UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`ARGENTUM PHARMACEUTICALS LLC, MYLAN PHARMACEUTICALS
`INC., BRECKENRIDGE PHARMACEUTICAL, INC., AND ALEMBIC
`PHARMACEUTICALS, LTD.,
`Petitioners,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`
`_____________________________
`
`IPR2016-002041
`Patent RE 38,551
`_____________________________
`
`
`
`PETITIONERS’ RESPONSE TO MOTION FOR OBSERVATIONS
`REGARDING THE CROSS-EXAMINATION OF DR. KATHRYN DAVIS
`
`
`
`1 Case IPR2016-01101, Case IPR2016-01242, and Case IPR2016-01245 have been
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`joined with this proceeding.
`
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`ARGENTUM PHARMACEUTICALS LLC, MYLAN PHARMACEUTICALS
`INC., BRECKENRIDGE PHARMACEUTICAL, INC., AND ALEMBIC
`PHARMACEUTICALS, LTD.,
`Petitioners,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`
`_____________________________
`
`IPR2016-002041
`Patent RE 38,551
`_____________________________
`
`
`
`PETITIONERS’ RESPONSE TO MOTION FOR OBSERVATIONS
`REGARDING THE CROSS-EXAMINATION OF DR. KATHRYN DAVIS
`
`
`
`1 Case IPR2016-01101, Case IPR2016-01242, and Case IPR2016-01245 have been
`
`joined with this proceeding.
`
`
`
`
`
`IPR2016-00204
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`
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`Petitioners file this Response to Patent Owner’s Motion for Observations on
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`Cross-examination of Dr. Kathryn Davis (Paper 70) in accordance with Due Date 5
`
`(Papers 20, 50). Petitioners respectfully disagree that Patent Owner’s Observations
`
`are relevant or demonstrate inconsistency for the reasons asserted by Patent
`
`Owner. Furthermore, several of Patent Owner’s Observations are argumentative.
`
`Petitioners respectfully reserve their right to present such argument during the oral
`
`hearing.
`
`Observation #1: Patent Owner’s Observation omits relevant testimony
`
`concerning the prior art compound levetiracetam and its known properties. See
`
`Ex.2195, 244:9-12 (¶¶43-45 “highlight the fact that levetiracetam was already
`
`being studied in animal studies and in humans prior to the lacosamide patent”);
`
`243:20-246:15; 127:25-142:24 (discussing references published before 1996
`
`reporting antiepileptic properties of levetiracetam).
`
`Observation #2: Patent Owner’s Observation omits relevant testimony and
`
`mischaracterizes Dr. Davis’s testimony. When asked to confirm that levetiracetam
`
`was not approved to treat epilepsy in 1996, Dr. Davis responded: “That is correct.
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`Although I assume the clinical trials were already ongoing or complete at that
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`point.” Ex.2195, 124:18-125:15. Dr. Davis testified that by 1996 levetiracetam
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`“was certainly in the drug pipeline and in discussion at conferences at that point,”
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`(id. at 125:17-126:4) and “[o]utside of clinical trials, would not be used clinically”
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`IPR2016-00204
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`in the United States “given its lack of FDA approval.” Id. at 127:1-2. Dr. Davis
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`also testified that antiepileptic properties of levetiracetam were known prior to
`
`1996. Id. at 244:9-12 (¶¶43-45 “highlight the fact that levetiracetam was already
`
`being studied in animal studies and in humans prior to the lacosamide patent.”);
`
`243:20-246:15; 127:25-142:24 (discussing references published before 1996).
`
`Observation #3: Patent Owner’s Observation omits relevant testimony
`
`concerning the availability of levetiracetam and its known properties. See Ex.2195,
`
`244:9-12 (“These paragraphs [¶¶43-45] highlight the fact that levetiracetam was
`
`already being studied in animal studies and in humans prior to the lacosamide
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`patent.”); 243:20-246:15; 127:25-142:24 (discussing references published before
`
`1996 reporting antiepileptic properties of levetiracetam). Further, Patent Owner’s
`
`Observation improperly cites to extended portions of the deposition transcript of
`
`ten pages.
