UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`HORIZON PHARMA USA, INC. and NUVO PHARMACEUTICALS
`(IRELAND) DESIGNATED ACTIVITY COMPANY,
`Patent Owners
`______________
`
`Case IPR2018-00272
`Patent 9,393,208
`______________
`
`DECLARATION OF DAVID R. TAFT PH.D. IN SUPPORT OF PATENT
`OWNER RESPONSE TO PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,393,208
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`Patent Owners' Ex. 2025
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`Page 1 of 50
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`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner
`
`v.
`
`HORIZON PHARMA USA, INC. and NUVO PHARMACEUTICALS
`(IRELAND) DESIGNATED ACTIVITY COMPANY,
`Patent Owners
`______________
`
`Case IPR2018-00272
`Patent 9,393,208
`______________
`
`DECLARATION OF DAVID R. TAFT PH.D. IN SUPPORT OF PATENT
`OWNER RESPONSE TO PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,393,208
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`Patent Owners' Ex. 2025
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`Table of Contents
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`Page
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`EDUCATIONAL BACKGROUND AND QUALIFICATIONS .................. 1
`I.
`TECHNICAL BACKGROUND .................................................................... 4
`II.
`III. LEGAL STANDARDS ................................................................................ 14
`A.
`The Person of Ordinary Skill in the Art ............................................. 14
`B.
`Conception and Reduction to Practice ............................................... 14
`C. Anticipation and Obviousness ............................................................ 15
`D.
`The Summary Judgment Opinion and Motion to Terminate ............. 18
`IV. OPINIONS .................................................................................................... 19
`A.
`The ’285 Patent Does Not Qualify As Prior Art ................................ 19
`B.
`The ’285 Patent Does Not Inherently Anticipate Claims 1-7 of
`the ’208 Patent .................................................................................... 20
`The ’285 Patent Does Not Render Obvious Claims 1-7 of the
`’208 Patent .......................................................................................... 24
`The ’285 Patent in view of the EC-Naprosyn® Label and
`Howden 2005 Do Not Render Obvious Claims 1-7 of the ’208
`Patent .................................................................................................. 24
`V. OBJECTIVE EVIDENCE OF NONOBVIOUSNESS ................................ 27
`VI. CONCLUSION ............................................................................................. 28
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`
`D.
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`C.
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`I, David R. Taft, Ph.D., declare as follows:
`1.
`I have been retained by Counsel for Horizon Medicines LLC,
`
`Horizon Pharma,
`
`Inc., Horizon Pharma USA,
`
`Inc., and Nuvo
`
`Pharmaceuticals (Ireland) Designated Activity Company (collectively
`
`“Patent Owner”) in the matter set forth in the caption above. I understand
`
`that the Patent Trial and Appeal Board (“PTAB”) has instituted Mylan
`
`Pharmaceuticals Inc.’s (“Mylan’s”) petition for inter partes review (“IPR”)
`
`of claims 1-7 of U.S. Patent No. 9,393,208 (“the ’208 patent”). I submit this
`
`expert declaration in support of Patent Owner’s Response to Mylan’s
`
`petition.
`
`I.
`
`EDUCATIONAL BACKGROUND AND QUALIFICATIONS
`2.
`I am a Professor at Long Island University’s Arnold & Marie
`
`Schwartz College of Pharmacy and Health Sciences in Brooklyn, New York.
`
`I have been in this position since 2008. I served as the Dean of the Arnold
`
`& Marie Schwartz College of Pharmacy and Health Sciences from 2008
`
`until 2013. I was previously an Associate Professor at the Arnold & Marie
`
`Schwartz College of Pharmacy and Health Sciences from 2000 until 2008
`
`and before that an Assistant Professor at the Arnold & Marie Schwartz
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`College of Pharmacy and Health Sciences from 1994 until 2000.
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`3.
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`I received my Bachelors of Science in Pharmacy from
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`University of Rhode Island’s College of Pharmacy in Kingston, Rhode
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`Island in 1987. In 1993, I received my Ph.D. in Pharmaceutical Science
`
`from the University of Connecticut’s School of Pharmacy in Storrs,
`
`Connecticut.
