`Inter Partes Review Of
`Patent No. 9,138,432
`
`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 No. 9,138,432
`
`--------------------------
`
`
`
`DECLARATION OF FREDERICK PETER GUENGERICH, Ph.D.
`
`
`
`
`
`June 7, 2016
`
`
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 1
`
`
`
`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`TABLE OF CONTENTS
`
`
`
`VI.
`
`Page
`TASK AND SUMMARY OF OPINIONS ................................................... 4
`I.
`PROFESSIONAL BACKGROUND QUALIFICATIONS ....................... 5
`II.
`A. Education ......................................................................................................... 6
`B. Academic Experience ...................................................................................... 6
`III. THE LEVEL OF ORDINARY SKILL IN THE ART ............................... 8
`IV. CYP2D6 ........................................................................................................ 11
`V.
`THE PRIOR ART TAUGHT THAT ILOPERIDONE IS NOT
`PRIMARILY OR SIGNIFICANTLY METABOLIZED BY
`CYP2D6 IN VIVO ........................................................................................ 15
`ILOPERIDONE THERAPY IS ASSOCIATED WITH QT
`PROLONGATION, BUT VERY LITTLE ELSE WAS
`KNOWN IN THE PRIOR ART ................................................................. 27
`VII. THE PRIOR ART TAUGHT THAT METHODS TO
`REDUCE THE RISK OF QT PROLONGATION WERE
`UNPREDICTABLE ..................................................................................... 28
`VIII. THE PRIOR ART TAUGHT THAT DRUG INTERACTIONS
`UNPREDICTABLY AFFECTED EXPOSURE TO THE
`DRUG AND ANY METABOLITES AS WELL AS SIDE
`EFFECTS AND THUS THE APPROPRIATE
`ILOPERIDONE DOSE WHEN COADMINISTERED WITH
`FLUOXETINE WAS UNPREDICTABLE ............................................... 30
`IX. THE ’432 PATENT INVENTION ............................................................. 45
`A. Drug Metabolism and Pharmacokinetic Studies ........................................... 46
`B. Clinical Study CILO522 0104 ....................................................................... 51
`C. Vanda’s Analysis that Led to the Invention .................................................. 63
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 2
`
`
`
`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`TABLE OF CONTENTS (cont’d)
`
`
`
`Page
`LEGAL STANDARDS ................................................................................ 68
`X.
`A. Obviousness ................................................................................................... 69
`XI. CLAIM 1 OF THE ’432 PATENT WAS NOT OBVIOUS AND
`THERE IS NOT A REASONABLE LIKELIHOOD THAT IT
`WAS OBVIOUS ........................................................................................... 70
`A. The References Relied Upon ......................................................................... 73
`1. The Mutlib Reference ...............................................................................73
`2. The Brøsen Reference and the Abilify (aripiprazole) Label ....................74
`3. The Mealy Reference ...............................................................................77
`4. FDA Guidance 1999 .................................................................................79
`B. It Was Unpredictable Whether CYP2D6 Drug Interactions Would
`Be Meaningful for Iloperidone Therapy ........................................................ 80
`C. It Was Unpredictable Whether Any Dosage Modification Will
`Reduce the Risk of Any Given Side Effects for CYP2D6 Poor
`Metabolizers, Including the Risk of QT Prolongation .................................. 81
`D. It Was Unpredictable What Dosage Modification Would Be
`Appropriate in Order to Reduce the Risk of QT Prolongation and
`Maintain the Efficacy to Treat Schizophrenia ............................................... 88
`
`
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 3
`
`
`
`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`TASK AND SUMMARY OF OPINIONS
`
`1.
`
`I have been retained by Paul, Weiss, Rifkind, Wharton & Garrison
`
`
`
`I.
`
`LLP, counsel for Vanda Pharmaceuticals Inc. (“Vanda”), to provide my expert
`
`testimony in this case.
`
`2.
