`
`Paper No. ___
`Filed: July 27, 2017
`
`
`
`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).
`
`
`
`
`
`
`
`
`
`Petitioner submits this Response to Allergan’s Motion for Observations on
`
`the Cross-Examination of Dr. Andrew Calman (“Observations”) pursuant to the
`
`Standing Order (Paper 9) and the Scheduling Order (Paper 10).
`
`Dr. Calman’s Opinions Regarding Thermodynamic Principles
`
`Allergan’s First Observation (Mot’n at 1-2) omits relevant testimony and
`
`mischaracterizes the cited testimony.
`
`• Dr. Calman testified that he is capable of competently discussing the
`
`pharmacokinetic studies in a clinical context. EX2082 at 157:21–24
`
`(“I believe I am qualified to discuss these issues and as well to put
`
`them in clinical context which neither of them [Drs. Amiji and
`
`Loftsson] is a clinician.); Id. at 158:8–16 (“[T]here are other aspects
`
`where I can provide a clinical context that’s missing.”).
`
`• Dr. Calman testified that he would “defer to the formulators”
`
`regarding “any equations regarding thermodynamic activity,” but
`
`that “with regard to the relationship of the bioavailability to the
`
`clinical efficacy, I’m a clinician and they’re not.” Id. at 158:12–16; id.
`
`at 158:2-22.
`
`• In his declaration, Dr. Calman testified regarding the “internal
`
`pharmacokinetic studies” relied upon by Dr. Loftsson in support of his
`
`thermodynamics theory and relied upon by Dr. Attar for her
`
`
`-1-
`
`
`
`
`
`declaration. EX1039, ¶¶76-81. Dr. Calman testified that their
`
`presentation by Dr. Attar “is problematic” and “scientifically
`
`improper,” with study designs that were “vastly different,” including
`
`because one was a steady-state study and the other was a single-dose
`
`study. Id., ¶77. Dr. Calman also testified that it was misleading to
`
`claim that “there are significant and material differences in the amount
`
`of CsA that each formulation delivered to the ocular tissue” because
`
`“each formulation delivered CsA to the cornea and conjunctiva well
`
`above the threshold required for therapeutic efficacy” and “there
`
`was no ‘dose-response’ effect” between the CsA formulations. Id.,
`
`¶¶78-81 (emphasis in original).
`
`Allergan claims that Dr. Amiji “provided no opinions regarding
`
`thermodynamic principles in his declaration or deposition testimony.”
`
`• Dr. Amiji explained that each of the formulations in Example 1 of
`
`Ding ’979 had a ratio of cyclosporin to castor oil sufficient to deliver
`
`therapeutic concentrations of CsA:
`
`Ding ’979 names “Examples 1A-1D” when discussing “formulations
`
`with cyclosporine” and the “cyclosporin containing castor oil
`
`emulsion,” for which emulsions it reports finding therapeutic levels of
`
`cyclosporin, “no difference” in toxicity as compared to the emulsions
`
`without cyclosporin, and no crystallization of cyclosporin after nine
`
`-2-
`
`
`
`
`
`months at room temperature. [EX1006] at col. 5, ll.18-30. Based on
`
`the disclosure of Ding ’979, a person of ordinary skill in the art would
`
`expect that any of the CsA amounts disclosed in Example 1, in
`
`combination with any of the vehicles disclosed in Example 2, would
`
`yield a non-irritating emulsion, useful in the treatment of dry eye
`
`disease/KCS if the ratio of CsA to castor oil falls within the preferred
`
`range taught by Ding ’979.
`
`E.g., IPR2016-01127, EX1002, ¶71; see also id., ¶¶67-68, 94, 105, 110, 113;
`
`EX1006, 3:15-28 (“No crystallization of cyclosporin was noticed after nine months
`
`at room temperature. Moreover, the cyclosporin emulsion is formulation in such a
`
`way that the drug has reasonably high thermodynamic activity, yet without the
`
`crystallization problem.”); id., 2: (describing problems with prior art “oily
`
`formulations’ as including “the crystallization problem” and “a low
`
`thermodynamic activity (degree of saturation) of cyclosporin which leads to poorer
`
`drug bioavailability”); EX2023 at 160:23-161:3 (Dr. Amiji testifying that Ding
`
`’979’s discussion of drawbacks of oily formulations is “just talking about
`
`dissolving cyclosporin in oil. They’re not talking about emulsions here.”).
