Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 1 of 401 PageID #: 24085
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`
`
`
`
`C.A. No. 18-924-CFC
`
`
`
`
`
`
`
`
`
`
`Plaintiffs,
`
`Defendant.
`
`
`GENENTECH, INC. and CITY OF HOPE,
`
`
`
`v.
`
`AMGEN, INC.,
`
`
`
`
`
`
`
`
`
`
`
`
`
`EXHIBITS 49-114 TO THE DECLARATION OF NORA Q.E. PASSAMANECK
`
`VOLUME 2 OF 3
`
`
`
`PUBLIC VERSION FILED: July 19, 2019
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 2 of 401 PageID #: 24086
`
`
`
`
`
`MCCARTER & ENGLISH LLP
`
`
`/s/ Michael P. Kelly
`Michael P. Kelly (#2295)
`Daniel M. Silver (#4758)
`Alexandra M. Joyce (#6423)
`Renaissance Centre
`405 N. King Street, 8th Floor
`Wilmington, Delaware 19801
`Tel.: (302) 984-6300
`Fax: (302) 984-6399
`mkelly@mccarter.com
`dsilver@mccarter.com
`ajoyce@mccarter.com
`
`Attorneys for Plaintiffs Genentech,
`Inc. and City of Hope
`
`Date: July 10, 2019
`
`Of Counsel:
`
`William F. Lee
`Lisa J. Pirozzolo
`Emily R. Whelan
`Kevin Prussia
`Andrew J. Danford
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`60 State Street
`Boston, MA 02109
`(627) 526-6000
`william.lee@wilmerhale.com
`lisa.pirozzolo@wilmerhale.com
`emily.whelan@wilmerhale.com
`kevin.prussia@wilmerhale.com
`andrew.danford@wilmerhale.com
`
`Robert J. Gunther Jr.
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`(212) 230-8800
`robert.gunther@wilmerhale.com
`
`Daralyn J. Durie
`Adam R. Brausa
`DURIE TANGRI LLP
`217 Leidesdorff St.
`San Francisco, CA 94111
`(415) 362-6666
`ddurie@durietangri.com
`abrausa@durietangri.com
`
`
`2
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 3 of 401 PageID #: 24087
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 3 of 401 PageID #: 24087
`
`EXHIBIT 49
`
`EXHIBIT 49
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 4 of 401 PageID #: 24088
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 4 Of 401 PageID #: 24088
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 5 of 401 PageID #: 24089
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 5 of 401 PageID #: 24089
`
`EXHIBIT 50
`
`EXHIBIT 50
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 6 of 401 PageID #: 24090
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 6 Of 401 PageID #: 24090
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 7 of 401 PageID #: 24091
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 7 of 401 PageID #: 24091
`
`EXHIBIT 51
`
`EXHIBIT 51
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 8 of 401 PageID #: 24092
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 8 Of 401 PageID #: 24092
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 9 of 401 PageID #: 24093
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 9 of 401 PageID #: 24093
`
`EXHIBIT 52
`
`EXHIBIT 52
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 10 of 401 PageID #: 24094
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 10 Of 401 PageID #: 24094
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 11 of 401 PageID #: 24095
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 11 of 401 PageID #: 24095
`
`EXHIBIT 53
`
`EXHIBIT 53
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 12 of 401 PageID #: 24096
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 12 Of 401 PageID #: 24096
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 13 of 401 PageID #: 24097
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 13 of 401 PageID #: 24097
`
`EXHIBIT 54
`
`EXHIBIT 54
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 14 of 401 PageID #: 24098
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 14 Of 401 PageID #: 24098
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 15 of 401 PageID #: 24099
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 15 of 401 PageID #: 24099
`
`EXHIBIT 55
`
`EXHIBIT 55
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 16 of 401 PageID #: 24100
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 16 Of 401 PageID #: 24100
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 17 of 401 PageID #: 24101
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 17 of 401 PageID #: 24101
`
`EXHIBIT 56
`
`EXHIBIT 56
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 18 of 401 PageID #: 24102
`Case 1:18-CV-00924-CFC Doooooot 313 Filed 07/19/19 Page 18 Of 401 PageID #: 24102
`
`
`
`THIS DOCUMENT HAS
`THIS DOCUMENT HAS
`
`BEEN REDACTED IN ITS
`BEEN REDACTED IN ITS
`
`ENTIRETY
`
`ENTIRETY
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 19 of 401 PageID #: 24103
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 19 of 401 PageID #: 24103
`
`EXHIBIT 57
`
`EXHIBIT 57
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 20 of 401 PageID #: 24104
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 20 of 401 PagelD #: 24104
`
`FDA
`
`List of Cleared or Approved Companion
`Diagnostic Devices (In Vitro and Imaging Tools)
`
`A companion diagnostic device can be in vitro diagnostic device or an imaging tool that provides
`information that is essential for the safe and effective use of a corresponding therapeutic product.