`
`Observation #4: Patent Owner’s Observation mischaracterizes Dr. Davis’s
`
`testimony. For example, when asked if she prescribed levetiracetam for all of her
`
`patients, if all of her patients are on levetiracetam, and if levetiracetam would have
`
`been inappropriate for her patients not on levetiracetam, Dr. Davis testified that
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`“the majority of my patients are on levetiracetam, meaning over 50%,” and that it’s
`
`“not always the case” that levetiracetam would be inappropriate for a patient not on
`
`levetiracetam. Ex.2195, 47:4-25. Dr. Davis testified selecting an AED involves
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`IPR2016-00204
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`considering if the patient is already tolerating a different medication well and if the
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`patient is so “very drug-resistant” that no known AED will work for them. Id. at
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`48:1-14. Dr. Davis testified that while there may be “multiple different medication
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`options, all of which work, she would also consider other medication options, all of
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`which work, and for young women, [who] potentially could get pregnant,” she
`
`thinks about “what’s safe in pregnancy. Id. at 48:15-50:3. Dr. Davis testified that
`
`“the lack of data available” makes her very uncomfortable using lacosamide in any
`
`woman of childbearing age,” while levetiracetam “has substantial evidence
`
`supporting its use as one of our safest options in females of childbearing age.
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`Ex.2195, 95:13-25, 99:4-11; see also, 232:9-17 (“it’s very clear that levetiracetam
`
`should be used prior to using lacosamide in that population [i.e., women of
`
`childbearing age] given that we have the safety data to us.”). Dr. Davis further
`
`testified that “I'm aware that some physicians are influenced by particularly drug
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`companies that will come and bring free lunches, coffees, et cetera, to promote
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`their product,” and that “It is my experience that the UCB drug representatives are
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`particularly persistent in comparison to other drug representatives within the field
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`of epilepsy.” Id. at 257:19 to 260:1.
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`Observation #5: Patent Owner’s Observation mischaracterizes Dr. Davis’s
`
`testimony. Dr. Davis testified that “about one third” of all epilepsy patients have
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`“drug-resistant epilepsy” (Ex.2195, 106:14-17) and “[f]or these patients . . . the
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`IPR2016-00204
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`only treatment option to date that can offer a cure [is] some kind of surgical
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`intervention, whether it be resection or laser ablation.” Id. at 102:20-103:7. Dr.
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`Davis testified that lacosamide “ha[s] not changed that number of drug-resistant
`
`epilepsy patients” and just “add[s] to the list of medicines that we have at our
`
`disposal but [does] not actually decrease the number of refractory epilepsy patients
`
`in the world. So if you’re arguing that this [lacosamide] is somehow more
`
`efficacious [than other AEDs], that has not been held true with clinical data or
`
`clinical experience.” Id. at 147:21-148:8. Dr. Davis testified: “I don’t disagree that
`
`lacosamide can help some patients. What is not clear, that it is in any way more
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`efficacious than other clinically available drugs[.]” Id. at 168:5-10.
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`When asked “how many AED prescriptions do you write each year?” Dr.
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`Davis testified: “I would say I probably prescribe 10,000 prescriptions.” Id. at
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`45:20-45:4. Dr. Davis testified: “[T]he majority of my patients are on
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`levetiracetam, meaning over 50 percent,” (id. at 47:6-10) and “similar to Dr. Bazil,
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`I actually have never used lacosamide as a first-line agent[.]” Id. at 54:1-11.
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`Observation #6: Patent Owner’s Observation mischaracterizes Dr. Davis’s
`
`testimony. Dr. Davis testified “about one third” of all epilepsy patients have
`
`“drug-resistant epilepsy.” Ex.2195, 102:6-25. Dr. Davis testified that lacosamide
`
`“ha[s] not changed that number of drug-resistant epilepsy patients” and just “add[s]
`
`to the list of medicines that we have at our disposal but [does] not actually decrease
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`-4-
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`IPR2016-00204
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`the number of refractory epilepsy patients in the world. So if you’re arguing that
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`this [lacosamide] is somehow more efficacious [than other AEDs], that has not
`
`been held true with clinical data or clinical experience.” Id. at 147:21-148:8.
`
`Observation #7: Patent Owner’s Observation mischaracterizes Dr. Davis’s
`
`testimony. Patent Owner states that Dr. Davis agreed that the Lennox-Gastaut
`
`syndrome population is 3.63% of the total epilepsy population when, in fact, she
`
`agreed that “the drug-resistant Lennox-Gastaut syndrome population is 3.63
`
`percent of the total epilepsy population.” Ex.2195, 108:10-22 (emphasis added).
`
`Dr. Davis confirmed that one-third of epilepsy patients are drug-resistant, two-
`
`thirds have “medically-controlled epilepsy,” 3.63% and 2.3% have drug-resistant
`
`Lennox-Gastaut syndrome or drug-resistant generalized epilepsy, respectively, and
`
`that these numbers add up to approximately 5.9% of the epilepsy population
`
`having drug-resistant Lennox-Gastaut syndrome or drug-resistant generalized
`
`epilepsy. Id. at 105:7-111:19. Dr. Davis testified that some patients with Lennox-
`
`Gastaut “have medically-controlled epilepsy” and clarified that 3.63% “is only
`
`highlighting those with drug-resistant or refractory epilepsy in the percentage.” Id.
