CA2952849A1

CA2952849A1 - Biological characterization of a glatiramer acetate related drug product using mammalian and human cells

Info

Publication number: CA2952849A1
Application number: CA2952849A
Authority: CA
Inventors: Michael Hayden; Fadi George TOWFIC; Sarah Elisabeth Kolitz; Benjamin James ZESKIND; David Ladkani; Tal Hasson; Liat Hayardeny; Iris Grossman
Original assignee: Teva Pharmaceutical Industries Ltd
Current assignee: Teva Pharmaceutical Industries Ltd
Priority date: 2014-07-01
Filing date: 2015-07-01
Publication date: 2016-01-07
Also published as: EP3164710A4; IL249686A0; EP3164710A2; UY36197A; TW201610169A; WO2016004250A2; WO2016004250A3

Abstract

The present invention provides a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of: a) obtaining a batch of the glatiramer acetate related drug substance or drug product; b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) determining the level of expression of at least one gene; thereby characterizing the glatiramer acetate related drug substance or drug product of step a).

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

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NOTE POUR LE TOME / VOLUME NOTE:

BIOLOGICAL CHARACTERIZATION OF A GLATIRAMER ACETATE RELATED
DRUG PRODUCT USING MAMMALIAN AND HUMAN CELLS
This application claims the priority of U.S. Provisional Application No. 62/162,308, filed May 15, 2015, U.S. Provisional Application No.
62/134,245, filed March 17, 2015, U.S. Provisional Application No.
62/078,369, filed November 11, 2014, U.S. Provisional Application No.
62/047,437, filed September 8, 2014, U.S. Provisional Application No.
62/025,953, filed July 17, 2014, U.S. Provisional Application No.
62/020,358, filed July 2, 2014, and U.S. Provisional Application No.
62/019,857, filed July 1, 2014, the contents of which are hereby incorporated by reference.
Throughout this application various publications are referenced by numerical identifiers in parentheses. Full citations of these references can be found following the Examples. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Multiple sclerosis (MS) is a chronic, debilitating autoimmune disease of the central nervous system (CNS) with either relapsing-remitting (RR) or progressive course leading to neurologic deterioration and disability. At time of initial diagnosis, RRMS is the most common form of the disease (1) which is characterized by unpredictable acute episodes of neurological dysfunction (relapses), followed by variable recovery and periods of clinical stability. The vast majority of RRMS
patients eventually develop secondary progressive (SP) disease with or without superimposed relapses. Around 15% of patients develop a sustained deterioration of their neurological function from the beginning; this form is called primary progressive (PP) MS. Patients who have experienced a single clinical event (Clinically Isolated Syndrome or "CIS") and who show lesion dissemination on subsequent magnetic resonance imaging (MRI) scans according to McDonald's criteria, are also considered as having relapsing MS. (2)

2 With a prevalence that varies considerably around the world, MS is the most common cause of chronic neurological disability in young adults. (3, 4) Anderson et al. estimated that there were about 350,000 physician-diagnosed patients with MS in the United States in 1990 (approx. 140 per 100,000 population). (5) It is estimated that about 2.5 million individuals are affected worldwide. (6) In general, there has been a trend toward an increasing prevalence and incidence of MS
worldwide, but the reasons for this trend are not fully understood. (5) Current therapeutic approaches consist of i) symptomatic treatment ii) treatment of acute relapses with corticosteroids and iii) treatment aimed to modify the course of the disease. Currently approved therapies target the inflammatory processes of the disease.
Most of them are considered to act as immunomodulators but their mechanisms of action have not been completely elucidated.
Immunosuppressants or cytotoxic agents are also used in some patients after failure of conventional therapies. Several medications have been approved and clinically ascertained as efficacious for the treatment of RR-MS; including BETASEROW AVONEXCO and REBIRD, which are derivatives of the cytokine interferon beta (IFNB), whose mechanism of action in MS is generally attributed to its immunomodulatory effects, antagonizing pro-inflammatory reactions and inducing suppressor cells. (7) Other approved drugs for the treatment of MS
include Mitoxantrone and Natalizumab.
Copaxonee (Teva Pharmaceutical Industries Ltd.) is a glatiramer acetate drug product approved for treatment of patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) (8). Glatiramer acetate drug substance (GA), the active substance of Copaxone , is a complex mixture of polypeptides and is the first member of the glatiramoid class; i.e., a complex mixture of synthetic polypeptides of varying sizes assembled from four naturally occurring amino acids: L-glutamic acid, L-alanine, L-lysine, and L-tyrosine, in a defined molar ratio (9).
GA elicits anti-inflammatory as well as neuroprotective effects in various animal models of chronic inflammatory and neurodegenerative

3 diseases (10-14) and has been shown to be safe and effective in reducing relapses and delaying neurologic disability in MS patients following long-term treatment (15).
The mechanisms underlying GA therapeutic activity are not fully elucidated, but GA activity on immune cells has been well demonstrated. GA appears to act as an altered peptide ligand (APL) of encephalitogenic epitopes within myelin basic protein (MEP) (16) and demonstrates cross-reactivity with MBP at the humoral and cellular levels (17-23). The unique antigenic sequences of the GA polypeptide mixture compete with myelin antigens for binding to MHC class II
molecules on antigen presenting cells (APCs) and presentation to the T cell receptor (TCR), resulting in the induction of anergy or deletion of autoreactive MBP-reactive T cells and proliferation of GA-reactive T cells. At initiation of Copaxone treatment, GA-reactive CD4+ T-cell lines from MS patients secrete both pro-inflammatory T helper type 1 (Thl) and anti-inflammatory Th2 cytokines (21, 24), but continued exposure to Copaxonee induces a shift in GA-reactive T cells toward the Th2 phenotype (21, 23, 25-28).
Copaxone also increases the number and suppressive capacity of CD4+CD25+FOXP3+ regulatory T cells, which are functionally impaired in MS patients (29-31). Furthermore, treatment leads to antigen-nonspecific modulation of APC function. Copaxone treatment promotes development of anti-inflammatory type II monocytes characterized by an increase in interleukin (IL)-10 and transforming growth factor-beta (TGF-8) and decreased production of IL-12 and tumor necrosis factor (TNF) (32).

4 SUMMARY OF THE INVENTION
The present invention provides a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) i) determining the level of expression of at least =one gene selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 (hereinafter Gene Group 1); ii) determining the level of expression of at least one gene selected from the group consisting of BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, IC1M1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA (hereinafter Gene Group 2), wherein if IL1B, IL10, or MMP9 is the at least one gene selected in part (c)(ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the level of expression of at least one gene selected from the group consisting of C130RF31, C140RF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, L0C100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7 (hereinafter Gene Group 3); iv) determining the level of expression of at least one gene selected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOX03B, HSD11B1, HSPD1P6, L0C387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27, SOD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7 (hereinafter Gene Group 4); v) determining the level of expression of at least one gene selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C130RF31, C5ORF13, C50RF32, C9ORF130, CAST, CCL2, CCL5,

5 CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, GOS2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL1ORA, IL411, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, L0054103, L0C388344, L00652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKH01, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1 (hereinafter Gene Group 5); vi) determining the level of expression of at least one gene selected from the group consisting of ACTN4, BTBD14A, C140RF10, CISH, CLK1, CRLF3, FAM62A, FBX045, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, L00648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566 (hereinafter Gene Group 6);
vii) determining the level of expression of at least one gene selected from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBBlIP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C90RF88, C90RF89, C1ORF21, C1ORF21, C100RF95, C130RF31, C210RF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP56400823, DKFZP68601327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IF130, IF144, IFNGR1,

6 IGFBP3, IL2RG, IL411, IL1ORA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, L0051334, L0C201895, L0C284262, L0051334, L00643424, L00643834, L00643847, L00644242, L00645238, L00650429, L00650446, L00652543, L00653610, L00653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFIl, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSUl, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGAll, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKH01, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1 (hereinafter Gene Group 7); viii) determining the level of expression of at least one gene selected from the group consisting of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C1ORF76, C1ORD121, C120RF24, C160RF73, C160RF74, C200RD27, C200RF103, C200RF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFIl, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, L0C201164, L0C284454, L0C387763, L00642083, L00648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1,

7 SPRY1, STEAP3, SYDE2, SYNP02, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1 (hereinafter Gene Group 8); ix) determining the level of expression of at least one gene selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP (hereinafter Gene Group 9); x) determining the level of expression of at least one gene selected from the group consisting of ADRB2, COTL1, L0C285758, L00644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1 (hereinafter Gene Group 10); xi) determining the level of expression of at least one gene selected from the group consisting of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, L0C100044068, L0C100862473, Mxl, Oasll, Phflld, Oyhinl, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2 (hereinafter Gene Group 11);
xii) determining the level of expression of at least one gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klkl, Scd2, Siglech, and Tspan2 (hereinafter Gene Group 12); xiii) determining the level of expression of at least one gene selected from the group consisting of Ahrr, AI607873, Atpl0a, AW011738, Casp44, Cxcl3, Gm9706, Ifi202b, Ifit2, Ifitm6, 1118, Lcn2, L0C100044068, Ms4a6d, Mxl, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2 (hereinafter Gene Group 13); xiv) determining the level of expression of at least one gene selected from the group consisting of Aldoc, Casp6, Ccdc711, Cox7al, Egln3, Fam162a, Gfil, Gpil, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgkl, Pkm, Tpil, and Trappc6a (hereinafter Gene Group 14); xv) determining the level of expression of at least one gene selected from the group consisting of 1600014C1ORik, 2810474019Rik, 6720475J19Rik, Adam8, Adar, Agrn, Ahrr, AI607873, Amigo2, Ankfyl, Apobecl, Arf4, Asb2, Ascc3, Atpl0a, Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chicl, Cmpk2, Csprs, Cxcl3, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emrl, Epstil, Evi2a, Fcgrl, Fcgr4, Ftsjd2, Gcntl, Gm11772, Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-110, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspalb, Ifi202b, Ifi203,

8 Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifihl, Ifitl, Ifit2, Ifit3, Ifitm3, 1118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrkl, Lgals3bp, Lgals9, L0C100041903, L0C100044068, L0C100503923, L0C100505160, L0C100862473, L00664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitdl, Mlkl, Mmp8, Mnda, Mndal, Ms4a4c, Ms4a6d, Mxl, Naa20, Ncehl, Ncoa7, Ngp, Nlrc5, Nmrall, Nqol, Nt5c3, Oasla, Oas2, Oas3, Oasll, Oas12, Ogfr, Papd7, Parp10, Parpll, Parp12, Parp14, Phflld, Pik3apl, P1a2g7, Plec, Pnptl, Ppmlk, Pydc4, Pyhinl, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1õ Slfnl, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9, St3ga16, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10, Torlaip2, Tor3a, Trafdl, Trim25, Trim30a , Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wntl0a, Xafl, Xafl, Zc3havl, Zcchc2, Zfyve26, Znfxl, and Zufsp (hereinafter Gene Group 15); xvi) determining the level of expression of at least one gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klkl, Scd2, Siglech, and Tspan2 (hereinafter Gene Group 16); xvii) determining the level of expression of at least one gene selected from the group consisting of CC12, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL411, MSC, NQ01, PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF (hereinafter Gene Group 17); xviii) determining the level of expression of at least one gene selected from the group consisting of BCL2, CACNA2D3, C130RF18, C200RF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049, L00645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1, and TDRD7 (hereinafter Gene Group 18); xix) determining the level of expression of at least one gene selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57, A1'TXA2, APBBlIP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6VOC, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C100RF22, C100RF54, C100RF56, C120RF35, C130RF31, C140RF43, C150RF39, C170RF32, C190RF58, C1ORF122, C1ORF144, C1ORF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C60RF166, C9ORF16, C90RF88, CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244,

9 CD300A, CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1A, , CHST11, CIDEC, CKB, CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1, DDB1, DGAT2, DKFZP68601327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489, FLJ20701, FLJ90013, FLR12, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HNRPLL, HPCAL1, ID!, ID2, IER5, IFI30, IFNGR1, IFNGR2, IGFBP3, MORA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, IL411, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, L0C113179, L0C338758, L0C440934, L0054103, L00644242 , L00648998 , L00650429, L00650446, L00651816, L00653524, L00653361, L00653840, L00653361, L00653506, L00653610, L00653840, L00653626, LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT!, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME!, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB!, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH!, NOTCH2NL, NPTX1, NQ01, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, FIR, PITPNA, PKM2, PLAU, PLAUR, PLEKH01, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4, PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSP03, RUNX3, SAMSN1, SAP30, SASH!, SAT!, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6, SLC37A2, 5LC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG, ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697 (hereinafter Gene Group 19); xx) determining the level of expression of at least one gene selected from the 5 group consisting of ABHD14B, ACTN1, ACY1L2, ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE, BSPRY, BTBD14A, C130RF18, C130RF18, C140RF106, C150RF41, C160RF73, C1ORF121, C1ORF63, ClQBP, C1S, C200RF103, C200RF112,

10 C200RF12, C3ORF14, C5ORF13, C60RF147, C70RF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALC00O2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2, CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DOT, EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOX83, HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L, L0C129285, L0C148203, L0C197322, L0C203274, L0C220594, L0C254559, L0C284702, L0C285084, L0C285758, L0C340061, L0C340061, L0C388189, L0C474170, L00643458, L00645919, L00646456, L0C90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H, MT1M, MTBP, MTHFD1,MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG, SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4, SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1, ST3GAL3, STAR , STRBP, SYNP02, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1, TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2, VLDLR, VP535, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92 (hereinafter Gene Group 20); xxi) determining the level of expression of at least one gene selected from the group consisting of CCL2, CCL5, CXCL10,

11 IL1RN, and MMP9 (hereinafter Gene Group 21); xxii) determining the level of expression of at least one gene selected from the group consisting of CCL5, CXCL10, and MMP9 (hereinafter Gene Group 22); xxiii) determining the level of expression of at least one gene selected from the group consisting of IL10 and CCL2 (hereinafter Gene Group 23); xxiv) determining the level of expression of at least one gene selected from the group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10 (hereinafter Gene Group 24); xxv) determining the level of expression of at least one gene selected from the group consisting of MMP9, CCL2, CCL5, CXCL1, and IL1B (hereinafter Gene Group 25); xxvi) determining the level of expression of at least one gene selected from the group consisting of MMP9, CXCL10, CCL2, and CCL5 (hereinafter Gene Group 26); xxix) determining the level of expression of at least one gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF (hereinafter Gene Group 29); or xxx) determining the level of expression of at least one gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5 (hereinafter Gene Group 30), thereby characterizing the glatiramer acetate related drug substance or drug product of step a).
The present invention also provides a process for discriminating between glatiramer acetate related drug substances or drug products comprising the steps of:
a) characterizing two or more glatiramer acetate related drug substances or drug products according to the process of the claimed invention to obtain characteristics of each of the glatiramer acetate related drug substances or drug products; and b) comparing the characteristics of the glatiramer acetate related

12 drug substances or drug products obtained in step a), thereby discriminating between glatiramer acetate related drug substances or drug products.
The present invention also provides a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) xxii) determining the protein level expression of at least one protein selected from the group consisting of RANTES, IP-10, and MMP-9 (hereinafter Protein Group A); xxiii) determining the protein level expression of at least one protein selected from the group consisting of IL10 and MCP-1 (hereinafter Protein Group B); xxiv) determining the protein level expression of at least one protein selected from the group consisting of IFNg, TNFa, MIP-la, IL-8, and IL-10 (hereinafter Protein Group C); xxv) determining the protein level expression of at least one protein selected from the group consisting of MMP-9, MCP-1, RANTES, Gro-a, and IL-lb (hereinafter Protein Group D); xxvi) determining the protein level expression of at least one protein selected from the group consisting of MMP-9, IP-10, MCP-1, and RANTES
(hereinafter Protein Group E); xxvii) determining the protein level expression of at least one protein selected from the group consisting of NIP-la, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-lb, MCP-2, IL-10, I-TAC, CXCL13, IF-b, MCP-3, CCL1, CXCL1, INF-g, CCL26, and MIF (hereinafter Protein Group F); or xxviii) determining the protein level expression of at least one protein selected from the group consisting of NIP-la, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-lb, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, MIF, IL-16, IL-6, TECK,

13 IL-2, MIP-3b, CXCL2, MIG, and CXCL5 (hereinafter Protein Group G), thereby characterizing the glatiramer acetate related drug substance or drug product of step a).
The present invention also provides a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) i) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 1; ii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 2, wherein if IL1B, IL10, or MMP9 is the at least one gene selected in part Cc) (ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 3; iv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 4; v) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 5; vi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 6; vii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 7; viii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 8; ix) determining the protein level expression of at least one protein produced by a

14 gene selected from the group consisting of Gene Group 9; x) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 10; xi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 11; xii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 12; xiii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 13;
xiv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 14; xv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 15; xvi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 16; xvii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 17; xviii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 18; xix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 19; xx) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 20; xxi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 21; xxii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 22; xxiii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 23; xxiv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 24;
xxv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 25; xxvi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 26; xxix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 29; or xxx) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 30, thereby characterizing the glatiramer acetate related drug substance 10 or drug product of step a).

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Framework of studies conducted in mouse splenocytes and human THP-1 monocyte cell line.
Figure 2: Roadmap for human THE-1 monocyte cell line study.
Figure 3: Levels of Copaxone measured over time in cell culture medium from human THE-1 monocyte cell line. Copaxone concentration in medium over time remains steady in the range of 44-52 pg/mL over 24 hours.
FIGS. 4A-D: Differentially expressed genes in human THE-1 monocyte cell line (a) Increased expression of IL10 with GA treatment at 6 hours for the single IL10 probeset on the array (207433 at) (FDR
adjusted p<3.1e-9); (b-d) Increased expression of IL1RN with GA
treatment at 6 hours for multiple probesets (adjusted p values as shown).
Figure 5: Pathways enriched in experimental systems in mouse splenocytes, human THE-1 monocyte cell line and PBMCs from MS patients among top genes modulated by Copaxone at 6 hours (subject to FC and adjusted p value filters of 1.5 and le-5, respectively). The volcano plot show - log (adjusted p value) for the enrichment plotted versus the fold enrichment score from DAVID for each pathway. A selected subset of pathways are labeled.
Figure 6: Probeset for cytokine-cytokine receptor interaction pathway genes significantly modulated by Copaxone at 6 hours in human THE-1 monocyte cell line (subject to FC and adjusted p value filters of 1.5 and le-5, respectively). The volcano plot show - log (adjusted p value) for differential pexpression plotted versus the fold change from LIMMA for each probeset.
Figure 7: MMP9 is significantly upregulated by Probioglat stimulation in human THP-1 monocyte cell line compared to Copaxone stimulation at 6 and 24 hours (FDR adjusted p values for each timepoint are 2.74e-6, 0.098, and 0.004 for 6, 12, and 24 hours, respectively).
Figure 8: CD14 expression in human THE-1 monocyte cell line is significantly higher with Probioglat stimulation compared to Copaxone stimulation at 6 hours.
Figure 9: Focus on the "response to LPS" pathway as differentially expressed by Probioglat versus Copaxone at 6 hours in human THP-1 monocyte cell line.
Figure 10: Pathway-level analysis depicts enrichment among genes upregulated by Probioglat stimulation compared with Copaxone at 6 hours in human THP-1 monocyte cell line (a) Pathways enriched among genes upregulated by Probioglat stimulation compared with GA at 6 hours. The volcano plot shows -log (adjusted p value) for the enrichment plotted versus the fold enrichment score from DAVID for each pathway; (b) Focus on response to LPS pathway, differentially expressed by Probioglat versus GA at 6 hours. The volcano plot shows -log (adjusted p value) for differential expression plotted versus the fold change from LIMMA for each probeset. A selected subset of pathways are labeled.
Figure 11: Each present probeset for ICAM1 is significantly upregulated by Probioglat stimulation compared to Copaxone =
stimulation at 6 hours in human T}-{P-1 monocyte cell line.
Figure 12: CISH is downregulated by Probioglat stimulation compared to Copaxone stimulation at 6 hours in human human THP-1 monocyte cell line.
Figure 13: Upregulation of IL10 with GA treatment in all three studies in mouse splenocytes, human THP-1 monocyte cell line and PBMCs from MS patients.
Figure 14: Overlap of genes significantly modulated by GA between studies in three model systems in mouse splenocytes, human THP-1 monocyte cell line and PBMCs from MS patients.

FIGS. 15A-B: Higher levels of (a) CD14 and (b) CD40 (bottom) are induced by a Probioglat generic than by Copaxone or other generics in human monocytes.
Figure 16: Expression of IL1B in Copaxonee and multiple generics in mouse splenocytes.
Figure 17: Expression of CD44 in Copaxone and Escadra generic in human monocytes.
Figure 18: IL27 expression in Copaxone and various generics in mouse splenocytes.
Figure 19: MMP9 expression induced by Copaxone , Probioglat, and other generics in human monocytes.
Figure 20: Significant gene expression difference are observed between Copaxone and the purported generics Natco and Escadra in many genes, including several relevant to MS.
Figure 21: MMP14 expression is significantly elevated by TV-5010 relative to Copaxone in mouse splenocytes.
Figure 22: The expression of PGRMC1 and IL1B shows significantly different expression following stimulation with proposed generics from different manufacturers in human THP-1 monocytes.
Figure 23: Pathway-level analysis depicts enrichment among genes upregulated by Copaxone stimulation compared with mannitol control at 6 hours in human THP-1 monocyte cell line.
Figure 24: IL1RN is significantly upregulated by Copaxone stimulation in human THP-1 monocyte cell line compared to mannitol control at 6 hours (FDR adjusted p value < 2.8e-10).

ak 02952849 2016-12-16 Fig. 25a: Higher level of CYP1B1 is induced by Polimunol generic than by Copaxone in human THP-1 monocyte cell line at 6 hours (FDR adjusted p values < 1.5e-10).
Fig. 25b: Higher level of GPR68 is induced by Polimunol generic than by Copaxone in human THP-1 monocyte cell line at 6 hours (FDR adjusted p values < 1.5e-5).
Figure 26: Lower level of ADRB2 is induced by Polimunol generic than by Copaxone in human THP-1 monocyte cell line at 6 hours (FDR adjusted p value < 0.009).
FIGS. 27A-E: Copaxone treatment in mouse splenocytes upregulated (a-b) anti-inflammatory cytokines and (c-d) markers of regulatory T
cells, and (e) downregulated pro-inflammatory cytokines.
Figure 28: Pathways enriched among probesets modulated by Copaxone relative to medium in splenocytes from mice immunized with Copaxone .
Figure 29: IL18 expression is reduced to a greater extent by Copaxone than Polimunol, regardless of which substance is utilized for the immunization in mouse splenocytes.
Figure 30: Pathways enriched among top probesets upregulated by Polimunol relative to Copaxone (in Copaxone-immunized mice).
Figure 31: Pathways enriched among top probesets upregulated by Polimunol relative to Copaxone (in Polimunol-immunized mice).
Fig. 32a: IL-18 signaling pathway (from Dinarello, Front Immunol, 2013; Figure 1).
Fig. 32b: Mice definicient for IL-18 are resistant to EAE (from Shi, J. Immuno, 2000; Figure la).

Figure 33: Type I interferon signaling pathway (from Trinchieri et al, Journal of Experimental Medicine, 2010; Figure 1) FIGS. 34A-C: Anti-inflammatory gene IL1RN is signfiicantly upregulated 5 by Copaxone in human THP-1 monocyte cell line.
Figure 35: Pathways enriched among top probesets modulated by Copaxone relative to mannitol control in human THP-1 monocyte cell line.
Figure 36: Genes in the cytokine-cytokine receptor interaction pathway modulated by Copaxone relative to mannitol control (each point represents a probeset, labeled with its gene annotation) in human THE-1 monocyte cell line.
Figure 37: CYP1B1 is significantly upregulated by Polimunol relative to Copaxone .
Figure 38: Pathways significantly enriched among top probesets differentially expressed between Polimunol and Copaxone .
Figure 39: Genes in the cytokine-cytokine receptor interaction pathway, which is significantly enriched among top probesets differentially expressed between Polimunol and Copaxone (each point represents a probeset, labeled with its gene annotation).
Fig. 40a: Volcano plot showing probesets driving the enrichment of the response to lipopolysaccharide pathway among probesets upregulated by Polimunol relative to Copaxone . The dashed line indicates significance level of adjusted p value < 0.05.
Fig. 40b: Volcano plot showing probesets driving the enrichment of the response to lipopolysaccharide pathway among probesets upregulated by Probioglat relative to Copaxone in prior study (FDA-2014-P-0933-0001 available at www.regulations.gov/#!documentDetail;D=FDA-2014-P-0933-0001, and also described herein). The dashed line indicates significance level of adjusted p value < 0.05.
Figure 41: Expression levels of genes differing between Probioglat and GA (a) MMP9 is significantly upregulated following stimulation by Probioglat compared to GA at 6 and 24 hours (FDR-adjusted p values for the single MMP9 probeset on the chip, 203936_s_at, are 2.74e-6, 0.098, and 0.004 for the 6, 12, and 24 hour timepoints, respectively);
(b) CD14 expression is significantly higher with stimulation by Probioglat compared to GA at 6 hours (the single CD14 probeset on the chip is shown, 201743_at); (c) Both present ICAM1 probesets are significantly upregulated following stimulation by Probioglat compared to GA at 6 hours (A: probeset 202637_s_at; B: probeset 202638_s_at); (d) CISH is downregulated following stimulation by Probioglat compared to GA at 6 hours (both present probesets are shown, A: probeset 223961_s_at; B: probeset 223377_x_at).
Figure 42: Expression levels of genes differing between Probioglat and GA by qRT-PCR in primary human monocytes.
CCL2 (p < 0.009), CCL5 (p < 0.029), CXCL10 (p < 0.020), MMP9 (p <
0.009), and IL1RN (p < 0.013) are expressed more highly under Probioglat stimulation relative to GA stimulation.
Figure 43: Principal Component Analysis (PCA; a multivariate approach) showed that the main effect in the first principal component remained due to treatment effects after batch correction (a) First principal component accounts for experimental factor (treatment time 6, 12, 24 hours); (b) PCA demonstrates batch effect correction required for scan date (legand as in (c)); (c) After batch correction, PCA shows more uniform distribution of scan dates.
Figure 44: Box plots showing maximum and minimum expression values for Probioglat (red lines) and Copaxone (blue lines).
FIGS. 45A-B: Protein levels at 24 hours are consistent with upregulation of pro-inflammatory mRNA markers by Probioglat vesus Copaxone treatment at 6h (a) CCL, CXCL10 and MMP-9 protein levels are higher with Probioglat versus Copaxone at 24 hr, consistent with mRNA level observations by RT-PCR and microarray in THP-1 cells; (b) CCL2 and IL-10 protein levels are higher with Probioglat versus Copaxone8 at 24 hr, consistent with mRNA level observations by microarray (not tested by RT-PCR in THP-1 cells.
Figure 46: Number of relapses reported to the Patient Support Program in Mexico.
FIGS. 47A_E: Levels of Secreted Protein with Polimunol Versus GA
Treatment: Levels of IFNg, TNFa, MIPla (CCL3), IL-8 (CXCL8), and IL-10 were higher with Polimunol versus GA treatment.
FIGS. 48A-E: Levels of Secreted Protein with Polimunol Versus GA
Treatment: Consistent with gene level data, levels of MMP-9, MCP-1 (CCL2), RANTES (CCL5), Gro-a (CXCL1), and IL-lb were higher with Polimunol versus GA treatment.
FIGS. 49A-E: Levels of Secreted Protein with Probioglat Versus GA
Treatment: Levels of IFNg, TNFa, MIPla (CCL3), IL-8 (CXCL8), and IL-10 were higher with Probioglat versus GA treatment.
FIGS. 50A-D: Levels of Secreted Protein with Probioglat Versus GA
Treatment: Consistent with gene level data, levels of MMP-9, MCP-1 (CCL2), RANTES (CCL5), and IP-10 (CXCL10) were higher with Probioglat versus GA treatment.

DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the Invention The present invention provides a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) i) determining the level of expression of at least one gene selected from the group consisting of Gene Group 1; ii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 2, wherein if IL1B, IL10, or MMP9 is the at least one gene selected in part (c)(ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 3; iv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 4; v) determining the level of expression of at least one gene selected from the group consisting of Gene Group 5; vi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 6; vii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 7; viii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 8; ix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 9; x) determining the level of expression of at least one gene selected from the group consisting of Gene Group 10; xi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 11; xii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 12; xiii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 13; xiv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 14; xv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 15; xvi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 16; xvii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 17; xviii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 18; xix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 19; xx) determining the level of expression of at least one gene selected from the group consisting of Gene Group 20; xxi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 21; xxii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 22; xxiii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 23; xxiv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 24; xxv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 25; xxvi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 26; xxix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 29; or xxx) determining the level of expression of at least one gene selected from the group consisting of Gene Group 30, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).

In some embodiments of the present invention step (c) comprises i) determining the level of expression of at least one gene selected from the group consisting of Gene Group 1; ii) determining the level of expression of at least one gene selected from the group consisting of 5 Gene Group 3; or vi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 6.
In some embodiments of the present invention, all genes Gene Group 1, are selected for determining the level of expression.
In some embodiments of the present invention, all genes ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6, are selected for determining the level of expression.
In some embodiments of the present invention, if the at least one gene selected in part(c)(i) is IL10, the process comprises the step of selecting at least a second different gene from the group of (c)(i) and (c)(ii) other than IL10.
In some embodiments of the present invention, if the at least one gene selected in part(c)(ii) is CARD15, CCL2, CCL5, CD14, IL10, THBD, or NFKBIA, the process comprises the step of selecting at least a second different gene from the group of (c) (1) and (c)(ii) other than CARD15, CCL2, CCL5, CD14, IL10, THBD, or NFKBIA.
In one or more embodiments of the present invention, if two or more genes are selected in step (c), then the second or additional gene selected is different from the other selected gene or genes In one or more embodiments of the present invention, the level of expression is determined for all genes identified in Table 5 or Table 12 to be involved in one or more than one pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 5 or Table 12 to be involved in at least one pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 5 or Table 12 to be involved in two or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 5 or Table 12 to be involved in three or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 5 or Table 12 to be involved in four or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 5 or Table 12 to be involved in five or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 5 or Table 12 to be involved in six pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene which is involved in only one pathway set forth in Table 5 or Table 12.
In one or more embodiments of the present invention, the level of expression is determined for at least two genes identified in Table 5 or Table 12 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least three genes identified in Table 5 or Table 12 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least four genes identified in Table 5 or Table 12 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least five genes identified in Table or Table 12 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least six genes identified in Table 5 or Table 12 to be involved in the same pathway.
5 In one or more embodiments of the present invention, the level of expression is determined for all genes identified in Table 6 to be involved in one or more than one pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 6 to be involved in at least one pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 6 to be involved in two or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 6 to be involved in three or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 6 to be involved in four or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 6 to be involved in five or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene identified in Table 6 to be involved in six or more pathways.
In one or more embodiments of the present invention, the level of expression is determined for at least one gene which is involved in only one pathway set forth in Table 6.
In one or more embodiments of the present invention, the level of expression is determined for at least two genes identified in Table 6 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least three genes identified in Table 6 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least four genes identified in Table 6 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least five genes identified in Table 6 to be involved in the same pathway.
In one or more embodiments of the present invention, the level of expression is determined for at least six genes identified in Table 6 to be involved in the same pathway.
In one or more embodiments of the present invention, contacting the mammalian cells in step (b) comprises i) administering to a mammal a predetermined amount of glatiramer acetate related drug substance or drug product of step (a), or ii) incubating the cells with an amount of the glatiramer acetate related drug substance or drug product of step (a), or a combination thereof; and wherein step (c) comprises i) determining the level of expression of at least one gene selected from the group consisting of Gene Group 1, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a).
In one or more embodiments of the present invention, contacting the mammalian cells in step (b) comprises i) administering to a mammal a predetermined amount of glatiramer acetate related drug substance or drug product of step (a), and ii) obtaining cells from the mammal at one or more predetermined time points; and wherein step (c) comprises determining the level of expression of at least one gene selected from the group consisting of Gene Group 1, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a).
In one or more embodiments, the mammal is human and the cells are peripheral mononuclear blood cells.

In one or more embodiments, the predetermined time point is 0, 1, 2, or 3 months.
In one or more embodiments, contacting the mammalian cells in step (b) comprises incubating monocytic cell line cells with an amount of the glatiramer acetate related drug substance or drug product of step (a); and wherein step (c) comprises determining the level of expression of at least one gene selected from the group consisting of Gene Group 1; ii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 2; iii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 3; iv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 4; v) determining the level of expression of at least one gene selected from the group consisting of Gene Group 5; vi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 6; vii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 7; viii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 8; ix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 9; x) determining the level of expression of at least one gene selected from the group consisting of Gene Group 10; xvii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 17; xviii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 18; xix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 19; xx) determining the level of expression of at least one gene selected from the group consisting of Gene Group 20; xxi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 21; xxii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 22; xxiii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 23; xxiv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 24; xxv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 25; xxvi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 26; xxix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 29; or xxx) determining the level 5 of expression of at least one gene selected from the group consisting of Gene Group 30, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a).
In one or more embodiments, contacting the mammalian cells in step (b) comprises incubating monocytic cell line cells with an amount of 10 the glatiramer acetate related drug substance or drug product of step (a); and wherein step (c) comprises i) determining the level of expression of at least one gene selected from the group consisting of Gene Group 2; ii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 3; iii)

15 determining the level of expression of at least one gene selected from the group consisting of Gene Group 4; iv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 5; v) determining the level of expression of at least one gene selected from the group consisting of Gene Group 6; vi) 20 determining the level of expression of at least one gene selected from the group consisting of Gene Group 7; or vii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 8; ix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 9; x) 25 determining the level of expression of at least one gene selected from the group consisting of Gene Group 10; xvii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 17; xviii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 18; xix) 30 determining the level of expression of at least one gene selected from the group consisting of Gene Group 19; xx) determining the level of expression of at least one gene selected from the group consisting of Gene Group 20; xxi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 21; xxii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 22; xxiii) determining the level of expression of at least one gene selected from the group consisting 31.
of Gene Group 23; xxiv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 24;
xxv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 25; xxvi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 26; xxix) determining the level of expression of at least one gene selected from the group consisting of Gene Group 29; or xxx) determining the level of expression of at least one gene selected from the group consisting of Gene Group 30, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).
In one or more embodiments of the present invention, the mammalian cells are THP-1 cells.
In one or more embodiments of the present invention, contacting the mammalian cells in step (b) comprises i) immunizing a mammal with a predetermined amount of glatiramer acetate related drug substance or drug product, ii) preparing a culture of cells from the mammal of step i) at one or more predetermined time points after immunization, and iii) incubating cells from the culture of cells obtained from the mammal with an amount of the glatiramer acetate related drug substance or drug product of step (a); and wherein step (c) comprises i) determining the level of expression of at least one gene selected from the group consisting of Gene Group 1; xi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 11; xii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 12; xiii) determining the level of expression of at least one gene selected from the group consisting of Gene Group 13; xiv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 14; xv) determining the level of expression of at least one gene selected from the group consisting of Gene Group 15; or xvi) determining the level of expression of at least one gene selected from the group consisting of Gene Group 16, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a).

In one or more embodiments of the present invention, the glatiramer acetate related drug substance or drug product of step (iii) is the same glatiramer acetate related drug substance or drug product of step (i).
In one or more embodiments of the present invention, the glatiramer acetate related drug substance or drug product of step (iii) is a different glatiramer acetate related drug substance or drug product of step (i).
In one or more embodiments of the present invention, the incubation is for about 24 hours, for about 12 hours, or for about 6 hours.
In one or more embodiments of the present invention, the predetermined time point after immunization is 3 days.
In one or more embodiments of the present invention, the contacting of step (b) is in a cell culture.
In one or more embodiments of the present invention, the culture is a primary culture.
In one or more embodiments of the present invention, the contacting of step (b) is in a mammal.
In one or more embodiments of the present invention, the mammal is a rodent or human.
In one or more embodiments of the present invention, the glatiramer acetate related drug substance or drug product is other than glatiramer acetate drug substance or drug product.
In one or more embodiments of the present invention, the cell is of a type i) selected from the group of cell types consisting of FoxP3+ T
cells, regulatory T cells, natural killer T cells, T helper 2 cells, CD8+ T cells, CD4+ T cells, B cells, macrophage cells, monocyte cells, eosinophils, dendritic cells, granulocytes, megakaryocytes, and myeloid progenitors; ii) selected from the group of cell types identified in Table 9; iii) selected from the group of cell types identified in Table 10; or iv) selected from the group of cell types identified in Table 11.
In one or more embodiments of the present invention, the process of characterizing two or more glatiramer acetate related drug substances or drug products further comprises obtaining characteristics of each of the glatiramer acetate related drug substances or drug products;
and comparing the characteristics of the drug related substances or drug products, thereby discriminating between glatiramer acetate related drug substances or drug products.
In one or more embodiments of the present invention, the mammal is a rodent or human.
In one or more embodiments of the present invention, the level of expression is determined in hematological cells.
In one or more embodiments of the present invention, the level of expression is determined in splenocytes.
In one or more embodiments of the present invention, the level of expression is determined in monocytes.
In one or more embodiments of the present invention, the monocytes are THP-1.
In one or more embodiments of the present invention, the level of expression is determined in peripheral blood mononuclear cells.
In one or more embodiments of the present invention, the peripheral blood mononuclear cells are from a human.
In one or more embodiments of the present invention, the human has previously been treated with a glatiramer acetate related drug substance or drug product.
In one or more embodiments of the present invention, the human is a naive human.
In one or more embodiments of the present invention, the human is a glatiramoid naive human.

In one or more embodiments of the present invention, the human is afflicted with RRMS.
In one or more embodiments of the present invention, the rodent is a mouse.
In one or more embodiments of the present invention, the mouse is a female (SJL X BALB/C) Fl mouse.
In one or more embodiments of the present invention, the mouse is about 8 to 12 weeks old.
In one or more embodiments of the present invention, the primary culture is a culture of spleen cells.
In some embodiments of the present invention, the primary culture is a culture of lymph node cells.
In some embodiments of the present invention, the primary culture of spleen cells is prepared about 3 days after immunization.
In one or more embodiments of the present invention, the glatiramer acetate related drug substance is a glatiramoid or the glatiramer acetate related drug product comprises a glatiramoid.
In one or more embodiments of the present invention, the glatiramer acetate related drug substance is a glatiramoid other than glatiramer acetate related drug substance, or the glatiramer acetate related drug product comprises a glatiramoid other than glatiramer acetate drug substance.
In one or more embodiments of the present invention, process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting a first group of mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a);

c) contacting a second group of mammalian cells of the same type with an amount of a reference standard; and d) determining a set of genes differentially expressed by the first group after the contacting of step (b) relative to genes 5 expressed by the second group after the contacting of step (c), thereby characterizing the glatiramer acetate related drug substance or drug product of step a).
10 In one or more embodiments of the present invention, the cells are THP-1 cells.
In one or more embodiments of the present invention, the reference standard is glatiramer acetate related drug substance or drug product.
In one or more embodiments of the present invention, the reference standard is mannitol In one or more embodiments of the present invention, the reference standard is medium.
In one or more embodiments of the present invention, the determining step (d) comprises comparing the expression of genes expressed by the first group to the expression of genes expressed by the second group.
In one or more embodiments of the present invention, the determining step (d) comprises comparing the expression of genes by bother the first group of cells and by the second group of cells to expression of the genes by the same type of cells exposed to mannitol or medium.
In one or more embodiments of the present invention, process for discriminating between glatiramer acetate related drug substances or drug products comprising the step of characterizing two or more glatiramer acetate related drug substances or drug products to obtain characteristics of each of the glatiramer acetate related drug substances or drug products; and comparing the characteristics of the glatiramer acetate related drug substances or drug products, thereby discriminating between glatiramer acetate related drug substances or drug products.
In some embodiments of the present invention in a process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug substance according to the process of any one of the above characterization methods; and b) i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 1 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; iii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; iv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 4 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; v) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; vi) including the batch of the glatiramer acdtate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; vii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 7, is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; viii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is downregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; or ix) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; x) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 10 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 11 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 12 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 13 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 14 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 15 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 16 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 17 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 18 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 19 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 20 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 21 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 22 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 23 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) including the batch of the glatiramer acetate 5 related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 24 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 25 is substantially identical to the level of expression by the same type of cells in the presence 15 of the glatiramer acetate drug substance under the same conditions; xxvi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 26 is substantially identical to 20 the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the 25 group consisting of Gene Group 29 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) including the batch of the glatiramer acetate related drug substance in the production of the drug product if 30 the level of expression of one or more genes selected from the group consisting of Gene Group 30 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
35 In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 1 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 4 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.

In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABI2, ARPC4, CD84, CLU, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; or ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABCF2, ACP6, AFG3L2, CHAF1A, COX11, LPHN1, NACA, OLAH, POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TSHZ1, TSPAN13, UBAP2, VDAC2, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises, if, one or more genes selected from the group consisting of ABI2, ARPC4, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, then including the batch of the glatiramer acetate related drug substance in the production of the drug product.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises, if, one or more genes selected from the group consisting of ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, then including the batch of the glatiramer acetate related drug substance in the production of the drug product.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCL2, CCL5, MMP1, MMP9, CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD, NFKBIA, IL10, PRDM1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CISH and HSPD1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; iii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CC124, CCR1, CSF1R, CX3CR1, IL27, IFNGR1, IL2RG, and IL7R is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate drug related substance under the same conditions; iv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of PGRMC1 is upregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; v) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of MMP14 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; vi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of IL1RN is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; or vii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of IL1B is substantially identical to the 5 level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing 10 the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 5 is substantially identical to the level of expression by the same type 15 of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing 20 the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6 is substantially identical to the level of expression by the same type 25 of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing 30 the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 7, is upregulated to the level of expression by the same type of cells 35 in the absence of the glatiramer acetate related drug substance under the same conditions.

In one or more embodiments of the present invention, in the process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is downregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions.
In some embodiments of the present invention in a process for releasing a drug product comprising a glatiramer acetate related drug substance, which process involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug product according to the process of any one of the above characterization methods; and b) i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 1 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions; ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions;
iii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; iv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 4 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; v) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions;
vi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; vii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 7, is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; viii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is downregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, ix) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; x) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 10 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions;
xi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 11 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 12 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 13 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 14 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 15 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 16 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 17 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 18 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 19 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 20 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 21 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 22 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 23 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 24 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 25 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxvi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more 10 genes selected from the group consisting of Gene Group 26 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 29 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) releasing the batch of the glatiramer acetate 20 related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 30 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
25 In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if 30 the level of expression of one or more genes selected from the group consisting of Gene Group 1 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions.
In one or more embodiments of the present invention, in the process 35 for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 4 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 5, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of A3I2, ARPC4, CD84, CLU, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions; or ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of ABCF2, ACP6, AFG3L2, CHAF1A, COX11, LPHN1, NACA, OLAH, POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TSHZ1, TSPAN13, UBAP2, VDAC2, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug substance further comprises, if, one or more genes selected from the group consisting of ABI2, ARPC4, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions, then releasing the batch of the glatiramer acetate related drug product.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises, if, one or more genes selected from the group consisting of ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions, then releasing the batch of the glatiramer acetate related drug product.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of CCL2, CCL5, MMP1, MMP9, CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD, NFKBIA, IL10, PRDM1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of CISH and HSPD1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; iii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of C0124, CCR1, CSF1R, CX3CR1, IL27, IFNGR1, IL2RG, and IL7R is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate drug related substance under the same conditions; iv) releasing the batch of the glatiramer acetate related drug product if the level of expression of PGRMC1 is upregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; v) releasing the batch of the glatiramer acetate related drug product if the level of expression of MMP14 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; vi) releasing the batch of the glatiramer acetate related drug product if the level of expression of IL1RN is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; or vii) releasing the batch of the glatiramer acetate related drug product if the level of expression of IL1B is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 5, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.
In one or more embodiments of the present invention, in the process 5 for releasing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group 10 consisting of Gene Group 7, is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions.
In one or more embodiments of the present invention, in the process for releasing a drug product comprising a glatiramer acetate related 15 drug substance which involves an array of testing, the characterizing the glatiramer acetate related drug product further comprises releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is downregulated to the level of expression 20 by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions.
In one or more embodiments of the present invention, a glatiramer acetate related drug product produced by a process of the present invention, wherein the glatiramer acetate related drug product is 25 other than glatiramer acetate drug product.
In one or more embodiments of the present invention, a glatiramer acetate related drug product other than glatiramer acetate drug product which is capable of inducing a level of expression of ABCF2, ABI2, ACP6, AFG3L2, ALMS!, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, 30 CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 that is not substantially identical to the level of expression of the genes induced in the same tpe of cells and under the same conditions in the 35 absence of the glatiramer acetate related drug product.

In one or more embodiments of the present invention, a glatiramer acetate related drug product, wherein the glatiramer acetate related drug product is capable of inducing a level of expression of Gene Group 1.
In one or more embodiments of the present invention, the glatiramer acetate related drug product, which is capable of upregulating genes A5I2, ARPC4, HFE, and IL10 relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product, and capable of downregulating genes ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1 relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product.
In one or more embodiments of the present invention, a glatiramer acetate related drug product other than glatiramer acetate drug product which is capable of inducing a level of expression of Gene Group 7 and Gene Group 8, that is not substantially identical to the level of expression of the genes induced in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product.
In one or more embodiments of the present invention, the glatiramer acetate related drug product, which is capable of upregulating genes Gene Group 7, relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product, and capable of downregulating genes Gene Group 8 relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product In some embodiments of the present invention, the process further comprises i) determining the one or more proteins produced by each of the one of more genes selected in step c); and ii) determining protein level expression for each protein in step i).
In some embodiments of the present invention, the process further comprises i) determining the one or more proteins produced by each of the one of more genes selected in step b); and ii) determining protein level expression for each protein in step i).
In some embodiments of the present invention, the process further comprises determining the set of proteins produced by each gene of the set of genes in step d).
In some embodiments of the present invention, in a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) xxii) determining the protein level expression of at least one protein selected from the group consisting of Protein Group A;
xxiii) determining the protein level expression of at least one protein selected from the group consisting of Protein Group B;
xxiv) determining the protein level expression of at least one protein selected from the group consisting of Protein Group C;
xxv) determining the protein level expression of at least one protein selected from the group consisting of Protein Group D;
xxvi) determining the protein level expression of at least one protein selected from the group consisting of Protein Group E;
xxvii) determining the protein level expression of at least one protein selected from the group consisting of Protein Group F;
or xxviii) determining the protein level expression of at least one protein selected from the group consisting of Protein Group G, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).
In some embodiments of the present invention, in a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and c) i) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 1; ii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 2, wherein if IL1B, IL10, or MMP9 is the at least one gene selected in part (c)(ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 3; iv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 4; v) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 5; vi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 6; vii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 7; viii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 8; ix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 9; x) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 10; xi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 11; xii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 12; xiii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 13;
xiv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 14; xv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 15; xvi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 16; xvii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 17; xviii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 18; xix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 19; xx) determining the protein level expression of at least one protein i produced by a gene selected from the group consisting of Gene Group 20; xxi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 21; xxii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 22; xxiii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 23; xxiv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 24;
xxv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 25; xxvi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 26; xxix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 29; or xxx) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Gene Group 30, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).
In some embodiments of the present invention the process, wherein contacting the mammalian cells in step (b) comprises incubating 5 monocytic cell line cells with an amount of the glatiramer acetate related drug substance or drug product of step (a); and wherein step (c) comprises xxii) determining the protein level expression of at least one protein selected from the group consisting of Protein Group A; xxiii) determining the protein level expression of at least one 10 protein selected from the group consisting of Protein Group B; xxiv) determining the protein level expression of at least one protein selected from the group consisting of Protein Group C; xxv) determining the protein level expression of at least one protein selected from the group consisting of Protein Group D; xxvi) 15 determining the protein level expression of at least one protein selected from the group consisting of Protein Group E; xxvii) determining the protein level expression of at least one protein selected from the group consisting of Protein Group F; or xxviii) determining the protein level expression of at least one protein 20 selected from the group consisting of Protein Group G, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a).
In some embodiments of the present invention, the process wherein the 25 mammalian cells are THP-1 cells.
In some embodiments of the present invention, the process, wherein the incubation is for about 24 hours.
30 In some embodiments of the present invention, the process, wherein contacting the mammalian cells in step (b) comprises i) immunizing a mammal with a predetermined amount of glatiramer acetate related drug substance or drug product, ii) preparing a culture of cells from the mammal of step i) at one or more predetermined time points after 35 immunization, and iii) incubating cells from the culture of cells obtained from the mammal with an amount of the glatiramer acetate related drug substance or drug product of step (a), thereby characterizing the glatiramer acetate related drug substance or drug product of step (a).
In some embodiments of the present invention, the process, wherein the glatiramer acetate related drug substance or drug product of step (iii) is the same glatiramer acetate related drug substance or drug product of step (i).
In some embodiments of the present invention, the process, wherein the glatiramer acetate related drug substance or drug product of step (iii) is a different glatiramer acetate related drug substance or drug product of step (i).
In some embodiments of the present invention, in a process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug substance according to the process of any one of the above characterization methods; and b) xxii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group A is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxiii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group B is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxiv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group C

is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group D is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxvi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group E is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxvii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group F
is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; or xxviii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group G is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions.
In some embodiments of the present invention, in a process for releasing a drug product comprising a glatiramer acetate related drug substance, which process involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug product according to the process of any one of the above characterization methods; and b) xxii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group A is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxiii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group B is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxiv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group C
is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group D is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxvi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group E is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxvii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group F is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; or xxviii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of Protein Group G is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions.
In some embodiments of the present invention, in a process for discriminating between glatiramer acetate related drug substances or drug products comprising the steps of:
a) characterizing one or more glatiramer acetate related drug substances or drug products according to the process of any one of the above characterization methods to obtain characteristics of each of the glatiramer acetate related drug substances or drug products;
b) obtaining characteristics of a glatiramer acetate drug substance or drug product; and c) comparing the characteristics of the glatiramer acetate related drug substances or drug products obtained in steps a) and b), thereby discriminating between glatiramer acetate related drug substances or drug products.

Additional Embodiments of the Invention In a process for producing a drug product comprising a glatiramer acetate related drug substance, the improvement comprising the steps of:
5 a) characterizing the glatiramer acetate related drug substance according to the process of any one of the above characterization methods; and b) i) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if 10 the level of expression of one or more genes selected from the group consisting of Gene Group 1 is substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; ii) discarding the batch of the glatiramer acetate 15 related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 2 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under 20 the same conditions; iii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is not substantially identical to the level of expression by the same 25 type of cells in the presence of the glatiramer acetate drug substance under the same conditions; iv) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene 30 Group 4 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; v) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of 35 expression of one or more genes selected from the group consisting of Gene Group 5 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; vi) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 6, is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; vii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 7, is downregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; viii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is upregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; ix) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 9 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; x) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 10 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xi) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 11 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 12 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions;
xiii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 13 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 14 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 15 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions;
xvi) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 16 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 17 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 18 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 19 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 20 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 21 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 22 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions;
xxiii) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 23 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 24 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 25 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions;
xxvi) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 26 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 29 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) discarding the batch of the glatiramer acetate related drug substance as unacceptable for inclusion in the drug product if the level of expression of one or more genes selected from the group consisting of Gene Group 30 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.

In a process for releasing a drug product comprising a glatiramer acetate related drug substance, the improvement comprising the steps of:
a) characterizing the glatiramer acetate related drug product according to the process of any one of the above characterization methods; and b) i) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene 10 Group 1 is substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions; ii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression 15 of one or more genes selected from the group consisting of Gene Group 2 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; iii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; iv) discarding the batch 25 of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 4 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug 30 product under the same conditions; v) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 5, is not substantially identical to the level of expression by the same type of cells 35 in the presence of the glatiramer acetate drug product under the same conditions; vi) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 6 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions;
vii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 7, is downregulated or substantially identical to the level of expression by the same type of cells in the absence of glatiramer acetate drug product under the same conditions; viii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is upregulated or substantially identical to the level of expression by the same type of cells in the absence of glatiramer acetate drug product under the same conditions; ix) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 9 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; x) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 10 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; xi) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 11 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 12 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 13 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 14 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 15 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvi) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 16 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 17 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 18 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 19 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 20 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 21 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 22 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiii) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 23 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 24 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 25 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxvi) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 26 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 29 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) discarding the batch of the glatiramer acetate related drug product as unacceptable for release if the level of expression of one or more genes selected from the group consisting of Gene Group 20 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.
In one or more embodiments of the present invention, in a process for identifying suboptimal activity of a glatiramer acetate related drug substance or drug product comprising the steps of:
a) administering a glatiramer acetate related drug substance or drug product to a mammal;
b) characterizing the glatiramer acetate related drug substance or drug product according to the process of any one of the above characterization methods; and c) i) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 1 is substantially identical to the 5 level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance or drug product under the same conditions; ii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more 10 genes selected from the group consisting of Gene Group 2 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance or drug product under the same conditions; iii) identifying the glatiramer acetate related drug substance or 15 drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 3 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance or drug product 20 under the same conditions; iv) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 4 is not substantially identical to the level of expression by the same 25 type of cells in the presence of the glatiramer acetate related drug substance or drug product under the same conditions; v) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group 30 consisting of Gene Group 5 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance or drug product under the same conditions; vi) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal 35 activity if the level of expression of one or more genes selected from the group consisting of Gene Group 6, is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance or drug product under the same conditions; vii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 7, is downregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance or drug product under the same conditions; viii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 8, is upregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance or drug product under the same conditions; ix) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 9 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance or drug product under the same conditions; x) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 10 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance or drug product under the same conditions; xi) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 11 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 12 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 13 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 14 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 15 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvi) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group

16 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group

17 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group

18 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group

19 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 21 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate

20 drug substance under the same conditions; xxii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 22 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiii) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 23 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 24 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 25 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxvi) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 26 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group 29 is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) identifying the glatiramer acetate related drug substance or drug product as causing a suboptimal activity if the level of expression of one or more genes selected from the group consisting of Gene Group is not substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate 25 drug substance under the same conditions.

V1/02010)04250 The Additional Embodiments described above can be readily applied and practiced with features of Embodiments of the Invention described in the section preceeding the Additional Embodiments.
For example, in a process for producing a drug product comprising a 5 glatiramer acetate related drug substance, where the batch of the glatiramer acetate related drug substance is included in the drug product if the level of expression of one or more genes selected from one or more Gene Groups is substantially upregulated relative to the level of expression by the same type of cells in the absence of the 10 glatiramer acetate related drug substance under the same conditions, then conversely the batch of the glatiramer acetate related drug substance is discarded if the level of expression of one or more genes selected from one or more Gene Groups is not substantially upregulated relative to the level of expression by the same type of cells in the 15 absence of the glatiramer acetate related drug substance under the same conditions as unacceptable for inclusion in the drug product.

Definitions As used herein, a "naive human" is a human that has not been treated with any multiple sclerosis drug.
As used herein, a "glatiramoid naive human" is a human that has not been treated with any glatiramoid drug. A glatiramoid naive human could have been treated with another multiple sclerosis drug.
As used herein, "in the blood of" is represented by peripheral blood mononuclear cells (PBMCs), lymphocytes, monocytes, macrophages, basophils, dendritic cells or other cells derived from a mammal's blood.
As used herein, a "reference standard" is a sample or value which serves as a point of comparison for another sample or value which differs from the reference standard with respect to one or more variables. With specific regard to a human, a "reference standard" is a value or range of values that characterizes a defined population in a defined state of health. For example, a reference standard can characterize a healthy human or a human afflicted with multiple sclerosis, and when the human is afflicted with multiple sclerosis the human can be naive or having received glatiramer acetate drug substance.
As used herein, the term "glatiramer acetate related drug substance"
(GARDS) is intended to include include polypeptides with a predetermined sequence as well as mixtures of polypeptides assembled from the four amino acids glutamic acid (E), alanine (A), lysine (K), and tyrosine (Y); from any three of the amino acids Y, E, A and K, i.e. YAK, YEK, YEA or EAK; or from three of the amino acids Y, E, A
and K and a fourth amino acid. Examples of glatiramer acetate related polypeptides are disclosed in U.S. Patents 6,514,938 Al, 7,299,172 B2, 7,560,100 and 7,655,221 B2 and U.S. Patent Application Publication No. US 2009-0191173 Al, the disclosures of which are hereby incorporated by reference in their entireties. Glatiramer acetate related substances include glatiramoids.

As used herein, a "glatiramer acetate related drug product" (GARDE) contains a glatiramer acetate related drug substance.
As used herein, a "glatiramer acetate related drug substance or drug product" is a glatiramer acetate related drug substance or a glatiramer acetate related drug product.
As used herein a "glatiramoid" is a complex mixture of synthetic proteins and polypeptides of varying sizes assembled from four naturally occurring amino acids: L-glutamic acid, L-alanine, L-lysine, and L-tyrosine, in a defined molar ratio. Examples of glatiramoids include glatiramer acetate drug substance (e.g. Copaxone ) as well as glatiramoids other than Copaxone , e.g. GA-Natco.
As used herein, a "glatiramer acetate drug substance" (GADS) is glatiramer acetate produced by Teva Pharmaceutical Industries, Ltd.
and is the active ingredient in a glatiramer acetate drug product.
As used herein, a "glatiramer acetate drug product" (GADP) contains a glatiramer acetate drug substance produced by Teva Pharmaceutical Industries, Ltd. which consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively, and has an average molecular weight of 5,000 - 9,000 daltons. (8) Copaxone is a glatiramer acetate drug product.
As used herein, a "glatiramer acetate drug substance or drug product"
is a glatiramer acetate drug substance or a glatiramer acetate drug product.
As used herein a "glatiramer acetate reference standard" is or contains the drug substance found in a glatiramer acetate drug product.
As used herein "suboptimal activity" refers to a negative response or to a response which is less than the response to glatiramer acetate drug substance or glatiramer acetate drug product produced by Teva Pharmaceutical Industries, Ltd.

As used herein, "release" of a drug product refers to making the product available to consumers.
As used herein, "about" with regard to a stated number encompasses a range of +10 percent to -10 percent of the stated value. By way of example, about 100 mg therefore includes the range 90-110 mg and therefore also includes 90, 91, 92, 93, 94, 95 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109 and 110 mg. Accordingly, about 100 mg includes, in an embodiment, 100 mg.
As used herein, "hematological cell" comprises neutrophils, erythrocytes, basophils, monocytes, eosinophils, platelets, lymphocytes, and splenocytes.
As used herein, an "array of testing" for a glatiramer acetate related drug substance or drug product includes, but is not limited to, any analytical method test such as in vitro tests or molecular weight tests, biological assays such as the ex vivo tests and clinical efficacy tests which characterize the GARDS or GARDP, or clinical trials. Examples of testing for a glatiramer acetate related drug substance or drug product are disclosed in U.S. Patent Application Publication Nos. US 2012-0309671 and US 2011-0230413, and in PCT
International Application Publication Nos. WO 2000/018794, WO
2012/051106, WO 2013/055683, WO 2014/058976, the disclosures of which are hereby incorporated by reference in their entireties.
It is understood that where a parameter range is provided, all integers within that range, tenths thereof, and hundredths thereof, are also provided by the invention. For example, "0.2-5 mg" is a disclosure of 0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg etc. up to 0.3 mg, 0.31 mg, 0.32 mg, 0.33 mg etc. up to 0.4 mg, 0.5 mg, 0.6 mg etc. up to 5.0 mg.
All combinations of the various elements described herein are within the scope of the invention.
It is understood that where "at least one" or "one or more" is recited along with a list, then 1, 2, 3, 4... or all members of that list are disclosed in every combination. For example, in a group of 43 genes, "at least one" and "one or more" is a disclosure of one gene, two genes, three genes, etc., in any combination, up to the forty three genes.
As used herein, "characterization" or "characterizing" is understood to include obtaining information which was produced in the same location or country, or a different location or country from where any remaining steps of the method are performed.
As used herein, processes of producing a glatiramer acetate related drug substance or drug product are known in the art. Examples of such manufacturing processes are disclosed in U.S. Patent 5,800,808, and in PCT International Application Publication Nos. WO 2005/032553, WO
2005/032395, WO 1999/22402, the disclosures of which are hereby incorporated by reference in their entireties.
Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.
This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

Experimental Details Methods The null hypothesis in traditional gene-expression studies, including Teva's studies with the glatiramoids, is that there are no significant 5 gene expression differences induced between the treatments. As such, the expectation is that regardless of the biological system used for testing, genes would show no statistically significant, nor biologically meaningful differences among the various treatments. Only in cases where the treatments induce significant observable effects, 10 genes differentially expressed between treatments will pass the stringent statistical tests, and false discovery rate (FDR) correction for multiple hypotheses (Benjamini and Hochberg, 1995). These stringent requirements were imposed a priori across all tests to ensure robustness of results and minimizing of spurious findings. Such 15 statistically significant differences, if biologically meaningful (i.e., related to the disease biology or any of the drug's known or putative targets and downstream pathways), warrant further studies, as two drugs that have identical activities in biological systems should not induce statistically observable and biologically enriched 20 differences when compared against each other.
These studies were not designed to establish a particular set of genes in a specific model system as a panel to evaluate sameness between differently manufactured glatiramoids. Instead, these were designed 25 to assess the degree of similarity in the impact of two glatiramoids on relevant biological pathways. The application of robust methodology (high number of replicates, conditions and time-points, where relevant) was aimed to describe pathways changed by different treatments out of the entire milieu of genomic patterns. The results 30 obtained across the tested experimental models revealed statistically significant differences between drugs, which were intended to be similar and to perform the same function, despite stringent statistical threshold requirements. This was noteworthy particularly in genes highly relevant to disease processes and drug response 35 mechanisms. In addition, the differences observed revealed a complex interplay between immunological pathways, such that some differences were common to multiple systems, while many others were dependent on the specific model system (for example, some key genes modulated in T
cells were not the same as in monocytes). This is not surprising for a process that involves multifaceted interactions between many immune system components, and is also exemplified in experimental studies of CopaxoneVs mechanism of action. Thus, no single model system, characterization method, or set of genes tested was sufficient to comprehensively capture the differences between the drugs. These observations indicate a need for in-depth investigation of comparative gene expression profiles in several relevant pre-clinical systems as key indicators of similarity and/or sameness between generic candidates and the original drug within the context of Non-Biological Complex Drugs (NBCD).
Ideally, the concordance between high-resolution physicochemical measures (e.g. ion motility mass spectrometry, IMMS), gene expression profiling and clinical trials would allow a more definitive assessment of equivalence in terms of patient benefit and safety.
Mice All experimental procedures conformed to accepted ethical standards for use of animals in research and were in accordance with Committee for the Care and Use of Experimental Animals guidelines and approved by the Teva Institutional Animal Care and Use Committee.
Preparation of Mouse Spleen Cell Cultures All experimental procedures conformed to accepted ethical standards for use of animals in research and were in accordance with Committee for the Care and Use of Experimental Animals guidelines and approved by the Teva Institutional Animal Care and Use Committee.
Mouse Splenocytes: Gene Expression Analysis In the first of the genomic studies, 8- to 12-week old female mice (N=8) of the (Balb/c x SJL) Fl variety (Harlan, Israel) were injected subcutaneously with glatiramer acetate (GA) in order to induce specific GA-reactive T cells as would be present in a Copaxone treated patient.

