LESLIE A. BENET, PH.D.
`MYLAN PHARMACEUTICALS INC. VS BIOGEN MA
`
`April 19, 2019
`1
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`vs.
`
`BIOGEN MA,
`
`INC. ,
`
`Patent Owner.
`
`Case NO.
`
`IPR2018—01403
`
`U.S. PATENT NO. 8,399,514
`
`VIDEO DEPOSITION OF LESLIE A. BENET, PhD
`
`April 19, 2019
`
`9:02 a.m.
`
`505 Howard Street, Suite 1000
`
`San Francisco, California
`
`Reported by:
`
`QUYEN N. DO, CSR NO. 12447
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`Biogen Exhibit 2062
`
`Mylan v. Biogen
`IPR 2018-01403
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`
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`9 Q
`=4 ES QIOBUE
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`Page 1 of 175
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`800.211.DEPO (3376
`EsquireSo/utionsxzongl
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`MYLAN PHARMACEUTICALS INC. VS BIOGEN MA
`
`April 19, 2019
`1
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`vs.
`
`BIOGEN MA,
`
`INC. ,
`
`Patent Owner.
`
`Case NO.
`
`IPR2018—01403
`
`U.S. PATENT NO. 8,399,514
`
`VIDEO DEPOSITION OF LESLIE A. BENET, PhD
`
`April 19, 2019
`
`9:02 a.m.
`
`505 Howard Street, Suite 1000
`
`San Francisco, California
`
`Reported by:
`
`QUYEN N. DO, CSR NO. 12447
`
`Biogen Exhibit 2062
`
`Mylan v. Biogen
`IPR 2018-01403
`
`
`
`9 Q
`=4 ES QIOBUE
`
`Page 1 of 175
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`800.211.DEPO (3376
`EsquireSo/utionsxzongl
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`April 19, 2019April 19, 20192
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 APPEARANCES:
`
` For Petitioner:
`
`2 3
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`4 PERKINS COIE LLP
`
`DAVID L. ANSTAETT, ESQ.
`5 33 East Main Street, Suite 201
`
`Madison, Wisconsin
`53703-3095
`6 608.663.5408
`
`608.663.7499 Fax
`7 DAnstaett@perkinscoie.com
`
`8
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`PERKINS COIE LLP
`
`9 COURTNEY M. PROCHNOW, PhD, ESQ.
`
`1888 Century Park East, Suite 1700
`10 Los Angeles, California
`90067-1721
`
`310.788.3284
`11 310.788.3399 Fax
`
`CProchnow@perkinscoie.com
`12
`
`13 For Patent Owner:
`
`14 FINNEGAN, HENDERSON, FARABOW, GARRETT &
`
`DUNNER, LLP
`15 PIER D. DEROO, ESQ.
`
`MARK J. FELDSTEIN, PhD, ESQ.
`16 901 New York Avenue, NW
`
`Washington, DC
`20001-4413
`17 202.408.2000
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`202.408.4400 Fax
`18 pier.deroo@finnegan.com
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`mark.feldstein@finnegan.com
`19
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`20 Also Present:
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`21 Keigo Painter, Videographer
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`22
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`23
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 INDEX TO EXAMINATION
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`April 19, 2019April 19, 20193
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` WITNESS: LESLIE A. BENET, PhD
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`2 3
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`4 EXAMINATION PAGE
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`5 By Mr. Feldstein 7, 160
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`6 By Mr. Anstaett 164
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`7 Afternoon Session 159
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`8 --oOo--
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 INDEX TO EXHIBITS
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`2 LESLIE A. BENET, PhD
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`
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`April 19, 2019April 19, 20194
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`3 MYLAN PHARMACEUTICALS INC. vs. BIOGEN MA, INC., et
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`4 al.
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`5 Friday, April 19, 2019
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`6 Quyen N. Do, CSR No. 12447
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`MARKED DESCRIPTION PAGE
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`7 8
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`9 Exhibit 2042 Document titled "Application of
` Pharmacokinetics to Patient
`10 Care" 13
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`Exhibit 2043 Document titled "Advances in
`11
` terbutaline pharmacokinetics" 18
`12
` Exhibit 2044 Document titled "Transplantation
`13 Proceedings" 24
`
`Exhibit 2045 Document titled "Basic &
`14
` Clinical Pharmacology," sixth
`15 edition 34
`
`Exhibit 2048 Document titled
`16
` "Pharmacokinetics of oral
`17 fumarates in healthy subjects" 111
`
`Exhibit 2046 Document titled "Long-term
`18
` safety aspects of systemic
`19 therapy with fumaric acid esters
` in severe psoriasis" 114
`20
` Exhibit 2047 United States Patent No.
