JOHN R. CORBOY, M.D.
`MYLAN PHARMACEUTICALS INC. VS BIOGEN MA INC.
`
`April 26, 2019
`1
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`UNITED STATES PATENT AND TRADEMARK OFFICE DISTRICT
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD COUNTY OF
`
`IPR2018—0143
`
`Patent No. 8,399,514
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
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`v-
`BIOGEN MA INC.,
`Patent Owner.
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`The Deposition of JOHN R. CORBOY, M.D. ,
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`taken on behalf of the Patent Owner, pursuant to
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`37 C-F-R-§ 42.53 at 9:03 a.m., at 1900 16th Street,
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`Suite 1400, Denver, Colorado, on April 26 , 2019,
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`before Patricia Vigil—Ladner, Registered
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`Professional Reporter and Notary Public within and
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`for the State of Colorado.
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`Biogen Exhibit.2063
`Mylan v. Blogen
`lPR 2018-01403
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`DEPOSIYION SOLUTIONS
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`800.211.DEPO (33 76)
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`MYLAN PHARMACEUTICALS INC. VS BIOGEN MA INC.
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`April 26, 2019
`1
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`UNITED STATES PATENT AND TRADEMARK OFFICE DISTRICT
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD COUNTY OF
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`IPR2018—0143
`
`Patent No. 8,399,514
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v-
`BIOGEN MA INC.,
`Patent Owner.
`
`|
`l
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`|
`|
`
`The Deposition of JOHN R. CORBOY, M.D. ,
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`taken on behalf of the Patent Owner, pursuant to
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`37 C-F-R-§ 42.53 at 9:03 a.m., at 1900 16th Street,
`
`Suite 1400, Denver, Colorado, on April 26 , 2019,
`
`before Patricia Vigil—Ladner, Registered
`
`Professional Reporter and Notary Public within and
`
`for the State of Colorado.
`
`Biogen Exhibit.2063
`Mylan v. Blogen
`lPR 2018-01403
`
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`1 A P P E A R A N C E S
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`
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`April 26, 2019April 26, 20192
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` ON BEHALF OF THE PETITIONER:
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`2 3 4
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`5 EMILY J. GREB, ESQ.
` Perkins Coie
`6 33 East Main Street, Suite 201
` Madison, Wisconsin 53703-3095
`7 608-663-7494
` EGreb@perkinscoie.com
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`8 9
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` COURTNEY M. PROCHNOW, ESQ.
` Perkins Coie
`10 1888 Century Park East, Suite 1700
` Los Angeles, California 90067-1721
`11 310-788-3284
` CProchnow@perkinscoie.com
`12
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`13
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`14 ON BEHALF OF THE PATENT OWNER:
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`15 ERIN M. SOMMERS, ESQ.
` Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`16 901 New York Avenue, NW
` Washington, DC 20001-4413
`17 202-408-4000
` erin.sommers@finnegan.com
`18
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`19 MARK J. FELDSTEIN, ESQ.
` Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`20 901 New York Avenue, NW
` Washington, DC 20001-4413
`21 202-408-4000
` mark.feldstein@finnegan.com
`22
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`23 ALSO PRESENT:
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`24 JERRY DEBOER, videographer
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`25
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`800.211.DEPO (3376)800.211.DEPO (3376)
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`1 INDEX OF EXAMINATION
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`April 26, 2019April 26, 20193
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`2 EXAMINATION PAGE
` April 26, 2019
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` JOHN R. CORBOY, M.D.
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`3 4 5
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`6 EXAMINATION BY MS. SOMMERS 5
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`7 8 9
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`10 INDEX OF EXHIBITS
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`11 FOR IDENTIFICATION REFERENCE
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`12 EXHIBIT 2053 9TH EDITION BOOK CHAPTER 6
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`13 EXHIBIT 2054 LANCET 2004 PUBLISHED ARTICLE 40
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`14 EXHIBIT 2055 DOCUMENT "COVER FOCUS" - TWO 78
` PAGES.
`15
` EXHIBIT 2056 SPECIAL ARTICLE 2003 87
`16
` EXHIBIT 1005 DOCUMENT DATED 1/9/06 103
`17 (PREVIOUSLY MARKED)
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`18 EXHIBIT 1006 COOLEY JOURNALS SUPPLEMENT 105
` (PREVIOUSLY MARKED)
`19
` EXHIBIT 1007 DOCUMENT READS: SIXTEENTH 110
`20 MEETING OF THE EUROPEAN
` NEUROLOGICAL SOCIETY
`21 (PREVIOUSLY MARKED)
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`22 EXHIBIT 1046 PATENT APPLICATION 113
` (PREVIOUSLY MARKED)
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`
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`April 26, 2019April 26, 20194
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`1 THE VIDEOGRAPHER: This is media Unit 1 to
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`2 the video deposition of Dr. John Corboy in the
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`3 matter of Mylan Pharmaceuticals Inc., versus Biogen
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`4 MA Inc., being heard before the United States patent
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`5 and trademark office before the patent trial and
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`6 appeal board. Patent Number 8399514.
