DAVID R.
`
`JANERO, Ph.D.
`
`component as well,
`
`in my opinion.
`
`Q.
`
`A.
`
`Mm—hmm.
`
`Nor did I state that these —— that this
`
`would be the only factor.
`
`Q.
`
`A.
`
`No.
`
`I understand.
`
`That would be a consideration. And,
`
`in
`
`fact,
`
`in my experience, it's always a
`
`consideration, and it should be a consideration
`
`with respect to any drug that has significant,
`
`enough CNS exposure to have any nervous
`
`system—related effect.
`
`Q.
`
`How does an agent —— how does a central
`
`nervous system become exposed to an agent?
`
`A.
`
`There are three general ways.
`
`Basically,
`
`though,
`
`the physiology is by crossing
`
`the blood—brain barrier.
`
`Q.
`
`A.
`
`Okay.
`
`It is a membrane system that delimits
`
`the central nervous system; specifically,
`
`the
`
`brain --
`
`Q.
`
`A.
`
`Mm—hmm.
`
`—-
`
`from the blood circulation.
`
`There
`
`are active transporters, both -- that can alter
`
`this transit across the membrane.
`
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`
`JANERO, Ph.D.
`
`component as well,
`
`in my opinion.
`
`Q.
`
`A.
`
`Mm—hmm.
`
`Nor did I state that these —— that this
`
`would be the only factor.
`
`Q.
`
`A.
`
`No.
`
`I understand.
`
`That would be a consideration. And,
`
`in
`
`fact,
`
`in my experience, it's always a
`
`consideration, and it should be a consideration
`
`with respect to any drug that has significant,
`
`enough CNS exposure to have any nervous
`
`system—related effect.
`
`Q.
`
`How does an agent —— how does a central
`
`nervous system become exposed to an agent?
`
`A.
`
`There are three general ways.
`
`Basically,
`
`though,
`
`the physiology is by crossing
`
`the blood—brain barrier.
`
`Q.
`
`A.
`
`Okay.
`
`It is a membrane system that delimits
`
`the central nervous system; specifically,
`
`the
`
`brain --
`
`Q.
`
`A.
`
`Mm—hmm.
`
`—-
`
`from the blood circulation.
`
`There
`
`are active transporters, both -- that can alter
`
`this transit across the membrane.
`
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`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Mm—hmm.
`
`And there are also situations where the
`
`Q.
`
`A.
`
`physiochemical property of the compound, small
`
`molecule, will be favorable for its partitioning
`
`into that membrane system and then partitioning
`
`potentially out of it into the nervous system
`
`compartment.
`
`Q.
`
`Okay.
`
`Now, you would agree with me
`
`that tolterodine,
`
`in the vast majority of
`
`patients, metabolizes into the active 5-HMT.
`
`Correct?
`
`A.
`
`Q.
`
`MS. WOOTEN: Objection.
`
`Form.
`
`In the vast majority of patients, yes.
`
`Okay.
`
`So isn't it fair to say that the
`
`reports of adverse events with respect to the
`
`central nervous system are a function of 5—HMT
`
`crossing into the central nervous system?
`
`A.
`
`O.
`
`A.
`
`Based upon these data, no.
`
`No?
`
`The 5-HMT would have to be tested
`
`independently, under the same conditions, at the
`
`same dosing regimen, with the same vehicle,
`
`independently of tolterodine,
`
`to make some sort
`
`of conclusion, comparative conclusion in that
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`DAVID R.
`
`JANERO, Ph.D.
`
`regard,
`
`in my opinion.
`
`In other words,
`
`tolterodine, alone, would
`
`have to be profiled.
`
`Q.
`
`A.
`
`profiled.
`
`Okay.
`
`I'm sorry.
`
`5—HMT would have to be
`
`Q.
`
`But a person of ordinary skill in the
`
`art,
`
`in 1998, would have understood the
`
`probability of any of these effects to be
`
`attributable to 5~HMT in the majority of
`
`patients? N0?
`
`M8. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I could not say in the majority of
`
`patients.
`
`Q.
`
`Okay.
`
`If -- so your testimony is that
`
`a person of ordinary skill in the art, familiar
`
`with tolterodine and its pharmacology and its
`
`metabolism,
`
`in 1998, did not understand that in
`
`the majority of patients,
`
`5—HMT was the active
`
`agent?
`
`Is that right?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`Mischaracterizes testimony.
`
`A.
`
`Q.
`
`No. That's not correct.
`
`That's not right?
`
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`
`DAVID R.
`
`JANERO, Ph.D.
`
`A.
`
`No.
`
`The understanding,
`
`in my opinion,
`
`would have been that the parent compound,
`
`tolterodine,
`
`is metabolized into 5—HMT, and the
`
`antimuscarinic effect of the parent, Detrol,
`
`tolterodine,
`
`is a consequence of both of these
`
`agents as active drugs.
