throbber
STEVEN E. PATTERSON, Ph.D.
`
`about separating tolterodine from 5—HMT and trying to
`
`administer a single active moiety.
`
`How would you feel
`
`comfortable describing that so I don't --
`
`A
`
`Q
`
`A
`
`Q
`
`A.
`
`Okay.
`
`That's what
`
`I meant by --
`
`How about let's just say isolation of 5—HMT.
`
`Okay.
`
`In the development of tolterodine, y©u have
`
`this known metabolite. Your synthetic chemist will
`
`make that in order to perform the analytical chemistry
`
`properly so that an authentic standard exists.
`
`Q
`
`A
`
`Okay.
`
`That's all the motivation necessary to
`
`prepare it and isolate it.
`
`Q
`
`A
`
`Uh—huh.
`
`Having that in hand,
`
`then you have the
`
`synthetic method,
`
`that facilitates further
`
`investigation of the molecule.
`
`Q
`
`Okay.
`
`So maybe let me ask it this way: Why
`
`would a person of ordinary skill in the art in 1998 not
`
`have tried to formulate 5—HMT in a formulation for
`
`delivery as distinguished from designing a prodrug?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`A medicinal chemist would
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0126
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`prepare a prodrug. That would be a
`
`formulation exercise, right,
`
`so that's not
`
`what we do.
`
`A medicinal chemist
`
`looking at the
`
`hydroxyls would recognize that esterification
`
`is not a particularly difficult task for most
`
`of us.
`
`It's relatively easy, and that's a
`
`method that's known to increase
`
`lipophilicity.
`
`So that's almost a knee-jerk
`
`response, prepare a set of esters, evaluate
`
`them.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor)
`
`And was that a knee-jerk
`
`response in 1998?
`
`A
`
`Such chemistry has been known for decades
`
`previous to 1998.
`
`Q
`
`Okay. Let me be a little more articulate,
`
`I
`
`hope.
`
`If the goal is to deliver 5—HMT —— well, let's
`
`step back.
`
`As
`
`I understand your declaration —— and maybe
`
`just to get us all at a right point,
`
`I think the
`
`discussion of prodrug design begins around paragraph
`
`105 --
`
`(Interruption in the proceedings.)
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0127
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`THE WITNESS:
`
`Pardon me. Let me turn
`
`this thing off so it doesn't bug us. Okay.
`
`Thanks for putting up with that.
`
`MR. TRAINOR: No, no.
`
`THE WITNESS:
`
`I
`
`am at paragraph 105.
`
`Q
`
`(By Mr. Trainor) Well,
`
`I guess I'm trying
`
`to —— what is the reason,
`
`in your view,
`
`that a skilled
`
`drug developer would have had to make 5—HMT more
`
`lipophilic?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`The log D value that was
`
`known of tolterodine, and so I would —— you
`
`know,
`
`that's relatively low.
`
`The log D value
`
`at around pH 7 was -- of that molecule was
`
`between 1 and 2.
`
`So we have now a more polar substrate of
`
`something with a relatively log D Value
`
`[sic].
`
`I might be —— I would be concerned
`
`that we would see a decrease in the
`
`hydroxymethyl's ability to decrease the gut.
`
`I wouldn't necessarily predict that such
`
`permeability would be zero, but
`
`I would
`
`predict that the permeability would be
`
`decreased;
`
`therefore,
`
`I would be ready to
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0128
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`attempt
`
`to increase that by increasing its
`
`lipophilicity, and the more lipophilic
`
`molecules to a point are known to be better
`
`candidates for oral absorption.
`
`Q
`
`(By Mr. Trainor) Okay.
`
`So do I understand
`
`that the hypothetical developer at that time would
`
`recognize from the lipophilicity that 5—HMT,
`
`if you try
`
`to deliver it per se, if you will, would not be
`
`sufficiently well absorbed?
`
`Is that --
`
`A
`
`Q
`
`It would recognize that's a possibility.
`
`Okay.
`
`So coming back to my first question:
`
`Wasn't one available solution for that to put it in a
`
`dosage form that would permit delivery of the 5—HMT
`
`notwithstanding concerns about its absorption?
`
`A
`
`That might be —— that might be an approach.
`
`A medicinal chemist would look to modify it chemically
`
`in order to solve that problem.
`
`Q
`
`Okay. Are there other members of the makeup
`
`of the skilled drug developer besides medicinal chemist
`
`who might
`
`look more toward the new dosage form?