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`7 This deposition is being held at 1900 16th
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`8 Street, Suite 1400, Denver, Colorado, on April 26,
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`9 2019, at 9:03 a.m.
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`09:03:12
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`09:03:14
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`09:03:18
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`09:03:22
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`09:03:26
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`09:03:31
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`10 My name is Jerry DeBoer, and I'm the videographer.
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`09:03:48
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`11 The court reporter is Patty Vigil.
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`12 Counsel, will you please introduce
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`13 yourselves and the witness will be sworn.
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`14 MS. SOMMERS: Erin Sommers on behalf of
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`15 Biogen, from Finnegan.
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`16 MR. FELDSTEIN: Mark Feldstein also on
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`17 behalf of Biogen.
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`18 MS. GREB: Emily Greb on behalf of Mylan
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`19 Pharmaceuticals Inc., from Perkins Coie.
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`20 MR. MURPHY: Courtney Prochnow on behalf of
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`21 Mylan Pharmaceuticals Inc., from Perkins Coie.
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`22 THE VIDEOGRAPHER: Would you please swear in
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`23 the witness.
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`1 JOHN R. CORBOY, M.D.,
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`
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`April 26, 2019April 26, 20195
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`2 having been first duly sworn, testified on oath as
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`3 follows:
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`4 EXAMINATION
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`5 BY MS. SOMMERS:
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`6 Q. Good morning. Erin Sommers again from
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`7 Finnegan.
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`8 How are you today?
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`9 A. Good.
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`10 Q. Good. I see you have a clean copy of
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`11 your --
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`12 A. I do.
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`13 Q. -- declaration. You confirm it's clean?
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`14 A. I can. You are welcome to look at it if
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`15 you'd like.
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`16 MS. SOMMERS: Counsel, would you like a
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`17 copy?
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`18 MS. GREB: I have one. Thank you.
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`19 Q. (By Ms. Sommers) In preparing your
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`09:04:35
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`09:04:37
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`09:04:38
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`20 declaration that you have in front of you, did you
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`09:04:55
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`21 consult with anybody?
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`09:04:58
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`22 A. I did. I consulted with the two lawyers on
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`09:05:00
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`23 the other side of the table.
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`24 Q. Anyone else?
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`25 A. No.
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`09:05:02
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`09:05:03
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`09:05:04
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`1 Q. It's all your own work?
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`2 A. All my own work.
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`
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`April 26, 2019April 26, 20196
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`3 (Exhibit 2053 marked for identification.)
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`09:05:05
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`09:05:08
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`09:05:10
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`4 Q. (By Ms. Sommers) I'd like to hand you what's
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`09:05:10
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`5 been marked as Exhibit 2053.
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`6 A. Okay.
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`7 Q. Take a minute and look at that.
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`8 A. I haven't seen this in a while.
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`9 Q. Do you recognize it?
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`10 A. I do. It's a book chapter from -- depends
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`09:05:18
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`09:05:18
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`09:05:33
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`09:05:35
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`09:05:36
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`09:05:38
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`11 on what year it was. We wrote it a couple of times,
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`09:05:41
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`12 and this is from the 2014 version.
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`13 Q. When is the earliest that you wrote this?
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`09:05:44
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`09:05:46
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`14 A. I'd have to look at my CV. We wrote it two
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`09:05:49
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`15 or three times. And it's subsequently been passed
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`16 on to others in our group, but I don't participate
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`09:05:53
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`09:05:53
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`17 in that anymore. It gets updated every two to three
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`09:05:53
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`18 years.
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`09:05:56
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`19 Q. So if you wrote it two to three times, maybe
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`09:05:56
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`20 2008 might have been the earliest?
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`21 A. Maybe somewhere in there.
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`22 MS. GREB: Objection to form.
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`23 THE DEPONENT: I just -- I can't remember
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`24 without looking.
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`25 Q. (By Ms. Sommers) Okay.
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`09:06:00
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`09:06:03
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`09:06:04
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`09:06:06
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`09:06:06
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`09:06:06
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`1 A. I'd have to consult my CV.