`
`Q.
`
`Mm—hmm.
`
`And what is the percentage of
`
`the population that are extensive metabolizers?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`I don't remember, offhand.
`
`Does 93 percent ring a bell?
`
`They may be extensive metabolizers.
`
`Mm—hmm. Yes.
`
`That simply means they have the
`
`capacity to do so.
`
`Q.
`
`Okay.
`
`Isn't it well reported in the
`
`prior art that in extensive metabolizers,
`
`the
`
`active agent is 5—HMT?
`
`A.
`
`But tolterodine also has activity as
`
`well.
`
`Q.
`
`Correct. But
`
`-— so you're saying that
`
`one of ordinary skill in the art would not assume
`
`that in the majority of those patients, whatever
`
`might be crossing into the central nervous system
`
`is tolterodine?
`
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`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`A.
`
`In terms of mesh action, yes. But
`
`in
`
`terms of having —- initiating or effecting a side
`
`effect or an event profile, we don't know.
`
`Q.
`
`Okay. Okay. And with respect to dry
`
`mouth, are you aware of any evidence which
`
`suggests that the activity leading to dry mouth
`
`is attributable to 5-HMT or tolterodine?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I don't believe 5—HMT,
`
`itself, has been
`
`tested in humans to that endpoint ~~ with that
`
`clinical endpoint.
`
`I am aware of the cat study I
`
`alluded to earlier in vivo by Nilvebrant, et
`
`al --
`
`Mm—hmm.
`
`A.
`
`-- that did look at, did compare 5-HMT
`
`and tolterodine in terms of effect on
`
`salivation --
`
`Q.
`
`A.
`
`Mm—hmm.
`
`—— and found that tolterodine had more
`
`of an effect than did 5-HMT in terms of affecting
`
`salivation, saliva production in the cat model
`
`in
`
`vivo.
`
`Okay. Did you not review the human
`
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`
`DAVID R.
`
`JANERO, Ph.D.
`
`Mm—hmm.
`
`—-
`
`in the Brynne paper?
`
`I have.
`
`I may not remember it. But if
`
`Q.
`
`A.
`
`you have the paper, I'll be glad to do it now.
`
`Q. We'll get
`
`to that. Let me just stick
`
`with the CNS --
`
`A.
`
`Q.
`
`Sure.
`
`-- concern for a moment.
`
`If it's the case that you didn't know
`
`whether it's 5~HMT or tolterodine which may be
`
`causing any CNS effects --
`
`A.
`
`Mm—hmm.
`
`Q.
`
`—— then why would you be so readily --
`
`motivated to isolate 5—HMT at the time?
`
`A.
`
`Q.
`
`To isolate 5-HMT?
`
`That's what you're trying to do.
`
`Right? They're both active. You're trying to
`
`segregate 5—HMT to deliver it only by a prodrug.
`
`Correct? That's the theory?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`That would be true. Yes.
`
`Right.
`
`That would be, yes. Yes.
`
`So how can I be motivated to improve
`
`upon the CNS profile of tolterodine if I'm not
`
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`DAVID R.
`
`JANERO, Ph.D.
`
`sure whether it's tolterodine or 5—HMT that's
`
`causing the CNS effects?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`That may not be the sole factor in
`
`terms of the motivation.
`
`As
`
`I alluded to
`
`earlier,
`
`there could have been many other
`
`factors, many other factors. And one may,
`
`indeed,
`
`show that by a prodrug,
`
`there may be a
`
`different pharmacokinetic, pharmacodynamic
`
`profile that might benefit a number of these
`
`Okay.
`
`The data would tell.
`
`Okay.
`
`But,
`
`a priori,
`
`I could not forecast
`
`aspects.
`
`Q.
`
`A Q
`
`.
`
`A
`
`Q.
`
`Okay. This is what I'm trying to do,
`
`is understand the basis for your opinion.
`
`A.
`
`Mm—hmm.
`
`Q.
`
`And we've got
`
`to the point where you
`
`say the skilled artisan would have been motivated
`
`to improve upon tolterodine in 1998 or 1999, and
`
`I'm trying to understand what about tolterodine
`
`needed to be improved.
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`Page 118
`
`DAVID R.
`
`JANERO, Ph.D.
`
`I believe that you said the CNS profile,
`
`the
`
`dry mouth issue and the polymorphism issue?
`
`A.
`
`Q.
`
`Right.
`
`If there are other factors, I'd like to
`
`know what
`
`they are. But if there aren't,
`
`then I
`
`want
`
`to take these one by one --
`
`A.
`
`Q.
`
`Sure.
`
`-- and ask you, you know, what the
`
`basis would be for each of them respectively.
`
`A.
`
`To me,
`
`the polymor— ~- the
`
`polypharmacology issue generating two active
`
`agents from one would be,
`
`to me,
`
`a prime
`
`motive --
`
`Q.
`
`A.