`
`at 107:15-21. The 5.9% figure cited by Patent Owner does not account for 67% of
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`IPR2016-00204
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`epilepsy patients, and does not undermine Dr. Davis’s testimony that
`
`approximately 20% of all epilepsy patients have one of these two conditions.
`
`Dr. Davis testified that lacosamide is “not used extensively, and it is not one
`
`of the first, second, or third-line choices for Lennox-Gastaut syndrome.” Id. at
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`75:7-13. Dr. Davis testified that in patients with Lennox-Gastaut or juvenile
`
`myoclonic epilepsy, lacosamide “either did not improve seizures at all, or they
`
`continued to have frequent breakthrough seizures.” Id. at 234:13-22.
`
`Observation #8: Patent Owner’s Observation mischaracterizes Dr. Davis’s
`
`testimony. Dr. Davis testified that only super-refractory status epilepticus patients
`
`“that have gone through the initial treatments . . . as outlined in our Penn protocol”
`
`would “even be considered for lacosamide. So it’s actually a quite small group.”
`
`Ex.2195, 250:10-251:8. Dr. Davis noted “in Dr. Bazil’s testimony he said
`
`something on the realm of 50 patients a year. . . . 50 patients a year is a very small
`
`number when you actually spread it out over the year. And I would say my clinical
`
`experience is similar, that probably we use lacosamide in approximately 50
`
`patients per year, but that represents only a very small percentage of the status
`
`epilepticus population.” Id. at 250:10-251:8 (emphasis added).
`
`Observation #9: Patent Owner’s Observation mischaracterizes Dr. Davis’s
`
`testimony. Dr. Davis did not ignore the distinction between monotherapy and
`
`adjunctive therapy, but rather testified that while not approved for monotherapy,
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`IPR2016-00204
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`“levetiracetam is, to my knowledge, the most commonly prescribed antiepileptic
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`drug in the United States and is very frequently used as a monotherapy agent,
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`including in my practice.” Ex.2195, 100:2-10; see also, 100:24-101:3 (“Although
`
`the FDA didn’t approve it [levetiracetam as a monotherapy], the statistics
`
`regarding usage and my experience as an epilepsy expert indicate that it is being
`
`used extensively as a monotherapy agent.”); 54:1-11 (“[S]imilar to Dr. Bazil, I
`
`actually have never used lacosamide as a first-line agent[.]”).
`
`Observation #10: Patent Owner’s Observation mischaracterizes Dr.
`
`Davis’s testimony. Dr. Davis’s testimony does not establish that “studies of
`
`lacosamide for treatment of generalized epilepsy and in children are currently
`
`underway under a similar timeline as was done for levetiracetam (Keppra),” as
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`Patent Owner claims. Dr. Davis testified: “I’ve used lacosamide off-label in a
`
`primary generalized epilepsy patient; and, unfortunately, had a very bad experience
`
`doing that, and I no longer do that.” Id. at 54:25-55:5. In response to a question on
`
`clinical trials of lacosamide for primary generalized epilepsy, Dr. Davis testified:
`
`[T]here was one abstract at American Epilepsy Society a few years
`ago with a small case series of patients . . . with primary generalized
`epilepsy that received lacosamide. Based upon that abstract, I did
`utilize lacosamide in some of these patients; but my personal
`experience in doing so did not result in efficacy. In fact, several of my
`patients worsened with the addition of lacosamide that have primary
`generalized epilepsy. So, although the trial is ongoing and I
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`IPR2016-00204
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`acknowledge that, myself and others in the field I don’t think are
`highly optimistic regarding the results of that trial.
`Id. at 62:5-23 (emphasis added).
