Petition for Inter Partes Review of USP 9,138,432
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`
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`In re Inter Partes Review of:
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`U.S. Patent No. 9,138,432 B2
`)
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`Issued: Sept. 22, 2015
`)
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`Application No.: 14/150,575
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`Filing Date: Jan. 8, 2014
`)
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`For: Methods for the Administration of Iloperidone
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`FILED VIA PRPS
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`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,138,432
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`I.
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`II.
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`Petition for Inter Partes Review of USP 9,138,432
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`TABLE OF CONTENTS
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`Page
`
`Introduction ...................................................................................................... 1
`
`Requirements For Petition For Inter Partes Review ....................................... 1
`
`A. Grounds for Standing (37 C.F.R. § 42.104(a)) ..................................... 1
`B.
`Notice of Lead and Backup Counsel and Service Information ............. 1
`C.
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................. 2
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 2
`Fee for Inter Partes Review .................................................................. 3
`E.
`F.
`Proof of Service ..................................................................................... 3
`
`III.
`
`Identification of Claims Being Challenged (37 C.F.R. § 42.104(B)) ............. 3
`
`IV. Description Of The Purported Invention ......................................................... 4
`
`A. Disclosure of the ’432 Patent ................................................................ 4
`B.
`Prosecution History ............................................................................... 8
`
`V.
`
`Claim Construction ........................................................................................ 14
`
`A. Applicable Law ................................................................................... 14
`B.
`Construction of Claim Terms .............................................................. 14
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`VI. The Person Of Ordinary Skill Of The ’432 Patent ........................................ 15
`
`VII. The State Of The Art Prior To The ’432 Patent ............................................ 16
`
`A.
`
`B.
`C.
`
`D.
`
`E.
`F.
`
`G.
`
`The Prior Art Taught Adjusting Drug Dosages Based on
`CYP2D6 Drug Interactions ................................................................. 16
`The Prior Art Taught that Fluoxetine is a CYP2D6 Inhibitor ............ 20
`The Prior Art Taught Halving the Dose of CYP2D6 Substrates
`Co-administered with Fluoxetine ........................................................ 21
`The Prior Art Taught that Iloperidone is Used to Treat
`Schizophrenia ...................................................................................... 24
`The Prior Art Taught that Iloperidone is a CYP2D6 Substrate .......... 24
`The Prior Art Taught that Increased Exposure to Iloperidone is
`Associated with a Risk of QT Prolongation ........................................ 25
`The Prior Art Taught Iloperidone Doses of 12 mg/day and 24
`mg/day ................................................................................................. 27
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`VIII. Relied Upon References ................................................................................ 29
`
`Petition for Inter Partes Review of USP 9,138,432
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`FDA Guidance 1999 (Ex. 1005) ......................................................... 29
`A.
`B. Mutlib (Ex. 1006) ................................................................................ 30
`C.
`Brøsen (Ex. 1007)................................................................................ 32
`D.
`The Abilify Label (Exs. 1008 and 1009) ............................................ 34
`E. Mealy (Ex. 1010) ................................................................................. 38
`
`IX. Motivation To Combine The Prior Art References ....................................... 39
`
`A. Motivation to Combine FDA Guidance 1999, Mutlib, Brøsen,
`and Mealy ............................................................................................ 40
`B. Motivation to Combine FDA Guidance 1999, Mutlib, the
`Abilify Label, and Mealy .................................................................... 45
`
`X.
`
`Precise Reasons For The Relief Requested ................................................... 47
`
`A. Ground 1: Claim 1 is Invalid Under 35 U.S.C. § 103 on the
`Ground That it is Rendered Obvious by FDA Guidance 1999 in
`View of Mutlib, Brøsen, and Mealy .................................................... 49
`Ground 2: Claim 1 is Invalid under 35 U.S.C. § 103 on the
`Ground That it is Rendered Obvious by FDA Guidance 1999 in
`View of Mutlib, the Abilify Label, and Mealy ................................... 55
`
`B.
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`XI. Secondary Considerations Fail To Overcome The Strong Evidence Of
`Obviousness ................................................................................................... 60
`
`XII. Conclusion ..................................................................................................... 60
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`ii
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`Petition for Inter Partes Review of USP 9,138,432
`
`
`Exhibit List
`
`1001 U.S. Patent No. 9,138,432 (the “’432 Patent”)
`
`1002
`
`File History for the ’432 Patent (from the USPTO public Patent
`Application Information Retrieval (PAIR) database, www.uspto.gov,
`excluding foreign references)
`
`1003 Declaration of David Fogelson, M.D. in Support of Petition for Inter
`Partes Review of U.S. Patent No. 9,138,432
`
`1004
`
`Curriculum Vitae of David Fogelson, M.D.
`
`1005 U.S. Department of Health and Human Services, Food and Drug
`(“FDA”), Guidance
`for
`Industry,
`In Vivo Drug
`Administration
`Metabolism/Drug Interaction Studies – Study Design, Data Analysis, and
`Recommendations for Dosing and Labeling (November 1999) (available
`at http://www.fda.gov/OHRMS/DOCKETS/98fr/994718gd.pdf) (accessed
`February 22, 2016) (“FDA Guidance 1999”)
`
`1006 A.E. 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 (September
`1998) (“Mutlib”)
`
`1007 K. Brøsen, Differences in Interactions of SSRIs, 13 INT’L CLINICAL
`PSYCHOPHARM. S45-47 (September 1998) (“Brøsen”)
`
`1008
`
`1009
`
`Physicians’ Desk Reference (58th ed. 2004) (Montvale, NJ; Thompson
`PDR, November 2003) (“PDR 2004”), comprising: Abilify Official
`Labeling, Bristol-Myers Squibb Company (revised May 2003) at 1034-
`38, and Otsuka America Pharmaceutical, Inc. (revised May 2003) at
`2496-500 (the “PDR Abilify Label”); and Strattera Official Labeling, Eli
`Lilly and Company (revised March 5, 2003) at 1850-54 (the “Strattera
`Label”)
`
`FDA Official Website, Drug Approval Package: Abilify (Aripiprazole)
`NDA #21-436, November 15, 2002 (the “Abilify Approval Package”)
`(available
`at
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/
`2002/21-436_Abilify.cfm) (webpage created March 7, 2003), linking to:
`“Approval Letter(s),” November 15, 2002 Letter from FDA to Otsuka
`
`iii
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`

