throbber
1
`
`us
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`10
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`13
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`1b
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`1g
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`al
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`24
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`a4
`5 THADYMED vs UNITED THERAPEUTICS CORPORATION
`
`
`
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 169
`=
`melts at 104, and I think the Phares melts the 107.
`
`So I'm not certain.
`
`QO
`
`Okay.
`
`Now,
`
`the Phares reference,
`
`that's -- that's a patent application written psy
`
`people at United Therapeutics; right?
`
`A
`
`Q
`
`Yes.
`
`Okay. Did you ask anyone at United
`
`Therapeutics: Hey, do you have informalion about
`
`that particular Form B that you made in the Phares
`
`patent?
`
`A
`
`Q
`
`No.
`
`But you knew they -- if amyone had that
`
`information,
`
`it would be United Therapeutics; right?
`
`A
`
`Q
`
`Presumably.
`
`Right.
`
`You don't think I'm going to have
`
`that information; richt?
`
`A
`
`Q
`
`No.
`
`Right.
`
`Amd if they were different --
`
`right? -- if the Form B in the Phares reference and
`
`the Form B in the '393 patent -- if they were
`
`different, don't you think that your counsel would
`
`have given you documents showing that they were
`
`different crystal forms?
`
`A
`
`All I know is what's stated in the
`
`
`
`
`
`
`
`
`documents .
`
`UT Ex. 2089
`
`P.189
`SteadyMed v. United Therapeuti
`[PR2016-00006
`
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, N¥
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2297 of 7113
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`IPR2020-00769
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`Page 2297 of 7113
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`

`STHADYMED vs UNITED THERAPRUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`
`Q
`
`A
`
`Q
`
`Theat you received.
`
`Yes.
`
`And you didn't ask for any further
`
`
`
`information on this issue?
`
`A
`
`Q
`
`to.
`
`Hn
`
`~]
`
`No. No.
`
`I didn't think there was a need
`
`So we were looking at the patent,
`
`Exhibit 1001, also known as "Williams Deposition
`
`Exhibit 3."
`
`I want to go Lo Lhe next paragraph that
`
`begins with,
`
`"At this stage .. ."
`
`Do you see that paragraph?
`
`In column 12.
`
`Okay.
`
`Column 12 and -- where -- okay.
`
`It's about line 53.
`
`A
`
`Q
`
`Page 170
`
`
`
`
`
`
`
`A Hmm-hmm .
`
`Q
`
`T'll read it into the record so we know
`
`where we are?
`
`A
`
`QO
`
`Okay.
`
`It Saye,
`
`"At this stage,
`
`if the melting
`
`point of the treprostinil diethanolamine salt is
`
`more than 104 degrees C, it was considered polymorph
`
`B.*
`
`A
`
`Oo
`
`Did I read that correctly?
`
`That's what it says.
`
`Okay.
`
`So if you're in the '393 patent,
`
`they are identifying whether a treprostinil
`
` P.170 SteadyMed v.
`
`Flisa Dreier Reporting Corp.,
`U.S. Legal Support Company
`950 Third Avenue, New York, NY
`10022
`
`
`
`UT Ex. 2083
`
`United Therapeuti¢s
`IPR2016-00095
`
`(212)557-5558
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2298 of 7113
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2298 of 7113
`
`

`

`diethanolamine salt is Form B by its melting point;
`
`richt?
`
`A
`
`Q
`
`Yes.
`
`Okay. And if the melting point is
`
`greater than 104,
`
`that indicates that it must be the
`
`Form B; correct?
`
`A
`
`Q
`
`Your question again?
`
`Let's just put it this way:
`
`The melzing
`
`point is a signature for Form B.
`
`A
`
`Tt's one characteristic, physical
`
`property, yes.
`
`Qo
`
`They're not just saying it's one
`
`characteristic property;
`
`they're saying it is the
`
`property which tells you it's Form 3.
`
`Isn't that
`
`what that sentence says?
`
`A
`
`Well,
`
`its X ray defraction pattern 1s
`
`going to be much more diagnostic.
`
`0
`
`Okay.
`
`I'm just asking: What does this
`
`sentence say?
`
`"At this stage if melting
`Well, it says,
`A
`point of the treprostinil diethanolamine salt is
`
`more than 104 degrees, it was considered polymorph
`
`B." That's what it says.
`
`Q
`
`Okay. Let me ask you this:
`
`The people
`
`Ww
`
`La
`
`14
`
`15
`
`16
`
`17
`
`18
`
`20
`
`ad
`
`22
`
`23
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`24
`
`25
`
`
`
`STHADYMED vs UNITED THERAPRUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 171
`
`
`
`
`|
`
`|
`
`|
`|
`
`at United Therapeutics,
`
`UT Ex. 2049
`they krow how to take PXRDs;
`P.t71
`SteadyMed v. United Therapeuti¢s
`IPR2016-000G6
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2299 of 7113
`
`IPR2020-00769
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`Page 2299 of 7113
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`

