1
`
`1
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`Civil No.
`JANSSEN PRODUCTS, L.P., et al., :
`10-cv-5954(WHW)
`Plaintiffs,
`:
`TRANSCRIPT OF
`: TRIAL PROCEEDINGS
`v.
`:
`LUPIN LIMITED, et al.,
`VOLUME 1
`:
`Defendants.
`--------------------------------x
`
`Newark, New Jersey
`March 18, 2014
`
`BEFORE:
`
`THE HON. WILLIAM H. WALLS, U.S.D.J.
`
`Reported by:
`CHARLES P. McGUIRE, C.C.R.
`Official Court Reporter
`
`Pursuant to Section 753, Title 28, United States
`Code, the following transcript is certified to be
`an accurate record as taken stenographically in
`the above entitled proceedings.
`
`s/CHARLES P. McGUIRE, C.C.R.
`
`CHARLES P. McGUIRE, C.C.R.
`
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`Lupin Ex. 1024 (Page 1 of 35)
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`THE COURT: I expect both sides to be wary and
`alert to the interests of their clients insofar as any
`alleged trade secrets are concerned. I shall rely upon
`their competence, and at this point, there's not been
`demonstrated to me any need to say I will close the
`courtroom to people, to members of the public.
`As a matter of fact, from a very practical
`standpoint, I doubt any members of the public, given the
`choice, would be sitting in. All right?
`MS. MAZZOCHI: I understand that, Your Honor.
` Thank you.
`THE COURT: Now, can I now turn to the motions in
`
`limine?
`
`MS. MAZZOCHI: Yes.
`THE COURT: I told you we will take them in the
`order in which I will deal with them because that will be
`easier for everyone.
`MS. MAZZOCHI: Thank you, Your Honor.
`THE COURT: All right.
`MS. MAZZOCHI: Although if it would be easier,
`Your Honor, one thing that we did want to suggest is that
`because there's a small number, only one or two witnesses
`that are potentially going today and tomorrow, we would be
`willing to address certain things when we get closer to
`that.
`
`CHARLES P. McGUIRE, C.C.R.
`
`31
`THE COURT: With regard to tomorrow, I have some
`other matters that will occupy me, and I don't think I can
`-- what's tomorrow; Wednesday, right?
`And I don't think I can start and get you until
`about 11, between 11 and 11:30. I have some sentences.
`Yes?
`MR. DISKANT: Your Honor, I would join with the
`view that the in limine's be put off until we need them.
` My concern is, we have two witnesses this week.
`Dr. Stoffels is our first witness, and he'll be on maybe an
`hour and a half or so, but our next witness, Piet Wigerinck,
`does not work for our company, he came over from Belgium to
`testify, and I'm very concerned, since we're not sitting on
`Thursday, about whether we can get in all of this testimony
`and cross-examination. So I was going to ask --
`THE COURT: So you join in seeking that we
`postpone the determination of the in limine matters; is that
`right?
`
`MR. DISKANT: Yes, I do, Your Honor. And I may
`ask if Your Honor can sit late, depending on how we go.
`We'll see how the day goes.
`THE COURT: Well, I expect to sit until 4:30
`
`today.
`
`MR. DISKANT: Okay.
`THE COURT: Is that all right?
`CHARLES P. McGUIRE, C.C.R.
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`MR. DISKANT: Thank you.
`THE COURT: If that be the case, do you wish to
`make your opening statements, or do you want to forego
`those, too?
`MR. DISKANT: I was going to make an opening.
` Should I forego it? I'll make --
`THE COURT: If you would be willing to make the
`sacrifice.
`(Laughter)
`MR. DISKANT: I'll make an opening, but I'll be --
`MR. RAKOCZY: One quick housekeeping matter, Your
`
`Honor.
` William Rakoczy for the Mylan Lupin Defendants.
`THE COURT: Yes.
`MR. RAKOCZY: How would Your Honor like to handle
`objections to exhibits and demonstratives for each
`particular witness; s they come, or before?
`THE COURT: Well, upon their proffer.
`MR. RAKOCZY: Pardon?
`THE COURT: Upon their proffer.
`MR. RAKOCZY: Okay. Thank you, Judge.
`THE COURT: So are we going to have opening
`remarks now?
`MR. DISKANT: Yes, sir.
`THE COURT: Is that why you brought everybody from
`CHARLES P. McGUIRE, C.C.R.
`
`33
`
`the firm?
`MR. DISKANT: There are a couple back there.
