Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 1 of 222 PageID #: 10195
`1408
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`:
`
`Civil Action
`
`ELAN PHARMA INTERNATIONAL
`LIMITED,
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`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-
`GREGORY BOKAR, ESQ.
`Counsel - Elan Drug Delivery
`Counsel for Plaintiff
`
`CIPLA EXHIBIT 1013
`Page 1 of 222
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`1408
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`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`:
`
`Civil Action
`
`ELAN PHARMA INTERNATIONAL
`LIMITED,
`
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`::
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`::
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`::
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`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-
`GREGORY BOKAR, ESQ.
`Counsel - Elan Drug Delivery
`Counsel for Plaintiff
`
`CIPLA EXHIBIT 1013
`Page 1 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 2 of 222 PageID #: 10196
`1409
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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, CA)
`Counsel for Defendant
`
`- - - - -
`THE COURT:
`Good morning.
`(Counsel respond "Good morning.")
`THE COURT:
`I understand we have an issue.
`MR. JACOBS: A couple of things, Your Honor.
`THE COURT:
`I hope they are short.
`MR. JACOBS: Two are short and one may take a
`few minutes. No. 1, we have reached a stipulation on a
`person of ordinary skill in the art.
`THE COURT:
`Good. I was wondering whether we
`were going to hear about that mystic person.
`MR. JACOBS: Procedurally, Your Honor, would you
`like Ms. Kruze to read it? It would have come up in
`Dr. Amiji's testimony. Ms. Kruze could just read the
`stipulation into the record, if that would be appropriate.
`MR. SCHEVE: Fine.
`
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`MR. JACOBS: No. 2, documents in evidence. How
`do we work? I am still a little confused.
`I know we have
`heard several times how this is supposed to work but we are
`at the level of mechanics, understanding what is in and what
`isn't, especially documents that are --
`THE COURT:
`All objections were overruled to
`documentary exhibits, unless raised again.
`I have not
`entertained any additional objections.
`So it's in.
`MR. JACOBS: On the original exhibits list, all
`those exhibits are in evidence.
`THE COURT:
`Are in. What you want the jury to
`consider is another matter. Is that where we are going with
`this?
`
`MR. JACOBS: No. I think there are documents --
`THE COURT:
`For your record, they are in.
`MR. JACOBS: For closing --
`THE COURT:
`That's evidence.
`MR. JACOBS: Terrific.
`THE COURT:
`Mr. Scheve, do you have any
`
`questions?
`
`MR. SCHEVE: That's exactly what I have
`understood, Your Honor.
`MR. JACOBS: Dr. Brittain, two alternative
`paths, from our standpoint.
`No. 1, we put him on the stand, he is here in
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 4 of 222 PageID #: 10198
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`the courtroom, by the way. We put him on the stand, and we
`examine him pursuant to the second Bench memo we filed
`yesterday, in which we elicit only -- I can hand Your Honor
`a copy.
`
`I got it yesterday, you say?
`THE COURT:
`MR. JACOBS: Yes. We didn't focus on it
`
`yesterday.
`
`Mr. Scheve?
`
`Honor.
`
`THE COURT:
`
`Have you seen the Bench memo,
`
`MR. SCHEVE: Yes.
`MR. JACOBS: We gave it to them yesterday, Your
`
`The main point of this Bench memo, Your Honor,
`is that when we ask him questions, we do not want him
`volunteering, we do not want counsel for Elan eliciting
`testimony beyond the specific and narrow facts that are
`already in the record from his deposition or from the
`documents.
`
`You know, counsel and those in the
`THE COURT:
`well, you can sit. It seems like this is going to take a
`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
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 5 of 222 PageID #: 10199
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`for Elan should be allowed to elicit additional testimony
`about what he did because he was instructed not to answer a
`whole range of questions about what he actually did at his
`deposition.
`
`Actually, the second path is that we do not put
`Dr. Brittain on the stand, and the Court explains to the
`jury what happened with the privilege log and why we are
`where we are. I prepared and gave to counsel for Elan
`yesterday a proposed statement from the Bench that would
`just lay out, very briefly, lay out exactly what happened.