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`
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`April 26, 2019April 26, 20197
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`2 Q. But you were an author on this particular
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`3 chapter for earlier versions, is that correct?
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`4 A. That is correct, yes.
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`5 Q. If we could turn to page 837.
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`6 A. Uh-huh.
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`7 Q. And taking a look at figure 39-1.
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`8 A. Right.
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`9 Q. What -- what does this figure represent?
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`09:06:08
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`09:06:10
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`09:06:14
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`09:06:17
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`09:06:18
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`09:06:26
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`09:06:27
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`09:06:33
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`09:06:34
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`10 MS. GREB: I'm sorry. What page are you on?
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`09:06:35
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`11 THE DEPONENT: Go back a page. Sorry.
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`09:06:35
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`12 MS. GREB: I see the pages are at the top.
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`09:06:44
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`13 837. Thank you. Got it.
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`09:06:46
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`14 THE DEPONENT: So this is a common schematic
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`09:06:50
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`15 representation of the -- a commonly held view of the
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`09:06:55
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`16 pathogenesis of multiple sclerosis. Pathogenesis
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`17 multiple sclerosis. P-A-T-H-O-G-E-N-E-S-I-S.
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`09:07:01
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`09:07:13
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`18 Q. (By Ms. Sommers) And I think you said this
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`09:07:13
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`19 is the 2014 edition. This was the pathogenesis of
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`09:07:15
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`20 multiple sclerosis that was commonly held as of
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`21 2014, is that correct?
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`09:07:15
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`09:07:20
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`22 MS. GREB: Objection as to form. Asked and
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`09:07:20
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`23 answered.
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`24 THE DEPONENT: Yes.
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`25 Q. (By Ms. Sommers) And did you make any
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`09:07:23
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`09:07:24
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`09:07:24
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
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`April 26, 2019April 26, 20198
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`1 changes to what's in Exhibit 391 -- or excuse me --
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`09:07:27
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`2 figure 39-1 from earlier versions that you indicated
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`09:07:33
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`3 you authored?
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`09:07:37
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`4 A. Couldn't tell without looking at the older
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`09:07:38
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`5 version.
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`6 Q. Do you have any recollection sitting here
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`7 today?
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`8 A. I don't.
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`9 Q. Do you think it's representative of your
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`10 earliest version that you wrote?
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`09:07:40
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`09:07:40
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`09:07:42
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`09:07:43
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`09:07:43
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`11 A. I don't have a recollection without seeing
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`09:07:47
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`12 it.
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`13 Q. So looking at this in the common
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`09:07:49
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`09:07:53
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`14 pathogenesis, could you explain a little bit of what
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`09:07:56
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`15 we're seeing. Specifically, if we take a look in
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`09:07:59
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`16 the upper half of figure 39.1. Explain to me what's
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`09:08:00
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`17 happening in that part of the figure.
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`18 A. Sure. So the line that's sort of going
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`09:08:05
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`09:08:07
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`19 across the top would be considered the blood-brain
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`09:08:10
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`20 barrier. And so what is on top of that is events
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`21 that are occurring outside of the blood-brain
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`09:08:16
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`09:08:19
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`22 barrier in the bloodstream, perhaps lymph nodes or
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`09:08:22
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`23 elsewhere, that's not behind the blood-brain barrier
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`09:08:25
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`24 and inside the nervous system.
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`25 What's happening below that is the
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`09:08:30
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
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`April 26, 2019April 26, 20199
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`1 theoretical construct as to what's happening inside
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`09:08:31
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`2 the blood-brain barrier and inside the nervous
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`3 system. And so, what's represented at the top is
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`4 the interactions that occur to stimulate and
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`09:08:36
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`09:08:40
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`09:08:44
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`5 activate white blood cells, which then enter through
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`09:08:49
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`6 the blood-brain barrier and enter into the nervous
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`09:08:52
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`7 system, and then presumably cause the abnormal mean
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`09:08:55
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`8 reaction inside the nervous system that ultimately
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`09:09:01
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`9 results in what we think of as multiple sclerosis.
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`09:09:04
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`10 Q. Just so we can be clear for the record,
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`11 above the blood-brain barrier you recognize the
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`12 circles that say CD4 Th1, is that what you're
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`13 referring to as the white blood cell?
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`14 A. That's one type of white blood cell, yes.
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`09:09:09
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`09:09:12
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`09:09:15
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`09:09:19
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`09:09:20
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`15 Q. Okay. Are there any other types above the
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`09:09:21
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`16 blood-brain barrier line that are represented in
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`17 this depiction?