`

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`Petition for Inter Partes Review of USP 9,138,432
`
`Pharmaceutical Co., Ltd. (the “Abilify Approval Letter”) (available at
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-
`436_Abilify_Approv.pdf); and “Printed Labeling,” Final Printed Labeling
`(available
`at
`(the
`“FPL
`Abilify
`Label”)
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21436_Abilify_
`prntlbl.pdf) (accessed February 23, 2016)
`
`1010 N.E. Mealy et al., Annual Review 2002: Psychopharmacologic Drugs, 27
`DRUGS OF THE FUTURE 995-1027 (October 2002) (“Mealy”)
`
`the Treatment of
`for
`1011 K.K. Jain, An Assessment of Iloperidone
`Schizophrenia, 9 EXPERT OPINION ON INVESTIGATIONAL DRUGS 2935-43
`(December 2000) (“Jain”)
`
`1012 U.S. Patent Publication No. 2003/0144220, “Use of CYP2D6 Inhibitors in
`Combination Therapies,” filed March 21, 2000, published July 31, 2003
`(“Obach”)
`
`1013
`
`1014
`
`S.M. Cheer et al., Fluoxetine, A Review of its Therapeutic Potential in the
`Treatment of Depression Associated with Physical Illness, 61 DRUGS 81-
`110 (January 2001) (“Cheer”)
`
`International Publication No. WO 01/79554, “Genetic Diagnosis for QT
`Prolongation Related Adverse Drug Reactions,” filed April 13, 2001,
`published October 25, 2001 (“Woosley”)
`
`1015 U.S. Department of Health and Human Services, Food and Drug
`Administration (“FDA”), Guidance for Industry, Drug Metabolism/Drug
`Interaction Studies in the Drug Development Process: Studies In Vitro
`(April 1997) (available at http://www.fda.gov/downloads/AboutFDA
`/CentersOffices/CDER/UCM142439.pdf) (accessed February 22, 2016)
`(“FDA Guidance 1997”)
`
`1016
`
`1017
`
`R.R. Shah, Pharmacogenetic Aspects of Drug-Induced Torsade de
`Pointes: Potential Tool for Improving Clinical Drug Development and
`Prescribing, 27 DRUG SAFETY 145-72 (March 2004) (“Shah”)
`
`Physicians’ Desk Reference (56th ed. 2002), Prozac Official Labeling,
`Dista Products Company (revised February 28, 2001, product information
`prepared June 2001) at 1238-43 (the “Prozac Label”)
`
`1018
`
`FDA Official Website, Drugs@FDA: FDA Approved Drug Products,
`
`iv
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`

