WILLIAM J. JUSKO, PH.D.
`
`Page 1
` UNITED STATES PATENT AND TRADEMARK OFFICE
` _________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _________________
` KVK-TECH, INC.
` Petitioner
` v.
` SHIRE PLC
` Patent Owner(s)
` ______________
` Case IPR2018-00290
` Patent 8,846,100 B2
`
` DEPOSITION OF WILLIAM J. JUSKO, Ph.D.
`
`DATE: September 27, 2018
`TIME: 9:32 a.m.
`HELD AT: Axinn, Veltrop & Harkrider LLP
` 90 State House Square
` Hartford, Connecticut 06103
`
` By: Sarah J. Miner, RPR, LSR #238
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`SHIRE EX. 2070
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`WILLIAM J. JUSKO, PH.D.
`
`Page 2
` UNITED STATES PATENT AND TRADEMARK OFFICE
` _________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _________________
` KVK-TECH, INC.
` Petitioner
` v.
` SHIRE PLC
` Patent Owner(s)
` ______________
` Case IPR2018-00293
` Patent 9,173,857
`
` DEPOSITION OF WILLIAM J. JUSKO, Ph.D.
`
`DATE: September 27, 2018
` 9:32 a.m.
`HELD AT: Axinn, Veltrop & Harkrider LLP
` 90 State House Square
` Hartford, Connecticut 06103
`
` By: Sarah J. Miner, RPR, LSR #238
`
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`WILLIAM J. JUSKO, PH.D.
`
`Page 3
`
`A P P E A R A N C E S:
`For the Patent Owner Shire PLC:
`Joseph R. Robinson, Esq.
`Troutman Sanders LLP
`875 Third Avenue
`New York, NY 10022
`joseph.robinson@troutman.com
`and
`Tanya Leavey, Ph.D., Patent Agent
`Troutman Sanders LLP
`875 Third Avenue
`New York, NY 10022
`tanya.leavey@troutman.com
`
`For the Petitioner KVK-Tech, Inc.:
`Thomas K. Hedemann, Esq.
`Axinn, Veltrop & Harkrider LLP
`90 State House Square
`Hartford, Connecticut 06103
`thedemann@axinn.com
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`WILLIAM J. JUSKO, PH.D.
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` I N D E X
`WITNESS: Page
`WILLIAM J. JUSKO, Ph.D.
`Direct Examination by Mr. Robinson 5
` E X H I B I T S
`Deposition
`Exhibits Description Marked
`Exhibit 300 U.S. Patent No.: 20
` 6,605,300
`Exhibit 301 Journal of the American 27
` Academy of Child &
` Adolescent Psychiatry
` Special Section: Assessment
` of Safety in Pediatric
` Psychopharmacology
`Exhibit 302 PDR 58 Edition 2004 34
` Product label
`Exhibit 303 Article: Multicompartment 44
` Pharmacokinetic Models
` and Pharmacologic Effects
`Exhibit 304 Correspondence: Case 45
` history of a pharmaceutical
` formulation failure
`Exhibit 305 NIH Public Access First-Dose 48
` Pharmacokinetics of Lithium
` Carbonate in Children and
` Adolescents
`Exhibit 306 NIH Public Access First-Dose 48
` Scaling Pharmacodynamics from
` In Vitro and Preclinical
` Animal Studies to Humans
`Exhibit 307 Foundations of 50
` Pharmacodynamic Systems
` Analysts
`Exhibit 308 Characterization of Four 55
` Basic Models of Indirect
` Pharmacodynamics Responses
`Exhibit 309 Context of Pharmacokinetics 57
`Exhibit 310 Pharmacokinetic Principles 63
` in Pediatric Pharmacology
`Exhibit 311 US Patent 9,173,857 65
`Exhibit 312 US Patent 8,846,100 65
`Exhibit 313 Declaration of William 65
` J. Jusko, Ph.D. '100 Patent
`Exhibit 314 Declaration of William 66
` J. Jusko, Ph.D. '857 Patent
` (The exhibits were included with the
`original transcript.)
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`WILLIAM J. JUSKO, PH.D.
