Rotella, Ph.D., David P.
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`Case: IPR2015-01340
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`December 2, 2016
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`1
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` UNITED STATES PATENT AND TRADEMARK OFFICE
` ______________________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` ______________________________
` MYLAN PHARMACEUTICALS INC.,
` WOCKHARDT BIO AG,
` TEVA PHARMACEUTICALS USA, INC.,
` AUROBINDO PHARMA U.S.A., INC.,
` Petitioners,
` v.
` ASTRAZENECA AB,
` Patent Owner.
` ______________________________
` Case: IPR2015-01340
` U.S. Patent No. RE44,186
` ______________________________
` DEPOSITION OF DAVID P. ROTELLA, Ph.D.
` Friday, December 2, 2016
` New York, New York
` 9:00 a.m.
`
`Reported by:
`Josephine H. Fassett, RPR
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`Page 1 of 159
`
`AstraZeneca Exhibit 2221
`Mylan v. AstraZeneca
`IPR2015-01340
`
`
`
`Case: IPR2015-01340
`
`December 2, 2016
`
`1
`
` UNITED STATES PATENT AND TRADEMARK OFFICE
` ______________________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` ______________________________
` MYLAN PHARMACEUTICALS INC.,
` WOCKHARDT BIO AG,
` TEVA PHARMACEUTICALS USA, INC.,
` AUROBINDO PHARMA U.S.A., INC.,
` Petitioners,
` v.
` ASTRAZENECA AB,
` Patent Owner.
` ______________________________
` Case: IPR2015-01340
` U.S. Patent No. RE44,186
` ______________________________
` DEPOSITION OF DAVID P. ROTELLA, Ph.D.
` Friday, December 2, 2016
` New York, New York
` 9:00 a.m.
`
`Reported by:
`Josephine H. Fassett, RPR
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`Page 1 of 159
`
`AstraZeneca Exhibit 2221
`Mylan v. AstraZeneca
`IPR2015-01340
`
`
`
`Rotella, Ph.D., David P.
`
`Case: IPR2015-01340
`
`December 2, 2016
`
`2
`
` Friday, December 2, 2016
` New York, New York
` 9:00 a.m.
`
` T R A N S C R I P T of the Deposition
`of DAVID P. ROTELLA, Ph.D., held at the offices of
`Wilson Sonsini Goodrich & Rosati, 1301 Avenue of
`the Americas, New York, New York, on Friday,
`December 2, 2016, at approximately 9:00 a.m.,
`pursuant to Notice, before Josephine H. Fassett,
`Registered Professional Reporter, Certified Court
`Reporter and Notary Public of the State of New
`York.
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`Case: IPR2015-01340
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`December 2, 2016
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`A P P E A R A N C E S :
`
`APPEARING ON BEHALF OF PETITIONER MYLAN
`PHARMACEUTICALS INC.:
` WILSON SONSINI GOODRICH & ROSATI
` 1700 K Street, N.W.
` Fifth Floor
` Washington, D.C. 20006-3817
` 202.973.8800
`BY: RICHARD TORCZON, ESQ.
` rtorczon@wsgr.com
` DAVID KNAPP, ESQ.
` dknapp@wsgr.com
`
`APPEARING ON BEHALF OF PATENT OWNER AZTRAZENECA
`AB:
` FINNEGAN, HENDERSON, FARABOW, GARRETT &
` DUNNER, LLP
` Two Freedom Square
` 11955 Freedom Drive
` Reston, Virginia 20190-5675
` 571.203.2700
`BY: CHARLES E. LIPSEY, ESQ.
` charles.lipsey@finnegan.com
` M. DAVID WEINGARTEN, Ph.D., ESQ.
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`Case: IPR2015-01340
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`December 2, 2016
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` david.weingarten@finnegan.com
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`Case: IPR2015-01340
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`December 2, 2016
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`-----------------------INDEX----------------------
`WITNESS PAGE
`DAVID P. ROTELLA, Ph.D.
