter partes review proceedings). Under that
`standard, and absent any special definitions, we give claim terms their
`ordinary and customary meaning, as would be understood by one of ordinary
`skill in the art at the time of the invention. See In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions for claim
`terms must be set forth in the specification with reasonable clarity,
`deliberateness, and precision. See In re Paulsen, 30 F.3d 1475, 1480
`(Fed. Cir. 1994).
`In our Decision on Institution, we construed “about” and “no food
`effect” consistent with their definitions in the specification of the ’857
`patent. Inst. Dec. 11–13. In particular, the ’857 patent specification defines
`“food effect” as “a significant difference in the bioavailability of a drug in a
`patient when the drug is administered in a fasted state compared to a fed
`state.” Ex. 1001, 12:4–9. Thus, we construe no “food effect” precisely as
`defined by the specification—no “significant difference in the bioavailability
`of a drug in a patient when the drug is administered in a fasted state
`compared to a fed state.” Neither party contested our construction of these
`
`
`6 The Office recently changed the claim construction standard applicable to
`an inter partes review. See Changes to the Claim Construction Standard for
`Interpreting Claims in Trial Proceedings Before the Patent Trial and Appeal
`Board, 83 Fed. Reg. 51,340 (Oct. 11, 2018). The rule changing the claim
`construction standard, however, does not apply to this proceeding because
`Petitioner filed its Petition before the effective date of the final rule, i.e.,
`November 13, 2018. Id. at 51,340 (rule effective date and applicability
`date), 51,344 (explaining how the Office will implement the rule).
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`terms and we see no reason to modify that construction in light of the record
`developed at trial.
`We have not identified any other terms that require construction for
`purposes of determining whether Petitioner has demonstrated unpatentability
`by a preponderance of the evidence. See 35 U.S.C. § 316(e); Nidec Motor
`Corp. v. Zhongshan Borad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed.
`Cir. 2017) (“[W]e need only construe terms ‘that are in controversy, and
`only 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)))
`E. Overview of the Prior Art
`Burnside (Ex. 1002)
`1.
`Burnside relates to “a multiple unit dosage form delivery system
`comprising one or more amphetamine salts for administering the
`amphetamine salts to a recipient.” Ex. 1002, 1:9–11.
`Burnside discloses examples in which amphetamine salts are layered
`onto sugar spheres for drug delivery and examples in which the
`amphetamine salts are further coated with a “protective layer” (enteric
`coating) to delay the drug release. Id. at 10:35–12:26. Burnside states that
`“suitable materials for the protective layer include cellulose derivatives such
`as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
`methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate
`copolymer, ethyl cellulose aqueous dispersions (AQUACOAT®,
`SURELEASE®), EUDRAGIT® RL 30D, OPADRY® and the like.” Id. at
`8:20–29.
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`
`Example 1 of Burnside discloses immediate release beads containing
`mixed amphetamine salts.7 Id. at 10:30–57.
`Example 2 of Burnside discloses the coating of mixed amphetamine
`salts with EUDRAGIT L. Id. at 10:60–11:8. “[T]he enteric coating delayed
`the drug release from the coated pellets until after exposure to pH 6 or
`higher.” Id. at 11:9–10. Figure 4 of Burnside is depicted below:
`
`
`Figure 4 illustrates the drug release profile of the coated pellets in Example
`2. Id. at 11:23–24.
`Example 3 discloses coating of mixed amphetamine salts with
`EUDRAGIT 4110D.8 Id. at 11:26–11:41. “[T]he enteric coating delayed
`the drug release from the coated pellets until the pH value reached 6.8 or
`higher.” Id. at 11:41–43. Figure 5 of Burnside is depicted below:
`
`
`7 The immediate release beads from Burnside’s Example 1 will be referred
`to as “Burnside’s Example 1 IR” beads.
`8 The delayed pulsed beads from Burnside’s Examples 2 and 3 are referred
`to as “Burnside’s Example 2 DPR beads” or “Burnside’s Example 3 DPR
`beads.”
`
`11
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`
`
`Figure 5 illustrates the drug release profile of the coated pellets in Example
`3. Id. at 11:56–57.
`Example 4 discloses applying an additional coating to the coated
`pellets from Example 2 or Example 3 by spraying SURELEASE coating on
`the outer surfaces of the coated pellets.9 Id. at 11:59–12:9. Burnside states
`that the “SURELEASE coating slightly sustained the drug release from
`EUDRAGIT® L 30D-55 coated pellets at pH 7.5 buffer, while the
`SURELEASE® coating delayed the drug release up to 2 hours after the
`buffer switched from pH 1 to pH 7.5.” Id. at 12:9–14. Figure 6 of Burnside
`is depicted below:
`
`
`9 The sustained release beads from Burnside’s Example 4 are referred to as
`“Burnside’s Example 4 SR” beads.
