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`UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
`
`______________________________
`UNITED THERAPEUTICS CORPORATION,
`
`Vs.
`SANDOZ, INC.,
`DEFENDANT
`______________________________
`
`CIVIL NO.
`12-1617 (PGS)
`13-316
`
`MAY 1, 2014
`CLARKSON S. FISHER COURTHOUSE
`402 EAST STATE STREET
`TRENTON, NEW JERSEY
`08608
`
`B E F O R E:
`
`THE HONORABLE PETER G. SHERIDAN
`U.S. DISTRICT COURT JUDGE
`DISTRICT OF NEW JERSEY
`
`TRIAL DAY 1 - TUTORIAL
`
`Certified as true and correct as required
`by Title 28, U.S.C. Section 753
`/S/ Francis J. Gable
`FRANCIS J. GABLE, C.S.R., R.M.R.
`OFFICIAL U.S. REPORTER
`(856) 889-4761
`
`United States District Court
`Trenton, New Jersey
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`MR. JACKSON: Unless the Court has questions for Dr.
`Miller, that concludes the tutorial about the gram negative
`killing and the bactericidal effect. We thought it would be
`useful to go through the disease with Dr. White, the bacteria,
`and then the other patent, which is the actual synthesis of
`the molecule next. Unless the Court has questions for Dr.
`Miller.
`
`No, I think I've got it. Thank you.
`THE COURT:
`DR. MILLER: Thank you.
`(Dr. Miller excused.)
`MR. CARSTEN: So, your Honor, Dr. White started out
`with the whole body, the patient if you'll have it, the
`medical doctor talking about the disease and talking about the
`manner in treating that disease.
`Dr. Miller just talked about smaller scale, the
`cells, the bugs as he called them, and the effect of the
`particular diluents or buffers on the growth or killing of
`those particular bugs.
`Now, if we, you know, take off our microscope
`glasses and get down to sort of even smaller, you know,
`molecule level, we're going to be talking about some
`chemistry.
`And we brought with us here Professor Robert
`Williams, from Colorado State University, a synthetic organic
`chemist, who's going to talk to you about the '117 patent and
`the chemistry involved in that patent.
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`So, Professor Williams?
`PROFESSOR WILLIAMS:
`Good afternoon, your Honor.
`THE COURT:
`Good afternoon. How are you today?
`PROFESSOR WILLIAMS:
`Good.
`So, my name is Robert Williams from Colorado State
`And on behalf of plaintiff
`University, I'm a professor there.
`I've been asked to give a simple tutorial, a basic tutorial on
`some organic chemistry basics, we're going to hear a lot about
`organic chemistry in the coming days. And I'll tell you a
`little bit about treprostinil and treprostinil sodium, and
`I'll also talk a little bit about the novel aspects of the
`'117 patent invention.
`THE COURT: All right, thank you.
`PROFESSOR WILLIAMS:
`So first on chemical bonding
`and molecular structures we're going to see a lot of chemical
`structures with respect to the '117 patent. And treprostinil
`is an organic molecule, and most organism molecules are
`composed of the elements carbon, hydrogen, nitrogen and oxygen
`atoms, and organic compounds sometimes contain additional
`elements, like sulphur, phosphorous, chlorine and so on.
`Treprostinil itself only contains carbon, hydrogen and oxygen.
`And chemistry is a convention to draw three
`dimensional molecules on two dimensional surfaces, and so
`there's an example here.
`And because the skeletons of organic
`molecules are composed of carbon, instead of drawing little Cs
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`all over the place we've adopted a convention where the
`intersection of lines represent carbon atoms. And then other
`elements like oxygen and so forth we would specifically label
`at their appropriate position.
`And so the lines in these structures represent
`chemical bonds connecting the atoms in the molecular
`structure.