`

`H
`
`UJ
`
`uw
`
`
`
`20
`
`21
`
`22
`
`24
`
`25
`
`
`
`|
`|
`
`
`YS
`
`
`STEADYMED
`UNITED THERAPEUTICS CORPORATION
`
`Page 172
`ROBERT on 08/26/2016
`WILLIAMS,
`
`right?
`
`MS. HASPER:
`
`Objection.
`
`Speculation.
`
`THe WITNESS:
`
`T'm not sure if they do
`
`that in in-house,
`
`or if they contract that out
`
`to
`
`
`
`another lab that has deep expertise in this or not.
`
`IT don't know if they do it in-house or not.
`
`
`IT agontt
`
`know.
`
`BY MR. POLLACK:
`
`Q
`
`Okay.
`
`They have access to the technique;
`
`ridght?
`
`A
`
`Qo
`
`sure.
`
`We saw in the Phares reference,
`
`they have
`
`a PKRD for Form B; right?
`A
`Yes.
`
`QO
`
`So presumably,
`
`they did a PXRD of what
`
`they did here in the '393 pakent, Exhibit 1001;
`
`right?
`
`MS. HASPER:
`
`Same objection.
`
`THE WETNRFSS: You're asking me
`
`presumably
`
`they did a PXRD?
`
`BY MR. POLLACEK:
`
`QO
`
`A
`
`Yeah.
`
`I don't know if there was data on that or
`
`not
`
`in here.
`
`QO
`
`There's no data in here.
`P.1f2
`
`
`
`UT Ex. 2099
`SteadyMed v. United Therapeutt
`_IPR2016-00006
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2300 of 7113
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2300 of 7113
`
`

`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLTAMS, ROBERT on 08/26/2016
`Page 173
`
`Let me ask it to you this way:
`
`Do you
`
`think that the people at United Therapeutics would
`
`have reported that this is Form B without do doing a
`
`PXRD?
`
`Is that your cpinion?
`
`A
`
`O
`
`I don't have an opinion.
`
`One way or the other?
`
`the people al United
`I mean,
`Okay.
`|
`| Therapeutics,
`they're not amateurs at these
`|
`techniques; right?
`i
`MS. HASPER: Objection.
`
`Scope.
`
`BY MR. POLLACK:
`
`QO
`
`A
`
`QO
`
`A
`
`You don't know?
`
`To don't know.
`
`Okay.
`
`We've been going for another an hour,
`
`could we possibiy have a break?
`
`THE ViIDECGRAPEER: This ends media No.
`
`2
`
`
`
`in the deposition of Robert M. Williams, Ph.D.
`
`We're off the record at 2:45 P.M.
`
`{Off the record}
`THE VIDECGRAPEERR: This begins Media
`in the deposition of Robert M. Williams, Ph.D.
`3
`No.
`We are back on the record.
`The time is 2:57 P.M.
`MR. POLLACKE:
`I'm going to mark as
`
`
`
`
`i
`
`|
`
`|
`|
`
`!
`|
`:
`
`UT Ex. 2086
`Williams Depogsilion Exhibil 18, a Guidance for
`P.173
`SteadyMed v. United Therapeutics
`iPR2016-00006
`
`Blisa Dreier Reporting Corp., U.S. Legal Support
`959 Third Avenue, New York, NY
`
`Company (212)557-5558
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2301 of 7113
`
`n
`
`10
`
`ai
`
`13
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`14
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`15
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`16
`
`17
`
`18
`
`193
`
`20
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`21
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`23
`
`24
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`25
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`IPR2020-00769
`United Therapeutics EX2006
`Page 2301 of 7113
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`

`

`
`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`
`
`WILLLAMS, ROBERT on 08/26/2016
`Page L74
`
`
`
`Industry from the FRA titled,
`
`"ANDAs:
`
`Pharmaceutical Solid Polymorphism. "
`
`(Exhibit 18 marked)
`
`BY MR. PCLLACK:
`
`Q
`
`I'm going to represent to you,
`
`this
`
`wasn't attached te your report. But I'm wondering
`
`if you've reviewed this document
`
`in the past in the
`
`; course of your varicus ANDA litigations or
`
`| consulting?
`
`|
`
`
`
`A
`
`Q
`
`Not that I can recall.
`
`Okay. This is -- well, can you explain
`
`to me whak is -- what this document
`
`is?
`
`A
`
`QO
`
`A
`
`Q
`
`No.
`
`Okay.
`
`I've never seen it before.
`
`Sure.
`
`Do you knew what a Guidance fox
`
`an
`
`Ww
`
` 1
`
`Industry is -- I méan -- from the FDA?
`
`A
`
`I've geen FDA guidance things.
`
`These are
`
`Ww
`
`things the FDA puts out to help pharmaceutical
`
`companies jump through all the hoops with the FDA to
`
`21
`
`22
`
`23
`
`24
`
`get approval .
`
`Q
`
`Okay. And I'm right -- this one is about
`
`pharmaceutical solid polymorphism?
`
`MS. HASPER: Objection.
`
`THE WITNESS: That's what it says.
`P.174
`
`
`UT Ex. 2099
`SteadyMed v. United Therapeuti¢s
`IPR2016-00006
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2302 of 7113
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`United Therapeutics EX2006
`Page 2302 of 7113
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`

