Page 1
`
`UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`-----------------------------X
`
`ALCON RESEARCH, LTD.,
`
`Plaintiff,
`
`Civil Action No.
`
`v.
`
`16-129(LPS)(SRF)
`
`WATSON LABORATORIES, INC.,
`
`Defendant.
`
`-----------------------------X
`
`VIDEOTAPED DEPOSITION
`
`OF
`
`MAUREEN DONOVAN, PH.D.
`
`New York, New York
`
`Friday, August 24, 2018
`
`Reported by:
`
`ANNETTE ARLEQUIN, CCR, RPR, CRR, CLR
`
`JOB NO. 145678
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`1 2
`
`3 4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`Opiant Exhibit 2052
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`Page 18
`
`Page 19
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
` And, again, nearly every product in
`the armamentarium of all drug products could
`have something done to it that would make
`somebody happier with it.
` Q. In the course of your work in this
`case, did you consider what options were
`available to the person of ordinary skill in the
`art in 2009 who wanted to improve the Nevanac
`product?
` A. Yes. I looked at, you know, what was
`known about ophthalmic formulations in 2009 and
`preceding that, or at least refreshed my memory
`regarding the specific date 2009 and what was
`already being done in the art; investigated
`regarding ophthalmic delivery; and, you know,
`looked at a little bit of information in
`specific about Nevanac.
` Q. And in your view, what options would
`the person of ordinary skill have considered in
`2009 if they wanted to improve the Nevanac
`product?
` A. Can you specify what improvement
`the --
` Q. Well, you said that, if I understood
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
`you correctly, that the person of ordinary skill
`would have thought there was room for
`improvement in the Nevanac product like there is
`room for improvement in many products.
` A. Um-hmm.
` Q. Fair?
` A. Right. Yes.
` Q. And the question I have is: Looking
`at the Nevanac product and thinking there may be
`ways to improve this product, what sorts of
`options would the person of ordinary skill have
`thought of as ways it could be improved,
`formulation steps that could be taken to improve
`it?
` A. Right. But I mean, each of those
`formulations steps is directed at improving an
`aspect --
` Q. Okay.
` A. -- or maybe a group of aspects or
`something. So I think I need a little bit more
`definition in the question of what aspect would
`you like me to focus on.
` Q. I'm asking you about -- let's ask
`this: What aspects do you think the person of
`
`Page 21
`
`Page 20
`
` M. Donovan, Ph.D.
`ordinary skill would have focused on in order to
`improve Nevanac?
` MR. JAGOE: Objection to form.
` A. So you're asking me to identify what
`I -- if I -- as a POSA, if I were to look at
`Nevanac and be asked to improve Nevanac, what
`approach would I use?
` Q. Yes. Or what options of approaches
`would be available to you?
` A. Well, there is a myriad of options,
`some of them already available in the commercial
`space and some of them that were research-based.
` So if my goal as a POSA was to bring
`another commercial product into the marketplace
`in a reasonable time period, there are many of
`the -- especially the things that were in the
`research realm that probably wouldn't be
`seriously considered.
` Q. And why is that?
` A. Well, they are just -- the
`understanding of how they work is probably
`underdeveloped, and the actual basic research
`effort to understand whether they apply to
`Nevanac would take a longer period of research
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
`and development time. And there would be other
`approaches that, again, were well-known in the
`art that could be brought forward that would get
`an additional product or an improved product
`into the marketplace in a faster way without
`having to do an excessive -- or not an
`excessive, but even just a battery of more R&D
`regarding a more unique formulation.
` So to go back to the question I think
`you asked, I'll identify it, so we were talking
`about maybe it would make sense to try to
`identify formulations that could be administered
`less than three times a day. That would be one
`potential improvement to the Nevanac product
`that a person of ordinary skill that is a
`formulator would be able to identify and would
`understand that there were known methods to
`bring forward to do that.
` Q. Okay. And let's back up for one
`second.
` You drew a distinction in your answer
`between the commercial space and what I think
`you called the research area or the research
`space.
`
`TSG Reporting - Worldwide 877-702-9580
`
`6
`
`Opiant Exhibit 2052
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`Page 42
`
`Page 43
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
` Q. Okay.
` Okay. And based on that, what is the
`answer to the question?
` A. Well, Figure 2 actually is a
`graphical depiction of how someone calculates
`the AUC and demonstrates the area under the
`curve.
