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 to Ault et al.
`
`Inter Partes Review IPR2017-01995
`
`DECLARATION OF DAVID C. METZ, M.D.
`
`1
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`

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`TABLE OF CONTENTS
`
`Page
`
`I.
`
`QUALIFICATIONS AND BACKGROUND ................................................ 4
`A.
`Education and Experience .................................................................... 4
`B. Materials Considered ............................................................................ 7
`C.
`Scope of Work ...................................................................................... 7
`SUMMARY OF OPINIONS .......................................................................... 8
`II.
`LEGAL STANDARDS .................................................................................. 9
`III.
`PERSON OF ORDINARY SKILL IN THE ART ....................................... 11
`IV.
`BACKGROUND ON NSAID-RELATED GASTRIC INJURY ................. 11
`V.
`VI. U.S. PATENT NO. 9,220,698 (Ex. 1001) .................................................... 12
`VII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ............. 17
`A.
`U.S. Patent No. 6,926,907 (Ex. 1004) ................................................ 17
`B.
`U.S. Patent No. 8,557,285 (Ex. 1005) ................................................ 21
`C.
`Howden 2005 (Ex. 1006) ................................................................... 24
`D.
`EC-Naprosyn Prescribing Information (Ex. 1009) ........................... 25
`E.
`Other Art that Informs Person of Ordinary Skill’s Knowledge ......... 25
`1.
`Zegerid (omeprazole) Powder for Oral Suspension
`Prescribing Information (2004) (Ex. 1010) ............................. 25
`Goldstein (Ex. 1011) ................................................................ 26
`2.
`Hochberg (Ex. 1012) ................................................................ 27
`3.
`VIII. UNPATENTABILITY OF THE ’698 PATENT ......................................... 28
`A.
`Claims 1-7 of the ’698 Patent Are Anticipated or Obvious over
`the ’285 Patent .................................................................................... 28
`1.
`The method of claim 1 is anticipated by or obvious over
`the ’285 patent .......................................................................... 28
`Claim 2 is anticipated by or obvious over the ’285 patent ...... 31
`Claims 3 and 4 are anticipated or obvious over the ’285
`patent ........................................................................................ 32
`
`2.
`3.
`
`2
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`TABLE OF CONTENTS
`(continued)
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`Page
`
`B.
`
`4.
`
`2.
`
`3.
`
`Claims 5 and 6 are anticipated or obvious over the ’285
`patent ........................................................................................ 32
`Claim 7 is anticipated or obvious over the ’285 patent ........... 33
`5.
`All Claims of the ’698 Patent Are Obvious Over the ’285 patent
`in View of Howden 2005 and EC-Naprosyn ..................................... 34
`1.
`The method of claim 1 is obvious over the ’285 patent in
`view of Howden 2005 and EC-Naprosyn ................................ 34
`Claim 2 is obvious over the ’285 patent in view of
`Howden 2005 and EC-Naprosyn ............................................. 35
`Claims 3 and 4 are obvious over the ’285 patent in view
`of Howden 2005 and EC-Naprosyn ......................................... 36
`Claims 5 and 6 are obvious over the ’285 patent in view
`of Howden 2005 and EC-Naprosyn ......................................... 36
`Claim 7 is obvious over the ’285 patent in view of
`Howden 2005 and EC-Naprosyn ............................................. 36
`IX. NO SUPPOSED SECONDARY CONSIDERATIONS OVERCOME
`THE OBVIOUSNESS ANALYSIS ............................................................. 37
`A.
`The ’698 Patent Does Not Demonstrate Any Unexpected Result ..... 37
`B.
`There Is No Evidence of Industry Skepticism of the ’698 Patent ...... 39
`C.
`The ’698 Patent Has Not Met Any Long-Felt, but Unmet Need ....... 39
`CONCLUSION ............................................................................................. 40
`
`4.
`
`5.
`
`X.
`
`3
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`

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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
`
`1.
`
`I, David C. Metz, M.D., have been retained by counsel for Petitioner
`
`Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan is petitioning for
`
`inter partes review (“IPR”) of U.S. Patent No. 9,220,698 to Ault et al. (“the ’698
`
`patent”) (Ex. 1001), which is assigned to Pozen Inc. and Horizon Pharma USA,
`
`Inc. (“Patent Owners”), to request that the United States Patent and Trademark
`
`Office cancel certain claims of the ’698 patent as unpatentable. I submit this
`
`expert declaration in support of Mylan’s IPR petition for the ’698 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`2.