`

`
`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 175
`——
`
`— M
`
`S. HASPER:
`
`Scope.
`
`
`
`
`lu
`
`oo
`
`
`
`2i
`
`22
`
`23
`
`24
`
`25
`
`BY MR. POLLACK:
`
`Q
`
`Okay. And in simple language, that's
`
`about different crystal forms of drugs; right?
`
`MS. HASPER:
`
`Same objection.
`
`THE WITNESS: Yes.
`
`BY MR. POLLACE:
`
`QO
`
`Okay.
`
`MS. HASPER: Counsel,
`
`if I could clarify:
`
`You said this was a -- Exhibit 18.
`
`I
`
`thought
`
`the
`
`previous exhibit was 18.
`
`THE REPORTER: No,
`
`the last one was 17.
`
`MS. HASPER:
`
`Thank you.
`
`I'll correct
`
`then.
`that,
`BY MR. POLLACK:
`Q
`Len me ask you: Are you familiar with
`any guidances from either the FDA or -- are you
`familiar with the ICH?
`A
`I'm trying to remember what the acronym
`
`stands for.
`
`I don't remember now.
`
`Q
`
`A
`
`Okay.
`
`But, yes, I've seen -- I've seen each
`
`before.
`
`I was trying to remember what the acronym
`
`:
`:
`:
`(
`|
`
`is.
`
`0
`
`
`UT Ex. 2059
`Have you looked at ary either ICH or FDA
`P.175
`SteadyMed v. United Therapeuti¢s
`|PR2018-00006
`
`__.
`
`
`Eliga Dreier Reporting Corp., U.S. Legal Support Company
`950 Third Avenue, New York, N¥
`16022
`
`(212)557-5558
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2303 of 7113
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`IPR2020-00769
`United Therapeutics EX2006
`Page 2303 of 7113
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`

`

`
`
`|
`
`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`WILLIAMS, ROBERT on 08/26/2016
`
`Page 176
`
`documents concerning polymorphism in the past?
`
`MS. HASPER: Objection. Relevance.
`
`Scope.
`
`THE WITNESS: Not that
`
`I can think of.
`
`BY MR. POLLACK:
`
`OQ
`
`Okay. Let me ask you just to turn to
`
`page 9 of Exhibit 18. You see here this is a -- a
`
`guidance setting forth specifications for polymorphs
`
`in drug substances for solid, aral, and suspension
`
`dosage-form products.
`
`And you see that in the first square,
`
`the
`
`question is:
`
`Ts there a polymorph specification in
`
`the USP -- the USP -- that's the United States
`
`Pharmacopeia?
`
`A
`
`Q
`
`A
`
`Pharmacopeia.
`
`What is the United States Pharmacopeia?
`
`Oh, it's a compendium of drug substances
`
`that is indexed and catalogued by this organization.
`
`Q
`
`Okay. And the organization which is
`
`known as the "USP";
`
`is that right?
`
`A
`
`Oo
`
`£ think so, yes.
`
`The USP puts in specifications for each
`
`drug substance,
`
`including things like purity,
`
`crystal form, melting point -- is that your
`
`understanding?
`
`UT Ex. 2099
`SteadyMed v. United Therapeutics
`P.176
`
`IPR2016-00006
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2304 of 7113
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`wn
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`n
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`19
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`
`a4
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`45
`
`IPR2020-00769
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`Page 2304 of 7113
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`

`

`
`STEADYMED vs UNITED YHERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 177
`
`A
`
`ZE dgon't recall off the top of my head
`
`exactly what cata's in there.
`
`Q
`
`A
`
`Q
`
`Okay. You've used the USP; right?
`
`tr have.
`
`Okay. What do you recall from your use
`
`of itP What that -- what is in there?
`
`A
`
`it's been a while since I
`
`looked at one,
`
`so I don't exactiy remember.
`
`one?
`
`QO
`
`A
`
`QO
`
`A
`
`Okay. About kow long did you look at
`
`i con't remember.
`
`More than a year ago?
`
`Well, you know, my father was a
`
`pharmacist, and he has a whole bunch of old ones
`
`that we just had to move from one place to another.
`
`T looked at those, but
`
`those are ancient.
`
`Q
`
`Okay. Have you ever looked at
`
`the
`
`U.S.
`
`-- you understand there will be a USP monograph
`
`for treprostinil?
`
`A
`
`Q
`
`Yeah.
`
`And there's also one for treprostinil
`
`diethanolamine salt; correct?
`
`A
`
`I guess so.
`
`I'll take your
`
`representation.
`
`
`
`17
`
`18
`
`1S
`
`20
`
`21
`
`22
`
`23
`
`
`
`|
`
`
`
`|
`
`G
`
`Okay.
`
`You haven't looked?
`P17?
`
`UT Ex. 2089
`SteadyMed v. United Therapeuti¢s
`IPR2016-00006
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
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`United Therapeutics EX2006
`Page 2305 of 7113
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`