`
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`
`
`Figure 6 illustrates the drug release profile of the coated pellets in Example
`4. Id. at 12:25–26.
`Example 5 of Burnside discloses a “pulsatile delivery system”
`achieved by combining Burnside’s Example 1 IR pellets with Burnside’s
`Example 2 DPR beads or Burnside’s Example 3 DPR beads.10 Id. at 12:29–
`31. Burnside discloses that pellets of both types equivalent to half of the
`total dose are “filled into a hard gelatin capsule to produce the oral pulsed
`dose delivery system. The delayed-release portion releases the amphetamine
`salts rapidly and completely, after a specified lag time.” Id. at 12:31–36.
`Figure 8 of Burnside is depicted below:
`
`
`10 The beads from Burnside’s Example 5, containing both IR and DPR
`beads, will be referred as “Burnside’s Example 5 two-bead system.”
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`
`
`Figure 8 is the in vivo drug release profile of the coated pellets in Example 5.
`Id. at 12:40–41.
`
`Adderall XR (Ex. 1003, 1031)
`2.
`Adderall XR is indicated for the treatment of Attention Deficit
`Hyperactivity Disorder (ADHD). Ex. 1031, 34. Adderall XR is
`administered as a capsule containing “two types of drug-containing beads
`designed to give a double-pulsed delivery of amphetamines, which prolongs
`the release of amphetamine” as compared to the Adderall IR formulation.11
`Ex. 1031, 14. In addition, food does not affect the extent of absorption of
`Adderall XR. Ex. 1031, 2.
`
`
`11 Petitioner’s declarant explains that Adderall XR is “a drug product
`comprising the same [drug] as Adderall IR®, but within immediate release
`and delayed pulsed beads with an enteric coating.” Ex. 1004 ¶ 32.
`14
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`F. Anticipation by Burnside
`Petitioner asserts that claims 1–19 and 29 of the ’857 patent are
`anticipated by Burnside under 35 U.S.C. § 102(a). Pet. 4, 17–34.
`A prior art reference that expressly or inherently contains each and
`every limitation of the claimed subject matter anticipates and invalidates.
`See, e.g., EMI Group N. Am., Inc., v. Cypress Semiconductor Corp., 268
`F.3d 1342, 1350 (Fed. Cir. 2001) (“A prior art reference anticipates a patent
`claim if the reference discloses, either expressly or inherently, all of the
`limitations of the claim.”). As discussed below, Petitioner has not carried its
`burden of establishing that Burnside anticipates claim 1 or any of the
`dependent claims. We focus our analysis on independent claim 1.
`Independent claim 1 recites a method for treating ADHD comprising
`administering to a patient in need thereof, a pharmaceutical composition
`comprising: (1) an immediate release bead (“the claimed IR bead”)
`comprising at least one amphetamine salt; (2) a first delayed release bead
`(“the claimed first DR bead”) comprising at least one amphetamine salt; and
`(3) a second delayed release bead (“the claimed second DR bead”)
`comprising at least one amphetamine salt; wherein the first delayed release
`bead provides pulsed release of the at least one amphetamine salt and the
`second delayed release bead provides sustained release of the at least one
`amphetamine salt; wherein the second delayed release bead comprises at
`least one amphetamine salt layered onto or incorporated into a core; a
`delayed release coating layered onto the amphetamine core; and a sustained
`release coating layered onto the delayed release coating, wherein the
`sustained release coating is pH-independent; and wherein the first delayed
`release bead and the second delayed release bead comprise an enteric
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`coating. Thus, the claimed method comprises administering a composition
`comprising three types of beads, each of which contains a core of
`amphetamine salt. The claimed first DR bead provides a pulsed release of
`the salt and comprises an enteric coating. The claimed second DR bead
`provides a sustained release of the salt, comprises a delayed release coating
`layered onto the core, and a sustained release coating layered onto the
`delayed release coating, wherein the sustained release coating is pH-
`independent and wherein the claimed second DR bead also comprises an
`enteric coating.
`Petitioner refers to Burnside’s Examples 1–5 in arguing that Burnside
`teaches each of the three beads in the composition claimed by claim 1. Pet.
`19–25. Petitioner also argues that Burnside teaches the combination of the
`beads disclosed in Examples 1–4 in the same way as in claim 1. Id. at 25–
`29 (citing Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1341 (Fed.