`THE COURT: All right. Let's go. Go ahead, sir.
`MR. DISKANT: Thank you.
`At any rate, Judge, we're very, very pleased to be
`here today, finally, after a long time in discovery for what
`is for us a very, very important case.
` Janssen, the Plaintiff, is the pharmaceutical arm
`of Johnson & Johnson, the world's largest health care
`company, and the drug that we're talking about is called
`Prezista, which is the leading protease inhibitor in the
`market. You're going to hear a lot about what that means,
`but basically, there's a cycle to the HIV virus, and
`scientists have attempted to intervene at many places along
`the cycle. The protease is one of them, and if you can
`block the protease, you can inhibit it, you can stop the
`virus from replicating, and that's what this drug does. It
`has sold $1.7 billion in sales last year, one million
`prescriptions. It's keeping people alive for years with no
`detectable trace of HIV in their body, something that would
`have been unheard of a generation ago.
`We remember the AIDS -- the Defendants, of course,
`are Mylan, Lupin, and Teva.
`The AIDS crisis of the 80's was a horrifying time
`for all of us who lived through it. It seemed like the
`CHARLES P. McGUIRE, C.C.R.
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`38
`familiar with them from the motions. One is on making this
`bis-THF, the left-hand side of the molecule; one is on
`making the whole molecule and tacking on the bis-THF, and
`one is making the ethanolate form of the molecule.
`All of this work was supervised by Dr. Piet
`Wigerinck, who will also be here to testify from Belgium,
`and in all cases, he came up with a formulation that went
`against the conventional wisdom and that resulted in a pure
`and efficacious commercial-scale process.
`Very simply, I'll review the three patents and our
`claims and sit down.
`Bis-THF is the first patent. This is the
`left-hand side. It's got three chiral centers. It's very
`difficult to fabricate, covered by the '015 patent, and Your
`Honor has found that both Teva and Lupin infringed that
`patented process precisely. So there's no infringement
`issue in the case. The only issue in the case is the
`validity of the '015 patent, and we will show that it is a
`novel patent, it is not something that's taught in the prior
`art, it starts with an unstable intermediate, it's not
`commercially available, it goes through a nitromethane step
`that is dangerous, it provides exquisite stereoselectivity
`so that it's possible to get exactly the right bis-THF that
`works in the fight against AIDS.
`The next patent is the '411 patent. That's on
`CHARLES P. McGUIRE, C.C.R.
`
`39
`darunavir synthesis, also designed by Pete Wigerinck. Your
`Honor has already found that Mylan infringes that patent,
`meaning the only issue for trial is going to be the validity
`of this patent, and this patent also is a valid patent. It
`is different than anything in the prior art. There were
`three prior processes. This is better and innovative. It
`uses a protecting group that increases the yield, that uses
`a novel coupling agent, that increases the yield even
`further and yields a pure product suitable for commercial
`manufacture.
`And the last of the patents is the ethanolate
`patent. The ethanolate is a crystal structure that's very
`unusual, depicting here the crystal structure with channels
`running through it. The channels contain ethanol, making it
`ethanolate. And basically, we have claims against all three
`Defendants on the ethanolate patent.
`Lupin admits that it uses darunavir ethanolate.
`Teva makes a darunavir hydrate, which it claims is different
`and we claim is equivalent. And Mylan makes, according to
`its published patent application, an amorphous form of
`darunavir which we contend contains traces of ethanolate
`because it starts with the ethanolate and can't get rid of
`them.
`
`The issues for trial are going to be whether
`that's infringed and also whether the patent is valid. We
`CHARLES P. McGUIRE, C.C.R.
`
`11
`
`40
`say and the proof will show that it is a novel and unusual
`form of a crystalline structure, a valid patent.
`That's basically it. We've sold a million
`prescriptions last year, keeping people alive, and we would
`like to keep on doing that under our patents.
`Thank you, Judge.
`THE COURT: Thank you.
`Who do I -- yes, sir.
`MR. RAKOCZY: Good morning, Your Honor.
` William Rakoczy again for the Mylan and the Lupin
`Defendants.
`Your Honor, we submit the evidence will require a
`finding of noninfringement for Mylan on the '645 patent.
`Mylan does mount an noninfringement defense to that patent,
`and the evidence will also clearly and convincing show that
`all three patents against Mylan and Lupin are invalid for,
`amongst other reasons, obviousness, which is the defense
`I'll focus on. There are other defenses in the pretrial
`order and that you will hear about from the experts.
