`1408
`
`IN THE UNITED STATES DISTRICT COURT
`
`IN AND FOR THE DISTRICT OF DELAWARE
`
`ELAN PHARMA INTERNATIONAL
`LIMITED,
`
`Civil Action
`
`Plaintiff ,
`
`v.
`
`ABRAXIS BIOSCIENCE INC.,
`
`Defendant.
`
`No. 06-438-GMS
`
`Wilmington, Delaware
`Tuesday , June 10, 2008
`8:45 a.m.
`SEVENTH DAY OF TRIAL
`
`BEFORE: HONORABLE GREGORY M. SLEET, Chief Judge,
`and a Jury
`
`APPEARANCES:
`
`JOHN G. DAY , ESQ.
`Ashby , Geddes
`-and-
`STEPHEN SCHEVE, ESQ.,
`LINDA M. GLOVER, ESQ. ,
`JEFFREY SULLIVAN, ESQ.,
`ROBERT RIDDLE , ESQ., and
`PAUL FEHLNER, ESQ.
`Baker Botts LLP
`(Houston , TX)
`-and(cid:173)
`GREGORY BOKAR , ESQ.
`Counsel - Elan Drug Delivery
`
`Counsel for Plaintiff
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`Apotex v. Abraxis - IPR201 8-00l 52. Ex. 1Ol3. p.OI 0[222
`
`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 2 of 222 PagelD #: 10196
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`APPEARANCES CONTINUED:
`
`ELENA C. NORMAN, ESQ. , and
`MICHELLE SHERETTA BUDICAK, ESQ.
`Young Conaway stargatt , Taylor , LLP
`-and-
`MICHAEL A. JACOBS, ESQ.,
`EMILY A. EVANS, ESQ.,
`ERIC S. WALTERS, ESQ. ,
`LISA CHIARINI, ESQ.,
`DIANA KRUZE , ESQ., and
`ERIK J. OLSON, ESQ.
`Morrison & Foerster
`(San Francisco, CAl
`
`Counsel for Defendant
`
`THE COURT: Good morning.
`
`(Counsel respond "Good morning.")
`
`THE COURT:
`
`I understand we have an issue.
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`MR. JACOBS: A couple of things , Your Honor.
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`THE COURT:
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`I hope they are short.
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`MR. JACOBS: Two are short and one may take a
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`few minutes. No.1 , we have reached a stipulation on a
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`person of ordinary skill in the art.
`
`THE COURT: Good.
`
`I was wondering whether we
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`were going to hear about that mystic person.
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`MR. JACOBS: Procedurally, Your Honor, would you
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`like Ms. Kruze to read it? It would have come up in
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`Dr. Amiji's testimony. Ms. Kruze could just read the
`
`stipulation into the record , if that would be appropriate.
`
`MR. SCHEVE: Fine.
`
`Apotex v. Abraxis - IPR201 8-001 52, Ex. 1Ol3, p.02 0[222
`
`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 3 of 222 PagelD #: 10197
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`MR. JACOBS: No.2, documents in evidence. How
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`do we work?
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`I am still a little confused.
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`I know we have
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`heard several times how this is supposed to work but we are
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`at the level of mechanics, understanding what is in and what
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`isn't, especially documents that are --
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`THE COURT: All objections were overruled to
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`documentary exhibits, unless raised again.
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`I have not
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`entertained any additional objections. So it's in.
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`MR. JACOBS: On the original exhibits list, all
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`those exhibits are in evidence.
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`THE COURT: Are in. What you want the jury to
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`consider is another matter.
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`Is that where we are going with
`
`this?
`
`MR. JACOBS: No.
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`I think there are documents
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`THE COURT: For your record, they are in.
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`MR. JACOBS: For closing --
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`THE COURT: That's evidence.
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`MR. JACOBS: Terrific.
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`THE COURT: Mr. Scheve, do you have any
`
`questions?
`
`MR. SCHEVE: That's exactly what I have
`
`understood, Your Honor.
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`MR. JACOBS: Dr. Brittain, two alternative
`
`paths, from our standpoint.