`
`• Dr. Amiji also confirmed that Ding ’979’s conclusions regarding
`
`therapeutic efficacy were based on “rabbit data,” and that “Rabbit data
`
`are informative about the therapeutic efficacy as well as the safety.”
`
`Id., 158:4-158:13. Dr. Amiji also testified that Ding’979 patent
`
`describes performing “slit lamp analysis of the corneal tissue and they
`
`-3-
`
`
`
`
`
`also mention that they tested for ocular bioavailability and the
`
`therapeutic levels of cyclosporin.” Id., 158:19-159:14.
`
`Dr. Calman’s Opinions Regarding Sall Figure 2
`
`Allergan’s Second Observation (Mot’n at 2-3) omits relevant testimony and
`
`mischaracterizes the cited testimony.
`
`• With regard to Allergan’s terminology “numerically superior,”
`
`Calman stated: “Well, I --‘numerically superior’ is a little bit of a
`
`loaded term. It is not statistically significantly different. The number,
`
`the average number, the mean is higher. All of these are very small
`
`changes. But the number -- the change is slightly higher for .05 on this
`
`particular time point.” EX2082 65:15–21.
`
`• Dr. Calman also states:
`
`To put that [Sall Fig. 2] in context, this is categorized Schirmer values
`
`with pitfalls that I discussed at length, as did Dr. Bloch, in our
`
`declarations, measured with anesthesia at the -- at a time point that --
`
`and which was measured only at two time points in contrast to most of
`
`the other measures. And at the time point that was not the key time
`
`point of six months as identified by Allergan, none of these emulsions
`
`achieve any significant change or seen -- none of these emulsions
`
`achieve a significant change compared to baseline at Month 3. But
`
`there was a statistically significant difference between .05 and vehicle
`
`but not between .05 and .1.
`
`Id. at 57:15–58:6.
`
`-4-
`
`
`
`
`
`• Regarding the 0.1% CsA formulation allegedly decreasing tear
`
`production in Sall Fig. 2, Dr. Calman states, “I think you’re taking
`
`that out of context . . . . . So as a person of ordinary skill, when I look
`
`at that, I’m thinking this is very strange. And I would like to see the
`
`underlying raw Schirmer data, which we asked for which the patent
`
`owner did not want to disclose.” Id. at 58:12–59:14.
`
`• With regards to Dr. Amiji’s statement, Dr. Calman states, “Well, it’s a
`
`literal -- it’s a literal statement that is not factually wrong. The context
`
`that I would add in addition to what I stated a few minutes ago is that -
`
`- because, you know, there is no statistically significant difference
`
`between the .01 -- the .1 and the .05, which is about .3 to .4 units,
`
`those are very small and potentially, you know, either very mildly
`
`clinically meaningful or not clinically meaningful.” Id. at 72:18–73:2.
`
`Dr. Calman’s testimony does not contradict his declaration or the petitioner,
`
`and there is no contradiction between Dr. Calman’s testimony and Dr. Amiji’s
`
`testimony.
`
`Dr. Calman’s Qualifications Regarding Clinical Studies in Sall and Stevenson
`
`Allergan’s Third Observation (Mot’n at 3-4) omits relevant testimony and
`
`mischaracterizes the cited testimony.
`
`-5-
`
`
`
`
`
`• Dr. Calman has acquired extensive knowledge including “27 years in
`
`clinical work plus 12 years in labs doing basic research. And through
`
`that knowledge, education, skills, training, and experience, I have
`
`acquired certain knowledge about pharmaceutical formulations,
`
`including ophthalmic formulations and their application in clinical
`
`practice, in clinical trials, et cetera.” Id. at 22:17–23:2.