`Your Honor obviously knows about the asserted
`claims of the patents-in-suit. I will just note for the
`record, Your Honor, from the proceedings yesterday, again,
`our understanding is now it's just 1 and 4 from the '645, 1,
`claim 1 from the '015 and claim 13 from the '411. My
`understanding is all claims will be dismissed with prejudice
`CHARLES P. McGUIRE, C.C.R.
`
`41
`
`and that will be the battleground for trial.
`THE COURT: I so ordered the stipulations that you
`and the other side worked out.
`MR. RAKOCZY: Okay. I had not seen it, Your
`
`Honor.
`
`THE COURT: Oh, you haven't even seen it.
`MR. RAKOCZY: Okay.
`THE COURT: Well, go ahead. I signed it this
`morning, but go ahead.
`MR. RAKOCZY: And you heard very briefly that
`darunavir falls into this class of protease inhibitors, also
`known as PIs. They are so named because they inhibit life
`protease. The only one thing I wanted to emphasize for
`background, Your Honor, so I can move along here is that I
`think you heard from Janssen basically that the challenge in
`this case, he said, is about a method of making darunavir
`and formulating darunavir.
` This case and the patents-in-suit are not about
`the darunavir molecule or the darunavir compound and any of
`its properties and clinical benefits.
` Darunavir is an old molecule. It was already
`tested and its anti-HIV properties were known as early as
`1988. It was in clinical trials by February 2002. So this
`case is not about designing a new darunavir molecule. That
`molecule was old and in the prior art. Matter of fact, it's
`CHARLES P. McGUIRE, C.C.R.
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`Lupin Ex. 1024 (Page 3 of 35)
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`102
`1 Q.
`Counsel just said a moment ago that, for example, the
`2
`formulation of Prezista had nothing whatever to do with
`3
`these results. Do you agree with that?
`4 A.
`I do not agree with that.
`5 Q.
`Why not?
`6 A.
`Because you -- we were -- without all the chemical and
`7
`pharmaceutical work, we never would have been able to give
`8
`the drug to patients.
`9 Q.
`And indeed, you told us earlier about the drug
`10
`Intelence. Do you recall that?
`11 A.
`Yes.
`12 Q.
`Which went from 36 pills to one or two a day?
`13 A.
`Two a day, yes.
`14 Q.
`Did the formulation matter?
`15 A.
`Absolutely.
`16 Q.
`Does the formulation matter for the success of
`17
`Prezista?
`18 A.
`Absolutely.
`19 Q.
`How about the process? You said it didn't matter --
`20
`THE COURT: Remember you're on direct.
`21
`MR. DISKANT: I'm sorry?
`22
`THE COURT: You're on direct.
`23
`MR. DISKANT: Okay.
`24
`THE COURT: All right?
`25 Q.
`Let me ask it this way: Did the process have any
`CHARLES P. McGUIRE, C.C.R.
`
`103
`
`1
`effect on these results?
`2 A.
`We were able to make the compound, and that benefited
`3
`the patients.
`4 Q.
`You talked earlier about your friend Jens that you
`5
`treated in '95 or thereabouts. Tell us how he came to be
`6
`treated with Prezista.
`7
` (Mr. Rakoczy rises)
`8 A.
`He failed --
`9
`THE COURT: I agree. We don't need to hear this.
`10
`Let's move on. He already told us that he was still alive
`11
`as of 2014. Go ahead.
`12 Q.
`When did FDA approve Prezista?
`13 A.
`In June 2006.
`14 Q.
`And look at PTX-591. Is that the press release
`15
`announcing its approval?
`16 A.
`Yes, the FDA commissioner issued a press release
`17
`telling the importance of the discovery and -- for patients.
`18 Q.
`Is Prezista recommended by the Department of Health
`19
`and Human Services for treatment?
`20 A.
`Yes, it's one of the two drugs that they recommend,
`21
`protease inhibitors recommended by Health and Human
`22
`Services.
`23 Q.
`And what's the other drug?
`24 A.
`Atazanavir.
`25 Q.
`And is there recent controlled clinical trials
`CHARLES P. McGUIRE, C.C.R.
`
`27
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`104
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`1
`comparing atazanavir with --
`2 A.
`Yes, recent control trials show that Prezista is
`3
`superior.
`4
`MR. RAKOCZY: Again, objection, Your Honor.
`5
`THE COURT: I agree. I sustain the objection.