`
`The use of an lVD companion diagnostic device with a specific therapeutic product is stipulated in
`the instructions for use in the labeling of both the diagnostic device and the corresponding
`therapeutic product, as well as in the labeling of any generic equivalents and biosimilar equivalents
`of the therapeutic product.
`
`This table lists devices in the order of approval, with most recently approved device at the top.
`
`BRACAnalysis CDx
`
`
`
` 514002055016
`
`Breast Cancer
`
`. Lynparza (olaparib) - NDA 208558
`Myriad Genetic
`Laboratories, lnc. . Talzenna (talazoparib)-
`NDA 211651
`
`Ovarian Cancer
`
`. Lynparza (olaparib) - NDA 208558
`
`0 Rubraca (rucaparib) — NDA 209115
`
`therascreen EGFR
`
`P120022/8018
`
`RGQ PCR Kit
`
`Qiagen
`Manchester, Ltd.
`
`Non-small cell lung cancer
`
`o
`lressa (gefitinib) - NDA 206995
`
`. Gilotrif (afatinib)- NDA 201292
`
`. Vizimpro (dacomitinib)- NDA 211288
`
`cobas EGFR
`Mutation Test v2
`
` 312001916019
`
`Roche Molecular Non-small cell lung cancer (tissue and
`Systems, lnc.
`plasma)
`. Tarceva (erlotinib) — NDA 021743
`
`
`
`. Tagrisso (osimertinib) - NDA 208065
`
`.
`
`lressa (gefitinib) — NDA 206995
`
`PD—L1 lHC 2203
`
` 315001318011
`
`pharme
`
`Dako North
`America, lnc.
`
`Non—small cell lung cancer, gastric or
`gastroesophageal junction
`adenocarcinoma, cervical cancer, and
`urothelial carcinoma
`
`0 Keytruda (pembrolizimab) -
`
`BLA 12551—-
`
`GNE-HER_002954090
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 21 of 401 PageID #: 24105
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 21 of 401 PagelD #: 24105
`
`
`
`VENTANA PD-
`L1(SP142) Assay
`
`
`516000255006
`
`Ventana Medical Non-small cell lung cancer and
`Systems, lnc.
`urothelial carcinoma
`. Tecentriq (atezolizumab) -
`sBLA 761034118012
`
`
`Abbott Molecular, Acute myeloid leukemia
`Abbott
`3170041
`
`lnc.
`. Tibsovo (ivosidenib) - NDA 211192
`RealTime lDH1
`
`
`K1 73492
`
`MolecularMD
`Corporation
`
`Chronic myeloicl leukemia
`. Tasigna (nilotinib) —
`NDA 02206818028
`
`MRDx BCR-ABL
`Test
`
`FoundationOne
`CDx
`
`
`"3170019
`
`Foundation
`Medicine, lnc.
`
`
`
`o
`
`Non—small cell lung cancer
`
`. Gilotrif (afatinib) - NDA 201292
`
`lressa (gefitinib) - NDA 206995
`
`
`0 Tarceva (erlotinib) - NDA 021743
`
`Tagrisso (osimertinib) NDA 208065
`
`
`
`0 Alecensa (alectinib) — NDA 208—3—-
`
`. Xalkori (crizotinib) - NDA 202570
`
`. Zykadia (ceritinib) — NDA 205755
`
`. Tafinlar (dabrafenib) —
`
`NDA 202806 in combination with
`
`Mekinist (trametinib) — NDA 204114
`
`Melanoma
`
`
`. Tafinlar (dabrafenib) — NDA 202806
`
`. Zelboraf (vemurafenib) -
`
`NDA 202429
`
`0 Mekinist (trametinib) -
`
`NDA 204 14 or Cotellic (cobimetinib)
`- NDA 206192 in combination with
`
`Zelboraf (vemurafenib) —
`NDA 202:429
`
`
`
`Breast cancer
`
`0 Herceptin (trastuzumab) —
`
`BLA 103792
`
`
`Perjeta (pertuzumab) - BLA 125409
`
`0
`
`0 Kadcyla(ado-trastuzumab
`
`emtansine) — BLA 125427
`
`Updated 03/11/2019
`
`2
`
`GNE-HER_002954091
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 22 of 401 PageID #: 24106
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 22 of 401 PagelD #: 24106
`
`
`
`Colorectal cancer
`
`
`Erbitux (cetuximab) - BLA 125084
`
`.