`
`Q.
`
`Okay.
`
`-- of the three listed.
`
`But you would agree with me that,
`
`just
`
`sticking with the CNS factor --
`
`A.
`
`Q.
`
`Mm—hmm.
`
`—— if, as you say, you can't be sure
`
`which agent is responsible for the CNS effects,
`
`then you,
`
`therefore, wouldn't be sure whether
`
`that is something that needed to be improved upon
`
`with tolterodine. Correct?
`
`A.
`
`Unless directly ——
`
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`DAVID R.
`
`JANERO, Ph.D.
`
`MS. WOOTEN: Objection to form.
`
`A.
`
`Unless directly tested.
`
`I agree.
`
`The
`
`only way to answer that question would be, as I
`
`mentioned earlier,
`
`a direct test of the various
`
`agents.
`
`Q.
`
`Okay. But you're not aware of any
`
`direct testing that was done or available at the
`
`time in 1998. Correct?
`
`A.
`
`Q.
`
`In humans,
`
`I'm not aware of any.
`
`Okay.
`
`MR. TRAINOR: Why don't we take
`
`break. Let's go off.
`
`THE VIDEOGRAPHER:
`
`The time now
`
`12:27, and we're off the record.
`
`(Lunch recess was taken.)
`
`THE VIDEOGRAPHER:
`
`The time now
`
`13:17. We're back on the record.
`
`BY MR. TRAINOR:
`
`Q.
`
`A.
`
`Q.
`
`Sorry. Okay, Dr. Janero, welcome back.
`
`Thank you.
`
`Pardon me.
`
`So we were talking before about
`
`the
`
`areas for improvement of tolterodine that you
`
`identified.
`
`Just to set the context, we had the
`
`CNS concerns,
`
`the dry mouth concern,
`
`the
`
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`DAVID R.
`
`JANERO, Ph.D.
`
`polymorphism concerns and patent concerns?
`
`A.
`
`Q.
`
`Mm—hmm.
`
`We just talked about
`
`the CNS.
`
`I want
`
`to turn to the dry mouth issue.
`
`A.
`
`Actually,
`
`I do want
`
`to finish one point
`
`about that,
`
`if I may.
`
`Q.
`
`A.
`
`Q.
`
`Okay.
`
`About which?
`
`The nervous system related.
`
`That's the central nervous system.
`
`A. Well, it could be in general, because
`
`the autonomic nervous system also has a component
`
`of control of, neuro control of salivary
`
`secretions,
`
`so that affects dry mouth.
`
`So I'm
`
`going to --
`
`Q.
`
`A.
`
`Okay.
`
`-- put
`
`them together for the sake of
`
`time and for the sake of discussion.
`
`The
`
`basic —— the question,
`
`I believe,
`
`that was posed
`
`is basically why -- why,
`
`in essence, would one
`
`find 5—HMT attractive in terms of improving some
`
`of these profiles.
`
`Is that correct?
`
`Q.
`
`Right now,
`
`I'm just sticking to the
`
`part about why one of ordinary skill would have
`
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`DAVID R.
`
`JANERO, Ph.D.
`
`recognized a need to improve tolterodine.
`
`A.
`
`Q.
`
`Okay.
`
`Then we'll save that.
`
`Okay.
`
`Thank you.
`
`Sorry.
`
`So turning to improving the dry mouth
`
`Mm—hmm.
`
`Mm—hmm.
`
`Q.
`
`-- of tolterodine,
`
`the improvement
`
`in
`
`dry mouth was really sort of the breakthrough
`
`with tolterodine,
`
`to begin with, at its launch.
`
`Right? Would you agree with that?
`
`A.
`
`It still had that as a side effect that
`
`is considered to be a common effect for
`
`antimuscarinic agents because of the population
`
`of receptors in the oral mucosa that are there.
`
`So it had a —— I'd have to look at the numbers to
`
`refresh my memory, but certainly it was a shared
`
`side effect in this class.
`
`The extent to which it was expressed versus
`
`others in the class,
`
`that,
`
`I don't remember.
`
`Q.
`
`Okay.
`
`And you're aware that it's just
`
`a matter of a couple of months, right, between
`
`the time that tolterodine or Detrol was approved
`
`and the first priority date of these patents in
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`DAVID R.
`
`JANERO, Ph.D.
`
`1998, right,
`
`roughly?
`
`A.
`
`Roughly. Yes.
`
`MS. WOOTEN: Objection. Calls for a
`
`legal conclusion.
`
`But
`
`I --
`
`Okay.
`
`So this is Exhibit 11,
`
`the
`
`Yes,
`
`I have that.
`
`Okay.
`
`Now, under the autonomic nervous
`
`system as you're just —~
`
`A.
`
`Yes.
`
`Q.
`
`—- referring to,
`
`that's where they list
`
`dry mouth as --
`
`A.
`
`Yes.
`
`Q.
