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`
`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 MICHAEL MAYERSOHN, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,393,208
`
`
`
`
`
`
`1 Petitioner Dr. Reddy’s Laboratories, Inc., from IPR2018-01341, has been joined
`as a Petitioner to this proceeding.
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 1
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`TABLE OF CONTENTS
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`Page
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`Introduction ..................................................................................................... 3
`I.
`Legal Standards .............................................................................................. 3
`II.
`III. Materials Reviewed ........................................................................................ 4
`IV. Definition of a Person of Ordinary Skill in the Art (POSA) .......................... 4
`V.
`The ’208 Patent Claims Were Anticipated By, or Would Have Been
`Obvious Over, the Prior Art to the ’208 patent .............................................. 6
`A.
`The ’285 Patent Anticipated the Claims of the ’208 Patent. ................ 6
`B.
`The Claims of the ’208 Patent Would Have Been Obvious to a
`Person of Ordinary Skill in the Art Over the ’285 Patent, Alone. ..... 14
`The Claims of the ’208 Patent Would Have Been Obvious to a
`Person of Ordinary Skill in the Art Over the ’285 Patent in
`View of the 2007 EC-Naprosyn Label and Howden 2005. ............... 17
`VI. Dr. Taft Failed to Establish Any Secondary Considerations of
`Nonobviousness ............................................................................................ 21
`VII. Conclusion .................................................................................................... 31
`
`C.
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 2
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`I.
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`Introduction
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`1.
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`I, Michael Mayersohn, Ph.D., have been retained by Mylan
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`Pharmaceuticals Inc. (“Mylan”) in the matter set forth in the caption above. I
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`submitted previously an expert declaration in this matter, dated November 30, 2017,
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`which was designated Exhibit 1003 (“Opening Declaration”). In that declaration, I
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`showed that claims 1-7 of U.S. Patent No. 9,393,208 to Ault et al. (“the ’208 patent”)
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`(Ex. 1001) were either anticipated by the prior art or would have been obvious to a
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`person of ordinary skill in the art, at their priority date. See generally Ex. 1003.
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`2. My qualifications, previous testimony, and compensation are provided
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`in my Opening Declaration.
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`3.
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`I submit this reply expert declaration in further support of my opinions
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`regarding the ’208 patent, and in reply to the opinions set forth in the February 27,
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`2019 Declaration of David R. Taft Ph.D. (“Taft Decl.”), filed on behalf of the Patent
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`Owners, which was designated Exhibit 2025.
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`II.
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`Legal Standards
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`4.
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`Counsel has confirmed for me that Mylan carries the burden of proving
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`unpatentability of the ’208 patent by a preponderance of the evidence, which means
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`that Mylan must show that unpatentability is more likely than not.
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 3
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`5.
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`Further, counsel has informed me that I should assume that the ’285
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`patent is prior art under 35 U.S.C. § 102(e), not subject to the provisions of 35 U.S.C.
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`§ 103(c).
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`III.
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`Materials Reviewed
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`6.
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`In forming my opinions set forth in this declaration, I considered the
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`materials listed on Attachment C or otherwise cited or identified in this report. I also
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`relied upon my many years of education, background, and experience in the field of
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`pharmaceutical sciences, as described in my Opening Declaration.
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`IV.
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`Definition of a Person of Ordinary Skill in the Art (POSA)
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`7.
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`It continues to be my opinion that the relevant field of art involves the
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`knowledge of a medical doctor and that of a pharmacologist or pharmacokineticist
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`with experience in dosage form design and evaluation. Thus, the hypothetical person
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`of ordinary skill in the art is a collaboration between a pharmacologist or
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`pharmacokineticist having a Ph.D. degree or equivalent training, or a M.S. degree
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`with at least two years of some experience in dosage form design and in in vitro and
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`in vivo evaluation of dosage form performance, and a medical doctor having at least
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`two years of practical experience treating patients in the gastroenterology field.