`6
`MR. RAKOCZY: Thank you, Your Honor.
`7
`THE COURT: You know my head is bowed. I'm
`8
`ignoring you. Go ahead.
`9
`MR. DISKANT: Okay. We're moving on.
`10
`THE COURT: Go ahead.
`11
`MR. DISKANT: Okay.
`12 Q.
`Today, let's talk about prescriptions for Prezista.
`13
`How have they grown over the years and how many are there
`14
`now?
`15 A.
`Today there are about one million prescriptions for
`16
`Prezista.
`17
`MR. RAKOCZY: Objection.
`18
`MR. DISKANT: This is commercial success.
`19
`THE COURT: I don't think there is any challenge
`20
`that is meaningful as to the -- and I mean this quite
`21
`deliberately -- the effectiveness of Prezista, nor its
`22
`worldwide appeal. I don't think anyone's challenging that.
`23
`And so that's already an issue that is not an issue.
`24
`MR. DISKANT: There is a challenge to --
`25
`THE COURT: As to what?
`CHARLES P. McGUIRE, C.C.R.
`
`Prezista.
`
`105
`MR. DISKANT: As to the commercial success of
`
`1
`2
`3
`THE COURT: Are you challenging commercial success
`4
`of this drug?
`5
`MR. RAKOCZY: We have an expert economist,
`6
`Your Honor, who specializes in analyzing how pharmaceutical
`7
`products fare in the market, and our view is, this type of
`8
`testimony is, in fact, expert testimony, and the purview --
`9
`THE COURT: That's not the question I asked you,
`10
`is it? Please be responsive to what I put to you.
`11
` I said, are you challenging the commercial success
`12
`of Prezista?
`13
`MR. RAKOCZY: Absolutely we are, Your Honor, yes.
`14
`THE COURT: You are?
`15
`MR. RAKOCZY: Yes.
`16
`THE COURT: All right. I'll permit it, then. All
`17
`right. That takes care of that.
`18 Q.
`So how is it doing in the marketplace?
`19 A.
`Well, today, last year, we had close to a million
`20
`prescriptions of Prezista.
`21 Q.
`That's Exhibit 910. It's a summary slide. How have
`22
`they grown over the years?
`23
`MR. RAKOCZY: Objection, Your Honor, if I may.
`24
`THE COURT: Yes. Yes, sir.
`25
`MR. RAKOCZY: Your Honor, we are challenging
`CHARLES P. McGUIRE, C.C.R.
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`right?
`
`118
`MR. RAKOCZY: Your Honor, that whole idea, 70 to
`1
`80 percent, that is expert opinion. That is not a lay
`2
`opinion if someone walks up the street --
`3
`THE COURT: That is why I was going to it, good
`4
`friend. Trust me sometimes. All right?
`5
`(Laughter)
`6
`MR. RAKOCZY: Thank you, Judge.
`7
`BY MR. DISKANT:
`8
`9 Q.
`In any event, in your view, what effect would losing
`these patent cases have --
`10
`THE COURT: No, I think you ought to finish. All
`11
`12
`MR. DISKANT: Okay. In that case, I'll ask one
`13
`last round of questions.
`14
`15 Q.
`We talked about enforcing patents here in the U.S.
`Does J & J have a different policy with respect to
`16
`sub-Saharan Africa and the least developed countries?
`17
`18 A.
`Yes, it does.
`MR. RAKOCZY: Objection, Your Honor.
`19
`THE COURT: I want to ask you about a movie, did
`20
`you see it, "A Bridge Too Far"?
`21
`(Laughter)
`22
`THE COURT: All right. That's it. We shall now
`23
`recess for lunch. We'll see you at two o'clock.
`24
`(Luncheon recess taken)
`25
`CHARLES P. McGUIRE, C.C.R.
`
`119
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` A F T E R N O O N S E S S I O N
`1
` THE COURT CLERK: All rise.
`2
`THE COURT: Good afternoon again.
`3
`Where is our witness?
`4
`Okay.
`5
`You may be seated.
`6
`(The witness resumed the stand.)
`7
`MR. RAKOCZY: Good afternoon, Your Honor.
`8
`THE COURT: Are you finished direct examination?
`9
`MR. DISKANT: Yes, Your Honor.
`10
`THE COURT: All right. Yes, sir.
`11
` MR. RAKOCZY: Good afternoon, Your Honor.
`12
`William Rakoczy for the Lupin and Mylan Defendants.
