`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF NEW JERSEY
`
`B5
`
`JANSSEN PRODUCTS, L.P. , et al.,
`
`Plaintiffs,
`
`v.
`
`LUPIN LIMITED, et al.,
`
`:
`
`:
`
`:
`
`Civil No.
`10—cv—5954(WHW)
`
`TRANSCRIPT OF
`TRIAL PROCEEDINGS
`
`VOLUME 2
`
`Defendants.
`1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11x
`
`Newark, New Jersey
`March 19, 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
`
`the following transcript is certified to be
`Code,
`an accurate record as taken stenographically in
`the above entitled proceedings.
`
`s/CHARLES P. McGUIRE, C.C.R.
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 1 of 54)
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`Case 2:10—cv—O5954—WHW—CLW Document 952 Filed 08/25/14 Page 71 of 167 Page|D: 55921
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`305
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`which we couldn't use. And then every day, everybody was
`
`trying and trying, and then after a number of weeks, finally
`
`one gay said, Piet,
`
`I think I have it, and one of the
`
`experiments succeeded. And typically,
`
`the first time is the
`
`most difficult one. Later, you can use some of the powder
`
`as seeds for the next experiment and then you don't need to
`
`do the scratching any more. But for the first time, with 20
`
`people, we were scratching for —— for over an hour in the
`
`morning, over an hour in the afternoon, and finding the
`
`right way to convert the oil to a powder.
`
`Q.
`
`Okay.
`
`I'm going to break that down a little bit in a
`
`second, but --
`
`A.
`
`Q.
`
`Yes.
`
`—— before we do that, you were referring to scratching
`
`tubes and illustrating them, and maybe we can give a
`
`physical demonstrative.
`
`MS. ROYZMAN: May I approach, Your Honor?
`
`THE COURT: Yes.
`
`Throughout the trial, all of you have the right to
`
`approach the various witnesses.
`
`But may I ask why you need to break it down?
`
`MS. ROYZMAN:
`
`I think I need to explain what
`
`techniques were being used. That's important to the case.
`
`THE COURT: What? You need to explain what?
`
`MS. ROYZMAN: Explain what techniques
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`24
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 2 of 54)
`
`
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`Case 2:10—cv—O5954—WHW—CLW Document 952 Filed 08/25/14 Page 72 of 167 Page|D: 55922
`
`Dr. Wigerinck was using, because that's important to the
`
`case.
`
`306
`
`THE COURT: What techniques he was using?
`
`MS. ROYZMAN: Yes.
`
`I have a couple --
`
`THE COURT: He‘s already explained what he was
`
`doing.
`
`He said he had 20 chemists scratching oil in vials.
`
`We don't know how long, but it took some time.
`
`How much
`
`more do I need to know?
`
`MS. ROYZMAN:
`
`Just a tiny bit in terms of solvents
`
`and conditions that they were using.
`
`THE COURT:
`
`Go ahead, but I doubt that it will be
`
`that important in the long run. But go ahead.
`
`MS. ROYZMAN: Okay.
`
`Q.
`
`You said you were using a contractor to try to help
`
`you get a powder; right?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`And the contractor failed; is that right?
`
`That was ChemShop.
`
`And was ChemShop using crystallization techniques to
`
`try to get your powder, TMC 114?
`
`A.
`
`Q.
`
`Yes.
`
`And did they succeed in crystallizing TMC 114 in any
`
`solvent whatsoever?
`
`A.
`
`Q.
`
`No.
`
`And what was your reaction to ChemShop's failure to
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`24
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`25
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 3 of 54)
`
`
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`Case 2:10—cv—O5954—WHW—CLW Document 952 Filed 08/25/14 Page 73 of 167 Page|D: 55923
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`307
`
`crystallize TMC 114?
`
`A.
`
`Set up the whole effort I mapped out a couple of
`
`minutes ago.
`
`THE COURT: You're involved in a recapitulation,
`
`almost. We've heard this.