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`8.
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`I understand that the Board adopted this definition of a POSA in its
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`Institution Decision, and that Dr. Taft applied this definition when rendering his
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 4
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`opinions. See Paper 9 (Institution Decision) at 8 (citing Paper 2 (Petition) at 7-8);
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`Ex. 2025 (Taft Decl.) at ¶ 34.
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`9.
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`I am offering my analysis from the perspective of the pharmacologist
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`or pharmacokineticist, described above. I understand that Patent Owners criticize
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`my opinions on invalidity, despite my expertise in the claimed subject matter,
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`because I did not “consult[] with” Dr. Metz before rendering my opinions in this
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`case. To my mind, this is an overly formalistic reading of the POSA definition
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`adopted by the PTAB. In my view, that definition simply means that both a medical
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`doctor and a pharmacologist or pharmacokineticist have a contribution to make in
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`understanding the claimed subject matter. I do not read that definition as requiring
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`the experts to sit down and discuss the claims to reach an agreement on their
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`invalidity. Indeed, were that the case, then Patent Owners’ experts would likewise
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`fail the POSA definition, and have nothing to say on invalidity of the petitioned
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`claims, because they did not collaborate on their ultimate conclusions. See Taft
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`Decl. ¶ 12 (stating that Dr. Taft only reviewed Dr. Johnson’s declaration and agreed
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`with it, but never mentioning any discussions with Dr. Johnson); Johnson Decl. ¶ 56
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`(stating that Dr. Johnson only reviewed Dr. Taft’s declaration and agreed with it, but
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`never mentioning any discussions with Dr. Taft).
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`10.
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`I further understand that Patent Owners, Dr. Taft, and Dr. Johnson
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`assert that the ’208 patent is entitled to a priority date of June 25, 2007, rather than
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 5
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`September 9, 2008, and therefore apply the earlier date in their analyses. I continue
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`to apply a September 9, 2008 priority date in this reply declaration, but my ultimate
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`conclusions and opinions would be the same even if June 25, 2007, were chosen as
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`the priority date.
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`V.
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`The ’208 Patent Claims Were Anticipated By, or Would Have Been
`Obvious Over, the Prior Art to the ’208 patent
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`A. The ’285 Patent Anticipated the Claims of the ’208 Patent.
`11. As stated in my original declaration, it remains my opinion that the
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`claims of the ’208 patent were anticipated by the ’285 patent, notwithstanding Dr.
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`Taft’s assertions to the contrary.
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`12. Dr. Taft asserts that “[t]he ’285 patent discloses a genus of
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`compositions comprising an acid inhibitor and an NSAID,” with the ’285 patent
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`therefore “disclos[ing] 1,000 possible combinations of a composition consisting of
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`an acid inhibitor and an NSAID.” Ex. 2025 ¶¶ 51-53.
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`13. Dr. Taft’s argument is not well taken because it remains the case that
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`the ’285 patent disclosed (and claimed) the particular combined dosage form having
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`NSAID (naproxen) and PPI (esomeprazole) that is recited in the claims of the ’208
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`patent. See Ex. 1005 at 22:8-28. This, on top of the fact that the ’285 patent
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`identified naproxen as “[t]he most preferred NSAID,” and esomeprazole as a
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`“preferred” proton pump inhibitor. Id. at 3:44-46, 4:11-12. The ’285 patent
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`therefore expressly disclosed the naproxen-and-esomeprazole combination recited
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`in the claims of the ’208 patent. Moreover, the disclosure of potentially “1,000
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`possible combinations of a composition consisting of an acid inhibitor and an
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`NSAID” is inflated. There are a limited number of NSAIDs and PPIs that could be
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`combined and a limit on the possible doses of each that can be incorporated into a
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`viable, therapeutically effective form. The latter being governed by the clinically
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`effective dose of each, which was well known in the prior art. There is nothing
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`arbitrary about combining doses.