`
`No.1, we put him on the stand, he is here in
`
`Apotex v. Abraxis - IPR201 8-001 52 , Ex. 1Ol3, p.03 0[222
`
`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 4 of 222 PagelD #: 10198
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`the courtroom, by the way. We put him on the stand, and we
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`examine him pursuant to the second Bench memo we filed
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`yesterday , in which we elicit only -- I can hand Your Honor
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`a copy.
`
`yesterday.
`
`Mr. Scheve?
`
`Honor.
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`THE COURT:
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`I got it yesterday, you say?
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`MR. JACOBS: Yes. We didn't focus on it
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`THE COURT: Have you seen the Bench memo,
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`MR. SCHEVE: Yes.
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`MR. JACOBS: We gave it to them yesterday, Your
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`The main point of this Bench memo, Your Honor,
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`is that when we ask him questions, we do not want him
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`volunteering, we do not want counsel for Elan eliciting
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`testimony beyond the specific and narrow facts that are
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`already in the record from his deposition or from the
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`documents.
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`THE COURT: You know, counsel and those in the
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`well, you can sit. It seems like this is going to take a
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`few minutes. There is no reason for you to have to stand.
`
`Mr. Jacobs.
`
`MR. JACOBS: There is only one question from the
`
`deposition that I need to ask him, which is, Did you perform
`
`studies on Abraxane? Beyond that, I don't believe counsel
`
`Apotex v. Abraxis - IPR201 8-001 52, Ex. 1Ol3, p.04 0[222
`
`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 5 of 222 PagelD #: 10199
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`for Elan should be allowed to elicit additional testimony
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`about what he did because he was instructed not to answer a
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`whole range of questions about what he actually did at his
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`deposition.
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`Actually, the second path is that we do not put
`
`Dr. Brittain on the stand, and the Court explains to the
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`jury what happened with the privilege log and why we are
`
`where we are.
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`I prepared and gave to counsel for Elan
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`yesterday a proposed statement from the Bench that would
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`just layout, very briefly , layout exactly what happened.
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`That way, we don't have to deal with uncertainties about
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`what Dr. Brittain might say when he testifies on this issue.
`
`THE COURT:
`
`I got to believe that Mr. Scheve
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`probably doesn't want the jury hearing about that from me.
`
`Maybe I am wrong about that.
`
`MR. SCHEVE: Well, after all day yesterday
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`asking witnesses, What did you have for breakfast?, and
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`hearing, Well, I had eggs right next to an order of
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`amorphous paclitaxel contained in Abraxis, all day, and now
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`to have counsel say , We really don't want any gratuitous
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`answers, or to go beyond -- they are now the sponsoring
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`witness, Your Honor. There is no expert report from him.
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`If they are going to ask fact questions , you know, it's my
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`decision, I would think, whether or not I wade into
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`something.
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`I will be very cautious about that. The idea
`
`Apotex v. Abraxis - IPR2018-001S2 , Ex. 1Ol3, p.OS 0[222
`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 6 of 222 PagelD #: 10200
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`that counsel can say, in advance , that I am restricted to
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`what I may ask --
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`THE COURT:
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`I am not going to do that ,
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`Mr. Jacobs. You will have to object.
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`MR. JACOBS: To be clear, Mr. Scheve instructed
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`Dr. Brittain at his deposition not to answer additional
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`questions.
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`THE COURT:
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`I think both sides know what the
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`issue is with Dr. Brittain. We have had an extensive
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`discussion about this.
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`I am tired of it. Let's move on.
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`Let's get this trial back underway.
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`Ms. Walker, bring in this jury.
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`MR. SCHEVE:
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`I do have an issue , Your Honor.
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`They have tendered something they want to either read to the
`
`jury or give to them that talks about your ruling that says,
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`Your Honor has ruled
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`THE COURT: That was the second path that he was
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`just talking about. Right?