`21 4,959,389 116
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`22 --oOo--
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`23 EXHIBITS PREVIOUSLY MARKED
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`24 Page Line
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`25 1003 7
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 EXHIBITS PREVIOUSLY MARKED (cont.)
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`2 Page Line
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`April 19, 2019April 19, 20195
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`3 1011 38
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`4 1020 80
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`5 1028 94
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`6 1024 100
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`7 1017 103
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`8 1046 115
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`9 1018 117
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`10 1012 132
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`11 1006 140
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`12 1005 145
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`13 1007 146
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`14 1023 168
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`15 1008 160
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`16 --oOo--
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`
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`April 19, 2019April 19, 20196
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`1 SAN FRANCISCO, CALIFORNIA;
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`2 FRIDAY, APRIL 19, 2019, 9:02 A.M.
`
` --oOo--
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` THE VIDEOGRAPHER: Good morning. We're on
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`09:03:42
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`3 4
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`5 6
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`7 the video record on April 19th, 2019, and the time
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`09:03:43
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`8 is 9:02. My name is Keigo Painter. I'm the legal
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`09:03:48
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`9 videographer, and the court reporter today is Quyen
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`09:03:53
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`10 Do. We are both here representing Esquire
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`09:03:55
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`11 Deposition Solutions in San Francisco, California.
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`09:03:58
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`12 This is the beginning of Disc 1 for the deposition
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`09:04:00
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`13 of Dr. Leslie Benet in the matter of Mylan
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`14 Pharmaceuticals Inc., vs. Biogen MA, Inc. Case
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`15 number is IPR2018-01403. We are located today at
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`16 505 Howard Street, Suite 1000, San Francisco,
`
`17 California 94105.
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`18 Counsel, would you please identify
`
`19 yourself for the record.
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`20 MR. FELDSTEIN: This is Mark Feldstein
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`21 from Finnegan Henderson, on behalf of the Patent
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`22 Owner, Biogen. With me today, also from Finnegan
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`23 Henderson, is my colleague, Pier Deroo.
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`09:04:03
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`09:04:07
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`09:04:12
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`09:04:21
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`09:04:26
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`09:04:27
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`09:04:27
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`09:04:30
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`09:04:31
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`09:04:34
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`09:04:37
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`24 MR. ANSTAETT: David Anstaett of Perkins
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`09:04:41
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`25 Coie on behalf Petitioner, Mylan
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`09:04:42
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`800.211.DEPO (3376)800.211.DEPO (3376)
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`
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`April 19, 2019April 19, 20197
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`1 Pharmaceuticals, Inc., and the witness. With me
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`09:04:45
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`2 today is my colleague, Courtney Prochnow, also with
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`09:04:47
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`3 Perkins Coie.
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`09:04:51
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`4 THE VIDEOGRAPHER: The court reporter may
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`09:04:52
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`5 swear in the witness.
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`6 --oOo--
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`7 LESLIE A. BENET, PhD,
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`8 having been first duly sworn, was examined and
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`9 testified as follows:
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`10
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`11 EXAMINATION
`
`12 BY MR. FELDSTEIN:
`
`13 Q Good morning, Dr. Benet. How are you?
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`14 A Good morning. Fine. Thank you.
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`15 Q Good. I see you already have a copy of
`
`16 your declaration from this case?
`
`17 A Yes.
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`09:04:53
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`09:04:53
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`09:04:53
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`09:04:53
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`09:04:54
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`09:04:54
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`09:04:54
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`09:05:11
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`09:05:12
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`09:05:14
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`09:05:15
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`09:05:16
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`09:05:18
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`18 Q Is there anything else that you have with
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`09:05:19
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`19 you here?
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`09:05:20
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`20 A I think they included my Exhibit A, which
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`09:05:21
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`21 is my CV.
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`09:05:24
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`22 Q Okay, and that's Exhibit 1003 and Exhibit
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`09:05:25
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`23 A to Exhibit 1003?
`
`24 A Yes.
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`09:05:28
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`09:05:30
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`25 Q And is that a marked or an unmarked copy?
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`09:05:30
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 A It's completely unmarked.
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`2 Q Okay.
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`
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`April 19, 2019April 19, 20198
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`3 A I didn't look at it, so unmarked.
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`4 MR. FELDSTEIN: Counsel, do you need
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`5 copies? We have extra copies.
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`09:05:32
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`09:05:33
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`09:05:33
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`09:05:37
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`09:05:38
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`6 MR. ANSTAETT: I'll take copies of any --
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`09:05:40
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`7 MR. FELDSTEIN: Okay.
