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` UNITED STATES PATENT AND TRADEMARK OFFICE
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` BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`__________________________________________
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` MYLAN PHARMACEUTICALS, INC., WOCKHARDT
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` BIO AG and TEVA PHARMACEUTICALS USA, INC.,
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` Petitioners,
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` v.
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` ASTRAZENECA AB,
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` Patent Owner.
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` __________________________________________
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` IPR2015-01340
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` Patent RE44,186
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` __________________________________________
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` CROSS-EXAMINATION OF ANN E. WEBER, Ph.D.
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` Washington, D.C
`.
` October 27, 2016
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`GregoryEdwards, LLC | Worldwide Court Reporting
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`MYLAN - EXHIBIT 1073
`Mylan et al. v. AstraZeneca
`IPR2015-01340
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`
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 2
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` Cross-Examination of ANN E. WEBER,
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`Ph.D., a witness herein, called for examination by
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`counsel for Petitioners in the above-entitled
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`matter, was taken on Thursday, October 27, 2016,
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`commencing at 8:07 a.m. at the law offices of
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`Wilson Sonsini Goodrich & Rosati, 1700 K Street,
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`N.W., Fifth Floor, Washington, D.C. 20006
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`before Cappy Hallock, Registered Professional
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`Reporter, Certified Realtime Reporter, Certified
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`Livenote Reporter and Notary Public in and for the
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`District of Columbia.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 3
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` A P P E A R A N C E S
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` On behalf of Petitioner Mylan
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` Pharmaceuticals, Inc:
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` DOUGLAS H. CARSTEN, ESQUIRE
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` Wilson, Sonsini, Goodrich & Rosati
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` 12235 El Camino Real, Suite 200
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` San Diego, California 92130
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` 858-350-2300 (P) 858-350-2399 (F)
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` dcarsten@wsgr.com
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` -and-
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` RICHARD TORCZON, ESQUIRE
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` DAVID KNAPP, ESQUIRE
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` Wilson, Sonsini, Goodrich & Rosati
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` 1700 K Street NW, 5th Floor
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` Washington, D.C. 20006
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` 202-973-8800 (P) 202-973-8899 (F)
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` rtorczon@wsgr.com
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` dknapp@wsgr.com
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 4
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` A P P E A R A N C E S (Continued)
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` On behalf of Petitioner Teva Pharmaceuticals
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` USA, Inc.
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` GARY J. SPEIER, ESQUIRE
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` Carlson Caspers Vandenburgh Lindquist &
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` Schuman, P.A.
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` 226 South Sixth Street, Suite 4200
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` Minneapolis, Minnesota 55402
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` 612-36-9600 (P) 612-436-9605 (F)
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` gspeier@carlsoncaspers.com
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` On behalf of Patent Owner AstraZeneca AB:
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` JOHN D. LIVINGSTONE, ESQUIRE
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` M. DAVID WEINGARTEN, ESQUIRE
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` Finnegan, Henderson, Farabow, Garrett
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` & Dunner, LLP
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` 271 17th Street NW, Suite 1400
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` Atlanta, Georgia 30363
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` 404-653-6400 (P) 404-653-6444 (F)
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` john.livingstone@finnegan.com
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` david.weingarten@finnegan.com
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 5
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` C O N T E N T S
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` Deposition of ANN E. WEBER, Ph.D.
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` October 27, 2016
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`EXAMINATION BY: PAGE
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` By Mr. Carsten 8
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` By Mr. Livingstone 103
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` -o0o-
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` E X H I B I T S
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` PREVIOUSLY MARKED EXHIBITS
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`Mylan Description Page
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`Exhibit 1001 U.S. Reissued Patent Number 17
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` RE44,186
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`Exhibit 1007 2-Cyanopyrrolidides as 42
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` Potent, Stable Inhibitors of
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` Dipeptidyl Peptidase IV
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`Exhibit 1010 Hanessian reference 71
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`///
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 6
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` E X H I B I T S (Continued)
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` PREVIOUSLY MARKED EXHIBITS
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`AstraZeneca Description Page
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`Exhibit 2056 8-3-16 Weber Declaration 11
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`Exhibit 2161 Article: Discovery of 46
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` JANUVIA (Sitagliptin) ...
