1
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`
`CIVIL ACTION
`
`(Consolidated)
`
`NO. 13-1206-LPS
`
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`
`UCB, INC., UCB PHARMA GMBH,
`RESEARCH CORPORATION
`TECHNOLOGIES, INC., and
`HARRIS FRC CORPORATION,
`Plaintiffs,
`
`v
`ACCORD HEALTHCARE, INC., et al.,
`Defendants.
`
`- - -
`Wilmington, Delaware
`Monday, November 9, 2015
`Bench Trial - Volume A
`- - -
`HONORABLE LEONARD P. STARK, Chief Judge
`BEFORE:
`- - -
`APPEARANCES:
`MORRIS NICHOLS ARSHT & TUNNELL, LLP
`BY: JACK B. BLUMENFELD, ESQ.,
`MARYELLEN NOREIKA, ESQ.,
`DEREK J. FAHNESTOCK, ESQ.,
`ETHAN HALLER TOWNSEND, ESQ.,
`MEGAN E. DELLINGER, ESQ., and
`ANTHONY D. RAUCCI, EQ.
`and
`COVINGTON & BURLING
`BY: GEORGE F. PAPPAS, ESQ.,
`PAUL J. BERMAN, ESQ.,
`JEFFREY B. ELIKAN, ESQ.,
`PRICILLA DODSON, ESQ., and
`MICHAEL A. CHAJON, ESQ.
`(Washington, District of Columbia)
`and
`
`Dale Hawkins
`Registered Merit Reporter
`
`Brian P. Gaffigan
`Registered Merit Reporter
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`Mylan Pharms. v. Research Corp. Techs., IPR2016-01248
`RCT EX. 2002 - 1/156
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`
`CIVIL ACTION
`
`(Consolidated)
`
`NO. 13-1206-LPS
`
`:
`:
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`::
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`::
`
`UCB, INC., UCB PHARMA GMBH,
`RESEARCH CORPORATION
`TECHNOLOGIES, INC., and
`HARRIS FRC CORPORATION,
`Plaintiffs,
`
`v
`ACCORD HEALTHCARE, INC., et al.,
`Defendants.
`
`- - -
`Wilmington, Delaware
`Monday, November 9, 2015
`Bench Trial - Volume A
`- - -
`HONORABLE LEONARD P. STARK, Chief Judge
`BEFORE:
`- - -
`APPEARANCES:
`MORRIS NICHOLS ARSHT & TUNNELL, LLP
`BY: JACK B. BLUMENFELD, ESQ.,
`MARYELLEN NOREIKA, ESQ.,
`DEREK J. FAHNESTOCK, ESQ.,
`ETHAN HALLER TOWNSEND, ESQ.,
`MEGAN E. DELLINGER, ESQ., and
`ANTHONY D. RAUCCI, EQ.
`and
`COVINGTON & BURLING
`BY: GEORGE F. PAPPAS, ESQ.,
`PAUL J. BERMAN, ESQ.,
`JEFFREY B. ELIKAN, ESQ.,
`PRICILLA DODSON, ESQ., and
`MICHAEL A. CHAJON, ESQ.
`(Washington, District of Columbia)
`and
`
`Dale Hawkins
`Registered Merit Reporter
`
`Brian P. Gaffigan
`Registered Merit Reporter
`
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`APPEARANCES: (Continued)
`COVINGTON & BURLING
`BY: ALEXA R. HANSEN, ESQ., and
`TED TOROUS, ESQ.
`(San Francisco, California)
`Counsel for Plaintiff
`SHAW KELLER, LLP
`BY: DAVID FRY, ESQ.
`and
`COHEN & GRESSER, LLP
`BY:
`RICHARD G. GRECO, ESQ., and
`GURPREET (RAY) SINGH WALIA, ESQ.
`(New York, New York)
`Counsel for Accord Healthcare, Inc.,
`and Intas Pharmaceuticals, Ltd.
`BAYARD, P.A.
`BY:
`SARA BUSSIERE, ESQ.