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`MR. SCHEVE: They have offered an instruction
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`which would
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`THE COURT:
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`I just rejected --
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`MR. SCHEVE:
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`It is a separate issue. On this
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`inference , they have offered an instruction, and they also
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`now want to read or show the jury, in writing, that Your
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`Honor has found that Elan, my client, has willfully or
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`Apotex v. Abraxis - IPR201 8-001 52 , Ex. 1Ol3, p.06 0[222
`
`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 7 of 222 PagelD #: 10201
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`wrongfully
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`THE COURT: We are not going to do that, either.
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`MR. SCHEVE:
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`It would be two comments on the
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`inference. That should be in the jury instructions.
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`THE COURT: That is where it will be.
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`MR. JACOBS:
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`I need to know what you have
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`decided on the jury instructions.
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`THE COURT: Are you talking about the final jury
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`instructions?
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`MR. JACOBS:
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`I am sorry, Your Honor.
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`I thought
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`you said to Mr. Scheve , on the jury instructions
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`THE COURT:
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`I am instructing this jury at this
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`point on Dr. Brittain.
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`I am going to give an instruction on
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`the final jury instruction -- you are going to be trial
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`lawyers and we are going to try this case with this witness
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`on the stand. You will interpose objections.
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`I will rule
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`on those objections. It is not unduly complicated.
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`MS. KRUZE: Your Honor , shall I read into the
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`record the person of ordinary skill?
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`THE COURT: Don't you want the jury to hear it?
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`MS. KRUZE: Yes.
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`THE COURT:
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`I certainly would like to hear it.
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`I think the jury would like to hear it.
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`We had a witness on the stand , Dr. Amiji.
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`Dr. Amiji, please.
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`Apotex v. Abraxis - IPR201 8-001 52, Ex. 1Ol3, p.07 0[222
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 8 of 222 PagelD #: 10202
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`Doctor , you are still under oath. Good morning.
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`(Jury enters courtroom at 9:07 a.m.)
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`THE COURT: Good morning on yet another hot day,
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`ladies and gentlemen. Have a seat. You will be comfortable
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`today, hopefully.
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`Ms. Kruze, you may continue with Dr. Amiji.
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`MANSOOR AMIJI , having been previously sworn
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`as a witness, was examined and testified further as.
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`follows ...
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`THE COURT: Do you want to start out with a
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`stipulation?
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`We have arrived at one of those stipulations I
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`talked with you about in the preliminary instructions, that
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`is an agreement, one of those rare events in this case
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`between the parties. Ms. Kruze is now going to tell you who
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`the ordinary person of skill in the art is , that is, give
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`you the definition of this person you have heard about, this
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`person of skill.
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`MS. KRUZE: The person of ordinary skill in the
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`art would have a Ph.D. or the equivalent in pharmaceutical
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`sciences, chemistry , chemical engineering, or biological
`
`sciences, and at least two years of practical experience in
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`formulating drug compositions at the time the application
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`for the '363 patent was filed.
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`Alternatively, the person of ordinary skill in
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`Apotex v. Abraxis - IPR201 8-001 52 , Ex. 1Ol3, p.08 0[222
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`
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`Case 1:0 cv-00438-GMS Document 625 Filed 06/24/08 Page 9 of 222 PagelD #: 10203
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`Amiji
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`the art could be someone with a Master's degree in
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`pharmaceutical sciences, or the equivalent , with two or more
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`years of practical experience , specifically in the
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`development of nanoparticulate pharmaceutical compositions.
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`THE COURT: Let me see counsel for just a second
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`before I say what I am thinking about saying.
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`It doesn't
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`need to be on the record.
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`(Sidebar conference not reported.)
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`THE COURT: Perhaps Ms. Kruze will direct you to
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`the place. You don't have to worry about having made notes
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`as to that definition.
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`It has been or will be provided to
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`you.
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`BY MS. KRUZE:
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`DIRECT EXAMINATION CONTINUED
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`Q.
`
`A.
`
`Q.
`
`Good morning, Dr. Amiji.
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`Good morning, Ms. Kruze.
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`Yesterday we were discussing enablement of the patent
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`relating to drug and surface modifier combinations.
`
`I
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`believe where we left off was Defendant's Exhibit 193. This
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`was the memo from Sarptodar and your comparison of that memo
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`to the patent claims.