`
`A
`
`A form --
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`Sorry. Yes,
`
`I think so.
`
`MR. TRAINOR: Okay.
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0129
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`Q
`
`(By Mr. Trainor)
`
`And a formulation chemist,
`
`Page 130
`
`is that what you were going to say?
`
`(Witness nods head affirmatively.)
`
`Okay.
`
`Sorry,
`
`I'm nodding. Yes.
`
`That's okay.
`
`A
`
`Q A
`
`Q
`
`So one alternative option would be to
`
`formulate 5—HMT per se in,
`
`for example,
`
`a
`
`controlled-release formulation;
`
`is that right?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`I'm not sure a controlled
`
`release would be the way to go.
`
`MR. TRAINOR: Okay.
`
`THE WITNESS:
`
`I'm -- not being a
`
`formulation chemist, it's difficult for me to
`
`say what formulation would work.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor) Well, without being a
`
`formulation chemist, do you believe that some type
`
`formulation would work to achieve delivering 5—HMT
`
`se --
`
`MS. WOOTEN: Objection,
`
`form.
`
`Q
`
`—— even if it's not a controlled—release
`
`formulation?
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0130
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`MS. WOOTEN:
`
`Sorry.
`
`Same objection.
`
`Objection,
`
`form.
`
`THE WITNESS: Difficult for me to say
`
`not being a formulation chemist.
`
`MR. TRAINOR: Okay.
`
`THE WITNESS: And I don't advocate
`
`sole —— you know, chemical modification as a
`
`sole response to solve a problem.
`
`A project
`
`manager might want
`
`to look at -- right,
`
`so
`
`this is just Simply the first thing just
`
`simply because the relative ease of
`
`esterification of the molecule that you would
`
`already have because you made it knowing it's
`
`a metabolite.
`
`Q
`
`(By Mr. Trainor) But if you do that, you're
`
`creating a new chemical entity, right?
`
`A
`
`That's probably going to be the case. There
`
`probably would not be known esters of that molecule.
`
`Q
`
`Okay.
`
`Now, what about administering 5—HMT
`
`per se, wouldn't you attempt to do that before going to
`
`the trouble of a prodrug?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`I would perform a KCO2
`
`assay for oral availability or have someone
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0131
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`do it for me.
`
`Q
`
`(By Mr. Trainor)
`
`And depending on the
`
`results,
`
`the simplest method would be just administer
`
`it per se, correct,
`
`5-HMT?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`If the results predicted
`
`low oral availability,
`
`I would commence
`
`preparation of prodrug.
`
`MR. TRAINOR: Right.
`
`Q
`
`(By Mr. Trainer)
`
`If the results were
`
`sufficient for oral availability,
`
`then you would agree
`
`it would be much simpler just to administer the 5—HMT
`
`per se, correct?
`
`A
`
`Q
`
`A
`
`Q
`
`I would -- right.
`
`Yes?
`
`Yes, yes.
`
`Okay. And a drug developer at the relevant
`
`time —— strike that.
`
`Would the drug developer at the relevant time
`
`attempt to do that before jumping to an analog or a
`
`prodrug approach just in case it worked?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Are you asking me if the
`
`synthetic lab would make such a prodrug
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0132
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`before performing a KCO2 predictor or before
`
`doing an oral availability?
`
`MR. TRAINOR: Yes.
`
`THE WITNESS: Okay. Maybe.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor) Okay. Why would that be
`
`reasonable in terms of resources?
`
`A.
`
`It would depend on how certain you were that
`
`you were going to need to do it.
`
`Q
`
`A
`
`Q
`
`Okay.
`
`That's why I say maybe.
`
`Okay.
`
`Now,
`
`the absorption of 5—HMT was not
`
`known prior to 1998, correct?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`I don't know the answer to
`
`that.
`
`It was not -- yeah,
`
`I don't know the
`
`answer to that.
`
`I don't think it was
`
`reported in the literature.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor)
`
`And you would agree that
`
`lipophilicity can be an indicator of oral absorption,
`
`but that's not always the case, correct?
`
`A
`
`It can —— it can, yes,
`
`it can be an indicator
`
`of whether or not a compound is likely to get
`
`in,
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0133
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`Okay, but it's not always the case?
`
`A
`
`There are exceptions where molecules are
`
`transported in.
`
`There are cases,
`
`though may
`
`understanding is they're quite rare, where it passes
`
`between the cells to get in.
