1
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`CIVIL ACTION NUMBER:
` 11-3962
`
` TRIAL
`WITH SEALED PORTIONS
`
` UNITED STATES DISTRICT COURT
` FOR THE DISTRICT OF NEW JERSEY
`__________________________________
`HELSINN HEALTHCARE, S.A. and
`ROCHE PALO ALTO, LLC,
` Plaintiffs,
` -vs-
`DR. REDDY'S LABORATORIES, LTD.,
`DR. REDDY'S LABORATORIES, INC.,
`TEVA PHARMACEUTICALS USA, INC.,
`and TEVA PHARMACEUTICAL
`INDUSTRIES, LTD.
` Defendants.
`__________________________________
` Clarkson S. Fisher United States Courthouse
` 402 East State Street
` Trenton, New Jersey 08608
` June 15, 2015
`B E F O R E: THE HONORABLE MARY L. COOPER
`
`UNITED STATES DISTRICT JUDGE
`
`Certified as True and Correct as required by Title 28, U.S.C.,
`Section 753
`
`/S/ Regina A. Berenato-Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
`
`United States District Court
`Trenton, New Jersey
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`Helsinn Healthcare Exhibit 2012
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`Page 1 of 8
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`A P P E A R A N C E S:
`
`PAUL HASTINGS
`BY: JOSEPH O'MALLEY, ESQUIRE
` ERIC W. DITTMANN, ESQUIRE
` ISAAC S. ASHKENAZI, ESQUIRE
`SAUL EWING
`BY: CHARLES M. LIZZA, ESQUIRE
`Attorneys for the Plaintiffs
`
`BUDD LARNER
`BY: STUART D. SENDER, ESQUIRE
` MICHAEL H. IMBACUAN, ESQUIRE
` HUA HOWARD WANG, ESQUIRE
` CONSTANCE S. HUTTNER, ESQUIRE
` KENNETH E. CROWELL, ESQUIRE
`Attorneys for the Defendant, Dr. Reddy's Laboratories
`
`WINSTON & STRAWN
`BY: JOVIAL WONG, ESQUIRE
` GEORGE LOMBARDI, ESQUIRE
` JULIA MANO JOHNSON, ESQUIRE
` BRENDAN F. BARKER, ESQUIRE
`LITE DePALMA, GREENBERG, LLC
` BY: MAYRA V. TARANTINO, ESQUIRE
`Attorneys for the Defendant, Teva
`
`United States District Court
`Trenton, New Jersey
`
`I N D E X
`
`WITNESS VOIR DIRECT CROSSREDIRECT RECROSS
` DIRE
`(Video deposition of Maurie Markman), 7
`(Video deposition of Valentino Stella), 28
`(Video deposition of Navin Vaya), 81
`(Video deposition of Limor Zahavi), 96
`
`GORDON AMIDON
`By Mr. Dittmann 126 143
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`United States District Court
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`Colloquy
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`(In open court. June 15, 2015, 9:30 a.m.)
`
`THE COURT: Good morning, everyone.
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`ALL: Good morning, your Honor.
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`THE COURT: How is everybody today?
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`ALL: Good.
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`THE COURT: Okay. What would you like to start with
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`this morning?
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`MR. ASHKENAZI: Your Honor, we're planning on playing
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`some deposition designations this morning.
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`THE COURT: All right. Is there any dispute about
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`them, these?
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`MR. ASHKENAZI: Not that I'm aware of.
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`MR. SENDER: Other than the sort of the standing 403
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`objection to our experts who did not appear, you know, we've
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`designated what we could out of it to try to provide some
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`context.
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`THE COURT: All right. Well, I'll see them, and I'll
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`rule at some point. But we'll definitely know what we're
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`delineating as your objection.
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`MR. SENDER: Thank you, your Honor.
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`MR. LIZZA: Your Honor, in that regard as requested
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`by your Honor for the line-by-line analysis, we've prepared a
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`chart with the designations and with our basis for relevance
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`and probative value. So if I may approach, I can hand that
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`chart up.
