throbber
Paper No. ____
`Filed November 23, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_________________________
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`BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
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`v.
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`MONOSOL RX, LLC
`Patent Owner
`_________________________
`
`Case IPR2015-00165 / Case IPR2015-00168 / Case IPR2015-00169
`US Patent No. 8,765,1671
`_________________________
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`
`
`REPLY
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`1 Per Scheduling Order, Paper 7, fn. 1, Petitioner hereby attests that “the word-for-
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`word identical paper is filed in each proceeding identified in the heading.” Where
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`there is a difference between documents filed in the three ‘167 IPRs, Petitioner
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`uses this format to identify pages or paragraphs in IPR2015-00165 / IPR2015-
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`00168 / IPR2015-00169, respectively.
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`Table of Contents
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`Page No.
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`I.
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`Introduction ...................................................................................................... 1
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`II.
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`PO Does Not Dispute the Preliminary Claim Construction—
`Which Does Not Distinguish Over the Cited Art ............................................ 1
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`III. PO Instead Requests “Further Construction” to Distinguish
`Over the Art ..................................................................................................... 4
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`IV. But PO’s Proposed Further Construction Does Not Avoid the
`Art .................................................................................................................... 6
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`V.
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`PO’s Evidence Supports the Petition or Lacks Relevance .............................. 9
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`1. Mr. Myers distracts from the relevant disclosure. ..................................... 9
`2. Dr. Goldberg miscalculates and applies the wrong standard. ................ 10
`3. Dr. Lin’s evidence is almost 10 years too late. ........................................ 13
`4. Dr. Peppas is misinformed and applies a double-standard. .................... 13
`5. Dr. Wyse lacks ordinary skill and withholds information. ....................... 16
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`VI. PO Invented a Problem that Had Already Been Solved ................................ 21
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`VII. Conclusion ..................................................................................................... 25
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`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
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`I.
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`Introduction
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`Patent Owner (PO) wants the Board to assume that there was an unmet need
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`for uniform pharmaceutical films. But PO offers no evidence that its films were
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`the first to meet an alleged regulatory standard of drug uniformity. The cited
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`references, and every reference in the background of the ‘167 patent, disclose
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`uniform pharmaceutical film.
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`II.
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`PO Does Not Dispute the Preliminary Claim Construction—Which Does
`Not Distinguish Over the Cited Art.
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`With the exception of an alleged typographical error, PO does not dispute
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`the claim construction in the institution decisions. Resp. 2-6. And under this
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`construction, the claims are not distinguished over the cited art.
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`Ingredients. There is no dispute that all the ingredients of the claims at
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`issue are disclosed in the cited art. And PO does not argue that either a particular
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`ingredient or combination of ingredients is necessary to achieve the claimed
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`uniformity. The 300 examples of the ‘167 patent evidence that the polymers,
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`actives, and anti-tacking agents were used interchangeably with no reported effect
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`on uniformity. Ex. 1001, US 8765167 (“167 patent”), Examples 1-300. And the
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`‘167 patent background acknowledges at least one reference that discloses uniform
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`films made with a variety of polymers, anti-tacking agents, and actives. Id. 1:48-
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`54 referencing Ex. 1052, US 4136145 (“Fuchs”), Examples 1-20.
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`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
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`Controlled Drying. The inventor, Mr. Myers, admits that it is possible that
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`controlled drying encompasses conventional drying. Ex. 1053, Myers Tr., 128:8-
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`12. It is not only possible, but reality: the ‘167 patent states that controlled drying
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`includes conventional drying. ‘167 patent 6:22-25 (“[C]ontrolled drying processes
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`include, but are not limited to, the use of the apparatus disclosed in U.S. Pat. No.
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`4,631,837 to Magoon”); 25:20-21 (“A specific example of an appropriate
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`[controlled] drying method is that disclosed by Magoon.”). The ‘167 patent
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`explains “the present inventors have adapted [Magoon’s film drying] process
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`toward the preparation of thin films.” Id. 25:22-23. In other words, the inventors
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`claim to have adapted old film drying technology for drying films.
