UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`POZEN INC. and HORIZON PHARMA USA, INC.,
`Patent Owners
`________________________
`
`U.S. Patent No. 9,220,698
`________________________
`
`Inter Partes Review IPR2017-01995
`________________________
`
`DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 9,220,698
`
` DRL EXHIBIT 1044 PAGE 1
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`B.
`
`I.
`II.
`
`IX.
`
`Introduction ..................................................................................................... 5
`Qualifications and Background ...................................................................... 5
`A.
`Education and Experience .................................................................... 5
`B.
`Bases for Opinions ............................................................................... 8
`C.
`Retention and Compensation ............................................................... 8
`Legal Standards .............................................................................................. 8
`III.
`IV. Definition of a Person of Ordinary Skill in the Art (POSA) ........................ 10
`V.
`Summary of Opinions ................................................................................... 11
`VI. Background on Pharmacokinetics and Pharmacodynamics ......................... 12
`VII. U.S. Patent No. 9,220,698 [Ex. 1001] .......................................................... 21
`A.
`The ’698 Patent Specification ............................................................ 22
`B.
`The Challenged Claims ...................................................................... 33
`VIII. Claim Construction ....................................................................................... 36
`A.
`Legal Standard .................................................................................... 36
`B.
`The Term “Target” Means “With The Goal of Obtaining” ............... 37
`The Prior Art ................................................................................................. 42
`A.
`Prior Art References Disclosed A Combined Dosage Form
`With Naproxen and Esomeprazole ..................................................... 42
`(a)
`U.S. Patent No. 8,557,285 (“’285 Patent”) [Ex. 1005] ............ 43
`(b) U.S. Patent No. 6,926,907 (“’907 Patent”) [Ex. 1004] ............ 45
`(c)
`Goldstein [Ex. 1011] ................................................................ 47
`(d) Hochberg [Ex. 1012] ................................................................ 48
`(e)
`Hassan-Alin [Ex. 1016] ........................................................... 50
`Prior art references disclosed the target pharmacokinetics of
`naproxen ............................................................................................. 52
`(a)
`EC-Naprosyn label [Ex. 1009] ................................................. 52
`
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`X.
`
`2.
`
`C.
`
`B.
`
`(b) Khosravan [Ex. 1017] .............................................................. 53
`(c)
`Jung [Ex. 1018] ........................................................................ 54
`(d) Davies [Ex. 1019] .................................................................... 55
`Prior Art References Disclosed The Target Pharmacokinetics
`of, and Pharmacodynamic Response To, Esomeprazole ................... 56
`(a)
`Howden 2005 [Ex. 1006] ......................................................... 56
`(b)
`Zegerid label [Ex. 1010] .......................................................... 57
`Esomeprazole is a Component of Omeprazole .................................. 59
`D.
`All Claims of the ’698 Patent Are Unpatentable .......................................... 60
`A.
`The ’285 Patent Anticipated the Claims of the ’698 Patent ............... 60
`(a)
`The ’285 Patent anticipated independent claim 1 .................... 60
`1.
`The ’285 patent taught a combined dosage form of
`naproxen and esomeprazole and its twice daily
`administration. ............................................................... 62
`The PK/PD elements are inherent in the twice-
`daily administration of the dosage forms disclosed
`in the ’285 patent. .......................................................... 63
`(b) Dependent claim 2 was anticipated ......................................... 66
`(c)
`Dependent claims 3 and 4 were anticipated............................. 66
`(d) Dependent claims 5-7 were anticipated ................................... 67
`Ground 2: U.S. Patent No. 8,557,285 Rendered Obvious the
`Claims of the ’698 Patent ................................................................... 69
`(a)
`The pharmacokinetic and pharmacodynamic properties of
`the claimed unit dose form would have been obvious ............. 69
`(b) Dependent claim 2 would have been obvious ......................... 71
`(c)
`Dependent claims 3 and 4 would have been obvious .............. 72
`(d) Dependent claims 5-7 would have been obvious .................... 73
`
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`C.
`
`D.
`
`Ground 3: U.S. Patent No. 8,557,285, in View of Howden 2005
`and the EC-Naprosyn Label, Rendered Obvious the Claims of
`the ’698 Patent .................................................................................... 75
`(a)
`Independent claim 1 would have been obvious ....................... 75
`1.