` By Mr. Lipsey 7,125
` By Mr. Torczon 123
`
` AFTERNOON SESSION - 86
`
`---------------EXHIBITS REFERENCED----------------
`Mylan Exhibit 1001
`Mylan Exhibit 1003
`Mylan Exhibit 1007
`Mylan Exhibit 1008
`Mylan Exhibit 1074
`AstraZeneca Exhibit 2001
`AstraZeneca Exhibit 2002
`AstraZeneca Exhibit 2003
`AstraZeneca Exhibit 2007
`AstraZeneca Exhibit 2014
`AstraZeneca Exhibit 2018
`AstraZeneca Exhibit 2028
`AstraZeneca Exhibit 2043
`AstraZeneca Exhibit 2045
`AstraZeneca Exhibit 2046
`AstraZeneca Exhibit 2047
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`December 2, 2016
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`---------------EXHIBITS REFERENCED----------------
`AstraZeneca Exhibit 2050
`AstraZeneca Exhibit 2056
`AstraZeneca Exhibit 2073
`AstraZeneca Exhibit 2081
`AstraZeneca Exhibit 2096
`AstraZeneca Exhibit 2098
`AstraZeneca Exhibit 2151
`AstraZeneca Exhibit 2158
`AstraZeneca Exhibit 2174
`AstraZeneca Exhibit 2176
`AstraZeneca Exhibit 2223
`AstraZeneca Exhibit 2226
`AstraZeneca Exhibit 2228
`AstraZeneca Exhibit 2229
`AstraZeneca Exhibit 2230
`AstraZeneca Exhibit 2231
`AstraZeneca Exhibit 2232
`AstraZeneca Exhibit 2233
`AstraZeneca Exhibit 2234
`AstraZeneca Exhibit 2235
`AstraZeneca Exhibit 2236
`AstraZeneca Exhibit 2237
`AstraZeneca Exhibit 2238
`AstraZeneca Exhibit 2239
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`202-220-4158
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`December 2, 2016
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`---------------EXHIBITS REFERENCED----------------
`AstraZeneca Exhibit 2241
`AstraZeneca Exhibit 2243
`AstraZeneca Exhibit 2244
`AstraZeneca Exhibit 2245
`AstraZeneca Exhibit 2246
`AstraZeneca Exhibit 2247
`AstraZeneca Exhibit 2254
`AstraZeneca Exhibit 2256
`AstraZeneca Exhibit 2257
`AstraZeneca Exhibit 2257A
`AstraZeneca Exhibit 2258
`AstraZeneca Exhibit 2259
`AstraZeneca Exhibit 2259A
`AstraZeneca Exhibit 2260
`AstraZeneca Exhibit 2261
`AstraZeneca Exhibit 2262
`AstraZeneca Exhibit 2263
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`Case: IPR2015-01340
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`December 2, 2016
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` (Whereupon, on the record.)
`D A V I D P. R O T E L L A, P h. D.,
`the witness, having been duly sworn, was examined
`and testified under oath as follows:
` EXAMINATION
`BY MR. LIPSEY:
` Q. Good morning, Dr. Rotella. Just for
`the formality of it, would you state your name and
`residence address for the record, please.
` A. My name is David P. Rotella. I reside
`at 78 Iroquois Avenue, Lake Hiawatha, New Jersey.
` Q. Okay. I'd like to show you what's
`been marked previously as Mylan Exhibit 1074,
`which is entitled Second Declaration of David P.
`Rotella, Ph.D.
` And that is your reply declaration
`filed in this IPR proceeding, correct?
` A. That's correct.
` Q. Now, simply because we may have
`occasion to refer to it today, I'd like to also
`show you what's previously been marked as Mylan
`Exhibit 1003, which is entitled Declaration of
`David P. Rotella, Ph.D.
` A. Thank you.
` Q. And that is your original declaration
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`December 2, 2016
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`filed in this IPR proceeding, correct?
` A. Correct. Mr. Lipsey, before we
`proceed.
` Q. Absolutely.
` A. In the reply declaration.
` Q. Okay.