`
`. Vectibix (panitumumab) —
`
`BLA 125147
`
`Ovarian cancer
`
`0 Rubraca (rucaparib) — NDA209115
`
`VENTANA ALK
`
`
`
` "314002518006
`
`(D5F3) CDx Assay
`
`Ventana Medical Non—small cell lung cancer
`Systems, lnc.
`. Zykadia (ceritinib) - NDA 205755
`
`Abbott
`RealTime lDH2
`
`Praxis Extended
`RAS Panel
`
`3170005
`
` 33160038
`
`. Xalkori (crizotinib) - NDA 202570
`
`
`. Alecensa (alectinib) - NDA 208/ 3
`
`Abbott Molecular, Acute myeloid leukemia
`lnc.
`.
`ldhifa (enasidenib) - NDA 209606
`
`Colorectal cancer
`
`lllumina, lnc.
`
`. Vectibix (panitumumab) —
`NDA 125147
`
`Oncomine Dx
`
` "3160045
`
`Target Test
`
`Life Technologies Non—small cell lung cancer
`Corporation
`. Tafinlar (dabrafenib) — NDA 202806
`
`
`
`. Mekinist (trametinib) - NDA 204114
`
`. Xalkori (crizotinib) - NDA 202570
`
`0
`
`lressa (gefitinib) - NDA 206995
`
`lnvivoscribe
`Technologies,
`lnc.
`
`Acute myelogenous leukemia
`. Rydapt (midostaurin) - NDA 201997
`. Xospata (gilterinib) - NDA 211349
`
`Foundation
`
`Ovarian cancer
`
`Medicine, lnc.
`
`o Rubraca (rucaparib) — NDA 209115
`
`Abbott Molecular, B-cell chronic lymphocytic leukemia
`lnc.
`o Venclexta (venetoclax) —
`NDA 208573
`
`LeukoStrat CDx
`FLT3 Mutation
`
`Assay
`
`FoundationFocus
`
`CDxBRCA Assay
`
`Vysis CLL FlSH
`Probe Kit
`
`
`
`
`
`3160018
`
`
`
`
`31 500-1-
`
`Aggressive systemic mastocytosis
`ARUP
`Laboratories, lnc. . Gleevec(imatinib mesylate)-
`
`NDA 021335
`
`KIT D816V Mutation H140006
`
`Detection by PCR
`for Gleevec
`
`Eligibility in
`Aggressive
`Systemic
`Mastocytosis (ASM)
`
`Updated 03/11/2019
`
`GNE-HER_002954092
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 23 of 401 PageID #: 24107
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 23 of 401 PagelD #: 24107
`
`
`
`
`
`
`
`
`
`
`
`PDGFRB FlSH for
`Gleevec Eligibility
`in Myelodysplastic
`Syndrome I
`Myeloproliferative
`Disease (MDSIMPD)
`
`ARUP
`Laboratories, lnc.
`
`Myelodysplastic
`syndrome/myeloproliferative disease
`. Gleevec (imatinib mesylate) w
`NDA 021335
`
`
`Roche Molecular Colorectal cancer
`cobas KRAS
`
`
`
`Mutation Test
`
`
`Systems, lnc.
`.
`Erbitux (cetuximab) - BLA12508A-
`
`. Vectibix (panitumumab) —
`
`BLA 125147
`
`therascreen KRAS
`RGQ PCR Kit
`
`P110030
`
`3110027
`
`Qiagen
`Manchester, Lid.
`
`Colorectal cancer
`
`.
`Erbitux (cetuximab) - BLA125084-
`
`. Vectibix (panitumumab) —
`BLA 125147
`
`
`
`Erbitux (cetuximab) - BLA12508A-
`
`pharme
`
`
` F’UBOO'1
`
`
`Dako North
`Colorectal cancer
`Dako EGFR
`
`
`
`
`America, lnc.
`.
`
`pharme Kit
`
`
`. Vectibix (panitumumab) —
`
`BLA 125147
`
`
`
`
`
`FerriScan
`, :Nt 800121’K124065 Resonance
`Non—transfusion-dependent thalassemia
`
`Health Analysis
`. Exjade (deferasirox) w NDA 021882
`
`Services Pty Ltd
`
`
` 304001 1
`Dako North
`Gastrointestinal stromal tumors
`Dako c—KlT
`
`
`America, lnc.