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`United States District Court
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`Colloquy
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`5
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`THE COURT: Sure. Have you served it?
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`MR. SENDER: No, they have not, your Honor.
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`MR. LIZZA: We're serving it now.
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`THE COURT: Okay. And, again, you don't need to
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`respond until you've had a chance to digest it and me, too.
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`Okay? Fine.
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`MR. ASHKENAZI: Your Honor, at this time, we'd like
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`to play the deposition designation of Dr. Maurie Markman who
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`is DRL's expert clinical oncologist. According to DRL, Dr.
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`Markman is the president of medicine and science at Cancer
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`Treatment Centers of America. Dr. Markman has more than 20
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`years of experience in cancer treatment. He has held
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`clinical, research, teaching and management positions in
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`several highly regarded medical institutions in the U.S.
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`Dr. Markman has extensive experience with all the 5-HT
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`3
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`receptor antagonist drugs approved in the U.S. Dr. Markman
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`was deposed regarding his expert opinions in this case.
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`And for the record, your Honor, we have a binder with
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`the corresponding deposition exhibits. Markman Deposition
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`Exhibit 1 corresponds to DTX-1206.
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`THE COURT: I'm sorry. Just a second, please. I'll
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`tell you when I'm ready.
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`MR. ASHKENAZI: Okay.
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`THE COURT: Was he deposed once or twice?
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`MR. ASHKENAZI: Once, your Honor.
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`Amidon - Direct
`
`And do you agree with Dr. Kirsch?
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`No, I do not.
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`Why not?
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`Well, I prepared a few slides to illustrate why the
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`Q.
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`A.
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`Q.
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`A.
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`compound in the Won publication would not be relevant to a
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`POSA looking at palonosetron, so -- this kind of gets kind of
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`technical.
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`THE COURT: For stability purposes?
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`THE WITNESS: For stability purposes, yes. This gets
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`kind of technical, Your Honor, but ask questions if you have
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`any questions.
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`THE COURT: Okay.
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`THE WITNESS: But, yeah, so we've looked at the
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`structures and the chemistry here, and I do not agree with
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`Dr. Kirsch.
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`BY MR. DITTMANN:
`
`Q.
`
`So why don't we take a look at the demonstrative you've
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`mentioned starting with PDX-712.
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`A.
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`Q.
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`A.
`
`Yes.
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`Can you explain what you see here, Doctor?
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`So, here I've highlighted in the chemistry -- the
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`chemical, the element difference between the Won compound
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`which is RG 12915, that's the compound that Dr. Kirsch
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`referred to, and here's the palonosetron.
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`You can see that the chemical difference here, this is
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`United States District Court
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`Amidon - Direct
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`called a linear amide. This is an amide. And this is an
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`amide, too, but it's connected to a cyclic. It's a cyclic
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`amide, so we call this a lactam, most common --
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`THE COURT: That's on the palonosetron side?
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`THE WITNESS: In the palonosetron, it's a cyclic
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`lactam. I mean, this is a six­membered lactam. I mean, the
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`lactams are famous, beta-lactam antibiotics, but this is not
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`anything like that.
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`But this is a cyclic amide, a very unique structure, as
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`opposed to the linear amide here. This is the amide bond and
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`this is the amide bond here.
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`BY MR. DITTMANN:
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`Q.
`
`It may be helpful if we can bring up PDX­713 and continue
`
`our discussion.
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`A.
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`Yeah, okay.
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`So, I think Dr. Kirsch was highlighting this
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`similarity, and that is true, obviously. There is a
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`quinuclidine -- well, okay, this is a tri- -- we'll get into
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`this, but this is a triamine, but it's a particular
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`quinuclidine, and that part of the molecule, just that part,
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`highlighted in the light green is the same.
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`THE COURT: In both?
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`THE WITNESS: In both molecules.
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`THE COURT: In both molecules?
