`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`MYLAN PHARMACEUTICALS INC. and
`DR. REDDY’S LABORATORIES, INC.,
`
`Petitioners
`
`v.
`
`HORIZON PHARMA USA, INC. and NUVO PHARMACEUTICALS
`(IRELAND) DESIGNATED ACTIVITY COMPANY,
`Patent Owners
`
`
`
`Case IPR2018-002721
`U.S. Patent No. 9,393,208 B2
`
`
`
`REPLY DECLARATION OF DAVID C. METZ, M.D.
`
`
`1 Petitioner Dr. Reddy’s Laboratories, Inc., from IPR2018-01341, has been joined
`as a Petitioner to this proceeding.
`
`MYLAN PHARMS. INC. EXHIBIT 1059 PAGE 1
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`TABLE OF CONTENTS
`
`B.
`
`II.
`
`B.
`
`C.
`
`
`INTRODUCTION .................................................................................................... 3
`MATERIALS REVIEWED ...................................................................................... 3
`LEGAL STANDARDS ............................................................................................ 4
`PERSON OF ORDINARY SKILL IN THE ART ................................................... 4
`I.
`NSAID-INDUCED GASTROINTESTINAL INJURY IS
`PRIMARILY THE RESULT OF SYSTEMIC EFFECTS. ................. 5
`A.
`The Risk of Injury Associated with NSAIDs Is
`Principally Due to Chronic Use. ................................................ 5
`Local, Acute Effects of NSAIDs are Minor and Far Less
`Clinically Relevant than Systemic, Chronic Effects
`Associated with Long Term Use of NSAIDs. ........................... 7
`STATE OF THE ART TREATMENT FOR REDUCING THE
`RISK OF GI INJURY ASSOCIATED WITH LONG-TERM
`ADMINISTRATION OF NSAIDS WAS THE CO-
`PRESCRIPTION OF A PPI. ................................................................ 7
`III. THE ’285 PATENT ANTICIPATES ALL CLAIMS OF THE
`’208 PATENT .................................................................................... 13
`IV. ALL CLAIMS OF THE ’208 PATENT WERE OBVIOUS. ............ 19
`A. All Claims of the ’208 Patent Were Obvious Over the
`’285 Patent. .............................................................................. 19
`All Claims of the ’208 Patent Were Obvious Over the
`’285 Patent in View of the 2007 EC-Naprosyn Label and
`Howden 2005 ........................................................................... 23
`SECONDARY CONSIDERATIONS DO NOT OVERCOME
`THE OBVIOUSNESS OF THE CLAIMS. ....................................... 27
`A. Vimovo Has Not Met a Long-Felt But Unmet Need. .............. 27
`B.
`There Is No Evidence that the ’208 Patent Exhibits Any
`Surprising or Unexpected Results. ........................................... 29
`AstraZeneca’s Internal Discussions on Whether to Co-
`Develop A PPI/NSAID Combination Formulation with
`Pozen Is Not Evidence of Industry Skepticism. ...................... 31
`
`
`V.
`
`
`
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
`
`
`INTRODUCTION
`
`1.
`
`I, David C. Metz, M.D., have been retained by counsel for Petitioner
`
`Mylan Pharmaceuticals Inc. (“Mylan”). I submit this reply expert declaration in
`
`support of Mylan’s reply materials in the inter partes review (“IPR”) proceedings
`
`regarding U.S. Patent No. 9,393,208 (“the ’208 patent”).
`
`2.
`
`I previously submitted the Declaration of David C. Metz, M.D. (“First
`
`Declaration”), dated December 3, 2017, concerning certain invalidity issues
`
`pertaining to the ’208 patent.
`
`3. My qualifications, previous testimony, and compensation are provided
`
`in my First Declaration.
`
`4.
`
`I have been asked to analyze, review, and respond to certain opinions
`
`expressed in the expert declarations of David A. Johnson and David R. Taft, dated
`
`March 1, 2019 and February 27, 2019, respectively. To the extent I do not
`
`expressly address a point made by Dr. Taft or Dr. Johnson, it does not mean that I
`
`agree with it.
`
`MATERIALS REVIEWED
`
`5.
