`
`Paper No. ___
`Filed: July 27, 2017
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC. and AKORN INC.,1
`Petitioners,
`v.
`ALLERGAN, INC.,
`Patent Owner.
`
`_____________________________
`
`Case IPR2016-01127 (US 8,685,930 B2)
`Case IPR2016-01128 (US 8,629,111 B2)
`Case IPR2016-01129 (US 8,642,556 B2)
`Case IPR2016-01130 (US 8,633,162 B2)
`Case IPR2016-01131 (US 8,648,048 B2)
`Case IPR2016-01132 (US 9,248,191 B2)
`_____________________________
`
`PETITIONERS’ RESPONSE TO PATENT OWNER’S MOTION FOR
`OBSERVATIONS ON THE CROSS-EXAMINATION OF DR. ANDREW
`CALMAN
`
`
`1 Cases IPR2017-00576 and IPR2017-00594, IPR2017-00578 and IPR2017-
`00596, IPR2017-00579 and IPR2017-00598, IPR2017-00583 and IPR2017-00599,
`IPR2017-00585 and IPR2017-00600, and IPR2017-00586 and IPR2017-00601,
`have respectively been joined with the captioned proceedings. The word-for-word
`identical paper is filed in each proceeding identified in the caption pursuant to the
`Board’s Scheduling Order (Paper 10).
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`Petitioner submits this Response to Allergan’s Motion for Observations on
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`the Cross-Examination of Dr. Andrew Calman (“Observations”) pursuant to the
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`Standing Order (Paper 9) and the Scheduling Order (Paper 10).
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`Dr. Calman’s Opinions Regarding Thermodynamic Principles
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`Allergan’s First Observation (Mot’n at 1-2) omits relevant testimony and
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`mischaracterizes the cited testimony.
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`• Dr. Calman testified that he is capable of competently discussing the
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`pharmacokinetic studies in a clinical context. EX2082 at 157:21–24
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`(“I believe I am qualified to discuss these issues and as well to put
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`them in clinical context which neither of them [Drs. Amiji and
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`Loftsson] is a clinician.); Id. at 158:8–16 (“[T]here are other aspects
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`where I can provide a clinical context that’s missing.”).
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`• Dr. Calman testified that he would “defer to the formulators”
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`regarding “any equations regarding thermodynamic activity,” but
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`that “with regard to the relationship of the bioavailability to the
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`clinical efficacy, I’m a clinician and they’re not.” Id. at 158:12–16; id.
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`at 158:2-22.
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`• In his declaration, Dr. Calman testified regarding the “internal
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`pharmacokinetic studies” relied upon by Dr. Loftsson in support of his
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`thermodynamics theory and relied upon by Dr. Attar for her
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`-1-
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`
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`declaration. EX1039, ¶¶76-81. Dr. Calman testified that their
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`presentation by Dr. Attar “is problematic” and “scientifically
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`improper,” with study designs that were “vastly different,” including
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`because one was a steady-state study and the other was a single-dose
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`study. Id., ¶77. Dr. Calman also testified that it was misleading to
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`claim that “there are significant and material differences in the amount
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`of CsA that each formulation delivered to the ocular tissue” because
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`“each formulation delivered CsA to the cornea and conjunctiva well
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`above the threshold required for therapeutic efficacy” and “there
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`was no ‘dose-response’ effect” between the CsA formulations. Id.,
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`¶¶78-81 (emphasis in original).
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`Allergan claims that Dr. Amiji “provided no opinions regarding
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`thermodynamic principles in his declaration or deposition testimony.”
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`• Dr. Amiji explained that each of the formulations in Example 1 of
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`Ding ’979 had a ratio of cyclosporin to castor oil sufficient to deliver
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`therapeutic concentrations of CsA:
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`Ding ’979 names “Examples 1A-1D” when discussing “formulations
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`with cyclosporine” and the “cyclosporin containing castor oil
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`emulsion,” for which emulsions it reports finding therapeutic levels of
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`cyclosporin, “no difference” in toxicity as compared to the emulsions
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`without cyclosporin, and no crystallization of cyclosporin after nine
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`-2-
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`
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`months at room temperature. [EX1006] at col. 5, ll.18-30. Based on
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`the disclosure of Ding ’979, a person of ordinary skill in the art would
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`expect that any of the CsA amounts disclosed in Example 1, in
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`combination with any of the vehicles disclosed in Example 2, would
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`yield a non-irritating emulsion, useful in the treatment of dry eye
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`disease/KCS if the ratio of CsA to castor oil falls within the preferred
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`range taught by Ding ’979.