`
`
`
`I
`
`then
`
`completed a postdoctoral
`
`fellowship
`
`in
`
`Pharmacokinetics at the University of North Carolina’s School of Pharmacy
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`in Chapel Hill, North Carolina in 1994.
`
`4.
`
`I have supervised the Ph.D. dissertations of twenty-two
`
`Doctoral students. I currently supervise a research group consisting of six
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`Ph.D. students.
`
`5.
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`I have over 100 peer reviewed publications and professional
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`meeting abstracts.
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`6.
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`I am a member of several professional societies and
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`organizations, including the American Association of Pharmaceutical
`
`Scientists, the International Society for the Study of Xenobiotics, Phi
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`Lambda Sigma Pharmacy Leadership Society, and Rho Chi Pharmacy
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`Honor Society.
`
`7.
`
`I have served on and continue to serve on the editorial boards
`
`for several peer reviewed journals, including the Journal of Pharmaceutical
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`
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`Sciences, Drug Development and Industrial Pharmacy, Current Drug
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`Discovery Technologies, and Current Medical Research and Opinion.
`
`8.
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`I have reviewed and continue to review publications for several
`
`peer-reviewed journals, including Antimicrobial Agents and Chemotherapy,
`
`Biochemical Pharmacology, Current Drug Discovery Technologies, Drug
`
`Development and Industrial Pharmacy, Drug Metabolism and Disposition,
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`Epilepsia, European Journal of Pharmaceutics and Biopharmaceutics,
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`International Journal of Pharmaceutics, International Brazilian Journal of
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`Urology, Journal of Antimicrobial Chemotherapy, Journal of Pharmaceutical
`
`Sciences, Journal of Pharmaceutical and Biomedical Analysis, Journal of
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`Pharmacokinetics and Pharmacodynamics, Kidney International, PDA
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`Journal of Pharmaceutical Science and Technology, Pharmaceutical
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`Research, Pharmaceutical Development and Technology, and the AAPS
`
`Journal.
`
`9.
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`I have served as a principal investigator in twenty-one grant and
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`contract funded projects, involving preclinical and clinical evaluation of
`
`novel therapeutic compounds and their formulations.
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`10. My curriculum vitae, which lists my professional experience
`
`and qualifications in greater detail, is attached as Exhibit 1.
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`11.
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`I am being paid $500 per hour for my time spent in study and
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`testimony in this matter.
`
`12.
`
`In preparing this declaration, I have reviewed Petitioner’s
`
`Petition, and the exhibits attached thereto, including the declarations of Dr.
`
`Metz and Dr. Mayersohn. I have also reviewed Patent Owner’s Response
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`and the Declaration of David A. Johnson, M.D. and I agree with the analysis
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`and conclusions therein.
`
`13.
`
`I reserve the right to prepare exhibits to summarize or support
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`the opinions set forth below.
`
`II.
`
`TECHNICAL BACKGROUND
`14. Biopharmaceutics
`is
`the study of
`
`the
`
`influence of
`
`the
`
`physicochemical properties of a compound (e.g., solubility, lipophilicity),
`
`the dosage form, and the route of administration on the rate and extent of
`
`drug absorption. Pharmacokinetics (“PK”) involves the study of absorption,
`
`distribution, metabolism, and excretion (“ADME”), and how these principles
`
`relate to the route of administration and drug dosage. Pharmacodynamics
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`(“PD”) refers to the relationship between drug concentration at the site of
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`action and the resulting effect.
`
`15. PK can be simply defined as the science that describes the time
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`course of drug disposition, including its ADME properties, following the
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`administration of a drug. Even more simply, it can be summarized as a
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`study of what the body does to a drug.
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`16. To evaluate the systemic exposure to a drug, it is standard to
`
`plot the measured drug concentrations in the plasma over time after drug
`
`administration. Any point on the curve shows the plasma concentration at
`
`that moment in time. The figure below illustrates a typical plasma
`
`concentration vs. time profile after oral administration of a drug.