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`14. As further evidence that the ’285 patent expressly disclosed a naproxen-
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`and-esomeprazole combination, Figure 2 of the ’285 shows a “naproxen core tablet,”
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`surrounded by an “enteric film coat,” further surrounded by an “acid inhibitor coat.”
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`The ’285 specification described the acid inhibitor coat as being “released . . .
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`immediately” and as a PPI, such as esomeprazole. Id. at Fig. 2, 3:44-46, 10:49-11:4.
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`15. Near-identical subject matter is disclosed in the ’907 patent, which is
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`the parent of the ’285 patent and issued more than three years before the priority date
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`of the ’208 patent. See Ex. 1004 at 3:48 (naproxen is the “most preferred NSAID”),
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`3:36-38 (esomeprazole is one of five identified proton pump inhibitors “that may be
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`effectively used”), 22:62-63 (claim 47, which, through its dependency from claim
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`42, claims treating a patient with naproxen and esomeprazole, as one of a handful of
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`disclosed proton pump inhibitors); 22:64-67 (claim 48, reciting “a single dosage
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`form providing for the coordinate release” of naproxen and esomeprazole).
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`16. Dr. Taft argues that the ’285 patent does not disclose the claimed
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`pharmacokinetic and pharmacodynamic parameters recited in the claims of the ’208
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`patent, suggesting that the ’285 patent does not meet the standard for anticipation set
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`forth in my declaration. Ex. 2025 ¶ 54 (“[A] prior art reference anticipates a claimed
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`invention if the prior art reference disclosed each of the claimed elements of the
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`invention.” (quoting Ex. 1003 ¶ 17)). Dr. Taft did not, however, recite the material
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`part of the test for anticipation, recited by me, which the ’285 patent meets: “A prior
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`art reference not expressly disclosing a claim element may still anticipate the
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`claimed invention if the missing element is necessarily present, or inherent, in the
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`single anticipating reference. The missing element, or characteristic, is inherent in
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`the anticipating reference if the characteristic is a natural result flowing from the
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`reference’s explicit disclosure.” Ex. 1003 ¶ 17.
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`17. As I made clear in my Original Declaration, the ’285 patent anticipated
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`the claims of the ’208 patent because the PK/PD values recited in the ’208 patent’s
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`claims are “necessarily present, or inherent,” in the formulation claimed in the ’285
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`patent; i.e., the PK/PD parameters are a “natural result flowing from the [’285
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`patent’s] explicit disclosure.” Ex. 1003 ¶ 17; see also ¶¶ 21, 131-141.
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`18. The claims of the ’285 patent (and its parent ’907 patent) recited
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`combined dosage forms having the same physical structure and pH-related release
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`properties as the formulations claimed in the ’208 patent (see, e.g., claim 1 of the
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`’285 patent, and claims 1, 24, and 37 of the ’907 patent). The pharmacokinetic and
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`pharmacodynamic parameters claimed in the ’208 patent are naturally present, or
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`inherent, properties of the naproxen/esomeprazole combination formulations
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`disclosed and claimed in the ’285 patent (and its parent ’907 patent). This is
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`necessarily true whether the claimed form was already tested in human subjects in
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`the prior art period or only tested after that time.
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`19.
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`In his deposition in related district court litigation, Dr. Plachetka agreed
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`that the pharmacokinetic parameters recited in the claims of the ’208 patent are the
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`result of administering the claimed formulation with 500 mg enteric-coated
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`naproxen and 20 mg immediate-release esomeprazole (designated “PN400/E20” in
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`the specification of the ’208 patent):
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`Q: Right. So the pharmacokinetic parameters are the natural result of
`administering of the PN-400 E20 formulation, right?
`A: They are the result. I don't know what you mean by natural result.
`But the -- if you -- there is no question if you take the drug, you are
`going to get blood levels of both Naproxen and Esomeprazole
`provided you absorb them.