` The bioavailability of a -- and we'll
`do this -- might as well stay -- well, the
`bioavailability of a drug product is a measure
`or a description of the amount of drug that the
`body was exposed to following administration of
`that formulation or dosage form.
` Okay. So the initial comparator is
`an intravenous or interarterial administration
`typically because you don't have absorption
`effects. You don't have other dosage form
`effects.
` So that is your baseline that you
`compare against is what were the distribution
`parameters when you gave something
`intravenously. And then when you added a
`formulation, delivery system, whatever, to that,
`how much drug, what time course and so forth as
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
`a comparison, you either -- either you
`understand that all of the drug you gave, the
`body was exposed to the same amount of drug and
`gave the same area under the curve, or it was
`not exposed to the same amount of drug, or it
`was exposed in a different time frame, which you
`may tease out of your data or whatever.
` So the bioavailability is a
`description relative to a well-understood
`control of what you're willing to represent as
`100 percent. It may not be 100 percent. And
`that's where relative bioavailability -- in my
`report, I chose to include that because whatever
`your reference is, whatever you're using as 100
`percent, what's your fractional comparison to
`that is the, is the bioavailability.
` But if you're using blood as a
`measure, for example, the built-in assumption to
`that is that blood represents the rest of the
`body, which it may or may not.
` So there's always assumptions on what
`your sampling matrix means regarding the rest of
`the systems exposure.
` Q. Okay. So let's go back to page 52.
`
`Page 45
`
`Page 44
`
` M. Donovan, Ph.D.
` (Witness complies.)
` Q. You say, "Although AUC is generally
`an indicator of bioavailability, formulations
`with different bioavailabilities can achieve the
`same efficacy results in clinical endpoint
`studies higher bioavailability may not produce
`any additional benefit."
` Do you see that?
` A. I see that.
` Q. Can you explain to me how it is that
`higher bioavailability may not produce any
`additional benefit?
` A. Well, because for the actual clinical
`results, and for a drug that has a receptor, a
`known receptor or a know ligand in the body
`where you're targeting the drug to go to have an
`effect, the standard or the understanding in
`pharmacology is that the dose response
`relationship is not linear and it doesn't go on
`forever. So that is you increase the dose, you
`don't necessarily get a proportional increase in
`response.
` And at some point in dosing or
`exposure concentration to the receptor that you
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
`don't have any more receptors to accept the
`drug, it can't have any more response regardless
`of how much more drug is in the system. And so
`you can have more drug in the system, it -- that
`more drug doesn't elicit more response.
` Q. I see.
` You say, "That appears to be the case
`for Nevanac and in Ilevro since these
`formulations have nearly the same effectiveness
`in clinical studies even when both are
`administered once a day."
` Is what you're saying there is that
`Ilevro has higher bioavailability than Nevanac,
`but it doesn't produce any additional clinical
`benefit?
` Am I understanding that correctly?
` A. That's not what I intended to
`communicate when I wrote this.
` Q. What did you intend?
` A. Well, the intention was, it's in the
`description in the paragraph about some of the
`clinical data that I was reviewing and that
`clinical data has -- some of the charts have
`information about concentration in various
`
`TSG Reporting - Worldwide 877-702-9580
`
`12
`
`Opiant Exhibit 2052
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`Page 54
`
`Page 55
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
` A. No, I didn't.
` Q. And since 1991, am I correct that you
`haven't worked as an employee for any
`pharmaceutical company?
` A. No, I haven't.
` Q. And have you ever the developed an
`ophthalmic suspension?
` A. I've worked on formulations in my
`laboratory that could have or, you know, even
`were applied in an experimental sense as -- I
`think they were suspensions. I don't even --
`the issue at hand that I'm thinking of was
`something that was a multi-component formulation
`that we were looking at. I don't remember
`whether all of the components were in suspension
`or whether one was in solution. But we've
`certainly looked at formulations that could have
`been used ophthalmically. I don't recall since
`I've been at Iowa actually personally being the
`principal investigator at least of a formulation
`development activity where we've actually tested
`anything even in an animal model for ophthalmic
`use.
` Q. Would it be fair to say, then, that
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
`you've never worked on an ophthalmic suspension
`formulation that had been administered to a
`human, at least to your knowledge?
` A. So "worked on" is -- that I've never
`developed a formulation for an ophthalmic
`suspension that was administered to a human?