`
`
`
`17. From this profile, there are a number of parameters that can be
`
`measured. After an oral dose is taken and as it is absorbed, the concentration
`
`of the drug in plasma increases until it reaches a maximum. The maximum
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`concentration of drug measured in plasma after dosage administration is
`
`referred to as “Cmax,” and it is an important measure of exposure. The time
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`at which Cmax is reached is called Tmax.
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`18. The area under the curve, or “AUC,” of concentrations over
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`time (shown in gray in the figure above) represents the total systemic
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`exposure over the time period. AUC is typically calculated from time 0
`
`(when dose is administered) to the time when the dose is virtually
`
`completely eliminated. However, AUC can also be calculated over a
`
`specified time period (for example, AUC0-10 is a measure of exposure for the
`
`first 10 hours after dosing).
`
`19. The type of drug formulation will affect these pharmacokinetic
`
`parameters after oral administration. The figure below depicts the plasma
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`concentration profile for an immediate-release dosage form and a delayed-
`
`release (e.g., enteric coated) dosage form. In general, compared to the
`
`delayed-release dose, an immediate release form will generally have a higher
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`Cmax, a lower Tmax, and approximately the same AUC.
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`20. Clearance (Cl) is perhaps the most important pharmacokinetic
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`parameter, and is defined as the ratio of the rate of drug elimination from the
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`body to plasma concentration. Clearance is the parameter that determines
`
`the relationship between the bioavailable dose and AUC, according to the
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`following equation, where F is bioavailability, D is dose, and Cl is clearance:
`
`AUC
`
`
`
`DF
`
`Cl
`
`
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`21. This equation demonstrates that, at any administered dose,
`
`AUC depends on bioavailability and clearance. Bioavailability (F) is
`
`defined as the fraction of administered dose reaching the systemic
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`circulation. In order for a drug to reach the systemic circulation, it must first
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`absorb across the intestinal lumen, and this depends on numerous factors
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`including solubility in GI fluids, membrane permeability, and stability in GI
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`fluids. Once in the intestinal cell, the drug is susceptible to intestinal
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`metabolism before entering the blood stream. Finally, the fraction of the
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`dose absorbed into the bloodstream must first pass through the liver and
`
`escape hepatic metabolism (termed the “first-pass effect”) before becoming
`
`systemically available.
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` The dependence of bioavailability on these
`
`processes can be described by the following equation:
`
`
`
`
`
`F
`
`
`
`f
`
`a
`
`
`
`f
`
`g
`
`
`
`f
`
`l
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`22.
`
`In the equation, fa represents the fraction of the dose absorbed
`
`into the intestine, fg is the fraction of dose absorbed into the intestine that
`
`escapes intestinal metabolism, and fl is the fraction of dose absorbed into the
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`bloodstream that escapes “first pass” hepatic metabolism. The equation
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`demonstrates that the overall bioavailability of a drug that is orally
`
`administered is the product of the fraction of drug that escapes loss in each
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`organ (stomach, intestine, liver).
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`23. Another important parameter is the volume of distribution (Vd),
`
`a proportionality constant relating the amount of drug in the body to plasma
`
`concentration. Elimination half-life (t1/2) is defined as the time it takes for
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`plasma concentration to decrease by 50%. It is important to note that half-
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`life is a dependent parameter; that is, a drug’s half-life depends on both
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`clearance and volume of distribution, as follows:
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`2/1t
`
`
`
`693.0
`
`Cl
`
`Vd
`
`
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`24. Another important aspect of any PK analysis is the study of
`
`multiple dosing regimens. Drugs are commonly prescribed to be taken on
`
`particular intervals or dosing frequency.