`
`09:05:42
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`8 MR. ANSTAETT: -- exhibits you use today.
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`09:05:42
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`9 That would be great.
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`10 MR. FELDSTEIN: Get out 1003.
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`11 Q (By Mr. Feldstein) Dr. Benet, did you
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`09:05:44
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`09:05:45
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`09:05:46
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`12 consult with anyone else in preparing your report,
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`09:05:49
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`13 your declaration, Exhibit 1003?
`
`14 A Except including the attorneys?
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`15 Q Sure.
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`16 A Consulted with the attorneys.
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`17 Q Just the attorneys?
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`18 A Just the attorneys.
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`09:05:51
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`09:05:54
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`09:05:55
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`09:05:55
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`09:05:56
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`09:05:57
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`19 Q So the work contained in Exhibit 1003 is
`
`09:05:59
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`20 all your own work?
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`21 A It is.
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`22 Q Based on your knowledge and experience?
`
`23 A It is.
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`24 Q Okay. And you've previously testified,
`
`25 Doctor, that you've never treated a patient for
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`09:06:03
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`09:06:04
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`09:06:04
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`09:06:06
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`09:06:07
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`09:06:12
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 multiple sclerosis, correct?
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`2 A That's correct.
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`3 Q And that's true, correct?
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`4 A That is correct.
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`
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`April 19, 2019April 19, 20199
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`5 Q You've also previously testified that
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`6 you've never prescribed any drugs for multiple
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`7 sclerosis; that correct?
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`8 A That's correct.
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`9 Q And -- and it's correct that you never
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`10 have?
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`11 A I never have.
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`09:06:16
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`09:06:18
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`12 Q And you've also previously testified that
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`09:06:30
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`13 you've never published a peer-review paper on MS; is
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`09:06:31
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`14 that true?
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`15 A That's true.
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`16 Q And likewise you've never published a
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`09:06:35
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`09:06:36
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`09:06:37
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`17 peer-review paper on role of cell degradation in the
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`09:06:38
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`18 progression of MS, correct?
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`19 A That's correct.
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`20 Q You've never published a peer-review
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`21 article related to Gd+ lesions in multiple
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`22 sclerosis, correct?
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`23 A That's correct.
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`09:06:41
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`09:06:43
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`09:06:43
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`09:06:47
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`09:06:51
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`09:06:53
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`24 Q Do you have understanding of the mechanism
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`09:06:57
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`25 by which fumarates affect multiple sclerosis disease
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`09:07:00
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`1 progression?
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`
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`April 19, 2019April 19, 201910
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`2 A Somewhat. That is not my major area of
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`3 expertise.
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`4 Q What's your understanding?
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`5 A Understanding is an effects on T-helper
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`6 Cell 1 and T-helper Cell --
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`7 (Reporter clarification)
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`8 THE WITNESS: I'm sorry.
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`9 It has an effects on T-help- -- Th1
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`10 (T-helper Cell 1), T-helper Cell 2, which are in
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`11 these types of diseases, immunomodulator-type
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`12 compounds. That's how their effect is.
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`13 BY MR. FELDSTEIN:
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`14 Q And is there some specific receptor or
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`15 receptors that fumarates bind to?
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`16 A You're out of my area of expertise.
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`17 Q Okay. Do you have understanding of the
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`18 treatment goals for MS around the time of 2006,
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`19 2007?
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`20 A I do.
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`09:07:07
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`09:07:08
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`21 Q What's your understanding of the treatment
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`09:08:03
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`22 goals?
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`09:08:04
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`23 A To decrease the lesions, the patients to
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`09:08:04
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`24 be . . . progress to normality.
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`25 Q In terms of lesions?
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`09:08:10
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`09:08:16
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`
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`April 19, 2019April 19, 201911
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`1 A In terms of lesions.
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`09:08:18
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`2 Q Any other goals that you're aware of for
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`09:08:19
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`3 the treatment of MS around 2006, 2007?
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`4 A Again, more than I know.
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`5 Well, I shouldn't say that, because
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`09:08:21
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`09:08:25
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`09:08:36
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`6 there -- there's a bunch of measurements that were
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`09:08:38
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`7 made in these studies, and they would like to -- the
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`09:08:40
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`8 EDRSS, the T -- the different characteristics that
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`09:08:44
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`9 they measure, they would all like those to improve.
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`09:08:48
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`10 Q So just to -- let me -- let me reask the
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`09:08:52
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`11 question. What treatment goals are you aware of for
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`09:08:53
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`12 multiple sclerosis around the time of 2006?