`Q: Right. So -- because Naproxen gets absorbed from the PN-400 E20
`formulation that you give, right?
`A: Yes.
`Q: And Esomeprazole, likewise, gets absorbed from the same PN-400
`E20 formulation that you give?
`A: Yes.
`Q: So it is 500 mg in the Naproxen in the PN-400 E20 formulation
`which is responsible for the observed pharmacokinetic parameters
`for Naproxen, right?
`A: Provided no other Naproxen was taken, yes.
`the
`taken,
`Q: So
`likewise,
`if no other Esomeprazole was
`pharmacokinetic parameters that you observe for Esomeprazole,
`they come from the 20 milligrams of Esomeprazole, located in the
`PN-400 E20 formulation that you give, right?
`A: In a single dose experiment with no administration of a drug, that is
`correct.
`Ex. 2016 (Plachetka Dep.) at 195:21-197:3 (objections removed).
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`20.
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`In short, the ’208 patent simply claims inherent properties of the
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`naproxen/esomeprazole formulations that had already been disclosed and patented
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`in the ’285 patent (and the ’907 patent before it). Even if not expressly stated, an
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`identical prior art formulation—such as that claimed in the ’285 patent—would not
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`simply target (i.e., set the goal of obtaining) the relevant PK/PD values; it would
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`actually achieve those values.
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`21. Dr. Taft does not expressly attack my opinion that the ’285 patent
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`disclosed a combined dosage form with 500 mg enteric-coated naproxen and 20 mg
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`immediate-release esomeprazole, instead citing to Dr. Johnson for the details. Ex.
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`2025 ¶ 55 (“I understand that Dr. Johnson also distinguishes the ’285 patent on the
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`ground that those [sic] patents do not disclose the claimed dosage amount of 500 mg
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`of naproxen and 20 mg of esomeprazole.”). Dr. Taft does not cite to a specific
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`passage in Dr. Johnson’s declaration for support.
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`22.
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`If Dr. Taft intended to identify Dr. Johnson’s paragraph 70, Dr. Taft’s
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`argument is not persuasive. Dr. Johnson’s paragraph 70 states, “[w]hile the claims
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`of the ’285 patent disclose a composition of esomeprazole and naproxen, the ’285
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`patent does not disclose the specific claimed dosage as required by the ’208 patent.
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`The ’285 patent discloses a range of naproxen from 200 to 600 mg, and a range of
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`esomeprazole from 5 to 100 mg.” Ex. 2026 ¶ 70.
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`23. Dr. Johnson correctly notes that the ’285 patent disclosed ranges of
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`dosages for the enteric-coated naproxen and the immediate-release esomeprazole in
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`the tablet described and claimed in the ’285 patent, with each range encompassing
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`the doses recited in the ’208 patent’s claims. But Dr. Johnson ignores that a POSA
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`is not an automaton.
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`24.
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`In my opinion, a POSA would have understood the ’285 patent’s
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`disclosure of a naproxen/esomeprazole combination dosage form, including 5 to 100
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`mg of esomeprazole, to teach the same combination dosage form with 20 mg of
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`esomeprazole. Similarly, a POSA would have understood the ’285 patent’s
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`disclosure of a naproxen/esomeprazole combination dosage form, including 250 to
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`500 mg of naproxen, to teach the same combination dosage form with 500 mg of
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`naproxen. See, e.g., Ex. 1005 at 7:9-14 (repeatedly describing 550 of naproxen
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`sodium as a typical or “preferred” amount; 550 mg naproxen sodium is equivalent
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`to 500 mg of naproxen).
