Item
`
`Page
`
`Item
`
`Page
`
`INDEX
`
`Accredited Animal Suppliers ......... .
`20
`Activity Thresholds of Common Systems ....... .
`4
`Alkaloid System .....
`23
`In Vitro ................. .
`Astrocytoma Assay -
`31
`Animal Weight Difference (T-C) ..... .
`27
`Biochemical Testing ...
`22
`Calculations for Mean and Median Survival Time
`16
`....... .
`C.S.C. (Control Status Code)
`10
`Cell Culture .....
`26
`Control Body Weight Change
`27
`Control Number ........ .
`11
`Cures
`27
`Date . . . . . . . . . . . . . . . . . . . . . . . . . .
`23
`11
`Date On . . . . . . . . . . . . . .
`.
`Day of Evaluation
`27
`9
`Day of 1st Injection
`DCT Screen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`Death Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
`Detail Test Comments . . . . . . . . . . . . . . . . . . . . . . . . 18
`Dose Per Injection . . . . . . . . . . . . .
`12
`Dose Units . . . . . . . . . . . . . . . . . .
`12
`.
`Evaluation Code - Natural Products
`23
`Evaluation Code - Synthetic ... .
`23
`First Screener . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`11
`3
`Flow of Drugs Through DCT Screen ............... .
`26
`Fold Growth ......... .
`29. 30
`Glossary of Terminology .... .
`19
`Host Group Codes ........ .
`Ho~t Codes In Vivo ........ .
`19
`Host Codes Other Than In Vivo
`19
`lnoculum Site
`21
`lnoculum Tissue .. .
`21
`lnoculum Level .. .
`21
`Interval ............ .
`9
`Log Cell Kill .............. .
`.... 13. 14. 15
`
`24
`M.C. (Material Classification) Natural Products
`25
`.
`M.C. (Material Classification) Synthetic
`Mean Survival Time . . . . . . . . . . . . . . . . .
`16
`Median Survival Time . . . . . . . . . . . . . . . . . .
`16
`Natural Products Number Range Classification
`20
`No-Takes ......... .
`27
`. . . . . . . . . . . . . . . . . . . . . . . . 27
`Number of Injections
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
`Other (Testing)
`Parameter . . . . . . . . . . . . . . . . . . . . . . . . . .
`17
`Partial Indication . . . . . . . . . . . . . . .
`22
`Percent (T /C) % ....................... .
`10
`22
`Product Type/Partial Indicator . . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . . . . . . 22
`(PllB) Publication Code
`24
`Q.N.S. (Quantity Not Sufficient)
`11
`Route of Administration . . . . . . . . . . . . . . . . . .
`17
`Sample Number . . . . . . . . . . . . . . . . . . . . . . . .
`Screener . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 12
`Screening Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5, 6, 7
`28
`Selection Priority for Computed CSC
`19
`Sex . . . . . . . . . . .
`27A
`Solubility . . . . . . . . . . . . . .
`10
`Special Study Codes .... .
`28
`Special System Messages ... .
`Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
`22
`Test/Control Death Patterns
`26
`Test Status Code
`8
`Test Systems . . .
`27
`Test Weigh Days
`9
`Total Injections . . . . . . .
`Toxicity Day
`12
`.
`Toxicity Day Survivors
`12
`Treatment Schedule ....
`':)
`27
`Tumored Survivors
`10
`.
`Tumor Evaluation
`18
`Vehicle ....... .
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 33
`
`

`

`SCREENING DATA SUMMARY
`DEVELOPMENTAL THERiPEUTICS PROGRAM
`DIVISION OF CANCER TREATMENT
`NATIONAL CANCER INSTITUTE, BETHESDA, MD
`SYNTHETIC PRODUCTS
`
`ED
`
`599
`
`DATE: 83/09/02 NSC
`
`20205
`
`~~
`
`tST SCR
`
`5. I. R.C./OATE
`
`999999
`PAGE
`
`14
`PUB
`
`ACQ M.C./DATE
`~
`QI
`7A
`790617
`---CONTINUED-----------------------------------------------------------------------------------
`RT: 1 TRTMT 5CHED= Q01DX05 DAY 1ST INJ=
`3LE31
`LVL=5
`TIS: 1
`TOTAL INJ=
`15
`
`OTHER
`
`QN5
`
`--
`-- -----. --e--. --------------------------- e·---------------------------------
`
`ABOVE _ scHrn _ REP EA TED_ oN_ DAYS_=_ o 1 o, 02olE) _________ G) ____ 1s T _Rx_ TIME_=_ n = 15 _ HRS lE) ________ _
`SMPL 5CR
`EXP
`DA TEON
`V FED
`TXSUR
`TED
`DOS/I NJ/U
`SOL
`C/NT /TS
`EVAL T/C¼
`BWD
`
`I
`
`NDOO
`90
`12345 830726
`02 030
`;;)017/04 018/01 019/01) KE=
`
`006/01 015/03 017/02 eE=
`
`E=
`KE=
`KE=
`
`l *
`
`~
`
`0 :*
`013/01 014/03 015/02
`012/0 1 013/01 014/04
`*
`012/03 014/02
`E){ #~I# COMMENT: ONE ANIMAL MISSING - WEIGHTS ADJUSTED
`*
`008/18 009/10 010/01
`0 11/0 1
`0
`E){ #1#1 COMMENT: RUN WITH 3LE31-12149
`
`G
`
`005 WDl/2: 1/
`4.43
`06/06
`
`200.00)
`
`0.09
`
`05/05
`
`12.50
`
`30/30
`
`CNTRL
`
`: ii)tf.;:;)e'H l: •:H)o:)~: H !fl{::
`---
`--0
`
`TSC=22P
`-3.6
`
`55C: L
`SEX:M
`00 00 00
`17.4
`1
`
`-0.8
`
`1
`
`00 00 00
`
`HOST:06
`
`ewe= 2. lf!J
`
`12.5
`
`8.4
`
`csc: 1
`
`~~~ i~
`
`170 W
`165
`148
`
`FOOTNOTE:
`
`;;i MORTALITY IS GIVEN AS DAY/DEATH COUNT CNOT SURVIVORS)
`
`SYN
`
`999999
`
`17
`
`80 Column Screening Data Summary Interpretations
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 33
`
`