`13
`Good afternoon, Dr. Stoffels.
`14
`Excuse me, Your Honor. May I proceed?
`15
`THE COURT: Yes. We're waiting for you.
`16
`MR. RAKOCZY: Thank you.
`17
` CROSS-EXAMINATION
`18
`BY MR. RAKOCZY:
`19
`20 Q.
`Afternoon, Dr. Stoffels.
`21 A.
`Good afternoon.
`22 Q.
`We haven't met. I represent the Lupin and Mylan
`Defendants. I'll have just a few questions for you.
`23
`24 A.
`Nice to meet you.
`25 Q.
`I would like to start with some of your demonstrative
`CHARLES P. McGUIRE, C.C.R.
`
`31
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`120
`
`slides, if we could.
`1
`MR. RAKOCZY: Could we please call back up
`2
`Stoffels 9?
`3
`Q. And I believe, Dr. Stoffels, this is your depiction of
`4
`the HIV life cycle you testified about; is that correct?
`5
`6 A.
`Yes.
`7 Q.
`And if we look on this Stoffels 9 demonstrative,
`there's an error at the bottom, it says protease inhibitor;
`8
`correct?
`9
`10 A.
`Correct, yes.
`11 Q.
`So the protease is actually inside the cell; correct?
`12 A.
`Protease enzyme is inside the cell, yes.
`13 Q.
`So this whole mechanism of inhibiting protease, that
`occurs intracellularly, correct?
`14
`15 A.
`That occurs intracellular to the formation of the
`virus, yes.
`16
`17 Q.
`All right. Now, let's turn to your next
`demonstrative, Stoffels 10, and this was a depiction where
`18
`you are depicting a pair of scissors as the protease;
`19
`correct?
`20
`21 A.
`I am doing that simplification, yes.
`22 Q.
`And then in Stoffels 11, you are depicting the
`protease inhibitor as it looks like a red pin that prevents
`23
`the scissors from closing; is that correct?
`24
`25 A.
`It's a depiction. Yes.
`CHARLES P. McGUIRE, C.C.R.
`
`121
`1 Q.
`All right. Now, my question is, if that red pin is a
`protease inhibitor, and in particular, if it's Prezista, or
`2
`Prezista, excuse me, then that's the actual darunavir
`3
`molecule that's inhibiting the protease; correct?
`4
`5 A.
`I just wanted to demonstrate how a protease inhibitor
`could be blocked depicted by the scissor and a nail, yes.
`6
`7 Q.
`So if that was Prezista, that would be the darunavir
`molecule that's blocking the protease; correct?
`8
`9 A.
`That's a depiction of that, yes.
`10 Q.
`That is not depicting the ethanolate or the
`ethanolate; correct?
`11
`12 A.
`I am not the expert to say that, the relationship
`between -- this is -- I can't say that.
`13
`14 Q.
`So you think that that inhibitor inside the cell could
`be the ethanolate, the actual ethanol inside the cell
`15
`inhibiting protease?
`16
`17 A.
`I'm not the expert to say that.
`18 Q.
`So you don't know one way or another what is actually
`inhibiting the protease.
`19
`20 A.
`I know it's a chemical molecule, which is synthesized
`and which is -- which is synthesized as an ethanolate, which
`21
`absorbs in the body. How it's then getting metabolized and
`22
`gets into the cell, I am not the expert to describe that to
`23
`you.
`24
`25 Q.
`
`Well, once the patient ingests Prezista, the drug
`CHARLES P. McGUIRE, C.C.R.
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`126
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`1
`effect." Correct?
`2 A.
`Yes.
`3 Q.
`And that's true; correct?
`4 A.
`That's true to a certain extent, that it does not work
`5
`on its own, but to make the plasma levels and the dosing
`6
`administration acceptable for patients, you boost it.
`7 Q.
`Now, the FDA has never approved the use of darunavir
`8
`alone as monotherapy; correct?
`9 A.
`That's correct because we didn't submit for that.
`10 Q.
`So it's never been approved for use without ritonavir
`11
`or some other ARV; correct?
`12 A.
`Yes, and that's for all HIV drugs like that.
`13 Q.
`Right. They're all used as --
`14 A.
`Combinations.
`15 Q.
`Correct. Thank you. You finished my sentence. Thank
`16
`you, sir.
`17
`Now, to your knowledge, darunavir has never even
`18
`been tested in large-scale human trials, clinical trials as
`19
`model therapy; correct?
