Trials@uspto.gov
`571.272.7822
`
`
`
`
`
`
`
`
` Paper No. 8
`
`
` Entered: August 30, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ROXANE LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`VANDA PHARMACEUTICALS INC.,
`Patent Owner.
`____________
`
`Case IPR2016-00690
`Patent 9,138,432 B2
`____________
`
`
`Before RAMA G. ELLURU, SHERIDAN K. SNEDDEN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
`
`
`
` Paper No. 8
`
`
` Entered: August 30, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ROXANE LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`VANDA PHARMACEUTICALS INC.,
`Patent Owner.
`____________
`
`Case IPR2016-00690
`Patent 9,138,432 B2
`____________
`
`
`Before RAMA G. ELLURU, SHERIDAN K. SNEDDEN, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`Case IPR2016-00690
`Patent 9,138,432 B2
`
`INTRODUCTION
`
`Roxane Laboratories, Inc. (“Petitioner”) filed a Petition requesting an
`inter partes review of claim 1 of U.S. Patent No. 9,138,432 B2 (Ex. 1001,
`“the ’432 patent”). Paper 2 (“Pet.”). Vanda Pharmaceuticals Inc. (“Patent
`Owner”) filed a Preliminary Response to the Petition. Paper 7 (“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 considering the Petition and the
`Preliminary Response, we determine that Petitioner has not shown a
`reasonable likelihood that it would prevail in showing the unpatentability of
`the challenged claim. Accordingly, the Petition is denied.
`Related Proceedings
`A.
`The ‘432 patent is at issue in a number of cases in the United States
`District Court for the District of Delaware including Vanda Pharm. Inc. v.
`Roxane Labs., Inc., No. 15-cv-00919 (D. Del.). Pet. 2–3; Paper 3, 1; Paper
`6, 2.
`
`The ’432 Patent is a continuation of U.S. Patent Application No.
`14/060,978, a continuation of U.S. Patent Application No. 11/576,178,
`which was issued as U.S. Patent No. 8,586,610 (“the ’610 Patent”). The
`’610 Patent is at issue in the United States District Court for the District of
`Delaware, including in Vanda Pharm. Inc. et al. v. Roxane Labs., Inc., Nos.
`13-cv-01973, 14-cv-00757 (D. Del.). Ex. 1001; Pet. 3; Prelim. Resp. 33;
`Paper 3, 1; Paper 6, 2–3.
`
`2
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`The ‘432 Patent and Relevant Background
`B.
`
`The ‘432 patent, entitled “Methods for the Administration of
`Iloperidone,” is generally directed to methods for lowering the risk for QT
`prolongation associated with the administration of iloperidone patients with
`lower than normal CYP2D6 activity arising from a patient’s genetic
`background, or by the concomitant administration of a CYP2D6 inhibitor,
`such as fluoxetine. Ex. 1001. According to the Specification, iloperidone
`has antipsychotic activity that renders it useful in the treatment of “all forms
`of schizophrenia.” Id. at 1:42–55. The Specification explains, however, that
`iloperidone or its metabolites have been associated with the prolongation of
`the electrocardiographic QT interval (“QTP”)1—an adverse event associated
`with the potentially fatal cardiac arrhythmias including “Torsades de
`Pointes.” Id. at 1:56–58; Pet. 44; Prelim. Resp. 8, Ex. 1003 ¶ 97; Ex. 2001 ¶
`46.
`The ’432 Specification discloses that the metabolism of iloperidone
`
`depends largely on the P450 enzymes CYP2D6 and CYP3A4. Ex. 1001,
`4:46–48. CYP3A4 converts the parent drug to the active metabolite p88,
`which is subsequently degraded by CYP2D6. Id. at 2:53–55; 6:63–64.
`CYP2D6 also metabolizes iloperidone to p94, which is converted to P95
`“after some additional reactions.” Id. at 4:48–50. Thus, both CYP2D and
`CYP3A4 play a role in the metabolic clearance of iloperidone.
`
`
`1 For convenience, we employ “QTP” to refer to all variants of the
`term “prolongation of the QT interval” or “QT prolongation.” “QT interval”
`refers to the time between the Q and T waves in an electrocardiogram
`tracing and encompasses the term “QTc,” which indicates that a QT interval
`measurement has been mathematically corrected for a patient’s heart rate.
`See e.g., Ex. 1001, 2:40–48; Pet. 5, n.2; Prelim. Resp. 8.