After 3 days, the mice were sacrificed and cells from their spleens (splenocytes) were isolated because such cells are representative of, and commonly utilized as a gold standard to study the immune system.
The aqueous activator samples, mannitol (the non-active excipient in Copaxone and all other marketed proposed generics) and medium were used as negative controls.
Given the robustness of the model established in our first mouse splenocyte study, we sought to expand the scope of the investigation using the exact same study design, but with an expanded set of treatments (Fig. 1). In addition to comparing Copaxone to a purported foreign generic version, we also sought to compare purported generics from various manufacturers to each other. Using the mouse splenocyte procedure described herein, we generated expression data in response to activation with proposed generic glatiramer acetate samples from Escadra (Argentina), Probioglat (Mexico; Probiomed), and Hangzhou (China: API). A total of 21 samples of Copaxone8 from 21 different batches were used, along with 10 samples from 2 lots of Escadra, 12 samples from 4 batches of Natco, 4 samples from 1 batch of Probioglat, 5 samples of Hangzhou from 2 batches, 12 samples of GA-RS from 1 batch, and 8 samples of medium.
Mouse Splenocytes: RNA Isolation and Microarray Expression Profiling Extraction of total RNA from activated splenocytes was extracted using PerfectPure RNA Cultures CEKK kit 50 (5Prime GmbH, Hamburg, Germany) and following the manufacturer's instructions. RNA quality was assessed using the absorbance ratio at 260/280 rim and gel electrophoresis (Experion, Bio-Rad, Hercules, CA, USA). Total RNA
extracted from samples was hybridized to Illumina Mouse WG-6_V2 microarray chips containing more than 45,200 transcripts.
Samples were randomized on the chips to avoid batch effects.
Illumina's BeadStudio software was utilized for image processing, quantification of signal intensity per bead, and background signal correction. Multiple probes were analyzed for a given gene were averaged and batch correction was conducted using Partek. Further analysis was conducted individually within the context of known pathways, and batch correction was conducted using ComBat, as implemented in the SVA R package sva: Surrogate Variable Analysis.
Available:
www.bioconductor.org/packages/release/bioc/html/sva.html). Briefly, ComBat is an empirical Bayesian approach utilizing location and scale metrics across several genes to adjust for batch effects in datasets, even datasets containing small sample sizes. Treatment labels were added as covariates to the batch correction in order to preserve relevant treatment effects. Principal Component Analysis (a multivariate approach) showed that the main effect in the first principal component remained due to treatment effects after batch correction.
Mouse Splenocytes: Gene Expression Analysis - Polimunol versus Copaxone Gene Expression Studies Mice All experimental procedures conformed to accepted ethical standards for use of animals in research and were in accordance with Committee for the Care and Use of Experimental Animals guidelines and approved by the Teva Institutional Animal Care and Use Committee. For these experiments, 8- to 12-week-old female (Balb/c X SJL) Fl mice (Janvier, France) were purchased. Mice were kept at 21 3 C; the relative humidity was 30-70%, the light/dark cycle was 12/12 h. Animals were maintained on a standard rodent pellet diet and sterile filtered tap water available ad libitum.
Preparation of mouse spleen cell cultures To stimulate induction of GA-reactive T cells, twelve mice were injected with 100 pL of a 2.5 mg/mL solution of GA reference standard (GA-RS) in phosphate-buffered saline (250 pg GARS per mouse). GA-RS
(Teva) is a selected GA drug substance batch defined as the standard batch and used as a reference in quality control release tests of all Copaxone batches. Another group of twelve mice were injected with 100 pL of a 2.5 mg/mL solution of Polimunol in phosphate-buffered saline (250 pg Polimunol per mouse). Polimunol is a proposed generic manufactured a company other than Teva. Mice were housed for 3 days after immunization; mice were then sacrificed and their spleens were aseptically removed and placed on ice in RPMI 1640. A single cell suspension was prepared. After red blood cells lysis, splenocytes from the same immunization group were pulled and resuspended to a final concentration of 10 x 106 cells/mL in defined cell culture media (DCCM1) (Biological Industries, Beit Haemek, Israel) (96.7% v/v) enriched with L-glutamine 2 mM (1% v/v), MEM Non-Essential Amino Acids 2 mM (1% v/v), sodium pyruvate 1 mM (1% v/v), antibiotic/antimycotic solution (0.2% v/v) and 2-mercaptoethanol 50mM (0.1% v/v).
In vitro cell activation Splenocytes were treated with activator samples diluted in medium (125 pL per well of 80 pg/mL solutions, final concentration in the well:
40 pg/mL) of: i) 3 different batches of GA drug product manufactured by Teva ii) one batch of proposed generic (Polimunol). Polimunol is a product marketed as generic GA and manufactured by a company other than Teva (i.e. Synthon). The activator samples, mannitol (the nonactive excipient in Copaxonee), and medium were added to 96-well tissue culture plates (three wells per sample). Splenocytes (125 pL
10 x 106 SPL cell/mL suspension) were added to the activator solutions.
Each activator sample was loaded in two different plates. One for the cells from mice immunized with GA and one for cells from mice immunized with proposed generic. Plates were incubated for 24 h at 37 C. Cells were collected from the wells and were centrifuged at 300g for 5 minutes. Supernatants were aspirated and cell pellets were resuspended in RLT buffer (from RNeasy mini kit of Qiagen, Cat # 74106) for cell lysis. The cell lysates were centrifuged and supernatants were collected and frozen at -70 C. Samples were sent for further processing.
Analysis Methods For additional detail on experimental methods used in mouse studies, please refer to publications [Bakshi et al; Towfic et all. Note that in this study, mice were immunized with either Copaxonee or Polimunol, and subsequently splenocytes were isolated and treated ex vivo with Copaxonee or Polimunol. RNA was extracted and expression profiled across the entire genome using the Affymetrix Mouse Genome 430 2 chip.

Three lots of Copaxone , and one lot of Polimunol were comparatively tested in six replicates each.
Outlier identification and normalization 5 Outlier samples were identified using the R package ArrayQCMetrics and excluded from further data processing steps. A sample was considered an outlier if it failed more than half of the included tests either before or after RMA normalization.
Data were RMA
normalized using the Affy R package.
Batch correction Correction for batch variation was performed using ComBat as described above (THP-1 methods). Date of microarray experiment was used as batch, and the combination of treatment and immunization was used as covariate. Principal Component Analysis (a multivariate approach) showed that the main effect in the first principal component remained due to treatment effects after batch correction.
Differential expression analysis Differentially expressed probesets were identified across conditions using linear models for microarray data (LIMMA; Smyth, G. K. (2004)), a standard R Bioconductor package. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Statistical Applications in Genetics and Molecular Biology 3, No. 1, Article 3). To compare GA and purported generic, comparisons were corrected to compare each treatment relative to mannitol control (e.g., [GA vs mannitol] was compared via LIMMA to [Polimunol vs mannitol]). Probesets were filtered by MAS5 calls of presence on the chip (to be considered present, a probeset was required to have on average a call of present or marginal across samples).
Probesets were mapped to genes using the annotation available for the Mouse 430 2 chip from Affymetrix. Unless otherwise noted, FDR adjusted p values reported for genes represent the lowest FDR adjusted p value for present probesets for that gene.

Pathway enrichment analysis Upregulated and downregulated probesets were analyzed separately for pathway enrichment, using DAVID (Huang et al, Nucleic Acids Res 2009).
Pathway enrichment results were visualized using volcano plots, plotting either -log adjusted p values or untransformed adjusted p values versus enrichment scores for the pathways. For comparisons between branded GA and Polimunol, upregulated or downregulated probesets with FDR-adjusted p values < 0.05 and fold changes (FC) with absolute value greater than 1.2 were used for pathway enrichment. For comparisons between branded GA and mannitol, upregulated or downregulated probesets with FDR-adjusted p values < 0.05 and FC with absolute value greater than 2 were used for pathway enrichment. DAVID
runs were conducted in December 2014 and January 2015.
Human Monocyte Cell Line: Gene Expression Analysis THP-1 human monocytes (TIB-202) were purchased from ATCCC,. Cells were maintained in recommended RPMI-1640 media containing FCS, L-Glutamine, Sodium Pyruvate, D-Glucose, HEPES, and 2-mercaptoethanol at 37 C and 5% CO2. Prior to treatment cells were passed and plated in a 6-well plate at a concentration of 1.0 x 106 cells/mL. Cells were allowed to recover for four hours after passage (prior to treatment). Using a predetermined non toxic concentration the cells were spiked with 50pg/mL of either Copaxone , GA/RS, Escadra, Probioglat, and Natco, and 100pg/mL mannitol was spiked as a negative control (vehicle). Each sample was analyzed in six replicates. Cells were treated for 6, 12, and 24 hours. Following treatment time cells were lysed using a Qiagen based lysis kit. Prior to RNA isolation samples were randomized in order to avoid batch effect. Total RNA was isolated using Qiagen RNeasy kit. RNA quality was assessed by determining the absorbance ratio 260/280nm as well as electrophoresis bioanalyzer with 260/280 ratio of 1.9-2.1 and RIN of above 9 were deemed acceptable. Gene expression was measured using Affymetrix@ U133 plus 2.0 format. Sample processing was executed according to established manufacturer protocols. The scheme in (Fig. 2) illustrates the general experimental outline.

Human Monocyte Cell Line: RNA Isolation and Microarray Expression Profiling RNA from THP-1 cells was extracted and expression profiled across the entire genome using the Affymetrix Human Genome U133 Plus 2.0 chip, interrogating a total of over 47,000 transcripts. Four batches of Copaxone and one batch of Probioglat were comparatively tested .
in six biological replicates each. Key identified genes were independently evaluated for level of gene expression by quantitative Real-Time PCR of samples collected in the same experiments.
Methods for studies using MS patient data Patient studies utilized a subset of MS patients treated with Copaxone from FORTE clinical trial with time-series PBMC expression profiling.
Timepoints of 0, 1, 2, 3 months were used. The study included 9 patients for a total of 36 samples.
Repeated-measures ANOVA
ANOVA was run taking into account multiple timepoints from each patient. Variability within patients across timepoints was taken into account in the p value calculation.
gRT-PCR analysis Key genes identified by differential expression analysis were assayed using qRT-PCR. RNA was utilized from each of 6 biological samples for each treatment (Copaxone and Probioglat) and 15 technical replicates were performed for each sample (a total of 90 observations per transcript per treatment). Since three Copaxone batches and one Probioglat batch were available, a total of 360 observations from each transcript were evaluated. To evaluate the data, the 2-8 ct approximation was utilized with GAPDH as reference transcript and vehicle control (mannitol) as calibrator. A one-sided t-test with unequal variance was used to compare the RNA expression from the two treatments.

Human Monocyte Cell Line: Gene Expression Analysis - Polimunol versus Copaxone Gene Expression Studies Experimental design Cells from a human monocyte cell line (THP-1) were stimulated with either branded glatiramer acetate - Copaxone8, or the purported generic Polimunol, or vehicle control (mannitol) for 6 hours. RNA was extracted and expression profiled in a blinded fashion across the entire genome, using the Affymetrix Human Genome U133 Plus 2.0 chip, interrogating a total of over 47,000 transcripts. Three lots of Copaxone (148, 164, 166) and one lot of Polimunol (XBN) were comparatively tested in six replicates each. This entire experiment was performed independently twice, using an identical study design, reagents and compounds by the same technicians on two separate days;
resulting in twelve replicates total per condition.
A priori power analysis Using the R statistical package ssize.fdr, power calculations were performed to determine the number of samples needed to detect differentially expressed genes with a fold-change between treatments of as low as 1.3 with 80% power. Based on the results of these power calculations, the experiment was designed to include six replicates of each condition. The order in which the samples were processed was randomized with respect to treatment and stimulation time in order to avoid creating confounding batch effects.
Outlier identification and normalization Outlier samples were identified using the R package ArrayQCMetrics and excluded from further data processing ,steps. A sample was considered an outlier if it failed more than half of the included tests either before or after RMA normalization. Data were RMA
normalized using the Affy R package.
Batch correction Correction for batch variation was performed using ComBat (Johnson et al, Biostat, 2007), as implemented in the SVA R package (Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2013) sva: Surrogate Variable Analysis.
Available:
www.bioconductor.org/packages/release/bioc/html/sva.html). Briefly, ComBat is an empirical Bayesian approach utilizing location and scale metrics across several genes to adjust for batch effects in datasets, even datasets containing small sample sizes. Date of experiment was utilized as batch. Treatment labels were added as covariates to the batch correction in order to preserve relevant treatment effects.
Principal Component Analysis (a multivariate approach) showed that the main effect in the first principal component remained due to treatment effects after batch correction.
Treatment labels were added as covariates to the batch correction to preserve relevant treatment effects. Principal Component Analysis showed the main effect in PC1 remained due to treatment effects after batch correction (Figure 43).
Differential expression analysis Differentially expressed probesets were identified across conditions using linear models for microarray data (LIMMA; Smyth, G. K. (2004)), a standard R Bioconductor package. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Statistical Applications in Genetics and Molecular Biology 3, No. 1, Article 3). To compare Copaxone and a purported generic, comparisons were corrected to compare each treatment relative to mannitol control (e.g., [GA vs mannitol] was compared via LIMMA to [purported generic vs mannitol]). For use in pathway analyses, probesets were filtered by MASS calls of presence on the chip for the relevant samples in the comparison (e.g., to be considered present, a probeset was required to have on average a call of present or marginal across samples). An additional QC step was performed to remove probesets determined to be highly variable between multiple THP-1 datasets, as follows: a probeset was deemed highly variable if across three THP-1 studies to date, that probeset was observed to be upregulated, downregulated, and not modulated by Copaxone across the three studies. This criterion resulted in filtering out 216 probesets.
Probesets were mapped to genes using the annotation available for the U133 Plus 2.0 chip from Affymetrix. FDR adjusted p values reported for genes represent the lowest FDR adjusted p value for present probesets for that gene.
Pathway enrichment analysis Upregulated and downregulated probesets were analyzed separately for pathway enrichment, using DAVID (Huang et al, Nucleic Acids Res 2009).
Pathway enrichment results were visualized using volcano plots, plotting -log p values versus enrichment scores. For comparisons between Copaxone and Polimunol, upregulated or downregulated 10 probesets with FDR-adjusted p values < 0.05 and fold changes (FC) with absolute value greater than 1.1 were used for pathway enrichment. For comparisons between Copaxone and mannitol, upregulated or downregulated probesets with FDR-adjusted p values < 0.05 and FC with absolute value greater than 1.3 were used for pathway enrichment.
15 DAVID runs were conducted December 5 and 10, 2014.
Protein Concentrations THP-1 cells were activated with GA or Probioglat as described above.
The supernatant (1.0 mL of cell culture media) was collected at the 20 24 hour timepoint (to account for the time duration required for translation relative to the 6 hour mRNA data reported herein).
A Luminex assay was utilized to measure the concentrations of a panel of 45 chemokines and cytokines (in pg/ml) using Bio-Plex Human 25 Chemokine (Bio Rad kit) and Luminex Performance Assay (R&D kit). Three of the genes that were found to significantly differ between GA and Probioglat by qRT-PCR (CXCL10, MMP9, and CCL5/RANTES) had corresponding proteins present in the Luminex panel. In addition, two other genes that were found to differ significantly between GA and 30 Probioglat using the genome-wide microarray mRNA data were also present in the Luminex panel (CCL2, IL10).
To calculate the fold change between the protein expression levels with Probioglat and with GA, the values for the four GA batches were 35 averaged together and compared to the value for Probioglat (Probioglat expression level/ average GA expression level).

Primary Human Monocyte Study 50 mL of blood was obtained from a healthy donor, and CD14+ cells were separated from whole blood using magnetic beads (Miltenyi Biotech).
Purity was determined by FACS analysis using the following antibodies:
CD14, CD15, CD16, CD45 (BD Biosciences).
Into each plate of the 6 well plate 0.5mL containing 1.0x106 cells was added. In addition 0.5mL of either Copaxone, Probioglat (100pg/mL) or mannitol (200pg/mL) was added, total volume in each well was lmL. Final concentration of Copaxone and Probioglat was 50pg/mL and mannitol final concentration was 100pg/mL. Cells were incubated for 6 hours at 37 C at 5% CO2 followed by centrifugation to pellet the cells. The cell pellets were then processed using a Qiagen RNeasy RNA purification protocol.
Expression levels of nine genes were measured using RT-PCR with GAPDH
as reference transcript. Analyses reported compared Probioglat samples to GA samples as calibrator. Similar results were obtained when using mannitol as reference (i.e., the same set of genes were significantly upregulated in Probioglat relative to Copaxone). Differences in expression levels were evaluated for significance using one-sided t-tests with unequal variance.

Example 1 Analysis of Time-sensitive Modulation of Genes by Copaxone Treatment in THP-1 monocyte cell line Three time points were tested to identify the time point reflecting the greatest impact of treatment in each model system. Examining the number of genes modulated by Copaxone relative to the mannitol control, the 6 hour time point demonstrated the largest number of genes significantly modulated by Copaxone (6,890 with an FDR-adjusted p < 0.05), over 2-fold more than at 12 hours (3,118 with FDR-adjusted p < 0.05) and nearly 4-fold more than at 24 hours (1,791 with FDR-adjusted p < 0.05) (Table 1). Subsequent analyses focused on the 6 hour time point, as the time point reflected the greatest impact of treatment in this model system.
Table 1. Numbers of genes significantly modulated by GA treatment in THP-1 monocyte cell line at each timepoint 6 hr 12 hr 24 hr Up- Lown- Up- Down- Up-regulat regulat regulat regulat regulat Down-ed ed ed ed ed .
regulated nominal p < 0.05 FDR

p < 0.05 FDR
p < le-5, 257 119 68 10 15 0 IFCI>=1.

FDR
p < le-5, 557 508 210 50 57 6 IFCI>=1.

* FC - Fold Change; FDR - False Discovery Rate correction GA mechanism of action To gain insight into GA's MOA, the effect of GA treatment on THP-1 human monocytes was examined, since as discussed above, antigen-presenting cells in general, including monocytes in particular, have been shown to be involved in GA treatment effects (Weber et al., Nat.

Med. 2007; Kim et al, J. Immunol. Batim. Md. 2004; Burger et al., Proc. Natl. Acad. Sci. 2009; Smyth, Stat. Appl. Genet. Mol. Biol.
2004; Comi et al., Neurol. Barc. Spain 2002). In particular, the THP-1 cell line has been used to examine GA effects (Rizvi et al., Int.
J. Nanomedicine, 2006). In addition, genes associated with monocytes in particular have previously been shown to be differentially expressed following treatment with a purported generic marketed by Natco in India, as compared with Copaxone (Huang et al., Nucleic Acids Res. 2009).
mRNA expression levels were compared between GA and control (mannitol) tested with 6 sample replicates for each of 4 batches of GA and for mannitol, using LIMMA (Sim et al., Nat. Biotechnol. 2011) (Methods).
Many genes were modulated significantly (FDR-adjusted p-value<0.05) at each timepoint by treatment with branded GA (Table 1; Table 2 lists top modulated probesets). For example, at 6 hours of GA treatment, 2824 genes were significantly increased in expression (here termed upregulated) by FDR-adjusted p-value<0.05 (3511 genes by nominal p-value<0.05) and 4066 genes were significantly decreased in expression (here termed downregulated) by FDR-adjusted p-value<0.05 (4909 genes by nominal p-value<0.05). Fewer genes were significantly modulated as treatment time increased, with approximately half as many modulated at 12 hours, and approximately one-quarter at 24 hours (Table 1)..We chose 6h for initial downstream analysis since this timepoint reflects the greatest impact of treatment. Levels of GA persisted in the cell culture medium in the range of 44-52 pg/mL over 24 hours (Figure 3), indicates that this observation is unlikely to reflect a decrease in concentration of drug. Rather, this decrease in number of genes affected from early to later timepoints represents an attribute of the response of the cells to the drug.
GA impacts expression most pronouncedly at 6h (Table 2). The use of this early timepoint may also be biologically relevant given that GA is thought to be rapidly degraded at the injection site, eventually without measurable blood levels (Vieira et al., J. Immunol. Baltim.
Md 1950, 2003; Thamilarasan et al., J. Neuroinflammation 2013; Comi et al, Neurol 2002, Rizvi et al, Int J Nanomed 2006).

The differentially expressed genes included several anti-inflammatory genes. For instance, IL10, the gene encoding the anti-inflammatory cytokine IL-10, was increased in expression (upregulated) at the 6 hour timepoint (FDR adjusted p value 3.1e-9; fold change (FC) 1.52;
Fig. 4a). Expression of IL1RN, encoding IL-bra, a protein that inhibits the activities of the pro-inflammatory cytokines IL-la and IL-lb, was increased (upregulated) at all three timepoints. Fig. 4b-d shows the 6h timepoint for all present probesets (FDR adjusted p values 6.7e-16, 1.7e-10, and 1.2e-9, and FC 1.43, 1.35, and 1.26, respectively).
To determine whether the differentially-expressed genes related to one another in a coordinated fashion, top significantly up- and down-regulated genes were examined for pathway enrichment using DAVID as described in Methods (Figure 5; Table 5). The top genes significantly upregulated by Copaxone in the human THP-1 cell line at 6 hours of treatment were enriched significantly (by Benjamini corrected p value < 0.05) for 114 pathways (Table 5), including many immune-related pathways (Figure 5). For example, the regulation of immune system process (GO:0002682) and cytokine-cytokine receptor interaction (hsa04060) pathways were both significantly enriched among the top upregulated genes. The top upregulated genes identified as members of the cytokine-cytokine receptor interaction pathway (hsa04060) are shown in Figure 6. In addition, 9 pathways were significantly enriched among genes downregulated by GA (Table 5).

Table 2. Human monocyte study: probesets significantly modulated by Copaxone relative to mannitol at 6 hours, subject to fold-change and adjusted p value filters of 1.5 and le-5 Upregulated:
ID Gene raw.FC AveExpr P_Value a dj.P_Val 201005_at CD9 327232321 10.8126963 1.14E-34 6.23E-30 206835_at STATH 752573433 10.4825707 1.00E-33 2.74E-29 1553982 a_at RAB7B 226468475 11.7452289 242871_at PAGR5 3.9374814 9.90015385 7.51E-31 1.01E-26 1555759_a_at CCL5 2.21501539 13.5769189 9.21E-31 1.01E-26 226766_at 23291844 10.5559717 3.35E-30 3.06E-26 209555 s_at C036 2A4281389 9.32514677 7.64E-29 5.66E-25 203939_at NT5E 5.3338766 8.32269063 829E-29 5.66E-25 208789_at PTRF 232016222 9.15275301 138E-28 1.14E-24, 230266_at RA878 2.23824891 11.7520076 2.34E-28 1_28E-24 206488_s_at CD36 2.15872949 10.6868374 3.67E-28 1.83E-24 208121_s at PTPRO 224699192 9.61795145 430E-28 1_96E-24.
203037_s_at MTSS1 3.1658517 11.4020576 739E-28 3.32E-24 1405 Lat CCL5 229122708 133028093 229E-27 1.06E-23 204655_at CCL5 225036905 13.1626051 2_90E-27 1_06E-23 206171_at ADDRA3 2.10036549 10.0753041 3.42E-27 1.17E-23 219386_s_at SLAM F8 2_98872777 10.0302719 3_80E-27 1.22E-23 226218_at 330148157 7.21345525 1.83E-26 555E-23 218559_s_at MAFB 2.64025573 12.4234341 3.40E-26 9.78E-23, 223125_s_at C1ORF21 221866076 11.0023707 4.15E-26 1.13E-22 203887_s_at TH BD 1.79337816 12.8191102 4.45E-26 1.15E-22 227265 at KIAA1505 230321069 935031558 4.61E-26 1.15E-22 205495_s_at GNLY 2A0116081 7_73128126 5.34E-26 1.27E-22 216250_s_at LPXN 21444933 11.2374219 1.42E-25 3.23E-22 237252 at TH BD 2.06547107 951011605 212E-25 4.86E-22 235457_at MAML2 2.62488399 8.91497905 5.79E-25 1_22E-21.
225171_at ARHGAP18 1.83225951 10.7080346 6.66E-25 1.35E-21 204684_at NPTX1 2.87807656 10.9346668 1.40E-24 2.74E-21 230925_at AI:43811P 134283823 122655513 232E-24 3.81E-21 201590 x_at ANXA2 1.68959054 13_1436175 3.46E-24 6.31E-21 206157_at PTX3 138670615 11.2102165 3.62E-24 638E-21 216080_s_at FADS3 227239911 9.71739825 3.75E-24 639E-21 221463_at CCL24 3.58807723 8.40481021 3.93E-24 539E-21 210427 x_at ANXA2 1.67415609 13.1118777 3.98E-24 6.39E-21 213503_x_at ANXA2 1_72399354 13.1135447 4.18E-24 6.51E-21 238681_at GDPD1 2.92185146 7.19901556 4.29E-24 6.51E-21 202458_at PRSS23 2.98100135 7.79000143 5.03E-24 7.43E-21 203761_at SLA 1.78030673 11.2608124 632E-24 9.38E-21, 1558397_at 2.20691751 9_17869031 8.35E-24 1.17E-20 ID Gene raw.FC AveExpr P.Value adj.P.Vai 214054_at 00K2 L67191836 121431311 8.80E-24 1.20E-20.
228937_at C13011F31 2_42816683 9.90878354 9.66E-24 129E-20.
211676 s_at IFNGR1 1.64276331 12.0995889 1.08E-23 1.41E-20.
230966_at I L411 3_68319718 10.6065738 1_18E-23 1.50E-20 208816 x_at ANXA2P2 1_61606927 113007732 1,33E-23 1.66E-20, 204912_at ILIORA L88097974 10.4596073 1.53E-23 1.83E-20, 220014_at L0051334 , 3.95258058 6.49298277 134E-23 1.83E-20, 218156 at TNFRSF21 1.97277863 11.9973199 2.06E-23 2.40E-20.
34210_at C052 1.74841624 11.3194919 2.57E-23 2.92E-20.
211564 s_at PDL1M4 2_13518707 9.68326105 2_72E-23 3.03E-20.
223502_s at TNFSF138 1.73530598 10.5512407 2.94E-23 3.21E-20, 202727_s_at IFNGR1 1.5463282 12.4669611 3.25E-23 3.48E-20, 201243_s at ATP1 B1 216738679 11.039008 4.33E-23 4.56E-20 209606_at PSCDBP 2.53767762 8.05776375 4.93E-23 5.08E-20 222670_s_at NIAFB 2.65652588 11.7521547 6.27E-23 6.35E-20.
223394 at SERTAD1 1_65031524 9_76915308 6.91E-23 6.87E-20, 214175_x_at PDL1M4 1.85137891 9.80931564 8.66E-23 8.45E-20, 223660_at ADORA3 1.89720977 9.3830598 9.01E-23 8.64E-20.
203217_s_at ST3GAL5 1_78903169 9.10901818 3_17E-22 1.11E-19, 204257_at FADS3 1_78672893 9.74459459 1.23E-22 1.14E-19_ 223398_at C90RF89 134418891 11.0771528 1.25E-22 1.14E-19.
211986_at ANNAK 1.64967948 12.0209047 163E-22 1.45E-19.
201278_at DAB2 136823308 9.36397364 1.64E-22 1.45E-19.
229797_at MCOLN3 2.09980647 10.05118 2.01E-22 1.75E-19.
202284_s_at CDKN1A 1_789083 1L1500265 2.69E-228579_at 1.73158064 8.85026747 140E-22 2.78E-19.
204653_at TFAP2A 1.98518712 832878609 5.70E-22 4.39E-19 201952_at ALCAM 132577304 12_9059918 6_14E-22 4.66E-19 202087_s_at CTSL 1.91284953 11.1924209 6.47E-22 4.84E-19 208978 at CR1P2 1.99640335 10.1060568 6.82E-22 5.04E-19.
219434_at TREM1 1.77683606 11.1148543 6.95E-22 5_07E-19, 235911_at MF12 131455526 10.1578351 7.75E-22 5.57E-19.
225173_at ARHGAP18 1.85956949 10.0159515 7_95E-22 5.65E-19.
204661_at C052 1.6752998 11.8608.631 9.08E-22 6.28E-19, 202756_s_at G PC1 1.88792383 8.93231998 9.08E-22 6.28E-19 227240_at NGEF 1.97393626 9.35225393 9.96E-22 6.66E-19 220484_at MCOLN3 2.10889009 9.93061659 9.98E-22 6.66E-19 214297_at CSPG4 1_98668454 8.74794884 9_99E-22 6.66E-19 203355_s_at PSD3 1.68707305 9.97354098 1.13E-21 7.47E-19 212386_at 1.80977269 8.4443852 L22E-21 7.91E-19, 201242_s_at _ATP1131 2.36020561 10_833866 1.62E-21 1.03E-18 203760_s_at SLA 1.76467647 10.2984296 1.71E-21 1.07E-18 ID Gene raw_FC AveExpr P _Value adj.P.Val .
204475_at MMP1 4.89045646 6.14908101 1.97E-21 1.21E-18 228964_at PRDM1 2_42316104 9.16116313 2_05E-21 1.24E-18 .
205566 at ABHD2 161609464 936280738 2_12E-21 1.27E-18 224990Lat L0C201895 1.75486717 9.56572435 2.15E-21 1.28E-18 214830_at 51C38A6 1_70065597 9.60777602 2.38E-21 1.38E-18 222876 sat CENTA2 1_62337809 9.52111995 3_45E-21 1.92E-18 218501 at ARHGEF3 1.72054917 9.02047119 3.66E-21 2.02E-18 .
206134_at ADAMDEC1 1_90734854 8.46538539 3.83E-21 2.10E-18 219385_at SLAM F8 2.3601546 8.87175449 4.64E-21 2.49E-18 212298_at NRP1 2.26706147 9.0154209 5.27E-21 2.77E-18 .
1556314 a_at - 1_94563197 9.96244884 197E-21 3.05E-18 204834_at FGL2 2.41220628 9.04212862 7.43E-21 3.63E-18 227052_at -- 1.7292497 9.65138189 8.49E-21 4.11E-18 223501_at - L77755998 10.4775991 938E-21 4_59E-18 238669_at PTGS1 1.79526928 9.00713066 1.52E-20 7.11E-18 203936_s_at MMP9 1.83742157 9.54268719 2_01E-20 9.33E-18 205128_x_at PTG51 1.50682893 10_8982825 2_46E-20 1_12E-17 223019_at C90R F88 1.71440506 9.42451447 2.48E-20 1.12E-17 , 213223_s_at PLEKHO1 1_76062083 9.13759715 2.55E-20 114E-17 .
226545_at C0109 122747108 10.1210564 2_62E-20 1_17E-17 37145_at GNLY 2.52474166 7.62618078 2.77E-20 1.21E-17 21166/ x_at PTAFR L65459655 9.40348625 320E-20 1.39E-17 223434_at GBP3 1.79281477 8.94069901 5.65E-20 2.39E-17 221011_s_at LE1H /1/ L00653743 2.14546482 731354368 6,67E-20 2.79E-17 .
227478_at L0C284262 2.55523487 8.16720299 7.57E-20 3.09E-17 205933_at SETBP1 2.06852059 831470678 9_65E-20 3.38E-17 223126_s_at C1ORF21 2.0098249 9.34926366 1_00E-19 3.99E-17 214255_at ATP10A 1_87404352 8.48741153 117E-19 4.64E-17 203888_at TH BD 1.74251135 12.1003768 132E-19 5.18E-17 239761_at GCNT1 1.60737016 9_89061934 1.78E-19 6.90E-17 .
205505_at GCNT1 1.68341734 9.51667582 1.80E-19 6.93E-17 203665_at HM OX1 2.77855009 12.0276078 1.83E-19 7.00E-17 228490_at ABHD2 1.7612845 9.44137483 L92E-19 7.27E-17 213428_s_at CO L641 1.6365876 921385826 2.21E-19 8.27E-17 202748_at GBP2 2.05214857 8.5030424 2.71E-19 1.01E-16 .
63825_at A61102 1.60237791 9_12592031 3_53E-19 1.28E-16 .
205542_at STEAP1 1.7513289 7.91561507 4.15E-19 1.49E-16 215813_s_at PTGS1 131668643 10.9189252 4.31E-19 1.53E-16 205891_at ADORA2E1 . 1.56662939 10.2505629 4_70E-19 1.66E-16 218613_at L00653754 1.55398123 9_29556045 4.95E-19 1.73E-16 205076_s_at MTMR11 139326395 112341764 5_05E-19 1_76E-16 212086_x_at .LM NA 130357006 12.1481348 114E-19 1.78E-16 ID Gene raw.FC Ave Exp r P.Value adj.P.Val 203104_at CSF1R 1.64383545 11.9446038 5.33E-19 1.83E-16 228368_at A RHGAP20 2.23117651 8.70947261 5.37E-19 1.84E-16 227889 at AYTU 159282395 10.8879284 5.43E-19 1.848-16 203797 at VSNL1 1.7623632 9.20419419 5.45E-19 1.84E-16 210145_at PLA2G4A 1.69920287 9.86166848 5.50E-19 1.846-16 220307_at CD244 1.51030196 11/887381 6.64E-19 2.20E-16 201280 s_at DAB2 16207775 8.250618 7.03E-19 205898_at CX3CR1 1.5334422 123392251 7.53E-19 2.45E-16 212171_x at VEGF 1.67886192 11.082533 8.08E-19 2.61E-16 205419_at E812 1.87963971 10.3117587 &24E-19 2.64E-16 242794_at MAML3 1.71070972 8.2000023 &71E-19 2.76E-16 1553141_at C130RF31 2.23957531 8.21534882 9.28E-19 2.90E-16 1556034 s_at NITMR11 1_54656669 10.734173 9.32E-19 2.90E-16 202436_s_at CYP1B1 2.02651623 1L7446834 1.35E-18 4.08E-16 205718_at 1TGB7 1.61859456 10.0388412 164E-18 4.92E-16 222062 at I L27RA 1.84145262 8.80213383 1.77E-18 5.26E-16 1565752_at FGD2 2.03973925 8.7032554 180E-18 5.32E-16 203140 at 5C16 1.6321005 9.84693758 188E-18 5.54E-16 209568_s_at RG Ll 1.79068455 9.03375054 2_04E-18 5.92E-16 212977 at C.XCR7 1.95857569 9_06724806 2_73E-18 7.74E-16 225809_at DKFZP56400823 2.61498482 6.81686381 3.21E-18 8.90E-16 223723_at M F12 1.83918768 7.73004392 3.45E-18 9.44E-16 204141 at -TUBB2A 1.92837874 7.9645182 3.55E-18 9.72E-16 219358_s_at CENTA2 1.61743685 103689956 3.67E-18 9.97E-16 218280 x_at H1ST2H2AA L0C653610/1/H2A/R 1.92645343 111017962 3.91E-18 1.05E-15 200884 at CKB 1.62119168 103585418 3.91E-18 1056-15 213265_at PGA5 LOC643834 /1/ L00643847 1.54256466 9.03735387 4.18E-18 1.12E-15 228499_at PFKFB4 1.54265427 8.78361163 4.58E-18 1.22E-15 214581 x_at INFRSF21 1.96726151 103862452 5.13E-18 1.35E-15 219256_s_at SH3TC1 1.81711933 8.14371592 5.59E-18 1.46E-15 227134_at SYTU 1.63431503 10/085878 5.74E-18 1.50E-15 210512 s at VEGF 1.61269337 121528461 5.88E-18 1.52E-15 220066_at CARD15 1.63208119 8.81134661 6.12E-18 1.58E-15 207610 s_at EMR2 1.96904599 7.45239164 6.31E-18 1.62E-15 225337 at A6HD2 1.52226303 10.585684 6.47E-18 1.65E-15 1553906_s_at FGD2 136817402 11.6738144 R I
9E-18 2.05E-15 210757 x_at DAB2 1.51596174 9.71603785 8.84E-18 2.22E-15 205306 x_at KM0 1.52538689 9.01246744 1.07E-17 2.64E-15 203980_at FABP4 2.44504844 7.91709543 L14E-17 2.81E-15 205798_at 1L7R 2.15224639 6.90018766 1.20E-17 2.94E-15 235299_at 2.92455443 6.38887226 1.23E-17 2.99E-15 201422_at I F130 133617841 121952 1.33E-17 3_23E-15 ID Gene raw_FC AveExpr P.Value adj.P.Val 201951_at A LCAM 136151412 11.2835836 1.36E-17 3.29E-15 219412_at RA1538 1.69022517 7.7984244 1_40E-17 3.36E-15 214290_5 at HIST2H2AANL0C653610/1/H2A/R 1_8793137 125116024 1.77E-17 4_19E-15 223092_4 ANKH 1.74621066 9_31182429 193E-17 4.53E-15 1552553_a_at CARD12 1.3300836 8.04038383 1.98E-17 4.61E-15 1565754 x_at FGD2 2.05302245 8.76658914 1.98E47 4_61E-15 1562475_at DKFZP68601327 1.84932663 8.38987825 2.25E-17 5_18E-15 202435_s at CYP151 196043252 11.8853309 2.26E-17 518E-15 222877_at NRP2 2.43002847 6.1162318 2.37E-17 5.41E-15 201125 s at TG85 1.55447321 9.61610321 2.48E-17 5.62E-15 204222 s at GUPR1 1.64989211 10.4691144 3.30E-17 7_31E-15 1553142_at C130RF31 2_72312753 7.05894337 3.42E-17 7.51E-15 201279_s at DAB2 1.51128632 9.36621678 3.53E-17 7.64E-15 203234 at UPP1 1.74587737 936780561 3_97E-17 3_52E-15 226136_at - 1.5023264 9.021618 4.37E-17 9.27E-15 206206_at CD180 1.61188665 9_82309399 6.95E-17 1.43E-14 212387_at -- 1.62401877 7.80816226 1.05E-16 2.07E-14 204268_4 S100A2 1.79310512 8.64238178 122E-16 2.38E-14 209122_at ADFP 1_61478632 13.4092966 1.23E-16 2_41E-14 219994_at AP13811P 1.87740546 9.6208094 1.42E-16 2.74E-14 210095_s at IGF13113 2.98798358 8.63072598 1.43E-16 2.74E-14 227948_at EGD4 1.62553487 7.73111329 154E-16 2.92E-14 243483_at TRPNI8 2.13837999 7.16652124 1.62E-16 3.04E-14 212062_at ATP9A 2.12888023 730745486 1.77E-16 3.29E-14 218502_s_at TRPS1 1.61387671 8.89822927 1.95E-16 3.60E-14 213891 s at - 1.67207935 8_30917084 2.03E-16 3_68E-14 200878_at EPAS1 131714595 9_20362299 2_04E-16 3.69E-14 201565_s at ID2 1_52829092 12.7810873 2.26E-16 4.06E-14 212190_at SERPINE2 1.92452066 9_90116936 2.57E-16 4.60E-14 224480_s at LPAAT-THETA 1_96245654 8.74709429 2.64E-16 4.67E-14 220333_at PAQR5 3.53344803 7.84174393 2.70E-16 4.76E-14 218589 at P2RY5 1_65149795 9.3651465 3.00E-16 5_23E-14 225166_at ARHGAP18 175622288 733398136 3.29E-16 5.64E-14 226066 at MITE 1.750697 7.87439597 3.35E-16 5.73E-14 221.211_s_at C210RF7 2.08949444 5.973895 3.41E-16 5.86E-14 225842 at PHIDA1 231724542 8.55236084 3.48E-16 5.89E-14 1554992_at RASGRE1 1.56735654 6.94135257 3.77E-16 6.35E-14 225097_at HIPK2 1_50753986 10.7130384 3.84E-16 6.45E-14 212464_s at FN1 1.70309888 9.26484812 4.53E-16 7.53E-14 240076_at - 13987436 8_40204375 4.66E-16 7.73E-14 203798_s_at VSNL1 1.91644457 7.87623269 4.84E-16 7.92E-14 204575_s_at MMP19/1/ L00652543 1.83367508 7_70439226 4.88E-16 7.96E-14 ID Gene raw.FC Ave Expr P.Va lue adj.P
.Va 1 204465 s_at INA L60147629 8.20221976 5.17E-16 8.36E-14 201566_x_at 1D2 /1/ 10213 137371123 10.7833858 5.52E-16 8.87E-14 230360_at GLDN 1.98086959 6.74193069 6.80E-16 1.07E-13 222146_s at TCF4 134556332 731472351 825E-16 1.28E-13 224341_x_at TI.R4 17396424 8.97197657 8.61E-16 1.32E-13 219637_at ARMC9 1.80286893 7.06720581 8E17E-16 1.35E-13 211138 s at KW) 1.54711526 3.79132849 9.12E-16 1.38E-13 202437_s_at CYP1B1 1.80921395 12.1893518 9.54E-16 1.43E-13 235458_at HAVCR2 2.48536941 7.7122454 9.75E-16 1.46E-13 203922_s_at CY813 1.58449815 103814577 1.07E-15 1.58E-13 212143_s at 1GF8P3 2.76854721 7.92968375 1_26E-15 1.82E-13 227716_at uants 1.51942114 9.002862 1.28E-15 1.83E-13 214211_at FTH1 1.55999567 12.4970466 1_33E-15 1.90E-13 229004 at 1.51039984 9.12368109 1.55E-15 218E-13 202609_at EP58 1.5924097 8.52061192 1.8.2.E-15 2.52E-13 217757 at A2M 1.67532065 8.4520092 1.98E-15 2.73E-13 1552798_a_at TLR4 1.62695353 9.04302518 2.09E-15 2.88E-13 57715_at FAM268 1.79873285 7.75582627 2_40E45 3.27E-13 226282_at 1.60485814 9.41013847 2.84E-15 3.80E-13 222838 at SLAMF7 1.86121844 7.05728625 3.11E-15 4_13E-13 216442_x_at FM 1.69780521 10.1409361 3.73E-15 4.87E-13 201324_at EMP1 2.82050293 6.11305975 3.81E-15 4_94E-13 210264 at GPR35 1.59109619 9_60072153 3.91E-15 5.05E-13 222858 s at DAPP1 1.6313133 10.6750257 4.54E-15 5.78E-13 209684 at R1N2 2.16288563 7.25953396 5.4-8E-15 6.84E-13 201069_at MMP2 1.51386957 8.69855532 6.09E-15 7.55E-13 204998 s at ATF5 1.63500149 10.6267979 6.14E-15 7.608-13 202434_s at CYP1131 2.2027314 9.83119314 6,94E-15 8.52E-13 205099 s_at CC:R1 1.57264838 9.76018397 7.25E-15 8.85E-13 207233 s at M 1TF 1.66865012 8.30250431 8.03E-15 9.72E-13 205552 s at DAS1 1.79452532 7.29881386 833E-15 1.02E-12 226550_at 1.79237731 7.77105086 9.20E-15 1.09E42 212096 s_at MTUS1 1.62315248 3.50418445 9.61E-15 1.13E-12 222651_5 at TRPS1 1.5940306 10.0878238 9.64E-15 1.13E-12 211719_x_at FN1 1.74293625 10.1007312 9.30E-15 1.15E-12 2276109_at EPST11 1.73531372 7.62913716 1.068-14 1.24E-12 1558105_a_at - 1.89855059 6_81046182 1.07E-14 1.25E-12 225207 at PDK4 2.24881528 8.76581849 1.0s8-14 1_25E42 237160_at CCDC83 2.26816884 5.8347316 1.15E-14 1.33E-12

21/026_s at MGU_ 1.80987658 8.99536888 1.33E-14 1.53E-12 229450_at 2.07979683 6.90012377 L42E-14 1.62E-12 215602_at FGD2 2.01984347 7.85983935 1.54E-14 1.74E-12 ID Gene raw_FC Ave Expr P.Value adj.P.Val 228708_at RA5278 175996236 85707E526 1.63E-14 183E-12 210258_at RGS13 2.4181722 5.06675503 1.77E-14 1.97E-12 210895_s at CD86 174036933 7.80363779 188E-14 2.07E-12 223672_at SGIP1 158033388 8.69396513 196E-14 2.141-12 210513_s at VEGF /62960752 9.66705476 2_08E-14 2.25E-12 212614_at ARID58 164330835 634592171 2.09E-14 2.26E-12 1553995_a_at NT5E 2_06345466 6.49987213 2.17E-14 2.32E-12 233540_s at CDK5RAP2 177928193 10.6899414 2.34E-14 2.48E-12 204059 s at ME1 178078662 11.5066468 2.46E-14 2_58E-12 211527_x_at VEGF 1.68079685 9.90807927 2.48E-14 2.60E-12 214724_at D0CDC1 155892061 7.67060007 2_63E-14 2.74E-12 227556_at NN1E7 2.07486651 9.31851129 2.92E-14 3.02E-12 237442_at AP13811P 1_97657406 7_17373032 3.09E-14 3.18E-12 224218_s_at TRPS1 1.52587932 8.15882094 338E-14 3.46E-12 225188 at RAPH1 1.90298066 6.31647018 3.68E-14 3.73E-12 244414_at MAML2 2.39160043 8_05798482 3.70E-14 3.74E-12 209906_at C3AR1 /62034968 8.32122922 3_73E-14 3.76E-12 210510_s at NRP1 1.56055098 73171434 3.77E-14 3.78E-12 226629_at SLC43A2 1_57641868 8_50211433 3.97E-14 3_94E-12 237030_at ACPP 1.53890938 8.05225501 4.15E-14 4.10E-12 213338_at ,TMEN4158 173773739 10.7585184 418E-14 4.13E-12 219926_at POPDC3 2.12181972 6.63647483 5.99E-14 5.68E-12 200897_5 at PALLD 1.64882729 8.35346573 6.07E-14 5.74E-12 208436 s at IRF7 155075885 8.74418094 6.34E-14 5.96E-12 228438_at TRPA1 , 165933581 10.3950157 6.81E-14 6.30E-12 227747_at - 1.55198677 7.93194342 6.84E-14 6.32E-12 1554867 a_at L0051334 1.86507425 7_40812044 6.90E-14 6.36E-12 1563445 x_at C7SLL3 182851184 6.84405898 9.09E-14 8.12E-12 242903_at IFNOR1 1.7678462 7.97757472 9.49E-14 8.42E-12 229900 at CD109 1.54089288 8.62103824 1.05E-13 9.24E-12 210495_x_at FN1 1.61505134 10.0973935 1.07E-13 9.43E-12 218854 at SART2 1_54263807 8_36626559 224989_at -- 1_78010467 7.75893731 1.17E-13 1.02E-11 233638_at SLC37A2 1.63842433 9_93438242 212382 at -- 1_60505834 7.06996616 1.35E-13 1.15E-11 209047 at AQP1 2_44653569 7.84720827 1.38E-13 1.17E-11 236345_at TB)LAS1 1.661360916 8.46774141 140E-13 1.18E-11 228873_at COL22A1 156093003 7.43196243 141E-13 1.19E-11 239519_at NRP1 2.19110297 5.55763801 1.43E-13 120E-11 220935_s at CDK5RAP2 184541222 10.4100106 1.54E-13 1.28E-11 1560228 at SNAI3 1_91948596 7.8146015 156E-13 1.30E-11 218934 s_at HSP137 , 1_65040526 8_10534113 2.40E-13 1901-11 ID Gene raw.FC AveExpr P.Value adj.P.Val 210146 x at LILRB2 13982938 6.76423766 2.86E-13 2_22E-11 209348 s_at MAP 136472875 8.72338323 3.17E-13 2.42E-11 1558569_at L00645238 135050375 7.56283286 3.25E-13 2.47E-11 243856 at 1.73115631 8.03640769 3.81E-13 2.86E-11 223798 at SLC41A2 1.94681117 634582797 3.90E-13 2_92E-11 215990 s_at BCL6 130671943 8.04953142 4.81E-13 352E-11 202869 at OAS1 1.63942747 6_73520018 530E-13 3.86E-11 225631 at KIAA1706 133753899 7.78142994 536E-13 4.03E-11 204116 at IL2RG 1.53970115 7.99806857 5.88E-13 4_22E-11 225189 s_at RAPH1 1.85367315 6.14549622 6.27E-13 4.47E-11 211066 x at PCDHGB2/j/PCDHGB111/ 138678656 10.4111947 7.90E-13 5.53E-11 PCDHGA11,111PCDHGA101//
PCDHGA9Ill PCDHGA7/1/ PCDHGA6 /j/ PCDHGA5 /11 PCDHGA4 ///
PCDHGA3 j1/PCDFIGA2 jjj PCDHGA1 221266 s_at TM7SF4 1.113671444 6.22762311 8.02E-13 5_60E41 1560485 at HIVEP 1 1.6480621 6.99003908 8.06E-13 5.62E-11 204881_s_at UGCG 1.5102382 9.51481557 8.38E-13 5.83E-11 235286 at CKLF 1.61741462 8_34288205 9.26E-13 6.36E-11 205003 at DOCK4 13112689 8/0388936 1.02E-12 6.92E-11 218686 s_at RHBDF1 131723286 7.92482272 1.05E42 7.08E-11

22/565 s_at FAM268 139642371 7.91366407 1.09E-12 7.32E-11 206675 s at SKIL 1.61042514 7.42083013 1.16E-12 739E-11 242358 at 2.20249712 6.04963315 1.24E-12 8.20E-11 241392 at TMEIVI39A 1.61384348 7.05009494 1.87E-12 1.19E-10 232333 at IVIAML2 1.68481156 8.01950459 2.06E-12 1.30E-10 228762 at LFNG 135190457 9.0403074 2.08E42 1_31E-10 242907 at GBP2 2_14738965 6.03707956 2.72E-12 1.64E-10 203753 at TCF4 130293239 7.66442858 2.78E-12 1_68E-10 207542_s_at AQP1 1.69421791 6.82177348 3.02E-12 1.81E-10 242157 at 137383098 8.76647265 3_26E-12 1.94E-10 204058 at ME1 1.73420796 931508263 333E-12 2.08E40 209921 at SLC7A11 1.94348494 919226579 3.63E-12 113E-10 211030 s at SLC6A6 131035569 737360007 3.78E-12 211E-10 209392 at ENPP2 1.82310668 5.23034508 4.76E-12 2.73E-10 243894 at SLC41A2 1.69547735 5.15085274 4.80E-12 2.75E-10 229937 x at ULRB1 138545389 7.41501062 5.00E-12 2.84E-10 214857 at C100RF95 1.60255368 7,13065345 5.02E-12 2.85E-10 230944 at MGC45491 135203348 7.47887362 5.53E-12 3.14E-10 228057_at 001141 1.68290143 9.61033195 6.99E-12 3.828-10 ID Gene raw.FC AveExpr P.Value adj_P_Val 204105 s_at NRCAM 2.27634648 6.95288228 7.49E-12 4.07E-10 205681 at 8CL2A1 1.64702983 930173198 8.19E-12 4.40E-10 242405_at MAML2 1.36052011 7.15057318 1.10E-11 5.73E-10 217678 at SLC7A11 1.75913555 8.8692241 122E-11 6.25E-10 211962_s at ZFP36L1 139912563 8.8232205 1.23E-11 617E-10 221060 s_at TLR4 153812487 8.81340284 2.27E-11 1.08E-09 200907_s at PALLD 1.50739688 7.44132987 2.28E-11 1.08E-09 223918 at SLC43A2 1.66364865 710166079 2.29E-11 1.09E-09 1555606 a_at GDPD1 1.51121338 6.61034166 239E-11 1.13E-09, 223450_at PLEKHA7 130941089 6.45253703 2.70E-11 1.26E-09 229221_at 160263592 839003199 4.03E-11 179E-09 229635 at L00643424 133074512 735215173 4.38E-11 1_94E-09 1569149 at , POLIM7 1.54849621 9.14969141 5.56E-11 2_41E-09 207433 at 1110 132400243 5.63708634 7.49E-11 3.14E-09 221815 at AB1-1D2 1.55904737 8.11542769, 1.01E-10 4.08E-09 203060_5 at PAPSS2 1.5764103 7.75963014 1.25E-10 4.94E-09 232746_at CXCR7 2.0719893- 6.54641126 1.43E-10 5.55E-09 1560960 at MOGA1 1.97885133 5_71541524 1.47E-10 5.70E-09 234645 at MAML2 1.87005824 633786268 1.72E-10 6.50E-09 223596 at SLC12A6 130709112 7_32492551 1.75E-10 6.60E-09 87100 at ABHD2 131939681 7.38326685 1.79E-10 6.75E-09 213931 at 1D2//110213 2.71874933 9.84931953 1.87E-10 7.02E-09 216874 at DKFZP68601327 170886875 5_93467446 244375 at EVL 136523772 7.93537524 2.24E-10 8.16E-09 1569150 x_at PDL1M7 1_54117409 937943359 2.24E-10 8.18E-09 214453 s at IF144 1.79674041 6.65852583 178E-10 9.87E-09 204999 s_at ATF5 1.64452594 9_14215678 PCDHGC4ifiPCDHGB711/ PCDHGB6 /ll PCDHGB5//7 PCDHGB3/1/
215336 s_at PCDHGB2M PCDHGB1/1/ 1.52441384 9.29079122 4.72E-10 160E-08 PCOHGA5 PCDHGA4 At/