`So, a line like this, just one line is a single
`bond; between those two carbons, and sometimes carbon engages
`in more than one bond to another carbon so we draw two lines,
`that would be a so-called double bond. Sometimes carbon atoms
`engage in three bonds between each other, so we draw three
`lines like shown here, that's a triple bond.
`Organic molecules sometimes have linear portions
`like this chain here, and sometimes there's ring structures
`like there aromatic ring.
`THE COURT:
`Where's the aromatic ring?
`PROFESSOR WILLIAMS:
`That's the six membered ring
`right here, and it's three double binds inside the ring. And
`so for example here I said other elements would be
`specifically identified, so there's an oxygen atom, it's
`bonded with the hydrogen, that's called an hydroxyl group; and
`we also -- chemists have lots of acronyms unfortunately, but
`-- and we'll hear about some of those, so Me is an acronym for
`a methyl group or a CHe group. And we'll hear about this
`acronym a little bit later in the litigation, THP, is a
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`so-called alcohol protecting group that's connected to an
`oxygen atom.
`Now, also in this figure chemists have a convention
`where because molecules are three dimensional we want to
`represent their three dimensional structures on a two
`dimensional surface, we have a convention where straight lines
`indicate projection of that bond in the plane of the paper or
`surface; a darkened wedge would indicate projection away from
`the plane of that surface toward you; and a hashed line would
`indicate projection of that bond behind the screen or away
`from you.
`
`Now, another term we're going to hear a lot about
`in the trial is the issue of stereoisomers, and what are
`stereoisomers.
`Well, stereoisomers are molecules, related
`molecules that have the same connectivity of atoms, but
`they're arranged in a different three dimensional
`configuration in space.
`Another term we're going to hear --
`and I'll illustrate this for you in just a minute with a
`little movie clip, another term we're going to hear is a terms
`called enantiomers, and this is an term chemists have used to
`describe molecules that are non-superimposable mirror images
`of each other, just like our left hand is a non-superimposable
`mirror image of our right hand. You know, if you try to put
`your left hand into a right-handed glove, it just doesn't feel
`quite right, it doesn't fit in there.
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`And because of this property, particularly in
`organic chemistry, molecules can be produced in both
`enantiomeric forms, and chemists can measure the enantiomeric
`excess of one stereoisomer over the other, and we express that
`by the term enantiomeric excess or ee, which is a measure
`of -- one measure of purity.
`So here to just drive home this concept of
`non-superimposable mirror images, here I have a carbon atom
`that I've just chosen four different colors, and carbon atoms
`that are bonded to four different groups, are called
`stereogenic centers or chiral centers.
`And so here's a carbon
`atom now bonded to four different groups or atoms, and just
`think of this as the right-handed version of that molecule.
`Now, if that molecule went up to a mirror, the image
`it would see reflected in the mirror is what's shown on the
`right. Now, to prove that these two images are
`non-superimposable, what I'm now going to do is I'm going to
`rotate, spin the molecule on the left, and then I'm going to
`move it over and try to superimpose it into a ghost image of
`the molecule on the right. And so you can see that the white
`and the red groups line up or superimpose, but the green and
`purple ones are in opposite places in space. So this is by
`definition non-superimposable. So those molecules are
`enantiomers.
`Just a little background on the treprostinil
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`molecule, which is not shown on this slide, I'll show it to
`you on the next one. It belongs to a family of very
`biologically active molecules, natural molecules that are
`derived from this 20 carbon molecule called -- called
`arachidonic acid. And in all cells arachidonic acid is
`present, and depending on the state of the cell and the
`tissue, the environment, arachidonic acid can be oxydatively
`converted by enzymes into this complex structure, called
`prostaglandin H2, or PGH2, which is an important gateway
`molecule for which a host of other very biologically important
`and active natural hormones can be produced.
`So for example, PGH2 can be selectively converted
`into the prostaglandins like PGE2 and PGF2 which are important
`in birth.
`So for example, PGF2 induces labor, and PGE2
`softens the cervix and induces uterine contraction.