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`To the extent that any drying parameters are read into the claims from the
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`specification—there is nothing new to read in. The Board has already found
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`“Chen teaches controlled drying…. The drying process of Chen is not sufficiently
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`distinguished from the general method of the ‘588 patent.” Ex. 1027, ‘588
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`Decision, 17. The section entitled “Drying the Film” in the ‘588 and ‘167 patents
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`are identical. Ex. 1041, 30-32.
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`Rapidly. With respect to the claim recitation of a controlled drying process
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`which “rapidly forms a viscoelastic matrix to lock-in said active in place within
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`said matrix and maintain said substantially uniform distribution,” the ‘167 patent
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`discloses this is also not new. For example, the ‘167 patent admits: “[t]he
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`Patent No. 8,765,167
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`apparatus of Magoon provides the films of the present invention with an efficient
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`drying time reducing the instance of aggregation of the components of the film.”
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`’167 patent 25:38-40. And the inventor acknowledged that it was known—well
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`prior to the invention—that “if drying is rapid enough, the time may be too short to
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`permit agglomeration.” Myers Tr. 139:10-141:5 (agreeing with the teaching in Ex.
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`1009, MODERN COATING AND DRYING, prior art cited in the ‘167 patent, 7).
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`Coating/Second Layer. MonoSol does not dispute the teachings of
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`Tapolsky as they were applied in the institution decision.
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`Claimed Uniformity. The Board found in its ‘588 patent reexamination
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`decision that Chen’s films met the requirement of no more than 10% variation of
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`active content per film unit dosage. ‘588 Decision 20. The Board has recently
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`issued two additional decisions finding claims reciting “active varies by no more
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`than 10%” were unpatentable over Chen. See Ex. 1056, ‘080 Decision, 33-41; Ex.
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`1057, ‘337 Decision, 28-39.
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`Chen itself contains evidence of uniformity using the same criteria as
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`specifically set forth in the ‘167 patent for determining uniformity. Petitions at
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`33-37 / 54-56 / 56-57. Dr. Reitman also confirmed uniformity of Chen Example 7
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`by visual inspection, by consistent unit dosage weights, and further by HPLC
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`testing. Ex. 1047, Reitman Dec., ¶¶ 26-27.
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`Patent No. 8,765,167
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`III. PO Instead Requests “Further Construction” to Distinguish Over the Art
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`PO proposes to further construe (but in reality, effectively amend) the term
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`“do not vary by more than 10% of the desired amount of the active component.”
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`Resp. 6-7.
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`First, the PO contends: “the ‘10%’ value is +/-10%.” Resp. 6. But its only
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`evidence is almost 10 years past the relevant time frame. PO identifies the time of
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`the ‘167 Patent as 2001. Resp. 19. But PO relies on its experts, who expressly rely
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`only on a transcript dated April 14, 2010 (Ex. 2008). Resp. 19-20; Ex. 2005, Lin
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`Dec., ¶¶ 13-21; Ex. 2002, Peppas Dec., ¶¶ 30-34. They also cite Ex. 2009 (dated
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`2009 and 2010) and Ex. 2010 (dated 2007 and 2013). See section on Dr. Lin
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`declaration below.
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`PO does not explain its inconsistent statement in another CIP of the ‘292
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`patent: “Currently, as generally required by various world regulatory authorities,
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`dosage forms may not vary more than 10-15% in the amount of active present.”
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`Ex. 1062, US 8663687, 2:3-6 (emphasis added).
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`Second, “Patent Owner respectfully submits that the ‘10%’ value is
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`calculated by a measurement against a ‘desired’ or predetermined, targeted, labeled
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`amount of active.” Resp. 6. And further submits: “The ‘dosage amount’ … is
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`the ‘desired amount’ in the claims.” Resp. 17 (emphasis in original) (citing
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`Peppas Dec. ¶ 27, Lin Dec. ¶¶ 10-11). Referring to these alternative constructions,
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`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
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`PO’s expert opines: “This and only this interpretation is consistent with the rest of
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`the language of the ‘167 patent.” Peppas Dec. ¶ 27.