208161 s_at ABCC3 1,61726316 8.40189868 5.05E-10 1.69E-08 202827_s at MMP14 1.62314882 10.2030389 5.39E-10, 1.78E-08 208712 at CCND1 13393933 7.40438263 6.16E-10 2.01E-OS
223939 at SUCNR1 137537424 8.40597144, 7.17E-10, 2.32E-08 205960 at P01(4 1.69465703 7_19094792 1.28E-09 3.84E-08 214841 at CM-t3 1.56253317 6.14111085 140E-09_ 4.15E-08 209993 at ABCB1 138407983 5.06380643 152E-09 4.48E-08 ID Gene raw.FC AveExpr P.Value adj.P.Val 1557938 s_at PTRF 1.50339198 6.8700736 1.62E-09 4.73E-08 232068 s_at TI.R4 1.74396268 6.76798691 184E-09 5.28E-08 242321_at 26662739 632856887 2.12E-09 5.99E-08 219574_at MARCH1 1.64000788 5.55000344 3.54E-09 9.43E-08 202638 s_at ICAM1 138753294 6.72394157 3.76E-09 9.97E-08 219496 at ANKRI357 130970429 7.47583744 4.86E-09 1.26E-07 1555756 a_at CLEC7A 1.65932872 7.0882743 5.25E-09 135E-07 241929 at CD36 1.82152709 332014251 5.66E-09 1_44E-07 1556423 at VASH1 135220936 7.02874938 8.01E-09 197E-07 229435_at CLIS3 1.5824943 4.92660385 8.07E-09 1.98E-07 217997 at PHLDA1 201871208 7.37991533 8.18E-09 2.00E-07 235944-at HMCN1 151434592 7331681 9.15E-03 2.21E-07 206637 at P2RY14 1.69022854 4.58701985 9.57E-G9 2.30E-07 213293 s_at TRIN122 1.54165851 6.59931282 9.57E-09 2.30E-07 238581 at GBP5 137383447 7.67594481 1.03E-08 246E-07 1558404 at L00650429 1.85121181 5.31545142 1.46E-08 335E-07 230559 x_at FGD4 1.51987215 5.45151267 1.69E-08 3.83E-07 1553151 at ATP6V0D2 152950999 6.78084809 1.69E-08 3.84E-07 1554285 at HAVCR2 1.64907555 7.49492704 3.00E-08 638E-07 244579 at TRPS1 1.5354261 3.45494277 5.93E-08 1.16E-06 228640 at 1.5809974 4581012.32 7.52E-08 1.43E-06 210004 at OLR1 139400178 5.25939608 8.40E-08 158E-06 243556 at NGEF 150840974 6.73352627 1.18E-07 2.14E-06 210360 s_at N1TSS1 1.7452905 6.18923946 1_40E-07 2.49E-06 217999 s at PHLDA1 1.73310668 6.08679858 2.07E-07 3.52E-06 227'4362 at TNCRNA 156840333 10.0441571 218E-07 3.69E-06 237904 at ADORA3 132521897 6.15098521 2.49E-07 4.15E-06 1563621 at K1AA1706 1.55572929 7.60284745 6.48E-07 9.74E-06 Downregulated:
ID Gene raw.FC AveExpr P.Value adj.P.VaI
207725 at P0U4F2 -2.8001105 9.19852692 2.12E-22 1.81E-19 212993 at -12809512 9.86599984 2.25E-22 1.89E-19 211421 s at RET -20125505 936968529 3.53E-22 2.84E-19 227899 at vrr -1.8754322 7.70929876 4.25E-22 336E-19 225224 at C200RF112 -2_04379 8.5964785 1.37E-21 8.79E-19 213361 at TDRD7 -1.8486643 10_2732718 2.93E-21 1.67E-18 214539 at SERPINI310 -2.1313083 8.01802953 3.16E-21 1.78E-18 235275 at OXCT2 -2.0229254 12A009174 4.06E-21 2_20E-18 203685 at &C12 -2.3112793 8.44431889 4.88E-21 2.59E-18 227037 at 10C201164 -1.5468442 9.38990462 5.65E-21 2.94E-18 219714 s_at CACNA2D3 -2.206206 9.82724428 5.72E-21 2.95E-18 206643 at HAL -13307917 928853464 6.18E-21 3.10E-18 TRG C2 TRGV2 fll TRGV9 /1/ TARP
211144 x at -13748474 10.586818 7.12E-21 3.54E-18 217521 at -1.7887534 8.38380263 7.38E-21 3.63E-18 208206 s_at RASGRP2 -1.9706562 9_9264082 1.25E-20 5.95E-18 228977 at 11.17D -2_1132305 731309566 119E-20 1.01E-17 209813 x at -1.6036338 10.7697475 3.87E-20 1.65E-17 filLOC642083 204614 at SERPINB2 -2.3610663 108353035 6.10E-20 2.57E-17 212110 at SLC.39A14 -1.682778 10.5673949 7.23E-20 3.00E-17 202444 s_at SPFH1 -1.8415073 9_34800962 7.37E-20 3.03E-17 2/6920 s_at 08 -1.5704575 11.3491957 8.78E-20 3_56E-17 202441 at SPFH1 -1.6532676 11.1411892 1.45E-19 5.66E-17 211919 s_at CXCR4 -15387599 11.0738986 3.40E-19 125E-16 204610 s at CCDC85B -1.729942 9.65009386 6.61E-19 2.20E-16 200999_s_at OCAP4 -1.6192.589 115934013 8.23E-19 2.64E-16 207865 s_at BMP8B -2.145585 9_11410521 9.38E-19 2_90E-16 217028 at CXCR4 -13274428 113438714 1.14E-18 3.50E-16 201968 s_at PGM1 -1.5051483 9.06546368 2.12E-18 6.10E-16 219463 at C200RF103 -1_5731957 10.0186106 235E-18 7.26E-16 212242 at TU BA1 -1.5626324 11.2879097 2.82E-18 7.96E-16 213484 at -1.5736546 8.53538561 3.16E-18 8.83E-16 209201 x at CXCR4 -1.5448129 11.1194624 3.16E-18 8.83E-16 218858 at DEPDC6 -1.7866919 735045943 5.06E-18 1.34E-15 202236_s_at SLC16A1 -13384699 10.1675739 9.26E-18 2_30E-15 208158 s at OSBPL1A -16142678 8.3746552 1.71E-17 4.06E-1.5 202932 at YES1 -1.6455703 8.57014581 2.47E-17 5.62E-15 243209 at KCNQ4 -2.2463943 6.9665965 2.56E-17 5.79E-15 215806 x at -13328764 110634752 331E-17 7.61E-15 ID Gene raw.FC AveExpr P_Value 204521 at C120RF24 -1.5676281 10.1844282 3.88E-17 8.36E-15 204301 at KBTBD11 -1.5574513 10.253905 4.37E-17 9.27E-15 227920_at KIAA1553 -1.6307063 8.01525239 5.17E-17 1.09E-14 218251 at M1011P1 -1559714 9.78570246 5.29E-17 1.11E-14 212646 at RFTN1 -1.658315 837843565 538E-17 1.12E-14 222799 at HSPC049 -1.5489442 8.60085628 1.10E-16 2.17E-14 227103 s at MGC2408 -1381709 8_7267591 1.30E-16 2.51E-14 206067 s_at WT1 -1_511783 9.85618462 1.37E-16 2.66E-14 214369_s_at RASGRP2 -1.5806582 9.41805033 1.69E-16 3.15E-14 206589 at GF11 -1.5996464 11_7281473 1.99E-16 3.65E-14 225619 at &Al N1 -22453839 7.41012008 2.01E-16 3.68E-14 212660 at P1-1F15 -1.69531 8.00752875 2.63E-16 4.66E-14 218971 s_at HSP0349 -1.5087203 9.12721477 3.08E-16 5.33E-14 201690 s at 1P052 -1.5492402 9.27038373 3.25E-16 5.59E-14 229638 at RX3 -1.5570492 11.8844594 3_38E-16 5.76E-14 223062 s_at PSAT1 -1.556602 9.43823571 4.70E-16 7.77E-14 225510 at OAF -1.6632727 10.1142626 6.67E-16 1.05E-13 209485 s_at OSE1P11A -13049308 8.36910929 7.34E-16 1_15E-13 204432 at S0X12 -1.7584476 6.5781916 8.71E-16 1.33E-13 205768 s_at SLC27A2 -1.6303006 7.69181894 8.98E-16 1.36E-13 211576 s_at SLC19A1 -13339487 9.8247482 9_81E-16 1.46E-13 201688 s_at TPD52 -1.6048433 8.55393713 9.93E-16 1_48E-13 50314 i at C200RF27 -1.561172 9.67877203 1.14E-15 1.66E-13 /553436_at IVILIC19 -164037 7_99717726 1.18E-15 1.71E-13 202800 at SI.C1A3 -13176496 8_18097955 1_51E-15 2.13E-13 41037 at TEAD4 -1.6405647 631029525 1.70E-15 2.36E-13 216953 s_at WT1 -13276508 7.76890727 2.15E-15 2.95E-13 228055 at NAPSB -13385754 1(11648177 2.61E-15 3.52E-13 218424 s at STEAP3 -1_7692882 73802R012 2.78E-15 3.74E-13 212855_at DCUN104 -1.508562 7.38887861 2.92E-15 3.90E-13 202933 s_at YES1 -1.5437793 9.12374841 3.76E-15 4.89E-13 1553138_a_at ANKRD41 -2.0146608 6_96935627 6_26E-15 7.73E-13 227242 s_at EBF3 -13363477 4.86769268 8.15E-15 9.84E-13 237265 at C160RF73 -1_5296704 9_74165113 9.60E-15 1.13E-12 213478 at KIAA1026 -1.8330762 7_39399329 1_16E-14 134E-12 225081_s_at CDCA71 -13491727 10.2951966 1.46E-14 1.66E-12 211299 s at FLOT2 -1.6145204 9.10864173 1.58E-14 1.79E-12 213568 at OSR2 -22462672 539962469 1.64E14 1.83E-12 227662_at SYNP02 -L5973696 8.52811124 1.76E-14 1.96E-12 200998 s at CKAP4 -1.6910951 9.77491302 2.08E-14 2_25E-12 209900 s at SLC16A1 -1.5885969 7.84437981 2.30E-14 2_43E-12 229084 at CNTN4 -13415136 7.72735571 2.30E14 2.43E-12 238694 at -1.5762461 7.26420148 338E14 3.46E-12 1555788 a_at TRIB3 -1_5022329 9.92495817 3.64E-14 3.70E-12 221900 at COLBA2 -1.5627579 101358313 4_09E-14 4.05E-12 225016 at APCDD1 -13872345 6_47036912 4_21E-14 4.14E-12 ID Gene raw.FC AveExpr P.Value adj.P_Val 225768 at NR1D2 -17351352 6.8044854 5.44E-14 5.24E-12 222095 s_at C10RF76 -17301956 7.38672115 6.40E-14 6.00E-12 229103 at WNT3 -17749895 5.55503782 7.978-14 7.218-12 205769 at SLC27A2 -13824201 7.67753108 153E-13 1.27E-11 201689 s_at TPD52 -1.645479 8_12663653 1.59E-13 1.31E-11 201350 at FLOT2 -1.5079906 11.0344.892 2.08E-13 1.68E-11 221648 s_at C1ORF121 -1517313 8.36815023 2.55E-13 2.00E-11 206078 s_at SNF111( -1397736 7.64505173 2.81E-13 2.18E-11 1562484_at FLI35848 -1.9050209 6.65405977 3.15E-13 2.41E-11 1555370 a_at CAMTA1 -1.7040191 5_36041757 3.26E-13 2.47E-11 218376 s at IvlICAL1 -13055354 11194367 3.44E-13 2.61E-11 204567_s_at A8CG1 -12330717 5.8226155 331E-13 2.66E-11 39966 at CSPG5 -1.5105172 7.68266153 4.12E-13 3.07E-11 218326_s_at LGR4 -1.696564 6.525917 5.28E-13 3.85E-11 212430_at RBM38 -13884137 8_88476901 5.78E-13 4.17E-11 227236 at TSPAN2 -13695047 6_96434119 7_37E-13 5.19E-11 204794 at DUSP2 -1.5957268 8.45706393 7.96E-13 5.57E-11 230888_at 1-15PC049 -1377802 7_20584208 9.14E-13 6.29E-11 212097_at CAV1 -1.66281331 739130877 9.63E-13 6.57E-11 209353 s_at C1ORF76 -17131519 7.30778535 1.02E-12 6.92E-U
201801 s at SLC29A1 -16246978 8.73200653 1.05E-12 7.08E-11 2/0279 at GPR18 -15350315 8.98079125 1.29E-12 8.49E-11 52651 at C012A2 -1.577706 9.9516637 1.318-12 8.57E-11 235758 at PNIVIA6A -1.5784572 7.8E091427 1.34E-12 8.77E-11 222162_s_at ADANITSI -1.842254 6.45805339 1_37E-12 8.95E-11 209369 at ANX.A3 -13449323 5_34631362 1.41E-12 9.18E-11 219911 s_at SLCO4A1 -15143987 8_17455361 130E-12 9.71E-11 1557919_a_at 100648232 -13028156 123466869 1338-12 1.11E-10 219497 s_at BCL11A -13825853 9_14635109 165E-12 1.18E-10 232271 at HNF4G -15978388 7.3715225 2.04E-12 1.29E-10 206653_at -1.5611734 6.70426513 2_13E-12 133E-10 225782 at WISRB3 -13020089 8.17316381 2.54E-12 1.55E-10 223704 s_at DIV1RT2 -1.6370445 6.61601092 5.67E-12 3.20E-10 1558613 at OAF -1.5776535 73183993 6.15E-12 3.44E-10 1555434 a_at SLC39A14 -13483414 7.91388969 6.53E-12 3.65E-10 1556194 a_at - -1.7264827 7.80933003 1_10E-11 5.73E-10 219304_s at PDGFD -1.5313053 8.14849618 1.10E-11 5_73E-10 200894 s at FKBP4 -1_6280907 8.06454238 1.28E-11 6.49E-10 210347_s_at KUM -13419237 7.82101671 1.36E-11 6.85E-10 221249 s art FAN1117A -13920148 8_42643515 1.45E-1.1 7.21E-10 239410 at -3 R21547 6.86497836 1.72E-11 8.468-10 206039 at RA833A -1_5487461 8.65562976 2.20E-11 1.05E-09 1554660_a_at C1ORF71 -1.5203911 7_61313106 2.54E41 1.19E-09 209776_s_at SLC19A1 -15451778 7.72495148 2.90E-11 1.34E-69 1560495_at - -16478409 7.28259363 3.01E-11 1.388-09 ID Gene raw.FC AveExpr P.Value adj.P.Val 202234 s_at SLC16A1 -1.5891823 736240785 4.97E-11 2.16E-09 207768 at EGRA -2166679 5.08097601 7.18E-11 3.02E-09 207717 s at PILP2 -1.5155863 43970225 1.26E-10 4.97E-09 213912 at K1AA0984 -13617265 6.49154577 1.30E-10 5.13E-09 222891_s at SCU1% -1_5929549 8.42933212 2.00E-10 7_44E-09 213268_at CAMTA1 -1.7460973 5.75010725 2.03E-10 7.52E-09 232007_at -1.5199738 9.70608088 2.60E-10 9.33E-09 227099 s at L0C387763 -13087957 6.4279952 2.97E-10 1.05E-08 232614 at BCL2 -1.6221488 7.30276639 2_99E-10 1.05E-08 222668_at KCTD15 -1.5400712 5.79509816 213610 s at 1(11-1123 -13730988 7.2326013 4.60E-10 1.56E-08 206935 at PCDH8 -1.6992238 5.66380311 6.65E-10 2.16E-08 203708 at P0E48 -1.5144333 7.44164625 8.10E-10 2.59E-08 1554298 a_at WDR49 -1.5642625 6.77053726 8.63E-10 2.73E-08 212558 at SPRY1 -1.6087624 5.95823849 1.41E-09 418E-08 242509 at C160RF74 -13318238 6.48465026 221E09 6.20E-08 201939_at P1.1(2 -1.5317787 7.43694303 5.43E-09 1.39E-07 242245_at SYDE2 -1_5851454 4.93022084 5.57E-09 1.42E-07 204557_s at DZ1P1 -1.5326546 5.01217049 5.85E-09 1.48E-07 204875 s at MIMS -17607496 6.33236847 9.81E-09 2.35E-07 204285 s at PIVTAIP1 -1.7424137 10_9563243 1.15E-08 2.73E-07 213046_at CEBPD -19902998 8_08295825 1.47E-03 3.38E-07 1554830 a_at STEAP3 -1.6156641 5.65856155 2.19E-08 4.84E-07 204286_s_at PMAIP1 -1.7353429 9.45448346 6.05E-08 118E-06 228325_at K1AA0146 -1.8819676 836526925 831E-08 1.57E-06 1569377 at TIVIOM67 -1.9524092 4.4888277 1.11E-07 2.04E-06 242892 at PER2 -2.1304461 6.97699912 1.72E-07 3.00E-06 1555847 a_at _.1_00284454 -2_1798177 938866319 1.88E-07 3.24E-06 Discussion - Example 1 The significant gene-expression changes observed in the human THP -1 cell line due to treatment with branded GA included changes consistent with previous literature (as discussed below), supporting the validity of the chosen model system and current study design for revealing relevant treatment effects.
For example, expression of the anti-inflammatory gene IL10 was increased at the 6 hour timepoint, consistent with known GA mechanism with regard to monocytes (Kim et al. J. Immunol. Baltim. Md 1950, 2004; Weber et al. Nat. Med. 2007; Mahad et al. Brain J. Neurol.
2006). GA is thought to induce an anti-inflammatory effect, mediated by secretion of IL-4, IL-10, and other anti inflammatory cytokines both in terms of T cells (Thl to Th2 shift) but also in terms of monocytes, resulting in a shift from monocyte production of IL-12 to anti-inflammatory IL-10. For example, monocytes from mice treated with GA secreted more IL-10 than monocytes from untreated mice (Weber, Nat Med 2007), and monocytes isolated from MS patients treated with GA
were shown to produce more IL-10 relative to untreated patients (Kim, J Immunol 2004). In addition, dendritic cells exposed to GA during maturation increased their production of IL-10 (Mahad et al. Brain J.
Neurol. 2006).
Another anti-inflammatory gene, IL1RN (encodingIL-lra, a protein that inhibits the activities of IL-la and IL-1b) showed increased expression at all three timepoints. These observations are consistent with work showing that blood levels of soluble ILl-ra increase with GA treatment in patients with MS as well as EAE mice, and that soluble ILl-ra is upregulated by GA treatment in human monocytes either stimulated with LPS or activated by T cell contact (Burger et al, PNAS
2009).
Branded GA significantly modulated many pathways (Table 5). At 6h, pathways enriched significantly among upregulated genes included broad categories such as immune response and regulation of immune processes, and more specifically cytokine-cytokine receptor interactions. Other significantly enriched pathways included adhesion, and other pathways with broad relevance to the disease process and/or proposed action of GA. Several of these pathways were also significantly enriched among genes modulated by GA in monocytes from RRMS patients (Rosenberg, The Lancet 2005).
Example 2 Differences in gene expression induced by Probioglat versus branded GA
To identify differences between branded GA and differently manufactured glatiramoids, differential gene expression analysis was performed to compare directly between profiles induced by branded GA
and by the purported generic glatiramoid, Probioglat. The standard R
LIMMA bioconductor package was utilized to measure differentially expressed probesets across the entire microarray. To compare GA and Probioglat, comparisons were corrected to compare each treatment relative to mannitol control (i.e., [GA vs mannitol] was compared via LIMMA to [Probioglat vs mannitol]). Probesets were filtered by calls of presence on the chip for the relevant samples in the comparison (to be considered present at a given timepoint, a probeset was required to have on average a call of present or marginal across the relevant samples at that timepoint). Probesets were mapped to genes using the annotation available for the U133 Plus 2.0 chip from Affymetrix. FDR
adjusted p values reported for genes represent the lowest FDR adjusted p value for present probesets for that gene.
Many significant differences were observed between GA and Probioiglat (Table 3). As expected based on the more extensive response to GA at 6h, the most differences were observed at the 6h timepoint.
Table 3. Dynamic profiles of differentially expressed RNA after stimulation of THP-1 cells by Probioglat versus Copaxone Stimulation time 6 hours 12 hours 24 hours Genes actb3uoi Genes Prphrcejs. Genes Ersthere$4 Significance threshold FDR-adjusted p 115 138 5 5 1 ) value< 0.05 (3111.1 9) Upregulated:
Nominal 2,597 3,310 1,296 1,560 1,625 1,959 p value <0.05 FDR-Total adjusted p 136 162 7 7 1 modulated (IIIMP9) value< 0.05 (up- and down- Nominal regulated): p value < 0.05 4,863 6,208 3,051 3,992 2,843 3,486 Numbers of genes and probeuismodulated by frobinglatrelative to GA
(percent of probesets detected as significantly differentiated between treatments as percentage of the total 47,000 probesets included in the Affymetrix U133 Plus 2.0 chip) See Table 4a for the full list of differentially-expressed probesets at 6h: 138 upregulated, 24 downregulated (126 upregulated, 22 downregulated after presence/absence filtering). These differences included proinflammatory genes that were increased in expression by Probioglat relative to GA, including CCL5, CCL2, MMP9, MMP1, CXCL10, CD14, ICAM1 and BIRC3 (all significant by FDR adjusted p value < 0.05) (Table 4a). At the same time, differences were observed in levels of anti-inflammatory genes. Probioglat downregulated anti-inflammatory genes CISH and HSPD1 relative to GA, and upregulated IL10 and PRDM1 relative to branded GA (all significant by FDR adjusted p value <
S 0.05).

Table 4a. Human monocyte study: probesets significantly modulated by Copaxonee relative to Probioglat Comparing GA to Prolix%tat fmannitol-corrected):
Unregulated:
61w:
Gene 10 raw.FC AveExpr t P.Value .. adj.P.Val MMP9 203936_s at-12926295 9.63366142 -9.0041791 5.02E-11 174E-06 13.793663 CXCL1O 204533_4 -1.4567769 5.93611913 -6.3101441 4.11E-08 0.043056203 s_11662055 PRDIV11 228964 _at -13131543 926923221 -6.9712916 2.48E-08 0_00056208 8.55501455 LPWN 216250 s_at-11374257 11315416 -6.3905168 319E-08 0_00056208 FABP4 203980_4 -13397081 8.03922119 -6.4609935 1.24E-07 0_00100306 7.15838496 240076 at -12154985 8.47153306 -6.4502687 1.28E-07 0_00100306 7_12879005 COU6A1 213428 s at-1.1799797 9.17734162 -6.5227006 1.02E-07 0_00100306 7_3284926 51C39A8 209267_s at-1_1409956 10.4538343 -63855772 1.58E-07 0,00107772 6_95009387 MGC5618 221477_s at-1.1617675 103471179 -6.2424898 2_48E-07 0.00135843 6_55382496 5LC3943 219869 s at-114866 101877136 -6.26941324 228E-07 0.001_35E43 6.62867956 226218_at -1.2937342 7.13564432 -6.1059571 3.84E-07 0_00140732 617456221 STEAP1 205542_at -1_195521 7.98610593 -6.0852841 4.10E-07 0.00140732 6.11705174 C1-15711 219634 at -1_1616563 9.51077621 -6.0764318 4.21E-07 0_00140732 6_09241933 C09 201005_at -1_1480015 10.9097322 -6.0774378 420E-07 0_00140732 5.09521866 TNFSF135 223502_s at-1_137131 10_6086468 -6.1814333 3.02E-07 0.00140732 LACTS 226354 at -1_1146026 10.6959136 -6.1724213 3.10E-07 0_00140732 635931437 ARL6IP5 200761 s at-1_1108957 11.9357889 -6.0645684 4.33E-07 0.00140732 5_05940234 NEKBIE 203927...at -1.1646409 10_11523732 -59997493 538E-07 0.00157615 5.87889543 SLIC1 228869 at -1.1244476 10.0277009 -5.994027 5.48E-07 0.00157615 5_36295139 NIMP1 204475_at -13039262 6.32353561 -5.9312361 6.69E-07 0.00174156 5_68791885 5002 215223_5 at-12035944 9.66361398 -5.9462273 6.38E-07 0.00174156 5.72972041 NFICBIA 201502_5 at-1.1701699-11.8415908 -5.9153553 7.04E-07 0.0017486 5.64362855 ADAMDEC1 2061.34 at -11861199 8.53747931 -5.7927992 1.04E-06 0.00247065 5.30158178 NIPEG1 226841_at -1141713 9.90354597 -5.7187643 132E-06 0.00231664 5.09479213 ANX4.2P2 208816_x_at-1.1086074 11.6486476 -5.7130844 1.34E-06 0.00281564 5.07892372 244434 at -12846909 6,48107186 -5.6742369 132E-06 0.00284109 4.97033261 CCL2 2165911_s_at-1.2516796 11.2421198 -5.6653825 1.56E-06 0.00284109 494564092 15020 204698_at -1.2176321 6.18754674 -5.677111 130E-05 0_00264109 4_97841335 MT551 203037_s_at-12132697 113042636 -5.6909681 1.44E-05 0.00284109 5_0171321 IFNGR1 211676_s_at-1.1076638 121480464 -5.6472459 1.65E-06 0.0029127 489496045 230795_at -11702144 9.26991641 -5.6333398 1.735-06 0.00294926 4.85610012 NFE2L3 236471...at -13257415 5.26403664 -5.6026446 1.90E-06 0.00315306 4.77032024 C036 209555_s_at-1_1414722 9.39991418 -5.5482888 226E-06 0.00363742 4.61841752 CYLII 221903_s at-11207309 9.54523467 -5.5045621 160E-06 0.00406002 449622693 ICANI1 202638 s at-1.4084929 6.8285265 -5.4886851 173E-05 0_00415135 4.45186392 KIA41505 227265_at -1_1673293 9.93164349 -5.4623712 2.97E-06 0.00423964 4.37834442 BID 227143_s_at-1_1112086 113740779 -5.471422 289E-05 0.0042.3964 4.40363069 BID 211725_s at-1.1017724 11.13106494 -5.4568423 3.02E-06 0_00423964 4.36289801 IL10 207433_at -12783883 5.71640286 -5.31301791 3.86E-06 0.0050E408 4.24877517 ANX4.2 201590 x_at-11067663 131932317 -53762172 3.91E-06 0.90508403 4.13771284 TNFA1P6 206026 s at-1.2533604 5.46505459 -5.3471287 4.28E-06 0.00544542 4.0565035 CD14 201743_at -1_1688628 9.56313815 -5.3162757 4.72E-05 0.00586803 3_97039297 ICAM1 202637_s_at -1.253703 7.7073627 -5.2602772 5.64E-06 0.00674579 3.81417E37 ANIX42 210427_x at-1.1021711 13.1600502 -5.2581893 5.68E-06 0_00674579 3.80835622 5'1'11.12 212828_at -1.1079961 9.8266126 -5.2259269 6.29E-06 0.00731141 3.71841109 GLIPR1 226142_4 -1.1476515 8.96232728 -5.2116592 6.57E-06 0_00744619 3.67864746 ECOP 238604 at -11291845 9.93048271 -52069623 6.67E-06 0.00744619 166555947 CD40 205153_5 at -11516665 8.96773222 -5.1878467 7.09E-06 0.00775153 3.61230284 IFIH1 219209 at -11839872 8.4216604 -5.1481808 8.03E-06 020036134 3.50134783 IL411 230965 at -1_21886142 10.7302425 -5.1035983 925E-03 000953971 3_3777992 MAFB 218559 s at -1.1661498 125070822 -5.0783026 LOOE-05 0.01013992 3_30746517 08 62 201278_at -1_1002534 9.408584219 -5.0704754 1.03E-05 001020405 328570957 P2RX4 2040611_at -1_11462 103804136 -5.0589302 1.06E-05 0.01039288 3_25362692 M1F1 204784 s_at -11629248 9.99075341 -5.0382007 L14E-05 0_01039897 3.19604331 5TATH 206835_at -12217631 10.6277925 -4.9970174 1.29E-05 001198544 308172746 GIMAP8 235306_at -11769391 7.15724646 -4.9534429 1.48E-05 0.01329267 TATDN3 235069_at -11552651 9.09091742 -4.9541849 1_43E-05 0_01329267 2_96296263 5514.12 216180 s at -1_1540719 8.13558041 -4.929194 1.60E-05 0.01372355 2.89373383 TREM1 219434 at -11280034 111714599 -4.9272524 1.61E-05 001372355 2.138835722 A4XA2 213503_x at -11003375 131627385 -4.8992037 1_76E-05 0.01434614 2_81072248 0052 213524 s_at -11355006 8.75639391 -4.864242 1_96E-05 0_01577044 2.71404776 ILlORA 204912_at -11199911 105172379 -4.8323374 117E-05 0.01717268 2.62592271 6IRC3 210538_s at -1257364 457445637 -4.8159991 128E-05 0_01765329 258033111 1413E 203939 at -1_2383789 8.4.5450557 -4.8143591 2.29E-05 0.01765329 2_57636644 CCL5 1555759. a_ -10910656 13_6361191 -4.8032103 2.37E-05 0.01802488 234555373 5RPX2 205499 at -1.224512 6.16138512 -4.767627 2.65E-05 0.01937153 2.4474547 ARL61P5 200760 s at -1_1107109 11.7204466 -4.7591131 2.72E-05 0.01959427 2_42405329 E513 219424_at -L1775996 7.06372735 -4.7474062 2.82E-05 001976554 239131393 C040 215345_at -1_1705995 8_77095715 -4.7439006 186E-05 001976554 2_38216714 SRA1 224130 s at -1.094757 105027383 -4.7442703 2.85E-05 0_01976554 2_38313441 238501_at -12105582 5.44953239 -4.73925 2_90E-05 0.01977223 2_36937124 SLIM 229045_at -1_1547536 827898536 -4.7357646 193E-05 0_01977223 2_35978293 C5ORF13 2.38411_x_at -1.1683694 3_79974787 -4.7297145 2.98E-05 0.01979262 2.34314234 CARD15 220066_at -1_1393669 8.86627619 -4.7275995 3.00E-05 0_01979262 2.33732587 PLEKHO1 2.18223_s_at -11393641 9.19617144 -4.7232262 3.05E-05 0_01932503 NFE2L3 204702_s_at -1.1949945 6.870022.51 -4.7001905 327E-05 0.02069819 226199661 P2R15 218589_at -1.1719902 9.42743243 -4.6980902 3_29E-05 0.02069819 225622666 P5COBP 209606 at -11833353 8.14303401 -4.6940255 3.34E-05 0_02072301 224507189 PTX3 206157_at -11323375 112731131 -4.6853645 3.43E-05 010210494 222128475 GFIRL 223862_at -1.184681 7.10722772 -4.6529266 3.79E-05 0_02252098 2.13230051 501131 223672_at -1_1713796 8.754430755 -4.6556052 3_76E-05 0_02252098 2_13964377 RPL1.3 M LO 214976_at -11498626 6.91302234 -4.6576183 3.73E-05 0.02252098 C130 RF31 1553141_at -12240082 8_3027252 -4.6445617 3.89E-05 0.022.86455 2_10937474 228573_at -1_0954948 101938031 -4.631833 4..05E-05 0.02353205 2.07450537 213891_s at -1_1613505 8_36985954 -4.6072376 4.37E-05 0.02.435882 2_00713586 C9ORF130 227893_at -11466602 7.47771908 -4.6095058 4.34E-05 0.02435582 2_01339098 VP533A 204590 x_at -1_1717825 7.44063872 -4.5964894 4.51E-05 0_0246793 1.97779156 LACTI1 1552486_s_a -1.1146334 9.43978855 -4.5992016 4.48E-05 0.0246793 1.95520746 RAB2713 225708_at -12146114 8_64471961 -4.5896791 4.61E-05 0.02495536 1_95917448 FXYD2. 207434_s_at -12391134 6.87935734 -4.5721048 4.87E-05 0.02609092 1.91116075 5002 216841_s_at -11587002 5.24547849 -4.5601654 5_05E-05 0.02658149 1_87856531 !NADI 214493_s at -1_1876014 5.13104061 -4.5382854 5.40E-05 0.02787086 1.81858217 BID 204493_at -1_0962323 11_1430522 -4.5406927 536E-05 0.02787086 1.82544538 BTS1 2413347_at -1.1577464 6.46143817 -4.5117153 5.86E-05 0.02941834 1_74649575 CENTA2 219358_s at -1,1328376 10.4221094 -4.5125113 5.85E-05 0.02941534 1.74866433 L0054103 213142_x_at -1.1327449 10.7990817 -4.5010122 6.06E-05 0.02485684 1.71736561 232297_at -11396433 8.4593213 -4.4977208 6.12E-05 0_02989176 1_7084108 THBD 2038.87_s_at -1.0360181 12.3670409 -4.4922535 6.23E-05 0.02996581 1.6935397 KYlU 210653_s at -11273404 10.5327662 -4.4730592 6.61E-05 0.031.24079 1.64136616 TATDN3 2281367_at -1.0979673 8.53193411 -4.4719767 6.63E-05 0_03124079 1.6384252 IT0 55 201125_s_at -1_1305667 9.66682508 -4.4663279 6.74E-05 0.03151651 1_62308225 HNRPLI. 225336_s_at -1_088481 10_9979975 -4.4.607622 6.86E-05 0.03178871 1.60796956 CRY582 206777_s at -1_1273748 9.09050704 4.4486878 7.12E-05 003248173 1_57520029 C055 1555950_3 J-1.101176 11.0430169 -44455718 7_19E-05 003245173 MPEG1 226818_3t -(102944 9.97050085 -4.4364675 7.39E-05 0.43312876 1.54205788 POPDC3 219926_3t -(2923154 6_73431127 -4.4296067 7.55E-05 00333342.9 13234.6112 PLAUR 214866_at -(1197536 101465619 -4.4291541 7.568-05 0.03333429 MGLL 239914 at -11755243 5.02263039 -4.4192631 7.79E-05 003354952 (49543825 8512 205419 at -11547466 103787766 -4.4209004 7.75E-05 0.03354952 1.49957275 TP5A51 /II T 20774 i_x_at -1154419 7.49088254 -4.4208416 7.76E-05 0.03354952 1.49971363.
SLAMF3 219386 s at-(1604525 101187042 -4.412321.3 7.96E-05 003370605 1.47664099 VSNL1 203797_at -1.1465556 9.26432896 -4.4080222 8.07E-05 0_03370605 1CAM2 213620 s at-Li-2.973A 7.80787761 -4.4083036 8.06E-05 0.03370605 KYNU 217388_s_at-1.1268071 11.2241113 -4.4076297 8.08E-05 0_03370605 1.4639412 ARFIGAP18 225166 at -11854012 7.40195979 -4.3979297 832E-05 0.03445978 1.43769541 WHIT 226066_at -11771135 7.94053593 -4.3803753 8_73E-05 0.03578326 MXD1 226275_at 41272655 838697195 -4.3782779 8.84E-05 0.03578326 1_35457024 241389 at -1.1324551 7.7082034 -4.3740933 8.95E-05 0.03597723 137327956 EGF 206254 art -1.2273072 5.23328013 -4.3445051 9.80E-05 003909529 MALT1 210017_at -11361187 7.35916694 -4.3417635 9.88E-05 0_03913524 1_28603152 AKR1C2 211653_x at-1214586 9.21551731 -4.3251491 0.00010361 0_03933789 LPAAT-THETJ2244813 s_at-12033445 8.82402466 -4.3329062 0.00010149 0.03933789 1_26216342 MM. 235911_at -1.1178645 102132798 -4.3339031 0.00010118 0.03933739 ARHGAP18 225171_at -1.1011604 10_7603262 -4.329986 0.0001024 0.03933789 1_25429744 TX13.2 209080 x at-1.0905642 111937357 -4.3267122 0.00010343 0.03933739 C055 201926_s_at4.0376425 11.012 54 -43312016 0.00010202 0.03933789 ADAM9 202331 at -11288776 10.068453 -4.2795249 0.00011941 0.114461757 1_11860933 058PL11 218304 s_at-11200967 8.30861724 -4.268338 0.00012355 0_04461757 1.08859065 C5ORF32 224707_3r -1_1088424 9.60174121 -42676443 0.00012381 0_134461757 1_05672987 C03004 2439933_5 at-(0919093 11.068246 -4.2779818 0.130011998 0.04461757 1_11446708 ATP2C1 237278_x_at-11252002 4.516837 -4.2604681 0.00012654 004474124 (06748681 TGM5 207911_s_at-1.0955729 10.9973837 -4.255458 0.00012548 0.04474124 1.05405768 CAST 208905 s_at-1.0958385 10.4613552 -4.2557149 0330012338 0.04474124 TNFR5F9 2.07536_s at-1.1669411 6.64800537 -42459826 0.00013222 0.04515347 (028-67283 HNIGE12. 243368_at -11602025 4.3-8716386 -4.2463169 0.00013209 0.04518347 1.02956514 INFAIP3 202644 s_at-1_1253187 10_6490533 -4.2424AN5 0.00013123 0.04518347 1.03531746 C1ORF21 223125_5 at-1_1101543 11_0658204 -42399019 0.00013469 0.04573895 1.01239127 212387 at -1.148179 7.86470579 -4.2245512 0.0001411 0.04762227 097132047 12 lir Gene 10 raw.FC AveExpr t P.Value adj.P.Val 5 PRDM1 228964 at -13131187 7.67111264 -8.6246024 1.41E-10 7.72E-06 11.3048141 RCSD1 239325_at -1.2917804 9.91539671 -6.452108 122E-07 0.0033307 6.31495199 BTG1 2413347_at -12562187 6.63516956 -5.7047112 1.33E-06 0.02422499 4.46209903 F6X045 225099_3t 1.13350791 9.69247626 551958363 2.40E-06 0.03282196 3.99779146 ZNF566 240239_at L211902406 6.20206745 5.35216774 4.09E-06 0_04477351 3.57707214 241w:
Gene ID raw.FC AveExpr t P.Va toe ad j.P.Val 5 MMP9 203936_s_at-1.2387837 076550502 -6.6308842 7.89E-08 0.00431641 6.03721142 Dawnregulated:
6 hr:
Gene ID raw_FC AveExpr t P.Value adj.P.val 5 LOC648342 1569392_at L25828385 546339373 531754607 L32E-06 0_00281664 5_09166798 E1T5014A 243431 at 131196093 8.69387594 5.37580876 3.90E-06 0_00505408 4.13936456 SERPIN82 204614 at L25751853 107388922 5.14040426 523E-06 0.00865761 3.45020227 MY13 204798 at 1.09897729 13.1513017 5_00361266 1.27E-05 0.01194194 3.10002645 5TT3E1 238303_at 1.2645975 600460112 4.9254338 1.62E-05 0_01372355 258332163 HSPD1 241716_4 1.30589927 5.02121553 4.922322.1 1.64E-05 0.01372355 2,87470616 ACT114 232058_at 1.19228742 8_60657642 4.91813847 L56E-05 0_01372355 2,55317939 F4.M62A 244234 at 1.14840119 7_29749849 4_78192868 2.54E-05 molagssas 2_48688527 1559600_at 117980654 838342055 4.76703429 2.66E-05 0.01937153 L4458524 OXCT2 2352.75_at 1.16642629 12.3300201 4.71420617 3.13E-05 0.02014951 230050545 228907_at 1_17599277 8_21E84465 4.6120071 4.30E-05 0_02435882 2.02023432 GAPDHS 222280 at 1.1646993 7.71035699 4_60723903 4.37E-05 0_02435882 2.00718978 SPFH1 2132441 at 1.12657525 11.0883546 4_55979394 5.06E-05 0.02658149 1.87755147 NAPS 1570441_4 1.202.57749 5_920733139 432511168 5.61E-05 0_02866712 1.78570418 HINRPO 213359_at 1.16588386 9.72519123 4_50340998 5.02E-05 0_02985684 1_72389004 OISH 223377 x at 1_09133621 9.01105134 4-49116936 525E-05 0_02996581 1_69059129 S FR.514 54371_4 1.12400512 8.1952891 4.44643142 7.17E-05 003248173 1.5690791 C140RF10 2391811 at 1_16314645 6.54591766 4_38855767 5.56E-05 003519543 1.4123519 232903_4 121778341 6_930513721 4.29620676 0_0001135 0.04279E181 1_15341547 HDAC4 232225_at 1.14445571 737327378 4_274E9999 0.00012111 0.04461757 1.10619611 CL1C1 2146133_s at 1.150507 9_27028545 4.255656 0.00012343 0_04461757 1_08944366 CRLF3 235803_at 1.19940674 9_07113133 4.2670238 0.00012404 0_04461757 1.03506571 2/4F250 241738_at 1.11389598 4_2390353 4.26401964 0.00012518 0.04473242 1_07700912 WC:1Pa 234157_4 120859908 539795409 4.25895039 0_00012712 0.04474124 1.06341818 12 hr:
Gene ID raw.FC AveExpr t P.valtre adj.P.Val 5 FBX045 2.25099_at 1.13350791 9_69247526 5.51958363 2.40E-06 0_03282196 3.99779146 211F566 240239_at 1_20902406 6_20206745 5_35216774 4.09E-06 0.04477351 337707114 Table 4b. Probioglat expression values for key genes compared to the range set by observed expression values under Copaxone treatment Red text indicates that the expression value for this Probioglat treated sample is outside of the observed range of all Copaxone samples.
Copaxone Expression Value Probioglat Expression Values Range Maxi- Mini- Sample Sample Sample Sample Sample Sample Probeset Gene mum mum 1 2 3 4 5 6 203936_s_at MMP9 9.97 953 1014 10.05 1112 10.14 1104 10.04 201.743_,A CD14 9.69 932 9J5 935 9.67 9.79 931 9.86 202637_s_at ICAM1 8.06 7.44 8.14 756 8.26 7.84 8.18 752 202638_s_at ICAMI 730 651 7.6/ /54 7A5 /32 7.19 654 223961_s_at C1SH 759 7/4 731 720 741 737 752 //3 223377_x_at C1SH 9A1 8.86 8.81 881 8.88 Discussion - Example 2 Pro-inflammatory Genes Gene-level differentiation analysis identifies specific pro-inflammatory markers when comparing Probioglat to Copaxone . Upon comparison of GA with Probioglat, significant gene-expression differences were seen (Table 3). Only one batch of Probioglat was available to compare to the four batches of GA, prohibiting the possibility to study batch-to-batch variability. However, the range of variation defined by the four GA batches represents a range of variation that has been demonstrated to be safe and effective by Copaxone's clinical trials. The fact that any single batch of Probioglat results in values outside of that range (as illustrated in Table 4b and Figure 44), coupled with lack of PM or PD markers to determine equivalence of the two glatiramoids, warrants further investigation.
The consistent confirmatory results obtained by single-probeset, pathway and independent qRT-POR analysis are particularly robust, given the stringent statistical framework employed. It should be noted that fewer genes were significantly modulated by GA relative to Probioglat than by GA relative to mannitol, an observation expected given the intended mimicry of structure between the compounds. Indeed many genes were modulated in the same direction by both GA and Probioglat versus control, but to differing extents (the cases for many genes discussed below, except where noted). It is striking that differences were observed between branded GA and the designed purported generic, Probioglat. Two drugs cannot be said to have identical effects if significant differences are manifest.
Importantly, the significant differences in gene expression observed between Probioglat and Copaxone were seen in genes tied to highly relevant disease pathoetiology and known GA mode of action (MOA).
Bioinformatic analysis of differentially expressed genes (by FDR
corrected p value) following Probioglat versus Copaxone stimulation of human monocytes at 6 hours identified a number of genes tied to important immune system functions, in particular inflammation: CCL5, CCL2, MMP9, MMP1, CXCL10, CD14, IC4M1 and BIRC3. Several of these genes have been reported in the literature as modulated by GA treatment in patients.
1. CCL5 (RANTES) is a key chemokine thought to attract inflammatory immune cells to the CNS, and was significantly upregulated in Probioglat treatment relative to Copaxone treatment at 6 hours (FDR adjusted p value 0.018, FC 1.09 in gene expression analysis; p value 4e-5, FC 1.12 in ciRT-PCR
confirmation). Indeed, an antibody blocking CCL5 was shown to reduce disease metrics including immune infiltration into the CNS in a viral MS model (Glass et al, Immunol Res, 2004;
Chirstensen et al. Mult. Scler. J. 2013). Expression of the CCL5 receptor, CCR5, on GA-reactive T cells from MS patients was shown to be downregulated by chronic (1 year) GA treatment (Allie et al, Arch Neurol 2005; Kouwenhoven et al. J.
Neuroimmunol. 2002). This gene was tested and confirmed to be upregulated with Probioglat treatment relative to GA
treatment in primary human monocytes (p < 0.029, FC 1.53).
2. Expression of MNIP9 (Matrix Metalloproteinase 9) was significantly higher with Probioglat versus GA stimulation at 6h (FDR-adjusted p-value 2.8e-6, FC 1.29 in gene-expression analysis, Figure 41a; p-value 0.02, FC 1.24 in qRT-PCR
confirmation), and at 24h (FDR-adjusted p-value 0.004, FC

ak 02952849 2016-12-16 1.25). The MMP9 gene was also upregulated with Probioglat relative to GA treatment in primary human monocytes (p <
0.009, FC 1.4). This protein is reported to increase access of immune cells to the CNS by contributing to disruption of the blood brain barrier (BBB) (Rosenberg et al, The Lancet 2005), and high levels of MMP9 have been associated with Multiple Sclerosis (Christensen et al, Mult. Scler 2013;
Milward et al., J. Neuroimmunol. 2008; Knop et al, Neurology 2013; Parks et al, Nat. Rev. Immunol 2004). MMP9 was upregulated with Probioglat relative to Copaxone stimulation at 6 hours (FDR adjusted p value 2.8e-6 in gene expression analysis; p value 0.02 in qRT-PCR confirmation). Expression levels of MMP9 at both the mRNA and protein level were increased in immature dendritic cells from MS patients relative to healthy controls (Kouwenhoven et al, J
Neuroimmunol 2002). Elevated MMP9 levels were reported in patients with gadolinium-enhancing lesions relative to patients without (Waubant et al, Dis Markers 2006; Antonelli et al, Autoimmun. Rev. 2014), and MMP9 has been proposed as a biomarker for both MS diagnosis and progression (Milward et al, J Neuroimmunol 2008; Peperzak et al, J. Immunol. Batim.
Md 1950, 2013). GA has been reported to inhibit MMP9 expression in healthy human peripheral blood mononuclear cells (PBMC) (Knop et al, Neurology 2013 (Meeting Abstract);
Adrem and Ulevitch, Nature 2000). Increased expression of MMP9 for Probioglat relative to Copaxone at multiple timepoints (Fig. 7).
3. The level of MMP1, another matrix metalloproteinase gene, was increased after Probioglat stimulation compared to Copaxone at 6 hours (FDR adjusted p value 0.002, FC 1.50 in gene expression analysis; p value 0.02, FC 1.25 in qRT-PCR
confirmation). Matrix metalloproteinases are known to cleave pro-inflammatory cytokines and chemokines to regulate inflammation (Parks et al, Nat Rev Immunol, 2004; Baumann et al, J. Exp. Med. 2010). Levels of MMP1 mRNA, as well as secreted MMP1, were observed to be higher in immature dendritic cells from MS patients relative to healthy controls (Kouwenhoven et al, J Neuroimmunol 2002; Parks et al, Nat Rev Immunol, 2004).
4. Expression of the chemokine CXCL10 was increased by Probioglat stimulation compared to Copaxone at 6 hours (FDR adjusted p value 0.0006, FC 1.46 in gene expression analysis; p value 0.0029, FC 2.28 in qRT-PCR confirmation). This finding was confirmed by qRT-PCR in primary human monocytes, where CXCL10 was upregulated by Probioglat relative to Copaxone treatment with p value < 0.02 and fold change of 2.1. CXCL10 level in peripheral fluids was previously shown as associated with host immune response, particularly with regard to Th-1 cells (Antonelli et al, Autoimm. Rev., 2014; Natarajan et al, J.
Nueroimmunol. 2013). CXCL10 is involved in recruiting CD8+
and Thl CD4+ effector T cells to sites of inflammation (Peperzak et al, J Immunol, 2013; Hedegaard et al, PLoS ONE
2011). A study using monocytes from RRMS patients demonstrated CXCL10 to be increased by GA therapy within the first two months of treatment (Thamilarasan et al, J Neuroinflammation 2013; Rosenberg, The Lancet 2005).
5. CD14 is a marker of monocyte activation known to enhance inflammatory responses. CD14 was upregulated in human monocytes stimulated by Probioglat versus Copaxone at 6 hours (FDR adjusted p value 0.006, FC 1.17; qRT-PCR not tested;
Figure 41b). CD14 was not modulated by GA treatment versus mannitol control. This marker of monocyte activation enhances inflammatory responses (Mycko et al, Ann. Neurol. 1998). In complex with LPS binding protein (LBP), CD14 interacts with LPS and helps to present it to toll-like receptor 4 (TLR4), activating downstream expression of inflammatory genes via NF-kB (Park et al, Exp Mol Med, 2013). CD14 has also been shown to be a coreceptor for other TLRs, and was demonstrated to be required for induction of proinflammatory cytokines via TLR7 and TLR9 in mouse and human cells in vitro (Baumann et al, J Exp Med, 2010; Bullard et al, J. Immunol. 2007).

Increased expression of CD14 for Probioglat was determined relative to Copaxone (Figure 8).
6. CARD15 (NOD2), another gene upregulated by Probioglat versus Copaxone at 6 hours (FDR adjusted p value 0.02, FC 1.14; qRT-PCR not tested), is also a key player in the immune response to LPS, participating in activation of NF-kB. Activation of NOD2 by peptidoglycan has been shown to induce CNS
demyelination in rats (Natarajan et al, 2013; Sellner et al, din. Exp. Immunol. 2013). In addition, a SNP in NOD2 was shown to affect the responses of Th2 and Th17 cells to myelin basic protein (MBP) in MS (Hedegaard et al, 2011; Bertrand et al, Immunity 2009).
7. BIRC3 expression was increased by Probioglat relative to Copaxone at 6 hours (FDR adjusted p value 0.018, FC 1.26;
qRT-PCR not tested). This gene codes for an Inhibitor of Apoptosis Protein (IAP-1), which in addition to its role in cell survival plays a role in both innate immunity (Bertrand, 2009; Kearny et al, J. Biol. Chem. 2013) and inflammation (Labbe et al, 2011; Ashburner et al, Nat. Genet. 2000), and has been suggested to have an immunomodulatory effect in autoimmune demyelination (Hebb et al, 2008; Kanehisa et al, Nucleic Acis Res. 2000). IAPs including IAP-1 are required for production of pro-inflammatory cytokines via several different pathways, including TLR4 activation (Tseng et al, 2010; Zanin-Zhorov et al, J. Clin. Invest. 2006) and NOD2 activation by TNFa (Kearney et al, JBC, 2012; Qin et al, Proc.
Natl. Acad. Sci. 2012).
CCL2 (MCP-1) is another pro-inflammatory cytokine that was also expressed significantly more highly with Probioglat treatment relative to Copaxone at 6 hours (FDR adjusted p value 0.003, FC 1.25; qRT-PCR not tested). CCL2 expression was decreased by GA treatment relative to mannitol control, and decreased to a lesser extent by Probioglat relative to mannitol control. CCL2 is thought to recruit inflammatory cells into the CNS in EAE and in MS (Mahad et al, 2006;
Waubant, Dis. Markers 2006). This gene was also confirmed to be upregulated with Probioglat relative to GA treatment in primary human monocytes (p < 0.009, FC 1.24).
8. ICAM1 expression was increased by Probioglat relative to Copaxone at 6 hours (FDR adjusted p value 0.004, FC 1.41;
qRT-PCR not tested; Figure 41c).
ICAM1 is an adhesion molecule that plays a key role in inflammatory processes by promoting leukocyte adhesion to the endothelium of the vascular wall, and is known to have an important role in inflammatory cell infiltration into the CNS in both EAE and MS (Mycko et al, Ann. Neurol. 1994; Labbe et al, Immunity 2011). In mice null for ICAM1, T cells produced significantly less IFNy and showed much less infiltration into the spinal cord (Bullard et al, J Immunol, 2007; Hebb et al, Mult. Scler.
Houndmills Basingstoke Engl. 2008). In PBMC from RRMS
patients, ICAM1 levels were higher versus healthy controls, and chronic treatment with GA affected surface ICAM1 levels in multiple immune cell types (Sellner et al, Clin Exp Immunol 2013; Tseng et al, Nat. Immunol. 2010). Increased expression of ICAM1 for Probioglat was determined compared to Copaxone stimulation (Figure 11).
Anti-inflammatory Genes As discussed herein, a number of pro-inflammatory genes and pathways were shown to be significantly upregulated by Probioglat as compared to Copaxone. At the same time, several anti-inflammatory genes were downregulated by Probioglat stimulation in comparison with Copaxone at 6 hours.
1. CISH, also known as SOCS (Suppressor of Cytokine Signaling), was expressed at lower level with Probioglat relative to Copaxone at 6 hours (FDR adjusted p value 0.03, FC -1.09;
Figure 41d). A closely related protein, SOCS3, has been shown in myeloid cells to protect from EAE, the mouse model of MS, via deactivating neuroinflammatory responses (Qin et al, PNAS

2012; Bakshi et al, Expert Opin. THer. Targets 2013). Both present probesets for this gene were affected in the same direction (Fig. 12). A SNP in SOCS1, another family member, has been identified as a risk factor for MS (Towfic et al, PLoS ONE 2014).
2. HSPD1, also known as HSP-60 (heat shock 60kDa protein 1), was downregulated in Probioglat relative to Copaxonee at 6 hours (FDR adjusted p value 0.01, FC -1.31).
Zanin-Zhorov et al (2006) showed that HSP60 as well as synthetic peptide derived from HSP60 act as co-stimulators of Tregs through the TLR2 pathway. Tregs are immune regulatory cells that inhibit lympho-proliferation and IFNG and TNF secretion by pro-inflammatory T cells. Zanin-Zhorov et al concluded that HSP60 can downregulate adaptive immune responses by upregulating Tregs. Thus, downregulation of HSPD1 may result in less inhibition of immune response by Probioglat compared to Copaxone .
It should be noted, however, the anti-inflammatory cytokine IL10, known to be relevant to the GA mechanism of action, was also expressed at a higher level subsequent Probioglat relative to Copaxone treatment at 6 hours (FDR adjusted p value 0.005, FC 1.28). The same observation holds for another gene at 6 and 12 hours, PRDM1 (Blimpl) (FDR adjusted p value 0.0006 and 7.7e-6, and FC 1.31 and 1.31 respectively), that when deleted results in inflammatory pathology (Chiang et al, PNAS 2013; Johnson et al, Biostat. Oxf. Engl. 2007).
Blimpl is a target of FOXP3 and is needed for production of IL10 by Tregs; its expression can also be induced by IL2 and proinflammatory cytokines in Tregs (Cretney et al, Nat Immunol. 2011; Leek et al, Surrogate Variabel Analysis 2013). However, it is not clear what these observations would imply for APCs such as monocytes. It is possible that higher Blimpl could be an attempted protective response to a higher inflammatory milieu. A statidtically significant difference in such a mechanistically relevant gene - in either direction - between two therapeutics intended to be identical presents motivation for further study.

Example 3 Pathway Enrichment Analysis Upregulated and downregulated genes were analyzed separately for pathway enrichment, using DAVID (Huang et al, Nucleic Acids Res 2009).
Pathway enrichment results were visualized using volcano plots, plotting -log p values versus enrichment scores. For GA MOA, to obtain top-gene lists of appropriate size (tens-hundreds) for use with DAVID, an absolute-value-fold-change cutoff of 1.5 and p-value cutoff of le-5 were utilized to obtain gene lists for pathway enrichment at 6h.
For comparisons between branded GA and Probioglat, upregulated or downregulated genes with FDR-adjusted p values < 0.05 were used for pathway enrichment.
DAVID runs were conducted May 21, 2014. Please note that the GO
databases are updated daily (as noted on the GO
site:www.geneontology.org/GO.downloads.ontology.shtml) and therefore performing the same enrichments on the same genesets may yield slightly varying results depending on the run date, as illustrated by the differences in Table 6 (results from runs on differing dates using broader or more restrictive subsets of GO). Thus, the pathway p values may change slightly between runs conducted at different times; the overall picture of enriched pathways, however, is expected to remain consistent. Three time points were tested to identify the fold change and p value filters were used to obtain top gene lists of appropriate size (i.e. tens to hundreds) for use with DAVID (Table 5).
No pathways were enriched significantly among downregulated genes, however 106 pathways were enriched significantly (Benjamin! corrected p value < 0.05) among genes upregulated by Probioglat relative to GA, including immune system process (GO:0002376), immune system process (GO:0002376) and immune response (GO:0006955) pathways (Benjamini-corrected p-values 1.5e-5 and 3.3e-4, respectively), and many other immune system related pathways, such as regulation of lymphocyte mediated immunity (GO:0002706, Benjamini-corrected p-value 0.007) and B cell proliferation (GO:0042100 Benjamini-corrected p-value 0.049) (Fig. 10 and Table 6). Multiple significantly enriched pathways were relevant to inflammation, including response to lipopolysaccharide (LPS) (GO:0032496; Figure 9), regulation of inflammatory response (GO:0050727), regulation of tumor necrosis factor production (GO:0032680), and NOD-like receptor signaling (hsa04621) (Benjamini-corrected p-values of 8.7e-4, 0.015, 0.028, and 0.027, respectively).
No pathways were enriched significantly among genes downregulated by Probioglat versus GA.
Genes analyzed for pathway enrichment (Tables 5 and 6), using DAVID
(conducted May 21, 2014). Performing the same enrichments on the same genesets may yield slightly varying results depending on the run date (GO databases are updated daily:
www.geneontology.org/GO.downloads.ontology.shtml).

cn IA 1-3 Pathways significantly enriched among top genes modulated by GA relative to mannitol control at 6 hours: (D
Top genes are defined by cutoffs of VC I >1.5 and p-valuecle-5 to obtain lists of appropriate size for use with DAVID. 0 o go 0 f.0 CD o Enriched among top dovinregulated genes:
)1 f.0 to LTI 1;
Fold = 1.1. = -a--, Term Pvahre Benjamini Probesets Genes Enrichinent 111 CZ
I207865_5_AT, 42037_AT, 201350 AT, 229638 AT, 222162_5 AT, 204557_5 AT, I lµ.) Uvi CZ
39966 AT, 52651 AT, 227242 S_AT, 227236 AT, 200894 S AT, 239410 AT, BARBEL
TEAD4, FL012,1633, ADAMTS1, D21P1, CSPG5, 1=' CO) RA/, ERB, TSPAN2, FKBP4, HK2P1, CXC.R4, GM, 217028 AT, 206539 AT, 711 /99_S_, __, __, 511__, GO:0007275-municellula AT 208078SAT 223704SAT 2016S ATF1072,511(1, OtART2, TPD52, TPD52, W12, TPD52, IR
2131689 S AT, 23.6953 S AT, 201690_S_, _, 2.13326__, _, r organismal 6.94E-06 2_168367347 0.00270611 AT 229103AT SAT 202800 AT, LGR4, SLC1A3, BC.L11A,13C1.2., SPRY1, PCDH8, 0 a 2_10347 S AT, 232614_AT, 71'c58 AT, 206935_AT, 229084 AT, 219497_S_AT, lt 0 development CN1N4 R0154, ECU, BMP8B, OCCR4, CAV1, WT1, 1-1 0 227103 S_AT, 235275 AT, 21.1919_5_AT, 212097 Al; 206067_S_AT, 243209 AT, KCNC14, IC
207725 AT, 209201 X AT, 213478_AT, 213568 AT, 211421 S AT, 221.900 AT, POU4F2, OfCR4, ICAZ., OSR2, RET, COI as', 00 222891 S_AT, 203685 AT, 207717 S BC1.1.1A, AT 6C12, P872 0 14 '0 ft 207865 S AT, 41037 AT, 201350_AT, 229638_AT, 277162 S AT, 39966_AT, 11 a) 0CB054,P al 1,187, , 1 E A D 47. s p A N, 2F, 1 OH K2 pT 2 , 21 70 f. (23 , A
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5.04E-06 2_396166134 0.00294797 229203 AT, 2111326_S_AT, 202800_AT, 232614_AT, 210347_S_AT, 212558 TPD52, TPCi52, WT2,1PD52, WHT3,16R4, SLC10.3, AT, B _ . _ , Bri 115 SPRY1, PI 11 development gL
2136935 AT, 229084 AT, 219497_S AT, 227103 S AT, 235275 AT, 21.1919_S
2 AT, PCD148, CNTN4, BO 11A FCC, CX -206067 S AT, 212097 AT, 243209 AT, 207725 AT, 209201 X AT, 213478 Al;
BMP8B, C.XCR4, W11, CAV1, KCI4Q4, P0U4F2, CR4, a) RET, COL8A2 05R2, , O. 2 vp 213568_AT, 211421_5 AT, 221900 AT, 222891_5 AT, 203685 AT, 207717_5 KAZ, AT
BOMA, KU, PKP2 4:1 u, tr 10 Ni 207865 S AT, 41037 AT, 201350 AT, 222162 5 AT, 52651_AT, 239410 AT, 14 t=1'I-1 o.
D. vp 217025 AT, 2065439_AT, 211/99_S_AT, 223704_S_AT, 201688_S_AT, 201689_S Al;
BMP8B, TEAD4, FLOT2, ADAMTS1, COU1A2, HI12P1, 0 o CXCR4, Gni, FLO72, MARTZ, 7P1152, TPD52, WT1, Ni 226953_5 , __, .91113_, 218326 _ S_AT, 232614_T, 210347 _ SAT, 0 P) 1-GQ0048513-organ AT 201690SAT 22 AT

0 o, 2.61E-06 2.760084926 0.00305609 71/458 AT, 206935 Al; 229084_AT, 219497_S_AT, 227103_S_AT, 2352.75_AT, 1 development TP052, WN13, 1.034,, SC12,11 SPRY', PCDH13, CNTN4, An 11A, ECU, BMP8B, C.XCR4, WT1, CAVI., Su 01 F'21191_9 S AT, 206067 S AT, 212097 AT, 243209_AT, 207725 Al; 209201_X_AT, 54 7 213478 AT, 211421 S_AT, 213563 AT, 221900 AT, 203685 AT, 7/1Rg1 KCHQ4, P01.14F2, S_AT, CXCR4, KAZ, RET, 0532, COLSA2, BC12, 0 0 ig 80.11A, PKP2 0 H.

a) 1C1 Ã 0 2071365_5 AT, 41037 AT, 201.350_AT, 229638 AT, 222162 S AT, 39966_AT, BMP8B, TEAD4, FLDT2, OM, ADANITS1, CSPG5, 52651 AT, 227236 AT, 239410_AT, 217028_AT, 206589 AT, 21_1259_5 AT, Cal RAI, TSPAN2, HK2P1, CXCR4, GFI1, FLOT2, DIART2, M Y.
223704 S AT, 201688_5 AT, a:I1689_S AT, 216953_5 AT, 201690 S_AT, GO:0046856-anatomical TP1352, TPD52, WT1, TPD52, WNT3, LGR4, 41 rl Al, 3.69E-05 2.164502165 0.00861537 229103_AT, 218326 S_AT, 202800 AT, 232614 Al;
210347 S AT, 212558_AT, P) $11 structure development 1302, BC111A,SPRY1, POWS, CNTN4,13C111A, ECU, ft 0 206935 AT, 2290B4 AT, 2.19497_S_AT, 227103 S AT, 235275 AT, 211919_S AT, BARBS, CXCR4, W11, CAV1, KCNC14, POU4F2, CXCR4, la- rt 206067 S AT, 212097 AT, 243209 AT, 2.07725 AT, 209201 X AT, 2L3478_AT, .4 F-1 ICAZ, OSR2, 0) k 213568 AT, 211421 S AT, 221900_AT, 222891 S AT, 203685 AT, 207717 S_AT RET, COI R57, 13C1_11A, KU, P872 it 0) IV
207865_5_AT, 213361 AT, 41037 AT, 229638 AT, 204557 S AT, 39966 AT, BMP813, TDR07, TEAD4, 1393, DZ1P1, CSPG5, TSPAN2, n 22723.6 Al; 217028 Al; 206583 Al; 208078_S Al; 201688_S_AT, 201639_S_AT, CXCR4, GF11, 51K1, TPD52,TPD52, Val, TPD52, WNT3, G0:0030154-cell 216953 5 AT, 201690_S AT, 229103_AT, 20213130_AT, 210347_S_AT, 232614 Al; . e 4.49E-05 2555555556 0.00871/388 13C111A, BC12, SPRY1, CNTN4, BC111A, ECU, 0 differentiation 2_12558_AT, 229084 AT, 219497 S AT, 227103 S AT, 235275 AT, 212097 AT, 0 0' BMPBB, WTI, CXCR4, 206067_5 AT, 211919_5 AT, 20772.5_AT, 209201 X AT, 213478 AT, 211471_5 AT, C.AV1, POU4F2, CXCR4, ICAZ, RET, Cr 0 ID lµ.) 80.11A, . o 222891 S AT, 2036E15 AT 8(12 H. M
ft 1-, Uvi 0 .
ru , Fold Term Pvalue Benjarnini Probesets Genes Enrichment 207865 S AT, 213361 AT, 41037 AT, 201350 AT, 229638 AT, 222162 S AT, CA
, 204557 S AT, 39966 AT, 52651 AT, 227242 S AT, 227236 AT, 200894 S_AT, EIMP88, TDRD7, TEAD4 FLOT2,1103, ADAMTS1, DZIP1, 239410 AT, 217028 AT, 206589 AT, 211299 S AT, 208078 S AT, 223704_S AT, C.SPG5, COL8A2, EBF3, TSPAN2, FKBP4, HK2P1, CXCR4, GQ.0032512-developme 201688 S_AT, 201689_5 AT, 216953_5 AT, 201690 S AT, 229103 AT Gni, FLOT2, DMRT2, TP052, TPD52, WTI, , 3_28E-05 1984126984 0.00955745 WNT3, L6R4, SLCIA3, 110_11A,130.2, SPRY1, PCD}{13, ntal process 218326_5 AT, 202800 AT, 210347 S AT, 232614 AT, 212558 AT, 206935 AT, 229084 AT, 219497 S AT, 227103 S AT, 235275_AT, 211919_S AT, 212097 AT, CNTN4, BCLL1A, ECE2, BMP8B, CXCR4, CAV1, WTI, 206067 S AT, 243209 AT, 207725 AT, 209201 X AT, 213478 AT, 213568-AT, KCNC14, POU4F2, CXCR4, KAZ, OSR2, RET, C0L3A2, 211421 S AT, 221900_AT, 222891 S AT, 203685 AT, 207717 S AT
SCLI1A, BC1.2, PKP2 G0:0003006-reproducti 213361 AT, 218326_5 AT, 232614 AT, 977162 S
AT, 204557 S AT, 206067 S AT, ve developmental 8_34E-05 6_25 0.01385786 71'1419_S AT, 2013894 S AT, 209201_X AT, 217028_AT, 203685 AT, 223704 SAT, TDR07, L43R4, SC12, ADAMTSI, DZIP1 WTI, CXCR4, process 216953 S_AT
FKBP4, CXCR4, CXCR4, Bell, DMRT2, WTI
207865 S AT, 213361_AT, 41037 AT, 225638 AT, 204557_5 AT, 39966 AT, 227236 AT, 217028 AT, 206589 AT, 208078 S AT, 201683 S_AT, 201689_5 AT, 8M88, 1ERD7, TEAD4, LW, DZ1P1, CSPG5, TSPAN2, CXCR4, GFII, TPD52, TP052, TPD52, WNT3, GO:0048869-celiular 2.16953 S AT, 201690 S AT, 229103 AT, 202800 AT, 210347 S AT, 232614 AT, 0.00010797 1410901468 0_01.56803 SLC1A3, developrriental process 717C58 AT, 229084 AT, 2I9497_S_AT, 227103_5 AT, 235275 AT, 212097 AT, 13CLI1A, Bell, SPRY1 CNTN4, ECE2, 206067 S AT, 711 419 S_AT, 207725 AT, 209201 X AT, 213478 AT, 211421_S AT, EIMP8B, CAVI, WTI, CXCR4, P0U4F2, CXCR4, RET, 222891 S AT, 203685 AT
BC:111A, 13CL2 41037 AT, 222162 S AT, 52651 AT, 217028 AT, 2065E19 AT, 201688 S AT, GO:0009653-5n50omical TEAD4 TPD52, WNT3, LGR4, SLC1A3, B8613, CNTN4, , ADAMTSI, , 201639 S_AT, 216953_8 AT, 201690_S AT, 229103 AT, 218326 S AT, 202800 AT, COI RA7 CXCR4, 6F11, TPD52, TPD52, 0.00030745 2_643171806 0_03921862 132614 AT, 229084 AT, 206935 AT, 206067 AT, 211919 S AT, 212097 AT, structure morphogenesis S PC.DH8, WT1, CXCR4, CAV1, KCNQ4, POU4F2, 0.582, 243209 AT, 207725 AT, 213568 AT, 211421 S AT, 209201 X AT, 221900 AT, RET, CXCR4, COLEA2, Bell c oe Enriched among top upregulated genes:

Fold Term Pvalue Benjamini Probesets Genes Enrichment CA
219358 S AT, 1553995 A AT, 210495 X AT, 229221 AT, 223723 AT, 212258_AT, 209555_S AT, 223660 AT, 211066_X AT, 219412_AT, 205798 AT, 228579 AT, ADAP2, NT5E, FN1, C044, MFI2, NRP1, C036, ADORA3, 230360 AT, 226545 AT, 247303 AT, 207610 S AT, 220307 AT, 226629 AT, PCDHOIA17, RAB38, 1178, KCNQ3, GLDN, CD109, 201590 X_AT, 203922 S AT, 229937 X AT, 214830 AT, 203104 AT, 2_12977 AT, IFNGR1, EMR2, C.D244, 51C4142, ANXA2P1, Calk 202756 S AT, 228766 AT, 230925 AT, 243556 AT, 201005 AT, 201242 S AT, 11131111, SLC38A6, CSF1R, CXCR7, 6PC1, CD36, APB81.1P, 242907 AT, 209122 AT, 2135128 X AT, 214211 AT, 237252 AT, 214297 AT, NGEF, 609, ATP1B1, 58P2, PLIN2, PTGS1, FTH13, THBD, 202727 S_AT, 221060 S AT, 211719_X AT, 223596 AT, 223501 AT, 205898_AT, CSPG4, IFNGR1, TLR4, FN1, SLC12A6, TNFSF138, 34210 AT, 205099 S AT, 218613 AT, 210146 X AT, 215836 SAT, 217678 AT, CY3CF31, 6052, CCR1, P503, LILRB2, PCDHGA12, 232068 S AT, 209047 AT, 238581 AT, 1554992 AT, 209906 AT, 243483 AT, S1C7A11, TLR4, ACLP1, 6BP5, RASGRF1, C3AR1, TIMM, 210510 S AT, 211030_5 AT, 211676 S AT, 208171 S_AT, 238669 AT, NRP'1, SLC6A6, IFNGR1, PTPRO, PTGS1, NRCAM, 204105 S AT, 219994 AT, 201175 S AT, 203355 S AT, 202638 S_AT, APBBIJP, I113135, P503, 1CAM1, A7P1331,1110RA, MNIP2, 201243_S AT, 204912 AT, 201069 AT, 206206 AT, 228918 AT, 222877 AT, CD180, 5LC43A2, NFLP2, SYT11,ST3GAL.5, C0109, GO:0005886-plasma 1_02E-19 2_419799407 2_113E-17 227134 AT, 203217 S AT, 229900 AT, 244375 AI", 206488_S AT, 206171 AT, 6036, ADORA3, PTRF, ATP6V0D2, NOD2, PCDH7, membrane 208789 AT, 1553151 AT, 220066 AT, 228640 AT, 237442 AT, 203939 AT, AF'BBIJP, NT5E, STEAP1, !PARS, SLC41A2, COL6A1, 205542 AT, 2189E3 AT, 243894 AT, 213428 S AT, 205851 AT, M3665 AT, 10C100131909, HMOX1, AQP1, GBP2, ANXA2P2, NRP1, 0 207542 S AT, 202748 AT, 208816 X AT, 239519 AT, 208161 S AT, 221266_S AT, ABCC3, TRI7SF4, SLC7A11, INFSF1315, PTRF, LIANA, 209921_AT, 223502 S_AT, 1557938 S AT, 21208Ã X AT, 220484 AT, MCOLN3, THB0,11.R4, SUCNR1, P2RY14, CLEC7A, Ui 203887 S_AT, 224341_X_AT, 223939 AT, 206637_AT, 1555756 A AT, 203392 AT, EhIPP2, A8C131, PTG51, EMP1, FN1, FH1, ANXA2P1, 209993_AT, 215813 S AT, 201324 AT, 212464 S_AT, 216442 X AT, 213503 X AT, NGEF, ANXA2P1, EPS8, DIXDC1,11.711, C052, PTAFR, 0 =
227240 AT, 210427 X AT, 202609 AT, 214724 AT, 2262113 AT, 204661 AT, 6086,1E27RA,11286, CXCR7, ANKH, RAPH1, LIMP14, 211661 X AT, 210695_5 AT, 222062 AT, 2041.16_AT, 232746 AT, 223092 AT, GPR183, SLC41A2, NIDGA1, ALCAM, RAPH1, 1184, 225188 AT, 202827 S AT, 205419 AT, 235299 AT, 1560960 AT, 201952 AT, 6PR35, ff6E17, ADORA3, THOU, S1L41A2, MTUS1, 225185 S AT, 1552798 A AT, 2111264_AT, 205718 AT, 237904 AT, 203888 AT, 86513, 0LR1, ADAP2, MCOLN3, PLEKH01, C036, 2237913 AT, 212096 S AT, 210258 AT, 210004 AT, 222876 S AT, 229797 AT, TREM1, ALCAM
218223_S AT, 241929 AT, 219434 AT, 203-951 AT
223723 AT, 229221 AT, 209555 S_AT, 223660 AT, 203217 S_A7, 206488 S AT, Mf12õ 6044, CD36, ADORA3, ST3rl5l 5 6036, A1]opA3, 206171 AT, 228579 AT, 228640 AT, 242903 AT, 205542 AT, 205891 AT, KCNQ3, PCDH7, IFNGR1, STEAP1, 10C100131909, 207542 S AT, 2'38161_5 AT, 203922 S AT, 203104 AT, 202756 S AT, ABCC3, CYBB, CSF1R, GPC1, 11.114,THBD, CD36, ENPP2, 224341 X_AT, 203887 S AT, 228766 AT, 209392 AT, 2011305 AT, 201242 S_AT, C139, ATP1131, THBD, CSPG4, IFN6R1, T1R4, EPS8, GO:0031226-intrinsic to 237252 AT, 214297 AT, 202727 S AT, 221460 S_AT, 202609 AT, 223596 AT, 1_09E-11 3.2E7558528 7.78E-10 S1C12A6, CD52, CD52, CX3CR1, CCR1, PTAFR,11.27RA, plasma membrane 34210 AT, 204661 AT, 205898 AT, 205099 S AT, 21.1661_X AT, 222062 AT, ELM, ULM, PAMP14, ANKH, AQP1, GPR183,1184, 204116_AT, 210146_X AT, 202827_S AT, 223092_AT, 209047 AT, 20541_9 AT.
C3AR1, MDGA1, SLUM, 6PR35, IFNGR1, PTPRO, TLR4, 232068 S AT, 209906 AT, 1560960 AT, 211030 S AT, 210264 AT, 211676 5 AT, 1T687, ADORA3, THRD, NRCAM, 0LR1õ C036, ITG85, 208121 S AT,1552798 A AT, 205718 AT, 237904 AT, 2038.88 AT, 204105 S AT, ICAM1, ATP1R1 210004 AT, 241929 AT, 201124 S AT, 202638 S AT, 201243 S AT
Ui oe Fold Term Pvalue Benjamini Probesets Genes 0 Enrichment 1553995 A_AT, 223723 AT, 212798 AT, 223660 AT, 222838 AT, 219412_AT, CA
205798 AT, 205960 AT, 22E579 AT, 238681 AT, 217997 AT, 226545 AT, 227747 AT, 205505 AT, 770107 AT, 226629 AT, 216080 S AT, 201590_X_AT, NT5E, MFI2, tan, ADORA3, SLAMF7, RAB39, RJR, L.) Uvi 243922 S AT, 218686 S AT, 223.815 AT, 203104 AT, 202756 S AT, 228766 AT, P01(4, KCHQ3, GDPD1, PHLDA1, C0109, MP713, GCNT1, 205128 X AT, 214211 AT, 214581_X AT, 63825 AT, 211719_X AT, 223501 AT, CO244, S1C43A2, FADS3, ANXA2P1, CYBB, RHELDF1, 205898 AT, 205099_5 AT, 219574 AT, 210146 X AT, 215836 S AT, 235944 AT, ABHD2, CSF1R, GPC1, 6036, PTGS1, FTHL3, TNFRSF71, 209047 AT, 240076 AT, 1554992 AL 219926 AT, 235458 AT, 211676 S AT, ABHD2, FN1, THFSF138, CX3CR1, 6681, MARCH1, 225842 AT, 238669 AT, 204257 AT, 204105_5 AT, 224983 AT, 206134 AT, ULM, PCDHGA12, HMCN1, ACIP1, GCNT1, RASGRF1, 202638_5 AT, 239761 AT, 201243_5 AT, 204912 AT, 238638 AT, 228918 AT, POPDC3, HAVCR2, IFNGRI, PHLDA1, PTGS1, FADS3, 227134 AT, 222877 AT, 212062 AT, 202434 S AT, 222858 S AT, 204222 S AT, NRCAM, C40RF34, ADAMDEC1, ICAM1, GCNT1, 229900 AT, 241392 AT, 206488 S AT, 208789 AT, 1553151 AT, 220066 AT, ATP1B1, IL1ORA, SLC37A2, SLC43A2, SYTL1, NRP2, 226640 AT, 205542 AT, 213338 AT, 203665 AT, 205891 AT, 202748_AT, ATP9A, CYP1131, DAPP1, GLIPR1, 613109, TM ENI39A, 208816 X AT, 239519 AT, 208161 5 AT, 218856 AT, 210145 AT, 223502_5 AT, 6036, MU, ATP6V0D2, N002, PCDH7, STEAP1, 227889 AT, 236345 AT, 1557938 S AT, 2050133 AT, 2/2086 X AT, 271939 AT, TMEM158, HMOX1, 106100131909, 68P2, ANXA2P2, 203887 S AT, 206637 AT, 211138 S AT, 1555756 A AT, 215813 S AT, NRP1, ARrrl, TNFRSF21, PLA2G4A, I11FSF1313, LPCAT2, 227240 AT, 210427 X AT, 226218 AT, 204661 AT, 225809 AT, 210895_5 AT, TRXAS1, PTRF, 000K4, LMNA, SUCNRI, THRD, P2RY14, 2221362 AT, 232746 AT, 210512 S_AT, 225188 AT, 211527_X AL 224990 AT, KMO, CLEC7A, PTGS1, NGEF, ANXA2P1, IL7R, 0:152, 1560960_AT, 201952_AT, 225169 S_AT, 210264 AL 205718 AT, 2111258 AT, PARM1, C086, 1127RA, CXCR7, VEGFA, RAPH1 VEGFA, GO:0016020-membrane 8.59E-12 L538151311 123E-10 210757 X AT, 222876 S AT, 2101304 AT, 229797 AT, 201280 AT, 2131951 AT, C40RF34, MDGA1, ALCAM, RAPH1, GP835, IT687, 220333 AT, 219358 S AT, 210495_X AT, 229221 AT, 209555_5 AT, 202435_5 AT, Rs,s11, DAB?, ADAP2, OLR1, MC0LN3, 0A132, ALCAM, 211066 X AT, 217999 S AT, 224480 S AT, 242671 AT, 214255_AT, 230360 AT, PAWLS, ADAP2, FN1, 6044, C036, CYP1131, PCDHGA12, 242903 AT, 228490 AT, 207E10 5_AT, 229937 X AT, 214830 AT, 227052 AT, PHLDA1, AGPAT9, PAQR5, ATP1CIA, OWN, IFNGR1, 217977 AT, 230925 AT, 243556 AT, 201005_AT, 201242_S_AT, 242907 AT, AFIHD2, EMR2, LILRB1, S1C38A6, 6408134, CXCR7, 209122 AT, 237252_AT, 217171 X AT, 214297 AT, 237030 AT, 202727 S_AT, APB811P, NGEF, 609, ATP1131, 68P2, PUNZ THEE), 221060 S AT, 223596 AT, 34210 AT, 205566 AT, 218613 AT, 217678 AT, VEGFA, CSPG4,ACPP, IFNGILL, TIM, SLC12A6, 0o52, 232068 S AT, 238581 AT, 57715 AT, 209906 AT, 243483 AT, 210510 S AT, ABHD2, P503, SLC7A11, 1184, GBPS, CALHM2, C3AR1, 210513 S AT, 211030 S AT, 208121 S AT, 223434 AT, 204881_9 AT, 225097 AT, TRPM3, NRP1, VEGFA, SLO6A6, PTPRO, 68P3, UGCG, 219994 AT, 205306 X AT, 203355_5 AT, 201125 S AT, 226136 AT, 201069 AT, HIPK2, APBBlIP, 1080, P5133, ff685, GUPR1, MMP2, 206206 AT, 2032_17_5 AT, 201278 AT, 244375 AT, 206171 AT, 218854 AT, CD180, ST3GAL5, 0A82, EVL, ADORA3, DSE, APBBlIP, 237442 AT, 203939 AT, 218589 AT, 243894 AT, 213428 S_AT, 202436 S AT, NT5E, LPAR6, SLC41A2, COL6A1, CYP1131, AQP1, 207542 S AT, 2219A5 S AT, 201279 S AT, 219386 S AT, 221266 S AT, CALHM2, DAB2, &AMES, TM7SF4, SLC7A11, ASH 02, 209921 AT, 225337 AT, 220484 AT, 224341 X AT, 228762 AT, 209392 AT, MCOLN3, 1184, LFNG, ENPP2, EMP1, ARCI31, 201324 AT, 209993 AT, 212464 S_AT, 1555606 A AT, 216442 X_AT, GDP101, FN1, ANXA2P1, 8A82713, EPS8, DIXDCI, FIRER, 213503 X AT, 228708 AT, 202609_AT, 214724 AT, 211661 X AT, 214841 AT, CNIH3,11286, PDX4, SLAMF8, MMP14, ANKH, ABH02, 204116 AT, 225207 AT, 219385 AT, 202827 S AT, 2_23092 AT, 87100 AT, GPRI83, CKLF, SLC41A2, HAVCRZ CYP181, 1184, THBD, L.) 2135419 AT, 235286 AT, 219,99 AT, 1554285 AT, 202437 S AT, 1552798 A AT, ADCIRA3,S1C4142, MTUS1, PLEKH01, 6036, TREM1 Uvi 203888 AT, 23791M AT, 223798 AT, 212096 S AT, 218223 S AT, 241929 AT, oe , Fold Term Pvalue Benjamini Probesets Genes 0 Enrichment 1.) 223723 AT, 229221 AT, 209555_5 AT, 223660 Al; 203217 S AT, 206488 S Ar, ,-, IVIFI2, 044, 0336, ADORA3, ST3GAL5, C.036, ADORA3, CA
20617/ AT, 228579 AT, 228640 AT, 242903 AT, 205542 AT, 205891 AT, KCH03, PCDH7, IFNGR1, STEAP1,10C100131909, AUL
Ci-s 2137542 S AT, 208161 S AT, 203922 S AT, 203104 AT, 202756 S AT, ABCC3, C1938, CSF1R, GF'Cl, T1134, THE113, co36, ENPP2, .1=.
224341 X AT, 203887_S_AT, 22E766 AT, 209392 AT, 201005_AT, 201242 S AT, 1.) 09, ATP1131, TH8D, CSPG4, 1FNGR1, TLR4, EPS8, Un GO:0005887-Integral to 237252 AT, 214297 AT, 202727_5 AT, 221060 S
AT, 202609 AT, 223596 AT, =
2_42E-11 3_249703017 1_046-09 SLC12A6, C052, 05', CX3CR1, CCR1, PTAFR, 11273A, plasma membrane 34210 AT, 204661 AT, 2135898 AT, 205099_5 AT, 211661 X AT, 222062 AT, IURG, 1iL382, MMP14, ANKH, AQP1, 6PR183, T1R4, 204116 AT, 210146 X AT, 202827_5 AT, 223092_AT, 209047 AT, 205419 AT, C3AR1, SLC6A6, GPR35, IFfiGR1, PTPRO, 11R4, ITG137, 232068 S AT, 209906 AT, 211030 S AT, 210264_AT, 211676 S AT, 208121_5 AT, A0ORA3, TH80, NRCAM, 0011, CD36, IT685,1CAM1, 1552798 A AT, 21757113_AT, 237904 AT, 203868 AT, 2114105 S AT, 210004 AT, 241929 AT, 20117S S AT, 202638 S AT, 201243 S AT
210495 X AT, 223723 AT, 223221 AT, 209555 S AT, 223660 AT, 227134 AT, 203217 S AT, 219412 AT, 2057913 AT, 206488 S AT, 244375 AT, 206171 AT, FN1, MF12, C1344, 036, ADORA3, SYTU, S13GA1S, 228579 AT, 208789 AT, 1553151 AT, 228640 AT, 237442 AT, 242903 AT, RA838, 11.73, C036, EVI_, ADORA3, KCN03, FTRF, 205542 AT, 203665 AT, 205891 AT, 207542_5 AT, 202748 AT, 220307 AT-, ATP6V002, PC13147, APE1811P,IFNGR1, STEAK, HMOX1, 208161 S_AT, 203922 S AT, 214830 AT, 1557938 S AT, 203104 AT, 1_6C100131909, AQ91, 613P2, CO244, ABCC3, CY1313, P
202756 S AT, 224341 X AT, 203887 S AT, 228766 AT, 1555756 A AT, SLC38A6, IMF, CSF1R, GPC1, T1R4, TH813, C036, o n, 230925 AT, 209392 AT, 201005 AT, 201242 S AT, 209993 AT, 242907 AT, CI
Fr'7A, AP81311P, EhIPP2, CD9, ATP1111, Al3C81, 6E1P2, u, n, I-' o GO:0044459-plasrna 212464 S AT, 237252 AT, 216442_X AT, 214297 AT, 202727 S AT, 221060 S AT, FM1, TH613, FM, CSPG4, IFNGRI., 11E4, FN1, Ens, .
1_97E-112.403721216 1.06E-09 u.) ,..
membrane part 211719 X_AT, 202609 AT, 214724 AT, 223596 AT, 226218 AT, 34210 AT, D1XDC1, SICI2A6,117R, CD52, 052, CX3CR1, CCR1, iP ND
204661 AT, 205898 _AT, 205099_3 AT, 211661 X AT, 210895 S AT, 218613 AT, PTAFR, 086, P303,1127RA,11236,1JL11.82, MMP14, o o , 222062 AT, 204116 AT, 210146 X_AT, 202627 S AT, 223092_AT, 225188 AT, ANKH, RAPHL AQP1, GPR183,11R4, G8F5, C3AR1, 1-n, 209047 AT, 205419 AT, 232068 S_AT, 238581 AT, 209306 AT, 1560960 AT, PADGAL 111PM8, ALCM, RAPH1, 5I.C6A6, GP335, 1 243483 AT, 201952 AT, 225189 S AT, 211030 S_AT, 210264 AT, 211676_5 AT, 1FNGR1, PTPRO, nm, IT6137, ADORA3, TH813, NRCAM, o 208121 S AT, 1552798 A AT, 20571B AT, 237904 AT, 203888 AT, 2.04105 S AT, 01.111, AP131311P, C036, P51)3,111105, ALCAM,ICAM1, 210004 AT, 21.9994 AT, 241929 AT, 203355_6 AT, 201125 S AT, 201_951 AT, 202638 S AT, 201243 S AT
' 2261_36 AT, 229221 AT, 223723 AT, 21.0495 X AT, 201069 AT, 212298_AT, 205798 AT, 204222 S AT, 22.9900_AT, 203936 S_AT, 226545_AT, 37145 AT, GLIPR1, C044, A4F12, FNL LIMP2, NRPL, 1173, GLIPRL
203665 AT, 21.3428 S AT, 208816 X AT, 239519 AT, 201590 X AT, 212190 AT, 13109, AMPS, 0109, ONLY, HAMM, COL6A1, 223502 S AT, 206157 _AT, 212143 S AT, 202458 AT, 203887 S_AT, 202756 S AT, AN)CA2P2, N3P1, ANXA2P1, SERPINE2, TNFSF1.38, P11(3, 201422 AT, 204834 AT, 205495 S_AT, 228873 AT, 249392 AT, 228762 AT, IGH3P3, PRS523, TH1313, GPCL 1E130, FG12, ONLY, IV
G0:0005576-extratellula 210095 S AT, 213265 AT, 2091.22 AT, 212464 S_AT, 237252 AT, 216442 X AT, C.01.22A1, EhIPP2, LING, IGF8P3, P6A5, PLJN2, Fin, n 1_376-10 2.823873071 4.90E-09 r region 237030 AT, 212171_X_AT, 213503 X AT, 204575 S
AT, 1405_1 Al; 210427 X AT, TH813, FN1, ACPP, VEGFA, ANXA2P1, IVIMP1.9, (II S, 211719_X AT, 226218 AT, 223501 AT, 206835 AT, 207433 AT, 227265 AT, ANXA2P1, FN1,1173, TNFSF138, STAIN, 1110, FGL2, Cl) 1.) 235944 AT, 210512 S AT, 202827 S AT, 221463 AT, 711S27_X AT, 204475 AT, HMCN1, VEGFA, PAMP14,CC124, VEGFA, MM171, exi F, 0 1-, 235286 AT, 217757_AT, 229004 AT, 204655 AT, 210510 S AT, 210513 S AT, A2M, ADAMTS15, CC15, NRP1, VEGFA, TH80, 0181, Un 203888 AT, 210004 AT, 206134 AT, 202087_6 AT, 1555759 A_AT, 1556423 AT, ADAMDE1, C1511, CC15, VASHL TREM1, ICAliAl Ci-s W
219434 AT, 202638 S AT
oe o o 1-, Fold Term Pvalue Benjamini Probesets Genes Enrichment h.) 0 ' 220333 AT, 1.553995 A AT, 225221 AT, 223723 AT, 212298 AT, 209555 S AT, PAQR5, NT5E, CD44, MHZ NRP1, C.D36, ADORA3, 223660 AT, 222838 AT, 211066 X AT, 2135798 AT, 224480_5 AT, 214255_AT, SLAMF7, PCDHGA12,117R, AGPA.19, ATP10A, PALMS, 242871 AT, 238661 AT, 228579 AT, 230360 AT, 226545 AT, 242503 AT, .6.
GDP131, Kaiak GLDN, C0109, IFNGR1, NIPZ13, A8H02, h.) 227747 AT, Z28490 AT, 207610 S AT, 205505 AT, 220307 AT. 226629 AT, CA
EMFt2, GCNT1, CO244, SLC41A1, FADS3, CY1313, RHIMF1, 216080_5 AT, 203922 S_AT, 218686_S_AT, 229937 X AT, 221815 AT, 214830_AT, 1.113131., ABHD2, 51E38A6, C40RF34, CSF1R, CX.CR7, 227052 AT, 203104 AT, 212977 AT, 202756 S_AT, 228766 AT, 201005_AT, GPC1, C036, C09, ATP1131, TNFFISF21,11-180, ACPP, 201242 S AT, 2145,51_X AT, 237252_AT, 237030 AT, 214297_AT, 61325_AT, CSPG4, ABH02, IFNGRI,TLR4, SLC12A6, TNFSF1.38, 202727 5 AT, 221060 5 AT, 223596 AT, 223501 AT, 205898 AT, 34210 AT, CX3CR1, C052, CCR1, A8H02, MARCH1,1111182, 205099_S_AT, 205566_AT, 219574_AT, 210146_X_AT, 21.5836_5_AT, 217678_AT, PCDH(3Al2, SLC7A11, 11.34, GCNT1, 1, CALHAl2, 232068 5 AT, 240076 AT, 209047 AT, 57715 AT, 209906 AT, 2434/33 AT, C3A11.1, TRPK48, NRP1, SLUM, HAVCR2, POPDC3, 210510_S_AT, 211030_S_AT, 235458_AT, 219926_AT, 211676_S_AT, 708121_8_AT, IFNGR1, PTPRO, FADS3, 68P3, C40RF34, NRCAM, 204257 AT, 223434 AT, 224989 AT, 204105_5 AT, 204881 S AT, 206134 AT, G0:0031224-intrinsic to 205306 X AT, 201125 S AT, 202638 5 AT, 239761 AT, 201243 5 AT, 226136 AT, UGCG, ADAMDEC1, KMO, ITG85, ICAM1, GCH11, 437E-10L6&3683734 1.53E-08 .
ATP1131, GUPRZ1L1DRA, 51C37A2, CD180, SLC43A2, membrane 204912 AT, 238638 AT 206206 AT, 228918 AT, 222877 AT, 203217 S AT, NRP2, ST3GALS, ATP9A, C0109, GLIPR1, C036, 212062 AT, 225900 AT, 204222 S AT, 206488 5 AT, 241392 AT, 206171 AT, TMEM39A, ADORA3, OSE, PCDH7, KBE, STEAPI, P
218354 AT, 22/1640 AT, 203939 AT, 205542 AT, 213338 AT, 218589_AT, TMEM158, LPAR6, SLC41A2, 10C100131909, AQP1, 243894 AT, 205891 AT, 207542 5 AT, 221565_5 AT, 23951.9 AT, 219386_5 AT, "
CALI1M2, NRP1, SLAWS, ABCC3, TM7SF4, SLC7A11, ' u, 208161 S AT, 221266 S AT, 209921 AT, 212856 AT, 210145 _AT, 227889_AT, Iv TNFRSF21, PLA2G4A,LPCAT2, INFSF1313, /WW2, I-` 0 223502_5 AT, 225337 AT, 236345 AT, 220484 AT, 2038.87_5_AT, 224341 X AT, La o.
TIDCA51, MCOLN3, 114130, TLR4, SUOMI., P2RY14, KMO, Ln .
223539 AT, 206637 AT, 211138 S AT, 1555756 A AT, 209392 AT, 228762 AT, Iv CLEC7A, ENPP2, LFNG, ABCB1, EMP1, GDP111, RA13278, 209993 AT, 201324 AT, 1555606 A AT, 228708 AT, 202609 AT, 2262I8_AT, v, EPS13, 3_73, C052, PARM1, PTAFR, Cht1H3, CUBS, 11273A, , 204661 AT, 225809 AT, 211661._X_AT, 214841 AT, 210895 S_AT, 222062_AT, C.XCR7, II2RG, &AMER, ANKH, MNIP14, GPR1133, Iv 232746 AT, 204116 AT, 219385 AT, 223092 AT, 202827 S AT, 205419 AT, A81402, C.KLF, C40RF34,SLC41A2, MDGA1, HAVCR2, o, 87100 AT, 2352E6 AT, 224990 AT, 235299 AT, 1560960 AT, 1554285 AT, ALCAM, TLR4, GPF135, IT087, ADORA3, THBD, 51C41A2, 201952 AT, 1552798 A AT, 210264 AT, 205718_AT, 237904 AT, 203888_AT, 01_31, MCOLN3, C036, TREM1, ALCAM
22.3798 AT, 210004 AT, 229797 AT, 241929 AT, 219434 AT, 201951_AT
220333_AT, 204912 AT, 229221 AT, 212298 AT, 209555 S AT, 223660 AT, 206206 AT, 222838 AT, 222877 AT, 205798 AT, 2064813_5 AT, 205960 AT, FM135,1103,4, CD44, NRP1, CD36, ADORA3, C0180, 206171 AT, 242871 AT, 200878 AT, 242903_AT, 218589 AT, 203760 S AT, SLAMF7, NRP2, IL7R, CD36, PDK4, ADORA3, PAQ115, 203665 AT, 205891_AT, 207610_5_AT, 220307_AT, 239519 AT, 2131156 AT, EPAS1, IFNGR1, LPAR6, SLA, HMOX1, LOC1001.31909, 218686_5 AT, 229937 X AT, 203104 AT, 217377_AT, 223939 AT, 224341 X AT, EMR2, CO244, NRP1, 11IFRSF21, RH80F1, LILRB1, 203887 S AT, 206637 AT, 228766 AT, 1555756 A AT, 209392 AT, 214581 X AT, CSF1R, CXCR7, SUCNR.1,11.114, TH8D, P2RY14, CD36, IV
60:0004871-signal n 1.04E-10 2337224567 2.51E-08 2.37252_AT, 214297 AT, 202727 S AT, 1405_1_AT, 221060 5 AT, 202609 AT, CLEC7A, ENPPZ TNFRSF21, THBEI, C5PG4, IFNGR1, CC1-5, transducer activity 214724 AT, 226218 AT, 205898_AT, 205099_5 AT, 211661 X AT, 210895_5 AT, 11.34, EPS8, DIXDC1,11.713, CX3C31, CCR1, PTAFR, C086, 222062 AT, 204116 AT, 232746 AT, 225207 AT, 210/46 X_AT, 235944 AT, 11.27RA,11236, CXCR7, P01(4,111.11132, HMCN1, GPR183, (/) h.) 205419 AT, 232068 S AT, 209906 AT, 243483 AT, 210510 S AT, 204655 AT, 71114, C3AR1, TRPM8, NRP1, cas, 001(2, IFNGR1, 0 1-, 214054 AT, 211676 S AT, 208121 S AT, 1552798 A AT, 210264 AT, PTPRO, 71.114, GPR35, 51(11,17G87,TH8D, A003A3, SLA, CA
206675 S AT, 205718 AT, 203888 ATõ 237904_AT, 203761 AT, 210258_AT, RGS13, 0131, CC15, CD36,1TG135, TREM1, ICAM1 W
210004 AT, 1555759 A AT, 241929 A7, 201125 S AT, 21_5434 AT, 202638 S AT
oe o o 1-, Fold Tenn Piralue Bernamini Probesets Genes 0 Enrichtnent 220333 AT, 20491.2_AT, 229221_AT, 212298 _AT, 209555 S AT, 223660 AT, CA
206206 AT, 22211118 AT, 222877 AT, 205798 AT, 206488_5 AT, 205960 AT, PAC/115,1110RA, C044, NRP1, CD36, ADORA3, C01110, 206171 AT, 242871 AT, 200878 AT, 242903_AT, 218589 AT, 203760_5 AT, SLAMF7, NRP2, L7R, C036, POK4, ADORA3, PAQRS, 203665 AT, 205891_AT, 207610_5 AT, 220307 AT, 239519 AT, 218856 AT, EPAS1, IFNGR1, LPAR6, SLA, HMOX1, 10C100131909, 218686 S AT, 229937 X AT, 203104 AT, 212977 AT, 223939 AT, 224341 X AT, EMR2, CO244, NRP1, INFRSF21, RH 80F2, LILRB1, 203887 S_AT, 206637 AT, 228766 AT, 1555756_A AT, 209392 AT, 214581_X AT, CSF1R, CXCR7, S1JCNR1, TLR4, THEO, P2RY14, C036, G0:0060083-molecular L04E-10 2337224567 231E-08 237252 AT, 214297 AT, 202727 S AT, 1405_1_AT, 221060 S AT, 202609 AT, CLEC7A, ENPP2, TNFRSF2.1., TH8D, C.SPG4, IFNGR1, transducer activity 214724_AT, 226218 AT, 205898 AT, zason S AT, 231661 X AT, 210895 S AT, I154, EPS8, DIXDC1,117R, CX3CR1, CCU, PTAFR, C086, 222062_AT, 204116 AT, 232746 AT, 225207 AT, 2.3.0146_x AT, 235944 AT, 11275A, 'LUG, CXCR7, P01(4, L11R82, HMCN1, GPR183, 205419 AT, 232068 S AT, 203906 AT, 243483 AT, 210510 S AT, 204655 AT, TLR4, C3AR1, TRPM8, NRP1, CCIS, 001(2, IFNGR1, 214054 AT, 211676_S_AT, 208121 S AT, 1552798 A AT, 210264 AT, PTPRO, 7154, GP535, SKIL, IT5137, 111I30, ADORA3, &LA, 206675_5 AT, 205718 AT, 203888 AT, 237504_AT, 203761 AT, 210258 AT, 56513, 0151, 035, C036, IT685, 111EM1, ICAM1 210004_AT,1555759 A AT, 241929 AT, 201125_5 AT, 219434 AT, 2.02638_5 AT
220333 AT, 229221. AT, 204912 AT, 712298 AT, 209555 S AT, 223660 AT, PAQR5, C044,1110RA, NRP1, 0D36, ADORA3, 03180, 206206 AT, 222838_AT, 222877 AT, 205798_AT, 206488 S AT, 206171_AT, SLAMF7, NRP2,1135, CD36, ADORA3, PAQR_S, IFNGR1, 242871 AT, 242903 AT, 218589_AT, 205891_AT, 20761.0_5 AT, 220307 AT, LPAR6, LOCID0131909, EM R2, 09244, NRP1, TNFRSF21., 239519_AT, naas6 AT, 218686_5 AT, 229937 X AT, 203104 AT, 212977 AT, RHBDF1, LILRB1, CSF1R, CXCR7, SUOMI, 1154, TH80, 223939 AT, 224341_X AT, 203887 S AT, 2211766 AT, 206637 AT, 1555756 A AT, GO:01304872-receptor 0336, P2RY14, CLEC7A, ENPP2, THFRSF21, TH8D, 6.20E-112576306146 239E-08 209392 AT, 214581 X AT, 237252 AT, 202727 S AT, 221060_S AT, 202609 AT, activityIFNGR1, TLR4, EPS/1,1175, CX3CR1, CCR1, PTAFR, C086, 2262111_AT, 205898_AT, 205099_5_AT, 211661_X_AT, 210895_S_AT, 222062_AT, 1127RA,11.256 CXCR7, ULF1112, HMCNT, GP5183, TLR4 204116 AT, 232746 AT, 210146 X AT, 235944 AT, 205419 A7, 232068 S AT, C3ARI, TFIPA48, NRP1, GP635, PTPRO, IFNGR1,11114, 209906 AT, 243483_AT, 210510 S AT, 210264 AT, 208121 S_AT, 211676 S AT, IT5137, ADORA3, THBD, 01R1, CD36, ITG85, TREM1, 1552798 A AT, 205718 AT, 237904 AT, 20388E1 AT, 210004 AT, 241929 AT, 201125 S AT, 2/9434 AT, 202638_5 AT
JI
oe Fold Term Pvalue Benjamini Probesets Genes Enrichment 1553995 AT, 220333 AT, 210495_X AT, 229221 AT, 223723_AT, 212298_AT, 209555 S_AT, 202435 S AT, 223660 AT, 222838_AT, 211066_X_AT, 219412_AT, NT5E, PAQR5, FN1, C044, MF12, NRP1, C036, CYP1.81, 205798 AT, 224480 S AT, 214255_AT, 242871_AT, 23E681 AT, 228579...AT, ADORA3, SLAMF7, PCDHGA.1.2, RA.1338, IL7R, AGPAT9, 1µ.) 230360 AT, 226545 AT, 227747_AT, 247_903_AT, 228430 AT, 207610_S_AT, Uvi ATP10A, PAQR5, G0P01, KCNC13, GUM, C0109, MPZ1_3, 205505 AT, 220307 AT, 226629 AT, 216080_S_AT, 203922_S_AT, 218686_S_AT, IFNGR1, ABHD2, EMF12, GCNT1, CO244, SLC43A2, 229937 X AT, 221815 AT, 214830 AT, 227052 AT, 203104 AT, 71 '7977_AT, FADS3, CYRIL 8118081, ULR111, ABHD2, 3LC38A6, 202756 S AT, 228766 AT, 230925 AT, 201005_AT, 201242_S_AT, 242907_AT, C40RF34, CSF1R, CXCR7, GPC1, C036, AP8611P, CDS, 209177 AT, 205128 X AT, 214581 X AT, 237252_AT, 237030_AT, 214297_AT, ATP181, G5F2, PUN2, FTScl TNFRSF21, THEID, ACPP, 63825 AT, 202727 S AT, 221000 S AT, 211719_X_AT, 223596_AT, 223501_AT, CSPG4 ABM", WNGRI,TLR4, FN1, SLC12A6, TNFSF138, 205898 AT, 34210 AT, 205099 S AT, 205566_AT, 219574 AT, 218613_AT, CX3CR1, CD52, CC11.1, AB1102, MARCH1, P503, ULR82, 210146 X AT, 215836 S AT, 217678 AT, 232068_S_AT, 240076_AT, 209047_AT, PCDHGA12, SLC7A11, T1R4, GCNT1, AQP1, 68P5, 238581 AT, 57715 AT, 209906 AT, 243483 AT, 210510 S AT, 211030_S_AT, CALI4M2 C3AR1, TRPME, NRP1, SLC6A6, HAVCR2, 235458 AT, 219926 AT, 208121 5_AT, 2.11676_S_AT, 238669_AT, 2042.57_AT, POPDC3, PTPRO, WNGR1, PTGS1, FADS3, 68P3, 223434 AT, 224989 AT, 204105 S AT, 204881 S_AT, 206134_AT, 205306_X_AT, C4ORF34, NRCAM, UGCG, ADAMDEC1, KARL AP81311P, 219994 AT, 201125 S AT, 203355 S AT, 202638_S_AT, 239761_AT, 201243_S_AT, 1115/35, P503, IC.AM1, GCNT1, ATP1B1, GLIPR1,11.113RA, 226136 AT, 204912 AT, 238638 AT, 206206 AT, 228918 AT, 222877_AT, GOM44425-membrane 5LC37A2, CD180, 5LC43A2, NRP2, SYTU, ST3GALS, L40E-09 L538980298 175E-08 227134 AT, 203217 S AT, 212062 AT, 202434_S_AT, 222858_S_AT, 201278_AT, putATP9A, CYP161, DAPP1, DAB2, CD109, GLIPR1, EV1, 229900 AT, 204222 S AT, 244375_AT, 206485 S AT, 241392 AT, 206171_AT, C036, TMEM39A, ADORA3, DSE, ATP6V0D2, PTRF, 218854 AT, 1553151_AT, 208789 AT, 228640 AT, 203539 AT, 237442_AT, PCD147, NT5E,AP8811P, STEAP1, TMEM158, SLC41A2, 245542 AT, 213338 AT, 243894 AT, 2113589 AT, 205891 AT, 203665_AT, LPAR6, L0C100131909, HMOX1, CYP1B1., CALHM2, 202436 S AT, 221565 S_AT, 207542 S AT, 201279_S_AT, 202748_AT, 239519_AT, AQP1, DA82, G8P2, NRP1, SLAMF8, AFICC3, TM7SF4, 219386 S_AT, 208161_5 AT, 221266 S AT, 209921_AT, 218856_AT, 210145_AT, SLE7A.11, TNFRSF21, PLA2G4A, LPCAT2, INFSF138, 227889 AT, 223502 S AT, 225337 AT, 236345_AT, 1557938 S AT, 205003_AT, ABH02, TEXAS1, PTRF, DOCK4, MCOLN3, THRD, T1.F14, 220484 AT, 203887_S_AT, 224341_X_AT, 223939_AT, 206637_AT, 211138_S_AT, SUCNR1, P2RY14, KMO, CLEC7A, ENPP2, LFNG, ABC81, 1555756 A AT, 209392 AT, 27_8762 AT, 205993 AT, 201324 AT, 215813_5_AT, EMP1, PTGS1, FN1, 60801, FN1, RA8278, EPS43, D1XDC1, 212464 S AT, 1555606 A RT, 216442_X AT, 228708_AT, 202609_AT, 214724_AT, 11.711 C052, PARM1, PTAFFt, CN1143, C086, IL27RA, 226218 AT, 204661_AT, 225809_AT, 211661 X_AT, 214841_AT, 210895_S_AT, aCR7,11.230, SLAM F8, ANKH, RAPH1, MM P14, 222C11, AT, 232746 AT, 204116 AT, 219385 AT, 223092 AT, 2251.88_AT, 6PR183, ABHD2, CKLF, C40RF34, SLCA1A2, ht0GAI., 202827 S AT, 205419 AT, 87100 AT, 235286 AT, 224990 AT, 2352.99_AT, ALCM, HAVCR2, CYP181, RAPH1, 11114, 6PR35, IT687, 1560960 AT, 201952_AT, 15542.85_AT, 202437_S_AT, 225189_5 AT, ADORA.3, TH8D, SLC41A2, 082, 0111, MCOLN3, 0A82, 1552798 A_AT, 210264 AT, 205718 AT, 237904 AT, 243868 AT, 223798_AT, C036, TREML ALCAM
210757_X AT, 210004 AT, 229797_AT, 201280 S AT, 241929 AT, 219434_AT, 1µ.) Uvi Cie Fold Tenn Pvalue Bernamini Probesets Genes 0 Enrichment .
h..1 220333 AT, 229221 AT, 223723 AT, 212298 AT, 209555 S AT, 223660_AT, CA
222E138 AT, 211066 X AT, 205798 AT, 2244E0 5 AT, 214255 AT, 242.871_AT, PAC015, 0)44, MR2, NRP1, C036, ADORA3, SLAMF7, 238661 AT, 226579 AT, 230360 AT, 242_903 AT, 227747 AT, 228490 AT, PCDHGA12,11-79, AGPA19, ATP111A, PAQ95, GDPD1, 0 207610 S AT, 205505 AT, 220307 AT, 226629 AT, 216080 5 AT, 203922 S AT, KCNC13, OWN, If NG91, MPZL3, A2HD2, E8192, GCNT1, 4=..
h..1 213686_5 AT, 229937 X_AT, 221815 AT, 214830 AT, 227052 AT, 203104 AT, CO244, S1C43A2, FAD.53, CYRES, RHBOF1,111681, ABH02, (A

21.2977_AT, 202756 S AT, 228766_AT, 201005 AT, 201242 S AT, 2145131 X AT, 51C311A6, C40RF34, CSF1R, C.XCR7, GPC1, 0)36, 0)9.
237252 AT, 237030 AT, 214297 AT, 63825 AT, 202727 S_AT, 221060_S AT, ATP1131õ114FRSF21., 7E8D, ACFP, CSPG4, A8H02, 223596 AT, 223501 AT, 205898 AT, 34210 AT, 205099 S_AT, 205566 AT, IFNG91,11114, SLCL7A6, TNFSF138, CX3CR1, 0)52, 219574_AT, 210146 X AT, 215836_S _AT, 217678 AT, 232068 S AT, 240076_AT, CCR1, A8E02, MARCH1,111.982, PCDHAA1 7, 31C7A11, 209047 AT, 57715 AT, 209906 AT, 1434133 AT, 210510_5_AT, 211030 5 AT, 11.94, 6C33T1., AQP1, CALE1M2, C3Aftl, TRPMS, NRP1, 235453_AT, 219926 AT, 211676 S_AT, 206121_5 AT, 204257 AT, 223434 AT, SLC6A6, HAVCR2, P070C3, IFNGFQ, PTPRO, FADS3, 224989 AT, 204105 5 AT, 204881 S AT, 206134 AT, 205306 X AT, 201125 S AT, 6873, C408F34, NRCAM, UGCG, ADA.MDEC1, KMO, G01:1016021-integral to 202638 S_AT, 239761 AT, 201243 S_AT, 226136 AT, 204912 AT, 238638 AT, 17085,1CAMI, GCNT1, ATP1131õ 0E1791,1110RA, 1.965-09 1_675513671 4.73E-08 membrane 206206 AT, 226918 AT,*222877 AT, 203217 5 AT, 212062 AT, 204222 S_AT, SLC37A2, CD180, SLC43A2, NR72, S13Ctol 6, ATP9A, 206488_5 AT, 241392 AT, 206171 AT, 218854 AT, 228640 AT, 205542 AT, GLIPR1, C1336, 1MEM39A, ADORA3, DIE, PCOH7, 213338 AT, 21.8589 AT, 243894 AT, 7_05891 AT, 2117542 S AT, 221 CAC S AT, STEAM., TMEM158, LPAR6, SLC41A2, 10C100131909, 239519 AT, 219386 S AT, 208161 S AT, 221266 S AT, 209921 AT, 2184156_AT, ACIPI, CAL4M2, NR71, SLAWS, A8C.C3, Th47574, P
210145 AT, 227889 AT, 223502 5 AT, 225337 AT, 236345 AT, 2204E14 AT, SLC7iL1l, TNFFL5F21, PLA2G4A, LPCAT2, 174768138, o 203E187 S AT, 224341 X AT, 223939 AT, 206637 AT, 211138_5 AT, A8E1122,113XAS1, MCOLN3,11030,11.94, SUCNR1, "
vp 1555756 A AT, 209392 AT, 228762_AT, 209993_AT, 2(11324 AT, 1555.606_A AT, P2RY14, ICMO, CLEC7A, EN772, LFNG, A8C81, EMP1, m Iv 1-, 202609_AT, 226218 AT, 2.04661 AT, 225809 AT, 2.11661 X_AT, 214841 AT, GDP131, EPS8, 9.76,0)52, PARM1, PTAFR, C.N1H3, COBS, vp 210895 5 AT, 222062_AT, 232746 AT, 2134116 AT, 219385 AT, 223092 AT, 112741A, CXCR7, 11296,113/478, ANKH, MMP14, co Iv 202827 S AT, 205419 AT, 87100 AT, 235286 AT, 224990 AT, 235299 AT, 679183, ABED2, aLF, C4ORF34, S1C41A2 HAVC92, 0 r 1554285 AT, 201952 AT, 1552798 A AT, 210264 AT, 205718 AT, 237904 AT, ALCAM, T1.94, 07635, IT0137, ADORA3, TRW, S1C41A2, o, F' 203888_AT, 223796 AT, 219004 AT, 22_9797 AT, 241929_AT, 219434_AT, OLR1, MCOLN3, C036, 16E811, ALCAM Iv , 201951_AT
r o, 237252 AT, 22922,1 AT, 216442_X AT, 210495 X AT, 201069 AT, 212171_X AT, TEED, CD44, FN1, FN1, 818172, VEGFA, ANXA2P1, 213503_X_AT, 204575 S_AT, 1405_1 AT, 210427 X AT, nvis X AT, 213) 501 AT, MMP19, CC15, ANXA2P1, FN1, 114755138, C0109, 1110, 229900 AT, 207433 AT, 227265 AT, 203936 S AT, 235944 AT, 210512 S_AT, 7612,141.MP9, HMCN1, VEGFA, MMP14, CCL24, CD109, G0:0044421-extracellu1a 202827_5 AT, 221463_AT, 226545 AT, 211527 X AT, 204475 AT, 235286_AT, 3_24E-09 3.610050499 6_97E-08 VEGFA, 818171,0(17, ONLY, HMOX1, C015A1, A21.4, r region part 37145 AT, 203665 AT, 213428 S AT, 217757 AT, 2290(14 AT, 295E116 X AT, ADAMTS15, ANXA272, CC15, VEGFA, ANXA271, 204655 AT, 210513 5 AT, 201590 X AT, 2.12250_AT, 223502_5 AT, 203668_AT, 5E97114E2, TNFSF138,11480,16F873,THEID, GPC1, FGL2, 212143_5 AT, 203687_5 AT, 202756 5 AT, 204834 AT, 205495 5 AT, 228873 AT, ONLY, C0122A1, CCIS, VASE', I06973, ICAM1, FN1 1555759 A AT, 1556423 ATõ 210095 S AT, 202636 S AT, 21.2464 S_AT
.0 237252_AT, 204912_AT, 2112413_AT, 209555_5_AT, 223660_AT, 202727_S_AT, 13480,111 GM, 48571, C1336õ WhIGR1, T1R4 n 221060 S AT, 222877 AT, 226218 AT, 205898 AT, 205099_5 AT, zuso. X_AT, 81172,13_79, CX3CR1, CCR1, PTAFR, 1179, COBS, 1127RA, 205798 AT, 206488 5 AT, 222062 AT, 204116 AT, 232746 AT, 206171 AT, 11.2RG, CXCR7, ADORA3, HMCN1,11.94, 0714183, Cr GO:0004888-transmemb 235944 AT, 232068 5_AT, 205419_AT, 242903 AT, 216589 AT, 209906_AT, h..1 - 235E-09 3.3F9930976 338E-07 178091, LPAR6, C3AR1, LOC100131909, EM92, 44971, race receptor activity 205891 AT, 207610 5 AT, 210510 S AT, 239519 AT, 210264 AT, 1552798 A AT, 0 NR71, GPR15,11114, 71790, 1FNGR1, ADORA3, TH8D, 208121 S AT, 211676 S AT, 237904 AT, 203888 AT, 203104 AT, 212977 AT, (A
CSF1R, CXCR7, TEED, TL94, sualat OLR1., CD36, 203887 S AT, 224341 X AT, 223939_AT, 210004_AT, 228766 AT, 206637 AT, P2RY14, ENP72, C1736,1CAM1 (....) 209392 AT, 241929 AT, 202638 S AT

V0..

1-, Fold Term Pealye Benjamin' Probe.sets Genes 0 Enrichment 2142_11 AT, 202869 AT, 212171)1 AT, 205552 S AT, 1405_1 AT, 221060 S AT, 206206 AT, 222838 AT, 226218 AT, 223501 AT, 205099_5 AT, 211661 X AT, F11413, OAS1, VEGFA, OAST, CC'S, TLR4, CD180, 205798 AT, 21.0895 S AT, 222062 AT, 204116 AT, 207433 AT, 210146 X AT, SLARIF7,11714, ITIFSF13B, CCR1, PTAFR,11.711, CD86, G0:0006955-immune 210512 S AT, 232068_S_AT, 221463 AT, 220066 AT, 205419_AT, 211527 X AT, 11.27RA,IL2RG, 1110, VEGFA,11.114, CCL24, N002, 9.81E-11) 3570488309 6.34E-07 response 238561_AT, 202748 AT, 204655 AT, 210513_5 AT, 1552798 A AT, 203922 S_AT, GPR183, VEGFA, GEP5, GBP2, CC/5, VEGFA, TLR4, C11313, 229937 X AT, 223502 S AT, 206157 AT, 223434 AT, 224341 X AT, 210004 AT, LIREil, THFSF138, P1X3, GRP3, 11114, 01/11, P2RY14, 206637 AT, 1555756 A AT, 1555755 A AT, 209392 AT, 219434 AT, 242907 AT, CLEC7A, CC15, ENPP2, TREM1, 68P2, ICAMI, TRIM22 202638 S AT, 213293_5 AT
210495 X AT, 22_9221 AT, 212298_AT, 209555 S AT, 223660 AT, 206206 AT, 206438 S AT, 206171_AT, 228490 AT, 203665_AT, 239519_AT, 203922 S AT, FN1, CD44, NRP1, 0)36, ADORA3, CD180, 13D36, 221815_AT, 206157 AT, 225337 AT, 224341_X AT, 203887 S AT, 228766 AT, ADORA3, ABH02, HMOXI, NRP1, CYRB, AR1402, P1X3, 1555756 A AT, 201005 AT, 203060 S AT, 212464 S AT, 237252 AT, ABHD2, TLR4 THEO, C1336, CLEC7A, CD9, PAPSS2, FN1, G0:0009611-response 3.29E-10 4.097150568 6.39E-07 216442_X AT, 63825 AT, 1405_1 AT, 221060 S AT, 211719_X AT, 205898 AT, THEO, FM, A81102, CC15,11.114, FN1, 03CR1, C.CR1, to wounding 205099 S AT, 211661 X AT, 205566 AT, 207433 AT, 211026 S AT, 235944 AT, PTAFR, AE1102,110, MGLL, HMCN1, 0E124, ABHD2, 221463 AT, 87100 AT, 232068_5 AT, 208436_5 AT, 204465 S AT, 209906 AT, TLR4,111F7, INA, C3A81, A2.64, NRP1, cos, NLRC4, TLR4, 217757 AT, 210510 S AT, 204655 AT, 1552553 A AT, 1552798 A AT, 203888 AT THEO, A008A3, 01/11, CCIS, C036 237904 AT, 210004 AT, 1555759 A AT, 241929 AT
Ul L.) up 229211 AT, 210495_X AT, 212298_AT, 209555 S AT, 7_23660 AT, 206206 AT, CD44, FN1, NRP1, CD36, ADORA3, C0180, NRP2, CD36, 222877 AT, 206488 S AT, 206171 AT, 202284 S AT, 220066 AT, 228490 AT, ADORA3, C.DKN1A, N002, ABHD2, HMIDX1, 203665_AT, 205891 AT, 239519 AT, 203922_5 AT, 2/0145 AT, 206157 AT, 10C100131909, NRP1, CYB13, PLA2G4A, PM, A81402, 221815 AT, 225337 AT, 224341 X AT, 203887 S AT, 228766 AT, 1555756 A AT, ABHD2,T1R4, THEO, CD36, CLEC7A, ENPP2, PAPSS2, G0:0009605-response 209392 AT, 203060 S AT, 201005 AT, 212464 S
AT, 237252_AT, 216442_X_AT, 726E-10 3127282815 7.04E-07 C09 FN1,114110 FM ABH02 CC1511.114NI.
, F, CX3CR1, to external stimulus 63825 AT, 1405_I_AT, 221060 S AT, 211719_X
AT, 205898 AT, 205099_5 AT, , , , , , PTAFR, ABHD2, MGLL, HI1/44011, MMP14, 211661 X AT, 205566_AT, 2117433 AT, 211026 S AT, 2_35944 AT, 202827 S AT, IRF7, CC124, ARH02, 11114, CKLF, INA, C3AR.1, A2k4, 208436 S AT, 221463_AT, 87100 AT, 232068 S AT, 235286 AT, 204465 S AT, NRP1, CL5, 209906 AT, 217757 AT, 210510 S AT, 204655 AT, 1552553 A AT, 1552798 A AT C
NIFIC4, 11.84, ADORA3, 114813, CCNDI, 01.81, COS, 13D36 237904 AT, 203888 AT, 208712 AT, 210004 AT, 1555759_A AT, 241529_AT
202869 AT, 205552 S AT, 206206 AT, 2228313 AT, 205798 AT, 203936 S_AT, 22_0066 AT, 200878 AT, 202748 AT, 201565 S AT, 221266 S AT, 203922 S AT, OAS1, OAS?, C0180, SLAMF7, IL7R, MMP9, N002, 229937_X AT, 223502_S_AT, 215990 S AT, 206137 AT, 201422 AT, 224341 X AT, EPAS1, GRP2, 102, TM7SF4, CYBR, URN, TNFSF138, 206637 AT, 1555756 A AT, 209392 AT, 242907_AT, 213293 S AT, 214211 AT, BC16, PTIC3, 110,11.114, P2RY14, CLEC7A, ENPP2, 68P2, G0:0002376-immune 71)171 X_AT, 1405 I AT, 201566 X AT, 221060_5 AT, 2262113_AT, 223501 AT, TRIM22, FTHL3, , VEGFA 5, ,102 T/114, , 11.7R
L92E-09 2_852452609 9.30E-07 system process 205099 S AT, 211661_X AT, 210895 S AT, 222062 AT, 204116 AT, 207433 AT, TNFSF1313, CCR1, PTAFR, 0086, 1127RA, 112116,1110, 210146 X AT, 210512_S_AT, 221463 AT, 205419 AT, 232068 S AT, 711427_X AT, ULM, VEGFA, m/4, 6883, 11114, VEGFA, GBP5, 238581 _AT, 235286 AT, 209906 AT, 203140 AT, 204655 AT, 210513 S AT, CKLF, C3AR1, 8136, 005, VEGFA, 1184, CRIP2, 102, 1/1 1552798 A AT, 208978 AT, 213931 AT, 223434 AT, 2.10004_AT, 1555759 A AT, GBP3, 01.111, CCIS, TREM1, ICAM1 2_19434 AT, 202638 S AT

Fold Term Pvalue Benjamini Probesets Enrichment Genes b.a 210495 X AT, 229221 AT, 202869_AT, 212298 AT, 209555 S AT, 202435_S_AT, 1-, 223660 AT, 222838 AT, 205798 AT, 1563621_AT, 202284 S AT, 242903 AT;

22E490 AT, 201565 S AT, 203922_S_AT, 229937_X_AT, 215990_S_AT, 221815_AT, FNL, C044, 0381, NRP1, C036, CYP181, ADORA3, 0:1 F7, 205,195 S AT, 228766 AT, 201005 AT, 203060_S_AT, 201242_9_AT, 242907_AT, 1175, EEP D1, CDKN1A, FNG51, ABH02, 102, CYBB, um. Bak ABHD2, ONLY CD36, CD9, PAP&V, , 4=.=
b.a 209122 AT, 213293 5 AT, 205123 X AT, 214211_AT, 237252_AT, 717171_X_AT, A
1. (3832, puN2. TRIA122, FTesi. miu, Tim .
'A
63825 AT, 202727_5 AT, 1405_1 AT, 221060_S_AT, 201566_X_AT, 211719_X_AT, , 223501 AT, 205898_AT, 204058 AT, 205099 S AT, 205566 AT, 207433 AT, VEGFA, ABHDI,IFF4651, fr r,11114,102, FN1, 210146 X AT, 235944 AT, 217678_AT, 209047_AT, 221463_AT, 232068_S_AT, TNFSF138, 013C51, ME1, CCR1, A814132,1110, LILRB2, 2118436_5_A.T, 238531 AT, 209906 AT, 1554992 AT, 243483 AT, 217757 AT, H61011, 51C7A11, Attn., ca.24,11114,15F7, 0BPS, C3A51, RASGRF1, 204059_5 AT, 210510_S_AT, 210513_5_AT, 211676_S_AT, 238669_AT, 223434 AT, TRPMS, A234, ME1, NRP1, VEGFA, 60:0050896-response 225631 AT, 225097 AT, 205306% AT, 2026311_5_AT, 201243_S AT, 201069 IFNG51, P7081, GBP3, EEPD1, HIPK2, KMO, ICAA41, _AT, 2_41E-09 L852150811 9307 205552 S AT, 227948 AT, 206206 AT, 222877_AT, 202434_5_AT, 206488_S_AT, A1, 8154P2, 0551, F604, C1/180, NRP2, CYP1B1, to stimulus 206171 AT, 220066 AT, 200878_AT, 37145 AT, 205891_AT, 203665_AT, CD36, ADORA3, N002, EPAS1, ONLY, 10C100131909, HMOX1, 202436 5 AT, 207542_S_AT, 214453 S AT, 202748_AT, 239519_AT, 209921_AT, CYP181, AC1P1,1F144, 6832, NIIP1, SLC7A11, 210145 AT, 206157 AT, 223502_5 AT, 225337_AT, 220484_AT, 224341_X_AT, PlA2G4A, PTX3, TNFSF1313, ABHD2, MCOLH3, T154, 203887 5 AT, 206637 AT, 211138 S AT, 1555756 A AT, 209392_AT, 209993_AT, THBD, P25814, IMO, CLEC7A, ENPP2, A13031, PTGS1, 215813 S AT, 212464 S AT, 216442_X_AT, 202609_AT, 226213_AT, 218934_S AT, FM1, FN1, 8358, 1175, H5PE17, PTAFR, C086, 327RA, 11.2116, 211661 X AT, 210895 S AT, 222062 AT, 204116_AT, 2111126_5_AT, 210512_S_AT, MGLL, VEGFA, ANKH, 6454P14, 581402, 6P5133, I
P
223092 AT, D12.827 S AT, 87100 AT, 205419 AT, 211527_X_AT, 235236_AT, VEGFA, CKLF, NA, BC1.6, FABP4, CCU, 1111.5C4, CYP1B1, 204465 S AT, 203140 AT, 203980 AT, 204655_AT, 1552553_A_AT, 202437_S AT, F604, 7154,102, THEM, ADORA3, C0101õ 01.111, 2 2 ,o 230559 X AT, 1552798_A _AT, 213931_AT, 203838 AT, 237904_AT, 208712_AT, MC01243, (TI c, C036, TREM1 1-' m 110004 AT, 229797_AT, 1555759_A_AT, 24192.1 AT, 219434_AT
up Iv i 219353 S AT, 220333 AT, 229221 AT, 21229B AT, 209555_5 AT, 202435_S AT, o, , 221011 5 AT, 205793 AT, 228579 AT, 203936 S_AT, 242871_AT, 209348_S_AT, AnAp2, pAcuts. c044, NRin. a)36, cynin, LaH. 93R, I-'7 230360 AT, 2022E4_5 AT, 227747 AT, 1569149 AT, 201565_S_AT, 201590_X_AT, ig 204653 AT, 204999 S AT, 226066 AT, 215990_S _AT; 203104_AT,200884_AT, KCNC13, MMP9, PALM, MAP, OWN, COKNU, BOZO, 228766 AT, 243556_AT, 201005 AT, 203060_S_AT, 210095_S_AT,205128_X_AT, POMO, 102, ANXA2P1, TFAP2A, ATF5, M1TF, Bab, 237252 AT, 214297 AT, 212171 X_AT, 221060_S_AT, 201566_X_AT, 223964_AT, CSF15, CKB, C036, NGEF, C09, PAPSS2,107833, P7651, 223596 AT, 218502 S AT, 206835 AT, 207433_AT, 235944_AT, 222670_5_AT, THBD, CSP64, VEGFA, 1154,102, PROM1,11r1756, TRPS1, STATH, 209047 AT, 232063 S AT, 209906 AT, 1554992_AT, 243483_AT, 21.13510_S_AT, 1110, HM011, MAFB, mri,17114, C3AR1, RASGRF1, TFIPM8 210513 S AT, 206675 5 AT, 238669 AT, 204105_S_AT, 212614_AT, 204881_S AT, , NRP1, VEGFA, SKIL, P1051, 225097 AT, 201069 AT; 224218_5 AT, 222877_AT, 202434_S_AT, 201276 AT, NRCAM, A51058, (1026, H1PK2, NIMP2, 18351, NRP2, 1131, 600032501-m ulticellula 206483_5 AT, 244375 AT, 211962_5 AT, 220066 AT, 2001178_AT, 204141 AT, CiP DAV, C036, EVL, ZFP3611, 14002, EPAS1, 111BB2A,10C100131909, HMOX1, CYP1B1, ROPE, 205891 AT, 203665 AT, 202436 S AT, 207542_S_AT, 201279_S_AT, 204998 _S_AT, r orgarusmal process 208816 X AT, 23951_9 AT, 271766_5 AT, 233540_S_AT, 210145_AT, 212190_A1 0, ATF5, A NRP1,7147SF4, COK5FtAP2,, eiA2G4A, sERputEz 16Fai,3, umtvi.moznia,ilm, 2121.43 S AT, 2121186_X AT, 220484 AT, 2.24341_X AT, 2113887_S_AT, TH8D, ClEC7A, LING, TRP51, AHNAK, FOSS, EMP1, .0 1555756 A AT, 228762_AT, 222651_5 AT, 21.1936_AT, 213265_AT, 201324_AT, n pmst, ANAA2pi, Ampo, NGEF, ArixA2pi, fink 215813 S AT, 213503_X AT, 204575 S AT, 227240_AT, 210427_X_AT, 202609_AT, 214724 AT, 226218 AT, 244579_AT,218559_S_AT, 211661_X_AT, 207233_S AT, DIXDC1,11.75,15PSI, MAFB, PTAFR, MITF, NPTICI., CP
204684 AT, 210512_5 AT, 223092 AT, 202827 S AT, 205419 AT, 204475 AT, VEGFA, ANKH, MMP14, GPR183, MMP1, VEGFA, (NA, .. 80.6, MI:16AI, MOW, ALCAM, FABP4, COKSRAP2_, b.a 211527 X AT, 204465 S AT, 203140_AT, 1560960_AT, 1569150_X_AT, 201352 AT, 1-, Nialc4, anal, nitt oup2.102, map. ccNoi,, DA82, 203980 AT, 220935 5 AT, 1552553_A AT, 202437 S AT, 1552798_A_AT, f 208978 AT, 213931_AT, 203838 AT, 208712 AT, 210757 X_AT, 222876_S AT, A05P2, 0151, 54C0t/i3, D0582, 0l36, ALCAM li (..r.) 210004 AT, 229797_AT, 201280 S AT, 241929 AT, 2131951_AT
DC
'41 1-, Fold TeiIII Nellie Beniamini Probesets Genes Enrichment b..) 210495 X_AT, 717798_AT, 209555_5 AT, 227548 AT, 205798 AT, 206488 5 AT, Cl/
I-, 214255 AT, 209345_5 AT, 1569149 AT, 203665 AT, 205891 AT, 204998_5 AT, FN1, NRP1, CD36, FGD4,1178, CD36, ATP1OA, MAP, 2015E5 S_AT, 239519_AT, 233540 5 AT, 204999 S AT, 226066 AT, 210145_AT, Cl/
Cl/
215990 S_AT, 212143_5 AT, 215602 AT, 224341 X AT, 228766 AT, 210095_5 AT, P0LIM7, HMOX1, LOC100131909, ATF5, 102, NRP1, COK5RAP2, ATF5, MITE, PLA2G4A, BM, IGERP3, FGD2, 4=.=
0013050793-regulation 212464 S_AT, 216442 X_AT, 212171 X_AT, 1553906_5 AT, 1405_1 AT, b..) T1.174, CD36, IGH3P3, FN1, FN1, VEGFA, FG02, GCB, ID!, /./1 of developmental 3_28E08 1160728606 9.08E-06 201566 X AT, 221060 5 AT, 211719 X AT, 226.218 AT, 215559 S_AT, Cl/
71.114, FN1,11.78, MAPS, MIFF, C086, STATH,1127FLA, process 207233 S AT, 210895_5 AT, 206835 AT, 222062 AT, 204116_AT, 207433_AT, 11286,1/10, VEGFA, ANXH, MAFB,TLR4, VEGFA, 6118, 21.13512_5_AT, 2.23092_AT, 7.22670_S_AT, 232068_S_AT, 211527_X_AT, 203140_AT, P011817, CDKSRAP2, 61W1õ VEGFA, FG04, FG102, issnso X AT, 220935 S AT, 210510 S_AT, 204655 AT, 210513_5 AT, 11.114, 102, FG02, 113401, NRCAM, cas, VASH1, C036 230559 X AT, 1565754 X AT, 1552798 A AT, 213931 AT, 1565752 AT, 208712 AT, 204105 5 AT, 1555759_A AT, 1556423 AT, 241929_AT
229221 AT, 2434113 AT, 214297 AT, 201952 AT, 220307 AT, 221060 S_AT, G0:0009897-external CD44, TRPM8, CSPG4, ALCAM, CO244, 11.84, 11174, 878, 1552798 A AT, 226218 Al; 205798 AT, 204205 5 AT, 210895_5 AT, 204216 AT, side of plasma 5.99E-07 6.496675192 1.17E-05 1L7R, NRCAM, an36, 11286,1154, GPC1, CLEC7A,71R4, 224341 X AT, 202756 S AT, 1555796 A AT, 232068_5_AT, 201951 AT, membrane ALCAM,ICAM1 212298 AT, 223660 AT, 205798 AT, 206171 AT, 209348 5 AT, 220066 AT, 200878 AT, 1569149 AT, 203665 AT, 205891 AL 204998 S AT, 208816 X AT, 65P1, ADORA3, 11312, ADORA3, MAF, 6002, SPAS!, 201565 5 AT, 239519 AT, 201590_X AT, 233540 5 AT, 204999_5 AT, 226066 AT, P011617,14610X1, LOC100131909, ATE5, ANXA2P2, 102, P
o 210145 AT, 215950_5 AT, 212143_5 AT, 224341 X AT, 1555756 A AT, 6891, AN8A2P1, CD1C5RAP2, ATF5, 611TE, PiA2G4A, Iv up G0:0051239-regulation zissn S_AT, 210095_5 AT, 205128 X AT, 212171 X_AT, 213503_X AT, 8116,1GFEIP3, 3I84, CLEC7A, F1051, IGHIP3, P1651, ul Iv of multicelanar 7.17E-0/1 2791593852 154E-05 1405_I_AT, 201566_X AT, 210427_X AT, 221060_5 AT, 226218_AT, 218934 S AT, VEGFA, ANICA2P1, 115, 102, ANXA2P1,17.R4, 11.7R, I--' 00 o.
organismal process 218559 S_AT, 207233 S AT, 210595_5 AT, 206835 AT, 222062 AT, 204116_AT, 65867, MAR, M1TF, 083, STATH, 11.278A,11.286,1110, IA ."
I-' ND
207433 AT, 210512_5 AT, 223092 AT, 222670 5 AT, 232068_5 AT, 211527_X AT, VEGFA, ANKH, MAFB, 71.34õ VEGFA, RASGRE1, W16, .
r 1554992_AT, 203140 AT, 1569150 X AT, 220935 S AT, 210510 S_AT, 204655 AT, P0111147, CIIK5RAP2, 'WI, CCL5, VEGFA, 1134,102, 01 210513 S AT, 1552798 A AT, 213531 AT, 238669 AT, 237904 AT, 204105 5 AT, FIGS1, ADORA3, NRCAM, 11501, COS, VASH1 I.i' 208712 AT, 1555759 A AT, 1556423 AT
ig 229221 AT, 216442 X_AT, 210455_X AT, 223660 AT, 1405 1 AT, 221060 5 AT, 044, Ff41, FP41, ADORA3, 0:15, 71.714, C0180, FN1, 206206 AT, 211719 X AT, 222838_AT, 205898 AT, 205099_5 AT, 211661_X_AT, SLAMF7, CC3CR1, CCR1, PTAFR, 11226A, ADORA3, 1110, 222062 AT, 206171 AT, 207433_AT 211026 5 AT, 210146 X Al; 208436 S AT, G011006952-defense MGLL, LILRB2,111F7,11.574, CC1.24, N0D2, ONLY, C3AR1, 6.906-08 1417964583 167E-05 232068 5 AT, 221463_AT, 220066 AT, 37145 AT, 209906 AT, 203665 AT, response HM0X1, L0C100131909, A264, CC.15, FILRC.4, 1184, 205891 AT, 217757_AT, 204655_AT, 1552.553_A AT, 1552798_A AT, 203922 5 AT
MB, P723, ADORA3, 0151,11.84, ONLY, CLEC7A, CLLS, 206157 AT, 237904_AT, 210004 AT, 224341 X AT, 205495 S_AT, 1555756 A_AT, FNI
1555759_A AT, 212464 S AT
210495 X AT, 2.16442_X AT, 229221 AT, 22.3660_AT, 1405_I_AT, 206206 AT, 221060 S AT, 211719 X AT, 2051199 S AT, 211661_X_AT, 211026 S AT, FN1, FN1, 0344, ADORA3, CCI.5, C0180,T1R4, FN1, G011006954-inflammato 206171_AT, 207433 AT, 232068 S AT, 221463 AT, 208436 5 AT, 209906_AT, CCR1, ri-AER, 61611, ADORA3, 1110,1184, O1154,1RF7, .0 n 8.726-08 4_475172847 1E9E-05 ry response 203665 AT, 217757 AT, 204655_AT, 1552553 A AT, 1552798 A AT, 203922_5 AT C3AR1, 6810311, AIM, cas, 611IC4, 11.54, C588, P123, 206157 AT, 237904 AT, 224341 X AT, 210004 AT, 1555755 A AT, 1555759_A AT
ADORA3, 11114, 07R1, CLEC7A, 1115, FM