`

`
`
`1019
`
`1020
`
`Petition for Inter Partes Review of USP 9,138,432
`
`at
`(available
`Details
`Drug
`Prozac
`https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseact
`ion=Search.DrugDetails) (accessed February 23, 2016)
`
`J. Kirchheiner et al., CYP2D6 and CYP2C19 Genotype-Based Dose
`Recommendations
`for Antidepressants: A First Step Towards
`Subpopulation-Specific
`Dosages,
`104
`ACTA
`PSYCHIATRICA
`SCANDINAVICA 173-92 (September 2001)
`
`FDA Official Website, Drug Approval Package: Strattera (Atomoxetine
`Hydrochloride) NDA #21-411, November 26, 2002 (available at
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-
`411_Strattera.cfm) (accessed February 23, 2016)
`
`1021 M.A. Raggi et al., Atypical Antipsychotics: Pharmacokinetics,
`Therapeutic Drug Monitoring and Pharmacological Interactions, 11
`CURRENT MED. CHEM. 279-96 (February 2004) (“Raggi”)
`
`1022
`
`1023
`
`1024
`
`Library of Congress Website, U.S. ISSN Center, ISSN is for Serials (ISSN
`Basics)
`(available at http://www.loc.gov/issn/basics/basics-brochure-
`serials.html) (accessed February 22, 2016)
`
`Bristol-Myers Squibb Company, Sec. & Exch. Comm’n Form 10-Q (filed
`May 14, 2003 for the period ending March 31, 2003)
`
`February 17, 2016 Email from Paul Buckman, FDA, Director of Online
`Communications, Center for Drug Evaluation and Research, to Timothy
`O’Brien re FDA Webpage Publication Date
`
`1025
`
`February 12, 2016 Email from PDR Customer Service Department to
`Timothy O’Brien re PDR 2004 ed. Publication Date
`
`v
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`

`
`I.
`
`INTRODUCTION
`
`Petition for Inter Partes Review of USP 9,138,432
`
`Roxane Laboratories, Inc. (“Roxane” or “Petitioner”), in accordance with 35
`
`U.S.C. § 311 and 37 C.F.R. § 42.100, hereby requests inter partes review of Claim
`
`1 of United States Patent No. 9,138,432, titled “Methods for the Administration of
`
`Iloperidone” (the “’432 Patent”). According to USPTO records, the ’432 Patent is
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`assigned to Vanda Pharmaceuticals Inc. (“Vanda”). Copies of the ’432 Patent and
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`its prosecution history are provided as Exhibits 1001 and 1002, respectively.
`
`II. REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Petitioner certifies that the ’432 Patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting inter partes review of
`
`the challenged claim of the ’432 Patent on the grounds identified herein.
`
`B. Notice of Lead and Backup Counsel and Service Information
`Pursuant to 37 C.F.R. §§ 42.8(b)(3), 42.8(b)(4), and 42.10(a), Petitioner
`
`provides the following designation of Lead and Back-Up counsel.
`
`Lead Counsel
`Daniel G. Brown (Reg. No. 54,005)
`daniel.brown@lw.com
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`885 Third Avenue
`New York, NY 10022-4834
`T: 212.906.1200; F: 212.751.4864
`Back-Up Counsel
`Emily C. Melvin (Reg. No. 66,586)
`
`Back-Up Counsel
`Robert Steinberg (Reg. No. 33,144)
`bob.steinberg@lw.com
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`355 South Grand Avenue
`Los Angeles, CA 90071-1560
`T: 213.485.1234; F: 213.891.8763
`Back-Up Counsel
`Timothy J. O’Brien (Reg. No. 68,264)
`
`1
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`