`The structurally related molecule that is also
`derived from the rearrangement of this precursor molecule
`PGH2, is prostacyclin, also known as PGI2.
`And the biological
`function of prostacyclin inhibits platelet aggregation and is
`a potent vasodilator. So prostacyclin is what keeps our blood
`fluid, inhibits blood platelets from aggregating together.
`Now another very important molecule has just the
`opposite effect of prostacyclin that's also derived from PGH2,
`is a molecule known as thromboxane A2.
`And what thromboxane
`does is this is a very potent inducer of platelet aggregation,
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`and is a potent vasoconstrictor. So when we get cut,
`thromboxane A2 is rapidly produced, we get a blood clot so our
`blood doesn't all flow out of us when we get injured, and so
`you can see that small differences in chemical structure
`between this family of molecules, is manifest as vastly
`different types of biological activities.
`THE COURT:
`Can you go back to that --
`PROFESSOR WILLIAMS:
`Sure.
`THE COURT:
`Can you just go through what the -- I
`can't say that word; arachidonic acid?
`PROFESSOR WILLIAMS: Arachidonic acid.
`THE COURT:
`So that goes into -- I can see on the
`bottom you regroup or -- I forget the word you used, but
`reformulate the PGH2, and you get these other PGF2 and PGE2,
`things of that nature --
`Correct.
`PROFESSOR WILLIAMS:
`THE COURT:
`But I don't get what the arachidonic
`
`acid does.
`
`This is the starting or the
`PROFESSOR WILLIAMS:
`substrate molecule, the ubiquitous substrate molecule, that is
`ultimately derived from phospholipid bilayers, it's a fatty
`acid present in all cells; and it can be recruited when
`needed. And so this function right here, this carboxylic acid
`appears there and there and there, and there; and this CH3
`group, the methyl group, so all of those same positions. As
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`we do some chemistry, forming bonds and adding oxygens to the
`center part that makes these different molecular structures.
`THE COURT:
`All right. So, the arachidonic acid is
`somehow engulfed in PGH2; is that what --
`PROFESSOR WILLIAMS:
`It's converted to PGH2.
`Oh it's converted. How?
`THE COURT:
`PROFESSOR WILLIAMS:
`How?
`THE COURT:
`How is it converted?
`PROFESSOR WILLIAMS:
`It's actually a very
`fascinating and complicated reaction, it involves the addition
`of two molecules of oxygen; one is right there, the other one
`is derived from there. And there's going to be a bond formed
`across here that forms this five membered ring that we see
`present in these three structures.
`THE COURT:
`So once you get the arachidonic acid
`converted to the PGH2, then you can reconvert to those other
`substances below.
`So depending on --
`Correct.
`PROFESSOR WILLIAMS:
`THE COURT:
`I said substances, that isn't the right
`
`word --
`
`Certain enzymes will be
`PROFESSOR WILLIAMS:
`recruited to convert PGH2 into the needed hormones, depending
`on what that cell or tissue or organ requires at that given
`time.
`
`THE COURT: All right.
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`Is that clear?
`PROFESSOR WILLIAMS:
`THE COURT:
`Well, I don't know about clear, but I
`understand somewhat.
`Okay. May I continue?
`PROFESSOR WILLIAMS:
`THE COURT:
`Yes, you may.
`PROFESSOR WILLIAMS:
`Here now is the structure of
`treprostinil on the right, it has a very complex molecular
`And
`structure like these hormones I just showed you.
`treprostinil, which is the active ingredient in Remodulin, is
`a structural analog of the natural hormone prostacyclin. So
`we can see some similar functionally; for example, up here is
`that carboxylic acid that we just talked about, and that's
`also present in treprostinil.
`And we had the same sort of
`side chain on the bottom with these oxygen atoms that you can
`see; this five membered ring and a five membered ring there.