` A. In reviewing this, I noticed a typo
`that I'd like to correct, please.
` Q. Absolutely.
` A. It is in Paragraph 24, which that
`Paragraph 24 starts on page 12 and goes to
`page 13.
` Q. Okay.
` A. The last phrase in that last paragraph
`there, I'll read what is written: Is not
`considered a much less bulky group. I'd like to
`eliminate the word "not." So I'd like to --
` Q. Okay.
` A. I'd like to eliminate the word "not."
` Q. Okay. As is customary in these
`proceedings, when there is an errata correction,
`both go into evidence, and your testimony is
`noted. And I will make the notation of your
`testimony in my copy.
` Would you like to mark the exhibit?
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`Case: IPR2015-01340
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`December 2, 2016
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` A. I'm good. Thank you.
` Q. Okay.
` A. And I apologize for not catching this
`previously, but.
` Q. Well, while we're at it, would you
`take a look at page 28 and Paragraph 50.
` The third line there you make
`reference to cis-4,5-cyclohexyl. Is that what you
`meant?
` A. Probably not.
` Q. Okay.
` A. That probably should be a -- well,
`that term is actually confusing. Confusing in the
`sense that I'm not sure exactly what it refers to.
`So...
` Q. Why are you confused?
` A. Well, it's not -- sorry. It's not --
`it's an inappropriate term that -- I'm assuming
`that Exhibit 2056 is the Magnin 2004 paper.
` Q. Well, I think I'm about to hand you
`Exhibit 2056, so let's --
` A. So I -- before we attempt to make a
`correction, I want to make sure I understand --
` Q. Okay.
` A. -- what we're referring to.
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`December 2, 2016
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` Q. I'd like to hand you what's previously
`been marked as AstraZeneca Exhibit 2056, which is
`the Declaration of Ann E. Weber, Ph.D., filed in
`these proceedings.
` By reference to 2056, can you clarify
`what you meant in Paragraph 50 of your reply
`report?
` A. Yes. Okay. So -- so this should be
`a -- the term cis-4,5-cyclohexyl group should be
`replaced with cis-4,5-cyclopropyl pyrrolidine.
` Q. Okay. With that correction, are you
`satisfied with the text?
` A. Yes, I am. Thank you.
` Q. Okay. And lastly, because we may have
`occasion to refer to it today, I'd like to hand
`you what's previously been marked as AstraZeneca
`Exhibit 2174, which is the transcript of your
`deposition. Do you see that?
` A. Yes.
` Q. Some of what I hope to do today is
`simply to crystallize the areas of dispute. I
`think there's much that we can probably agree on
`and much that we'll never agree on, and as long as
`we can sort out what those two things are in a way
`that the reader of our transcript can understand
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`Case: IPR2015-01340
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`December 2, 2016
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`what we're talking about, then we've advanced the
`ball.
` I would like to start by showing you a
`demonstrative exhibit that I've marked for
`identification as AstraZeneca 2226.
` MR. TORCZON: Is this already in the
` record in some point?
` MR. LIPSEY: No. It's a
` demonstrative exhibit for facilitating
` cross-examination.
` Q. I've noted the sources of the
`information here, but just to be clear.
` Dr. Weber had suggested that the lead
`compounds that a person seeking to make a DPP-4
`inhibitor at the relevant time would select, would
`be the two DPP-4 inhibitors that were in the
`clinic NVP-DPP728 and P32/98. Is that your
`understanding?
` A. Yes, it is.
` Q. Okay. And would you agree that -- for
`purposes of our reader -- we correctly depicted
`what those structures are here on Exhibit 2226?
` A. Yes.
` Q. Okay. And as indicated in the red
`circles NVP-DPP728 as an N-linked P2 group, right?
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` A. Yes.
` Q. And as depicted for P32/98, it has no
`cyano group or other electrophilic group on the P1
`group, correct?
` A. It does not have a cyano group, that's
`correct.