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`According to the Specification, the two main metabolites of
`iloperidone, P88 and P95, have different pharmacological effects. Id. at
`4:54–62. Whereas “P88 has a pharmacological profile including affinity for
`the HERG channel similar to that of iloperidone,” P95 has a “very low
`affinity for the HERG channel” and “is regarded being pharmacologically
`inactive.” Id. By way of background, HERG channels are voltage-gated ion
`channels associated with QTP and cardiac arrhythmias. Ex. 1016, 151–154;
`see also Prelim. Resp. 14 (stating that, as of the time of the invention, QTP
`induced by drugs other than iloperidone “ha[d] been linked to inhibition of
`the hERG channel, a cardiac potassium channel . . . that helps regulate the
`heart rate”) (citing Ex. 2001 ¶ 47).
`The Specification discloses a series of studies evaluating blood levels
`of iloperidone and its major metabolites in patients with varying levels of
`endogenous CYP2D6 activity (e.g., patients with genotypically high and low
`CYP2D6 levels), including before and after the coadministration of
`CYP2D6 and CYP3A4 inhibitors. Ex. 1001, 2:32–11:14. The Specification
`discloses that “[a]ddition of the CYP2D6 inhibitor[,] fluoxetine, along with
`iloperidone[,] resulted in increases of the area under the curve (AUC) for
`iloperidone and P88 of 131% and 119% respectively,” whereas, “[a]ddition
`of the CYP3A4 inhibitor ketoconazole . . . resulted in a 38-58% increase in
`the concentrations of iloperidone and its main metabolites P88 and P95.” Id.
`at 4:51–57.
`Levels of iloperidone and its main metabolites in subjects were also
`compared to changes in the QT interval. Statistical analyses showed that
`increased levels of the parent drug and the active P88 metabolite were
`associated with increased risk of QTP. See, e.g., id. at 10:9–10 (“QTc
`prolongation is correlated to the ratios of P88/P95 and
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`iloperidone+P88)/P95.”). Because decreased CYP2D6 activity results in
`increased amounts of the active moieties, iloperidone and P88, as compared
`to the inactive metabolite, P95, which ratios correlate with the risk of QT
`prolongation, the Specification recommends decreasing the dose of
`iloperidone in patients having reduced CYP2D6 activity due to either
`genetic background or concomitant treatment with CYP2D6 inhibitors. See
`e.g., id. at 2:20–26, 2:65–3:3, 11:46–52. Also with respect to the
`concomitant treatment of iloperidone with CYP2D6 inhibitors such as
`fluoxetine, the Specification further discloses that “[a]nother aspect of the
`invention is a method for obtaining regulatory approval for the
`administration of iloperidone based, in part, on labeling that instructs the
`administration of a lower dose if the patient is already being administered a
`CYP2D6 inhibitor, e.g., paroxetine, etc.” Id. at 14:34–38.
`Challenged Claim
`C.
`Claim 1, the sole claim of the ’432 patent recites:
`1. A method of decreasing a risk of QT prolongation in a
`patient being treated for schizophrenia with iloperidone,
`the method comprising:
`administering to the patient a dose of iloperidone that
`is 24 mg/day if, and because, the patient is not being
`treated with fluoxetine; and
`administering to the patient a dose of iloperidone that
`is 12 mg/day if, and because, the patient is being
`treated with fluoxetine.
`
`5
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`The Asserted Prior art and Grounds of Unpatentability
`D.
`Petitioner asserts the following grounds of unpatentability (Pet. 4):
`
`References
`FDA Guidance 1999,2 Mutlib,3
`Brøsen,4 and Mealy5
`FDA Guidance 1999, Abilify
`Label,6 Mutlib, and Mealy
`
`Basis
`§ 103
`
`§ 103
`
` In addition to the teachings of the references, Petitioner relies on the
`Declaration of David L. Fogelson, M.D. Ex. 1003.
`
`
`
`ANALYSIS
`
`A.
`
`Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable constructions in light of
`
`
`2 U.S. Department of Health and Human Services, Food and Drug
`Administration (“FDA”), Guidance for Industry, In Vivo Drug
`Metabolism/Drug Interaction Studies – Study Design, Data Analysis, and
`Recommendations for Dosing and Labeling (November 1999) (“FDA
`Guidance 1999” or “the Guidance”). Ex. 1005.