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`25. The ability to readily predict the expected plasma levels
`
`following administration of any given dose is based on the concept of linear
`
`pharmacokinetics. For a drug that follows linear pharmacokinetics,
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`parameters such as Cl and F are constant, and plasma concentrations and
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`AUC are proportional to dose. Additionally, these parameters do not change
`
`over time when a drug that follows linear pharmacokinetics is administered
`
`on a multiple dosing schedule. While linear pharmacokinetics can be
`
`applied in most situations, some medications show dose- or time-dependent
`
`(nonlinear) pharmacokinetics.
`
` When a drug’s pharmacokinetics
`
`is
`
`nonlinear, dose selection is difficult and plasma levels are not predictable.
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`26. Like omeprazole, esomeprazole is known to demonstrate time-
`
`dependent (nonlinear) pharmacokinetics, where the AUC increases greater
`
`than anticipated at steady state relative to the initial dose. Because this
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`phenomenon has been observed following both IV and oral dosing, it
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`indicates that esomeprazole reduces its own clearance with repetitive dosing.
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`Since the medication undergoes presystemic metabolism, reduced clearance
`
`will in turn increase bioavailability by increasing fl. The net result is a
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`greater enhancement of AUC following oral dosing by a combination of
`
`reduced clearance and increased bioavailability
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`27. References previously cited by Dr. Mayersohn support this
`
`opinion. For example, the conclusion of Hassan-Alin 20001 states:
`
`
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`28. Other references have similarly reported: “The decreased
`
`metabolic rate of esomeprazole resulting in the increased AUC of
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`esomeprazole with repeated doses has been shown to be because of a
`
`combination of decreased first-pass elimination and decreased systemic
`
`clearance. . . . A likely explanation for the decreased first-pass elimination
`
`and decreased systemic clearance is competitive inhibition of the major
`
`esomeprazole metabolizing enzyme, CYP2C19, either by esomeprazole
`
`itself, or more likely, by the sulphone metabolite which has been
`
`1 See Exhibit 2069.
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`demonstrated
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`to
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`inhibit
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`the CYP2C19-mediated hydroxylation and
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`demethylation steps.”2
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`29. Other references demonstrate
`
`that some PPIs, such as
`
`lansoprazole and pantoprazole, exhibit predictable linear pharmacokinetics
`
`with multiple dosing. This is in contrast to esomeprazole and omeprazole
`
`that exhibit nonlinear, time-dependent pharmacokinetics.3
`
`30. Pharmacodynamics (“PD”) is the study of what a drug does to
`
`the body. A drug can have different effects in the body, which can include
`
`changes in bodily processes or levels of endogenous compounds. The
`
`relationship between pharmacodynamics and pharmacokinetics (denoted
`
`PK/PD) is also routinely studied during drug development. The relationship
`
`between pharmacokinetics (concentration) and pharmacodynamic effects of
`
`a compound are determined by examining data from clinical studies where
`
`patients are administered a drug, and plasma concentrations and
`
` From these measurements,
`
`pharmacodynamic effects are measured.
`
`2 Exhibit 2033 (Andersson et al., Pharmacokinetic Studies with
`Esomeprazole, the (S)-Isomer of Omeprazole, CLIN. PHARMACOKINET.,
`40(6):411-26 (2001)).
`3 Exhibit 2034 (Tolman et al., The Effects of Oral Doses of Lansoprazole
`and Omeprazole on Gastric pH, J. CLIN. GASTROENTEROL., 24(2):65-70
`(1997); see also Exhibit 2035, Hartmann et al., Twenty-four-hour
`intragastric pH profiles and pharmacokinetics following single and repeated
`oral administration of the proton pump inhibitor pantoprazole in
`comparison to omeprazole, ALIMENT PHARMACOL. THER., 10:359-66
`(1996)).
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`pharmacokinetic and pharmacodynamic effects can be studied, and
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`relationships between the two determined, if present. One such relationship
`
`is the Emax model, where the pharmacodynamic response to changes in
`
`plasma concentration of a drug eventually approaching a maximum value
`
`beyond which greater effect is not expected.