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`25. Focusing on Examples 9-10 of the ’285 patent, Dr. Taft argues that the
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`’285 patent does not disclose twice daily administration. Ex. 2025 ¶¶ 56-61. But
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`Dr. Taft ignores that naproxen was well known in the art before the priority date of
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`the ’208 patent, was known to have a half-life of 12 to 15 hours and was known to
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`be administered twice daily. See, e.g., Ex. 1005 at 6:29-32 (“[e]xamples of long-
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`acting NSAIDS are…naproxen or naproxen sodium with half-lives of about 12 to
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`15 hours”); Ex. 1064 (2000 EC-Naprosyn PDR) at 5 (“plasma half-life of the
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`naproxen anion…ranges from 12 to 17 hours”), 7 (twice daily dosing); Ex. 1076
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`(2002 EC-Naprosyn PDR) at 5, 7 (same). From this information, present in
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`Examples 9 and 10 of the ’285 patent and the general background knowledge of the
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`art, a POSA would have known that a combined dosage form including naproxen
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`and esomeprazole would be administered twice a day.
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`26. Dr. Taft also takes issue with my citing Examples 9 and 10 of the ’285
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`patent because those examples: do not specify whether the omeprazole is enteric
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`coated, identify an acid inhibitor as famotidine, do not describe a coordinated-release
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`solid oral dosage form, and do not state how much time elapsed between dosages.
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`Ex. 2025 ¶¶ 57-60. But my citation to Examples 9 and 10 of the ’285 patent plainly
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`reflect a POSA’s knowledge
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`that naproxen-containing dosage forms are
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`administered twice daily. See, e.g., Ex. 1003 ¶¶ 123-30. A POSA reviewing the
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`’285 patent would have understood from Examples 9 and 10 that a combined dosage
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`form containing naproxen and uncoated esomeprazole should be administered twice
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`daily. Id.
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`27.
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`In their response, Patent Owners assert that the ’285 patent teaches “two
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`broad classes” of enteric coatings, one class that releases based on pH and the other
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`that releases over time. Paper 32 at 33. Patent Owners do not appear to rely on any
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`expert opinion for this assertion. Further, Patent Owners’ assertion ignores that the
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`’285 patent disclosed that even the enteric coating released over time has a “rate
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`adjusted” to release based on a particular pH. As such the two “broad classes” of
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`enteric coatings are actually equivalent. Related, Patent Owners assert that
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`esomeprazole’s AUC may be impacted by an enteric coating. Patent Owners offer
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`no evidence supporting their theory that esomeprazole’s AUC will vary significantly
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`based on the enteric coating, citing information related only to “omeprazole
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`administered with buffer.” Resp. at 33 (citing Ex. 2029 at 90:22-91:11). I note that
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`Figure 2 of the ’907 and ’285 patents disclosed an “immediate release” (i.e.,
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`uncoated) acid inhibitor (a proton pump inhibitor like esomeprazole, in the case of
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`the ’285 patent (see ’285 patent at 3:44-46, 10:66-11:2)), which is encompassed by
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`the ’285 patent’s claims. Regardless, contrary to Patent Owners’ assertion, whether
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`esomeprazole is only partially uncoated rather than completely uncoated would not
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`be expected to impact AUC because a dosage form in which “at least a portion of
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`[the] esomeprazole is not surrounded by an enteric coating” will allow the coating
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`to lose its structural integrity, while the bulk of the esomeprazole disintegrates
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`rapidly and is released, as if there were no coating present, in contrast to a buffering
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`agent.
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`B. The Claims of the ’208 Patent Would Have Been Obvious to a
`Person of Ordinary Skill in the Art Over the ’285 Patent, Alone.
`In my opinion, claims 1-7 of the ’208 patent would have been obvious
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`28.
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`to a person of ordinary skill in the art over the ’285 patent, alone, notwithstanding
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`Dr. Taft’s assertions to the contrary.