`

`
`
`Petition for Inter Partes Review of USP 9,138,432
`
`emily.melvin@lw.com
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`330 North Wabash Avenue, Suite 2800
`Chicago, IL 60611
`T: 312.876.7700; F: 312.993.9767
`
`timothy.obrien@lw.com
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`330 North Wabash Avenue, Suite 2800
`Chicago, IL 60611
`T: 312.876.7700; F: 312.993.9767
`
`
`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney for Petitioner is attached.
`
`Petitioner consents to service at the email addresses provided above.
`
`C. Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`Roxane is the real-party-in-interest for this proceeding. Petitioner also
`
`identifies Boehringer Ingelheim Corp. (“BI”), Roxane’s current owner, as a real-
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`party-in-interest for this Petition.1 No other parties exercised or could have
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`exercised control over this Petition; no other parties funded or directed this
`
`Petition. See Office Patent Trial Practice Guide, 77 Fed. Reg. 48759-60.
`
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`Vanda Pharm. Inc. v. Roxane Labs., Inc., No. 15-cv-00919 (D. Del.). Vanda
`
`Pharm. Inc. v. Taro Pharm. USA, Inc. et al., No. 15-cv-00920 (D. Del.). Vanda
`
`Pharm. Inc. v. Inventia Healthcare Pvt. Ltd., No. 15-cv-00921 (D. Del.). Vanda
`
`Pharm. Inc. v. Apotex Inc. et al., No. 15-cv-00922 (D. Del.). Vanda Pharm. Inc. v.
`
`1 Additionally, Hikma Pharmaceuticals PLC has announced that it plans to acquire
`
`Roxane from BI. If and when the acquisition is completed, Petitioner will file an
`
`updated notice of the real-parties-in-interest reflecting the change in ownership.
`
`2
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`

`

`
`Lupin Ltd. et al., No. 15-cv-01073 (D. Del.). Vanda Pharm. Inc. v. Inventia
`
`Petition for Inter Partes Review of USP 9,138,432
`
`Healthcare Pvt. Ltd., No. 15-cv-00362 (D. Del.).
`
`According to USPTO records, no patent claims priority to the ’432 Patent.
`
`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 Vanda
`
`Pharm. Inc. et al. v. Roxane Labs., Inc., Nos. 13-cv-01973, 14-cv-00757 (D. Del.).
`
`Fee for Inter Partes Review
`
`E.
`The Director is authorized to charge the fee specified by 37 C.F.R.
`
`§ 42.15(a) to Deposit Account No. 506269.
`
`Proof of Service
`
`F.
`Proof of service of this petition on the patent owner at the correspondence
`
`address of record for the ’432 Patent is attached.
`
`III.
`
`IDENTIFICATION OF CLAIMS BEING CHALLENGED (37 C.F.R.
`§ 42.104(B))
`
`Claim 1 of the ’432 Patent is unpatentable in view of the following prior art:
`
`• 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,” attached as Ex. 1005);
`
`3
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`

`

`
`
`Petition for Inter Partes Review of USP 9,138,432
`
`• 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,” attached as Ex. 1006);
`
`• Brøsen, Differences
`
`in Interactions of SSRIs, 13 INT’L CLINICAL
`
`PSYCHOPHARM. S45-47 (1998) (“Brøsen,” attached as Ex. 1007);
`
`• The Abilify Label, including as 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); and
`
`• Mealy et al., Annual Review 2002: Psychopharmacologic Drugs, 27 DRUGS
`
`OF THE FUTURE 995-1027 (2002) (“Mealy,” attached as Ex. 1010).
`
`Specifically, the challenged claim is unpatentable on the following grounds:
`
`• Ground 1: Claim 1 is invalid under 35 U.S.C. § 103 because it is rendered
`
`obvious by FDA Guidance 1999 in view of Mutlib, Brøsen, and Mealy.
`
`• Ground 2: Claim 1 is invalid under 35 U.S.C. § 103 because it is rendered
`
`obvious by FDA Guidance 1999 in view of Mutlib, the Abilify Label, and
`
`Mealy.
`
`IV. DESCRIPTION OF THE PURPORTED INVENTION
`A. Disclosure of the ’432 Patent
`
`4
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`