`
`Observation #11: Dr. Davis’s statements at 72:19-73:23 regarding the
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`absence of trials establishing either equivalency or superiority of lacosamide over
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`levetiracetam do not contradict her declaration at ¶71 that “lacosamide is not
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`deemed to be superior, or even equivalent, to levetiracetam” in treating elderly
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`patients or juveniles with CNS disorders. Patent Owner’s Observation
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`mischaracterizes Dr. Davis’s testimony. For instance, Dr. Davis testified: “[I]n
`
`primary generalized epilepsy syndrome, there’s, for the vast majority of cases, no
`
`evidence that a specific broad-spectrum antiepileptic drug is more efficacious,
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`whether it be levetiracetam or lamotrigine or topiramate or zonisamide, for
`
`instance.” Ex.2195, 48:21-49:2; see also, 51:10-14 (“if you’re not sure what kind
`
`of epilepsy someone has, it’s safer to go with a broad-spectrum antiepileptic drug,
`
`such as levetiracetam, lamotrigine, topiramate, zonisamide, valproic acid.”);
`
`254:25-258:16 (preference of broad-spectrum levetiracetam over agents only for
`
`partial-onset epilepsy, such as lacosamide: “I see tremendous advantage in using
`
`levetiracetam more broadly; and I think that's one of the reasons it is used more
`
`broadly and has the numbers it has in terms of utility, usage currently[.]”
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`Observation #12: Patent Owner’s Observation omits relevant testimony
`
`regarding levetiracetam being regarded as superior to lacosamide for treating status
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`IPR2016-00204
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`epilepticus, as stated by Dr. Davis in ¶89 of her declaration. When asked if ¶89
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`provided a supporting citation, Dr. Davis testified, “it’s not directly cited, but it’s
`
`cited in other parts of the declaration.” Ex.2195, 81:17-82:8. Patent Owner’s
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`Observation further mischaracterizes Dr. Davis’s testimony. See, e.g., id. at 82:9-
`
`17 (“[P]rotocols . . . are all included as exhibits to my declaration include
`
`levetiracetam as an option for the second line treatment after benzodiazepines.”);
`
`83:2-15 (“[T]hose guidelines do reference many studies that have looked at
`
`levetiracetam in the setting of status epilepticus. . . . [A]s evidenced by experts
`
`beyond myself and my group at Penn, it is felt at this time that levetiracetam is
`
`appropriate to use as an option as a second-line agent for the treatment of status
`
`epilepticus[.]”); id. at 85:5-12 (“So Exhibit 1129 . . . was included in order to
`
`highlight that levetiracetam has been studied outside of just humans, . . . directly
`
`regarding status epilepticus[.]”; id. at as 250:1-254:12 (describing treating status
`
`epilepticus: “[W]e use lacosamide in approximately 50 patients per year, but that
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`represents only a very small percentage of the status epilepticus population. . . .
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`And I would also say that every single one of them would have already been
`
`exposed to levetiracetam . . . and [would] still be receiving levetiracetam.”
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`(emphasis added)).
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`Observation #13: Dr. Davis’s statements at 149:1-7, 23-150:9 regarding
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`the absence of trials establishing either equivalency or superiority of lacosamide
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`IPR2016-00204
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`over levetiracetam do not contradict Petitioners’ argument that “[l]acosamide
`
`cannot claim superiority to other AEDs because no such benefit has been
`
`demonstrated through head-to-head clinical trials.” Paper 52 at 20. Patent Owner’s
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`Observation further mischaracterizes Dr. Davis’s testimony. Dr. Davis explained
`
`the advantage of a broad-spectrum anticonvulsant, such as levetiracetam, over non-
`
`broad-spectrum anticonvulsants, such as lacosamide. Ex.2195, 48:21-49:2 (“[I]n
`
`primary generalized epilepsy syndrome, there’s, for the vast majority of cases, no
`
`evidence that a specific broad-spectrum antiepileptic drug is more efficacious[.]”);
`
`id. at 51:10-14 (“[I]f you’re not sure what kind of epilepsy someone has, it’s safer
`
`to go with a broad-spectrum antiepileptic drug, such as levetiracetam, lamotrigine,
`
`topiramate, zonisamide, valproic acid.”); id. at 254:25-258:16 (discussing
`
`preference of broad spectrum levetiracetam over agents only for partial onset
`
`epilepsy, such as lacosamide: “So I see tremendous advantage in using
`
`levetiracetam more broadly; and I think that’s one of the reasons it is used more
`
`broadly and has the numbers it has in terms of utility, usage[.]” (emphasis added)).
`
`Dr. Davis also testified about the preference of levetiracetam and other
`
`anticonvulsants over lacosamide for women of childbearing age: “[T]he lack of
`
`data . . . makes me . . . very uncomfortable using lacosamide in any woman of
`
`childbearing age.” Id. at 95:21-25. Dr. Davis further testified: “[L]evetiracetam
`
`across the multiple pregnancy registries that are available has substantial evidence
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`-10-
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`IPR2016-00204
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`supporting its use as one of our safest options in females of childbearing age.” Id.
`
`at 99:7-11. Dr. Davis testified: “[I]t’s very clear that levetiracetam should be used
`
`prior to using lacosamide in that population [i.e., women of childbearing age]
`
`given that we have the safety data[.]” Id. at 232:9-17 (emphasis added).