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` Thornberry and Weber
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`Exhibit 2096 Article: Dipeptidyl- 58
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` peptidase IV hydrolyses ...
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` Mentlein, Gallwitz and Schmidt
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`Exhibit 2013 U.S. Patent No. 6,166,063 63
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`Exhibit 2151 Article: Pyrrolidides: 64
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` synthesis and structure-activity
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` relationship ... Augustyns
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`Exhibit 2007 Article: The Unique 65
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` Properties of Dipeptidyl-
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` peptidase IV ... Augustyns
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`Exhibit 2001 Article: 4-Cyanothiazolidides 76
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` as Very Potent, Stable ...
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` Ashworth
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 7
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` E X H I B I T S (Continued)
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` PREVIOUSLY MARKED EXHIBITS
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`AstraZeneca Description Page
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`Exhibit 2210 Curriculum Vitae 107
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`Exhibit 2098 Article: Dipeptidyl Piptidase 114
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` IV Inhibitors for the Treatment
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` of ... Weber
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 8
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` P R O C E E D I N G S
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` - - - - - -
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`WHEREUPON,
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` ANN E. WEBER, Ph.D.,
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` A Witness called for examination, having
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`been first duly sworn, was examined and testified
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`as follows:
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` EXAMINATION
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`BY MR. CARSTEN:
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` Q Good morning, Dr. Weber.
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` A Good morning.
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` Q It's very nice to see you again.
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` A Nice to see you.
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` Q So we met before.
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` A Yes, we have.
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` Q I had the great pleasure of conducting
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`your cross examination at trial in a district
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`court action pertaining to saxagliptin.
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` Now, when we last had occasion to talk
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`we were talking about invalidity of a particular
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`patent, correct, the RE'186 patent?
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` A Correct.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 9
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` Q And we were discussing it in the
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`context of an opinion or series of opinions by
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`Dr. Powers, correct?
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` A Correct.
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` Q You understand that today we are going
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`to be talking also about the validity or
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`invalidity of the RE'186 patent, right?
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` A Yes.
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` Q But this time we will be focused on a
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`slightly different set of opinions relating to the
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`alleged invalidity of that patent, right?
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` A That's my understanding.
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` Q And those are the ones that have been
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`tendered by Dr. Rotella, correct?
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` A Yes.
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` Q You understand that you took an oath
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`here today to tell the truth, correct?
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` A Yes.
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` Q And there is no reason you would have
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`any difficulty in testifying completely and
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`accurately and truthfully today; is that fair?
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` A That's correct.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 10
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` MR. LIVINGSTONE: I don't want to
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`interrupt the examination. Did you take an oath?
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` THE WITNESS: Yes.
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` MR. LIVINGSTONE: Sorry. I was over
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`here writing something down. My apologies. It's
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`early morning.
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` Q Dr. Weber, I have tons of materials
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`here. So, as you know, Dr. Rotella had a
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`declaration that had a bunch of exhibits, right?
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` A Yes.
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` Q And you had a declaration that had a
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`bunch of exhibits; is that fair?
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` A There were exhibits, yes.
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` Q Sure.
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` I have done my level best to have at
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`our fingertips, should you need them, the lion's
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`share of the exhibits. If for some reason there
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`is something else that you want to look at that I
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`don't have here, just ask and we can take a quick
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`break and I can get whatever you need to look at
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`printed. This isn't designed to be a memory test.
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`It's not designed to trick you in any way. If you
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 11
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`need to see something in order to fully and
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`completely answer a question, just feel free to
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`ask. Okay?
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` A Okay.
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` Q What I would like to do as the first
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`order of business, though, is put your declaration
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`in front of you.
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` MR. CARSTEN: This has been marked
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`previously as AstraZeneca Exhibit 2056.
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` (Previously marked AstraZeneca Exhibit
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`No. 2056, first referral.)
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`BY MR. CARSTEN:
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` Q If I could trouble you to look at that
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`document and make sure it is accurate to the best
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`of your knowledge.
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` A Yes, this looks like my report.
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` Q Okay.
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` It's a declaration, correct?