`
`In forming my opinions contained in this report, 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
`
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`conducting numerous clinical trials, as well as the materials listed on Attachment A
`
`or identified in this report.
`
`LEGAL STANDARDS
`
`6.
`
`Counsel has informed me that, for the purposes of my analysis, I
`
`should assume that the ’285 patent is prior art under 35 U.S.C. § 102(e) and is not
`
`subject to 35 U.S.C. § 103(c).
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`7.
`
`I continue to apply the definition of the person of ordinary skill in the
`
`art (“POSA”) described in my First Declaration: 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.
`
`8.
`
`Counsel has informed me that Patent Owner has asserted that I do not
`
`meet my own definition of the POSA because I have not reviewed Dr.
`
`Mayersohn’s opening declaration or otherwise conferred with Dr. Mayersohn.
`
`Patent Owner’s assertions are incorrect. In providing my invalidity opinions, I
`
`have relied on some of Dr. Mayersohn’s opinions. Moreover, certain aspects of
`
`the claims relate to a medical doctor’s expertise, and other aspects of the claims
`
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`relate to a pharmacologist or pharmacokineticist’s expertise. Here, I have
`
`collaborated with the pharmacologist or pharmacokineticist by providing my
`
`opinions which, when combined with Dr. Mayersohn’s opinions, render the claims
`
`unpatentable. My opinions thus fall within the meaning of “collaboration” in the
`
`POSA definition.
`
`9.
`
`I understand that Patent Owners, as well as Dr. Johnson and Dr. Taft,
`
`apply a priority date of June 25, 2007, rather than September 9, 2008. While I
`
`apply a September 9, 2008 priority date, my opinions would be the same even if
`
`the priority date were June 25, 2007, or any date between June 25, 2007, and
`
`September 9, 2008.
`
`I.
`
`NSAID-INDUCED GASTROINTESTINAL INJURY IS PRIMARILY
`THE RESULT OF SYSTEMIC EFFECTS.
`A. The Risk of Injury Associated with NSAIDs Is Principally Due to
`Chronic Use.
`10. By focusing on the short-term, acute, local injury from the use of
`
`NSAIDs, Dr. Johnson ignores the clinically relevant goal of PPI treatment in
`
`patients receiving long-term, chronic NSAID therapy for arthritic conditions.
`
`Rather, the overarching goal of co-administration of a PPI with an NSAID is to
`
`reduce the long-term morbidity that results from an NSAID’s negative systemic
`
`effects on prostaglandin levels, which otherwise have a protective effect on the
`
`gastric mucosa. Ex. 1063 (Brown) at 3-4.
`
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`11. Dr. Johnson opines at paragraphs 28-30 of his declaration on the
`
`epidemiology of NSAID use and gastrointestinal injury. Importantly, the adverse
`
`outcome data that Dr. Johnson cites is the result of chronic, or long-term, and not
`
`short-term or sporadic administration of NSAIDs. For example, at paragraph 29,
`
`Dr. Johnson states that “as many as 25% of chronic NSAID users will develop
`
`ulcer disease.” See Ex. 1063 (Brown) at 2 (15 to 25% of patients “taking NSAIDs
`
`regularly”). And at paragraph 30, Dr. Johnson reports that “13 of every 1000
`
`patients with rheumatoid arthritis who take NSAIDs for one year have a serious
`
`gastrointestinal complication.” While NSAID-associated injury can develop
`
`within the first month of exposure, this too is likely from systemic inhibition of
`
`prostaglandin production since cytoadaption (a process of recovery to restore
`
`balance between cellular loss and restitution by the body) begins to counteract the
`
`acute local effects of NSAID exposure within a week or so. Ex. 1073 (Ekström) at
`
`5.
`
`12. The articles that Dr. Johnson relies on for his epidemiological review
`
`are concerned primarily with long-term, or chronic use of NSAIDs, and not short-
`
`term or sporadic administration of NSAIDs. The references cited by both Dr.
`
`Johnson and I show that a POSA would have been well aware of the effects from
`
`the chronic use of NSAIDs.
`
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`
`B.
`
`Local, Acute Effects of NSAIDs are Minor and Far Less Clinically
`Relevant than Systemic, Chronic Effects Associated with Long
`Term Use of NSAIDs.