`and
`CARLSON CASPERS VANDENBURGH LINDQUIST & SHUMAN
`BY: JEFFER ALI, ESQ., and
`SARAH M. STENSLAND, ESQ.
`(Minneapolis, Minnesota)
`Counsel for Alembic Pharmaceuticals Ltd.
`and Alembic Limited in Civil Action
`No. 13cv1207-LPS
`PHILIPS GOLDMAN & SPENCE, P.C.
`BY: JOHN C. PHILLIPS, JR., ESQ.
`and
`WINSTON & STRAWN, LLP
`BY: GEORGE C. LOMBARDI, ESQ., and
`MAUREEN L. RURKA, ESQ., and
`JOHN R. McNAIR, ESQ.
`(Chicago, Illinois)
`and
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`APPEARANCES: (Continued)
`
`3
`
`WINSTON & STRAWN, LLP
`BY: CHARLES B. KLEIN, ESQ., and
`EIMERIC REIG-PLESSIS, ESQ.
`(Washington, District of Columbia)
`Counsel for Amneal Pharmaceuticals, LLC,
`Amneal Pharmaceuticals of New York, LLC,
`Aurobindo Pharma Ltd., Aurobindo Pharma
`USA, Inc., Breckenridge Pharmaceutical,
`Inc., Vennoot Pharmaceuticals, LLC,
`Sun Pharma Global FZE, Sun Pharmaceutical
`Industries, Ltd., Watson Laboratories,
`Inc. – Florida (n/k/a Actavis
`Laboratories FL, Inc.), Watson Pharma,
`Inc. (n/k/a Actavis Pharma, Inc.) and
`Actavis, Inc
`
`MORRIS JAMES, LLP
`BY: KENNETH L. DORSNEY, ESQ.
`and
`TAFT STETTINIUS & HOLLISTER, LLP
`BY: RICHARD T. RUZICH, ESQ., and
`IAN SCOTT, ESQ.
`(Chicago, Illinois)
`Counsel on behalf of Apotex Corp. and
`Apotex Inc.
`
`YOUNG CONAWAY STARGATT & TAYLOR, LLP
`BY: ADAM W. POFF, ESQ.
`and
`WILSON SONSINI GOODRICH ROSATI, P.C.
`BY: DAVID S. STEUER, ESQ.
`(Palo Alto, California)
`and
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`APPEARANCES: (Continued)
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`4
`
`WILSON SONSINI GOODRICH ROSATI, P.C.
`BY: NICOLE STAFFORD, ESQ., and
`ADEN ALLEN, ESQ.
`(Austin, Texas)
`and
`
`WILSON SONSINI GOODRICH ROSATI, P.C.
`BY: YONGDAN LI, ESQ.
`(Los Angeles, California)
`Counsel for Mylan Pharmaceuticals Inc.
`and Mylan Inc.
`
`MURPHY & LANDON
`BY: FRANCIS J. MURPHY, ESQ.
`and
`LOCKE LORD, LLP
`BY: MICHAEL J. GAERTNER, ESQ., and
`DAVID B. ABRAMOWITZ, ESQ.
`(Chicago, Illinois)
`Counsel for Zydus Pharmaceuticals (USA)
`Inc. and Cadila Healthcare Limited
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`67
`
`Heathcock - direct
`(A brief recess was taken.)
`*
`*
`*
`(Proceedings reconvened after recess.)
`THE COURT: You may call your witness.
`MR. KLEIN: Good morning, Your Honor. I was
`introduced, but my name is Chuck Klein. I'm with Winston &
`Strawn.
`
`And the defendants call as their first witness
`Dr. Clayton Heathcock.
`THE COURT: Okay.
`MR. KLEIN: Your Honor we have some binders.
`May I bring them up?
`THE COURT: Yes.
`MR. KLEIN: Where would you like them?
`THE COURT: Just leave them there. Thank you.
`(Binders passed forward.)
`... CLAYTON HEATHCOCK, having been first duly
`sworn, was examined and testified as follows ...