`
`Q
`
`Okay.
`
`Now, based on the calculated
`
`lipophilicity —— did you do that?
`
`I'm looking at the
`
`section -- in any event, your View of the calculated or
`
`theoretic lipophilicity of the 5—HMT structure itself
`
`was that it would not be sufficiently absorbed;
`
`is that
`
`right?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Are you referring to
`
`Professor Rouse's calculation?
`
`MR. TRAINOR: Did you do a calculation?
`
`THE WITNESS:
`
`I did not.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor)
`
`So without doing the
`
`calculation, how would you arrive at the conclusion
`
`that 5—HMT needed to be more lipophilic?
`
`A
`
`Because the parent,
`
`tolterodine,
`
`isn't
`
`particularly lipophilic; its log D is less than 2. And
`
`so you make the thing more polar by putting hydroxy
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0134
`
`

`
`Page 135
`
`STEVEN E. PATTERSON, Ph.D.
`
`group on there,
`
`the lipophilicity is going to go down.
`
`My experience with polyols is that many of them don't
`
`get in passively very well.
`
`Q
`
`Okay. Was that routine,
`
`in 1998,
`
`to
`
`extrapolate the propensity to be absorbed from one
`
`analog to another based on lipophilicity?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`So based on structure, it
`
`was to predict a relative.
`
`So you put a
`
`polar moiety on the thing, you would predict
`
`it would have a lesser lipophilicity than its
`
`parent molecule.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor)
`
`I
`
`think earlier you agreed
`
`that tolterodine seemed to be well absorbed.
`
`A
`
`Q
`
`Yes.
`
`So even if the —— even if 5—HMT structure
`
`suggested a lower lipophilicity, how could you conclude
`
`that 5-HMT would not itself be sufficiently orally
`
`absorbed?
`
`A
`
`I wouldn't conclude with certainty as you
`
`expressed it.
`
`I would say it might not be adequately
`
`absorbed.
`
`Q
`
`Okay, but wouldn't you want
`
`to go on more
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0135
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`than the possibility before going to the process of
`
`designing a prodrug?
`
`A
`
`Well, design of an ester is really quite
`
`easy, and that's routinely done with polyols.
`
`I would
`
`do the KCO2 assay before initiating a synthetic effort.
`
`Q
`
`Okay. And what about
`
`the option of making
`
`analogs of 5—HMT that aren't necessarily prodrugs, but
`
`just chemical analogs to --
`
`A
`
`Right.
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`I'm sorry.
`
`The reason I
`
`wouldn't consider that as a first—pass
`
`approach or first approach —— let's not say
`
`first pass,
`
`so I apologize for that, but as a
`
`first approach,
`
`is that it's known that 5—HMT
`
`is quite potent, it's equipotent to a
`
`molecule that was taken to the clack
`
`[phonetic].
`
`So the structural modifications,
`
`what if that, you know, abolishes the
`
`activity.
`
`MR. TRAINOR: Okay.
`
`THE WITNESS: Right? Now,
`
`that might be
`
`something I would be interested in doing had
`
`I enough people in my lab to prepare
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0136
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`synthetic analogs, but that wouldn't be my
`
`first approach.
`
`Q
`
`(By Mr. Trainor) But it's equally possible
`
`that you could make an analog that would actually
`
`increase 5—HMT's potency, correct?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: That might be —— yeah,
`
`that might be the case.
`
`If you're making
`
`analogs,
`
`ideally that's what you want
`
`to
`
`do.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor)
`
`Now,
`
`just sticking again
`
`with the absorption part of it, would you agree that
`
`the theoretical log P of —— I'm sorry,
`
`let me reask the
`
`question.
`
`Is it log P or log D that is the preferred
`
`indicator of lipophilicity?
`
`A
`
`Both are used.
`
`I
`
`think both are very
`
`similar.
`
`Q
`
`A
`
`Okay.
`
`I
`
`think both can be used, you know,
`
`in, you
`
`know,
`
`ranking, right.
`
`Q
`
`Okay.
`
`So how about
`
`I ask it this way:
`
`However appropriately measured, would you agree that
`
`the calculated lipophilicity for 5—HMT, based on its
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0137
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`structure, fell within the range of other compounds
`
`that had been deemed to be sufficiently absorbed?
`
`A
`
`Can you --
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Oh,
`
`I'm sorry.
`
`Can you
`
`show me an example where someone calculated
`
`the --
`
`MR. TRAINOR:
`
`I can.