`
`Education and Experience
`
`I am Professor of Medicine in the Department of Medicine at the
`
`University of Pennsylvania, Philadelphia, Pennsylvania. I am also Associate Chief
`
`for Clinical Affairs in the Division of Gastroenterology, Director of the Acid
`
`Peptic Disorders Program, Co-Director of the Gastrointestinal (GI) Physiology
`
`Lab, Co-Director of the Penn Program for Swallowing Disorders, and Co-Director
`
`of the Penn Neuroendocrine Tumor Program.
`
`3.
`
`I have been practicing medicine in the field of gastroenterology for
`
`over 30 years with a special emphasis on upper gastrointestinal (GI) tract disease
`
`states. I am board certified in gastroenterology and in internal medicine, and listed
`
`in Best Doctors in America (Northeast Region). The majority of my clinical
`
`activity revolves around the treatment of patients with acid-peptic conditions, and I
`
`4
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`have conducted many research protocols involving Proton Pump Inhibitors (PPIs).
`
`As part of my medical practice, I have thousands of patients under my care.
`
`4.
`
`I received a Bachelor of Medicine and Bachelor of Surgery from the
`
`University of the Witwatersrand Medical School, in Johannesburg, South Africa, in
`
`1982. A Bachelor of Medicine and Bachelor of Surgery is the South African
`
`equivalent of a doctor of medicine degree in the United States. In 1983, I interned
`
`at the Johannesburg General Hospital in General Medicine and General Surgery.
`
`From 1984 to 1985, I was in private practice, first in South Africa, and later in
`
`London, England.
`
`5.
`
`From 1986 to 1988, I did an internship and residency in internal
`
`medicine at the Albert Einstein Medical Center, Philadelphia, Pennsylvania. From
`
`1989 to 1991, I completed a fellowship in gastroenterology in a combined program
`
`with Georgetown University, the Washington Veteran’s Affairs Medical Center,
`
`and the National Institutes of Health. From 1991 to 1993, I was a senior staff
`
`fellow in the Digestive Diseases Branch of the National Institutes of Health,
`
`Bethesda, Maryland, where I studied Zollinger-Ellison Syndrome, the prototypical
`
`acid hypersecretory condition, the management of which requires, amongst other
`
`interventions, therapy with PPIs.
`
`6.
`
`In 1993, I became an Assistant Professor of Medicine in the
`
`Department of Medicine at the University of Pennsylvania, Philadelphia,
`
`5
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`Pennsylvania. In 1998, I was promoted to Associate Professor of Medicine. In
`
`2003, I became Professor of Medicine, a position I continue to hold today.
`
`7.
`
`In addition to the hospital and administrative appointments noted
`
`above, I am also currently Lead Physician for the GI division at the Hospital of the
`
`University of Pennsylvania, and have clinical privileges in the Division of
`
`Gastroenterology, at Penn Medicine at Radnor, Radnor, Pennsylvania, and
`
`Presbyterian Hospital, Philadelphia, Pennsylvania.
`
`8.
`
`From 2001 to 2005, I served on the FDA advisory board for
`
`gastroenterology, where my duties included participating in advisory meetings that
`
`are open to the public for matters pertaining to FDA approval of new drugs,
`
`including PPIs.
`
`9.
`
`I hold numerous professional society memberships. These include the
`
`American Gastroenterological Association (AGA), in which I have held many
`
`leadership positions; the American College of Gastroenterology; and the North
`
`American Neuroendocrine Tumor Society, in which I am a member of the Board
`
`of Directors. I previously represented the AGA on the American Board of Internal
`
`Medicine Liaison Committee on Recertification.
`
`10.
`
`I have held several editorial positions for peer-reviewed medical
`
`journals, including Gastroenterology and the American Journal of
`
`Gastroenterology. I also serve as a reviewer for several medical journals. I have
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`lectured by invitation over 400 times, and have published over 100 scientific
`
`articles in peer-reviewed journals, and over 100 abstracts. I lecture annually to the
`
`second year students at the Perelman School of Medicine at the University of
`
`Pennsylvania on the pathophysiology of the stomach. I also lecture annually on
`
`the physiology and pathophysiology of gastroduodenal diseases and upper GI
`
`bleeding at the premier board review course for Gastroenterology in Washington,
`
`D.C.