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` A Excuse me, my declaration.
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` Q And your declaration, if you turn
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`to -- there are two series of pages at the bottom.
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`There is a set that actually has the page number
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 12
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`of the document, so I, II, and then 1, 2,
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`et cetera. And there is another series that says
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`Page X of 129. We might have some difficulties
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`here. I will do my best to make clear which I am
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`referring to.
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` If you turn to Page 126 of the
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`document. It's the last page. It's also 129 of
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`129.
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` A So 126 of 129 -- no, 129 of 129.
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` Q Yup, the very last page.
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` A Yes.
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` Q And that's your signature?
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` A It is.
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` Q Okay, and you say, "In signing this
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`declaration," reading from Paragraph 1265, "I
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`understand that the declaration will be filed as
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`evidence in a contested case before the Patent
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`Trial and Appeal Board of the United States
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`Patent & Trademark Office."
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` Have I read that correctly?
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` A Yes.
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` Q And you say, "I acknowledge I may be
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 13
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`subject to cross-examination in the case, and that
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`cross-examination will take place within the
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`United States." Correct?
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` A Correct.
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` Q And, "If cross-examination is required
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`of me, I will appear for cross-examination within
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`the United States during the time allotted for
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`cross-examination." Correct?
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` A Correct.
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` Q And then Paragraph 264 says, "I
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`declare under penalty of perjury that the
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`foregoing is true and correct." Right?
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` A Correct.
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` Q Are there any corrections you would
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`like to make to this declaration?
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` A No.
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` Q To the best of your knowledge, it is
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`truthful and accurate?
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` A Yes.
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` Q Let's turn to some of the legal
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`standards that you were asked to apply in this
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`document. So I'm looking at, starting at Page 14
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 14
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`of 129. And there there is a Section V called
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`Legal Standards.
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` Do you see that?
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` A I do.
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` Q You said that you've relied upon
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`AstraZeneca's counsel for the applicable legal
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`standards governing your analysis and opinions,
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`right?
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` A That's correct.
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` Q And if you turn to the following page,
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`Paragraph 41, there you say, "I understand that
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`for a prima facie case of obviousness, structural
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`similarity between the claimed compound and the
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`prior art compound is not enough. The prior art
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`must also have suggested making the specific
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`modifications necessary to achieve the claimed
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`invention."
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` Have I read that correctly?
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` A You have.
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` Q Is that the legal standard that you
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`were directed by AstraZeneca's counsel to apply in
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`this case?
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 15
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` A That is part of the legal standard,
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`yes.
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` Q And you did use that legal standard in
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`forming your opinions with respect to the opinions
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`you have tendered in this case?
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` A I did.
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` Q The next paragraph, Paragraph 42 says,
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`"I understand that a 'lead' compound is one that
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`is most promising to modify and that selection of
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`a lead compound is guided by all of the compound's
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`pertinent properties."
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` I have read that correctly?
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` A You have.
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` Q Is that a legal standard that you were
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`asked to rely upon by AstraZeneca's counsel?
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` A Yes, it is.
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` Q And is that a -- is that a legal
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`standard that you did apply in forming your
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`opinions in this case?
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` A I did.
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` Q On the Paragraph 40, which bridges the
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`two pages we have been discussing here, Pages 14
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 16
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`of 129 and 15 of 129, the bridging sentence says,
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`"I have been told by AstraZeneca's counsel to
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`assume the 'time of the invention' mentioned above
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`to be no later than October 2000."
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` Is that an instruction that you
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`received from AstraZeneca's counsel with respect
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`to your opinions in this matter?
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` A It is.
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` Q You further say, "My opinion would not
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`differ, however, if the filing date of February
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`16, 2001 applied." Correct?
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` A That's correct.
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` Q You didn't do any independent analysis
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`to determine what the appropriate date to frame
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`your analysis was. Instead you rather relied
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`solely upon what AstraZeneca's counsel told you;
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`is that correct?
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` A That's correct. I relied on these
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`dates.
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` Q So you didn't look at provisional
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`applications, et cetera, to determine when
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`saxagliptin compound was first included in any of
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 17
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`those preliminary applications and so forth,
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`correct?