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`A.
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`Q.
`
`Yes.
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`And we were discussing , did the patent applicants
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`disclose, for example, that Tween 80 reached 3 ,0 00
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`nanometers?
`
`Apotex v. Abraxis - IPR2018-00152 , Ex. 1Ol3, p.09 0[222
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`
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`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 10 of 222 PagelD #: 10204
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`A .
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`Q.
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`No , they did not.
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`Let's take a quick look at what the patentees did tell
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`the Patent Office. That's JX-81 at Columns 3 through 4.
`
`I
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`believe it's in Column 4, in the second paragraph.
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`Did the patentees tell the Patent Office that
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`Tween 80 was a particularly preferred surface modifier?
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`A .
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`Q.
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`A .
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`Q.
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`Yes , they did.
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`But internally, that surface modifier had failed?
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`That's correct, yes.
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`Let's switch to DDI06.
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`Did you review any other documents regarding
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`Elan's efforts to make a nano-piposulfan product?
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`A .
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`Q.
`
`Yes , I reviewed several other documents.
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`Could you read some of the statements that you found
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`in those documents? This , for the record , is JX-47 , JX-55 ,
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`JX-81 , DX-2S8 and DX-286.
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`MR. SCHEVE: Your Honor ,
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`I object to just
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`reading documents. It ' s inappropriate form.
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`THE COURT:
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`I will sustain the objection.
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`BY MS. KRUZE:
`
`Q.
`
`Did you review any other documents regarding Elan's
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`efforts to make a piposulfan project?
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`A .
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`Q.
`
`A .
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`Yes , I did.
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`What did those documents say to you?
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`So here we can see from the different time points , we
`
`Apotex v. Abraxis - IPR201 8-001 52. Ex. 1Ol3. p.1O 0[ 222
`
`
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`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 11 of 222 PagelD #: 10205
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`have , in the case of August of '92, the '363 inventors
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`discuss that piposulfan is physically unstable.
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`In '93, the
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`inventors of piposulfan, was difficult to stabilize.
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`In '96
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`here, again, same problems with generating a stable
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`nanocrystalline suspension proved to be challenging.
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`In '96, formulation does have its problems.
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`And even today, in 2008 , we still do not have a
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`nano-piposulfan product.
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`Q.
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`Dr. Amiji, did Elan also try to make a NanoCrystal
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`formulation of paclitaxel using albumin?
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`A .
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`Q.
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`Yes.
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`Did you review laboratory notebooks regarding those
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`experiments?
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`A .
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`Yes, I reviewed several different laboratory
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`notebooks.
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`Q.
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`Was Elan successful in making a NanoCrystal version of
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`paclitaxel in albumin?
`
`A .
`
`Q.
`
`No, they were not.
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`What is the significance to you that as late as 2006,
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`Elan couldn't make a NanoCrystal version of paclitaxel in
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`albumin?
`
`A .
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`Well, because of the technology involved in the
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`milling process, I believe that a protein stabilizer such as
`
`albumin would not be very effective in making a
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`nanocrystalline because of the fact that it requires 120
`
`Apotex v. Abraxis - IPR2018-00l 52. Ex. 1Ol3. p.ll 0[222
`
`
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`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 12 of 222 PagelD #: 10206
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`hours of milling. The protein , typically , would not be a
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`very effective stabilizer under those conditions , having to
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`have to mill for that long a time.
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`Q.
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`Did you review any other documents regarding Elan's
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`efforts to make a NanoCrystal version of just paclitaxel in
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`general?
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`A .
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`Q.
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`Yes , I have.
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`Can you please bring up , Mr. Broyles, OD41.
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`Are you familiar with this interrogatory , this
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`is a legal question that Abraxis asked Elan?
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`A .
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`Q.
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`A .
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`Yes , I am.
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`What did Abraxis ask Elan?
`
`Abraxis asked Elan if they had made a NanoCrystal
`
`paclitaxel formulation.
`
`Q.
`
`A .
`
`Q.
