Trials@uspto.gov
`571-272-7822
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`Paper No. 10
`Entered: April 12, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`RANBAXY INC.,
`Petitioner
`
`v.
`
`JAZZ PHARMACEUTICALS, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-00024
`Patent 8,772,306
`____________
`
`
`
`Before ERICA A. FRANKLIN, BRIAN P. MURPHY, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`

`

`IPR2016-00024
`Patent 8,772,306
`
`I.
`
`INTRODUCTION
`
`Ranbaxy, Inc. (“Petitioner”) filed a Petition (Paper 1, “Pet.”),
`requesting institution of an inter partes review of claims 1–34 of
`U.S. Patent No 8,772,306 (Ex. 1001, “the ’306 patent”). Jazz
`Pharmaceuticals Ireland Ltd. and Jazz Pharmaceuticals, Inc. (collectively,
`“Patent Owner”) timely filed a Preliminary Response (Paper 8,
`“Prelim. Resp.”). 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 Petition and the Preliminary Response, and
`for the reasons explained below, we determine that Petitioner has shown a
`reasonable likelihood it would prevail with respect to some of, but not all,
`the challenged claims. We, therefore, institute an inter partes review of
`claims 19–34 of the ’306 patent.
`
`A. Related Proceedings
`Petitioner and Patent Owner have identified the following related
`litigation proceedings in which the ’306 patent is being asserted: Jazz
`Pharm. Inc. et al. v. Lupin Ltd. et al., 2:15-cv-06548 (D.N.J.); Jazz Pharm.
`Inc. et al. v. Wockhardt Bio AG et al., 2:15-cv-05619 (D.N.J.); Jazz Pharm.
`Inc. et al. v. Roxane Laboratories, Inc., 2:15-cv-01360 (D.N.J.); Jazz Pharm.
`Inc. et al. v. Amneal Pharms., LLC, 2:15-cv-01043 (D.N.J.); Jazz Pharm.
`Inc. et al. v. Watson Laboratories, Inc., 2:14-cv-07757 (D.N.J.); Jazz Pharm.
`Inc. et al. v. Ranbaxy Laboratories Ltd. et al., 2:14-cv-06151 (D.N.J.); Jazz
`Pharm. Inc. et al. v. Par Pharmaceutical Inc., 2:14-cv-06150 (D.N.J.); Jazz
`
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`Pharm. Inc. et al. v. Par Pharmaceutical Inc., 2:14-cv-05824 (D.N.J.). Pet.
`2.
`
`Patent Owner also identified two other cases, Jazz Pharmaceuticals,
`Inc. v. Amneal Pharmaceuticals, LLC, 2:15-cv-6562 (D.N.J.) and Jazz
`Pharmaceuticals, Inc. v. Par Pharmaceutical, Inc., 2:15-cv-7580 (D.N.J.),
`concerning a patent related to the ’306 patent. Paper 7, 1–2.
`In addition Par Pharmaceutical, Inc. and Amneal Pharmaceuticals
`each filed separate petitions for inter partes review of the ’306 patent. See
`IPR2016-00002; IPR2016-00546.
`B.
`The ’306 Patent (Ex. 1001)
`The ’306 patent issued on July 8, 2014, and claims a priority date as
`early as March 1, 2013. See Ex. 1001, Title Page. It names Mark Eller as
`the sole inventor. Id.
`The ’306 patent relates generally to methods for improving the safety
`and efficacy of the administration of gamma-hydroxybutyrate (“GHB”) or a
`salt thereof to a patient. Id., Abstract. More specifically, the ’306 patent is
`concerned with treating patients suffering from certain disorders such as
`cataplexy or narcolepsy, who are concomitantly receiving treatment with
`valproate, with a reduced dose of GHB. Id. at 1:15–36. The specification
`states that valproate can increase or prolong the effects of GHB, resulting in
`unsafe conditions such as excessive daytime sleepiness. Id. at 15:19–16:21.