`
`MS. ROYZMAN:
`
`I'm just trying to get at what the
`
`crystallization efforts were, just --
`
`THE COURT: Well,
`
`they were futile.
`
`MS. ROYZMAN: Yes.
`
`THE COURT:
`
`So we know that.
`
`MS . ROYZMAN: Okay.
`
`Q.
`
`And were you using different solvents to try to
`
`crystallize TMC 114 initially?
`
`A.
`
`Yes, and as part of that exercise,
`
`I was —— I went
`
`back into the lab myself. Normally I did not work in the
`
`lab any more, but I went back into the lab and instructed
`
`the people every day, checked with them to come to a
`
`solution.
`
`Q.
`
`Did you and ChemShop try to crystallize TMC 114
`
`straight from ethanol?
`
`A.
`
`We tried many times.
`
`THE COURT: When did you start scratching, before
`
`or after crystallization?
`
`THE WITNESS: You scratch to obtain the first
`
`crystal.
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 4 of 54)
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`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 1 of 216 Page|D: 55265
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF NEW JERSEY
`
`MH
`
`JANSSEN PRODUCTS, L.P. , et al.,
`
`Plaintiffs,
`
`v.
`
`LUPIN LIMITED, et al.,
`
`:
`
`:
`
`:
`
`Civil No.
`10—cv—5954(WHW)
`
`TRANSCRIPT OF
`TRIAL PROCEEDINGS
`
`VOLUME 3
`
`Defendants.
`1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11x
`
`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
`
`the following transcript is certified to be
`Code,
`an accurate record as taken stenographically in
`the above entitled proceedings.
`
`s/CHARLES P. McGUIRE, C.C.R.
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 5 of 54)
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`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 172 of 216 Page|D: 55436
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`5%
`
`cause it to crystallize, and what we want to do is reduce
`
`the solubility of the material that we're looking for.
`
`So the oldest crystallization process is,
`
`in fact,
`
`salt, because people made salt from seawater going back to
`
`ancient times, and what they did is they let the seawater
`
`into a —— to a —— basically a container that had a lot of
`
`surface area, and they'd let the sun evaporate the water,
`
`and because when you evaporate water you increase the
`
`concentration, eventually,
`
`the concentration exceeds that
`
`which is the solubility of salt in the seawater and you get
`
`crystalline sodium chloride.
`
`So that's the simplest example
`
`of a crystallization process.
`
`The other ways you can crystallize things is, you
`
`can use the fact that most things‘ solubility is a function
`
`of temperature, so hot fluids dissolve more than cold
`
`fluids.
`
`So if you heat something up and you dissolve all
`
`you can from the material in it and then you cool it back
`
`down then you can cause crystals to form.
`
`The third method we've heard something about in
`
`the trial so far is called antisolvent crystallization, or
`
`changing solvent composition.
`
`So if you have something
`
`dissolve in a particular solvent, and you add another
`
`solvent where the material is not soluble,
`
`that mixed
`
`solvent system now reduces the solubility, and eventually,
`
`you should get a crystal.
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`24
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 6 of 54)
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`
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`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 173 of 216 Page|D: 55437
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`W4
`
`Now,
`
`this all assumes that the material easily
`
`crystallizes.
`
`There are many things where you do —— you
`
`attempt to do this,
`
`then you get something called an
`
`amorphous solid or an oil. That can happen for a variety of
`
`reasons:
`
`Impurities, rate, or the complexity of the
`
`molecule.
`
`Q.
`
`Okay.
`
`So are all drug products, solid pills or
`
`tablets that we take, are they all crystalline forms?
`
`A.
`
`No.
`
`There are drug products in which the active
`
`ingredient are amorphous, meaning they're solids but not
`
`crystalline, and there are also drug products where the
`
`active ingredient is actually dissolved inside a fluid
`
`that's inside the tablet or capsule,
`
`like Liquigel, for
`
`example.
`
`Q.
`
`Now, can a single drug molecule, a drug like darunavir
`
`or aspirin or any other drug, can it crystallize in more
`
`than one way or more than one form?