`13. Dr. Johnson opines at paragraphs 31-36 of his declaration on the
`
`causes (i.e. etiology) of NSAID-induced gastrointestinal injury.
`
`14.
`
`In paragraph 34 of his declaration, Dr. Johnson admits that “minor
`
`mucosal injury occurs regularly” and that “the majority of mucosal injury does not
`
`lead to clinically significant disruption of the function of the upper GI tract.” But
`
`he does not specify that the increased susceptibility to mucosal injury associated
`
`with the administration of NSAIDs is over the long-term administration of
`
`NSAIDs, not the short-term.
`
`15.
`
`In paragraphs 35-36 of his declaration, Dr. Johnson again does not
`
`specify that the increased risk for clinically significant events, including ulceration,
`
`is predominantly a consequence of long-term continuous administration of
`
`NSAIDs and not their short-term periodic use.
`
`II.
`
`STATE OF THE ART TREATMENT FOR REDUCING THE RISK
`OF GI INJURY ASSOCIATED WITH LONG-TERM
`ADMINISTRATION OF NSAIDS WAS THE CO-PRESCRIPTION OF
`A PPI.
`In paragraphs 37-52 of his declaration, Dr. Johnson describes what he
`16.
`
`considers to be the “state of the art” (preventative) treatment options as of 2007 for
`
`gastrointestinal injury available to a POSA for patients on long-term NSAID
`
`therapy. Notably, Dr. Johnson does not include in this discussion United States
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`Patent Nos. 8,557,285 and 6,926,907, both of which were directed to a
`
`combination dosage form of an uncoated PPI with an NSAID, as described in my
`
`First Declaration. Ex. 1002 (Metz Decl.) ¶¶ 38-55, 66-69. It is my understanding
`
`that these patents are prior art to the ’208 patent, despite Dr. Johnson’s statements
`
`to the contrary as to the ’285 patent. This major oversight thus skews Dr. Johnson
`
`entire analysis of the state of the art.
`
`17. Regardless, setting aside this error and that a combination dosage
`
`form of an uncoated PPI and coated NSAID was already disclosed in the ’907 and
`
`’285 patents, Dr. Johnson relies on a 1999 review article by Dr. Michael Wolfe and
`
`notes that Dr. Wolfe does not “suggest or describe the creation of a single
`
`formulation combining an NSAID and a gastric injury-prevention component.”
`
`Ex. 2026 (Johnson Decl.) ¶ 37. The fact that a single review article does not raise
`
`this issue does not in any way diminish the prior art that clearly disclosed the use
`
`of a combination formulation of NSAIDs and PPIs to reduce the risk of gastric
`
`injury. For example, and setting aside the invention claimed in both the ’907 and
`
`’285 patents, the ’907 patent specification discloses that “[r]ecognizing 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.” Ex. 1004 (’907 patent) at 2:20-29 (citing U.S. Pat. Nos.
`
`5,204,118 (“the ’118 patent”); 5,417,980; 5,466,436; 5,037,815; and 6,365,184).
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`18. Although Dr. Johnson recites several treatment options as discussed
`
`by Dr. Wolfe in his review article, which he claims were “still standard in the art as
`
`of 2007” (Ex. 2026 (Johnson Decl.) ¶¶ 37-40), not all of these treatments would
`
`have been considered equally effective or attractive to a POSA as of 2007 (Dr.
`
`Johnson’s priority date), let alone by September 9, 2008 (which is my
`
`understanding of the priority date). These options included: sucralfate, histamine
`
`H2-receptor antagonists, and prostaglandins.
`
`19. Dr. Johnson simply ignores statements by Dr. Wolfe concerning each
`
`of these treatments. Specifically: (1) sucralfate showed “no significant benefit;”
`
`(2) “the use of [histamine] H2-receptor antagonists for the prevention of NSAID-
`
`associated ulcers cannot be recommended”; and (3) “[a]lthough misoprostol is
`
`highly effective for preventing NSAID-induced ulcers . . . it has a number of
`
`adverse effects. . . . includ[ing] diarrhea . . . abdominal pain . . . and . . .