`
`11. A copy of my curriculum vitae, which lists my publications and
`
`describes my qualifications in detail is Exhibit A, attached hereto.
`
`B. Materials Considered
`
`12.
`
`In forming my opinions set forth in this declaration, I considered and
`
`relied upon my education, background, and years of experience in the practice of
`
`medicine in the field of gastroenterology, including treating many patients and
`
`conducting numerous clinical trials, as well as the materials listed on Exhibit B, or
`
`identified in this declaration, and cited herein.
`
`C.
`
`13.
`
`Scope of Work
`
`I have been retained by counsel for Mylan in connection with this
`
`matter. I am being compensated for my consulting work at the rate of $700 per
`
`hour. My compensation in this case is in no way dependent on the outcome of the
`
`case.
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`It is my opinion that the person of ordinary skill in the art would have
`
`been motivated to administer a combination dosage form containing the NSAID
`
`naproxen and the PPI esomeprazole, prior to the earliest patent application filing
`
`date to which the ’698 patent claims priority, September 9, 2008, that results in the
`
`pharmacokinetic and pharmacodynamic (or “PK / PD”) values recited in the
`
`claims. The person having ordinary skill in the art would have known that the
`
`combination of naproxen and esomeprazole at the claimed dosages had been
`
`patented in the same multilayer structure as the dosage form described and claimed
`
`in the ’698 patent.
`
`15.
`
`To the extent the Patent Owners argue that the precise PK / PD values
`
`in the claims were not known prior to the ’698 patent was filed, it is my
`
`understanding that Mylan’s expert on PK / PD, Dr. Michael Mayersohn, explains
`
`in his declaration supporting Mylan’s petition (Ex. 1003), that a person having
`
`ordinary skill in the art would have been motivated to target the claimed PK / PD
`
`values recited in the claims because these values were known to be in the effective
`
`range. Dr. Mayersohn also explains that the person having ordinary skill would
`
`have had a reasonable expectation of success because it would have been routine to
`
`make and test the prior art formulation at the claimed dosages of 500 mg naproxen
`
`and 20 mg esomeprazole because the prior art formulation is already claimed for
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`these dosages. See Ex. 1003. Therefore, the method of administration recited in
`
`the claims is anticipated or obvious over the prior art to the person having ordinary
`
`skill.
`
`16.
`
`It is also my opinion that there is no evidence of unexpected results or
`
`industry skepticism for the claimed method of administration because the
`
`formulation that results in the claimed pharmacokinetic and pharmacodynamic
`
`values, and a method for administering it were already patented. And even if the
`
`Patent Owners could establish that a long-felt, unmet need has been met, that need
`
`would have been met by the prior art patents on the same drug.
`
`III. LEGAL STANDARDS
`
`17. Counsel has informed me of certain legal principles to guide me in my
`
`analysis. Counsel has informed me that Mylan carries the burden of proving
`
`unpatentability by a preponderance of the evidence, and that this means Mylan
`
`must show that unpatentability is more probable than not.
`
`18. Counsel has informed me that the question of whether the claims of a
`
`patent are anticipated or obvious is to be considered from the perspective of the
`
`person of ordinary skill in the art. Whether an invention would have been
`
`anticipated or obvious is ascertained at the time the invention was made.
`
`19. Counsel has informed me that an obviousness analysis involves
`
`ascertaining the scope and content of the prior art, the level of the person of
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`ordinary skill in the pertinent art, the differences between the claimed invention
`
`and the prior art and whether there are additional factors present that may
`
`nevertheless weigh against obviousness such as unexpected results attributable to
`
`the invention or whether the invention has met a long-felt, but unmet need.
`
`20. Counsel has informed me that under the existing law 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 combination was
`obvious to try might show that it was obvious under § 103.
`
`21. Counsel has informed me that a prior art reference may anticipate a
`
`claimed invention if the prior art reference discloses each of the claim elements
`
`either expressly or inherently. A claim element is inherent in the anticipating
`
`reference if that element, or characteristic, is the natural result that flows from the
`
`reference’s explicit limitations.