`
`
`
`
`31. Although esomeprazole is the S-enantiomer of omeprazole,
`
`there are differences in pharmacokinetics between the two medications, as
`
`discussed in references that Dr. Mayersohn relies on. For example, Lind
`
`2000 shows that esomeprazole has a higher Cmax and AUC compared to
`
`omeprazole at equal doses.4 These differences are due, in part, to
`
`differences in hepatic metabolism between them.
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`32. Drug-drug interactions are also an important issue to consider
`
`in drug or formulation development, as they can impact drug safety and
`
`efficacy.
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`4 Exhibit 1028 at Table 3.
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`33. Drug-drug interactions (DDIs) occur when one medication
`
`alters either
`
`the concentration (pharmacokinetic
`
`interactions) or
`
`the
`
`biological effect of another medication (pharmacodynamics interactions).
`
`The most common pharmacokinetic DDIs are those involving drug
`
`metabolism mediated by the CYP enzymes including CYP1A2, CYP2C9,
`
`CYP2C19, CYP2D6, and CYP3A4.5 PPIs interact with CYP enzymes not
`
`only as substrates, but also as enzyme inhibitors and inducers.6 A CYP
`
`inhibition DDI will reduce the clearance of the victim drug, resulting in
`
`increased systemic exposure (i.e., higher AUC). An induction DDI, on the
`
`other hand, increases clearance of the victim drug and reduces systemic
`
`exposure. Among PPIs, omeprazole has been associated with a number of
`
`metabolic DDIs. The prescribing information for Prilosec warns that
`
`omeprazole can prolong the elimination of drugs metabolized by CYPs (e.g.,
`
`diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines),
`
`and this requires monitoring and determining the need for dose adjustments.7
`
`On the other hand, pantoprazole and rabeprazole have a low potential for
`
`
`5 Exhibit 2036 (Leucuta et al., Pharmcokinetics and Metabolic Drug
`Interactions, CURRENT CLINICAL PHARMACOLOGY, 1:5-20 (2006)).
`6 Exhibit 2037 (Meyer, Interaction of Proton Pump Inhibitors with
`Cytochromes P450: Consequences for Drug Interactions, YALE J. BIOL.
`MED., 69:203-09 (1996)).
`7 Exhibit 2038 at 18 (Prilosec label).
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`metabolic DDIs with other drugs,8 and this may be an advantage in their
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`clinical use.9
`
`III. LEGAL STANDARDS
`The Person of Ordinary Skill in the Art
`A.
`34. For the purposes of my analysis below, I have applied the
`
`POSA definition adopted by the Board: a person of ordinary skill in the art
`
`at the time of the invention is a collaboration between “a pharmacologist or
`
`pharmacokineticist having a Ph.D. degree or equivalent training, or an M.S.
`
`degree with at least two years of some experience in dosage form design and
`
`in in vitro and in vivo evaluation of dosage form performance, and a medical
`
`doctor having at least two years of practical experience treating patients in
`
`the gastroenterology field.”10
`
`B.
`35.
`
`Conception and Reduction to Practice
`I understand that a patent is entitled to the earliest priority date
`
`by which the invention disclosed therein was conceived of and reduced to
`
`practice. I have been informed that “conception” occurs when the idea of
`
`the invention is formed in the mind of the inventor. I have been further
`
`informed that there are two types of reduction to practice: (1) constructive
`
`8 Exhibit 2037 (Meyer 1996); Exhibit 2039 (Vanderhoff et al., Proton Pump
`Inhibitors: An Update, AMERICAN FAMILY PHYSICIAN, 66:273-80 (2002)).
`9 Exhibit 2040 (Arnold, Safety of proton pump inhibitors-an overview,
`Aliment Pharmacol. Ther., 8(Suppl. 1):65-70 (1994)).
`10 Paper 9 at 8 (citing Paper 2 at 7-8).
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`reduction to practice, which occurs upon the filing of a patent application of
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`the claimed invention, and (2) actual reduction to practice, which occurs
`
`upon proof that the claimed invention works for its intended purpose.
`
`36.