`
`A.
`
`Q.
`
`Yes. That's a phenomena known as polymorphism.
`
`Okay, and we have an example not relating to drugs,
`
`but to carbon.
`
`Can you explain this concept of polymorphism
`
`a little bit more?
`
`A.
`
`Yes.
`
`Those of us who work in the field like to use
`
`this as an example.
`
`Polymorph means compounds that can
`
`crystallize in more than one structure. When they're
`
`applied to elements,
`
`they're called allotropes, but same
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 7 of 54)
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`
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`W5
`
`basic concept.
`
`So if we look at graphite and we look at
`
`diamond,
`
`they're both crystalline forms of carbon.
`
`The only
`
`difference is the way the atoms are bonded together in their
`
`three—dimensional lattice structure. And we all know that
`
`they have very different properties: We put graphite in
`
`pencils, and we put diamonds on women's fingers.
`
`Q.
`
`Now, crystal is a three—dimensional structure as
`
`you've described.
`
`Is it sometimes also appropriate to
`
`describe polymorphism in a two—dimensional format just for
`
`simplicity?
`
`A.
`
`For simplicity, we can demonstrate in a
`
`two—dimensional way, which is what we have in this
`
`demonstrative.
`
`Q.
`
`So what's the difference between Polymorph 1 and
`
`Polymorph 2 in this exhibit?
`
`A.
`
`The regular structure,
`
`the way the molecules are
`
`arranged are different from each other, and that difference
`
`would propagate in all directions as we expand it.
`
`Q.
`
`Okay. Now, we've been talking so far about what I
`
`think you referred to earlier as a single component crystal.
`
`Can you explain a little bit more what you mean by that?
`
`A.
`
`Sure.
`
`So when we talk about polymorphs, we're talking
`
`about crystals of a given molecule, okay, with no other
`
`species present in the crystal except possibly a little bit
`
`of an impurity, but generally we just mean that the single
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 8 of 54)
`
`
`
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`576
`
`component we're interested in is forming the crystal.
`
`Q.
`
`Okay.
`
`So if we go back to the diamond and graphite
`
`example, is it just one kind of molecule carbon that is
`
`arranged in a particular three—dimensional order?
`
`A.
`
`Yes.
`
`In this case, an element, but yes, that's
`
`correct.
`
`Q.
`
`Okay. Are there also crystals that have more than one
`
`component?
`
`A.
`
`Q.
`
`That's correct.
`
`Okay.
`
`So can you explain,
`
`then, how —— what a solvate
`
`is and how that compares to a single component crystal?
`
`A.
`
`Yes.
`
`So a solvate is a crystalline solvent in which
`
`solvent is part of the crystalline structure. And we have
`
`an example here of a solvate just showing solvent molecules
`
`in a regular position with respect to the API or the solute
`
`molecules.
`
`Q.
`
`Okay.
`
`So that's slide seven of the demonstratives,
`
`the solvate.
`
`And what is the relationship between the green
`
`solvent molecules and the orange blocks,
`
`the underlying
`
`molecule; how are they connected to one another, if they are
`
`at all?
`
`A.
`
`Well,
`
`in this type of solvate,
`
`they would be bonded in
`
`the structure.
`
`Just like the molecules of the drug or the
`
`API, if we're talking about a drug, would be bonded
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`24
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`25
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 9 of 54)
`
`
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`
`W7
`
`together,
`
`the molecules of the solvent would also be bonded
`
`to the drug in the crystalline structure.
`
`Q.
`
`Okay. Now, we've also heard some talk in the trial so
`
`far about a channel solvate.
`
`Can you explain using this
`
`Demonstrative 8 what that is?
`
`A.
`
`Yes.
`
`A channel solvate is a special kind of solvate.
`
`In a channel solvate, we have channels running through the
`
`three—dimensional crystal structure, and the solvent is all
`
`inside the channel, so the solvent fills up the channels and
`
`stabilizes, normally stabilizes the structure by being in
`
`those channels, and typically,
`
`the solvent is weakly bonded
`
`to the API within the channel.