Cr b..) 229221 AT, 216442 X AT, 210495_X AT, 201069 AT, 213428 5 AT, 717171 X AT, Cl/
C1244, FN1, FN1, 6714P2, COL6A1, VEGFA, ANXA2P2, 213503 X AT, 204575_5 AT, 208816 X AT, 229004 AT, 210513 S Al;
/A
GOIXIG1012-ertracellula fA81P19, ANXA2P2, ADAMTS15, VEGFA,ANXA2P1, 1518-06 51117117426 2.70E-05 210427 X AT, 201590 31 AT, 211719_X
Al;202756 S AT, 22/1873 AT, Cl/
r matrix ANXA2P1, Fri I, GPC1, C01.22A1, MMPS, HMCN1, (.././
203936_S_AT, 235544_AT, 210512_S_AT, 202827_5_AT, 2I1527_X_AT, 204475_AT, VEGFA, MM P14, VEGFA, Pl, EN1 VI/
Cl/
I-, Fold Term Pvalue Benjamini Probesets Genes Enrichment L..) 1553995 A AT, 212171 X AT, 213503_X_AT, 227948 AT, 1405_1_AT, NTSE, VEGFA, ANXA2P1, FGEK, COS, AfiXA2P1,11114, 2.10427_X_A2, 221060_5_AT, 22.6218_AT, 2.23501_A2, 205798_AT, 210895_5_AT, 038, TNFsF138, toR, 0286,112 755, 1110, VEGFA, 01 222062._AT, 207433 AT, 210512_S_AT, 220066_AT, 232068_S_AT, 203436_5_AT, G00048583-regulation N002, T1114, 01E-7, VEGFA, NT5E, C3AJ11 1364051,0 1.68E-07 3.612684989 2_96E-05 211527_X_AT, 203939 AT, 205906 AT, 203665 AT, 205891 AT, 203140 AT, of response to stimulus L0C100131909, BCL6, A2M, FA8P4, ANXA2P2, OM, 4=, k.) 217757 AT, 203980_AT, 208816_X_AT, 204655_AT, 210513_S_AT, 23.0559_X_AT, VEGFA, FGD4, ANXA2P1, 7284, P1A2G4A, INFSF138, f/1 201590 X_AT, 1552798 A AT, 210145_AT, 223502 S AT, aisaso S AT, BCL6,TLR4, H1PK2, CLEC75, CC15, ICAM1 224341 X AT, 225097_AT, 1555756 A_AT, 1555759 A_AT, 202638_S_AT
216442 X AT, 2_10495_X AT, 201069 AT, 213423_5 AT, 212171 X_AT, 1131,1131, WW2, C016A1, VEGFA, ANXA2P1, MA4P19, 213503_X AT, 204575 S AT, 20:5816_X_AT, 225004 AT, 21.0513_5 AT, 60:0005578-protemace ANXA2P2, ADAMTS15, VEGFA, ANXA2P1, ANXA2P1, 2_00E-116 5.309782603 3.07E-05 210427 X_AT, 201590_X AT, 211719_X AT, 202756 S AT, 228873 AT, ous extraceliular matrix. FN1, GPO., COL22A1, MIAP9, HAACNI., VEGFA, tAMP14, 203936 3 AT, 235944_AT, 210512_5 AT, 202E27_5 AT, 211527 X_AT, 234475_AT, VEGFA, A4MP1, F131 22.9221_AT, 214297_AT, 212.171_X_AT, 209555_S_AT, 221060_S_AT, nsns_A-r, , CSPG4, VEGFA, 0236, 11R4 1.17R, 117R, C036, 205798_AT, 206483 5_AT, 210895_5 AT, 2043.16_AT, 210512_5 AT, 220066_AT, 0286,11286, VEGFA, 13002,1164, VEGFA, TRPM3, G03009986-cell surface 188E436 4.06706753 3.10E-05 232068 S AT; 211527 X_AT, 243483 AT, 201952_AT, 220307 AT,21.0513 S AT, MCAM, 02244, VEGFA, TA475F4,11.114, NRCAM, 21114, 221266 S AT, 1552798_A AT, 204105 S AT, 224341_X AT, 202756 S AT, OKI, 0336, CLEC75, 0D36, A8C51, ALCAM, 1CAM1 22.5766 AT, 1555756 A AT, 241929_AT, 209993_AT, 201951 AT, 202338 S_AT
P
229221 AT, 212171 X AT, 1405 1 AT, 201536_X AT, 221060_5 AT, 226213_AT, ip Iv 223501_AT, 218559_5_AT, 205793 AT, 207233 S AT, 210895_S _AT, 222062 AT, C044, VEGFA, CCL5, 102,11.84,278, TNFSF1311, MATS, in is GO:0002632-regu1ation 204116 AT, 207433 AT, 210512 S AT, 202.2E4 S AT, 222670 S AT, 220066 AT, la& MITF, C036,11.278A,11.2156, 1110, VEGFA CDICN1A, i.-' Iv no of immune system 3.21E-07 3.763213531 9.19E45 232068 S AT, 211527 X AT, 209906 AT, 203665 AT, 205891 AT, 2E13140 AT, MAFB, 13002,11.64, VEGFA, C3AR1, 1398051, il=i in in process 217757 AT, 21746.55_AT, 210513 S AT, 201565 S AT, 1552798 A AT, 226066 AT, mammals, Bak 5264, CCIS, VEGFA, 102, T1114, 11) Iv 223502 S_AT, 213931 AT, 215990 S AT, 224341 X AT, 1555756 A AT, MITF, 113E85138,102, BUG, 71114, CLEC7A, CC15, ICAM1 1E'i o, 1555759 A_AT, 202638_5 AT
ri I
237252 AT, 210495_X AT, 216442_X AT, 201069 AT, 212171 X AT, 1405 I_AT, THED, 1,41, FN1, MIAP2, VEGFA, CCU, FN1,TNESF1311, r o, 21.1719_X_AT, 223501_AT, 229900_AT, 207433_AT, 2272.65_AT, 2113936_S_AT, C0109,1110 1612,649819, VEGFA, CD109, cam, GO:0005615-extracellida 210512 S AT, 226545_AT, 221.463_AT, 211527_X AT, 235286_AT,37145_AT, 3_96E-06 3_371290545 9.986.05 VEGFA, CILF, ONLY, 1398051, A2M, CC15, VEGFA, r space 203635 AT, 217757 AT, 204655 AT, 210513 S AT, 212190 AT, 223502_S_AT, SERP114E2, TNFSF133,1GFBP3, THBD, 73380, GM, 212143_S_AT, 2038.88_AT, 203887_S_AT, 202756_S_AT, 2115495_5_AT, 704.534_AT, ONLY, F61.2õ VASH1,1GFEP3, ICAM1õ 1131 1555759_A AT,1556423 AT, 210095 S AT, 202638_5 AT, 212464 S AT
219358 S AT, 229221 AT, 201069 AT, 217798 AT, 224215 S AT, 222E77 AT, 205798_AT, 244375 AT, 211962_5 AT, 209348 S A7, 203936 S AT, 202284 S AT, ADAPT, C044, MA412, /41111, 15151, N1112, L1JR, EV1, 230360 AT, 200878 AT, 204141_AT, 1569149 AT, 203665 AT, 204998 S AT, ZIP36L1,1498, 986419, COKN1A, 01.013, EP551, TUBB2A, 208816 X_AT, 201565 S AT, 239519 AT, 201590 X AT, 2212156 S A7, PDUA47, HA40X1, ATF5, ANXA2P2, 102,13811, ANXA2P1, 233540 S AT, 204999_5 AT, 204653_AT, 210145 AT, 226066 AT, 217190 AT, 1747114, CIIK5RAP2, ATF5, TFAP2A, P1.A264A, MOT, .0 215990 S AT, 212143 S_AT, 2120E6 X AT, 220484 AT, 200884_AT, 228762_AT, SERNNE2,110.6,1618P3, LMNA, MC011/3, CKB, LENG, n GO:0048731-system 243556 AT, 203060S AT, , , , , 201005 AT 222651_S AT 211986 AT 210095 S AT, NGEF PAPS62, OM, TRP51, AliNAK,IGEBP3, EMP1, 736E-07 1917675905 0.00010967 development 201324 AT, 213503_X_AT, 214297 AT, 212171 X AT, 204575_5 AT, 227240_AT, A9411A211, CSPG4, VEGFA, 6498119, NGEF, 102, 201566 X AT, 21.0427_X AT, 22.8964_AT, 226218 _AT, 244579 AT, 2311559 S_AT, ANXA2P1, PREM41, 17R, TR151, MATS, MITT, STATH, EP
L..) 207233_5 AT, 206835_AT, 218502 S AT, 204684 AT, 207433_AT, 202827 S AT, 26151, N11711, KW, MMP14, ANKH, MATS, VEGFA, 223092 AT, 222670 S AT, 210512 S AT, 205419 AT, 211527 X AT, 204465 S AT, 618183, VEGFA,1NA, RAS613F1, 8C16, 640G51, POL1147, f/1 1554992 AT, 203140 AT, 1560960 AT, 15691.50_X AT, 201952 AT, 220935_S_AT, MOW, CD1C5RAP2, 13811., VEGFA, CR112, 102, NRCAM, 210510 S AT, 210513 S_AT, 208978 AT, 213931 AT, 204105 S AT, 2138712 AT, CCN131, 5411058, UGCG, ADAP2, A4C01/13, AMARA (../.) 212614 AT, 204E31 5 AT, 222876 S AT, 229797 AT, 2.01951_AT

...
_______________________________________________________________________________ _ -, I-i , Fold Term PvaMe 8eMan:1M Probesets Genes Enridunent k...) 237252 AT, 14E15_1 AT, 202727 S AT, 221060 S AT, 211661 X AT, 222062 AT, 1-, THED, CC15, iFfiG61, 7114, PTAFR, 1127RA, 610,1164, CA
207433 AT, 232068_5 AT, 220066_AT, 208436 5 AT, 242503_AT, 37145_AT, NOD2, 1RF7, IFNGR1, ONLY, 1F144, rd i 5, NLRC4, TLR4, 60:0051707-response 125E-06 4.4259178 0.00017294 214453 S AT, 204655_AT, 1552553_A AT, 1552798 A_AT, 211676 S_AT, 1FNGR1, 1..11.1161, PLA2G4A, PTX3, THBO, 1164, THEID, to other organism 229937 X_AT, 2.10145 AT, 206157 AT, 203888 AT, 224341_X_AT, 203837 S AT, 4a..
k..f GNLY, CLEC7A, CCL5, TRIM 22 205495_5 AT, 1555756 A AT, 1555759 A AT, 213293 S AT
(A

220333 AT, 219358 S_AT, 22_9221 AT, 201069 AT, 21.2298_AT, 224218 S_AT, 221011 S_AT, 222877 AT, 201273 AT, 205798 AT, 244375 AT, 211962_5 AT, PAQF15, ADAP2, CD44, Wan, NRP1, TRP51, 1.61-1, NRP2, 209348 5 AT, 242871_AT, 203936_S_AT, 7.02284_5_AT, 230360_AT, 2.00878_AT, , 1L78, EVL, rfP3611, MAP, PAWLS, RAMPS, 204141 AT, 1569149 AT, 203665_AT, 201279_S_AT, 204998_S_AT, 208816_X_AT, CDKN25, 610fi, EPAS1, TUBB2A, POLIM7, HMOXI, 201565 S AT, 239519 AT, 201590_X AT, 221266 S_AT, 233540 S AT, 0A112, ATF5, ANXA2P2, 02, NRP1, APOCA2P1, TM7SF4, 204999 S AT, 204653 AT, 210145_AT, 226066 AT, 212190 AT, 215990 S_AT, COKSRAP2, ATF5, TFAP2A, PLA2G4A, M1TF, SERPINE2, 212143 S AT, 203104 AT, 212086_X_AT, 220484_AT, 200884_AT, 203887_S_AT, BC1.6, 83F8P3, CSF1R, LIANA, MCOLI43, CKB, 11480, 60:0007275-multicellula 221762 AT, 243556_AT, 203060_S_AT, 201005_AT, 222651_5_AT, 2.11.986_AT, LENG, NGEF, PAPSS2õ TRPS1, AHNAK, IGH3P3, r organismal 221E-06 1342406265 0.00032825 210095 S_AT, 201324_AT, 2372.52_AT, 2.12171_X_AT, 213503_X_AT, 214297_AT, ER4P1, THBO, VEGFA, ANXA2P1, CSP64, hiMP19, NGEF, development 204575 S AT, 227240 AT, 201566 X AT, 2113427 X AT, 228964 AT, 214724 AT, 102, ANXA2P1, PR0M1, 00(DC1, 11714, TRPS1., MAFB, 22621.8 AT, 244579 AT, 218.559_5_AT, 207233_S_AT, 206835_AT, 218502_S_AT, MITF, STATH, TRPS1, Finn, 11.10, tAMP14, ANKH, P
204684 AT, 207433_AT, 202327_5_AT, 223092_AT, 2.10512_5_AT, 222670_5_AT, FA, B, 6P11133, VEGFA, MA, RASGRF1, 8C.16, 0 Iv , 205419_AT, 211527 X AT, 204465_S_AT,1554992_AT, 203140_AT, 1560960_AT, 8.4 1, PDLIA47 ALCAM, CDK5RAP2, NRP1, VEGFA, up ul 1569150 X AT, 2131952_AT, 220935 S AT, 210510_5 AT, 210513 S AT, Iv CR1P2, SKIL, 102, TH130, NRC.AM, CCND1, ARID5B, UGCG, 1-' a, 208978 AT, 206675 S_AT, 213931_AT, 203838 AT, 204105 5 AT, 208712_AT, DAV, ADAP2, HIP1C2, MCOLN3, 0A82, ALCAM
.
212614 AT, 204831_5 AT, 210757_X AT, 222876 5 AT, 225097 AT, 22_9797 AT, 1.0 Iv o 201280 S AT, 201951 AT
r o, I-' 1553995 A AT, 205891 AT, 203140_AT, 212171_X_AT, 213503_X_AT, 217757_AT, E, 1OC100131.909 BC16, VEGFA, ANXA2P1, A2M, i' ig 601032101-regulation 203980 AT, 203816_X_AT, 14415_1_AT, 204655_AT, 21051.3_5_AT, 22.1060_5_AT, FABP4, APIXA2P2, CC1.5, (TI
________________________________________________________________________ c, VEGFA, 1164, ANXA2P1, of response to external 2.59E-06 6287901039 0.00033427 210427 X AT, 201590_X_AT, 1552798 A AT, 210145 AT, 215990_S_AT, ANXA2P1, um, PLA2G4A, Bak 71114, 1110, VEGFA, stimulus 224341 X_AT, 207433 AT, 210512_5 AT, 1555759_A AT, 232068 S AT, M 5, 71.64, VEGFA, NTSE
211527 X AT, 203939 AT
229221 AT, 210495 X AT, 21.6442_X_AT, 212298 AT, 209555_5 AT, 1405 I AT, CD44, FN1, Ffil, NRP1, CD36, CCLS, FM!, SLAMF7, 211719 X AT, 222.838_AT, 210360 S AT, 222877_AT, 211066 X AT, 205898_AT, MTS51, NRP2, PC13116Al2, CX3C.R1, CCR1, C036, 205099_5 AT, 206488_5 AT, 215836_5 AT, 225188 AT, 228640 AT, 227747 AT, -PCDHGAL 7 RAPH1, PC1)147, MPZ13, 01651, ALCAM, 60:121122610-biological 3.65E-06 2140010571 010039282 213428 S_AT, 201952 AT, 204655 AT, 210510_5 AT, 225189_5 AT, 239519_AT, GCB, NRP1, RAPH1, NRP1, MTSS1, IT6137, LPXN, adhesion 203037 S AT, 205718 AT, 216250 S AT, 204105 S AT, 210604 AT, 228766 AT, NRCAM, 01111, C036, CLEC7A, C0L22A1, COS, CD36, 1555756_A_AT, 228873_AT, 1555759 A_AT, 241929_AT, 201125_S_AT, 2011105_AT
IT685, C09, AI CAM, ICAMI, FN1 .0 201951 AT, 202638 S AT, 212464 5 AT
n 229221 AT, 2113495 X AT, 216442_X AT, 7t98 _AT, 209555 S AT, 1405 I AT, C044, FN1, F1,11, NRP1, C.D36, CCIS, Flu, SLAMF7, 211719 X AT, 222338 AT, 210360 S AT, 222377 AT, 211066 X AT, 205398 AT, LI) MTS51, NRP2., PCDHGA12., CX3C111, CCI21, 036, k...) 205099 S AT, 2064813_5_AT, 215836 S AT, 225188 AT, 228640 AT, 227747 AT.

60:0007155-cell PCDHGA12, RAPH1, PCDH7, MPZ13, COL6A1, ALCAM, 1-, 3_47E-06 2948386669 000039594 213423 S AT, 201952 AT, 204355_AT, 210510_5_AT, 225139_S_AT, 239519_AT, CM, NRP1, HI, NRP1, IVITSSI, 11687, LPXN, (A
adhesion 203037 5 AT, 205718 AT, 216250_5 AT, 204105_5 AT, 210004 AT, 228766_AT, NRCAM, CHM, C036, CLEC7A, COL22A1, CC15, 036, CA) 1555756 A AT, 228873 AT, 1555759 A_AT, 241929 AT, 201125_5_AT, 201005_AT rmas, an, , IcAml, FNI cc 201951 AT, 202638 S AT, 212464_5 AT

1-, Fold Genes Term Pvalue Emichment Senjamini Pr sets 1,4 219358 S AT, 210495 X AT, 22.9221 AT, 2131069 AT, 212298 AT, 224212_5_AT, 1-, Ch 222/377_AT, 20127S AT, 205798 AT, 244375_AT, 211962_6_AT, 20934.9_S_AT, ADAP2, Fill, C044, MNIP2, NRP1, TRPS1, NE??, 0A82, 203936 S AT, 2022E4 S AT, 230350 AT, 2008711_AT, 204141_AT, 1569149_AT, ILTR, Evi., up36u, A4AF., mA4p9, cDKNIA, um, 0 .6, 203665 AT, 201279 SAT, 204998_S_AT, 2081316_X_AT, 201565_S_AT, 239519 AT, EPAS1, TUE182A, PDLIM7, MAUI, 0A32, ATF5, 1,4 vl 201590_X AT, 22.1266_S_AT, 233540_S_AT, 204999_S_AT, 204653_AT, 210145_AT, p2, 02, Hui, AmxA2p1 , TAI7 sF4, coKsitAp2, 226066 AT, 212190 AT, 215990_5 AT, 212143_S_AT, 212086_X_AT, 220484_AT, ATF5, TFAP2A, PLA2G4A, MIT?, SERP1NE2, 8C16, IGHIP3, 200384_AT, 2-78762 AT, 243556 AT, 2133060_S_AT, 201005_AT, 222651_S_AT, LMNA, MCOLI43, CKB, LF NG, NGEF, PAPSS2, CDS, TRPS1, G0:0046856-anatomica1 4_111-06 1_792006443 00041952 211986 hi, 210E05 S AT, 201324 AT, 212464_S_AT, 216442_X_AT, 213503_X_AT, , IGHIP3, EM??, Fill, Fill, AfiXA2P1, CSPG4, 0.
structure development 214297 AT, 212171 X AT, 204575_5 AT, 227240_AT, 201566_X_AT, 210427_X_AT, vEGFA, Aim 1.19, HOE?, 10, __ ANXA2P1, PRI31141, Fla, 228964_AT, 211719 X AT, 22621,9_AT, 244579_AT, 218559_S_AT, 207233_S_AT, H.TH, si, MA? B, AHTF, mm.1, Thesi, Hima., Hag, 206835 AT, 21.8502 S AT, 204684 AT, 207433 AT, 202827 S_AT, 223092_AT, MISP14, ANKH, MAF8, VEGFA, GPRIE3, VEGFA, INA, 222670_5 AT, 210512 S AT, 205419_AT, 211527 X_AT, 204465 S_AT, RASGRF1, 80.6, MDGA1, PDLIM7, ALCMS, CDK5RAP2, 1554992 AT, 203140 AT, 1560960_AT, 1569150_X_AT, 201952_AT, 220935_S_AL
NRP1, VEGFA, CRIP1 102, NRCAlvi, CCND1, AR1D58, 210510_5 AT, 210513 S AT, 208978 AT, 213931_AT, 2041115_S_AT, 2138712_AT, UGCG, 03132, kICOLN3, DAV, ALCMS
212614 AT, 204831 S AT, 210757 X AT, 222876 S AT, 229797_AT, 201280_S_AT, P
223723 AT, 210495 X AT, 2122943_AT, 2139555_5 AT, 202435_S_AT, 227948_AT, 205798 AT, 2131278 AT, 202434_S_AT, 206488_S_AT, 214255_AT, 2022134_S_AT, MF12, Fill, NRP1, CD36, CYP181, FGD4,11.7R, DA82, .
ul 2008713_AT, 203665 AT, 205291 AT, 202436 S AT, 131279_S_AT, 208816_X_AT, Iv CYP1131, CD36, ATP10A, COKNIA, EPAS1, HMOX1, H m 2015E5 S AT, 239519 AT, 201590_X_AT, 210145_AT, 223502_S_AT, 215990_S_AT, 10C100131909, CYP181, DA112, ANXA2P2, 102, NRP1, 2003E4_AT, 215602 AT, 203887 S AT, 224341_X_AT, 201422 AT, 22.8766_AT,IA
ANXA2P1, PLA2G4A, TNFSF1313, BC16, CX13, F6E12, THEID, C,' 203060 S AT, 201005 AT, 215813 S AT, 201324_AT, 205128_X_AT,112464_S_AT, T1114, IFI30, C036, PAPSS2, 0)9, F1051, EMP1, P1051, r o, G0:8065008-regulation 575E-06 1067363531 00050661 214211_AT, 237252 AT, 216442 X AT, 717171 X AT, 2135133_X_AT, Fill, FTHL3, THI3D, Fill, VEGFA, ANXA2P1, F602, rrt c, . 0.
"

of biological quality 1553906 S AT, 1405 _LAT, 221060 S_AT, 201566 X
AT, 210427 X_AT, TLR4, 1132, AtOtA2P1, Fill, S1C12A6, 1178, TtiFSE138, 211719 X AT, 223596 AT, 77K7111_AT, 223501_AT, 34210 AT, 204661_AT, C052, CD52, Call, STATH,11.10, HMCN1, VEGFA, IRF7, 205099 S AT, 206835 AT, 207433 AT, 235944_AT, 210512_S_AT, 208436_S_AT, TLR4, VEGFA, C3AR1, RASGRF1, BCL6, TRPM8, FAI3P4, 232068 S_AT, 711427 X_AT, 209906_AT, 1554992_AT, 203140_AT, 2444141_AT, GCB, NRP1, VEGFA, CYP1B1, F0134, FGE)2, 11114,102, 203960_AT, 204655_AT, 210510_S_AT, 21.0513_S_AT, 202437_S_AT, 230559_X_AT, THI3D, FTGS1, FGD2, DA82, CCLS, C1336, DAM, SERTAD1 1565754 X_AT, 1552798 A AT, 213931 AT, 203888 AT, 238669 AT, 1565752_AT, 210757_X AT, 1555759 A AT, 241.929_AT, 201280 S_AT, 223394_AT
212298_AT, 223660 AT, 210360 S AT, 242794_AT, 205799 AT, 244375_AT, NR171, ADORA3, MTSSI, MAM L3,11_711, EVI_, ADORA3, 206171 AT, 232333 AT, 212589_AT, 205891 AT, 207610_5 AT, 239519 AT, MAML1 LPAR6, 10C100131909, EMR2, NRP1, MAML2, 234645_AT, 2261366 AT, 203104 AT, 212977 AT, 223939 AT, 206637_AT, MIT?, CSF1R, CXCR7, S1ICNR1, P2R914, a.EC7A, ENPP2, G0:8007166-ce11 surface 1555756 A_AT, 209392_AT, 212171_X_AT, 1405_I_AT, 235457_AT, 202609_AT, VEGFAõ MAML2, EPS8, DIXDC1,11.7R, CX3CR1, IV
n receptor linked signal 531E-06 2/4578872 0_00051425 214724 AT, 226213 AT, 205898_AT, 205099_5_AT, 211661_X_AT, 207233_S_AT, CCR1, PTAFR, MIT?, 11.27RA, OCCR7,11111112, VEGFA, transduction 222862 AT, 232746 AT, 210146 X AT, 210512 S AT, 205419 AT, 211527 X_AT, GPR18.3, VEGFA, MAML2, C3AR1, MAA41_2, REP?, CC15, 244414 AT, 209906 AT, 242405 AT, 210510_5_AT, 204655_AT, 210513_S_AT, VEGFA, 8062, M
GPR35, IT087, ADORA3, CCAID1, CP
214054_AT, 203037 S_AT, 210264 AT, 205718_AT, 237904_AT, 208712_AT, 381058, 80513, ADAMDEC1, HIPX2, CCI3,1T0135 1,4 212614 AT, 210258_AT, 206134_AT, 225097_AT, 1555759 A AT, 201125_S_AT
vl G0:0050727-regulation 1553995 A AT, 203140_AT, 205891 AT, 217757 AT, 203980 AT, 1405_1_AT, NT5E,1302, L0C100131909, A2M, FA8P4, COS, CaS, -1 of inflammatory 532E-06 8270431894 0.00052809 204655 AT, 221060 S AT, 1552798_A AT, 210145 AT, 215990_S_AT, 11114,1184, PLA2G4A,13a6,11.10, 1110, CCI_S, r134, c,.) oe 224341 X AT, 207433_AT, 1555759 A AT, 232068 S AT, 203939_AT tiT5E
response _ 1-, FOICI

Term Pvalue Enrichment Benjamini Probesets Genes 210435 X AT, 229221_AT, 201069_AT, 212298 AT, 209555 SAT, 227948 AT, 223660 AT, 206206_AT, 277848 AT, 206488_5_AT, 206171 Al; 21322114_S_AT, F141, CD44, MMP2, NRP1, C036, F6134, ADORA3, CD180, 1561611 AT, 220066 AT, 2130878_AT, 37145 AT, 228490 AT, 203665 AT, 11AX4F7, cres, A0ORA3, CDKN1A, EEPD1, N002, 205891_AT, 239519 AT, 203322 S_AT, 210145 AT, 215990 S AT, 211815_AT, EPASL GNLY, ABHD2, HMOX1, Lociooulsos. NRP1, 206157 AT, 225337 AT, 224341 X AT, 203887_5 AT, 205495 S AT, 2211766_AT, CY138, P1.A2G4A, BUZ, ABHD2, PTX3, ABHD2, 1184, 2111.38_5_AT, 1555756_A AT, 201005 AT, 2133060 AT, 201242 S_AT, THBD, GNLY, CD36, KMO, C12C7A, C09, PAPS.52, 215813 S_AT, 212464 S AT, 205128 X AT. 237252 AT, 216442 X AT, ATPUIL PTGS1, FNI, PTGS1, TH8D, PHi, VEGFA, GO:000,5350-resporise 6_47E-06 L896821914 00005449 212,171 X AT, 63825 AT, 1405 _I AT, 221060_5_AT, 211719_X_AT, 218334_5_AT, A81032, 021.5, 1184, Eta, 11.5P 87, CX3CR1, CCR1, PTAFR, to stress 205898 AT, 205099_5 AT, 211661 X AT, 205566 AT, 2221362 AT, 211026 S_AT, ASH 02, 11.2713A, NIGU., 1110, UL882, HAMM., MR4P14, 207433_AT, 210146 X_AT, 235944_AT, 202827_5_AT, 210512_5_AT, 221463_AT, VEGFA ,4, ABHD2, 1154, I6F7, VEGFA, INA, MARI., 87100 AT, 232068 AT, 208436_S_AT, 211527_X_AT, 204465_5_AT, 209906_AT, Bus, TRpma, _ WW1, CC15, MAGI, F6134, VEGFA, 203140 AT, 243483 AT, 217757_AT, 210510 S AT, 204655 AT, 1552.553_A_AT, TLR4, PTG51, THEID, ADORA3, CCND1, 01.111, EEPD1, 230559 X AT, 210513 S AT, 1552798 A AT, 238669_AT, 203888_AT,237904_AT, HIPK2, lIMO, rn c, CD36, ATP1111 208712 AT, 210004 AT, 225631 AT, 225097 AT, 205306 X AT, 1555759_A_AT, 24192.9 AT, 201243 S_AT
219358 S AT, 220333_AT, 229221 AT, 210495_X AT, 212298_AT, 221011_S_AT, 205798 AT, 203936 S AT, 242871_AT, 2.09348_S_AT, 230360_AT, 202284_S_AT, ADAp2, p , 0344, FP11õ, NRP1, IBM, 117R, 'AMP%
1569149 AT, 201565 S AT, 201590 X_AT, 204653_AT, 2114939_S_AT, 226066_AT, PAQI1SMAP, GUM, CDKN1A, PDLIA47, 02, ANXA2P1., 215990 S AT, 203104_AT, 20014,4_AT, 243556_AT, 201005_AT, 203060_5_1,T, TFAP2A, ATF5, MIFF BC16, CSF1R, 04.13, NGEF, 0)9, 210095 S AT, 205128_X AT, 237252 AT, 214297 AT, 212171 X AT, 1405_I_AT, PAPSS2, 1GFBP3, PTGS1, THB13, CSP64, VEGFA, CCIS, 201566 X AT, 211719 X AT, 22.5964_AT, 2113502_S_AT, 206835_AT, 207433_AT, 1102, Ffil, PREIML TRPS1, STATH, 810, MARI, RASGRFL
222670 S AT, 1554992 AT, 210510_5 AT, 210513 S AT, 206675 S AT, NRP1, VEGFA, SKIL, FTGS1, AR105B, NRC.AM, UGCG, Ul 238669_AT, 212614 AT, 204105 S_AT, 2048111_S_AT, 225097_AT, 201069_AT, HtPK2, MA4P2,TRPS1, NRP2, DAV, EVL, ZFP3611, 224218 S AT, 222877_AT, 201278_AT, 244375_AT, 2.1.1962_S_AT, 200878_AT, EPA51,TUBB2A, HMOXI, 0A132, AlTS, ANXA2P2, NRP1, G0:0032502-deve10pme 9.45E-06 L642672573 0110073237 204141 AT, 203665 AT, 21)1279_5_AT, 204998_5_AT, 208816_X_AT, 239519_AT, nA7sp4, =sun, sEppipia. PLA2G4A, 161883, ntal process 221266 AT, 233540 5 AT, 212190LAT, 210145 AT, 212143 S AT, 212086 X_AT, LMNA, MCOLN3, THIRD, LF14G, AHNAK, EMPL
220484 AT, 203887 S AT, 2213762 AT, 7/7651 5 AT, 211986 AT, 201324 AT, PTGS1, FN1, FN1, ANXA2P1, MMP19, NGEF, ANXA2P1, 215813 5 AT, 212464_5 AT, 216442 X AT, 213503_X AT, 204575 S_AT, DIXDC1, 8.78, TRPS1, MAR, MITE, 8815.1., VEGFA, 227240 AT, 210427_X AT, 214724 AT, 226218 AT, 244579 AT, 238559 S AT, ANKH, MMP14, 688183, VEGFA, INA, &C1.6, 1.41ViA1 207233 S AT, 204684_AT, 210512_S_AT, 2.23092_AT, 202827_S_AT, 205419_AT, PDLIM7 ALCAM, FABP4, CDIG8A82, C.C15, CRI82, ID2, 211527_X_AT, 204465 S AT, 203140 AT, 1560960_AT, 1569150_X_AT, 201952_AT, map, atm, Aran, mcoLN3, Cri 203980 AT, 220935 S AT, 204655 AT, 20E378 AT, 213931 AT, 203888 AT, ,CAM
208712 AT, 222376_5 AT, 210757 X AT, 229797 AT,1555759_A_AT, 201280 AT, 201951 AT
1553995 A AT, 205891 AT, 203140 AT, 217757 AT, 203980 AT, 1405_1_AT, WISE, L0C100131909, RCM, A2M, FA8P4, CCU, CCLS, 60:0031347-regulation 204655 AT, 221060 S AT, 1552798 A AT, 210145_AT, 215390 AT, 1184, 1154, PLA2G4A, Bak 1154,1120, CLEC7A, CCL5, 3.45E-06 5.519379845 0.0007628 of defense response 224341 X AT, 207433_AT, 1555756 A_AT, 1555759 A
AT. 232068 S_AT, TUI4, 111F7, NOM, WISE
20E1436 S_AT, 220066 AT, 203939 AT
137252 AT, 1405 LAT, 202727 S_AT, 2211160 AT, 218934 S AT, 211661_X_AT, 2221362 AT, 207433_AT, 232053_S AT, 220066 AT, 208436 S_AT, 242903 AT, 11180, 0215, IFNGR1, 11.84, RSPB?, PTAFR, 1127RA, 8_10, G0-0003607-response 37145_AT, 214453_5 AT, 204655_AT, 1552553 A AT, 211676 5 AT, 11.114, N0132, IRF7, IFNGR1, ONLY, 11344, CCL5, NLRC4, L20E-05 3.375586386 0.00089042 to biotic stimulus 1552798 A AT, 223937 X AT, 210145_AT, 206157 AT, 203888 AT, 20871.2_AT, FF1081, TU14, 18.8E11, PLA2G4A, FTX3, THBD, CCND1, 224341 X AT, 203E187_5 AT, 205495 S AT, 1555756 A AT, 1555759 A_AT, 1184, THEO, GNLY, CLEC7A, M 4, TRIM22 C0 ............ ... .
.... . ... ., Fold Term Pvalue Benjamini Probesets Genes Enrichment 204912 AT, 209555 S_AT, 217757 AT, 20272.7 S_AT, 226218 AT, 211676 S AT, ILIORA, CD36, A21.4, IFNGRI.õ11.78, IFNGR1, CX3CR1, tNa G0.0019955-cytokine 0:1 1.09E-05 6.970960427 00013192.6 205898 AT, 205099 5 AT, 205798 AT, 203104 AT, 206488 S AT, 2221162 AT, CCR1,11.7R, CSF1R, CD36,1127RA, IL2RG, C1336, C036, I-I
binding 204116 AT, 228766_AT, 241923_AT, 242903_AT

.
0:1 209906 AT, 203665 AT. 2.05891 ST, 203140LAT, 2.17757_AT, 221060_S_AT, 0:1 C35111, HMOX1, LOC100131909,13C16, A2M,T1.84, 60:0050776-regu1ation 1552795 A AT, 226218_AT, 223501 AT, 223502_S_AT, 215990_S_AT,2115798_AT, tNa 2.06E-05 4.292.850991 0.00147588 11.84,11.78, INFS61313,TriFSF1.38, 861.6, 11.7R, 085, IA
of immune response 210895_S_AT, 221862 AT, 224341_6_AT, 207433 AT, 1555756_A_AT, 220066 AT, 1127RA,11.114,11.10, CLEC7A,14002,111114, ICALI1 0:1 232068 S AT, 202638_5 AT
210495_X_AT, 216442_X_AT, 223221_AT, 212295_AT, 1405_I_AT, 211719_X_AT, 161, 161, C044, N RP1, COS, 1141, 6892, CX3C141, 222877_AT, 2051338_AT, 204268_AT, 205099_S_AT, 211661_X_AT, 2.07413_AT, 5100A2, CCR1, PTAFR, 1110, MMP14, CC124, CXLF, G00040011-focomotion 238E-05 3.210251542 0.00164377 202827_5 AT, 221463 AT, 23528.6_AT, 209906_AT, 1560960 AT, 204655 AT, C33111, MOGA1, 0215, 6811, 6811, ARI055, NRCAM, 210510 S AT, 239519 AT, 212614 AT, 204105 S AT, 1555759 A AT, 209392_AT, CCU, E6112, CAUL FN1 202635 S AT, 212464_5 AT
1553995 A AT, 213503 X AT, 227948_AT, 1405 _LAT, 210427_X_AT, EiT5E, ANXA211, 1804, CCLS, 5655211, 1184,810, 221060 S AT, 207433 AT, 220066 AT, 232068 S AT, 208436 S AT, 113939 AT, G00080134-regulation 13002,11114,1111'7, WISE, EIC16, LOC100131909, A2M, 2.54E-05 3.700142913 000169407 203140 AT, 205231 AT, 211757 AT, 203980 AT, 208.816_X_AT, 204655_AT, of response to stress FABP4, ANXA2P2, 0.5, 1804, 51455211, 1154, 230559 X_AT, 201590 X_AT, 1552798 A_AT, 210145 AT, 215990 S AT, 1152845, 80.6,1164, HIPS?, CLEC7A, CCL5 . 224341_X AT, 225097 AT, 1555756 A AT, 1555759_A_AT
209906 AT, 1455_I AT, 204655 A, 202609 AT, 222877_AT, 205898 AT, C3A.R1, CC15, C0.5, E158, 6812, 00011, CCR1, PTAFR, P
GO0007626-locomotory 3.53E-05 4.081231576 0.00227722 205099 S AT, 211661_X AT, 2211454 AT, 225097_AT, 207433 AT, 229797 AT, MCOLN3, HIM, 1110, MCOLN3, ANKH, COS, ENPP2, 0 behavior Iv 223092 AT, 1555759 A_AT, 209192_AT, 221463_AT, 235256 AT
C0.24, CKIF to .
m Iv 203906 AT, 205591_AT, 203140 AT, 212171 X_AT, 210513 S AT, 221060 S AT, H 0) C3581,, LOC10Q131.909, 801, VEGFA, VEGFA, 11314, IA ei 0001822684-po91ive 22621B AT, 1552793 A_AT, 223501_AT, 223502 S AT, 215950 S AT, 205798 AT, to 1178, TI.R4, TNFSF1313, TNFSF138, BC16, 5.711, C086, regulatn of immtme 409E-05 4.024547504 0.00255401 21.0895 S
AT, 222062 AT, 204116_AT, 2.24341_1( AT, 1555756 A AT, Iv 1127RA,112110, TIM, CLEM, VEGFA, CDKNIA, 6002, system pstKess 210512_5 AT, 202284 S_AT, 220066 AT, 232068_5 AT, 211527 X AT, r 11.114, VEGFA, ICAM1 ce 202638_S_AT
I
r Iv 1553995 A AT, 202569 AT, 209555_5 AT, 2172435_5_AT, 205552_5_AT, r 227134 AT, 211066_X AT, 222877_AT, 219412 AT, 202434 S AT, 206488_S_AT, 675E, OAS1, CUSS, CYP1E11, 0551, 51711, PCDRGA12, ce 208789 AT, 203939 AT, 203564 _AT, 2132416_5 AT, 216030_S_AT, 201590 X AT, NIIP2, 85I338, CYP1B1, C036, PTRF, NTSE, HAMM, 208161 S_AT, 210145 AT, 22.3502_5_AT, 236345_AT, 1557930 SAT, CYP113.1., FADS3, ANXA2P1, ABCC3, PLA2G4A,TAIFSF1313, 000000257-ceII 212086 X AT, 228766 AT, 209993 AT, 201324_AT, 215813 S AT, 205128 11_ AT MASI, 1181', 16565. 0336, ASCII, EMP1, PTG31, 0.00027348 1.99311488 030366864 fraction 213503 X_AT, 1405_1 AT, 210427_X AT, 202_603 AT, 223596 AT, 223501 AT, P11311, 5655211, C0.5, ANXA2P1, EVA S1.C12A6, 204058 AT, 34210 AT, 20460 AT, 218613_AT, 210146_X AT, 215536 S AT, 1615/138, 1-461, C052, cosz, P103.111882, PCORGA12, 1554992 AT, 204059 S AT, 203980_AT, 204655 AT, 202437 S AT, 238669 AT, 8556881, MU, 15814, 0.5, CY1151, PTGS1, 15053, 204257_AT, 204881_5 AT, 210004 AT, 202067 S AT, 1555759_A AT, 241929_AT, UGCG, OLIO, CTSL1, 035, 035, 1303 203355_S_AT
000045028-punnergic nucleotide receptor Luso AT, 205891 AT, 223939 AT, 206637 AT, 223660 AT, 206171_AT, 17586, 10CD:10131909, SUCNR1,12.11714, 500853, .0 512E-05 13.86354232 000411604 n activity, G-protein 205419 AT, 237904 AT
ADORA3, 0181113, 500853 coupled 00:0001608-budeotide 2.18559_AT, 205231_AT, 223939_AT, 206617_AT, 223660_AT, 2/26171_AT, LPAR6,1.0C100131909, SUCNR1, F2RY14, ADORA3, tNa receptor activity, G- 512E-05 13.88854232 00(1411604 0:1 205419 AT, 237904 AT
ADORA3, 018183, 580853 protein coupled I-I
IA
218589 AT, 209906 AT, 205891 AT, 207610_5 AT, 223660_AT, 210264_AT, [PARS, C3AR1,IDC100131909, EMR2, ADORA3, GPR35, 0:1 00:0004930-6-protein Lai 4.66E-05 4.292644053 0.00449193 205898 AT, 205039 S AT, 211661_X AT, 237904 AT, 212977_AT, 232746 AT, CX3CR1, CCR1, PTAFR, 500853, CXCR7, CX017, 00 coupled receptor ectivity 223939 AT, 206637 AT, 206171 AT, 205419 AT
SUCNR1, P211Y14, ADORA3, 818183 1.0 0:1 I-I

Fold Term Pvalue Benjarnini Probesets Genes 0 Enrichment G0.00.16502-nucleotide 21E589 AT, 205891 AT 223939 AT, 206637 AT, 223660 AT, 206171 AT, LPAR6, LOC100131909, P2RY14, ADDRA3, 8.64E-05 12.54772877 0.00594437 CA
receptor activity 7115419_AT, 237904 AT
ADORA3, GPR183, ADORA3 G0:0001614-purinergic 218589 AT, 205891 AT, 223939 AT, 206637_AT, 223660 AT, 206171 AT, LPAR6, MC100131909, Waal, P2RY14, ADORA3, 8_64E-05 1234772877 0.00534437 nucleotide receptor 205419_AT, 237904 AT
ADORA3, GPR183, ADORA3 1553995 A AT, 2021169 AT, 209555 S_AT, 205552 S AT, 202435 AT, 202609 AT, 223596_AT, 222877 AT, 227134 AT, 211066 X AT, 204661_AT, /415E, OAS1, C036, OAS1, CYP1B1, EPS8, 51C12A6, 34210_AT, 219412 AT, 202434 S AT, 218613 Al; 206488_5 AT, 210146_X AT, NRP2, SY1U, PCDHGA12, C052, C052, RA838, CYP1131, GO:0005626-insoluble 215836 S AT, 208789 AT, 203939 AT, 1554992 AT, , , , , , , 203665 AT 202436 S AT P503 CD36 LILRB2 PCDHGA12 PTRF, NYSE, RASGRFI, 0.00050614 2_119636435 0.00638231 fraction 202437 AT, 216080_5 AT, 208161 S AT, 210145 AT, 1557938 S AT, HMOX1, CYP1131, CYPIE1, FADS3, ABCC3, PLA2G4A, 236345_AT, 238669 AT, 204257 AT, 212086 X AT, 2048131 S AT, 210004 AT, PTRF, TEUCASI, PT651, FADS3, LAMA, UGCG, 228766 AT, 241929 AT, 203355_5 AT, 209993 AT, 215813 AT, 201324 AT, C036, C036, P5133, A8C131, PTGS1, EMP1, PTGS1 219358 S AT, 229221 AT, 201069 AT, .217298 AT, 222877 AT, 205798 AT, ADAP2, C044, MMP2, NRP1, NRP2,117Ft, EV1, ZFP361.1 244375 AT, 211962 S AT, 203936_6 AT, 209348 S AT, 202264 S_AT, 200878 AT, AAMP9, MAF, CDKN14, EPAS1, HMOXI, ANXA2P2, 2.03665_AT, 208816_X_AT, 23951.9_AT, 201565_S_AT, 201590_X_AT, 221266_S_AT, win, 102, pi, .042sp4, TpAp2A, 233540 S AT, 204653 AT, 226066_AT, 210145 AT, 215990 S AT, 212086 X AT, wrf, PLA2G4A,BCL6, MINA, MC01.143, cm+, IING, G0:0048513-organ 220484 AT, 200834 Al; 228762 AT, 201324 AT, 213503 X AT, 214297 AT, 0.00010948 1_8456524% 0_00640896 EMP1, ANXA2PI, CSPG4, VEGFA, MPAP19, ANXA2P1, 1-' 00 development 212171_X_AT, 204575 S_AT, 210427 X AT, 201566_X AT, 228964_AT, 22623.8_AT, 102, PRDA41, 11711, M.RFE1, tArrF, STATH, 11_10, VEGFA, 218559 5 AT, 207233_5 AT, 206E35 AT, 207433 AT, 210512 5 AT, 2132827 5 AT, MMP14, MAFB, GPR183, VEGFA,1NR, BUS, MDGA1, 222670 AT, 205419 AT, 211527 X AT, 204465 S AT, 203140 AT, 1560960 AT, CDK5RAP2, NRP1, VEGFA, C111122, 102, CCN01, AR1D5B, 2.711935_5 AT, 210510 AT, 210513 S AT, 208978 AT, 213931 AT, 208712_AT, UGCG, ADAP2, MCOLN3 212614 AT, 204881 S AT, 222876 5 AT, 229797_AT
GO:0002697-regulation 205738 Al; 203665 AT, 205891 Al; 203140 AT, 222062 AT, 217757 AT, 11711, HMOX1, L0C100131409, EICL6,1127FtA, A2M, 1110, of immune effector 0.00010851 6.003002251 0.00655072 207433 AT, 220066 Al; 226218 Al; 202638_6 AT, 215990 S_AT
N002,117R, 'CAUL BUS
process G0:0051384-response 208712_AT, 217757 AT, 203980 AT, 207433_AT, 204655 AT, 1405_1 AT, CCND1, A2M, FABP4, 1110, CM, CCU, CDKAI1A, CCL5, to giucocorticoid 0.00011695 7.046016E23 0.00664447 202284 5 AT, 1555759 AT, 215813 S AT, 210145 AT, 205128_X AT, PTGS1, PlA2G4A, P165I, P1651 stimulus 238669 AT
oe Fold Term Pvalue Benjamini Probesets Genes 0 Enrichment 1553995_A AT, 202869 AT, 209555 S AT, 2.05552 S AT, 202435 S AT, NTH, OAS1, C036, OAS1, CYP1B1, EPS8, S1C12A6, CA
202609 AT, 223596_AT, 222E77 AT, 227134 AT, 211066 X AT, 204661 AT, NRP2, SITLI, PCDHGAL2, CD52, CD52,11A838, CYP181, -tC3 34230 AT, 219412 AT, 202434_S AT, 2186/3 AT, 206488 S AT, 210146_X_AT, 60:0005624-merribrane P593, C036, ULF182, PCDHGA12, PTRF, NT5E, RASGRFI, 0.00064098 2128169382 01/0762936 215836 S AT, 208789 AT, 203939 AT, 1554992 AT, 203665 AT, 202436 S AT, fraction 14M0X1, CYP181, CYP1B1, FADS3, ABOC3, PLA2G4A, 202437 S AT, 216080 S_AT, 2W1161 S AT, 210145 AT, 1557938 S AT, PTRF, TBXAS1, PTGS1, FADS3, UGCG, 0181, C036, 0736, 236345 AT, 238669 AT, 204257_AT, 204881 S AT, 210004 AT, 228766 AT, PSD3, A8031, PTGS1, EMP1, PTGS1 241929_AT, 203355_S_AT, 209993 AT, 215813_5 AT, 201324 AT, 205128 X AT
214581_X AT, 204912_AT, 212171_X AT, cytokine receptor 7.836-05 3310866911 0-00816277 202721_S AT, 1405_1 AT, 204655 AT, TNERSF21,11.1.08A, VEGFA, IFNGR1, 0 S, 00.5, VEGFA, hsa04060:Cytokine-210513 01)08162772W513_5 _T, 211676_5 AT, 226218 AT, 223501 AT, 2_18856 AT, 205898 AT, IMO:11,1178, TRIFSF138, INFRSF21, CX3011, ThIF5F138, 223502_5 AT, 205039 S AT, 203104 AT, 205798_AT, 204116 AT, 207433 AT, CC81, CSF1R,11.711, 11286,1110, VEGFA, CC'S, CC124, interaction 210512 S AT, 1555759 A AT, 221463 AT, 211527_X AT, 242903 AT
VEGFA,1FNGR1 6010031349-posnive 205891 AT, 203980 AT, 1405_1 AT, 204655 AT, 221060 S AT, 1552798 A AT, 10C100131909, FABP4, COS, CC'S, T1114, 11I14, regulation of defense 01)0015337 6_7584243 0.00827779 210145 AT, 224341_X AT, 1555756 R AT, 1555759 A AT, 2320611 S AT, PiA2G4A,11114, C1.EC7A, CCL5, 11.94, 111F7, N002.
response 208436_5 AT, 220066 AT
209906 AT, 205991 AT, 7121.71 _X AT, 203980 AT, 1405_1 AT, 204655 AT, C3A111, L0C100131909, VEGFA, FAE1P4, CC15, CCL.5, 60:0048584-pasitive 210513_5 AT, 221060 S AT, 1552798 A AT, 223501 AT, 210145 _AT, VEGFA,11114, T1R4, TALFSF138, P1A2G4A, TNFSF1313, regulation of response to 0.00015308 3_789715034 0.00844122 223502 S AT, 222062_AT, 224341 X AT, 225097 AT, 1555756 A AT, 112711A,11114, H1PK2, C1.EC7A, VEGFA, cas, N002, stimulus 210512 S AT, 1555759 A AT, 220066 AT, 232068 S AT, 208436 5 AT, T184, 111E7, VEGFA
Co 60:0031360-resportse 208712 AT, 217757 AT, 203980 AT, 207433 AT, 204655 AT, 1405_1 AT, CCNC11, A2141, FABP4, 1110, CC1.5, CC15, CDKN1A, CCI..5, to corticosterold 0.00017474 6_623255814 0.00911158 202284 S AT, 155575.9 A
AT, 215813 S AT, 210145 AT, 205128_X AT, PTGS1, P1A2G4A, PTGS1, PTGS1 stimulus 238669_AT
a 229221 AT, 201069 AT, 202435 S AT, 222877 AT, 202434 S AT, 202_284_5 AT, 220066 AT, 200878 AT, 203665 AT, 207542 S AT, 202436 S AT, 201565 S_AT, C044, NIMP2, CYP1B1, N8P2, CYP1B1, CDKN1A, NO02, 209921 AT, 210145 AT, 224341 X AT, 203887 S AT, 1555756 A AT, 203392 AT, EPAS1, HiA0X1, AQP1, CYP1B1, 102, SLC7A11, P1A2G4A, 201242 S AT, 209993 AT, 215813_5 AT, 209122 AT, 205128 X AT, 237252 AT, 71.114, TH80, C1.EC7A, ENPP2, A1P1131, ABC81, PTGS1, 60:0042221.-response 212171 X AT, 1405 1 AT, 201566 X AT, 221060 S
AT, 202609_AT, 218934 S AT, PUNT, PTGS1, THBD, VEGFA, 00_5,102,1184, EPS8, 0_00023157 1879298045 0.01115792 to chemical stimulus 204058 AT, 205898 AT, 205099 S AT, 211661 X
AT, 207433_AT, 217678 AT, HSPB7, MEI, 00CR1, CCM, PTAFR,11_11), S1C7A11, 210512 S AT, 202827 S AT, 209047 AT, 221463 AT, 232068 S AT, 211527 X AT, VEGFA, NIMP14, AQP1, CCL24, 1184, VEGFA, CIELF, 235286 AT, 209906_AT, 217757 AT, 204059_5 AT, 203980 AT, 204655_AL
C3AR1, A2.1v1, ME1, FA8P4, COS, VEGFA, CYP1B1, 11.114, 210513_5 AT, 202.437 S AT, 1552758 A AT, 213931_AT, 238669 AT, 2038E8 AT, 102,, PTGS1, THEO, CCN01, GIRL C0.5, ATP1131 208712 AT, 210004 AT, 1555759 A_AT, 201243_5 AT
JI
oe Fold Term Pv1u Beniamini Probesets Genes Enrichment 21_3891 AT, 1553995_A AT, 223723 A7, 212298 AT, 223660 AT, 222838_AT, 219412 AT, 205798_AT, 205960 AT, 299348 S AT, 217997_AT, 237333 AT, 225 in AT, 7_20307 AT, 201565_5 AT, 201590 X AT, 230266 AT, 209684 AT, 204999 S AT, 204653 AT, 226066 AT, 215990 S_AT, 221815 AT, 2031134 AT, TCF4, N11E, MFI2, NRPL AOORA3, SL.Pdt4F7, RA1338, 200884 AT, 204834 AT, 222146 S AT, 228766 AT, 210095 S AT, 205128 X_AT, 113R, P064, MAF, PHLDAL MAML2, ARHGAP18, CO244, 214211 AT, 1560485 AT, 214581_X AT, 63825_AT, 1405_1 AT, 201566 X AT, 102, ANTIA2P1, RAB713, RiN2, ATE5, TFAP2A, MITE, 13116, 228964 AT, 211719 X AT, 223501_AT, 212387_AT, 205898_AT, 205099 S AT, Al3H02, CSF1R, CKB, E6L2, TCF4, C036, IGF8P3, PTGS1, 218502 5 AT, 206835 AT, 207433 AT, 235944 AT, 222670 S_AT, 232382_AT, FTHL3, MEP', TNFFISF21, ABHD2, CCL5, 102, PROM1, 1554992 AT, 217757 AT, 1565754_3 AT, 209606 AT. 211676 S AT, 206675 S AT, FN1, TNFSF1313,TCF4, 03CR1, CCR1,TRPS1, STATH, 225842_AT, 216250 AT, 23860 AT, 1565752 AT, 204105 S_AT, 206134_AT, RIO, HMCN1, FAAFB, TCF4, RASGRF1, A2M, F6132, 202638 S AT, 227948 AT, 242794 AT, 7_02434_5 AT, 222858 S_AT, 206488_S _AT, CYT1P, IENGR1, SKI)., PHLOAL 11104, FTG51, FG132, 211962 S_AT, 225173 AT, 208789 AT, 220066 AT, 200878 AT. 225166 AT, NRCAM, ADAA4DEC1, ICAM1, F604, MA8413, C3P1B1, 203665 AT, 205891 AT, 208816 X_AT, 239519 AT, 233540_5 AT, 218856 AT, DAPP1, C1336, ZFP3611, ARHGAP18, PTRF, N002, EPAS1, 210145 AT, 212L90 AT, 223502_5 AT, 212143 S_AT, 1557938 S_AT, 215602 AT, ARHGAP113, HMOX1, L0C103131909, ANXA2.172, NRP1, 2.23939_AT, 203887 5 AT, 2067637 AT, 1555756_A AT, 222651_5 AT, 031C5RAP2, TNFRSF21, P1.A2G4A, 5E81.04E2, THFSF1313, 215813 AT, 218501_AT, 227240 AT, 210427 X AT, 226218 AT, 2111934_S_AT, IGE8P3, P7RF, FG1312, SUOMI, TH80, P29114, CLEC7A, 244579 AT, 204661_AT, 207233_5 AT, 210895 S_AT, 222062 AT, 232746 AT, TRPS1, P1051õ ARHGEF3, N661, ANXA2P1,11.711, H5P137, 2.27265_AT, 210512_5 AT, 2251101 AT, 711527 X AT, 244414 AT, 203140_AT, TRP51, C052, MITE, C086,11.27RA, CXCR7, F012, VEGFA, 60:0065007-biological 242405 AT, 1569150 X AT, 201952 AT, 203980 AT, 225189 5 AT, 230559_3 AT, RAPH1, VEGFA, MAML2, KU, MAML2, POLIM7, 0 0_00022752 123581669 0.01124356 1.7 regulation 210254 AT 711931 AT, 71117S8 AT, 222876 S_AT, 210757 X AT, 201280 S AT, ALCAM, FAI3P4, RAPH1, F604, 6PR35, 102, 5G513, 1.7 201951 AT, 219358 5 AT, 210495 X A7, 229221_AT, 209555 S_AT, 202435_5 AT, ADAP2, 04132, 0A82, ALCAM, ADAP2, FNS, C1344, C036, 221011_5 AT, 210360 AT, 217999 S AT, 224480 S_AT, 203936 S AT, CVP1131, LEH, MTSS1, PHIJIAL AGPAT9, MIMP9,1301741, 2281357 AT, 214255 AT, 2022E4 S AT, 242903 AT, 1569149 AT, 228490 AT, ATPIDA, CO6N1A, WNGR1, POLIM7, 885)02,89882, 2137610 S AT, 209568 5 AT, 203753 AT, 1553982 A_A7, 212917 AT. 201422 AT, RG1.3.,TCF4, 54878, CtCR7, 11330, AP8811P, NGEF, C09, 2.30925_AT, 243556 AT, 201005 AT, 2030613 AT, 213253 S AT, 237252_AT, PAPSS2, TRIM22,71010, VEGFA, CSPG4, IF146111, 1.7 212171 X AT, 214297 AT, 202727 S AT, 235457 AT, 221060 S_AT, 223536_AT, MA0412, TIM, SLC12A6, 0352, CSORFA9, AHNO2, P5113, 34210 AT, 7_73330 AT, 205566 AT, 218613 AT, 221463 AT, 232068 S AT, CC124, 1154, IRE7, C3AR1, TRPM0, NRP1, VEGFA, 208436 S_AT, 2099436 AT, 243483 AT, 210510 AT, 210513 5 A7, 212614 AT, AR11358, TCF4, HIPIC2,APBBIIP, VASH1, P103,16251, 7173136 AT, 225097 AT, 219994 AT, 1556423 AT, 203355_5 AT, 224218 S_AT, 0882, ADORA3, SNA13, AP81311P, N75E, LPARS, CYP181, 201278 AT, 206171 AT, 15602211 AT, 237442 AT, 203939 A7, 218589 AT, 0882, ATF5, MAML2, P7)3, ABH132, 71.114, ENPP2, GLIS3 202436 S_AT, 203.279 S AT, 204998 S_AT, 234645_AT, 205157 _AT, 225337 AT, EMP1, RCL/A1, FNL FN1, ANXA2P1, F60l, RA82713, 224341_X AT, 2119392_AT, 229435_AT, 201324 AT, 205681 AT, 212464 AT, EPS13, MAF8, PTAFR, 04013,112R6, P064, MMP14, 216442 X AT, 2_13503_X AT, 1553906 5 AT, 728703 AT, 202609 AT, ANKH, GPR183, A8H02, ARHGAP20, C0IGRAP2, CC.15, 218559 5 AT, 211661 X AT, 214341 AT, 204116 AT, 225207 AT, 202E27 5 AT, NLRC4, CYP1B1, MTSS1, 0062,7184, CRIP2,TH813õ
223092 AT, 205419 AT, 87100 AT, 228368 AT, 220935 S_AT, 204655 AT, ADORA3, CCH01, CCU, C036, 0409, 151981, SERTAD1 1552553 A AT, 202437_5 AT, 203037 5 AT., 214054 AT, 1552798_A AT, 208978 AT, 203888 AT, 237904_AT, 208712 A7, 1555759 A AT, 241929 AT, 242157 _AT, 219434 AT, 223394 AT
203665 AT, 203140_AT, 205891_AT, 221060 AT, 1552798 A AT, 226218_AT, HMOX1., 80.8, LOC100131909,11.34, 71.114,11.713, GCLOCI50865-regulation 0_00022283 4_295743747 0131130118 223501 AT, 223502_5 AT, 215990_5 AT, 205798_AT, 210895_5 AT, 222062 AT, THFSF1313, TNFSF1313,11C16,11713, 0.186, 1127RA, 71.124, of cell activation 224341 X AT, 204116 AT, 207433 AT, 202254 S_AT, 232068_5 AT 11.2176, 11.10, C136N1A, 71134 60:0048545-respanse 203665 AT, 207542_5 AT, 203980 AT, 2_17757 AT, 14051_AT, 204655_AT, HM031, AQP1, cas, PI.A2G4A, to steroid hormone 0.00025981 4.216192937 0.0122074 210145 AT, 238669 AT, 208712 AT, 207433_AT, 1555759 A AT, 202E127_5 AT, PTGS1, CCNIM, 11.10, CCL5, MMP14, COKNIA, AUL

stimulus 202284_5 AT, 209047_AT, 215813 S AT, 205128_X AT
PTGS1, P7651 ' Fold Term Pvalue Benjamini Probesets Genes Enrichment k...) 209906 AT, 207433 A7,204655 AT, 1405_1 AT, 1555759 A AT, 209392 AT, C3AR1,11.10, CC15, C.C13, CC15, ENPP2, en 74, NRP2, GO:0006935-chernotaxis 0.00027256 4_651162791 0.01249951 CA
22I463_AT, 222877 AT, 235286 AT, 205898 AT, 205099 S AT, 211661_X AT CK15, CX3CR1, CC111., PTAFR 0 209906 AT, 207433 AT, 204655 AT, 1405_I_AT, 1555759 A AT, 209392 AT, OAR1, 1110, CC/5, CCLS, tri 5, ENPP2, CC124, NRP2, 4a, G011042330-taxis 0.00027256 4.651162791 0.01249951 k...) 221463 AT, 222877 AT, 235286 AT, 205898 AT, 205099_S AT, 211661 X AT CKLF, CX3C11.1, CCR1, PTAFR

