CULLEY C. CARSON, III, M.D.
`
`trospium chloride patients (after an average of
`
`14.3 days.)
`
`Do you see that?
`
`A
`
`Q
`
`I do, yes.
`
`Are those -- are with —— is withdrawal an
`
`important consideration in whether or not an
`
`overactive bladder drug is efficacious?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`It doesn't have anything to do with
`
`efficaciousness, but it has to do with tolerability
`
`of the patient.
`
`So it's a very important issue.
`
`BY MR. OELKE:
`
`Q
`
`I should say -- yeah,
`
`I'm sorry,
`
`I should
`
`say effective, whether it's an effective OAB
`
`treatment?
`
`A
`
`Again, and it can be effective, but the
`
`patients can't tolerate it,
`
`so they stop taking it.
`
`Q
`
`A
`
`Okay.
`
`And that's —— that's the case with
`
`oxybutynin.
`
`Q
`
`Okay.
`
`Now,
`
`for most OAB patients that
`
`are put on —— on drugs, how long does it —— does it
`
`take for the patient to get the —— the desired
`
`effect from the drug?
`
`A
`
`It's extraordinarily variable.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0091
`
`
`
`trospium chloride patients (after an average of
`
`14.3 days.)
`
`Do you see that?
`
`A
`
`Q
`
`I do, yes.
`
`Are those -- are with —— is withdrawal an
`
`important consideration in whether or not an
`
`overactive bladder drug is efficacious?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`It doesn't have anything to do with
`
`efficaciousness, but it has to do with tolerability
`
`of the patient.
`
`So it's a very important issue.
`
`BY MR. OELKE:
`
`Q
`
`I should say -- yeah,
`
`I'm sorry,
`
`I should
`
`say effective, whether it's an effective OAB
`
`treatment?
`
`A
`
`Again, and it can be effective, but the
`
`patients can't tolerate it,
`
`so they stop taking it.
`
`Q
`
`A
`
`Okay.
`
`And that's —— that's the case with
`
`oxybutynin.
`
`Q
`
`Okay.
`
`Now,
`
`for most OAB patients that
`
`are put on —— on drugs, how long does it —— does it
`
`take for the patient to get the —— the desired
`
`effect from the drug?
`
`A
`
`It's extraordinarily variable.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0091
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`Okay.
`
`And it can be as quickly as a few days,
`
`Q
`
`A
`
`but most often it's several weeks before they have
`
`the maximum effect.
`
`One has to realize that when you do a
`
`study of any of the overactive bladder drugs,
`
`there's a significant placebo effect for many
`
`patients.
`
`As many as 30 percent of patients will
`
`have some placebo response.
`
`So you could give them
`
`a Vitamin B and about a third of them would feel
`
`better.
`
`So it's a little hard to tease that out.
`
`But —— but generally it takes several
`
`weeks for them to have a maximum effect.
`
`Q
`
`And an OAB drug is -- will only get
`
`approved if it shows an efficacy over placebo,
`
`though, right?
`
`A
`
`That's correct.
`
`MR. OELKE: Let's mark as 9, an article
`
`entitled Characterization of Darifenacin as a Novel
`
`Radioligand for the Study of Muscarinic M3
`
`Receptors by Carolyn Smith and Rob Wallis.
`
`(Deposition Exhibit 9 marked.)
`
`THE WITNESS:
`
`Thank you.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0092
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`BY MR. OELKE:
`
`Have you seen Carson 9 before?
`
`I have not.
`
`Okay.
`
`Not that I know of.
`
`I mean, it's a long
`
`Q A
`
`Q
`
`A
`
`time ago,
`
`so I may have but I don't think so.
`
`Q
`
`Okay.
`
`So I don't think we need to spend
`
`too much time on it then.
`
`But you recognize it's an article
`
`concerning darifenacin?
`
`A
`
`Q
`
`A
`
`Q
`
`Yes.
`
`And it's dated 1997?
`
`Correct.
`
`So at least as of 1997, darifenacin was
`
`being studied as a selective M3 inhibitor,
`
`right?
`
`A
`
`Q
`
`Yes.
`
`And there were other compounds also being
`
`studied for selective M3 inhibition, right?
`
`A
`
`Q
`
`Yes.
`
`And why was selective M3 inhibition being
`
`studied as a —— as a possible lead for OAB drugs in
`
`the 1998-1999 time frame?
`
`MS. WOOTEN: Objection,
`
`form.
`
`In the bladder,
`
`the predominant
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0093
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`muscarinic receptors are M2, which has the largest
`
`number. M3, second largest number. But M3 is the
`
`most functionally responsible receptor,
`
`so it's the
`
`one that you'd want
`
`to target.
`
`Unfortunately, M3 is also present in the
`
`salivary glands and in the gut.
`
`So even being
`
`selective doesn't necessarily eliminate all of
`
`those side effects.
`
`But if you could just target a clean drug
`
`that was only effective on M3,
`
`then you have a
`
`higher chance of affecting the overactive bladder
`
`with diminished side effects.
`
`BY MR. OELKE:
`
`Q
`
`And was darifenacin successful
`
`in
`
`reducing adverse side effects?
`
`A
`
`To an extent.
`
`The trouble with
`
`darifenacin is the bioavailability was variable.
`
`So at this —— you know,
`
`if it was really
`
`very well bioavailable, it would have changed
`
`the —— changed the landscape of overactive bladder
`
`treatment, but it just wasn't or isn't.
`
`Q
`
`So in 1998, would a reasonable path for
`
`research by GAB researchers to make a more
`
`bioavailable version of darifenacin?
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0094
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`Certainly would have been a thought.
`
`BY MR . OELKE :
`
`Q
`
`Okay. And it would have been a
`
`reasonable path, right?
`
`A
`
`Yes.
`
`MS. WOOTEN: Objection,
`
`form.
`
`BY MR . OELKE :
`
`Q
`
`And solifenacin, was it successful as a
`
`M3 selective inhibitor?
`
`A
`
`Also similar to darifenacin, selective,
`
`yes, but bioavailable not so much -- not as —- not
`
`as much as one would like.
`
`Q
`
`Okay. And is constipation a prominent
`
`side effect for those -- those two compounds?
`
`A
`
`Q
`
`For many patients, yes.
`
`So would a reasonable approach have been
`
`to try to make a —— to start with darifenacin or
`
`solifenacin and make it —— make it compounded that
`
`had fewer side effects with respect to
`
`constipation?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`I mean,
`
`that would be a thought, but
`
`because there's M3 receptors in the bowel, it would
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0095
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`be a little hard to separate the bladder and the
`
`bowel and the three receptors.
`
`So if you're going
`
`to affect one, you're going to affect the other.
`
`BY MR. OELKE:
`
`Q
`
`But there's M3 receptors in salivary
`
`glands,
`
`too, right?
`
`A
`
`Q
`
`Yes, that's correct.
`
`Did darifenacin or solifenacin show a
`
`benefit with respect to dry mouth?
`
`A
`
`Well,
`
`they all had dry mouth and dry
`
`eyes, so,
`
`a benefit, no.
`
`A complication or a side
`
`effect, yes.
`
`Q
`
`Okay.
`
`MR. OELKE:
`
`I would like to mark as
`
`Carson Exhibit 10, Abstracts of Paper —- well,
`
`it's —— I'll just give the Bates numbers,
`
`two
`
`pages. MYLB_FESO—OO27337 to 0338.
`
`(Deposition Exhibit 10 marked.)
`
`THE WITNESS:
`
`Thank you.
`
`BY MR. OELKE:
`
`Q
`
`This is an abstract from April of 1997.
`
`Do you see that?
`
`A
`
`Yes.
`
`It was presented at the American Chemical
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0096
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`Society National Meeting?
`
`A
`
`Q
`
`Right.
`
`And if you look at the abstract that's
`
`046.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`It's entitled
`
`1,2,3,4-tetrahydro-2-isoquinolinecarboxylate
`
`derivatives.
`
`MR. OELKE:
`
`Sorry about that.
`
`A
`
`Yes.
`
`BY MR. OELKE:
`
`Q
`
`A Novel Class of Selective Muscarinic
`
`Antagonists.
`
`Do you see that?
`
`A
`
`Yes.
`
`And the first named author is Takeuchi?
`
`Yes.
`
`And that's —-
`
`they were at Yamanouchi
`
`A
`
`Q
`
`Pharmaceutical, right?
`
`A
`
`Q
`
`Right.
`
`And Yamanouchi is the company that
`
`developed solifenacin?
`
`A
`
`Q
`
`Uh—huh, yes.
`
`And do you understand this abstract
`
`concerns solifenacin?
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0097
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`A
`
`No, but —— I don't know the chemical
`
`for solifenacin to be honest.
`
`Q
`
`Okay.
`
`It's my understanding this is
`
`early abstract that concerns solifenacin.
`
`A
`
`Q
`
`Okay.
`
`Now,
`
`if you look in that —— in that
`
`paragraph in the abstract,
`
`five lines down, it
`
`says, Among those compounds, and then it lists
`
`same compound.
`
`A
`
`Q
`
`Okay.
`
`I won't —— I won't write it out, but
`
`a —-
`
`I won't read it out, but it's YM-53705 is
`
`shorthand for it.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`It said, It showed high affinity for
`
`receptor and a Ki value;
`
`is that right?
`
`A
`
`Q
`
`That's what it says.
`
`Of 12 nano —— of l2nm and 10-fold
`
`selectivity between rhythmic contraction and
`
`salivary secretion.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`So does this indicate that -- that M3
`
`selectivity is —— is between or at least they had
`
`tested it for between an effect on the bladder
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0098
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`and —— and the salivary?
`
`A
`
`Q
`
`Yes.
`
`Okay. And their conclusion is that
`
`YM—53705 will be expected as a drug for the
`
`treatment of urinary incontinence without side
`
`effects such as dry mouth.
`
`A
`
`Q
`
`A
`
`Q
`
`Yes.
`
`Do you see that?
`
`It's kind of a hopeful statement there?
`
`Yes.
`
`Okay. But at least there —— there's an
`
`indication that the dry mouth would be less?
`
`A
`
`Would be less, right.
`
`MR. OELKE:
`
`I would like to mark as
`
`Carson 11 an article entitled Anti-muscarinic
`
`Potency and Bladder Selectivity of PNU—200577,
`
`a
`
`Major Metabolite of Tolterodine.
`
`(Deposition Exhibit 11 marked.)
`
`THE WITNESS:
`
`Thanks.
`
`BY MR. OELKE:
`
`Q
`
`Do you recognize Carson Exhibit 11 as an
`
`article by Dr. Nilvebrant and others?
`
`A
`
`Q
`
`Yes.
`
`Do you understand Dr. Nilvebrant was one
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0099
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`of the inventors of tolterodine?
`
`A
`
`Q
`
`Q
`
`Yes.
`
`Do you know Dr. Nilvebrant?
`
`I do not.
`
`Now, do you understand that PNU—200577 is
`
`another term that's used for 5—HMT?
`
`A
`
`Q
`
`Yes.
`
`Okay. And if you look at the abstract of
`
`this article,
`
`four lines up from the bottom, it
`
`says:
`
`Thus, PNU—200577 is similar to tolterodine
`
`in terms of anti—muscarinic potency, functional
`
`selectivity for the urinary bladder in vivo and
`
`absence of selectivity for muscarinic receptor
`
`subtypes in vitro.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`So the conclusion of Dr. Nilvebrant,
`
`based on these studies,
`
`is that tolterodine and --
`
`and 5—HMT are similar in terms of anti—muscarinic
`
`potency, right?
`
`A
`
`Q
`
`Yes.
`
`And —— and similar in their terms of
`
`their functional selectivity in vivo, right?
`
`A
`
`Q
`
`Yes.
`
`Now, Dr. Nilvebrant conducted studies
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0100
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`in cats, right?
`
`Yes.
`
`And some of that is discussed here?
`
`I
`
`think this was not cats,
`
`though.
`
`If you look at the in vivo results.
`
`It was guinea pigs as well, so...
`
`Q
`
`Right,
`
`there is in vitro studies in
`
`guinea pigs.
`
`A
`
`Q
`
`Yeah.
`
`But if you look on Page 170, it says,
`
`In
`
`Vivo Studies.
`
`It says:
`
`The anti—muscarinic
`
`effects of PNU-200577 in vivo were studied in the
`
`anesthetized --
`
`A
`
`Q
`
`A
`
`Oh, right.
`
`-- anesthetized cat. Right?
`
`Correct. Yeah.
`
`They also used bladder
`
`strips from the guinea pigs,
`
`so they did both --
`
`Q
`
`A
`
`Q
`
`Right.
`
`—— both things,
`
`in vivo and in vitro.
`
`Are you familiar with these -- these
`
`anesthetized cat studies?
`
`A
`
`I'm familiar with them, I've never done
`
`Okay.
`
`If you look in the Discussion
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0101
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`section of this article on Page 171.
`
`It says:
`
`In the anesthetized -- did I
`
`say that right? —— cat, PNU—200577 produced a
`
`dose—dependent inhibition of acetylcholine—induced
`
`urinary bladder contraction and electrically
`
`stimulated salivation, and was almost three times
`
`more potent for inhibition of urinary bladder
`
`contractions compared with salivation. Right?
`
`A
`
`Q
`
`Yes.
`
`So these studies established or at least
`
`suggested that the tolterodine metabolite was more
`
`active in the bladder than in the salivary gland,
`
`right?
`
`A
`
`That's what ——
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`That's what it's suggesting. Whether
`
`that translates into a clinical advantage or not
`
`I
`
`guess remains to be seen based on this.
`
`BY MR. OELKE:
`
`Q
`
`Right.
`
`It's not necessary that what's seen in
`
`cats is going to translate to humans,
`
`for instance?
`
`A
`
`Q
`
`Correct.
`
`Okay.
`
`If you look at the last paragraph
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0102
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`in this —— in this article, it says:
`
`In summary,
`
`the pharmacological
`
`in vitro and in vivo profiles
`
`of PNU—200577 are almost identical to those of
`
`tolterodine,
`
`the parent compound.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`So, again,
`
`this is supporting the concept
`
`that extensive metabolizers and poor metabolizers
`
`are going to end up getting the same net effect
`
`from the administration of tolterodine orally,
`
`right?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`I'm not sure that you can totally say
`
`that because, again, of the —— because of the
`
`protein binding issues.
`
`I
`
`think that —— that
`
`has -- certainly has an effect on the effect in --
`
`in patients and humans. But as far as in a
`
`laboratory setting,
`
`the two are equivalent.
`
`BY MR. OELKE:
`
`Q
`
`Okay.
`
`MR. OELKE:
`
`I would like to mark as
`
`Carson 12 an article entitled Influence of CYPZD6
`
`polymorphism on the pharmacokinetics and
`
`pharmacodynamics of tolterodine. First author
`
`Niclas Brynne.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0103
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`(Deposition Exhibit 12 marked.)
`
`THE WITNESS:
`
`Thank you.
`
`BY MR. OELKE:
`
`Q
`
`Have you seen the Brynne article before,
`
`Dr. Carson?
`
`A
`
`Q
`
`Yes,
`
`I have.
`
`The -- the objective of this study was to
`
`determine whether 2D6 is involved in the metabolism
`
`of tolterodine, right?
`
`A
`
`Q
`
`Yes.
`
`And also to investigate potential
`
`differences of tolterodine in 5—HMT between poor
`
`and extensive metabolizers, right?
`
`A
`
`Q
`
`Correct.
`
`And the conclusion of the study is that,
`
`if you look there in the abstract, it says:
`
`Tolterodine is extensively metabolized by -- by
`
`CYPZD6 with high specificity. Despite the effect
`
`on pharmacokinetics,
`
`the CYPZD6 polymorphism does
`
`not appear to be of great
`
`importance in the
`
`anti—muscarinic effect, probably because of the
`
`additive action of parent drug and the active
`
`metabolite. Right?
`
`A
`
`Yes.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0104
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`Q
`
`So the —— the authors of this article,
`
`including Niclas Brynne, was that tolterodine and
`
`5—HMT had an additive action, right?
`
`A
`
`Q
`
`Yes.
`
`And that poor metabolizers and extensive
`
`metabolizers receive the same net effect?
`
`A
`
`Q
`
`In this study,
`
`that's correct.
`
`And this was a study that was specific to
`
`tolterodine, right?
`
`A
`
`Q
`
`Yes, it was.
`
`So the conclusion of both the Brynne
`
`article,
`
`the Nilvebrant —— so the conclusion of the
`
`Nilvebrant article which was Carson Exhibit 11 --
`
`A
`
`Q
`
`Uh—huh.
`
`-- the Brynne article which is Carson
`
`Exhibit 12, and the label for Detrol, which is
`
`Carson Exhibit 7,
`
`is that the net activity for poor
`
`metabolizers and extensive metabolizers is the
`
`same, right?
`
`A
`
`Q
`
`Yes.
`
`Okay.
`
`MR. OELKE:
`
`I would like to mark as
`
`Carson Exhibit 13 a document entitled Tolterodine,
`
`A new muscarinic receptor antagonist,
`
`is
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0105
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`metabolized by cytochromes P450 2D6 and 3A in human
`
`liver microsomes, by Postlind and others.
`
`(Deposition Exhibit 13 marked.)
`
`THE WITNESS:
`
`Thank you.
`
`BY MR. OELKE:
`
`Q
`
`Q
`
`Have you seen Carson Exhibit 13?
`
`Yes,
`
`I have.
`
`And this is a study in human liver
`
`microsomes for tolterodine?
`
`A
`
`Q
`
`Yes.
`
`And the conclusion that's stated in the
`
`abstract is: We conclude from these studies --
`
`this is the last sentence —— We conclude from these
`
`studies that the formation of 5—HM —— and you
`
`understand that 5—HM,
`
`is 5-HMT, right?
`
`A
`
`Q
`
`Yes.
`
`That
`
`the formation of 5—HM is —— is
`
`catalyzed by CYP2D6 and that the formation of
`
`N—dealkylated tolterodine is predominantly
`
`catalyzed by CYP3A isoenzymes in human liver
`
`microsomes. Right?
`
`A
`
`Q
`
`Yes.
`
`Now,
`
`in your report, your opening report
`
`you cite to the Postlind article, right?
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0106
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`I do, yes.
`
`If you look at Page 18.
`
`Okay.
`
`On Page 18 you cite to a paragraph that's
`
`A Q
`
`A
`
`Q
`
`on Page 292 of Postlind,
`
`so it's at the end.
`
`Now,
`
`the last paragraph of Postlind
`
`starts: Clinical studies have demonstrated that
`
`individuals with reduced CYP2D6—mediated metabolism
`
`represent a high—risk group in the population with
`
`a propensity to develop adverse drug effects.
`
`Right?
`
`A
`
`Q
`
`Yes.
`
`And it cites to Smith 1986.
`
`And you state in your report that this
`
`paragraph,
`
`in Paragraph 63, you say: This
`
`information is important to a clinician because it
`
`helps to inform the risks associated with dosing
`
`tolterodine. Right?
`
`A
`
`Q
`
`Yes.
`
`Now,
`
`this statement -- first of all,
`
`Postlind didn't study, did he,
`
`the net activity of
`
`tolterodine in 5—HMT, right,
`
`in humans?
`
`MS. WOOTEN: Objection,
`
`form.
`
`Can you say that again?
`
`I'm not quite
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0107
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`sure about that.
`
`BY MR. OELKE:
`
`Q
`
`A
`
`Q
`
`This Postlind article isn't --
`
`Yeah.
`
`—— about
`
`the activity of tolterodine in
`
`5—HMT in humans when it's dosed orally,
`
`is it?
`
`A
`
`No, it's not.
`
`MS. WOOTEN: Objection,
`
`form.
`
`BY MR. OELKE:
`
`Q
`
`A
`
`Q
`
`It's about liver microzymes, right?
`
`Right.
`
`Microsomes, sorry.
`
`And it does not have any conclusion in it
`
`about whether there are certain risks associated
`
`with poor metabolizers for the administration of
`
`tolterodine orally to patients, right?
`
`A
`
`Well,
`
`I mean, basically he does say in
`
`his discussion that, you know, clinical studies
`
`have demonstrated that individuals with reduced or
`
`poor metabolizers represent a high risk group in
`
`the —— in the population with a propensity to
`
`develop adverse drug effects.
`
`So he states that in
`
`his --
`
`Q
`
`Right.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0108
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`—— in his discussion, right.
`
`But that statement is citing to Smith in
`
`A
`
`Q
`
`l986, right?
`
`A
`
`Q
`
`Yes.
`
`Smith 1986 doesn't have anything to do
`
`with tolterodine, does it?
`
`A
`
`Q
`
`A
`
`But it has to do with cytochrome 2D6.
`
`Right.
`
`And that basically has something to do
`
`with tolterodine as well, right, so...
`
`Q
`
`But 1986, when Smith was written,
`
`tolterodine hadn't even been invented yet, right?
`
`A
`
`It hadn't, but cytochrome P450 2D6 had
`
`been identified and --
`
`Q
`
`A
`
`Right.
`
`—— was being studied and had been
`
`Right.
`
`And Smith is talking about other drugs,
`
`not tolterodine, right?
`
`A
`
`That's correct. He's talking about other
`
`drugs, but he's talking about that enzyme system.
`
`Q
`
`Right. But we've also established that
`
`there were studies that were done specifically on
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0109
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`tolterodine, right?
`
`A
`
`Q
`
`Correct.
`
`And those studies, which we just looked
`
`at, Brynne, Nilvebrant and also it's in the label,
`
`they all come to the conclusion that the net effect
`
`is the same for poor metabolizers and extensive
`
`metabolizers, right?
`
`A
`
`Yes.
`
`MS. WOOTEN: Objection,
`
`form.
`
`BY MR. OELKE:
`
`Q
`
`So this concern that's discussed here in
`
`Smith was found not
`
`to be applicable to tolterodine
`
`and 5—HMT, right?
`
`A
`
`In the studies that are reported,
`
`that's
`
`correct,
`
`the ones we've talked about.
`
`Q
`
`Okay.
`
`MR. OELKE: Let's take a break.
`
`VIDEO TECHNICIAN: Going off the record.
`
`(Recess taken 11:26 a.m.)
`
`VIDEO TECHNICIAN: Back on the record,
`
`ll:43.
`
`BY MR. OELKE:
`
`Q
`
`Now,
`
`in 1998-1999,
`
`there were no
`
`long—acting OAB drugs on the market, right?
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0110
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`A
`
`That's correct,
`
`they were all multiple
`
`day dosing.
`
`Q
`
`Okay. And at some point once daily drugs
`
`did become available, right?
`
`Yes,
`
`they did.
`
`Okay. And when was that?
`
`Roughly 2001.
`
`Okay.
`
`A
`
`Q A
`
`Q
`
`MR. OELKE:
`
`I would like to mark as
`
`Exhibit 14 an article, Fesoterodine is an effective
`
`anti—muscarinic for patients with overactive
`
`bladder
`
`(OAB): Results of a Phase 2 Trial by Nitti,
`
`et al.
`
`(Deposition Exhibit 14 marked.)
`
`THE WITNESS:
`
`Thank you.
`
`BY MR. OELKE:
`
`Q
`
`A
`
`Q
`
`Have you seen this article, Dr. Carson?
`
`I have, yes.
`
`Okay. And this is a study of
`
`fesoterodine, right?
`
`A
`
`Q
`
`Yes, that's correct.
`
`And they tested 4,
`
`8 and 12 milligram
`
`doses of fesoterodine once daily?
`
`A
`
`Yes.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0111
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`Okay. And placebo, right?
`
`Yes.
`
`And if you look at the Concluding Message
`
`Q
`
`A
`
`Q
`
`which is on the second page: Determined that All
`
`3
`
`doses of fesoterodine led to significant and
`
`clinically relevant improvements from baseline in
`
`several parameters, e.g.,
`
`frequency, urge
`
`incontinence and voided volume per micturition.
`
`Right?
`
`A
`
`Q
`
`Yes.
`
`Okay. And so do you recall when
`
`fesoterodine was first introduced into the market?
`
`A
`
`Q
`
`I
`
`think it was in the 2004 range.
`
`Okay. And what would —— did you at that
`
`time prescribe fesoterodine to patients?
`
`A
`
`Q
`
`Yes.
`
`Okay. And what was your clinical
`
`experience with fesoterodine?
`
`A
`
`It was good.
`
`I had no —— you know,
`
`they
`
`all work some and they all have side effects in
`
`some and some patients respond better to one than
`
`another,
`
`so -- but generally it was good.
`
`Q
`
`Okay. And it's —— it's approved at
`
`4 milligrams and at
`
`8 milligrams, right?
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0112
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`That's correct.
`
`Q
`
`Okay. And so were there some patients
`
`that you prescribed 8 milligrams of fesoterodine
`
`to?
`
`A
`
`Q
`
`Yes.
`
`And were some of those patients that you
`
`had tried dosing tolterodine?
`
`A
`
`Q
`
`Yes.
`
`Okay. And why did you switch those
`
`patients from tolterodine to fesoterodine?
`
`A
`
`Couple of reasons. No.
`
`l is, it's a
`
`newer drug,
`
`so you always want to try something
`
`different.
`
`No.
`
`2 thing is,
`
`is that there were
`
`purportedly fewer side effects.
`
`No.
`
`3 thing is,
`
`is that there are
`
`actually a couple of studies that looked at
`
`head—to—head experience between tolterodine max
`
`dose and fesoterodine max dose, and it showed that
`
`the maximum dose of fesoterodine was more
`
`effective.
`
`And finally,
`
`that, you know,
`
`there --
`
`there were, again, active marketing of the drug,
`
`so
`
`we wanted to try new things. And as an academic
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0113
`
`
`
`Page ll4
`
`CULLEY C. CARSON, III, M.D.
`
`urologist,
`
`I feel it's my responsibility or part of
`
`it to try the latest drugs.
`
`Q
`
`So these —— these head—to—head studies of
`
`8 milligrams of fesoterodine to 4 milligrams of
`
`tolterodine,
`
`those studies were of the —— the
`
`maximum dose approved for each of those drugs,
`
`right?
`
`A
`
`Maximum approved dose, yeah.
`
`I mean,
`
`whether you could actually compare the doses or not
`
`is a matter of dispute, but
`
`those are the
`
`maximum—approved doses.
`
`Just like when we talked about
`
`the
`
`oxybutynin study, it was the maximum approved doses
`
`of each of the —— each of the agents.
`
`Q
`
`So it's a very common thing when you're
`
`doing a head—to—head study to compare a
`
`maximum—approved dose of each drug?
`
`A
`
`In —— in —— in post marketing trials,
`
`it's almost always done that way.
`
`Q
`
`Okay. But going back to the Nitti
`
`article, his conclusion is that for all of these
`
`different doses, 4,
`
`8 and 12,
`
`they actually tested
`
`12 milligrams here as well,
`
`that they led to
`
`significant and clinically relevant improvements
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0114
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`for the parameters they tested which were
`
`frequency, urge incontinence and voided volume per
`
`micturition, right?
`
`A
`
`Q
`
`Yes.
`
`Okay. And those are all important
`
`parameters, correct?
`
`A
`
`That's what you're trying to really
`
`treat. That's what
`
`the patients are bothered by.
`
`Q
`
`Okay. And he also concluded that
`
`improvements were seen as early as two weeks after
`
`randomization.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`Was that a benefit of fesoterodine that
`
`it showed early improvement?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`There are -- there are studies that show
`
`that it was quicker —— a quicker onset than some of
`
`the ones that were already on —— on the market,
`
`yes.
`
`BY MR. OELKE:
`
`Q
`
`All right. And that —— was that a
`
`surprising result for fesoterodine?
`
`A
`
`Not so much.
`
`I —— you know, it —— it was
`
`one of those things that most of the other drugs
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0115
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`didn't have those trials, rapidity of onset trials.
`
`So some of the —— some of the trials that
`
`are done are done for marketing purposes and that
`
`was a marketing trial in my opinion.
`
`Q
`
`Okay.
`
`MR. OELKE:
`
`I would like to mark Carson
`
`Exhibit 15, an article entitled Role of
`
`Pharmacokinetics and Metabolism in Drug Discovery
`
`and Development by Lin and Lu, production numbers
`
`PFEO1847326 to 372.
`
`(Deposition Exhibit 15 marked.)
`
`THE WITNESS:
`
`Thanks.
`
`BY MR. OELKE:
`
`Have you seen this article before?
`
`I have not.
`
`Okay.
`
`Not that I know of.
`
`Looks interesting,
`
`Q A Q
`
`A
`
`though.
`
`Q
`
`Just give me a second.
`
`If you look in your opening report of the
`
`materials considered.
`
`Okay.
`
`I
`
`think if you look at —— it's on --
`
`Got it, Exhibit 2.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0116
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`Q
`
`Table of exhibits.
`
`If you look at the
`
`table of exhibits at the front of the --
`
`A
`
`Q
`
`A
`
`Q
`
`Yeah.
`
`The front.
`
`I guess I have seen this, yeah.
`
`Yeah,
`
`I
`
`think if you look at
`
`Paragraph 33, you cite to it.
`
`A
`
`Q
`
`Yeah, yeah,
`
`I did see this.
`
`Okay. And it's an article that discusses
`
`metabolism in drug development, right?
`
`A
`
`Yes.
`
`And drug discovery.
`
`And if you look at —— there's a section
`
`that starts at Page 436.
`
`A
`
`Q
`
`Okay.
`
`Which is PFEOl847359.
`
`Right.
`
`Q
`
`And that section's called
`
`Pharmacogenetics of Drug Metabolism.
`
`A
`
`Q
`
`Yes.
`
`If you look at the end of —— it gives a
`
`number of examples, but if you look at the end of
`
`that section on Page 439,
`
`the last paragraph.
`
`It
`
`says there:
`
`As described above, genetic
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0117
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`polymorphism in drug metabolism is undesirable and
`
`can at times be problematic.
`
`Excuse me.
`
`Do you see that?
`
`Yes.
`
`Q
`
`A
`
`What does polymorphism refer to there?
`
`Basically differences in the ability of a
`
`patient to metabolize drugs.
`
`The —-
`
`the high
`
`metabolizers of —— and —— and nonmetabolizers of
`
`D2 -— of 2D6 are examples of that polymorphism.
`
`Q
`
`A
`
`Q
`
`Okay.
`
`Some patients do,
`
`some patients don't.
`
`It goes on to say: However, it should be
`
`emphasized that even if a large proportion of the
`
`metabolism of a compound is subject to genetic
`
`polymorphism,
`
`this should not influence its
`
`development as a drug.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`Careful evaluation of clinical relevance
`
`of polymorphic metabolism has to be taken into
`
`consideration in making the go/no—go decisions.
`
`Right?
`
`A
`
`Q
`
`Yes, uh—huh.
`
`So with respect to tolterodine,
`
`that
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0118
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`careful evaluation of clinical relevance is
`
`described in -- in the Nilvebrant and Brynne
`
`article and the Detrol label, right?
`
`A
`
`Q
`
`It is, yes.
`
`They took a look at whether polymorphism
`
`was a problem for tolterodine, right?
`
`A
`
`They did.
`
`MS. WOOTEN: Objection,
`
`form.
`
`BY MR. OELKE:
`
`Q
`
`And the conclusion that they drew was
`
`that the net activity for tolterodine and 5—HMT was
`
`the same, right?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`They showed there was an effect, but
`
`overall clinical effect was -- was minimal.
`
`BY MR. OELKE:
`
`Q
`
`Right.
`
`The overall difference in
`
`clinical effect --
`
`A
`
`Q
`
`Exactly.
`
`-- was minimal,
`
`right?
`
`And so with respect to the example of
`
`tolterodine —— in fact,
`
`the genetic polymorphism
`
`turned out not
`
`to be undesirable with respect to
`
`tolterodine, right?
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0119
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`I wouldn't say that.
`
`I wouldn't make
`
`that strong a statement, but
`
`I would say that --
`
`that in a —-
`
`in a clinical experience it really
`
`didn't make a difference as far as the clinical
`
`outcomes are concerned.
`
`BY MR. OELKE:
`
`O
`
`Okay.
`
`You can set that aside.
`
`MR. OELKE:
`
`I
`
`think let's take a break
`
`It will be easier.
`
`VIDEO TECHNICIAN: Marks the end of Video
`
`Off the record,
`
`ll:57.
`
`(Lunch recess.)
`
`VIDEO TECHNICIAN: Marks the beginning of
`
`Video 3. Deposition Culley Carson, M.D. Back on
`
`the record.
`
`Time 12:52.
`
`BY MR. OELKE:
`
`Q
`
`A
`
`Good afternoon, Dr. Carson.