`20 A.
`No. It's ethical not just to do that.
`21 Q.
`So in all instances, Prezista is administered either
`22
`with ritonavir and sometimes with ritonavir and other
`23
`antiretroviral agents; correct?
`24 A.
`Typically HIV is treated with three different drugs to
`25
`have long-lasting effect, yes.
`CHARLES P. McGUIRE, C.C.R.
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`127
`1 Q.
`Okay, and that was getting to my next question. You
`2
`mentioned your good friend, and I apologize if I --
`3 A.
`Yes.
`4 Q.
`-- butcher his name. Is it Jens Van Roey?
`5 A.
`Yes.
`6 Q.
`And you mention that that he was taking Prezista;
`7
`correct?
`8 A.
`He is now taking Prezista, yes.
`9 Q.
`But he doesn't just take Prezista, right? He takes a
`10
`combination therapy, Prezista, ritonavir, and something
`11
`else; correct?
`12 A.
`Yes.
`13 Q.
`So he's on a triple combo.
`14 A.
`Yes, absolutely.
`15 Q.
`Now, if he was taking just darunavir alone as
`16
`monotherapy without ritonavir and without any other
`17
`antiretroviral therapy, he would develop resistance;
`18
`correct?
`19 A.
`We didn't show that, but most likely over time he
`20
`would develop resistance.
`21 Q.
`Now, very briefly, you mentioned darunavir's
`22
`properties in preventing resistance. You weren't suggesting
`23
`in your testimony that patients don't develop resistance on
`24
`Prezista, were you?
`25 A.
`I'm not suggesting patients don't develop resistance
`CHARLES P. McGUIRE, C.C.R.
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`33
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`128
`1
`on Prezista. One thing it does is that it takes many, many
`2
`years before it develops resistance.
`3 Q.
`But they still do, correct? Patients on Prezista can
`4
`still develop resistance?
`5 A.
`Patients can, but it depends on compliance. If people
`6
`take their pills, many patients now, between 50,-
`7
`and 100,000, are 10 years on Prezista.
`8 Q.
`All right. Now, I'd like to turn back, go back in
`9
`time a little bit to -- let's say go back to '98, '99, and I
`10
`apologize if I drop down into different terminology.
`11
` I'm correct, right, that darunavir is the same
`12
`thing as TMC 114; correct?
`13 A.
`Yes, it was the same. It was the name for the same --
`14
`that was the name, darunavir is a generic name for what was
`15
`the TMC 114.
`16 Q.
`Now, you testified in your direct examination about
`17
`Tibotec's development of darunavir; correct?
`18 A.
`Yes.
`19 Q.
`Now, just so the record is clear, now, Tibotec or
`20
`Janssen did not invent or conceive darunavir; correct?
`21 A.
`Tibotec team synthesized darunavir, but before us,
`22
`Ghosh had synthesized darunavir separately.
`23 Q.
`Okay. So that's what I was -- exactly, and thank you
`24
`again, you finished my next question. So so the record is
`25
`clear, then, Tibotec did not invent darunavir; it had been
`CHARLES P. McGUIRE, C.C.R.
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`129
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`1
`invented and patented before Tibotec started testing it,
`2
`correct?
`3 A.
`Somebody synthesized the molecule, but we found that
`4
`it was active on multidrug-resistant strains, and that was
`5
`our invention.
`6 Q.
`And I understand that, sir. I just want to make sure
`7
`it's clear, though: Tibotec did not invent the darunavir
`8
`molecule; correct?
`9 A.
`We did not invent it.
`10 Q.
`Okay. That had been invented and patented in a Searle
`11
`patent; correct?
`12 A.
`Correct.
`13 Q.
`I'm sorry, I meant to interrupt you. We have to make
`14
`sure the record's clear.
`15
` The darunavir molecule had been invented and
`16
`patented in a Searle patent; correct?
`17 A.
`It was described in a Searle patent.
`18 Q.
`And Dr. Arun Ghosh, for whom darunavir was named, was
`19
`the first to, to your knowledge, synthesize the darunavir
`20
`molecule; correct?
`21 A.
`He published it in a paper that he synthesized that
`22
`molecule.
`23 Q.
`And that's the Ghosh 1998 publication; correct?
`24 A.
`I don't know -- remember that date or the -- I know it
`25
`was a publication, but I don't know what date it was.
`CHARLES P. McGUIRE, C.C.R.