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`But the ‘167 patent and the ‘292 patent only refer to uniformity between
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`dosage units or areas of film, and not with respect to a target/label/expected
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`amount in the ‘167 patent. Ex. 1058, Mathiowitz Dec., ¶¶ 27-29, 33. In Dr.
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`Mathiowitz’s view, “MonoSol and its declarants cite a sentence from the ‘167
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`specification that does not support their arguments.” Id. ¶ 31, 34 (“[T]his
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`interpretation of the cited “world regulatory” passage … is inconsistent with the
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`plain reading of that sentence, particularly in the context of the rest of the
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`specification of the ‘167 patent.”).
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`Returning to the term “dosage amount,” the ‘167 patent uses that term
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`exactly once—and PO relies on it. ‘167 patent, 18:46-54; Resp. 17, Peppas Dec. ¶
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`26. The ‘167 patent states that the dosage amount is “determined by the size of the
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`film and the concentration of the active.” Resp. 17 (quoting ‘167 patent, 18:49-
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`51). But PO is conflicted as to what it wants this to mean. Dr. Wyse and Mr.
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`Myers repeatedly testify that “desired amount” is the concentration of the active as
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`a percentage. See, e.g., Ex. 1054, Wyse Tr., 166:23-170:25; Myers Tr., 279:20-25.
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`And Dr. Peppas testifies that it is the weight of the active. Peppas Dec. ¶ 65. But
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`perhaps “desired amount” has no special meaning.
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`Dr. Cohen and Dr. Mathiowitz agree that the “desired amount” is simply the
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`amount that is desired. Cohen Tr., 200:6-7; Mathiowitz Dec. ¶¶ 36-38. Dr.
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`Mathiowitz opines that neither the claims nor the specification supports PO’s
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`proposed further construction of “desired amount.” Id. ¶¶ 30-34. First, PO’s new
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`construction does not make sense in the context of claims that are not limited to
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`pharmaceutical films. Id. ¶ 30. Indeed, Mr. Myers admitted that he does not know
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`how to determine a “desired amount” in the context of a vitamin. Myers Tr.
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`276:22-277:23. Second, in the context of the specification, Dr. Mathiowitz finds
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`no comparison to a target/label/expected amount of active in the ‘167 patent.
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`Mathiowitz Dec.¶ 33.
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`Finally, without any discernible evidentiary foundation, PO’s attorneys
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`characterize Dr. Cohen’s declaration as “suspect” because he allegedly does not
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`understand the term “desired amount.” Resp. 14-15 (citing Ex. 2014, Cohen Tr.,
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`194:16; 199:7-8). But even a cursory reading of the cited testimony reveals that
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`Dr. Cohen testified he did not know what PO’s attorney meant by “desired” or
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`“desired amount.” When asked, Dr. Cohen explained his understanding of
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`“desired amount.” Cohen Tr. 200:3-8.
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`IV. But PO’s Proposed Further Construction Does Not Avoid the Art
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`Uniformity between films. PO, through Dr. Peppas, challenges Dr.
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`Reitman for not showing uniformity between two different films. Peppas Dec. ¶¶
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`54-68. But the claims require uniformity within a film, not between films. Dr.
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`Peppas’ comparison between films is relevant to neither Dr. Reitman’s declaration
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`nor the claims.
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`In addition, even if uniformity between films were claimed—which it is
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`not—Dr. Peppas makes up a non-existent dosage size of 5 cm2 for Chen’s Example
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`7 to calculate a desired dosage weight—in an effort to distinguish Chen. Peppas
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`Dec. ¶ 56. But Chen does not identify a dosage size for Example 7. On the
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`contrary, Chen explains that “[t]he film may be cut into a size … according to the
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`dosage required.” Chen 16:5-6. Chen notes that “[t]he dosage form was 25-250
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`mg in various, shapes, sizes, and thicknesses.” Id. 17:18-19. PO’s inventor, Mr.
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`Myers, agrees. Myers Tr. 247:8-11 (agreeing that “you can create a piece of film
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`whose size enables you to meet a particular target dose”); 259:5-261:7.