`The prior art provided motivation to target (i.e.,
`have the goal of obtaining) the PK and PD
`elements. ........................................................................ 76
`The prior art provided a reasonable expectation of
`success in setting the PK and PD elements as
`targets. ............................................................................ 88
`(b) Dependent claim 2 would have been obvious ......................... 90
`(c)
`Dependent claims 3-4 would have been obvious .................... 90
`(d) Dependent claims 5-7 would have been obvious .................... 92
`There Are No Unexpected Results Arising From The Claimed
`Method. ............................................................................................... 94
`
`2.
`
` DRL EXHIBIT 1044 PAGE 4
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`

`

`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`
`I, Michael Mayersohn, Ph.D., do hereby declare:
`
`I.
`
`Introduction
`
`1.
`
`My name is Michael Mayersohn. I have been retained by Mylan
`
`Pharmaceuticals Inc. (“Mylan”) in the matter set forth in the caption above. I
`
`understand that Mylan is petitioning for inter partes review (“IPR”) of claims 1-7
`
`of U.S. Patent No. 9,220,698 to Ault et al. (“the ’698 patent”) [Ex. 1001]. I submit
`
`this expert declaration in support of Mylan’s IPR petition for the ’698 patent.
`
`II.
`
`Qualifications and Background
`
`A. Education and Experience
`
`2.
`
`I am Professor Emeritus of Pharmaceutical Sciences in the College of
`
`Pharmacy at the University of Arizona, in Tucson, Arizona.
`
`3.
`
`I earned my Bachelor of Science degree in Pharmacy from the
`
`College of Pharmaceutical Sciences at Columbia University, in New York, in 1966.
`
`I earned a Ph.D. in Pharmaceutics from the State University of New York at
`
`Buffalo, in 1970. From 1971 until 1976, I was an assistant and then an associate
`
`professor in the Faculty of Pharmacy at the University of Toronto. In 1976, I
`
`joined the faculty of the University of Arizona, as an associate professor in the
`
`College of Pharmacy. In 1983, I became a professor in the University of Arizona
`
`College of Pharmacy, and am currently a Professor Emeritus there.
`
` DRL EXHIBIT 1044 PAGE 5
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`5 MYLAN PHARMS. INC. EXHIBIT
`
`1003 PAGE 5
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`

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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`
`4.
`
`My research, training, and experience are all in the area of
`
`pharmaceutical
`
`sciences generally, and
`
`specifically
`
`in
`
`the areas of
`
`pharmacokinetics, pharmaceutics, biopharmaceutics, and pharmacodynamics. My
`
`research has involved pharmaceutical formulation development and evaluation,
`
`including examining the relationship between the physical-chemical characteristics
`
`of a drug and its dosage form; the fate and performance of that drug in the body;
`
`and the design of rational drug dosing regimens based upon analytical,
`
`mathematical, and clinical data. My extensive research in these areas includes in
`
`vitro experimentation and in situ and in vivo studies in animals and humans,
`
`including evaluating and analyzing immediate-release and extended-release solid
`
`oral dosage forms. I have also conducted theoretical, or in silico, analyses and
`
`simulations of drug behavior in the body.
`
`5.
`
`I am the author of numerous book chapters related to drug absorption
`
`and pharmacokinetics, and over 160 original scientific peer-reviewed articles in the
`
`pharmaceutical sciences, many relating to biopharmaceutics and pharmacokinetics,
`
`and about 15 professional and educational publications. I have published over 160
`
`abstracts of research studies that were presented at international and national
`
`scientific or professional meetings.
`
`6.
`
`I have received several professional awards for my research, and I
`
`have been elected a fellow of several professional organizations, including the
`
` DRL EXHIBIT 1044 PAGE 6
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`6
`
`DRL EXHIBIT 1003 PAGE 4 EXHIBIT 1003
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`PAGE 6
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`

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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`
`Academy of Pharmaceutical Sciences (American Pharmaceutical Association), the
`
`American Association of Pharmaceutical Scientists, and the American College of
`
`Clinical Pharmacology. Fellowship elections are recognition by my scientific
`
`peers of my valuable contributions to my field.
`
`7.
`
`Between 1995 and 1998, I was a member of the U.S. Food and Drug
`
`Administration’s (“FDA”) Generic Drug Advisory Committee (currently the
`
`Pharmaceutical Sciences Advisory Committee).