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`E.g., IPR2016-01127, EX1002, ¶71; see also id., ¶¶67-68, 94, 105, 110, 113;
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`EX1006, 3:15-28 (“No crystallization of cyclosporin was noticed after nine months
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`at room temperature. Moreover, the cyclosporin emulsion is formulation in such a
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`way that the drug has reasonably high thermodynamic activity, yet without the
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`crystallization problem.”); id., 2: (describing problems with prior art “oily
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`formulations’ as including “the crystallization problem” and “a low
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`thermodynamic activity (degree of saturation) of cyclosporin which leads to poorer
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`drug bioavailability”); EX2023 at 160:23-161:3 (Dr. Amiji testifying that Ding
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`’979’s discussion of drawbacks of oily formulations is “just talking about
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`dissolving cyclosporin in oil. They’re not talking about emulsions here.”).
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`• Dr. Amiji also confirmed that Ding ’979’s conclusions regarding
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`therapeutic efficacy were based on “rabbit data,” and that “Rabbit data
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`are informative about the therapeutic efficacy as well as the safety.”
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`Id., 158:4-158:13. Dr. Amiji also testified that Ding’979 patent
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`describes performing “slit lamp analysis of the corneal tissue and they
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`-3-
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`also mention that they tested for ocular bioavailability and the
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`therapeutic levels of cyclosporin.” Id., 158:19-159:14.
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`Dr. Calman’s Opinions Regarding Sall Figure 2
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`Allergan’s Second Observation (Mot’n at 2-3) omits relevant testimony and
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`mischaracterizes the cited testimony.
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`• With regard to Allergan’s terminology “numerically superior,”
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`Calman stated: “Well, I --‘numerically superior’ is a little bit of a
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`loaded term. It is not statistically significantly different. The number,
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`the average number, the mean is higher. All of these are very small
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`changes. But the number -- the change is slightly higher for .05 on this
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`particular time point.” EX2082 65:15–21.
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`• Dr. Calman also states:
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`To put that [Sall Fig. 2] in context, this is categorized Schirmer values
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`with pitfalls that I discussed at length, as did Dr. Bloch, in our
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`declarations, measured with anesthesia at the -- at a time point that --
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`and which was measured only at two time points in contrast to most of
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`the other measures. And at the time point that was not the key time
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`point of six months as identified by Allergan, none of these emulsions
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`achieve any significant change or seen -- none of these emulsions
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`achieve a significant change compared to baseline at Month 3. But
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`there was a statistically significant difference between .05 and vehicle
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`but not between .05 and .1.
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`Id. at 57:15–58:6.
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`-4-
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`• Regarding the 0.1% CsA formulation allegedly decreasing tear
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`production in Sall Fig. 2, Dr. Calman states, “I think you’re taking
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`that out of context . . . . . So as a person of ordinary skill, when I look
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`at that, I’m thinking this is very strange. And I would like to see the
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`underlying raw Schirmer data, which we asked for which the patent
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`owner did not want to disclose.” Id. at 58:12–59:14.
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`• With regards to Dr. Amiji’s statement, Dr. Calman states, “Well, it’s a
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`literal -- it’s a literal statement that is not factually wrong. The context
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`that I would add in addition to what I stated a few minutes ago is that -
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`- because, you know, there is no statistically significant difference
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`between the .01 -- the .1 and the .05, which is about .3 to .4 units,
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`those are very small and potentially, you know, either very mildly
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`clinically meaningful or not clinically meaningful.” Id. at 72:18–73:2.
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`Dr. Calman’s testimony does not contradict his declaration or the petitioner,
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`and there is no contradiction between Dr. Calman’s testimony and Dr. Amiji’s
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`testimony.
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`Dr. Calman’s Qualifications Regarding Clinical Studies in Sall and Stevenson
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`Allergan’s Third Observation (Mot’n at 3-4) omits relevant testimony and
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`mischaracterizes the cited testimony.
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`-5-
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`• Dr. Calman has acquired extensive knowledge including “27 years in
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`clinical work plus 12 years in labs doing basic research. And through
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`that knowledge, education, skills, training, and experience, I have
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`acquired certain knowledge about pharmaceutical formulations,
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`including ophthalmic formulations and their application in clinical
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`practice, in clinical trials, et cetera.” Id. at 22:17–23:2.