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`Uniformity with respect to two interpretations of desired amount. PO
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`suggests that Dr. Reitman testified that uniformity with respect to desired amount
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`could not be calculated from the information in her declaration. Resp. 43. But this
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`is not true. Ex. 2012, Reitman Tr., 201:2-10. In her Declaration, Dr. Reitman
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`provides all the data necessary. Applying Dr. Peppas’ formulas, Dr. Reitman’s
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`data demonstrates uniformity under either proposed interpretation of desired
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`amount.
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`Weight. Dr. Reitman’s data demonstrates the uniformity of her film using
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`weight of active as the desired amount. Dr. Peppas multiplies the “desired
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`(targeted) weight percent of active present” by “weight of …dosage sample.”
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`Peppas Dec. ¶¶ 64-65. For Chen Example 7, Dr. Peppas calculates a “desired
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`(targeted) weight percent of active present” of 12.38%. Id. ¶¶ 63-65. Dr.
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`Reitman’s declaration reports her samples consistently weighed 34 mg. Reitman
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`Dec. ¶ 7 (Table 2). Applying Dr. Peppas’ formula yields a “desired amount” of 4.2
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`mg oxybutynin. Applying the proposed uniformity of +/- 10% from the “desired
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`amount” in weight, uniformity is demonstrated if Dr. Reitman’s samples fell
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`between 3.78 mg and 4.62 mg oxybutynin (i.e., 90-110% of the 4.2 mg “desired
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`amount”). Dr. Reitman reports the oxybutynin weight in her samples ranged from
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`4.1 mg to 4.4 mg—well within the allowed range of 3.78 mg and 4.62 mg.
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`Reitman Dec. ¶ 8.
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`Concentration. Dr. Reitman’s data also demonstrates the uniformity of her
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`film using concentration of active as the desired amount. Applying the proposed
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`uniformity of +/- 10% from the “desired amount” in concentration, uniformity is
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`demonstrated if Dr. Reitman’s samples fell between 11.14% and 13.61%
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`oxybutynin (i.e., 90-110% of the 12.38% “desired amount”). The oxybutynin
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`percentage in each film that Dr. Reitman produced using Chen’s Example 7
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`process may be calculated for each sample—by dividing the measured oxybutynin
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`weight by the total sample weight. Reitman Dec. ¶¶ 6-7 (for data). Dr. Reitman’s
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`Patent No. 8,765,167
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`samples A-E featured 12.94%2, 12.94%, 12.65%, 12.94%, and 12.06%
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`oxybutynin—well within the allowed range of 11.14% to 13.61%.
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`Regardless of the construction, “[t]he person of ordinary skill in the art
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`reading Example 7 of Chen would understand that, in order to increase or decrease
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`the amount of active per unit or sample, one need only increase or decrease the size
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`of the unit or sample.” Mathiowitz Dec. ¶ 43. “Alternatively, the person of
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`ordinary skill in the art would understand that she could adjust the amount of
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`active added … to achieve some ‘desired amount’ of active.” Id. ¶ 41.
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`V.
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`PO’s Evidence Supports the Petition or Lacks Relevance
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`1. Mr. Myers distracts from the relevant disclosure.
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`The Declaration of Mr. Myers appears to be offered as support for PO’s
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`proposed further construction of “desired amount” as a pharmaceutical dosage
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`amount. Resp. 19, 21 (citing Ex. 2004, Myers Dec.). But Mr. Myers only
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`addresses the meaning of “desired amount” in the context of pharmaceuticals. The
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`challenged claims are not limited to pharmaceuticals as the active component, and
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`include, as one possible alternative, vitamins. ‘167 patent, claim 1, 16, and 17
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`(each reciting “said active component is selected from the group consisting of
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`cosmetic agents, pharmaceutical agents, vitamins…”). Mr. Myers, a named
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`inventor of the ’167 patent, admitted that he does not know how to determine a
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`2 4.4 mg oxybutynin / [0.034 g total sample weight (1000 mg / 1 g)] = 12.94%.
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`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
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`“desired amount” in the context of a vitamin. Myers Tr. 276:17-277:23.