`3 Mutlib et al., Application of Liquid Chromatography/Mass
`Spectrometry in Accelerating the Identification of Human Liver Cytochrome
`P450 Isoforms Involved in the Metabolism of Iloperidone, 286 J. PHARM.
`& EXPERIMENTAL THERAPEUTICS 1285-93 (1998) (“Mutlib”.
`Ex. 1006.
`4 Brøsen, Differences in Interactions of SSRIs, 13 INT’L CLINICAL
`PSYCHOPHARM. S45-47 (1998) (“Brøsen,”). Ex. 1007.
`5 Mealy et al., Annual Review 2002: Psychopharmacologic Drugs, 27
`DRUGS OF THE FUTURE 995-1027 (2002) (“Mealy”). Ex. 1010.
`6 “[A]s published in: the Physicians’ Desk Reference (58th ed. 2004)
`(“PDR 2004,” attached as Ex. 1008); and FDA Official Website, Drug
`Approval Package: Abilify (Aripiprazole) NDA #21-436 (“Abilify Approval
`Package,” attached as Ex. 1009).” Pet. 4.
`
`6
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`Case IPR2016-00690
`Patent 9,138,432 B2
`the Specification of the patent in which they appear. See 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`(2016) (upholding the use of the broadest reasonable interpretation
`standard). Under the broadest reasonable construction standard, claim terms
`are presumed to have their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art in the context of the entire
`disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007).
`In the present case, neither party contests the meaning of any claim
`term, but do take opposing positions regarding whether the preamble of
`claim 1 is limiting. See Pet. 14–15, 49–50; Prelim. Resp. 17–20. The
`parties, nevertheless, agree that whether the preamble is limiting is not
`dispositive with respect to the obviousness issue before us. See Pet. 49–50
`(arguing that the preamble is not limiting but “if the preamble is found to
`express a claim limitation, Mealy fully discloses any such limitation”);
`Prelim. Resp. 19 (arguing that “[t]he preamble is essential to understand the
`terms ‘patient’ and ‘if, and because’ in the body of the claim” but “[s]hould
`the Board determine [] that the preamble is not limiting, that does not affect
`the validity of claim 1, or the analysis of the relevant prior art”).
`Our reviewing court counsels that only those terms that are in
`controversy need be construed, and only to the extent necessary to resolve
`the controversy. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`795, 803 (Fed. Cir. 1999). For purposes of this decision, we determine that
`no claim term requires express construction, nor need we determine here
`whether the preamble is limiting.
`
`7
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`Case IPR2016-00690
`Patent 9,138,432 B2
`Principles of Law
`B.
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). A
`decision on the ground of obviousness must include “articulated reasoning
`with some rational underpinning to support the legal conclusion of
`obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The
`obviousness analysis “should be made explicit” and it “can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine the elements in the way the claimed new invention
`does.” KSR, 550 U.S. at 418.
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`C.
` The Person of Ordinary Skill in the Art
`Petitioner states that a person or ordinary skill in the art at the time of
`the invention would have had, approximately, “graduate degree in medicine,
`pharmacy, pharmacology, or a related field; at least 2-3 years of practical
`experience in the field of psychiatry and/or clinical pharmacology; and
`familiarity with adjusting drug dosages based on a patient’s drug
`metabolism.” Pet. 15–16 (citing Ex. 1003 ¶¶ 31, 32). Patent Owner
`
`8
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`disagrees with this proposed definition because it “includes individuals who
`would not have been expected to be familiar with or have any reason to
`make use of Roxane’s primary reference, FDA Guidance 1999 (Ex. 1005),
`which is intended for individuals and companies engaged in drug
`development, not the day-to-day treatment of patients.” Prelim. Resp. 22
`(citing Ex. 2001 ¶ 16). Accordingly, Patent Owner urges that a person of
`ordinary skill in the art should have “experience with drug metabolism
`and/or drug-drug interactions and at least some experience with preclinical
`and/or clinical drug development.” Id. at 21 (citing Ex. 2001 ¶ 14).
`We agree with Patent Owner. The level of ordinary skill in the art is
`informed by the prior art asserted in the Petition. See Okajima v. Bourdeau,
`261 F.3d 1350, 1355 (Fed. Cir. 2001). In this case, the asserted FDA
`Guidance 1999 is expressly directed “to sponsors of new drug applications
`(NDAs) and biologics license applications (BLAs) for therapeutic biologics
`(hereafter drugs) who intend to perform in vivo drug metabolism and
`metabolic drug-drug interaction studies.” Ex. 1005, 4. Indeed, Petitioner
`appears to recognize that the person of ordinarily skill in the art has
`experience in drug development insofar as it casts its argument for the
`combination Guidance with Mutlib, Brøsen, and Mealy in terms of a person
`“involved in iloperidone’s development and clinical administration.” Pet.