`And one of the big differences that treprostinil
`being a synthetic molecule, totally synthetic molecular as
`you'll see, is called and you'll see this in the patent
`language as well, is a 9-Deoxy PGF1 type compound. So with
`carbon 9, in the natural hormone there's an oxygen, whereas in
`treprostinil at that same carbon atom in that five membered
`ring, we don't have an oxygen but rather we have a carbon atom
`at that position.
`May I proceed?
`THE COURT:
`Yes, you may. Well, if you could go
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`It means like it's a model, it
`
`back to that prior -- so we're doing the treprostinil now, but
`how is the treprostinil related to the chart before that one?
`PROFESSOR WILLIAMS:
`So it's not derived from
`arachidonic acid, as we see it's synthesized from completely
`different types of molecules, but once it's assembled parts of
`the treprostinil molecule over-layer look like or resemble the
`natural hormone prostacyclin.
`So treprostinil is not made
`from arachidonic acid.
`All right. So when you use the word
`THE COURT:
`analog, what does that mean?
`PROFESSOR WILLIAMS:
`looks very similar to.
`Oh, okay.
`THE COURT:
`It resembles prostacyclin in
`PROFESSOR WILLIAMS:
`It has structural features which are very similar,
`many ways.
`which imparts its biological activity.
`THE COURT:
`All right, thank you.
`PROFESSOR WILLIAMS:
`As we just talked about this
`concept of stereoisomerism, the treprostinil molecule actually
`contains five of these so-called stereogenic centers or chiral
`centers; in other words, carbon atoms that have four different
`groups bonded to each of those carbons, and I've highlighted
`those in red. And because each of those stereogenic centers
`or chiral centers can be either left-handed or right-handed,
`chemists use a nomenclature convention, we call those R or S.
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`And so since each of those stereogenic centers can be left or
`right-handed.
`Within this connectivity of atoms represented by
`this structure, the total number of possible stereoisomers
`that that molecular structure can represent, is the product of
`all of the stereogenic centers. So two times two times two
`times two times two which is 32, possible centers that can
`have the same connectivity as we see here for treprostinil.
`Now, to just show complicated this is, I've taken
`the trouble of drawing, even though the resolution of this is
`not all that easy to see, you might see it better on your
`screen here. But treprostinil is just one of those 32
`possible stereoisomers, okay.
`And so all those other isomers
`will differ at their configuration at those stereogenic
`centers at one or more positions.
`Now, the treprostinil compound is not and can never
`be one hundred percent pure in the real world. And so
`Remodulin as is depicted here which contains treprostinil as
`the active pharmaceutical ingredient, typically has with it
`small amounts of other stereoisomers based on that same
`molecular structure. And so these are boxed and have some
`code names; so treprostinil, the important active ingredient,
`also as a result of the chemical synthesis process,
`manufacturing process, also contains some of this other isomer
`1AU90, 2AU90, and 3AU90.
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`why?
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`And just typical average impurities in a typical
`clinically used sample of treprostinil, Remodulin would be
`mostly treprostinil, but contained in that vial also would be
`small amounts, .047 percent of 1AU90, .04 percent of 2AU90,
`and .25 percent of 3AU90. And those again are averages
`because these amounts vary from batch to batch.
`THE COURT: And it's always those three?
`PROFESSOR WILLIAMS:
`Those are always identified as
`trace impurities in the treprostinil product.
`THE COURT: And they show up in the treprostinil
`Because --
`It's a result of the chemical
`PROFESSOR WILLIAMS:
`synthesis process that inadvertently or unfortunately does
`produce some other small amounts of these stereoisomers.
`THE COURT:
`Okay.
`I also want to introduce you to
`PROFESSOR WILLIAMS:
`-- you're going to hear treprostinil is the acid in
`treprostinil sodium, and just so you know what these two
`substances are, treprostinil as the acid, this is the acid
`functional group right there; when you put it into water,
`depending on the pH, will rapidly dissociate in solution like
`water. And in the presence of a base like sodium hydroxide,
`the hydrogen atom on that acid right there, that hydrogen atom
`will get donated to the OH here in sodium hydroxide, making a
`water molecule, and then the sodium as a result of losing the
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`Can I proceed?