`
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`Petition for Inter Partes Review of USP 9,138,432
`
`The ’432 Patent is directed to the well-known practice of reducing the
`
`dosage of a drug administered to a patient if the patient has decreased ability to
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`metabolize the drug. Ex. 1003, Declaration of David Fogelson, M.D. in Support of
`
`Petition for Inter Partes Review of U.S. Patent No. 9,138,432 (“Fogelson Decl.”) ¶
`
`36. It purports to invent the discovery that, when a known drug (iloperidone),
`
`which is known to be metabolized by the CYP2D6 enzyme, is known to produce a
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`side effect—prolongation of the electrocardiographic QT interval2—a lower dose
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`of the drug is safer for a patient with reduced CYP2D6 enzyme activity. Ex. 1001,
`
`’432 Patent at 2:21-27; Ex. 1003, Fogelson Decl. ¶ 36.
`
`The ’432 Patent claims this practice in the context of treating a patient with
`
`iloperidone, a CYP2D6-metabolized antipsychotic drug, while the patient is
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`concurrently receiving the antidepressant fluoxetine, a CYP2D6 enzyme inhibitor.
`
`Ex. 1001, ’432 Patent at 2:65-3:3; Ex. 1003, Fogelson Decl. ¶ 38. Claim 1 recites:
`
`
`2 The QT interval is a measure of the duration of a cardiovascular electric potential,
`
`and its prolongation is a well-known side effect associated with many drugs. See
`
`Sections V.B and VII.F infra; Ex. 1003, Fogelson Decl. ¶ 37. The ’432 Patent
`
`also references a corrected QT interval, “QTc,” equivalent to the QT interval
`
`corrected by a mathematical formula, such as the Fridericia formula (QTcF). Ex.
`
`1001, ’432 Patent at 2:40-48; Ex. 1003, Fogelson Decl. ¶ 41.
`
`5
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`

`

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`Petition for Inter Partes Review of USP 9,138,432
`
`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.
`
`Ex. 1001, ’432 Patent at Claim 1; Fogelson Decl. ¶ 38.
`
`The ’432 Patent states that iloperidone was known to treat schizophrenia.
`
`Ex. 1001, ’432 Patent at 1:45-53; Ex. 1003, Fogelson Decl. ¶ 39. As the ’432
`
`Patent acknowledges, iloperidone methods of use and dosages were known in the
`
`art by September 2004. Ex. 1001, ’432 Patent at 1:42-44, 11:15-22; Ex. 1003,
`
`Fogelson Decl. ¶ 39.
`
`The ’432 Patent further describes that variations in a patient’s ability to
`
`metabolize a drug can be dangerous to the patient where an “increased
`
`concentration of a non-metabolized drug or its metabolites is capable of producing
`
`unwanted physiological effects.” Ex. 1001, ’432 Patent at 1:29-34; Ex. 1003,
`
`Fogelson Decl. ¶ 40. It provides as background that “[a]mong the unwanted
`
`physiological effects associated with an increased concentration of iloperidone or
`
`its metabolites is prolongation of the electrocardiographic QT interval.” Ex. 1001,
`
`’432 Patent at 1:56-58; Ex. 1003, Fogelson Decl. ¶ 40.
`
`Moreover, the ’432 Patent admits that, by September 2004, iloperidone was
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`6
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`

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`known to be metabolized by the CYP2D6 enzyme, as were many other drugs.3 Ex.
`
`Petition for Inter Partes Review of USP 9,138,432
`
`1001, ’432 Patent at 1:35-42; Ex. 1003, Fogelson Decl. ¶ 43. Iloperidone is
`
`therefore referred to as a CYP2D6 “substrate.” Ex. 1001, ’432 Patent at 4:46-48;
`
`Ex. 1003, Fogelson Decl. ¶ 43. The ’432 Patent further describes that another CYP
`
`enzyme, CYP3A4, also contributes to iloperidone’s metabolism. Ex. 1001, ’432
`
`Patent at 4:46-50; Ex. 1003, Fogelson Decl. ¶ 43.
`
`According to the ’432 Patent, by September 2004, mutations in the CYP2D6
`
`genotype were associated with drug metabolism-related phenotypes,4 including
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`extensive metabolizer (EM) and poor metabolizer (PM) phenotypes. Ex. 1001,
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`’432 Patent at 1:58-63; Ex. 1003, Fogelson Decl. ¶ 44. As the ’432 Patent also
`
`acknowledges, “lower CYP2D6 activity in a CYP2D6 poor metabolizer may be
`
`
`3 As the ’432 Patent notes, CYP enzymes are also referred to as “P450” enzymes,
`
`and the CYP2D6 enzyme is also referred to as “P450 2D6” and “debrisoquine
`
`hydroxylase.” Ex. 1001, ’432 Patent at 1:35-37; Ex. 1003, Fogelson Decl. ¶ 42.
`
`Herein, unless otherwise noted, Petitioners use “CYP2D6” to reference the
`
`CYP2D6 enzyme, and “CYP2D6 genotype” to reference the genotype that encodes
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`the CYP2D6 enzyme. Ex. 1003, Fogelson Decl. ¶ 42.
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`4 “Genotype” refers to an individual’s genetic make-up, whereas “phenotype”
`
`refers to their set of observable characteristics. Ex. 1003, Fogelson Decl. ¶ 44.
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`7
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`