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`• Dr. Calman has also gained experience in developing a CsA
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`ophthalmic product: “I was working with professors as a resident in
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`ophthalmology, and we certainly used ophthalmic cyclosporin
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`formulations at that time.” Id. at 24:1-7.
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`• Dr. Calman is similarly well versed in clinical research studies: “And
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`we discussed earlier today some of the various clinical research
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`studies I was involved in where excipients and formulation were key
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`aspects of the study design.” Id. at 155:21–156:13.
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`• Dr. Calman also testified that some of the clinical trials in which he
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`participated involved treatments for dry eye patients and that he
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`believed they involved “monitoring modalities” related to dry eye to
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`evaluate the impact of the drugs on the “ocular surface while treating
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`the glaucoma.” EX2082 at 30:10-31:17.
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`-6-
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`• Dr. Calman also testified that he is familiar with the Schirmer tear test
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`and uses it in his own clinical practice. Id., 44:11-45:5.
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`The testimony cited by Allergan does not demonstrate a lack of qualification
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`by Dr. Calman to provide expert testimony regarding the clinical studies in Sall
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`and Stevenson.
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`Dr. Calman’s Analysis of Sall Figure 2
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`Allergan’s Fourth Observation (Mot’n at 4-5) omits relevant testimony and
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`mischaracterizes the cited testimony.
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`• The passage Allergan cites reads in full, “If I had to present this data
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`at a medical conference, I would be deeply apologetic at the fact that
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`whoever was providing the data to me had given me an incomplete
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`data set.” Id. at 107:6-9.
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`• Dr. Calman emphasized that he did the best work he could with the
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`limited data set supplied by Allergan. Id. at 106:03–07.
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`• While Dr. Calman did not purport to literally and fully reverse
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`engineer the underlying data from Sall Figure 2, he testified that this
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`part of his analysis focused on whether the differences reported in Sall
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`Figure 2 were clinically material. Id., 103:1-105:19. (“I’m not trying
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`to oversell this. I’m saying that this is an attempt to determine if the
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`-7-
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`changes are small or large….I’m just trying to get an idea of the
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`magnitude of the change in the population.”).
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`• Dr. Calman testified during his deposition that “there was no
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`statistically significant difference reported between the .05 and the .1”
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`CsA formulations in Sall Figure 2, and that the changes “were small”
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`from a clinical perspective. Id., 163:4-164:21.
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`• Dr. Calman elaborated that even the largest change from baseline,
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`which was larger than any difference between the two formulations,
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`was, “at the most, 0.4 for Schirmer, quote/unquote, units [and]
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`correspond[s] to a small increase in actual Schirmer score on the order
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`of 2 millimeters. Maybe it’s 1, maybe it’s 3, maybe it’s 2. None of
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`those are, in my experience, material.” Id., 163:4-164:21; see also Id.
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`at 99:3-10 (“[W]e can quibble over whether they’re going from 3
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`millimeters to, you know, 3.5 millimeters. I don’t care if it’s 4
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`millimeters to 4.5 or 5 millimeters to 5.5. We’re still talking about
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`small changes.”); id. at 106:16–21 (“It’s hard to see how it would
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`even be 3 millimeters.”).
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`The testimony cited by Allergan does not demonstrate unreliability or lack
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`of accepted scientific practice in Dr. Calman’s analysis.
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`Dr. Calman’s Scope of Work and EX2078
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`-8-
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`Allergan’s Fifth Observation (Mot’n at 5-6) mischaracterizes the record, as
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`Allergan did not produce Exhibit 2078 with its Patent Owner Responses and did
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`not rely on any data from Exhibit 2078 in its Patent Owner Responses for any
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`purpose, including to establish criticality or unexpected results of the 0.05% CsA
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`formulation as compared to the 0.10% CsA formulation. Whether or not Dr.
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`Calman reviewed documents that Allergan failed to produce or rely upon to satisfy
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`its burden of production is irrelevant to his analyses. Allergan’s characterization of
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`EX2078 as establishing that the 0.05% formulation “works differently” is
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`unsupported and incorrect.
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`The Kaswan Article’s Proof of Therapeutically Effective CsA Levels
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`Allergan’s Sixth Observation (Mot’n at 6-7) omits relevant testimony and
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`mischaracterizes the cited testimony.
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`• Dr. Calman testified that Kaswan teaches the intraocular level of CsA
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`in the aqueous humor understood at the time to be sufficient to control
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`of uveitis. Id. at 132:2–4.