`
`I sort of didn't
`
`have that in my order here,
`
`so maybe we'll
`
`come back to it.
`
`THE WITNESS:
`
`I'll be happy to rest a
`
`minute or --
`
`MR. TRAINOR: Okay.
`
`THE WITNESS:
`
`—— whatever is most
`
`convenient for you.
`
`MR. TRAINOR: Okay, okay.
`
`Q
`
`(By Mr. Trainor) All right.
`
`So about the
`
`prodrugs, you said it's relatively easy for a medicinal
`
`chemist to make an ester, correct, and that was the
`
`case in 1998, 1978, probably?
`
`A
`
`Q
`
`Yes, sir.
`
`Okay, but just making an ester of a compound
`
`does not mean that it will be a prodrug, correct?
`
`A
`
`I
`
`think —— well,
`
`the enzymes that hydrolyze
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0138
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`esters are widely distributed. They're in pretty
`
`much —— they're in serum,
`
`they're in liver,
`
`they're in
`
`most cells.
`
`So it's reasonable to expect that if you
`
`make an ester,
`
`the esterases will cleave that ester.
`
`Q
`
`Okay. But, again, even if you make an ester
`
`and esterases cleave that ester,
`
`that doesn't
`
`necessarily mean that you've made a prodrug, correct?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Well, now,
`
`if the drug is
`
`cleaved in vivo,
`
`I would say that you have a
`
`prodrug.
`
`MR. TRAINOR: Okay.
`
`THE WITNESS:
`
`It may not be a perfect
`
`prodrug.
`
`MR. TRAINOR: Okay.
`
`THE WITNESS: But it is,
`
`in fact, if it
`
`releases the active.
`
`Q
`
`(By Mr. Trainor) Well, according to
`
`Bundgaard, which is another one of the papers that you
`
`rely on —— let me get that for you. Exhibit 1012.
`
`Let me keep talking and I'll hand it -- the accepted
`
`definition by those skilled in the art in 1998 of a
`
`prodrug was one where the delivering molecule is
`
`inactive, Correct?
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0139
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`If you wish to argue that,
`
`you know,
`
`that doesn't affect what you're
`
`trying to accomplish,
`
`in my opinion.
`
`You can
`
`call it something else if you like.
`
`If your
`
`modified derivative has some affinity for
`
`your target receptor,
`
`it still, you know,
`
`crosses,
`
`the drug is liberated,
`
`the desired
`
`drug is liberated by the esterases, and
`
`you've accomplished your task.
`
`So the —- you may say that, well, by the
`
`strictest definition,
`
`this isn't a prodrug,
`
`but what we've done is made our target
`
`molecule appropriately bioavailable.
`
`MR. TRAINOR: Okay.
`
`THE WITNESS: And that's our goal.
`
`Q
`
`(By Mr. Trainor)
`
`I understand that that's
`
`the goal, but
`
`I want to figure out what
`
`the definition
`
`was,
`
`to your understanding,
`
`in 1998 to skilled
`
`artisans.
`
`MR. TRAINOR:
`
`So just for the record,
`
`I've handed Dr. Patterson what is
`
`Exhibit 1012 to both of his declarations.
`
`This is a series of chapters, maybe the whole
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0140
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`book, but first author is Bundgaard.
`
`Q
`
`(By Mr. Trainor)
`
`And I believe —— do you
`
`have reason to believe that Bundgaard,
`
`in this treatise
`
`that you rely upon, does not define a prodrug as
`
`inactive?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`You know,
`
`I don't recall
`
`if Bundgaard defines prodrugs as active or
`
`inactive. What
`
`I will say is that people are
`
`Very often sloppy because we talk about
`
`prodrugs as being active —— or inactive,
`
`I'm
`
`sorry, until, you know,
`
`some activation event
`
`happens, either metabolic or spontaneous.
`
`Nucleosides are molecules that require
`
`metabolic activation in order for them to
`
`inhibit the polymerases for which they're
`
`designed.
`
`People don't usually refer to
`
`nucleosides as prodrugs, but if we accept
`
`that strict definition,
`
`they are,
`
`in fact,
`
`prodrugs.
`
`I won't argue, you know,
`
`such
`
`small points.
`
`Q
`
`(By Mr. Trainor) Okay. Well,
`
`I don't think
`
`it's a small point because the majority of your opinion
`
`as to the obviousness of making a prodrug of 5-HMT
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0141
`
`

`
`Page 142
`
`STEVEN E. PATTERSON, Ph.D.