G0:0002703-regu1ation 205798 AT, 203665 AT, 205891 AT, 203140 AT, 222062 AT, 207433 AT, IL7R, HMOX1, LGC1001_31909, 8C16, 1127RA, ILIO, of leukocyte mediated 0.0003028 7.429934407 0. 01355657 220066 AT, 226218 AT, 2i5990 _S AT N0132, 117R, 8C16 immunity G0:0002822-regulation .
of adaptive immune response based on somatic recombination 205798 AT, 203140 AT, 210895_6 AT, 222062_AT, 207433 AT, 220066 AT, IL7R, sax, C086,11.2711A 1110, N002,1178, TNFSF138, 0.00034918 7.244186047 0.01492816 of immune receptors 226212 AT 223501 AT, 223502_6 AT, 215990_6 AT
THFSF138,13CL6 built from imrnunoglobulin superfamily domains P
229221 AT, 203665_AT, 201069 AT, 214297 AT, 212298 AT, 213503 X AT, C044, HMOX1, MIMP2, CSPG4, hIRPI, A8LXA2P1, VEGFA, o no vo G0-00(115641-blood 212171 X AT, 104575 S AT, 202416 X AT, 210510 S_AT, 239519 AT, PAMPA MIXA2P2, NRP1, NRP1, AJIXA2P1, VEGFA, ul 0.00034714 3.471867967 0.01517609 "
vessel development 210427_X AT, 210513 S AT, 201590 X AT, 222877 AT, 211962 S_AT, ANXA2P1, N8P2, ZFP361.1, MMP14, VEGFA, VEGFA, H co o.
202827 S AT, 210512_6 AT, 211527 X_AT, 200878_AT EPAS1Ul vo Iv o 220333_AT, 21.0495_X AT, 229221 AT, 212298 AT, 222877_AT, 205738 AT, r o, 201278 AT, 211962 S AT, 242871 AT, 203936 S AT, 209348 S AT, 230360 AT, PAGRS, Ril, C044, NRP1, NRP2,1178, DAB2, 7E.361.1, I-, 2.04141 AT, 200878 AT, 1569149 AT, 201279 S AT, 2049943_6_AT, 239519 AT, PACIR5, 841vIP9, MAP, GLDN, TUBB2A, EPAS1, PD111.47, Iv I-, 201565 6 AT, 221266 S_AT, 233540 S AT, 204999_6 AT, 226066 AT, 212190_AT, 0A82, ATF5, NRP1, 102, TM7SF4, CDX5RAP2, ATF5, o, 215990 S AT, 212143 S AT, 220484 AT, 243556 AT, 210095_6 AT, 201324 AT, M1TF, SERPINE2, BCI.6, IGFBP3, MCOLN3, NGEF, I0H3P3, G0:0030154-ce11 0.00037713 139379845 0.015766012.12464 $ AT, 21.6442_X _AT, 212171 _IC AT, 214297 AT, 204575_6 AT, 227240 AT, EMP1, H11, FN1, VEGFA, CSPG4, MMP19, NGEF, 102, differentiation 201566 X AT, 211719 X AT, 228964 AT, 226218 AT, 207233_6 AT, 207433 AT, F811, PRDMI, 1178, MDT, 1110, VEGFA, MMP14, GPR183, 210512 S AT, 202827 S AT, 205419 AT, 211527 X AT, 204465 S AT, VEGFA, INA, RASGRF1, gas, IVIDGA1, ALCAM, P0111.17, 1554992 AT, 203140_AT, 1560960 AT, 20L952 AT, 1569150_X_AT, 2039130 AT, FA8P4, COIC5FIAP2, NRP1, VEGFA, IO2, NRCAM, CCND1, 220935_6 AT, 210510 S_AT, 210513 S AT, 213931 AT, 204105_6 AT, 2011712_AT, DAB2, MCOLN3, 0A82, AL.C.A.M
210757 X AT, 229797 AT, 201280 S AT, 201951 AT
229221 AT, 203665 AT, 201069 AT, 214297_AT, 212298 AT, 213503 X AT, CD44, HMOX1, MM P2, CSPG4, NRP1, A14XA2P1, VEGFA, 60:0001944-vasculature 71217I_X AT, 204575 S AT, 208816_X_AT, 210510 S
AT, 23951.9_AT, MARP19, ANXA2P2, NRP1, NRP1, AttKA2P1, VEGFA, 0.00033042 3.42764035 0.01597268 .0 development 210427 X_AT, 210513 S_AT, 201590 X AT, 222877 AT, 211962_S_AT, ANXA2P1, NRP2, ZFPqAll MMP14, VEGFA, VEGFA, n 202827 S AT, 210512 S AT, 211527 X AT, 200878 AT EPAS1 00:0002819-re4ulation 205798 AT, 203140 AT, 210895_6 AT, 222062 AT, 207433 AT, 220066 AT, 1128, BC16, CD86, 11278A, ILIA 81002,11.78, TNFSF13B, k...) of adaptive immune 0.00040094 7.067498582 0.0160609 226218 AT, 223501 AT, 223502_6 AT, 215990 S_AT
TNFSF1.311, 8C160 response 1-, f../1 G0-.0051241-negative 203665 AT, 203140 AT, 205891 AT, 213503 X AT, 212171 X_AT, 208816 X AT, HMOX1, 8C16, L0C100131909, ANXA2P1, VEGFA, 0 (....) regulation of 00004538 4.902080783 0.01.743952 2.10427_X AT, 210513 S_AT, 201590 X_AT, 215990 S_AT, 206835 AT, 207433 AT, AN1CA2P2, ANXA2P1, VEGFA, ANXA2P1, Bafi, STATH, 00 multicellular organismal 210512_S_AT, 220066 AT, 211527 X AT 1110, VEGFA, 81002, VEGFA V0 1-, Fold Term Pvatue Ben:1mnd Prohesets Genes Enrichment tNa 237252 AT, 202727_5 AT, 1405_t_AT, 221060 S AT, 205898 AT, 211651 X AT, amass S AT, 222062 AT, 204116 AT, 232746 AT, 207433_AT, 208436_5 AT, TH80,046E11, CCI-5, 1164, CX3C61, PTAFR, a}}16, 01 220066 AT, 232068 S AT, 134475 AT, 242903 AT, 37145_AT, 214453_S AT, 1127RA, 11.266, CCM, 11.10,1617,110192, 1164, ailk4P1, 60.0051704-m 0.00044925 2_222559065 0.01751538 204655 AT, 1552553 A AT, 211576_5 AT, 1552798 A_AT, 229937 X_AT, IFNG61, ONLY, 11144, CCL5, ILL6C4, IFTIGRI., 11.64, organism process tNa 2101.45_AT, 206157 AT, 203888_AT, 21.2977_AT, 224341 X AT, 203887 S AT, 1I1.8E11, PLA2G4A,1116, THBD, OtC67,11.64, THBD, tit 225097 AT, 205495 S AT, 1555755 A AT, 1355759 A AT, 202638 LAT, 14I182, ONLY, CLEC7A, cos, ICAM1,161M22.
213293 S_AT
21229.8_AT, 209555_5_AT, 227948_AT, 223560_AT, 210350:8_AT, 2.1941.2_AT, 14 811, C036, 1004, RA3, MTS51, HABIB, DAPP1, 222858_S_AT, 205738_AT, 206488_S_AT, 205960_AT, 206171_AT, 225173_AT, 11.78, 036, Polo, ,Afoismoi, Nora, EpAsi, 220066 AT, 200878 AT, 237442_AT, 242903_AT, 225166 AT, 218589_ATõ
APBEILP, 1111011, ARHGAP18, LIARS, 1481051, 203665_AT, 205891_AT, 207610_5_AT, 225171_AT, 209568_5_AT, 220307_AT, 00131909, EMU, A81413A1111,1401.1, CO244, NRP1, 239519 AT, 230266_AT, 269684 AT, 218856 AT,1553982 A AT, 223502 S AT, RA678, 81142, 114183121,88378, 111151138, CSF1R, 2303104 AT, 212977_AT, 774439_AT, 224341 X_AT, 2041234_AT, 206537_AT, CXC117, SUCNR1,1164, F6L2, P2RY14, C036, C1.EC7A, G0:0007165-sign al 228755 AT, 1555756 A AT, 230925 AT, 214581 X AT, 214297 AT, 216501_AT, 0.00048801 1.565926487 0.01837796 AP11011P,TILF65121, CSPG4, ARHGEF3, 1114661, CC15, transduction 202727_5_AT, 1405_I_AT, 22.8708_AT, 221060_S_AT, 2.132609_AT, 226218_AT, RA827B, 11.144 1.158,1176,174151136, OL3C.R1, COM
223501 AT, 205898 AT, 205099_5 AT, 211661 X AT, 214841 AT, 204116 AT, PTAFR, CNI143,11260, OCR?, P064,1110, F&2, RAPH1, 232746 AT, 225207 AT, 207433_AT, 227265_AT, 225188 AT, 221463 AT, CC124, 018183, 1184, C3A111, ARHGAP20, RAS' 01111, 235419 AT, 232068_5 AT, 209905 AT, 228358_AT, 1554992 AT, 201952_AT, ALCAM, NWT, CCLS, MPH', 16194, 00112, A47551, 210510 S AT, 204655 AT, 225139_5 AT, 230559 X AT, 214054 AT, 203037 S AT, 01835, IFHGR1, 1184, 111(8, A008A3, CCN01, 141152, 210264_AT, 211676_S_AT, 1552798_A_AT, 215250_S_AT, 237904_AT, 208712_AT, ApBBlif, c036, Than. Ammo 225037 AT, 219994 AT, 1555759 A AT, 241929_AT, 219434_AT, 201951 AT
1-t 237252 AT, 1405 I_AT, 204555 AT, 1552553 A_AT, 221060_8 AT, 1552798 A_AT, 1880, CCLS, CCLS, N16C4,11.64, R64, PLA2G4A, THBD, G013009617-response 0.00051926 4.267561735 0..01317123 210145 AT, 203838 AT, 211661_X AT, 2.22062_AT, 224341_X AT, 203867 S AT, PTAFR,11.2711A,11.114, THIM, 1110, GNLY, CC.1.5, N002, to baaenum ca 207433_AT, 205495 _S AT, 1555759 A_AT, 220066 AT, 232068 S AT, 37145 AT T1.64, ONLY
213831 S AT, 1353395 A AT,11,/q8 AT, 224218_5 AT, 2057911 AT, 201278 AT, 228057 AT, 202264 S AT, 220066 AT, 203939_AT, 228450 AT, 203E65 AT, TCF4, NT5E,141111,11051, 11.711,15A82, DDIT4L, CDKN1A, ca 205891 AT, 201279_5 AT, 204398 S AT, 208815 X AT, 201565 S AT, 239519_AT, 14002, NT5E, A8H02, HAIM, 0:C100131909, 1129', 293753_AT, 201590 X AT, 204399 S AT, 225066 _AT, 223502_5 AT, 215990 S AT, ATF5, AMA:11.2,102, NP.P1,TCF4, ANXA2P1, ATFS, 221815 AT, 225337 AT, 212143 S_AT, 224341 X AT, 201422 AT, 222146 S_AT, MITF, TNFSF1313, IICL6, A81402, ABHD2,1011313,11.114, 222651 5 AT, 229435 AT, 201005 AT, 2158'3_5 AT, 210095_S _AT, 205681_AT, 11130, 1CF4, 18151, 01(33, C09, P1051,161813, BC12.41, G0IX148519-negative 205128 X_AT, 214211_AT, 1560485_AT, 2.12171_X AT, 21.3503_X_AT, 63825 AT, PTGS1, 111413, HP/Eli, VEGFA, ANXA2P1, ABH02, pas, regulation af biological 0.00057125 1.628669462 0.01993331 1405_I_AT, 221060 S AT, 210427 X AT, 201566 X AT, 226964 AT, 225218 AT, 11R4, ANXX2P1,102, PROM 1, 8.76, 181S1138, 1C14, process 223501 AT, 212387 AT, 223398 AT, 244579_AT, 218559 S AT, 205566 AT, 908189, TRPS1, MM'S, 831402, MIFF, 112784, 18151, 207233 S AT, 222052 AT, 218502_5 AT, 206835_AT, 207433_AT, 210512 AT, STATH, 1110, VEGFA, 811014, MAFB,16F7,T1114, 202827_S_AT, 222670 AT, 2138436 S_AT, 232068 S AT, 87100 AT, 881402, VEGFAJCF4, 80.6, 11614, A2A4, CCLS, 14811, 211527 X_AT, 212382_AT, 203140 AT, 203980_AT, 217757_AT, 2.04655_AT, VEGFA, 11114, SKI1,102, PTOS1, 831058, coon, RGS13, 210510 S AT, 210513_5 AT, 1552798_A AT, 206675 AT, 213931 AT, 0A82, TC14, ADAM0EC1, 14I11(2, COS, VASH1, 0832, 238669_AT, 212614_AT, 2087/2_AT, 21.0256_AT, 2/0757_X_AT, 2123116_AT, 2136134 AT, 2253997 AT, 1555759_A_AT, 1.556423_AT, 201280 S AT, 223394_AT
60:0050854-regu1ation 203140 _AT 222062 AT, 204116 AT, 207433_AT, 202284 AT, 27_3501 ATõ BUS, 1127RA, 1.1.26G, 1110, CDKN1A, 18151138,tNa 0.00055871 8.564554932 0.0202092 of B cell activation 223502 S AT, 215990 S AT THFSF138, 80.6 tit 203665 AT, 214297_AT, 213503 X AT, 212171_S AT, 2122.98_AT, 204575_5 AT, HMOX1, CSPG4, ANXA2P1, VEGFA,N811, MAAP19, 600001525-angtogenes 0.00055006 4124015187 0.02027648 206816 11 AT, 210510_S AT, 210427 X_AT, 210513_S_AT, 239519 AT, AILXA2P2, 14811, ANXA211, VEGFA, 8811, ANXA2P1, is 201590 X_AT, 2221177_AT, 202627_5 AT, 210512_5 AT, 21.1.527_X AT, 200878 AT
14812, NIMP14, VEGFA, VEGFA, EPAS1 Fold Term Pvalue Seniamini Probesets Genes Enrichment 220333 AT, 210495 X AT, 229221_AT, 212298 AT, 222877 AT, 205798_AT, 201273_AT, 211962_5 AT, 242871_AT, 203936_5 AT, 209348_5_AT, 230360 AT, PA0JR5, Rfl, C044, NRPI, NRP2,1176, DASZ 2FP3611, 204141 AT, 200878 AT, 1569149_AT, 2.01179_S_AT, 204998 S AT, 239519 AT, PA0115, MA4P9, MAF, OWN, TU8B2A, EPASZ PD11817, 201565_5 AT, 221266 S_AT, 233540 S_AT, 204999 S AT, 226066 AT, 21219E1 AT, DA132, ATF5, NF1111, 102,1557514, CDICSRAP2, ATF5, 215990 AT, 212143_6 AT, 220484 AT, 201005 AT, 243556 AT, 210095 S_A7, MIFF, SEFIPINEZ 8C16, MC011113, C09, NGEF, 60.1111466164-cel1u1ar 0.00059519 1.735654039 0.02039323 201324 AT, 212464_5 AT, 216442_X AT, 212171 X AT, 214297 AT, 204575 S AT, 106814, EMP1, FNI, FN1, VEGFA, CS1'G4, KAMP19, NGEF
developmental process 227240 AT, 201366 X AT, 211719_X AT, 228964 AT, 226218_AT, 207233 S AT, 102, FN1, P60551, 117R, MITF, 1110, VEGFA, IAMP14, 207433 AT, 210512_6 AT, 2021327 S AT, 205419_AT, 21 1527 X A7,204465 S AT, 614183, VEGFA, INA, RASGR1'1, Bras, MOGA1, ALCAM, 1554992 AT, 203140_AT, 1560960 AT, 201952 AT, 1569150 X AT, 203980 AT, PDLIW, FABP4, COK5RAP2, NRPI, VEGFA, 102, tiFtC.AM, 220935 S AT, 210510 S_AT, 210513 S AT, 2_13931 AT, 204105 S AT, 208712 AT, CCND1, DAB2, MCOLN3, 0032, ALCAM
210757 X AT, 229797 AT, 201280 AT, 201951_AT
203140_AT, 205891_AT, 203665 AT, 2,621.8_AT, 223501 AT, 215990 AT, GO:0002694-regulation9C16, )DC100131909, HMOXI,11311, THFSFI3B, 8116, 0110064956 4.139534884 01)2184996 223502 S_AT, 205798 AT, 710445_6 AT, 222062 AT, 204116_AT, 2.07433_AT, of leukocyte activation THFSF1313,11.711, COBS, 1127RA, 11.260, 1110, 0, tai---Krt-IA
202284_5 AT
0013044243-multice5ula r organional catabolic 0.00070212 20.69767442 002313544 201069_AT, 204575_5 AT, 203336 S AT, 204475 AT
555514, NIMP19, Mh4P9, MRAP1 process GCL0030574-collagen 0.00070212 20.69767442 0.02319544 201069_AT, 204575 S AT, 20.3936_5 AT, 20447S
AT MIVIPZ 5555149, MA4119, MAII'l catabolic process 216442_X_AT, 210495_X_AT, 229221_AT, 1560560_AT, 212238_AT, 21051.0_5_AT, FNI, FN1, CII44, MDGAZ NRP1, COS, CCU, G00016477-cell 1405 J AT, 2134655 AT, 239519 AT, 211719 X AT, 222877 AT, 204268 AT, UT
1100071879 3.203211517 0.02334233 NRP1, FN1, NRP2, S100A2, NRCAM, ARIL/58,810, migration 204105 S AT, 212614 AT, 207433 AT, 202827_6 AT, 1555759 A AT, 235286 AT, MRAP14, 005, OCLF, ICAM1, Fffl 202638 S_AT, 212464_5 AT
212258_AT, 209555 AT, 1405_1_AT, 201.566_X AT, 221.060 S AT, 22621ELAT, 203559_5 AT, 205738_A7, 207233 S AT, 206488_5 AT, 210895 S_AT, 2.04116_AT, NRP1, C636, C115,102, 1134,11.713, MAF13,11.76, MITF, 209348 5 AT, 222670 S_AT, 232.068_5 AT, 1.569149_AT, 203140_AT, C036, 085, 11.260, MAF, MAFB, TIR4, P011557,8115, 60:0045595-re4u12ti00 0.0007682 2_517284727 0112373537 1569150_X AT, 204998 S AT, 220935_5 AT, 2111510_5_,AT, 204655 AT, P01.047, ATF5, COKSRAP2, NRP1, CCU, NRP1,102, TIM, of cell differentiation 239519 AT, 201565 AT, 1552798 A AT, 231540 S_AT, 204999 S AT, C0K5RAP2, ATFS, MITF, SC16,162, IGFHP3, NRCAM, 226066 AT, 215990 AT, 213931 AT, 212143_5 AT, 204105_5 AT, 208712_AT, CCND1,11.114, C036, CCL5, C036, IGFTOP3 224341 X_AT, 228766 AT, 1.555759_A_AT, 241929_AT, 210095_5_AT
2122.98 AT, 212171 X AT, 209555_5 AT, 6152.5_AT, 228708 AT, 205566 AT, fiRF1, VEGFA, C036, A8NO2, RA112713, ASH D2, C036, 2136488_S_AT, 207433_AT, 203936_S_AT, 210512_5_AT, 87100_AT, 2211066_AT, 1110, ItiMP9, VEGFA, A5H02, N002, VEGFA, A8H02, 211.527_X_AT, 228490_AT,203665_AT, 203140_AT, 2051391_AT, 21051.0_S_AT, G0.01132879-regulation Wan, 8116,LOC100131909õ NRP1, NRPL. VEGFA, 0.0007822 2.358709335 0.02378398 239519 AT, 21(1513_5 AT, 212190_AT, 210145_AT, 22181.5_AT, 215990 AT, of i0CiltiZatirgi SERP1NE2, P1A264A, A8FI02, 8116, P11(3, IGFBP3, 206157 AT, 212143 S AT, 22.5337_AT, 2311669 AT, 228766 AT, 1555756 A_AT, A8/102õ PTGS1, C036, C1EC7A, EfiPP2, VASH1,=C036, 2.09392_AT, 1556423_AT, 241929_AT, 210095_5_AT, 21.51313_5_,AT, 202638_5_AT, IGFSP3, P1601, ICAM1, F1051 205128_X_AT
GO-9050729-positive 2115E91 AT, 224341I AT, 2.133980_AT, 204655 AT, 1405_I AT, 221060 S AT, 10C100131909, TIM, FASP4, CCIS, COS, 7184, CCU, regulation of 000076295 11.49870801 0.0239569 1555759 A AT, 232068 S AT, 1552798 A AT, 210145_AT 1134,11114, inflammatory rttsponse 2113589 AT, 209906 AT, 2051191_AT, 2076113_5 AT, 223660 AT, 1405_1 AT, LPAR6, C3ARI, 10C100131909, UtiR2, ADORA3, GCB, G0110071116-0-proteln 204655 AT, 210264_AT, 205838 AT, 205099_5 AT, 237904 AT, 2.11661_6_AT, CC15, 61435, CX3CRI, CCM., P.13G6A3, PTAFR, C6CR7, coupled receptor protein 0.00075328 2325619677 0.0240464 (..n) 212977 AT, 210258_AT, 232746 AT, 223939_AT, 206171 AT, 206637 AT, 66.513, CXCR7, SUCNR1, ADORA3, P26514, cams, 00signaBog pathway 1555759_A_AT, 209392 AT, 205419_AT ENPP2, 014183 Fold Term Pvalue Benjamin' Probesets Genes Enrichment 228490 AT, 204445 AT, 203140_AT, 212298 AT, 212171 X_AT, 64825 AT, ABHD2, HMOXI, 8C16, NRP1, VEGFA, ABH02, NRP1, 5013051270-regula0cm 210510 S AT, 219519 AT 2105135 AT 22.2190 AT
, _ 215990 S AT 221815 AT , A, SERPINE2,13CL6, ABH02, 5F8P3, ABH132, NRP1 VEGF 1 Of4140R15 L5 3_642790698 0112491336 _ , _ , _ Of cell motion 717143_5 AT, 205566 AT, 225337_AT, 203936 S AT, 210512 S AT, 209392 AT, AlitH132, AIMP9, VEGFA, ENPP2, VASH1, ABHI32, VEGFA, 1556423_AT, 871130 AT, 211527 X AT, 210095 AT, 202638_5 AT 15F8P3,1CAM1 JI
213891 S AT, 229221 AT, 212298_AT, 209555_5 AT, 227948 AT, 777A48 AT, 242794 AT, 205798 AT, 206488_S_AT, 217999 S AT, 217997 AT, 209348_S_AT, TCF4, C044, NRP1, CD36, F504, SLAMF7, MAML3,11.711, 203936 S_AT, 202.284_5_AT, 220066_AT, 747133_AT, 200978_AT, 1569149_AT, c0 36, piatoa, F141 rim MAT, enx.NIA. N002, 205891 AT, 203665 AT, 201555_5 AT, 239519_AT, 203753 AT, 234645_AT, MANIL2, EPAS1, POLIM7, LOC100131909, HMOKI, 1132, 210145_AT, 2261366_AT, 215990 S AT, 206157_AT, 223502_5_AT, 212143_5_AT, 14RP1, TCF4, MA6412, PLA254A, MOT, 8C/6, PTX3, 215602 AT, 224341 X AT, 222146 S AT, 22_8766 AT, 1555756 A AT, 243556_AT, 229435 AT, 715613_5 AT, 210095_S_AT, 205128_X_AT, 212171_K_AT, 2111501_AT, 174FSF138, IGF8P3, P502,11.84, TCF4, CUSS, CLIC7A, 5011048518-positive NGEF GillS, PTGSI, 615F8P3, P3651,51, VEGFA, ARHGEF3, 1553906 S_AT, 227240_AT,1405_1_AT, 201566_X_AT, 235457_AT, 221060_S_AT, reralatit,n of biological 0.0009722 1359204424 0.02858412 228964 AT, 226218 AT, 22_3501_AT, 212387 AT, 218559 S AT, 207233_S_AT, F502, NGEF, CO5,102, MAML2,11.84, PRDM1, 117R, process TNESF138, TCF4, MAPS, MITF, (2386, 1127RA, 11.285, 210895_5 AT, 2.2.2062_AT, 204116 AT, 207433_AT, 222670_5_AT, 210512_S_AT, 1110, MAFB, VEGFA, 11R4,1897, VEGFA MAAAL1, TCF4, 2_32068_5 AT, 208436 S_AT, 211527_X_AT, 244414_AT, 217447_AT, 2099136_AT, C3AR1, RASGRFI, 8CL6, PDLIM7, MATALI, FA8P4, HILF1, 1554992 AT, 203140 AT, 1569150_K_AT, 242405_AT, 203980_AT, 210510_5_AT, CCL5, NLRC4, F504, VEGFA, F5132, TLR4, CF11P2, 204655 AT, 1552553 A AT, 230559 X AT, 210513_5 AT, 1565754_X AT, PHLDA1,102, PTG51, F502, NRCAM, CC3401, TCF4, 1552798 A AT, 208978 AT, 2251342_AT, 213931 AT, 238669 AT, 1565752 AT, CCL5, C036, ICAM SERTAD1 204105_5 AT, 208712_AT, 212386 AT, 27_5097 AT, 1555759 A AT, 241479 AT, ("I
202638 S AT, 223394 AT

50=01816-cookine 224341 X AT, 203980_AT, 1552553 AT, 209348_5 AT, 221060 5 AT, TLR4, FABP4, NL8C4, MAT, 11.84, (9002, 11.84,11.84, 0.00105123 7.526427061 0.0299652 production 220066 AT, 232068 S_AT, 1552798 A_AT, 211661 X
AT PTAFR
ICAn 209906 AT, 1554992 AT, 1405_1 AT, 204655 AT, 202609 AT, 222877 AT, C3 ARI, RASGRF1, GCB, CCL5, MB, NRPZ, CLICR1, 50330076101se8avior 0_00104771 2_759689922 0.03031177 205898 AT, 205099_5 AT, 211661 J AT, 220484 AT, 225097 AT, 207433_AT, CC111, FTAFR, MCOLN3, HIPK2,11.10, MCOLN3, ANKH, 229797 AT, 223032 AT, 1555759 A AT, 209392 AT, 221463 AT, 235286_AT CCLS, ENPP2, CC124, CKLF
237252 AT, 21.3503_X AT, 209555 AT, 208816 X AT, 210427 X AT, THBD, ANKA2P1, CD36, ANKA2P2, ANKA2P1, ANXA2P1, 50=50/78-regulation 0.00117703 4.87004104 0.03300809 201590 X AT, 203888 AT, 206488 5 AT, 206835 AT, 203887 5 AT, 228766 AT, 111813, CD36,5TATH,711130, CD36,14MCN1., C036, COS, of body fluid levels 235944 AT, 241929_AT, 2011105_AT, 203060 S AT P89552 237252 AT, 1405 I AT, 204655_AT, 221060_S_AT, 1552758_A_AT, 210145_AT, 50:0032496-response 1141313, 0C15, cas, TL14, TLR4, P1A2G4A, 11480, PTAFR, 0_0013154 5.681714546 0.03578575 203888 AT, 211E61 IC AT, 224341 It AT, 203887 AT, 207433_AT, 11.14, THEM, 11113, cas,11.R4, N002 to lipopolysiodlaride 1555759 A_AT, 232068 S AT, 220056 AT
50:0002683-negative 205798 AT, 203665 AT, 203140 AT, 222062 AT, 217757 AT, 207433 AT, 11.78, HMOX1, 13C16, I127RA, A2M,11.10, N002, 1L7R, 0.0013154 5.681714546 0.03578575 regulation of immune 220066 AT, 226218 AT, 215990 S AT sas 216442 X AT, 21.0495_X_AT, 229221._AT, 1560960_AT, 717248_AT, 210510_5_AT, FN1, FN1, CD44, MOGAi ran, ran, rn mu, 5011051674-locadization 1405_1 AT, 204655 AT, 239519 AT, 211715 _IC AT, 222877 AT, 204263 AT
0.00131424 2.989664083 0.0362E342 , N891, FN1, NFLP2, 51.110A2, NRCAMõ ARID513, 1110, of cell 204105 S AT, 212614 AT, 207433_AT, 202827 AT, I555759_A_AT, 235286_AT, MAAP14õ CKLF, ICAMI, FN1 202638_5 AT, 212464 S AT
216442 X AT, 210495_1(_AT, 229221_AT, 1560960_AT, 212298_AT, 21.0510_S_AT, Ft11, FN1, C1344, MDGA1, NRPI, NRPI, CCLS, cas, col 1405 I AT, 204655 AT, 239519 AT, 2L1.719 X AT, 222877 AT, 204268 AT, Ga.0048870-cell motility 0.00131424 2919664063 0_03626342 N891, FN1, N892, 5100A2, NRCAM, A81358,11.10, 204105_5 AT, 212614 AT, 207433_AT, 202127 S_AT, 1555759_A_AT, 235286_AT, MAAP14õ MS, ICAM1, FN1 202638 AT, 212464_5 AT

Fold Tenn Pyalue Bemamini Probesets Genes 0 Enrichment r..i 203665 AT, 205851 AT, 207542_6 AT, 213503 X AT, 201279_6 AT, 218816_X AT, iltsIOX1, 10C100131909, AQP1, ANXA2P1., 0562, 1=
I-t 60:0046903-seaetion 0.00135387 3.163975707 0.036848341405_1 AT:104655.AT, 210427_X AT, 1552553 A AT, 201.590 X_AT, 227134 AT, ANXA2P2, GC15, GUS, ANX.A2P1õ NLI1C4, ANXA2P1, 01 223501 AT, 223502 S AT, 201278_AT, 206835 AT, 210757 X_AT, 1555759 A_AT, SYTL1,TNFSF138, TH55F138, DAI32, STATti, DMZ, CC15, 1=
2.09047_AT, 201230 S AT, 235286 AT
ACLP1, 0A82, OUP 1=
4=..
r..i 2.10495_X_AT, 216442_X_AT, 225221_AT, 212298 AT, 1.405_1_AT, 211719_X_AT, 1.11 FN1, FN1, G044, NRP1, CCL5, FN1, MTSS1, N11P2, 210360 5 AT, 222877_AT, 204263 AT, 207433_AT, 202327_5_AT, 235286_AT, 1=
51.00A2,1110, NIMP14, GUS, MOGAI,ALCAM, CCU, G03006928-cell motion 0_0013311 2.465196246 01137021E9 1560960 AT, 201552 AT, 204355_AT, 210510_5_AT, 239519_AT, 203037_S_AT, NRP1, NAM, hitTSS1, AR11:1511, NRCAM, CC15, ENPP2, 212614 AT, 204105 S AT, 1.555755_A_AT, 209392_AT, 201005_AT, 201.551_AT, . , I
1, FN1 . 202633_5 AT, 212464 S AT
203665_AT, 214297 AT, 213503_X_AT, 212171_X_AT, 217753_AT, 204575_5_AT, HM0X1, C51'64, A8/XA2P1, VEGFA,NRP1, Mtv1P19, G03043514^b1ood 2/18816 X AT, 210510_6 AT, 239519 AT, 210427 X_AT, 210513 S AT, 0.00142405 3398125651 0.037L7335 ANXA2P2, NRP1, NRP1,ANXA2P1, VEGFA, ANXA2P1, vessel mambo-genesis 201590_X_AT, 222377 AT, 211962_5 AT, 202.327_S_AT, 21.0512_5_AT, N8P2, 2693611, AAMP14, VEGFA, VEGFA, 69851 211527 X AT, 200878 AT .
201069 AT, 213503_X_AT, 1569150_X_AT, 210427_X_AT, 201.590_X_AT, Mt4P2, ANXA2P1, PDUM7, ANXA2P1, ANXA2P1, 16951, G0:0001501-skeletal 224218_5 AT, 204653 AT, 244579_AT, 217143_5_AT, 21.2614_AT, 206335_AT, 0.00146721 3.143950545 0.03772332 imp2A. 16951, 16E2,3, 6810.58, sum, TRpsi, mmis9, system diopinent 218602_S _AT, 203936 S_AT, 202827 S_AT, 223092 AT, 222651_S_AT, MMP14, ANKH, 16951, PAPSS2,16F3P3, PD111.17 203060 S AT, 210095_6 AT, 1569149 AT
P
GO:0050867-positive 203140 AT, 205851 AT, 221060 5 AT, 1552798 A AT, 226213 AT, 223501 AT, 8C16, 1.00.00131909,11.34,11114, 117R, 1ALF5F138, regulation of cell 0.00151561 4.664264653 0.03853451 22.3502 S_AT, 215990 S AT, 205798 AT, 210855_5 AT, 22.4341_X_AT, 204116_AT, TNFSF138, RG16, 11711, GD36, 71114, 1121113, allallA, to m a aivation 202284 5 AT, 232068 S AT
11114 Iv H
a) 229221 AT, 216442 X AT, 21.0455_X AT, 212-171 X AT, 210513_S_AT, GOD030247-polysaccha CD44, FIVI., FN1, VEGFA, VEGFA, P111,566911122, P113, t1=. Iv 0.0007648 5243823948 0.04514131 211719 X_AT, 212.190_AT, 206157_AT, 1555756_A_AT, 210512_5_AT, 220066_AT, o ride binding ClEC7A, VEGFA, N002, EN1'P2, VEGFA, FN1 r 209392 AT, 211527_X AT, 212464_5_AT
T
1:-', 229221 AT, 216442_X AT, 210455_X AT, 212171_S AT, 210513_5_AT, GOD001371-pattern G044, FN1,1141, VEGFA, VEGFA, FNI., SERPINE2, PTX3, IL
0.0007648 5.243323948 0.04514181 2117195 AT, 212190 AT, 206157_AT, 1555756_A_AT, 220512S AT, 22.0066_AT, o, binding GLEC7A, VEGFA, 11002, ENPP2, VEGFA, FN1 209392 AT, 711527_5 AT, 212464 S_AT
GO:0004222-metalloend 201069 AT, 206134 AT, 204575 S_AT, 229004_AT, 203936 S_AT, 202827 S_AT, NIMP2, ADAMDEC1, MMP19, ADAMTS15, DAMPS
0.00087418 6_148387097 0114535047 opeptidase activity 204475 AT
60014, IAMP1 G0D0026.98-negative regulation of immune 0.00156103 15.05285412 0.0468232 205798 AT, 2036.65 AT, 203140 AT, 217757 AT, 226213_AT, 215990_5_AT 11711, HMOX1, BC/6, A2h4,11711, BUS
effector process G0:003210.3-positive 205851 AT, 212171 X AT, 203930_AT, 1405_1 AT, 204655_AT, 221060 S_AT, 10C100131909, VEGFA, FABP4, LL15, M '1,11114, regulation of response to 0.00201705 6336107711 0104892858 210513 S AT, 1.552.758_A AT, 210145_AT, 224341_X_AT, 1555759_A_AT, VEGFA, 11114, PLA2G4A,1134, cas, VEGFA, 11114, external stimulus 210512 S_AT, 232068 S AT, 71'1427 X AT VEGFA .0 n 237252 AT, 229221_AT, 202435_5_AT, 1405_1_AT, 201.566_X_AT, 221060_5_AT, 11450õ G244, GYP131, COS, 102,1134, EPS8, HSPB7, 2112605_AT, 213934_5_AT, 204058_AL 211661_X_AT, 202434_S_AT, 207433_AT, CA
hAE1, PTAFR, C1P1111, 1110, MIAP14, CDKN1A, AQ91, r..i GO:0010033-response 202827 S_AT, 202284_S_AT, N19047_AT,220066_AT, 232068_5_ATõ 203665_AT, 0002,.n.R4, Hmax4 mei, cypituõ
5214, mEt 1=
0.00159539 2_04r814 = 09 0_04902907 207542 S AT, 202436 S_AT, 217757_AT, 2.04059_5_AT, 203980_AT, 204655_AT, I-t to organic substance FABP4, CCL5, CYP181,102,11.114, PLA2G4A,11112,THBD, fli 202437_S_AT, 201565_5_AT, 1552798_A_AT, 210145_AT, 213931_AT, 203888_AT, PTG51, C0.101,111310,11.84, CLEC7A, fcl 5, PTGS1, 1=
238669 AT, 208712 AT, 203837_5 AT, 224341 X AT, 1555756 A_AT, P11142, P11351 GO
1555759 A AT, 215813 S AT, 209122 AT, 20512.3_X_AT
V:1 1=
I-t _ tg 1-3 Pathways significantly enriched among genes upregulated by Probioglat relative to GA (mannitol-corrected comparison) at 6 hours: 'A 0 CD I-I w 0 ID o 1-, 0 0% CA
Term Pvalue Fold Enrichment Etenjamini Probesets Genes It) = Ci3 M
213503 X_AT, 210427 X_AT, 205153 S AT, 214866 AT, ANXA2P1, ANXA2P1, CD40, PLAUR, C040, 614111, 1 Uvi 215346 AT", 223862 AT, 22621.11_AT, 226142 AT, 216598 S_AT, IL7R, GLIPR1, CC12, STAIN, 1110, FGL2, PAMPS, r Dl206835 AT, 207433 AT, 227265 AT, 203936 S AT, 204475 AT, o 0 GO:0005576-extracellular _MMP1, ADAMS, COL6A1, CD14, ANXA2P2, 7_59E-09 4.042562158 2.49E-07 202381 AT, 213428 S AT, 201743 AT, 208816 X AT, 205499 AT, region - SRPX2, ANXA2P1, TNIFSF1.38, PDC3, EGF, ID 0 201390_X_AT, 223502_S_AT, 206157_AT, 206254_AT, 226573_AT, 0. 0 AN
, map, ADAMDEC1, ICAM1, CCIS, 2038,87_5 AT, 206134 AT, 202637 S AT, 1555759 A AT, tr 0 TREM1 O&
, ICAM1 219434 AT, 707638_3 AT
1=4 0 IC
10 ri=
209933 S AT, 210017 AT, 205153 S AT, 215346 AT, o 201502 S AT, 204590 X AT, 226218 AT, 216598 S AT, CD300A, MALT], C040, C040, NFKB1A, VPS33A, tr Le 207433 AL 203936 S AT, 221477 S AT, 2054 AT, 220066 AT, 11.711, CCL2, IU, !A
DMPS, $002, GPR163002, I-.= rt GO:0002376-irnmune 19 , N

1.04E-08 4156626506 1_53E-05 201926 S AT, 217386 S AT, 1555950 A_AT, 215223 S AT, 0)55, KYNU, C055, S002, ADAM9, 0D14, lel O.
system process 202381 AT, 201743 AT, 223502_3 AT, 2061.57 AT, num. S AT, TNFSF1313, P1)0,5002, ICAM1, 1F1141, CGS, ID = =

_S _AT, 219209 AT, 1555759 A AT, 2047E14 S AT, tALF1, ICYNU, TREM1, ICAM1 cl- 0 ND
210563 S AT, 219434 AT, 202638 S AT
'CI
Pi pi.
u, ND
M tt 1-` a , 213503 X AT, 210017 AT, 203980 AT, 2081316_X AT, I--I 0. Ui a.
ANXA2P1, MALT1, FABP4, ANICA2P2, ANXA2P1, 0 in ND
210427_X_AT, 205153 S_AT, 201502 S_AT, 201590 X AT, ct pi 0 G0:0048583-regulation of 0)40, NFKBIA, APDIA2P1, 0)40, 61481, JUR, 1_56E-07 5397095846 0.000115129 215346_AT, 223862 AT, 226216 AT, 223502 S AT, 207433 AT, 1 response to stimulus TNFSF138, 11.10, ICAM1, COS, 14002, 0)55, 4 0 1-202637 S A7,1555759 A_AT, 220066 AT, 201926 S Al', (1) ND

N73E, CD55, ICAM1LO 1-203939 AT, 1555950 A AT, 202638 S AT
' ta 213428 S AT, 202381 AT, 213503 X AT, 208816 X AT, COIKA1, ADAMS, ANXA2P1, ANXA2P2, 210427_X_AT, 201590_K AT, 223862 AT, 216598 S AT, 0 p.
G0:0044421-extracellularANXA2P1, ANXA2P1, GHRL, CCU, TNFSF1313, 0 it 2.87E-06 4.664494797 0.000225327 223502_S AT, 206254 AT, 203887 S AT, 207433 AT, t0 I.'.region partEGF, THEID, IUD, ICAM1, FGU, MMP9, CC'S, 0 a 202637 S AT, 227265 AT, 203936 S AT, 1.555759_A AT, MMP1, ICAM1 M pi 204475 AT, 202638 S AT

0 rr ID
213891 S AT, 203927 AT, 213503_X AT, 210017 AT, TCF4, NFKBIE, ANXA2P1, MALT1, ANXA2P1, 210427 X AT, 204088 AT, 201502 S AT, 228964 AT, 223862 AT
RI a) ' P2RX4, NFKBIA, PRDM1, GHRL,11.311, TCF4, IV
226218 AT, 27.2387 AT, 21E698_3 AT, 218559 S_AT, 20127ELAT
rt 0 n G 0:0C48519-negative ' CCL2, tv1AFB, DA82, STATH, 1110, NOM, S002, 11 206835_AT, 207433 AT, 220066 AT, 221.477 S_AT, 203.939 AT, 01 I.,.
regulation of biological 6.21E-07 2.625285194 0.000305261 NOSE, ARL61P5, BIRC3, 5002, THFRSF9, ARL6IPS, 200761 S AT, 210538 S AT, 215223 S AT, 207536_3 AT, n process FABP4, ANXA2P2, ANXA2P1, CHST11, mar, W 0. cp 200760 S_AT, 203980 AT, 208816 X AT, 201590 X AT, TNFSF138, EU, 50172, THFALP3, ADAMOEC1, g 0 1 219634 AT, 226066 AT, 223502 S AT, 206254 AT, 216841_5 AT, cas, CD9 Ul co Uvi 202644 S AT, 206134 AT, 1555759 A AT, 201005 _AT
=
9 Ci3 W
0 oe til o 1-, Term Pvalue Fold Enrichment Benjamini Probesets Genes z:tt 209933 S AT, 210017 AT, 201743 AT, 7.26218 AT, 216598 S AT, CA
223502_S AT, 206157 AT, 219209 AT, 202637_S AT, 207433 AT, CD300A, MALT1, CD14, IL7R, C.C1_2, TNF5f 13B, GO:0006955-immune-ttC3 1105-136 4_644030668 0.000325195 1555759 A AT, 220066 AT, 205419_AT, 210663 5 AT, PTX3, 1F1H1, ICAM1, IUD, CCI 5, N0132, GPR133, 0 response 4a-201926 S AT, 217388 S AT, 219434 AT, 1555950_A AT, KYNU, C055, KYNU, TRE331, C055,1CAM1 IA
202633 S_AT
z:tt 00:0002237-response to 201827 S_AT, 210017_AT, 201743 AT, 207433 AT, 201502_5 AT, TH8D, (HALT', CD14, 11.10, MBA. MI 6, N002, 1.131.E-06 1453261321 0_000370434 molecule of bacterial origin 1555759 A AT, 220066 AT, 216593 5 AT
rci 7 219358 S AT, 20491_2 AT, 209933 S AT, 2.1.3503_X AT, 209555 S_AT, 210427 X AT, 204088 AT, 207434 S AT, ADAP2,11.10RA, CD300A, ANXA2P1, CD36, 205153 S_AT, 214866 AT, 215346 AT, 204590 X AT, 226218_AT, ANXA2P1, P2RX4, FXYD2, C040, PLAUR, CD40, 229045 _AL 216180 S AT, 212828 AT, 20.5419 AT, 220066 AT, VPS33A, 117R, SNX20, SYN12, SYNI2, GPR183, G0:00:15836-plasma 201926 S AT, 203939 AT, 1555950 A AT, 205542 AT, N002, CD55, NT5E, C.1355, STEA51, LPAR6, 7.17E-06 2132725656 0_000375322 membrane 218589 AT, 202381 AT, 213428 S AT, 207536 5 AT, 201743 AT, ADAMS, COL6A1, TNFRSF9, CD14, ANXA2P2, 208816_X AT, 201590 X AT, 211676 5 AT, 223502 S AT, ANXA2P1, WNGR1, TNFSF138, 5NX20, EGF, P
228E69 AT, 206254 AT, 228573 AT, 203887 S AT, 202637 S AT, ANTXR2, TH80,1CA141, PLEICH01, GPR34, .
ni 213273 S AT, 244434 AT, 201173 5 AT, 201005_AT, 219434 AT, rrGas, C09, TREhil, ICAN11 to ui 202638 S_AT
1-, ni trt th to 203887 S AT, 2113017 AT, 201743 AT, 21.9209_AT, 207433 AT, Lti G0:0051707-response to THED, MALT1, 0314, IFIH1 1110, NFK8IA, C0.5, O' 2.07E-06 2289156627 0.000507682 201502 S AT, 1555759 A AT, 220066 AT, 211676 S AT, other organism NOD2, IFNGFL1, CCU, PTX3 216598_5 AT, 206157_AT
12,i' 206835 AT, 213503 X AT, 209555_5_AT, 203887 S AT, G0:005087B-regulation of STATH, ANXA2P1, C036, Than, AUXA2P2, iL
2_72E-06 1258047114 0.000572071 208816_X_AT, 210427 X AT, 205153 S AT, 214866 AT, body fluid levels ANXA2P1, C.D40, PLAUR, ANXA2P1, CD40, C09 201590 X AT, 215346 AT, 201005 AT
202381 AT, 203927 AT, 209555_5 AT, 200760 S AT, 228708 AT
' ADAMS, NFKBIE, CD36, ARL6IP5, RA8278, G0:0032879-regulation of 204038 AT, 205153 S AT, 201502 S_AT, 215346 AT, 223862 AT, 274E-06 4523428902 0.000688621 P28X4, CD40, NFILEIIA, CD40, GHRL, P13.3, SOP, localization 206157 AT, 206254 AT, 207433 AT, 202637 S
AT, 203936 S AT, 1110, ICANt1, tv04P9,1.1002, ARL61P5, ICAM1 220066 AT, 200761 5 AT, 202638 S AT
GO:0032446-response to 203887 5 AT, 201743 AT, 207433 AT, 201502_5_AT, 6_46E-06 14.75060241 0.0006650114 TH8D, CD14, 11.10, NFKRIA, cos, hIOD2, Cci 7 lipopolysaccharide 1555759 A AT, 220066 AT, 216598_5 AT
IV
n 204912_AT, 209933_S_AT, 2139555_5_AT, 210017_AT, 204038_AT, 11.10RA, CL/300A, CD36, MALT1, P2RX4, 205153 S AT, 215346_AT, 214866_AT, 223862 AT, 226218_AT, CP
CD40, PLAUR, GHRL, 1L7R, CCL2, GPR133, G0:0060089-molecular 216598 S_AT, 205419 AT, 218569 AT, 207536 5 AT, 201743_AT, 5.73E-06 2807496252 11000876051 LPAR6, TNFRSE9, CD14, SRA1, WNGR1, EGF, transducer activity 224130 S AT, 21_1676 S AT, 206254 AT, 228573_AT, 1-i Minn, TH8D, ICAM1, C.C13, ITG135, GPR34, IA
203837 S AT, 200637 5 AT, 1555759 A AT, 201125 S AT, -tti7.5 TREM1,1CA1M1 W
244434 AT, 219434_AT, 202633 S AT
oe .
o o 1-, Term Pvalue Fold Enrichment Benjamini Probesets Genes 0t,..) 1-, CA
204912 AT, 209933 S AT, 209555 S_AT, 210017 AT, 204068 AT, Ci5 ILICIRA, CD300A, C036, MALT1, P2RX4, CD40, 205153_S_AT, 215346 AT, 214866 AT, 223862_AT, 226218 AT, 4=.
CD40, MAUR, GHRL, 117R, CCI.2, GPR183, G 0:0004671-signal 216598 S AT, 205419 AT, 218589 AT, 207536 S AT, 201743_AT, Uvi 5.73E-06 2_807436252 0_000876051 LPAR6,7NFRSF9, CD14, SRA1, IFHGR1, EGF, 0 transducer activity 224130 S_AT, 211676_3 AT, 206254 AT, 278573 AT, 203887 S AT, 202637 S AT, 1555759 A AT, 201125_3 AT
ANTXR2,TH8D, ICAM1, CC15, IT085, 6PR34,, TREM1, 244434 AT, 219434 AT, 202638_3 AT
IC.AM1 219358 S AT, 213891_S_AT, 209555 S AT, 210017 AT, 204088 AT, 236471 AT, 201502_5 AT, 204590 X AT, 201278 AT, 224480 S AT, 203936 S AT, 221477 S AT, 220066 AT, 203939 AT, 1555950_A AT, 225166 AT, 210538 S AT
ADAP2, TCF4, C036, MALT1, P2RX4, NFE2L3,, N
215223 S AT, 218589 AT, 202381 AT, 207536 S AT, FKBIA, VPS33A, DAB2, AGPAT9, MMP9, 5002, NO02, NT5E, CD55, ARHGAP18, BIRC3, 5002, 200760 S AT, 225171 AT, 208816 X AT, 211725_S_AT, P
201.590_X AT, 204702 S AT, 219634 AT, 226066 AT, 206157 AT LPAR6, ADAPSI9, , THFRSF-9, AR1_61125, AR3IGAP18, n, ANXA2P2, BID, AINIXA2P1, NFE21.3, CHST11, 223502 S AT, 206254 AT, 226275 AT, 216841_3 AT, u, n, MITF, P7X3, TNFSF13B, EGF, MXD1, SOD2, F-, 00 60:0065007-biological 2031387 S AT, 202644 S_AT, 201005 AT, 204493_AT, U-1 A.
...
536E-06 1.477358354 0_000877763 THBD, THFAIP3, CD9, BID, GLRX3, P488818,regulation 209060 X_AT, 203927 AT, 2.13503_X AT, 228708 AT, 205153 S AT, 210427 X AT, 214866 AT, 228964 AT, 215346 AT ANXA2P1, RA5278, C040, ANXA2P1, FLAIR, 1-' PRD641, 223862_AT, 226218_AT, 216598_5 AT, 212387 AT, 218559 SAT
CD40, GHR1,11.711, CCU, TCF4, IvIAFB,, - 1-n, HNRPLI., BD, STA1H, 1110, F012, GPR1113, CD55, = 1 22_5386 S AT, 2_27143_S AT, 206835 AT, 207433 AT, 227265 AT, 205419 AT, 201926_S AT, 200761 S AT, 203980 AT, 201743 AT ARL6IPS, FABP4, C014, INFAIP6, SRA1, MISS?,, CYTIP,IF14GRI, CAST, 11004, ADAMDEC1,1F1H1, 206026 S AT, 224130 S AT, 203037 S AT, 209606 AT, !CAM?, CCL5, GPR34, TREM1, ICAlvil 211676 S AT, 208908 S AT, 216250 S AT, 206134 AT, 219209 AT, 202637_5 AT, 1555759 A AT, 244434 AT, 219434 AT, 202638 S AT
203927 AT, 213503 X AT, 209555 S AT, 2040873 AT, 210427 X AT, 205153 S AT, 201502 S_AT, 215346 AT, NFXBIE, ANXA2P1, C036, P2RX4, ANIA2P1, IV
214866 AT, 223862_AT, 226218_AT, 216596 S AT, 227143 S AT , n ag o, NFICERA, C040, PLAUR, GHRL, 17R, CC12, GO:0065008-reguiation of 203278 AT, 206635 AT, 267433 AT, 221477 S AT, 201926 S AT, 639E-06 2.671224233 0_000941783 BID, DAL12, STATH, 1110, S002, CD55, CD55, biological quality 1555950 A AT, 215223 S AT, 203980 AT, 208816 X AT, CP
211725 S AT, 201590 X AT, 223502 S AT, 216841 S AT

203867 S AT, 1555759 A AT, 201005 AT, 204493 AT

TNFSF138, 5002, BD, CC15, C09, BID, 0181(31-, , , 5002, FABP4, THANXA2P2, BID, Uvi 2009080_X AT
Ci5 W
oe o o 1-, Term Pvalue Fold Enrichment Benjamin' Probesets Genes 0 219358 S AT, 213891_5 AT, 209555 S AT, 210017 AT, CA
204088 AT, 236471 AT, 201502 S AT, 204590 X AT, 201278 AT, 224480 S AT, 203936 S_AT, 221477 S_AT, 220066 AT, ADAP2, TCF4, 6036, MALT', P2RX4, NFE213, Uvi 203939_AT, 1555950 A AT, 225166 AT, 210538 S AT, NFKBIA, VPS33A, DAB?, AGPAT9, /AMPS, S002, 215223 S AT, 218589 AT, 202381 AT, 207536_5 AT, N002, NT5E, CD55, ARHGAP18, 8I8C3, S002, 200760 S AT, 225171 AT, 208816 X AT, 211725 S AT, LPAR6, ADAMS, TNFRSF9, AR6610, ARHGAP18, 201590_X AT, 204702 S AT, 219634 AT, 226066 AT, 206157 AT
ANKA2P2, BID, ANXA2P1, NFF_213, CHST11, 223502 S AT, 206254 AT, 226275 AT, 216841 S AT, kinT, P11E3, TNFSF1313, EGF, MXD1, 5002, G0:0050789-regulation of 203 0.661202644 S AT, 201005 AT, 234493 AT, 209030 X AT, 203927 AT
INFAIP3, DS, BID, GLX3, NFKBIE, AN/a2P1,biological process 7706 213503 X AT, 228708 AT, 205153_5 AT, 210427 X AT, 84I32713, CD40, ANXA2P1, PIAUR, PRDR41, 214E66 AT, 228964 AT, 215346 AT, 223862 AT, 226218 AT, 6040, GHRL, 2.78, CCU, TCF4, MAPS, HNRPU, 216598 S AT, 212337 AT, 218559 S AT, 225386 S AT, BID, STATH, ILlS, FG12, 0PR183, CD55, ARL6IP5, 227143 S AT, 206835 AT, 207433 AT, 227265_AT, 205419 AT, FABP4, CD14, THFAIP6, SRA1, MTSS1., CYT1P, 201926 S_AT, 200761 S AT, 203980 AT, 201743 AT, IFNGR1, LPXN, ADAMDEC1,1F1H1, ICAM1, CCL5, 206026_5 AT, 224130 S AT, 203037 S AT, 209606 AT, GPR34, TREAA1,1CAM1 211676 S AT, 216250 S AT, 206134 Al; 21920 AT, 202637 S AT, 1555759 A AT, 244434 AT, 219434 AT, 2n7638 S AT
co 203927 AT, 202381 AT, 200760 S AT, 228708 AT, 205153 S AT, NFKB1E, ADAMS, ARL6IP5, RA132713, CD40, G0:0051049-regulation of 13_87E-06 549711891 0.00100533 204088 AT, 2_15346 AT, 201.502 S
AT, 223862 AT, 206157 AT, P28)14, CD40, NFKBIA, GHRL, PTX3, EGF, 11_10, transport 2062_54 AT, 207433 AT, 220066 AT, 200761 S_AT
NOD2,ARL61P5 218589 AT, 204912 AT, 209933_5 AT, 207536 S AT, LPAR6, 1L1ORA, CD300A, TNFRSFS, 6035, 6014, 209555 S AT, 201743 AT, 2o4oas AT, 205153 5 AT', 2141166 AT, G0:0004872-receptor P28X4, CD40, PLAUR, 5841, 6040, 4_04E-06 3357399833 0.001236866 224130 S AT, 215346 AT, 223862 AT, 211676 S AT, 226218 AT, activity IFNGRI.,11.711, ANTXR2, THBD, ICAM1, 6PR133, 2213573 AT, 203837 S AT, 202637 S AT, 205419 AT, 244434 AT, GPR34, I10135, Tamit ICAM1 201175 S AT, 219434 AT, 202633 S AT
215223_5 AT, 209555 S AT, 201743 AT, 205153 S AT, 5002, C1)36, 6014, CD40, CD40, INFAIP6, 60:0009611-response to 215346 AT, 206026 S AT, 214866 AT, 216598 S AT, 206157 AT, 1.27E-05 4.789156627 0_001249473 pLAUR, rra P11(3,5002, THI3D, 1110, CC'S, wounding 216841_5 AT, 203887 S AT, 207433 AT, 1555759 A AT, 5002, CD9, CD55, CD55 221477 S AT, 201005 AT, 201926 AT, 1555950 A AT
tisa040611Cytokine- 204912 AT, 207536 S AT, 207433 AT, 205153_5 AT, 215346 AT, Uvi IL1ORA, TNFRSF9, 11.10, C040, CD40, CCIS, cytokine receptor 173E-05 6112389381 0.001276815 1555759 A AT, 211676 S
AT, 22.62113 AT, 216598_5 AT, IFN6R1,1178, CCU, THFSF1.3B, EGF
oe interaction 2235E12 S AT, 206254 AT

Term Pvalue Fold Enrichment Benjamini Probesets Genes l,..) z:z 1-, 21001.7 AT, 205153 SAT, 215346 AT, 201502 S AT, 226218 AT, CA
MALT1, CD40, CD40, NFKBIA, 1173, MOT, 60:0002682-regulation of 226066 AT, 223502 S_AT, 218553_5 AT, 207433_AT, 123E-05 5312341804 0.001290482 TNFSF13B, MAFB, 1110, ICAM1, CCM, NO132, z:z immune system process 202637 S AT, 1555759 A AT, 220066 AT, 201926 S AT, 4a.
C055, CD55,1CAM1 1555950 A AT, 202638 S AT
Uvi z:z 213891 S_AT, 209555_5 AT, 210017 AT, 204088 AT, 205153 S AT, 201502 S_AT, 2.15346 AT, 778464 AT, 223862 AT, . TCF4, C036, MALT1, P2RX4, C1340, NFXBIA, 226218 AT, 212387 AT, 216598 5 AT, 218559 S_AT, C040, PRDIv11, GHRL, 11.7R, TCF4, CCU, MAFB, G0:0048518-pos3ive 2253136 S AT, 227143 S_AT, 207433 AT, 203936 S AT, HNRPLL, 8113,1110, LIMPS, N002, S002, CD55, regulation of biological 162E-05 2.290466213 0.001326312 220066 AT, 221477 S AT, 201926 S AT, 1555950 A AT, C055, $002, ADAK49, INFRSF9, FABP4, C014, process 295223 S_AT, 202381._AT, 207536 S AT, 203980 AT, 201743 AT, BID, SRA1, M1TF, TNFSF1.3B, PT13, EGF, S002, 211725 S AT, 224130_5 AT, 226066 AT, 223502_5 AT, ICAN11, CC1.5, BID, ICAM1 206157 AT, 206254 AT, 216841_5 AT, 202637 S AT, -1Cc4759 A AT, 204493 AT, 202638 5 AT
P
21350 X AT, 210017 AT, 201743_AT, 2.1113616_X AT, 204088 AT

IV
' ANXA2P1, MALT1, C014, ANXA2P2, P2RX4, .
60:0051239-regulation of 210427_X AT, 205153 S AT, 201502 S_AT, 201590 X_AT, u, IV
ANXA2P1, CD40, NFKBIA, ANXA2P1, C040, H

multicellular organismal 1-72E-05 3.498329255 0.001330564 215346 AT, 223862 AT, 226218_AT, 216598 S AT, 226066 AT, .i.
GHRL, 1173, CCU, K411F, MAFB, EGF, STATH, process 218559 S AT, 206254 AT, 205835_AT, 207433 AT, 10 n, 1110, CO3, N002 o 1555759 A AT, 220066 AT

.