`That way, we don't have to deal with uncertainties about
`what Dr. Brittain might say when he testifies on this issue.
`THE COURT:
`I got to believe that Mr. Scheve
`probably doesn't want the jury hearing about that from me.
`Maybe I am wrong about that.
`MR. SCHEVE: Well, after all day yesterday
`asking witnesses, What did you have for breakfast?, and
`hearing, Well, I had eggs right next to an order of
`amorphous paclitaxel contained in Abraxis, all day, and now
`to have counsel say, We really don't want any gratuitous
`answers, or to go beyond -- they are now the sponsoring
`witness, Your Honor. There is no expert report from him.
`If they are going to ask fact questions, you know, it's my
`decision, I would think, whether or not I wade into
`something.
`I will be very cautious about that. The idea
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 6 of 222 PageID #: 10200
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`that counsel can say, in advance, that I am restricted to
`what I may ask --
`I am not going to do that,
`THE COURT:
`Mr. Jacobs. You will have to object.
`MR. JACOBS: To be clear, Mr. Scheve instructed
`Dr. Brittain at his deposition not to answer additional
`questions.
`
`I think both sides know what the
`THE COURT:
`issue is with Dr. Brittain. We have had an extensive
`discussion about this. I am tired of it. Let's move on.
`Let's get this trial back underway.
`Ms. Walker, bring in this jury.
`MR. SCHEVE: I do have an issue, Your Honor.
`They have tendered something they want to either read to the
`jury or give to them that talks about your ruling that says,
`Your Honor has ruled --
`That was the second path that he was
`THE COURT:
`just talking about.
`Right?
`MR. SCHEVE: They have offered an instruction
`which would --
`I just rejected --
`THE COURT:
`MR. SCHEVE: It is a separate issue. On this
`inference, they have offered an instruction, and they also
`now want to read or show the jury, in writing, that Your
`Honor has found that Elan, my client, has willfully or
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 7 of 222 PageID #: 10201
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`inference.
`
`wrongfully --
`We are not going to do that, either.
`THE COURT:
`MR. SCHEVE: It would be two comments on the
`That should be in the jury instructions.
`THE COURT:
`That is where it will be.
`MR. JACOBS: I need to know what you have
`decided on the jury instructions.
`THE COURT: Are you talking about the final jury
`instructions?
`MR. JACOBS: I am sorry, Your Honor. I thought
`you said to Mr. Scheve, on the jury instructions --
`THE COURT:
`I am instructing this jury at this
`point on Dr. Brittain. I am going to give an instruction on
`the final jury instruction -- you are going to be trial
`lawyers and we are going to try this case with this witness
`on the stand. You will interpose objections. I will rule
`on those objections. It is not unduly complicated.
`MS. KRUZE:
`Your Honor, shall I read into the
`record the person of ordinary skill?
`THE COURT:
`Don't you want the jury to hear it?
`MS. KRUZE:
`Yes.
`THE COURT:
`I certainly would like to hear it.
`I think the jury would like to hear it.
`We had a witness on the stand, Dr. Amiji.
`Dr. Amiji, please.
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 8 of 222 PageID #: 10202
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`Good morning.
`Doctor, you are still under oath.
`(Jury enters courtroom at 9:07 a.m.)
`THE COURT:
`Good morning on yet another hot day,
`ladies and gentlemen. Have a seat. You will be comfortable
`today, hopefully.
`Ms. Kruze, you may continue with Dr. Amiji.
`... MANSOOR AMIJI, having been previously sworn
`as a witness, was examined and testified further as.
`follows...
`
`THE COURT:
`
`Do you want to start out with a
`
`stipulation?
`
`We have arrived at one of those stipulations I
`talked with you about in the preliminary instructions, that
`is an agreement, one of those rare events in this case
`between the parties. Ms. Kruze is now going to tell you who
`the ordinary person of skill in the art is, that is, give
`you the definition of this person you have heard about, this
`person of skill.
`The person of ordinary skill in the
`MS. KRUZE:
`art would have a Ph.D. or the equivalent in pharmaceutical
`sciences, chemistry, chemical engineering, or biological
`sciences, and at least two years of practical experience in
`formulating drug compositions at the time the application
`for the '363 patent was filed.