`
`stems from this Bundgaard reference, who's published a
`
`whole book on prodrugs.
`
`I have it here.
`
`If you turn
`
`to the very first page --
`
`A
`
`Q
`
`Okay.
`
`—— page 8, Chapter l, "Design of Prodrugs,"
`
`in the very first paragraph.
`
`A
`
`Page 8 of the exhibit or page 8 of the
`
`reference?
`
`Q
`
`I'm sorry, it's page 8 of the Exhibit 1012.
`
`A
`
`Q
`
`Okay.
`
`There I am, okay.
`
`In the middle of that introductory paragraph,
`
`it says,
`
`"The prodrug per se is an inactive species,
`
`and therefore, once its job is completed,
`
`intact
`
`prodrug represents unavailable drug."
`
`Do you see that?
`
`A
`
`Q
`
`Okay.
`
`So is it fair to say that at least according
`
`to this prior art reference,
`
`the definition of a
`
`prodrug is one that remains inactive even if it's
`
`not —— if it doesn't convert?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Okay. According to
`
`Bundgaard,
`
`the way he defines it there.
`
`MR. TRAINOR: Okay.
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0142
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`Q
`
`(By Mr. Trainor)
`
`So is it your view that
`
`that is not
`
`the appropriate definition that's used in
`
`this treatise?
`
`A
`
`I'm okay with that even if my attempt to --
`
`or my attempt isn't to make an inactive; it's to get
`
`the target molecule into the blood and have the target
`
`molecule released by the esterases.
`
`Q
`
`A
`
`Q
`
`A
`
`Right. That is a --
`
`You're right.
`
`That is a goal?
`
`So if you wish to say that's not a prodrug,
`
`I'll accept your correction.
`
`Q
`
`Okay. Well, let's say that you esterify a
`
`compound and it cleaves, but a certain percentage of
`
`that prodrug doesn't convert.
`
`It's quite important
`
`that that prodrug remain biologically inactive,
`
`correct; otherwise, we're just back at the problem that
`
`we had with tolterodine that you wanted to eliminate,
`
`no?
`
`A
`
`Q
`
`A
`
`That might present some concern.
`
`Okay.
`
`But the main problem to eliminate by
`
`prodrugging is the variable metabolism by CYP2A.
`
`Q
`
`Understood.
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0143
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`Uh—huh.
`
`And prodrugs are designed for all sorts of
`
`A
`
`Q
`
`reasons, correct?
`
`A
`
`Q
`
`A
`
`Q
`
`Yes.
`
`Including improving absorption?
`
`Yes.
`
`But so my point was simply, you would agree
`
`with me that just esterifying a compound and Confirming
`
`that it cleaves does not necessarily mean that you have
`
`made a successful prodrug to the extent that the
`
`prodrug is active, Correct?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: What
`
`I would say is, you
`
`know,
`
`just because of an ester, what -- my
`
`response to that is if that becomes a
`
`concern,
`
`I
`
`think that among a —- you know, a
`
`selection of esters,
`
`I would find one with
`
`the desired properties.
`
`MR. TRAINOR: Right.
`
`THE WITNESS: So...
`
`Q
`
`(By Mr. Trainor)
`
`And until you find one that
`
`meets that definition of a prodrug, correct?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`If I care about that,
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0144
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`so...
`
`Q
`
`(By Mr. Trainor) Well,
`
`if you don't care,
`
`then you might end up with what you termed a
`
`prodrug-like compound like tolterodine, correct?
`
`A
`
`Q
`
`Yes.
`
`And then we now have three entities:
`
`the
`
`promoiety,
`
`the potentially active prodrug, and the
`
`metabolite.
`
`In that event, doesn't that further
`
`exasperate the concerns you had with the complex
`
`metabolism of tolterodine?
`
`A
`
`Well,
`
`the esterases are typically efficient,
`
`so I would be less concerned that the ester were
`
`metabolically stable.
`
`Q
`
`I understand that preliminarily, at least,
`
`that's got
`
`to be your first concern;
`
`if it doesn't
`
`cleave, it doesn't convert,
`
`then you're on to the next
`
`one. But my question is:
`
`If your prodrug is not
`
`inactive,
`
`then you haven't solved the very problem that
`
`you've identified as tolterodine having, correct?
`
`MS. WOOTEN: Objection,
`
`form.