`
`proton from here, get together to form treprostinil sodium.
`And so these two species are always present in
`aqueous solution, and their relative ratio or proportion is a
`direct function of the pH, and Dr. Miller just told us a
`little bit about the pH scale. So depending on the pH, that
`will determine the relative ratio of these two species, but in
`any pH there will be some acid and some of the salt.
`THE COURT:
`Okay.
`PROFESSOR WILLIAMS:
`THE COURT:
`You may.
`Okay. So, just to introduce
`PROFESSOR WILLIAMS:
`some aspects of the '117 patent, this was the first invention
`where stereoselectively produced treprostinil was made
`possible.
`The '117 patent also brought vastly improved yields
`as we'll see in a minute, that this is a synthetic compound
`and yields are very important, in the synthesis of the
`molecule.
`And a commercially viable and practical synthesis
`of any drug molecule including treprostinil when there are
`stereoisomers at issue, must make mostly one of those possible
`32 stereoisomers.
`That third point you just raised there,
`THE COURT:
`commercially viable and practical synthesis must make one of
`the possible 32 --
`PROFESSOR WILLIAMS:
`possible 32 stereoisomers --
`
`Must make mostly one of those
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`Why is that important, Doctor?
`THE COURT:
`PROFESSOR WILLIAMS:
`Because only the stereoisomer
`that has a configuration, a stereochemical configuration --
`let me go back for a minute.
`Can you bring me back?
`Here. Only the stereoisomer that has the same
`configuration at those centers, one, two, three, four, five,
`are the same one, two, three, four, five centers, those are
`the same as the natural hormone prostacyclin. And
`treprostinil bonds to the same biological receptor that the
`natural hormone prostacyclin bonds to. So that three
`dimensional display of atoms is extremely important to the
`proper biological function of this drug.
`Other stereoisomers may have no biological effect or
`a deleterious biological effect. So that's why it's extremely
`important when there's other stereoisomers possible that the
`manufacturing process must make mostly one, the desire of
`biologically active isomer.
`THE COURT:
`Okay, thank you.
`PROFESSOR WILLIAMS:
`Okay?
`Can we go back to the -- forward where to where I
`
`was?
`
`So just -- we're going to be seeing the claims at
`issue in the '117 patent, so just some background on what
`these claims are going to look like, again we're going to be
`seeing lots of these chemicals formulas, these molecular
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`SteadyMed v. United Therapeutics
`IPR2016-00006
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`structures. And representative claim 1 reads: A
`stereoselectively produced compound; okay, so this would be
`this more generic like structure represents treprostinil.
`Treprostinil fits into that first structure, so it's a
`stereoselectively produced compound. And it's going to be
`made using as a starting material this novel starting enyne;
`that term enyne refers to the double bond down here, and the
`yne part of the triple bond. So novel starting enyne is going
`to have a structure just like this --
`THE COURT:
`When you say the novel starting enyne,
`what do you mean by novel?
`That this hadn't been described
`PROFESSOR WILLIAMS:
`elsewhere, and that this is a unique structural feature of the
`starting compound that's going to be used to manufacture the
`final drug.
`Okay. So when you have treprostinil,
`THE COURT:
`right, and I guess whatever it was known before you engaged in
`assembling this patent, does it have that novel starting enyne
`in it?
`
`No, so there was a prior
`PROFESSOR WILLIAMS:
`synthesis of treprostinil that used a completely different
`chemical route, and did not use this type of novel enyne as a
`starting material.
`All right.
`THE COURT:
`PROFESSOR WILLIAMS:
`So the '117 patent brings forth
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`IPR2016-00006
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`50
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`this novel starting material structure, that is then converted
`by a novel reaction that I'll describe in just a minute to
`make the next material --
`THE COURT:
`So how did you get to the novel starting
`enyne? You had this stereoselectively produced compound;
`right?