`
`-- an adverse event. And I
`
`think, as
`
`you pointed out,
`
`in the text of this label there
`
`are also some textual comments about dry mouth
`
`being the frequently reported adverse event.
`
`My question is similar to the CNS—related
`
`question,
`
`is isn't it also true that based upon
`
`what was available at the time,
`
`in 1998,
`
`including this label, it was not known which
`
`chemical entity 5~HMT, on the one hand, or
`
`tolterodine, on the other hand, was responsible
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`DAVID R.
`
`JANERO, Ph.D.
`
`for the dry mouth side effect. Correct?
`
`A.
`
`I believe so, because to my knowledge,
`
`5—HMT was itself not directly studied in this
`
`paradigm,
`
`in the clinic.
`
`Q.
`
`Okay.
`
`So this is just the report of
`
`you administer tolterodine, and most of the
`
`population is extensive metabolizers,
`
`there's
`
`some poor metabolizers, but
`
`the events don't
`
`discriminate between tolterodine and 5—HMT?
`
`A.
`
`I couldn't say that from this,
`
`from
`
`this table.
`
`Q.
`
`A.
`
`Q.
`
`From the label. Right?
`
`From the label. Right.
`
`Okay.
`
`So irrespective of the label,
`
`are you aware of any evidence or information that
`
`was available to a skilled artisan at that time
`
`that would have allowed them to recognize which
`
`of the two active entities was responsible for
`
`the dry mouth side effect?
`
`A.
`
`There was the -— there is the
`
`preclinical study that was published by
`
`Nilvebrant, et al,
`
`in vivo in the cat.
`
`Q.
`
`Mm-hmm.
`
`A. Which was shown —— which I believe
`
`TSG Reporting — Worldwide
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`DAVID R.
`
`JANERO, Ph.D.
`
`showed that both agents, both tolterodine,
`
`Detrol, and 5-HMT, did affect salivation in that
`
`model.
`
`Q.
`
`A.
`
`Mm—hmm.
`
`But
`
`the differential between the
`
`potencies at which relaxation was affected in the
`
`bladder and salivation was affected was less
`
`differential for tolterodine versus 5-HMT,
`
`despite the fact that 5-HMT was around, as I
`
`recall, around sevenfold more potent,
`
`a smooth
`
`muscle relaxant, an antimuscarinic smooth muscle
`
`relaxant.
`
`Q.
`
`Mm—hmm.
`
`So relevant to my question,
`
`what is the implication?
`
`Do you believe a person
`
`of ordinary skill would have understood
`
`tolterodine to be more responsible for dry mouth
`
`as distinguished from 5-HMT?
`
`A.
`
`I
`
`think from those data,
`
`the person of
`
`ordinary skill in the art, at that time, would
`
`have concluded that 5-HMT could have less
`
`propensity to induce dry mouth.
`
`Q.
`
`Okay. And so,
`
`therefore,
`
`that would
`
`support your opinion that tolterodine's dry mouth
`
`profile could be improved upon by isolating
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`DAVID R.
`
`JANERO, Ph.D.
`
`5—HMT.
`
`Is that right?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`That would be —— that could be one
`
`possible route, but not
`
`the only possible route.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`I understand. But --
`
`Right.
`
`—- just on this issue of dry mouth.
`
`Right.
`
`Okay.
`
`By the way, can we have that
`
`Nilvebrant paper?
`
`I
`
`think ~-
`
`I hope I have the
`
`one that you're referring to, because I don't
`
`want you to be operating in a vacuum here.
`
`There was a Nilvebrant paper, Exhibit 8,
`
`I
`
`showed you before.
`
`You said that was not
`
`the
`
`one --
`
`I have it here.
`
`I have it here.
`
`Q.
`
`—- that you had in mind and that you
`
`referenced here.
`
`So let me show you this.
`
`MR. TRAINOR: This will be number 12,
`
`I
`
`(Document Bates—stamped
`
`MYLB_FESO_0O027l29 through -7132 marked
`
`Exhibit 12.)
`
`A.
`
`This is the paper to which I was
`
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`877-702-9580
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`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0125
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`referring. Yes.
`
`Q.
`
`Okay. Let me just introduce it for the
`
`A.
`
`Oh.
`
`Q.
`
`I asked the court reporter to mark as
`
`Janero Exhibit 11 a publication entitled
`
`"Antimuscarinic Potency and Bladder Selectivity
`
`of PNU—200577, A Major Metabolite of
`
`Tolterodine."
`
`The lead author is Nilvebrant,
`
`copyright date 1997.
`
`It bears Mylan Bates
`
`numbers 27129 through 32.
`
`And I'm sorry, Dr. Janero, you were saying
`
`that this is the paper you had in mind?
`
`A.
`
`Q.
`
`Yes,
`
`it is the paper. Yes.