`
` This Committee reviews,
`
`comments on, and provides direction to FDA on issues of drug bioavailability and
`
`bioequivalence;
`
`this work
`
`then forms
`
`the regulatory standards for
`
`the
`
`pharmaceutical industry through, for example, issuance of FDA Guidances.
`
`8.
`
`I was a member of the Dissolution and Bioavailability Expert
`
`Committee of the United States Pharmacopeia for a 5-year term. I also served as
`
`Vice Chair of the same expert committee, renamed the Biopharmaceutics
`
`Committee of the United States Pharmacopeia, for an additional 5-year term. The
`
`Committee sets the official standards for dissolution and bioavailability metrics
`
`that are applied throughout the pharmaceutical industry.
`
`9.
`
`I have been the director and principal instructor of a one-week course,
`
`“Principles of Pharmacokinetics and Toxicokinetics for the Industrial Scientist,”
`
`which has been given in Tucson, Arizona, for 15 years, with over 750 scientists
`
`having attended. In the past, I gave a version of this course on-site to many
`
` DRL EXHIBIT 1044 PAGE 7
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`

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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`
`companies
`
`in
`
`the pharmaceutical
`
`industry
`
`as
`
`“Selected Topics
`
`in
`
`Pharmacokinetics,” and over the years about 1,000 scientists attended. I also gave
`
`a short course on the same topic sponsored by the American Chemical Society at
`
`their annual meetings.
`
`10. A copy of my curriculum vitae, which lists my publications and
`
`describes my qualifications in detail, is attached as Attachment A.
`
`B. Bases for Opinions
`
`11.
`
`In forming my opinions set forth in this declaration, I have considered
`
`and relied upon my education, background, and decades of experience in the field
`
`of pharmaceutical sciences, including pharmaceutics and formulation science,
`
`biopharmaceutics, pharmacokinetics, and pharmacodynamics. I have also relied
`
`on the materials listed in Attachment B.
`
`C. Retention and Compensation
`
`12.
`
`I am being compensated for my consulting work on this case at my
`
`usual rate of $800.00 per hour plus expenses. My compensation in this proceeding
`
`is not dependent on its outcome.
`
`III.
`
`Legal Standards
`
`13. Counsel has informed me that certain legal principles should guide me
`
`in my analysis. Counsel has informed me that Mylan carries the burden of proving
`
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`

`

`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`unpatentability by a preponderance of the evidence, which means Mylan must
`
`show that unpatentability is more likely than not.
`
`14. Counsel has informed me that the question of whether the claims of a
`
`patent are anticipated by, or obvious in view of, the prior art is to be considered
`
`from the perspective of the person of ordinary skill in the art (“POSA”). Counsel
`
`has further informed me that the answer to this question is ascertained as of the
`
`time the invention was made.
`
`15. Counsel has informed me that performing an obviousness analysis
`
`involves ascertaining, as of the time the invention was made, the scope and content
`
`of the prior art, the level of skill of the POSA, the differences between the claimed
`
`invention and the scope and content of the prior art, and whether there are
`
`additional factors present that may argue against a conclusion of obviousness (i.e.,
`
`“secondary considerations”), such as unexpected results attributable to the
`
`invention, or whether the invention met a long-felt but unmet need.
`
`16. Counsel has informed me that an invention may be found obvious:
`
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified,
`predictable solutions, a person of ordinary skill has good
`reason to pursue the known options within his or her
`technical grasp. If this leads to the anticipated success, it
`is likely the product not of innovation but of ordinary
`skill and common sense. In that instance the fact that a
`
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`

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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`
`combination was obvious to try might show that it was
`obvious under § 103.
`
`17. Counsel has informed me that a prior art reference anticipates a
`
`claimed invention if the prior art reference disclosed each of the claimed elements
`
`of the invention. A prior art reference not expressly disclosing a claim element
`
`may still anticipate the claimed invention if the missing element is necessarily
`
`present, or inherent, in the single anticipating reference. The missing element, or
`
`characteristic, is inherent in the anticipating reference if the characteristic is a
`
`natural result flowing from the reference’s explicit disclosure.