`. Gleevec (imatinib mesylate) -
`
`
`NDA 021335
`
`
`
`
`0 Glivec (imatinib mesylate) —
`
`NDA 021588
`
`
`
`
`
`Ventana Medical Breast cancer
`
`lNFORM HER-Zlneu
`
`
`
`?
`
`Systems, lnc.
`
`. Herceptin (trastuzumab) —
`BLA 103792
`
`Patthsion HER-2
`DNA Probe Kit
`
`
`
`"3980024
`Abbott Molecular Breastcancer
`lnc.
`. Herceptin (trastuzumab) -
`BLA 103792
`
`PATHWAY anti-
`
`
`‘3990081ISOO1—8028 Ventana Medical Breast cancer
`
`Primary Antibody
`
`HerZIneu (435)
`Rabbit Monoclonal
`
`Systems, lnc.
`
`. Herceptin (trastuzumab) -
`BLA 103792
`
`Updated 03/11/2019
`
`4
`
`GNE-HER_002954093
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 24 of 401 PageID #: 24108
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 24 of 401 PageID #: 24108
`
`
`
`lnSite Her-Zlneu KIT
`
`
`
` 304-0030
`
`Biogenex
`Laboratories, inc. 0 Herceptin (trastuzumab)-
`BLA 103792
`
`Breast cancer
`
`SPOT-LiGHT HER2
`CISH Kit
`
`
`"3050040f8001—8003
`
`Bond Oracle HER2
`
`
`3090015
`
`lHC System
`
`HER2 ClSH
`
`pharme Kit
`
`
`
` P100024-
`
`Life Technoiogies Breast cancer
`Corporation
`. Herceptin (trastuzumab) -
`BLA 103792
`
`Leica Biosystems Breast cancer
`. Herceptin (trastuzumab) —
`BLA 103792
`
`Dako Denmark
`AIS
`
`Breast cancer
`
`0 Herceptin (trastuzumab) ~
`BLA 103792
`
`AIS
`
`INFORM HER2 Dual
`lSH DNA Probe
`Cocktail
`
` W Ventana Medical
`Systems, inc.
`
`HercepTest
`
` '3980018f8018
`
`Dako Denmark
`
`Breast cancer
`
`. Herceptin (trastuzumab) —
`BLA 103792
`
`Breast cancer
`
`. H-erceptin (trastuzumab) -
`BLA 103792
`
`
`Perjeta (pertuzumab) — BLA 125—-
`
`Kadcyia (ado-trastuzumab
`emtansine) _ BLA125427
`
`Gastic and gastroesophogeai cancer
`0 Herceptin (trastuzumab) ~
`BLA 103792
`
`HER2 FISH
`
`pharme Kit
`
` 3040005718009
`
`Dako Denmark
`AIS
`
`Breast cancer
`
`0 Herceptin (trastuzumab) -
`
`BLA 103792
`
`
`
`
`
`Perjeta (pertuzumab) — BLA 125—09
`
`0 Kadcyia(ado—trastuzumab
`
`emtansine) - BLA125—-27
`
`Gastic and gastroesophogeai cancer
`. Herceptin (trastuzumab) —
`BLA 103792
`
`Updated 03/11/2019
`
`GNE-HER_002954094
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 25 of 401 PageID #: 24109
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 25 of 401 PagelD #: 24109
`
`THXI D BRAF Kit
`
`
`512001;;
`
`bioMérieux Inc.
`
`Melanoma
`
`Braftovi (encorafenib) in combination
`with Mektovi (binimetinib) — NDAw
`210496 and NDA 210498
`
`
`
`
`
`Mekinist (tramat-enib) - NDA 201111
`
`Tafinlar (dabrafenib) — NDA 202806
`
`
`carcinoma Tec-entriq (atezoiizumab) w
`
`Vysis ALK Break
`Apart FISH Probe
`Kit
`
`cobas 4800 BRAF
`V600 Mutation Test
`
`
`3110012
`
`Abbott Molecular
`Inc.
`
`Non—smalI cell lung cancer
`
`0
`Xalkori (crizotinib) — NDA 202570
`
`
`
`33110020/8016
`
`
`Roche Molecuiar
`
`Melanoma
`
`Systems, Inc.
`
`.
`
`Zelboraf (vemurafenib) -
`
`NDA 202429
`
`CoteIlic (cobimetinib) -
`NDA 206192 in combination with
`
`Zelborat (vemurafenib) —
`
`NDA 202—29
`
`VENTANA PD-
`
`
`
`316000218009
`
`L1(SP142) Assay
`
`
`V-entana Medical
`
`Systems, Inc.