`

`Bia'lk = Not new thts: run
`New this run.
`Data modified this run by the DPC.
`Packs rerned by the Screener I these data affected I.
`Packs revised by the Screener (these data ;.inaffected).
`
`C
`R
`S
`
`Death Pattern Data IDAY/OTHS) - Maximum of 3 entries
`per line; use multiple lines as necessary.
`
`Log Cell Kill Reduction.
`
`Designates data appearing on this and subsequent lines as
`applicable to Control (CNTR L) Group.
`
`Host Code for~ animals in the experiment (Test and
`Control).
`
`BWD = Animal ~ody ~eight _Qifference which is computed
`by subtracting the Control Group body weight change from
`the Test Group body weight change.
`
`BWC = .!!.ody Y?eight ~hange calculated as final average
`body weight minus initial average body weight. This item
`is calculated for the Control Group only.
`
`DATEON = Date the experiment was initiated. (YYMMDD)
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`SMPL = Compound Sample Number.
`
`SCR = Screener Code.
`
`V = Vehicle Code.
`
`FED= Final Evaluation Day.
`
`TED= Toxicity Evaluation Day.
`
`TXSUR = Surviving animals/total animals on Toxicity
`Evaluation Day.
`
`DOS/INJ/U Dose amount per injection, normally ex•
`pressed as mg/kg of animal body weight/injection. Units
`other than mg/kg/inj are flagged with a "unit" code under
`the "U".
`
`i7
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`·w 01.'2: 1, 5" = This item identifies initial ( 1) and f,nal 12)
`animal weigh days. (In this example, the days are 1 end 5.)
`
`"TSC:22P" = This item identifies the Test Status Code
`Inactive
`(TSC) and TSC suffix. P - Active Test, F -
`Test. or R - Erratic Test (unreliable data).
`
`"SSC:L" = This item identifies any Special Study Code
`(SSC) associated with the test. ( In this example, the SSC
`is "L".)
`
`"CSC:1" = This item identifies the Control Status Code
`(CSC) associated with the experiment. ( In this example,
`the CSC is "1".)
`
`EVAL = The calculated value of the Test Group and/or
`Control Group evaluation based on the test system evalua(cid:173)
`tion parameter.
`
`TIC % = The test evaluation expressed as a percent of the
`control evaluation, providing a measure of effectiveness of
`the compound being tested. Survival systems indicate a
`degree of success when T /C percents exceed 125. • Tumor
`inhibition systems indicate a degree of success when the
`TIC percents do not exceed 42. • Minus values (only occur·
`ring for tumor inhibition systems) reflect the percent of
`tumor regression between initial and final tumor volume.
`
`;;+tc/pr Comment= Indicates a Screener comment applicable
`to the data immediately preceeding the comment line.
`
`3 L E 3 1 = Test System used
`
`1l= '"' m ;_,m ;m.,m
`
`Parameter of evaluation (i.e., 2 = mean sur(cid:173)
`vival time; 3 = median survival time; etc.).
`
`26
`
`27
`
`28
`
`LVL:5 = A one or two position field where the left-most
`position is a coded representation of the inoculum level,
`and the right-most position (if present) represents a multi·
`plier value.
`
`RT:1 = Route of Administration for compound (or vehicle)
`being tested. See pg. 11
`
`TRTMT SCH ED= The treatment schedule followed in
`administering the compound being tested, taking the
`form: See pg. 9
`
`Basic Schedule:
`
`M
`ONN H X PP
`
`D T 7:. Number of injections associated with the
`
`basic schedule.
`
`''Times",
`
`Interval unit (M = minutes, H = hours,
`D = days).
`
`L - - - - Treatment interval (Q = every). 015 =
`every 15; 003 = every 3; and 004 =
`every 4.
`
`DAY 1ST INJ = RR
`-c__ First day basic schedule
`initiated.
`
`TOTAL INJ
`
`= SS
`7:.___ Total injections to be
`administered.
`
`ABOVE SCHEO REPEATED ON DAYS:
`TTT, TTT, TTT ... TTT
`' - - - - - - - Each day the basic schedule
`is to be re-initiated (if
`appropriate).
`
`13:15 HRS
`._ _ _ _ Time of 1st INJ (if provided)
`in military time (13:15 =
`1:15PM).
`
`16
`
`C/NT /TS= Cures(CI/No-Takes(NT)/Tumored Survivors
`(TS) as reported by the Screener.
`
`._ _ _ _ _ Animal Host Group (i.e., 3 = mice; 5 = rats;
`7 = hamsterst.
`
`Tumor Code (LE= L 1210 Leukemia).
`
`1ST RX TIME
`
`25
`
`TIS:1 = Type of Tumor lnoculum.
`
`29
`
`Same Test System, Tissue, Level, Route, and Treatment
`Schedule as from Previous Page.
`
`*Varies by Test System,
`
`80 Column Screening Data Summary Interpretations
`
`30
`
`SOL= Compound Solubility.
`
`31
`
`Screener or Supplier number.
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 33
`
`

`

`FLOW OF DRUGS THROUGH OCT SCREENS
`
`Synthetic compounds and pure natural
`products chosen from acqws,tions
`from industrial l1a1son, literature
`monitoring and voluntary submissions
`
`110,0001
`
`Compounds selected to by•pass pre·screen
`based on data from
`
`- Other Ant1tumor Screens
`- Other B1olog1\:al Assays
`- B1ochem1cal Assays
`
`DCT PRE SCREEN
`
`Mouse Leukemia P388
`In Vivo
`
`_ __ __ ..__(500 - 600) _ __________________ _.
`
`I Actives
`
`200 - Materials chosen on
`basis of existing data,
`uniqueness, and availability
`
`Selected
`Actives
`and
`lnact1ves
`
`'' Human
`
`Tumor
`Colony
`Forming
`Assays
`In Vitro
`
`DCT PANEL
`In Vivo
`
`--------------
`
`-
`...,.~---Actives-----;
`
`-----Act1ves----1-~
`
`Mouse
`L1210
`816
`MX1
`M5076
`Human Breast
`Xenograh
`
`More challenging assays
`based on prior results
`
`- Different Tumor Treatment
`Sites
`-Advanced Tumors
`-Ant1metastas1s Screens
`
`- Cross Resistance
`- Less Sens1t1ve Mouse
`Tumors !mammary, colon!
`
`Ac:,.,,, u,ns1derea for tur1her development leading to selection for cl1n1c f..
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 33
`
`