`
`22. Counsel has also informed me that when a composition is claimed in
`
`terms of its function, property, or characteristics that it possesses, and that
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`composition is in the prior art, that the claimed invention may be anticipated or
`
`obvious in view of the prior art reference.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`
`23.
`
`The field of art here 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
`
`form performance, and a medical doctor having at least 2 years of practical
`
`experience treating patients in the gastroenterology field.
`
`24.
`
`For the purposes of this report, I will be offering my opinion from the
`
`perspective of the physician described above as of September 9, 2008, i.e., a
`
`medical doctor in the field of gastroenterology with at least 2 years of experience
`
`treating patients.
`
`V.
`
`BACKGROUND ON NSAID-RELATED GASTRIC INJURY
`
`25. Non-steroidal anti-inflammatory drugs, commonly referred to as
`
`“NSAIDs,” are a class of drugs used to treat pain and inflammation, including pain
`
`and inflammation associated with arthritis. The class includes aspirin, naproxen,
`
`ibuprofen, and diclofenac. NSAIDs are among the most commonly prescribed
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`medications in the world and have been in use for a long time. Naproxen was first
`
`approved by the FDA in 1976 under the trade name Naprosyn. Ex 1020, 1.
`
`26. NSAIDs can cause a variety of side effects that vary in severity.
`
`Chronic use of NSAIDs to treat chronic conditions such as arthritis can increase
`
`the risk of more serious gastric (stomach) injury, such as stomach erosions and
`
`ulcers, and more serious complications such as bleeding, perforation, or
`
`obstruction that can lead to hospitalization or death. These NSAID-induced side
`
`effects are commonly called NSAID-related injury or gastropathy.
`
`27.
`
`Long-term NSAID use may cause systemic injury by reducing the
`
`amount of prostaglandin in a patient’s body, which is a chemical required for
`
`proper maintenance of the stomach’s protective mucosal layer. This reduction
`
`decreases the stomach’s protective layer and increases the risk of gastric injury.
`
`This injury can be reduced by controlling acid in the stomach through concomitant
`
`administration of a prophylactic acid inhibitor with the NSAID.
`
`VI. U.S. PATENT NO. 9,220,698 (Ex. 1001)
`
`28.
`
`I have read U.S. Patent No. 9,220,698 (“the ’698 patent”), entitled
`
`“Method for Delivering a Pharmaceutical Composition to Patient in Need
`
`Thereof.” The ’698 patent was filed on September 3, 2009, and claims priority to
`
`provisional application no. 61/095,584, filed on September 9, 2008. The inventors
`
`are listed as: Brian Ault, Mark Sostek, Everardus Orlemans, and John Plachetka.
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`29.
`
`The ’698 patent “is directed to a method for delivering a
`
`pharmaceutical composition to a patient in need thereof, comprising:
`
`administering to said patient a pharmaceutical composition in unit dose form
`
`comprising naproxen . . . and esomeprazole.” Ex. 1001, 1:13-17.
`
`30.
`
`The ’698 patent explains that “[o]ver 15 million Americans take
`
`nonsteroidal anti-inflammatory drugs (NSAIDs) each day as a treatment for pain or
`
`inflammation,” and that “NSAIDs are associated with a high incidence of
`
`gastrointestinal complications, including gastritis, dyspepsia, gastroduodenal
`
`ulcers, perforations, and bleeding.” Id. at 1:19-24.
`
`31.
`
`The ’698 patent also explains that proton pump inhibitors (“PPI”),
`
`such as esomeprazole, are effective at improving NSAID tolerability, and work by
`
`inhibiting stomach acid secretion. Id. at 1:27-37. Cited as one example is the prior
`
`art U.S. Patent No. 6,926,907 (discussed in detail below), which “is directed to [a]
`
`dosage form comprising a [PPI and] . . . an NSAID,” and “can be effective in
`
`improving NSAID tolerability through dosages of esomeprazole and naproxen that
`
`produce the desired pharmacodynamic response and pharmacokinetic values.” Id.
`
`32. According to the ’698 patent, “[t]here is a need for a clinically
`
`effective therapy that delivers to a patient in need thereof . . . esomeprazole . . . for
`
`a duration sufficient to achieve an intragastric pH of about 4 or greater and a
`
`plasma level of naproxen that is efficacious.” Id. at 1:42-48.
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`33.