`
`Q.
`
`Okay.
`
`So if we look at these side by side, can you
`
`just quickly explain the difference again between
`
`non—channel and channel solvates?
`
`A.
`
`Sure.
`
`In a non—channel solvate, we have the solvent
`
`molecules in regular -- in positions within the crystalline
`
`lattice where they're individually bonded to the solute or
`
`the API molecules.
`
`In the channel solvate --
`
`THE COURT: What is API again?
`
`THE WITNESS:
`
`I'm sorry, I'm using that as active
`
`pharmaceutical ingredient, but I can --
`
`THE COURT: No,
`
`I just want to make sure that --
`
`THE WITNESS: Okay.
`
`Sure.
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 10 of 54)
`
`
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`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 177 of 216 Page|D: 55441
`
`THE COURT:
`
`Go ahead.
`
`W8
`
`A.
`
`And in the channel solvate, we would have the solvent
`
`only in these channels that are between layers, for example,
`
`of solute or API molecules, and they're weakly bonded,
`
`typically,
`
`to the solute molecules or the API molecules
`
`within the channel and typically stabilizing the structure
`
`that way.
`
`THE COURT: What causes the channel?
`
`THE WITNESS:
`
`The channel -- the only --
`
`THE COURT:
`
`How do they come about?
`
`THE WITNESS: Oh.
`
`So when you're crystallizing
`
`something, it turns out that the only way that you can form
`
`a stable three—dimensional structure is by forming these
`
`channels with the solvent inside. Typically things --
`
`THE COURT:
`
`So that's the creation of a chemist.
`
`THE WITNESS:
`
`It's --
`
`THE COURT:
`
`Isn't it? Go ahead.
`
`THE WITNESS: Yes, it's something you discover
`
`when you're looking for solid forms. Often things that are
`
`channel solvates won't form any other crystals because you
`
`need the solvent to stabilize the structure, but they tend
`
`to be unique structures and not as common as non—channel
`
`solvates.
`
`THE COURT: All right.
`
`Go ahead.
`
`BY MR. ZALESIN:
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 11 of 54)
`
`
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`W9
`
`Q.
`
`A.
`
`Q.
`
`And what kind of solvate does darunavir form?
`
`Darunavir is a channel solvate.
`
`All right, and we've seen this picture,
`
`I think, on
`
`Mr. Diskant's opening, but can you explain what we're
`
`looking at here in slide 10?
`
`A.
`
`Yes. This is actually the crystal structure of
`
`darunavir shown in -- with these lines,
`
`they show the
`
`darunavir molecules and how they're oriented to each other
`
`in three dimensions, and we've made these —— these yellow
`
`circles to demonstrate where the channels are.
`
`So those
`
`yellow circles, if you go in them,
`
`that would be the
`
`direction the channels would be.
`
`Q.
`
`Okay. Now, let's just get some terminology straight
`
`before we move forward.
`
`You were talking about solvent that can go inside
`
`these channels. Are there different solvents that can
`
`appear inside a channel solvate like darunavir?
`
`A.
`
`Yes. Typically what determines what can go inside the
`
`channels is basically the size of the channels, right?
`
`So
`
`any molecule —— any solvent molecule that's not too big can
`
`often fit inside the channel and stabilize the structure.
`
`Q.
`
`All right, and we've heard the term "ethanolate" used
`
`during the course of the trial.
`
`Can you explain what an
`
`ethanolate is in this context?
`
`A.
`
`Yes.
`
`An ethanolate is a solvate which the solvent is
`
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 12 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 179 of 216 Page|D: 55443
`
`ethanol.
`
`Q.
`
`All right, and we've also heard, for example,
`
`isopropanolate.
`
`I imagine that's a solvate in which the
`
`solvent is isopropanol?
`
`580
`
`A.
`
`Q.
`
`that?
