IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
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`544
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`Civil Action
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`VANDA PHARMACEUTICALS INC.,
`Plaintiff,
`
`v.
`ROXANE LABORATORIES, INC.,
`Defendant.
`
`No. 14-757-GMS
`
`)
`- - -
`Wilmington, Delaware
`Wednesday, March 2, 2016
`9:00 a.m.
`Trial Day 3
`- - -
`BEFORE: HONORABLE GREGORY M. SLEET, U.S.D.C.J.
`APPEARANCES:
`KAREN JACOBS, ESQ., and
`ETHAN H. TOWNSEND, ESQ.
`Morris Nichols Arsht & Tunnell LLP
`-and-
`NICHOLAS GROOMBRIDGE, ESQ.,
`ERIC ALAN STONE, ESQ.,
`KIRA A. DAVIS, ESQ.,
`JASON L. MEIZLISH, ESQ.,
`JOSEPHINE YOUNG, ESQ., and
`DANIEL KLEIN, ESQ.
`Paul, Weiss, Rifkind, Wharton & Garrison LLP
`(New York, NY)
`
`Counsel for Plaintiff
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`01:16:36
`01:16:36
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`Vanda Exhibit 2022 - Page 1
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`
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`)
`)
`
`544
`
`Civil Action
`
`))
`
`))
`
`))
`
`VANDA PHARMACEUTICALS INC.,
`Plaintiff,
`
`v.
`ROXANE LABORATORIES, INC.,
`Defendant.
`
`No. 14-757-GMS
`
`)
`- - -
`Wilmington, Delaware
`Wednesday, March 2, 2016
`9:00 a.m.
`Trial Day 3
`- - -
`BEFORE: HONORABLE GREGORY M. SLEET, U.S.D.C.J.
`APPEARANCES:
`KAREN JACOBS, ESQ., and
`ETHAN H. TOWNSEND, ESQ.
`Morris Nichols Arsht & Tunnell LLP
`-and-
`NICHOLAS GROOMBRIDGE, ESQ.,
`ERIC ALAN STONE, ESQ.,
`KIRA A. DAVIS, ESQ.,
`JASON L. MEIZLISH, ESQ.,
`JOSEPHINE YOUNG, ESQ., and
`DANIEL KLEIN, ESQ.
`Paul, Weiss, Rifkind, Wharton & Garrison LLP
`(New York, NY)
`
`Counsel for Plaintiff
`
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`Vanda Exhibit 2022 - Page 1
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`
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`545
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`APPEARANCES CONTINUED:
`DAVID E. MOORE, ESQ.
`Potter Anderson & Corroon LLP
`-and-
`KENNETH G. SCHULER, ESQ.,
`EMILY C. MELVIN, ESQ.,
`DANIEL BROWN, ESQ.,
`MELISSA BRAND, ESQ.,
`MICHAEL R. SERINGHAUS, ESQ., and
`DAMION JURRENS, ESQ.
`Latham & Watkins LLP
`(Chicago, IL)
`
`Counsel for Defendant
`- - -
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`Vanda Exhibit 2022 - Page 2
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`Ratain - cross
`how iloperidone is metabolized. Correct?
`Can you point me to a specific page?
`A.
`If we go to Page 6, for example -- I am sorry, Page
`Q.
`13.
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`574
`
`Let's blow up Table 1 there, try and get that as
`large as we can, please, Mr. Lee.
`That is talking about the various enzymes that
`are involved in metabolizing iloperidone. Correct?
`That's correct.
`A.
`And there are 11 of them?
`Q.
`There are 11 P450 enzymes that have some level of
`A.
`activity on the metabolism of iloperidone.
`CYP2D6 is one out of the 11. Correct?
`Q.
`Yes. It's one out of the 11 and was the most
`A.
`efficient in the formation of metabolite P94, which is the
`precursor to P95.
`While we are on that, the Percent of Total column,
`Q.