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`THE WITNESS: Molecules, yeah.
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`Amidon - Direct
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`a cyclic lactam versus a linear lactam, and you have a
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`benzofuran here. You do not have that. And you have
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`cyclohexane with a fairly rigid structure here -- I'm sorry.
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`THE COURT: Can you slow down just a little with the
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`words.
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`THE WITNESS: I'm sorry. Okay. Where do you want me
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`to back up to?
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`Okay. So that this is a linear amide, and this is a
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`cyclic lactam, this is a cyclic amide, a more rigid structure
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`indicated by the -- the dash lines here indicate the
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`stereochemistry of this molecule that's not indicated here.
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`Because there isn't stereochemical issues here in this
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`molecule, but these there are.
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`And you can see the difference in the chemical
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`structures in this two­dimensional representation of the
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`chemical structure. So the chemistries of these two molecules
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`are quite different.
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`BY MR. DITTMANN:
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`Q.
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`Now, Dr. Amidon, just to make the record clear, if we
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`could, going back to the Won molecule starting on the left,
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`the top part of the molecule, here, can you explain with the
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`O, H, and N, next to the --
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`A.
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`Q.
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`A.
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`So this is --
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`Can you explain what that is again?
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`Okay. Well, this is the bonding -- this is what would be
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`Amidon - Direct
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`But the -- the rest of the molecules are quite
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`different.
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`And so the chemistry is, of course, highly dependent on
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`the actual chemical structure and chemical bonding. So these
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`are quite different molecules.
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`BY MR. DITTMANN:
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`Q.
`
`Bring up PDX-714.
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`THE COURT: The fact that you've got a ring, a ring
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`structure in the palonosetron, connecting up -- please forgive
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`me. I'm not a chemist --
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`THE WITNESS: I -- I --
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`THE COURT: -- the O, the N, and the H.
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`THE WITNESS: Yes.
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`THE COURT: You say that that's a -- that's a tighter
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`structure than the linear one that the Won has connecting
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`those three atoms?
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`THE WITNESS: Yes, yes. It's more rigid, it's more
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`structurally fixed spatially, yes, because of the bonding
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`structure of carbon and nitrogen, yes.
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`BY MR. DITTMANN:
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`Q.
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`And do you have a slide discussing this rigidity you're
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`mentioning?
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`A.
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`Q.
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`Yes, I think I've illustrated that on another slide.
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`Can we bring up PDX­714?
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`Can you discuss what we see here, Doctor?
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`Amidon - Direct
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`Amidon - Direct
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`A.
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`Yes. So, here, it's kind of summarizing that point, Your
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`Honor, here. This is a more flexible, you're going to have
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`cis and trans, this quinuclidine versus the hydrogen, this
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`part.
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`THE COURT: You have what?
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`THE WITNESS: I'm sorry. Okay.
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`BY MR. DITTMANN:
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`Q.
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`A.
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`Q.
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`Doctor, what might be helpful if you --
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`I'm sorry.
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`-- point to the left side, and say, we're talking about
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`Won and then we'll move to the right side next. Is that okay?
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`THE COURT: Yeah. We have two things we're
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`contending with here. We're making a record, so the pointer,
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`when it's on, one --
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`THE WITNESS: You don't -- yeah.
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`THE COURT: -- one drawing or another, the words have
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`to say, now I'm comparing what we see here on the left with
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`what we see here the right. And the other, of course, is the
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`comprehension, the communication gap.
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`THE WITNESS: Okay. Okay. Well, just slow me down.
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`THE COURT: And also, the other thing is that the
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`court reporter has to be able to get these words down.
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`THE WITNESS: I understand. I understand. Just slow
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`me down.
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`THE COURT: Just take your time.
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`THE WITNESS: The stability is very dependent on the
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`electronic structure and the elemental structure of the
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`molecule.
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`BY MR. DITTMANN:
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`Q.