`
`Page 5
` THE VIDEOGRAPHER: Good morning. We are now 09:32:17
`on the video record. The time is 9:32 a.m. The date 09:32:18
`is September 27th, 2018. This is media unit Number 1 09:32:23
`of the video recorded deposition of Dr. William Jusko, 09:32:29
`in the matter of KVK-Tech, Incorporated versus Shire, 09:32:32
`PLC. This deposition is being held at Axinn, Veltrop 09:32:41
`& Harkrider, located at 90 State House Square. 09:32:44
` My name is Brian Capouch, representing 09:32:45
`Veritext, Incorporated. The court reporter is Sarah 09:32:48
`Miner. She is also from Veritext. 09:32:52
` Counsel, please introduce yourselves for the 09:32:54
`record, after which the court reporter will swear in 09:32:56
`the witness. 09:32:59
` MR. ROBINSON: Joseph Robinson and Tanya Levy 09:33:00
`for patent owner. 09:33:02
` MR. HEDEMANN: Thomas Hedemann of Axinn, 09:33:03
`Veltrop & Harkrider, on behalf of petitioner. 09:33:06
` THE VIDEOGRAPHER: Thank you very much. You 09:33:07
`can swear in the witness, please. 09:33:09
` WILLIAM J. JUSKO, Ph.D., 09:33:28
`having first been duly sworn by Sarah J. Miner, LSR, a 09:33:28
`Notary Public in and for the State of Connecticut, was 09:33:28
`examined and testified as follows: 09:33:28
` DIRECT EXAMINATION 09:33:28
`BY MR. ROBINSON: 09:33:29
`
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`WILLIAM J. JUSKO, PH.D.
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`Page 6
` Q. Thank you for coming to the deposition today, 09:33:33
`Dr. Jusko. I will be asking you some questions. 09:33:35
` You realize that there are two IPRs that we 09:33:39
`are having depositions for today. Correct? 09:33:42
` A. Yes. 09:33:46
` Q. And they involve two patents? 09:33:46
` A. Yes. 09:33:48
` Q. Okay. And we are going to be referring 09:33:49
`mostly to U.S. Patent 8846100, but please have your 09:33:51
`answers to any of my questions address the additional 09:33:56
`patent in these IPRs. Okay? 09:34:00
` A. As best I can. 09:34:03
` Q. Okay. Could you give us your name, address 09:34:04
`and occupation? 09:34:07
` A. William Joseph Jusko. I am at the University 09:34:08
`of Buffalo, professor of pharmaceutical sciences. 09:34:14
` Q. Okay. And you submitted a declaration in 09:34:20
`each of these IPRs. Correct? 09:34:21
` A. Yes. 09:34:24
` Q. And is everything in your declarations 09:34:25
`correct? 09:34:28
` A. Yes. 09:34:29
` Q. Is there a goal of drug delivery? 09:34:33
` A. I have two hearing aids, and sometimes I have 09:34:38
`difficulty hearing. So if you don't mind speaking a 09:34:42
`
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`WILLIAM J. JUSKO, PH.D.
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`Page 7
`little bit louder. 09:34:45
` Q. Of course. Usually I am told I speak too 09:34:47
`loud and too fast. 09:34:50
` Is there a goal of drug delivery? 09:34:52
` A. Is there a goal of drug delivery? 09:34:54
` Q. Yes. 09:34:57
` A. Well, drugs need to enter the body, so, yes, 09:34:58
`they need to be delivered. 09:35:02
` Q. Okay. Is there a goal for oral drug 09:35:04
`delivery? 09:35:08
` A. Yes, there is. 09:35:10
` Q. And what would that goal be? 09:35:11
` A. It would depend on the therapeutic purpose of 09:35:17
`the drug being administered. Sometimes it is just 09:35:20
`fluoride for the teeth. Sometimes it is more 09:35:24
`complicated. 09:35:29
` Q. Are there any steps that an oral dosage form 09:35:29
`must go through to reach the goal of oral drug 09:35:34
`delivery? 09:35:38
` A. Steps in manufacture or steps in biologic -- 09:35:40
` Q. Steps upon administration. 09:35:44
` A. Okay. Once more. 09:35:47
` Q. Steps upon administration. 09:35:48
` A. Yes. 09:35:56
` Q. What are those steps? 09:35:56
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`WILLIAM J. JUSKO, PH.D.