`
`• Dr. Calman has also gained experience in developing a CsA
`
`ophthalmic product: “I was working with professors as a resident in
`
`ophthalmology, and we certainly used ophthalmic cyclosporin
`
`formulations at that time.” Id. at 24:1-7.
`
`• Dr. Calman is similarly well versed in clinical research studies: “And
`
`we discussed earlier today some of the various clinical research
`
`studies I was involved in where excipients and formulation were key
`
`aspects of the study design.” Id. at 155:21–156:13.
`
`• Dr. Calman also testified that some of the clinical trials in which he
`
`participated involved treatments for dry eye patients and that he
`
`believed they involved “monitoring modalities” related to dry eye to
`
`evaluate the impact of the drugs on the “ocular surface while treating
`
`the glaucoma.” EX2082 at 30:10-31:17.
`
`-6-
`
`
`
`
`
`• Dr. Calman also testified that he is familiar with the Schirmer tear test
`
`and uses it in his own clinical practice. Id., 44:11-45:5.
`
`The testimony cited by Allergan does not demonstrate a lack of qualification
`
`by Dr. Calman to provide expert testimony regarding the clinical studies in Sall
`
`and Stevenson.
`
`Dr. Calman’s Analysis of Sall Figure 2
`
`Allergan’s Fourth Observation (Mot’n at 4-5) omits relevant testimony and
`
`mischaracterizes the cited testimony.
`
`• The passage Allergan cites reads in full, “If I had to present this data
`
`at a medical conference, I would be deeply apologetic at the fact that
`
`whoever was providing the data to me had given me an incomplete
`
`data set.” Id. at 107:6-9.
`
`• Dr. Calman emphasized that he did the best work he could with the
`
`limited data set supplied by Allergan. Id. at 106:03–07.
`
`• While Dr. Calman did not purport to literally and fully reverse
`
`engineer the underlying data from Sall Figure 2, he testified that this
`
`part of his analysis focused on whether the differences reported in Sall
`
`Figure 2 were clinically material. Id., 103:1-105:19. (“I’m not trying
`
`to oversell this. I’m saying that this is an attempt to determine if the
`
`-7-
`
`
`
`
`
`changes are small or large….I’m just trying to get an idea of the
`
`magnitude of the change in the population.”).
`
`• Dr. Calman testified during his deposition that “there was no
`
`statistically significant difference reported between the .05 and the .1”
`
`CsA formulations in Sall Figure 2, and that the changes “were small”
`
`from a clinical perspective. Id., 163:4-164:21.
`
`• Dr. Calman elaborated that even the largest change from baseline,
`
`which was larger than any difference between the two formulations,
`
`was, “at the most, 0.4 for Schirmer, quote/unquote, units [and]
`
`correspond[s] to a small increase in actual Schirmer score on the order
`
`of 2 millimeters. Maybe it’s 1, maybe it’s 3, maybe it’s 2. None of
`
`those are, in my experience, material.” Id., 163:4-164:21; see also Id.
`
`at 99:3-10 (“[W]e can quibble over whether they’re going from 3
`
`millimeters to, you know, 3.5 millimeters. I don’t care if it’s 4
`
`millimeters to 4.5 or 5 millimeters to 5.5. We’re still talking about
`
`small changes.”); id. at 106:16–21 (“It’s hard to see how it would
`
`even be 3 millimeters.”).
`
`The testimony cited by Allergan does not demonstrate unreliability or lack
`
`of accepted scientific practice in Dr. Calman’s analysis.
`
`Dr. Calman’s Scope of Work and EX2078
`
`-8-
`
`
`
`
`
`Allergan’s Fifth Observation (Mot’n at 5-6) mischaracterizes the record, as
`
`Allergan did not produce Exhibit 2078 with its Patent Owner Responses and did
`
`not rely on any data from Exhibit 2078 in its Patent Owner Responses for any
`
`purpose, including to establish criticality or unexpected results of the 0.05% CsA
`
`formulation as compared to the 0.10% CsA formulation. Whether or not Dr.