`
`I understand that the ’208 patent on its face claims priority to
`
`Provisional application No. 61/095,584 filed on September 9, 2008.
`
`However, I have been informed that the clinical study that provided the data
`
`disclosed in the ’208 patent was completed on June 25, 2007.11 I have
`
`reviewed the contents of the Final Clinical Study Report PN400-104, and
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`confirmed that the pharmacokinetic results disclosed therein match those in
`
`the ’208 patent. I have been asked to assume that the invention claimed by
`
`the ’208 patent was conceived and actually reduced to practice by June 25,
`
`2007.
`
`C.
`37.
`
`Anticipation and Obviousness
`I understand that the claims of an issued patent are presumed to
`
`be valid, and a party seeking to prove that the claims of an issued patent are
`
`invalid must do so with clear and convincing evidence.
`
`38.
`
`I understand that a patent can be found invalid as anticipated
`
`under 35 U.S.C. § 102 if each and every aspect of the subject matter claimed
`
`was disclosed in a single prior art reference at the time of invention.
`
`
`11 Exhibit 2017 at 1 (Final Clinical Study Report PN400-104) (indicating
`“Study Completion Date” as “25 June 2007”).
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`39.
`
`I understand that a patent can be found invalid under 35 U.S.C.
`
`§ 103 if the subject matter claimed would have been obvious to a person of
`
`ordinary skill in the art at the time of the invention. It is also my
`
`understanding that in assessing the obviousness of the claimed subject
`
`matter, one should evaluate obviousness over the prior art from the
`
`perspective of one of ordinary skill in the art (and not from the perspective
`
`of either a layman or a genius in that art). It is also my understanding that in
`
`assessing the obviousness of a claimed subject matter, one must evaluate
`
`obviousness over the prior art, not in hindsight, but with foresight at the time
`
`the invention was conceived.
`
`40.
`
`It is my further understanding that the question of obviousness
`
`is to be determined based on:
`
` The scope and content of the prior art;
`
` The difference or differences between the subject matter of the
`
`claim and the prior art;
`
` The level of ordinary skill in the art at the time of the invention of
`
`the subject matter of the claim; and
`
` Any relevant objective factors (the “objective indicia,” “secondary
`
`indicia,” or Graham Factors)
`
`indicating non-obviousness,
`
`including evidence of any of the following:
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`o A long-felt, but unresolved need for the invention;
`o Unexpected results achieved by the alleged invention;
`o
`o
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`Copying of the alleged inventions by others in the field;
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`Expression of surprise by experts and those skilled in the art
`
`at the subject matter of the claim; and
`o Whether the patentee proceeded contrary to accepted
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`wisdom of the prior art.
`
`41.
`
`I understand that objective factors can often be the most
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`probative evidence in determining whether claimed subject matter was non-
`
`obvious.
`
`42.
`
`I also understand that multiple prior art references can be
`
`combined to show that a claim is obvious. However, I understand that most
`
`inventions rely on building blocks already long known in the field of the
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`invention. I understand that most, if not all, inventions require a
`
`combination of known elements. The mere existence and knowledge of
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`elements in the prior art does not by itself render a combination of those
`
`elements obvious; some reason for combining the elements must exist. I
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`also understand that it can be important, for a claim of obviousness of a
`
`combination of elements, to identify a reason that would have prompted a
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`-17-
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`Patent Owners' Ex. 2025
`IPR2018-00272
`Page 19 of 50
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`person of skill in the art at the time of the invention to combine the elements
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`as claimed in the patent.
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`D.
`43.
`
`The Summary Judgment Opinion and Motion to Terminate
`I understand that the ’208 patent was also at issue in Hatch-
`
`Waxman patent litigation filed by the Patent Owner in the U.S. District
`
`Court for the District of New Jersey. I understand that the district court
`
`adopted Mylan’s proposed construction of the term “target” in the ’208
`
`patent to mean “set as a goal.” Ex. 2073 at 11. I understand that Mylan then
`
`moved for summary judgment, arguing that the claims of the ’208 patent
`
`were invalid as indefinite. The district court granted Mylan’s motion and
`
`concluded that “it is not possible to discern what the target clauses are telling
`
`you to do or not to do.” Ex. 2075 at 10. The district court therefore found
`
`the ’208 patent invalid for indefiniteness.