`
`spontaneous abortion.” Ex. 2042 (Wolfe 1999) at 7-8. With respect to PPIs,
`
`however, Dr. Wolfe states that “these agents appear to be effective in preventing
`
`the recurrence of ulcers during continued use of NSAIDs.” Id. at 7; see also Ex.
`
`1060 (Hawkey) at 1 (maintenance therapy with omeprazole more effective than
`
`misoprostol, and better tolerated); Ex. 1061 (Yeomans) at 4-5 (maintenance
`
`therapy with omeprazole more effective than ranitidine).
`
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`20. As Dr. Johnson admitted, concomitant therapy with sucralfate is
`
`clearly suboptimal for gastric ulcer prophylaxis in patients receiving NSAIDs. Ex.
`
`1075 (Johnson Trial Testimony) at 1177:10-20, 1138:10-14; Ex. 2026 (Johnson
`
`Decl.) ¶ 38; see also Ex. 2042 (Wolfe 1999) at 7. The study by Agrawal et al. (see
`
`Ex. 2042 (Wolfe 1999) at 7, citing Agrawal (Ex. 1062)) showed this agent to be
`
`inferior to misoprostol at 200 µg 4 times daily.
`
`21. While concomitant therapy with histamine H2-receptor antagonists
`
`was shown to be effective at preventing NSAID-associated duodenal ulcers (see
`
`Ex. 2042 (Wolfe 1999) at 7), studies showed suboptimal effects with respect to
`
`NSAID-associated gastric ulcers. Ex. 1061 (Yeomans) at 1, 6; Ex. 1063 (Brown)
`
`at 6-7. There clearly is no way to know whether an individual patient will develop
`
`an NSAID-associated gastric or duodenal ulcer a priori such that the prescribing
`
`physician needs to be sure to protect against both when prescribing NSAID
`
`prophylaxis therapy. Wolfe reports that only high dose famotidine was felt to be
`
`effective for GU prophylaxis (see Ex. 2042 (Wolfe 1999) at 7). It was also well-
`
`established by 2007 that PPIs were more potent than histamine H2-receptor
`
`antagonists. Thus, this class of therapy cannot be considered as effective as PPIs
`
`or misoprostol for preventing GI injury.
`
`22. Dr. Wolfe specifically discloses that omeprazole was better than
`
`misoprostol and that “sucralfate has no proven benefit in the treatment or
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`prevention of NSAID-related gastric ulcers,” Ex. 2042 (Wolfe 1999) at 6, and
`
`states after review of the treatment options that: “These observations suggest that
`
`proton-pump inhibitors can heal gastroduodenal ulcers more effectively than H2-
`
`receptor antagonists, whether or not NSAIDs are continued.” Id.
`
`23. Concomitant therapy with PPIs was known to be effective at
`
`preventing NSAID gastropathy, as Wolfe describes. Id. at 7. In fact, the New
`
`England Journal of Medicine studies by Yeomans and Hawkey, both published in
`
`1998, showed a clear benefit for PPIs over histamine H2-receptor antagonists and
`
`misoprostol (twice daily), indicating the PPIs were known to be superior to both of
`
`these classes of therapies at preventing NSAID gastropathy by 2007. Ex. 1061
`
`(Yeomans) at, e.g., 1 (omeprazole superior to ranitidine); Ex. 1060 (Hawkey) at,
`
`e.g., 1 (omeprazole superior to misoprostol).
`
`24. The ’907 patent specification reinforces this point. “In general, more
`
`potent and longer lasting acid inhibitors, such as proton pump inhibitors, are
`
`thought to be more protective during chronic administration of NSAIDs than
`
`shorter acting agents, e.g., histamine H2 receptor antagonists. (H-2 blockers) (N.
`
`Eng. J. Med. 338:719-726 (1998); Am. J. Med. 104(3A):56S-61S (1998)).” Ex.
`
`1004 (’907 patent) at 1:41-46.