`In certain embodiments, the reduced amount of GHB ranges from 1% to
`50% of the effective dose normally given to the patient. Id. at 1:32–36.
`C. Illustrative Claims
`Petitioner challenges claims 1–34 of the ’306 patent. All of the
`challenged claims are directed to methods of treating certain sleep disorders
`
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`by orally administering a reduced dosage of GHB to patients who are
`concomitantly receiving valproate.
`Claims 1, 11, 19, 30, and 33 are independent. Independent claims 1
`and 19 are illustrative, and reproduced below:
`
`1. A method for treating a patient who is suffering from
`excessive daytime sleepiness, cataplexy, sleep paralysis, apnea,
`narcolepsy, sleep time disturbances, hypnagogic hallucinations,
`sleep arousal, insomnia, or nocturnal myoclonus with gamma-
`hydroxybutyrate (GHB) or a salt thereof, said method
`comprising:
`orally administering to the patient in need of treatment at
`least 5% decrease in an effective dosage amount of the
`GHB or salt thereof when the patient is receiving a
`concomitant administration of valproate, an acid, salt, or
`mixture thereof.
`19. A method for treating a patient who is suffering from
`narcolepsy, said method comprising:
`administering a therapeutically effective amount of a
`formulation containing a GHB salt to a patient starting
`at a concentration of between 350 and 750 mg/ml with a
`pH of between 6 and 10;
`determining if the patient is also being administered
`valproate, an acid, salt or mixture thereof;
`warning of a potential drug/drug interaction due to the
`combination of valproate, an acid, salt or mixture
`thereof and the GHB salt; and
`recommending reducing the dose of the GHB salt at least
`15%.
`
`D. The Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of the claims of the ’306 patent
`on the following grounds:
`
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`
`References
`Maitre1 and the Xyrem PI2
`
`Okun3 and the Xyrem Titration
`Schedule4
`Okun, the Xyrem Titration
`Schedule, and Cook5
`Maitre, the Xyrem PI, and
`Sandson6
`
`
`II. DISCUSSION
`
`A. Claim Construction
`
`Basis
`§ 103(a)
`
`§ 103(a)
`
`Claims challenged
`1–5, 7–16, 18–26, and
`28–34
`1–5, 7–16, 18, 30, 31,
`and 33
`
`§ 103(a)
`
`19–26, 28, 29, 32 and 34
`
`§ 103(a)
`
`6, 17, and 27
`
`We interpret claims using the “broadest reasonable construction in
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`§ 42.100(b); see also In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278–
`79 (Fed. Cir. 2015) (“Congress implicitly approved the broadest reasonable
`
`
`1 Maitre, Michel, The γ-Hydroxybutyrate Signalling System in Brain
`Organization and Functional Implications, Vol. 51, Progress in
`Neurobiology, at 337–361 (1997)(Ex. 1003).
`2 The Xyrem® Package Insert entry in the Physician’s Desk Reference
`Edition, at 1688–1692, (2007)(Ex. 1005).
`3 Okun, Michael S., GHB: An Important Pharmacologic and Clinical
`Update, Vol. 4(2), J. Pharm. Pharmaceut. Sci., at 167–175 (2001)(Ex. 1005).
`4 Xyrem® Titration Schedule, Jazz Pharmaceuticals (2008) (Ex. 1006).
`5 U.S. Patent No. 6,780,889, issued August 24, 2004 (“Cook et al”) (Ex.
`1007).
`6 Sandson et al., An Interaction Between Aspirin and Valproate: The
`Relevance of Plasma Protein Displacement Drug-Drug Interactions, Vol.
`163, Am. J. Psychiatry, at 1891–1896 (2006)(Ex. 1023).