`THE COURT: Good morning, Dr. Heathcock. And
`welcome to you.
`You may proceed when you are ready.
`THE WITNESS: May I put these over there?
`THE COURT: Yes, feel free to use the counter.
`DIRECT EXAMINATION
`
`BY MR. KLEIN:
`
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`68
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`Heathcock - direct
`Good morning, Dr. Heathcock.
`Q.
`Good morning.
`A.
`What is your full name?
`Q.
`Clayton Heathcock.
`A.
`Where do you work?
`Q.
`I am emeritus professor of chemistry, the University
`A.
`of California-Berkeley, and I am now retired.
`Q.
`Did the defendants retain you as an expert to testify
`in this case?
`A.
`Yes, they did.
`Q.
`What is your area of expertise?
`A.
`My area of expertise is organic and medicinal
`chemistry.
`Q.
`What is organic chemistry?
`A.
`Organic chemistry is one of the traditional subfields
`of chemistry that deals specifically with compounds based on
`carbon, dealing with carbon.
`Q.
`What is medicinal chemistry?
`A.
`Medicinal chemistry is that subsection of organic
`chemistry in which the compounds of carbon have properties
`such that they can interact with biological systems and
`have the potential to be used as medicine or to be used to
`study diseases.
`Q.
`On the screen is DDX-76. It's a snapshot of
`DTX-2184. Can you identify this document, please?
`
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`69
`
`Heathcock - direct
`Yes. That is the first page of my curriculum vitae.
`A.
`How long have you been a chemist?
`Q.
`Two years ago, I got my 50 year pin from the American
`A.
`Chemical Society.
`Q.
`And can you summarize your professional education?
`A.
`I was raised in San Antonio, Texas and attended the
`high school there.
`I attended college in Abilene, Texas, received a
`Bachelor of Science Degree in Chemistry there in 1958.
`After two years working as a chemist in
`industry, I entered a graduate program at the University of
`Colorado. Boulder, Colorado. I received a doctorate there
`in organic chemistry and natural products, synthetic
`chemistry of natural products.
`I did one year of additional training at
`Columbia University as a post-doctoral associate '63 to '64.
`Q.
`Please summarize your work history.
`A.
`While I was at Columbia University, I was offered and
`accepted a position at the University of California in
`Berkeley. I went there and began work as an assistant
`professor in 1964.
`I continued in that position for my entire
`career. I went through the normal academic ranks:
`associate, full professor.
`During my time at Berkeley, I was Chair of the
`
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`70
`
`Heathcock - direct
`Chemistry Department for three years.
`And for the last six years, I was Dean of the
`College of Chemistry.
`I retired as Dean in 2005 and was recalled as
`Chief Scientist for a disciplinary research institute called
`California Institute for Quantitative Biosciences. I held
`that position for three years and finished that job in 2008.
`Since then, I have continued as a volunteer but
`I am not on the payroll anymore.
`Q.
`Have you published any articles?
`A.
`About 250 articles in my career. Mostly
`peer-reviewed articles in journals of chemistry. Some
`books, book chapters and two patents.
`Q.
`Have you published textbooks?
`A.
`I have a textbook of which I am coauthor. It has had
`four editions. It is entitled, Introduction to Organic
`Chemistry.
`Q.
`Have you also edited peer-reviewed journals?
`A.
`Yes, I served as Editor in Chief for the Journal of
`Organic Chemistry for I think 11 years.
`I have also been a member of advisory boards,
`editorial advisory boards for other journals and, of course,
`as all scientists do, I have given my opinion as a reviewer
`of manuscripts to a number of different journals.
`Q.
`Have you consulted for pharmaceutical companies?
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`71
`
`Heathcock - direct
`Yes. I have three long-term retainer-type
`A.
`consultancies: one with Merck, one with Abbott, one with
`Plexxikon. These were each for periods of about 10 years.
`In addition to that, I have done one- and
`two-day ad hoc consultancies for many companies over my
`career. These usually involve giving a seminar, signing a
`confidentiality agreement, and then consulting with the
`researchers for a day or two on their projects to give them
`advice.