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`Page 8
` MR. HEDEMANN: Objection, scope. 09:35:59
` THE WITNESS: Okay. The patient must be able 09:36:04
`to open the container that has the drug. There will 09:36:06
`be instructions on how to take the drug. So the 09:36:15
`patient must follow those instructions. The drug may 09:36:17
`be intended for administration like under the tongue, 09:36:24
`sublingual or buccal, where there would be 09:36:29
`instructions how to do that. Many drugs are 09:36:35
`swallowed. They are intended to act either in the GI 09:36:39
`tract or act systemically. So the drug product after 09:36:46
`being swallowed moves down the GI tract. It has to be 09:36:54
`released from the dosage form. It has to reach the 09:36:58
`membranes where it is absorbed. And then it gets into 09:37:03
`the body. 09:37:07
`BY MR. ROBINSON: 09:37:12
` Q. Have you ever done any work with amphetamines 09:37:12
`other than these IPRs? 09:37:14
` A. I have some teaching material with 09:37:18
`amphetamines, yes. 09:37:23
` Q. What teaching materials do you have with 09:37:24
`amphetamines? 09:37:27
` A. I teach in the general area of 09:37:30
`pharmacokinetics and pharmacodynamics. And sometimes 09:37:35
`I may use drugs like amphetamines as examples for 09:37:37
`particular circumstances. 09:37:42
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`WILLIAM J. JUSKO, PH.D.
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` Q. How would you use amphetamines for an example 09:37:43
`of pharmacokinetics and pharmacodynamics? 09:37:46
` A. Amphetamines are weak basis. Sometimes we 09:37:55
`talk about differences in absorption, differences in 09:37:59
`properties of small drug molecules that are acids 09:38:03
`bases or neutral molecules. Sometimes we look at 09:38:09
`measurements of serum or plasma concentrations and 09:38:18
`talk about how to do calculations in using those kinds 09:38:26
`of measurements. Sometimes we connect those 09:38:29
`measurements to the actions of drugs and develop 09:38:32
`quantitative methods or mathematical models or 09:38:37
`computer methods to display the essential properties 09:38:41
`of -- of those kinds of drugs. 09:38:48
` Q. And have you -- in your teaching materials, 09:38:49
`have you talked about the properties of amphetamines 09:38:53
`in particular? 09:38:57
` A. I probably have, yes. 09:38:58
` Q. What did you say about the properties of 09:39:00
`amphetamines? 09:39:02
` MR. HEDEMANN: Objection, scope. 09:39:03
` THE WITNESS: Let me think. Again, I 09:39:13
`probably described their pharmacokinetics and I 09:39:19
`probably described their CNS actions. 09:39:23
`BY MR. ROBINSON: 09:39:33
` Q. And how -- 09:39:33
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` A. Central nervous system actions. 09:39:33
` Q. How did you describe their pharmacokinetics? 09:39:33
` MR. HEDEMANN: Objection, scope. 09:39:38
` THE WITNESS: Well, their pharmacokinetics 09:39:41
`are very simple. I would describe them in terms of 09:39:44
`what the volume of distribution would be, half-life 09:39:46
`clearances, the basic kinetic properties. 09:39:50
`BY MR. ROBINSON: 09:39:55
` Q. Did you discuss any other properties in your 09:39:55
`materials of amphetamines? 09:39:57
` MR. HEDEMANN: Objection, scope. 09:40:00
` THE WITNESS: I used them to talk about 09:40:03
`pharmacodynamics. 09:40:09
`BY MR. ROBINSON: 09:40:10
` Q. And what did you discuss about amphetamine 09:40:11
`pharmacodynamics in your teaching materials? 09:40:14
` MR. HEDEMANN: Objection, scope. 09:40:16
` THE WITNESS: One example is where I show the 09:40:18
`effects on blood pressure and described the 09:40:24
`relationship between plasma concentrations and changes 09:40:28
`in blood pressure. 09:40:32
`BY MR. ROBINSON: 09:40:33
` Q. Any other pharmacodynamic effects of 09:40:33
`amphetamines? 09:40:37
` MR. HEDEMANN: Objection, scope. 09:40:38
`
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`WILLIAM J. JUSKO, PH.D.