`
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`interpretation standard in enacting the AIA,” 7 and “the standard was
`properly adopted by PTO regulation.”), cert. granted, sub nom. Cuozzo
`Speed Techs. LLC v. Lee, 136 S. Ct. 890 (mem.) (2016). Under the broadest
`reasonable construction standard, claim terms are given their ordinary and
`customary meaning, as would be understood by one of ordinary skill in the
`art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d 1249,
`1257 (Fed. Cir. 2007). “Absent claim language carrying a narrow meaning,
`the PTO should only limit the claim based on the specification . . . when [it]
`expressly disclaim[s] the broader definition.” In re Bigio, 381 F.3d 1320,
`1325 (Fed Cir. 2004). “Although an inventor is indeed free to define the
`specific terms used to describe his or her invention, this must be done with
`reasonable clarity, deliberateness, and precision.” In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994).
`We determine that no explicit construction of any claim term is
`necessary to determine whether to institute a trial in this case.8 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. Prior Art Relied Upon
`Petitioner relies upon the following prior art in its challenges.
`
`
`
`7 The Leahy-Smith America Invents Act, Pub. L. No. 112−29, 125 Stat. 284
`(2011) (“AIA”).
`8 We address, however, whether certain claim limitations constitute non-
`limiting “printed matter” in the context of our analysis below.
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`
`1. Maitre (Ex. 1003).
`Maitre provides an overview of the GHB signaling system in the
`brain. Maitre teaches the major metabolic pathway for GHB degradation in
`the brain involves 1) conversion of GHB to succinic semialdehyde (“SSA”),
`a reaction catalyzed by an enzyme known as SSA reductase or GHB
`dehydrogenase, followed by 2) conversion of SSA into gamma-aminobutyric
`acid (“GABA”). Ex. 1003, 340 (right column)–342. Antiepileptic drug
`compounds, such as valproate, were known inhibitors of GHB
`dehydrogenase such that, “[w]hen administered in vivo, most of these
`compounds induce an increase in brain GHB levels.” Id. at 340 (left
`column), see also id. at 343 (left column (“an accumulation of GHB is
`induced following acute treatment with [valproate]”)). Maitre discloses that
`valproate, as a GHB-dehydrogenase inhibitor, “block[s] the conversion of
`GHB into GABA and lead[s] to the accumulation of GHB in brain after in
`vivo administration.” Id. at 351 (left column).
`2. Okun (Ex. 1004).
`Okun teaches that medicinal uses of GHB include narcolepsy,
`depression, alcohol withdrawal, epilepsy, and anesthesia. Ex. 1004, 167
`(left column). Okun teaches “[a] therapeutic effect with decreased
`cataplexy, as well as improved nocturnal sleep quality was demonstrated” in
`narcoleptic patients treated with GHB. Id. at 169 (left column).
`Okun further teaches that “[b]ecause GHB has been used in the study
`of epilepsy, there is a question regarding the necessity, benefits and risks
`associated with the use of anticonvulsants in the treatment of GHB-induced
`seizures,” and “[v]alproate [is] thought to decrease the GABA-like effect at
`the GABA B receptor by inhibition of GHB dehydrogenase.” Id. at 170
`
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`(right column). Okun notes “[t]here is no clear answer” to the question of
`“whether the use of anticonvulstants will alter the respiratory depression and
`CNS side effects of GHB in humans.” Id.
`3. Xyrem PI (Ex. 1005).
`Xyrem PI is an excerpt from the 2007 Physicians’ Desk Reference
`disclosing the prescribing information for an oral administration of sodium
`oxybate (i.e., a GHB salt), a central nervous system depressant, for treating
`excessive daytime sleepiness and cataplexy in patients with narcolepsy. Ex.
`1005, 1688. Xyrem PI recommends a starting dose of GHB of 4.5 g/night,
`divided into two equal doses of 2.25 g. Id. at 1692. Xyrem PI also
`recommends increasing the dosage to a maximum of 9 g/night in increments
`of 1.5 g/night (0.75 g per dose), and further discloses that the effective dose
`range is 6 to 9 g/night. Id.