`
`If you look at Paragraph l4 of your
`
`opening report, Exhibit 1, would you just confirm
`
`this is the Nilvebrant paper that's referenced
`
`there?
`
`A.
`
`From pharmacology and toxicology, yes.
`
`Pharmacol,
`
`toxicol.
`
`Q.
`
`Okay.
`
`Now, it's a short paper, but --
`
`you can take a minute to review it, but
`
`I want
`
`to
`
`ask you: Where in this paper is there a
`
`disclosure that you're referring to with respect
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0126
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`—— let's start with the potency issue?
`
`A.
`
`I was referring specifically to the in
`
`vivo study in the cat model.
`
`Q.
`
`A.
`
`Okay.
`
`And that's on Page 171,
`
`left column,
`
`about a third down under the heading "In vivo
`
`Studies."
`
`Q.
`
`A.
`
`Okay.
`
`The second sentence gives the mean
`
`ID50. That means mean inhibitory dose,
`
`50 percent inhibition for acetyl,
`
`for PNU, of
`
`15 nanomole per kilogram. And that's for
`
`acetylcholine—induced urinary bladder
`
`contraction.
`
`(Reporter clarification.)
`
`A.
`
`For acetylcholine—induced urinary
`
`bladder contraction.
`
`So that's one piece of data.
`
`Q.
`
`Okay. Okay.
`
`For the record, can we
`
`note PNU 200577 is 5-HMT. Correct?
`
`A.
`
`Q.
`
`Yes. Yes.
`
`That is correct.
`
`Okay.
`
`I'll refer to it subsequently as 5~HMT.
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0127
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Q.
`
`Now, what does that tell us about the
`
`relative potencies of 5—HMT in tolterodine?
`
`A.
`
`Now,
`
`if we retain that figure ——
`
`Right.
`
`and we proceed on to the —— in the
`
`A.
`
`—— and we go to Page 172,
`
`left column,
`
`first paragraph ——
`
`Q.
`
`A.
`
`Mm~hmm.
`
`—— third line in that, "Although 5—HMT
`
`is more potent
`
`than the parent compound in vivo,
`
`IDSO values for tolterodine were 101 nanomole per
`
`kilogram respectively for inhibition of urinary
`
`bladder contraction and salivation."
`
`Q.
`
`A.
`
`Mm—hmm.
`
`"A likely explanation for the higher
`
`potency of 5—HMT in vivo is that available
`
`percentage of tolterodine is unbound in serum,
`
`whereas over 30 percent of 5—HMT exists as the
`
`unbound drug."
`
`So I compare the 101 nanomole per kilogram
`
`IDSO for tolterodine with the stated, on the
`
`previous page,
`
`15 nanomole per kilogram, as mean
`
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`ID5O for 5—HMT to conclude that 5—HMT is about
`
`sevenfold more potent
`
`than tolterodine in this
`
`model, as an antimuscarinic bladder—relaxing
`
`agent
`
`in response to acetylcholine—induced
`
`bladder contraction."
`
`Q.
`
`Okay. But at the conclusion of that
`
`paragraph that you were just reading from on
`
`172 --
`
`Uh-huh.
`
`Q.
`
`~— the next sentence discusses the
`
`likely explanation for the higher potency in
`
`vivo --
`
`A.
`
`Q.
`
`Yes.
`
`—— is the very low percentage of
`
`tolterodine in unbound serum relative to the
`
`percentage of 5—HMT that is unbound. Correct?
`
`A.
`
`Yes.
`
`Q.
`
`Okay. Doesn't that mean that
`
`pound—for—pound,
`
`if you will,
`
`the potency is the
`
`same?
`
`A.
`
`We can't —— we can't equil— —— we can't
`
`make equivalent the bound component of either
`
`drug to the free, because only the free will be a
`
`ligand, will be able to bind to muscarinic
`
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`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`receptor.
`
`Q.
`
`A.
`
`Mm—hmm.
`
`That portion that is sequestered in any
`
`plasma protein, plasma lipoprotein will not be
`
`able to bind as that complex.
`
`It must be freed.
`
`Q.
`
`A.
`
`Right.
`
`So they're not —- so we can't say
`
`pound-per—pound, because they're in different
`
`states in terms of drug ability.
`
`Q.
`
`A.
`
`Mm~hmm.
`
`So in terms of the less than 5 percent
`
`versus greater than 30 percent of 5-HMT that's
`
`available as an active agent
`
`in vivo --
`
`Q.
`
`A.
`
`Right.
`
`-- they're different.
`
`Q. Well,
`
`the free is what is unbound in
`
`serum. Correct?
`
`A.
`
`And that,
`
`in the case of 5—HMT,
`
`is
`
`greater than 30 percent.
`
`In the case of
`
`tolterodine, it is less than 5 percent.
`
`Q.
`
`Right. And is it just a coincidence
`
`that that's also a factor of six or seven?
`
`A.
`
`It may be.