`
`44.
`
`I understand from counsel that the Patent Owner filed a Motion
`
`to Terminate this IPR proceeding in light of the district court’s finding the
`
`’208 patent invalid for indefiniteness. Paper 25. I understand from counsel
`
`that a claim cannot be both indefinite and anticipated; therefore, if a claim is
`
`found to be indefinite—as it was by the district court—then the Board
`
`cannot consider prior art challenges in an inter partes review.
`
`
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`-18-
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`Patent Owners' Ex. 2025
`IPR2018-00272
`Page 20 of 50
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`IV. OPINIONS
`A. The ’285 Patent Does Not Qualify As Prior Art
`45.
`I understand from counsel that a reference may be used as prior
`
`art under 35 U.S.C. § 102(a) if the reference was patented or described in a
`
`printed publication in this or a foreign country, before the invention thereof
`
`by the applicant for patent. The ’285 patent issued on October 15, 2013,
`
`after the effective filing date of the ’208 patent. Therefore, the ’285 patent
`
`does not qualify as prior art under 35 U.S.C. § 102(a).
`
`46.
`
`I understand from counsel that a reference may be used as prior
`
`art under 35 U.S.C. § 102(b) if the reference was patented or described in a
`
`printed publication in this or a foreign country or in public use or on sale in
`
`this country, more than one year prior to the date of the application for
`
`patent in the United States. The ’285 patent issued on October 15, 2013,
`
`after the effective filing date of the ’208 patent. Therefore, the ’285 patent
`
`does not qualify as prior art under 35 U.S.C. § 102(b).
`
`47.
`
`I understand from counsel that a reference may be used as prior
`
`art under 35 U.S.C. § 102(e) if the reference was (1) an application for
`
`patent, published under section 122(b), by another filed in the United States
`
`before the invention by the applicant for patent or (2) a patent granted on an
`
`application for patent by another filed in the United States before the
`
`
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`-19-
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`Patent Owners' Ex. 2025
`IPR2018-00272
`Page 21 of 50
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`
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`invention by the applicant for patent. The ’285 patent was filed on August
`
`23, 2011 and lists John R. Plachetka as the sole inventor.
`
`48.
`
`I understand from counsel that it is not enough that the ’208
`
`patent lists Dr. Plachetka as one of four inventors and has a later effective
`
`filing date in order for the ’285 patent to qualify as prior art “by another”
`
`against the ’208 patent. I understand from counsel that the inquiry is
`
`dependent on who the inventor of the underlying subject matter asserted as
`
`prior art is, as compared to the claimed subject matter at issue.
`
`49.
`
`In my opinion, the claimed subject matter at issue in the ’208
`
`patent is comparable to the underlying subject matter of the ’285 patent.
`
`50.
`
`In my opinion, the ’285 patent does not qualify as prior art “by
`
`another” as there is a common inventor, John R. Plachetka, for both the
`
`underlying subject matter in the ’285 patent and the claimed subject matter
`
`of the asserted claims of the ’208 patent.
`
`B.
`
`The ’285 Patent Does Not Inherently Anticipate Claims 1-7
`of the ’208 Patent
`51. The ’285 patent discloses a genus of compositions comprising
`
`an acid inhibitor and an NSAID. More specifically, the specifications of the
`
`’285 patents disclose a variety of acid inhibitors and NSAIDs that may be
`
`used
`
`in combination: cimetidine,
`
`ranitidine, ebrotidine, pabutidine,
`
`lafutidine, loxtidinem, famotidine, omeprazole, esomeprazole, pantoprazole,
`
`
`
`
`
`-20-
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`Patent Owners' Ex. 2025
`IPR2018-00272
`Page 22 of 50
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`
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`lansoprazole, rabeprazole, pariprazole, leminoprazole, tenatoprazole, AZD-
`
`0865, AR-H047108, CS-526, pumaprazole, revaprazan, soraprazan, H-
`
`335/25; Sch-28080; Sch-32651 and SK&F-96067. Moreover, the ’285
`
`patent discloses that H2 blockers are the preferred compounds for acid
`
`inhibitors.