`
`Q
`
`(By Mr. Trainor)
`
`You haven't eliminated a
`
`pathway, you haven't eliminated an active, correct?
`
`A
`
`Well,
`
`I wouldn't say that I haven't
`
`eliminated a pathway because I've eliminated the CYPZD6
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0145
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`pathway of concern.
`
`Q
`
`A
`
`Q
`
`Okay.
`
`Okay?
`
`But you -- in that example that I just
`
`provided, you would still have two active ingredients,
`
`correct, or two active moieties, correct?
`
`A
`
`You know,
`
`if it were active and it would —— I
`
`think it would also depend on the degree of activity.
`
`You know,
`
`some actives we define, you know, have
`
`activity that's so low that it's not clinically
`
`relevant.
`
`Q
`
`A
`
`Okay, but you have to confirm that, correct?
`
`It would be a matter of routine testing.
`
`Is that right?
`
`How routine would that be?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Well, since the assays are
`
`established in this case, you use the
`
`existing assays.
`
`Q
`
`(By Mr. Trainor) Well, but
`
`in order to
`
`confirm that you have an inactive prodrug, you've got
`
`to test that in humans, no?
`
`A
`
`You would know that what —~ by the cell
`
`culture methods discussed with the CHO cells, whether
`
`it had an affinity for the M3 -- or the muscarinic
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0146
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`receptors.
`
`Q
`
`Why don't you turn to page 4 of Bundgaard,
`
`please.
`
`A
`
`Q
`
`Four of the --
`
`I'm sorry, page 4 of Bundgaard, page 10 of
`
`the exhibit.
`
`A
`
`Okay.
`
`I
`
`thought you said page 4 of the
`
`actual text.
`
`I just want
`
`to make sure we're on the
`
`same page.
`
`Q
`
`Okay.
`
`Now,
`
`in this first full paragraph that
`
`begins "Sometimes," this paragraph is reporting about
`
`these penicillin esters that I want
`
`to get to.
`
`You
`
`mentioned them in your declaration.
`
`For the moment,
`
`I just want
`
`to focus your
`
`attention on —— if you look at the second sentence --
`
`third sentence, rather, it says,
`
`"Although various
`
`simple alkyl and aryl esters of the thiazolidine
`
`carboxyl group hydrolyzed rapidly to the free
`
`penicillin acid in animals,
`
`such as rodents,
`
`they
`
`proved to be far too stable in man to have any
`
`therapeutic potential. This illustrates also, as do
`
`many other examples,
`
`the occurrence of marked species
`
`differences in the in vivo hydrolysis of ester
`
`prodrugs."
`
`Do you see that?
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0147
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`Yes.
`
`And that would suggest
`
`to you that you would
`
`A
`
`Q
`
`have to take your prodrug all the way into humans to
`
`determine whether or not it has therapeutic potential
`
`or therapeutic drawbacks, correct?
`
`A
`
`Certainly not.
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Oh, sorry.
`
`(By Mr. Trainor)
`
`No?
`
`Certainly not, no.
`
`How do you reconcile that with this --
`
`The comment --
`
`MS. WOOTEN: Hold on.
`
`THE WITNESS: Okay.
`
`Sorry.
`
`MS. WOOTEN: Whatever the question is,
`
`be clear about who's talking.
`
`THE WITNESS: Okay. Sorry.
`
`MR. TRAINOR: Sorry.
`
`WITNESS:
`
`I didn't mean to step on
`
`MR. TRAINOR: That's okay.
`
`THE WITNESS:
`
`I'm eager to answer
`
`because this is —— routinely is.
`
`You use
`
`human serum. Esterases are abundant in human
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0148
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`serum.
`
`In addition,
`
`they're abundant in
`
`human liver,
`
`so you could use,
`
`for example,
`
`the S9 fraction or the cytosolic fraction of
`
`liver homogenates without going in vivo.
`
`Q
`
`(By Mr. Trainor) Right, but that's not going
`
`to tell you anything about whether that unmetabolized
`
`prodrug binds to certain off—targets, correct?
`
`A.
`
`which you also and big pharma also have
`
`established assays in order to measure those.
`
`Q
`
`A
`
`which are? what were those in 1998?
`
`I don't have a laundry list of them, but, you
`
`know, you would use the same established assays that --
`
`used as a routine to translate for clinical translation
`
`of the parent drug.
`
`Q
`
`Okay, but can you just explain that to me?
`
`How do you assay for activity at nontarget receptors
`
`without administering the prodrug to subjects?