` Q. Correct. That's the question.
` A. Yes, that's true.
` Q. And have you ever developed an
`FDA-approved product of any kind?
` A. No. My work is not focused on trying
`to develop FDA-approved products.
` Q. Now your CV is at the end of your
`opening report, but you may not need it for this
`question.
` Am I correct over the years you've
`published a number of articles and abstracts in
`professional scientific journals; is that
`correct?
` A. Yes.
` Q. Would it be fair to say that you have
`published many articles related to the nasal
`administration of drugs?
` A. Yes, I think it's fair to say.
`
`Page 57
`
`Page 56
`
` M. Donovan, Ph.D.
` Q. How many articles have you published
`that are focused on ophthalmic administration?
` A. That's probably one article out of
`what I've published.
` Q. And can you identify for me which
`article that is?
` A. It's the first article on the
`publication list and it's -- the pages are not
`numbered on Exhibit A, but it's page 2 of
`Exhibit A.
` Q. And it's the Miller & Donovan --
` A. Yes.
` Q. -- effect of poloxamer gels
`article --
` A. Yes.
` Q. -- from International Journal of
`Pharmaceutics in 1982?
` A. Yes.
` Q. And was that about ophthalmic
`suspensions?
` A. The test agent we were using in that
`formulation, the drug was in solution I believe
`in those products.
` MR. PERLMAN: Okay. Should we take a
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` M. Donovan, Ph.D.
` short break?
` MR. JAGOE: Sounds good.
` THE VIDEOGRAPHER: The time is
` 9:12 a.m. We are off the record.
` (Recess is taken.)
` THE VIDEOGRAPHER: The time is
` 9:24 a.m. We are on the record.
`BY MR. PERLMAN:
` Q. Doctor, before the break, we had
`spoken about how in an ophthalmic suspension,
`some of the API is dissolved in solution and the
`rest is in the form of undissolved particles in
`the suspension.
` Do you recall that?
` A. Yes.
` Q. And am I correct that in order for
`the undissolved particles to be absorbed and
`used by the eye, they have to first dissolve
`into the solution?
` A. That's the general understanding of
`things unless they're really small and there is
`another biological mechanism that's actually
`taking them into the body.
` Q. As a general matter?
`
`TSG Reporting - Worldwide 877-702-9580
`
`15
`
`Opiant Exhibit 2052
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`Page 318
`
`Page 319
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
` ERRATA SHEET
`
`Case Name:
`
`Deposition Date:
`
`Deponent:
`
`Pg. No. Now Reads Should Read Reason
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
`___ ___ __________ __________ ____________________
`
` _____________________
`
` Signature of Deponent
`
`SUBSCRIBED AND SWORN BEFORE ME
`
`THIS ____ DAY OF __________, 2018.
`
`____________________
`
`(Notary Public) MY COMMISSION EXPIRES:__________
`
` I N D E X O F E X H I B I T S(Cont'd.)
`DESCRIPTION PAGE
`Plaintiff's Donovan Exhibit 6, U.S. 131
`Patent No. 6,486,138
`
`Plaintiff's Donovan Exhibit 7, U.S. 170
`Patent No. 7,128,928
`
`Plaintiff's Donovan Exhibit 8, 219
`Chowhan Patent Application
`Publication
`
`Plaintiff's Donovan Exhibit 9, 237
`Supplemental Report of Maureen
`Donovan, Ph.D.
`
`Plaintiff's Donovan Exhibit 10, U.S. 245
`Patent No. 5,145,684
`
`Plaintiff's Donovan Exhibit 11, U.S. 253
`Patent No. 5,429,824
`
`Plaintiff's Donovan Exhibit 12, 261
`Printed FDA website to the inactive
`ingredients database as of 2009
`
`Plaintiff's Donovan Exhibit 13, 285
`Article published in International
`Journal of Pharmaceutics entitled
`"Pharmaceutical Nanotechnology -
`Nanosuspension as an opthalmic
`delivery system for certain
`glucocorticoid drugs
`
`Plaintiff's Donovan Exhibit 14, 297
`International Application -
`Publication No. WO 02/05815
`
`1 2
`
`3
`
`4
`
`5 6
`
`7 8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`TSG Reporting - Worldwide 877-702-9580
`
`81
`
`Opiant Exhibit 2052
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`