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` A I'm aware of the preliminary
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`applications, and I certainly had access to them,
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`but I did not do that particular analysis.
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` Q Okay.
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` We will come back from time to time
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`over the course of the day to Exhibit 2056, your
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`declaration. I put it in front of you early, sort
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`the first thing out of the gate, so you would have
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`it handy in the event you wanted to look at it for
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`any purpose over the course of the day as well.
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`Okay?
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` A Okay.
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` MR. CARSTEN: So I would like to hand
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`to you what has been marked as Exhibit 1001.
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` (Previously marked Mylan Exhibit No.
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`1001, first referral.)
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` MR. CARSTEN: I have copies for you as
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`well.
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` MR. LIVINGSTONE: Thank you.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 18
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`BY MR. CARSTEN:
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` Q I hope and trust this is a document
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`that looks familiar to you.
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` A Yes, it does.
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` Q This is the re-issue '186 patent; is
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`that correct?
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` A Yes, that's correct.
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` Q Okay.
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` And you considered this document and
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`reviewed it carefully in connection with rendering
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`your opinions in this case; is that fair?
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` A Yes, I considered this document and
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`reviewed it in the case.
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` Q You reviewed it carefully.
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` A Yes, I read it and I reviewed it. I
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`guess it depends on what you mean by carefully.
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` Q Well --
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` A But yes, I read it.
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` Q You're tendering opinions --
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` A Yes.
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` Q -- relating to the validity of the
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`claims of the patent, correct?
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 19
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` A Yes.
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` Q You wouldn't do that if you hadn't
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`read the document carefully, I presume; is that
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`fair?
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` A If that's your definition, yes.
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` Q Let's turn to Column 88, if we could.
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`That's towards the back. It's in the claims
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`section.
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` Now, if we look at -- have you got
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`claim 8?
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` A I do.
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` Q Now, if you look at claim 8 there are
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`one, two, three, four, five, six, seven, eight
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`different compounds identified in claim 8 plus
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`pharmaceutically acceptable salts; is that
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`correct?
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` A That is correct.
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` Q Now, with respect to the first
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`compound depicted under claim 8, so that's Column
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`88 starting around Lines 45 to 52 or so. Have you
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`got that compound?
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` A I have.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 20
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` Q In this patent there's no data
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`presented for this compound relating to potency
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`against DPP-4, correct?
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` A I would have to go back and just --
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` Q Feel free.
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` A -- glance.
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` Q Sure.
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` A I believe that is correct. Again,
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`there is likely, for example, mass spec data.
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`There may be -- so if you're referring to
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`biological data --
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` Q The question was there is no data
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`relating to potency of that compound as the DPP-4?
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` A That is correct.
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` Q And by potency you understand I'm
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`referring to in vitro data; is that correct?
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` A That's correct. I would assume that
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`you are referring to an IC50 or a Ki at DPP-4
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`enzyme.
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` Q And those would be in vitro measures
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`of potency?
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` A Ki and IC50 are in vitro measures of
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 21
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`potency.
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` Q With respect to the compound we have
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`been discussing, the first one under claim 8 in
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`Column 88, there is no data presented relating to
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`activity in any in vivo studies; is that correct?
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` A Actually, let me just -- can I just
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`have a minute to check something?
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` Q Absolutely. Again, as I said, it's
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`not intended to be a memory contest. Feel free.
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` A So that is correct. There is no
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`in vivo data.
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` Q Okay.
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` And there is no information presented
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`here in the patent relating to the activity of any
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`metabolites of that compound against DPP-4,
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`correct?
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` A I think there would be not enough
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`information in the patent to definitively say that
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`there was no metabolite of this particular
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`compound that may have been covered by the patent.
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` Q I'm asking about whether there is any
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`data presented relating to data --
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 22
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` A If you are referring to in vitro
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`potency data, then that would be correct.
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` Q And if I'm describing in vivo activity
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`of a metabolite of that compound, that is also
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`correct, right?
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` A That would be correct. There is no in
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`vivo data for any potential metabolite of that
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`compound.
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` Q Okay.
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` And there is no data provided
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`regarding the interaction of this compound with
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`the DPP-4 enzyme in the patent, correct?