`Cir. 2016)). In support, Petitioner refers to Burnside’s statements that “the
`drug delivery system of the present invention preferably comprises one or a
`number of beads or beadlets in a dosage form” and “the present invention
`provides an oral multiple unit pulsed dose delivery system for amphetamine
`salts.” Id. (citing Ex. 1002, 6:33–35, 3:33–35, 1:9–11 (emphasis omitted)).
`In addition, Petitioner refers to Burnside’s Example 5 two-bead system and
`acknowledges that Example 5 teaches combining pellets from Example 1
`with those of either Examples 2 or 3. Id. at 24.
`
`Patent Owner argues that because Burnside’s Example 4 and 5 beads
`were never combined and arranged as in claim 1, Burnside does not
`anticipate the claim. PO Resp. 19–21, 25–26. With supporting testimony of
`its declarant, Dr. Trout, Patent Owner argues that Burnside’s disclosure of
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`“one or a number of beads in a dosage form” does not teach using more than
`two types of beads, but rather “means a plurality of IR beads and a plurality
`of DPR beads. This provides multiple (i.e., two) pulses.” Prelim. Resp. 33
`(citing Ex. 2001 ¶¶ 66–71); PO Resp. 26.
`
`In our Decision on Institution, we indicated that we are not
`sufficiently persuaded by Petitioner’s argument and evidence that Burnside
`discloses the claimed composition of claim 1—a composition comprising the
`claimed IR bead, the claimed first DR bead, and the claimed second DR
`bead. Inst. Dec. 32–34. In particular, we determined that “[w]ithout an
`express disclosure of the claimed composition or a disclosure within
`Burnside to combine the three types of claimed beads, Burnside does not
`disclose all elements of claim 1 within the four corners of the document as
`arranged in the claim.” Id. at 34. Without the composition of claim 1, a
`skilled artisan could not practice the method of claim 1. Petitioner did not
`further argue anticipation in its Reply or Response to Patent Owner’s Sur-
`Reply. Accordingly, we find that Petitioner has not shown by a
`preponderance of the evidence that Burnside anticipates claim 1, or any
`dependent claim.
`G. Obviousness over Burnside
`Petitioner asserts that claims 1–29 are unpatentable under 35 U.S.C.
`§ 103 as obvious over Burnside. Pet. 4, 35–36; 52–57; Pet. Reply 1–17; Pet
`Resp. to Sur-Reply 1–15.
`Obviousness is a question of law based on subsidiary findings of
`fact. In re Van Os, 844 F.3d 1359, 1360 (Fed. Cir. 2017). An obviousness
`determination requires finding both “that a skilled artisan would have been
`motivated to combine the teachings of the prior art . . ., and that the skilled
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`artisan would have had a reasonable expectation of success in doing
`so.” Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359,
`1367–68 (Fed. Cir. 2016). Whether a skilled artisan would have been
`motivated to modify or combine teachings in the prior art, and whether she
`would have had a reasonable expectation of success, are questions of
`fact. Id. at 1366. Moreover, Petitioner has the burden to show a motivation
`to combine and a reasonable expectation of success. See Redline Detection,
`LLC v. Star Envirotech, Inc., 811 F.3d 435, 449 (Fed. Cir. 2015) (“When
`asserting that a claimed invention would have been obvious, that party ‘must
`demonstrate . . . that a skilled artisan would have had reason to combine the
`teachings of the prior art references to achieve the claimed invention, and
`that the skilled artisan would have had a reasonable expectation of success
`from doing so.’” (quoting PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d
`1186, 1193 (Fed. Cir. 2014))); see also 35 U.S.C. § 316(e) (“In an inter
`partes review instituted under this chapter, the petitioner shall have the
`burden of proving a proposition of unpatentability by a preponderance of the
`evidence.”). As discussed below, Petitioner has not carried its burden of
`establishing a motivation to combine the teachings of the prior art to achieve
`the claimed composition12 that would enable a skilled artisan to practice the
`method of claim 1, and that a skilled artisan would have had a reasonable
`expectation of success in doing so.
`
`12 Although claim 1 is directed at a method of treatment, both parties focus
`their arguments on the composition recited in claim 1 that is administered in
`the method of treatment and claimed in the ’100 patent. We adopt this focus
`with the understanding that the method of treatment cannot be practiced
`without the recited composition. In addition, we do not analyze the
`dependent claims due to our finding that Petitioner has not established that
`independent claim 1 is unpatentable as challenged.