` Q. Okay. Now, rather than those two
`compounds, you selected as your lead compound one
`of the compounds from Ashworth I. And so that we
`know what we're talking about, I'd like to show
`you Mylan Exhibit 1007.
` And that's the document we've been
`referring to in these proceedings as Ashworth I,
`right?
` I need an audible answer.
` A. That's correct.
` Q. Okay. And you selected as your lead
`compound compound 25 out of Ashworth I, right?
` A. That's correct.
` Q. Okay. Now, I saw in your reply
`report, Mylan Exhibit 1074, multiple references to
`bulky P2 groups. Is that a fair characterization?
` A. There are multiple references to that
`term, yes.
` Q. Okay. Now, by reference to
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`Ashworth I, Mylan Exhibit 1007, Dr. Ashworth
`doesn't say "bulky," she says "beta branched,"
`right?
` A. She uses the term beta branched. The
`term bulky, is a term that a medicinal chemist in
`the year 2000, and the year 2016, that's a term
`that is commonly understood and it is sort of
`innately well understood. It's also a term that
`was used by others. For example, Mentlein in 1993
`used the term bulky amino acid.
` Q. Okay. But --
` A. And so a beta branched amino acid is,
`or could be, a bulky group, depending on how it is
`branched, what branching occurs, and on the
`specifics of that structure.
` Q. But the fact of the matter is that
`Ashworth did not use the term bulky to describe
`the P2 groups in Ashworth I, Mylan Exhibit 1007,
`correct?
` A. As I've said, Ashworth did not use the
`term, however, a medicinal chemist in the year
`2000 understands what the term bulky means.
` Q. I'm going to ask you one more time,
`and then I'm going to move to strike your answer,
`if you don't answer my question. And the only
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`December 2, 2016
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`reason -- I'm not trying to be nasty, it's just
`we'll never get done if we don't do it this way.
` Ashworth does not use the word "bulky"
`to describe her P2 groups in Mylan Exhibit 1007,
`Ashworth I, correct?
` A. That's correct.
` Q. Thank you.
` Now, referring to Table 2 in
`Ashworth I, Mylan Exhibit 1007, those are the
`cyanopyrrolidine-based inhibitors that Ashworth I
`made and published here, correct?
` A. Yes.
` Q. And I know that we probably have a
`disagreement of sorts on the word to be used here.
` So, to try to get around that, I'd
`like to show you a demonstrative I've made and
`marked for identification as AstraZeneca
`Exhibit 2261.
` And as reflected there, can we agree
`that Ashworth I's largest P2 group, compound 28,
`was less stable?
` A. Compound 28 is clearly less stable
`compared to compound 25. And it's your
`description, largest, that I think is misplaced.
` Q. Well, let's try to get around it this
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`way: Ashworth I uses the phrase Lys(Z)?
` A. Yes.
` Q. And for the lay reader, have I
`correctly drawn out the structure of what that
`molecule 28 in Ashworth I would look like as
`compound 28?
` A. Yes.
` Q. Okay. And have I correctly drawn out
`what compound 25, your lead compound, would look
`like?
` A. That's correct.
` Q. Okay.
` A. But I'd like to point out that a
`medicinal chemist in the year 2000, and in the
`year 2016, and in the year 1990, would understand
`that there is a significant and material
`difference in the bulkiness of those two groups
`based on their structures. And I would not equate
`the term large with bulky because they are -- they
`describe two different features.
` Q. Okay. Before we leave the concept of
`beta branching -- and, again, for the edification
`of our reader -- I'd like to show you a
`demonstrative exhibit I've made and marked for
`identification as AstraZeneca Exhibit 2223 that
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`deals with the issue of nomenclature of some beta
`branched molecules.
` And can we agree that the two
`molecules in the left-hand panel are beta branched
`with a so-called tertiary beta carbon?
` A. And just to be sure you and I are
`looking at the same thing. You're referring to
`the C that's at the point where all three of those
`red lines come together?
` Q. Correct.
` A. Yes.
` Q. Okay. And both molecules on the
`right-hand panel, the one with the t-butyl
`substituent and the one with the adamantyl
`substituent have what is called a quaternary
`carbon at the beta position?