`Alternatively, the person of ordinary skill in
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 9 of 222 PageID #: 10203
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`Amiji
`the art could be someone with a Master's degree in
`pharmaceutical sciences, or the equivalent, with two or more
`years of practical experience, specifically in the
`development of nanoparticulate pharmaceutical compositions.
`THE COURT:
`Let me see counsel for just a second
`before I say what I am thinking about saying. It doesn't
`need to be on the record.
`(Sidebar conference not reported.)
`THE COURT:
`Perhaps Ms. Kruze will direct you to
`You don't have to worry about having made notes
`the place.
`as to that definition. It has been or will be provided to
`you.
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`DIRECT EXAMINATION CONTINUED
`
`BY MS. KRUZE:
`Good morning, Dr. Amiji.
`Q.
`Good morning, Ms. Kruze.
`A.
`Yesterday we were discussing enablement of the patent
`Q.
`relating to drug and surface modifier combinations. I
`believe where we left off was Defendant's Exhibit 193. This
`was the memo from Sarptodar and your comparison of that memo
`to the patent claims.
`Yes.
`A.
`And we were discussing, did the patent applicants
`Q.
`disclose, for example, that Tween 80 reached 3,000
`nanometers?
`
`CIPLA EXHIBIT 1013
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 10 of 222 PageID #: 10204
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`Amiji - cross
`
`No, they did not.
`A.
`Let's take a quick look at what the patentees did tell
`Q.
`the Patent Office.
`That's JX-81 at Columns 3 through 4. I
`believe it's in Column 4, in the second paragraph.
`Did the patentees tell the Patent Office that
`Tween 80 was a particularly preferred surface modifier?
`Yes, they did.
`A.
`But internally, that surface modifier had failed?
`Q.
`That's correct, yes.
`A.
`Let's switch to DD106.
`Q.
`Did you review any other documents regarding
`Elan's efforts to make a nano-piposulfan product?
`Yes, I reviewed several other documents.
`A.
`Could you read some of the statements that you found
`Q.
`in those documents?
`This, for the record, is JX-47, JX-55,
`JX-81, DX-258 and DX-286.
`MR. SCHEVE: Your Honor, I object to just
`reading documents.
`It's inappropriate form.
`THE COURT:
`I will sustain the objection.
`BY MS. KRUZE:
`Did you review any other documents regarding Elan's
`Q.
`efforts to make a piposulfan project?
`Yes, I did.
`A.
`What did those documents say to you?
`Q.
`So here we can see from the different time points, we
`A.
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 11 of 222 PageID #: 10205
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`Amiji - cross
`have, in the case of August of '92, the '363 inventors
`discuss that piposulfan is physically unstable.
`In '93, the
`inventors of piposulfan, was difficult to stabilize. In '96
`here, again, same problems with generating a stable
`nanocrystalline suspension proved to be challenging.
`In '96, formulation does have its problems.
`And even today, in 2008, we still do not have a
`nano-piposulfan product.
`Dr. Amiji, did Elan also try to make a NanoCrystal
`Q.
`formulation of paclitaxel using albumin?
`Yes.
`A.
`Did you review laboratory notebooks regarding those
`Q.
`experiments?
`Yes, I reviewed several different laboratory
`A.
`notebooks.
`Was Elan successful in making a NanoCrystal version of
`Q.
`paclitaxel in albumin?
`No, they were not.
`A.
`What is the significance to you that as late as 2006,
`Q.
`Elan couldn't make a NanoCrystal version of paclitaxel in
`albumin?
`Well, because of the technology involved in the
`A.
`milling process, I believe that a protein stabilizer such as
`albumin would not be very effective in making a
`nanocrystalline because of the fact that it requires 120
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 12 of 222 PageID #: 10206
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`Amiji - cross
`hours of milling. The protein, typically, would not be a
`very effective stabilizer under those conditions, having to
`have to mill for that long a time.
`Did you review any other documents regarding Elan's
`Q.
`efforts to make a NanoCrystal version of just paclitaxel in
`general?
`Yes, I have.
`A.
`Can you please bring up, Mr. Broyles, DD41.