`
`I have been asked to respond to the factual allegations set forth in
`
`Roxane’s petition for inter partes review of claim 1 of U.S. Patent No. 9,138,432
`
`(“the ’432 Patent”), including the opinions set forth in the declaration of Roxane’s
`
`expert, Dr. David Fogelson (Exhibit 1003).
`
`3.
`
`I disagree with Roxane and Dr. Fogelson that claim 1 of the’432
`
`Patent is obvious. Roxane and Dr. Fogelson’s opinions focus on only isolated
`
`portions of the prior art and leave out the prior art evidence that teaches away from
`
`the invention claimed in the ’432 Patent.
`
`4.
`
`Roxane and Dr. Fogelson’s opinions are premised on statements in the
`
`prior art that iloperidone is metabolized by an enzyme, CYP2D6, in vitro. Roxane
`
`and Dr. Fogelson, however, ignore the prior art teachings that CYP2D6
`
`metabolism is not significant for iloperidone’s metabolism in vivo. Based on the
`
`prior art as a whole, a person of ordinary skill in the art at the time of the invention
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 4
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`
`
`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`
`
`of the ’432 Patent would not have been motivated to study the effect of CYP2D6
`
`inhibition on any side effects, including iloperidone-induced QT prolongation, as
`
`iloperidone was not understood to be significantly metabolized by CYP2D6 in vivo
`
`by skilled artisans in 2004.
`
`5. Moreover, Roxane and Dr. Fogelson overlooked the teachings of the
`
`prior art that, as recognized by the Patent Office during its original examination of
`
`the ’432 Patent, make clear that the necessary dosage adjustments to minimize the
`
`risk of side effects were unpredictable. Based on the entirety of the prior art, a
`
`person of ordinary skill in the art would not have had a reasonable expectation that
`
`administering 12 mg/day of iloperidone to patients being treated with fluoxetine
`
`and administering 24 mg/day of iloperidone to patients who are not treated with
`
`fluoxetine would reduce the risk of QT prolongation.
`
`II.
`
`PROFESSIONAL BACKGROUND QUALIFICATIONS
`
`6.
`
`I am the Tadashi Inagami Professor of Biochemistry at Vanderbilt
`
`University School of Medicine (Nashville, Tennessee). I was appointed Assistant
`
`Professor of Biochemistry in 1975, and was promoted to Associate Professor in
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 5
`
`
`
`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`
`
`1980 and to Professor in 1983. I served as Director of the Center in Molecular
`
`Toxicology from 1980 to 2011.
`
`A. Education
`
`7.
`
`I received a B.S. (Agricultural Science) from the University of
`
`Illinois, Urbana-Champaign, with University Honors (Bronze Tablet) in 1970. In
`
`1973 I received a Ph.D. in biochemistry from Vanderbilt University. I trained as a
`
`research fellow at the University of Michigan Medical School (Biological
`
`Chemistry) from 1973–1975.
`
`B. Academic Experience
`
`8.
`
`I have attached my curriculum vitae and a list of publications as
`
`Exhibit 2002. On the basis of my education and the experience described above
`
`and in my curriculum vitae, I believe I am qualified to give the opinions set out
`
`herein.
`
`9.
`
`I have considerable experience in the field of the biochemistry and
`
`pharmacology of drug metabolism. My laboratory first purified what are now
`
`known as human CYP 1A2, 2A6, 2C8, 2C9, 2D6, and 3A4 enzymes from human
`
`liver cells. See, e.g., L.M. Distlerath, et al., Purification and Characterization of
`
`the Human Liver Cytochromes P-450 Involved in Debrisoquine 4-Hydroxylation
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 6
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`
`
`and Phenacetin O-Deethylation, Two Prototypes for Genetic Polymorphism in
`
`Oxidative Drug Metabolism, J. Biol. Chem. 260, 9057–9067 (1985) (Exhibit 2005
`
`at 1–11); T. Shimada, et al., Human Liver Microsomal Cytochrome P-450
`
`Mephenytoin 4-Hydroxylase, a Prototype of Genetic Polymorphism in Oxidative
`
`Drug Metabolism. Purification and Characterization of Two Similar Forms
`
`Involved in the Reaction, J. Biol. Chem. 261, 909–921 (1986) (Exhibit 2006 at 1–
`
`13); F. P. Guengerich, et al., Characterization of Rat and Human Liver
`
`Microsomal Cytochrome P-450 Forms Involved in Nifedipine Oxidation, a
`
`Prototype for Genetic Polymorphism in Oxidative Drug Metabolism, J. Biol.