`what does that mean?
`The percent of the total metabolites formed. This
`A.
`data comes from data that would have been submitted by the
`sponsor. I would have to, to really talk about this with
`any degree of certainty, I would really have to look at the
`submission data.
`Fair enough. But this is telling us, at least in some
`Q.
`fashion, the relative amounts of different metabolites.
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`Vanda Exhibit 2022 - Page 3
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`Ratain - cross
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`575
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`Correct?
`Yes. One would really have to see the submission data
`A.
`to really understand it. I think what one can primarily
`understand from this is that CYP2D6 was the most efficient.
`That is the conclusion of the FDA in regard to the data
`submitted by the sponsor.
`Now, the list of items in the right-hand column, those
`Q.
`are different metabolites. Correct?
`Yes.
`A.
`And they are all prefixed with a P?
`Q.
`That's correct.
`A.
`So one of the ones that we see here is P88, for
`Q.
`example. Am I right?
`Yes. I see that.
`A.
`If we look down the table, CYP2D6 is shown as creating
`Q.
`something called P94. Isn't that right?
`That's right.
`A.
`It's known now that P94 is subsequently converted into
`Q.
`P95. Correct?
`Yes.
`A.
`But you are not suggesting that the knowledge was in
`Q.
`the prior art, are you?
`I am suggesting that the prior art made it very clear
`A.
`that CYP2D6 was -- CYP2D6 activity was highly correlated
`with the metabolism of iloperidone from the Mutlib prior art
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`Vanda Exhibit 2022 - Page 4
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`Ratain - cross
`
`576
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`reference.
`I am going to come to Mutlib.
`Q.
`To be clear, are you or are you not suggesting
`that in the prior art there was a teaching that metabolite
`P94 was converted by whatever process to metabolite P95?
`There is not anything in the prior art that refers to
`A.
`P94.
`Now, just so we see here, there is also a reference to
`Q.
`CYP3A4. Correct?
`Yes.
`A.
`And that's another major metabolic pathway for the
`Q.
`metabolism of iloperidone. Correct?
`That's a non-inheritable metabolic pathway. That is a
`A.
`very major important one, but for which no one has really
`found useful genetic predictors.
`Let's tease that apart a little.
`Q.
`First of all, we will agree that the CYP3A4 is a
`major metabolic pathway in the metabolism of iloperidone.
`Fair?
`Yes.
`A.
`And you mentioned it being non-inheritable. What that
`Q.
`means is I don't have variations in the part of my genetics
`that code for 3A4. Right?
`Not for 3A4. For 3A5, but not for 3A4.
`A.
`Unlike 2D6, where, as we have heard quite a lot, I can
`Q.
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`Vanda Exhibit 2022 - Page 5
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`Ratain - cross
`have those variations that I inherit. Right?
`You do.
`A.
`By the way, while we are at it, there are other
`Q.
`enzymes here, such as 2C19, for which there are such
`inherited variations. Right?
`That's right.
`A.
`Would you agree that this is a complex metabolic
`Q.
`regime?
`I mean, it's not as complicated as this table makes it
`A.
`look. I think the Mutlib teaching is quite straightforward.
`It teaches that there is a high correlation between CYP2D6
`activity and the metabolism of iloperidone.
`Doctor, I am going to get to Mutlib. Right now I just
`Q.
`want to establish the facts as we now know them.
`Let's turn to Page 15 and look at the bottom.
`Do you see close to the bottom a heading there that says,
`"What is the proposed metabolic scheme for iloperidone"?
`I see that.
`A.
`If we turn to Page 16, the top half of the page is
`Q.
`that proposed metabolic scheme. Right?
`Yes.
`A.
`Would you agree that that is a complex metabolic
`Q.
`scheme?
`It is atypical. I mean, we can either say all
`A.
`pharmacology is complicated and unpredictable or we can say
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`Vanda Exhibit 2022 - Page 6
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