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`Just to take one step back, Doctor, to make sure that the
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`record is clear, you were talking about the chlorine and
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`oxygen on the Won molecule, if you see on the left side of the
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`demonstrative, and we see here there are labels "activator"
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`next to both. Can you explain what you mean by "activator"?
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`A.
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`Well, there's -- for chemical reactivity, there would be
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`more reactive, more chemically reactive.
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`Chlorine has got more electrons around it as an atom
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`and oxygen has got two -- lone pairs, so there's more
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`electron -- lone-pair electrons. Lone-pair electron, that's a
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`function of the bonding structure of chlorine and oxygen. So
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`there's more electron freedom, more electrons free in the
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`oxygen and the chlorine.
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`So activator is -- that's just illustrating that these
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`compound -- the Won compound on the left with the chlorine and
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`oxygen is electronically a very different structure than the
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`palonosetron compound on the right.
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`BY MR. DITTMANN:
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`Q.
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`So, turning to the palonosetron on the right, do you see
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`any such activators present in the structure of that molecule?
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`A.
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`No.
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`Amidon - Direct
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`175
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`THE WITNESS: This is not an environment I'm used to
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`teaching in so...
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`So, on the left, with the Won compound, the RG 12915,
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`this structure is free to move, in fact, the hydrogen and this
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`carbon can change position and we call it cis/trans. And so
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`this is more flexible here. While this cyclic structure fixes
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`this nitrogen in a chemical position. Okay? So that was
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`my -- that was the essential point of that.
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`THE COURT: Okay. And you've used the term
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`"flexible" for the Won at that location, and "rigid" for the
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`palonosetron at that location?
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`THE WITNESS: Correct. Correct. Correct.
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`And then I highlighted here also that there's
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`different elements. There's a chlorine and an oxygen in the
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`Won compound, which would make the chemistry of the Won
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`compound quite different.
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`So, in conclusion, this is maybe getting a little
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`technical, but the Won -- the compound on the left, the Won
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`compound, is a different chemical structure than the
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`palonosetron, and so a POSA would look at it and say, it's not
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`much help to me with regard to predicting palonosetron
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`properties.
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`THE COURT: Including stability?
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`THE WITNESS: Including stability.
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`THE COURT: Okay.
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`Amidon - Direct
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`177
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`Q.
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`Now, just to summarize, what -- where we are so far, you
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`know, what would a POSA infer, if anything, with respect to
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`stability looking at the structural differences between these
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`two molecules?
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`A.
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`I believe that the Won compound on the left would be of
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`no help, so there'd be no useful information from the Won
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`compound that you would extrapolate to the palonosetron
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`compound. So I would say you would learn nothing about
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`palonosetron from the Won compound.
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`THE COURT: Now, Doctor, this drawing, chemical
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`drawing of the palonosetron molecule, doesn't show up in the
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`'333 patent. That's what we've heard so far in the evidence.
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`Would you agree with that?
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`THE WITNESS: The chemical -- okay.
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`THE COURT: Chemical drawing.
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`THE WITNESS: The chemical drawing of the Won
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`compound on the left is only generically included in the '333
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`patent.
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`THE COURT: But I'm talking about the palonosetron on
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`the --
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`THE WITNESS: I'm sorry, the palonosetron, okay. The
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`palonosetron compound in the '333 patent, I'm sorry. I was
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`confused, Your Honor.
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`Correct, the palonosetron compound in the '333 patent
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`is included only in the generic Formula I with the A, B, Cs
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`Amidon - Direct
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`and the symbols that they have in there.
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`If you assemble -- if you look into that in all of
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`the potential compounds, you will find palonosetron is one of
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`the compounds in that -- that's contained in the structures
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`that were in the '333 patent.
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`THE COURT: That I get.
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`THE WITNESS: Yeah.
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`THE COURT: I just wanted to establish, you've looked
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`at the '333 patent, and this chemical drawing of the
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`palonosetron molecule is not drawn in the '333 patent. But
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`what we've learned so far in the evidence here, I just want to
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`check with you on this, the actual palonosetron molecule is
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`verbally described in the '333 patent, it is called out and
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`described.