`Do you have any experience in the area of
`Q.
`antiepileptic drugs?
`A.
`I was a member of the National Institutes of Health,
`the medicinal chemistry study section, in the late 1970s,
`early 1980s for four years. I actually chaired that group
`for two of those four years.
`During that general period, there was an NIH
`RFP, that is, Request For Proposals, for people to submit
`grant proposals for anticonvulsives and particularly
`epilepsy drugs.
`We received -- they received about 110
`applications. I was appointed to the special study group to
`evaluate those 110 applications and did so along with about
`15 other people.
`We studied the applications, ranked them, and
`the NIH presumably awarded funding for the better ones.
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`72
`
`Heathcock - direct
`So that's the time when I first became familiar
`with the field of anticonvulsive drugs. I haven't done any
`independent research in my own laboratory, however.
`THE COURT: Does your CV accurately list your
`publications and honors over the course of your career.
`A.
`Yes, it does. That's the later pages of my CV lists
`all my publications, and there is a summary of honors on
`this first page.
`MR. KLEIN: Let's turn to that.
`And, Your Honor, I'll introduce the exhibits at
`the end, if that is okay.
`THE COURT: That's fine.
`BY MR. KLEIN:
`Q.
`Please summarize the most notable honors you received.
`A.
`Well, I'll just single out the two or three of these.
`The award for Creative Work in Synthetic Organic
`Chemistry is one of the American Chemical Society awards.
`That had some special significance for me at that time.
`The Prelog Medal, the one that is listed in the
`middle, is a prize that is given annually by the Swiss
`Federal Institute of Technology, chemistry group. It's
`named in honor of Vladimir Prelog who was a Noble laureate.
`That one really stands out in my memory because it was a
`special time. My wife and I were flown to Zurich to receive
`the dinner and have a dinner with Dr. Prelog and his wife.
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`73
`
`Heathcock - direct
`That is still a very cherished memory for me.
`And then I guess the third thing I will mention
`is that I was elected a Fellow of the National Academy of
`Sciences about 20 years ago, and that is a special honor for
`any scientist.
`Q.
`What does it mean to be elected to the National
`Academy of Sciences?
`A.
`This is a group of scientists that is convened to not
`only for -- it's not only an honors group but actually does
`provide advice to the president from time to time on science
`matters.
`
`About five or six chemists are elected each
`year, and you have to be voted on not only by other chemists
`but by other scientists generally. So you do have to
`achieve enough stature that biologists and other scientists
`are willing to vote for you.
`Q.
`Have you testified as an expert in a patent case
`before?
`Yes, I have.
`A.
`How about in Delaware?
`Q.
`I think this is my seventh appearance in Delaware in
`A.
`this court building.
`Q.
`And have both branded and generic pharmaceutical
`companies retained you as an expert or a consultant with
`regard to litigation?
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`Heathcock - direct
`
`74
`
`A.
`
`Yes.
`
`MR. KLEIN: Your Honor, at this time we tender
`Dr. Heathcock as an expert in organic and medicinal
`chemistry.
`
`MR. BLUMENFELD: No objection, Your Honor.
`THE COURT: He is so recognized.
`BY MR. KLEIN:
`Q.
`Let's turn to DDX-78.
`Do you have slides to assist the Court with your
`testimony today?
`A.
`Yes, I do.
`Q.
`And can you summarize the key opinions you intend to
`present?
`A.
`Well, I have opinions on these three, in these three
`areas.
`
`In my opinion the claims are anticipated by the
`LeGall thesis, which disclosed the lacosamide structure.
`If the Court were to decide that that is not the
`case, it is my opinion the claims are at least obvious in
`view of that thesis and other prior art, including the '729
`patent, which is an earlier patent that covers, that
`includes lacosamide.
`And then, finally, it is my opinion that the
`claims are not patentably distinct from the '301 patent
`claims that cover lacosamide.