`
`A.
`
`Q.
`
`That's correct.
`
`All right, and then hydrate; what kind of solvate is
`
`That's a solvate where the solvent in water.
`
`All right. Now, a little bit more,
`
`then, on channel
`
`solvates.
`
`How do the properties of these channel solvates
`
`typically compare to the single component —— or, excuse me,
`
`the other kind of nonchannel solvate that you describe? Are
`
`there any differences between channel solvates and
`
`non—channel solvates in terms of how they behave?
`
`A.
`
`Well,
`
`typically, channel solvates will give up their
`
`solvent when put in —— can give up their solvent or actually
`
`gain additional solvent when put in an environment where you
`
`have vapor of that solvent present.
`
`Q.
`
`Okay. And we have —— first of all, before we do that,
`
`20
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`21
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`22
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`23
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`24
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`25
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`the patent defines solvate in a particular way.
`
`Can you
`
`just review that? And this was part of the claim
`
`construction proceeding —— and Your Honor ruled on this --
`
`but can you just explain what is meant here and the
`
`definition of solvate in the patent,
`
`this stoichiometric
`
`versus non—stoichiometric business?
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 13 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 180 of 216 Page|D: 55444
`
`A.
`
`Sure. Well, as the term "solvate" is defined, it's a
`
`crystal form that contains either stoichiometric or
`
`non—stoichiometric amounts of solvent.
`
`Now, stoichiometric solvates are much more common.
`
`5&
`
`Those would be like the first type of solvate we were
`
`looking at, meaning that there's always a fixed number of
`
`solvent molecules per API molecule, so it could be
`
`one—to—one or two to one or three to one or half to one.
`
`And that also can be the case in channel solvates, but
`
`channel solvates can also be non—stoichiometric if they're
`
`exposed to certain conditions that causes more solvent to
`
`pack in the channel or less solvent to come out of the
`
`channel, you can start having odd numbers, "odd" meaning
`
`non—integer numbers.
`
`Q.
`
`A.
`
`Can you remind us non—math majors what that means?
`
`That means numbers —— in fact,
`
`to even be more
`
`specific, numbers that are not one,
`
`two,
`
`three, four or
`
`five, or a half or one and a half or two and a half —
`
`numbers more like .37, something like that.
`
`Q.
`
`Okay. All right. Now, you were talking about this
`
`tendency of channel solvates to either lose their solvent or
`
`gain a different solvent.
`
`We have an animation here. Maybe you can just
`
`talk us through this, explain what we're looking at.
`
`A.
`
`Sure.
`
`If we're looking at a channel solvate, and this
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 14 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 181 of 216 Page|D: 55445
`
`582
`
`is an ethanolate, which has the molecule and has ethanol in
`
`the channel, and if we take that and we put it in an
`
`environment where there's a lot of water vapor,
`
`then the
`
`water vapor is going to go in and push out the ethanol, and
`
`now you're going to have a hydrate.
`
`Q.
`
`Now, when that happens, will that have any effect on
`
`the structure of the crystal lattice?
`
`A.
`
`Well, what we're looking at here are what we call
`
`isostructural channel solvates, meaning that the structure
`
`doesn't really change when we change the solvent molecule.
`
`The only thing that actually happens is the lattice can flex
`
`a little bit if the size of the molecules are bigger or
`
`smaller, so it just kind of pushes up the channel a little
`
`bit or the channel contracts a little bit. But basically
`
`the structure remains essentially the same.
`
`Q.
`
`Now, you also mentioned that channel solvates can lose
`
`their solvent in certain conditions.
`
`Is there a term that
`
`refers to that?
`
`A.
`
`Yes.
`
`The process of removing solvent from a solvate
`
`is called desolvation, and desolvation normally results in a
`
`very high percentage of cases in the structure collapsing
`
`and you getting what we call an amorphous solid.
`
`Q.
`
`All right.
`
`So if we look at this channel solvate, and
`
`what happens when the solvent leaves, we saw they collapse.