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`due to factors other than genotype,” such as if a patient is being administered a
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`Petition for Inter Partes Review of USP 9,138,432
`
`CYP2D6 inhibitor (such as fluoxetine). Ex. 1001, ’432 Patent at 10:4-8; Ex. 1003,
`
`Fogelson Decl. ¶ 45. Accordingly, the ’432 Patent defines all “[p]atients who have
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`lower than normal CYP2D6 activity” as “Poor Metabolizers.” Ex. 1001, ’432
`
`Patent at 2:29-30; Ex. 1003, Fogelson Decl. ¶ 46. As the ’432 Patent recognizes,
`
`“[w]here a particular drug is capable of producing unwanted physiological effects
`
`in its metabolized or non-metabolized forms, it is desirable to determine whether a
`
`patient is a poor metabolizer of the drug prior to its administration.” Ex. 1001,
`
`’432 Patent at 1:63-67; Ex. 1003, Fogelson Decl. ¶ 46.
`
`The ’432 Patent’s specification describes a study concerning concentrations
`
`of iloperidone and its metabolites in patients with various CYP2D6 genotypes as
`
`well as concentrations before and after administration of a CYP2D6 inhibitor,
`
`paroxetine. See Ex. 1001, ’432 Patent at 4:24-41, 5:28-10:67; Ex. 1003, Fogelson
`
`Decl. ¶ 47. With regard to the known CYP2D6 inhibitor fluoxetine, the ’432
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`Patent provides only the following statement: “Addition of the CYP2D6 inhibitor
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`fluoxetine, along with iloperidone resulted in increases of the area under the curve
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`(AUC) for iloperidone and P88 of 131% and 119% respectively.” Ex. 1001, ’432
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`Patent at 4:51-54; Ex. 1003, Fogelson Decl. ¶ 47.
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`Prosecution History
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`B.
`During prosecution of the ’432 Patent, Claim 1 was only allowed based on
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`8
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`

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`the specific 12 and 24 mg/day dosages that it recites. Ex. 1002, ’432 Patent
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`Petition for Inter Partes Review of USP 9,138,432
`
`Prosecution History Excerpts (“Prosecution History”) at 4/22/2015 Applicant
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`Summary of Interview at Continuation Sheet (stamped page 319); Ex. 1003,
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`Fogelson Decl. ¶ 49. The Examiner repeatedly rejected nearly identical claims that
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`only differed from Claim 1 by reciting ranges of dosages (such as 12-24 mg/day
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`and 12 mg/day or less), recognizing that the prior art provided motivation to lower
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`iloperidone’s dose in a patient also receiving fluoxetine. Ex. 1002, Prosecution
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`History at 6/2/2015 Notice of Allowance at Interview Summary, 4/28/2015
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`Applicant Amendment After Final at 3, and 4/22/2015 Applicant Summary of
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`Interview at Continuation Sheet (stamped pages 361, 330, 319); Ex. 1003,
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`Fogelson Decl. ¶ 49. And the Examiner maintained throughout prosecution that
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`“to the extent that the use of a lower known dosage of iloperidone reduces the risk
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`of QT prolongation, this is an inherent benefit of the use of such [] dosage (and the
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`dosage is suggested by the teachings of the art).” Ex. 1002, Prosecution History at
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`1/28/2015 Office Action at 15 (stamped page 292); Ex. 1003, Fogelson Decl. ¶ 50.
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`For completeness, the prosecution history is summarized further below:
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`The ’432 Patent issued from U.S. Patent Application No. 14/150,575 (the
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`“’432 Patent Application”), which was filed on January 8, 2014 with claims
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`directed to methods for administering reduced dosages of iloperidone to a patient
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`receiving a CYP2D6 inhibitor. Ex. 1002, Prosecution History at 1/8/2014
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`9
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`