`Xyrem PI discloses that excess dosing of GHB could have adverse
`effects, including coma or death. Id. at 1688 (left column, “WARNING”),
`1692 (left column, “OVERDOSAGE . . . Signs and Symptoms”). Xyrem PI
`includes a black box warning on the first page that the drug “[s]hould not be
`used with alcohol or other CNS depressants.” Id. at 1688. Additionally,
`Xyrem PI indicates “[s]odium oxybate is contraindicated in patients with
`succinic semialdehyde dehydrogenase [SSADH] deficiency.” Id. at 1689
`(middle column, “CONTRAINDICATIONS”).
`4. Xyrem Titration Schedule (Ex. 1006).
`The Xyrem Titration Schedule is a one page document providing that
`the “[r]ecommended starting dose [for GHB] is 4.5 g/night,” and that the
`“[d]osage should be titrated to effect in increments of 1.5 g/night . . . to a
`maximum dose of 9 g/night.” Ex. 1006.
`
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`
`5. Cook (Ex. 1007).
`Cook is directed to solutions of GHB salt for the treatment of sleep
`disorders, including narcolepsy. Ex. 1007, Title. Cook discloses several
`aqueous solutions having a concentration of GHB of 500 mg/mL and a pH
`of 7.5. Id. at cols. 40–41, Table 18. Cook also discloses solutions having a
`concentration of 750 mg/ml. Id. at col. 43, Table 19.
`6. Sandson (Ex. 1023).
`Sandson teaches that aspirin-valproate interaction is a significant
`contributor to valproate toxicity. Ex. 1023, 1891. Specifically, Sandson
`discloses that “[w]hen aspirin and valproate are coadministered, aspirin
`increases the ratio of free valproate concentration to total valproate
`concentration at a given dose.” Id. at 1893 (right column).
`
`C. Analysis of Petitioner’s Patentability Challenges
`1. Obviousness of Claims 1–5, 7–16, 18–26, and 28–34 Based
`on Maitre and the Xyrem PI
`2. Obviousness of Claims 6, 17, and 27 Based on Maitre, the
`Xyrem PI, and Sandson
`
`Petitioner contends that claims 1–5, 7–16, 18–26, and 28 are obvious
`based on the combination of Maitre and the Xyrem PI. Pet. 17–34.
`Petitioner further contends that claims 6, 17, and 27 are obvious based on the
`additional teachings of Sandson. Id. at 49–50. In addition to the teachings
`of the references, Petitioner relies upon the Declaration of David P. Rotella,
`Ph.D. for these challenges. Ex. 1002.
`Petitioner has treated independent claims 1 and 11 similarly, noting
`that the only difference between them is that claim 11 recites a method of
`“safely administering GHB” (not a method for treating) and recites a step for
`
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`determining if a patient has taken or will take valproate concomitantly with
`GHB. Pet. 21 (citations omitted). We accordingly consider claims 1–18
`together for purpose of our analysis. Petitioner, however, has raised an
`additional argument with regard to the “warning” and/or “recommending”
`limitations of independent claims 19, 30, and 33 (Pet. 23, 25), and we
`therefore address claims 19–34 separately.
`
`a. Claims 1–18
`Independent claim 1 requires orally administering at least a 5%
`decrease in an effective dosage amount of GHB “when the patient is
`receiving a concomitant administration of valproate.” Independent claim 11
`requires a) determining if the patient has taken, or will take, a concomitant
`dose of valproate, and b) orally administering a reduced amount of GHB
`“wherein the reduction is at least 5% compared to a dose without
`concomitant administration of valproate.” As presented in the Petition and
`Preliminary Response, the key issue with regard to both claims 1 and 11 is
`whether it would have been obvious to administer such a reduced dosage of
`GHB when valproate is concomitantly administered.
`Petitioner asserts that, based on the Xyrem PI’s teaching that GHB
`should be “titrated to effect” and Maitre’s teaching that valproate increases
`GHB levels in the brain, the skilled artisan would have, “through mere
`routine optimization,” reduced the GHB dose when a patient was
`concomitantly being administered valproate. Pet. 18–20. According to
`Petitioner, because valproate causes a “significant” increase of GHB in the
`brain, the skilled artisan would logically lower the GHB dose administered
`to patients on valproate. Id. at 19 (citing Ex. 1002, ¶¶ 49–50, 53)).