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`09:08:57
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`13 A Okay. So I would only know from what is
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`09:09:00
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`14 written in my report in terms of reading the
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`15 information provided in the references that I
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`16 reviewed.
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`17 Q Okay. And do you know, around the 2006
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`18 time frame, what was required to show activity in
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`19 treating MS?
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`20 MR. ANSTAETT: Objection to form.
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`21 THE WITNESS: Well, their primary goal,
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`22 whether the gadolinium positive lesions for
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`23 decrease, that -- that was their primary outcome.
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`24 (Reporter clarification)
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`25 THE WITNESS: Gadolinium,
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`09:09:03
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`09:09:05
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`09:09:09
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`09:09:10
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`09:09:22
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`09:09:24
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`09:09:30
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`09:09:30
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`09:09:32
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`
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`April 19, 2019April 19, 201912
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`1 g-a-n-d-o-l-i-n-i-u-m [sic] lesions, decrease those
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`09:09:32
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`2 spontaneous lesions.
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`3 BY MR. FELDSTEIN:
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`4 Q And are you--?
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`5 MR. ANSTAETT: Sorry. It looks like
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`6 you're struggling.
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`7 (Discussion off the record)
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`09:09:40
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`09:09:41
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`09:09:42
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`09:09:42
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`09:09:49
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`8 THE VIDEOGRAPHER: Going off the record,
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`09:09:51
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`9 the time is 9:08.
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`10 (Off the record)
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`11 THE VIDEOGRAPHER: Going back on the
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`12 record, the time is 9:09.
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`13 BY MR. FELDSTEIN:
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`09:09:51
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`09:10:23
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`09:10:26
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`09:10:26
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`09:10:28
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`14 Q And, Doctor, in terms of the Gd+ lesions,
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`09:10:28
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`15 you referred to a decrease. How much of a decrease
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`09:10:33
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`16 is going to provide a clinical effect, to your
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`17 understanding?
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`18 A Outside of my area of expertise.
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`09:10:36
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`09:10:39
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`09:10:40
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`19 Q And, in terms of study design, do you know
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`09:10:51
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`20 what's required to show whether a potential MS drug
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`09:10:54
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`21 is going to have clinical efficacy?
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`22 MR. ANSTAETT: Objection to form.
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`09:10:57
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`09:11:01
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`23 THE WITNESS: Study design . . . probably
`
`09:11:01
`
`24 not.
`
`25 MR. FELDSTEIN: Okay.
`
`09:11:10
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`09:11:10
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201913
`
`1 THE WITNESS: And you obviously have seen
`
`09:11:10
`
`2 that I was on the Fingolimod case, also, so -- but I
`
`09:11:13
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`3 only look at the data that is presented and analyze
`
`09:11:17
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`4 the data.
`
`5 BY MR. FELDSTEIN:
`
`6 Q Okay. So maybe I'll go to -- if not
`
`09:11:21
`
`09:11:22
`
`09:11:22
`
`7 current, at least more home turf territory for you.
`
`09:11:31
`
`8 I want to ask you about some of your publications.
`
`09:11:38
`
`9 We're going to mark, as IPR2018-01403, Exhibit 2042.
`
`09:11:43
`
`10 (Exhibit 2042 marked)
`
`11 BY MR. FELDSTEIN:
`
`09:11:51
`
`09:12:07
`
`12 Q Dr. Benet, is Exhibit 20- -- can you just
`
`09:12:08
`
`13 clarify, on the record, that it's 2042?
`
`14 A Pardon me? Are you asking --
`
`15 Q I'm sorry.
`
`16 A -- me.
`
`09:12:14
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`09:12:18
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`09:12:19
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`09:12:19
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`17 Q I was talking to the reporter, actually.
`
`09:12:19
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`18 A Okay.
`
`09:12:22
`
`19 Q Dr. Benet, Exhibit 2042, can you confirm
`
`09:12:22
`
`20 this is a publication of yours from 1982 or so?
`
`21 A Okay. It's marked 2032, but --
`
`09:12:27
`
`09:12:31
`
`22 Q Okay, well, hand it back to the reporter.
`
`09:12:35
`
`23 Thank you. You get that next, actually.
`
`09:12:35
`
`24 I understand that the reporter, after the
`
`09:12:43
`
`25 deposition, is going to put formal --
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`09:12:45
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`1 A Okay.
`
`2 Q -- labels on it.
`
`
`
`April 19, 2019April 19, 201914
`
`09:12:46
`
`09:12:46
`
`3 A So I was a part of the symposium that then
`
`09:12:47
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`4 got published.