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`190
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`1
`THE WITNESS: So all of the chemists -- we
`2
`discussed ideas at the moment we had to decide, and then
`3
`they would write it down.
`4
`THE COURT: You would report these and then use
`5
`what you had reported as indications of what you're planning
`6
`to do in research?
`7
`THE WITNESS: Yes. Correct.
`8
`THE COURT: I'll permit that. I'll permit it. I
`9
`note your objection.
`10
`(Exhibit PTX-346 marked in evidence)
`11
`THE COURT: And with regard to whether it goes
`12
`beyond the patent, I can always as a fact finder ignore it
`13
`if necessary.
`14
`MS. BRODY: Thank you, Your Honor.
`15
`THE COURT: All right. Go ahead.
`16
`BY MS. ROYZMAN:
`17 Q.
`Did Tibotec test compounds with the various
`18
`replacements that you had made for the bis-THF moiety?
`19 A.
`So every compound we did make, we did tests to try to
`20
`find good activity against HIV, yes.
`21 Q.
`And what were the results that you obtained with the
`22
`various replacements for bis-THF?
`23 A.
`Well, they were quite sobering in the sense that
`24
`unfortunately, none of these compounds showed strong
`25
`activity. You couldn't compare them. Most were in effect
`CHARLES P. McGUIRE, C.C.R.
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`191
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`1
`inactive to our big surprise, because they were pretty
`2
`close. Some showed some activity, but they were ways off,
`3
`or almost inactive, to be honest.
`4 Q.
`And when you say inactive, you're referring to
`5
`inactive against --
`6 A.
`Yes. Yes.
`7 Q.
`-- all HIV, or multidrug-resistant HIV?
`8 A.
`Well, the first test hurdle was to turn it on the wild
`9
`type, which are the easy ones, and most compounds didn't
`10
`pass that bar, so...
`11 Q.
`Did you draw any conclusions based on your testing of
`12
`compounds without bis-THF?
`13 A.
`Well, the conclusion was that bis-THF was special and
`14
`crucial. It was very difficult to find something that gave
`15
`me -- we could not find anything that we could use as an
`16
`alternative, so we had to find a way to make bis-THF,
`17
`alcohol, we call it, on a big scale.
`18 Q.
`I'd like to turn to PTX-82 in your binder.
`19
`You had mentioned that you identified a Searle
`20
`patent in early '99, that you identified a Searle patent.
`21
`Is this the Searle patent that you were referring
`22
`to?
`23 A.
`Yes, it is one of them.
`24 Q.
`I'd like to go specifically to Table 3K of PTX-82,
`25
`which is at page 53.
`
`CHARLES P. McGUIRE, C.C.R.
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`49
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`192
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`1
`Is the molecule in Prezista on this page?
`2 A.
`Well, indeed, so if you take the total structure here
`3
`and you attach the example which is down here to where it
`4
`has to come, you have the structure of Prezista.
`5
`THE COURT: If you take the molecule in the lower
`6
`left and attach it where?
`7
`THE WITNESS: Well, where -- in the top structure,
`8
`it's put R. We typically use the symbol R for a variable,
`9
`something we're going to modify.
`10
`THE COURT: All right.
`11
`THE WITNESS: And so if you do that in that
`12
`structure, you have the exact structure of Prezista, the
`13
`single intact isomer that's called Prezista.
`14 Q.
`You used the term isomer. What's that?
`15 A.
`Well, the stereoisomer, so if we would have made a
`16
`drawing differently, we could have admixture, but these are
`17
`the single compounds. That's a single optical isomer.
`18 Q.
`So it was one of the 32.
`19 A.
`Yes, one specific, yes.
`20 Q.
`Did Searle ever make this compound, to your knowledge?
`21 A.
`Not to my knowledge.
`22 Q.
`Were you interested in making TMC 114, based on your
`23
`review of the Searle patent?
`24 A.
`Well, the Searle patent covered thousands of thousands
`25
`of molecules, so there was no way we could make all of them,
`CHARLES P. McGUIRE, C.C.R.
`
`193
`1
`and so the patent only had one type information, there was
`2
`not a single data point, not a single indication of activity
`3
`on the other viruses that were determined to be
`4
`drug-resistant. So it was an idea from Searle let's say
`5
`like that.
`6
`MS. ROYZMAN: I'd like to offer PTX-82 into
`7
`evidence.
`8
`MS. BRODY: No objection, Your Honor.
`9
`THE COURT: Without objection, into evidence.