`
`Is that what you mean by amorphous?
`
`20
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`21
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`25
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 15 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 182 of 216 Page|D: 55446
`
`5%
`
`A.
`
`Yes.
`
`An amorphous solid is a solid that does not have
`
`long—range order; it's not crystalline, but it's still
`
`solid. Typically,
`
`the example most people like to use with
`
`an amorphous solid is window glass, which is a solid, and
`
`it's amorphous, but it's not crystalline.
`
`Q.
`
`So you've been talking about these quirks or
`
`properties of channel solvates,
`
`their ability to exchange
`
`solvent or sometimes even lose their solvent and collapse
`
`into amorphous.
`
`Do those characteristics have any implications for
`
`the use of channel solvates in drug products?
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`What are they?
`
`Well, generally, you don't like to use solvates in
`
`drug products as a general rule, for —— the first reason is,
`
`most solvents have some toxicity, right? Other than water,
`
`and to a lesser degree ethanol, you don't want to ingest
`
`solvents, right? You don't want to have methanol or
`
`isopropanol or isotone in your drug.
`
`So that's one reason
`
`that you don't like to have solvates in drugs.
`
`The second reason is processing.
`
`So when you --
`
`after you isolate your active ingredient, let's say there's
`
`a solvate, you then have to go into what we call secondary
`
`manufacturing, which is manufacturing when you're making a
`
`tablet, for example, and that typically involves taking the
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 16 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 183 of 216 Page|D: 55447
`
`584
`
`active pharmaceutical ingredient, blending it with
`
`excipients in something that looks a lot like a blender, and
`
`then if it's a simple formulation,
`
`then you would take that
`
`and put it in a tablet press, where you actually put lots of
`
`pressure on the solid and make your tablet, and then
`
`typically you might coat it. You put a coating on it, which
`
`involves putting some kind of polymeric material or sugar
`
`with some moisture and then you have to dry it.
`
`Now, each of those operations can result in
`
`desolvation, right? When you are putting a lot of pressure
`
`on something, you're mixing something up with a blender or
`
`you're heating something up,
`
`those can result in
`
`desolvation, which is a problem. You don't want that to
`
`happen.
`
`So generally the pharmaceutical industry always
`
`prefers to use non—solvated forms where possible. Of
`
`course, sometimes, it's not possible, and they'll attempt to
`
`develop a solvate form.
`
`Q.
`
`Okay. And with that background, Dr. Myerson, why
`
`don't we now take a closer look at the '645 patent, which,
`
`again, is Exhibit 1, PTX1,
`
`the first tab in your binder.
`
`And the first thing I'd like to go to is the
`
`summary of the invention, which is at column 2, beginning at
`
`line 46, and can you just describe for us in general
`
`terms
`
`what this patent teaches and what the invention is about?
`
`20
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 17 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 948 Filed 08/25/14 Page 184 of 216 Page|D: 55448
`
`5%
`
`A.
`
`Well,
`
`the invention is about pseudopolymorphic forms,
`
`which you've already defined, which can be used in
`
`pharmaceutical formulations, and in the summary, it says
`
`pharmaceutical and formulation in improved stability and
`
`bioavailability and can be manufactured in sufficient high
`
`purity to be acceptable for pharmaceutical use.
`
`Q.
`
`Okay.
`
`So let's understand a little bit about those
`
`three terms you used, stability, bioavailability, and
`
`purity.
`
`Stability I think you talked about in terms of
`
`manufacturing and their ability to withstand external
`
`pressures.
`
`Is that what you mean?
`
`A.
`
`Well,
`
`there are two types of stability that we need to
`
`talk about which have already been talked about in the
`
`trial. One is chemical stability; that is, is the compound
`
`going to decompose or not under certain conditions?
`
`The other type of stability when we're talking
`
`about the solid forms is solid—form stability; that is,
`
`there's a solid form going to maintain the same solid form
`
`during processing, or is it going to become amorphous or
`
`change to another solid form.