`
`5 Q And this is a publication of yours from
`
`6 around 1982, correct?
`
`7 A That's what it says, yes.
`
`8 Q Okay. You'll take as much time as you
`
`09:12:53
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`09:12:53
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`09:12:56
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`09:12:58
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`09:12:59
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`9 need to refamiliarize yourself, but when you have a
`
`09:13:06
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`10 chance, I want to turn your attention to page 14,
`
`11 using the page numbering at the top.
`
`12 A Okay.
`
`09:13:09
`
`09:13:12
`
`09:13:17
`
`13 Q Do you have an understanding of generally
`
`09:13:19
`
`14 what's shown in Figure 1.5?
`
`15 A Yes.
`
`09:13:21
`
`09:13:24
`
`16 Q Can you explain generally what's shown in
`
`09:13:25
`
`17 Figure 1.5?
`
`18 A So this is looking at the plasma
`
`19 concentration in lidocaine versus the plasma --
`
`09:13:28
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`09:13:29
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`09:13:32
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`20 in -- in heart-failure patients versus the same dose
`
`09:13:38
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`21 in patients that are healthy volunteers.
`
`09:13:41
`
`22 Q And just for the written record, can you
`
`09:13:45
`
`23 describe generally what -- what it's showing in that
`
`09:13:48
`
`24 comparison?
`
`09:13:50
`
`25 A It's a -- a seven heart-failure patients
`
`09:13:51
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201915
`
`1 given a 50-milligram IV bolus dose, looking at the
`
`09:13:55
`
`2 plasma concentrations versus the plasma
`
`3 concentrations [reporter clarification] as a
`
`4 function of time, following an IV intravenous
`
`09:14:02
`
`09:14:04
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`09:14:09
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`5 injection of lidocaine versus what you would see in
`
`09:14:14
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`6 control healthy volunteers.
`
`09:14:18
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`7 Q And what does it show as a difference, if
`
`09:14:20
`
`8 any, between the heart-failure patients and the
`
`9 controls?
`
`09:14:23
`
`09:14:25
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`10 A Higher concentrations in the heart-failure
`
`09:14:26
`
`11 patients.
`
`09:14:27
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`12 Q And why would that be the case if the same
`
`09:14:28
`
`13 dose in heart-failure patients would have a higher
`
`09:14:32
`
`14 plasma concentration than healthy control patients?
`
`09:14:35
`
`15 A Well, this is a high-traction-ratio drug,
`
`09:14:39
`
`16 high-clearance drug, and it's going to be affected
`
`09:14:42
`
`17 by blood flow. And the blood flow is going to be
`
`09:14:46
`
`18 decreased in heart-failure patients, and, therefore,
`
`09:14:51
`
`19 its elimination is not going to be as fast as it
`
`20 would be in the healthy controls.
`
`09:14:53
`
`09:14:56
`
`21 Q Does this example here fall in the general
`
`09:14:57
`
`22 category that disease state affects pharmacokinetics
`
`09:15:00
`
`23 a drug?
`
`24 MR. ANSTAETT: Objection to form.
`
`25 THE WITNESS: It does, and that's what
`
`09:15:03
`
`09:15:04
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`09:15:05
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201916
`
`1 this book is, the -- the book that I edited, the
`
`09:15:06
`
`2 effects of disease state on drug pharmacokinetics.
`
`09:15:09
`
`3 BY MR. FELDSTEIN:
`
`09:15:11
`
`4 Q And can you explain that general concept a
`
`09:15:13
`
`5 little bit about how disease state affects drug
`
`6 pharmacokinetics?
`
`09:15:15
`
`09:15:19
`
`7 A So disease state affects the organs in the
`
`09:15:20
`
`8 body. In terms of the elimination capacity, primary
`
`09:15:23
`
`9 organs, the kidney, and the liver; and it also
`
`09:15:25
`
`10 affects the volumes of distribution, the space where
`
`09:15:27
`
`11 the drug distributes in the body; and, therefore, it
`
`09:15:30
`
`12 can affect half-life, which is a function of both
`
`13 those parameters (the clearance and the volume).
`
`09:15:32
`
`09:15:35
`
`14 Q And does -- does this phenomenon tell you
`
`09:15:38
`
`15 anything about whether -- when you're doing a study,
`
`09:15:41
`
`16 whether your control patients should be at the same
`
`09:15:45
`
`17 disease state or a different disease state?
`
`18 MR. ANSTAETT: Objection to form.
`
`19 THE WITNESS: I think you need to be
`
`20 clearer what you're asking.