`
`MS. WOOTEN: Objection,
`
`form.
`
`Q
`
`(By Mr. Trainor)
`
`Can you just explain the
`
`assay to me?
`
`A
`
`There is a -- since I'm not an entomologist,
`
`I'm not going to attempt
`
`to go into the technical
`
`details.
`
`Q
`
`Okay.
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0149
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`A
`
`These things exist. There is a Chinese
`
`hamster ovary cell model that exists for the muscarinic
`
`ones.
`
`Q
`
`Okay.
`
`In any case, can we just talk about
`
`the —— let's just talk about the properties that are
`
`required of a prodrug in your view or in your opinion
`
`as of the View of the skilled artisan in 1998.
`
`So it
`
`needs to convert, Correct?
`
`A
`
`Q
`
`(No verbal response.)
`
`You may be looking for a certain rate of
`
`conversion, Correct? Yes?
`
`A
`
`Q
`
`Yes.
`
`Sometimes you want a very rapid rate of
`
`conversion, correct?
`
`A
`
`Q
`
`A
`
`Q
`
`Yes.
`
`Other times not so rapid?
`
`Depending on your reason for it.
`
`Okay. And if your reason is to improve
`
`absorption, what rate of conversion are you looking
`
`for?
`
`A
`
`I would look for a relatively rapid rate of
`
`conversion.
`
`Q
`
`Okay.
`
`Now, let's just continue on.
`
`So then
`
`the prodrug needs to be stable pre-administration,
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0150
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`correct?
`
`A
`
`Q
`
`Yes.
`
`And would you describe lability as the same
`
`thing as conversion rate?
`
`A
`
`That would depend on the context. We could
`
`discuss enzymatic lability, chemical lability, right?
`
`Q
`
`Uh—huh. Okay.
`
`You need to ensure that the
`
`prodrug is inactive; we discussed that.
`
`You would also
`
`need to ensure that the promoiety is not itself toxic
`
`or active, Qorrect?
`
`A
`
`Q
`
`Yes.
`
`And are there any other properties of a
`
`prodrug that you're looking for in designing one?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS:
`
`You covered the major
`
`ones,
`
`I believe.
`
`MR. TRAINOR: Okay.
`
`Q
`
`(By Mr. Trainor)
`
`So —— and in the prior art
`
`by 1998, it was known that simple alkyl esters often
`
`had poor stability, correct?
`
`A
`
`Well, poor enzymatic stability can isolate
`
`most simple alkyl esters.
`
`Put
`
`them in a bottle.
`
`Q
`
`Okay.
`
`So you do not agree that the prior art
`
`reported simple alkyl esters were not always stable?
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0151
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`A
`
`Well, were not always stable,
`
`that I
`
`think is
`
`Page 152
`
`true.
`
`Q
`
`A
`
`Okay.
`
`Most of them,
`
`the simple alkyl ones, you can
`
`isolate and put
`
`in a bottle, keep in a lab. They're
`
`reasonably stable.
`
`Q
`
`Okay. And would you agree that in the prior
`
`art prior to 1998,
`
`there were a number of examples
`
`where simple alkyl esters did not sufficiently convert?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: Bundgaard mentions some
`
`specific examples.
`
`Q
`
`(By Mr. Trainor) Are these the Ampicillin --
`
`the penicillin prodrugs?
`
`A
`
`Q
`
`That's one.
`
`Okay.
`
`So now let's look back
`
`reference.
`
`So if you look at the table
`
`A
`
`Q
`
`Is it page 4?
`
`Yeah, well, I'll just go back to the first
`
`page because I got caught up looking at the rat issue
`
`with you.
`
`So the introduction, he's discussing, you
`
`know, use of prodrugs and active drug species
`
`containing hydroxyl groups can be converted. And as he
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0152
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`gets down to page 2 with this brief intro, it says --
`
`at the end of the text on page 2, before the table, it
`
`says, "Various reviews have dealt with esters as
`
`prodrug types, and therefore this important class will
`
`only be briefly treated herein."
`
`Do you see that?
`
`A
`
`Right, past esters have been considered as
`
`prodrug types.
`
`Q
`
`Q
`
`Right.
`
`Yes,
`
`I see that.
`
`Did you —— did you ever review those
`
`references that he cites as previously treating, you
`
`know, basic ester prodrugs,
`
`6 and 7
`
`there?