`Furthermore, Petitioner asserts that the skilled artisan would have decreased
`
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`the GHB dose by the amounts recommended in the Xyrem PI, i.e., the GHB
`dose would be lowered from 9 g/night to 7.5 g/night (i.e., a 16.7%
`reduction), from 7.5 g/night to 6 g/night (i.e., a 20% reduction), from 6
`g/night to 4.5 g/night (i.e., a 25% reduction), or from 4.5 g/night to 3.0
`g/night (i.e., a 33.3% reduction). Id. (citing Ex. 1002, ¶¶ 50–51).9
`Patent Owner argues that the prior art, as a whole, would have taught
`the skilled artisan that the co-administration of GHB and valproate would
`result in unpredictable effects. Prelim. Resp. at 9–24. Patent Owner also
`argues that the prior art expressly teaches away from the claimed inventions.
`Id. at 24–29. Patent Owner further argues that none of the prior art relied
`upon discloses, teaches, or suggests reducing the GHB dose in a patient
`taking valproate. Id. at 29–35. Lastly, Patent Owner argues that reducing
`the GHB dose to the levels suggested by Petitioner would have caused side
`effects and would have been ineffective for treating sleep disorders. Id. at
`35–39.
`We determine that Petitioner has not demonstrated a reasonable
`likelihood of prevailing with respect to this challenge. As an initial matter,
`Petitioner does not account for the prior art’s teaching away of the co-
`
`
`9 Petitioner contends that “the person of ordinary skill in the art at the time
`of the alleged invention would have had an advanced degree, or access to
`those with advanced degrees, in medicine or pharmacy, including a medical
`doctors, and/or pharmacists,” “would also have had advanced knowledge of
`medicinal chemistry, and would have collaborated with a person having
`advanced knowledge of pharmacology, and familiarity with, typical methods
`for evaluating the potential impact of drug-drug interactions,” and “would
`have had an understanding of the drug’s pharmacokinetics and
`pharmacodynamics, and the risks of the pharmacokinetics of drug
`combinations.” Pet. 7; Ex. 1002, ¶ 30. We apply that understanding in our
`analysis.
`
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`administration of GHB and valproate. A reference teaches away from a
`claimed invention if it “criticizes, discredits, or otherwise discourages”
`modifying the reference to arrive at the claimed invention. In re Fulton, 391
`F.3d 1195, 1201 (Fed. Cir. 2004); see also KSR Int'l Co. v. Teleflex Inc., 550
`U.S. 398, 416 (2007) (“[W]hen the prior art teaches away from combining
`certain known elements, discovery of a successful means of combining them
`is more likely to be nonobvious.”). Here, we find it particularly relevant that
`Petitioner does not address the explicit black box warning of the Xyrem PI,
`that GHB should not be taken with other CNS depressants, despite the fact
`that valproate is a CNS depressant. Ex. 1005, 1688; Ex. 2009 ¶ 56. Nor
`does Petitioner address the Xyrem Label’s contraindication of GHB in
`patients with SSADH deficiency, despite reports that valproate was known
`to inhibit SSADH activity. Ex. 1005, 1689; see also Ex. 1018, 285–286
`(Valproate “of questionable use in patients with SSADH deficiency”). This
`warning and contraindication teaches away from the co-administration of
`any amount of GHB with valproate.
`Moreover, even if the prior art did not teach away from reducing the
`effective dosage of GHB by at least 5% when valproate is co-administered,
`Petitioner has not demonstrated sufficiently that a skilled artisan would have
`had a reasonable expectation of success in treating the claimed sleep
`disorders with such a reduced dosage of GHB. Relying upon the Xyrem
`PI’s indication that GHB should be “titrated to effect,” Petitioner asserts that
`GHB dosing should be treated as a result-effective variable, and such result-
`effective variables are natural candidates for routine, obvious optimization.