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` THE WITNESS: I also described their effects 09:40:40
`in a study where volunteer subjects took amphetamines 09:40:46
`and there were psychomotor tests that were 09:40:54
`administered. 09:40:58
`BY MR. ROBINSON: 09:41:01
` Q. What were the results of the psychomotor 09:41:02
`tests? 09:41:05
` MR. HEDEMANN: Objection, scope. 09:41:06
` THE WITNESS: There were measurements of -- 09:41:11
`let's see, the subjective feelings of the subjects and 09:41:15
`how one would characterize the time course of those 09:41:21
`subjective feelings. 09:41:24
`BY MR. ROBINSON: 09:41:26
` Q. And how did one characterize the time course 09:41:26
`of those subjective feelings? 09:41:30
` MR. HEDEMANN: Objection, scope. 09:41:34
` THE WITNESS: If one makes a graph of those 09:41:37
`subjective feelings, the effects versus concentrations 09:41:43
`and I would describe the kind of curves, the 09:41:46
`relationships that resulted. 09:41:50
`BY MR. ROBINSON: 09:41:51
` Q. And what was the time course of those 09:41:51
`subjective feelings? 09:41:53
` MR. HEDEMANN: Objection, scope. 09:41:55
` THE WITNESS: I believe I was demonstrating 09:42:00
`
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`hysteresis and the relationship between concentrations 09:42:04
`and effects. 09:42:08
`BY MR. ROBINSON: 09:42:09
` Q. And what is hysteresis? 09:42:09
` MR. HEDEMANN: Objection, scope. 09:42:11
` THE WITNESS: When we first examine 09:42:15
`pharmacologic effects, we make a plot of effect versus 09:42:18
`concentration. And if the effect does not track right 09:42:23
`alongside the concentrations, there is this phenomenon 09:42:29
`called hysteresis. 09:42:31
`BY MR. ROBINSON: 09:42:35
` Q. And what was the relationship between 09:42:35
`concentration effect that you discussed -- 09:42:37
` MR. HEDEMANN: Objection, scope. 09:42:41
`BY MR. ROBINSON: 09:42:42
` Q. -- for amphetamines? 09:42:42
` MR. HEDEMANN: Sorry. Objection, scope. 09:42:44
` THE WITNESS: Sometimes the hysteresis goes 09:42:47
`in a certain direction, we call it clockwise. 09:42:50
`Sometimes hysteresis goes in the other direction, we 09:42:53
`call it counterclockwise. 09:42:57
`BY MR. ROBINSON: 09:42:59
` Q. What does clockwise hysteresis indicate? 09:42:59
` MR. HEDEMANN: Objection, scope. 09:43:03
` THE WITNESS: The direction of hysteresis is 09:43:06
`
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`determined by whether the effects are going up like an 09:43:08
`increase in blood pressure or the effects are going 09:43:13
`down like a decrease in blood pressure. 09:43:16
`BY MR. ROBINSON: 09:43:18
` Q. So clockwise means it is going up and 09:43:19
`counterclockwise means it is going down? 09:43:21
` MR. HEDEMANN: Objection, scope. 09:43:24
` THE WITNESS: I think clockwise is the 09:43:27
`effects are going up, yes. 09:43:29
`BY MR. ROBINSON: 09:43:31
` Q. Okay. What did the hysteresis that you 09:43:31
`talked about with amphetamines indicate with respect 09:43:34
`to concentration and the effect on amphetamines? 09:43:38
` MR. HEDEMANN: Objection, scope. 09:43:44
` THE WITNESS: Well, it is indicating that 09:43:45
`there was a discordance between the time course of 09:43:47
`effect and the time course of plasma concentration. 09:43:52
`BY MR. ROBINSON: 09:43:57
` Q. What do you mean by discordance? 09:43:57
` A. The presence of hysteresis means a 09:43:59
`discordance between effects and concentrations. 09:44:03
` Q. What does the word discordance mean? 09:44:04
` MR. HEDEMANN: Objection, scope. 09:44:08
` THE WITNESS: Usually these graphs are made 09:44:12
`to determine if there is a simple relationship between 09:44:14
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`WILLIAM J. JUSKO, PH.D.