`
`Calman reviewed documents that Allergan failed to produce or rely upon to satisfy
`
`its burden of production is irrelevant to his analyses. Allergan’s characterization of
`
`EX2078 as establishing that the 0.05% formulation “works differently” is
`
`unsupported and incorrect.
`
`The Kaswan Article’s Proof of Therapeutically Effective CsA Levels
`
`Allergan’s Sixth Observation (Mot’n at 6-7) omits relevant testimony and
`
`mischaracterizes the cited testimony.
`
`• Dr. Calman testified that Kaswan teaches the intraocular level of CsA
`
`in the aqueous humor understood at the time to be sufficient to control
`
`of uveitis. Id. at 132:2–4.
`
`• Although Nussenblatt reports therapeutic levels of cyclosporin in
`
`serum, Dr. Calman testified that therapeutic levels of CsA in blood
`
`were informative of the CsA levels in tissue:
`
`I’ve explained how similar serum levels are required for efficacy in a
`
`variety of solid tissues, which indicates that—including the eye as
`
`based on Nussenblatt, which indicates there is not something magical
`
`-9-
`
`
`
`
`
`about the eye or any other tissue that tends to concentrate or reduce
`
`the concentration of cyclosporin in tissue with regard—compared to
`
`the blood. And, furthermore, in the Nussenblatt study, we actually do
`
`have a comparison. You know, we do have an actual tissue level of
`
`cyclosporin in the vitreous which is very comparable. Instead of you
`
`know, 100 to 400, it’s 160 to 580. You know, we’re in that same
`
`ballpark. You know, I’m convinced as a scientist reading the totality
`
`of this data that those are the kinds of tissue levels that are adequate
`
`for efficacy in a variety of tissues.
`
`Id., 149:23-152:25.
`
`• Dr. Calman reiterated, “[I]t’s not a high school student but a POSA, a person
`
`that would understand that if a wide variety of tissues are achieving adequate
`
`levels to control disease with these types of levels in the blood, that these are
`
`likely to be applicable to other types of tissues as well.” Id. at 148:16–
`
`149:11.
`
`• Dr. Calman also explained that Nussenblatt and Oellerich each demonstrate
`
`that the CsA levels were neither “dramatically higher nor dramatically lower
`
`in the tissues than they are in the bloodstream that supplies them.” Id. at
`
`149:12–22.
`
`• Dr. Calman testified that Nussenblatt injecting cyclosporin directly into the
`
`eye resulted in “mean cyclosporin levels between 160 and 580 nanograms
`
`per grams,” that these concentrations “worked” in the tissue, that these levels
`
`-10-
`
`
`
`
`
`were “roughly comparable to all these other ranges we’ve been discussing
`
`with regard to serum levels,” and that “we can quibble is it 50 to 300 [as
`
`reported in Kaswan] or is it 160 to 580 [as reported in Nussenblatt] or is it
`
`100 to 400 [as reported in Oellerich]. All of these are in the same ballpark.”
`
`Id., 135:2-137:6; see also id., 141:22-142:25.
`
`• Dr. Calman testified that Kaswan is “very much responsive to an inquiry as
`
`to tissue levels of cyclosporin in relevant tissues…with a view towards
`
`ameliorating Sjogren’s syndrome and KCS, among other things.” Id.,
`
`145:10-146:29.
`
`• Allergan’s counsel also elicited testimony from Dr. Calman confirming that
`
`“Kaswan at 653” states “In dogs with KCS, topical CsA ameliorated the
`
`chronic keratitis and increased the average Schirmer test by 9 millimeters
`
`per minute.” Id., 144:3-12.
`
`• Dr. Calman also testified that Nussenblatt and Kaswan disclose by
`
`implication CsA concentration that were therapeutically effective for
`
`increasing tear production because they discuss “what is believed in the field
`
`to be adequate concentrations for uveitis, for example, which is an example
`
`of a severe ocular inflammatory condition. Id., 160:9-161:13. Dr. Calman
`
`testified that uveitis is “an example of a severe ocular inflammatory
`
`condition” that is “often vision-threatening inflammation.” Id., 161:1-2. Dr.