`

`ACTIVITY THRESHOLDS OF COMMON SYSTEMS
`DRUG
`RT/SCHED
`
`PARAMETER
`
`CODE
`
`ACTIVE T/C%
`MCI
`DN2
`
`MODEL
`
`PRESCREEN
`
`IP P388 LEUKEMIA
`
`3PS31
`
`IP/QIDXS
`
`MED SURVIVAL TIME
`CONFIRMING TEST
`
`;;;,, 127
`;;;,, 120
`
`;;;,, 175
`;;;,, 175
`
`IP/QIDX9
`
`MED SURVIVAL TIME
`
`IP/QIDX9
`
`MED SURVIVAL TIME
`
`IP/QIDXI
`
`MED TUMOR WT CHANGE
`
`IP/Q7DX2
`
`MED TUMOR WT
`
`IP/QIDX9
`
`MED SURVIVAL TIME
`
`IP/Q4DX4
`
`MED SURVIVAL TIME
`
`;;;,, 125
`
`;;;,, 140
`
`¾ 20
`
`¾ 42
`
`;;;,, 125
`
`;;;,, 125
`
`;;;,, 150
`
`;;;,, 150
`
`¾
`
`0
`
`< IO
`
`;;;,, 150
`
`;;;,, 150
`
`IP/Q4DX4
`
`MEAN TUMOR WT CHANGE
`
`¾
`
`20
`
`¾ 10
`
`TRANSPLANTED MOUSE TUMORS
`
`*IP B16 MELANOMA
`
`SC B16 MELANOMA
`
`SC CD8Fl MAMMARY
`
`SC COLON 38
`
`*IP L1210 LEUKEMIA
`
`*IP MS SARCOMA
`
`HUMAN TUMOR XENOGRAFTS
`
`SRC CX-1 COLON
`
`SC CX· 1 COLON
`
`SRC LX-1 LUNG
`
`SC LX-1 LUNG
`
`*SRC MX-1 MAMMARY
`
`3B131
`
`3B132
`
`3CDJ2
`
`3C872
`
`3LE31
`
`3M531
`
`3C2G5
`
`3C2H2
`
`3LKG5
`
`3LKH2
`
`3MBG5
`
`IP/Q4DX3
`
`MEAN TUMOR WT CHANGE
`
`IP/Q4DX3
`
`MEAN TUMOR WT CHANGE
`
`IP/Q4DX3
`
`MEAN TUMOR WT CHANGE
`
`IP/Q4DX3
`
`MEAN TUMOR WT CHANGE
`
`¾ 20
`
`¾ 20
`
`¾ 20
`
`¾ 20
`
`¾ 20
`
`¾ 10
`
`¾ 10
`
`¾ 10
`
`¾ 10
`
`¾ 10
`
`SC MX-1 MAMMARY
`
`3MBH2
`
`IP/Q4DX3
`
`MEAN TUMOR WT CHANGE
`
`* DEB TUMOR PANEL
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 33
`
`