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`29. Dr. Taft asserts that the ’285 patent did not disclose 20 mg immediate-
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`release esomeprazole because the ’285 patent “taught away from [the 20 mg] dosage
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`strength by disclosing that a 40 mg dose was preferred.” Ex. 2025 ¶ 63. I have been
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`informed by counsel that a teaching away from an invention requires more than
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`simply saying something else was preferred; a teaching away requires that the
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`reference criticize, discredit, or otherwise discourage investigation into the invention
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`claimed. In other words, simply teaching that one composition may be preferred
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`does not criticize, discredit, or otherwise discourage investigation into other similar
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`compositions. On that understanding, I conclude that Dr. Taft is incorrect because
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`there is no hint in the ’285 patent that the use of 20 mg immediate-release
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`esomeprazole is criticized, discredited, or otherwise discouraged.
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`30. Dr. Taft also argues that the claims of the ’285 patent would not have
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`rendered obvious the claims of the ’208 patent because the ’285 patent is not prior
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`art to the ’208 patent. Ex. 2025 ¶¶ 64-65. This argument is not based on any facts
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`recited in Dr. Taft’s declaration. Dr. Taft cites to paragraphs 45-50 as support for
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`his understanding that the ’285 patent is not prior art, but the cited paragraphs have
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`nothing to do with the ’285 patent, reflecting, instead, Dr. Taft’s “understand[ings]
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`from counsel” and conclusory legal arguments. Ex. 2025 ¶¶ 45-50.
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`31. Further, as I have noted repeatedly, the ’285 patent (and its parent, the
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`’907 patent) disclosed the use of 500 mg of naproxen and that a typical dose of
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`omeprazole is from 5 mg to 50 mg. Ex. 1005 at 16:38-40, 53. The ’285 patent also
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`claimed a combined dosage form of immediate-release esomeprazole and enteric-
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`coated naproxen, and recited dosage amounts for each that disclosed the use of 500
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`mg naproxen and 20 mg esomeprazole. Id. at 22:8-28. Especially given the many
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`analyses in the prior art of 20-mg and 40-mg doses of omeprazole and esomeprazole,
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`a POSA would have known that there was a limited number of doses for these active
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`ingredients that would have been used in a combined dosage form. See, e.g., Ex.
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`1007 (U.S. Patent No. 5,877,192) at Tables 1-2; Ex. 2033 (Andersson 2001) at Fig.
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`7, Table V; Ex. 1028 (Lind 2000) at Table 2.
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`32. Further, I note that esomeprazole was approved as Nexium® nearly ten
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`years before the earliest possible priority date of the ’208 patent. See generally Ex.
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`1043. Nexium® was, and is, approved for use in 20 mg and 40 mg dosage forms
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`taken once a day. Id. at 21. At the earliest possible priority date of the ’208 patent,
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`I was aware of esomeprazole, as well as the claimed 20 mg dose, because Nexium®
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`was a well-known drug with significant sales, at least $5 billion in 2007. Nexium’s
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`approved 20 mg and 40 mg doses reflected the same doses claimed in the ’208
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`patent, which are 20 mg per combined dosage form, and 40 mg total dosed per day
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`(because the method calls for administering the dosage form twice per day). Ex.
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`1001 at 46:35-38. Thus, both the 20 mg (individual dosage form) and 40 mg (total
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`dose per day) esomeprazole doses were well known to a POSA as of the ’208
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`patent’s priority date.
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`33. The ’285 patent disclosed that “a skilled pharmacologist may adjust the
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`amount of drug in a pharmaceutical composition or administered to a patient based
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`upon standard techniques well known in the art.” Ex. 1005 at 6:47-50. In my
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`opinion and experience, the PK/PD elements claimed in the ’208 patent are the
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`products of routine testing of the claimed formulation, once constructed, and would
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`have been easily accessible to a POSA. There is nothing inventive about such
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 16
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`testing. The assertion that the inventors “discovered” the PK/PD properties that
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`naturally flow from the use of a formulation containing an unprotected esomeprazole
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`component, and an enteric-coated naproxen component, already disclosed and
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`described in the ’907 and ’285 patents, does not make those properties nonobvious.