`
`25. Dr. Wolfe’s article, as summarized by Dr. Johnson, mentions that
`
`scientists were also trying to develop “safer” NSAIDS, which included COX-2
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`inhibitors and nitric oxide-containing NSAIDs. Ex. 2026 (Johnson Decl.) ¶¶ 50-
`
`52; Ex. 2042 (Wolfe 1999) at 8. The ’907 and ’285 patents disclose that the so-
`
`called “safer” COX-2 inhibitors were both ineffective at relieving some types of
`
`pain and were associated with significant cardiovascular risks, citing multiple
`
`publications. Ex. 1004 (’907 patent) at 2:40-45; Ex. 1005 (’285 patent) at 2:47-52.
`
`As Dr. Johnson acknowledges, while the COX-2 inhibitors did make it to market,
`
`their efficacy was limited by side effects and all except celecoxib have been
`
`discontinued. Ex. 2026 (Johnson Decl.) ¶ 51. All but one COX-2 inhibitor are
`
`now off the market due to cardiovascular dangers. Id. Similarly, NO-containing
`
`NSAIDs were only in their infancy with early studies evaluating short-term
`
`prophylaxis only. Furthermore, this class of drugs still has not made it to market,
`
`indicating a lack of a benefit over existing NSAIDs.
`
`26.
`
`I disagree with Dr. Johnson’s contention in Paragraph 46 that PPIs
`
`have a higher incidence of side-effects than histamine H2-receptor antagonists.
`
`Since their introduction, PPIs have been known for their safety, efficacy, and
`
`tolerability and they have become one of the most prescribed medications,
`
`generally displacing histamine H2-receptor antagonists. Ex. 1063 (Brown) at 2
`
`(omeprazole better tolerated than misoprostol); Ex. 1060 (Hawkey) at 1 (same);
`
`Ex. 1061 (Yeomans) at Abstract (“[O]meprazole healed and prevented ulcers more
`
`effectively than did ranitidine.”). In fact, PPIs are the second-leading, most
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`commonly prescribed class of agents for long-term therapy. Histamine H2-receptor
`
`antagonists have their own set of side effects, including bradycardia (slow heart
`
`rate), renal or hepatic dysfunction, cytopenias (low blood counts), gynecomastia,
`
`and impotence (amongst others). PPIs are more potent at inhibiting acid and
`
`therefore are better at controlling acid production over the long term. This makes
`
`PPIs a much more attractive combination therapy than histamine H2-receptor
`
`antagonists for reducing the risk of GI injury during the treatment of arthritis using
`
`NSAIDs.
`
`27.
`
`I disagree with Dr. Johnson’s opinion that a person of skill in the art
`
`would not have known to use uncoated PPI by the priority date, as described in
`
`more detail below. In fact, use of uncoated PPIs alongside an NSAID in a single
`
`dosage form was disclosed in, inter alia, the ’907 and ’285 patents, as described in
`
`my First Declaration. Ex. 1002 (Metz Decl.) ¶¶ 38-55, 69.
`
`III. THE ’285 PATENT ANTICIPATES ALL CLAIMS OF THE ’208
`PATENT
`In my opinion, the claims of the ’208 patent are anticipated by the
`28.
`
`’285 patent, notwithstanding Dr. Johnson’s and Dr. Taft’s opinions.
`
`29. Dr. Johnson and Dr. Taft assert that “[t]he ’285 patent discloses a
`
`genus of compositions comprising an acid inhibitor and an NSAID,” and suggest
`
`that the number of possible combinations of acid inhibitors and NSAIDs disclosed
`
`in the ’285 patent means that the ’208 patent claims are not anticipated. Ex. 2026
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`(Johnson Decl.) ¶¶ 63-65; Ex. 2025 (Taft Decl.) ¶¶ 51-53. Dr. Johnson overlooks
`
`that the ’285 patent also discloses particular species of PPI-NSAID combination
`
`tablets. For example, the ’285 patent claims only the naproxen-esomeprazole
`
`species claimed by the ’208 patent. Ex. 1005 (’285 patent) at 22:8-29. The ’285
`
`patent therefore expressly disclosed the naproxen-esomeprazole combination, and
`
`that should end the inquiry.
`
`30. Dr. Johnson also asserts, without explanation, that a POSA would not
`
`have had any motivation to administer esomeprazole and naproxen in combination.