`
`Chem. 261, 5051–5060 (1986) (Exhibit 2007 at 1–10). My work in this area has
`
`been highlighted in Human Cytochrome P450s: The Work of Frederick Peter
`
`Guengerich, J. Biol. Chem. 287, 15798–15800 (2012) (Exhibit 2008 at 1–3).
`
`10.
`
`I have received a number of awards, many for the pioneering work
`
`with human cytochrome P450 enzymes and their roles in the metabolism of drugs
`
`and toxicants, including the John Jacob Abel Award (1984) and Bernard B. Brodie
`
`Award in Drug Metabolism (1992) from the American Society for Pharmacology
`
`and Experimental Therapeutics; the Achievement Award (1982) and Merit Award
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 7
`
`
`
`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`
`
`(2013) from the Society of Toxicology; the North American Scientific
`
`Achievement Award (2003) and R.T. Williams Distinguished Scientific
`
`Achievement Award (2010) from the International Society for the Study of
`
`Xenobiotics; the President’s Distinguished Service Award from the American
`
`College of Toxicology (2004); the Founders’ Award from the Division of
`
`Chemical Toxicology, American Chemical Society (2011); the AACR Award for
`
`Outstanding Achievement in Chemistry in Cancer Research from the American
`
`Association for Cancer Research (2009); and the William C. Rose Award from the
`
`American Society for Biochemistry and Molecular Biology (2005).
`
`11.
`
`I was the Institute for Scientific Information (ISI)’s 3rd Most-cited
`
`Author in Pharmacology & Toxicology, 1993–2003. See http://www.in-
`
`cites.com/scientists/pha-10-aug2003.html.
`
`12.
`
`I was ranked by Drug Metabolism Research as first in world based on
`
`total citation score (2006–2014). See http://www.cytochrome.net.
`
`III. THE LEVEL OF ORDINARY SKILL IN THE ART
`
`13.
`
`I understand that patents must be read, and the art evaluated, from the
`
`perspective of a “person of ordinary skill” in the relevant art at the time the
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 8
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`
`
`invention was made. I understand this to be a hypothetical person of ordinary
`
`creativity, imparted with knowledge of all of the relevant publicly available art,
`
`and the education and skills ordinarily associated with carrying out research in that
`
`particular field.
`
`14. The ’432 Patent is directed to a method of decreasing the risk of QT
`
`prolongation associated with the treatment of schizophrenia using iloperidone,
`
`wherein the dosage is modified based whether the patient is also administered
`
`fluoxetine, a CYP2D6 inhibitor. Thus, I believe a person of ordinary skill in the
`
`art would have a graduate degree or equivalent laboratory experience in medicine,
`
`pharmacy, pharmacology, or a related field such as biochemistry, with experience
`
`with drug metabolism and/or drug-drug interactions and at least some experience
`
`with preclinical and/or clinical drug development. In addition, I believe a person
`
`of ordinary skill in the art could be a person or persons who have experience
`
`treating individuals with schizophrenia and who are qualified to prescribe
`
`psychotropic medications, including iloperidone. I believe this definition includes,
`
`among others, physicians with an M.D. or D.O. degree, including psychiatrists,
`
`psychologists with a Ph.D. or Psy.D. who are authorized to prescribe psychotropic
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 9
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`
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`medication, and registered nurses or physician’s assistants with prescription-
`
`writing privileges.
`
`15. Roxane and Dr. Fogelson provide a different definition, namely that
`
`the skilled artisan should have experience in the field of psychiatry or clinical
`
`pharmacology, including pharmacogenomics, and that the skilled artisan should
`
`have familiarity with adjusting drug dosages based on a patient’s drug metabolism
`
`or drug regimen.