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`18 MS. GREB: Objection. Form.
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`09:09:23
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`09:09:27
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`09:09:27
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`19 THE DEPONENT: The other white blood cells
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`09:09:29
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`20 are primarily below there. Macrophages are a
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`09:09:31
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`21 different type of cell that's produced by the immune
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`09:09:35
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`22 system that participates and is both on the outside
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`09:09:38
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`23 and on the inside of the blood-brain barrier.
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`09:09:42
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`24 Q. (By Ms. Sommers) So what cell in particular
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`09:09:45
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`25 are you referring to as a macrophage, just so I
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`09:09:48
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
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`April 26, 2019April 26, 201910
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`1 understand?
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`2 A. The one on the far right, it says --
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`3 Q. The --
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`4 A. M5, yeah.
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`5 Q. Okay.
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`09:09:51
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`09:09:51
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`09:09:51
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`6 MS. GREB: And can I just request you both
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`09:09:57
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`7 -- you're cutting each other off a little bit. I
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`8 need time to object.
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`9 THE DEPONENT: No problem.
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`10 Q. (By Ms. Sommers) So looking below the
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`11 blood-brain barrier, I understand this is what
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`09:09:57
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`09:09:57
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`09:10:10
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`09:10:10
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`09:10:14
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`12 happens inside the central nervous system, is that
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`09:10:16
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`13 correct?
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`14 A. Yes.
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`09:10:18
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`09:10:18
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`15 Q. And the white blood cells that are outside,
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`09:10:19
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`16 they enter into the blood-brain barrier. How does
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`09:10:22
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`17 that happen?
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`09:10:25
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`18 A. Well, the theory is that there are a number
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`09:10:26
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`19 of different enzymes and perhaps other molecules
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`20 that can poke holes in the blood-brain barrier,
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`21 allowing the activated cells to enter through the
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`09:10:29
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`09:10:37
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`22 blood-brain barrier and then be sequestered behind
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`09:10:45
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`23 the blood-brain barrier inside the nervous system.
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`09:10:49
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`24 Q. And outside the blood-brain barrier, so in
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`09:10:52
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`25 the top half of the picture above that line, are the
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`09:10:56
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`April 26, 2019April 26, 201911
`
`1 white blood cells that are represented there
`
`2 abnormal in any way?
`
`3 MS. GREB: Object as to form.
`
`4 THE DEPONENT: They are not -- depends on
`
`5 what your definition of abnormal is. They are
`
`6 altered compared to their resting state. That
`
`7 doesn't make them abnormal in the sense of being
`
`8 like a cancer cell. It makes them activated in a
`
`9 different state. So I think the better term would
`
`10 be activated, not abnormal.
`
`09:11:00
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`09:11:03
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`09:11:05
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`09:11:08
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`09:11:10
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`09:11:14
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`09:11:17
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`09:11:21
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`09:11:22
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`09:11:25
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`11 Q. (By Ms. Sommers) So how are they activated?
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`09:11:27
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`12 A. They are activated presumably by what's
`
`09:11:30
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`13 occurring on the left-hand side of the top, that is
`
`09:11:32
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`14 an APC or an antigen presenting cell, would in
`
`15 theory present a piece -- what's referred to as
`
`16 apitope -- a piece of a protein, which is taken
`
`17 typically in many cases from a virus, a bacteria,
`
`09:11:36
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`09:11:39
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`09:11:43
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`09:11:48
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`18 other pathogen, and is presented to cells to activate
`
`09:11:52
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`19 them.
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`20 And this activation of the cells changes
`
`21 their function and allows them to signal to other
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`22 white blood cells and to interact with other white
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`23 blood cells and other nonimmune base cells.
`
`24 For example, might interact with nervous
`
`09:11:52
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`09:11:56
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`09:11:59
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`09:12:02
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`09:12:06
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`09:12:10
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`25 system cells, and by that then the cells are able to
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`09:12:13
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
`
`April 26, 2019April 26, 201912
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`1 enter into, in this particular case, inside the
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`2 nervous system and activate an immune response
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`3 inside the nervous system.
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`09:12:17
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`09:12:22
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`09:12:26
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`4 Q. What's to the APC that you've identified in
`
`09:12:29
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`5 the top left-hand corner, figure 39-1, is there a
`
`6 known APC for MS?
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`7 MS. GREB: Object as to form.
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`8 THE DEPONENT: There are many different
`
`9 antigen presenting cells. There are probably
`
`10 multiple ones involved. One that is explicitly
`
`11 involved in MS. There is probably more than one.