`
`Are y o u familiar with Elan's answer to that?
`
`Yes.
`
`Can y o u bring up DD42, Mr. Broyles.
`
`Is this the answer that Elan gave that you are
`
`familiar with?
`
`A .
`
`Yes. This is the response to the interrogatory that ,
`
`for almost 20 years Elan has been trying to make
`
`nano crystalline paclitaxel. And these are the different
`
`types of products that have been tried.
`
`Q.
`
`And we have
`
`MR. SCHEVE: Your Honor , if I may , since the
`
`Apotex v. Abraxis - IPR201 8-00l 52. Ex. 1Ol3. p.12 0[ 222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 13 of 222 PagelD #: 10207
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`rules allow us under Rule 34 , in response to a discovery
`
`request , to provide citation to specific documents , I would
`
`ask that at least that be explained to the jury. Because
`
`what this is --
`
`THE COURT: Let me see counsel f o r a moment.
`
`(The following took place at sidebar.)
`
`THE COURT:
`
`I really don ' t want to get into
`
`having to describe and explain to the ladies and gentlemen
`
`of the jury the Federal Rules of Civil Procedure.
`
`It
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`shouldn't be necessary in the case.
`
`MS. KRUZE: Maybe I sho uld explain where I am
`
`going with this.
`
`Basically, what we want to do is we want to
`
`enter into evidence DX-44 , which is a compilation of all
`
`those d o cuments , which Elan, it's a party admission , has
`
`admitted with all their paclitaxel documents. That's what I
`
`am trying to get across.
`
`THE COURT: But is there something more
`
`expressive , more descriptive , more helpful that you might
`
`have ?
`
`MS. KRUZE: We have the documents.
`
`THE COURT:
`
`I am not sure the documents are
`
`helpful.
`
`I am not sure it is really worth the trouble. You
`
`try the case the way you want to try it.
`
`But why don ' t you react to this.
`
`Apotex v. Abraxis - IPR201 8-00l 52, Ex. 1Ol3, p.13 0[ 222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 14 of 222 PagelD #: 10208
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`MR. SCHEVE: My objection is they have shown an
`
`interrogatory answer where my client under Rule 33 and 34
`
`referred them to the specific documents in this list.
`
`THE COURT:
`
`I don't want a discovery dispute in
`
`front of the jury. Go ahead.
`
`MR. SCHEVE:
`
`So we would object that it is
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`prejudicial, it's confusing, under Rule 403 , to just put
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`that up, if the jury is not allowed to understand that we
`
`satisfied our discovery obligations.
`
`MS. KRUZE: My response is it is a party
`
`admission, Your Honor. We are entitled to use it in court.
`
`It is a binding response that Elan made.
`
`MR. SCHEVE: We don't deny that we made the
`
`response.
`
`It doesn't change the fact that it's confusing to
`
`the jury, likely to mislead the jury, when all you do is
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`show an answer to interrogatory that is five columns of
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`citations to Bates numbers of the documents that in any way
`
`might relate to what was done with paclitaxel.
`
`THE COURT:
`
`Is there a contention -- I guess
`
`it's not your contention that there was anything wrong
`
`procedurally with the response.
`
`It's, this is the response,
`
`and we want you to draw an inference from this response,
`
`directly from this response that they had difficulty.
`
`MS. KRUZE: My next question may clear this up.
`
`It was simply are these documents all collected in the
`
`Apotex v. Abraxis - IPR2018-001 52, Ex. 1Ol3, p.14 0[222
`
`
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`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 15 of 222 PagelD #: 10209
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`courtroom. Then they can just see the five boxes of
`
`documents. That way they don't have to focus on the
`
`numbers. The idea is that Elan tried very hard to do this.
`
`THE COURT: Do you object to them having a
`
`visual aid , the jury?
`
`MR. SCHEVE: No. That would be the next
`
`question , Your Honor.
`
`I take it question by question.
`
`I
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`was objecting to put up a discovery response.
`
`THE COURT:
`
`I am going to sustain the objection
`
`to this question.
`
`I understand what you are trying to do.