`
`Triple-Negative Breast
`Carcinoma (TNBC), Non~small
`ceIl lung cancer and urothelial
`
`
`
`
`SBLA 761D3—-!SD1 2
`
`Updated 03/11/2019
`
`GNE-HER_002954095
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 26 of 401 PageID #: 24110
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 26 of 401 PageID #: 24110
`
`EXHIBIT 58
`
`EXHIBIT 58
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 27 of 401 PageID #: 24111
`
`HercepTest™
`Code K5204
`
`11th edition
`
`For immunocytochemical staining.
`
`The kit is for 35 tests (70 slides).
`
`PD04086US_01/K520421-5 p. 1/56
`
`GNE-HER_002953700
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 28 of 401 PageID #: 24112
`
`Intended Use
`For in vitro diagnostic use.
`HercepTest™ is a semi-quantitative immunocytochemical assay to determine HER2 protein
`overexpression in breast cancer tissues routinely processed for histological evaluation and
`formalin-fixed, paraffin-embedded cancer tissue from patients with metastatic gastric or
`gastroesophageal junction adenocarcinoma. HercepTest™ is indicated as an aid in the
`assessment of breast and gastric cancer patients for whom Herceptin® (trastuzumab) treatment is
`being considered and for breast cancer patients for whom PERJETA TM (pertuzumab) treatment or
`KADCYLA ™ (ado-trastuzumab emtansine) treatment is being considered (see Herceptin®,
`PERJETA™ and KADCYLA™ package inserts).
`NOTE for breast cancer only: All of the patients in the Herceptin® clinical trials were selected
`using an investigational immunocytochemical clinical trial assay (CTA). None of the patients in
`those trials were selected using the HercepTest™. The HercepTest™ was compared to the CTA
`on an independent set of samples and found to provide acceptably concordant results. The actual
`correlation of the HercepTest™ to Herceptin® clinical outcome has not been established.
`
`NOTE for gastric cancer only: All of the patients in the phase 111 B018255 (ToGA) study
`sponsored by Hoffmann-La Roche were selected using Dako HercepTest™ (IHC) and Dako HER2
`FISH pharmDx™ Kit (FISH). However, enrollment in the B018255 study was limited to patients
`whose tumors were HER2 protein overexpressing (IHC 3+) or gene amplified (FISH+; HER2/CEN-
`17 ratio 2:: 2.0). No patients were enrolled whose tumors were not gene amplified but HER2 protein
`weakly to strongly overexpressing [FISH(-)/IHC 2+], therefore it is unclear if patients whose tumors
`are not gene amplified but HER2 protein overexpressing [i.e., FISH(-), IHC 2+ or 3+] will benefit
`from Herceptin® treatment. The study also demonstrated that gene amplification and protein
`overexpression (I HC) are not as correlated as with breast cancer, therefore a single method should
`not be used to determine HER2 status.
`
`Gastric or gastroesophageal junction adenocarcinoma is also referred to as gastric cancer in this
`document.
`
`For breast cancer application, please refer to pages 5-27.
`For gastric cancer application, please refer to pages 28-50.
`
`Important: Please note for breast cancer tissue and gastric cancer tissue differences
`especially in the Interpretation of Staining Sections.
`
`PD04086US_01/K520421-5 p. 4/56
`
`GNE-HER_002953703
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 29 of 401 PageID #: 24113
`
`Breast Cancer
`
`Summary and Explanation - Breast
`
`Background
`The human HER2 gene (also known as ERBB2 or NEU) encodes a protein often referred to as
`HER2 protein or p185HER2
`. The HER2 protein is a membrane receptor tyrosine kinase with
`homology to the epidermal growth factor receptor (EGFR or HER1) (1-8). The HER2 protein is a
`normal component expressed by a variety of epithelial cell types (8).
`
`In a fraction of patients with breast cancer, the HER2 protein is overexpressed as part of the
`process of malignant transformation and tumor progression (9). Overexpression of the HER2
`protein on the surface of breast cancer cells suggested that it could be a target for an antibody
`therapeutic. Herceptin® (trastuzumab) is a humanized monoclonal antibody (10) that binds with
`high affinity to the HER2 protein and has been shown to inhibit the proliferation of human tumor
`cells that overexpress H ER2 protein in vitro and in vivo ( 11-13).