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`Q.
`
`A.
`
`75
`
`Heathcock - direct
`If we go to the next slide.
`What are the topics that you intend to present?
`These are three broad areas of my testimony:
`I'll first briefly review the asserted claims.
`Then I have a little background and tutorial
`
`section.
`
`And then I will go through my invalidity
`
`opinions.
`Q.
`Let's turn to DDX-80 on the screen is JTX-001.
`Can you identify this document?
`Yes. This is the front page of the '551 patent.
`A.
`This is the patent-in-suit. It was a reissued patent. It
`was originally the '475 patent. It was published as a
`reissue in 2004. It claimed priority to an original
`application in March of 1996. The inventor is Harold Kohn.
`And it was -- I guess that is all I really need
`to say about this.
`Q.
`Okay. You mentioned the March 15th, 1996 date. Is
`that the critical date or the date you used to determine
`prior art?
`A.
`Yes. That is the date that I consider the priority
`date, and publication before that time would be prior art.
`Q.
`Turning to slide DDX-81.
`Is this the independent claim of the '551 patent?
`Yes. This is the basic independent claim of that
`
`A.
`
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`76
`
`Heathcock - direct
`patent. It covers that genus described here in the R
`configuration, all molecules described by that structure in
`the R configuration.
`It has a few variables, Ar, Q. Q1 isn't really
`a variable because it says that has to be methyl, but it has
`two variables and there may be 2,000 compounds.
`Q.
`Turning to DDX-82.
`Can you explain what claim 8 covers?
`Yes. So the asserted claims are 9, 10, and 13, but 9
`A.
`immediately refers to claim 8. So claim 8 names a compound,
`only one compound from that claim 1. And it is the compound
`that is described by that highlighted name, (R)-N-benzyl
`2-acetamido-3-methoxypropionamide.
`Now, it has no other limitations in that main
`
`compound.
`
`Claim 9 -- did you ask me to go ahead?
`Before we get to claim 9, does the compound that is
`Q.
`highlighted have another name?
`A.
`Well, that is the compound that is now known as
`lacosamide. Yes.
`Q.
`Was lacosamide a novel compound as of 1996?
`A.
`Well, no, it wasn't. Because it had been disclosed
`in this LeGall thesis that we have already heard about this
`morning.
`Q.
`And did you review the prosecution history for this
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`Heathcock - direct
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`77
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`patent?
`Yes.
`A.
`Was the LeGall thesis reviewed by the Patent Office
`Q.
`in connection with the issuance of the '551 patent?
`A.
`No, it does not seem to have been disclosed in that
`case.
`Okay. And I think you covered already there are
`Q.
`three asserted claims in the case?
`A.
`Yes.
`Q.
`Can you just very briefly summarize their scope?
`A.
`Okay. Claim 9, the first asserted claim is to a
`substance that comprises at least 90 percent of that main
`compound, 90 percent of the R stereoisomer of that main
`compound.
`
`Claim 10 is essentially a dosage form. It's a
`therapeutic composition of an anticonvulsant effective
`amount along with a carrier. It would be a pill or a
`capsule or something.
`And then claim 13 is a method of using that dose
`to treat a mammal to treat CNS, the anticonvulsant
`properties in a mammal.
`Q.
`Dr. Heathcock --
`A.
`In a human, specifically. I'm sorry. I said mammal
`but it was a human. We are mammals.
`Q.
`Do you have slides providing a tutorial of the
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`relevant science and underlying facts of this case?
`A.
`Yes.
`Q.
`What are you disclosing in DDX-84?
`A.
`Okay. I said that organic chemistry is the field of
`chemistry that deals with the compound of carbons. So I
`just want to describe what I meant by that.
`This is the simplest compound of carbon. Carbon
`is the element C. It is carbon always has four bonds. In
`this case, the four bonds are to four different hydrogens.
`So that molecule has a name. It is methane. It
`has a form, CH4, and that is the simplest organic compound.
`It is written as a flat structure on the left with the
`carbon just attached to those four hydrogens by lines.