`Pet. 19–20. We are not persuaded, however, that Petitioner has made a
`sufficient showing that the dosing of GHB would have been recognized as a
`
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`matter of mere routine optimization for treating the specifically claimed
`sleep disorders, especially when the patient is concomitantly being
`administered valproate. See In re Antonie, 559 F.2d 618, 620 (CCPA 1977)
`(obviousness not established where “parameter optimized was not
`recognized to be a result-effective variable”) (emphasis added).
`We recognize that Maitre teaches that valproate can cause an
`accumulation of GHB levels in the brain after in vivo administration. Ex.
`1003, 351. Maitre, however, does not purport to predict the efficacy or
`safety of the co-administration of valproate and GHB at any dosing level.
`Moreover, Patent Owner points to evidence of record showing that GHB is
`eliminated from the body through alternate pathways that are not inhibited
`by valproate, and these alternate elimination pathways may actually
`decrease GHB levels, which contributes to the overall unpredictability of
`combining the two drugs when treating patients for the claimed sleep
`disorders. Prelim. Resp. 9–18. Petitioner does not sufficiently account for
`the effect of valproate on these other pathways by which GHB may be
`eliminated. Petitioner, therefore, has not identified a sufficient basis on this
`record that the skilled artisan would have had a reasonable expectation that
`any increased brain levels of GHB caused by valproate could have been
`predictably compensated for, as a matter of routine optimization, by simply
`decreasing (as opposed to altogether eliminating) the amount of GHB
`administered to patients being treated for the claimed sleep disorders. At
`best, the record demonstrates that the skilled artisan would have had to
`conduct further experimentation (e.g., drug-drug interaction studies) to
`determine the appropriate dose of GHB to treat the claimed sleep disorders
`when valproate is concomitantly administered. Cf. In re Cyclobenzaprine
`
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`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063,
`1070 (Fed. Cir. 2012) (“While it may have been obvious to experiment with
`the use of the same PK profile when contemplating an extended-release
`formulation, there is nothing to indicate that a skilled artisan would have had
`a reasonable expectation that such an experiment would succeed in being
`therapeutically effective.”).
`Because Petitioner has not demonstrated a reasonable likelihood of
`establishing the obviousness of independent claims 1 and 11, we also
`determine that Petitioner has not made a sufficient showing with respect to
`the corresponding dependent claims. See In re Fine, 837 F.2d 1071, 1076
`(Fed. Cir. 1988) (“Dependent claims are nonobvious under section 103 if the
`independent claims from which they depend are nonobvious.”).
`We, therefore, decline to institute an inter partes review of claims 1–
`18 based on Petitioner’s obviousness challenges.
`
`b. Claims 19–34
`Independent claims 19, 30, and 33 each require (a) administering a
`therapeutically effective amount of a GHB salt and (b) determining if the
`patient is also being administered valproate. Independent claim 19
`additionally requires “warning of a potential drug/drug interaction” due to
`the combination of the GHB salt and valproate, and “recommending
`reducing the dose of the GHB salt at least 15%.” Independent claim 30 and
`33 both require “recommending a 20% decrease in the starting dose of the
`GHB salt.”
`In addition to the arguments discussed above with respect to claims 1
`and 11, Petitioner raises an issue that the “warning” and/or “recommending”
`steps recited in claims 19, 30, and 33 constitute “printed matter” not entitled
`
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`to any patentable weight. Pet. 23, 25 (citing King Pharm., Inc. v. Eon Labs,
`Inc., 616 F.3d 1267, 1279 (Fed. Cir. 2010); In re Ngai, 367 F.3d 1336, 1339
`(Fed. Cir. 2004)). Patent Owner does not address this issue in its
`Preliminary Response.