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` A That is correct.
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` Q And there is no data relating to the
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`safety of this compound, correct?
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` A There is no safety data in the patent,
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`that is correct.
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` Q There is no efficacy data relating to
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`this compound in the patent, correct?
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` A That's correct. There is no efficacy
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`data for that compound in the patent.
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` Q And this compound, to your knowledge,
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 23
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`was never advanced to any clinical trials,
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`correct?
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` A I'm not aware of any clinical trials
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`that were conducted with that compound.
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` Q And this compound was never FDA
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`approved, correct?
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` A That's correct.
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` Q So under your analysis in this case,
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`and we will get to some of this a little later,
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`but this compound would be a failure, exhibit a
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`failure of others in connection with your work in
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`this case, correct?
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` A So this compound by virtue of the fact
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`that it was not FDA approved, and that was the
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`standard I used for failure of others, yes, this
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`would be a failure.
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` Q So just to be clear, the standard you
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`applied for your assessment of failure of others
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`was FDA approval, correct?
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` A That is correct.
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` Q And was that a legal standard that you
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`were asked to apply by AstraZeneca's counsel in
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 24
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`connection with forming your opinions in this
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`case?
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` A That -- can I have a minute, please?
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` Q Sure.
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` A So the legal standard that I was asked
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`to apply, this is for the objective evidence of
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`obviousness, was the failure of others in the
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`prior art to fill -- to fill the need. And so the
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`standard I applied was whether the compounds were
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`in the prior art and whether they were able to
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`fill the need for a diabetes medication in the
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`United States. So that was FDA approval of
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`compounds that were in the prior art prior to
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`that, to the date of October 2000.
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` Q And that legal standard that you just
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`described, was that provided to you by Astra's
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`counsel?
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` A Yes. Yes, it was.
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` Q So they are the ones that selected the
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`threshold question or the litmus test of FDA
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`approval as indicative of failure or nonfailure;
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`is that fair?
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 25
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` A Well, they provided me with the
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`understanding that the failure of others in the
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`prior art to fill the need. And so if you were
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`talking about, if I was talking about filling the
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`need for a compound to treat diabetes in the U.S.,
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`then that would be FDA approval.
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` Q Now, as of the priority date there had
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`been no FDA approved DPP-4 treatment for diabetes;
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`is that fair?
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` A There were no FDA approved -- FDA
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`approved DPP-4 inhibitors for the treatment of
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`type 2 diabetes as of the priority date?
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` Q Yes, that is correct.
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` A That is correct.
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` Q In fact, the first FDA approved
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`diabetes treatment was sitagliptin; is that
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`correct?
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` A If you are referring to the first FDA
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`approved DPP-4 inhibitor for the treatment of
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`type 2 diabetes and not a compound in the prior
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`art, yes, the first one to be approved was
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`sitagliptin that wasn't in the prior art.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 26
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` Q And sitagliptin is your compound?
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` A Sitagliptin is Merck's compound, and I
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`did work on that, yes.
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` Q Your team won what I think you
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`referred to at trial as the Nobel Prize of
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`medicinal chemistry for your work on sitagliptin,
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`correct?
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` A Yes, we did.
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` Q You are a member of the Medicinal
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`Chemistry Hall of Fame in part because of your
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`work on sitagliptin?
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` A I would imagine, yes.
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` Q By any measure you would consider
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`sitagliptin a success?
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` A So if you're referring to sitagliptin
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`as a success because it is FDA approved, yes. It
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`would be a success.
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` Q Well, even taking it away from that
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`framework, you yourself, you consider sitagliptin
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`to be a success in your career, don't you?
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` A Well, I would consider sitagliptin to
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`be a compound that I worked on that achieved FDA
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 27
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`approval and is being used to treat patients with
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`type 2 diabetes.
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` Q You are aware that it's the biggest
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`selling of the four FDA approved gliptin
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`compounds, correct?
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` A That's correct.
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` Q And you are aware that it's the
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`biggest selling of the ten worldwide approved
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`gliptin compounds, correct?
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` A That's correct.
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` Q Let me just ask. Is there any way in
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`which you think sitagliptin is not successful?