`Q.
`Are you familiar with this interrogatory, this
`is a legal question that Abraxis asked Elan?
`Yes, I am.
`A.
`What did Abraxis ask Elan?
`Q.
`Abraxis asked Elan if they had made a NanoCrystal
`A.
`paclitaxel formulation.
`Are you familiar with Elan's answer to that?
`Q.
`Yes.
`A.
`Can you bring up DD42, Mr. Broyles.
`Q.
`Is this the answer that Elan gave that you are
`familiar with?
`Yes.
`This is the response to the interrogatory that,
`A.
`for almost 20 years Elan has been trying to make
`nanocrystalline paclitaxel. And these are the different
`types of products that have been tried.
`And we have --
`Q.
`MR. SCHEVE: Your Honor, if I may, since the
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 13 of 222 PageID #: 10207
`1420
`Amiji - cross
`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 --
`Let me see counsel for a moment.
`THE COURT:
`(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
`shouldn't be necessary in the case.
`MS. KRUZE:
`Maybe I should 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 documents, which Elan, it's a party admission, has
`admitted with all their paclitaxel documents. That's what I
`am trying to get across.
`But is there something more
`THE COURT:
`expressive, more descriptive, more helpful that you might
`have?
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`We have the documents.
`MS. KRUZE:
`I am not sure the documents are
`THE COURT:
`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.
`
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`Amiji - cross
`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
`prejudicial, it's confusing, under Rule 403, to just put
`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
`It doesn't change the fact that it's confusing to
`response.
`the jury, likely to mislead the jury, when all you do is
`show an answer to interrogatory that is five columns of
`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
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`1422
`Amiji - cross
`Then they can just see the five boxes of
`courtroom.
`That way they don't have to focus on the
`documents.
`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
`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:
`Dr. Amiji, if I could direct your attention to DX-484,
`Q.
`which is the five boxes --
`THE COURT:
`We are going to take this down.
`BY MS. KRUZE:
`There are five boxes of documents.
`Q.
`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 would.
`
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`CIPLA EXHIBIT 1013
`Page 15 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 16 of 222 PageID #: 10210
`1423
`Amiji - cross
`(Banker's box held up.)
`That is what they are
`That is a banker's box.
`talking about, five of those filled with paper.
`BY MS. KRUZE:
`Do these five boxes of documents, do they contain any
`Q.
`failures that Elan had with paclitaxel?
`Yes.
`There were a lot of failures.
`A.
`Did Elan disclose those five boxes of failures to the
`Q.
`Patent Office?
`No, they did not.
`A.
`Why is this important?
`Q.
`Well, because, you know, in the patent itself, there
`A.
`is an example of the paclitaxel that did work, whereas you
`had all these other failures that were not disclosed.
`Based on your review of all these Elan documents, how
`Q.
`long has Elan been trying to make a NanoCrystal version of
`paclitaxel?
`I believe it's been about 20 years now.
`A.
`Dr. Amiji, to summarize, can many of the possible
`Q.
`combinations covered by the '363 patent form usable
`pharmaceutical compositions?
`No, they cannot.
`A.
`And in your opinion, will many of those combinations
`Q.
`of drugs and surface modifiers fail to form usable
`compositions?
`
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`CIPLA EXHIBIT 1013
`Page 16 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 17 of 222 PageID #: 10211
`1424
`Amiji - cross
`
`Yes, they will.
`A.
`Do you have an opinion today that is relevant to the
`Q.
`requirement that the '363 patent be enabled like we saw in
`the patent video?
`Yes.
`A.
`And do you hold that opinion to a reasonable degree of
`Q.
`scientific certainty?
`Yes, I do.
`A.
`At the time the patent was filed, did the '363 patent
`Q.
`enable ordinary scientists to make and use the claimed
`inventions without undue experimentation?
`No, they wouldn't.
`A.
`Do you have an opinion today that is relevant to the
`Q.
`requirement that the '363 patent have an adequate written
`description?
`Yes, I do.
`A.
`Do you hold that opinion to a reasonable degree of
`Q.
`scientific certainty?
`Yes, I do.
`A.
`Could you tell the jury what your opinion is?
`Q.