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`THE WITNESS: That's my understanding, it was called
`
`out and described but not structurally presented, yes.
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`THE COURT: Okay.
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`THE WITNESS: Yeah.
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`BY MR. DITTMAN:
`
`Q.
`
`Do you understand that Dr. Kirsch relies on a Clark 1993
`
`reference, DTX­282, in asserting that those -- the prior art
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`recognized similarities between the Won molecule and
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`palonosetron?
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`A.
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`Q.
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`Yes, I'm familiar -- I'm aware of that testimony, yes.
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`And do you understand Dr. Kirsch has contended that a
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`pharmacophore model -- models which was research -- a research
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`effort in the 1990s to try and reverse engineer a receptor,
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`and they're looking for 5-HT receptor antagonists, things that
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`bind to this receptor. And they wanted to reverse engineer
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`what the receptor looked like.
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`It's -- it was not a very successful line of research,
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`but that's what this paper -- my point is, this paper focused
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`on a pharmacophore model and based on the crystal structure of
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`the molecules. So it had little -- little applicability to
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`solution conformation which would be more freedom in the
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`solution than in the solid state. So this -- this paper is
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`of, I would say, no help to a formulation scientist.
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`Q.
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`Just to be clear, was Clark 1993, in your view,
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`addressing any stability­related issues?
`
`A.
`
`Q.
`
`No.
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`Can we turn to Page 5, please. I want to focus on the
`
`right column, yeah, you have it there, correct.
`
`A sentence I'll read into the record that states: "In
`
`fact, a crystal structure of another 5-HT
`
`3
`
` antagonist (44) has
`
`the conformation of the quinuclidine ring system in a similar
`
`conformation to the overlap conformation of (S,S)-37." Do you
`
`see that, Doctor?
`
`A.
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`Q.
`
`Yes.
`
`And, first, do you understand this to be a sentence that
`
`Dr. Kirsch focused on in his testimony?
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`POSA would have focused on the Clark 1993 for whatever
`
`information they can glean about compounds that are related to
`
`palonosetron that may inform them about their efforts to
`
`develop a stable palonosetron formulation?
`
`A.
`
`Well, I think a POSA might -- might have been aware of
`
`the Clark reference, but the Clark reference was focused on
`
`developing a pharmacophore model and used crystal structure,
`
`so I think it would be of little assistance. But I think I
`
`have some transparencies on that, but I did look at the Clark
`
`article and I think it does not say anything regarding
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`chemical stability.
`
`Q.
`
`Can we bring up the Clark reference, DTX-282? And,
`
`first, if we can focus on the abstract. Thank you.
`
`Can you -- I think you started to summarize this,
`
`Doctor, but can you explain to the Court what Clark 1993 was
`
`focusing on?
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`A.
`
`Well, okay. There's a lot of technical chemical details
`
`in here.
`
`I would just point to the last line in the abstract.
`
`Computer modelling here, computer modelling studies were
`
`performed, and previously forward -- previously reported 5-HT
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`3
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`receptor antagonists -- previously reported -- I'll speak more
`
`slowly -- 5-HT
`
` receptor antagonist pharmacophore models were
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`3
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`refined to include a lipophilic binding domain.
`
`So this was focused -- this was focused on a
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`A.
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`Yes. This is my understanding that the sentence that --
`
`that Dr. Kirsch referred to, and the sentence particularly
`
`focuses on the quinuclidine part, just that upper right­hand
`
`part of the molecule. And those two, the -- that's a
`
`tricyclic with a nitro- -- bridge nitrogen, that's a very
`
`fixed structure, so this is not really saying anything other
`
`than that's fixed. That's the same in the two molecules.
`
`Q.
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`Just for context, if we can bring up the structures below
`
`that sentence, just to make sure we're all following along.
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`A.
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`Q.
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`Yeah. This is the quinuclidine part.