`
`16. First, I disagree that an ordinary artisan needs experience in the field
`
`of psychiatry or clinical pharmacology, including pharmacogenomics. The
`
`invention claimed in the ’432 Patent deals with the recognition that the risk of a
`
`particular side effect, QT prolongation, associated with iloperidone therapy is
`
`higher for patients that have impaired metabolism via CYP2D6. Ordinary artisans
`
`do not need experience in psychiatry or pharmacogenomics to recognize the nature
`
`of the problem or to understand the relevant prior art. Rather, ordinary artisans
`
`should have experience with drug metabolism and/or drug-drug interactions and at
`
`least some experience with preclinical and/or clinical drug development.
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 10
`
`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`17. Second, I disagree that a person of skill in the art needs any
`
`
`
`experience with adjusting drug dosages based on a patient’s drug regimen. Rather,
`
`Roxane and Dr. Fogelson’s definition of a person of ordinary skill in the art
`
`presupposes that the person of ordinary skill would know that the solution to the
`
`problem of drug-induced QT prolongation is dosage adjustment.
`
`18. Regardless of which definition is used, I am a person of at least
`
`ordinary skill in the art. Moreover, my opinion regarding the validity of the ’432
`
`Patent does not change based on either definition of the person of ordinary skill.
`
`19.
`
`I am informed that the relevant time frame for understanding the ’432
`
`Patent is September 2004.
`
`IV. CYP2D6
`
`20. By 2004, it was known that drugs and other environmental chemicals
`
`that enter the body are modified by a vast array of enzymes.
`
`21. The biochemical transformations performed by these enzymes can
`
`alter the compound to render it beneficial, harmful, ineffective, or some
`
`combination thereof. The processes by which biochemical reactions alter drugs
`
`within the body are collectively called drug metabolism or drug biotransformation.
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 11
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
`
`22. Generally speaking, drug biotransformation can alter drugs in four
`
`
`
`important ways:
`
`• An active drug may be converted to an inactive metabolite.
`
`• An active drug may be converted to an active or toxic
`
`metabolite.
`
`• An inactive prodrug may be converted to an active drug.
`
`• A drug with some therapeutic activity may be converted to a
`
`more active drug.
`
`The way in which a given drug is altered by drug biotransformation is not limited
`
`to one of these paths. Combinations of the above are possible, as is the case for
`
`iloperidone, which is discussed in more detail later in this declaration. Nor are
`
`these paths exclusively one-way.
`
`23.
`
`In the body, these transformations happen in various ways, including
`
`through reactions catalyzed by enzymes. For example, oxidation reactions involve
`
`membrane-associated enzymes expressed in the endoplasmic reticulum of liver
`
`cells and, to a lesser extent, of cells in other tissues. The enzymes that catalyze
`
`these reactions are typically oxidases; the majority of these enzymes are heme
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 12
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`
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`protein mono-oxygenases of the cytochrome P450 class (often referred to generally
`
`as P450s). Cytochrome P450 (sometimes abbreviated CYP) enzymes are also
`
`known as microsomal mixed-function oxidases. They are involved in the
`
`metabolism of approximately 75% of all drugs used today (or, more appropriately,
`
`75% of drugs that are cleared by metabolism).
`
`24. The cytochrome P450 enzymes first attracted interest because of their
`
`potential relevance to the metabolism of drugs, steroids, and carcinogens. There
`
`are 57 human P450s. One of the P450s involved in drug metabolism is CYP2D6.
`
`My laboratory was the first to purify human CYP2D6 from human liver. J. Biol.
`
`Chem. 287, 15798–15800 (2012) (Exhibit 2008 at 1–3).
`
`25. There is considerable variation in the efficiency of the CYP2D6
`
`enzyme between individuals—certain individuals will eliminate CYP2D6-substrate
`
`drugs quickly (ultrarapid metabolizers) while others will do so slowly (poor
`
`metabolizers). In addition, certain external factors, such as administration of a
`
`CYP2D6 inhibitor like fluoxetine, can inhibit CYP2D6 function.