`
`Ex. 2026 (Johnson Decl.) ¶ 68. As an initial matter, it is my opinion that the ’285
`
`patent anticipates the method claimed in the ’208 patent, and counsel have
`
`informed me that no motivation is necessary to prove anticipation. The ’285 patent
`
`disclosed the combination of a PPI and an NSAID, and the combination of
`
`esomeprazole and naproxen in particular, along with methods of administering
`
`such combinations. Moreover, the ’285 patent itself described why a POSA would
`
`have been motivated to administer esomeprazole and naproxen in combination.
`
`For example,2 the ’285 patent explained that the combination tablet provided “a
`
`new method for reducing the risk of gastrointestinal side effects in people taking
`
`NSAIDs for pain relief and for other conditions, particularly during chronic
`
`2 I reserve the right to rely on other statements in the’285 patent that describe the
`
`benefits provided by the disclosed combination tablet.
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`treatment.” Ex. 1005 (’285 patent) at 3:11-14. The ’285 patent also notes that
`
`“[t]he invention also provides a method for increasing compliance in a patient
`
`requiring frequent daily dosing of NSAIDs by providing both an acid inhibitor and
`
`NSAID in a single convenient, preferably coordinated, unit dosage form, thereby
`
`reducing the number of individual doses to be administered during any given
`
`period.” Id. at 5:57-62. A POSA would have also been motivated to use naproxen
`
`and esomeprazole, in particular, because that combination species is explicitly
`
`called out in the ’285 patent’s claims, and naproxen and esomeprazole were among
`
`the most well-known and widely-used NSAIDs and PPIs, respectively, as of the
`
`priority date. Id. at 22:8-29.
`
`31. Dr. Johnson further opines that “[w]hile the claims of the ’285 patent
`
`disclose a composition of esomeprazole and naproxen, the ’285 patent does not
`
`disclose the specific claimed dosage as required by the ’208 patent. The ’285
`
`patent discloses a range of naproxen from 200 to 600 mg, and a range of
`
`esomeprazole from 5 to 100 mg.” Ex. 2026 (Johnson Decl.) ¶ 70. As Dr. Johnson
`
`notes, the ’285 patent disclosed limited dosage ranges for the naproxen and
`
`esomeprazole in the combined tablet, each of which taught the specific doses
`
`recited in the ’208 patent’s claims. Ex. 1005 (’285 patent) at 22:8-29. A POSA
`
`would have understood that disclosure of a combined esomeprazole-naproxen
`
`tablet, with 5 to 100 mg of esomeprazole, taught a combined esomeprazole-
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`naproxen tablet with 20 mg of esomeprazole. Id. Similarly, a POSA would have
`
`understood that disclosure of a combined esomeprazole-naproxen tablet, with a
`
`“particularly useful” dose range of 250 to 500 mg naproxen, teaches a combined
`
`esomeprazole-naproxen tablet with 500 mg naproxen. Id.; see also id. at 7:9-10.
`
`And, as discussed in my First Declaration and herein, a POSA reading the ’285
`
`patent would have immediately envisioned a combined esomeprazole-naproxen
`
`tablet with 20 mg esomeprazole and 500 mg naproxen. Ex. 1002 (Metz Decl.)
`
`¶ 68. Specifically, naproxen was available in the 500 mg dose, dosed twice daily,
`
`and esomeprazole was available in doses of 20 mg and 40 mg, dosed once a day.
`
`Ex. 1043 (Nexium 2001 label) at 1, 21; Ex. 1009 (EC-Naprosyn 2007 label) at 2,
`
`24. The ’285 patent also noted that “about 40 mg” of esomeprazole is preferred,
`
`Ex. 1005 (’285 patent) at 8:10, which is similar to 20 mg dosed twice daily.
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`Moreover, the ’285 patent explained that “[i]t is expected that a skilled
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`pharmacologist may adjust the amount of drug in a pharmaceutical composition or
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`administered to a patient based upon standard techniques well known in the art.”
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`Ex. 1005 (’285 patent) at 6:47-50. This disclosure further confirms that the
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`specific doses of esomeprazole and naproxen recited in the ’208 patent claims were
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`known, disclosed by the ’285 patent, and routine to determine.
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`32. Dr. Johnson also criticizes my reference to Nexium on the basis that
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`the esomeprazole in Nexium is enteric-coated. Ex. 2026 (Johnson Decl.) ¶¶ 66-67.