`1
`
`2
`
`3
`
`4
`5
`
`6
`
`7
`
`8
`
`3
`
`
`
`10
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`12
`13
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`14
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`1é
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`
`22
`
`23
`
`24
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`25
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`
`STEADYMED vs UNITHD THERAPHUTICS CORPORATION
`WILLIAMS, ROBERT on 08/26/2016
`
`_
`
`Page 178
`
`A
`
`Q
`
`No.
`
`Okay. Ncw, you see here, one of the
`
`things that the FDA asks the ANDA applicant to do is
`
`to look if there's a polymorph specification in the
`USP, and then it says, for example, "melting point."
`
`
`
`|
`|
`
`
`
`|
`|
`
`|
`
`Do you see that?
`
`A
`
`Yeah,
`
`I see that.
`
`MS. HASPEFR: Objeclion.
`
`Scope,
`
`BY MR.
`
`POLLACEK:
`
`Q
`
`So melting point is one of the things the
`
`FDA calls out.
`
`In fact, it's the only thing in here
`
`that they give as an example as associated with a
`polymorph.
`Do you see that?
`
`MS. HASPER:
`
`Same objection.
`
`THE WITNESS:
`
`It says,
`
`"example."
`
`"For
`
`example."
`
`BY MR. POLLACE:
`
`Q
`
`A
`
`QO
`
`There's olher things; right?
`
`Certainly.
`
`Right. But melting point is the one that
`
`they gave in this document?
`
`A
`
`As an example.
`
`MS. HASPER:
`
`Same objection.
`
`BY MR. POLLACK:
`
`Q
`
`
`.
`
`Because melting point is something that
`
`P.178
`
`SteadyMed v. United Therapeis
`
`UT Ex, 2058
`
`IPR2016-00095
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2306 of 7113
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2306 of 7113
`
`

`

`
`
`/
`|
`!
`|
`:
`
`STEBEADYMED vs UNITED THERAPEUTICS CORPORATION
`Page 179
`WILLIAMS, ROBERT on 08/26/2016
`
`uniquely identifies a polymorph; right?
`
`iN)
`
`tad
`
`MS. HASPER:
`
`Same objection.
`
`Mischaracterizes the underlying document.
`
`THE WITNESS:
`
`I would not necessarily
`
`agree with that.
`
`MR. POLLACK: Let me mark as Williams
`
`Deposition Exhibit 19 a document that's been called
`
`"Exhibit 2030" in this case.
`
`It's an article by --
`
`vather than try to say the name, it's an article
`
`that appeared in the International Gournali of
`Pharmaceutics in 2006.
`(Exhibit 19 marked)
`BY MR. POLLACK:
`Is Williams Depositicn
`Q
`Let me ask you:
`Exhibit 19 an article you relied upon in your
`
`Declaraticn?
`
`A
`
`Q
`
`Yes.
`
`Okay.
`
`Do you have any idea how to
`
`pronounce the author's first name?
`
`A
`
`Q
`
`article?
`
`A
`
`QO
`
`"Adhiyamar."
`
`Okay. We'll call this the Adhiyaman
`
`Okay.
`
`Okay.
`
`Now,
`
`in the Adhiyaman article, we
`
`gee -- I think my understanding of this -- or at
`UT Ex. 2099
`IPR2016-00098
`
`SteadyMed v. United Therepuis
`
`P.17o
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
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`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2307 of 7113
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`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 180
`
`
`
`|
`
`least of your opinion of it -- is that there are a
`
`number of crystals of certain chemical called
`
`"dipyridamole"?
`
`Is that a decent pronunciation of
`
`it, or how would you pronounce that?
`
`A
`0
`
`"Dipyridamole."
`Okay. And they're all made in different
`
`soivents;
`
`is that fair?
`
`A
`
`QO
`
`Yes.
`
`Okay. And each of them has a different
`
`PXRD pattern;
`
`is that fair?
`
`A
`
`I
`
`think that's what they're illustrating
`
`in the article, yes.
`
`Qo
`
`Okay.
`
`TIen't it correct that a different
`
`PXRD pattern means that the crystal has a different
`
`three-dimensional structure in a solid form?
`
`A
`
`Qo
`
`Yes.
`
`Okay.
`
`So each of these is really a
`
`different crystal form of the same drug;
`
`is that
`
` solvents, you get different crystal forms of the
`
`fair?
`
`A
`
`Qo
`
`t
`
`think that's fair.
`
`Okay.
`
`So what we learned about
`
`in this
`
`article is sometimes when you use different
`
`oy
`
`oo
`
`
`
`same drug; right?
`
`A
`
`Yes.
`
`UT Ex. 2039
`SteadyMed v. United Therapeuties
`P.180
`IPR2016-00096
`
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2308 of 7113
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`IPR2020-00769
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`