`

`l (LPC-1)
`
`AA Nontumored Animals (Toxicity Test)
`*AC Carcinoma, Adrenal Cortex (No.2)
`AD ADJ-PC-22 Plasma Cell
`AG Ll210 Leukemia/8-Azaguanine; NSC 749
`AK Lymphoma AKR (Transplanted)
`AM Amelanotic Melanoma (No. 4)
`AS Rat AC Glioma
`A2 ADJ-PC-20 Plasma Cell
`A3 Lieberman Plasma Cell No.
`*AS ADJ-PC-5 Plasma Cell
`A6 ADJ-PC-6
`*BA Clone Derived Amelanotic B16
`BC Ll210 Leukemia/BCNU; NSC 409962
`*BM Clone Derived Melanotic Bl6
`BP P388 Leukemia/BCNU; NSC 409962
`Bl Bl6 Melanoma
`CA Adenocarcinoma 755
`CD Mammary Adenocarcinoma CD8Fl
`CH Chang Liver (Cell Culture)
`CL NCI-H460 Large Cell Carcinoma of the Lung
`CM Dunning Leukemia/Mitomycin C; NSC 26980 (Solid)
`CP P388 Leukemia/Cis DDPT; NSC 119875
`*CR Ll210 Leukemia/Cytoxan & Ara-C;NSC 26271 ,NSC 63878
`CS Dunning Leukemia/Cycloleucine; NSC 1026 (Solid)
`CX L1210 Leukemia/Cytoxan; NSC 26271
`*CY Colon 36
`CZ Colon 51
`CZ HT29;CX-l Human Adenocarcinoma (MER+)
`*C3 C3H Mammary Tumor
`C4 CX-2 Colon Xenograft
`CS CX-3 Colon Xenograft
`C6 Colon 26 Adenocarcinoma
`C7 CX-4 Colon Xenograft
`CS Colon Carcinoma 38
`C9 CX-5 Colon Xenograft
`*DA Dunning Leukemia (Ascites) (See DL)
`DH Dunning Leukemia/Hexamethylmelamine; NSC 13875
`(Solid)
`DL Dunning Leukemia (Ascitic)
`DM DMBA Induced Mammary Adenocarcinoma
`DN Dunning Leukemia/A Nitrogen Mustard; NSC 51845
`(Solid)
`DP Ll210 Leukemia/Cisplatin II; NSC 119875
`*DR Dunning Leukemia/A Thiopurine; NSC 29189 (Ascitic)
`(Ascitic)
`*DX Dunning Leukemia/Cytoxan; NSC 26271
`*Dl Adenocarcinoma, Duodenum (Hamster & Cell Culture)
`EA Ehrlich Ascites Tumor
`EC B-Galactoside Phage
`EM Ependymoblastoma
`*EN Adenocarcinoma, Endometrium
`EP Ependymoblastoma
`FM Friend Virus Erythroleuk2rnia Ascites
`(P.Marks' Line DS-19)
`*Tumor unavailable in Screening Program
`
`SCREENING MODELS
`*FR P815/5-Fluorouridine; NSC 27640 (Ascitic)
`*FS Fibrosarcoma (No. 2)
`FU P815/5-Fluorouracil; NSC 19893 (Ascitic)
`FV Friend Virus Leukemia (Solid)
`GA Lymphosarcoma Gardner 6C3HED
`GE Adl Gardner 6C3HED Lymphosarcoma/1-Asparaginase;
`NSC 109229
`*GL Lymphosarcoma LePage Gardner 6C3HED Sensitive to
`Ara-A; NSC 404241
`*GS 239PU-Induced Osteogenic Sarcoma
`Gl Glioma 261
`G2 Glioma ?6
`HD Hep2.1orna 134
`HE Hepatoma 129 (Mouse)
`l) (Hamster)
`*HE Cystadenocarcinoma, Liver (No.
`HE HeLa Human Carcinoma (Ce]l Culture)
`HF Hep 2/2-Fluoroadenine; NSC 27364
`HG Hep 2/2-Flouroadenine & 2-Fluoroadenosine;
`NSC 27364, NSC 30605
`HH HEP 2/6-MP & 6-Methylthiopurine Ribonucleos,de &
`2-Fluoroadenine; NSC 755, NSC 4911, NSC 27364
`HL HL-60 Human Promyelocytic Leukemia Xenograft
`HM Hep 2/6-Methylthiopurine Ribonucleoside;
`NSC 491 l
`HN HEP 2/6-MP & 6-Methylthiopurine Ribonucleoside;
`NSC 755, NSC 4911
`HR Hep 2/6-Mercaptopurine; NSC 755
`HU Ll210 Leukemia/Hydroxyurea; NSC 32065
`HX Hep 2/Methotrexate; NSC 740
`Hl HSl Human Sarcoma (Egg)
`H2 Hep 2 Human Epidermoid Carcinoma
`H3 Hep 3 Human Epidermoid Carcinoma
`*IC L1210 Intracerebral Inoculation (See LE)
`*IC Dunning Leukemia Intracerebral Inoculation (See DL)
`JA NCI-H23 Human Lung Adenocarcinoma
`JB NCI-H324 Human Lung Adenocarcinoma
`JC NCI-H522 Human Lung Adenocarcinoma
`JD NCI-Hl25 Human Lung Adenosquamous Carcin0ma
`JE NCI-H358 Human Lung Bronchiolo-Alveolar Carcinoma
`JF NCI-H292 Human Lung Mucoepidermoid Carcinoma
`KB Human Epidermoid Carcinoma of the
`Nasopharynx (Cell Culture)
`K4 AK4 Lymphoid Leukemia
`*LA Ll210 Leukem a/Azacytidine; NSC 102816
`*LB L1210 Leukem a/BIC; NSC 82196
`LC Ll210 Leukem a/Cytosine Arabinoside; NSC 63S78
`LD Ll210 Leukem a/DTIC; NSC 45388
`LE Ll210 Leukem a
`*LF Ll210 Leukem a/Methotrexate & Dichloromethotrexate;
`NSC 740, NSC 29630
`*LG Ll210 Leukem a/Guanazole; NSC 1895
`LH Ll210 Leukem a/Cyclocytidine; NSC 145668
`LJ Ll210 Leukem a/L-Alanosine; NSC 153353
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 6 of 33
`
`

