`
`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. DANIEL A.
`BLOCH
`
`
`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).
`
`
`
`
`
`
`
`
`
`Petitioner submits this Response to Patent Owner Allergan’s Motion for
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`Observations on the Cross-Examination of Dr. Daniel Bloch (“Observations”)
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`pursuant to the Standing Order (Paper 9) and the Scheduling Order (Paper 10).
`
`Dr. Bloch’s Analysis of the Data in Sall Figure 2
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`1)
`
`Allergan omits relevant testimony and mischaracterizes the cited
`
`testimony. Observations at 1. Dr. Bloch characterized his measurements as “very
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`good approximations,” EX2083 at 79:16, which he was able to obtain from Sall
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`Figure 2 using a ruler with demarcations in “fractions of millimeters.” Id. at 42:22–
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`23; see also id. at 43:15–19 (Dr. Bloch made “very accurate measurement[s]” with
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`his ruler). Moreover, Dr. Bloch has used this method before in peer reviewed
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`publications (Id. at 52:21–54:13), and he performed the measurements “many
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`times to verify. [He] replicated it like a good scientist would do.” Id. at 44:2–3.
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`2)
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`Allergan omits relevant testimony and mischaracterizes the cited
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`testimony. Observations at 1. Dr. Bloch stated in his declaration and during his
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`deposition that he only calculated P values where Sall did not disclose P values.
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`EX1040, ¶43 n. 3 (“The p-values in Table 2 for ‘B vs A’ at months 3 and 6 and ‘C
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`vs A’ at month 6 are the values reported in Sall. Hence I did not need to measure
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`the vehicle mean difference and standard error at month 6. In the Table ‘N/A’
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`means not applicable. I calculated the p-values for the remaining comparisons that
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`were not reported in Sall.”). Dr. Bloch explained that he did not calculate these
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`-1-
`
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`
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`values because they were “disclosed already by Sall,” and because Sall “had the
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`actual values or he was given the P values I believe that somebody else then
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`actually had the values for. And when he did that, I reported that the ones he did.
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`I only calculated P values for the ones that he did not do or to disclose in his
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`publication.” EX2083 at 80:19–81:4. Dr. Bloch further testified, “It would not be
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`correct for me to present P values when in fact the correct P values are actually
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`known.” EX2083 at 89:14–18.
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`3)
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`Allergan omits relevant testimony and mischaracterizes the cited
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`testimony. Observations at 1. While P values Allergan’s attorney calculated using
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`Dr. Bloch’s measurements of Sall Figure 2 to compare the 0.05% CsA formulation
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`to vehicle are slightly lower (more indicative of significance) than those reported
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`by Sall based on the underlying data, Dr. Bloch testified that this minor variation is
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`to be expected because Allergan withheld the underlying data. EX2083 at 88:23–
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`24 (“Well, it would be off by something. It had to be. I didn’t have the actual
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`data.”). Dr. Bloch confirmed that the P values Allergan’s counsel calculated were
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`very similar to those reported in Sall and that Dr. Bloch was confident in the
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`accuracy of his measurements:
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`I knew [my] measurements were accurate. I knew that. The difference
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`in the ratio to get a 0.004 P value versus 0.009 is minuscule. Because
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`if you know anything about T distributions with 500 observations,
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`which is 250 or more than that, 580 observations, is that the P value, if
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`-2-
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`
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`
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`you just move a small amount when you’re that extreme the P value
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`will become vanishingly smaller very quickly because of the
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`exponential tail-off of the T distribution. It goes down very, very
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`rapidly as you get out to the tails. So the ratio would have been almost
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`identical. . . .
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`Id. at 91:4–20. Dr. Bloch also testified that if he had calculated the P value using
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`his measurements he
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`would have reported a [P value of] 0.004 and the conclusion, I think,
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`would have been ‘Oh, well, Bloch wasn’t -- he’s more conservative
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`than the truth is.’ In other words, the P value [0.009 in Sall] is twice
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`as high here than I would [get using my measurements] -- actually, it
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`[the P value reported in Sall] should even be smaller…. Yeah. My
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`own measurements would have given them a smaller P value.
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`Id. at 89:6–90:4. See also EX1007 (Sall) at 635 (“CsA 0.05% group significantly
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`greater than the vehicle group (P = 0.009).”); EX2080 (calculating P value of
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`0.0037, ~0.004); EX2083 at 85:12–88:14 (discussing EX2080 and 2081, marked
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`respectively as deposition Exhibits 2081 and 2080).