`

`
`STEADYMED vs UNLED THERAPEUTICS CORPORATION
`Page 118i
`WELLIAMS, ROBERT on 08/26/2016
`
`
`
`Q
`
`Okay.
`
`Seo there's nathine in here saying
`
`that two crystals that have the same crystal form
`
`anc same PXRD structure made from different solvents
`
`are different?
`
`MS. HASPER: Objection.
`
`Mischaracterizes
`
`the document.
`
`THE WITNFSS:
`
`Please state your question
`
`one more time?
`
`BY MR. POLLACK:
`
`Q
`
`Sure.
`
`Sure.
`
`So there are no -- let me make
`
`che
`
`following clear: There ere no examoles in Williams
`
`Deposition Exhibit 19 of two crystals having the
`
`same PXRD pattern but which are different crystal
`
`forms.
`
`A
`
`Q
`
`You'll have to ask me that one more Lime.
`
`Sure. There are no examples in Williams
`
`Deposition Exhibit 19 of two crystals, made with
`
`different solvents, having the same PERD pattern but
`
`different -- but are different crystal forms?
`
`A
`
`I'm not sure I can come to that
`
`conclusion.
`
`And what I did cite from this article is
`
`that the conclusion, which I quoted in my
`
`UT Ex. 2098
`Declaration, and it's also based on my experience of
`P.184
`SteadyMed v. United Therapeuti
`IPR2018-000
`
`Elisa Dreier Reporting Corp., U.&.
`950 Third Avenue,
`
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`New York, WY
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2309 of 7113
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`N t
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`al
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`at
`
`aw
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`
`
`20
`
`21
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`22
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`23
`
`24
`
`25
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`

`

`
`STRADYMED vs UNITED THERAPEUTICS CORPORATION
`WILLIAMS, ROBERT on 08/26/2016 Page 182
`
`
`
`
`crystallizing the same compound on different days
`
`from different solvents under slightly different
`
`conditions, you can get a different melting point.
`
`And it depends on the scale and lots of things.
`
`QO
`
`Okay. But could you get a different
`
`melting point because you've gotten a different
`
`crystal form.
`
`isn't that the issue?
`
`A
`
`Qo
`
`Not necessarily.
`
`So your Lestimony today is,
`
`I can have --
`
`let me ask you this:
`
`Tf
`
`TI have two crystals that
`
`have the same PXRD pattern, can I get two different
`
`melting points?
`
`A
`
`Q
`
`Yes.
`
`Okay. And what is the reason for that in
`
`your opinion?
`
`MS. HASPER: Objection.
`
`Scope.
`
`THE WITNESS:
`
`So the way these melting
`
`points, which are done typically today wilh Lhis
`
`differential scanning calorimetry,
`
`the melting
`
`ranges can depend on the rate of heating,
`
`the sample
`
`size, and even the individual
`
`instrument that's
`
`used. There can be variability.
`
`BY MR. POLLACK:
`
`|
`
`\a
`
`WH
`
`4
`
`
`
`17
`
`18
`
`1%
`
`2G
`
`21
`
`a2
`
`23
`
`9
`
`Sure. You're saying there can be errors
`
`25
`
`in the measurement?
`
`
`
`P.182
`
`UT Ex, 2059
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`Blisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, N¥
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2310 of 7113
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2310 of 7113
`
`

`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`Page 183
`WILLIAMS, ROBERT on 08/26/2016
`
`ba
`
`tal
`
`1B
`
`
`
`1é
`
`13
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`
`
`A
`
`0
`
`Yes.
`
`Fair enough. Okay.
`
`But assuming that the appropriate scan
`
`rate is used and appropriate sample sizé is used and
`
`all of those chings are the case, will two crystals
`
`which have the same PXRD pattern have the same
`
`melting point?
`
`A
`
`ZF don't know if that's ubiquitously true.
`
`T wouidn't agree with that.
`
`Q
`
`Do you not know, or do you formally
`
`disagree with that?
`
`A
`
`Q
`
`I disagree.
`
`Okay.
`
`De you have any -- is there
`
`anything in this article that supports your opinion?
`
`A
`
`Well,
`
`the conclusion is that -- it says
`
`vight here, "In conclusion, it can be said that the
`
`erystallization conditions" --
`
`Q
`
`A
`
`Read that slowly.
`
`Sorry.
`
`"Tr conclusion, it can be said that the
`
`erystallization conditions and the medium used have
`
`a major effect on dipyridamole crystais habit
`
`modification under ambient conditions.
`
`The crystals
`
`showed significant. changes in the shape, size,
`
`
`
`UT Ex. 2098
`meiting points, dissolution rate, KRD patterns and
`P.183
`SteadyMed v. United Therapeuti¢s
`IPR2018-00096
`
`Elisa Dreier Reporting Corp., U.S. Legai Support Company
`950 Third Avenue, New York, NY
`10022
`
`(212)557-5558
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2311 of 7113
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`IPR2020-00769
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`Page 2311 of 7113
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`