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`09:12:33
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`09:12:38
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`09:12:40
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`09:12:42
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`09:12:44
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`09:12:47
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`09:12:52
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`12 Q. (By Ms. Sommers) Do you know which APCs are
`
`09:12:54
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`13 involved?
`
`09:12:57
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`14 A. The ones that are listed there: Dendritic
`
`09:12:57
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`15 cells, macrophages and B lymphocytes or B cells.
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`16 THE REPORTER: I'm sorry.
`
`09:13:01
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`09:13:01
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`17 THE DEPONENT: Dendritic cells, macrophages
`
`09:13:01
`
`18 and B lymphocytes or B cells. They are probably all
`
`09:13:09
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`19 relevant.
`
`09:13:10
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`20 Q. (By Ms. Sommers) When you say probably, is
`
`09:13:11
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`21 it unknown that for sure that they are relevant?
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`22 MS. GREB: Object as to form.
`
`09:13:12
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`09:13:15
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`23 THE DEPONENT: The pathogenesis of multiple
`
`09:13:18
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`24 sclerosis is not known in concrete. So the reality
`
`09:13:21
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`25 is is that there are probably multiple presenting
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`09:13:25
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
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`April 26, 2019April 26, 201913
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`1 cells.
`
`09:13:29
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`2 Q. (By Ms. Sommers) So if we go down below the
`
`09:13:30
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`3 blood-brain barrier, now could you explain in a
`
`09:13:32
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`4 little bit of detail what's happening once the white
`
`09:13:34
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`5 blood cells get into the CNS?
`
`6 A. So a number of different cells may enter
`
`09:13:38
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`09:13:41
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`7 from the external environment. White blood cells,
`
`09:13:46
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`8 lymphocytes, such as the CE4 cells. Other
`
`09:13:51
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`9 lymphocytes as well that are not listed there. For
`
`09:13:55
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`10 example, the CD8 cells that are noted on the left.
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`09:13:58
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`11 B lymphocytes as well and macrophages.
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`12 There are also resident cells inside the
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`13 nervous systems that are already present, such as
`
`09:14:01
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`09:14:05
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`09:14:10
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`14 astrocytes, oliogodendrocytes, which make the mylo
`
`09:14:14
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`15 wrapping around the exons. And then also
`
`09:14:16
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`16 microgleon, which are the residents, scavenger cells
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`09:14:18
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`17 of the macrophage family. They are already present
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`09:14:26
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`18 inside the nervous system. And though not
`
`19 completely understood mechanisms, there are
`
`20 activation of what are considered to be
`
`09:14:28
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`09:14:31
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`09:14:34
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`21 pro-flammatory cells, as noted by the Th1, Th17, the
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`09:14:37
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`22 sort of in the middle right portion of that portion
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`09:14:43
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`23 inside the nervous system. And those are activated.
`
`09:14:46
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`24 There you see a significant amount of
`
`09:14:52
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`25 traffic back and forth between the different types
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`09:14:58
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
`
`April 26, 2019April 26, 201914
`
`1 of cells, and there are many different cells that
`
`09:15:01
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`2 are noted there. In addition on the left, there are
`
`09:15:04
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`3 some other cells that are noted.
`
`4 At the bottom there are some other cells
`
`09:15:08
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`09:15:10
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`5 that are noted, and there is a complex milieu of a
`
`09:15:12
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`6 variety of different cells, which are interacting
`
`7 that ultimately result in an immune reaction that
`
`8 results in like mechanisms not completely
`
`9 understood.
`
`10 Damage to the axon, as well as the myelin
`
`09:15:15
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`09:15:18
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`09:15:24
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`09:15:28
`
`09:15:29
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`11 wrapping around the axon, scavenging of the damaged
`
`09:15:34
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`12 materials and ultimately drop out of the axons and a
`
`09:15:39
`
`13 variety -- and the neurons themselves.
`
`09:15:45
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`14 Q. Okay. So -- just so I can be clear for the
`
`09:15:49
`
`15 record, I want to list some of these cells that we
`
`09:15:53
`
`16 talked about. There is the activated Th1 one Th17,
`
`09:15:55
`
`17 is that correct?
`
`18 A. That would be one, yes.
`
`09:16:01
`
`09:16:01
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`19 Q. Is that one in the same cell or is that two
`
`09:16:03
`
`20 different types of T-cells?
`
`21 A. That would be one in the same cell there.
`
`09:16:07
`
`09:16:11
`
`22 They would express -- express or secrete IL-17, for
`
`09:16:14
`
`23 example.