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`In his Declaration, Mr. Myers “analyzes” Examples X, Y, and Z in an
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`apparent effort to show that the patent demonstrates its films meet the recited
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`substantially uniform distribution. Myers Dec. ¶¶ 12-29. But Examples X, Y, and
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`Z only disclose the amount of active in one dose in each example. Ex. 1035, ‘292
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`patent, 25:10-51. A single dose cannot provide enough information to draw a
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`conclusion about the claimed “substantially uniform distribution … measured by
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`substantially equal[ly] sized individual unit doses which do not vary by more than
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`10% of said desired amount of said active component.” See ’167 patent, claims 1,
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`16, 17, 110 (emphasis added); see also Mathiowitz Dec. ¶¶ 46-49, ¶ 48 (“Cutting a
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`single sample from a single film simply cannot show the uniformity of the film.”).
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`Dr. Wyse agrees. Wyse Tr. 52:20-24 (“Q. How many samples of a film would
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`you need to determine whether that film features a uniform distribution of active?
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`… A. More than one.”).
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`2. Dr. Goldberg miscalculates and applies the wrong standard.
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`Dr. Goldberg uses miscalculation and the wrong standard to challenge three
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`Board decisions. The most glaring problem in Dr. Goldberg’s declaration is that
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`she reports the wrong average weights and standard deviations for her hypothetical
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`data. Ex. 1060, Dec., ¶ 12. This is a problem because Dr. Goldberg’s incorrect
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`average weights and standard deviations are the basis for her entire opinion. For
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`example, she incorrectly reports an average weight of 0.0284 for her first
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`hypothetical example. Ex. 2006, Goldberg Dec., ¶19 (Table A). But the correct
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`average weight of her first hypothetical is 0.028575. Lavin Dec. ¶12 (Table 1).3
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`This value rounds to 0.029, not Chen’s 0.028 as she also incorrectly reports. Id. ¶
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`12. Almost every calculation in Table A is wrong. Id. ¶ 12, Table 1.
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`In addition to her incorrect calculations, Dr. Goldberg applies the wrong
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`standard. “The ‘167 Patent, through incorporation by reference of the ‘292
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`Patent’s content, explicitly provides examples of the success of the invention in,
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`among other things, making uniform films….” Meyers Dec. ¶ 12. In the ‘292
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`patent, uniformity of active is demonstrated by consistent dosage weight in whole
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`centigrams. ’292 patent 19:64-20:56 (“The individual dosages were consistently
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`0.04 gm, which shows that the distribution of the components within the film was
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`consistent and uniform”). According to the ‘292 patent, “when the components of
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`different densities are combined in a uniform manner in a film, as in the present
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`invention, individual dosages forms from the same film of substantially equal
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`dimensions, will contain the same mass.” Id. 20:58-61. In other words, according
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`to the ‘292 patent (incorporated into the ‘167 patent), where individual dosages
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`from a film have consistent weights in whole centigrams, uniformity of the active
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`is confirmed.
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`3 Average Wt for Example 1 = (0.0305+0.0274+0.028+0.0284)/4 = 0.028575 g.
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`Dr. Lavin opines that applying the proper standard (the ‘167 patent standard)
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`to Dr. Goldberg’s hypothetical examples (by rounding to whole centigrams), every
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`single dose is consistently 0.03 g. Lavin Dec. ¶ 17 and Table 2. In short, Dr.
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`Goldberg’s hypothetical films meet the standard set by the ‘167 patent to
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`demonstrate uniformity of active.
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`In response to Dr. Goldberg, Dr. Lavin ran his own calculations applying the
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`standard of the ‘167 patent. Id. ¶ 18. He found that “for a sample of four to
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`conform to Chen’s 0.028 average grams per dosage film and Chen’s 0.001 g
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`standard deviation, each of the four samples must weigh 0.03 g when rounded to
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`whole centigrams.” Id. ¶ 19. Dr. Lavin “further calculated that the minimum
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`standard deviation would be at least 0.002 g if any sample weight differed from
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`0.03 g when rounded to whole centigrams.” Id.