`
`Right.
`PROFESSOR WILLIAMS:
`THE COURT: And then how do you get down to the
`novel starting enyne? Or is that just part of that --
`PROFESSOR WILLIAMS:
`I'm going to show you that in
`just in a minute, I'll show you how we get there.
`THE COURT:
`Oh, okay.
`It's a complex multi stage
`PROFESSOR WILLIAMS:
`synthetic process to get there, but I'll show you in just a
`minute.
`
`Okay. The next part of the claim is that that novel
`starting enyne is going to be converted by an intramolecular
`cyclization, I'll describe that reaction in just a minute,
`into this three ring or tricyclic cyclized intermediate. Down
`here and you can see that that has part of but not all of the
`structural features of the molecule up at the top, the final
`drug molecule, treprostinil.
`So the claims at issue in the '117 patent, claims 1
`through 4, all have these basic characteristic starting
`compounds and cyclized intermediate.
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`SteadyMed v. United Therapeutics
`IPR2016-00006
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`

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`51
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`Okay. So when they used the
`THE COURT:
`intramolecular cyclization process, how does that occur?
`PROFESSOR WILLIAMS:
`I'm going to show you that
`So the '117 patent introduced a ground breaking
`right now.
`stereoselect reaction that's known as the Pauson-Khand
`reaction, which is named after the two inventors of this
`process -- of this reaction rather, the cyclization type
`reaction.
`And what happens, since you asked about how the
`cyclization proceed, down at the bottom of the slide here's
`our novel starting enyne, right there, now with a little bit
`more structural detail shown; and the Pauson-Khand reaction
`uses a very special reagent, specific reagent that's called
`dicobalt octacarbonyl.
`And what this reagent does is it makes this triply
`bonded carbon and that doubly bonded carbon form a new bond
`together right there by that dotted line; and then a carbon
`monoxide unit from this reagent shown right here, is going to
`be stitched in and we're going to form a new carbon carbon
`bond there and a new carbon carbon bond over here, to form now
`this novel tricyclic intermediate.
`So that's how that cyclization process occurs. And
`the '117 patent is the very first industrial application -- I
`think that's still true today, of the Pauson-Khand reaction to
`be used on an industrial scale.
`THE COURT:
`So when you say in your chart there, it
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`

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`says that, regardless of the stereochemistry if any of the
`reactants; what does that mean?
`Sure. So, as called out in the
`PROFESSOR WILLIAMS:
`patent claims, it says stereoselectively produced compound, if
`a compound is stereoselectively produced, it's going to
`produce predominantly one stereoisomer in the product
`regardless of whether or not there was any type of
`stereochemistry in the starting reactants or the starting --
`THE COURT:
`I see.
`So in this particular case,
`PROFESSOR WILLIAMS:
`here's our starting enyne, it actually has two existing
`stereogenic or chiral centers; and in the cyclization process
`we're going to form a new stereogenic center, right there,
`that's our new stereogenic center.
`So a stereoselectively
`produced product will be one that produces mostly or
`predominantly that one desired stereochemistry, the same as
`the natural hormone, prostacyclin; and by contrast a
`non-stereoselectively produced compound will be one where the
`product would be a mixture of the left-handed and the
`right-handed stereoisomers at that center.
`THE COURT:
`I got you.
`PROFESSOR WILLIAMS:
`Okay? So it's very important
`in manufacturing that would get a stereoselectively produced
`product because it's only that natural hormone stereochemistry
`that has the desired biological function.
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`SteadyMed v. United Therapeutics
`IPR2016-00006
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`

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`53
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`Are we good?
`I'm good.
`THE COURT:
`Okay. And so another thing
`PROFESSOR WILLIAMS:
`that we're going to hear about in this litigation is the idea
`-- the concept of use of protecting groups in synthetic
`organic chemistry; chemists also call these masking groups or
`blocking groups.
