`
`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
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`
`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.)
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`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
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`STEVEN E. PATTERSON, Ph.D.
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`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.
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`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?
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`
`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
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`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
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`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,
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`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
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`
`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
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`
`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
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`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
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`
`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
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`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?
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`
`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
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`
`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
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`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.
`
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`
`
`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.
`
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`
`
`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,
`
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`
`
`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
`
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`
`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
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`
`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?
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`
`
`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
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`
`
`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.
`
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`
`
`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,
`
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`
`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?
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`
`
`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
`
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`
`
`
`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
`
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`
`
`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.
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`
`
`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.
`
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`
`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