`
`-11-
`
`
`
`
`
`Calman testified that experimental autoimmune uveitis (“EAU”), the animal
`
`model used in Nussenblatt as a proxy for uveitis, is “another pretty big-time,
`
`high-powered anti-inflammatory disease.” Id., 136:24-137:2.
`
`• Dr. Calman explained what he meant by “severe” and “high-powered”
`
`disease by explaining that uveitis is a serious condition:
`
` [W]here oftentimes we’re having patients put in our most potent
`
`steroid every one or two hours, sometimes around the block. In
`
`contrast, there are other conditions where we may use steroids, either
`
`short-term or long-term, where much lower concentrations or
`
`frequency is effective. Examples of that include KCS and certain
`
`types of ocular allergy where very low dose, such as a once or twice a
`
`day of administration of our lowest potency steroid drop, may be
`
`sufficient for clinical effect. So that was my—that was my—just
`
`trying—again, my job here in part is to put all of these things into
`
`clinical context.
`
`Id., 161:14-162:18.
`
`Allergan incorrectly asserts (Mot’n at 7) that Kaswan’s teaching regarding
`
`therapeutic levels of CsA are inaccurate, incorrectly asserts that the therapeutic
`
`levels was unknown prior to September 15, 2003, and incorrectly asserts that a
`
`POSA would not have expected substantially equivalent efficacy in increasing tear
`
`production from the 0.05% and 0.10% CsA formulations.
`
`Dr. Calman’s Analysis Regarding Relevant Information to Tear Production
`
`-12-
`
`
`
`
`
`Allergan’s Seventh Observation (Mot’n at 8-9) omits relevant testimony and
`
`mischaracterizes the cited testimony.
`
`• When asked whether the STT with anesthesia measures basal aqueous
`
`tear production, Dr. Calman responded, “Well, with the caveats I’ve
`
`expressed.” Id. at 47:2–4.
`
`• Dr. Calman also explained:
`
`And in my experience, the variability is even worse with the
`
`Schirmer’s with anesthesia because, if you think about it, when you
`
`put that eye drop in, it’s hard to get all of that anesthetic eye drop out.
`
`The anesthetic eye drop itself sometimes causes some reflect tearing
`
`because it stings. And so that’s why I’ve been careful all along to say
`
`to a first approximation, Schirmer’s with anesthesia reflects basal
`
`tearing because it’s an imperfect test. And in my experience, it’s more
`
`variable than the Schirmer’s without. Because if you’ve got that eye
`
`drop left over in the eye, that’s going to give you a few millimeters
`
`right there. You know, if you’ve got reflexive tearing because the
`
`patient’s getting stinging from the aesthetic, that’s going to potentially
`
`give you more millimeters there.
`
`Id. at 104:8–23.
`
`Contrary to Allergan’s characterizations (Mot’n at 8-9), Dr. Calman’s
`
`deposition testimony cited by Allergan does not contradict Dr. Calman’s testimony
`
`that “there was no material difference between the 0.05% CsA formulation and the
`
`0.1% CsA formulation,” his testimony that “both of the CsA formulation were
`
`-13-
`
`
`
`
`
`therapeutically effective in treating dry eye, including by increasing aqueous tear
`
`production from the lacrimal glands,” or his testimony that the POSA “would not
`
`have selectively limited an analysis of comparative efficacy to solely data reported
`
`for the STT with anesthesia.”
`
`
`
`Contrary to Allergan’s contentions (Mot’n at 9), Dr. Calman’s testimony
`
`does not prove that Sall Figure 2 was the only data in Sall reporting basal tear
`
`production or that the POSA would focus on Sall Figure 2 to compare the CsA
`
`formulations’ with respect to basal tear production.
`
`Dated: July 27, 2017
`
`
`
`
`
`Respectfully submitted,
`
`
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
`
`
`
`
`
`
`-14-
`
`
`
`
`
`
`
`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
`
`Cross-Examination of Dr. Andrew Calman 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.
`
`
`
`-15-
`
`
`
`
`
`
`
`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
`
`
`
`
`
`-16-
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