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`Page 14
`effects and concentrations or if there are more 09:44:25
`complexities between plasma concentrations and 09:44:28
`effects. So it is a simple first step in determining 09:44:31
`if it is what we call a simple direct effect or 09:44:34
`whether there is a further complication. 09:44:38
`BY MR. ROBINSON: 09:44:41
` Q. And discordance means that there is a further 09:44:41
`complication? 09:44:44
` MR. HEDEMANN: Objection, scope. 09:44:46
` THE WITNESS: Yes. 09:44:47
`BY MR. ROBINSON: 09:44:48
` Q. And did you conduct the experiments that you 09:44:48
`discussed concerning hysteresis -- 09:44:51
` MR. HEDEMANN: Objection, scope. 09:44:54
`BY MR. ROBINSON: 09:44:55
` Q. -- of amphetamines? 09:44:55
` A. It was not a study conducted in my 09:44:57
`laboratory, no. 09:45:02
` Q. Who conducted that study? 09:45:04
` MR. HEDEMANN: Objection, scope. 09:45:06
` THE WITNESS: There was a publication. 09:45:07
`BY MR. ROBINSON: 09:45:08
` Q. Do you know who the author was? 09:45:09
` A. I am sorry? 09:45:10
` Q. Do you know who the author was? 09:45:11
`
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` MR. HEDEMANN: Objection, scope. 09:45:13
` THE WITNESS: I can't remember the name of 09:45:14
`the author, no. 09:45:16
`BY MR. ROBINSON: 09:45:17
` Q. Do you know what the publication was 09:45:21
`published? 09:45:23
` MR. HEDEMANN: Objection, scope. 09:45:24
` THE WITNESS: A long time ago. I can't say. 09:45:28
`Twenty -- it could be 25 years ago. 09:45:30
`BY MR. ROBINSON: 09:45:32
` Q. Could the name be Greenhill? 09:45:32
` A. Sorry? 09:45:35
` MR. HEDEMANN: Objection, scope. 09:45:36
`BY MR. ROBINSON: 09:45:40
` Q. Greenhill. 09:45:40
` A. I wouldn't remember any of the authors. 09:45:41
` Q. Other than your discussions in your 09:45:50
`teachings, have you done any work with amphetamines? 09:45:54
` A. No direct experimental work, no. 09:46:03
` Q. So you haven't conducted any in vitro 09:46:06
`studies on amphetamines. Is that correct? 09:46:08
` A. Not in my laboratory, no. 09:46:11
` Q. And have you conducted any in vitro 09:46:12
`experiments or studies on formulations of 09:46:15
`amphetamines? 09:46:18
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` A. No, I have not. 09:46:19
` Q. Does one conduct in vitro dissolution studies 09:46:21
`on an oral drug formulation? 09:46:24
` MR. HEDEMANN: Objection, scope. 09:46:27
` THE WITNESS: It is commonly done, yes. 09:46:30
`BY MR. ROBINSON: 09:46:32
` Q. Why is it done? 09:46:33
` MR. HEDEMANN: Objection, scope. 09:46:34
` THE WITNESS: It is partly a quality control 09:46:40
`procedure to make sure the product is releasing the 09:46:42
`drug. 09:46:46
`BY MR. ROBINSON: 09:46:47
` Q. Are there any other reasons why in vitro 09:46:47
`dissolution studies are conducted on an oral drug 09:46:51
`formulation? 09:46:54
` MR. HEDEMANN: Objection, scope. 09:46:56
` THE WITNESS: In many cases, the in vitro 09:46:59
`dissolution rate allows one to anticipate the release 09:47:02
`of the drug in the body. 09:47:07
`BY MR. ROBINSON: 09:47:09
` Q. How does the in vitro study allow one to 09:47:09
`anticipate the release of the drug in the body? 09:47:15
` MR. HEDEMANN: Objection, scope. 09:47:18
` THE WITNESS: There is often a good 09:47:22
`correlation between in vitro dissolution and the in 09:47:25
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`vivo release of the drug. 09:47:29
`BY MR. ROBINSON: 09:47:31
` Q. How does one establish whether or not there 09:47:42
`is an in vitro dissolution versus in vivo release of 09:47:44
`the drug correlation from a drug formulation? 09:47:54