`
`26. An individual’s CYP2D6 function, or phenotype, may influence the
`
`person’s response to different doses of drugs that CYP2D6 metabolizes. The
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 13
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`
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`person’s response, however, does not depend only on the person’s CYP2D6
`
`function, but also on the extent to which the drug is processed by CYP2D6,
`
`whether other metabolic pathways will compensate for poor metabolism via
`
`CYP2D6, whether the processing of the drug by CYP2D6 results in a chemical that
`
`has an effect that is similar, stronger, or weaker than the original drug, or no effect
`
`at all, etc.
`
`27.
`
`In September 2004, most pharmaceutical companies avoided
`
`development of a drug that was deemed to be metabolized primarily by a highly
`
`polymorphic enzyme such as CYP2D6, because such polymorphisms may lead to
`
`wide inter-individual variability in drug response. Indeed, some companies
`
`dropped promising candidates simply because they were being metabolized, even
`
`just in part, by polymorphic cytochrome P450 enzymes such as CYP2D6. F.P.
`
`Guengerich et al., “Diversity in the oxidation of substrates by cytochrome P450
`
`2D6: lack of an obligatory role of aspartate 301-substrate electrostatic bonding,”
`
`Biochemistry, 41(36):11025–11034 (2002) (Exhibit 2009 at 3–12).
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 14
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`
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`V. THE PRIOR ART TAUGHT THAT ILOPERIDONE IS NOT
`PRIMARILY OR SIGNIFICANTLY METABOLIZED BY CYP2D6 IN
`VIVO
`
`28. There is broad variability in the pharmacokinetic profiles of the
`
`antipsychotic drugs on the market. This is based, at least in part, on the different
`
`metabolic pathways and enzymes involved in their metabolism.
`
`29. By 2004, some but not all aspects of iloperidone metabolism were
`
`known or theorized, with much left to be discovered. Iloperidone metabolism is
`
`complex and unpredictable. Indeed, looking at just possible metabolism by the
`
`P450 family, iloperidone has at least 19 different sites that could be oxidized by a
`
`P450 enzyme as a first step in the overall metabolic pathway.
`
`30.
`
`In 1995, Mutlib and Strupczewski published a paper describing some
`
`of the metabolites of iloperidone based on the analysis of human plasma and urine,
`
`as well as in vivo and in vitro studies using rats and dogs. A.E. Mutlib et al.,
`
`“Application of hyphenated LC/NMR and LC/MS techniques in rapid identification
`
`of in vitro and in vivo metabolites of iloperidone,” Drug Metabolism and
`
`Disposition 23(9): 951–964 (1995) (Exhibit 2010 at 1–14) (“Mutlib &
`
`Strupczewski”).
`
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 15
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`Guengerich Declaration
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`Patent No. 9,138,432
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`31. Below is a figure of the metabolic pathways that Mutlib and
`
`
`
`Strupczewski proposed:
`
`
`
`Figure 1: Proposed metabolic pathways for iloperidone. Exhibit 2010 at 2,
`
`Figure 1.
`
`32. Mutlib and Strupczewski did not find any CYP2D6 metabolites in
`
`vivo. Rather, in human plasma, Mutlib and Strupczewski found the CYP3A4
`
`metabolite, P89 (referred to as Metabolite E in the paper), and the reduced
`
`metabolite, P88, (referred to Metabolite F in the paper), with P88 being the major
`
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 16
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`Guengerich Declaration
`Case IPR2016-00690
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`Patent No. 9,138,432
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`metabolite. Similarly, in human urine, P88 was the major metabolite detected,
`
`with only trace amounts of iloperidone and P89 detected. Thus, Mutlib and
`
`Strupczewski did not determine that CYP2D6 metabolism was important in
`
`humans in vivo and did not detect any CYP2D6 metabolites in their assays.1
`
`33.