`44.
`
`Patent Owner, however, goes too far in asserting that one of ordinary
`skill in the art need not have familiarity with adjusting drug dosages based
`on a patient’s drug metabolism or drug regimen as the asserted prior art
`(discussed below) clearly indicates that dosage reductions are appropriate for
`some drugs in some instances. See Prelim. Resp. 22. FDA Guidance 1999,
`for example, provides labeling template language regarding dose reductions
`
`9
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`Case IPR2016-00690
`Patent 9,138,432 B2
`in some instances where “an interacting drug causes increased
`concentrations of the substrate but the administration of both drugs may
`continue with appropriate dosage adjustment.” Ex. 1005, 15, see id. at 16.
`In view of the above, we accept Petitioner’s definition of a person of
`ordinary skill in the art, with the caveat that the ordinarily skilled artisan also
`has experience with drug metabolism and/or drug interactions and at least
`some experience with preclinical and/or clinical drug development.
`D. Overview of the Asserted References
`We begin our discussion with a brief summary of the references
`asserted.
`i. FDA Guidance 1999 (Ex. 1005)
`FDA Guidance 1999 “reflects the [FDA’s] current view that the
`metabolism of an investigational new drug should be defined during drug
`development and that its interactions with other drugs should be explored as
`part of an adequate assessment of its safety and effectiveness.” Ex. 1005, 1.
`Consistent with that view, the document “provides recommendations to
`sponsors of new drug applications (NDAs) . . . who intend to perform in vivo
`drug metabolism and metabolic drug-drug interaction studies.” Id. These
`recommendations encompass guidance regarding in vivo drug metabolism
`interaction studies, including study design and data analysis, as well as
`recommendations for dosing and labeling based on the results of those
`studies. See, e.g., id. at Title.
`The Guidance outlines a number of general concepts underlying its
`recommendation’s including that:
`• Adequate assessment of the safety and effectiveness of a
`drug includes a description of its metabolism and the
`contribution of metabolism to overall elimination.
`
`10
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`Case IPR2016-00690
`Patent 9,138,432 B2
`
`• Metabolic drug-drug interaction studies should explore
`whether an investigational agent is likely to significantly
`affect the metabolic elimination of drugs already in the
`marketplace and, conversely, whether drugs in the
`marketplace are likely to affect the metabolic elimination
`of the investigational drug.
`. . .
`• In some cases, metabolic drug-drug interaction studies
`cannot be informative unless metabolites and prodrugs
`have been identified and their pharmacological properties
`described.
`
`. . .
`• A specific objective of metabolic drug-drug interaction
`studies is to determine whether the interaction is
`sufficiently large to necessitate a dosage adjustment of the
`drug itself or the drugs it might be used with, or whether
`the interaction would require additional therapeutic
`monitoring.
`
`. . .
`• In some instances, understanding how to adjust dosage in
`the presence of an interacting drug, or how to avoid
`interactions, may allow marketing of a drug that would
`otherwise have been associated with an unacceptable level
`of toxicity.
`
`Id. at 3–4.
`The Guidance further provides that the desired goal of drug-drug
`interaction studies “is to determine the clinical significance of any increase
`or decrease in exposure to the substrate in the presence of the interacting
`drug.” Id. at 11. “When a drug-drug interaction is clearly present (e.g.,
`comparisons indicate twofold or greater increments in systemic exposure
`
`11
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`Case IPR2016-00690
`Patent 9,138,432 B2
`measures for S+I7) the sponsor should be able to provide specific
`recommendations regarding the clinical significance of the interaction,”
`which may include “recommendations in the package insert with respect to
`either the dose, dosing regimen adjustments, precautions, warnings, or
`contraindications.” Id. at 12.
`The Guidance also provides examples of drug-drug interactions
`involving the P450 enzymes CYP3A4 and CYP2D6, including “(3)
`increased levels of desipramine with fluoxetine, paroxetine, or quinidine
`(inhibition of CYP2D6).” Id. at 2–3. More generally, the Guidance states
`that:
`
`Many metabolic routes of elimination, including most of those
`occurring via the P450 family of enzymes, can be inhibited,
`activated, or induced by concomitant drug treatment. Observed
`changes arising from metabolic drug-drug interactions can be
`substantial- an order of magnitude or more decrease or increase
`in the blood and tissue concentrations of a drug or metabolite-
`and can include formation of toxic metabolites or increased
`exposure to a toxic parent compound.