`
`So you're pointing to the upper right portion of the
`
`molecule?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`Compound 44?
`
`Yes.
`
`Okay. If you go back to --
`
`THE COURT: With the jagged line through it?
`
`THE WITNESS: Yes, that means it's a tricyclic. This
`
`is the cycle, this is a cycle and this is -- this is a very
`
`rigid structure that you can do. Six­membered rings are
`
`common in organic chemistry.
`
`BY MR. DITTMANN:
`
`Q.
`
`Now, in the sentence we were looking at from Clark 1993,
`
`44 is a reference to this Compound 44 shown below, the text
`
`we're looking at?
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`compound is very stable at 1 milligram per mL.
`
`Q.
`
`And with respect to the 60-degree Celsius temperature,
`
`the eight-week period we see where the solution remains very
`
`stable, that corresponds roughly to the two-month period set
`
`forth in your book, correct, for assessing stability?
`
`A.
`
`Yes, right. Yeah --
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`THE COURT: Two­year?
`
`BY MR. DITTMANN:
`
`Q.
`
`I'm sorry. The two-month period for assessing
`
`accelerated stability that we discussed, and maybe we can turn
`
`back to that in your book, the table we were looking at?
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`A.
`
`Yes.
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`THE COURT: I believe you.
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`THE WITNESS: Yeah. Okay. So it's very stable at
`
`two weeks. This would extrapolate to a two to -- okay, at two
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`weeks, the stability would extrapolate to a two- to three­year
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`shelf life, yes, because the reaction rate increases threefold
`
`for every 10 degrees. That's what's taught in the other part
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`of the textbook.
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`And so between 30 and 60 degrees is ten -- three times
`
`three times three, that's what, three times nine -- 27, that's
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`what, 81? So 81 times two weeks, that's 160 weeks? 162
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`weeks? How many -- that's -- what? Three years.
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`So it's a two to three -- this, I mean, that's an
`
`extremely rough calculation, but this would extrapolate to a
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`In a 2 mL injectable vial, yes.
`
`Based on the 1-milligram-per-milliliter data we see here,
`
`A.
`
`Q.
`
`would there be any stability-related reason to want to use
`
`lower concentrations of palonosetron?
`
`A.
`
`No, no. I mean, it's out of the clinical range, the
`
`expected clinical range, and your concentration of a milligram
`
`per mL is stable, so there's no reason to go to lower
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`concentrations.
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`Q.
`
`Now, as we saw earlier, the claims that you've analyzed
`
`in the case, they specify 0.05 milligrams per milliliter
`
`palonosetron concentration, correct?
`
`A.
`
`Q.
`
`Yes. Correct.
`
`So if we can pull out of the -- zoom in here and look at
`
`the table.
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`And I want you now to assume, Doctor, that a POSA in
`
`this case would have wanted to focus on this 0.05 milligram
`
`per milliliter concentration. Are you with me so far?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`You want me to assume?
`
`To assume --
`
`Assume that, okay.
`
`-- just focusing now on 0.05 milligram per milliliter
`
`palonosetron concentrations.
`
`A.
`
`Q.
`
`Um-hum. Okay.
`
`So, with that assumption, what would the data we see here
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`in the Bonadeo declaration, if anything, regarding the need to
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`two- to three-year shelf life. That's an extrapolation. It
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`wouldn't be believed -- I mean, because it's like -- okay, a
`
`POSA looking at this would say, we're in pretty good shape,
`
`from the point --
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`THE COURT: It's an indication?
`
`THE WITNESS: Yes, yes, yes.
`
`BY MR. DITTMANN:
`
`Q.
`
`Do the preformulation data concerning this
`
`1-milligram-per-milliliter solution support your opinion that
`
`a POSA would not want to add any excipients like a chelating
`
`agent?
`
`A.
`
`Q.
`
`Yeah, absolutely, yes.
`
`Is this because of the principle we discussed earlier,
`
`the golden rule that you don't add excipients unless
`
`absolutely necessary for I.V. solutions?