`
`In 1998, Mutlib published another paper based on further analysis of
`
`the metabolic pathways for iloperidone. A.E. Mutlib & J.T. Klein, “Application of
`
`Liquid Chromatography/Mass Spectrometry in Accelerating the Identification of
`
`Human Liver Cytochrome P450 Isoforms Involved in the Metabolism of
`
`Iloperidone,” J. Pharmacol. & Experimental Ther. 286(3): 1285–1293 (1998)
`
`(Exhibit 1006 at 6–14) (“Mutlib”). This is the paper cited by Roxane and Dr.
`
`Fogelson.
`
`34. Using human liver microsomes (essentially ground up liver cells that
`
`have been partially fractionated), Multib determined that the major iloperidone
`
`metabolite in vitro is P94, based on CYP2D6 metabolism, followed by P88 via
`
`
`1 Mutlib and Strupczewski also noted that that there are significant differences in
`
`the metabolism of iloperidone by humans and the two other animal species they
`
`tested, rats and dogs.
`
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 17
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`Guengerich Declaration
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`Inter Partes Review Of
`Patent No. 9,138,432
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`carbonyl reduction and then P89 via CYP3A4. Roxane and Dr. Fogelson rely on
`
`this evidence to argue that iloperidone is significantly metabolized by CYP2D6.
`
`See Petition at 24–25, 30–32; Fogelson Declaration ¶¶ 92–93, 109–112.
`
`35. That, however, is not the entire story. Although Mutlib did find a
`
`significant amount of CYP2D6 metabolite in vitro, Mutlib found only trace
`
`amounts, if any, of P94 in vivo, based on analysis of both human plasma and urine.
`
`Mutilb at 1286 (Exhibit 1006 at 7).
`
`36. Unable to find meaningful amounts of the CYP2D6 metabolite, P94,
`
`in the body, Mutlib postulated that P94 was further metabolized to form
`
`“Compound 5” (now known as P36.3). Below is a figure from the Mutlib paper
`
`that describes his proposed metabolic pathways for iloperidone.
`
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 18
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`Figure 2: Mutlib (Exhibit 1006 at 7), Figure 1. Mutlib determined that
`
`
`
`iloperidone’s CYP3A4 metabolite is P89 (Compound 2) and that the
`
`reduced metabolite is P88 (Compound 3). Murtlib hypothesized that
`
`iloperidone is metabolized by CYP2D6 to P36.3 (Compound 5) in
`
`vivo via P94 (Compound 4). Id. We now know that is wrong. It was
`
`later determined that P36.3 (Compound 5) is not a major iloperidone
`
`Vanda Pharm. Inc.
`Exhibit 2001
`Page 19
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`metabolite and is not the ultimate CYP2D6 metabolite; it is now
`
`hypothesized that P95 is the CYP2D6 metabolite. See NDA No. 22-
`
`192, Clinical Pharmacology and Biopharmaceutics Review(s) (Exhibit
`
`2012).
`
`37.
`
`“Compound 5,” or P36.3, however, is not a major metabolite of
`
`iloperidone. Exhibit 2012 (NDA No. 22-192, Clinical Pharmacology and
`
`Biopharmaceutics Review(s)) at 16. Roxane concedes as much in its proposed
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`label for generic iloperidone. Exhibit 2008. Indeed, after the publication of Mutlib
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`(Exhibit 1006), no further work on “Compound 5” was reported.
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`38. That the ultimate metabolite that Mutlib identifies, P36.3 (Compound
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`5), is not the actual metabolite that results from CYP2D6 metabolism, see Exhibit
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`2012 (NDA No. 22-192, Clinical Pharmacology and Biopharmaceutics Review(s))
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`at 16, highlights the complexity of the various metabolic pathways for iloperidone
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`and the difficulties scientists faced trying to characterize them.