` A. That's correct.
` Q. Okay. And I think you mentioned
`Mentlein. Let's take a look at that.
` I'd like to show you what's been
`marked as AstraZeneca Exhibit 2096, which is a
`copy of the Mentlein publication appearing in
`1993.
` Is that the Mentlein publication you
`were referring to in your earlier answer?
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` A. Yes, it is.
` Q. Okay. Now, you did not cite that
`publication in your opening report, correct?
` A. I did not. This was cited by
`Dr. Weber in a report that she -- or a response
`that she submitted, if memory serves.
` Q. Okay. And just so that we're clear
`about what Mentlein is talking about. He's
`talking about natural substrates for the DPP-4
`enzyme, right?
` A. That's correct.
` Q. And those are molecules that the DPP-4
`enzyme actually cleaves, right?
` A. Yes.
` Q. And the groups in the natural
`substrates for DPP-4 that would be in what he
`calls the P2 position are tyrosine and histidine,
`correct?
` You can look at Figure 1, if you'd
`like.
` A. Yes.
` Q. Okay. And none of the molecules in
`any of that prior art that you've relied on used
`tyrosine or histidine in the P2 position of a
`DPP-4 inhibitor, correct?
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` A. None of the references that I've cited
`employ either of those amino acids.
` Q. And, again, for the edification of our
`reader. If you could take a look at Dr. Weber's
`declaration, AstraZeneca Exhibit 2056. And
`specifically at Paragraph 57 that bridges pages 18
`and 19.
` A. Okay.
` Q. Okay. That has the structure of amino
`acids, correct?
` A. Yeah. These are -- these are
`structures of the 20 commonly occurring amino
`acids.
` Q. Okay. And among them is tyrosine
`there in the bottom row on page 18, right?
` A. Uh-hum.
` Q. And the substituent there is a benzyl
`group with an OH on it, right?
` A. Yes.
` Q. And if we go to page 19, we see
`histidine?
` A. Yes.
` Q. And that has a 5-membered heterocyclic
`ring, including carbon and nitrogen, joined to the
`amino acid through a CH2 group, correct?
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` A. Yes.
` Q. And those are what Mentlein was
`referring to as bulky groups, correct?
` A. Yes.
` Q. Now, I guess I'd like to show you next
`what's been marked as Mylan Exhibit 1008, which is
`the Villhauer WO 98/19998 publication.
` That's one of the references that you
`relied upon in your obviousness opinion, correct?
` A. Yes, it is.
` Q. And if I understand your opinion
`correctly, it's your view that this publication
`would have led a person of ordinary skill in the
`art to replace the cyclohexyl group in Ashworth I,
`compound 25, with an adamantyl group; is that
`fair?
` A. This is part of the argument, yes.
` Q. Okay.
` A. There are other references that were
`cited in my original declaration that contribute
`to that conclusion.
` Q. And, as I understand your opinion, you
`have focused in Mylan Exhibit 1008 at the text at
`the bottom of page 5, which describes even more
`preferred compounds; is that right?
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` A. Yes. The even more preferred, of
`course, is Villhauer's term.
` Q. Okay.
` A. Which I presume to infer that those
`compounds are particularly of interest for reasons
`that they understood and appreciated.
` Q. Okay. And just so that we don't have
`to quarrel about it later. Can we agree that the
`number of different molecules that are embraced by
`the description in that paragraph is in the many
`of hundreds?
` A. That's true. This is a generic
`description that is commonly used in patents to
`describe classes of compounds.
` Q. Okay. And in this particular --
` A. One --
` Q. In this particular publication, when
`we get to page 21 of Mylan Exhibit 1008, the
`Villhauer 19998 publication, he states there: The
`agents of Examples 1, 3, 5, 8 and 12 are the
`preferred agents of the invention. Do you see
`where I've read?
` A. Yes.
` Q. And he includes data on those
`molecules at various places in the application.
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`Do you recall seeing that?