`Id. at 2. “Depending on the extent and consequence of the interaction, the
`fact that a drug's metabolism can be significantly inhibited by other drugs
`and that the drug itself can inhibit the metabolism of other drugs can require
`important changes in either its dose or the doses of drugs with which it
`interacts, that is, on its labeled conditions of use.” Id. at 3.
`ii. Mutlib (Ex. 1006)
`Mutlib reports on the metabolism of iloperidone based on in vitro and
`in vivo studies. With respect to the former, Mutlib discloses that
`“[i]loperidone was extensively metabolized in vitro via hydroxylation,
`
`7 The Guidance uses “S” to denote the “substrate” drug under study,
`and “I” to denote an “interacting drug.” Id. at 6.
`
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`Case IPR2016-00690
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`reduction and O-demethylation to produce [metabolites 4, 3, and 2] in
`decreasing order of abundance.” Ex. 1006, Abstract. Mutlib further
`determined that metabolites 4, 3, and 2 were formed by CYP2D6, mainly
`cytosolic enzymes, and CYP3A4, respectively. Id.
`In contrast to the in vitro results, metabolite 3 was the most abundant
`metabolite in plasma and urine, with metabolite 4 detectable in only trace
`amounts. Id. at Abstract, 1286, 1289. An additional metabolite, metabolite
`5, was also present in these samples. Id. at Fig. 1; see also Fig. 2 (showing
`“[s]elected ion monitoring (SIM) LC/MS trace of a hydrolyzed human urine
`extract showing the presence of unhanged iloperidone and metabolites 2, 3,
`and 5 [and a]n unidentified metabolite with the same MH+ as metabolite 4 []
`detected at a different retention time”). Mutlib postulates that the low levels
`of metabolite 4 in plasma and urine samples indicates that the compound is
`either “eliminated in bile as a conjugate or further metabolized [compound
`5]” Id. at Abstract, 1286.
`In the Discussion section, Mutlib states that:
`[o]nce the enzymes responsible for the metabolism of a
`particular drug are known, predictions may be made concerning
`the genetic, environmental (e.g. drug-drug interactions) and
`physiological factors likely to influence the pharmacokinetics,
`therapeutic response and development of adverse reactions in the
`specific patient groups (Andersson et al., 1993; Miners et al.,
`1995). The present work has clearly indicated that CYP2D6 is
`primarily responsible for the production of the major in vitro
`human microsomal metabolite 4. By comparison with those
`factors known to alter the in vivo metabolism of the prototypic
`CYP2D6 and CYP3A4 substrates, certain predictions concerning
`the regulation of iloperidone metabolism in humans may now be
`made. For example, taking into account the relative plasma
`concentrations and apparent Km values, mutual competitive
`inhibition of metabolism is a possibility when iloperidone is
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`coadministered with a range of other CYP2D6 and CYP3A4
`drug substrates.
`Id. at 1292.
`iii. Brøsen (Ex. 1007)
`Brøsen reports on pharmacokinetics of SSRIs including their potential
`for causing pharmacokinetic interactions through inhibition of species of the
`cytochrome P450 enzyme system.” Ex. 1007, Abstract, S45. Brøsen
`teaches that “[a] cytochrome P450 based interaction is likely to become
`important if a drug[], which is almost exclusively eliminated by a single
`cytochrome P450 is co-administered with another drug which is a potent or
`an effective inhibitor of the P450 in question.” Id. at S46.
`The clinical consequence of an interaction may either be an
`enhancement of an adverse effect or an enhancement of the
`drug's desired effect. Alternatively the consequence may be a
`weakening of the desired effect but only very rarely an
`interaction shows a qualitative change in the known effects of a
`drug. Hence interactions can nearly always be predicted and
`avoided by rational use of the drugs known pharmacological
`characteristics.
`Id. at S45–S46. Brøsen teaches the CYP2D6 “is the source of important
`drug-drug interactions” and whereas “all SSRIs inhibit CYP2D6 [,]
`fluoxetine, norfluoxetine and paroxetine are particularly potent.” Id. at S47.