`
`18. Counsel has informed me that if a patent claims a composition in
`
`terms of a function, property, or characteristic, and the composition itself is in the
`
`prior art, then the claim may be anticipated or obvious in view of the prior art
`
`reference disclosing the composition.
`
`IV.
`
`Definition of a Person of Ordinary Skill in the Art (POSA)
`
`19.
`
`The field of art involves the knowledge of a medical doctor and that
`
`of a pharmacologist or pharmacokineticist with experience in dosage form design
`
`and evaluation. Thus, the hypothetical person of ordinary skill in the art is a
`
`collaboration between a pharmacologist or pharmacokineticist having a Ph.D.
`
`degree or equivalent training, or a M.S. degree with at least 2 years of some
`
`experience in dosage form design and in in vitro and in vivo evaluation of dosage
`
` DRL EXHIBIT 1044 PAGE 10
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`

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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`form performance, and a medical doctor having at least 2 years of practical
`
`experience treating patients in the gastroenterology field.
`
`20.
`
`I am offering my analysis from the perspective of the pharmacologist
`
`or pharmacokineticist described above.
`
`V.
`
`Summary of Opinions
`
`21.
`
`First, a POSA would have understood
`
`that
`
`the
`
`targeted
`
`pharmacokinetic (PK) and pharmacodynamic (PD) values recited in claims 1 and 2
`
`of the ’698 patent are the natural result of administering the pharmaceutical
`
`composition disclosed and claimed in U.S. Patent No. 8,557,285 (“’285 patent”).
`
`A POSA would have also understood that the targeted PK and PD values recited in
`
`claims 1 and 2 of the ’698 patent are a function, property, or characteristic of the
`
`pharmaceutical composition disclosed and claimed in the ’285 patent.
`
`22.
`
`Second, it would have been routine for a POSA to make and test the
`
`pharmaceutical composition disclosed and claimed in the ’285 patent as containing
`
`500 mg naproxen and 20 mg esomeprazole. A POSA would have measured and
`
`obtained the PK and PD values resulting from administration of the composition
`
`described and claimed in the ’285 patent by routine testing and recording methods.
`
`23.
`
`Third, a POSA would have been motivated to target the claimed PK
`
`and PD values recited in the claims of the ’698 patent because these values were
`
`known to be in the therapeutically effective ranges for naproxen and a proton pump
`
` DRL EXHIBIT 1044 PAGE 11
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`inhibitor, such as esomeprazole. Further, a POSA would have had a reasonable
`
`expectation of success in targeting the claimed PK and PD values because a skilled
`
`artisan would routinely target PK and PD values associated with marketed drugs
`
`known to be effective.
`
`24.
`
`Fourth, all elements recited in the ’698 patent’s dependent claims
`
`were disclosed in the ’285 patent, as well as other prior art.
`
`VI.
`
`Background on Pharmacokinetics and Pharmacodynamics
`
`25.
`
`“Pharmacokinetics” (PK) describes the body processes associated
`
`with drug movement
`
`into (absorption or
`
`input), within (distribution or
`
`translocation) and out of (metabolism and excretion) the body. These processes
`
`are often referred to by the mnemonic ADME, which stands for Absorption,
`
`Distribution, Metabolism and Excretion. Ex. 1021 at 5. While pharmacology is
`
`often described as studying the “effect of the drug on the body,” PK is often
`
`described as the opposite: studying the “effect of the body on the drug.” The two
`
`areas of study are, however, inextricably connected.
`
`26.
`
`“Pharmacodynamics” (PD) describes how the concentration of a drug
`
`at its site of action is related to the magnitude of the clinical effect observed.
`
`Pharmacodynamics studies the relationship between a drug’s biochemical and
`
`physiological effects and its mechanism of action. Ex. 1021 at 9.
`
` DRL EXHIBIT 1044 PAGE 12
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`27. While the science of pharmacology tends to be qualitative, the science
`
`of pharmacodynamics is quantitative, describing the course of a pharmacological
`
`or clinical effect over time. The PD properties of a drug are often studied in
`
`combination with its PK properties. These two properties are then used to develop
`
`PK/PD models of the drug, in both individuals and populations of patients. See
`
`generally Ex. 1022. One of the most basic skills for a clinical pharmacologist or
`
`pharmacokineticist is the ability to test a drug and gather the PK/PD data that
`
`describe the drug’s behavior.
`
`28.