`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 184
`
`Bo
`
`Ua
`
`ul
`
`4a
`
`
`
`
`
`DSC curves."
`
`And I quoted that in my --
`
`Oo
`
`But here,
`
`they pointed ovt they all had
`
`different XRD patterns, right?
`
`A
`
`Q
`
`Okay.
`
`Right?
`
`And,
`
`in fact, that's what
`
`the data shows
`
`in here.
`
`They all had different KRD patterns?
`
`A
`
`Q
`
`Hmm-hmm.
`
`Right.
`
`I'm asking about
`
`two crystals
`
`having the same XRD pattern.
`
`A
`
`So in my own research, we do a lot of
`
`x-ray crystallography. And I work pretty closely
`
`with an expert crystallographer, Orrin Anderson.
`
`And we've had crystals that had the exact same XRD
`
`pattern that were produced on different days that
`had slightly different melting points.
`So I've seen
`this myself.
`o
`Okay.
`A
`So what you're trying to say is just
`
`simply not ubiquitously true.
`
`Qo
`
`Okay.
`
`Do you have any literature or any
`
`papers -- other thar your own personal anecdotal
`
`experience, do you have any scientific literature or
`
`
`
`|
`:
`:
`|
`|
`
`papers that support chat opinion?
`
`
`
`P.184
`
`UT Ex. 2089
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company
`950 Third Avenue, New York, NY
`10022
`
`(212) 557-5558
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2312 of 7113
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`IPR2020-00769
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`Page 2312 of 7113
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`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`Page 185
`
`A
`
`I'm sure I could find it if I was asked
`
`to, but that was based on my own experience.
`
`Oo
`
`A
`
`Okay.
`
`And that's -- it happened not just once.
`
`It's happened numerous times.
`
`Q
`
`Okay. But as part of this proceeding,
`
`you didn't look for any papers that supported that
`
`opinion?
`
`A
`
`Well,
`
`I think the main point here is that
`
`you can't compare the polymorph form and Phares to
`
`what's in the '393. That was the main underlying
`
`theme here.
`
`Q
`
`Right. But your opinion on that was
`
`baged on the idea that tne same polymorph could have
`
`two different melting points; correct?
`
`MS. HASPER: Objection. Mischaracterizes
`
`the document and the testimony.
`
`THS WITNESS:
`
`I mean, what's
`
`characterized is the same polymorph -- or what's
`
`called -- but
`
`there wasn't enough information to
`
`ascertain that that was the case.
`
`BY MR. POLLACK:
`
`QO
`
`The people who called it the same
`
`polymoroh, that's United Therapeutics?
`
`
`
`A
`
`Okay.
`
`P.185
`
`UT Ex. 2099
`SteadyMed v. United Therapeuti¢s
`_ AP R2016-00096
`
`Ww
`
`ug
`
`
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2313 of 7113
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`IPR2020-00769
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`

`STEADYMED vs UNITED THHRAPERUTICS CORPORATION
`
`WILLIAMS, ROBERT cn 08/26/2016
`Page 186
`
`
`IPR2016-000G6
`
`|
`
`Q
`
`A
`
`0
`
`A
`
`QO
`
`A
`
`Q
`
`
`The people you're working for; richt?
`
`That doesn't mean they're infallible.
`
`Okay.
`
`It wasn't -- it wasn't me; right?
`
`No
`
`
`Tt wasn't Dr. Winkler?
`
`No
`
`No?
`
`And -- okay.
`
`You think maybe they made a
`
`Mistake in identifying the polymorphs?
`
`MS. HASPER: Objection.
`
`Mischaracterizes -- testimony.
`
`THE WITNESS: Yeah.
`
`I was addressing
`
`Dr. Winkler's analysis.
`
`BY MR. POLLACK:
`
`Oo
`
`That's not what
`
`fF asked you.
`
`I said, do you think they made a mistake
`
`in identifying the polymorphs of each of those
`
`papers? United Therapeutics made a mistake?
`
`MS. HASPER: Objection. Mischaracterizes
`testimony. Asked and answered.
`
`THE WITNESS:
`
`I cannot be 100 percent
`
`
`
`Ww
`
`m o
`
`n
`
`oa
`
`\o
`
`certain.
`
`BY MR. POLLACE:
`
`QO
`
`Okey.
`
`You didn't do anything to
`
`investigate whether they made a mistake in
`P.186
`
`
`
`SteadyMed v. United Therapeuti
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company
`950 Third Avenue, New York, NY
`10022
`
`(212)557-5558
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2314 of 7113
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`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WELLIAMS, ROBERT on 08/26/2016
`
`identifying those two polymorphs?
`
`read.
`
`A
`
`Q
`
`No.
`
`I just have the documents as they
`
`And the documents called both of those
`
`"polymorphs Form B"?
`
`A
`
`Yes. Made under different conditions,
`
`and Phares doesn't provide any information on
`
`solvent that was used, scale, source of the
`
`treprostinil, and so on.
`
`So it's just not enough
`
`there.
`
`QO
`
`You know, you've brought up the term
`
`"scale" several
`
`times in Lhis deposition.
`
`Looking
`
`back at Exhibit 1001,
`
`is there anything --
`
`What's Exhibit 1001?
`A
`|
`Exhibit 1001 is the '393 patent. Tris
`Q
`|
`: also known as "Williams Deposition Exhibit 3."
`|
`A
`Okay.
`|
`oO
`I'd like you tc look at claims in the
`
`'393 patent.
`
`Do you see anything in there that says
`
`what scale the reaction is being carried out at?
`
`No.
`
`Okay.
`
`Sa the reaction covers any scale;
`
`uw
`
`a
`
`10
`
`11
`
`12
`
`13
`
`14
`
`16
`
`17
`
`1s
`
`19
`
`29
`
`21
`
`
`
`A
`
`Q
`
`right?
`
`A
`
`Q
`
`Page
`
`L387
`
` 6
`
`Certainly.
`
`Could be bench;
`
`_
`
`UT Ex. 2059
`like
`laboratory reaction,
`P.187
`SteadyMed v. United Therapeutics
`iPR2016-000g
`
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`10022
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`IPR2020-00769
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`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`Page 188
`WILLIAMS, ROBERT on 08/26/2016
`
`Moriarty did in his Journal of Crganic Chemistry
`
`| article?
`|
`A
`
`Yes.
`
`QO
`
`That could be included -- and it could be
`
`ut
`
`a large clinical batch; correct?
`
`A
`
`Q
`
`Yes.
`
`Okay. Let me go back to the Phares
`
`reference, Exhibit 1005, known as "Williams
`
`Deposition Exhibit 16."
`
`If you could Lurn to
`
`page 42. And we have a lot of page 42s here,
`
`so let
`
`mé@ be a little more specific.
`
`
`
`Page 42 in the lower right-hand corner of
`
`the document, original page 40 of the reference --
`
`A
`
`Q
`
`Yes.
`
`I'm there.
`
`Okay.
`
`»
`
`Io was wondering if you could
`
`help me understand some of the chemistry in -- you
`
`see there's a synthesis at the top of page; right?
`
`A
`
`Q
`
`Yes.
`
`Okay. Here's what
`
`I was not fully
`
`understanding: There's -- if you go to this
`
`synthesis scheme,
`
`there's a structure on the lower
`
`right-hand corner in the scheme. And next to it,
`
`there's an arrow, and there's a letter "L" above it.
`
`Do you see that?
`
`A
`
`Yes.
`
`
`
`Le
`
`iL
`
`12
`
`1.3
`
`
`
`20
`
`2l
`
`aa
`
`aa
`
`25
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company
`950 Third Avenue, New York, NY
`10022
`
`P.188
`
`SteadyMed v.
`
`
`
`UTEx. 2089
`
`United Therapeutics
`[PR2016-00006
`
`(212) 557-5558
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2316 of 7113
`
`IPR2020-00769
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`