`
`A.
`
`Q.
`
`Yes, correct, yes.
`
`And do you understand that plaintiffs' clinical expert,
`
`Dr. Keith Candiotti, testified as to the palonosetron
`
`concentrations that would be preferred from a clinical
`
`perspective?
`
`A.
`
`Q.
`
`Based on the prior art, yes, I understand, yes, sir.
`
`And using Dr. Candiotti's most preferred 1 to 2
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`milliliter volume that you mentioned earlier, this would
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`include a 1-milligram-per-milliliter concentration for a
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`2-milligram dose, correct?
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`add a stabilizing agent like a chelating agent?
`
`A.
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`Well, you can see that at the concentration of .01, .1
`
`and 1, the compound, palonosetron, is quite stable, and
`
`particularly in this range of .05, which is in between .01 and
`
`1. There's no -- there's no instability here. A POSA would
`
`not expect there to be any difference between instability for
`
`a .05, if that's what you're asking. So there's no stability
`
`reason, even at that low concentration, to add anything to the
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`formulation.
`
`Q.
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`And the .05-milligram-per-milliliter concentration would
`
`be roughly in the middle of the two --
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
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`Q.
`
`Yeah, halfway in between, yeah.
`
`-- concentrations we're looking at here, 0.01 --
`
`Yeah, right in between.
`
`-- and 0.1?
`
`Yes.
`
`And is it correct that up until 60 degrees Celsius,
`
`there -- well, can you tell us, through 60 degrees Celsius,
`
`what, if any, degradation are we seeing for either
`
`concentration?
`
`A.
`
`I see none. None.
`
`THE COURT: In fact, you're coming up with one
`
`percentage point more than you started with?
`
`THE WITNESS: Yes. That would presumably be the
`
`analytical sensitivity. Although there isn't an initial --
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`this is only one week. So that may be just in the initial
`
`form -- you know, they had 101 initially, that's my
`
`expectation.
`
`THE COURT: Okay.
`
`BY MR. DITTMANN:
`
`Q.
`
`Can we zoom in just on the very top line what we are
`
`seeing here, the title? And do we see, Doctor, that the
`
`experiments we are discussing were performed at a pH of 7.4?
`
`A.
`
`Q.
`
`Yes.
`
`Does this pH level have any significance to you in
`
`interpreting the stability results we are looking at?
`
`A.
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`Well, okay, at first thought a POSA would say, well
`
`this -- I don't know if this is the optimal pH or not, and so
`
`what I do know from the preformulation report that this was --
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`7.4 was not the most stable pH. So the most stable pH from
`
`subsequent preformulation work was pH 5.
`
`Q.
`
`So is it correct a POSA would expect even better results
`
`in terms of stability if the solutions were maintained at the
`
`optimal pH of 5?
`
`A.
`
`Yes, yes.
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`THE COURT: Before we leave this chart, I think I
`
`misunderstood. The last column there, Doctor, that has
`
`number -- that has the results at eight weeks.
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`THE WITNESS: The eight week one?
`
`THE COURT: Yes.
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`milligram per mL. Maybe there self-association,
`
`micellization, something complicated. And I know that the --
`
`that you can speculate, but I don't know that it's -- we don't
`
`know what's going on there.
`
`Q.
`
`Now, with this unusual temperature data we are looking at
`
`for the 10 milligram per milliliter solutions, have suggested
`
`to a POSA that oxidation was involved here?
`
`A.
`
`No, no. Because this is not what -- not at all what
`
`you'd expect. High temperatures, you have more instability
`
`because you've got higher thermal energy and more vibration
`
`associated with the chemical bonding, so this is very unusual.
`
`Q.
`
`Now, putting aside for a moment this unusual data, is it
`
`correct that palonosetron concentrations at 10 mg per
`
`milliliter and higher were found to be unstable in the
`
`preformulation experiments?
`
`A.
`
`Q.