`
`21 BY MR. FELDSTEIN:
`
`22 Q Sure. If you're doing, for example,
`
`09:15:49
`
`09:15:51
`
`09:15:52
`
`09:15:54
`
`09:15:55
`
`09:15:56
`
`23 placebo control in a study of disease, is it proper
`
`09:15:59
`
`24 to have the placebo control patients to have the
`
`09:16:02
`
`25 same disease state as the -- as the patients being
`
`09:16:05
`
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201917
`
`1 treated?
`
`2 A And so am I doing a study where I'm
`
`09:16:12
`
`09:16:13
`
`3 looking at the outcome measure of the drug? Is that
`
`09:16:14
`
`4 what you're asking me?
`
`5 Q Yes.
`
`09:16:17
`
`09:16:18
`
`6 A Yes. That -- you would want the control
`
`09:16:19
`
`7 the -- the -- the outcome of the drug would be
`
`8 somebody with the same disease.
`
`9 Q Okay. And so, similarly, does it fall
`
`10 under this general concept, that in order to know
`
`11 what the pharmacokinetics are going to be in a
`
`09:16:21
`
`09:16:25
`
`09:16:28
`
`09:16:31
`
`09:16:34
`
`12 particular disease population, you need to look at
`
`09:16:37
`
`13 the pharmacokinetics in that disease population as
`
`09:16:40
`
`14 opposed to some other diseases population?
`
`15 MR. ANSTAETT: Objection to form.
`
`16 THE WITNESS: In general, yes.
`
`17 BY MR. FELDSTEIN:
`
`09:16:43
`
`09:16:45
`
`09:16:46
`
`09:16:48
`
`18 Q Okay. How variable can pharmacokinetics
`
`09:16:49
`
`19 be between different disease states?
`
`09:16:57
`
`20 A Could be variable, quite variable. Could
`
`09:16:59
`
`21 be three- to fourfold differences.
`
`22 Q Enough to have a clinical difference?
`
`23 A Yes.
`
`24 MR. FELDSTEIN: Going to mark, as
`
`25 Exhibit 2043, a 1982 publication, "Advances in
`
`09:17:01
`
`09:17:05
`
`09:17:07
`
`09:17:22
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`09:17:23
`
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`Page 17 of 175
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`1 terbutaline pharmacokinetics."
`
`2 (Exhibit 2043 marked)
`
`
`
`April 19, 2019April 19, 201918
`
`09:17:31
`
`09:17:43
`
`3 MR. ANSTAETT: And, as Mr. Feldstein told
`
`09:17:45
`
`4 you, take all the time you need to familiarize
`
`5 yourself with it.
`
`09:17:46
`
`09:17:49
`
`6 THE WITNESS: Terbutaline is how you say
`
`09:17:49
`
`7 it.
`
`8 BY MR. FELDSTEIN:
`
`09:17:52
`
`09:17:52
`
`9 Q You know, fortunately, in the transcript,
`
`09:17:53
`
`10 it comes up exactly the same.
`
`11 Can you take a look at Exhibit 2043,
`
`09:17:54
`
`09:18:02
`
`12 Dr. Benet, and confirm this is also a publication of
`
`09:18:04
`
`13 yours from around 1984?
`
`14 A Yeah. It says '83 on it, but it is a
`
`15 publication of mine.
`
`09:18:08
`
`09:18:10
`
`09:18:13
`
`16 Q On the -- the -- the top of the third page
`
`09:18:15
`
`17 of the document, it says, "Eur[opean] Resp Dis
`
`18 (1984)."
`
`19 A Right. European Journal of Respiratory
`
`20 Diseases.
`
`21 Q Where did you get the 1983 from?
`
`22 A From the -- on the page.
`
`23 Q Copyright page on --
`
`24 A Yeah --
`
`25 Q -- page 2?
`
`09:18:20
`
`09:18:24
`
`09:18:26
`
`09:18:26
`
`09:18:28
`
`09:18:31
`
`09:18:36
`
`09:18:36
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`09:18:36
`
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`Page 18 of 175
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`1 A -- copyright page, yeah.
`
`2 Q I see.
`
`
`
`April 19, 2019April 19, 201919
`
`3 What generally is Exhibit 2043 directed
`
`4 to?
`
`09:18:37
`
`09:18:38
`
`09:18:42
`
`09:18:46
`
`5 A It's listing out, in Table 1, my opinion
`
`09:18:49
`
`6 of the pharmacokinetic parameters that you need to
`
`09:18:53
`
`7 characterize to -- to find a drug substance.