`
`The diagram below depicts the relationship between pharmacokinetics
`
`and pharmacodynamics:
`
`Ex. 1022 at 6.
`
`Figure A
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` DRL EXHIBIT 1044 PAGE 13
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`29. As shown, PK/PD events overlap.
`
` The driving force for
`
`pharmacodynamic (i.e., clinical or toxic) events following drug dosing is generally
`
`the concentration of drug in the blood (or plasma). In other words, the PD effects
`
`of a drug are driven by its concentration in the plasma, and the time course of the
`
`PD effects is driven or controlled by the PK properties of the drug and its dosage
`
`form. Ex. 1021 at 5-8. Because of this, it is worthwhile to be able to describe the
`
`plasma concentration-time profile of a drug after administering it to a patient. A
`
`stylized single-dose plasma concentration-time profile resulting from oral dosing is
`
`depicted below.
`
`Figure B
`
`See, e.g., Ex. 1022 at 21 (displaying exemplary curve with identified parameters).
`
`30.
`
`To develop a single-dose plasma concentration-time profile, the
`
`clinical pharmacologist or pharmacokineticist will, after administering a drug (e.g.,
`
` DRL EXHIBIT 1044 PAGE 14
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`administering orally), take frequent blood samples for a time sufficient to
`
`characterize the entire profile. The blood samples, or a fluid derived from blood
`
`(e.g., plasma or serum), are treated and submitted to an analytical procedure from
`
`which one can obtain a quantitative value for the concentration of the drug (and/or
`
`metabolites of that drug) in the blood sample. The resulting concentration-time
`
`profile can be plotted and analyzed, by using either a computer-based method to
`
`obtain a mathematical model that best describes the data, or a model-independent
`
`method. Either way, one obtains estimates of the values of the PK parameters for
`
`the drug.
`
`31.
`
`Following a single oral dose of a drug, the plasma concentration-time
`
`profile can be used to estimate the Cmax (maximum plasma drug concentration
`
`achieved), the Tmax (time after dosing corresponding to the Cmax), the t½ (half-life of
`
`the drug in the body), and the AUC (extent of absorption or total exposure to the
`
`drug, as measured by the total area under the plasma concentration vs time curve)
`
`from time zero to time infinity. The AUC is a function of the amount of drug that
`
`gets absorbed into the systemic circulation. The figure above is that of a
`
`characteristic plasma concentration-time curve for an immediate-release dosage
`
`form, i.e., one designed not to delay release and subsequent absorption.
`
`32. Often, a POSA will want to depict graphically the PK profile of a
`
`dosage form established in a study of multiple subjects. Placing the profile for
`
` DRL EXHIBIT 1044 PAGE 15
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`

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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`each subject on a single graph may, however, be cumbersome and confusing. It is
`
`therefore common for a POSA to prepare an average plasma concentration-time
`
`profile by plotting the average plasma concentrations over all subjects at each
`
`sample time. Such a graph provides a useful indication of the PK behavior of the
`
`dosage form across multiple subjects. A graph of this type is similar to the one
`
`included in ¶ 29, but derives its data from a population (as described), rather than
`
`an individual.
`
`33.
`
`The drug’s dosage form and its formulation affect the shape of the
`
`plasma concentration-time curve. In other words, immediate-release solid drug
`
`dosage forms will result in a relatively high Cmax that occurs a short time after
`
`dosing (i.e., small Tmax). In contrast, a “delayed-release” solid drug dosage form
`
`will have a Tmax typically occurring later than that of an immediate-release dosage
`
`form. Delayed release often is accomplished by coating a solid dosage form with
`
`an enteric (or other polymer) layer, which is designed not to dissolve and release
`
`the drug until the dosage form reaches the relatively higher pH of the small
`
`intestine. For an enteric-coated dosage form, the delay in absorption can be quite
`
`prolonged, governed by the nature and characteristics of the enteric coating, the
`
`time needed for gastric emptying to occur, and the presence of food in the stomach.
`
`34.
`
`Some single unit dosage forms, like Vimovo®, provide “pulsatile”
`
`release; i.e., multiple drug releases occurring at different times after ingestion, for
`
` DRL EXHIBIT 1044 PAGE 16
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`either the same drug or different drugs. This design, sometimes referred to as
`
`“repeat action,” was well known in the art. A repeat action is commonly achieved
`
`by having an inner core of one drug (the second, or “repeat” dose) covered by an
`
`enteric coating that delays release. An exemplary repeat-action dosage form,
`
`comprising delayed-release naproxen and immediate-release esomeprazole, is
`
`shown below.