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`C. The Claims of the ’208 Patent Would Have Been Obvious to a
`Person of Ordinary Skill in the Art Over the ’285 Patent in View
`of the 2007 EC-Naprosyn Label and Howden 2005.
`In my opinion, claims 1-7 of the ’208 patent would have been obvious
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`34.
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`to a person of ordinary skill in the art over the ’285 patent in view of the 2007 EC-
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`Naprosyn Label and Howden 2005, notwithstanding Dr. Taft’s assertions to the
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`contrary.
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`35.
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`Initially, I note that in his declaration, Dr. Taft criticizes the 2007 EC-
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`Naprosyn Label and Howden 2005 exhibits, but he neither addresses nor rebuts my
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`opinions that the 2007 EC-Naprosyn Label and Howden 2005 (and the Zegerid label)
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`disclosed AUC ranges for naproxen and esomeprazole that overlap with the
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`parameters claimed in the ’208 patent. Compare, e.g., Ex. 1003 ¶¶ 183-93, 199-202,
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`with Ex. 2025 ¶¶ 66-72. The 2007 EC-Naprosyn Label, for example, disclosed
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`pharmacokinetic data that a POSA would have known for nearly a decade before the
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`priority date of the ’208 patent. See, e.g., Ex. 1064 (2000 EC-Naprosyn PDR) at 5-
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`7 (disclosing values for EC-Naprosyn’s Cmax, Tmax, AUC0-12, half-life, and dosing
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`frequency); Ex. 1076 (2002 EC-Naprosyn PDR) at 5-6 (same).
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 17
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`36. Dr. Taft further does not address or dispute that a POSA would have
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`been motivated to target the PK/PD values claimed in the ’208 patent for naproxen,
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`esomeprazole, and gastric pH. Compare, e.g., Ex. 1003 ¶¶ 182, 183, 186, 187, 190,
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`192, 194-96, 201, with Ex. 2025 ¶¶ 66-72.
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`37. Dr. Taft first asserts that he understands that the 2007 EC-Naprosyn
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`label is not prior art to the ’208 patent. Ex. 2025 ¶ 66. Dr. Taft provides no facts or
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`analysis on this point.
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`38. Dr. Taft next asserts that the EC-Naprosyn label does not teach various
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`aspects of the claimed subject matter of the ’208 patent, such as a combination of
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`enteric-coated naproxen and immediate-release esomeprazole in a single dosage
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`form providing for coordinated release of the esomeprazole and naproxen. Ex. 2025
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`¶ 67. These points are unpersuasive because each of these elements was disclosed
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`(and claimed) in the prior art ’285 patent and disclosed and described in the earlier
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`’907 patent. See, e.g., Ex. 1005 at 22:8-18 (claim 1); Ex. 1004 at 22:25-33, 41-46,
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`54-61. As noted earlier, Dr. Taft does not dispute the points for which the EC-
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`Naprosyn label was actually cited, including “the PK parameters resulting from
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`administering enteric-coated naproxen to a patient,” among others. Ex. 1003 ¶ 180.
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`39. Dr. Taft concedes that “Howden 2005 describe[d] the pharmacokinetic
`
`behavior of Zegerid, an immediate-release but protected omeprazole,” and then
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`recites the unremarkable fact that PPIs are known to be acid labile (i.e., that they
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 18
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`degrade in an acidic environment). Ex. 2025 ¶ 68. But Dr. Taft goes further, and
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`states that the prior art taught away from the administration of unprotected PPIs. Id.
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`Dr. Taft’s assertions are unpersuasive because they are directly contradicted by the
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`teachings of the ’907 and ’285 patents, which disclosed and described the
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`administration of unprotected PPIs in combination dosage forms well before the
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`priority date of the ’208 patent; in the case of the ’907 patent, several years before
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`the priority date. See, e.g., Ex. 1005 at 16:1-17:47 (combined dosage form including
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`unprotected omeprazole); Ex. 1004 at 14:38-16:17 (same). The prior art could not
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`have “taught away from the administration of unprotected PPIs” when it disclosed
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`and described exactly that.