`

`LK Human Lung LX-1 Xenograft
`LL Lewis Lung Carcinoma
`LM L1210 Leukemia/Dichloromethotrexate; NSC 29630
`LN A549 Human Adenocarcinoma of Lung with
`characteristics of Type II Alveolar Epithelial cells
`LO Human Amelanotic Melanoma (LOX)
`*LP Liposarcoma (No. 1)
`*LO Ll210 Leukemia/Methane Sulfonate; NSC 102627
`*LR L1210 Leukemia/6-t+lPR; NSC 40774
`LS L1210 Leukemia/L-PAM; NSC 8806
`LT L1210 Leukemia/Ftorafur; NSC 148958
`LU L1210 Leukemia/5-Fluorouracil; NSC 19893
`LV NCI-H322 Human Lung Bronchiole-Alveolar Carcinoma
`LW Ll210 Leukemia/A Terephthalanilide; NSC 38280
`LX L1210 Leukemia/Methotrexate; NSC 740
`LY Lewis Lung Carcinoma/PALA; NSC 224131
`L2 Lymphoma 2
`L2 Leiomyosarcoma (No. 2)
`L4 Lymphoma 4
`LS L5178Y Lymphatic Leukemia
`L8 Lymphoma 8
`L9 L5178Y Lymphatic Leukemia/L-Asparaginase; NSC 109229
`MA 13762 Mammary Adenocarcinoma
`MB Human Mammary Carcinoma MX-i Xenograft
`*MC Adenocarcinoma, Breast
`MD Madison 109 Lung Carcinoma
`ME Lymphosarcoma Mecca
`MF Human Breast MX-2 Xenograft
`MG Human Breast MX-3 Xenograft
`*MH EMT6 Fibrosarcoma
`ML Ll210 Leukemia/Methyl-GAG; NSC 32946
`MM Melanotic Melanoma
`MP Ll210 Leukemia/6-MP & 6-Thioguanine;
`NSC 755, NSC 752
`MS Lymphosarcoma Murphy-Sturm
`MT Human Mesothelioma
`MX MXT Hormone Dependent Transplantable Mammary
`Adenocarcir.oma
`*MY Myeloid Leukemia i:1 RFM/UN :1ouse
`M2 MPC-2 Plasma Cell
`MS Sarcoma M5076
`M6 M5076/Cisplatin II; NSC 119875
`M7 Agrobacterium Tumefaciens Microbial Assay
`M8 Candida Albicans Microbial Assay
`M9 Zanthomona Compestris Microbial Assay
`NH Novikoff Hepatoma
`*NL Nova Leukemia NRL-1871
`*NP Plasmacytcma No. 1/BCNU; NSC 409962
`*NR Neurilemmoma Nol
`OC Human Ovarian Carcinoma
`OG Osteogenic Sarcoma
`OS Osteogenic Sarcoma HE 10734
`OT Human Ovarian Sarcoma
`*Tumor unavailable in Screening Program
`
`SCREENING MODELS
`PA P388 Leukemia/Adriamycin; NSC 123127, Developed at
`Ser 08
`PB P388 Leukemia/Daunomycin; NSC 82151
`PC P388 Leukemia/ARA-C; NSC 63878
`PD P388 Leukemia/Actinomycin-D; NSC 3053
`PE P388 Leukemia/AMSA; NSC 249992
`*PF P388 Leukemia/Dihydroxy Anthracenedione; NSC 299195
`PG P388 Leukemia/DON; NSC 7365
`PH P388 Leukemia/Acivicin; NSC 163501
`PJ P388/Bleomycin; NSC 125066
`PK P388 Leukemia/Ellipticine; NSC 71795
`PL P815/Vinblastine; NSC 49842
`*PM Plasmacytoma No. 1/Triethylenemelamine; NSC 9706
`PN Adenocarcinoma, Pancreas No.
`l
`PO P388 Leukemia/Cytoxan; NSC 26271
`PP P388 Leukemia/L-PAM; NSC 8806
`PQ P388 Leukemia Bristol Strain
`*PR Adenocarcinoma, Prostate
`PS P388 Leukemia
`*PT Carcinoma, Pitutary
`PU P388 Leukemia/5-Fluorouracil; NSC 19893
`PV P388 Leukemia/Vincristine; NSC 67574
`PW P388 Leukemia/A Terephthalanilide; NSC 38280
`*PX Plasmacytoma No. 1/Cytoxan; NSC 26271
`*PY PY89 Sarcoma
`PZ P388 Leukemia/5-Azacytidine; NSC 102816
`*Pl Plasmacytoma No.
`l
`P2 P388 Leukemia/ARA-A & 2'-Deoxycoformycin;
`NSC 404241, NSC 218321
`(AOL)
`*P3 Pl534/Methotrexate; NSC 740
`P4 Pl534 Leukemia
`P6 P388 Leukemia/L-Alanosine; NSC 153353
`P7 P388 Leukemia/Methotrexate; NSC 740
`P8 P815 Mast Cell Leukemia (Ascitic)
`P9 P329 Reticulum Cell Sarcoma
`RC Adenocarcinoma, Kidney
`*RE Renal Cell Carcinoma
`RO Osteogenic Sarcoma Ridgway
`RS Reticulum Cell Sarcoma (Kelley Mouse)
`*RS Reticulum Cell Lymphosarcoma No. 5 (Hamster)
`*RX Ros/Cytoxan; NSC 26271
`SA Sarcoma 180
`SB Adenocarcinoma, Small Bowel (Ileum)
`SC Human Tumor Colony Forming Assay
`ST Special Testing, Biochemical Assay (Host98)
`*TC Ll210 leukemia/Picolinaldhyde, Thiosemicarbazone,
`NSC 729
`TE TE-671 Human Meduloblastoma
`TG Du,~ing Leukemia/Thioguanine Riboside; NSC 29422
`TR P388 Leukemia/Tiazofurin; NSC 286193, Developed at
`Sc r 08
`UG U-251 Human Glioma
`VA Colon Xenograft CS-1
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 7 of 33
`
`