`
`24 Q. What is IL-17?
`
`09:16:21
`
`09:16:21
`
`25 A. IL-17 is a messenger cell, it's a cryptopine
`
`09:16:24
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`1 that interacts with other cells.
`
`
`
`April 26, 2019April 26, 201915
`
`2 Q. Does the Th1, Th17 cell release any other
`
`3 cytokines?
`
`09:16:29
`
`09:16:31
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`09:16:35
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`4 A. It releases a variety of other cytokines, it
`
`09:16:36
`
`5 might depend on the circumstances. It might be
`
`6 different at different times.
`
`7 Q. Different at different times for MS or --
`
`8 A. MS is not one thing, it's many different
`
`9 things. So it might change and be different at
`
`10 different times.
`
`11 Q. Explain that a little bit.
`
`12 A. The pathogenesis of MS is not 100 percent
`
`09:16:39
`
`09:16:42
`
`09:16:43
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`09:16:47
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`09:16:47
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`09:16:49
`
`09:16:49
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`09:16:51
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`13 clear. I don't think you should take from this that
`
`09:16:56
`
`14 this is some concrete thing. That this is
`
`09:16:59
`
`15 everybody. This is the only thing that happens with
`
`09:17:00
`
`16 multiple sclerosis.
`
`09:17:03
`
`17 This is a schematic that is a broad design
`
`09:17:04
`
`18 of the concept that you would have a
`
`19 pro-inflammatory state that occurs, and that is
`
`09:17:07
`
`09:17:10
`
`20 often referred to as the Th1 state, compared to the
`
`09:17:15
`
`21 Th2 state, which is an antiinflammatory state. And
`
`09:17:19
`
`22 the different molecules that are secreted at one
`
`09:17:26
`
`23 point in time may be different and not exactly the
`
`09:17:29
`
`24 same at all phases of the time and are not perfectly
`
`09:17:32
`
`25 understood.
`
`09:17:37
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`Page 15 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`
`
`April 26, 2019April 26, 201916
`
`1 So I would not take from this that this is
`
`09:17:37
`
`2 the only way and this is 100 percent way and this is
`
`09:17:40
`
`3 anything that occurs and this is all that happens in
`
`09:17:44
`
`4 MS. This is a schematic that is a broad view that
`
`09:17:46
`
`5 changes over time as more information becomes
`
`6 available.
`
`7 So it would depend greatly on when you're
`
`8 talking about it, what the stimulation was for it
`
`09:17:50
`
`09:17:53
`
`09:17:53
`
`09:17:56
`
`9 and other things. So we can't -- we can't say that
`
`09:17:58
`
`10 there is any one thing that happens with this at all
`
`09:18:02
`
`11 times.
`
`12 Q. You mention that this represents a
`
`09:18:05
`
`09:18:05
`
`13 pro-inflammatory state as depicted in this schematic
`
`09:18:08
`
`14 and that was the Th1 state, is that correct?
`
`15 A. Yes.
`
`09:18:14
`
`09:18:17
`
`16 Q. How do you know that it's a Th1 states based
`
`09:18:18
`
`17 on what's disclosed here in the picture?
`
`09:18:21
`
`18 A. The data comes from a variety of different
`
`09:18:24
`
`19 sources over time, and the different white blood
`
`09:18:27
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`20 cells are associated with the secretion of variety
`
`09:18:35
`
`21 of different white blood cells called cytokines.
`
`22 Cytokines are messenger molecules they
`
`23 interact with other ones, with other white blood
`
`24 cells then by receptor-driven mechanics, and they
`
`25 result either in increasing or decreasing
`
`09:18:38
`
`09:18:42
`
`09:18:45
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`09:18:49
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`09:18:52
`
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`Page 16 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`1 inflammation in a very broad sense.
`
`
`
`April 26, 2019April 26, 201917
`
`2 Q. Is -- are Th1 -- is the Th1 state always
`
`3 pro-inflammatory in MS?
`
`4 A. Not necessarily, no.
`
`5 MS. GREB: Objection to form.
`
`6 Q. (By Ms. Sommers) And with respect to the
`
`7 Th2 state that you indicated is a noninflammatory
`
`8 state, is that an accurate characterization?
`
`9 MS. GREB: Objection to form.
`
`10 THE DEPONENT: All of these are relative
`
`11 terms, and I think if you're trying to make
`
`09:18:56
`
`09:18:57
`
`09:19:02
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`09:19:04
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`09:19:05
`
`09:19:07
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`09:19:08
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`09:19:12
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`09:19:15
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`09:19:17
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`09:19:18
`
`12 everything concrete into yes-no concepts, you're --
`
`09:19:20
`
`13 that's not an accurate way to look at it.