`
`Naproxen
`
`Enteric Coating
`Esomeprazole
`
`Figure C
`
`35.
`
`The initial dose (or the other drug dose) that covers the enteric coating
`
`provides the immediate release. An illustration of a plasma concentration-time
`
`profile for a unit dose, repeat-action tablet is below.
`
` DRL EXHIBIT 1044 PAGE 17
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
`
`Figure D
`
`36.
`
`The solid line represents the total drug plasma concentration for a
`
`repeat action or pulsatile dose form. Thus, the drug concentration first rises from
`
`immediate release of drug A1 from the outer coating of the tablet. Total drug
`
`concentration then declines until release of drug A2 (second pulse of A) or B (first
`
`pulse of new drug—as with the dosage form shown in Figure C above) from the
`
`enteric-coated inner core. The dashed line concentration shown as A2 or B is
`
`added to the A1 concentration curve to produce the total drug concentration-time
`
`solid line. Note that for a pulsatile dosage form, one would see the A1 drug
`
`concentration line continue to decrease according to the descending dashed line;
`
`and some time later, concentrations from the other drug, B, will rise and decline
`
`(second dashed line), with plasma concentrations for drug B being delayed relative
`
`to plasma concentrations for drug A.
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` DRL EXHIBIT 1044 PAGE 18
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`37. Many times, it is useful to characterize the pharmacokinetics of a drug
`
`and its dosage form after multiple oral dosing. With multiple dosing, a drug
`
`accumulates in the body until a maximum plasma concentration is achieved, such
`
`that the concentration-time profile repeats after every dosing interval. When this
`
`occurs, commonly after about 4 or 5 half-lives, a so-called “steady state” has been
`
`obtained. This is a fluctuating steady state in which the drug concentrations repeat
`
`but rise and fall periodically. A true steady state involves constant drug
`
`concentrations with time, occurring when the rate of drug entry into the body
`
`equals the rate of elimination of drug from the body. A stylized plasma
`
`concentration-time profile, showing the rise from initial dosing to a fluctuating
`
`steady state, is depicted below. Cmax, Tmax, and AUC(0-t)
`
`1 are added as illustrated.
`
`1 “AUC(0-t)” refers to the area under the curve from time zero to an arbitrary time, t.
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`Cmax
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`AUC(t)
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`Tmax
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`Ex. 1022 at 43.
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`Figure E
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`38.
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`The concentration-time profile can be analyzed once steady state has
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`been achieved. Both Cmax and Tmax will have the same meaning as for single
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`dosing, but the total area under the curve (AUC) is measured for a defined interval
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`(often the dosing interval τ (“tau”) (AUCτ)). Two other parameters that may be
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`calculated at steady state include the minimum plasma concentration, Cmin, often
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`occurring just before the next dose, and the average steady state plasma
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`concentration, Cave. The latter value is not the average of Cmax and Cmin, but rather
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`is calculated as a time-averaged concentration, AUCτ/τ, the units of which are
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`EXHIBIT 1003 – DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`concentration. For example, if the dosage interval is 24 hours, Cave will refer to the
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`area under the curve for the 24-hour dosing period, divided by 24, i.e., AUC24/24.
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`39. During a dosing interval at steady state, one can characterize different
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`dosage forms of a given drug by the PK parameters. For example, an immediate-
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`release product may have a rapidly-achieved Cmax and a low Cmin, depending upon
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`the dosing interval (the longer the interval, the lower the Cmin; the shorter the
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`interval, the greater the Cmin).
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`VII.
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`U.S. Patent No. 9,220,698 [Ex. 1001]
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`40. U.S. Patent No. 9,220,698 (“’698 patent”) issued on December 29,
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`2015, and is entitled “Method for Delivering A Pharmaceutical Composition to a
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`Patient in Need Thereof.” See Ex. 1001 at [54]. The ’698 patent issued from U.S.
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`Patent Application No. 12/553,107, filed on September 3, 2009, which claims
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`priority to U.S. Provisional Patent Application No. 61/095,584, filed on September
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`9, 2008. Id. at [21], [22], [60].