`
`I
`
`think the
`
`author is Bodor or something like that, B—O—D—O—R.
`
`A
`
`Q
`
`I don't recall looking at those specific --
`
`Okay.
`
`So then he transitions to say —— I
`
`could paraphrase —— here's what's new or what's going
`
`on with the ester prodrugs, and he gets into that in
`
`Section 2. And then it carries over onto page 4, and
`
`as you just suggested,
`
`there's a discussion of these
`
`penicillin esters.
`
`Do you see that?
`
`A
`
`Q
`
`Okay.
`
`And there are three examples,
`
`I believe, of
`
`penicillin esters that have been made and are being
`
`reported on.
`
`I
`
`think you referenced them in your
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0153
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`declaration. But
`
`in any case, what Bundgaard teaches
`
`here is that the simple alkyl esters for use as
`
`penicillin prodrugs didn't quite work, correct?
`
`A
`
`Q
`
`Uh—huh.
`
`And so the solution was to make these special
`
`double esters;
`
`is that right?
`
`A
`
`Q
`
`Is that Scheme 1?
`
`I'm reading the middle of the paragraph
`
`there.
`
`It says,
`
`"A solution to the problem was found
`
`in l965...who showed that a double ester type" --
`
`"a special double ester type of benzylpenicillin was
`
`hydrolyzed rapidly."
`
`A
`
`Q
`
`Okay.
`
`So what do you understand him to be reporting
`
`there about
`
`the simple alkyl esters and the need for
`
`double esters?
`
`A
`
`In this specific case,
`
`the simple alkyl ester
`
`didn't work,
`
`so he used a different type of ester in
`
`order to solve the problem.
`
`Q
`
`Okay.
`
`So this would be at least one example
`
`where the simple alkyl ester just won't work with a
`
`particular compound as a prodrug, correct?
`
`A
`
`For the these beta lactam —— or the
`
`beta—lactam penicillin,
`
`that appears to be the case.
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0154
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`Q
`
`Okay.
`
`Now, if you have to make a double
`
`ester,
`
`is it —— is the resulting prodrug any less
`
`beneficial than a simple alkyl ester?
`
`MS. WOOTEN: Objection,
`
`form.
`
`THE WITNESS: You've accomplished the
`
`prodrugging task.
`
`I might be,
`
`in this case,
`
`a little concerned about
`
`the release of
`
`formaldehyde, depending on the dose, but
`
`you've still accomplished the task.
`
`Q
`
`(By Mr. Trainor) Okay.
`
`Now,
`
`the double
`
`ester that he's describing here —— I'm trying to see --
`
`I think it's Scheme 1,
`
`like you said.
`
`A
`
`Q
`
`correct?
`
`A
`
`Q
`
`A
`
`Uh—huh.
`
`So that is a two-step metabolic process,
`
`No.
`
`No?
`
`The first step is enzymatic, and the second
`
`is spontaneous.
`
`Q
`
`I see. But
`
`in any event,
`
`that's more
`
`complicated than your simple one-step --
`
`A
`
`Right,
`
`this is a case where —— and keep in
`
`mind, organic chemists like me sometimes say it's
`
`steric.
`
`In this case,
`
`I
`
`think it is,
`
`in fact, steric.
`
`TSG Reporting — Worldwide — 877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2020 - 0155
`
`

`
`STEVEN E. PATTERSON, Ph.D.
`
`That position is rather sterically —— is very
`
`sterically congested, and Bundgaard says, well, what
`
`you do is you get the promoiety a little bit further
`
`away and then let the second step happen spontaneously.
`
`And that's a special case, you know, given as an
`
`exception, and I don't think that's meant to be
`
`interpreted as a general example.
`
`Q
`
`Right, but it nonetheless is an example of
`
`how you design a prodrug in instances where a simple
`
`alkyl ester or simple aryl ester may not work?
`
`A
`
`Q
`
`That's right.
`
`Okay.
`
`Now, does the double ester penicillin
`
`prodrugs -- strike that.
`
`Do the double ester penicillin prodrugs have
`
`more carbons than the simple alkyl esters?
`
`A
`
`I haven't sat down to count that.
`
`I
`
`think it
`
`would depend on the —— in this case,
`
`the type of
`
`alcohol used to make the simple ester and then the type
`
`of acid used to make, you know, what you refer to as a
`
`double ester.
`
`Q
`
`Okay.
`
`So some of them might;
`
`some of them might
`
`Okay.
`
`In so

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket