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`THE COURT: Good morning. Please, take your
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`seats. We are going to have to be here -- I am not sure
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`exactly how long, actually. I know some work is being done
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`on the audiovisual system in my courtroom, which is has
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`really plaguing us of late. Fortunately, Judge Robinson is
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`on vacation. I am going to have to get used to this very
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`different configuration that her predecessor and mine, Rod
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`McKelvie, decided to build. He is gone now, so I can't say
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`too much about him.
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`Let's start out with introductions. Mr.
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`Blumenfeld.
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`MR. BLUMENFELD: Good morning, Your Honor.
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`Jack Blumenfeld from Morris Nichols for the
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`plaintiffs' Pfizer and UCB. Can you hear?
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`THE COURT: This is strange. Can the folks in
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`the well of the court hear?
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`MR. BLUMENFELD: I will speak up and get a
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`little closer to the mike. I guess we will all try to do
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`that.
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`At counsel table from White & Case are Jeff
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`Oelke, Jim Trainor, and behind them are Robert Counihan and
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`Lauren Moran.
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`(Counsel respond "Good morning.")
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`MR. BLUMENFELD: Also from White & Case.
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`In the first row, Stephane Drouin, Jurgen Hassa
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`4
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`from UCB. And in the second row Chase Romick, who is here
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`from Pfizer.
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`THE COURT: Good morning.
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`Ms. Farnan.
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`MS. FARNAN: I will start, Your Honor. Good
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`morning. Kelly Farnan from Richards Layton Finger. I am
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`representing Accord and Amneal and Alkem. I also have with
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`me my colleague from my office Christine Hayes.
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`THE COURT: Good morning.
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`MS. FARNAN: Then on behalf of Accord and Amneal
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`I am working with Sughrue Mion, we have Mike Dzwonczyk,
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`Renita Rathinham, and Alton Hare is in the back.
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`Also here on behalf of Amneal from the company
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`in the back as well, Ken Cappel, Brian Sommese, and Lars
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`Tavolla.
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`THE COURT: Good morning.
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`MS. FARNAN: I also represent Alkem, Your Honor.
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`And I am working with Wiley Rein. At counsel table is
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`Rachel Hunnicutt and Neal Seth.
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`THE COURT: Good morning, counsel.
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`MS. FARNAN: Thank you, Your Honor.
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`THE COURT: Mr. Poff?
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`MR. POFF: Good morning, Your Honor. Adam Poff
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`from Young Conaway on behalf of Sandoz. Working with me is
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`Kristen Venegas and Shon Lo from McDermott, Will & Emery.
`07/13/2015 06:28:50 PM
`
`NO. 13-1110(GMS)
`CONSOLIDATED
`
`Civil Action
`
` IN THE UNITED STATES DISTRICT COURT
` IN AND FOR THE DISTRICT OF DELAWARE
` - - -
`PFIZER INC. and UCB PHARMA GMBH,)
` )
` Plaintiffs, )
` )
` v. )
` )
`ALKEM LABORATORIES LTD., et al.,)
` )
` Defendants. )
` - - -
` Wilmington, Delaware
`
`Monday, July 13, 2015
`
`9:00 a.m.
`
`Day 1 of Trial
` - - -
`BEFORE: HONORABLE GREGORY M. SLEET, U.S.D.C.J.
`APPEARANCES:
`
`JACK B. BLUMENFELD, ESQ.
`
`Morris Nichols Arsht & Tunnell LLP
` -and-
`
`JAMES S. TRAINOR, JR., ESQ.,
`
`JEFFREY J. OELKE, ESQ.,
`
`ROBERT E. COUNIHAN, ESQ.,
`
`RYAN JOHNSON, ESQ., and
`
`LAURA MORAN, ESQ.
`
`White & Case LLP
`
`(New York, NY)
` Counsel for Plaintiffs
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`08:57:17
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`09:22:24
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`09:33:40
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`APPEARANCES CONTINUED:
`
` KELLY E. FARNAN, ESQ.
` Richards, Layton & Finger, P.A.
` -and-
` RACHEL K. HUNNICUTT, ESQ., and
` NEAL SETH, ESQ.
` Wiley Rein LLP
` (New York, NY)
` Counsel for Defendant
` Alkem Laboratories Ltd.
`
` ADAM W. POFF, ESQ., and
` PILAR KRAMAN, ESQ.
` Young Conaway Stargatt & Taylor LLP
` -and-
` KRISTEN VINK VENEGAS, ESQ., and
` SHON LO, ESQ.
` McDermott Will & Emery LLC
` (Chicago, IL)
` Counsel for Defendant Sandoz Inc.
`
` KELLY E. FARNAN, ESQ., and
` CHRISTINE HAYNES, ESQ.
` Richards, Layton & Finger, P.A.
` -and-
` MICHAEL R. DZWONCZYK, ESQ.,
` RENITA A. RATHINAM, ESQ., and
` ALTON L. HARE, ESQ.
` Sughrue Mion, PLLC
` (Washington, D.C.)
` Counsel for Defendant/
` Counterclaimant Accord
` Healthcare Inc., USA and
` Defendant Amneal Pharmaceuticals,
` Inc.
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`1 of 79 sheets
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` J. CLAYTON ATHEY, ESQ.
` Prickett, Jones & Elliott, P.A.
` -and-
` WILLIAM D. HARE, ESQ., and
` GABRIELA MATERASSI, ESQ.
` McNeely, Hare & War LLP
` (Princeton, N.J.)
`
` Counsel for Defendants
` Amerigen Pharmaceuticals, Inc.
` and Amerigen Pharmaceuticals Ltd.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2006 - 0001
`
`

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`And from my office, Pilar Kraman.
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`THE COURT: Good morning.
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`All right. Counsel.
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`MR. ATHEY: Good morning, Your Honor. Clayton
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`Athey from Prickett, Jones & Elliott from the Amerigen
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`defendants. With me today are William Hale and Gabriela
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`Materassi. Also from Amerigen, Jonathan Nichol.
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`THE COURT: Good morning.
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`I think that's it. Right?
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`Counsel, are there any housekeeping matters we
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`need to talk about before we begin?
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`MR. OELKE: I don't believe so, Your Honor.
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` MR. DZWONCZYK: Not from defendants, Your Honor.
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`THE COURT: Let's start with the opening
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`statements then.
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`MR. OELKE: Your Honor, I have some slides.
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`THE COURT: Mr. Buckson will take those from
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`you.
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`I am going to ask you to see what you can do
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`about keeping as close to the mike as you can without being
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`uncomfortable so that everyone can hear.
`
`MR. OELKE: Good morning, Your Honor.
`
`Your Honor, the invention in this case arose
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`amid an active field of pharmaceutical research. And that
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`was an active field to look for a better treatment for
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`or the '650 patent. It has a priority date of November 16,
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`1999. And that patent concerns specific salt forms of
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`compounds, and the asserted claims concern specific salt
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`forms of fesoterodine, which we will talk about, and a
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`method of using, of administering those salt forms.
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`Now, some of these claims do encompass more than
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`just fesoterodine. The issue here will be about this
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`compound, fesoterodine, which is on the screen, Your Honor.
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`Fesoterodine, that is the structure of the
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`compound with the salt, the fumarate salt. We have
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`highlighted a few things here just to give a short preview
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`of the portions of the compound we are going to be talking
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`about in the case.
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`You see the ester group there circled in blue,
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`or at least it's blue on my slide. I am not sure if it's
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`blue for you, Your Honor. That ester group is one location
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`on the ring for potential substitution. The alcohol group
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`is another location on the ring for another possibility for
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`substitution, which we will be talking about more during the
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`trial. Finally, in yellow is the fumarate, the salt portion
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`of the compound.
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`This compound arose out of that research that
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`the Schwarz scientists conducted. And the result of that
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`compound was it benefited the most difficult-to-treat
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`patients, many of which were failures on the prior art drugs
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`07/13/2015 06:28:50 PM
`
`To orient the plaintiffs in this case, Your
`
`Honor, in 2006, Pfizer entered into an agreement with
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`Schwarz concerning the compound that came out of this
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`research. That is fesoterodine. So they are one of the
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`plaintiffs. And then UCB later acquired Schwarz in 2007.
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`So they are the other plaintiff.
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`Now, the work of the Schwarz scientists resulted
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`in five patents that are at issue here. We have them up on
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`the screen. There is 12 asserted claims from these patents.
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`Four of the patents are related. We refer to
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`them as the compound patents. They have a priority date of
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`May 12th, 1998. They all concern compounds and methods of
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`treatment administering those compounds. And the asserted
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`claims all concern fesoterodine, the drug at issue.
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`urinary incontinence, a condition that is also going to be
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`referred to in this case as overactive bladder or OAB.
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`In the late 1990s, a number of different
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`research organizations were looking into developing a better
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`drug to treat this condition. But the invention here
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`occurred because a group at a small German pharmaceutical
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`company, Schwarz Pharma, took a different path. They
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`started in 1997. And they tried to develop an OAB drug
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`taking a different path than all these other research
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`groups.
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`The fifth patent we refer to as the salt patent
`Page 5 to 8 of 196
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`that we will be talking about.
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`If we could go to the next slide.
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`Now, overactive bladder, Your Honor, it
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`affected, at the time frame, as I said, 1998-1999, it
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`affected over 45 million people in North America alone at
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`that time. Over 500 million worldwide. And it was an
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`underserved population. A lot of people were not getting
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`treatment for it.
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`There were severe consequences for some of these
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`people. I mean, consequences of anxiety, depression, shame.
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`I mean, these were real issues for some of these patients.
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`So some of the coping mechanisms, the
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`traditional coping mechanisms, a lot of people wore diapers.
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`Other people did toilet mapping, which basically meant
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`before they left their house they mapped out every place
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`they were going to stop along the way to their destination.
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`Some just never left their house. It got to that point for
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`some of these patients.
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`In this time frame, there were some drug
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`options. These drug options were all what were called
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`antimuscarinics. These antimuscarinics all work on
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`muscarinic receptors that reside in the bladder. So here
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`are three of the drugs that existed at that time in 1998.
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`The problem with a muscarinic receptor is it's
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`not just in the bladder. It's also in the heart. It's also
`2 of 79 sheets
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2006 - 0002
`
`

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`9
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`in the brain. It's also in the salivary glands.
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`So these drugs all had deficiencies with each of
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`them.
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`Oxybutynin, for instance, had a severe dry mouth
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`problem. Most people that took oxybutynin, up to 70 percent
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`of people that took it had a dry mouth issue. In some it
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`was so severe they couldn't take the drug. They had to go
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`off of it.
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`Propantheline was another antimuscarinic. It
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`had a wide variety of absorption. Some patients needed a
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`huge amount. Some patients didn't need as much. And
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`doctors really didn't know how to dose it.
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`Tolterodine was the new drug on the market. In
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`March of 1998, tolterodine was introduced. And the trade
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`name for that was Detrol. That drug came on the market in
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`1998. And it solved some of these issues. But it had a
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`problem with it as well. That was a dose ceiling. You
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`could only give four milligrams a day of tolterodine. The
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`reason for that was because of a condition called urinary
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`retention. Basically, in some patients, if you went above
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`four milligrams a day, it froze their bladder. So then they
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`couldn't urinate at all. And that is called a backup. That
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`wasn't just an uncomfortable side effect, that could be a
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`serious side effect. It could actually lead to kidney
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`failure.
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`to work on the same compounds as these other companies.
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`They worked on tolterodine. They started with tolterodine.
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`One of the inventors of fesoterodine that came to work with
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`Schwarz had been an inventor on tolterodine. And they
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`started with tolterodine, and then they decided, well, let's
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`focus on the metabolite of tolterodine. Then, not only
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`that, they decided, let's make a prodrug.
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`A prodrug, no one had made a prodrug in this
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`area. No one had made a prodrug with antimuscarinic. And
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`no one had made a drug with an OAB drug at that point. So
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`they were working on a blank slate in this area. No one had
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`made an antimuscarinic prodrug.
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`Just to give you a concept quickly, Your Honor,
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`of what a prodrug is, this is kind of our crude
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`representation of how it works. The idea is that if you
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`have an existing drug and it has a problem associated with
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`it, for instance, you can't get it through a membrane. If
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`you have an oral dosage form, it can't get through the gut
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`wall. So it just passes through the body. You see here, it
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`just can't make it through the gut wall.
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`So the possibility with a prodrug is, ideally,
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`if it would work, is that it would deliver that drug across
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`the gut wall, and then when it gets to the intended site of
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`action, an enzyme cleaves off the prodrug group, leaving the
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`intended drug at the appropriate site.
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`So doctors just would not go above that ceiling
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`of four milligrams a day with tolterodine.
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`These were the options that existed.
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`So there were a large number of research groups
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`that were looking at OAB drugs at this time knowing there
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`might be a better solution.
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`Here are some of the targets that they were
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`looking at. Of course, a number of them were looking at the
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`muscarinic receptors and trying to find out whether they
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`could make a selective antimuscarinic compound, one that
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`would work on the bladder and not work on the other areas of
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`the body to the same extent.
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`Others were looking at other pathways in the
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`bladder. There are other receptors that act on the bladder.
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`So they were looking at calcium channels, potassium
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`channels, adrenergic receptors. All of these were
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`different. What they did is they decided, we are not going
`3 of 79 sheets
`Page 9 to 12 of 196
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`possibilities.
`
`Here you can see, all of these companies on the
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`left were looking at ways to make a novel, active compound
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`that would work on OAB.
`
`Looking at all of these different possibilities,
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`some were looking at muscarinic receptors. Some were
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`looking at other pathways.
`
`What the scientists at Schwarz did was
`
`But there is a reason no one was looking at
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`prodrugs at that time, because prodrugs are a very difficult
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`set of compounds to try to develop because you are
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`essentially trying to thread a series of needles to get a
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`prodrug to work. We see here, you have to balance stability
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`and volatility at the same time. You want it to be stable
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`like any drug when it's being stored and manufactured, and
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`you want it to be stable when it's going through the GI
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`tract. But once it gets to the intended location, you want
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`it to be volatile. You want it to convert to the drug.
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`It has to have an appropriate balance of
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`absorption and solubility. Those two things are the
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`intention, but it has to meet both of those. It has to be
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`water-soluble if it is an oral dosage form but yet it has to
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`be able to penetrate the stomach wall.
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`Finally, it has to be nontoxic, like any drug,
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`and yet not nontoxic to just the one drug, it has to be
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`nontoxic as to the prodrug and to the portion that cleaves
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`off.
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`So there is multiple components that you have to
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`worry about with toxicity.
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`Now, this is understood, there are treatises
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`and there has been court decisions that talk about how
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`prodrugs are disfavored and how they are an option of last
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`resort. So the Schwarz scientists were really going against
`07/13/2015 06:28:50 PM
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2006 - 0003
`
`

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`the grain when they decided let's try to make a prodrug in
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`this field. No one had ever done it before.
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`Now, the issue of obviousness, where we're going
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`to start, there are four issues, Your Honor, that remain in
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`the case: obviousness, anticipation, indefiniteness I
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`believe, and then one small issue of infringement as to
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`Sandoz on two of the 12 claims. But obviousness is the
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`issue that touches on all of the claims. I'm going to spend
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`my time speaking about that issue first.
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`The issue of obviousness is addressed from the
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`person from the standpoint of a person of ordinary skill
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`and what that person of ordinary skill would have been
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`confronted with at this point in 1998, a series of
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`questions. And these series of questions all have to be
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`answered in a particular way in the defendants' favor for
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`them to carry their prima facie burden.
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`Now, the first question is what is the classic
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`compound you are going to look at. As we saw, there are
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`more than just antimuscarinics that were possibilities. The
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`defendants say you just focus on antimuscarinics.
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`But even if a person of ordinary skill decides,
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`okay, well, I'll focus on antimuscarinics, you go to the
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`next step. You go to the second step. And there you have a
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`number of possibilities. These are all compounds that were
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`either, that were either antimuscarinics or in development
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`on 5-HMT, but the defendants will give two reasons why you
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`would switch. You would look at tolterodine first and once
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`you are looking at tolterodine, then you would look over to
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`the metabolite.
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`They'll say, well, variability of metabolism was
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`an issue with tolterodine.
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`There were two groups of patients, Your Honor.
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`One would be extensive metabolizers and the other would be
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`poor metabolizers. The reason for this is the enzyme in the
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`body that works on tolterodine to convert it into the
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`metabolite, what is called CYP2D6, you will hear that, that
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`enzyme some people just don't have it or they don't have
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`much of it in their body. So those patients don't convert
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`to the metabolite or very little. They're called poor
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`metabolizers.
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`But what the prior art shows is it doesn't
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`matter, because both tolterodine and its metabolite are
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`active at the bladder. And so the label for Detrol actually
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`states the net activity of Detrol tablets is expected to be
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`similar in extensive and poor metabolizers.
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`So there really was not an issue here. When a
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`patient came into the doctor's of office, the doctor didn't
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`try to figure out is the patient a extensive metabolizer or
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`a poor metabolizer because the label said it doesn't make a
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`difference. Both get the same effect.
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`He was working in the field at the time.
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`The defendants will say you focused on
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`tolterodine because it was the hot new drug that had just
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`come out. But these were all possibilities here.
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`And once defendants say, well, lets focus on
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`tolterodine, then they actually want you to switch. They
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`want to say, well, follow what the inventors did and look
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`over at the metabolite. But there is reasons why you
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`wouldn't look at that metabolite, and the metabolite is
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`5-HMT, just so when you see that name, that is referring to
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`the metabolite. That's the compound we have up there.
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`Now, 5-HMT would not have been an attractive
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`lead compound for a number of reasons. One, it has never
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`been studied as a drug. It had only been studied as a
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`metabolite. It was a metabolite of tolterodine, but no one
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`had ever dosed it as a drug. So there was no experience
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`with the compound as a drug, only as a metabolite.
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`There was no expected differentiation from
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`tolterodine because the two compounds both work on the
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`bladder which we'll discuss.
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`It had never been orally administered.
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`or some companies were looking at it and Dr. Maag, who was a
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`prodrug specialist and a medicinal chemist who worked at
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`Roche at this time will testify about these possibilities.
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`14
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`16
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`So these are all reasons why you wouldn't focus
`Page 13 to 16 of 196
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`The second reason they're going to give is
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`they're going to say, well, it's known that 5-HMT, the
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`metabolite, is more potent than tolterodine, but the
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`information they cite to for that is early clinic,
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`pre-clinical work in cats.
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`That did not prove to be the case in humans. In
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`humans, they're equipotent. They have the same potency.
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`You shouldn't focus on the cat data once you have the data
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`in humans.
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`So that basis for focusing on 5-HMT also did not
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`hold up.
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`But, Your Honor, even if you decide to focus on
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`5-HMT, you have a number of options once you start with that
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`as a lead compound. And that is what we have labeled as No.
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`3 on this slide.
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`You can make a structural analog of the
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`compound. You can make a structural analog of tolterodine
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`or you could make a formulation. If there really is an
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`issue with 5-HMT, then you can make a formulation.
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`The defendants are going to say the reason you
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`have to alter 5-HMT into a prodrug is because there is an
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`absorption problem of 5-HMT, but this goes back to what I
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`talked about before. No one has ever actually tried dosing
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`5-HMT as a drug, so we don't even know if there is an
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`absorption problem.
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`4 of 79 sheets
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`Patent Owner, UCB Pharma GmbH – Exhibit 2006 - 0004
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`17
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`If you did have an absorption problem, you could
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`address it through a formulation or you could address it
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`through making a structural analog. The prodrug would be
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`your last approach. The defendants say that is what you
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`would go to first.
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`Now, if you do go to a prodrug, Your Honor, even
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`then you have the number of options for the types of
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`prodrugs.
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`And we have labeled this as No. 4. You have
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`ethers, you have esters, you have phosphates, carbamates,
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`carbonates. These are all possibilities.
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`Defendants are going to say, well, you only
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`focus on esters. Just try ester prodrugs. They say those
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`are the old prodrugs that have been around since the '60s or
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`'70s so start there.
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`But by 1998, the time of the invention, many of
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`these other types are being used. And one of the reasons is
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`because ester prodrugs have an issue with them. They
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`convert in the stomach in many cases because the enzyme that
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`converts ester prodrugs is in the stomach. So you have an
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`early conversion problem with ester prodrugs in some cases
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`and it would have been a concern for 5-HMT if you decided to
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`make a prodrug of 5-HMT.
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`But even then, Your Honor, if you decide to make
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`an ester prodrug, you still have to decide where am I going
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`If you go to the next slide.
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`They will point to two references, Your Honor,
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`19
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`prodrug secondary references; and one is called the Drustrup
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`reference. This reference concerns morphine. It has
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`nothing to do with antimuscarinic or OAB. The structure as
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`you can see is very different. It's a very rigid structure
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`morphine, and, of course, it is not meant for OAB. It's an
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`analgesic.
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`And this reference actually discusses how it's a
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`very slow conversion, which is the last thing you would want
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`if you are making a prodrug of 5-HMT.
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`The only way you would get to Drustrup is if
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`you needed just for focusing on one of the two locations.
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`A person of ordinary skill looking at the
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`problem that was confronting people in the OAB field is not
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`going to look at a morphine reference, Your Honor.
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`If you go to the next slide.
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`Even if you decide where you are going to put
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`that prodrug group, then you have to decide what group am I
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`going to put at that location, or at both locations.
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`And what defendants will say is you would
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`naturally go to the isobutyryl group which is in
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`fesoterodine. That is what we show here as the final
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`compound. But, of course, this is just one of many
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`possibilities, as Dr. Roush will testify.
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`18
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`Your Honor. Sorry.
`5 of 79 sheets
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`and both locations together.
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`And then you have to consider, well, if I make
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`one ester at one location and a different ester at another
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`location, these are all possibilities.
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`The calculation that Dr. Roush, our medicinal
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`chemist expert has made is that it would be over 7,000
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`possibilities, and that is with a very conservative estimate
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`because it is only going to up six carbons. There are
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`prodrug references showing carbons of more than six which
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`would means the possibilities are even greater. So these
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`are allocations that are -- both these locations are
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`possibilities for where you would locate an ester.
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`Then you have yet another question. Well, let
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`me back up to the defendants' prior art that they will cite,
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`to put that ester?
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`If you look at the structure again that we put
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`up earlier, now this structure we're going to put up is
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`actually 5-HMT, but again it has the two rings and it has
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`the two locations on the ring: the phenolic location which
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`we highlighted in blue, and the benzylic position or the 5
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`position which we highlighted in green. Those are both
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`possibilities of where you could put an ester and, in fact,
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`most of the prior art taught you put an ester in both
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`locations so you would have to consider both locations alone
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`The defendants will going to point to the Daas
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`reference to say you would focus on the isobutyryl group
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`but, Daas has nothing to do with antimuscarinics, it has
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`nothing to do OAB. It has to do with Parkinson's decease.
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`It is a drug that is used to treat Parkinson's. Again, the
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`structure is very different. It has one OH group.
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`So this compound again, the only reason you
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`would look at it, is if you needed a justification to get to
`
`what the inventors did.
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`In the end, Your Honor, if you look at the -- if
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`you go to the next slide, if you look along the path here,
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`this is the path where an inventor would have to consider
`
`all of these possibilities and the person of ordinary skill
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`would have to consider all of these possibilities from the
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`beginning.
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`The only way to make your way along this path is
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`to start at the fend end with the claimed compound and get
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`all the way back to the beginning. But the inventors didn't
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`have the benefit of this roadmap, of this blueprint, and
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`neither would a person of ordinary skill.
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`Now, if you would go to the next slide.
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`As to the '650 patent, it concerns salt forms,
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`and there are a few additional reasons why that patent, why
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`those claims would not be obvious. They argue that the
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`claims of that patent are obvious as well. And those relate
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`Patent Owner, UCB Pharma GmbH – Exhibit 2006 - 0005
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`21
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`23
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`to whether or not you would expect this prodrug, what
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`resulted would have been obvious to make into a salt form.
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`And Dr. Chyall who is an expert in salt screening and
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`selectivity will talk about there were a number of options
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`and he will also talk about when you get to the salt form,
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`how unpredictable it is which salt will actually crystalize,
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`if any of them will work.
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`Go to the next slide.
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`The resulting compound, Your Honor,
`
`fesoterodine, it has this balance of properties. These are
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`all properties in comparison to the prior art compounds, and
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`in comparison to all the other prodrug candidates that these
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`scientists made at Schwarz. They didn't just go right to
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`fesoterodine by any means. They spent many, many days and
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`many weeks, many months and years getting to trying all
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`those locations on the ring, trying different types of
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`prodrug groups.
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`And this is what fesoterodine resulted in. It
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`was well absorbed, did not have off-target effects.