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`• Although Nussenblatt reports therapeutic levels of cyclosporin in
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`serum, Dr. Calman testified that therapeutic levels of CsA in blood
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`were informative of the CsA levels in tissue:
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`I’ve explained how similar serum levels are required for efficacy in a
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`variety of solid tissues, which indicates that—including the eye as
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`based on Nussenblatt, which indicates there is not something magical
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`-9-
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`about the eye or any other tissue that tends to concentrate or reduce
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`the concentration of cyclosporin in tissue with regard—compared to
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`the blood. And, furthermore, in the Nussenblatt study, we actually do
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`have a comparison. You know, we do have an actual tissue level of
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`cyclosporin in the vitreous which is very comparable. Instead of you
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`know, 100 to 400, it’s 160 to 580. You know, we’re in that same
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`ballpark. You know, I’m convinced as a scientist reading the totality
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`of this data that those are the kinds of tissue levels that are adequate
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`for efficacy in a variety of tissues.
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`Id., 149:23-152:25.
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`• Dr. Calman reiterated, “[I]t’s not a high school student but a POSA, a person
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`that would understand that if a wide variety of tissues are achieving adequate
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`levels to control disease with these types of levels in the blood, that these are
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`likely to be applicable to other types of tissues as well.” Id. at 148:16–
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`149:11.
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`• Dr. Calman also explained that Nussenblatt and Oellerich each demonstrate
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`that the CsA levels were neither “dramatically higher nor dramatically lower
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`in the tissues than they are in the bloodstream that supplies them.” Id. at
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`149:12–22.
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`• Dr. Calman testified that Nussenblatt injecting cyclosporin directly into the
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`eye resulted in “mean cyclosporin levels between 160 and 580 nanograms
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`per grams,” that these concentrations “worked” in the tissue, that these levels
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`-10-
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`were “roughly comparable to all these other ranges we’ve been discussing
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`with regard to serum levels,” and that “we can quibble is it 50 to 300 [as
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`reported in Kaswan] or is it 160 to 580 [as reported in Nussenblatt] or is it
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`100 to 400 [as reported in Oellerich]. All of these are in the same ballpark.”
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`Id., 135:2-137:6; see also id., 141:22-142:25.
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`• Dr. Calman testified that Kaswan is “very much responsive to an inquiry as
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`to tissue levels of cyclosporin in relevant tissues…with a view towards
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`ameliorating Sjogren’s syndrome and KCS, among other things.” Id.,
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`145:10-146:29.
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`• Allergan’s counsel also elicited testimony from Dr. Calman confirming that
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`“Kaswan at 653” states “In dogs with KCS, topical CsA ameliorated the
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`chronic keratitis and increased the average Schirmer test by 9 millimeters
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`per minute.” Id., 144:3-12.
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`• Dr. Calman also testified that Nussenblatt and Kaswan disclose by
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`implication CsA concentration that were therapeutically effective for
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`increasing tear production because they discuss “what is believed in the field
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`to be adequate concentrations for uveitis, for example, which is an example
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`of a severe ocular inflammatory condition. Id., 160:9-161:13. Dr. Calman
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`testified that uveitis is “an example of a severe ocular inflammatory
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`condition” that is “often vision-threatening inflammation.” Id., 161:1-2. Dr.
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`-11-
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`Calman testified that experimental autoimmune uveitis (“EAU”), the animal
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`model used in Nussenblatt as a proxy for uveitis, is “another pretty big-time,
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`high-powered anti-inflammatory disease.” Id., 136:24-137:2.
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`• Dr. Calman explained what he meant by “severe” and “high-powered”
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`disease by explaining that uveitis is a serious condition:
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` [W]here oftentimes we’re having patients put in our most potent
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`steroid every one or two hours, sometimes around the block. In
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`contrast, there are other conditions where we may use steroids, either
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`short-term or long-term, where much lower concentrations or
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`frequency is effective. Examples of that include KCS and certain
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`types of ocular allergy where very low dose, such as a once or twice a
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`day of administration of our lowest potency steroid drop, may be
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`sufficient for clinical effect. So that was my—that was my—just
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`trying—again, my job here in part is to put all of these things into
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`clinical context.
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`Id., 161:14-162:18.