`

`SCREENING MODELS
`
`VG BREAST XENOGRAFT BS-3
`VH BREAST XENOGRAFT BS-4
`i/I LUt:G xrnoGRAFT LS-1
`VJ PAtlCREAS XEilOGRAFT PS-1
`VK SARcc;:A XEtiOGR,\FT SS-1
`VL SAPCO~A XENOG~AFT SS-2
`t'.'::LA(l0'.1A X me G~ .'. FT
`t·15- 1
`\/M
`I.IN F1EL Mrn:·1A X morn~~ FT r15-2
`VO MELANO~A XE~OG1AFT MS-3
`VP
`'.'.ELAtiCMA XE:lOG'.'.:.1-.FT
`t·iS-4
`\IQ MEL A Nc:1 A xn, OG:!A FT ns- 5
`VK M::LA.NC~1A XEtiOGRAFT t15-6
`VS
`:'1ELANC:1A XENOGRAFT rlS-7
`VT
`t1EL MiC:1A XEIJOGRAFT
`t~S-8
`(SUBCUTANEOUS)
`l.JA
`t,'ALKER CARCHlOSARCO~~A 256
`*WC WALKER CARCINO~A/CYTOXA~; NSC 25271
`*m t!ALKER CARCitlOSAP.COMA 256 C ItHRt,PERITCNEAL)
`( SEE WA)
`M!~11
`l-:ALKER CARCHWSARC0'.·1A 256
`( ItiTR/'.MUSCUU,R)
`(SEE WA)
`i, 1~ P ~l A L K ER C.t, R C IN O 5 A RC O :1 A 2 5 6 ( P U L:~ C : : ~- RY ) C S E E L-! A )
`XE ERLICH A SCITES TUi'.GR E~,.ZY~ES C BIOCH::r-1ICAL ASSi'\Y)
`XL L1210 LEUKEMIA CDIOCHE~ICAL ASSAY)
`XM HUt:/:.~1 LEU:<EMI!\ CELL EMlY1iE CBIOCHE'.1IC/\L ASSAY)
`XN HUi·ir',N EP.YTHROCYTE EtlZY'.'.E CEIC'CHE:'.IC/,L ASSAY)
`XR HU,i-'-.tl RBC [t! 1!CJLEJ CI:I'JCH!:t1Ict.L
`!,SSAY)
`XS HUM.t,J1 RBC
`[Ut:SPECIFIED] <BIOCHE:iICAL ASSAY)
`XX HUi~Ml RBC
`[BROKEl1] CBIOCHE,1ICAL ASSAY)
`XY HUriM1 LIV ER
`*YC MYELOID LEUKEMIA/ARA-C; NSC 63878 IN RFM/UN MOUSE
`*10 COLON CYSTADENOCARCIND~A 10/A
`* 11 COLQ~j A.DENOU.RCH;onA 11/A
`*12 COLON CYSTADEHOCA:!CINOMA 12/A
`13 C3H MAt~:·iA.RY ADENOCt-.RCrt:OMA 13/C
`
`14 C3H MAM~ RY ADENOCA CINOMA 14/C
`16 C3~ MAr,ti RY ADENOCt. crnor~A 16/C
`17 C3H M: .. ;:.: ~y f..C[~·oc,\ crnc:,A 17/C
`18 C3H
`i':/-.t'.''. F:Y CYSTt,J:: OURCitlOi:A 18/C
`2P pn;cRUT C u.~cr~::::1
`02
`*2R P333 LEU E~IA/TIAZO U~IN; NSC 236193,DEVELOPED AT
`U~CB, DTP, Dl T, t,CI
`tiSC 237513
`2S P388 LEU!~EiiLV.;~iETA~ITRC~lE,
`2T P333 LEUKE~I~/ADRIAMYCIN; NSC 123127, DEVELOPED AT
`SCR 06 & 41
`2U P3B8 LEUKEMIA/AD2IAMYCIN; NSC 123127, DEVELOPED AT
`SCR 01
`2X P288 LY~PHOCYTIC LEUKEMIA/M~THOTREXATE; NSC 740
`23 C3H MM'.:,:,::;y ADENOCARCINO~A 23/C
`25 c:.;;crt;c:'.:, 1025
`28 PUS LY:'.PHOCYTIC LEU'<EMIA
`*4A L(1946 LYi1PH,\TIC LEUKE'.IA/Azt,SERHlE; NSC 742
`49 LttStt6 LYt:PHATIC LEUKEnA (SOLID)
`5P P335 LEU~E~IA
`*6A COLON 06/,\
`*6M L1210 LEU'.".Er:IA/6-MP & 6-i~'.1PR & 6-THIOGUAiiINE;
`NSC 755, ~SC 40774, NSC 752
`6T L1210 LEUKE:1IA/6-THIOCUAMH1E;
`7A COLO:l 07/A
`*7P CJ\ 755/6-i'.E'.;Ct.PTOPURH:E; NSC 755
`M8A COLC~l 03/A
`DC Pl798/CCRT!SO E; NSC 9703
`3 P P 1 7 9 3 L ff P H C S ~ CO i~ A
`31 P1031 CHLORCL U~EMIA
`91 S-91 CL (cid:143) us;: \;1 nELft.'.iOTIC MELAtiOMt1
`93 C1498 MYELO:::D LEU,".Ei~IA
`
`tlSC 752
`
`*Tumor unavailahle in Screenitrn Program
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 8 of 33
`
`