`
`The ’698 patent describes a series of embodiments in the form of
`
`pharmacokinetic and pharmacodynamic values that result from administering a
`
`unit dose form (i.e., a single tablet) containing naproxen and esomeprazole in the
`
`AM and PM. Id. at 6:46-24:20.
`
`34.
`
`The ’698 patent contains two examples. Example 1 describes a 9-day
`
`study of “twice daily oral administration of three PN400 formulations (enteric
`
`coated naproxen 500 mg combined with non-enteric coated esomeprazole 10, 20,
`
`or 30 mg) versus the effect of twice daily oral administration of a separate 500 mg
`
`non-enteric coated naproxen tablet and once daily oral administration of a separate
`
`EC[, i.e., enteric coated,] esomeprazole (20 mg) capsule (Nexium® 20 mg
`
`capsule).” Id. at 24:43-53. The study measured 24-hour intragastric pH and
`
`certain pharmacokinetic parameters.
`
`35.
`
`The ’698 patent states that “[t]he PN400 tablet is a multilayer tablet
`
`comprising an inner core of naproxen surrounded by a first layer comprising an
`
`enteric coating and a second layer comprising non-enteric coated esomeprazole.”
`
`Id. at 24:56-59.
`
`36.
`
`Example 2 describes a study that evaluated PN400 (delayed-release
`
`500 mg/immediate release esomeprazole 20 mg) tablet to administrations of EC
`
`naproxen (EC Naprosyn®) plus EC esomeprazole (Nexium®), or EC naproxen
`
`alone, or EC esomeprazole alone. Id. at 46:26-33.
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`37.
`
`The ’698 patent contains seven (7) claims. Claim 1 is representative
`
`and recites:1
`
`1. A method for treating osteoarthritis, rheumatoid
`arthritis, or ankylosing spondylitis comprising orally
`administering to a patient in need thereof an AM unit
`dose form and, 10 hours (±20%) later, a PM unit dose
`form, wherein:
`
`the AM and PM unit dose forms each comprises:
`naproxen, or a pharmaceutically acceptable salt thereof,
`in an amount to provide 500 mg of naproxen, and
`
`esomeprazole, or a pharmaceutically acceptable salt
`thereof, in an amount to provide 20 mg of esomeprazole;
`
`said esomeprazole, or pharmaceutically acceptable salt
`thereof, is released from said AM and PM unit dose
`forms at a pH of 0 or greater,
`
`the AM and PM unit dose forms target:
`
`i) a pharmacokinetic (pk) profile for naproxen where:
`
`1 The ’698 patent contains a certificate of correction. The claim recitation above
`
`contains the corrections that appear on the certificate.
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`a) for the AM dose of naproxen, the mean Cmax is 86.2
`μg/mL (±20%) and the median Tmax is 3.0 hours
`(±20%); and
`b) for the PM dose of naproxen, the mean Cmax is 76.8
`μg/mL (±20%) and the median Tmax is 10 hours
`(±20%); and
`
`ii) a pharmacokinetic (pk) profile for esomeprazole
`where:
`a) for the AM dose of esomeprazole, the mean area
`under the plasma concentration-time curve from
`when the AM dose is administered to 10 hours
`(±20%) after the AM dose is administered (AUC0-
`10,am) is 1216 hr*ng/mL (±20%),
`b) for the PM dose of esomeprazole, the mean area
`under the plasma concentration-time curve from
`when the PM dose is administered to 14 hours
`(±20%) after the PM dose is administered (AUC0-
`14,pm) is 919 hr*ng/mL (±20%), and
`c) the total mean area under the plasma concentration-
`time curve for esomeprazole from when the AM
`dose is administered to 24 hours (±20%) after the
`AM dose is administered (AUC0-24) is 2000 hr*ng/
`mL (±20%); and
`
`the AM and PM unit dose forms further target a mean %
`time at which intragastric pH remains at about 4.0 or
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`greater for about a 24 hour period after reaching steady
`state that is at least about 60%.
`
`38. Claims 2-7 recite additional elements that relate to the intragastric pH
`
`levels, the length of administration of the dosage forms, structural aspects of the
`
`dosage form, and chemical makeup of the tablet.
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES
`A. U.S. Patent No. 6,926,907 (Ex. 1004)
`39. U.S. Patent No. 6,926,907 (“the ’907 patent,” Ex. 1004) issued on
`
`August 9, 2005, from application no. 10/158,216, that was filed on May 31, 2002.