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`Petitioner argues that Burnside alone renders claim 1 obvious because
`Burnside Example 5 “teaches each and every limitation associated with the
`immediate and first delayed release beads of claim 1, and Example 4 teaches
`the second delayed release beads of claim 1.” Pet. 36. In other words,
`Petitioner argues that a skilled artisan would have combined Burnside’s
`Example 4 SR beads with Burnside’s Example 5 two-bead system to arrive
`at the claimed invention. Patent Owner does not contest that Burnside
`teaches the three types of beads required by claim 1. See PO Resp.,
`generally. Patent Owner, however, argues that a skilled artisan would not
`have been motivated to combine Burnside’s Example 4 SR beads with
`Burnside’s Example 5 two-bead system to arrive at the composition of claim
`1 and would not have had a reasonable expectation of success in doing so.
`PO Resp. 29–59. Accordingly, we focus our analysis on these issues.
`As an initial matter, Petitioner’s position that a skilled artisan would
`have been motivated to make the claimed composition and would have had a
`reasonable expectation of success in doing so rests on Burnside’s disclosure
`of separate in vitro release profiles for the immediate release, delayed pulsed
`release, and sustained release beads, and in vivo results solely for the
`combination of immediate release and delayed pulsed release beads (i.e.,
`Example 5). See Ex. 1004, Example 4, Figs. 6, 7, 8. Burnside does not
`disclose in vivo data for Burnside’s Example 4 SR beads or, more
`importantly, for a combination that includes Example 4’s SR beads. Yet,
`relying on the testimony of Drs. Burgess and Jusko, Petitioner contends that
`the skilled artisan would have been motivated to combine as proposed,
`because Burnside’s Example 4 SR beads are “capable of releasing additional
`amphetamine in [a] patient after release of [the] amphetamine active in the
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`two-bead systems of Example 5” and because a skilled artisan “would
`understand that such later release of amphetamine is necessary to provide
`prolonged therapeutic efficacy.” Pet. 53 (citing Ex. 1004 ¶¶ 160, 161;
`Ex. 1006 ¶¶ 19, 34–41, 48). Petitioner’s argument is unavailing.
`We are not sufficiently persuaded that a skilled artisan’s knowledge of
`the individual in vitro release profile of Burnside’s Example 4 SR beads
`(i.e., alleged claimed second DR bead) and the in vivo release profile of
`Burnside’s Example 5 two-bead system (alleged claimed IR and first DR
`bead) would have led a skilled artisan to the claimed composition. See
`Ex. 1024, 26 (“[C]urrent in vitro methods of evaluating enteric coatings may
`not accurately predict in vivo performance. It is, therefore, important that
`enteric coated dosage forms be subjected to in vivo evaluations.”). It is not
`disputed that the formulation of Burnside’s Example 4 SR beads is different
`than Burnside’s Example 5 two-bead system, and that there was no in vivo
`data for Burnside’s Example 4 SR beads. “[W]hether the skilled artisan can
`extrapolate in vivo success from in vitro results is highly fact specific.”
`Nantkwest, Inc. v. Lee, 686 F. App’x 864, 870 (Fed. Cir. 2017).
`Petitioner’s contention that in vitro release profiles translate to in vivo
`release profiles is based on Drs. Jusko’s and Burgess’s opinions. See Tr.
`8:21–9:7. However, we give little weight to these opinions because they are
`not sufficiently factually supported. Dr. Jusko opines that a skilled artisan
`“would understand that adding the delayed sustained release beads of
`Example 4 to Adderall XR®, or to Example 5 of Burnside, would release
`significant additional amphetamine active after all the active in the
`immediate and delayed pulsed beads has been released.” Ex. 1006 ¶ 37.
`Dr. Jusko’s opinion, however, is based solely on Burnside’s in vitro data.
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`Id. (citing Ex. 1002, Fig. 6). Dr. Jusko’s opinion is conclusory because, for
`example, he does not sufficiently explain how the in vitro release
`environment disclosed in Burnside’s examples would translate to in vivo
`conditions. In Nantkwest, “there were specific studies undertaken to
`determine whether the [cell line at issue] would be useful for in vivo
`therapy.” 686 F. App’x at 869. Petitioner does not cite to any such studies
`here relating to whether the in vitro data for Example’s 4 SR beads would
`correlate to in vivo results. Indeed, Dr. Jusko testified that such studies are
`necessary when asked how one would establish whether there is a
`correlation between an in vitro dissolution profile and in vivo release of the
`drug: “In part, it is a well-accepted expectation between in vitro dissolution
`and in vivo behavior, but, in part, it needs to be established by an actual
`study in human subjects.” Ex. 2070, 17:3–10.
`Dr. Burgess’s testimony that “[o]ne possibly could predict [in vivo
`phar