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`Accordingly, Goldberg has failed to prove the Board misunderstood or
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`misapplied Chen. The ‘588 Board Decision states “[t]he measured weight per
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`dosage film as described in Chen is consistent with the additive weight test
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`described in the ’588 patent for determining uniformity.” ‘588 Decision 19. The
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`‘588 Board explains that consistent individual dose weights satisfy the less than
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`10% active content variation because the ‘588 patent says so. Id. 19-20. So does
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`the ‘167 patent because the incorporated ‘292 patent sets forth the same example of
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`uniformity and the same explanation. Compare Ex. 1026, ‘588 patent, 29:1-9 to
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`’292 patent 20:53-61. Since the institution decisions, the Board has reached this
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`same conclusion two more times. Ex. 1056, ‘080 Decision, 41; Ex. 1057, 337
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`Decision, 35-36. The Board applied Chen correctly in each of its three Decisions.
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`3. Dr. Lin’s evidence is almost 10 years too late.
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`Dr. Lin, who describes himself as an FDA expert, provides his interpretation
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`of “desired amount” in the claims. Lin Dec. ¶¶ 6-21. But he does not opine on
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`how the person of ordinary skill in the art (POSA) would interpret it. And he does
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`not rely on references from the time he identifies as relevant—before 2001. Id. ¶¶
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`16-17. Lin expressly relies on a transcript dated April 14, 2010 (Ex. 2008). He
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`also cites Ex. 2009 (dated 2009 and 2010) and Ex. 2010 (dated 2007 and 2013). Id.
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`¶¶ 18-20. His declaration interprets the claims as if they were limited to
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`pharmaceuticals; but they are not.
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`4. Dr. Peppas is misinformed and applies a double-standard.
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`Mystery photomicrographs. Dr. Peppas claims to opine on “several
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`photomicrographs that Dr. Wyse took of films he made of Example 8 of Chen.”
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`Peppas Dec. ¶ 46. But in his deposition, Dr. Wyse reluctantly admitted that he did
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`not take any photomicrographs of a Chen Example 8 film (Film A or Film B).
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`Wyse Tr. 214:7-219:7; Wyse Dec. ¶ 20 (identifying Film A and B as the “films
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`prepared as described in Chen Example 8”); Wyse Tr. 218:2-4 (“I did not do
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`microscopy on what we’ve been referring to today as the Film A and Film B, or
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`samples.”); 218:25-219:7 (admitting he took no photomicrographs of Film A or
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`Film B); 215:16-17 (“It could have been clearer in characterizing the films in
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`[paragraph] 39.”). Dr. Wyse testified that he did not remember ever
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`communicating with Dr. Peppas. Wyse Tr. 23:17-22; 23:2-5. In short, it is clear
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`from Dr. Wyse’s admissions that Dr. Peppas did not examine “several
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`photomicrographs that Dr. Wyse took of films he made of Example 8 of Chen.”
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`Mystery photomicrographs reveal nothing. “When I look at the images in
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`Dr. Peppas’ declarations …, it is very hard to reach any conclusion from the
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`images because critical information is missing.” Mathiowitz Dec. ¶ 55. The
`
`images lack (a) a ruler or other standardized indication of size, and (b) comparative
`
`photographs of film under lower magnification and/or film without estradiol. Id.
`
`¶¶ 55, 57. Moreover, “the person of ordinary skill in the art would not interpret
`
`60X magnification to be ‘naked eye or under slight magnification’.” Id. ¶ 56. So
`
`these photos are not relevant to the ‘167 patent standard for visual inspection to
`
`determine uniformity. See id.
`
`Reitman’s reproduction of Example 7. Dr. Peppas makes up a non-
`
`existent dosage size of 5 cm2 for Chen’s Example 7 to calculate a desired dosage
`
`weight—in his effort to distinguish Chen. Peppas Dec. ¶ 56. Dr. Peppas appears
`
`to believe that comparing two films is relevant to confirming uniformity of active
`
`in a single film. But the claims and the inventor, Mr. Myers, confirm that Dr.
`
`
`ME1 21072657v.2
`
`14
`
`

`
`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
`
`
`Peppas is wrong:
`
`Q·· How many runs of film must one check to determine whether a
`
`single film featured uniformity of active?