`
`I don't have all of
`
`those data --
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0130
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Mm—hmm.
`
`—-
`
`to look and see what
`
`the absolute
`
`Q.
`
`A.
`
`kinetics would be --
`
`Q.
`
`A.
`
`Mm—hmm.
`
`—— and what
`
`the distribution of those
`
`kinetics would be, what
`
`the distribution of both
`
`compounds would be over time.
`
`The important point here,
`
`I
`
`think,
`
`is that
`
`both compounds were looked at.
`
`5—HMT,
`
`in
`
`particular, was examined separately.
`
`Q.
`
`Now --
`
`THE WITNESS:
`
`Excuse me.
`
`Q.
`
`—— does it surprise you that given the
`
`same dose to the same subject,
`
`in this case,
`
`in
`
`animal,
`
`that the value of potency that is
`
`measured is greater for the entity which has a
`
`higher free percentage by a factor of six or
`
`seven?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`Those two factors would correlate, but
`
`the higher free need not translate into greater
`
`efficacy --
`
`Q.
`
`A.
`
`Mm~hmm.
`
`—- or higher potency.
`
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Q.
`
`But you would agree that, at least
`
`according to this author,
`
`that's the likely
`
`explanation for the difference in potency in
`
`vivo. Correct?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`Actually,
`
`I refer to the sentence that
`
`follows that --
`
`Q.
`
`A.
`
`Mm—hmm.
`
`—— that begins "since," and after the
`
`comment, "the response observed in vivo following
`
`oral administration of tolterodine is likely to
`
`be,
`
`in part,
`
`the result of the activity of
`
`unbound 5—HMT."
`
`So it would be difficult,
`
`in the case of
`
`tolterodine, where we have the polypharmacology,
`
`we have two active agents going on,
`
`to parse out
`
`quantitatively the way y©u're suggesting.
`
`It
`
`would be difficult for me, at least,
`
`to do that
`
`quantitatively.
`
`Q.
`
`A.
`
`Okay.
`
`Because we have the same effect;
`
`in
`
`other words, relaxation of acetylcholine-induced
`
`bladder contraction.
`
`In one case, we're looking
`
`at 5—HMT.
`
`In another case, we're looking at some
`
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`dynamic combination of bound—unbound tolterodine
`
`and bound-unbound 5—HMT, either one of which has
`
`different proportions of bound and unbound.
`
`Q.
`
`Okay.
`
`Now,
`
`if you assume that all
`
`things being equal,
`
`the two agents are
`
`equipotent,
`
`then that would explain the
`
`difference in the potency measure,
`
`that being the
`
`difference in percentage bound. Correct?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I don't believe that's an explanation,
`
`because there are other factors involved, one of
`
`which that's not -- that's not dealt with in this
`
`paper,
`
`in the discussion,
`
`is the idea that the
`
`bound portion is not —— is dynamic.
`
`Q.
`
`A.
`
`Mm-hmm.
`
`It can enter and exit plasma proteins,
`
`plasma lipoproteins.
`
`So although it is true that
`
`the muscarinic receptor, muscarinic receptors
`
`cannot bind drug that's bound to plasma protein
`
`or plasma lipoprotein,
`
`that doesn't mean that
`
`it's permanently bound there.
`
`There are on and off, so-called "on and off
`
`rates" associated with this —— with this -- with
`
`these complexes.
`
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`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Okay.
`
`And this happens to be one of the --
`
`Q.
`
`A.
`
`one of the areas I studied in my —— my postdoc at
`
`Hopkins.
`
`Q.
`
`Okay.
`
`Now,
`
`in that next paragraph,
`
`the
`
`first sentence indicates that,
`
`in vitro,
`
`the
`
`potency —— the potencies of 5—HMT and tolterodine
`
`are identical. Correct?
`
`A.
`
`I don't read that statement.
`
`I read
`
`the statement
`
`to say "that the pharmacological
`
`profile in vitro."
`
`Q.
`
`A.
`
`Mm—hmm.
`
`The pharmacological profile goes much
`
`beyond, but may include potency and efficacy.
`
`Q.
`
`Okay.
`
`If you look at the next
`
`paragraph, at the bottom of the column,
`
`the
`
`sentence says, "In summary,
`
`the pharmacological
`
`in vitro and in vivo profiles of 5—HMT are
`
`identical to those of tolterodine,
`
`the parent
`
`compound."
`
`Do you see that?
`
`Yes.
`
`That is almost identical to
`
`Yes.
`
`I see that.
`
`Okay.
`
`So do you have any understanding
`
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`why the author would conclude that the
`
`pharmacological profiles are identical?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I believe the next sentence gives a
`
`clue, because both compounds have high
`
`antimuscarinic potency.
`
`They both have protein
`
`bound, but one has a different degree of protein,
`
`of plasma protein,
`
`lipoprotein binding. And they
`
`have good serum concentrations in humans after
`
`oral administration.