`Brøsen further states that when fluoxetine or paroxetine are administered in
`combination with a CYP2D6 substrate, it “is usually recommended that
`doses of the substrate are reduced to about 25-50% of the standard dose.”
`Id.
`
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`iv. Abilify Label (Exs. 1008, 1009)8
`Abilify Label discloses that AbilifyTM (aripiprazole) is an
`psychotropic drug indicated for the treatment of schizophrenia. Ex. 1008,
`1034–1035. “Elimination of aripiprazole is mainly through hepatic
`metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.” Id. at
`1034. With respect to the former, Abilify Label indicates that:
`Coadministration of a 10-mg single dose of aripiprazole with
`quinidine (166 mg/day for 13 days), a potent inhibitor of
`CYP2D6, increased the AUC of aripiprazole by 112% but
`decreased
`the AUC of
`its active metabolite, dehydro-
`aripiprazole, by 35%. Aripiprazole dose should be reduced to
`one-half of its normal dose when concomitant administration of
`quinidine with aripiprazole occurs. Other significant inhibitors
`of CYP2D6, such as fluoxetine or paroxetine, would be expected
`to have similar effects and, therefore, should be accompanied by
`similar dose reductions.
`Id. at 1036.
`v. Mealy (Ex. 1010)
`Mealy discloses that iloperidone is “[a]member of a new class of
`drugs for schizophrenia known as the SDAs (serotonin/dopamine receptor
`agonists)” that is “presently completing a global phase III development
`program for the treatment of schizophrenia.” Ex. 1010, 1008. Mealy
`discloses that iloperidone may be dosed at 12 mg/day and 24 mg/day for the
`treatment of schizophrenia. Id. at 1008, 1010. With respect to QTP, Mealy
`states that iloperidone therapy is “roughly comparable to ziprasidone.” Id. at
`1010.
`
`
`8 Petitioner states that the relevant portions of Exhibits 1008 and 1009
`are identical. Pet. 34 n.11. Unless otherwise indicated, we cite to Exhibit
`1008.
`
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`E. Obviousness Analysis
`With respect to Ground I, Petitioner contends that claim 1 of the ’432
`patent is obvious based on the combination of FDA Guidance 1999, Mutlib,
`Brøsen, and Mealy. Pet. 40–45, 47–55. Petitioner argues that “POSAs
`involved in iloperidone’s development and clinical administration were
`motivated to minimize iloperidone’s risk of QT prolongation by accounting
`for iloperidone’s potential drug interactions, which each of FDA Guidance
`1999, Mutlib, and Brøsen teaches may be associated with changes in a
`drug’s blood concentration levels and adverse effects.” Pet. 44 (citations
`omitted); see also id. at 40 (persons of ordinary skill in the art motivated to
`combine references “in order to reduce the likelihood of adverse effects
`arising from iloperidone treatment”).
`In particular, Petitioner argues that, as reflected in FDA Guidance
`1999, “in order to safely administer a drug like iloperidone to a patient, a
`POSA needed to first review the drug’s metabolic pathways, identify all of
`the patient’s concurrent medications, and determine what dose adjustments
`might be necessary based on potential drug interactions.” Pet. 40–41 (citing
`Ex. 1003 ¶125). According to Petitioner, the Guidance “motivates a POSA
`to look to Mutlib for identification of iloperidone’s metabolic pathways” and
`“affirms that iloperidone’s metabolism can be predicted based on factors
`known to alter the metabolism of CYP2D6 substrates generally.” Id. at 41
`(citations omitted). Mutlib, in turn, “motivates a POSA to look to Brøsen,
`which reviews one of the most well-known, important categories of
`CYP2D6-based drug interactions, the inhibition of CYP2D6 by common
`SSRIs such as fluoxetine.” Id. (citations omitted). Petitioner further argues
`that “Mutlib discloses that iloperidone is a CYP2D6 substrate, and Brøsen
`recommends reducing the standard dose of CYP2D6 substrates by 50-75%
`
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`Case IPR2016-00690
`Patent 9,138,432 B2
`when co-administered with fluoxetine. These teachings motivate reference
`to Mealy, which summarizes iloperidone’s clinical trials, the principal
`resource at that time for determining iloperidone’s safe, effective, standard
`dosages.” Id. at 42 (citations omitted).