`
`09:18:58
`
`8 Q And on page -- it has page No. 46 in the
`
`09:19:01
`
`9 top left corner.
`
`10 A Yes.
`
`11 Q There's a sentence that begins on the
`
`12 second line, "However" -- says:
`
`09:19:05
`
`09:19:05
`
`09:19:08
`
`09:19:09
`
`13 "However, since pharmacokinetics has
`
`09:19:14
`
`14 no inherent use unless these parameters
`
`09:19:18
`
`15 provide the clinician with a more rational
`
`09:19:18
`
`16 dosage regimen, a number of additional
`
`17 pharmacokinetic parameters must be
`
`18 evaluated in the patient population for
`
`19 whom the drug has been devised."
`
`20 Do you see that?
`
`21 A I do.
`
`09:19:21
`
`09:19:25
`
`09:19:26
`
`09:19:28
`
`09:19:32
`
`09:19:32
`
`22 Q And this may relate to what we're talking
`
`09:19:33
`
`23 about, but can you explain why it must be evaluated
`
`09:19:36
`
`24 in a patient population for whom the drug has been
`
`09:19:40
`
`25 devised?
`
`09:19:43
`
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201920
`
`1 A Because all of those parameters can
`
`09:19:44
`
`2 change, and as we saw in the previous reference, the
`
`09:19:45
`
`3 time course of the drug can change.
`
`4 Q And then the next sentence says:
`
`09:19:48
`
`09:19:52
`
`5 "In addition, the effects of disease
`
`09:19:54
`
`6 state, particularly those diseases which
`
`09:19:56
`
`7 may not be related to the action of the
`
`09:19:58
`
`8 drug, are critical in determining how the
`
`09:20:01
`
`9 body will treat a particular drug
`
`10 substance and thus modify the
`
`11 pharmacodynamic response observed in an
`
`12 individual patient."
`
`09:20:03
`
`09:20:05
`
`09:20:10
`
`09:20:12
`
`13 Can you explain what that sentence means?
`
`09:20:13
`
`14 A Okay, so you could have, for example, a
`
`09:20:22
`
`15 drug being dosed to a patient that has nothing to do
`
`09:20:27
`
`16 with the kidneys, but if the patient has renal
`
`09:20:32
`
`17 failure, it will change the pharmacokinetics of that
`
`09:20:36
`
`18 drug; and, therefore, the plasma concentrations will
`
`09:20:39
`
`19 change even though the drug has no effect on the
`
`20 kidney.
`
`21 Q And the part at the end about modifying
`
`22 the pharmacodynamic response observed in an
`
`09:20:41
`
`09:20:43
`
`09:20:44
`
`09:20:48
`
`23 individual patient, can you explain what that means?
`
`09:20:52
`
`24 A Because pharmacokinetics and
`
`25 pharmacodynamics are the outcome, so the
`
`09:20:55
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`09:20:59
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`Page 20 of 175
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201921
`
`1 pharmacokinetics drives the pharmacodynamics. If
`
`2 the pharmacokinetics change, then the outcome can
`
`3 change.
`
`4 Q The outcome of pharmacodynamics --
`
`5 A Right.
`
`6 Q -- then leading to the -- the clinical
`
`7 effect.
`
`8 A Right.
`
`9 Q Okay. Thanks.
`
`10 And if you could an turn to the page
`
`09:20:59
`
`09:21:01
`
`09:21:05
`
`09:21:05
`
`09:21:08
`
`09:21:09
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`09:21:10
`
`09:21:11
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`09:21:12
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`09:21:13
`
`11 that's numbered 54 at the top . . . the third line
`
`09:21:15
`
`12 down says, "Most drugs appear to follow
`
`13 multicompartment pharmacokinetics."
`
`14 A Yes.
`
`15 Q Can you explain what that means?
`
`09:21:22
`
`09:21:25
`
`09:21:28
`
`09:21:28
`
`16 A Because drugs distributed in the body and
`
`09:21:30
`
`17 they're generally lipophilic, they -- you put them
`
`09:21:31
`
`18 into the blood, but they will distribute all over
`
`19 the body, and it takes time to do that. And,
`
`20 therefore, you're going to see time course that's
`
`21 not just related to elimination, you'll see time
`
`09:21:35
`
`09:21:37
`
`09:21:40
`
`09:21:43
`
`22 course related, also, to distribution. And, to be
`
`09:21:46
`
`23 able to explain that, you have to have more than one
`
`09:21:49
`
`24 parameter to explain it.