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`Contrary to Allergan’s arguments that Dr. Bloch’s analysis “was
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`scientifically unsound and inaccurate,” (Observations at 1) the “difference”
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`Allergan relies upon actually demonstrates that Dr. Bloch’s measurements were
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`very careful and accurate, and showed caution in Allergan’s favor. Dr. Bloch
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`confirmed in his deposition that there were no statistically significant differences
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`between the 0.05% and 0.10% CsA formulation in Sall Figure 2:
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`-3-
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`
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`• EX2083 at 81: 16–85:11 (P value of 0.246 for Sall Figure 2 was not
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`statistically significant: “[T]he answer here is that it’s very likely it’s
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`just a chance finding. The answer [P value] is 0.246. It’s very, very
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`far away from being statistically significant.”);
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`• id. at 106:8–10 (“However, if it’s not statistically significant, what
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`you don’t know is if in fact the result you see is real, if it’s
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`reproducible.”);
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`• id. at 107:4– 9 (“But to answer your question, if you don’t have
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`statistical significance, you just don’t know whether or not the result
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`is real. It could just be a chance finding. That’s not okay for
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`scientists. They want to know if it’s okay, if it’s really real.”);
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`• EX1040, ¶35 (reporting P values of 0.898, 0.914, 0.480, and 0.665
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`when evaluating the 0.05% and 0.10% CsA formulations for corneal
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`staining in Sall Fig. 1); id. at ¶43 (reporting P value of 0.115 for Sall
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`Figure 2 at month 3 and 0.251 at month 6).
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`Dr. Bloch’s Scope of Work and EX2078
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`Allergan contends that “Dr. Bloch Failed to Review Clinical Evidence
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`Demonstrating the 0.05% CsA Formulation Works Differently than the 0.1% CsA
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`Formulation,” referring specifically to Exhibit 2078. Observations at 2. Petitioner
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`objected during the deposition to Allergan’s presentation of Exhibit 2078 as “a
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`-4-
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`
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`new exhibit, presumably new data, as something that could have been provided
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`earlier but was not.” EX2083 at 95:25–96:5. Allergan did not produce Exhibit
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`2078 with its Patent Owner Responses and did not rely on any data from Exhibit
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`2078 in its Patent Owner Responses for any purpose, including to establish
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`criticality or unexpected results of the 0.05% CsA formulation as compared to the
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`0.10% CsA formulation. Whether or not Dr. Bloch reviewed documents that
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`Allergan failed to produce or rely upon to satisfy its burden of production is
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`irrelevant to Dr. Bloch’s analyses. Dr. Bloch testified that he was retained to
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`provide statistical analyses for the clinical data reported in Stevenson and Sall
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`Figures 1-2 and Allergan’s animal PK studies used in Dr. Attar’s Exhibit B.
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`EX1040, ¶10. As Dr. Bloch states, “I mean to me the FDA is tangential to this
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`matter in terms of my own participation through my declaration.” Id. at 95:16–22.
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`• When asked whether he had ever seen Exhibit 2078 before, Dr. Bloch
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`answered “No. I mean I actually don’t know if I have. What is this?”
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`Id. at 96:6–9.
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`• Dr. Bloch testified that he had “reviewed medical reviews from the
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`FDA” in the past but that he was “not familiar with this one.” Id. at
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`97:25–98:2.
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`• Dr. Bloch testified that he was “more confident” that the medical
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`reviews he reviewed “would have come from the FDA” rather than
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`-5-
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`
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`from CDER and that it was unclear what was the purpose of the
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`reviews in EX2078. Id. at 98:17–99:3.
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`• Dr. Bloch testified that it was unclear from the EX2078 how the
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`response arose and who requested that it be created, and stated: “I
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`don’t understand what this even is, honestly.” Id. at 100:9–20.
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`• Dr. Bloch testified: “This is not part of the FDA’s documents. It’s
`
`CDER document. So I’m kind of confused about how this fits in.”
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`Id. at 100:22–24.
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`• Dr. Bloch stated: “I mean who asked for this report to even be done
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`in the first place? Perhaps Allergan did.” Id. at 102:11–12.
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`With respect to Table 4 on page 26 of EX2078, Dr. Bloch testified that the
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`reviewer’s comment was a “post-hoc analysis ‘dredging,’ to put one term on it.”
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`Id. at 103:19–104:20.
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`• When asked whether he had any reason to believe that FDA didn’t approve
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`Restasis based on Table 4 on page 26 of EX2078, Dr. Bloch testified: “I
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`sincerely believe they paid most attention to the investigational plans or the
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`studies as such rather than somebody’s post-hoc opinion.” Id. at 105:1–8.
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`• Dr. Bloch also testified: “You know, these P values I would question as to
`
`whether or not they’re even correct given the post-hoc nature of this
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`analysis” and that “I would so advise the FDA….” Id. at 105:16–20.
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`-6-
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`Dr. Bloch’s Critiques of Dr. Attar’s Analyses
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`Allergan omits relevant testimony and mischaracterizes the cited testimony.
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`Observations at 2–4.