`
`09:19:24
`
`14 Perhaps if you told me what you're looking
`
`09:19:27
`
`15 for, I'd be happy to try and help you with it.
`
`09:19:29
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`16 Q. (By Ms. Sommers) I'm trying to understand
`
`09:19:32
`
`17 this because it sounds like it's a complicated
`
`18 pathogenesis.
`
`19 A. That's exactly correct. It is.
`
`20 Q. So with respect to Th2, how would you
`
`21 characterize that as it's depicted here in the
`
`22 scheme 39.1?
`
`09:19:34
`
`09:19:38
`
`09:19:38
`
`09:19:40
`
`09:19:43
`
`09:19:45
`
`23 MS. GREB: Objection as to form. Asked and
`
`09:19:47
`
`24 answered.
`
`25 THE DEPONENT: In a broad sense, Th1 is
`
`09:19:51
`
`09:19:52
`
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`Page 17 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`
`
`April 26, 2019April 26, 201918
`
`1 considered a pro-inflammatory. And in a broad sense
`
`09:19:54
`
`2 Th2 is considered an anti-inflammatory milieu.
`
`09:19:57
`
`3 Q. (By Ms. Sommers) Can Th2 be inflammatory in
`
`09:20:01
`
`4 MS?
`
`5 A. I'm not sure that that's 100 percent
`
`6 certain. Within the immune system things are
`
`09:20:04
`
`09:20:05
`
`09:20:07
`
`7 complicated and sometimes molecules, cytokines can
`
`09:20:11
`
`8 act in one fashion and sometimes they can act in
`
`9 another fashion.
`
`09:20:14
`
`09:20:17
`
`10 In a broad sense it is generally agreed upon
`
`09:20:18
`
`11 within the MS world, as well as with a variety of
`
`12 other autoimmune disorders, that Th1 is
`
`13 pro-inflammatory and Th2 is anti-inflammatory.
`
`09:20:21
`
`09:20:24
`
`09:20:28
`
`14 Q. So with that consideration in mind, why is
`
`09:20:34
`
`15 there a Th2 cell shown then below the blood-brain
`
`16 barrier if this is a pro-inflammatory state?
`
`09:20:36
`
`09:20:40
`
`17 A. Because this is a complex milieu with many
`
`09:20:43
`
`18 different types of cells, and there is a ying-yang
`
`09:20:46
`
`19 going on where there is both an anti-inflammatory
`
`09:20:49
`
`20 and a pro-inflammatory, where there is a regulatory,
`
`09:20:52
`
`21 the T reg cell, for example, that is noted there as
`
`09:20:55
`
`22 a regulatory cell, that alter dynamics.
`
`09:21:01
`
`23 So this is a fluid circumstance that changes
`
`09:21:03
`
`24 over time and is not one fixed thing. It is many
`
`25 different things that changes over time, and so
`
`09:21:06
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`09:21:09
`
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`Page 18 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`
`
`April 26, 2019April 26, 201919
`
`1 there is always going to be a complicated collection
`
`09:21:14
`
`2 of different cells that are available inside the
`
`3 nervous system as well as outside.
`
`09:21:16
`
`09:21:19
`
`4 Q. If I hear you correctly, you're saying that
`
`09:21:22
`
`5 the Th1, Th2 dichotomy is kind of a balance, one
`
`6 between the other, is that correct?
`
`09:21:24
`
`09:21:29
`
`7 MS. GREB: Objection as to form. Asked and
`
`09:21:31
`
`8 answered.
`
`9 THE DEPONENT: That is the theory.
`
`10 Q. (By Ms. Sommers) Whose theory?
`
`09:21:35
`
`09:21:37
`
`09:21:38
`
`11 A. It's a collective theory that is agreed upon
`
`09:21:40
`
`12 by many different people who study immunology.
`
`13 Q. Let's look back at figure 39-1. You
`
`14 mentioned IL-17, which I actually don't see here.
`
`09:21:43
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`09:21:49
`
`09:21:52
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`15 So does this depiction not capture the entirety of
`
`09:21:55
`
`16 what's understood for the pathogenesis of MS?
`
`09:22:00
`
`17 A. I think it is true that the pathogenesis is
`
`09:22:04
`
`18 not completely understood, so it almost assuredly
`
`09:22:07
`
`19 does not include everything that is related to the
`
`09:22:11
`
`20 pathogenesis of MS.