`
`09:21:52
`
`25 Q And you may have just explained it, but I
`
`09:21:55
`
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201922
`
`1 wonder if you can take it down a level and just
`
`2 explain what multicompartment means --
`
`3 A Okay.
`
`4 Q -- in this context.
`
`09:21:57
`
`09:22:00
`
`09:22:02
`
`09:22:02
`
`5 A So, when you look at drug levels, like we
`
`09:22:03
`
`6 looked at the lidocaine levels in the previous
`
`7 reference, that was a log plot. That was a log
`
`09:22:06
`
`09:22:09
`
`8 concentration time plot. If drugs were only being
`
`09:22:12
`
`9 eliminated, that plot would be a straight line if
`
`10 clearance was a constant. But there's other
`
`09:22:16
`
`09:22:20
`
`11 processes going on. Therefore, you can't just have
`
`09:22:23
`
`12 a single compartment describing the drug. You must
`
`09:22:25
`
`13 characterize in different compartments where that
`
`14 drugs goes to be able to describe the
`
`09:22:30
`
`09:22:32
`
`15 characteristics. In general, just looking at blood
`
`09:22:35
`
`16 levels, at most you probably need three
`
`17 compartments.
`
`18 Q And is a compartment a theoretical
`
`09:22:38
`
`09:22:41
`
`09:22:42
`
`19 construct, or is it referring to a physical part of
`
`09:22:46
`
`20 the body?
`
`21 A It does not refer to a physical part of
`
`22 the body. It's a mathematical construct.
`
`09:22:49
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`09:22:50
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`09:22:52
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`23 Q And so, when you're -- you're -- what --
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`09:22:58
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`24 you're saying here that most drug -- the pharma- --
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`09:22:59
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`25 excuse me. Let me start over.
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`09:23:05
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`800.211.DEPO (3376)800.211.DEPO (3376)
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`EsquireSolutions.comEsquireSolutions.com
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
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`
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`April 19, 2019April 19, 201923
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`1 The pharmacokinetics of most drugs follows
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`09:23:07
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`2 a multicompartment model, meaning that you need to
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`09:23:10
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`3 have multiple parameters to model their plasma
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`4 concentration?
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`5 MR. ANSTAETT: Objection to form.
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`6 THE WITNESS: Well, basically, what you
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`7 could do is, you could say the body is like a
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`09:23:15
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`09:23:19
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`09:23:20
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`09:23:21
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`09:23:22
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`8 bathtub. You know, you put drug in, and it goes out
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`09:23:25
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`9 the drain. That would be a one compartment.
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`10 MR. FELDSTEIN: Mm-hm.
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`09:23:29
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`09:23:31
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`11 THE WITNESS: But this is no -- it isn't
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`09:23:32
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`12 just the bathtub. You need something connected to
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`09:23:34
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`13 the bathtub to be able to explain what's happening
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`09:23:37
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`14 in the bathtub. Okay.
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`15 BY MR. FELDSTEIN:
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`16 Q And does -- does multicompartment
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`09:23:39
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`09:23:40
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`09:23:41
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`17 pharmacokinetics have relationship to dose response,
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`09:23:45
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`18 or is it separate?
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`19 MR. ANSTAETT: Objection to form.
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`20 THE WITNESS: The reason you're
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`09:23:47
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`09:23:49
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`09:23:50
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`21 pharmacokinetics is to be able to predict outcome.
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`09:23:52
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`22 And so concentrations predict outcome, or least
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`23 integrated concentrations predict outcome always.
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`09:23:54
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`09:24:01
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`24 And so you want to have a characteristic of the drug
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`09:24:05
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`25 that will allow you to predict outcome.
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`09:24:08
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`800.211.DEPO (3376)800.211.DEPO (3376)
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`EsquireSolutions.comEsquireSolutions.com
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`Page 23 of 175
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`LESLIE A. BENET, PH.D.LESLIE A. BENET, PH.D.
`
`MYLAN PHARMACEUTICALS INC. vs BIOGEN MAMYLAN PHARMACEUTICALS INC. vs BIOGEN MA
`
`
`
`April 19, 2019April 19, 201924
`
`1 BY MR. FELDSTEIN:
`
`09:24:10
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`2 Q So, you probably answered it, and I didn't
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`09:24:12
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`3 understand. But does -- is -- what -- can you
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`4 explain what the connection is, if any, between
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`5 multicompartment pharmacokinetics and a
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`6 dose-response relationship?
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`09:24:15
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`09:24:19
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`09:24:23
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`09:24:25
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`7 A Okay, so dose is just saying, I'm going to
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`09:24:27
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`8 take this dose that somebody takes, and I'm going to
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`0
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