`

`TEST SYSTEMS
`
`S position Test System 1 = Host Group. Tumor. Parameter. Site
`' -v - ' - - - , - ' -¥ - '
`(5.6.i) @ @
`@)
`
`(See indicated pages for definition)
`
`3AArl
`3AA2
`3AA21
`3AA3
`3A.A4
`3AD12
`3AG21
`3AKF3
`3AK31
`3AK33
`3A212
`3A331
`3A332
`3A336
`3A512
`3A631
`3A632
`3BA3 l
`3BA32
`3BC21
`3BC27
`3BC32
`3BM31
`3BP31
`3BU31
`3B1D2
`3B1E2
`3B1 lE
`3B13E
`3B131
`38132
`38136
`38137
`3B139
`3B172
`3CA12
`3CCJ2
`3CC12
`3CD32
`3CD72
`3CD82
`3CLG5
`3CL31
`
`3CP31
`3CR31
`3CX21
`3CX29
`3CX31
`3CX39
`3CY32
`3CY37
`3CY72
`3CZ31
`3CZ32
`3CZ37
`3CZ72
`3C2G5
`3C2H2
`3C3D2
`3C3E2
`3C33B
`3C332
`3C339
`3C4G5
`3C4H2
`3C5G5
`3C5H2
`3C631
`3C632
`3C637
`3C639
`3C672
`3C682
`3C8J2
`3C816
`3C838
`3C831
`3C832
`3C872
`3C876
`3C882
`3C9G5
`3C9rl2
`3DP21
`3DP31
`3EA 11
`
`3EA31
`3EA32
`3EM12
`3EM32
`3EM37
`3EP12
`3EP32
`3EP37
`3FM31
`3FR41
`3FS32
`3FU21
`3FV12
`3GA31
`3GA41
`3GE31
`3GL31
`3GS32
`3GS37
`3G137
`3G232
`3G233
`3G237
`3HD31
`3HE12
`3HE31
`3HL31
`3HL32
`3HL72
`3HU21
`3HU31
`3JAG5
`3J8G5
`3JCG5
`3JDG5
`3JEG5
`3JFG5
`3K431
`3 L.A3 l
`3L821
`3L831
`3LC21
`3LC27
`
`3LC29
`3LC31
`3LD21
`3LD31
`3LE1 E
`3LE12
`3LE21
`3LE22
`3LE27
`3LE29
`3LE3E
`3LE31
`3LE32
`3LE36
`3LE37
`3LE39
`3LF21
`3LF31
`3LF32
`3LG21
`3LH31
`3LJ21
`3LKG5
`3LKH2
`3LL1E
`3LL12
`3LL16
`3LL22
`3LL29
`3LL38
`3LL3E
`3LL31
`3LL32
`3LL36
`3LL.37
`3LL39
`3LL72
`3LL76
`3LL82
`3LL86
`3LM21
`3L"132
`3LNG5
`
`3LNJ2
`3LN3i
`3LOG5
`3L03F
`3l03S
`3L031
`3L032
`3L039
`3LQ31
`3LR21
`3LS21
`3LS31
`3LT31
`3LU21
`3LU31
`3LVG5
`3LW21
`3LW31
`3LX21
`3LX22
`3LX32
`3LY32
`3L221
`3L43l
`3L829
`3L831
`3l841
`3L931
`3MBG5
`3M8H2
`3M8H5
`3MD32
`3MD36
`3MD72
`3ME31
`3ME41
`3MFG5
`3MFH2
`3MGG5
`3MGH2
`3MGH5
`3MHEF
`3MH3F
`
`3MH32
`3MH36
`3Ml21
`3ML22
`3MP21
`3MP22
`3MP29
`3MP31
`3MP37
`3MT3F
`3MT3S
`3MT31
`3MT32
`3MT39
`3MX32
`3MX72
`3MY39
`3M212
`3M5J2
`3M51E
`3M512
`3M53E
`3M531
`3M532
`3M539
`3M572
`3M631
`3M632
`3M672
`30C3F
`30C3S
`30C31
`30C32
`30C39
`30S12
`30T31
`3PA31
`3PB31
`3PC31
`3PC37
`3PD31
`3PE31
`3PF31
`
`3PG31
`3PH31
`3PJ31
`3PJ32
`3PK31
`3PL31
`3PM21
`3P031
`3P039
`3PP31
`3PQ31
`3PS21
`3PS31
`3PS32
`3PS36
`3PS37
`3PS39
`3PU31
`3PV31
`3PW31
`3PY12
`3PZ31
`3P231
`3P331
`3P421
`3P431
`3P631
`3P731
`3P831
`3P841
`3P931
`3RE35
`3R032
`3R039
`3R072
`3RS31
`3RX32
`3SA12
`3SA31
`3SA32
`3SA82
`3TC21
`3TE37
`
`3TR31
`3UG37
`3VAH2
`3VBH2
`3VCG5
`3VDG5
`3VEG5
`3VEH2
`3VFG5
`3VGG5
`3VHG5
`3VIG5
`3VIH2
`3VJG5
`3VKH2
`3VLG5
`3VMG5
`3VNG5
`3VNH2
`3VOG5
`3VPG5
`3VQG5
`3VRG5
`3VRH2
`3VSG5
`3VTG5
`3WA16
`3YC39
`31032
`31132
`31232
`31332
`31339
`31432
`31437
`31472
`31631
`31632
`31637
`31639
`31672
`31732
`31832
`
`32P32
`32R31
`32T31
`32U31
`32X31
`32332
`32512
`32831
`32841
`34A22
`34922
`35P21
`36A32
`36M21
`36T21
`36T31
`37A31
`37A32
`37Pl2
`38A32
`38Cl2
`38C82
`38Pl2
`38P22
`38P31
`38P32
`38P82
`38121
`39112
`39131
`39831
`SAA
`5AA3
`5AA4
`5CM42
`5CS42
`5DH42
`5DL31
`5DL32
`SD:...37
`5DN42
`5DR3 l
`5DX3 l
`
`SHl 12
`5H312
`5L822
`5MS16
`SNHl 2
`5NH16
`5NH31
`5NL32
`5NL37
`5TG42
`5WA12
`5WA16
`5WA21
`5WA27
`5WA31
`5WA32
`5WA36
`5WA46
`5WA86
`5WC12
`7AA4
`7AC12
`7AM12
`7D112
`7EN12
`7FS12
`7HE12
`7LP12
`7L212
`7MC12
`7t-'Ml2
`7NP12
`7NR12
`70Gl2
`7PM12
`7PN12
`7PR12
`7PT12
`7PX12
`7P 112
`7RC12
`7RS12
`7SB12
`
`8Hl l 8
`9ASK
`9CH5
`9C25
`9D15
`9ECL
`9HE5
`9HF5
`9HG5
`9HL5
`9HM5
`9HR5
`9HX5
`9H25
`9JA5
`9JB5
`9JC5
`9JD5
`9JE5
`9JF5
`9KB5
`9LE5
`9LN5
`9L05
`9LV5
`9PS5
`9SCM
`9XEB
`9XLC
`9XMC
`9XNC
`9XRB
`9XSB
`9XXB
`9XYC
`
`1 Frequently test system is specified as a 6 position field. In this instance, the two position host strain code is used in heil of the single position host group
`codes now in this table. A four position test system always infers tile absence of an inoculum site.
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 9 of 33
`
`

`

`TREATMENT SCHEDULE
`
`The treatment schedule for administration of a compound in a test
`is comprised of six parts as follows:
`
`Special Codes - The following special treatments may be used and are
`coded in the interval field Q __ with the interval unit left blank:
`
`Code
`#A
`#8
`#C
`#D
`#(J-9; A-M)
`
`##
`#X
`
`#Y
`
`Meaning_
`Daily. twice a day (hourly interval not specified)
`Daily. three times a day (hourly interval not specified)
`Ad lib in water
`Ad lib diet
`Hourly
`interval specified but daily
`(consult input data)
`Other (see input data)
`Infusion - The continuous administration of a com(cid:173)
`pound to an entire animal over a period of time with the
`compound entering the general body circulation. (See
`total injections field)
`Perfusion - The continuous administration of a com(cid:173)
`pound to an isolated site (tumor, organ, or a limb) over
`a period of time without the compound entering the
`general body circulation. (See
`total
`injections field)
`
`irregular
`
`interval
`
`INPUT INTERVAL CODES FOR COMBINATION CHEMOTHERAPY
`
`Interval
`Interval unit
`Basic number of injections per cycle
`Time of day of administration of initial dose
`(optional)
`Day of 1st injection
`Restart days ( optional)
`Total in_jections
`
`Interval - The time between treatments expressed in terms of minutes
`(M) or hours (H) or days (D).
`
`Interval Unit - Desigm,tion of the interval as either minutes (M) or
`hours (H) or days (D).
`
`Basic Number of Injections - The number of injections associated with
`one cycle of the treatment schedule (e.g., daily 1-9 would
`involve nine injections in one complete cycle).
`
`Time of Day of Administration of Initial Dose - An optional field
`permitting the screener to specify the time of day for the
`initial injection. Times are expressed in military time ( e.g.,
`00:01 thru 24:00 representing 12:01 AM thru 12:00 mid(cid:173)
`night).
`
`Day of 1st Injection* - The day, relative to day zero (inoculation
`day). when the 1st treatment is to be initiated.
`
`Restart Day(s) -- An optional field specifying day(s) when the com(cid:173)
`plete treatment cycle is to be reinitiated.
`Example: A treatment schedule of Q0JDX9 Time: 13:30
`Day = 1,17 would be interpreted - daily treatment at I: 30
`PM on days 1-9 and I 7-25. Day 17 is defined as a restart
`day.
`
`Total Injections -- The total number of injections intended to be
`administered for
`this test. In the case of infusion or per(cid:173)
`fusion indicates the total number of hours involved.
`
`MINUTES
`
`00 thru 60
`actual
`minutes
`
`HOURS
`+ - blank
`1-9 - hours 1-9
`0 - 10 hours
`A - 11 hours
`
`I - daily {also
`single
`2 - every other day
`3 - every 3rd day
`
`DAYS
`4 - every 4th day
`etc. thru
`9 - every 9th day
`0 - every 10th day
`
`B - 12 hours etc.
`thru
`M -23 hours
`X -infusion
`# - See Special
`Codes
`
`A - every 11th day
`etc. thru
`Z - every 36 days
`# - See Special
`Codes
`Time interval between each treatment. If # symbol is
`used
`in either hours or day columns, the individual
`codes for hours and day do not apply; see Special Codes
`ahove for definition.
`* an a,IE'risk in lieu of an actual day means day 27 ~r .&!_«:at er for pre-October 1978 testing only. Consult the microiilm for actual <lay.
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 10 of 33
`
`