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`MYLAN PHARMS. INC. EXHIBIT 1059 PAGE 16
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`That is irrelevant—the ’285 patent disclosed a combined PPI-NSAID tablet with
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`uncoated esomeprazole. Esomeprazole, as well as the claimed 20 mg dose, was
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`further well-known to a POSA because Nexium was a well-known drug. Nexium
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`was available in 20 mg and 40 mg doses, the same doses claimed in the ’208 patent
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`(20 mg per tablet, and 40 mg per day). While it is my opinion that every
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`reasonable esomeprazole dose in the 5 to 100 mg range disclosed in the ’285 patent
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`would have been immediately envisioned by a POSA, 20 mg and 40 mg doses
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`would have been especially immediately envisioned by a POSA, due in part to
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`background knowledge of Nexium and the ’285 patent’s listings of a 40-mg dose
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`as preferred.
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`33. Finally, Dr. Johnson states that “the ’285 patent does not disclose the
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`desirability
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`of
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`targeting
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`the
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`specific
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`claimed
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`pharmacokinetic
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`and
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`pharmacodynamics profiles as required by the claims of the ’208 patent.” Ex.
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`2026 (Johnson Decl.) ¶ 69. This point is also irrelevant. Drs. Johnson and Taft do
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`not dispute that the claimed PK/PD profiles are inherent in the claimed dosage
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`form—they only dispute that the claimed dosage form was anticipated by the ’285
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`patent. I understand from counsel that when a claim element is inherent in the
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`prior art, the prior art need not expressly teach it for the prior art to anticipate.
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`Because it is my opinion that the claimed dosage form was anticipated by the ’285
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`patent, and I understand that Dr. Mayersohn opines that the claimed PK/PD values
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`MYLAN PHARMS. INC. EXHIBIT 1059 PAGE 17
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`are inherent in the claimed dosage form, it is therefore also my opinion that all
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`claims of the ’208 patent are anticipated even though the ’285 patent did not
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`expressly disclose the specific PK/PD values claimed.
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`34. Dr. Taft asserts that the ’285 patent does not disclose twice daily
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`administration. But the ’285 patent explained that “[i]t is expected that a skilled
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`pharmacologist may adjust the amount of drug … administered to a patient based
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`upon standard techniques well known in the art.” Ex. 1005 (’285 patent) at 6:47-
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`50. Naproxen was well-known in the art for many years before the priority date,
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`and it was understood that naproxen is administered twice daily. See, e.g., Ex.
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`1064 (EC-Naprosyn 2000 PDR) at 7. Moreover, while Dr. Taft criticizes reliance
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`on Example 9 of the ’285 patent because it does not specify whether the
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`omeprazole is enteric coated, and Example 10 because the acid inhibitor is
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`famotidine, Ex. 2025 (Taft Decl.) ¶¶ 56-61, Examples 9 and 10 of the ’285 patent
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`reflect the prior art knowledge that naproxen must be administered twice daily. A
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`POSA reading Examples 9 and 10 of the ’285 patent therefore would have
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`understood that a combination dosage form with naproxen, including the claimed
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`enteric-coated naproxen-uncoated esomeprazole dosage form, should also be
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`administered twice daily.
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`MYLAN PHARMS. INC. EXHIBIT 1059 PAGE 18
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`IV. ALL CLAIMS OF THE ’208 PATENT WERE OBVIOUS.
`A. All Claims of the ’208 Patent Were Obvious Over the ’285 Patent.
`In my opinion, all claims of the ’208 patent were obvious over the
`35.
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`’285 patent, notwithstanding Dr. Johnson’s and Dr. Taft’s opinions.
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`36. Dr. Johnson asserts that a POSA would not have been motivated to
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`use the specific claimed doses of esomeprazole and naproxen. Ex. 2026 (Johnson
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`Decl.) ¶¶ 71-74. Dr. Taft similarly opines, without explanation, that the ’285
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`patent taught away from the 20 mg esomeprazole dose. Ex. 2025 (Taft Decl.) ¶ 63.