`Petitioner further argues that “analysis of a drug’s metabolic
`interactions and dosing adjustments was a routine part of drug development
`explicitly recommended by the FDA” and, therefore, “POSAs involved in
`the development of a drug like iloperidone were motivated to combine the
`teachings of FDA Guidance 1999, Mutlib, Brøsen, and Mealy in order to
`secure FDA approval.” Id. at 42–43 (citing Ex. 1003 ¶ 130). In particular,
`Petitioner argues that the teaching of FDA Guidance 1999 to study drug-
`drug interactions, particularly with respect to the enzyme systems involved
`in their metabolism, provides motivation to consult Mutlib, which provides
`that information with respect to iloperidone. Id. at 43 (citations omitted).
`Petitioner further argues that the FDA Guidance’s teaching to examine
`inhibitors of the metabolic pathways at issue, along with its identification of
`fluoxetine as a CYP2D6 inhibitor, provides motivation to consider
`Bronsen’s review of CYP2D interactions of SSRIs, including fluoxetine. Id.
`at 43–44 (citations omitted).
`With respect to Ground II, Petitioner contends that claim 1 of the ’432
`patent is obvious based on the combination of FDA Guidance 1999, with
`Mutlib, Abilify Label, and Mealy. Pet. 45–47, 55–60. Despite substituting
`Abilify Label for the Brøsen reference of Ground I, Petitioner takes a similar
`position with respect to motivation to combine, in particular, that “FDA
`Guidance 1999 comprehensively motivates review of these references,
`instructing on the study of drug interactions both as part of standard clinical
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`Case IPR2016-00690
`Patent 9,138,432 B2
`practice and in order to secure a drug’s FDA-approval.” Id. at 45 (citations
`omitted).
`In regards to Abilify Label, Petitioner argues that “based on FDA
`Guidance 1999, Mutlib, and Mealy, POSAs involved in the development or
`administration of iloperidone would have been strongly motivated to
`consider the FDA-approved guidelines for Abilify, a contemporary drug
`with indications and metabolism similar to those of iloperidone.” Pet. 46
`(citing Ex. 1003 ¶ 139). Petitioner appears to argue that, in light of Mutlib’s
`teaching that iloperidone is metabolized by CYP2D6 and CYP3A4, one of
`ordinary skill in the art would have been motivated to look to Abilify
`Label’s instructions to halve the dose of aripiprazole (a substrate for both
`CYP2D6 and CYP3A4) when aripiprazole is co-administered with the
`CYP2D6 inhibitor, fluoxetine, “and to apply that instruction to the standard
`iloperidone dosages taught by Mealy.” Id. at 46–47 (citations omitted).
`Petitioner argues that such boot-strapping is recommended by the following
`passage in FDA Guidance 1999:
`In certain cases, information based on clinical studies not using
`the labeled drug under investigation can be described with an
`explanation that similar results may be expected for the labeled
`drug. For example, a strong inhibitor of CYP3A4 does not need
`to be tested with all 3A4 substrates to warn against an interaction.
`Pet. 47 (quoting Ex. 1005, 13-14) (citing Ex. 1003 ¶ 142).9
`
`
`9 We do not read this passage as supporting Petitioner’s argument
`because the passage qualifies the statement as applying in “some [undefined]
`cases,” does not indicate whether, or how close structural, pharmacokinetic,
`or pharmacodynamic relationships are required between the drugs under
`consideration for the comparison to apply, and does not make clear that
`“warning against an interaction” contemplates a dose reduction, let alone the
`50% dose reduction claimed.
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`Case IPR2016-00690
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`
`In response, Patent Owner argues that FDA Guidance 1999,
`Petitioner’s primary reference, provides only “an invitation to experiment”
`without any indication of whether the interaction of fluoxetine with
`iloperidone would be clinically meaningful “or what conclusions would be
`reached by drug companies following its recommendations.” Prelim. Resp.
`24–25, 38–47. We find this argument persuasive. As set forth in section
`II(D)(i), above, the Guidance states that drug-drug interactions “should be
`explored as part of an adequate assessment of [a new drug’s] safety and
`effectiveness,” and provides recommendations regarding the conduct,
`design, analysis of those studies. See Ex. 1005, 1 (italics added)
`
`The Guidance also emphasizes that one of ordinary skill in the art
`must determine whether any observed drug-drug interaction is clinically
`meaningful, e.g., “whether the interaction is sufficiently large to necessitate
`a dosage adjustment” or “recommendations in the package insert with
`respect to either the dose, dosing regimen adjustments, precautions,
`warning
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