`
`Q.
`
`All right. And what about bioavailability; what is
`
`the role of a pseudopolymorph or solvate in bioavailability
`
`of a drug?
`
`A.
`
`Okay. Well, bioavailability of the drug, if it's the
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 18 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 960 Filed 08/25/14 Page 1 of 199 Page|D: 57505
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF NEW JERSEY
`
`1569
`
`JANSSEN PRODUCTS, L.P. , et al.,
`
`Plaintiffs,
`
`v.
`
`LUPIN LIMITED, et al.,
`
`:
`
`:
`
`:
`
`Civil No.
`10—cv—5954(WHW)
`
`TRANSCRIPT OF
`TRIAL PROCEEDINGS
`
`VOLUME 9
`
`Defendants.
`— — — — — — — — — — — — — — — — — — — — — — — — — — — — — — ——x
`
`Newark, New Jersey
`
`April 1, 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
`
`the following transcript is certified to be
`Code,
`an accurate record as taken stenographically in
`the above entitled proceedings.
`
`s/CHARLES P. McGUIRE, C.C.R.
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 19 of 54)
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`1
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`M H
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`N 2
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`0
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`
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`Case 2:10—cv—O5954—WHW—CLW Document 960 Filed 08/25/14 Page 113 of 199 Page|D: 57617
`
`1681
`
`rule or not.
`
`THE COURT:
`
`He did. He's already answered that
`
`question. You can pursue it.
`
`He already said he wasn't
`
`aware of it.
`
`He told us that.
`
`Neither one of you listen to what the witnesses
`
`say.
`
`So you want to move on?
`
`MR. ZALESIN:
`
`I'm going to move on.
`
`THE COURT: We'll move on.
`
`I'm still going to see
`
`if I can find a case. All right?
`
`MR. ZALESIN:
`
`It's noteworthy, Your Honor, while
`
`we're waiting for the witness,
`
`that the Defendants want to
`
`put in a lot of deposition testimony of the inventors of
`
`this ‘645 patent, so I'm not really sure what their position
`
`ultimately is going to be, but I think we've had the
`
`witness‘ testimony, and we can move on to another subject.
`
`THE COURT: You do any and everything to win
`
`within the rules.
`
`MR. ZALESIN: Okay.
`
`THE COURT: When you stretch the rules, you do
`
`that,
`
`too, if you have a gullible court. All right?
`
`THE WITNESS:
`
`Come on up, sir, and we're moving
`
`on.
`
`(The witness resumed the stand.)
`
`BY MR. ZALESIN:
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`25
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`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 20 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 960 Filed 08/25/14 Page 114 of 199 Page|D: 57618
`
`1682
`
`Q.
`
`Okay. Dr. Zaworotko, let's talk about your opinion
`
`that darunavir was a compound of interest in this time frame
`
`leading up to May 10th, 2002,
`
`the priority date for the ‘645
`
`patent.
`
`First of all, we can agree that that is an
`
`essential premise of your opinion:
`
`If the person of skill
`
`wouldn't have had any motivation to work on darunavir,
`
`then
`
`they certainly wouldn't have found any new crystal forms of
`
`it; correct?
`
`A.
`
`Q.
`
`Yes,
`
`that was step one of my pathway.
`
`Okay. And that's true even if it would have turned
`
`out to be a routine exercise to do the experiments on
`
`darunavir,
`
`there was no motivation if it wasn't a compound
`
`of interest,
`
`then they would have never gotten to the
`
`invention; correct?
`
`A.
`
`If darunavir was not known, and if darunavir was not
`
`known to be a very potent molecule in terms of its activity
`
`against HIV protease inhibitors,
`
`there would have been no
`
`motivation to conduct a crystallization screen.
`
`Q.
`
`Right. Now, it was well known by May of 2002 that
`
`crystalline forms of a drug substance could profoundly
`
`affect dissolution and bioavailability as well as properties
`
`such as stability and —— stability to humidity and
`
`temperature; correct?
`
`A.