`

`QO
`
`Okay. And now, what's -- to the right of
`
`the arrow with the letter "H," that's the mirror
`
`image of the -- gome of the compounds that are shown
`
`in claim 9 of the '393 patent;
`
`is that richt?
`
`A
`
`So which -- which structures are you
`
`asking me to compare?
`
`Oo
`
`Yeah. Let's take a look at -- there's a
`
`structure called "5" in claim 3g.
`
`STEADYMED vs UNITED THERAPHUTLICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016 Page 189
`
`
`
`
`
`
`
`
`
`
`|
`!
`|
`|
`
`on page 42 also known as "46," in the lower
`
`right-hand corner?
`
`A
`
`That would be 11-B where R is H. That
`
`would be the mirror image of the benzindine triol.
`
`Q
`
`Okay. Thanks.
`
`And then in step {1),
`
`if you look down in
`
`the paragraph, it tells you what step (1)
`
`is. And
`
`step (1)
`
`seems to have two parts to it; is that
`
`faix?
`
`There's a little (i) and then a two
`
`little (ii) part?
`
`A
`
`Q
`
`Yes.
`
`Okay.
`
`I
`UT Ex. 2098
`Those are two separate steps in
`P.189
`SteadyMed v. United Therepeuti¢s
`IPR2016-00006
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`
`Okay. That's the so-called "benzindine
`
`A
`triol."
`Hmm-hmm. And is that structure and
`Q
`claim 5 -- is that the mirror image of the structure
`
`
`
`oO
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Page 2317 of 7113
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`

`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT om 08/26/2016 Page 190
`
`(1); right?
`
`|
`|
`:
`
`Yes.
`A
`Okay. And the first step -- the
`Q
`letter -- single (1) step where it says,
`"CL,"
`
`"CH2,"
`
`"CN," and then it says "K2," "CO3"
`
`-- is that
`
`the -- is that the alkylating step like is done in
`
`
`step (a) of claim 9, except for the mirror-image
`
`compound?
`
`A
`
`0
`
`Yes.
`
`Okay. And then there's a step where it
`
`Says "“KOHCH30H reflux 83 percent."
`
`Is that the
`
`hydrolyzing step of -- which is called "step {b}" in
`
`the '393 patent being applied to the mirror-image
`
`compound?
`
`A
`
`Q
`
`Yes.
`
`Okay.
`
`So what we see here is there's an
`
`alkylating step (a) and a hydrolyzing step (b) on
`
`
`page 42 of the Phares reference.
`
`A
`
`Yes.
`
`MR. POLLACK:
`
`I'm going to mark as
`
`Williams Deposition Exhibit 20 an excerpt
`
`from
`
`Exhibit 1002, and it's a small section from that
`
`exhibit which was the prosecution history. And it's
`
`called the "Declaration of David Walsh."
`
`i
`
`
`
`
`(Exhibit 20 marked)
`UT Ex. 2099
`SteadyMed v. United Therapeuti¢s
`P.190
`IPR2016-00008
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company (212)557-5558
`950 Thira Avenue, New York, N¥
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2318 of 7113
`
`10
`
`il
`
`12
`
`13
`
`i4
`
`i5
`
`16
`
`i7
`
`18
`
`i9
`
`ai
`
`22
`
`23
`
`24
`
`25
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2318 of 7113
`
`