`
`Pertuzumab is a recombinant humanized monoclonal antibody that binds to sub-domain II of the
`extracellular part of the HER2 protein thereby blocking its ability to form heterodimers with other
`members of the HER family including HER1 (EGFR), HER3, and HER4 (14-16). PERJETA ™
`(pertuzumab) has shown to be effective and safe in treatment of breast cancer patients with HER2
`protein overexpression. During clinical studies of pertuzumab, HER2 overexpression was
`demonstrated directly by IHC or indirectly evidenced through correlation of HER2 gene
`amplification to protein overexpression as demonstrated by FISH. However, in the randomized
`trial, data were available for a limited number of patients (8/808) for whom the FISH results were
`positive but the IHC results were negative (0, 1+) (17, 18).
`
`Ado-trastuzumab emtansine is a novel antibody-drug conjugate specifically designed for the
`treatment of HER2-positive cancer. It is composed of the potent cytotoxic agent DM1 (a thiol­
`containing maytansinoid anti-microtubule agent) conjugated to trastuzumab via a linker molecule.
`Ado-trastuzumab emtansine binds to HER2 with an affinity similar to that of trastuzumab; such
`binding is required for its anti-tumor activity. It is hypothesized that after binding to HER2, ado­
`trastuzumab emtansine undergoes receptor-mediated internalization, followed by intracellular
`release of DM1 and subsequent cytotoxicity (19). A number of clinical studies have shown that
`trastuzumab emtansine is effective and safe in treatment of HER2-positive breast cancer patients
`(20-23).
`
`Characteristics
`HercepTest ™ was developed to provide an alternative to the investigational CTA used in the
`Herceptin® clinical studies. The performance of HercepTest™ for determination of HER2 protein
`overexpression was evaluated in an independent study comparing the results of the HercepTest™
`to the CT A on 548 breast tumor specimens, none of which were obtained from patients in the
`Herceptin® clinical studies. The results indicated a 79% concordance between the results from the
`two assays on these tissue specimens.
`
`The concordance data also indicates that a 3+ reading with HercepTest™ was highly likely to
`correspond with a positive reading on the CT A, which would have met the entry criteria for the trial
`(2+ or 3+). A finding of 2+ on HercepTest™ did not correlate as well with the CTA results.
`Approximately 42% (53/126) of HercepTest™ 2+ results were negative by CTA (0 - 1+) which
`would not have allowed entry into the Herceptin® clinical trials.
`
`HercepTest™ is interpreted as negative for HER2 protein overexpression (0 and 1+ staining
`intensity), weakly positive (2+ staining intensity), and strongly positive (3+ staining intensity).
`HercepTest™ is not intended to provide prognostic information to the patient and physician and
`has not been validated for that purpose.
`
`PD04086US_01/K520421-5 p. 5/56
`
`GNE-HER_002953704
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 30 of 401 PageID #: 24114
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 30 of 401 PageID #: 24114
`
`EXHIBIT 59
`
`EXHIBIT 59
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 31 of 401 PageID #: 24115
`
`-..c:
`
`.!!l
`Cl
`C: w
`
`Bond™ Oracle™ HER2 IHC System
`for Leica BOND-MAX System
`Instructions For Use
`
`For use on Leica Biosystems' BOND-MAX fully automated, advanced staining system.
`
`Product Code TA9145 is designed to stain 60 tests (150 slides):
`60 test slides with HER2 Primary Antibody
`60 test slides with HER2 Negative Control
`15 HER2 Control Slides with HER2 Primary Antibody
`15 positive in-house tissue controls with HER2 Primary Antibody
`
`G(E:
`
`Leica Biosystems Newcastle Ltd
`Ballio1Business Park
`Benton Lane
`Newcastle Upon Tyne NE12 BEW
`United Kingdom
`l 411912154242
`
`1111
`
`Leica Biosystems Canada
`71 Four Valley Drive
`Concord, Ontario L4K 4V8
`Canada
`~ +1800248 0123
`
`Leica Biosystems Inc
`1700Leiderlane
`Buffalo Grove IL 60089
`USA
`~ +1800248 0123
`
`Leica Biosystems Melbourne
`Ptyltd
`495BlackburnRoad
`Mt Waverly VIC 3149
`Australia
`l "'6128870 3500
`
`Page 1 of23
`
`Lei ca Biosystems Bond Oracle HER2 IHC System Instructions for Use TA9145-EN-US-Rev_B 27/10/2014
`
`GNE-HER_002953546
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 32 of 401 PageID #: 24116
`
`...