`
`A· · You can make a single batch, a single run, and evaluate whether
`
`the process gives you the uniform films.
`
`Myers Tr. 189:14-19; see also ’167 patent, claims 1, 16, 17, 110.
`
`Double standard. Dr. Peppas applies a different standard to the ‘167 patent
`
`than he does to Dr. Reitman’s work. With respect to the ‘167 patent, Dr. Peppas
`
`opines that a single dose from one film is all that is necessary to “describe and
`
`enable the manufacture of individual unit doses” with the claimed uniformity.
`
`Peppas Dec. ¶ 35. That is, with respect to the ‘167 patent, Dr. Peppas apparently
`
`adopts Mr. Myers’ analysis without any critical review. See id. ¶¶ 29, 35. In the
`
`words of Dr. Mathiowitz, “Dr. Peppas fails to identify the clear problem with Mr.
`
`Myers’ analysis.” Mathiowitz Dec. ¶ 49 (noting Dr. Peppas’ failure to realize that
`
`Mr. Myers is assuming uniformity in the film in order to prove uniformity based on
`
`a single dose).
`
`Construction of “desired amount.” Dr. Peppas’ opinions on FDA
`
`requirements and the “world regulatory authorities” passage suffer from the same
`
`deficiencies as Dr. Lin’s opinions. Peppas Dec. ¶¶ 25-34. See section on Dr. Lin’s
`
`declaration above.
`
`
`ME1 21072657v.2
`
`15
`
`

`
`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
`
`
`Chen’s Figure 2. Dr. Peppas opines that “Chen Figure 2 does not show or
`
`describe an oven having controlled air flow.” Peppas Dec. ¶ 70. But Chen’s
`
`Figure 2 explicitly illustrates and identifies a “Drying Oven with Aeration
`
`Controller 11.” Chen Fig. 2. Dr. Peppas also appears to criticize Chen’s Figure 2
`
`for not showing “what the specific parameters of drying are.” Peppas Dec. ¶ 69.
`
`But, as a named inventor, Mr. Myers testified that controlled drying does not
`
`require the control of all of the parameters that Dr. Peppas identified. Compare
`
`Myers Tr. 126:2-4 (explaining that controlled drying does not require controlled
`
`humidity) with Peppas Dec. ¶ 70 (criticizing Chen for not disclosing relative
`
`humidity). Dr. Peppas criticizes Chen for lacking details that are not disclosed in
`
`the ‘167 patent. Id. ¶¶ 69-71 (criticizing Chen for not disclosing specific
`
`impingement angle and nozzle distance). But Dr. Peppas opines that the ‘167
`
`patent demonstrates the process without disclosing those parameters—once again
`
`applying a double standard. Id. ¶ 35. In any event, the claims recite no specific
`
`drying parameters. See, e.g., ’167 patent claims 1, 16, 17 and 110.
`
`5. Dr. Wyse lacks ordinary skill and withholds information.
`
`Dr. Wyse Lacks Ordinary Skill. The ‘167 patent is directed to film. See,
`
`e.g., ‘167 patent title, claims 1, 16, 17, 110; Ex. 1007, Cohen Dec., ¶ 13. Dr.
`
`Cohen identified the POSA as having “several years of practical experience in the
`
`manufacture, engineering, and/or research and development of film.” Cohen Dec.
`
`
`ME1 21072657v.2
`
`16
`
`

`
`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
`
`¶ 14. Dr. Mathiowitz agrees with that definition of the POSA. Mathiowitz Dec. ¶¶
`
`24-25. Neither PO nor its experts disputed Dr. Cohen’s definition of the POSA.
`
`Yet Dr. Wyse discloses only one film experience, which he admits is work
`
`done for counsel for PO. Wyse Dec. p. 32 (“Leading team which replicated a
`
`patented process for preparing a buccal delivery film.”); Wyse Tr., 21:9-22:25. Dr.
`
`Wyse admitted he started making film in the spring of 2015. Id. 111:4-7. He
`
`therefore lacks the “years of practical experience” with film to qualify as a POSA.
`
`Mathiowitz Dec. ¶¶ 58-62.