`
`Observation #14: Patent Owner’s Observation mischaracterizes Dr.
`
`Davis’s testimony. In response to the questions noted in Observation 14, Dr. Davis
`
`referred to the fact that, on the referenced page of Ex.1079, levetiracetam was
`
`indicated as having fewer side effects than lacosamide, and noted “a very similar
`
`pattern on all of the pages” of Ex.1079. Ex.2195, 156:23-157:8. Dr. Davis further
`
`testified: “[I]n clinical practice and also noted here, there are just, by number
`
`alone, more side effects noted with lacosamide, and . . . the dropout rate from side
`
`effects and the overall -- like, for instance, side effects of dizziness, were quite
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`high with lacosamide.” Id. at 157:10-158:7 (emphasis added). Further, Patent
`
`Owner’s observation inappropriately cites to extended portions of the deposition
`
`transcript of ten pages.
`
`Observation #15: Patent Owner’s Observation mischaracterizes Dr.
`
`Davis’s testimony on the importance of case reports. See, e.g., Ex.2195, 172:21-
`
`173:13 (“[I]t’s very helpful to have this kind of information so if you have another
`
`patient that has that kind of side effect, you think it’s within the realm of
`
`possibility that it could be related to the medication. . . . [O]ften these more rare
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`-11-
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`IPR2016-00204
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`side effects don’t come out until post-marketing.”). Neither Dr. Bazil nor Dr. Davis
`
`say one cannot rely exclusively on case reports; rather one cannot rely on an
`
`isolated case report.
`
`Observation #16: Patent Owner’s Observations mischaracterize Dr.
`
`Davis’s testimony. See, e.g., Ex.2195, 199:20-25 (“[M]any drugs used in
`
`neurology have multiple different purposes.”); 200:1-6 (“[L]acosamide is . . . one
`
`of the only drugs . . . used by neurologists that doesn’t have multiple purposes[.]”);
`
`205:3-16 (“[B]ipolar disorder does not require an anticonvulsant. However, some
`
`of the best tolerated medications for bipolar disorders are anticonvulsants, the --
`
`another medication that’s not an anticonvulsant used for bipolar disorder is lithium,
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`which . . . [has] a significant rate of side effects and tolerability issues. So it is
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`very common that bipolar patients are treated with anticonvulsants, particularly
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`lamotrigine, also carbamazepine.”); 206:20-207:3 (“[I]f you have a patient who has
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`bipolar disorder or significant depression . . . it makes perfect sense to try to tailor
`
`your antiepileptic drug treatment to their other comorbid conditions, whether it be
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`bipolar disorder or depression. So using a mood-stabilizing antiepileptic drug in
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`that patient population is very advantageous.”); 207:10-21 (“[W]hen faced with
`
`using a medication that doesn’t have any mood-stabilizing effects in a patient that
`
`has significant psychiatric complaints versus one that does have mood-stabilizing
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`-12-
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`IPR2016-00204
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`effects, the vast majority of epileptologists that I know would choose the
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`medication that potentially could help both disorders.”).
`
`Respectfully,
`
`
`
`/ Matthew J. Dowd/
`Matthew J. Dowd
`Reg. No. 47,534
`Dowd PLLC
`1717 Pennsylvania Avenue, NW
`Suite 1025
`Washington, D.C. 20006
`mjdowd@dowdpllc.com
`
`William G. Jenks
`Reg. No. 48,818
`Jenks IP Law
`1050 17th ST NW
`Suite 800
`Washington, D.C. 20036
`Phone: (202) 412-7964
`wjenks@jenksiplaw.com
`
`Counsel for Argentum
`
`
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`-13-
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`
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`Date: January 6, 2017
`
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`IPR2016-00204
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`CERTIFICATE OF SERVICE
`37 CFR §42.6(e)
`
`I certify that, on January 6, 2016, this PETITIONERS’ RESPONSE TO
`MOTION FOR OBSERVATIONS REGARDING THE CROSS-EXAMINATION
`OF DR. KATHRYN DAVIS was served on Research Corporation Technologies at
`the following service electronic addresses:
`
`
`
`Andrea G. Reister
`
` areister@cov.com
`
`Jennifer L. Robbins
`
` jrobbins@cov.com
`
`Enrique D. Longton
`
`elongton@cov.com
`
`
`Dated: 6 January 2017
`
`
`
`
`
`/ Matthew J. Dowd /
`Matthew J. Dowd, Reg. No. 47,534
`
`-14-
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