`..c:
`.!!l
`g>
`w
`
`Intended Use
`For in vitro diagnostic use
`Bond Oracle HER2 IHC System for BOND-MAX is a semi-quantitative immunohistochemical
`(IHC) assay to determine HER2 (Human Epidermal Growth Factor Receptor 2) oncoprotein
`status in formalin-fixed, paraffin-embedded breast cancer tissue processed for histological
`evaluation following automated staining on the BOND-MAX slide staining instrument. The Bond
`Oracle HER2 IHC System for BOND-MAX is indicated as an aid in the assessment of patients
`for whom Herceptin® (trastuzumab) treatment is being considered.
`Note: All of the patients in the Herceptin® clinical trials were selected using an investigational
`immunohistochemical Clinical Trial Assay (CTA). None of the patients in those trials were
`selected using the Bond Oracle HER2 IHC System for BOND-MAX. The Bond Oracle HER2
`IHC System for BOND-MAX has been compared to the Dako HercepTesf' on an independent
`set of samples and found to provide acceptably concordant results. The actual correlation of the
`Bond Oracle HER2 IHC System for BOND-MAX to clinical outcome has not been established.
`
`Summary and Explanation
`
`Background
`The Bond Oracle HER2 IHC System for BOND-MAX contains the mouse monoclonal anti-HER2
`antibody, clone CB11. Clone CB11, originally developed by Corbett et al (1) and manufactured
`by Novocastra Laboratories Ltd (now Leica Biosystems Newcastle Ltd), is directed against the
`internal domain of the HER2 oncoprotein.
`In a proportion of breast cancer patients, the HER2 oncoprotein is overexpressed as part of the
`process of malignant transformation and tumor progression (2). Overexpression of the HER2
`oncoprotein found in breast cancer cells suggests HER2 as a target for an antibody-based
`therapy. Herceptin® is a humanized monoclonal antibody (3) that binds with high affinity to the
`HER2 oncoprotein and has been shown to inhibit the proliferation of human tumor cells that
`overexpress HER2 oncoprotein both in vitro and in vivo (4-6).
`Since the first immunoperoxidase technique, reported by Nakane and Pierce (7), many
`developments have occurred within the field of immunohistochemistry, resulting in increased
`sensitivity. A recent development has been the use of polymeric labeling. This technology has
`been applied to both primary antibodies and immunohistochemical detection systems (8).
`The Compact Polymer™ detection system utilized by the Bond Oracle HER2 IHC System for
`BOND-MAX is part of a family of novel, controlled polymerization technologies that have been
`specifically developed to prepare polymeric HRP-linked antibody conjugates. As this polymer
`technology is utilized in the Oracle product range, the problem of nonspecific endogenous biotin
`staining, which may be seen with streptavidin/biotin detection systems, does not occur.
`
`Expression of HER2
`The HER2 oncoprotein is expressed at levels detectable by immunohistochemistry in up to 20%
`of adenocarcinomas from various sites. Between 10% and 20% of invasive ductal carcinomas
`of the breast are positive for HER2 oncoprotein (9). 90% of cases of ductal carcinoma in situ
`(DCIS) of comedo type are positive (10), together with almost all cases of Paget's disease of
`the breast (11 ).
`Clinical Concordance Summary
`The Bond Oracle HER2 IHC System for BOND-MAX was developed to provide an alternative
`to the investigational Clinical Trial Assay (CTA) used in the Herceptin® clinical studies. The
`performance of the Bond Oracle HER2 IHC System for BOND-MAX for determination of HER2
`oncoprotein overexpression was evaluated in an independent study comparing the results of
`the Bond Oracle HER2 IHC System for BOND-MAX to the Dako HercepTest on 431 breast
`tumor specimens, of US origin. None of these tumor specimens were obtained from patients
`in the Herceptin® clinical trials. The results indicated a 92.34% concordance in a 2x2 analysis
`(95% confidence intervals of 89.42% to 94.67%) and 86.54% in a 3x3 analysis (95% confidence
`intervals of 82.95% to 89.62%) between the results from the two assays.
`
`Page 3 of23
`
`Lei ca Biosystems Bond Oracle HER2 IHC System Instructions for Use TA9145-EN-US-Rev_B 27/10/2014
`
`GNE-HER_002953548
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 33 of 401 PageID #: 24117
`
`-..c:
`
`.!!l
`Cl
`C: w
`
`and the quality control requirements of the CAP Certification Program for lmmunohistochemistry
`and/or CLSI
`(formerly NCCLS) Quality Assurance
`for
`lmmunocytochemistry, Approved
`Guideline (12). These quality control procedures should be repeated for each new antibody lot,
`or whenever there is a change in assay parameters. Human invasive (infiltrating) ductal breast
`carcinoma with known HER2 oncoprotein staining intensities from O to 3+ and other suitably
`negative tissues are appropriate for assay verification.