`
`The ’907 patent claims priority to a provisional application filed on June 1, 2001.
`
`Ex. 1004, cover page. John Plachetka is listed as the inventor.
`
`40.
`
`The ’907 patent concerns treatments for the risks of gastrointestinal
`
`ulcers and bleeding associated with long-term treatment with NSAIDs. Id. at 1:22-
`
`40. The ’907 patent specification also recognizes that the problem of NSAID-
`
`induced gastropathy (such as the development of gastroduodenal ulcers and other
`
`gastric injury) was well known in the art. Id. at 1:22-40.
`
`41.
`
`The ’907 patent notes that “more potent and longer lasting inhibitors,
`
`such as proton pump inhibitors, are thought to be more protective during chronic
`
`administration of NSAIDs than shorter acting agents” because gastric acidity was
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`known to play such a significant role in the development of gastroduodenal lesions.
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`Id. at 1:41-44, 1:26-34 (citing studies of effective treatment with acid inhibitors).
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`42.
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`The ’907 patent goes on to note that it would have been well known to
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`the person of ordinary skill in the art, prior to the claimed priority date of June 1,
`
`2001, that unit dosage forms combining NSAIDs and PPIs were present in the art
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`and were effective at reducing NSAID-induced gastropathy, even in the absence of
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`coordinated release:
`
`Recognizing the potential benefits of PPIs for the prevention of
`NSAID-induced gastroduodenal damage, others have disclosed
`strategies for combining the two active agents for therapeutic
`purposes.
`
`Id. at 2:21-24 (emphasis added).
`
`43. According to the ’907 patent applicant, however, the earlier-patented
`
`formulations had two drawbacks: (1) no coordinated release; and (2) no reduction
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`in gastric acid levels before release of the NSAID:
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`However, these suggestions do not provide for coordinated release or
`for reducing intragastric acid levels to a non-toxic level prior to the
`release of NSAID (U.S. Pat. Nos. 5,204,118; 5,417,980; 5,466,436;
`5,037,815).
`
`Id. at 2:24-28.
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`44. According to the Detailed Description of the Invention in the ’907
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`patent, the “present invention is based upon the discovery of improved
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`pharmaceutical compositions for administering NSAIDs to patients.” Id. at 5:12-
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`14. The “compositions include acid inhibitors that are capable of raising the pH of
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`the GI tract . . . and provide for the coordinated release of therapeutic agents, i.e.,
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`for the sequential release of acid inhibitor followed by [NSAID].” Id. at 5:15-19;
`
`see also, e.g., id. at Abstract, 1:11-18, 4:47-51.
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`45. Regarding the mechanism for formulating the claimed dosage forms,
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`the ’907 patent concedes that “[m]ethods for making appropriate formulations are
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`well known in the art.” Id. at 5:40-43 (citing a leading treatise, Remington’s
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`Pharmaceutical Sciences (16th ed. 1980)).
`
`46.
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`Figure 2 of the ’907 patent depicts a schematic example of the
`
`claimed composition:
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`47.
`
`“FIG. 2 illustrates a three layer dosage form. An acid inhibitor . . . is
`
`released immediately after ingestion by a patient in order to raise the pH of the
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`[GI] tract to above a specific pH, e.g., above 4. The innermost layer contains
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`naproxen. Thus, the dosage form has a naproxen core, an enteric film coat and an
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`acid inhibitor film coat.” Id. at 5:1-7.
`
`48.
`
`The ’907 patent also teaches the administration of the disclosed
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`formulation to patients. In particular, the specification describes “administering
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`[the] coordinated release . . . dosage form to achieve pain and symptom relief with
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`a reduced risk of developing gastrointestinal damage . . . .” Id. at Abstract; see
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`also, e.g., id. at 1:11-18, 3:5-7, 3:14-17, 4:18-20, 4:28-31, 4:53-60, claims 51 & 52.