`

`
`
`|
`
`BY MR.
`
`POCLLACK:
`
`Q
`
`You've reviewed this document in
`
`preparation for this deposition and for -- in
`
`preparing your Declaration; correct?
`
`A
`
`oC
`
`Yes.
`
`I think we discussed earlier that
`
`according to this document -- if we turn to the
`
`document called "Page 345" in the lower right-hand
`
`corner.
`
`I
`
`think we discussed earlier how for the
`
`treprostinil diethanolamine sait, that's what's
`
`presented at the top of the pace -- the salt?
`
`acid?
`
`A
`
`Q
`
`A
`
`Q
`
`Yes.
`
`Okay. And then below that is the free
`
`Yes.
`
`Okay. And we see in the free acid,
`
`the
`
`impurities are 0.2 percent; right? Tetal related
`
`substances.
`
`A
`
`Q
`
`No.
`
`Oh,
`
`I'm sorry. What is the impurities by
`
`HPLC for total related substances for the
`
`treprostinil free acid on the Walsh Declaration?
`
`A
`
`Oh, you were asking me about
`
`the salt,
`
`which is .1 pertinence.
`
`
`
`LL
`
`12
`
`13
`
`14
`
`16
`
`17
`
`18
`
`21
`
`22
`
`a3
`
`24
`
`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`WILLIAMS, ROBERT on 08/26/2016
`__
`Page 191
`
`:
`|
`|
`
`i
`
`Q
`
`UT Ex. 2059
`I'm sorry. Misspoke, phen. Twas not --
`SieadyMed v. United Therapeuii¢s
`IPR2016-00098
`
`194
`
`Elisa Dreler Reporting Corp., U.S. Legal Support Company (212)557-5558
`LO022
`950 Third Avenue, New York, NY
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2319 of 7113
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2319 of 7113
`
`

`

`nh
`
`f
`
`4
`
`tw
`
`STEADYMED vs UNITED THERAPEUTICS CORPORATION
`
`
` WILLIAMS, ROBERT on 08/26/2016 Page 192
`
`okay -
`
`acid?
`
`Want
`
`to do the salt first or the free
`
`A
`Q
`A
`0
`A
`0
`
`You're asking the questions.
`Okay .
`You pick the order.
`All right. Let's do the free acid.
`Okay.
`Am I correct that the total related
`
`substances for the free acid is 0.2 percent?
`
`A
`
`Q
`
`Yes.
`
`And for the treprostinil diethanolamine
`
`salt,
`
`the total related substances is 0.1 percent?
`
`|
`:
`:
`:
`|
`!
`|
`:
`|
`
`A
`
`Qo
`
`Yes.
`
`Okay.
`
`So,
`
`let me ask you this:
`
`
`
`in fact,
`
`there are -- well,
`
`The treprostinil free acid,
`
`it's made the same way as the diethanclamine salt,
`
`except step (d)
`
`is then executed;
`
`is that correct?
`
`A
`
`Q
`
`That's correct.
`
`Okay. And so when step (d) was executed,
`
`the amount of total related substances actually
`
`increased; correct?
`
`A
`
`Yeas.
`
`
`
`i
`
`Q
`And,
`in fact,
`the spec, even, for
`
`treprostinil free acid made using the step (d}
`is
`UT Ex. 20
`P.192
`SteadyMed v. United Therapeuti¢s
`IPR2016-00096
`
`
`Elisa Dreier Reporting Corp., U.S. Legal Support Company {(212)557-5558
`950 Third Avenue, New York, NY
`10022
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2320 of 7113
`
`IPR2020-00769
`United Therapeutics EX2006
`Page 2320 of 7113
`
`

`

`STEADYMED vs UNITED ‘THERAPEUTICS CORPORATION
`Page 193
`WILLIAMS, ROBERT on 08/26/2016
`
`
`
`actually set ta not more than 3 percent.
`
`Do you see
`
`that?
`
`Ud
`
`A
`
`Qo
`
`Yes.
`
`And for the salt,
`
`the level of impurities
`
`ils set to only not more than 1-1/2 percent.
`
`
`Do we
`
`see that?
`
`A
`
`Q
`
`Yes.
`
`So carrying out an additional step,
`
`step (d), on the treprostinil diethanolamine salt
`
`actually increases the imourity level of the
`
`product; right?
`
`MS. HASPER: Objection. Mischaracterizes
`
`the document.
`
`THE WITNESS:
`
`So what's going on here --
`
`this is actually fairly easy to understand.
`
`BY MR. POLLACK:
`
`Q
`
`A
`
`Okay -
`
`-- is that the salt, which is incredibly
`
`pure.
`
`Seven to eight impurities is not present.
`
`The only thing that's detectable is an tiny amount
`
`of the enantiomer 3AU$0. All
`
`the others have been
`
`eliminated. And when you treat the salt with acid,
`
`the impurities that mow come back are the two
`
`dimers:
`
`750W93, 751W93; and the ethyl ester.
`
`Li
`
`12
`
`13
`
`
`
` UTEx. 2099
`And that's because those are formed by
`
`P.193 SteadyMed v.United Therapeuties
`IPR2016-00006
`
`Elisa Dreier

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