`So to help you understand the concept of what a
`protecting group is, very very much like what a painter uses
`when painting say a door, and you apply masking tape which is
`like a protecting group; for the trim around the door we only
`want to get the paint on the door not on the trim.
`And so the first step when using a protecting group
`is you put it on, just like a painter would do; then we're
`going to do our chemical process step, in this analogy we're
`going to now paint the door red. Our protecting group is
`there, and so when we're done painting, we're then going to
`remove the protecting group and remove the masking tape and
`then we have our finished product.
`So protecting groups are temporary, they do not --
`they're not actually part of the final product.
`They're
`temporarily installed to protect another functional group from
`an undesired chemical reaction. We then do our desired
`chemical step, and then when we're done, we're done with the
`protecting group, we essentially remove it and then throw it
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`IPR2016-00006
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`away, we're done -- it's done its job.
`Okay. I'm sorry, Doctor, could you just
`THE COURT:
`go back to your prior -- there you go. So, the Pauson-Khand
`reaction --
`Yes.
`PROFESSOR WILLIAMS:
`THE COURT:
`Where does it show on that screen?
`PROFESSOR WILLIAMS:
`Okay. Right there is the
`Pauson-Khand reaction. So, the Pauson-Khand reaction
`specifically uses this reagent, dicobalt octacarbonyl, and
`what it does -- I'm just showing down here in a little bit
`more detail what's going on here, that the Pauson-Khand
`reaction, even though it doesn't show the cobalt, the net
`result is that one of those COs, this one right here, the
`carbon monoxide, gets added in to help form that new five
`membered ring.
`Okay. So the upper right then, so to
`THE COURT:
`speak, that's the final product?
`PROFESSOR WILLIAMS:
`That's -- this is the tricyclic
`-- the novel tricyclic intermediate; this is then going to be
`converted by more chemical steps as I'll show you in just a
`minute, into the final drug molecule treprostinil.
`THE COURT:
`Okay, thank you. When they were doing
`the Pauson-Khand reaction, there was these two scientists
`hanging around the lab, and they just decided to -- what made
`them do that? That's what the invention is?
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`So the Pauson-Khand
`No.
`PROFESSOR WILLIAMS:
`reaction was already known in the literature, it's just that
`the '117 patent is the first implementation of that chemical
`reaction to make stereoselectively produced treprostinil.
`Thank you.
`THE COURT:
`So you asked about how -- now
`PROFESSOR WILLIAMS:
`the whole picture fits together, so in the '117 patent in
`example 1, the entire synthesis of treprostinil is described.
`And as you can see it's a complex molecule which requires a
`complex synthesis.
`And so organic synthesis is a lot like
`carpentry, you take building materials and you nail them
`together in a sequential fashion to finally build up the final
`structure.
`
`And so in the case of treprostinil, the '117 patent
`described what's called a convergent synthesis, where there's
`a four-step process to make this compound right here; so that
`would be made say in one set of reactors. And then separately
`there's another four-step process to make that fragment down
`there, and then those are going to be joined together
`chemically. So just think of it as a carpenter nailing two
`boards together, we're going to join those two pieces to make
`now this molecule, which now you can see is starting to
`resemble our enyne, the novel enyne that's going to be used in
`the Pauson-Khand step, which is this portion right there.
`THE COURT:
`I see.
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`When you say the tricyclic
`
`Okay? And the treprostinil,
`PROFESSOR WILLIAMS:
`the final product down here, is ultimately going to be made
`after we've made that tricyclic intermediate. There's more
`chemical steps to --
`THE COURT:
`intermediate you're --
`That's this one.
`PROFESSOR WILLIAMS:
`THE COURT:
`That's right where the --
`PROFESSOR WILLIAMS:
`That's the Pauson-Khand step
`right here. So this is the PK, that's the Pauson-Khand step
`right the

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