`
`Dr. Wyse’s process for making film confirms his lack of skill. When
`
`casting both Film A and Film B, Dr. Wyse created notable discontinuities. Wyse
`
`Tr. 158:19-20, 160:7-8 (Film A and Film B both featured holes), 163:9-166:3 (the
`
`castings of Film A and Film B each included holes, which are better described as a
`
`lines or gaps without film). A POSA would have considered such castings
`
`unacceptable. Mathiowitz Dec. ¶ 66. Nonetheless, instead of trying to cast a film
`
`without discontinuities, Dr. Wyse dried the defective wet film castings. Wyse Tr.
`
`164:21-165:13. A POSA would not have done this:
`
`[T]he person of ordinary skill in the art would immediately understand
`
`that “holes” or “lines” in the cast film indicate serious problems with
`
`the casting process. The person of ordinary skill in the art would
`
`correct the problems and then start over. The person of ordinary skill
`
`in the art would not continue to dry and cut films containing such
`
`
`ME1 21072657v.2
`
`17
`
`

`
`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
`
`
`holes or lines for any pharmaceutical film. A reference, such as Chen,
`
`would not need to instruct the reader to “cast a film that does not have
`
`holes or lines.” It would be the most basic common sense to a person
`
`of ordinary skill in film-making the art.
`
`Mathiowitz Dec. ¶¶ 66, 64-73. “In my opinion, Dr. Wyse made numerous
`
`mistakes in making and analyzing the films he reported as Films A and B
`
`that a [POSA] would not have made.” Id. ¶¶ 63, 64-85. “As far back as
`
`1979, pharmaceutical films with a variety of actives … have been reported
`
`as having a ‘uniformly homogenous distribution of active’.” Mathiowitz
`
`Dec. ¶ 61.
`
`Incomplete samples. According to Mr. Myers, a named inventor, an
`
`individual unit dose would not be cut from an edge. Myers Tr. 165:3-11. Dr.
`
`Wyse’s Film A and Film B were square films only large enough to take 16
`
`samples. Wyse Tr. 41:2-24, 121:1-5 (square film). Dr. Wyse identified the 16
`
`samples from each film by the location from which they were cut. Id. 166:12-14
`
`(“Each sample was assigned a number, you know, left to right, top to bottom on
`
`the film.”). Most of Dr. Wyse’s samples do not qualify as “individual unit doses”
`
`because they were cut from an edge of Film A or Film B. Wyse Dec. ¶31 (Table
`
`C) (improperly identifying edge samples A1, A4, A9, A12, A13, A14, A15, A16,
`
`B1, B2, B3, B4, B5, B8, B9, B13 and B14 as “individual unit doses”). Yet he used
`
`them to analyze the films anyway. And even according to Dr. Wyse, more than a
`
`
`ME1 21072657v.2
`
`18
`
`

`
`Case Nos. IPR2015-00165, IPR2015-00168, IPR2015-00169
`Patent No. 8,765,167
`
`
`third of the samples of Film A and Film B were “incomplete.” Wyse Tr. 205:16-
`
`207:3 (testifying that 11 of the 32 total samples were incomplete).
`
`Dr. Wyse did the wrong dissolution experiment. Table D reports the
`
`average total estradiol released at 4, 7, 15, 20, 25 minutes. Wyse Dec. ¶¶ 33-35.
`
`Based on the same experiment, Table B reports total estradiol based on a sample
`
`taken at 25 minutes as if it were the total amount of estradiol in each sample.
`
`Wyse Tr. 192:1-15. Dr. Mathiowitz explains “Dr. Wyse did the wrong
`
`experiment.” Mathiowitz Dec. ¶¶ 81, 82-85 (as the POSA would know, “one
`
`should let each sample dissolve completely and then run HPLC on each sample”).
`
`Dr. Wyse excluded data he didn’t like. Dr. Wyse vaguely admits to
`
`excluding “values that were not used.” Wyse Tr. 57:8-10; see also 56:13-16
`
`(admitting “[t]here were samples at some time points which had results that were
`
`not consistent that I viewed as being an outlier, and they were pulled from the data
`
`set u

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