`That it wouldn't enable.
`A.
`At the time the patent was filed, did the patent
`Q.
`convey that Elan was actually in possession of the full
`scope of the patent claims?
`Yes.
`A.
`
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`CIPLA EXHIBIT 1013
`Page 17 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 18 of 222 PageID #: 10212
`1425
`Amiji - cross
`In other words, at the time the patent was filed, was
`Q.
`Elan in possession of all the drug and surface modifier
`combinations?
`No, they were not.
`A.
`And while the patent application was pending, did Elan
`Q.
`tell the Patent Office about these bad tests that we
`reviewed or all the failures that you were speaking of?
`No, they did not.
`A.
`And did these bad tests or failures contradict
`Q.
`statements that Elan was making to the Patent Office?
`Yes.
`A.
`Dr. Amiji, let's talk about contamination.
`Q.
`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?
`Yes, I do.
`A.
`What is the method for making nanoparticles that's
`Q.
`disclosed in the '363 patent?
`So the '363 patent mentions this grinding process, the
`A.
`wet grinding process, which uses the grinding media, and
`reduces the particle size from larger crystals into smaller
`crystals.
`Could you bring up DD107, which is from Elan's
`Q.
`website.
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`Is this a depiction of how the large crystals
`
`CIPLA EXHIBIT 1013
`Page 18 of 222
`
`
`
`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 19 of 222 PageID #: 10213
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`Amiji - cross
`
`become smaller?
`Yes, it is.
`A.
`And if you could go to JX-81 again at Column 6. What
`Q.
`types of instruments does the patent tell one to use to make
`these crystals go from smaller to -- or bigger to smaller?
`So it uses the milling equipment, which is a ball
`A.
`mill, and then there is the grinding media.
`The grinding
`media or these beads are made from zirconium oxide,
`zirconium silicate, and glass.
`And let's turn to Column 7. How long does the patent
`Q.
`teach one to grind?
`In the simple screening method, for instance, it says
`A.
`up to 120 hours, which is more than five days.
`Just to clarify for the jury, what is zirconium oxide?
`Q.
`Zirconium oxide is a metal, a heavy-metal oxide. It
`A.
`has this oxygen and a heavy metal.
`Silicate, what is that?
`Q.
`Silicate is, again, a compound from silica.
`A.
`one of the major constituents of sand.
`Do you have an animation that illustrates the
`Q.
`manufacturing process of the '363 patent that would help the
`jury's understanding?
`Yes, I do.
`A.
`Let's play that animation.
`Q.
`Can you narrate what's happening?
`
`Silica is
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`CIPLA EXHIBIT 1013
`Page 19 of 222
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`
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 20 of 222 PageID #: 10214
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`Amiji - cross
`
`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, 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 or 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
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`CIPLA EXHIBIT 1013
`Page 20 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 21 of 222 PageID #: 10215
`1428
`Amiji - cross
`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.
`Eventually, it creating these very, very tiny
`particles or nanoparticles.
`And those grinding beads, again, in terms of the '363
`Q.
`patent, are made out of?
`Zirconium oxide, zirconium silicate, or glass.
`A.
`Dr. Amiji, can milling with metal or glass beads cause
`Q.
`any problems?
`Yes. Again, this milling procedure, especially
`A.
`because it is ongoing for such a long time, will cause
`contamination.
`How does this contamination occur exactly?
`Q.
`So here, again, we have an animation that illustrates
`A.
`that.
`Let's play that.
`Q.
`So the animation here will show you exactly how the
`A.
`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.
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`CIPLA EXHIBIT 1013
`Page 21 of 222
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`
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 22 of 222 PageID #: 10216
`1429
`Amiji - cross
`But as you enlarge this, 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 points.
`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.
`What were those white flakes or silver flakes that we
`Q.
`just saw?
`That is the contamination that occurs because of the
`A.
`fact that two grinding, two or more grinding media colliding
`with each other.
`What are some of the problems with contamination in
`Q.
`pharmaceutical compositions?
`Contamination is a big problem in pharmaceuticals
`A.
`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 contamination.