`It really has a shape. The little picture on
`the right sort of symbolizes that it is a three-dimensional
`object. You can think of the carbon in the middle, which is
`the black ball, as being the center of that molecule. And
`then the four hydrogens are arranged around it at the
`corners of a regular tetrahedron. So this is the shape of a
`compound, the compound methane.
`Q.
`Turning to DDX-85. Are there more complicated carbon
`compounds?
`A.
`Yes. What makes organic chemistry a whole field
`is that carbon is very versatile in forming bonds to other
`elements. And, in particular, it can form bonds to other
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`carbons. So you can have larger compounds built up
`basically from carbon frameworks.
`So I have shown on this slide the top two
`structures both have five carbons. The one on the left, the
`five carbons are all joined to each other in a chain. And
`then each of those carbons has enough hydrogens so that it
`has a total of four bonds.
`That compound has a name, pentane. Pentane
`comes from the Greek word "pentose." Pentose means five,
`and it has a formula, C5H12.
`The compound on the right also has five carbons
`but now they're arranged in a ring. And that compound is
`called cyclopentane. It has the formula C5H10. Each carbon
`there is joined to two other compounds, its neighbors, and
`to two hydrogens so each of those also has four bonds.
`Furthermore, carbons can form bonds to other
`elements than carbon and hydrogen. Carbon and hydrogen are
`the most common elements found in any compound. But what
`makes compounds of this nature have chemical reactivity is
`the fact that they can be bonded to oxygens or nitrogens and
`other elements as well but oxygens and nitrogens are
`particularly common.
`But the compound on the left has five carbons
`like pentane does but it also has an OH group attended to
`the end, and that makes it an alcohol. And it has a name,
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`1-hydroxy pentane.
`Oxygen, unlike carbon, only wants to be bonded
`to two other things. So it is bonded to the carbon and one
`hydrogen.
`
`The compound on the right is what we call an
`amine. There, one of the carbons is bonded to a nitrogen,
`and nitrogen has the property, because of its place in the
`periodic table of elements, that it wants to be bonded to
`three things. And it is bonded here to a carbon and two
`hydrogens. So that is an example of an amine.
`Q.
`Are there shorthand ways to depict carbon compounds?
`A.
`Yes. What you will see when you read the prior art
`in the patents is generally all of these carbons and
`hydrogens aren't written specifically. Organic chemists
`agreed long ago to use the shorthand notation in which for
`pentane, for example, we don't write five carbons each with
`a number of hydrogens displaying out from it but we write a
`simple zig-zag line that has two Ns and three vertices, and
`each of those points, including the three vertices, is
`understood by us to refer to a carbon. And we also don't
`show the hydrogens explicitly unless they are particularly
`important for something we're talking about.
`And for pentane, we just draw the zig-zag line.
`We understand that each end and each of the vertices stands
`for a carbon, and we further understand at each of these
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`carbons there are enough hydrogens attached so the carbon
`has four bonds.
`And so cyclopentane would be represented by a
`simple pentagon. The bottom two structures show how we
`would represent hydroxyl pentane or 1-pentanol, and amino
`pentane or 1-pentane amine.
`Those, we do show the Hs when they're attached
`to the oxygen or nitrogen simply because those are
`frequently involved in chemical reactions and it is just a
`tradition that we don't omit those hydrogens.
`Q.
`So this is what the shorthand looks like?
`A.
`This is what these four compounds look like in our
`shorthand. As you look at it, you looked at most of the
`prior art publications in this case, for example, all we see
`this is the way compounds are represented.
`Q.
`If we move on to slide DDX-87, can you explain what
`isomers are?
`A.
`Yes. So this compound at the top is another example
`such as those. This one now has four carbons, so its name
`is butane. It has a formula C4H10. Then on the lower left
`of this panel, is shown 1-butanol, that is like the
`1-pentanol that I showed in the previous slide. But now I
`have also shown that you can attach that OH not only at the
`end but at one of the other carbons.