`
`Yes. Correct.
`
`Can we bring up PDX-717? Can you explain what we see
`
`here, Doctor?
`
`A.
`
`Well, here is kind of my take away from the
`
`preformulation studies, which as I said are not part of the
`
`prior art. But these are part of the confidential studies to
`
`show the uniqueness of the palonosetron compound. And first
`
`is that lower concentrations have good stability illustrated
`
`by the .01, .1, and 1 concentrations, while the concentrations
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`of 10 milligrams per mL and higher have poor, non-linear
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`THE WITNESS: Yes.
`
`THE COURT: Those are milliliters, right?
`
`THE WITNESS: No, that's -- that's percentage --
`
`THE COURT: It is a percentage?
`
`THE WITNESS: Percentage, yes. It is the chemical
`
`stability, so that's the percentage.
`
`THE COURT: All right.
`
`THE WITNESS: This says, "percent drug remaining,"
`
`yeah.
`
`THE COURT: Okay. Fine. I did understand.
`
`THE WITNESS: Yeah, okay.
`
`BY MR. DITTMANN:
`
`Q.
`
`Now, could we zoom in now on the 10 milligram per
`
`milliliter data? And can you explain, Doctor, what, if
`
`anything, these results would have explained to a POSA who
`
`performed these preformulation studies?
`
`A.
`
`Well, I think a POSA, and even myself, would look at this
`
`and say this is unusual. We're seeing here, in the extreme at
`
`8 weeks, you can see the potency is decreasing, and then it's
`
`increasing at these very high temperatures. That means
`
`something physical, chemically, odd or funny is happening.
`
`Maybe there is some compound that's melting or there is some
`
`chemical transition you're not aware of or change in reaction
`
`mechanism. But this is saying there is some complicated
`
`non-linearity occurring here at this high concentration of 10
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`stability. And while we didn't show that 50 milligram, but it
`
`was similar. The 50 milligram per mL concentration, and no
`
`mechanism for oxidation or chemical instability can explain
`
`this data.
`
`The higher concentrations of 10 milligram per mL and
`
`higher have poor non-linear stability, and no mechanism of
`
`oxidation or chemical instability can explain this data.
`
`Q.
`
`Now, Doctor, I want you to assume for purposes of my next
`
`few questions, that a POSA was convinced that oxidation was an
`
`issue in palonosetron. Are you with me so far?
`
`A.
`
`Q.
`
`Okay.
`
`And I understand you disagree, but I want you to assume
`
`they were concerned about oxidation.
`
`A.
`
`Q.
`
`Um-hum.
`
`How many different methods would a POSA have tried in an
`
`attempt to address such an oxidation problem?
`
`A.
`
`Well, I think there's several, many methods, and I think
`
`I illustrate that in a transparency taken from my textbook on
`
`Chemical Stability of Pharmaceuticals, and I think we have a
`
`transparency on that.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Yes --
`
`I think I list nine different methods.
`
`Can we bring up PDX-718, please.
`
`So here I have listed from our Chemical Stability of
`
`Pharmaceuticals in the lower right handbook, and this is the
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`different methods. Here are things that you would do. You
`
`would purify out contaminants. That's always an objective
`
`because they can accelerate degradation, react with your API.
`
`But you can remove oxygen, you can adjust the pH, ionic
`
`strength, as well as buffer capacity. Adjust the
`
`concentration of the API, depending on the reaction mechanism.
`
`Protect it from light like put it in amber bottles or
`
`something.
`
`THE COURT: So light has a -- has an effect on
`
`oxidation, not just on the thing that is light engendered?
`
`What's the name of that?
`
`THE WITNESS: Okay. There is photolytic degradation
`
`and oxidation.
`
`THE COURT: Right.
`
`THE WITNESS: And they are two different mechanisms,
`
`yeah, yeah.
`
`THE COURT: But light can affect oxidation?
`
`THE WITNESS: It can -- light can affect oxidation,
`
`y