`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
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`CIPLA EXHIBIT 1013
`Page 22 of 222
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`
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 23 of 222 PageID #: 10217
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`Amiji - cross
`and as best as possible.
`When we are talking about intravenous administration,
`Q.
`things that go directly into the bloodstream, are the risks
`greater with contamination?
`Yes, they are, because, first of all, the FDA requires
`A.
`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
`either give another product and have that drug stop being
`absorbed.
`But once you give a product in the bloodstream,
`it is always going to be there. There is not an opportunity
`to take that product out.
`The other thing is that contamination in
`product, in pharmaceutical product, even if it occurs in one
`product, one vial of 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.
`What about with drugs that are administered routinely,
`Q.
`like most anticancer drugs?
`Again, the problem of contamination becomes even more
`A.
`magnified, because once you give a product, as it is given
`continuously to patients, what you find is that the
`
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`CIPLA EXHIBIT 1013
`Page 23 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 24 of 222 PageID #: 10218
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`contaminant level starts to increase in the body. And
`especially in the cases like zirconium, which concentrates
`in organs like the ovaries, the contamination will start to
`increase in those organ systems.
`Let's start with the patent and pull up DD-102. Does
`Q.
`the patent require that the particles be free of
`contamination?
`Yes, it does.
`A.
`And do the patent examples in the '363 patent disclose
`Q.
`the level of contamination?
`No, there is not any mention of contamination in the
`A.
`patent examples.
`Let's pull up JX-81. Let's go to Column 8, second
`Q.
`paragraph.
`
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`Were you here in the courtroom when
`Dr. Liversidge testified to some sort of cleaning method?
`Yes, I was.
`A.
`What was he referring to?
`Q.
`So in the example, Example 1, there is a cleaning
`A.
`method that is present. And this cleaning method is using
`sulfuric acid, I think further down.
`That looks like it.
`I think it's around -- there.
`Q.
`It says the zirconium
`So it starts out right here.
`A.
`oxide beads are first cleaned using one normal sulfuric acid
`and rinsing with several rinses of deionized water.
`
`CIPLA EXHIBIT 1013
`Page 24 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 25 of 222 PageID #: 10219
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`This cleaning method is going to clean the beads
`before they are put into the grinding media, but it doesn't
`stop the grinding media from colliding with each other and
`producing this contamination.
`Is this sufficient to avoid contamination?
`Q.
`No, it is not.
`A.
`Dr. Amiji, did you review any internal documents
`Q.
`regarding contamination problems that Elan was having?
`Yes, I did.
`A.
`And what did these documents show?
`Q.
`They showed significant levels of contamination,
`A.
`especially zirconium, silica, and other types of metal
`contamination.
`Let's go to DD110. Dr. Amiji, you can turn to DX-243,
`Q.
`also.
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`What did Elan's toxicology department tell the
`patent applicants?
`So here is a memo from the toxicology department
`A.
`saying that zirconium oxide and zirconium silicate are
`acceptable in one record, but then they cause the zirconium
`levels that are produced, that accumulates in the organs,
`such as the ovaries.
`Just to confirm for the jury, I don't think that
`Q.
`zirconium oxide is acceptable because --
`Correct. Yes, I don't think that zirconium oxide is
`A.
`
`CIPLA EXHIBIT 1013
`Page 25 of 222
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`Case 1:06-cv-00438-GMS Document 625 Filed 06/24/08 Page 26 of 222 PageID #: 10220
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`
`acceptable.
`So Elan's toxicology department was telling the
`Q.
`patentees that this type of technology was not acceptable?
`That's correct, yes.
`A.
`And can you confirm that the date of this is 1990?
`Q.
`Yes, it is. It is the September 12th, 1990.
`A.
`Let's turn to DD1?
`Can you tell the jury what this
`Q.
`is?
`These are other memos and other documents from Elan.
`A.
`Again, looking at the issue of toxicology of various
`contaminants from these grinding media. ZR stands for
`zirconia.
`It says toxicology has recommended the non-use of
`zirconium grinding media. This leaves us with glass as an
`acceptable alternative. At the bottom you can see it says
`high levels of lead being found in dispersions from the
`lead-free glass. Even in the case of lead-free glass,
`because of this long milling period, t
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