`
`21 The Th17 would reflect that. Th17 cells
`
`22 would be secreting IL-17.
`
`09:22:13
`
`09:22:15
`
`09:22:20
`
`23 Q. And if I'm reading this correctly, does it
`
`09:22:23
`
`24 mean that there are also secreting IL-10, for
`
`25 example?
`
`09:22:25
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`09:22:31
`
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`Page 19 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
`
`
`
`April 26, 2019April 26, 201920
`
`1 MS. GREB: Objection as to form.
`
`2 Q. (By Ms. Sommers) And if you need me to
`
`3 point out where, I can do that?
`
`09:22:31
`
`09:22:33
`
`09:22:36
`
`4 A. Presuming that means at the top there. I'm
`
`09:22:37
`
`5 not certain. I'd have to look at that again because
`
`09:22:43
`
`6 they are actually, where the IL-10 is listed there
`
`09:22:45
`
`7 is actually in between several so that the B
`
`09:22:49
`
`8 regulatory CD-20 cell is secreting IL-10. I believe
`
`09:22:51
`
`9 actually the IL-10 is -- and IL-4 and IL-5 are
`
`10 actually coming from the Th2 in that -- in that
`
`09:22:56
`
`09:23:01
`
`11 sense, not the other direction. It may not be clear
`
`09:23:03
`
`12 on the -- on the actual schematic.
`
`09:23:06
`
`13 Q. How -- how do you understand the IL-4, the
`
`09:23:11
`
`14 IL-5 and the IL-10 to be coming from what cell?
`
`15 MS. GREB: Objection to form.
`
`16 THE DEPONENT: Primarily those are
`
`17 considered antiinflammatory cytokines. So they
`
`09:23:15
`
`09:23:19
`
`09:23:21
`
`09:23:22
`
`18 would be coming from the regulatory molecules, the
`
`09:23:27
`
`19 Th2 cells, for example, the B regulatory cell there,
`
`09:23:29
`
`20 those that are perhaps more on the anti-inflammatory
`
`09:23:33
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`21 side.
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`09:23:37
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`22 Q. (By Ms. Sommers) So they are not coming out
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`09:23:38
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`23 of the Th1, Th17 cell, as you understand this being
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`09:23:39
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`24 depicted in 39-1?
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`25 A. Correct.
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`09:23:44
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`09:23:47
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`800.211.DEPO (3376)800.211.DEPO (3376)
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`EsquireSolutions.comEsquireSolutions.com
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`Page 20 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.MYLAN PHARMACEUTICALS INC. vs BIOGEN MA INC.
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`
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`April 26, 2019April 26, 201921
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`1 Q. With respect to below the Th1, Th17 cell,
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`09:23:48
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`2 there's two arrows forming a circle. Explain what's
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`09:23:52
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`3 happening there.
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`4 A. IL-12 and IL-23 are also pro-inflammatory
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`09:23:57
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`09:23:58
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`5 cytokines. Interferon gamma is a pro-inflammatory
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`09:24:03
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`6 cytokine. Macrophages are primarily scavenger
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`09:24:08
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`7 cells, and they interact with a number of different
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`09:24:11
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`8 molecule -- cells inside the nervous system. As
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`9 well as do other things. They are depicted below
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`09:24:15
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`09:24:21
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`10 that, and that would be an amplification system for
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`09:24:24
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`11 amplifying the pro-inflammatory component of the
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`12 immune attack that's going on inside the nervous
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`13 system.
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`14 Q. How does the amplification system work?
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`15 A. I can't tell you that in detail. I don't
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`16 know.
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`09:24:28
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`09:24:32
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`09:24:35
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`09:24:35
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`09:24:39
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`09:24:41
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`17 Q. When you say amplification, what do you mean
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`09:24:41
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`18 is occurring?
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`19 A. There is an expansion of cells.
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`20 Q. What cells?
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`09:24:44
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`09:24:45
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`09:24:51
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`21 A. The Th1 cells. Cells don't just come in and
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`09:24:51
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`22 sit there. The cells replicate and will reproduce,
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`09:24:57
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`23 and so what that reflects is that. And then there
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`09:25:01
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`24 is two parts perhaps replicating as well as
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`25 secretion of pro-inflammatory cytokines.
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`09:25:05
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`09:25:08
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`800.211.DEPO (3376)800.211.DEPO (3376)
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`EsquireSolutions.comEsquireSolutions.com
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`Page 21 of 142
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`JOHN R. CORBOY, M.D.JOHN R. CORBOY, M.D.
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`MYLAN PHARMACEUTICALS INC
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