60:0060341-regulation of 203927 AT,,07381 AT, 207433 AT, 228708 AT, 205153 S AT, NFK81E, ADAMS, 1110, 3A8278, C040, NFKBIA, 1-1.61E-05 7136801752 0_001398752 IV
cellular localization 201502 S AT, 115346_AT, 220066 AT, 223862_AT, 206254 AT C040, N002, GHRL, EGF IL
60:0051046-regulation of 202381_AT, 207433_AT, 228708 AT, 204088 AT, 205153 S AT, ADAM9,11.10, 3A62713, P2RX4, CD40, 0340, 157E-05 9.688408808 0.001446097 secretion 215346 AT, 220066 AT, 223862_AT, 206254 AT N002, GHRL, EGF
60:0002822-regulation of adaptive immune response based CM somatic 210017 AT, 207433 AT, 205153_5 AT, 215346 AT, 220066 AT, MALT1, 1110, CI340, CD40, N0132, IL7R, recombination of immune 3.26E-05 15.80421687 0.001846658 226218 AT, 22.3502 S AT

receptors built from immunoglobulin IV
superfarnity domains n 215223 S AT, 202381_AT, 207536 S AT, 210017 AT, 204088 AT, 211725 S_AT, 201502_6 AT, 223862 AT, 219634 AT, 5002, ADAMS, TNFR5F9, MALT1, P2RX4, BID, CP
60:0043067-regulation of 216598 S AT, 226066 AT, 223502 S AT, 227143 5 AT, NFKBIA, GHRL, CHST11, CCL2, MITE, TNFSF138, 2_93E-05 3.182057087 0.001877378 z:z programmed cell death 216841 5 AT, 202644 5 AT, 219209 AT, 207433 AT, 810, 5002, TNFA1P3, IF1111,1110, MMP9, 50132, Uvi 203336 S AT, 221477 5 AT, 220066 AT, 204493 AT, N002, BID, BIRC3 Ci-z W

on z:z 1-, Term Pvalue Fold Enrichment Benjarnini Probesets Genes 1µ.) 215223 S AT, 202381 AT, 207536 S AT, 210017 AT, 204088 AT, CA
211725 S AT, 201502 S AT, 223862 AT, 2_19634 AT, 5002, ADAM9,TNFRSF9, MALT1, P2RX4, BID, 60:0010941-regulation of 3.06E-05 3171414756 00 216598 S AT, 226066 AT, 223502 S AT, 227143 S AT, NFKBEA, GHRL, CHST11, C.C12, MIFF, THFSF13B, 0.1878077 1µ.) cell death 216841_5 AT, 202644 S AT, 219209 AT, 207433 AT, BID, 5002, THFAIP3, WIH1, 1110, MMP9, 5002, Uvi 203936S_AT, 221477 S AT, 220066 AT, 204493 AT, NOD2, BID, 8IRC3 G0:000:9617-response to 3.20E-05 8.689603776 0_001836839 203887_5 AT, 210017 AT, 20/743 AT, 207433 AT, 201502 S AT, THBD, MALT1, CD14,11.10, NFKBIA, CCU, N002, bacterium 1555759 A AT, 220066_AT, 216598_5 AT

215223_5_AT, 202381 AT, 207536 S AT, 210017 AT, 204088 AT, 211725 S_AT, 201502 S AT, 223862 AT, 219634 AT, 5002, ADAM9,174FRSF9, MALT1, P2RX4, BID, 60:0042981-regulation of 216.598 5 AT, 226066 AT, 223502 S AT, 227143_5 AT, NFK81,4, GHRL, CHST11, CCL2, MIFF, THFSF13B, 2_57E-05 3.21441699 0_001895789 apoptasis 216841 S AT, 202644 S AT, 219209 AT, 207433_AT, BID, 5002, THFA1P3, IFIH1, 1110, MMP9, 5002, 203936 S AT, 221477_5 AT, 220066 AT, 204493 AT, N002, BID, BIRC3 210017 AT, 202637 S AT, 207433 AT, 205133 S AT, GO:0050776-regulation of MALT1, ICAM1, 1110, CD40, NFKBIA, CD40, 2_88E-05 7238572611 0.001326271 201502 $ AT, 2_15346 AT, 220066 AT 201926 SAT 226218 AT, immune responseNOD2, CC/55,117R, THFSF1313, ICAM1, 0D55 223502 S AT, 202638 AT, 1555950 A_AT

219358 S AT, 213503_X AT, 210017 AT, 210427_X AT, 226964 AT, 214866 AT, 223862_AT, 204590 X AT, 226218 AT, ADAP2, ANXA2P1, MALT1, ANXA2P1, PRDM1, 216598_S AT, 218559 S AT, 206835 AT, 207911_5 AT, PLAUR, GHRL, VPS33A, 1178, CCL2, MARI, 60:0048513-organ 2_80E-05 2_616968956 0.001962303 207433 AT, 203936 $ AT, 221477_S AT, 205419 AT STATH, TGM5,1110, MMP9, 5002, GPR183, development 206777 S_AT, 215223_S_AT, 202381 AT, 208816_X AT, CRYBE12, SOD2, ADAM, ANXA2P2, ANXA2P1, 201.590_X AT, 219634 AT, 226066 AT, 206254 AT, 216841 5 AT, CHST11, MITF, EGF, 5002, MLF1 204784 S_AT
60:0002619-regulation of 210017 AT, 207433 AT, 205153$ AT, 215346 AT, 220066 AT, MALT1 1110 0)40, C040, N0D2, 1178, 3.69E-05 15.41874816 0.002010277 adaptive immune response 226218 AT, 223502 S AT

215223 S AT, 209555 S AT, 201743 AT 205153 S AT, 214866 AT, 215346 AT, 206026 S AT, 223862 AT, 216598 S AT 5002, 0)36, CD14, 0)40, PLocUR, CD40,, 60:0009605-response to INFAIP6, GHRL, CCU, ei X3, 5002, TH8D, 1110, 427E-05 3.433366669 0.002243592 206157 AT, 216841S AT, 203887 S AT, 207433 AT, external stimulus CC15, 5002, N002, KYNU, CD9, CD55, KYNU, 1555759_A AT, 221477_5 AT, 220066 AT, 210663 S AT, (/) 201005 AT, 201926 S AT, 217388 S AT, 1555950 A AT
Uvi Term Nalue Fold Enrichment Benjamini Probesets Genes 0 t..i . 0 1-, 60:0045428-regulation of CA
215223 S AT, 21E1841 S , , T, SOD2, CID2, W., , , ,, nitric oxide biosynthetic 4.62E-05 23.94578313 0.002345211 AT 202637SAT 207433A S 'CA 1110 P2RX4 SOD2 ICAM1, Ci5 204088 AT, 221477 S AT, 202638 S AT, 206157 AT
PTX3 =
process 4=.
t..i Uvi 60:0051171-re3ulation of 539E-05 10.2434739 0.002644616 203927 AT, 202381 AT, 207433_AT, 205153 S AT, 201502 S AT, NFKB1E, ADAM9, 1110, CD40, NFKBIA, C040, =
protein transport 215346_AT, 22.0066_AT, 206254_AT
N002, EGF
60:0009607-response to 203887 S AT, 210017 AT, 201743 AT, 219209 AT, 207433 AT, 5_71E-05 4.995585791 0_002709622 201502 S AT, 1555759 A AT, 220066 AT, 211676 S AT
THBO, MALT1, C014, 1H-11,11.10, NFXBIA, CCL5,, biotic stimulus 21E598 S_AT, 206157 AT
N002, IFN6R1, rn 2, P
60:0005615-extracellular 202381 AT, 203887 S AT, 202637 S AT, 207433 AT, 227265 AT, 7_88E-05 4_831639194 0_00306733 203936 S AT, 1555759 A AT, 223862 AT, 216598 S AT
ADAM9, THBO, ICAM1, 1110, FGI2, MMP9,, space cas, GfiRL, CCU, TNFSF13B, ICAM1, EGF
223502 S AT, 202638 S AT, 206254 AT
60:0051241-negative regulation of multicellular 7.32E-05 9_704343691 0.0033662 206835 AT, 213503 X AT, 208816 X AT, 207433_AT, 204088_AT, STATH, ANXA2P1, ANXA2P2, 1110, P2RX4, 210427 X AT, 201590 X AT, 220066 AT, 2238.62 AT
ANXA2P1, AffiLA2P1, NOD2, GHRI. P
organismal process o n, G0:0032101-regulation of 213503 X AT, 2039E0 AT, 208816 x AT, 207433 AT, .
u, n, o response to external 8.47E-05 9.455514365 000366669 210427 X AT, 201590 X AT, 1555759 A AT, 223862 AT
ANXA2P1, FABP4, ANXA2P2, 11_10, ANXA2P1, I-, AfIXA2P1, al c , GHRL, NTSE
cn A.
stimulus 203939_AT
I--' Iv , o G0:0070201-regulation of o 203927 AT, 202381 AT, 207433_AT, 205153 S AT, 201502 S AT, NFKB1E, ADAMS, 11.10, C.D40, NFKBIA, CD40, 1 establishment of protein 8.47E-05 9_455514365 0_00366669 1-n, localization 215346 AT, 220066 AT, 206254 AT
NOD2, EGF
IL
215223 S AT, 202381 AT, 209555 S AT, 205153 S AT, 5002, ADAM9, CD36, CD40, NF1031A, co40, 60:0050793-regulation of 201502_5_AT, 215346 AT, 223862 AT, 204590 X AT, 226218 AT
8.33E-05 3.669304082 a003713809 ' developmental process 226066 AT, 218559 S AT, 206254 AT, 216841 S AT,. 206835_AT GHRL, VPS33A, 1L7R, MITF, MAFB, EGF, S002, , STATH,1110, en c, 50D2 207433 AT, 1555759_A AT, 221477 S AT
213891_5 AT, 209555 S_AT, 210017 AT, 204088 AT, 205153 S AT, 201502 S AT, 215346 AT, 223862 AT, 226218 AT, TCF4, CD36, filA1T1, P2RX4, CD40, NFXBIA, IV
212387 AT, 216598 S AT, 218559_5 AT, 225386 S AT, n 60:0048522-positive CD40, GH14.1, 8.7R, TCF4, CCU, MAFB, HNRP1.1., 227143 S AT, 207433 AT, 203936 S AT, 220066 AT, regulation of cellular 9.67E-05 212534329 0.00406592 BID, 11.10, MN1P9, NOD2, SOD2, SOD2, ADAMS, 221477 S AT, 215223 S AT, 202381 _AT, , process AT
207536 S AT TNFRSF9, FABP4, BID, SRA1, MITT, TNFSF1_3B, CP
t..) 203980 AT, 211725 S AT, 224130 S AT, 226066 AT, EGF, PTX3, S002, ICAM1, CGS, BID, ICAM1 223502 S AT, 206254 AT, 206157 AT, 216841 S AT, Uvi 202637 S AT, 1555759_A AT, 204493 AT, 202638 S AT
Ci5 W
oe o o 1-, Term Pvafoe Fold Enrichment Benjainini Probesets Genes 0 A./

1-, 219358 S_AT, 213503 X AT, 209555 SAT, 210017_AT, CA
Ci5 210427 X AT, 20408.8 AT, 235153 S AT, 214866 AT, 226964 AT, ADAP2, AlsIXA271, 0)36, AAALT1, ANXA2P1, 0 4=.
215346 AT, 204590 X AT, 223862_AT, 22621.8_AT, 216598 S AT, P26X4, CD40, PLAUR, PRON11, C040, VPS33A, Uvi 218559 S AT, 201278 AT, 206835 AT, 207311_S AT, 2137433 AT, GHR1,1578, CCL2, MATS, 0A132, STATH, TGA45, 0 G0:0032501-multicellular 0_000104285 1.660570435 0.004260994 203936 S AT, 205419 AT, 220066 AT, 221477 5 AT, 204475 AT, 1110, NIAAP9, GPR183, N002, S002, FAMP1, arganismal process 210538 S AT, 206777_6 AT, 21.5223 S AT, 202381 AT, BIRO, CRYI3112, SOD2, ADAM% FABP4, 203980 AT, 208816 X AT, 201590_X AT, 219-634 AT, 226066 AT, ANXA2P2, ANXA2P1, CHST11, MITE, EGF, 206254 AT, 211653 X AT, 226275 AT, 216841_6 AT, AKR1C2, MX01, 5002, THEM, M151, 0)9 203887 S AT, 204784 S AT, 201005 AT
218589 AT, 202361 AT, 210017_AT, 201743 AT, 205153 S AT, , 60:0007166-cell surface 201502 S_AT, 215346 AT, 223862 AT, 203037 5 AT, 226218 AT LPAR6 ADAMS, MALT1, 0D14, CI340, NFKBIA, , C040, , , , receptor linked signal 0_000113804 2_856183771 0_004523702 216598 SAT 226066 AT 206254 AT, 206134 AT GHRL MTS51 11.78 CCU, MITE EGF
, transduction 1555759 A AT, 205419 AT, 244434 AT, 201125 S AT, ADANIDEC1, CCL5, 6PR18.3, 6PIL34, ITGEIC, P
210538_5 B1RC3 AT o 1., 215223 S AT, 216841 S AT, 202644 S AT, 210017 AT, .
u-, 60:0006916-anti- 5002, S002, TNFA1P3, MALT1, 1110, NFKBIA, 1., 0.000124449 5.889770261 0.004815965 207433 AT, 201502 S AT, 22/477 S AT, 2238E2 AT, 1- o apoptosis S0132, GHRI, CCU, TNFSF13B, B1RC3 0µ A.
216598_5 AT, 223502_6 AT, 210538 S AT
to N, 215223 S AT, 210017_AT 201502 S AT, 223862 AT, 219634 AT, 5002, MALT1, NEKBIA, GHRL, CHST11, CCU, o , 60:0043066-negative1-0.000129722 4_527249623 0.004891125 216598 S AT, 226066 AT, 223502 S AT, 216841_S AT, mn-F,TNESF138, 6002, TNFAIP3, 11.10, S002, "
, regulation of apoptosis 202644 S AT, 207433 AT, 221477 5 AT, 210538 S AT B1RC3 o 714773_5 AT, 210017_AT, 201502 5 AT, 223862 AT, 219634 AT, 8002, h4ALT1, NFK131A, GHRL, CHST11, CCU., 60:0060548-negative 0.000147362 4.457599629 0.005158736 216598 S AT, 226066 AT, 223502 S AT, 216841 S AT, MITF, TNFSF1313, 5002, TNFA1P3,1110, 5002, regulation of cell death 202644 S AT, 207433 AT, 221477 S AT, 210538 S AT BIRC3 60:0043069-negative 215223 S AT, 210017_AT, 201502 5 AT, 223E62 AT, 219634 AT, 50132, MALT1, NFK81A, 614121, CHST11, CCL2, regulation of programmed 0_000142772 4.474810439 0_00524771.2 216598 S AT, 226066 AT, 223502_5 AT, 216841 S AT, MITT, TNFSF138, S002, TNFAIP3,1110, 50132, cell death 202644 S AT, 207433_AT, 271477_S AT, n 213891_6 AT, 215223 S AT, 202381 AT, 204088 AT, 205153_6_AT, 201532 5 AT, 224130_S AT, 215346 AT, TCF4, 5002, ADANI9, P2RX4, C040, NFKB1A, CP
60:0009893-positive regulation of metabolic 0.000147162 2_926706827 0.005277077 226964 AT, 212387 AT, 226066_AT, 223502 S AT, 218559 S AT, SRA1, 0)40, PRDM1, TCF4, MITE,174FSF1.36, 0 1-, 2116254 AT, 206157 AT, 225386 S AT, 216841 S AT, MAFB, EGF, PTX3, HNRPLI, 5002, ICAlv11, 1110, Uvi process 202637 S AT, 207433 AT, 221477 S AT, 220066 AT, 5002, N002, ICAM1 Ci5 W

oe o o 1-, Term Pvalue Fold Enrichment Benjamini Probesets Genes 0 t.) 1-, 60:0031347-regulation of 203980 AT, 207433_AT, 201502_5 AT, 1555759 AT, CA
0.000165947 8381024096 0.005672844 A
FABP4,1110, NFKBIA, CC1.5, NOD2, GHRL, NTH
defense response 220066 AT, 223862 AT 203939 AT
Ci5 .1=.
210017 AT, 201743 Al; 205153 S AT, 206026 S Al; 215346 AT, w MALT1, 0D14, CD40, TNFA1P6, CD40, CCU, 60:0006952-defen_se 216598 S Al; 206157 AT, 219209 AT, 207433 AT, 0_000177009 3.963439967 0_005912766 P1X3, 111, 1110' LC15, N002, KYNU, CDS%
response 1555759 A AT, 220066 AT, 210663_5 AT, 201926 5 AT, KYNU, CD55 217388 S AT, 1555950 A_AT .
60:0050708-regulation of 202381 AT, 207433 AT, 205153_5 AT, 215346 AT, 220066 AT, 11000186347 16.99378158 0.00608588 206254 AT ADAM9,11_10, CD40, 0)40, N002, EGF
protein secretion 210017 AT, 201743 AT, 201502_5 AT, 223862 AT, 211676 S AT, MA111, C014, NFKB1A, 61-121, IFNGR1, CC12, 60:0051704-multi- 216598 S AT, 206157 AT, 203887 S AT, 702637 S AT, 0.000215223 3337240364 0.006727739 P1)13 THBD ICAM1, 11_10 IF1H1, CCU, N002, organism process 207433 AT, 219209 AT, 1555759 A AT, 220066 AT, 204475 AT, , , , MM1'1, ICAM1 60:0032880-regulation of 203927 AT, 202381 AT, 207433 AT, 205153 5 AT, 201502 S AT, NFKB1E, ADAM9, 11.10,0)40, NFKB1A, 0040, P
0130021195 8_016631744 0_006769334 protein localization 215346 AT, 220066 AT, 206254 AT
N002, EGF 0 IV
t.0 60:0002697-regulation of 210017 AT, 202637 S AT, 207433 AT, 205153 S AT, 215346 AT, fv1A11-1, ICAMI., 1110, CD40, C040, N002, 117R, u, 0.000233713 10.53614458 0.007006643 I-, n, immune effector process 220066 AT, 226218_AT, 202638 S AT
ICAM 1 01 A.
,..
t...i 60:0002706-regulation of IV
210017 AT, 207433 Al; 205153_5 AT, 215346 AT, 220066 AT, lymphocyte mediated 0_000238915 15_96385542 0.007019312 226218 AT MALT1,1110, 0)40, ago, NOD2, 117R 1-immunity N) 213503 X_AT, 203980 AT, 208816_X Al; 207433 AT, 60:0080134-regulation of ANXA2P1, FAHP4, ANXA2P2, 1110, ANXA2P1., .., 0_000230106 5387801205 0.007042074 210427 X AT, 201502 5 Al; 201590_X AT, 1555759 A Al;
response to stress NFKEIIA, ANX112P1, CCI.5, NOD2, GHRL, NT5E
220066_AT, 223562_AT, 203939_AT
.
219358 S AT, 213503 X_AT, 210017 AT, 210427 X AT, ADAP2, ANXA2P1, MA1T1, ANXA2P1, PlAUR, 214866 AT, 228964_AT, 204590 X AT, 223862 AT, 226218 AT, PRDM1, VPS33A, GH111, 0_7R, CCU, MAFB, 216598 S_AT, 218559 S AT, 201278 AT, 207911 S_AT, DAB2,TGIV15, STATH, 1110, MMP9, 5002, 60:0032502-development 206835 AT, 207433 AT, 203936_5 AT, 721477 S AT, 205419 AT, 0.000273185 1291259305 0.007865563 GP11183, $002, CRYBE12, ADAM9, FABP4, al process 215223 S AT, 206777 S AT, 202381 AT, 203980 AT, ANXA2P2, ANXA2P1, SRA1, CAST, aisni, 208816 X AT, 201590 X AT, 224130 S AT, 208908 S AT, IV
MITF, EGF, MXD1, $002, THBD, Mill, CCIS, n 219634 AT, 226066 AT, 206254 AT, 226275 AT, 216841 S AT, 203887 S AT, 204784 S AT, 1555759 A AT, 201005 AT
CP
. t.) 60:0048584-pasitive 210017_AT, 203980_AT, 201502 S AT, 1555759_A AT, 0 MALT1, FABP4, NFKBIA, LC15, N002, 61-im., regulation of response to 0.000283953 6.152493184 0.008017793 220066 AT, 223862 AT, 201926 S AT, 223502 S AT, CD55,TNFSF138, CD55 Ci5 stimulus 1555950 A AT
ta oe o o 1-, Term Pvalue Fold Enrichment Benjarnini Probesets Genes 0 209933_5 AT, 213428 S AT, 202381_AT, 209555_5 AT, CA
C0300A, COLSAI, ADAMS, CD36, THFAJP6, 206026 S AT, 203037 S_AT, 216598 S_AT, 216250 S AT, GO:0007.155-cell adhesion 0.000307737 3_718639263 0.008523348 MTSS1, CCI2, LF"XN, ICAM1, GUS, ITG85, CD9, 202637 S_AT, 1555759 A AT, 201125 S AT, 201005 AT, Uvi 209933 S AT, 213428 S AT, 202381 AT, 209555 5_AT, CD300A, COL6A1, ADAMS, 0336, TNFAIK, G00022610-biological 206026 S , , , , 0.000315593 1707734162 0.008578876 AT 203037SAT 216598SAT 216250SAT rr3 LPXN, ICAM1, CCL5, rm as, cos, adhesion 202637 S_AT, 1555759 A AT, 201125 S
AT, 201005 AT, 202638_S_AT
G0:0002684-positive 210017 AT, 202637 S AT, 205153 S AT, 201502 S AT, MALT1, ICAM1, CD40, NFKB1A, CD40, NOD2, regulation of immune 0.0003241134 6_020654045 0.008651883 215346 AT, 710066 AT, 201926 S AT, 226218 AT, 223502 S AT, 0355,117R, THFSF1313, ICAM1, CD55 system process 202638_5 AT, 1555950 A AT
202381 AT, 2_10017 AT, 202637_5 AT, 207433_AT, 204088 AT, ADAMS, MALT1, ICAM1, 11_10, P2RX4, CD40, G0:0001775-ce11 activation 0.000386538 4_990805327 0.010124588 205153 S AT, 215346 AT, 205419 AT, 201005 AT, 226218 AT, CD40, GPR183, CD9,11.711, ICAM1 202638_5 AT

GO:0045429-positive 215223_5_AT, 216841 S AT, 202637 S AT, 204088 AT, 50D2, SOD2, ICAM1, P2RX4, 5002, ICAM1, regulation of nitric oxide 0.000407508 26.34036145 0.010484798 221477 S AT, 202638 S AT, 206157 AT PEG
biosynthetic prw-Pc5 G00002703-regulation of 210017 AT, 207433 AT, 205/53 S AT, 2.15346 AT, 220066 AT, leukocyte mediated 0.00041591 13_86334813 0_01051636 226218 AT MALT1, 1110, CD40, CD40, NOD2.,117R
immunity 219358 S AT, 213503 X AT, 210017 AT, 210427 X AT, 7q54_, 214866 AT, 204590 X AT, 223862 AT, 226218 AT, ADAPT, ANXA2P1, MALT1, ANXA2P1, PROM?, 216598_5 AT, 218559 S AT, 201278 AT, 207311 S AT, PLAUR, VPS33A, GHR1,117R, CCL2, MAPS, DA82, G0:0048856-anatomical 0.000458417 2_018715984 0_011389929 206835 AT, 207433 AT, 203936 S AT, 221477 S AT, 205419 AT, TGA45, STATH,1110, MMP9, 50D2, GPR183, structure development 215223 S AT, 206777 S_AT, 202381 AT, 208816 X_AT, SOD2, C.RYBB2, ADAMS, AAIXA2P2, ANXA2P1, 201590 X AT, 208908 S AT, 219634 AT, 226066 AT, 206254 AT, CAST, CHST11, MITE, EGF, 5002, FALF1, CD9 216841 S_ATõ 204784_S_AT, 201005_AT
201278 AT, 206835 AT, 213503 X AT, 2081316 X AT, 0A82, STATH, ANXA2P1, ANXA2P2, ANXA2P1, G0:0046903-secretion 0.000554725 5.509095204 0.013539046 2.10427 X AT, 201590 X AT, 1555759 A AT, 204590 X_AT, ANXA2P1, 03.5, VPS33A, &HU, INFSF138 2231362 AT, 223502 S AT
G00050727-regulation of 0.000612986 12.54302926 0_01470747 203980 AT, 207433 AT, 1555759 A AT, 223862 AT, 203939 AT FABP4, 11.10, CCL5, GHRL, NTSE
inflammatory response _ Term Pvalue Fold Enrichment Benjamini Probesets Genes 1.) 1-, 219358 S AT, 213503 X AT, 210017 AT, 210427 X AT, CA
Ci5 228964 AT, 214866 AT, 223862 AT, 204590 X AT, 226218 AT, ADAP2, APIXA2P1, fiAALT1, ANXA7,1, PRDM1, 0 4=.
216598 S_AT, 218559 S AT, 206835 AT, 207911_6 AT, PLAUR, GHRL, VPS33A, 117R, CCL2, MAR, 1.) 60:0048731-system Uvi 0.000635394 2.065910702 0.014997197 207433 AT, 203936_6 AT, 221477 S AT, 205419 AT, STATH, TGM5,11.10, PAMP9, 6002, GPR1.83, 0 development 215223 S AT, 206777 S_AT, 202381 AT, 208816 X AT, 5002, CRY882, ADAM9, ANXA2P2, ANXA2P1, 201590 X_AT, 219634 AT, 226066_AT, 206254_AT, 216841 S AT, CHST11, MITF, EGF, S002, MLF1, COS
204784 S AT, 201005_AT
202381 AT, 207536 S AT, 209555 S AT, 204088 AT, 207434 S AT, 205153 S AT, 215346 AT, 211676 S AT, ADAM9, THERSF9, C.D36, P2RX4, FXYD2, C040, G0:0031.226-intrinsic to 0_000511383 2_901401351 0_015933223 203887 S AT, 202637 S_AT, 205419 AT, 201005 AT, CD40, IFN6R1, TH80, ICAM1, GPR1/33, COO, plasma membrane 201926 S AT, 201125 S AT, 244434 AT, 1555950 A AT, CO55,17685, 6PR34, CUSS, STEAP1,1CAM1 205542 AT, 202638 S AT
60:0051051-negative 201927 AT 2007606 AT 207433 AT 201502 S
AT, 223862 AT NFKBIE
0.00074669 8.209982788 0.017324877 , _ , , , , ARL61P5, RIO, NFIGRA, GHRL, ARL61P5, P
regulation of transport 200761 S AT, 206254 AT EGF

IV
60:0051050-positive 202381 AT, 207433 AT, 204088 AT, 201502_5 AT, 220066 AT, ADAM9, P210(4, NFKBIA, NOM, GHRL, ' u, 0.000772048 6303676243 0.017630825 IV
regulation of transport 2231162 AT, 206157_AT PTX3 l- 00 A.
tn .
60:0051384-response to 202381 AT, 203980 AT, 207433 AT, 1555759 A AT, tri IV
0_000868651 11_45233106 0.019513971 ADAM9, FABP4, IUD, CCL5, CCL2 0 glucocorticoid stimulus 216598 S AT

112.,' 215223 S_AT, 21.3503_X AT, 203980 AT, 210427_X AT, S002, ANXA2P1, FAE1P4, ANXA2P1, ANXA2P1, 60:0005625-so1ub1e 201590_X AT, 223502 S AT, 206254 AT, 216841 S AT, 1-0_0007680013 4_517856389 0.019903205THF5F138, EGF, 5002, frtS, 5002, KYNU, fraction 1555759 A AT, 221477 5 AT, 210663 S AT, 244434 AT, GPR34, 0055, KYNU, CD55 201526 S AT, 217388 S AT, 1555950_A AT
213891 S AT, 215223_5 AT, 202391 AT, 204088 AT, TCF4, 5002, ADAM9, P2RX4, CD40, NFXBIA, 60-.0031325-positive 205153 S AT, 201502 S_AT, 224130 5 AT, 215346 AT, SRA1, C040, TCF4, MITF, MAFB, EGF, P113, regulation of cellular 0.000976424 2.701575533 0_021581183 212387 A7, 226066 AT, 218559_6 AT, 206254 AT, 206157 AT, HNRPLL, 5002, ICAM1, 11.10,5002, N002, metabolic prorAc 225386 S_AT, 216841_6 AT, 202637 S AT, 207433 AT, 221477 S_AT, 220066_AT, 202638 S AT
209555_S AT, 203887 S_AT, 205153 S AT, 214866 AT, 60:0050817-coagulation 0.001021169 10.9751506 0.022226472C036, TH80, C040, PLAUR, CD40, COOIV
215346_AT, 201005_AT
n 60:0007596-biood 209555 S AT, 203887_5 AT, 2.05153 S AT, 214866_AT, 0_001021169 103751506 0.022226472 CD36, TH80, 0)40, PlAUR, 0)40, COOcoagulation 215346 AT, 201005_AT
CP
1.) 60:0031360-response to 202381 AT, 203980 AT, 2.07433_AT, 1555759 A AT, 0 0.001104078 10_75116794 0.023661309 ADAMS, FABP4, 1110, CCL5, CCL21-, corticosteroid stimulus 216598_S AT
Uvi 60:0051047-positive Ci5 0.001104078 1075116794 0.023661309 202381 AT, 207433 AT, 204088 AT, 220066 AT, 223862 AT ADAMS, 1110, P2RX4, N002, GHRL W
regulation of secretion oe o o 1-, Term Pvalue Fold Enrichment Benjamini Probesets Genes 215223 S_AT, 216841 S AT, 210017 AT, 207433 AT, CA
5002,50132, MALT1, 1110, Allv1P9, MLF1, S002, G0:0030097-hemopoiesis 0.001226255 4116523236 0.025151654 203936 S AT, 204784 S AT, 221477 S AT, 205419_AT, 6PR183, VPS33A,117R
204590 X_AT, 226218 AT
219358 S AT, 213503_X AT, 2.113017 AT, 210427 X AT, ADAP2, ANXA2P1, MALT1, ANXA2111, PlAUR, 214866 AT, 2289E4 AT, 204590 X AT, 223862 AT, 226218 AT, PROW., VP533A, GHRL, 11711, ca2, MARI, 21E398 S AT, 218559 S AT, 201278 AT, 2079 AT, GO:0007275-multicellutar 11 DAB2, TGM5, STATH, 1110, M MP9, 5002, 0.001712098 1.856892321 0.025215437 206835 AT, 207433 AT, 203936_5 AT, 221477 S AT, 205419 AT, organismal development 6PR1113,5002, CRYB82, ADAM9, ANXA2P2, 2152.23 S AT, 206777 S AT, 202381 AT, 208816_X AT, ANXA2P1, CHST11, MDT, EGF, MXD1, S002, 201590_X AT, 219634 AT, 226066 AT, 206254 AT, 226275 AT, TH80, Mtn, CD9 216841 S AT, 203887 S AT, 204784 S AT, 201005 AT
202381 AT, 201743 AT, 203980_AT, 210017 AT, 20443811 AT, G0:0010033-response ADAA49, C014, FABP4, MALT1, P2RX4, NFKBIA, -to 201502 S AT, 223862 AT, 216598_5 AT, 203887 S AT, 0001204931 2.951937059 0.025426793 GHRL, CCU, THBD, CCL5, N002, KYNU, .organic substance 207433 AT, 1555759 A_AT, 220066 AT, 210663 S AT, KYNU
217388_5 AT

lisa04621.1400-like 202644 S AT, 201502 S AT, 1555759 A AT, 220066 AT, 0_000725707 7.947169811 0.026503364 THFAIP3, NFKB1A, Cr 5, N002, CCI2, BIRC3 receptor signaling pathway 216598 S AT, 210538_5 AT

G0:0002252-immune 202637 S_AT, 220066 AT, 201926 S AT, 226218 AT, ICAMI, 11002, C055,117R, THFSF138, ICAM1, 0.00136637 7.18373454 0.027603619 effector process 72/CO2 S AT, 202638 S AT, 1555950 A AT, 206157 AT 0D55, PT13 G0:0032680-regulation of tumor necrosis factor 0.001395324 1736024096 0-027800016 201743 AT, 207433 AT, 220066_AT, 223862 AT
0)14,1110, N0132, GHRL
production 201743 AT, 207433 AT, 205153 S AT, 215346 AT, 206026 S AT, 60:0006954-inflammatory com,1110, C040, C040, THFAIP6, CC13, ass, 0.001443579 4682730924 0_028365247 1555759 A AT, 201926_S AT, 215598 S AT, 1555950 A AT, response(II 7, 0355, PTX3 206157_AT
209555 S_AT, 203887 S AT, 205153 S AT, 214866 AT, G0:0007595-hemostasis 0.001483225 9939759036 0.1328750558 0336, THBD, 0)40, PLAUR, 0)40, 0)9 215346 AT, 201005_AT
G0:0051173-positive 213891 S_AT, 215223 S AT, 205153 5 AT, 2044388 AT, TCF4, 5002, 0)40, P2RX4, SRA1, 0340, NFKBIA, regulation of nitrogen 224130_S_AT, 215346 AT, 201502 S AT, 212387_AT, 226066 AT, 0.001639177 3.039272475 0.03014551 TCF4, mar, PTA MAF13, HNRPU, 5002,1110, compound metabolic 206157 AT, 218559 S AT, 225386 S AT, 216841 AT, 1CAM1, 50132, IC.AM1 process 207433_AT, 202637 S AT, 221477 S AT, G0:005124Crpositive 210017 AT, 201743_AT, 205153_5 AT, 215346 AT; MALT1, C014, C040, C040, CC13, N002, GHRL, regulation of multicellular 0.001622601 5.463186078 0.030221815 1555759 A AT, 220066 AT, 223862_AT, 216598 S AT C.C12 arganismat process oe =

Term PitaMe Fold Enrichment Benjamin' Probesets Genes 0 1,4 .

215223 S_AT, 207536_5 AT, 203980 AT, 205153_5 AT, 5002, THFRSF9, FABP4, CD40, CD40, NFKB1A, CA
60:0042127-regulation of 215346 AT, 201502 S_AT, 223862 AT, 219634 AT, 216598 S AT, Ci5 0_00158235 2.859496441 0,0302467 GHRL, CHST11 U
CC
MITE, THFSF1313, EGF, cell proliferation 226066_AT, 223502 S AT, 206254 AT, 216841_S_AT, 207433_AT, , , 0 5002, RIO, S002, CD94=.
1,4 221477 S AT, 201005 AT
Uvi .

207536 S AT, 209555 S AT, 204088 AT, 207434 S AT, 205153_S AT, 215346 AT, 211676 S_AT, 203687 S AT, TNFRSF9, C036, P2RX4, FXYD2, CD40, CD40, 60:0005887-integral to 0.001373673 2358590942 0.0303602E4 202637 S_AT, 205419_AT, 201005 AT, 201926 S AT, IFN6F11, TH80, ICAM1, 6PR183, CD9, CD55, plasma membrane 201125 S AT, 244434 AT, 1555950 A AT, 205542 AT, IT13135, GPR34, CD55, STEAP1, ICAM1 , 209933 S AT, 209555 S_AT, 210017 AT, 204088 AT, 205153_S_AT, 201502_S_AT, 214666_AT, 215346_AT, 223862_AT, CD300A, CD36, MALT1, P2RX4, C040, NFKBIA, 226218 AT, 216598 S AT, 207433_AT, 220066 AT, 221477 S AT, PLAUR, CD40, GHRL, IL7R, CC12, IUD, NOD2, 205419 _AT; 201926 S AT, 217388 S AT, 1555950_A AT, G0:0050896-response to S002, GPR183, 0355, KYNU, CD55, 5002, 0.0016107 1333869102 0.030387009 215223_5 AT, 206777 S_AT, 202381 AT, 203980 AT, 201743 AT, P
stimulus CRYBB2, ADA/v19, FA8P4, C014, THFAIP6, 206026 S AT, 211676 S AT, 223502 S AT, W6157 AT, IFNGR1, INFSF1313, PTX3, S0D2,11010, IFIH1, n, 216841 S AT, 203887 S AT, 2L9209 AT, 202637 S AT, ' u, ICAM1, CCL5, KYNU, C09, 111EM1,1CAM1 IV
1.555759 A_AT, 210663 S AT, 201005 AT, 219434 AT, I-. 00 cn A.

--1 .
IV

601002700-regulation of production of molecular 0.001768391 16.2094532 0.032085435 210017 AT, 207433_AT, 205153 S AT, 215346 AT, 220066 AT MALT1, 1110, C040, CD40, NOD2 N) mediator mediator of immune IL
G0:0042113-8 cell 210017_AT, 207433 AT, 205153_S AT, 215346 AT, 205419_AT, 0.001821278 9.407271945 0.032628793MALT1, [110, CD40, C040, 6PR1113, IL7R
activation 226218 AT
.
209555_S_AT, 210017_AT, 228708_AT, 204088_AT, 214866_AT, CD36, MALT1, RA1327B P2RX4, PLAUR, NFKBIA, 201502 S AT, 223862_AT, 226218 AT, 216598 S AT, 207433_AT, 61-011, IL7R, CCU, 1110, F612, N002, GPR183, G0:0007165-si3nal 227265 AT, 220066 AT, 205419 AT, 225166 AT, 218589 AT, 0101988349 1.864144476 0.03472E937 ARHGAP18, OARS, AIDAM9, ARHGAP18, transductkin 202381 AT, 225171 AT, 206026 S AT, 203037 S AT, TNFAIP6, MTSS1, IFN6R1, TNFSF138, EGF, LPXN, 211676 S AT, 223502 S AT, 206254 AT, 216250 S AT, CCL5, 6PR34, TREM1 1555759 A AT, 244434 AT, 219434 AT
.
IV
601048534-hemopoietic 215223_5 AT, 216841 S AT, 210017_AT, 207433_AT, n SOD2, S002, MALT1, RIO, IVIMP9, FALF1, S002, or lymphoid organ 0.001967993 4.436271401 0.034791097 203936 S AT, 204784 S AT, 771477 S AT, 205419 AT, GPR183, VP533A, IL7R
development 204590 X_AT, 2262113 AT
CP
1,4 202381_AT, 204088_AT, 211725_S_AT, 203037_S_AT, 223862_AT, A
9, P2RX4, BID, MTSS1, GHRL, CCU, 60:0005102-receptor 216598 $ AT, 223502 S_AT, 206254 AT, 227143 S AT, Uvi 0100373426 3379393637 0.037380038 THFSF1.38, EGF, BID, ADAMDEC1, ICAN11, 1110, Ci5 binding 206134 AT, 202637_6 AT, 207433_AT, 227265 AT, F612, CC15, BID, ICAtv11 W
1555759 A AT, 204493 AT, 202638_5 AT
oe o .
o 1-, Term Pvalue Fold Enrichment flenjamini Probesets Genes 0 CA
219358 S AT, 213891 S AT, 209555 S AT, 210017 AT, 204088 AT, 236471_AT, 201502_5 AT, 201278 AT, 224480 S AT, AOAP2, TCF4, C036, MALT1, P2RX4, NFE2.13, 203936 S AT, 220066 AT, 221477_5 AT, 210538 S AT, Uvi NFK.B1A, CiA132, AGPAT9, AAMPS, NO02, S002, 225166 AT, 215223_5 AT, 218589 AT, 2073At AT, 207536 S AT, 8111C3, ARHSAP18, SOC12,1PAFt6, ADAMS, 225171 AT, 211725 AT, 204702 S AT, 219634 AT, 226066 AT, TNFRSF9, ARFIGAP18,BID, NFE.213, CHST11, 206157 AT, 223502 S AT, 206254 AT, 226275 AT, 216841 S AT, AMU, PTX3, THFSF1313, EGF, MX01, 50132, 60:0050794-regulation of 202644 S AT, 201005 AT, 204493 AT, 209080 X AT, 203927_AT, 0.002340559 1349482027 0.040285453 INFAIP3, C09,1310, 61.RX3, NEK131E, RAB27B, cellular process 228708 AT, 205153_5 AT, 214866 AT, 228964 AT, 71 c346 AT, CD40, PLALIFI, PROM 1, C040, GM:11,117R, TCF4, 223862 AT, 226218 AT, 212387 AT, 216598_S_AT, 218559 S AT, CCU, MAFB, HNRPL1,13113,1110, FGL2, GPR1133, 225386 S_AT, 227143 S AT, 2137433 AT, 227265 AT, 205419 AT, FA8P4, SRA1, TNFA1P6, PATSS1,1FNGR1, cyriP, 203980_AT, 224130_S _AT, 206026 S AT, 203037 S AT, LPXN, ADAMDEC1, IF1111,1C.AM1, CCU, GPR34, 211676_5 AT, 209606 AT, 216250 S AT, 206134 AT, 219209 AT, TREM1,1CAM1 202637 S AT, 1555759 A AT, 244434 AT, 213434 AT, NO
60:0046651-lymphocyte 0-002435526 14.53261321 0_041404807 210017 AT, 207433_AT, 205153_5 AT, 215346 AT, 226218 AT MALT1, 1110, C040, CD40,117R
proliferation co 60:0070661-leukocyte 0.002687978 14.04813277 0_045084782 210017 AT, 207433 AT, 205353_6 AT, 215346 AT, 226218 AT MALT1,11.10, 0340, C1340, 117R
proliferation Term ?value Fold Enridiment Ilenjarnini Probesets Genes 60:0032943-mononuclear 0.002687978 14.04819277 0.045084732 210017 AT, 207433 AT, 205153 S AT, 215346 AT, 226218 AT fv1A1T1,11.10, C040, CD40,1178 cell proliferation 215223_6 AT, 216341 S AT, 210017 AT, 207433 AT, 60:0002520-immune SODZ 5002, MALT1, 1110, MMP9, MLF1, $0112, 0.002858408 4_152175203 0.047340765 203936 S AT, 204784 S AT, 221477 S AT, 205419 AT, system development GPR183, VPS33A,1L7R
204590 X AT, 22621.8_AT
60:0042394-cytoplasmic sequestering of 0.002996132 35.12048193 0.049019173 203327_AT, 2137433 AT, 2015132 S AT NFKB1E, 1110, NFKBlA
transcription factor 60:0042100-13 cell 0.002936182 35_12043193 0.043019173 207433 AT, 205153 S AT, 215346 AT, 226218 AT 1110, C040, CD40,11711 proliferation Uvi oe Pathways significantly enriched among genes upregulated by Probiogiat relative to GA (mannitol-corrected comparison) at 6 hours, earlier run including Kegg and GO BP only:

h./
Fold Category Term Pathway PValue Benjamini Probesets Genes Enrichment 204912 AT, 204533 AT, 207536_S AT, 207433 AT, 205153_5 AT, -a-, 1(800 _PATH Cytokine-cytakine receptor11.1.0RA, CXCL10, TNFRSF9, 1110, CD40, CD40, 0 hsa04060 435698707 1.278-04 0.009767343 215346 AT; 1555759AAT, 211676_5 AT, 226218_AT, 4=, WAY interaction _ _ C.C15, IFNGR1,1176, 1f17 TNFSF1.313, EGF
216598 S AT, 223502 S AT, 206254 AT
tit KEGS _PATH NOD-like receptor signaling 202644_5 AT, 201502 S AT, 1555759 A_AT, 220066 AT, 0 tua04621 10.04279131 262E-04 0_010033132 TNFAIP3, NFKBIA, ill c, NOD2, CCL2, BIRC3 WAY pathway 216598_5_AT, 210538_5 AT
response to molecule of 203887_5 AT, 210017 AT, 201743_AT, 207433_AT, 201502 S AT, THBD, MALT1, C1014, 1110, NFKBIA, fri c., NOD2, G0_BP G00002237 13_53138285 1_858-06 0.002747953 bacterial origin 1555759 A_AT, 220066 AT, 216598_5 AT CCU
209933 S AT, 210017_AT, 201743 AT, 219424 AT, 22621.8_AT, CD300A, MALT1, CD14, 8E113, 117R, ri, 7 216598_5_AT, 223502_S_AT, 206157_AT, 204533_AT, 2192129_AT, TNFSF138, P11(3, CXCL.10, RM., ICAM1, 11.10, 00_BP G00006955 immune response 3.794670407 3_41E-06 0.002530005 20.2637_5_AT, 207433_AT, 1555759_A AT, 2113663_5 AT, 0015, KYNU, NOD2, GPR183, 6055, KYNU, 220966 AT, 205419_AT, 201926_5 AT, 217383 5 AT, 219434 AT
' TREM1, C055, ICAM1 1555950 A AT, 202638 S AT
215223 S AT, 202381 AT, 207536 5 AT, 210017_AT, 204088 AT, 2L1.725_5 AT, 201502 S_AT, 223862 AT, 219634 AT, 5002, ADAMS, TNFRSF9, MALT1, P2RX4, BID, 216598_5_AT,226066 AT, 223502_5 AT, 227143 S AT, NFKBIA, GHR1.õ 045711, 0612, MOT, ThIFSF136, P
GO_BP G00042581 regulation of apoptosis 3.437543465 6.44E-06 0_003180733 o 240347 AT, 216841 S AT, 2025445 AT, 21.9209 AT, 207433_AT; 810, BTG1, S002, TNFAIP3, IFIF11,1110, AMPS, ND
VD
203936 S AT, 221477 S AT, 220066 AT, 204493_AT, 5002, NOD2, BID, BIRC3 Ul ND
ii.
210538_5 AT
.
01 o 715223_5 AT, 202381 AT, 207536_5 AT, 210217 AT, 2134088 AT, %I) iv 211725 S AT, 201502_S_AT, 213862 AT, 219634 AT, 5002, ADAMS, TNFR5F9, MALT1, P2RX4, BID, 1-o regulation of programmed 216598 S_AT, 226066_AT, 223502 S AT, 227143_S_AT, NFKBIA, G1011, CHST11, CCU, MITF, TNFSF138, GO_BP 00.0043067 3.403676042 7_38E-06 0_002735716 1-Iv cell death 240347 AT, 216841 S AT, 202644 S AT, 219209 AT, 207433_AT, BID, BTG1, 5002, INFAIP3,1F1H1, 1110, RAMPS, , 203936 5 AT, 221477 S AT, 220066 AT, 204493 AT, 5002, N002, BID, BIRC3 o 215223_5 AT, 202381 AT, 207536 5 AT, 210017 AT, 204088 AT, 211725_5 AT, 201502_5 AT, 223862 AT, 219634 AT, 5002, ADAMS, TNFRSF9, MALT1, P2RX4, BID, 216598_5 AT, 226066 AT, 223502 5 AT, 227143 S AT, NFKBIA,-GHRL, CHST11, CCL2, M Of, TNFSF13B, GO BP
_ 60:0010941 regulation of cell death 3391147173 7/7E-06 0_00230315 240347 AT, 216841_5 AT, 202644 S AT, 219209_AT, 207433_AT, BID, BM, 5002, TNFAIP3, IfIH1, IUD, IVIMP9, 203936 S_AT, 221477 S AT, 220066 AT, 204493 AT, 5002, N002, BID, BIRC3 210538 S_AT
IV
n cp w , .
u, -a-, oe o o 1-, Fold Category Term Pathway PValue Benjamini Probesets Genes 0 Enrichment 215223 5 AT, 209555 S AT, 201743 AT, 205153 S AT, 1-i 215346 AT, 206E126_5 AT, 214866 AT, 7 I K498_5_AT, 2061.57 AT, 5002, 0036, C014, C040, 0040, TNFA1P6, CA
GO_BP G00009611 response to wounding 4.116859404 1.28E-05 0.003159383 204533_AT, 216841_5 AT, 203887 S_AT, 207433 AT, 239914_AT, PIAUR, CM, P11(3, CXCLIO, S002, THBD, 11.10, -a-, 1555759 A AT, 221477 S AT, 201005 AT, 201926 S AT, MOLL, CC:15, 5002, C09, 0055, CD55 4a, 3555950_A_AT
(Jli .
response to 203837_S AT, 201743 AT, 207433 AT, 201502 S AT, GO_ElP G00032496 13.22385142 1.35E-05 0_0028572THEO, 0014, 11.10, NEKBIA, 0215, N002, C.CL2 lipopolysaixharide 1555759 A_AT, 220066 AT, 216598_5 AT
regulation of nitric oxide 215223S AL 2161341 S
AT, 202537_S AT, 207433 AT, 5002,5002, !CAW., DSO, P2RX4, 50E12, ICAM1, GO_EiP 00.4)045428 26_93747511 3.12E-05 0.005768335 biosynthetic process 204088 AT, 221477 5 AT, 202638 S_AT, 206157_AT P113 210017 AT, 205133 S AT, 215346 AT, 219424 AT, 201502_5 AT, MALT1, C040, 0040, E813, NFKBIA, IL7R, positive regulation of GO_BP 6031402684 6_1118641 3.39E-05 0.005574201 226218 AT, 223502 S AT, 241389 AT, 202637_S AT, 220066 AT, TNFSF138, CH81882,1CAM1, N002, 0055, 0055, immune system process 201926 5 AT, 1555950_A _AT, 202638 5 AT

regulation of adaptive immune response based on .
somatic recombination of 210017 AT, 207433 AT, 205153_5 AT, 715346 AT, 220066 AT, MALT1,11.10, 0040, CD40, 610E/2,117R, P
GO BP 60.000282215.8686217 3.47E-05 0_005133166 immune receptors built 226218 AT, 223502 S

Iv from immunoglobidin ui Iv superfarnily domainsI-' a .
. --I w regulation of adaptive 210017_AT, 207433 AT, 205153 S AT, 215346 AT, 220066 AT, NIALT1, 1110, CD40, 0040,61002, 1L78, 0 Iv GO_RP 00:0002819 15_58525346 3.79E-05 0.005096778 0 immune response 226218 AT, 223502 S

203927_AT, 202381_AT, 2413E19 AT, 207433 AT, 228708_AT, regulation of cellular NFKB1E, ADAMS, CHRNB2, 11.10, RAB278, CD40, GO_BP 00:0060341 5.865417967 4.67E-05 0.005763766 205153_5 AT, 201502 5 AT, 215346 AT, 220066 AT, 223862 AT, I
localization NFKBIA, 0040, N0112, GRILL, EGF 1-206254_AT
206835 AT, 213503 X AT, 209555_5 AT, 203587 S AT, regulation of body fluid STATH, ANXA2P1, 0036, THI3D, ANYA2P2, GO_BP GO:0050878 8_253183863 4_82E-05 0.005486427 20E1816 X_AT, 210427 X AT, 205153_5 AT, 214866 AT, levels ANXA2PI, 04)40, PLAUR, ANXA2P1, CD40, C09 201590_X AT, 215346 AT, 201005_AT
210017 AT, 201743 AT, 205153_5 AT, 215346 AT, 206026 5 AT, IsAALT1, 0014,0040, CD40, INFAIP6, erl 2, 216598 5 AT, 206157 AT, 204533 AT, 207741 IC _AL 2.19209_AT, GO_BP 60.0006952 defense response 3547862575 6.58E-05 0.006947618 P11(3, CXCL10, TPSAB1, IFIlil, ILIA, RAGU_, CCL5, 207433 AT, 239914 AT, 1555759 A AT, 220066 AT, 61002, KYNU, C055, ICYNU, 0055 110663 S AT, 201926 S_AT, 217388_5 AT, 1555950 A_AT
IV
202381 AT, 2413 AT, 207433 AT, 228708 AT, 204088_AT, ADAM9, CHRNI32, 1110, RA82713, P2RX4, 0040,40, GO_BP GO 0051046 regulation of secretion 6_480996487 6.85E-05 0.006751625 89 n 205153_5 AT, 215346_AT, 220066_AT, 223862 AT, 2206254_AT C040, 61002, GHRL, EGF
CP
1-i (Jli -a-, oe ,z, .
.
, Fold Category Term Pathway Enrichment Ptialue Etenjamini Prohesets Genes 0 215223 S AT, 207536 S AT, 203980 AT, 205133 S AT, =
30132, TNFRSF9, FABP4, C040, NFKBIA, 6813, "
201302_$ AT, 219424 Al; 2.15346_AT, 223862_AT, 219634_AT, regulation of cell c040, GHRt Tit cat mifF, TtosF13B, CA
GO_BP 000042127 3.142134962 7.26E-05 0.006714161 216598 S AT, 226066 AT, 223502 S AT, 206254 AT, 240347 AT,proliferation EGF, BTG1, CXCLID, S002, CHRN/32, 1110, SO02, 204533 AT, 216841_5 AT, 241389 AT, 207433 AT,. 221477 S AT, 4w tit 215223 S_AT, 216841 S AT, 202E44 S AT, 210017_AT, $002, S002, TNFAIP3, MALT1, 1110, NFKBIA, GO_EIP G0:0006916 anti-aisoprnis 6.355151995 7.86E-05 0.006835343 207433 AT, 201502_5 AT, 221477 S AT, 223862 AT, 5002, GM., CCL2, THFSF130, BIFIC3 216598 S AT, 223502 S AT, 210538_5 AT _ regulation of protein 203927 AT, 202381 AT, 207433 AT, 205153 S AT, 201502 S AT, NFKB1E, ADAMS, 1110, C040, NFKBIA, C040, G0_8? 60:0051223 8931999642 124E-04 0.010183221 transport 215346 AT, 220066 AT, 206254_AT NO02, EGF
215223 S AT, 210017_AT, 201502 S_AT, 223862 AT, 219634_AT, 5002, MALT1, NFKBIA, Gliftl., CHST11, CC12, negative regulation of GO_BP G00043066 452001701 1.423-04 0.011048668 216598 S AT, 226066_AT, 223502 S AT, 216841_5 AT, MIT?, THFSF138, 5002, TNFA1133, 1110, S002, apoptosis 202644 S AT, 207433_AT, 221477 S_AT, 210538_5 AT

202381_AT, 210017_AT, 241389_AT, 2112.637_5_AT, 2137433_AT, ADAMS, MALT1, CH8N132, ICAM1,11_10, P2.11X4 GO BP 000001775 cell activation 5.068375108 1.43E-04 0.010557063 204088 AT, 205153_5 AT, 215346 AT, 205419 AT, 201005 AT, C040, CD40, GPR183, C09, 11_711, 1CAM1 P
2262.18_AT, 20:2638_S_AT

IV
VD
215223 S Al; 210017 Al; 201502_S_AT, 223862 AT, 219634 AT, 5002, MALT1, NFICI31A, GHRL, CHSTU, CCL2, a negative regulation of Iv GO_IIP G00043069 4.457064127 1.551-04 0.01120592.3216598 S Al; 226066_T, 223502_5 Al;AT, 216841_S_AT, mrif,INFSF1313, 5002, THFAIP3, 1110, 5002, I--1 1,3 programmed cell death --a ."
202644 S_AT, 207433 AT, 221477_5 AT, 210538 S AT
BIRO I-. IV

1:1 I
215223_5 Al; 210017 AT, 201502 S_AT, 2231362_AT, 219634 AT, S002, MALT1, NFKBIA, 01-1/11, CHST11, CCU, negative regulation of cell IV
GO_EIP 00:0060548 4.444683393 1.63E-04 0.010942714 216598 S AT, 226066_AT, 223502_5 Al; 216841_5 AT, MITE, TNFSF1.38, S002, TNFAIP3,1110, SOD2, 1 death 202644_S_AT, 207433 AT, 221477 S AT, 210538 S AT
EURC3 a 210017 Al; 241389_AT, 207433 Al; 205153_5 AT, 215346 Al; MALT1, CHRN82,1110, CD40, 0o40, 6PRI23, GO_OP G00042113 8 cell activation 1148387097 1651-04 0.010566072 205419 AT, 22621.8_AT

regulation of establishment 203927 AT, 202381 Al; 207433 AT, 205153 5 Al; 201502 S Al; NFKIIIE, ADAMS, 11.10,0)40, NFKBIA, C1340, GO_BP 000070201 8.415178175 1721-04 0.01059381 of protein localization 215346 AT, 22E1066 AT, 2062_54 AT 14002, EGF
201278 AT, 204533 AT, 206835 AT, 213503 X_AT, 241389 AT, DAB2, CXCL10,STATH, ANXA2P1, CHRNI32, GO_BP G0:0046903 secretion 4.84874552 195E-04 0.011766402 208816_ILAT, 210427 X AT, 201590_X AT, 1555759_A AT, ANXA2P2, ANXA2P1, ANXA2P1, CC15, VP533A, 204590_X_AT, 223862_AT, 223502_S_AT
GHM, TNFSF1311 IV
n cp w -.
u, -a-, cao o 1-, ., Fold Category Term Pathway PValue Benjarnini Probesets Genes 0 Enrichment h./
203887_S_AT, 2111017 AT, 201743 AT, 207433 AT, 201502 S AT, THBD, MALT1, C014, 1110, NFXB1A, era c, N002, o 60 8? G00009617 response to bacterium 6.02952E1107 3_40E-04 0.019214892 1-, 1555759 A AT, 220066 AT, nesiLS AT
CCU 07, -a-, 202381 AT, 210017_AT, 201743_AT, 203380 AT, 204033 AT, ADAMS, FAALTI., 014, FABP4, P2RX4, NFXBIA, 4=, response to organic 201502 S AT, 223862 AT, 243368 216 h..) 6051' 00:0010033 . 3_026262807 3.46E-04 0.018859624 AT, 598 SAT, GHFtL, 14MG82, CCU, THHD, 0-1131182, ILA Uri substance 203387 S AT, 241389 AT, 207433 AT, 1555759 A AT, 0 err c, N002, KYNU, KYNU
220066 AT, 210663_5 AT, 217388 S AT
regulation of protein 203927 AT, 202381 AT, 207433 AT, 205153 S AT, 201502_S AT, NFKB1E, ADAMS, 11.10, C040, NFKB1A, C040, GO__ELP Gaoousao 7378525791 331E-04 11018439313 localization 71C146 AT, 220066 AT, 206254_AT NOD2, EGF
204533 AT, 201743 AT, 2.07433_AT, 239914 AT, 205153 S_AT, CXC110, C.1314 GO_BP G00006954 inflammatory response 4.475765095 3.60E-04 0.013262369 215346 AT, 206026 S AT, 1555759_A
AT, 201.926_S _AT, ,1110, Mal, CD40, C040, TNFA1P6, CGS, CD55, CCL2, C055, PTX3 216598 S AT, 1555950 A_AT, 206157 AT
positive regulation of nitric 215223 S AT, 216841 S AT, 202637 S AT, 204088_AT, 5002,50132, ICAktl, P2RX4, 5002, ICAM1, G0_13P G00045429 2730711726 330E-04 0.018161517 oxide biosynthetic process 221477_5 AT, 202638 S AT, 206157 AT P11(3 regulation of lymphocyte 210017 AT, 207433_AT, 2.115153_5_AT, 215346_AT, 220066_AT, GO_BP 00:0002706 13.46873755 4.89E-04 0.023119461 MALT111.10 CD40 CD40 NOD
mediated mediated immunity 226218 AT
, , , , P
regulation of lymphocyte 210017 AT, 241389 AT, 207433 AT, 2051.53_S_AT, 219424_AT, MALT1, CHRN82,1110, C1340, 511113, 040, 11.711, GO BP GO0051243 6.879976751 510E-04 0.023373393 activation 215346 _AT, 226218_AT, 223502 VD
Ul positive regulation of 210017 AT, 241389 AT, 205153_5 AT, 219424_AT, 215346 AT, MALT1, CHRNB2, CD40, 51313, CD40, UR, IV
GO_IIP G00051251 8397672093 5.13E-04 0.022828997 I-' ix, A.
lymphocyte activation 226218 AT, 223502 S AT
INFSF1313 --1 ,o NJ
IV
regulation of immune 210017 AT, 202637_5 AT, 207433 AT, 205153 S_AT, 215346_AT, MALT1, ICAM1, 1110, CD40, CD40, N002,11311, GO_BP 00:0002697 8.641328649 6_186-04 0.026609275 effector process 220066 AT, 226218 AT, 202638 S AT ICA1V11 .
i iv regulation of protein 202381 AT, 207433 AT, 205153_5 AT, 215346 AT, 220066_AT, i GO _B? G0:0050708 113398591 6.42E-04 11026859383 206254 AT
ADAMS, CD40, CD40, NO02, EGF 1-secretion a 213503_X AT, 2039 AT, 208816 X AT, 207433 AT, regulation of response to 30 ANXA2P1, FA8P4, ANXA2P2,11.10, ANXA2P1, GO_BP 000032101 6.404003517 7.44E-04 0.030210271 210427_X Al;
201590 X AT, 1555759 A AT, 223862 AT, external stimulus ANXA2P1, CCLS, Gia, NTSE

positive regulation of 210017_AT, 241389_AT, 205153_5 Al; 219424 Al; 215346 AT, MALT', CHRNB2, CD40, 5813, C040, 11711, GO_BP 60:000206 8.233713807 7.70E-04 0.030405582 leukocyte activation 226218 AT, 223502 S AT
Th1FSF1311 G01_8P 600002703 regulation of leukocyte 1132314472 7175434 0.029935725 210017 AT, 207433 AT, 205153_5 AT, 215346 AT, 220066 AT, 1V1ALT1, 1110, C040, C040, NOD2, IL7R
mediated immunity 226218 AT
IV
n cp w u, -a-, ,,0 Fold Categoty Term Pathway Enrichrnent PValue Beniamini Probesets Genes 0 h.) positive regulation of 202381 AT, 241389_AT, 207433 AT, 204088 AT, 201502_5_AT, ADAMS, CHRNB2,1110, P2RX4, NEKB1A, t4002,0 GO_BP G00051050 5 91R;80828 8.05E-04 0.030169382 1-i transport 220066 _AT, 223862 AT, 206157 AT GHRL, PI)G CA
' 209933_5_AT, 213428 S AT, 202381 AT, 209555 S AT, -a-, C0300A, COL6A1, ADAMS, 0D36, ATP2C1, AT, GOB? G00007155 cell adhesion 2.909247312 8.70E-04 0.031759691237278X 206026SAT, 203037SAT, 2136205AT, h.) 2165911 5 AT, 216250 S_AT, 202637_S_AT, 1555759 TNFAIP6, MISS1,1CAM2, CCU, LPXN, KAML A_AT, 1/1 fel 5, C09,17085, ICAM1 201005_AT, 201125 5 AT, 202638 S AT
, positive reguiation of 202381_AT, 241389_AT, 207433 AT, 204088 AT, 220066 AT, GO_BP 000051047 8.007102693 833E-04 0.031121915 223862_AT ADAM9, CHRN82, 1110, P2884, NOD2, 131481secretion negative regulation of GO_BP GO:0051241 multicellular organisinal 6.208755507 8.74E-04 0.03043604120683S AT, 213503 X AT, 208816 X_AT, 207433 AT, 204088_AT, STAT14, AhLitA2P1, AN XA2P2, 1110, P2RX4, 210427 X AT, 201590 X AT, 220066 AT, 223862 AT
ANXA2P1, ANXA291, P4002,61481 process .
209933 S AT, 113428 S AT, 202381 AT, 209555_5 AT, CD3130A, COL6A1, ADAMS, CD36, ATP2C1, AT
GO_BP G0:0022610 biological adhesion 2905097173 8.81E-04 0.029967386237278X, 206026SAT, 203037SAT, 211690_S_AT, TNFA1P6, MTS.51,1C.AM2, CC12, LPXN, ICAML
216598 S AT, 216250 S_AT, 202637_S_AT, 1555759 A AT, CC15, C09,11685, ICAM1 20100S_ATõ 207114_5 AT, 202638 5 AT
regulation of 8 cell P
GO_BP 130:0030888 20.78033794 8_82E-04 0.029309007 241389_AT, 207433 AT, 205153_5 AT, 215346_AT, 223502 5 AT CHRN82,1110, C040, C040, THFSF138 proliferation0 Iv regulation of leukocyte 210017 AT, 241389 AT, 207433_AT, 205153_5 AT, 2L9424 AT, MALT1, CHRN132, 11.10,0)40, EBB, CD40,11711, 0 GO_BP GO:0032694 6.133955176 931E-04 0_030258714 oi activation 215346_AT, 226218 AT, 2235132 5 AT TNISF138 I-' Iv a positive regulation of cell 210017 AT, 241389 AT, 205153 S AT, 219424 AT, 215346 AT, MALT1, CHRN82, CD40, E813,, CD40, 178, -...1 A.
60_8P 600050867 7_862830573 9.481-04 0_030175427 l.,./
activation 2262.18_AT, 223502_5 AT
TNESF138 Iv 110017 AT, 203980 AT, 201502 5 AT, 1555759 A_AT, positive regulation of MALT1, FA8P4, NEKBIA, CCL5,14002, 6HRE., 1 00_11P GO0048584 4930927647 0.001120224 0_034771388 220066 AT, 223862 AT, 201926_5 AT, 223502S AT, 1-response to stanulus CD55,TNESF1.313, CD55 1555950_A_AT
L
215223 5 AT, 216841 S_AT, 210017 AT, 207433 AT, GO_BP G00030097 hemopoiesis 4330927647 0.001120224 0.034771388 203936 S AT, 204784 S AT, 221477 S AT, 205419 AT, 50E32, SOD2, MALT1, 1110, MMP9, MLF1, S002, GPR1113, W513;01711 2045913_X_AT, 226218_AT
regulation of tumor GO_ElP 000032680 18.7693375 0.00119195 0.03620158 201743 AT, 207433 AT, 220066_AT, 223862 AT
CD14,1110, 14002, GHRL
necrosis factor production 210017 AT, 24L3119 AT, 207433 AT, 205153 S AT, 2L9424 AT, MALT1, CHRN82, 1110, CD40, 81313, CD40, 117R, GO_BP GO0050865 regulation of cell activation 5.818494624 0_001173425 0.0363%133 215346_AT, 2262.18_AT, 223502 5 AT

GO_BP GO:0045321 leukocyte activation 4_808673243 0.00129524 0.037737147 202381_AT, 2113017_ATõ 241389_AT, 202637_5 AT, 207433 AT, ADAMS, MALT1, CHRNI32, 1CAM1, 110, C040, 205153 5 AT, 215346_AT, 205419 AT, 226218 AT, 202638 S AT CD40, 6P81/13,11711, -ed n c.4 w u, -a-, õ

,,0 Fold Category Term Pathway Plialue lienjamini Probesets Genes Enrichment lµ.) .