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` A Not if you are referring to success in
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`the marketplace or success in treating patients
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`with type 2 diabetes, but no. No.
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` Q Now, vildagliptin, you are aware of
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`the compound vildagliptin, correct?
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` A I am.
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` Q I don't want to quibble with you about
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`terminology here. I understand that the compound
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`that is now known as vildagliptin is a prior art
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`compound to saxagliptin; is that correct?
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 28
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` A That is correct.
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` Q Now, I recognize that at the time,
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`October 2000, vildagliptin was not known commonly
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`as vildagliptin but rather the structure of the
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`compound itself was known at that point, correct?
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` A That is correct.
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` Q Okay.
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` Vildagliptin, under your standard in
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`this case, is a failure, correct?
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` A That is correct.
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` Q Now, vildagliptin is approved in
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`Europe for treatment of type 2 diabetes as a DPP-4
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`inhibitor, correct?
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` A Vildagliptin is approved in Europe.
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` Q Okay.
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` Going back to the patent, you were
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`talking about Exhibit 1001. We were talking about
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`the compounds listed under claim 8. We had just
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`finished discussing the first compound under
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`claim 8. I would like to ask the same series of
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`questions with regard to the second compound.
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` So with respect to the second
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 29
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`compound, the one that has the cyclobutane ring in
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`it, do you have that, Dr. Weber?
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` A I do.
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` Q Is there any data presented in the
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`specification of the RE'186 patent pertaining to
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`potency data for that compound against DPP-4?
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` A No. There is no specific IC50 or Ki
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`for this compound.
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` Q Is there any data presented with
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`respect to that second compound under claim 8 with
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`respect to in vivo data against DPP-4 or type 2
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`diabetes?
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` A That's correct. No in vivo data
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`presented in the patent.
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` Q And there is no data presented
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`regarding activity of a metabolite of that
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`compound against DPP-4?
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` A That's correct.
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` Q And there is no data about the safety
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`of that compound?
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` A No data about the safety of the
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`compound in the patent.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 30
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` Q No data about the efficacy of the
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`compound in the patent?
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` A No data about the efficacy in the
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`patent.
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` Q To your knowledge, it's never advanced
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`to clinical trials?
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` A To the best of my knowledge, this
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`compound has not advanced to clinical trials.
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` Q And it is not FDA approved?
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` A It is not FDA approved.
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` Q And under your analysis in this case
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`that compound is also a failure?
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` A That's correct.
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` Q Okay.
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` With respect to the third compound
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`under claim 8, the one at the bottom of Column 88
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`that has got the cyclohexyl group, do you see
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`that?
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` A I do.
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` Q There is no data in the patent
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`pertaining to in vitro activity against DPP-4?
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` A That's correct. No IC50 or Ki.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 31
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` Q And no data presented relating to
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`in vivo activity of that compound?
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` A No in vivo activity.
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` Q No information provided relating to
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`interaction of that compound with the DPP-4
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`enzyme?
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` A That's correct.
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` Q No information provided regarding
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`activity of a metabolite of that compound against
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`DPP-4?
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` A No information about metabolites of
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`this compound.
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` Q No information provided relating to
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`safety of this compound in the patent?
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` A No information on safety.
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` Q No information about efficacy of this
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`compound in the patent?
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` A That's correct. No efficacy data.
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` Q Under your analysis in this case that
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`compound is also a failure, correct?
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` A This compound was not approved by the
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`FDA and is a failure.
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`Ann E. Weber, Ph.D. - October 27, 2016
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`Page 32
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` Q Okay.
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` There are five compounds at the top of
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`Column 89 which is also part of claim 8, correct?
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` A That is correct.
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` Q Okay.
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` Now, one of the five compounds is
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`saxagliptin; is that correct?
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` A That's correct.
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` Q With respect to the four compounds
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`that are not saxagliptin, I'm just going to ask
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`the same series of questions for expediency sake.
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` With respect to those four compounds,
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`is there any data presented in the specification
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`of the RE'186 patent relating to in vivo -- excuse
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`me, in vitro activity against DPP-4?
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` A There is no specific in vitro data
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`presented.
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` Q With respect to the four compounds
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`that are not saxagliptin on the top