`

`EVALUATIONS
`
`CONTROL (CONTLl
`
`. \kasu1-e of 1111111,r progre.,sion in untreated animals using indicated param(cid:173)
`l'll'f. (See page 17. survival time. tumor weigh I. ete.) l'nils are specified in
`indi\ idual JHoloL·ol.
`
`I-or paramL'lns G. H & J 1his field deviates from the norm. Be(cid:173)
`cau.,e an oplimum evalualion day is selected from two or more
`possible ,-valuation days for eaeh dose, control evaluation mav
`varv from dose to dose within a dose response. What is displaye~I
`is the aclual control evalualion for the evaluation dav determined
`lo Ill.' optimum for a parlicular lesl. Additionallv. \~here the test
`naluation and the T /C'; column arc negative. tl;e control evalua(cid:173)
`tion column for parameters G. Hand J does not contain a con(cid:173)
`trol e\alualion al all hut 1he initial weigh! of the test group.
`In tlll'se instances 1he test lumor weight change (test evaluation)
`is divided hy the test tumor initial weight so that the T/C'.'lr col(cid:173)
`umn is actually a T /T'i- and reflects the amount of actual test
`SO':;." in the T /C'lr column means the test
`regression. i.e .. "
`tumor diminished to one half of its initial size.
`
`:\OTI·:
`
`TEST
`
`\kasure of rcsponsc in lrt'ated animals using indicated parameter. (See
`page 17, survival time, tumor weigh I. etc.) l'nits are specified in individual
`protocol.
`
`T /C (PERCENT)
`
`Ratio of test (T) evaluation to control (Cl evaluation
`expressed as a percentage .
`
`SPECIAL STUDY CODES (SSC)
`
`Special Study Code (SSC) is a two position field. Where the code
`is only one position in length, it should be right justified in the
`two position field.
`CODE
`A
`B
`C
`D
`E
`F
`G
`H
`J
`K
`L
`M
`N
`P
`R
`S
`T
`U
`W
`
`DATA TYPE
`Comparison Study (analogs)
`- - --~
`Scheduk Dependency
`Combination Chemotherapy
`Not Processable
`Special Request
`Special Colon Tumor Protocol Testing
`Special Statistical Studies
`Radiation Sensitizers
`Comparison-Schedule Dependency
`Spontaneous AKR Testing
`Ll210 1-5 VS 1-9 Study
`Special Synthetic Protocol
`Special Natural Products Protocol
`Delayed Treatment Schedule
`Sensitive Matching Control for Resistant Tumot Exnerirnent
`Not Submitted
`'
`Screener 28 only
`Special P388 Testing
`Panel Statistical Studies
`
`CONTROL STATUS CODE
`
`( CS C)
`
`In Vivo
`
`I
`2
`3
`4
`S
`6
`7
`
`8
`
`Satisfactory control
`- Excessive control deaths by control early death day
`Excessive control no-takes on control no-take dav *
`Mean or median tumor weight or survival tiine outside limits
`-- Other reasons (contamination. etc.I
`- Excessive deaths and excessive no-takes ( 2 + JI
`Excessive deaths and mean tumor weight or survival time
`outside limits ( 2 + 4)
`-
`Excessive no-takes and mean tumor weigh I or survival time
`outside limits (3 + 4)
`
`E
`
`9
`A
`
`-- T /C of positive control uutside limits at standard dose
`- Test of positive control compound at standard dose is tcnic
`in other""ise satisfactorv control
`- Quality control limits 1101 e,tablished. Screener assigned
`only if other CSC codes are 1101 applicable.
`* for TSC 85 and a paramett'r of G indicate, mor,' dtan 10',
`control regressors.
`
`In Vitro
`
`(Blank)
`-1
`9
`
`Sali.,tacllH} Control ((SC-I I
`Fold growth outside l11ni1,
`Positive control outside limih
`
`NOVARTIS EXHIBIT 2045
`Breckenridge v. Novartis, IPR 2017-01592
`Page 11 of 33
`
`

`

`DATE ON
`
`Date experiment started.
`
`Left to right.
`
`First two positions:
`
`Second two positions:
`Third two positions:
`
`Last two digits
`of calendar year
`1-12 number of month
`1-31 day of month
`
`CONTROL NUMBER
`
`Experiment identification number. Numbers
`are assigned by screening laboratory sequen(cid:173)
`tially within each test system. Control num(cid:173)
`bers are comprised of a prefix. core and
`suffix defined as follows:
`
`Prefix The prefix is optional and