` MR. HEDEMANN: Objection, scope. 09:47:57
` THE WITNESS: In part, it is a well-accepted 09:48:01
`expectation between in vitro dissolution and in vivo 09:48:05
`behavior, but, in part, it needs to be established by 09:48:10
`an actual study in human subjects. 09:48:17
`BY MR. ROBINSON: 09:48:21
` Q. What are the criterion necessary for an in 09:48:22
`vitro dissolution study to make it correlate with an 09:48:26
`in vivo -- strike that question. 09:48:30
` You have not conducted any in vivo studies on 09:48:33
`amphetamines, have you? 09:48:37
` A. Not experimentally, no. 09:48:41
` Q. You have not conducted any therapeutic 09:48:45
`efficacy studies on amphetamines or amphetamine 09:48:49
`formulations, have you? 09:48:53
` A. No, I have not. 09:48:56
` Q. Does one conduct therapeutic efficacy studies 09:48:57
`on a drug formulation? 09:49:02
` A. Sometimes yes, sometimes no. 09:49:12
` Q. Why would one conduct therapeutic efficacy 09:49:14
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`studies on a drug formulation? 09:49:18
` MR. HEDEMANN: Objection, scope. 09:49:21
` THE WITNESS: It would depend on the stage of 09:49:25
`-- of development of the therapeutic agents or the 09:49:27
`drug product. If it is an old, established drug, 09:49:31
`studies may not be done. But if it is a new drug, 09:49:35
`then it would need very careful study. 09:49:38
`BY MR. ROBINSON: 09:49:41
` Q. So there are no formulations of an old drug 09:49:46
`that you would conduct therapeutic efficacy studies 09:49:50
`for. Is that correct? 09:49:54
` MR. HEDEMANN: Objection scope. 09:49:55
`BY MR. ROBINSON: 09:49:56
` Q. In other words, if one has an old drug, a 09:49:56
`drug that has been used before, and one has a new 09:49:58
`formulation, one would not conduct therapeutic 09:50:03
`efficacy studies of that formulation. Is that 09:50:05
`correct? 09:50:08
` MR. HEDEMANN: Objection, scope. 09:50:08
` THE WITNESS: If it is an old drug and it is 09:50:11
`an immediate release type of formulation, it is not 09:50:16
`required to do in vivo studies. 09:50:19
`BY MR. ROBINSON: 09:50:21
` Q. If it is an old drug and it is not an 09:50:21
`immediate release formulation, would one do 09:50:23
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`therapeutic efficacy studies of a drug formulation? 09:50:27
` MR. HEDEMANN: Objection, scope. 09:50:34
` THE WITNESS: Not necessarily, no. 09:50:38
`BY MR. ROBINSON: 09:50:39
` Q. Why would one not do the studies? 09:50:40
` MR. HEDEMANN: Objection, scope, relevance. 09:50:43
` THE WITNESS: Well, therapeutic efficacy 09:50:48
`means one is assessing how real patients are behaving 09:50:50
`with the drug formulation. In many cases, all that is 09:50:55
`required is what is called a bioavailability or 09:50:59
`bioequivalent study to establish that the drug is 09:51:03
`absorbed and what the plasma concentrations are. 09:51:07
`BY MR. ROBINSON: 09:51:12
` Q. So one would not conduct therapeutic efficacy 09:51:12
`studies of a drug formulation unless it is required. 09:51:15
`Is that what you are saying? 09:51:19
` MR. HEDEMANN: Objection, scope, relevance. 09:51:20
` THE WITNESS: It depends on the nature of the 09:51:28
`drug and the nature of its indication. You know, 09:51:29
`there is a wide spectrum of possibilities. 09:51:31
`BY MR. ROBINSON: 09:51:35
` Q. Well, let's go back to the word required. 09:51:35
`Required by whom? 09:51:37
` MR. HEDEMANN: Objection. 09:51:39
` THE WITNESS: Say again. 09:51:39
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`BY MR. ROBINSON: 09:51:40
` Q. Required by whom? 09:51:40
` MR. HEDEMANN: Objection, scope, relevance. 09:51:42
` THE WITNESS: Many times study are done