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`Allergan incorrectly asserts (Mot’n at 7) that Kaswan’s teaching regarding
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`therapeutic levels of CsA are inaccurate, incorrectly asserts that the therapeutic
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`levels was unknown prior to September 15, 2003, and incorrectly asserts that a
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`POSA would not have expected substantially equivalent efficacy in increasing tear
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`production from the 0.05% and 0.10% CsA formulations.
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`Dr. Calman’s Analysis Regarding Relevant Information to Tear Production
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`-12-
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`Allergan’s Seventh Observation (Mot’n at 8-9) omits relevant testimony and
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`mischaracterizes the cited testimony.
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`• When asked whether the STT with anesthesia measures basal aqueous
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`tear production, Dr. Calman responded, “Well, with the caveats I’ve
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`expressed.” Id. at 47:2–4.
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`• Dr. Calman also explained:
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`And in my experience, the variability is even worse with the
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`Schirmer’s with anesthesia because, if you think about it, when you
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`put that eye drop in, it’s hard to get all of that anesthetic eye drop out.
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`The anesthetic eye drop itself sometimes causes some reflect tearing
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`because it stings. And so that’s why I’ve been careful all along to say
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`to a first approximation, Schirmer’s with anesthesia reflects basal
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`tearing because it’s an imperfect test. And in my experience, it’s more
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`variable than the Schirmer’s without. Because if you’ve got that eye
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`drop left over in the eye, that’s going to give you a few millimeters
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`right there. You know, if you’ve got reflexive tearing because the
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`patient’s getting stinging from the aesthetic, that’s going to potentially
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`give you more millimeters there.
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`Id. at 104:8–23.
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`Contrary to Allergan’s characterizations (Mot’n at 8-9), Dr. Calman’s
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`deposition testimony cited by Allergan does not contradict Dr. Calman’s testimony
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`that “there was no material difference between the 0.05% CsA formulation and the
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`0.1% CsA formulation,” his testimony that “both of the CsA formulation were
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`-13-
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`therapeutically effective in treating dry eye, including by increasing aqueous tear
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`production from the lacrimal glands,” or his testimony that the POSA “would not
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`have selectively limited an analysis of comparative efficacy to solely data reported
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`for the STT with anesthesia.”
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`Contrary to Allergan’s contentions (Mot’n at 9), Dr. Calman’s testimony
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`does not prove that Sall Figure 2 was the only data in Sall reporting basal tear
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`production or that the POSA would focus on Sall Figure 2 to compare the CsA
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`formulations’ with respect to basal tear production.
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`Dated: July 27, 2017
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`Respectfully submitted,
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`
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
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`-14-
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`CERTIFICATE OF SERVICE
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`This is to certify that I caused to be served true and correct copies of the
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`foregoing Petitioners’ Response to Patent Owner’s Motion for Observations on the
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`Cross-Examination of Dr. Andrew Calman on this 27th day of July, 2017, on the
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`Patent Owner at the correspondence address of the Patent Owner as follows:
`
`Dorothy P. Whelan
`Michael Kane
`Susan Morrison Colletti
`Robert M. Oakes
`Jonathan Singer
`Fish & Richardson P.C.
`3200 RBC Plaza
`60 South Sixth Street
`Minneapolis, MN 55402
`Email: IPR13351-0008IP1@fr.com
`Email: IPR13351-0008IP2@fr.com
`Email: IPR13351-0008IP3@fr.com
`Email: IPR13351-0008IP4@fr.com
`Email: IPR13351-0008IP5@fr.com
`Email: IPR13351-0008IP6@fr.com
`Email: PTABInbound@fr.com
`
`And on the remaining petitioners as follows:
`
`
`Gary Speier
`Mark Schuman
`CARLSON, CASPERS, VANDENBURGH,
`LINDQUIST & SCHUMAN, P.A.
`225 South Sixth Street, Suite 4200
`Minneapolis, MN 55402
`Email: gspeier@carlsoncaspers.com
`Email: mschuman@carlsoncaspers.com
`Attorneys for Teva Pharmaceuticals USA, Inc.
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`-15-
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`Michael Dzwonczyk
`Azadeh Kokabi
`Travis Ribar
`SUGHRUE MION, PLLC
`2100 Pennsylvania Ave., NW
`Washington, DC 20037
`Email: mdzwonczyk@sughrue.com
`Email: akokabi@sughrue.com
`Email: tribar@sughrue.com
`Attorneys for Akorn Inc.
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`Dated: July 27, 2017
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`Respectfully submitted,
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
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`-16-
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