`
`52. The specification of the ’285 patent lists the following 40
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`NSAIDs that may be used in the combination: celecoxib, rofecoxib,
`
`lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-
`
`745,337, NS398,
`
`aspirin,
`
`acetaminophen,
`
`ibuprofen,
`
`flurbiprofen,
`
`ketoprofen, naproxen, oxaprozin, etodolac,
`
`indomethacin, ketorolac,
`
`lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone,
`
`diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin,
`
`fenoprofen,
`
`suprofen, benoxaprofen, aceclofenac,
`
`tolfenamic acid,
`
`oxyphenbutazone, azapropazone, and phenylbutazone.
`
`53. Taken together, in my opinion the ’285 patent discloses 1,000
`
`possible combinations of a composition consisting of an acid inhibitor and
`
`an NSAID.
`
`54.
`
`It is also my opinion that the ’285 patent does not disclose the
`
`specific claimed pharmacokinetic and pharmacodynamics profiles that are
`
`set forth in the claims of the ’208 patent. As Dr. Mayersohn explains, “a
`
`
`
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`-21-
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`Patent Owners' Ex. 2025
`IPR2018-00272
`Page 23 of 50
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`
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`prior art reference anticipates a claimed invention if the prior art reference
`
`disclosed each of the claimed elements of the invention.”12 In my opinion,
`
`the ’285 patent does not meet this standard.
`
`55.
`
`I understand that Dr. Johnson also distinguishes the ’285 patent
`
`on the ground that those patents do not disclose the claimed dosage amount
`
`of 500 mg of naproxen and 20 mg of esomeprazole.
`
`56. Dr. Mayersohn cites to Examples 9 and 10 of the ’285 patent as
`
`the examples of disclosures of “orally administering the unit dose form twice
`
`daily.”13 It is my opinion that while Examples 9 and 10 of the ’285 patent
`
`involve clinical studies of drugs given twice per day for five days and seven
`
`days, respectively, those studies did not involve the claimed coordinated
`
`release solid oral dosage form comprised of immediate release omeprazole
`
`and enteric coated naproxen required by the ’208 patent.
`
`57.
`
`In Example 9 of the ’285 patent, patients were given either (a)
`
`550 mg of naproxen sodium; (b) 40 mg of famotidine given with 550 mg of
`
`naproxen sodium or famotidine followed 90 minutes later by 550 mg of
`
`naproxen sodium; or (c) 20 mg omeprazole followed by 550 mg naproxen.
`
`58. Example 9 described a study of the relationship between gastric
`
`pH and NSAID-induced gastric ulcers. Example 9 does not state whether
`
`12 Exhibit 1003 ¶ 17.
`13 Exhibit 1003 ¶ 127.
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`
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`-22-
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`Patent Owners' Ex. 2025
`IPR2018-00272
`Page 24 of 50
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`the omeprazole was unprotected or protected, and does not provide any
`
`description of the effectiveness of omeprazole. Further, this example does
`
`not describe the use of a coordinated release solid oral dosage form and does
`
`not state how much time elapsed between the administration of the
`
`omeprazole and the naproxen sodium.
`
`59.
`
`In Example 10 of the ’285 patent, patients received twice daily
`
`dosing of (a) 500 mg enteric coated naproxen or (b) 40 mg famotidine
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`followed by 500 mg enteric coated naproxen.14
`
`60. Example 10 described a study to demonstrate the effectiveness
`
`of “combining acid inhibition with enteric coating of NSAID.”15 Example
`
`10 contains no PPI, enteric coated or otherwise, and does not describe the
`
`use of a coordinated release so
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