` A. Yes, I do.
` Q. And just, again, for the benefit of
`our reader, I'd like to show you a demonstrative
`exhibit that I've marked for identification as
`AstraZeneca Exhibit 2263 where I have collected
`the structural formula for those five examples and
`the data about them published throughout the
`application. Can we agree on that?
` A. If you don't mind, I'd like to just be
`sure.
` Q. Sure. And to the extent it would
`help, this information is also in Paragraph 201 of
`Dr. Weber's report on page 94.
` A. So, yes, I'll agree that the
`structures that you've listed here are those from
`the patent.
` Q. Okay. And the data is correctly
`reported? I think we've all looked at this a lot
`over the years.
` A. Yes.
` MR. TORCZON: Object to the scope.
` Q. Okay. Now, all of the DPP-4
`inhibitors in the Villhauer 19998 publication,
`Mylan Exhibit 1008, are N-linked, correct?
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` A. That's correct.
` Q. And, as such, those P2 groups of those
`inhibitors will occupy a different position in
`space than they would were those P2 groups
`C-linked, correct?
` A. That's unknown. I would -- and I have
`no opinion on that, on what position those groups
`would occupy in space.
` Q. I'd like to show you a demonstrative
`exhibit that I've made based on Dr. Weber's
`report. It's marked for identification as
`AstraZeneca Exhibit 2259, which is a space filling
`model of an N- and C-linked adamantyl containing
`inhibitor.
` MR. LIPSEY: For the record, this is
` in Paragraph 200 of Dr. Weber's report.
`BY MR. LIPSEY:
` Q. And you're familiar with space filling
`models, correct?
` A. I am.
` Q. And so, at least based on this space
`filling model, it suggests that that P2 group in
`an N-linked molecule was going to occupy a
`different position in space than it would if it
`were C-linked, correct?
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` A. That's not my conclusion and I would
`not -- these represent static pictures, they do
`not represent the dynamics of a molecule in
`solution, and so I would hesitate to draw any firm
`conclusions about what position in space these
`groups occupy.
` Q. Okay. Now, the N-linkage in the
`Villhauer DPP-4 inhibitors that Novartis was
`making and publishing on was generally believed to
`enhance the stability of those molecules, correct?
` A. I wasn't asked to comment on the
`stability, and I wasn't asked to provide opinions
`on the stability of molecules in the Villhauer
`patent. But I'll note that stability is a feature
`that one has to pay attention to in a DPP-4
`inhibitor that contains a cyano functional group.
` Q. I'd like to show you a document that's
`been marked for identification as AstraZeneca
`Exhibit 2262, that we actually discussed in your
`deposition, that's entitled Analogue-Based
`Discovery II.
` Okay. The Analogue-Based Drug
`Discovery publications are reliable scientific
`authorities on matters that they address, correct?
` A. Yes. And I'll note for the record
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`that this was published in 2010, which is past the
`priority date for the patent in question here.
` Q. Okay. And the article purports, in
`part, to describe the history of the development
`of the DPP-4 inhibitor field, correct?
` A. It does.
` Q. And on page 115, extending over to
`116, Analogue-Based Drug Discovery II states:
`Apart from the demonstrated clinical efficacy and
`the facile synthetic access, there might be yet
`another reason why the N-alkylglycine inhibitors
`became very popular throughout the industry in the
`following years: It was generally perceived that
`they had a superior chemical stability. As
`already mentioned, cyanopyrrolidine DPP-4
`inhibitors, and other substrate-based inhibitors
`with an electrophilic serine-interacting motif,
`are chemically unstable in solution. This
`solution instability is due to an intramolecular
`reaction between the amino function and the
`electrophilic motif, as depicted in Scheme 5.1.
`The short solution half-life typically of a few
`hours was causing problems for formulation and was
`made responsible for the short in vivo half-life
`of some compounds.
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` To overcome this limitation, many
`research groups explored N-alkylglycines with
`sterically hindered amines, which would undergo
`cyclization less readily.
` Did I correctly read that?