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`As discussed above, a POSA would have immediately envisioned the claimed 20
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`mg esomeprazole and 500 mg naproxen doses from the ranges taught by the ’285
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`patent. A POSA would have also been motivated to use the claimed esomeprazole
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`and naproxen doses because they were the doses used by esomeprazole and
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`naproxen products already on the market. See Ex. 1065 (Nexium 2007 label); Ex.
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`1009 (EC-Naprosyn 2007 label); Ex. 1066 (EC-Naprosyn 2004 label); Ex. 1064
`
`(EC-Naprosyn 2000 PDR). To the extent a POSA would have had any doubt, a
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`POSA would have been motivated to perform a small dose-finding study to
`
`identify the optimal dose—a study that the ’285 patent explained is routine and
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`within the POSA’s skill. Ex. 1005 (’285 patent) at 6:47-50 (“It is expected that a
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`skilled pharmacologist may adjust the amount of drug in a pharmaceutical
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`MYLAN PHARMS. INC. EXHIBIT 1059 PAGE 19
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`composition or administered to a patient based upon standard techniques well
`
`known in the art.”).
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`37. Dr. Johnson further opines that “clinicians rarely—if ever—prescribed
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`the 20 mg dose of esomeprazole.” Ex. 2026 (Johnson Decl.) ¶¶ 49, 74. I disagree.
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`In my clinical experience, the 20 mg dose was prescribed prior to the alleged
`
`invention date3 and is still prescribed. Dr. Johnson omits that the 40 mg dose was
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`usually prescribed for more severe conditions, such as GERD.4 But that does not
`
`mean that the 20 mg dose was not prescribed. Moreover, there is a plethora of
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`research from AstraZeneca and others that support clinical use of both doses. See,
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`3 Either September 9, 2008 – the filing date of the provisional patent application,
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`leading to the issuance of the’208 patent, or as Patent Owner now alleges: June 25,
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`2007 – the completion date of the clinical study allegedly disclosing the claimed
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`invention. See, e.g., Ex. 2026 (Johnson Decl.) ¶ 21.
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`4 See, e.g., Ex. 1067 (Katz 2004) at Abstract (“Patients with refractory gastro-
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`oesophageal reflux disease, extra-oesophageal reflux symptoms, Barretts’s
`
`oesophagus, or Zollinger-Ellison syndrome may require greater acid suppression
`
`than that obtained with once-daily esomeprazole” further suggesting that 40 mg
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`twice daily provides greater acid suppression than once daily and may be
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`reasonable consideration for patients requiring greater acid suppression for acid-
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`related diseases).
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`MYLAN PHARMS. INC. EXHIBIT 1059 PAGE 20
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`REPLY DECLARATION OF DAVID C. METZ, M.D.
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`e.g., Ex. 1067 (Katz 2004) at 4, Fig. 1 (comparing 20 mg and 40 mg doses); Ex.
`
`1068 (Junghard 2002); Ex. 1069 (Hammer 2004). If the 20 mg dose would not
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`have been used then—and now—AstraZeneca would not have marketed Nexium®
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`20 mg to begin with and would not continue to market it today. Moreover,
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`Prilosec’s launch preceded the Nexium launch, and the 20 mg dose of Prilosec was
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`commonly prescribed. AstraZeneca would not have bothered to develop and
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`market a 20 mg dose for its next-generation Nexium product if clinicians found it
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`ineffective.
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`38. Ultimately, I do not believe that obviousness turns on the frequency
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`with which the 20 mg and 40 mg esomeprazole doses were prescribed. Both doses
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`were well-known in the prior art, and a POSA would have found either of them
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`obvious. While the ’285 patent was informative because it disclosed doses for the
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`unprotected esomeprazole/naproxen combination formulation, in my opinion a
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`POSA would have also found the claimed esomeprazole and naproxen doses
`
`obvious based on common knowledge among practitioners of the Prilosec,
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`Nexium, and EC-Naprosyn doses.
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`39. Dr. Johnson also contends that a POSA would have had no motivation
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`to substitute esomeprazole for omeprazole. Ex. 2026 (Johnson Decl.) ¶ 75. As an
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`initial matter, this point is irrelevant to whether the ’208 patent’s claims were
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`obvious over t