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`41.
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`The ’698 patent names as joint inventors Brian Ault, Mark Sostek,
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`Everardus Orlemans, and John Plachetka. See id. at [75]. The ’698 patent is
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`assigned on its face to Pozen Inc. and Horizon Pharma USA, Inc. Id. at [73].
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`42.
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`The ’698 patent contains seven claims, of which claim 1 is the only
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`independent claim. Claims 2–7 depend from, and further limit, the subject matter
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`recited in claim 1. Id. at 52:25-53:29.
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`43. As issued, the ’698 patent contains several errors in at least its claims.
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`The U.S. Patent and Trademark Office (“USPTO”) issued a Certificate of
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`Correction for the ’698 patent, addressing some of those errors, on April 19, 2016.
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`The USPTO issued a second Certificate of Correction on July 12, 2016.
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`Throughout this declaration, I address the claims as corrected.
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`A. The ’698 Patent Specification
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`44.
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`The ’698 patent relates to methods for treating a patient having
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`osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, with a unit dose form
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`containing 500 mg of enteric-coated naproxen and 20 mg of immediate-release
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`esomeprazole to target a range of PK and PD values for naproxen and
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`esomeprazole. Ex. 1001 at 52:25-67. The ’698 patent refers to an exemplary
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`dosage form, having 500 mg naproxen and 20 mg esomeprazole, as “PN400/E20,”
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`Ex. 1001 at 26:44-45, or “PN400,” Ex. 1001 at 46:43-44. The ’698 patent
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`describes the results of treating a patient population with PN400/E20, and the
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`claims recite the reported PK/PD values. See, e.g., Ex. 1001 at cols. 35-49, Tbls. 6,
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`8, 11, 13, 16-17; 52:25-67 (claim 1).
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`45.
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`The ’698 patent describes and claimed PK parameters for the dosage
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`forms that were well-known to a POSA, including “Cmax,” “Tmax,” and “AUC,”
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`each of which is described and explained above. See, e.g., Ex. 1001 at 52:25-67
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`(claim 1). The ’698 patent also reports these PK parameters as the average (mean)
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`or median values plus or minus a variation. Id. The ’698 patent also describes and
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`claims the variation in these parameters as coefficients of variation (e.g., claiming
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`±20% variation), which reflects the variability inherent in biological and analytical
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`processes both within a patient, across multiple measurements, and between
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`patients in a population. Id. The percentage coefficient of variation (%CV) is
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`calculated as the standard deviation (SD) divided by the mean or average value,
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`multiplied by 100. Ex. 1001 at 5:55-56.
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`46.
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`The ’698 patent acknowledges that NSAIDs were known to increase
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`the risk of gastrointestinal injury, such as ulcers, when used long-term. Ex. 1001 at
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`1:19-24. A POSA would have known, and the ’698 patent states, that stomach acid
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`was “[a] major factor contributing to the development of gastrointestinal lesions”
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`in these circumstances. Id. at 1:24-25. The ’698 patent also states that strategies
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`were known “to reduce the gastrointestinal risk associated with taking NSAIDs by
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`administering agents that inhibit stomach acid secretion, such as, for example,
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`proton pump inhibitors with the NSAID.” Id. at 1:27-30.
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`47.
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`The ’698 patent specifically identifies U.S. Patent No. 6,926,907
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`(“’907 patent”) [Ex. 1004], as directed to a drug dosage form that includes a proton
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`pump inhibitor (“PPI”), that is “effective in improving NSAID tolerability through
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`dosages of esomeprazole and naproxen that produce the desired pharmacodynamic
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`response and pharmacokinetic values.” Id. at 1:34-37.
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`48.
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`The ’285 patent and the ’907 patent disclose the same combined
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`dosage form claimed in the ’698 patent, used in the same way: a unit dosage form
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`containing 500 mg of delayed-release naproxen and 20 mg of immediate-release
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`esomeprazole. The elements of the ’698 patent’s claim 1 that were disclosed by
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`the prior art ’285 patent are shown in the table below:
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`Claimed by the ’698 Patent
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`Disclosed by the Prior Art ’285 Patent
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`Method for treating osteoarthritis,
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`Although the method may be used for
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`rheumatoid arthritis, or ankylosing
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`any condi