` MR. TORCZON: Objection. Hearsay.
` MR. LIPSEY: It's all part of the
` transcript.
` A. You correctly read it. And that
`represents this author's opinion because those are
`his words.
` Q. Okay. And, in fact, you were one of
`those researchers that experimented extensively
`with N-alkylglycine; in other words, N-linked
`DPP-4 inhibitors, correct?
` A. In work that I've carried out at
`Bristol-Myers Squibb, that was one area of
`investigation.
` Q. Okay.
` A. The purpose of that investigation was
`subsequent to the discovery of saxagliptin.
` Q. Okay. And we saw that reflected in
`your target sheets from your time at BMS, which we
`saw in your deposition, which I've marked for
`identification as AstraZeneca Exhibit 2260,
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`correct?
` A. And it -- yeah, this is correct. And
`it is worth noting that these molecules do not
`contain a cyano group. These target molecules do
`not contain cyano groups.
` Q. Would you turn, please, in AstraZeneca
`Exhibit 2260 to page 5 of 20.
` A. (Complies.)
` Q. The bottom compound on the right-hand
`side is an N-linked DPP-4 inhibitor with a cyano
`group, correct?
` A. That's correct.
` Q. Okay.
` A. And so I'll note again that these
`molecules were -- the design and synthesis of
`these molecules was based on information that --
`or based on strategic objectives that the company
`provided to us to use for our work. And so -- and
`this occurred, of course, after the discovery of
`saxagliptin.
` Q. Okay. I'd like shift gears a little
`and I'd like to show you the Augustyns 1997
`publication which has been marked as AstraZeneca
`2151.
` And I would also like to show you what
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`we've been calling the Ashworth II publication,
`which has been marked as AstraZeneca 2001.
` Now, again, for the benefit of our
`reader, one of the things that both Augustyns and
`Ashworth looked at was the effect of changing the
`ring size in the P1 group of the DPP-4 inhibitor,
`correct?
` A. In two different classes of DPP-4
`inhibitors, that's correct.
` Q. Okay.
` A. And so I will -- I'd like to note that
`observations that one makes in one class of
`molecules may not necessarily be predictable, or
`translatable, always, to others. Sometimes they
`are and sometimes they aren't.
` Q. And, again, in an effort to kind of
`decode these documents for the reader, I'd like to
`show you a demonstrative exhibit that I've marked
`for identification as AstraZeneca Exhibit 2228
`that depicts the molecules in the structural
`formula of the data bearing on ring size out of
`Augustyns 1997.
` A. Okay.
` Q. Okay. Have I correctly captured that
`information?
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` A. Yes.
` Q. Okay. And so that we can talk about
`it all at once, I'd like to show you a
`demonstrative exhibit I've marked as AstraZeneca
`Exhibit 2230 that captures information bearing on
`ring size out of Ashworth II.
` A. Okay.
` Q. Have I correctly captured that
`information?
` A. Yes.
` Q. Okay. So both Augustyns 1997 and
`Ashworth II have data indicating that a 6-membered
`ring in a pyrrolidine or cyanopyrrolidine-based
`DPP-4 inhibitor would substantially reduce
`activity, correct?
` A. I'm sorry, could you repeat the
`question, please?
` Q. I'll try.
` Both Augustyns 1997, Exhibit 2151, and
`Ashworth II, Exhibit 2001, have data indicating
`that use of a 6-membered ring in a pyrrolidine or
`cyanopyrrolidine-based DPP-4 inhibitor
`substantially reduces activity, correct?
` A. If you're referring to a comparison to
`the 5-membered ring, the smaller 5-membered ring,
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`that's correct.
` Q. Okay. Thank you.
` Now, the fact of the matter is that a
`cyanopyrrolidine ring with a cyclopropyl group in
`the 4,5-position would, according to the IUPAC --
`I-U-P-A-C -- naming conventions be named as a
`6-carbon molecule, correct?
` A. I'm not an expert on IUPAC
`nomenclature and so I would bow to them and assume
`that they'r
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