`So the compound on the bottom panel right is
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`2-butanol because the two means that the OH is attached at
`the second carbon. Both of those compounds, one butanol and
`2-butanol has the same formula, C4H10. In chemistry language
`compounds of that sort are called isomers. Isomers are two
`compounds that have the same formula, but they are connected
`differently. So these have the same C4H10 formula, but the
`ends are connected in a different way.
`Q.
`What are stereoisomers?
`A.
`The 2-butanol structure that's shown here in this
`slide isn't a complete, a fully complete representation of
`the possible structures that are -- that can exist with that
`arrangement. Because if you imagine the four carbons of the
`butane as sort of lying in the plane of the board,
`remembering that there is going to be two things attached to
`that second carbon, one of them is the oxygen and the other
`is the hydrogen that we don't normally show, the oxygen
`could be pointing out towards us into the courtroom, and the
`hydrogen could be pointing back away behind the screen or
`into the back wall of the courtroom. Or I could put it
`together the other way with the oxygen pointing away from us
`and the hydrogen pointing towards us. So those are two
`different compounds. Those are two different structures,
`two different molecules. They still have the same formula.
`They also have the same connectivity, but they differ in
`this three dimensional aspect.
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`They are called stereoisomers. Stereo is from a
`Greek having to do with the spatial. So this is, these two
`are stereoisomers to each other.
`Q.
`And so would a chemist seeing the formula for
`2-butanol know that the 2-butanol has stereoisomers?
`A.
`Yeah, this is a basic principle that carbon makes
`four bonds and this structure does not, this structure does
`not give any further information other than that there are
`four different things attached to that number two carbon,
`and I as a chemist understand, any chemist would understand
`that there are two forms of that 2-butanol molecule and that
`those are the two forms that are written over at the right.
`Q.
`Can you explain what chirality means?
`A.
`Molecules like that that have the mirror image
`related stereoisomeric forms are call chiral. So 2-butanol
`is a chiral molecule. Your hands are chiral. And you have
`already seen this demonstration. Your hands are mirror
`images of each other, but they're not the same. So your
`hands are chiral. 2-butanol is chiral. So they have
`exactly the same, chiral molecules have handedness we say.
`When you have a 50/50 mixture of the two chiral enantiomers,
`that's called a racemic mixture or a racemate.
`Q.
`I'm not sure you explained what an enantiomer is.
`Can you do that, please?
`A.
`Yeah. The two different mirror image compounds have
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`what we call an enantiomeric relationship. Your hands have
`an enantiomeric relationship. They are mirror images, but
`they are not the same.
`Q.
`Do you have a demonstrative model to help illustrate
`your testimony with regard to chirality and enantiomers?
`A.
`Yeah, I made a three-dimensional finger toy model.
`MR. KLEIN: Your Honor, may I approach?
`THE COURT: You may.
`THE WITNESS: Okay. Let me -- it's been in the
`box, so let me get it out. I'm going to take the label and
`put it a little bit more out of the way. This is a DDX
`label.
`
`So this would be, this would be one of these,
`one of these molecules, and this would be -- excuse me for a
`second while I line it up right.
`These would be the two forms I'm talking about.
`You can see that the zigzag is in the same arrangement and
`the OH is pointing towards you in this case, and towards me
`in this case, and if I put these together, you see that
`although they're mirror images of each other, this is the
`mirror, they are not the same. So these are -- there are
`also attached a label to each one to indicate its name. And
`we will talk about that.
`THE COURT: I'm not sure for the record, did we
`identify what demonstrative exhibit number?
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`Heathcock - direct
`THE WITNESS: This is DDX-181.
`MR. KLEIN: Thank you, Your Honor.
`THE COURT: Thank you.
`BY MR. KLEIN:
`Q.
`Please explain the naming conventions for
`enantiomers?
`A.