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`39. Although Roxane and Dr. Fogelsen focus on Mutlib’s statement that
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`“CYP2D6 is primarily responsible for the production of the major in vitro human
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`microsomal metabolite 4 [i,e., P94],” Mutlib at 1292 (Exhibit 1006 at 13), and that
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`Exhibit 2001
`Page 20
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`P94, the hydroxylation of iloperidone, was “the major metabolite produced in
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`vitro,” Mutlib at 1285–1286 (Exhibit 1006 at 6–7), Roxane and Dr. Fogelsen
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`ignore Mutlib’s statements that P94 “was present in very small quantities in human
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`plasma and urine,” Mutlib at 1286 (Exhibit 1006 at 7), and that P88, formed
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`through carbonyl reduction, and not CYP2D6 “was the major drug related
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`component in plasma (in addition to iloperidone) and urine samples” —not P94,
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`Mutlib at 1286, 1291 (Exhibit 1006 at 7, 12). One of skill in the art would have
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`understood that the clinical significance of Mutlib’s in vivo data would trump the
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`in vitro data. See, e.g., FDA Guidance 1997 (Exhibit 1015).
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`40. Thus, one of skill in the art would have understood Mutlib to teach
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`that CYP2D6 was not a major or significant metabolic pathway for iloperidone
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`metabolism in vivo. This understanding was confirmed by several review articles
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`that Roxane and Dr. Fogelson do not mention, including two published in 2004: J.
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`Kirchheiner et al., “Pharmacogenetics of antidepressants and antipsychotics: the
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`contribution of allelic variations to the phenotype of drug response,” Molecular
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`Psychiatry 9: 442–473 (2004) (Exhibit 2013 at 1–32) (“Kirchheiner 2004”); M.A.
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`Raggi, et al., “Atypical Antipsychotics: Pharmacokinetics, Therapeutic Drug
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 21
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`
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`Guengerich Declaration
`Case IPR2016-00690
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`Monitoring and Pharmacological Interactions,” Current Medicinal Chemistry
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`11(3):279–296 (2004) (Exhibit 1021 at 6–23) (“Raggi 2004”); see also Silvio
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`Caccia, “New antipsychotic agents for schizophrenia: Pharmacokinetics and
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`metabolism update,” Current Opinion in Investigational Drugs 3(7): 1073–1080
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`(2002) (Exhibit 2015 at 1–8) (“Caccia”).
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`41. Specifically, Kirchheiner 2004 is a review article that categorizes
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`iloperidone as being metabolized by CYP1A2, CYP2B6, or CYP3A4, and does not
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`categorize iloperidone as being metabolized by CYP2D6. Exhibit 2013 at 4, Table
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`1. Similarly, Raggi 2004 is a review article that discloses several atypical
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`antipsychotics being developed at the time, including iloperidone, Exhibit 1021 at
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`18–19, and teaches that certain atypical antipsychotics are substrates of CYP2D6,
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`id. at 8, Table 1. Raggi 2004, however, does not categorize iloperidone as a drug
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`that is metabolized by CYP2D6. Id. at 8. In Caccia, it was reported that the main
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`pathway for iloperidone metabolism is through cytosolic reduction, while
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`metabolites produced by the CYP1A2, CYP2D6, and CYP3A enzymes are the
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`results of minor pathways. Exhibit 2015 at 2, Table 1.
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 22
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`Guengerich Declaration
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`Inter Partes Review Of
`Patent No. 9,138,432
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`42. To the extent Roxane and Dr. Fogelson seem to argue that Obach,
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`
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`U.S. Patent Application Publication No. 2003/01442202—which was not cited as
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`part of their obviousness combination—confirms their understanding that CYP2D6
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`is a major metabolic pathway for iloperidone, Petition at 25; Fogelson Declaration
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`¶ 92, Obach does not go that far. Specifically, Obach states as follows:
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`Examples of other drugs for which the major clearance mechanism in
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`humans is CYP2D6 mediated oxidative biotransformation are the
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`following: mequitazine (J. Pharmacol. Exp. Ther., 284, 437442
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`(1998)); tamsulosin (Xenobiotica, 28, 909–22 (1998)); oxybutynin
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`(Pharmacogen., 8, 449–51 (1998)); ritonavir (Clin. PK, 35, 275–291
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`(1998)); iloperidone (J. Pharmacol. Exp. Ther., 286, 1285–93
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`(1998)); ibogaine (Drug Metab. Dispos., 26, 764–8 (1998));
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`delavirdine (Drug Metab. Dispos., 26, 631–9 (1998)); tolteridine
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`(Clin. Pharmcol. Ther., 63 529–39 (1998)); promethazine
`
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`2 Obach was cited by the Patent Examiner during the examination of the ’432
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`Patent at the Patent Office against Vanda, and Vanda successfully argued that
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`Obach does not make claim 1 of the ’432 Patent obvious.