`On this record, Petitioner has provided adequate evidence and
`argument to support its contention that the “warning” step of claim 19 and
`the “recommending” steps of claims 19, 30, and 33 constitute “printed
`matter” bearing no functional relationship to the claimed methods. “Printed
`matter [is subject] matter claimed for what it communicates,” which is not
`entitled to patentable weight unless the “claimed informational content has a
`functional or structural relation” to the claimed invention. In re Distefano,
`808 F.3d 845, 850 (Fed. Cir. 2015). “Printed matter” is not limited to the
`addition of written information to a known product, but rather “extends to
`the situation . . . wherein an instructional limitation is added to a method . . .
`known in the art.” King Pharm., 616 F.3d at 1279. For such claim
`elements, the relevant inquiry is whether the instructional limitation has a
`“new and unobvious functional relationship” with the known method. Id. In
`King Pharmaceuticals, the court held that a limitation of “informing the
`patient” about increased bioavailability of a drug when taken with food was
`not entitled to patentable weight because “[i]nforming a patient about the
`benefits of a drug in no way transforms the process of taking the drug with
`food.” Id. Likewise, in the obviousness context, the court has held that a
`claim step of “providing information” about a previously undiscovered
`correlation between renal failure and bioavailability was not entitled to any
`weight because “nothing in the claim requires that the dosage be adjusted in
`
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`response to the providing of the information.” In re Kao, 639 F.3d 1057,
`1072–73 (Fed. Cir. 2011).
`On the present record, the “warning” and “recommending” steps
`claimed in the ’306 patent claims 19, 30, and 33 read as instructional
`limitations similar to those at issue in the King Pharmaceuticals and Kao
`cases. As with informing a patient about the bioavailability of a drug, the
`steps of “warning” the patient about a potential drug/drug interaction and
`“recommending” a further course of action (i.e., a reduced dose) appear to
`be content claimed for what they communicate, and do not have a structural
`or functional relationship to the process of administering GHB for the
`treatment of narcolepsy recited in these method claims. Accordingly, at this
`stage of the proceeding, we do not give the “warning” and “recommending”
`limitations patentable weight and do not consider them in our obviousness
`analysis. We further invite the parties to address the “printed matter” matter
`doctrine more fully in their post-institution filings.
`In the absence of any weight accorded to the instructional limitations,
`we determine that Petitioner has demonstrated a reasonable likelihood that
`claims 19, 30, and 33 are obvious over the prior art presented in the Petition.
`Claims 19, 30, and 33 each require “administering a therapeutically effective
`amount of formulation containing a GHB salt.” Claim 19 specifies “starting
`at a concentration of between 350 and 750 mg/ml with a pH of between 6
`and 10,” while claim 33 specifies oral administration of the GHB salt.
`Petitioner has pointed out that the Xyrem PI discloses a formulation that is
`an “oral solution [that] contains 500 mg of sodium oxybate [i.e., a GHB salt]
`per milliliter of USP Purified Water, neutralized to pH 7.5 with malic acid.”
`Pet. 24 (citing Ex. 1005, 1688). Accordingly, Petitioner has shown
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`sufficiently that the administering steps of these claims are taught by the
`Xyrem PI.
`Claims 19, 30, and 33 also each require “determining if the patient is
`also being administered valproate, an acid, salt or mixture thereof.”
`Petitioner asserts that “[a] person of ordinary skill in the art would have
`determined if a patient was taking valproate before concomitantly
`administering GHB in order to safely administer GHB to a patient in need
`thereof.” Pet. 21 (citing Ex. 1002, ¶¶ 61–63). We find that Petitioner has
`demonstrated sufficiently that it would have been obvious to at least
`determine if a patient who is being administered GHB is also being
`administered valproate. As noted by Petitioner, Maitre discloses that
`valproate increases levels of GHB in the brain, and the Xyrem PI taught that
`excess dosing of GHB could have adverse effects, including coma or death.
`Id. at 18 (citing Ex. 1003, 340, 343, 351; Ex. 1005, 1688, 1692). As further
`noted above, valproate is contraindicated for patients taking Xyrem. Ex.