`
`In order to answer that question,
`
`I would need to know
`
`1
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`3
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`5
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`19
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`22
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`23
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`24
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`25
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 21 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 960 Filed 08/25/14 Page 115 of 199 Page|D: 57619
`
`1
`
`the context.
`
`1683
`
`Q.
`
`Well, how about the context of your declaration in
`
`this case? On December 23rd, 2013, at paragraph 141, you
`
`told the Court: "...it was well—known by May 16, 2002,
`
`that
`
`the crystalline form of a drug substance could ‘profoundly
`
`affect dissolution and bioavailability‘ as well as other
`
`properties such as stability to humidity and temperature."
`
`Correct?
`
`A.
`
`Q.
`
`Correct.
`
`Okay. And you've also told us that the chemical
`
`structure and the potency, at least in a test tube, of
`
`darunavir was known no later than Dr. Ghosh‘s 1998 paper;
`
`correct?
`
`A.
`
`I can't remember if the ‘775 patent was available
`
`before the Ghosh 1998, but it would have been around 1998.
`
`Q.
`
`The ‘775 patent was June of 2001, okay?
`
`So at least
`
`-— at least as of 1998 in your testimony by Ghosh‘s
`
`publication, darunavir and its potency were known; right?
`
`A.
`
`I'm relying on other witnesses as part of my opinion
`
`20
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`21
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`22
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`23
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`24
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`25
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`in this matter,
`
`in particular the testimony of Drs. Marshall
`
`and Zingman, and I also relied on Ghosh 1998 and the ‘775
`
`patent.
`
`Q.
`
`Okay.
`
`From the publication of Ghosh 1998 up until the
`
`‘645 patent, we can agree that no one had published a recipe
`
`for how to make a solid crystalline form of darunavir;
`
`CHARLES P. MCGUIRE, C.C.R.
`
`Janssen Ex. 2029
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 22 of 54)
`
`
`
`Case 2:10—cv—O5954—WHW—CLW Document 961 Filed 08/25/14 Page 1 of 204 Page|D: 57704
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF NEW JERSEY
`
`1768
`
`JANSSEN PRODUCTS, L.P. , et al.,
`
`Plaintiffs,
`
`v.
`
`LUPIN LIMITED, et al.,
`
`:
`
`:
`
`:
`
`Civil No.
`10—cv—5954(WHW)
`
`TRANSCRIPT OF
`TRIAL PROCEEDINGS
`
`VOLUME 10
`
`Defendants.
`— — — — — — — — — — — — — — — — — — — — — — — — — — — — — — ——x
`
`Newark, New Jersey
`
`April 2, 2014
`
`BEFORE:
`
`THE HON. WILLIAM H. WALLS, U.S.D.J.
`
`Reported by:
`CHARLES P. MCGUIRE, C.C.R.
`
`Official Court Reporter
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`Pursuant to Section 753, Title 28, United States
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`the following transcript is certified to be
`Code,
`an accurate record as taken stenographically in
`the above entitled proceedings.
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`s/CHARLES P. McGUIRE, C.C.R.
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`CHARLES P. MCGUIRE, C.C.R.
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`Janssen Ex. 2029
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`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
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`(Page 23 of 54)
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`Case 2:10—cv—O5954—WHW—CLW Document 961 Filed 08/25/14 Page 24 of 204 Page|D: 57727
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`1791
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`crystallization process, he testified to that.
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`THE COURT: He's got that in his report?
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`MR. ZALESIAN: Certainly he discusses the
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`three—step crystallization process.
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`THE COURT:
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`I haven't read the report, so I have
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`to go on what has occurred.
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`MS. MAZZOCHI: Your Honor,
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`I can assure you that
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`the word "seed" does not appear anywhere in Dr. Myerson's
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`expert report. Nor does he ever offer the opinion that you
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`somehow need to go through some isopropanol crystal before
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`you can get to the ethanol solvate.
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`THE COURT:
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`I will permit that. As far as the
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`s