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`Application at 25-26 (stamped pages 42-43); Ex. 1003, Fogelson Decl. ¶ 52. The
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`Petition for Inter Partes Review of USP 9,138,432
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`’432 Patent claims priority to U.S. Provisional Patent Application No. 60/614,798
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`filed on September 30, 2004. Ex. 1002, Prosecution History at 1/8/2014
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`Application Data Sheet at 3 (stamped page 8); Ex. 1003, Fogelson Decl. ¶ 52.
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`On July 15, 2014, the Examiner issued an Office Action rejecting all
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`pending claims. Ex. 1002, Prosecution History at 7/15/2014 Office Action at 1
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`(stamped page 181); Ex. 1003, Fogelson Decl. ¶ 53. The Examiner rejected
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`pending claim 1—directed to administering 12-24 mg/day of iloperidone, or 12
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`mg/day or less when co-administering a CYP2D6 inhibitor—as obvious over
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`Jain’s disclosure of iloperidone dosages of 8-32 mg/day. Ex. 1002, Prosecution
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`History at 3/21/2014 Applicant Response at 2, and 7/15/2014 Office Action at 6-7
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`(stamped pages 172, 186-87) (“As discussed in MPEP 2144.05, optimization of
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`conditions that are already generally disclosed in the prior art is not considered
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`inventive absent evidence of the criticality of a particular range[.]”); Ex. 1011,
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`K.K. Jain, An Assessment of Iloperidone for the Treatment of Schizophrenia, 9
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`EXPERT OPINION ON INVESTIGATIONAL DRUGS (2000) (“Jain”) at 2940-41; Ex.
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`1003, Fogelson Decl. ¶ 53. On the same grounds, the Examiner also rejected
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`pending dependent claims directed to the specific dose of 24 mg/day. Ex. 1002,
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`Prosecution History at 3/21/2014 Applicant Response at 3 (claims 8, 9), and
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`7/15/2014 Office Action at 7 (stamped pages 173, 187); Ex. 1003, Fogelson Decl.
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`10
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`

`
`¶ 53.
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`Petition for Inter Partes Review of USP 9,138,432
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`Additionally, the Examiner rejected pending claim 1 based on Jain in view
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`of Obach and Cheer. Ex. 1002, Prosecution History at 7/15/2014 Office Action at
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`8-11 (stamped pages 188-91); Ex. 1012, U.S. Patent Publication No. 2003/0144220
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`(“Obach”) at [0028], [0042], [0052-53]; Ex. 1013, S.M. Cheer et al., Fluoxetine, A
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`Review of its Therapeutic Potential in the Treatment of Depression Associated with
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`Physical Illness, 61 DRUGS (2001) (“Cheer”) at 82, 90; Ex. 1003, Fogelson Decl. ¶
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`54. The Examiner referenced the following: Obach teaches that iloperidone is
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`metabolized by CYP2D6; Obach teaches adjusting the dosages of CYP2D6
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`metabolized drugs co-administered with CYP2D6 inhibitors; and Cheer teaches
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`that fluoxetine is a CYP2D6 inhibitor. Ex. 1002, Prosecution History at 7/15/2014
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`Office Action at 8-11 (stamped pages 188-91); Ex. 1003, Fogelson Decl. ¶ 54.
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`Moreover, the Examiner rejected pending claim 5, directed to the specific reduced
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`dose of 12 mg/day, based on the dose ranges taught by Jain. Ex. 1002, Prosecution
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`History at 3/21/2014 Applicant Response at 3, and 7/15/2014 Office Action at 11
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`(stamped pages 173, 191); Ex. 1003, Fogelson Decl. ¶ 55.
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`The Examiner also found pending claim 2 non-limiting, where claim 2
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`recited “wherein the risk of QT prolongation is reduced in a patient that is also
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`being treated with a drug that inhibits CYP2D6.” Ex. 1002, Prosecution History at
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`3/21/2014 Applicant Response at 2, and 7/15/2014 Office Action at 5, 7, 9-10
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`11
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`