`
`I think you are entitled to do it. Quite frankly , I think
`
`it is a better avenue.
`
`Why don't you go ahead.
`
`(End of sidebar conference.)
`
`BY MS. KRUZE:
`
`Q.
`
`Dr. Amiji, if I could direct y o ur attention to DX-484 ,
`
`which is the five boxes
`
`THE COURT: We are going to take this down.
`
`BY MS. KRUZE:
`
`Q.
`
`There are five boxes of documents.
`
`I don't want to
`
`roll them into the courtroom.
`
`THE COURT: Ladies and gentlemen, may I see a
`
`banker ' s box , please? Would you display one to the jury
`
`that is representative of the boxes of documents that
`
`Ms. Kruze is referencing. Just hold it up , if you wo uld.
`
`Apotex v. Abraxis - IPR20l 8-00I S2. Ex. 1Ol3. p.IS 0[ 222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 16 of 222 PagelD #: 10210
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`(Banker's box held up.)
`
`That is a banker's box. That is what they are
`
`talking about , five of those filled with paper.
`
`BY MS. KRUZE:
`
`Q.
`
`Do these five boxes of documents, do they contain any
`
`failures that Elan had with paclitaxel?
`
`A .
`
`Q.
`
`Yes. There were a lot of failures.
`
`Did Elan disclose those five boxes of failures to the
`
`Patent Office?
`
`A .
`
`Q.
`
`A .
`
`No , they did not.
`
`Why is this important?
`
`Well, because , you know , in the patent itself , there
`
`is an example of the paclitaxel that did work , whereas you
`
`had all these other failures that were not disclosed.
`
`Q.
`
`Based on your review of all these Elan documents , how
`
`long has Elan been trying to make a NanoCrystal version of
`
`paclitaxel?
`
`A .
`
`Q.
`
`I believe it's been about 20 years now.
`
`Dr. Amiji, to summarize , can many of the possible
`
`combinations covered by the '363 patent form usable
`
`pharmaceutical compositions ?
`
`A .
`
`Q.
`
`No , they cannot.
`
`And in your opinion, will many of those combinations
`
`of drugs and surface modifiers fail to form usable
`
`compositions?
`
`Apotex v. Abraxis - IPR201 8-001 52. Ex. 1Ol3. p.16 0[ 222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 17 of 222 PagelD #: 10211
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`A .
`
`Q.
`
`Yes, they will.
`
`Do you have an opinion today that is relevant to the
`
`requirement that the '363 patent be enabled like we saw in
`
`the patent video?
`
`A .
`
`Q.
`
`Yes.
`
`And do you hold that opinion to a reasonable degree of
`
`scientific certainty?
`
`A .
`
`Q.
`
`Yes, I do.
`
`At the time the patent was filed, did the '363 patent
`
`enable ordinary scientists to make and use the claimed
`
`inventions without undue experimentation?
`
`A .
`
`Q.
`
`No, they wouldn't.
`
`Do you have an opinion today that is relevant to the
`
`requirement that the '363 patent have an adequate written
`
`description?
`
`A .
`
`Q.
`
`Yes, I do.
`
`Do you hold that opinion to a reasonable degree of
`
`scientific certainty?
`
`A .
`
`Q.
`
`A .
`
`Q.
`
`Yes, I do.
`
`Could you tell the jury what your opinion is?
`
`That it wouldn't enable.
`
`At the time the patent was filed, did the patent
`
`convey that Elan was actually in possession of the full
`
`scope of the patent claims?
`
`A .
`
`Yes.
`
`Apotex v. Abraxis - IPR2018-00l52 . Ex. 1Ol3. p.17 0[222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 18 of 222 PagelD #: 10212
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`Q.
`
`In other words, at the time the patent was filed , was
`
`Elan in possession of all the drug and surface modifier
`
`combinations?
`
`A .
`
`Q.
`
`No , they were not.
`
`And while the patent application was pending , did Elan
`
`tell the Patent Office about these bad tests that we
`
`reviewed or all the failures that you were speaking of?
`
`A .
`
`Q.
`
`No , they did not.