`
`49. Claim 1 of the ’907 patent recites:
`
`1. A pharmaceutical composition in unit dosage form
`suitable for oral administration to a patient, comprising:
`
`(a) an acid inhibitor present in an amount effective to
`raise the gastric pH of said patient to at least 3.5 upon the
`administration of one or more of said unit dosage forms;
`
`(b) a nonsteroidal anti-inflammatory drug (NSAID) in an
`amount effective to reduce or eliminate pain or
`inflammation in said patient upon administration of one
`or more of said unit dosage forms; and
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`wherein said unit dosage form provides for coordinated
`release such that:
`
`i) said NSAID is surrounded by a coating that, upon
`ingestion of said unit dosage form by said patient,
`prevents the release of essentially any NSAID from said
`dosage form unless the pH of the surrounding medium is
`3.5 or higher;
`
`ii) at least a portion of said acid inhibitor is not
`surrounded by an enteric coating and, upon ingestion of
`said unit dosage form by said patient, is released
`regardless of whether the pH of the surrounding medium
`is below 3.5 or above 3.5.
`
`50. Claim 5 recites:
`
`5. The pharmaceutical composition of claim 1, wherein
`said acid inhibitor is a proton pump inhibitor selected
`from the group consisting of: omeprazole, esomeprazole,
`lansoprazole, pantoprazole and rabeprazole.
`
`B. U.S. Patent No. 8,557,285 (Ex. 1005)
`51. U.S. Patent No. 8,557,285 (“the ’285 patent,” Ex. 1005) issued on
`
`October 15, 2013, from application no. 13/215,855, filed on August 23, 2011. The
`
`’285 patent claims priority to the same provisional application as the ’907 patent.
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`Ex. 1005, cover page. Like the ’907 patent, John Plachetka is the only named
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`inventor.
`
`52. My review of the ’285 patent indicates that the specification of the
`
`’285 patent is nearly identical to the specification of the ’907 patent. Because the
`
`same language appears in the specification of the ’285 patent that is discussed
`
`above with respect to the ’907 patent (with some variation in the column and line
`
`numbers), that discussion will not be repeated here. Suffice it to say that the ’285
`
`patent discloses the same pharmaceutical composition and methods of treatment
`
`disclosed in the ’907 patent. See, e.g., Ex. 1005, 6:16-18 (“The present invention
`
`is based upon the discovery of improved pharmaceutical compositions for
`
`administering NSAIDs to patients.”); id. at 6:18-23 (“In addition to containing one
`
`or more NSAIDs, the compositions include acid inhibitors that are capable of
`
`raising the pH of the GI tract . . . and provide for the coordinated release of
`
`therapeutic agents, i.e., for the sequential release of acid inhibitor followed by
`
`[NSAID].”); id. at 6:44-45 (“Methods for making appropriate formulations are
`
`well known in the art.”); id. at Fig. 2; id. at 6:5-10 (“FIG. 2 illustrates a three layer
`
`dosage form. An acid inhibitor . . . is released immediately after ingestion by a
`
`patient in order to raise the pH of the [GI] tract to above a specific pH, e.g., above
`
`4. The innermost layer contains naproxen. Thus, the dosage form has a naproxen
`
`core, an enteric film coat and an acid inhibitor film coat.”); id. at Abstract
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`(describing “administering [the] coordinated release . . . dosage form to achieve
`
`pain and symptom relief with a reduced risk of developing gastrointestinal damage
`
`. . . .”); id.at 3:14-20.
`
`53.
`
`The ’285 patent contains four (4) claims.
`
`54. Claim 1 recites:
`
`1. A pharmaceutical composition in unit dosage form
`comprising therapeutically effective amounts of:
`(a) esomeprazole, wherein at least a portion of said
`esomeprazole is not surrounded by an enteric coating;
`and
`(b) naproxen surrounded by a coating that inhibits its
`release from said unit dosage form unless said dosage
`form is in a medium with a pH of 3.5 or higher;
`wherein said unit dosage form provides for release of
`said esomeprazole such that upon introduction of said
`unit dosage form into a medium, at least a portion of said
`esomeprazole is released regardless of the pH of the
`medium.
`
`55. Claim 4 recites:
`
`4. The pharmaceutical composition of claim 1, wherein
`naproxen is present in said unit dosage form in an
`amount of between 200-600 mg and esomeprazole in an
`amount of from 5 to 100 mg per unit dosage form.
`
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`EXHIBIT 1002 – DECLARATION OF DAVID C. METZ, M.D.
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`C.
`
`Howden 2005 (Ex. 1006)
`
`56. Howden, C.W., “Review article: immediate-release proton-pump
`
`inhibito