`
`The conclusion is that, as stated here by
`
`the authors,
`
`that 5—HMT may contribute to the
`
`therapeutic action of tolterodine.
`
`So,
`
`in other
`
`words, both the 5—HMT and tolterodine are acting
`
`to effect the muscarinic relaxation in response
`
`to acetylcholine contraction in the bladder.
`
`That's how I would interpret that.
`
`Q.
`
`Can you look at the abstract on the
`
`first page.
`
`A.
`
`Q.
`
`abstract.
`
`A.
`
`Q.
`
`Yes.
`
`The second to last sentence in the
`
`Yes.
`
`I see.
`
`It says, "Thus,
`
`5—HMT is similar to
`
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`tolterodine in terms of antimuscarinic potency."
`
`Do you see that?
`
`A.
`
`Q.
`
`Yes,
`
`I do.
`
`As a reader, how would you reconcile
`
`that with your conclusion that the data suggests
`
`5—HMT is more potent?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`The data --
`
`Tolterodine —— sorry.
`
`Yes.
`
`The data I'm referring to are in
`
`Q.
`
`A.
`
`the in vivo study. They're not referring to the
`
`radioligand binding studies or the in vitro
`
`studies, where it could be a similar —— there
`
`could be a similar potency or similar profile
`
`there.
`
`In other words,
`
`in the in vitro testing,
`
`biochemical testing, differences or similarities
`
`need not quantitatively transfer into the intact
`
`animal.
`
`And that's why I would put myself,
`
`in terms
`
`of drug discovery and development,
`
`in terms of
`
`pharmacology, more weight on the difference in
`
`vivo than I would in a binding study, because
`
`both of these, we know both of these compounds
`
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`877-702-9580
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`are,
`
`indeed, muscarinic receptor agents with good
`
`ligand binding properties.
`
`Q.
`
`Are you aware of any evidence, other
`
`than this cat data, which speaks to the
`
`relevant —— relative potencies of 5—HMT and
`
`tolterodine that was available in 1998?
`
`A.
`
`I have not
`
`looked at that point
`
`extensively.
`
`My impression, generally, has been
`
`that 5—HMT itself has rarely been tested.
`
`Q.
`
`Mm-hmm.
`
`Now, can you just -- my
`
`question is: As
`
`to the relative potencies of the
`
`two entities, are you aware of anything else, as
`
`you sit here, other than this cat data, which
`
`speaks to the relative potencies?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`Let me just say in terms of this
`
`particular data set or in terms of any other?
`
`Q.
`
`Anywhere.
`
`I mean,
`
`I see what you're
`
`saying here.
`
`I see this paper.
`
`A.
`
`Q.
`
`Yes.
`
`I
`
`just want to know if —— are you aware
`
`of anything else that you read or reviewed that
`
`suggests that 5—HMT is more potent than
`
`tolterodine?
`
`TSG Reporting — Worldwide
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`In vivo?
`
`In vivo,
`
`in vitro. Anything?
`
`As
`
`I say, my focus was on in vivo in
`
`A.
`
`Q.
`
`A.
`
`studying this, and in vivo,
`
`I, at this moment,
`
`don't —— cannot cite any other references --
`
`Q.
`
`A.
`
`Q.
`
`Okay.
`
`—-
`
`than this.
`
`In your opening report, Page 17,
`
`Paragraph 55 --
`
`A.
`
`Q.
`
`Yes.
`
`—— in that paragraph, you're providing
`
`a couple of different reasons as to why,
`
`in your
`
`view,
`
`a person of ordinary skill in the art would
`
`have been motivated to improve upon 5—HMT.
`
`I'm not sure if you meant tolterodine there,
`
`but
`
`the second reason that you provided, it says,
`
`"It was known that 5—HMT's affinity for the M3
`
`receptor was comparable to tolterodine."
`
`A.
`
`Mm—hmm.
`
`Q.
`
`A.
`
`Q.
`
`Do you see that?
`
`Yes,
`
`I do.
`
`Okay.
`
`So if you thought —- if your
`
`view of the prior art was that 5~HMT was more
`
`potent, why would you suggest that they were
`
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`Page 139
`
`DAVID R.
`
`JANERO, Ph.D.
`
`comparable in your report there, at Paragraph 55?
`
`A.
`
`The data,
`
`in terms of the biochemical
`
`parameters,
`
`in terms of competition binding to
`
`the receptor,
`
`shows that within,
`
`in my opinion,
`
`statistical error,
`
`they are comparable.
`
`They are both high—affinity ligands for the
`
`muscarinic type, Subtype 3 receptor.
`
`Q.
`
`A.
`
`Okay.
`
`And that —— pardon me, I'll just
`
`conclude by connecting my point earlier, as I
`
`say, but
`
`the —— that in vitro affinity in an
`
`isolated biochemical, not a living system, need
`
`not quantitatively translate to a complex mammal
`
`in vivo,
`
`such as a human or experimental animal.