`
`And did these bad tests or failures contradict
`
`statements that Elan was making to the Patent Office?
`
`A .
`
`Q.
`
`Yes.
`
`Dr. Amiji, let's talk about contamination.
`
`Mr. Broyles, if you could bring up JX-81 on the
`
`screen, Column 6. Do you have testimony today relevant to
`
`the enablement requirement in terms of contamination?
`
`A .
`
`Q.
`
`Yes , I do.
`
`What is the method f o r making nanoparticles that's
`
`disclosed in the ' 363 patent?
`
`A .
`
`So the '363 patent mentions this grinding process , the
`
`wet grinding process , which uses the grinding media , and
`
`reduces the particle size from larger crystals into smaller
`
`crystals.
`
`Q.
`
`Could you bring up DD107, which is from Elan's
`
`website.
`
`Is this a depiction of how the large crystals
`
`Apotex v. Abraxis - IPR201 8-00l 52. Ex. 1Ol3. p.18 0[ 222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 19 of 222 PagelD #: 10213
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`become smaller?
`
`A .
`
`Q .
`
`Yes , it is.
`
`And if you could go to JX-81 again at Column 6. What
`
`types of instruments does the patent tell one to use to make
`
`these crystals go from smaller to -- or bigger to smaller?
`
`A .
`
`So it uses the milling equipment, which is a ball
`
`mill, and then there is the grinding media. The grinding
`
`media or these beads are made from zirconium oxide ,
`
`zirconium silicate , and glass.
`
`Q .
`
`And let's turn to Column 7. How long does the patent
`
`teach one to grind?
`
`A .
`
`In the simple screening method , for instance , it says
`
`up to 120 hours , which is more than five days.
`
`Q .
`
`A .
`
`Just to clarify for the jury , what is zirconium oxide?
`
`Zirconium o xide is a metal, a heavy-metal oxide.
`
`It
`
`has this oxygen and a heavy metal.
`
`Q .
`
`A .
`
`Silicate , what is that?
`
`Silicate is, again , a compound from silica. Silica is
`
`one of the major constituents of sand.
`
`Q .
`
`Do you have an animation that illustrates the
`
`manufacturing process of the '363 patent that wo uld help the
`
`jury ' s understanding?
`
`A .
`
`Q .
`
`Yes ,
`
`I do.
`
`Let's play that animation.
`
`Can you narrate what's happening?
`
`Apotex v. Abraxis - IPR201 8-001 52. Ex. 1Ol3. p.19 0[ 222
`
`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 20 of 222 PagelD #: 10214
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`A .
`
`This is Abraxane.
`
`Here is the animation, ladies and gentlemen , for
`
`the NanoCrystal technology based on the documents that I
`
`reviewed from Elan.
`
`This is the ball mill that we are talking about ,
`
`which has this report, and these are the grinding media that
`
`we have talked about. And these are about one to three
`
`millimeters in diameter. And they are put inside this ball
`
`mill. The report here is going to be the one that will
`
`basically create the tumbling action.
`
`The next thing here is the premix I which the
`
`inventors call the premix. That is basically water and
`
`these larger drug crystals. These are the starting material
`
`for making the NanoCrystal product. Here we start with
`
`larger crystals. These crystals are then suspended o r put
`
`in water. That's what leads to this premix ; the product
`
`that is then put inside the ball mill.
`
`Because of the size differences, we depict that
`
`as simply a green hue.
`
`Now we will see the starting of this ball mill.
`
`See them tumbling, the rotor is tumbling and these beads ,
`
`the larger grinding beads , are starting to then get
`
`suspended in the premix. As they get suspended , and they
`
`get in contact with the crystal, the drug crystal and these
`
`other grinding beads , they will start to collide with one
`
`Apotex v. Abraxis - IPR201 8-001 52. Ex. 1Ol3. p.20 0[ 222
`
`
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`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 21 of 222 PagelD #: 10215
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`another , as you see. And as these collide, they break up
`
`into smaller particles.
`
`That collision continues. This milling process
`
`continues for a long time. And each time this leads to more
`
`and more fragmentation of the crystals into smaller and
`
`smaller particles.