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`40.
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`In paragraphs 69 and 70, Dr. Taft opines that a POSA would have
`
`known that omeprazole and esomeprazole have different PK/PD properties and
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`understands from Dr. Johnson that a POSA would not have simply swapped out one
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`PPI for another. However, a POSA would have known from the prior art that certain
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`PK/PD parameters were associated with effective therapies, including from the use
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`of omeprazole, Ex. 1003 ¶¶ 111-118, 178, 186-90, and would have known to target
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`those PK/PD parameters with esomeprazole, a conclusion that Dr. Taft does not
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`dispute. A POSA certainly would have known, as described above, that the same
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`dose of esomeprazole and omeprazole can yield different values for AUC and
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`percentage time that gastric pH was greater than 4. But a POSA also would have
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 19
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`expected an effective AUC for omeprazole to also be effective for esomeprazole
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`because esomeprazole is a component of the omeprazole racemate. Ex. 1003 ¶¶ 119-
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`20, 190. For at least the same reason, a POSA would have had a reasonable
`
`expectation of success in setting the PK/PD values of omeprazole as a target for
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`esomeprazole and would have known that esomeprazole could reasonably be used
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`in place of omeprazole.
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`41. Dr. Taft goes on to assert that the Zegerid label does not provide a
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`reasonable expectation of success in making the claimed invention because it
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`described the use of sodium bicarbonate buffer to reduce degradation, and Dr.
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`Williams opined in an earlier case that such a buffer could not feasibly be added to
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`a solid oral dosage form. Ex. 2025 ¶ 71. This argument is unpersuasive and does
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`not defeat the obviousness of the claims.
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`42. As I explained in my Opening Declaration, and Dr. Taft does not
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`dispute, Zegerid disclosed that immediate-release omeprazole produced PK and PD
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`values within the ranges claimed by the ’208 patent, which a POSA would have
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`known would also apply to esomeprazole. See, e.g., Ex. 1003 ¶¶ 115-120, 178, 186.
`
`Dr. Taft also does not appear to dispute that knowledge of these effective PK/PD
`
`values would have motivated a POSA to target them. As further noted in my
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`Opening Declaration, the additional presence of sodium bicarbonate in Zegerid
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`would not have dissuaded a POSA from targeting its disclosed PK/PD values
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`MYLAN PHARMS. INC. EXHIBIT 1074 PAGE 20
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`EXHIBIT 1074 – REPLY DECLARATION OF MICHAEL MAYERSOHN, PH.D.
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`because it was the existence of Zegerid’s AUC values as a target that was the
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`important disclosure, not how those AUC values were obtained. Ex. 1003 ¶ 191.
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`VI.
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`Dr. Taft Failed to Establish Any Secondary Considerations of
`Nonobviousness
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`43. Dr. Taft asserts that he “understand[s] that objective evidence of
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`nonobviousness may include a long felt but unsolved need, skepticism, unexpected
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`results, copying, and licensing.” Ex. 2025 ¶ 73. But none of the paragraphs
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`following Dr. Taft’s understanding presents evidence of long felt but unsolved need,
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`skepticism, unexpected results, copying, or licensing.
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`44. Dr. Taft first argues a point that I understand is not a secondary
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`consideration of nonobviousness, but a part of the obviousness inquiry: reasonable
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`expectation of success. Ex. 2025 ¶ 74. But even setting aside that issue, Dr. Taft’s
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`argument flies in the face of the state of the art at the ’208 patent’s priority date. Dr.
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`Taft asserts that “a person of skill in the art would have understood that PPIs are
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`acid-labile, degrading rapidly in stomach acid. As a result, the art mostly taught tha
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