`1005, 1688. We note claims 19, 30, and 33 do not appear to require the
`concomitant administration of valproate with GHB based on the outcome of
`the determining step.10 As such, the present record demonstrates adequately
`that the skilled artisan would have found it obvious to determine if valproate
`is being administered in order to avoid adverse drug/drug interactions by
`discontinuing (not merely reducing) the concomitant administration of either
`GHB or valproate to the patient.
`
`
`10 In their post-institution filings, the parties are requested to address whether
`claims 19, 30, and 33, or any of their dependent claims, require the
`concomitant administration of valproate and GHB.
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`Accordingly, on the present record, Petitioner has demonstrated a
`reasonable likelihood of establishing that claims 19, 30, and 33 would have
`been obvious based on the combination of the Xyrem PI and Maitre. We
`have also considered the parties’ arguments with respect to the
`corresponding dependent claims and determine, on this record, that
`Petitioner has demonstrated a reasonable likelihood of establishing that
`claims 20-26, 31, 32, and 34 would have been obvious based on the
`combination of the Xyrem PI and Maitre, and that claim 27 would have been
`obvious based on the further teachings of Sandson. See Pet. 26–34, 49–50;
`Ex. 1002, ¶¶ 95–100, 102–117.
`
`3. Obviousness of Claims 1–5, 7–16, 18, 30, 31, and 33 Based
`on Okun and the Xyrem Titration Schedule
`4. Obviousness of Claims 19–26, 28, 29, 32 and 34 Based on
`Okun, the Xyrem Titration Schedule, and Cook
`
`Petitioner contends that claims 1–5, 7–16, 18, 30, 31, and 33 are
`obvious based on the combination of Okun and the Xyrem Titration
`Schedule. Pet. 34–43. Petitioner additionally contends that claims 19–26,
`28, 29, 32 and 34 are obvious based on the combination of Okun, the Xyrem
`Titration Schedule, and Cook. Id. at 44–49. In addition to the teachings of
`the references, Petitioner relies upon the Dr. Rotella’s Declaration for these
`challenges. Ex. 1002.
`Petitioner’s arguments based on the combination of the Xyrem
`Titration Schedule and Okun are similar to the arguments it presents based
`on the combination of Xyrem PI and Maitre. In particular, Petitioner relies
`upon the Xyrem Titration Schedule’s recommended starting dose of 4.5 g
`g/night, and its teaching that “[d]osage should be titrated to effect in
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`increments of 1.5 g/night (0.75 g per dose) to a maximum dose of 9 g/night.”
`Ex. 1006; Pet. 35–36. We have already considered this teaching in the
`Xyrem PI. Ex. 1005, 1692. Petitioner further relies upon Okun’s teaching
`that valproate inhibits GHB dehydrogenase. Ex. 1004, 170; Pet. 35. We
`have already considered the same teaching in Maitre. Ex. 1003, 351. Thus,
`for the reasons discussed above, we determine that Petitioner has not
`presented a reasonable likelihood that claims 1–5, 7–16, and 18 would have
`been obvious based on the combination of the Xyrem Titration Schedule and
`Okun.
`As also discussed above, we have determined that Petitioner has
`demonstrated, on this record, a reasonable likelihood of prevailing with
`respect claims 19–34 based on the combination of the Xyrem PI and Maitre.
`Petitioner also contends that claims 30 and 31 would have been obvious
`based on the teachings of the Xyrem Titration Schedule and Okun, and that
`claims 19–26, 28, 29, 32, and 34 would have been obvious based on the
`further teachings of Cook. Petitioner relies upon Cook’s teaching of
`aqueous solutions having a GHB concentration of 500 mg.ml and a pH of
`7.5. Pet. 45 (citing Ex. 1007, 23–24, cols. 40–41, Table 18). We have
`already considered GHB formulations at that concentration and pH in the
`Xyrem PI. Ex. 1005, 1688. As such, Petitioner has not pointed to any
`material differences between these challenges and the challenges based on
`the Xyrem PI and Mait