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`• While Dr. Bloch did use a magnifying glass and ruler to measure the
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`value of the bars on Dr. Attar’s Exhibit B, such a procedure allowed
`
`him to produce “very accurate measurement[s]” with a resolution on
`
`the order of .005. Id. at 43:15–19; 47:10–13.
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`• Dr. Bloch testified that his conclusion that Dr. Attar used the lower
`
`conjunctiva, rather than the combination of the lower and upper, was
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`“not debatable.” Id. at 39:1–40:17. Given the accuracy of his
`
`measurements, Dr. Bloch testified that he could clearly discern the
`
`difference between ratios of 0.29 and 0.32. Id. at 47:14–18 (“And the
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`difference between, as you used the combination, as she changed her
`
`testimony to indicate that difference would have been 0.29 versus
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`0.32. That’s a large difference, there’s no question I could see that.”).
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`• Dr. Bloch declined to accuse Dr. Attar of lying. Id. at 52:14–15.
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`Instead, Dr. Bloch stated, “I believe she was trying to make a point
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`that because…there were no studies that directly compared 0.05
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`cyclosporine with 0.625 castor oil to 0.05 cyclosporin with 1.25 castor
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`oil. They didn’t exist. So this was a way for her to try to act as if you
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`-7-
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`
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`
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`could actually compare those two studies. But you can’t. There is no
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`comparison and this doesn’t work either.” Id. at 68:6–14; see also id.
`
`at 74:5–8 (“I have read the aims and scope of what the pharmacology
`
`studies are and the 163 had no aim contrasting 0.05/0.625 formulation
`
`to 0.05/1.25 formulation. That was not part of their aims.”); id. at
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`70:6–8 (“So if you want to compare 0.05/0.625 to 0.05/1.25, you have
`
`to do a study to do it, to show it. It doesn’t exist.”). He also stated, “I
`
`think that has to do with…her way of --in her role in helping Allergan
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`in this matter.” Id. at 69:3–5.
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`• Dr. Bloch characterized Dr. Attar’s statements as “simply not true”
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`and “misleading.” Id. at 49:11–15 (“So she says, for example, there
`
`was more cyclosporin A present [in the tissue] with the formulation
`
`containing 0.05 percent by weight cyclosporin and .0625 percent,
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`than, for example, the 0.1. Well, that’s simply not true.”); id. at
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`69:11–13 (“That’s what she says. But that is misleading because she
`
`has hidden the fact that the relative is not the same.”); id. at 49:17–
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`50:12 (“So the statement that she actually writes down is wrong. It’s
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`not that the absolute amount of cyclosporin is less and that’s
`
`surprising, it’s simply a misleading statement.”). Dr. Bloch further
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`stated, “Dr. Attar’s declaration contained no information for me to
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`-8-
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`
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`
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`understand this. So I knew there was something -- there was some
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`funny business going on with this figure . . . .” Id. at 41:08–13. Upon
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`his own examination of the underlying data, Dr. Bloch understood
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`how Dr. Attar’s declaration was misleading. Id. at 41:23–42:19 (“Oh
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`boy, that’s a nice way to hide something.”).
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`• Dr. Bloch also explained that Dr. Attar’s declaration gave the false
`
`impression that she was comparing apples to apples:
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`[W]hat she’s doing is taking a ratio A divided by B. She’s taking
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`another ratio C divided by D. And then she’s hidden the fact that B
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`and D are different. So she’s -- the reader would understand or I
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`believe would falsely, without question, believe that what she is doing
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`is comparing A divided by B to C divided by B again. But it isn’t --
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`that is a misrepresentation and she -- if you do it properly there is no
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`such graphic way. What she wants -- where’s the problem?: there is
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`no direct comparison with 0.05 with 0.625. There is no way you can
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`really do it. The data does not exist.
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`Id. at 69:16–70:3.
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`• Dr. Bloch also testified that Dr. Attar’s analysis would have been deficient
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`regardless of whether she compared the lower and upper conjunctiva: “I
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`believe [Dr. Attar’s] point would have been essentially identical. It’s just the
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`height of the bar instead of being 0.32 would have been 0.29. It would still
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`have the same misrepresentation. Qualitatively it makes no difference.” Id.
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`-9-
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`
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`at 76:12–17 (emphasis added). As Dr. Bloch stated, “I was saying that you
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`cannot draw the conclusion, reliable conclusion as she is making from this
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`type of analysis that she made.” Id. at 75:21–24.
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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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`-10-
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`
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`CERTIFICATE OF SERVICE
`
`This is to certify that I caused to be served true and correct copies of the
`
`foregoing Petitioners’ Response to Patent Owner’s Motion for Observations on the
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`Cross-Examination of Dr. Daniel A. Bloch on this 27th day of July, 2017, on the
`
`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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`-11-
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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.
`
`Dated: July 27, 2017
`
`
`
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
`
`
`
`
`-12-
`
`
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