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`Eventually , it creating these very, very tiny
`
`particles or nanoparticles.
`
`Q.
`
`And those grinding beads, again, in terms of the '363
`
`patent, are made out of?
`
`A .
`
`Q.
`
`Zirconium o xide , zirconium silicate , or glass.
`
`Dr. Amiji, can milling with metal or glass beads cause
`
`any problems?
`
`A .
`
`Yes. Again, this milling procedure , especially
`
`because it is ongo ing f o r such a long time, will cause
`
`contamination.
`
`Q.
`
`A .
`
`that.
`
`Q.
`
`A .
`
`How d o es this c o ntamination occur exactly?
`
`So here , again, we have an animation that illustrates
`
`Let's play that.
`
`So the animation here will show you exactly h o w the
`
`contamination occurs. So we are starting here from where we
`
`left off in the previous animation. The grinding media and
`
`the ball mill with the crystals being basically broken into
`
`smaller and smaller fragments.
`
`Apotex v. Abraxis - IPR201 8-00l 52. Ex. 1Ol3. p.2 l 0[ 222
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`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 22 of 222 PagelD #: 10216
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`But as you enlarge this I what you observe is
`
`that , yes, there is going to be decrease in the size of the
`
`crystals. But at the same time, these grinding media will
`
`collide with each other. As they collide with each other ,
`
`they fragment as well. Especially as you get into longer
`
`and longer time po ints.
`
`So this grinding media colliding with each other
`
`causes the contamination because of these metal and glass
`
`grinding media that is present inside this ball mill.
`
`Q.
`
`What were those white flakes or silver flakes that we
`
`just saw?
`
`A .
`
`That is the contamination that occurs because of the
`
`fact that two grinding, two or more grinding media colliding
`
`with each other.
`
`Q.
`
`What are some of the problems with contamination in
`
`pharmaceutical compositions ?
`
`A .
`
`Contamination is a big problem in pharmaceuticals
`
`because you clearly want this product to be safe and
`
`effective. And safety, not only from the drug point of
`
`view, but from the purity and from the quality control point
`
`of view. You want to make sure that the product will not
`
`have any contamination, any type of c o ntaminatio n.
`
`Pharmaceutical products , especially those are intended for
`
`administration into the bloodstream you really have to be
`
`very careful about making sure that the quality is as pure
`
`Apotex v. Abraxis - IPR201 8-001 52. Ex. 1Ol3. p.22 0[ 222
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`
`
`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 23 of 222 PagelD #: 10217
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`and as best as possible.
`
`Q.
`
`When we are talking about intravenous administration ,
`
`things that go directly into the bloodstream , are the risks
`
`greater with contamination?
`
`A .
`
`Yes , they are , because, first of all, the FDA requires
`
`a much more stringent requirement for any product that is
`
`given into the bloodstream. And the reason is you don't
`
`have any way to reverse the problems.
`
`If you take a pill orally , one could easily
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`either give another product and have that drug stop being
`
`absorbed. But once you give a product in the bloodstream ,
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`it is always going to be there. There is not an oppo rtunity
`
`to take that product out.
`
`The other thing is that contamination in
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`product , in pharmaceutical product, even if it o ccurs in one
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`product , one vial o f a large number of vials , it is not
`
`possible to tell which vial has that contamination and the
`
`patient who will get that.
`
`So it is an unpredictable event and you don't
`
`want that kind of risk.
`
`Q.
`
`What about with drugs that are administered routinely ,
`
`like most anticancer drugs ?
`
`A .
`
`Again , the problem of contamination becomes even more
`
`magnified , because once you give a product, as it is given
`
`continuously to patients, what y ou find is that the
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`Apotex v. Abraxis - IPR201 8-001 52. Ex. 1Ol3. p.23 0[ 222
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`Case 1:06 cv-00438-GMS Document 625 Filed 06/24/08 Page 24 of 222 PagelD #: 10218
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`Amiji - cross
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`contaminant level starts to increase in the body. And
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`especially in the cases