`
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 23
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`Guengerich Declaration
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`Inter Partes Review Of
`Patent No. 9,138,432
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`(Rinshoyakon, 29, 231–38 (1998)); pimozide, J. Pharmacol. Exp.
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`Ther., 285, 428–37 (1998)); epinastine (Res. Comm. Md. Path.
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`Pharmacol., 98, 273–92 (1997)); tramodol (Eur. J. Clin. Pharm., 53,
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`235–239 (1997)); procainamide (Pharmacogenetics, 7, 381–90
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`(1997)); methamphetamine (Drug Metab. Dispos., 25,1059–64
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`(1997)); tamoxifen (Cancer Res., 57, 3402–06 (1997)); nicergoline
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`(Br. J. Pharm., 42, 707–11 (1996)); and fluoxetine (Clin. Pharmcol.
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`Ther., 60, 512–21 (1996)). All of the foregoing references are
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`incorporated herein by references in their entireties.
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`Exhibit 1012 at 4, [0028] (emphasis added). The article cited for iloperidone
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`is Mutlib. Thus, Obach merely relies on Mutlib to support its disclosure of
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`iloperidone and does not do any independent analysis to determine whether
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`CYP2D6 is a major clearance mechanism for iloperidone. Moreover, as
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`discussed above, Mutlib does not disclose, and review of the prior art as a
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`whole shows that a person of ordinary skill would not have understood, that
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`CYP2D6 is relevant to the in vivo metabolism of iloperidone. Indeed, that is
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`the case for many of the drugs listed by Obach. For example, oxybutynin is
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 24
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`marketed as DITROPAN; the Ditropan label notes that Ditropan is
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`metabolized by the P450 enzymes, particularly CYP3A4. The Ditropan
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`label does not state that CYP2D6 is a major clearance mechanism.
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`Similarly, ritonavir is marketed as NORVIR; the Norvir label states that it is
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`not significantly metabolized by any liver enzymes (including CYP2D6) in
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`the body.3 Thus, Obach does not reliably disclose drugs that are primarily or
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`significantly metabolized by CYP2D6 in vivo.
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`43. Contrary to Roxane’s and Dr. Fogelson’s remarks, Petition at 25;
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`Fogelson Declaration ¶ 93, I did not see any evidence that Vanda “acknowledged”
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`that Obach teaches that the major clearance mechanism for iloperidone is
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`CYP2D6. Rather, Vanda, at most, acknowledged that Obach asserts and the
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`Examiner believed that Obach teaches that CYP2D6 is relevant to iloperidone
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`3 Somewhat akin to what was thought to be the case with iloperidone, the Norvir
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`label states that the in vitro data shows that CYP3A4 plays a major role and
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`CYP2D6 can contribute to the formation of one of ritonavir’s metabolites;
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`however, the in vivo data demonstrates that ritonavir is not significantly
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`metabolized by CYP2D6.
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`Vanda Pharm. Inc.
`Exhibit 2001
`Page 25
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`
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`Guengerich Declaration
`Case IPR2016-00690
`Inter Partes Review Of
`Patent No. 9,138,432
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`
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`metabolism: “With respect to iloperidone, Obach purports to teach only that
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`iloperidone is a drug for which the major clearance mechanism is CYP2D6
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`mediated oxidative biotransformation.” Oct. 14, 2014 Response to Office Action
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`(Exhibit 1002 at 242) at 13. That is all.
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`44. Roxane and Dr. Fogelson also wrongly assert that the “Background of
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`the ’432 Patent admits that ‘[a] large number of dr