`Because these are different compounds they have to
`have different names. There is a systematic unambiguous way
`of naming them. It's called the R S rule, it's something
`that suits undergraduates so it's something one of ordinary
`skill knows how to do. I won't go through how you do it,
`but it's a way of ranging the four different things that are
`attached to a carbon like this. And there that has four
`different things and then assigning an unambiguous label to
`the two different forms. These two that I illustrated one
`has the name R and one has the name S. Given that name, the
`chemist can construct the right model or given that model a
`chemist can assign the correct name.
`Q.
`Are there alternative names?
`A.
`There is a traditional nomenclature that goes way
`back to the early 1900s, perhaps even back into the 1800s
`where compounds were given a family name, particularly amino
`acids, and compounds were grouped into two families, the D
`family and the L family based on their common
`three-dimensional shapes.
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`And so you'll see that some of the prior art in
`this case talks about compounds as having the D
`configuration or the L configuration, and other prior art
`talks about them having the R configuration or the S
`configuration. So for purposes of the important compounds
`that we are concerned with, the compounds in the D family
`have the R configuration, so D is synonymous with R and L is
`synonymous with S.
`Q.
`Would a skilled artisan understand that in 1996?
`A.
`Yeah, certainly for the compounds that are going to
`be of importance to us, any person of ordinary skill would
`be able to understand that compounds of the D family have
`the R configuration.
`Q.
`Turning to slide DDX-90, on the screen is DTX-2225.
`Can you identify this document, please?
`A.
`This is an article from the European Journal of
`Clinical Pharmacology published in 1984, and the author is
`E.J. Ariens.
`Q.
`What is the article explaining with regard to what
`was known at the time concerning stereoisomers and
`enantiomers?
`A.
`Well, one of the conclusion statements, I'll just
`jump to the bottom of that slide is sort of obvious, that in
`developing drugs, it is preferable to use compounds with as
`few impurities as possible, that's just common knowledge
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`that you don't use impure materials as drugs. And the real
`import of this paper was to be aware, certainly in 1984, was
`aware that stereoisomers are different compounds, as I just
`illustrated. These two stereoisomers are 2-butanol or
`different compounds. And it highlights that stereo
`selectivity in drug action means that when using a mixture
`of such isomers, only one is therapeutically active. This
`is generally the case. And that the inactive isomer in such
`cases is nothing more than an impurity. For example, in a
`racemate this would be a fifty percent pure drug, the other
`half would be an impurity because it had no therapeutic
`activity.
`Q.
`Before 1996, what would a skilled artisan understand
`to be a pure compound with as few impurities as possible in
`connection with an enantiomer, what level of impurity?
`A.
`Certainly it was within the skill set of ordinary
`artisans at that time to make compounds and to separate
`purified compounds to very close to a hundred percent
`enantiomeric purity.
`Q.
`Let's turn to slide DDX 91. It's DTX-2230. Can you
`identify this document, please?
`A.
`This is an article from the journal by the name
`Chirality. Chirality as I said is the property of spatial,
`it's a spatial property wherein compounds are not
`superimposable and they're mirror image of different
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`compounds. And it is authored by a Wilson DeCamp.
`It states what is stated in the title to be the
`FDA perspective on the development of stereoisomers. I
`think they mean on the development of drugs that have this
`stereoisomeric property. And a couple of things that I have
`highlighted here, one passage from his article, DeCamp
`indicates that it has become routine to separate racemates
`and obtain optically pure material. Optical pure material
`means the same thing as an enantiomeric pure material. The
`enantiomeric composition was traditionally measured using an
`optical technique when a chemist says something is optically
`pure, that was the same as saying it was enantiomerically
`pure.
`
`Another passage in this, DeCamp advises that in
`cases like this, the enantiomers should be separated or they
`should be synthesized independently.
`Q.
`What's the difference between separating an
`enantiomer and synthesizing an enantiomer independently?
`A.
`If one wants to have an enantiomerically homogeneous
`compound, there are really two ways you can go about getting
`it. One you can take a sample that is a racemic mixture and
`you could separate it in some way. There are a number of
`ways that chemists have developed to separate enantiomers
`from each other. One is a method called chiral
`chroma
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