`
`Interpretation of Staining
`For the determination of HER2 oncoprotein expression, only membrane staining pattern and
`intensity should be evaluated using the scale presented in Table 4. A pathologist using a bright(cid:173)
`field microscope should perform slide evaluation. For evaluation of the immunohistochemical
`staining and scoring, an objective of 1 Ox magnification is appropriate. The use of 20-40x
`objective magnification should be used in the confirmation of the score. Cytoplasmic staining
`should be considered as nonspecific staining and is not to be included in the assessment of
`membrane staining intensity (14). To aid in the differentiation of 0, 1 +, 2+, and 3+ staining, refer
`to the Bond Oracle HER2 IHC System for BOND-MAX Interpretation Guide for representative
`images of the staining intensities. Only specimens from patients with invasive breast carcinoma
`should be scored. In cases with carcinoma in situ and invasive carcinoma in the same specimen,
`only the invasive component should be scored.
`
`lmmunohistochemical Staining Pattern
`
`Score
`
`Assessment
`
`No staining is observed or membrane staining is observed in
`less than 10% of the tumor cells.
`
`0
`
`Negative
`
`Faint/barely perceptible membrane staining is detected in
`more than 10% of the tumor cells. The cells are only stained in
`part of their membrane.
`
`1+
`
`Negative
`
`Weak to moderate complete membrane staining is observed
`in more than 10% of the tumor cells.
`
`2+
`
`Equivocal
`(Weakly Positive)
`
`Strong complete membrane staining is observed in more than
`10% of the tumor cells.
`
`3+
`
`Strongly Positive
`
`Table 4. Interpretation of HER2 staining
`
`Bond Oracle HER2 IHC System for BOND-MAX staining results are interpreted as negative
`for H ER2 oncoprotein expression with scores of O and 1 + staining intensity, equivocal (weakly
`positive) with a score of 2+ staining intensity, and strongly positive with a score of 3+ staining
`intensity. Bond Oracle HER2 IHC System for BOND-MAX is not intended to provide prognostic
`information to the patient and/or physician and has not been validated for that purpose. For each
`staining assessment, slides should be examined in the order presented below to determine the
`validity of the staining run and enable semi-quantitative assessment of the staining intensity of
`the sample tissue.
`
`Page 11 of23
`
`Lei ca Biosystems Bond Oracle HER2 IHC System Instructions for Use TA9145-EN-US-Rev_B 27/10/2014
`
`GNE-HER_002953556
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 34 of 401 PageID #: 24118
`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 34 of 401 PageID #: 24118
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EXHIBIT 6O
`
`EXHIBIT 60
`
`
`
`
`
`
`
`

`

`Case 1:18-cv-00924-CFC Document 313 Filed 07/19/19 Page 35 of 401 PageID #: 24119
`
`PATHWAY anti-HER-2/neu (485) Rabbit Monoclonal
`Primary Antibody
`I REF I 790-2991
`11vo1 W5o
`
`05278368001
`
`INDICATIONS AND USE
`
`Intended Use
`
`This antibody is intended for in vitro diagnostic use.
`Ventana Medical Systems, lnc.'s (Ventana) PATHWAY anti-HER-2/neu (4B5) Rabbit
`Monoclonal Primary Antibody (PATHWAY HER2 (4B5)) is a rabbit monoclonal antibody
`intended for laboratory use for the semi-quantitative detection of HER2 antigen in sections
`of formalin-fixed, paraffin-embedded normal and neoplastic tissue on a VENT ANA
`automated immunohistochemistry slide staining device. 11 is indicated as an aid in the
`assessment of breast cancer patients for whom Herceptin treatment is considered
`Note All of the patients in the Herceptin clinical trials were selected using a clinical trial
`assay None of the patients in those trials were selected using PATHWAY anti-HER-2/neu
`(4B5). PATHWAY anti-HER-2/neu (4B5) was compared to PATHWAY HER-2 (clone
`CB11) Primary Antibody on an independent sample set and found to provide acceptably
`concordant results. The actual correlation of PATHWAY anti-HER-2/neu (4B5) to clinical
`outcome has not been established.
`The VIAS Image Analysis System is an adjunctive optional computer-assisted image
`analysis system functionally connected to an interactive microscope. 11 is intended for use
`as an aid to the pathologist in the detection, classification and counting of cells of interest
`based on marker intensity, size and shape using appropriate controls to assure the validity
`of the VIAS scores.
`Prescription use only.
`
`Summary and Explanation
`
`PATHWAY anti-HER-2/neu is a rabbit monoclonal antibody (clon