`
`Good afternoon.
`
`MR. OELKE:
`
`I would like to mark as
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0120
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`Carson Exhibit l6 an article entitled Superiority
`
`of Fesoterodine 8—milligram versus 4-milligram in
`
`reducing urgency urinary incontinence episodes in
`
`patients with overactive bladder: results of the
`
`randomized, double—blind, placebo—controlled EIGHT
`
`trial with Chapple, et al. as authors. Bates range
`
`is PFEOl843522 to 530.
`
`(Deposition Exhibit 16 marked.)
`
`THE WITNESS:
`
`Thanks .
`
`BY MR. OELKE:
`
`Have you seen Carson Exhibit 16 before?
`
`Yes,
`
`I have.
`
`And are you familiar with Chris Chapple?
`
`Yes, very familiar.
`
`I know him
`
`Q A
`
`Q
`
`A
`
`personally.
`
`Q
`
`A
`
`Q
`
`A
`
`Q
`
`Okay. And is he a urologist?
`
`Yes, he is.
`
`Is he a well—respected urologist?
`
`Very much so.
`
`Okay. And this is a study concerning
`
`8 milligrams versus 4 milligrams of fesoterodine,
`
`right?
`
`A
`
`Q
`
`Yes, it is.
`
`And if you look at the conclusions, it
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0121
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`states there:
`
`In a 12-week,
`
`prospectively—designed, superiority trial,
`
`fesoterodine 8 milligrams showed statistically
`
`significantly superior efficacy versus fesoterodine
`
`4 milligram and placebo, as measured by reductions
`
`in UUI episodes and other diary variables,
`
`diary-dry dry rate, and improvements in measurement
`
`—— measures of symptoms -- symptom bother, HRQL,
`
`and other PROS.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`And it says: Clear evidence of
`
`dose—dependent efficacy is unique to fesoterodine
`
`among anti—muscarinics and other oral agents for
`
`treatment of OAB.
`
`Do you see that?
`
`A
`
`Q
`
`Yes.
`
`So is it your understanding that prior to
`
`this trial, no other OAB treatment had been shown
`
`to have dose dependent efficacy?
`
`A
`
`There were other trials that look at
`
`different doses and showed different outcomes,
`
`so
`
`—— but this showed a —— you know,
`
`if you raise it
`
`this much,
`
`then you raise the effects by the same
`
`amounts.
`
`Q
`
`Okay. And prior to this study,
`
`there had
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0122
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`never been a demonstration of such a dose—dependent
`
`efficacy relationship in a -- a designed --
`
`prospectively—designed trial, right?
`
`A
`
`Correct.
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`Okay. This trial was designed to show
`
`that particular thing. Other trials were basically
`
`subgroup analyses and post hoc analyses of —— of
`
`other —— of larger trials.
`
`BY MR. OELKE:
`
`Q
`
`Are you aware of any other OAB drug that
`
`has shown dose—dependent efficacy effect?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`Well,
`
`they all do better at the higher
`
`dose than they do at the lower dose, and, you know,
`
`that's been demonstrated in a lot of studies.
`
`But as far as showing —— showing it as --
`
`as specifically as this,
`
`this is the only trial
`
`that I'm aware of that showed that re —— that
`
`result.
`
`BY MR. OELKE:
`
`Q
`
`Okay. Was that an important result for
`
`fesoterodine?
`
`MS. WOOTEN: Objection,
`
`form.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0123
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`A
`
`I
`
`think it was —— yeah,
`
`I
`
`think it was
`
`important for the marketing of fesoterodine for
`
`sure.
`
`BY MR. OELKE:
`
`Q
`
`Well, was it important for —— not for the
`
`marketing of fesoterodine, but for —— in comparison
`
`to other OAB drugs, did it demonstrate something
`
`that was important to urologists?
`
`MS. WOOTEN: Objection,
`
`form.
`
`A
`
`That's a little hard to say because
`
`urologists always try to up dose patients if
`
`they're not responding well.
`
`And we know that for patients on
`
`fesoterodine, about 50 percent of them are up dosed
`
`anyway in a -- as a clinical -- as a -- as a
`
`clinical reality.
`
`And so at —— at the end of the day this
`
`showed what we all sort of already knew,
`
`I guess,
`
`is what I'm —— what I'm trying to get at.
`
`BY MR. OELKE:
`
`Q
`
`A
`
`Did you ever tell Dr. Chapple that?
`
`Not that specific thing.
`
`I mean,
`
`I know
`
`Chris Chapple extremely well, but
`
`I —— I'm not sure
`
`that we talked about this particular paper
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2026 - 0124
`
`
`
`CULLEY C. CARSON, III, M.D.
`
`together.
`
`Q
`
`Okay. Dr. Chapple certainly didn't
`
`indicate that this was just a confirmation of what
`
`was already known about OAB drugs,
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