`

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`(stamped pages 172, 185, 187, 189-90); Ex. 1003, Fogelson Decl. ¶ 56. The
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`Petition for Inter Partes Review of USP 9,138,432
`
`Examiner stated that pending claim 2 “appears to simply recite an inherent benefit
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`of the method of claim 1; the claim does not specify any further active or
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`manipulative steps that are to be performed.” Ex. 1002, Prosecution History at
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`7/15/2014 Office Action at 9-10 (stamped pages 189-90); Ex. 1003, Fogelson
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`Decl. ¶ 56. And the Examiner noted, “Woosley establish[es] that impaired
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`CYP2D6 function is associated with QT interval elongation resulting from
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`accumulation of drugs metabolized by CYP2D6,” and that subjects with impaired
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`CYP2D6 function (such as those treated with CYP2D6 inhibitors) “will inherently
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`benefit from receiving lower dosages of drugs metabolized by CYP2D6.” Ex.
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`1002, Prosecution History at 7/15/2014 Office Action at 10 (stamped page 190);
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`see Ex. 1014, International Pub. No. WO 01/79554 (“Woosley”) at 3:5-16, 11:9-
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`13; Ex. 1003, Fogelson Decl. ¶ 57.
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`In response, the Applicants restricted pending claim 1 to the CYP2D6
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`inhibitor fluoxetine and attempted to traverse the remaining obviousness rejections.
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`Ex. 1002, Prosecution History at 10/14/2014 Applicant Response at 5, 10, 11
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`(stamped pages 234, 239-40); Ex. 1003, Fogelson Decl. ¶ 58. On January 28,
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`2015, the Examiner issued a Final Rejection rejecting all pending claims as
`
`obvious, again, based on Jain, Obach, Woosley, and Cheer. Ex. 1002, Prosecution
`
`History at 1/28/2015 Office Action at 9-16 (stamped pages 286-93); Ex. 1003,
`
`12
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`Fogelson Decl. ¶ 58.
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`Petition for Inter Partes Review of USP 9,138,432
`
`The Examiner subsequently held an interview with the Applicants on April
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`16, 2015. In advance of the interview, the Applicants submitted an Agenda in
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`which the Applicants stated that, “taking the references collectively … what the
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`skilled person learns is that: iloperidone was shown to be safe and effective in
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`clinical trials at doses of 4-16 mg/day, or at 8-32 mg/day, and that iloperidone may
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`be prescribed with a CYP2D6 inhibitor and, if it is co-prescribed, then the normal
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`dose of iloperidone … may need to be adjusted … as much as an order of
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`magnitude lower than the normal dose on up to greater than the normal dose.” Ex.
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`1002, Prosecution History at 4/22/2015 Applicant Summary of Interview,
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`Interview Agenda at 5 (stamped page 324); Ex. 1003, Fogelson Decl. ¶ 59.
`
`The Examiner maintained the prior obviousness rejections, but agreed to
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`allow new pending claim 20 (which would become Claim 1 of the ’432 Patent)
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`based on its specific claimed dosages of 24 mg/day and 12 mg/day. Ex. 1002,
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`Prosecution History at 4/22/2015 Applicant Summary of Interview, Interview
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`Agenda at 3 (stamped page 322); Ex. 1003, Fogelson Decl. ¶ 60. The Applicants
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`subsequently canceled all other pending claims, and a Notice of Allowance was
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`issued as to pending claim 20. Ex. 1002, Prosecution History at 4/28/2015
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`Applicant Response at 3, and 6/2/2015 Notice of Allowance at Interview Summary
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`(stamped pages 330, 361); Ex. 1003, Fogelson Decl. ¶ 60.
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`13
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`

`Petition for Inter Partes Review of USP 9,138,432
`
`
`V. CLAIM CONSTRUCTION
`A. Applicable Law
`In deciding whether to institute inter partes review, “[a] claim in an
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`unexpired patent shall be given its broadest reasonable construction in light of the
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`specification of the patent in which it appears.” 37 C.F.R. § 42.100(b).5 Under the
`
`broadest reasonable interpretation, “claims should always be read in light of the
`
`specification and teachings in the underlying patent.” Microsoft Corp. v.
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`Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015). Any ambiguity regarding
`
`the “broadest reasonable construction” of a claim term is resolved in favor of the
`
`broader construction absent amendment by the patent owner. Final Rule, 77 Fed.
`
`Reg. 48680, 48699 (Aug. 14, 2012).
`
`B. Construction of Claim Terms
`Petitioner respectfully submits that none of the terms of the ’432 Patent
`
`require construction for this Petition. All claim terms have therefore been
`
`accorded their broadest reasonable interpretation as understood by a person of
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`5 The district court, in contrast, affords a claim term its “ordinary and customary
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`meaning … to a person of ordinary skill in the art in question at the time of the
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`invention.” Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005).
`
`Petitioner expressly re