`10
`(Exhibit PTX-82 marked in evidence)
`11 Q.
`I'd now like to turn to an article by Arun Ghosh from
`12
`1998, a few years after this. It's at PTX-484 of your
`13
`binder.
`14
`You had testified earlier today that you became
`15
`aware of the chemical structure for TMC -- for what you now
`16
`call TMC 126 as a result of a Ghosh article. Was this the
`17
`Ghosh article you were referring to?
`18 A.
`Correct.
`19 Q.
`Does this article also report on the molecule that you
`20
`referred to as TMC 114, the molecule in Prezista?
`21 A.
`Yes, it does.
`22 Q.
`Were you interested in making TMC 114 based on the
`23
`Ghosh 1998 article?
`24 A.
`Well, in the article, there are experimental data that
`25
`show that the Prezista molecule is less active than the 126,
`CHARLES P. McGUIRE, C.C.R.
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`Lupin Ex. 1024 (Page 7 of 35)
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`1
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`402
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`Civil No.
`JANSSEN PRODUCTS, L.P., et al., :
`10-cv-5954(WHW)
`Plaintiffs,
`:
`TRANSCRIPT OF
`: TRIAL PROCEEDINGS
`v.
`:
`LUPIN LIMITED, et al.,
`VOLUME 3
`:
`Defendants.
`--------------------------------x
`
`Newark, New Jersey
`March 21, 2014
`
`BEFORE:
`
`THE HON. WILLIAM H. WALLS, U.S.D.J.
`
`Reported by:
`CHARLES P. McGUIRE, C.C.R.
`Official Court Reporter
`
`Pursuant to Section 753, Title 28, United States
`Code, the following transcript is certified to be
`an accurate record as taken stenographically in
`the above entitled proceedings.
`
`s/CHARLES P. McGUIRE, C.C.R.
`
`CHARLES P. McGUIRE, C.C.R.
`
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`17
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`463
`1
`the bis-THF alcohol on its own, the bicyclic small moiety,
`2
`or the full protease inhibitor?
`3 Q.
`Do you understand the phrase bis-tetrahydrofuranyl to
`4
`be bis-THF?
`5 A.
`Bis-THF alcohol, but then that's the small piece.
`6 Q.
`Are you aware if Tibotec ever -- as you just defined
`7
`with the alcohol piece any tests as a protease inhibitor?
`8 A.
`I think for fun, we did this.
`9 Q.
`But those tests showed a very weak affinity for the
`10
`enzyme; correct?
`11 A.
`Yes.
`12 Q.
`And bis-THF alone was not as effective as darunavir as
`13
`an HIV protease inhibitor; correct?
`14 A.
`Yes.
`15 Q.
`So is it fair to say that bis-THF has very weak
`16
`pharmacologic activity?
`17 A.
`On its own, yes.
`18 Q.
`And darunavir has a much stronger activity as a
`19
`protease inhibitor as compared to bis-THF, then; correct?
`20 A.
`Yes.
`21 Q.
`And you're not aware of Tibotec or Janssen conducting
`22
`any clinical trials on bis-THF as a protease inhibitor;
`23
`correct?
`24 A.
`That would be unethical.
`25 Q.
`So it's correct?
`CHARLES P. McGUIRE, C.C.R.
`
`465
`1 Q.
`Now, I believe you also had mentioned that DSM had a
`2
`role in the synthesis process for bisfuranyl; is that
`3
`correct?
`4 A.
`Correct.
`5 Q.
`And that role included further optimizing the process
`6
`that Bart Kesteleyn had developed in-house at Tibotec; is
`7
`that correct?
`8 A.
`That included optimization, that there was also the
`9
`safety assessment.
`10 Q.
`And Bart Kesteleyn is a name mentioned on the '015
`11
`patent; is that correct?
`12 A.
`Correct.
`13 Q.
`And Bart Kesteleyn was one of the medicinal chemists
`14
`you supervised at Tibotec; is that correct?
`15 A.
`Correct.
`16 Q.
`Now, in making a compound or drug, is it necessary at
`17
`least at some point to characterize the physical
`18
`characteristics of the compound?
`19 A.
`Correct.
`20 Q.
`And you understand that it is a regulatory requirement
`21
`to characterize the polymorphs of a drug; correct?
`22 A.
`Correct at certain stages and depending on what you
`23
`use, you have to characterize it.
`24 Q.
`And that's a regulatory requirement in your
`25
`understanding?
`
`CHARLES P. McGUIR