`
`Q.
`
`A skilled artisan in drug development
`
`setting out
`
`to dedicate resources into developing
`
`a new drug in 1998,
`
`in your view, how much weight
`
`would they put on that cat data,
`
`in the absence
`
`of other data speaking to the potency of 5—HMT?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`As an outsider who was not at —— in the
`
`development or discovery stream in the company,
`
`I
`
`do not know that there were no -- I would not
`
`know there would be no other data. But I'll take
`
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`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`it as an assumption that I would not know.
`
`My experience as a drug discovery and
`
`development person has taught me over many
`
`decades that internal data need not appear in
`
`publications,
`
`in print,
`
`in any form.
`
`Q.
`
`A.
`
`Right.
`
`So, given that, and given the fact
`
`that -- and we'll set that aside -- the fact that
`
`these data in this particular paper,
`
`in this
`
`particular model, address the very -- the
`
`fundamental basis for bladder contraction;
`
`namely, acetylcholine—induced smooth muscle
`
`relaxation via an antimuscarinic mechanism,
`
`I
`
`believe that these data would hold significant
`
`credence in terms of a drug discovery campaign.
`
`Q.
`
`Okay.
`
`My question was simply:
`
`If you
`
`were going to develop a new drug and the idea was
`
`that to target an entity because it had shown
`
`better potency than what existed at the time,
`
`would you really undertake that endeavor on the
`
`basis of a study in cats?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I would need to know the whole context
`
`in order to answer your question.
`
`TSG Reporting — Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0140
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Okay.
`
`Specifically,
`
`I would need to know any
`
`Q.
`
`A.
`
`other data.
`
`On the other hand,
`
`I realize again from my
`
`experience in drug discovery and development,
`
`that we're operating here at a more sophisticated
`
`level of in vivo animal
`
`than is usually done in
`
`pre—clinical; namely, mouse, rat,
`
`rodent.
`
`Q.
`
`Mm—hmm.
`
`You do know that,
`
`in terms of
`
`invalidating the patent,
`
`that it's not really the
`
`perspective of these inventors or this company.
`
`It's what this hypothetical ordinary person would
`
`do with the information that's available.
`
`Correct?
`
`A.
`
`Yes.
`
`I'm simply taking those data,
`
`for
`
`example --
`
`Q.
`
`A.
`
`Q.
`
`Okay.
`
`—— at face value.
`
`All right. Let's move on to the
`
`polymorphism issue. Where in the art or what
`
`evidence do you have to support the fact that --
`
`or the supposition that the polymorphism
`
`exhibited by those given tolterodine was,
`
`in
`
`fact,
`
`a problem or something that needed to be
`
`TSG Reporting — Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0141
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`improved upon?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I suggest that we want
`
`to clarify.
`
`was talking about polypharmacology.
`
`I was not
`
`equating that with polymorphism.
`
`We can discuss
`
`polymorphism, but my point was different.
`
`My point was the idea that when a mammal,
`
`man, administered tolterodine two active agents
`
`result.
`
`That is what
`
`I was calling
`
`polypharmacology.
`
`Q.
`
`A.
`
`Mm—hmm.
`
`The polymorphism is the genetic
`
`variance in metabolizing enzymes,
`
`so we're
`
`talking about
`
`the latter.
`
`Q.
`
`A.
`
`Okay.
`
`Are we?
`
`I just want
`
`to be sure.
`
`Q. Well, let's just —— let's just step
`
`back and say the fact —— we agree that there are
`
`two active agents with tolterodine. Correct?
`
`A.
`
`Q.
`
`A.
`
`We agree. Yes.
`
`That's a little unique. Correct?
`
`I haven't done a complete survey of all
`
`known drugs in the pharmacopeia,
`
`so I would not
`
`know how unique it is.
`
`TSG Reporting — Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2027 - 0142
`
`
`
`DAVID R.
`
`JANERO, Ph.D.
`
`Q.
`
`Are you familiar with any other drugs
`
`that exhibit that type of double agent activity?
`
`MS. WOOTEN: Objection.
`
`Form.
`
`A.
`
`I have certainly encountered drugs that
`
`have active metabolite.
`
`Q.
`
`Mm—hmm. And the parent or the starting
`
`compound is also active?
`
`A.
`
`Q.
`
`Yes.
`
`Are those compounds that are
`
`commercialized?
`
`A.
`
`They probably would be.
`
`I can't name
`
`any, but
`
`I know I've run into them in my own drug
`
`discovery and development.
`
`Q.
`
`Okay. Maybe we should start out with
`
`this:
`
`Can you explain to me what
`
`the difference
`
`is between polypharmacology and polymorphism?
`
`A.
`
`Yes.
`
`Polypharmacology, as I'm
`
`referring to,
`
`is the condition whereby we have
`
`multiple active
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