213391 S AT, 215223 S_AT, 205153_5 AT, 204088 _AT, positive regulation of 224130 S AT, 215346_AT, 201502_5 AT, 243363 AT, 717187 AT, TCF4, SOD2, C.D40, P2RX4, SRA1, C040, NFKMA, 07, -a-, G0_8? 60:0051173 nitrogen compound 2.9363521 0.001352769 0_038623899 226066 AT, 218559_5 AT, 206157 AT, 225386 S AT, 834G82, TCF4, MIFF, MAFB, PDG, liNft1411., 0 4w metabolic process 216341_5 AT, 202637 S AT, 207433 AT, 221477 S AT, 30D2, ICAM1, IL10, 30D2,1CAM1 lµ.) (A

positive regulation of GO_BP 60.0051240 multicellular organ8mal 4_769257838 0.00135811,2 0.038042262100h7_, 241389 AT, 2111743_AT, 205153 S_AT, 71;146 AT; MALT1, CHRNB2, CD.1.4, CD40, CD40, CC15, 1555759 A AT, 220066 AT, 223862 AT, 216598 S AT
NOD2, 6118.1., CCU
process regulation of cytokine 210017 AT, 201743 AT, 207433_AT, 205153_S_AT, 219424_AT, MALT1, C014, 1110, CD40, 813, C040, NOD2, GO_BP 600001817 5425616349 0.001454089 0,039925244 production 215346 AT, 220066 AT, 223862 regulation of inflammatory GO_IIP 600050727 9_569892473 0.001768848 0.047488977 203980 AT, 207433 AT, 1555759 A AT, 223862 AT, 203939 AT FABP4,1110, CCL5, GliRL, NTSE
response positive regulation of cell 210017 AT, 241389 AT, 204038 AT, 237278 X AT, 205153_5 AT, MALT', CHRH82, P2RX4, ATP2C1, CD40, CD40, GO_BP G0,00106473379213648 0.001776941 0.046854541 communication 215346 AT, 220066 AT, 2.23862_AT, 216593 S AT, 206254 AT N002, 61431; CCU, EGF
202637_S_AT,207433_AT, 219424 AL 220066_AT, 201926_S_AT, i t, 1110, Fin, Nom, Coss, icAmi, CUSS P
GO_BP 600002250 adaptive immune response 9.445608155 0.001356176 0_048042002 202338_S_AT, 1555950 A AT
c, Iv u u, adaptive immune response IV
based on somatic =
1-4 a, .a.

u, recombination of immune 202637_5 AT, 207433 AT, 219424 AT, 220066_AT, 201926 S AT, IP
GO_BP 60.0002460 9.445608155 0.001856176 0.048042002 ICAM1,11.10, EBB, NO02, CUSS, !Well, CDS5 IV
o receptors built from 202638 S AT, 1555950 A AT
1-=
immunoglobulin I
I-' IV
superfamily domains .
. i-=
response to gluccicarticoid 202381 AT, 203980_AT, 207433_AT, 1555759 A AT, GO_B? G0:0051384 9_324510615 0.00194645 0.049460316 ADAMS, FABP4, 1110, CCLS, CCL2 stimulus 216598_5 AT
215223 S AT, 216841_S_AT, 210017 AT, 207433 AT, hemopoietic or lymphoid SOD2, S002, MALT1,11W, MM?9, MLF1, 5002, G0_8? 6040411534 4.475765095 0_001951531 0.048752558 203936 S AT, 204784_S AT, 221477 S AT, 205419 AT, organ developmentG143183, VP533A,11.73 204590 X AT, 226218 AT
response to steroid 202381 AT, 203980 AT, 207433_AT, 1555759_A AT, 223862 AT, ADAM9, FABP4,1110, CC13, GlaftL, 864682, GO_BP 60.0048545 5303315412 0.001961629 0.048188649.
hormone stimulus 243368 AT, 216598 S_AT
Ca 3 219424 AT, 205419 AT, 201926_5 AT, 219434 AT, 216598 S AT
G0_11? G011006959 htunoral immune response 9.206478335 0.00203972 0,049246639 ' EBB, GP8183, CUSS, TREMI., ca2, CD55 1555950_A AT
IV
n c.4 w u, -a-, ,,0 Example 4 Validation of pro-inflammatory markers' upregulation by stimulation with Probioglat compared to Copaxone (qRT-PCR analysis) Key genes identified by differential expression analysis were assayed using qRT-PCR. RNA was utilized from each of 6 biological samples for each treatment (Copaxone and Probioglat) and 15 technical replicates were performed for each sample (a total of 90 observations per transcript per treatment). Since three Copaxone batches and one Probioglat batch were available, a total of 360 observations from each transcript were evaluated. To evaluate the data, the 2- act approximation was utilized with GAPDH as reference transcript and vehicle control (mannitol) as calibrator. A one-sided t-test with unequal variance was used to compare the RNA expression from the two treatments.
To validate the results from the microarrays comparing Probioglat with Copaxone for key inflammation and MS-related genes, two chemokines (CCL5, FDR p-value < 0.02 and CXCL10, FDR p-value < 0.0006), two matrix metalloproteinases (MMP1, FDR p-value < 0.002 and MMP9, FDR p-value < 2.8e-6) and a non-secreted cell surface marker (CD9, FDR p-value < 0.002 with FC 1.15) that is a component of myelin and a marker of myelinogenic progenitor cells (Allie et al., Arch. Neurol. 2005) were tested independently by robust qRT-PCR analysis. Three Copaxone batches and one Probioglat batch were available for use, and a total of 360 observations from each transcript were evaluated. Statistical analysis utilized a one-sided t-test with unequal variance to compare the RNA expression from the two treatments. All the genes tested were significantly differentially expressed between Probioglat and Copaxone as expected based on the microarray analysis (Table 7).

Table 7. Differential expression (p value and fold change) of key immunological genes following Probioglat stimulation compared with Copaxone Gams CCIS CD9 CXCL10 MaMP1 MiMP9 Method FC pvgue FC pvalue FC pvgue FC pvgme FC pvalue flEga 1.12 4_05E-05 1_11 0.0004 2.28 0.0029 1.25 0_0201 1.24 0.0168 FDR-adjusted 1.09 0.02 1.15 0.002 1.46 0_0006 1_5 0.002 1.29 180E-06 Microarray FC: fold change; qr,0,; quantitative RT-PCR; FDR: For the microarray data, since all x4=4 on the microarray were tested, p values were adjusted using FDR for testing multiple hypotheses_ Table 7 shows p-values from single-tailed t-test with unequal variance (for qPCR results) and FDR-adjusted p-values from LIMMA comparison of microarray data between human monocytes treated with Copaxone and Probioglat.
Discussion - Examples 3-4 The genes significantly upregulated (FDR adjusted p value < 0.05) in Probioglat relative to Copaxone treatment at 6 hours were found to be enriched significantly (Benjamini corrected p value < 0.05) for 106 pathways annotated in the GO (Biological Process, Cellular Component, and Molecular Function) and Kegg databases (The Gene Ontology Consortium. Gene ontology: tool for the unification of biology, Nat. Genet., May 2000; Kanehisa et al, KEGG: Kyoto Encyclopedia of Genes and Genomes, NAR, 2000) (Figure 10; Table 6) .
These include immune system process (GO:0002376), response to lipopolysaccharide (LPS) (GO:0032496), and immune response (GO:0006955) pathways (Benjamini corrected p values 1.5e-5, 8.7e-4, and 3.3e-4, respectively). Several of these pathways are relevant to inflammation (e.g., regulation of inflammatory response (GO:0050727) and regulation of tumor necrosis factor production (GO:0032680), Benjamini corrected p values of 0.015 and 0.028, respectively).
Branded GA significantly modulated many validated pathways. At 6 hours, pathways enriched significantly among upregulated genes included broad categories such as immune response and regulation of immune processes, and more specifically cytokine-cytokine receptor interactions. Other significantly enriched pathways included adhesion; extracellular region; plasma membrane; membrane; response to external stimulus; response to stress; response to wounding;
defense response; inflammatory response; and immune system process, all pathways with broad relevance to the disease process and/or proposed action of GA. Several of these pathways (e.g., extracellular region; immune system process; defense response; regulation of leukocyte activation) were also seen significantly enriched among genes modulated by GA in monocytes obtained from RRMS patients within the first two months of treatment (Thamilarasan, J Neuroinflammation 2013).
As another example, NOD-like receptor signaling (hsa04621, Benjamini corrected p value 0.027) regulates inflammatory and apoptotic responses. The response to LPS pathway (GO:0050727; Figure 9) includes the genes CD14, CCL5, THBD, CARD15, NFKBIA, and CCL2, all upregulated in Probioglat treatment versus GA at 6 hours. This pathway was also significantly enriched among probesets upregulated by GA treatment at 6 hours, though with a lower enrichment score (14.8 vs 2.7) and higher p value (0.00087 vs 0.036). The strong enrichment induced by Probioglat relative to GA of this prototypical pro-inflammatory pathway warrants further investigation with respect to safety.
Interestingly, about half of the pathways (58 out of 114) significantly enriched (Benjamini corrected p value < 0.05) among genes upregulated by GA treatment versus mannitol control at 6 hours were also significantly enriched among genes upregulated by Probioglat relative to GA treatment. An additional 48 pathways were significantly enriched among genes upregulated by Probioglat relative to GA (and not modulated by GA relative to mannitol control). These include pathways relevant to inflammation, such as response to molecule of bacterial origin (GO:0002237), regulation of tumor necrosis factor production (GO:0032680) and NOD-like receptor signaling pathway (hsa04621), as well as other immune pathways including regulation of lymphocyte mediated immunity (GO:0002706) and B cell proliferation (GO: 0042100) Example 5 Integrated Analysis Spanning Multiple Species and Cell Types Analyses were conducted to elucidate the gene expression changes induced by Copaxone in the following systems:
1) primed, ex vivo mouse splenocytes;
2) THP-1 human monocyte cell line; and 3) samples from MS patients.
Genes, pathways and immune cell types modulated by Copaxone were investigated, in order to determine which aspects of Copaxone s mechanism were observed across all systems utilized, and which were detectable only in certain systems, but not others.
Genome-wide expression profiles in cells from three different datasets in two different species (human, mouse) were studied. LIMMA was utilized to identify a genome-wide list of differentially expressed genes induced by GA in the primed and ex vivo stimulated mouse splenocytes, as well as in the THP-1 human monocyte cell line.
Repeated-measures ANOVA was utilized to find a genome-wide list of genes modulated by GA in treated MS patients. Advanced enrichment algorithms were then applied to elucidate the pathways and cell types modulated by GA.
Upregulated expression of the IL-10 gene, a key indicator of the well-studied Th2-shift induced by GA, was consistently demonstrated in all 3 systems (mouse splenocytes, human monocytes and MS patient PBMCs) (Fig. 13). GA
induces an anti-inflammatory effect, mediated by secretion of IL-4, IL-10, and other anti-inflammatory cytokines. This effect involves both a shift in T cell populations (from pro-inflammatory Thl to anti-inflammatory Th2) and a shift from monocyte production of IL12 to anti-inflammatory IL10. For example, in vitro GA treatment increased the proportion of IL10-producing Treg cells in blood from MS patients (Putheti, J Neuroimmunol 2003). Dendritic cells exposed to GA during maturation increased their production of IL10 (Vieira et al, 3 Immunol 2003), monocytes from mice treated with GA

secreted more IL10 than monocytes from untreated mice (Weber et al, Nat Med 2007), and monocytes isolated from MS patients treated with GA were shown to upregulate IL10 relative to untreated patients (Kim et al, J Immunol 2004).
The genes modulated by GA treatment in multiple studies were examined for enrichment in particular immunological cell types. 39 genes were modulated significantly by GA in all three studies (Fig. 14). Table 8 shows the expression level of each gene as modulated by Copaxone compared to baseline (human PBMC), mannitol (human monocyte) or medium (mouse splenocytes). Although some genes are significantly differentially expressed in the same direction across all compartments and systems, other genes are modulated differently across the different systems. This shows that Copaxone may induce pathways or cell types differently depending on a given experimental setup and a well-designed genome-wide assay is required to ascertain mechanism and effect of Copaxone . Starred genes did not meet effect size cutoff of 0.5 employed in human PBMC study for conducting enrichments.

Table. 8. Genes significantly modulated by Copaxoneg treatment in all three studies Direction in Direction in DWctionii human human mouse pante rnanocytes spienocytes (Coy:axone (Copencone (Copexane refittne to relative to relative to Gene baseline) Manning) Mesistrni ABU UP UP UP

AFG3t2 DOWN DOWN UP

cau UP UP DOWN

CW UP UP DOWN
COMA DOWN DOWN UP

ftUl UP DOWN DOWN
Fern UP DOWN DOWN
GYPC UP DOWN DOWN
HFE UP UP UP
IUD" UP UP UP

NACA* DOWN DOWN UP
OtAH DOWN DOWN UP

PDKI. UP DOWN DOWN
POLI DOWN DOWN DOWN

RMS. DOWN UP DOWN

SYNCRIP DOWN DOWN DOWN

TPfiel . UP DOWN DOWN
Tara DOWN DOWN DOWN

1.16APZ DOWN DOWN UP

VDACZ DOWN DOWN UP

Example 6 Cell Type Enrichment Analysis In addition to the shared induced effects discussed above, each system and platform clearly captured different aspects of GA's impact on the immune system. In mouse splenocytes, genes associated with FOXP3+
regulatory T cells (Tregs), B cells, T cells in general, macrophages, and dendritic cells were significantly modulated upon ex vivo stimulation with GA after prior inoculation (Table 9). In human monocyte (THP-1) cells, upregulated genes were associated with monocytes along with NK cells, dendritic cells, and granulocytes (Table 10). In human PBMCs, genes associated with immune cell types were modulated early in treatment (by month 3), including certain cell types affected in prior systems, but also distinct cell types, such as megakaryocytes and myeloid progenitors (Table 11).
Table 9. Immunological cell type enrichment for genes modulated by GA
treatment in mouse splenocytes a) Upregulated (top 20 results) Dataset Namel Score p.val adj.p.val SC.MEP.BM.rnk 641.2372079 0 0 T.8EffSp.OT1.12hr.LisOva.rnk 683.0376678 0 0 T.8EffSp.OT1.48hr.LisOva.mk 587.7303361 0 0 T.DPbI.Th.mk 659.3284877 0 0 T.ISP.Th.mk 584.8660167 0 0 preB.FrC.BM.rnk 620.1611981 0 0 proB.FrBC.FL.mk 595.3446445 0 0 DC.LC.Sk.mk 709.8843317 2.89E-15 6.96E-NK.H..MCMVI.Sp.mk 770.77198 7.11E-15 1.52E-13 DC.103.11b..PolyIC.Lu.mk 704.9643794 1.44E-14 2.65E-NK.MCMVI .Sp.rnk 793.3059033 1.51E-14 2.65E-T.8Eff.Sp.OT1.24hr.LisOva.mk 661.8125467 5.97E-14 9.61E-13 B.GC.Sp.mk 602.4630175 1.01E-12 1.39E-Tgd.vg2.24ahi.e17.Th.mk 619.9621246 9.88E-13 1.39E-DC.103.11b.24..Lu.rnk 738.2608372 8.91E-12 1.15E-T.4FP3.25..AA.rnk 697.5960229 2.76E-11 3.14E-Tgd.vg3.24a1o.e17.Th.mk 620.789896 2.72E-11 3.14E-10 proB.FrA.FL.mk 578.5853958 7.17E-11 7.69E-preT.DN3B.Th.mk 567.9618687 1.64E-10 1.67E-preT.DN3.4.Th.rnk 560.7279837 2.96E-10 2.86E-b) Downregulated (top 20 results) Dataset Name Score p.val adj.p.val GN.Arth.BM.rnk 1217.738372 0 0 SC.CDP.BM.rnk 1077.505969 0 0 T.4SP24int.Th.rnk 1040.246786 0 0 T.8Nve.Sp.OT1.rnk 1095.134864 0 0 proB.CLP.FL.rnk 1115.01089 0 I All immunological cell type terminology in Tables 5-7 as defined via lmmgen (www.immgen.org/).

GN.BM.rnk 1212.480897 1.11E-16 3.57E-15 GN.Bl.rnk 1184.87043 6.66E-15 1.84E-13 GN.UrAc.PC.rnk 1145.080376 5.87E-14 1.37E-12 GN.Thio.PC.rnk 1197.163456 6.39E-14 1.37E-12 GN.Arth.SynF.rnk 1160.159783 2.72E-11 5.25E-10 DC.Ilhilang.103.11blo.SLN.rnk 1112.24759 5.07E-08 8.90E-07 DC.Ilhilang.103.11b..SLN.rnk 1151.229363 9.94E-08 1.60E-06 DC.8.4.11b..SLN.rnk 1116.686609 1.86E-07 2.77E-06 proB.CLP.BM.rnk 1181.133013 1.35E-06 1.86E-05 Mo.6C.II..BM.rnk 1094.697148 1.71E-06 2.20E-05 DC.103.11b..LuLN.rnk 1151.971571 2.47E-06 2.98E-05 SC.GMP.BM.rnk 1340.719659 1.56E-05 0.000164843 SC.MDP.BM.rnk 1206.224359 1.56E-05 0.000164843 Mo.6C.Ilint.Bl.rnk 1106.765118 1.62E-05 0.000164843 Table 10. Immunological cell type enrichment for genes upregulated by GA treatment in human monocytes.
Dataset Name Score p.val adj.p.val MONO2.rnk 108.0701335 0 0 NKA1.rnk 97.70225302 2.00E-15 3.80E-14 MON01.rnk 104.5121531 8.28E-13 1.05E-11 GRAN2.rnk 97.10283117 1.17E-09 1.11E-08 GRAN3.rnk 91.49890345 1.27E-07 9.40E-07 DEN DA2.rnk 100.4177838 1.48E-07 9.40E-07 DEN DA1.rnk 111.2455747 7.78E-05 0.000422143 E0S2.rnk 94.29494842 0.000223937 0.001063701 MEGA2.rnk 101.6956549 0.007442566 0.031424168 Table 11. Immunological cell type enrichment for genes modulated by GA treatment in human PBMC.
a) Upregulated, by cluster resulting from consensus k-means clustering on gene expression profiles Cluster 0:
Dataset Name Score p.val adj.p.val Genes in list >=
threshold PTPN18,ILK,RAB27B,FHL1,EPOR,FYN,MA
MEGA2.rnk 32.42631137 1.24E-12 4.70E-11 X,PARVB,TUBB1,TPM1,VCL,TPM4 Cluster 2:
Dataset Name Score p.val adj.p.val Genes in list >= threshold IGL@,TOP2A,NUSAP1,IRF4,IGHM
PRE_BCELL3.rnk 57.93896297 3.98E-08 1.51E-06 ,1GL@,BIRC5 IGL@,TOP2A,NUSAP1,IGHM,MYL
4,MK167,IGL@,H2AFX,RPIP8,GYP
ERY5.rnk 64.22953395 9.88E-07 1.88E-05 C,BIRC5 BUB1B,TOP2A,NUSAP1,MCM4,T
ERY2.rnk 32.83132369 8.43E-05 0.001067894 UBB,MYL4,CDC6,BIRC5 TOP2A,NUSAP1,TUBB,MYL4,MKI
ERY4.rnk 69.43612767 0.000141687 0.001346024 67,CDC2,RPIP8,GYPC,BIRC5 BUB1B,TOP2A,NUSAP1,TUBB,MY
L4,MK167,CDC2,RPIP8,GYPC,BIRC
ERY3.rnk 84.61769579 0.000286865 0.002180171 5 IGHG1,IGL@,TOP2A,NUSAP1,IRF
GRAN1.rnk 55.17000868 0.000557705 0.003532132 4,IGHM,IGL@,BIRC5 E0S2.rnk 62.69263216 0.002286284 0.012411257 IGL@ARF4,IGHM,IGL@
BAS01.rnk 87.29704767 0.003219714 0.013594346 IGL@,IGHM,IGL@
BUB1B,NUSAP1,MCM4,TUBB,MS
ERY1.rnk 28.25494881 0.003043224 0.013594346 4A2,BIRC5 TOP2A,NUSAP1,MCM4,TUBB,MS
MEP.rnk 30.5446045 0.009387769 0.035673524 4A2,BIRC5 Cluster 4:
Dataset Name Score p.val adj.p.val Genes in list >= threshold PARD3,GNB5,C5ORF4,LIMS1, ACTN1,ITGB3,ITGA2B,GPX1,1GF2BP
MEGA2.rnk 64.4584783 4.41E-12 1.67E-10 3,CLU,LTBP1 HMGA2,LIMS1,ACTN1,ITGB3, MEGA1.rnk 38.04817949 4.66E-09 8.86E-08 ITGA2B,GPX1,1GF2BP3,LTBP1 HMGA2,LIMS1,ACTN1,ITGB3, ERY2.rnk . 47.24788403 4.70E-06 5.96E-05 ITGA2B,IGF2BP3,CLU,LTBP1 GMP.rnk . 33.12681006 0.000142682 0.001355477 ACTN1,GPX1,IGF2BP3,LTBP1 HMGA2,LIMS1,GPX1,IGF2BP3, HSC3.rnk 45.40525942 0.000287455 0.002184658 HIST1H3D,LTBP1,INPP4B
CLCN3,C5ORF4,1TGB3,GPX1, ERY5.rnk . 73.41821315 0.000980846 0.006212027 IGF2BP3,LTBP1 CMP.rnk . 23.1944575 . 0.002214239 0.010517637 HMGA2,IGF2BP3 RAB6B,CLCN3,C5ORF4,GPX1, ERY4.rnk . 77.37714483 0.001966408 0.010517637 IGF2BP3,LTBP1 HMGA2,GPX1,1GF2BP3,MALL, ERY1.rnk 45.00063371 0.002587112 0.010923363 LTBP1 RAB6B,CLCN3,C5ORF4,GPX1, ERY3.rnk 90.0166825 0.009061135 0.031302103 IGF2BP3,LTBP1 ACTN1,ITGB3,GPX1,1GF2BP3, GRAN2.rnk 35.17942767 0.008750011 0.031302103 LTBP1 b) Downregulated, by cluster resulting from consensus k-means clustering on gene expression profiles (as described in methods) Cluster 0:
Dataset Name Score p.val adj.p.val Genes in list >= threshold 25.7667964 0.00042007 0.01596274 BCELLA2.rnk 6 2 9 ITSN1,ZNF365,GYG2 19.1117069 0.00273680 0.02599968 BCELLAl.rnk 8 9 6 ITSN1,ANK3,ZNF365,GYG2,EXTL2 20.1130156 0.02599968 BCELLA3.rnk 6 0.00138472 6 ITSN1,ZNF365,GYG2 21.5131815 0.02599968 BCELLA4.rnk 3 0.00253799 6 ITSN1, LI LRA4,GYG 2,EXTL2 Discussion - Examples 5-6 The diversity of the cell types enriched from the list of 1200 genes (B cells, T cells, monocyte progenitors, megakaryocytes) indicates the wide-ranging effects of Copaxone on the immune system. Similar to what was observed in the splenocyte data, it is difficult to define a small panel of genes to use as quality-control measures against a given Copaxone lot due to the wide-ranging effect of the drug. Using genome-wide gene-expression arrays, the gene expression from the human PBMC data, mouse splenocytes and human THP-1 monocyte cell line were compared and discovered that although there are genes that are consistently modulated by Copaxone across all those experimental systems (e.g., IL10), some gene-expression signatures and cell types (e.g., B-cells) were seen only in one system (e.g., human PBMC data) but not as clearly in the other systems (e.g., monocytes and splenocyte data). Looking at genome-wide gene expression signatures can yield a good characterization of the impact of Copaxone on a single system (e.g., THP-1 monocytes) but well-powered experiments in multiple systems are necessary to characterize the biological impact of Copaxone .
The generic glatiramer acetate manufactured by Probioglat induced significantly higher expression of CD14 than Copaxone did (adj. p =

0.0135; Fig. 15a) and also induced significantly higher expression of CD40 than Copaxone did (adj. p = 0.0128, Fig. 15b).
One key element of Copaxone's putative mechanism of action is the ability to shift the immune response from a Thl/Th17 phenotype, typically associated with MS pathoetiology and severity, to a Th2 response type that may mitigate the harmful effects of MS. Across multiple studies, we observed concerning differences between Copaxone and proposed generics was observed in their impact on key genes associated with maintaining the balance between Th2 and Thl/Th17.
Interleukin-1 beta (IL1B) is a cytokine that stimulates a variety of immune system cells, and may contribute to the development of MS by promoting Th17 cell development. Consistent with these observations, IL1B has also been found to be associated with late disability progression and neurodegeneration in MS. Glatiramer acetate, on the other hand, was reported to significantly reduce interleukin-lbeta levels under chronic inflammatory conditions in vitro in human monocytes (p = 0.028).
A variety of glatiramoids were significantly less effective than Copaxone at downregulating IL1B: Copaxone induced significantly lower IL1B expression than a Natco purported generic in our first mouse splenocyte study (adjusted p = 0.043 by ANOVA). Copaxone was also extremely effective in downregulating IL1B relative to medium (adjusted p = 5.72 x 10-7), while the Hangzhou purported generic (API, China) did not significantly downregulate IL1B relative to medium (adjusted p = 0.159) (Fig. 16).
Other Th17-associated genes also seem to be modulated less effectively by purported generics than by Copaxone. In human monocytes, CD44 was upregulated to a greater extent by Escadra635 than by Copaxone (adj.
p = 0.04 by LIMMA at 6 hrs; Fig. 17). CD44 has an established role in Th17 differentiation, specifically: "deletion of CD44 inhibited Thl/Th17 differentiation while simultaneously enhancing Th2/regulatory T cell differentiation.

Th17 associated genes also vary from one batch of generics to another.
In mouse splenocytes, IL27 was upregulated to significantly different extents by different batches of Escadra, namely Escadra635 and Escadra253 (Fig. 18). IL27 has been proposed to have therapeutic effects in MS, due to its ability to suppress Th17 cells and stimulate neuroprotective factors.
In human monocytes, Probioglat induces significantly higher expression of MMP9 than Copaxone does (Adj. p = 2.07 x 10-5 by LIMMA for Copaxone vs. Probioglat at 6 hrs in human monocytes; Fig. 19). MMP9 is an established biomarker and potential predictor of disease activity in MS. This finding is particularly concerning given the fact that MMP9 facilitates T-cell migration into the CNS, playing a key role in the disruption of the blood-brain barrier (BBB) and thus in the pathogenesis of MS.
Example 7 Compositional differences of GARDPs and GARDSs Due to its molecular diversity, characterizing even a single, large polypeptide (assuming it could be isolated) would present significant technological and scientific barriers making full characterization, as well as a demonstration of active ingredient sameness, impossible.
Analysis of Additional Purported Generics Reveals Limitations of Focused Gene Panels Certain methods have been publicly described in patent application filings by manufacturers seeking to develop purported generics (including International Publication Number W02008/157697 by Momenta Pharmaceuticals, Inc.), suggesting that glatiramoids can be compared by analyzing a panel comprising only a small subset of proteins and/or the genes coding for those proteins. To evaluate the effectiveness of such comparisons, we applied the same methods used to study Probioglat and Copaxone in human monocytes to also study purported generics Escadra (Raffo, Argentina) and Glatimer (Natco, India). Both purported generics modulated many genes to a significantly different extent than Copaxone. These differentially expressed genes included genes with relevance for multiple sclerosis. For instance, both Natco and Escadra differed significantly from Copaxone in expression of CD9, a component of myelin and a marker of myelinogenic progenitor cells (Sim et al, Nature Biotechnology, 2011). As another example, Escadra differed significantly from Copaxone in expression of CD44, the receptor for hyaluronan which accumulates in demyelinated lesions (Back et al, Nature Medicine, 2005). Despite significant differences such as these between Copaxone and the purported generics in expression of biologically relevant genes, when we examined only the small subset of genes coding for proteins identified in the Momenta patent, there were no significant differences in expression (Fig. 20).
This demonstrates that methods focusing on only a small selected subset of genes may miss important differences between two glatiramoids.
Compositional differences can be observed between Copaxone and other generics TV-5010 was developed by making slight changes to the manufacturing process for Copaxone, in order to produce a higher average molecular mass (in the range of 13,500-18,500 Daltons) and investigate whether such a change in molecular mass would be clinically beneficial.
Surprisingly, TV-5010 proved toxic in long-term animal studies, inducing fibrosis, nephropathy, increases in eosinophil counts, and severe injection site lesions, including subcutaneous necrosis, vascular necrosis, cavity formation, and inflammation; in some cases these lesions were associated with mortality in both rats and monkeys, possibly related to vascular damage, hemorrhage, thrombus formation, and septicemia. These toxicities were never seen in any of the development programs for Copaxone, and led to the termination of TV-5010's development. Some patients treated with TV-5010 showed injection site reactions and/or developed anti-drug antibodies, but the clinical studies were completed in time to prevent any of the chronic toxicities observed in long-term animal studies from potentially occurring in humans. Because Copaxone and TV-5010 had many similarities, with the two key differences that (1) TV-5010 had a higher average molecular mass than Copaxone, and (2) Copaxone was safe while TV-5010 induced toxicity in long-term animal studies, we sought to determine if there were genes differentially expressed in response to the two medicines that could have predicted toxicity prior to the initiation of long-term animal studies. Having generated gene expression profiles for TV-5010-stimulated splenocytes using the same procedures described above, we applied LIMMA to create a ranked list of genes with significantly different expression levels in response to TV-5010 compared to Copaxone, with both analyzed relative to medium. Among the genes with fold changes greater than 1.5, the gene with the lowest (best) p-value was Matrix Metalloproteinase 14 (MMP14). MMP14 expression was significantly higher in response to TV-5010 than in response to Copaxone as determined by both ANOVA (adj p < 4.53 x 10-7) and LIMMA (adj P < 1.07 x 10-5) (Fig. 21).
The observed upregulation of MMP14 was striking because MMP14 has been associated with fibrosis and eosinophil-related disorders in the literature, the very same toxicities seen in animals following long-term treatment with TV-5010. MMP14 levels increase to over 250% of control correlating with the pattern of fibrosis manifestation in rats, and MMP14 activity is chronically elevated in a mouse model of dermal fibrosis. Moreover, in patients with the eosinophil-related disorder Eosinophilic Esophagitis (EoE), MMP14 is expressed at a 5.3-fold higher level than in controls. In addition to MMP14, another gene, Signal Transducer and Activator of Transcription 3 (STAT3), which has also been linked to fibrosis, also showed significantly elevated expression in response to TV-5010 relative to Copaxone . Overall, our findings with TV-5010 lend further support to the utility of mouse splenocyte gene expression studies for predicting drug safety issues.
Example 8 Clinical Implications of the Use of Purported Generics Purported "generics" are not only different from Copaxone in many ways, but also different from each other, causing differential effects in a variety of pathways modulating immunological processes that could have clinical and biological significance. The differences among "generics" highlight the importance of the manufacturing process for glatiramer acetate, and demonstrate that even slight changes in the manufacturing process can alter the biological properties of the resulting medicine (Fig. 22).
As part of Teva's ongoing commitment to better understand Copaxone , Teva also has studied Copaxone@'s effect at the level of gene expression across the entire genome (unbiased, without prior hypothesis about the genes for which expression pattern may be altered and without choosing which genes to focus on or study). Genes encode proteins which carry out an array of biological processes in the body, including processes that are essential to the immune system response manifested by exposure to Copaxone . So-called gene "microarray technology" allows scientists to observe which genes are "turned on"
(in scientific terms, "upregulated"), as well as which genes are "turned off" (in scientific terms, "downregulated") after exposure to various conditions, including stimulation by pharmaceutical products, via measuring the level of mRNA, which is the transitional phase between genes and proteins along the translation process. Teva's gene expression analysis of mouse splenocytes, as well as a human monocyte cell line (THE-1), exposed to Copaxone , reveals favorable, upregulation of anti-inflammatory genes. These studies provide support for the vast experimental evidence that Copaxone exerts its well-established therapeutic benefits in part by modulating the immune system to turn on beneficial (i.e. anti-inflammatory and neuro-protective) genes and turn off harmful ones (i.e. pro-inflammatory).
Several competitors have sought approval to market putative generic versions of the drug in foreign countries. Although many of those jurisdictions have required applicants to conduct clinical trials as a condition of approval¨and none of those jurisdictions has approved a generic version of Copaxone ¨others have not been as careful, and those countries since have allowed purported Copaxone generics to enter the market without proof of the equivalence of the putative generics to Copaxone .
In particular, the findings for Probioglat discussed below should be carefully addressed, given the serious clinical reports from Mexico following introduction of this purported generic to the market. The complaints expressed by MS patients treated with Probioglat in Mexico included adverse reactions (increased injection site reactions and post injection reactions) and increased occurrence of relapses, even in patients who had been stable for years under Copaxone treatment.
These effects may be underlined by a biological imbalance between anti-inflammatory and pro-inflammatory processes, which may be discernible in gene expression differences such as those described herein. The pro-inflammatory signal identified in pre-clinical analyses and its potential association with boosting of the autoimmune mechanisms of disease following switching to Probioglat treatment should raise concerns for the potential health consequences of these differences.
The Teva Patient Support Program in Mexico has an extensive database.
Given that patients can switch between branded and purported generic GA, all patients are kept within the database and are provided with patient support services. Interestingly, the database shows differences in patient reports between 2012, when patients in the program were receiving only Copaxone , vs 2013, when patients were receiving both Copaxone and Probioglat.
The number of relapses reported by patients in Teva's Patient Support Program on a monthly basis during the years 2012 and 2013 i. It is again clear that when Copaxone alone was in use (i.e. throughout 2012) the overall, as well as per-month number of relapses was lower than that reported when Probioglat was present in the market (i.e.
throughout 2013).
Discussion - Examples 7-8 Gene expression data presented herein for Copaxone further demonstrates the highly complex mechanism of action of GA, given that many of the GA-induced functional pathways in these experiments coincide with known mechanisms of GA activity in MS patients.
Furthermore, the data suggests that other glatiramoids are associated with a significantly altered gene expression profile and thus would probably not behave the same as Copaxone. Most importantly, these biological differences could lead to a marked difference in safety or efficacy profile over the course of chronic treatment.
Probioglat, a purported generic of Copaxone , has been in commercial use in Mexico since January 2013. The introduction of Probioglat has resulted in a spike of injection site reactions and post injection reactions, as well as occurrence of relapses, even in patients who had been stably in remission for years. Accordingly, several pharmacovigilance reports have been issued by HCPs, and patients expressed complaints in the local media and in Teva's Patient Support Program.
The high occurrence of relapses and adverse events after the treatment switch to Probioglat may be due to an immunological imbalance favoring pro-inflammatory effects, instead of the well recorded beneficial effect that Copaxone induces, reducing pro-inflammation and boosting anti-inflammation.
Overall, similarities in the physicochemical properties of the glatiramer acetate mixture are observed between Copaxone and Probioglat, as well as other purported generics, particularly when using common non-specific analytical methods. However, clear differences are observed between Copaxone and purported generics when applying high resolution methodologies targeted at characterizing functionally relevant elements, e.g. IMMS analyses concomitantly capturing composition, size and charge distribution; and gene expression analyses capturing pro-inflammation distinctly upregulated by purported generics but not Copaxone .
Gene expression studies thus help explain the biological impact of the physicochemical differences observed, providing insight into some of the factors that may underlie the observed reduction in efficacy and parallel increase in adverse events reported with purported generic glatiramer acetate, notably Probioglat in Mexico.
As part of Teva's ongoing commitment to better understand Copaxone , Teva studies its effect at the level of gene expression across the entire genome (unbiased, without prior hypothesis about the genes for which expression pattern may be altered and without choosing which genes to focus on or study) in a variety of immunologically relevant model systems, including mouse splenocytes, human monocytes, and peripheral blood mononucleated cells (PBMCs) from MS patients. The genome-wide approach is critical, because two glatiramoids can appear identical based on a small panel of genes, yet differ significantly in their impact on other genes that are potentially highly relevant to safety and/or efficacy. Using multiple model systems is equally critical, since acting as an antigen, Copaxone significantly impacts a variety of immunological cell types. The unbiased approach allows identification of genes and pathways with subtle, yet robust, differential expression patterns following stimulation by different glatiramoids in different experimental contexts. The functionality of identified genes and pathways is then described based on experimental data reported in the peer-reviewed literature. The research has also shown that various model systems capture different aspects of Copaxone's mechanism of action, such that no single cell type or system tested was sufficient to fully characterize the biological impact of this medicine.
Example 9 Differences in gene expression induced by. Polimunol versus branded GA
To identify differences between Copaxone and differently manufactured glatiramoids, differential gene expression analysis was performed in this study to compare directly between profiles induced by Copaxone and by the purported generic Polimunol. Based on previous power calculations (using the R package ssize.fdr), to detect differentially-expressed genes with a fold-change between treatments of as low as 1.3 with 80% power the experiment was designed to include six replicates of each condition. The order of sample processing was randomized with respect to treatment in order to avoid creating confounding batch effects.
Cells from a human monocyte cell line (THP-1) were stimulated with either Copaxone, purported generics from several manufacturers including Polimunol by Synthon, or vehicle control (mannitol) for 6 hours. The 6 hour timepoint was selected because the greatest effects across all treatments were observed at this timepoint in the previous study described above in Example 1. RNA was extracted and expression profiled genome-wide using the Affymetrix U133 Plus 2.0 chip. Three batches of Copaxone and one batch of Polimunol were comparatively tested in six replicates each. RNA processing was performed by Expression Analysis (NC, USA).
Differentially-expressed probesets were identified across conditions using linear models for microarray data (LIMMA). For comparing Copaxone ("GA") and purported generic, comparisons were corrected for mannitol control (i.e., [GA vs mannitol] was compared to [purported generic vs mannitol]). Probesets were filtered by calls of presence on the chip for the relevant samples in the comparison (to be considered present at a given timepoint, a probeset was required to have on average a call of present or marginal across the relevant samples at that timepoint). Probesets were mapped to genes using the U133 Plus 2.0 chip annotation from Affymetrix. Unless otherwise specified, all probesets called present for a gene showed the effect discussed above; where all multiple probesets were present for a gene, p values are reported for the most significant probeset.
Upregulated and downregulated genes were analyzed separately for pathway enrichment, using DAVID [Huang, D. W., Sherman, B. T. &
Lempicki, R. A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1-13 (2009)]. Pathway enrichment results were visualized using volcano plots, plotting -log p-values versus enrichment scores.
For GA MOA, to obtain top-gene lists of appropriate size (tens-hundreds) for use with DAVID, an absolute-value fold-change cutoff of 1.5 and p-value cutoff of le-3 were utilized to obtain gene lists for pathway enrichment. For comparisons between GA and Polimunol, upregulated or downregulated genes with FDR-adjusted p-values<0.05 were used for pathway enrichment. DAVID runs were conducted on Sept.
12, 2014. Please note that the GO databases are updated daily (as noted on the GO
site:www.geneontology.org/GO.downloads.ontology.shtml) and therefore performing the same enrichments on the same genesets may yield slightly varying results depending on the rundate. Pathway p-values may change slightly between runs conducted at different times; the overall picture of enriched pathways, however, is expected to remain consistent.

Genes differentially expressed between Copaxoneg and mannitol control are enriched with a variety of pathways in Kegg and GO (molecular function (MF), biological process (BP), and cellular component (CC)), many of which affect immunological responses, demonstrating Copaxone's complex mechanism of action, as shown in Figure 23.
Pathways enriched among top probesets modulated by Copaxone versus mannitol control are shown in Table 12. More than 80% of the pathways that enriched among top upregulated genes in the previous study were also enriched among top upregulated genes in the current study.
As an example at the individual gene level, IL1RN was significantly upregulated (adjusted p<2.8e-10), as shown in Figure 24, which is consistent with the previous study described in Example 1 above. This gene encodes for the protein IL-lra, which inhibits the activities of pro-inflammatory cytokines IL-la and IL-lb.
The probeset for IL10, which had been observed to be upregulated by Copaxone above in Example 1, was called absent in this experiment, but was nominally upregulated (p < 0.029). However, the IL10 receptor =ORA was significantly upregulated (for the single probeset for this gene, which was called present) (adjusted p < 2.8e-14).
Genes analyzed for pathway enrichment (Table 12), using DAVID
(conducted September 12, 2014). Performing the same enrichments on the same genesets may yield slightly varying results depending on the run date (GO databases are updated daily:
www.geneontology.org/GO.downloads.ontology.shtml).

Table 12. Human monocyte study: pathways significantly enriched among genes significantly upregulated by Copaxone relative to mannitol at 6 hours PM5','5÷5WSSligq4 .!;,.., W
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3 IR g 4 ra 4 3 uf, f2 ww, 35i wµ , Category Term Count 94 Pvalue List Total Pop Hits Pop Total Fold Bonferroni Benjamin' FOR Genes Enrichment GOTERM GO:0048519-n 74 21.51 1.50E-07 291 1214 8731 1.829 0.00032738 1.13E-05 0.00026041 201464_X_AT, 213891_5_AT, 227069_AT, 201465_5_AT, 219028_AT, 212298_AT, 2101.36_AT, 4:7 _EIP_ALL egative 2161334_AT, 201471_5 AT, 235739_AT, 2072128_5 AT, 205067 AT, 236561 AT, 797.1159_X AT, 3N41 regulation o 202284_5 AT, 201170_5 AT, 203729 AT, 22&190 AT, 216017_5_AT, 212099 AT, 201147_5 AT, f 201565_5 AT, 201590 X AT, 103753 AT, 221815 AT, 1.5523114_A_AT, 225115 AT, 222146 5 AT, 4:7 biological 203508_AT, 205312 AT, 201005_AT, 233220 AT, 210095_5_AT, 214211 AT, 160020 AT, process 212171_X_AT, 218248_5_AT, 63825 AT, 39442_AT, 205463_5_AT. 1405 I_AT, 201566 X AT, 228964 AT, 223501 AT, 223398 AT, 229830 AT, 212337 AT. 205566_AT, 218502 AT, 206135 AT, 239818 X AT, 222670 S_AT, 208436_5.AT, 206320_I _AT, 201150 5 AT, 201148_5 AT, 202768 AT, 217757_AT, 213281 AT, 210513_5_AT, 238669 AT, 203233 AT, 239451 AT, 212386 AT, 225097 AT, 219257_5_AT, 212303 AT, 217591_AT, 217279_0_AT, 37152_AT, 221841_5_AT, 224218_5_AT, 21.3763_AT, 1566901_AT, 220066 AT, 203939_AT, 202388_AT, 205891_AT, 203665_AT, 204998_5 AT, 208816_X_AT, 201149_5_AT, 239519_AT, 27.5116 AT, 201466 AT, 223502_5 AT, 225337_AT, 212143_5 AT, 204035_AT, 225368_AT, 202988 S AT, 208937_5_AT, 222651_5 AT, 224859_AT, 201012_AT, 205681_AT, 713503_X_AT, 204622_0_AT, 241722_X AT, 210427_X AT, 226218_AT.
200748_5 AT, 218559_5_AT, 222062_AT, 203940 5_AT, 200921_,S_AT, 219845 AT, 219908 AT, 210512 5 AT, 202827_5 AT, 87100 AT, 211527 X AT, 203140 At 220266_5 AT, 202243_AT, 204655_AT, 203935 AT, 210258_AT, 227697 AT, 1555759 A AT, 216302 AT, 223394_AT
GOTERM GO:01332101-7 15 4.36 1.86E-07 291 77 8731 5.845 0.00040597 1.35E-05 .
0.00032294 2051491_AT, 7.113140_AT, 212171 X AT, 21350.3_X_AT, 2.17757_AT, 205463_5_AT, 2118816_0_AT. 0 _BP_ALL egulation of 14415 J_AT, 204655_AT, 7.10513_5_AT, 210427_0_AT, 201590_,X_AT, 22911.30_AT, 1552914 A AT, NI
to response to 204035_AT, 203508_AT, 210512 AT, 1555759_A AT, 202059 X_AT, 211527_0_47, 209827_5_AT, 203939_AT, 224859 AT,233220_AT
NI
external stimulusNI
t.0 F' NI

=
UT I
CA) 1-s Category Term Count % Pvalue List Total Pop Hits Pop Total Fold Bonferroni Benjamini FDA Genes Enrichment GOTERM G031065008-r 57 16.57 1.97E-07 291 836 8731 2-046 0.00042941 1.39E-05 0.0003416 201464_1(_AT, 210495_X_AT, 223723_AT, 201465_5_AT, 371.52_AT, 210136_AT, 212298_AT, _BP_ALL egulation of 209555_5 AT, 202435_5_AT, 227948 AT, 211924_5 AT, 203074_AT, 241938_AT, 202434_S_AT, biological 206488_5 AT, 219255 AT, 20.5067_AT, 202284_5 AT, 236561_AT, 2001178_AT, 201925_5 AT, 201170,1AT, 203729_AT, 217173_5_AT, 216017_5 AT, 2175891_AT, 203665_AT, 202435_5 AT, quality 2081316_6_AT, 201565_5_AT, 235519_AT, 201590_0_AT, 201466_5 AT, 223502_5 AT, 215602_AT, 203987_5 AT, 728766_AT, 210845_5 AT, 241773 AT, 201005 AT, 201324_AT, 212469_S_AT, 219211_AT, 737257 AT, 216442_X_AT, 213503_X AT, 212171 X_AT, 39402_AT, 241722_X AT, 1405õLAT, 201566_X AT, 210427_3_AT, 214866 AT, 211719 X AT, 225218 AT, 223501 AT, 204661_AT, 202.191_5_AT, 34210_,AT, 200748_5_AT, 205099_5 AT, 204401 AT, 206815 AT, 200921_5 AT, 23594.4 AT, 20540_5 AT, 210512_5_AT, 200920_5 AT, 208436_5_AT, 211527_0 AT, 1562467 AT, 209906 AT, 1354992 AT. 203140 AT, 213281 AT, 204655 AT, 202437 5 AT, 210513_5_AT, 202068_5_AT, 1565754_X_AT, 238,669 AT, 212372 AT, 2038813 AT, 1565752 AT, 7.39451_AT, 15sssA1_A_AT, 219257_5_AT, 212803 AT, 1555759_A AT, 291929 AT, 202067_5 AT, 215688 AT, 205098_AT, 223394 AT
GOTERM GO1I005578-p 16 4.65 5.27E-07 305 100 9576 5.023 0.00014321 1.43E-05 0.00069309 1611020_AT, 210495_0_AT, 216442_X_AT, 201069_AT, 212171_X_AT, 223503 X AT, 210427_x_AT, _CC_ALL roteinaceous 211719_0 AT, 221731_X AT, 202820_S_AT, 235994 AT, 210512_5 AT, 202827_5 AT, 211527_X_AT, extracellular 204475_AT, 201150_5 AT, 201148_5_AT, 2.13428_5 204359_AT, 204620_5_AT, 229004 AT, matrix 208816 X AT, 201.149_5_AT, 210513_S_AT, 201147_5_AT, 215696 S AT, 704619_5 AT, 201590_X AT, 202756_5 AT, 22/1873_AT, 216546 5_AT, 217279_X_AT, 211571_5_AT, 212464_5_AT

ts.) co GOTERM GO:0048646-a 25 7.27 2.19E-07 291 218 8731 3.441 0.00047903 LOSE-OS
0.06038107 201464_X_AT, 160020_AT, 201465_5_AT, 229221_AT, 201069_AT, 212171_0 AT, 213503_X_AT, ax.
_11P_AU. natnmiCal 212298_AT, 214297_AT, 39402 AT, 205463 S AT, 2211341 5 AT, 217014 X
AT, 210427 X_AT, structure 201473_AT, 222877_AT, 210916_5 AT, 225030 AT, 1557905_5 AT, 20287.8_S_AT, 1566901_AT, 1,7 formation 205067 AT, 210512_5_AT, 203827_5 AT, 202859_0_AT, 211527_0 AT, 200878 AT, 204489_5_AT, 203665 AT, 204736_5 AT, 204490 S_AT, 2211266_5_AT, 213281 AT, 212099_AT, 208816_X AT, cA
involved in 210513_5 AT, 239519_AT, 209835_0 AT, 201.590_X AT, 204653_AT, 201.456_5_AT, 212372 AT, morphogenesis 204035 AT, 203935_AT, 208937_5_1ff, 217279_X_AT, 201005_AT
GOTERM GO:0048870-c 22 6.40 2,495-07 291 173 8731 3.81.5 0.00054426 L65E-05 0.00043298 202540_5_AT, 160020_AT, 27.9221_AT, 210495_X_AT, 216492_X_AT, 37152_AT, 212298_AT, _BP_ALL ell motility 216248_S_AT, 39402_AT, 204622_0 AT, 1405_1 AT, 212014_0_AT, 221731 X_AT, 211719_0_67, 2221377Ja, 210916_5_AT, 2092631 AT, 7.35739_AT, 223220_5_,AT, 1557905 S_AT, 200921_5_AT, 202828_5_AT, 205067 AT, 21721159_X AT, 2172827_5 AT, 236561_AT, 200920 AT, 203827_5,,AT, 2044139_5_AT, 204990_5_AT, 204620_5 AT, 204655 AT, 234519_AT, 204619_5_AT, 215646 s_AT, 209835 X_AT, 212372_AT, 2041135 AT, 203935 AT, 2041115_5 AT, 2013937_5_AT, 1555759 A AT, 217279 X AT, 211571_5 AT, 202539_5 AT, 212464_5_AT
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, Category Term Count % Pyalue List Total Pop Hits flop Total Fold Elonferronl 8enjamini FOR Genes tµJ
Enrichment GOTERM 60.0055082-cellular 18 5.23 0.00017635 291 189 8731 2.957 0.31957946 0.00505548 030588299 214211_AT, 201464_X_AT, 223711 AT. 201405_S_AT, 37252.1,1. 2.10136_AT, 39402 AT, 1405J_AT, _8FL/di chemical homeostasis 241938_AT, 204661_AT, 34210_AT, '205099_5_AT, 200746 AT, 815067 AT, 201925 5_AT, 1562467 AT, 209906_AT. 71E017_5_0T, 213181 AT, 834055_AT, 201456 5_AT, 219451_AT, 05"549_A
_ST
7,809_0, 1655759_A_AT, 201773,87, 203005 _AT, 205058_AT
L,J
GOTERM 500002684-posit05e 15 4.36 0.00018897 291 138 8731 3.261 0.33816687 0.00534594 0.32772523 209906_AT, 2051191_AT, 103140_AT, 212.171,_AT, 39401_AT, 110513 5 AT, 226118 AT, 2.23.501_AT, C./1 __BP_ALL regulation of immune 223500_5.AT, 1552.914_0_AT, 204923_AI, 203233_AT, 222062_61, 205067_AT, 110511_5_AT, system proems 2021.114_5_AT,217552_0_AT,22.8066_AT,213527 0_AT,214459_AT, 20192_5_5 AT
GOMM GO:0002703 -regulatio 8 2.33 0.00021596 291 38 8731 6.317 0.37607009 9.00595331 9374465u 201665_AT, 205691_AT, 2.03140_AT, 22.2062_AT, 39402_47, 205067_AT, 220066_AT, 2.28218_AT, n of leukocyte 204923 AT
mediated immunity GOTERM 60:0032496-response 9 2.62 0.00021432 291 50 8731 5.401 0.37382152 0.00598356 0.37161469 237152_AT, 201464_8_AT, 202465_s_AT, 39402_AT, 202241_AT, 2132111_AT, 1405_i_AT.
706559_AT, _13P_ALL to fipopolysaccharide 209112.9_AT, 201466_5_AT, 20382.8_AT, 211661_0_AT, 7396.18_1LAT, 2113887_s_AT, 127697 AT, 205007 AT,155.5759_A_AT, 220066 AT
KEGG_PA Is5a04640:Hematopoiet 9 2.62 0.00012756 123 41 3163 5.645 0.01343153 0.00673847 0.14304552 22.9221_AT, 204489_5_AT, 204090 5 AT, 2.09555_5_AT, 39402_4T, 2121114_6_AT, 209835_0_AI, 0 THWAY ic cell lineage 27.61111_AT, 110016 S_AT, 203104 AT,1557905_5 A7,103233 AT.2.064811_5_AT, 228766 A7.785067 AT, 55 217551 X AT, 241929 AT, 201005_AT, 201925.8_AT

1,2 M 0) 60.
GOTERM G0:0002822-regula1io 8 233 0.00025583 291 39 8731 6.155 0.42810616 0.00696069 0.44344237 203140_AT, 203233_AT, 222062_AT, 38102_AT, 146067_AT. 210066_AT, 726208_AT, 22.1501_AT, _BP_ALL n of adaptive immune 22.3502_5_AT, 204923 AT
t13 1,2 response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GOTERM 60:0051704-multi- 30 8.72 0.00026472 291. 436 8731 2.064 0.43910546 0.00711313 045881825 211454_n ST. 237252_01, 201405_5_AT, 371.52_AT, 239028_AT. 38402_AT, 14051_AT, 203473 AT, _13O_ALL organism prouss 2112788 5 AT, 202086 AT, 211661_% AT, 2.13763_AT, 2Ø38.82_AT, 22.2062_AT, 23981.8_%_AT, 1.05067_AT, 200561 AT, 208436_5 AT, 720066_AT, 209827 S AT, 834475 AT, 217173 S_AT, 214453 5 AT, 213281 AT, 202.141_AT, 204651_AT, 1552553_A AT, 209189 AT, 202058 5 AT, 111676 5 AT, 725116_AT, 229937 X AT, 201465 5 AT, 206157 AT. 203868_AT, 225115 AT, 212977 A7.203857_5 AT, 127697 A7. 215097_AT, 205495_5_4T, 12.536a AT, 1555759 A_AT, 202067_s_AT.
200438_S _AT, 213293 S_AT
GOTERM 010200113008-system 31 9.01 0.00029081 291 460 8731 2-022 0.47018397 0.00771672 0.50393593 201464_8_AT, 2.112.540_5_AT, 2111465 S_AT,37151_AT,210136_AT,202435_5_AT,241938_AT.2_11941LAT, J1 P_A11. process 228083 A7,202034_5 AT, 205067 A-7,100878 AT, 117173_5 AT, 216017 5 AT, 205891 AT, 203665 AT, 202436 S_AT, 201149 S_AT, 201147 S_AT. 201466_5 AT, 120484 AT, 201005_AT, 2.13270_AT, 202539_5_A7, 112171 % AT, 39402_AT, 204401 AT, 1552690 A AT, 206815 AT, 204684 AT, 2.35944_AT, 210511_5_0, 209017 AT, 211527_0_AT, 201150_9 AT, 1562457 AT, 2.01140_S
1554992_AT, 109906 A7,113261 AT, 202417 S_AT, 209169_AT, 110513_5 AT. 202068 5_AT, 212371 AT, 238669 AT, 1536583_A_AT, 229797 AT, 2.1.7.833_AT, 202067_S AT.215688_AT
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GOTERM G04005125-c 9 2_62 0.00055115 297 60 9375 4.735 0.27946423 0.03992449 050944965 212171..X.AT, 39402_AL 216243_3_4T, 1405_LAT, 204655_42, 210513_5_4T, 22.1SGLAL.
_MF_ALL ytokine activity 223502,7_AT, 204033AT, 212557_SJ,T, 203067,..AT, 210512_5_,ST, 1.555759.A_AT, 202459)LAT, 121463 X7,211527% AT. 7.09427AAT
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GOMM G05048146-p 5 1.45 0.00252304 291 23 8731 8.334 0.99598326 0.04155265 4.2931463 20,5463õLAT,212124_,A.T.
21.92.37_3_AT,1566301_41; 7.027.24_3_47. 223430_47 _111, ALL *skive regulation of 601E4464 G05044420-e 7 2.113 0.00313139 305 46 9576 4.778 057389694 0.04175683 4.04432272 2011411.3õAT, 214442_X_AT, 7.10495_0_AT, 213421.3,),T, 21.2.171,XAT.
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23.5444AT,21.0312,3_47, 211.373õ)LAT.203.1.30_sja. 212464_3_4T
21043_PA hsa04610:Com 6 1.74 4700122148 123 22 3163 7.013 0.12151451 0.04226609 1.36209977 137252_AT.
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r GOl'ERM G031043069-n 19 5.52 0.00267451 291 261 8731 2.184 0.99711711 0.04366649 4.5452909 219024.AT, 212171A.AT, 21.6249_S_AT. 13402..g. 204622,A.AT, 241722_X_AT, 123501At, 0, _BP ALL egative 201471_3 AT, 233739 AT, 213733 AT, 205667,..g, 736561,,AT, 202234 S AT, 210512_5.AT, r Iv regulation of 111317-A-At 203140_47, 203.345AT., 261994J.J.T. 210513_5_4T, 2.25114_47, 27.1.401_5_47, 1 204033,AL 203335_AL 22311S_AT, 2394SLAT, 2274SLAT, 225097Ja, 113257_5õ,AT, 223 ifia_At. 1-programmed 0, 301012_4T, losset_Ar cell death GOTERM 601)060548rn 19 5.52 040277099 291 262 8731 2.176 0.99766616 0.04487296 4.70554415 719411_41, 211.171)LAT, 215240_s_AT, 35402_4T, 204422_X_AT, 24172.2.A.AT.
221301_4T.
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The gene expression patterns induced by Copaxone and Polimunol treatment were compared directly. The differential expression results were filtered based on the variability in observed control treatment effects relative to previous studies, to obtain a conservative subset of highest-confidence probesets. These analyses found that 27 highest-confidence probesets, representing 21 distinct genes, differed significantly by adjusted p value in expression between the two treatments (14 probesets downregulated, 13 upregulated by Polimunol relative to Copaxone ). The upregulated and downregulated probesets are illustrated in Table 13 and Table 14, respectively.
Table 13. Human monocyte study: probesets upregulated by Polimunol relative to Copaxonee ID Gene raw.FC AveExpr P.Value adj.P.Val 202436 s at CYP1B1 1.328778115 10.99251935 2.76E-15 1.51E-10 202435 s at CYP1B1 1.291947504 11.106902761.98E-11 2.70E-07 202434 s at CYP1B1 1.34300307 8.896124188 5.54E-10 3.79E-06 229055 at GPR68 1.233303306 7.906128859 3.58E-09 1.50E-05 202437 s at CYP1B1 1.283470087 11.35502759 5.53E-09 1.96E-05 212665 at TIPARP
1.170151206 9.316307674 2.29E-07 0.000543566 1554966_a_at DOC1 1.127401263 8.443050186 5.83E-07 0.001274168 204684 at NPTX1 1.121904593 10.50026157 4.27E-06 0.00556324 229354 at 1.082379299 10.56416164 8.47E-06 0.009858651 /// AHRR
206710 s at EPB41L3 1.17828072 6.6832855063.11E-05 0.021766496 204135 at DOC1 1.093724798 8.5408048214.46E-05 0.028883673 1569690 at CCDC36 1.140648392 5.595578016 5.04E-05 0.030714439 211067 s at GAS7 1.080052886 9.66677524 5.29E-05 0.031621345 Table 14. Human monocyte study: probesets downregulated by Polimunol relative to Copaxone ID Gene raw.FC AveExpr P.Value adj.P.Val 230927 at -1.171546521 6.290190151 2.87E-06 0.004124895 206170 at ADRB2 -1.142744253 8.033661912 7.30E-06 0.008675631 228826 at RNF43 -1.090334004 8.930697832 9.19E-06 0.010052917 1554676 at PRG1 -1.337462167 7.452885159 1.08E-05 0.010571079 1557359 at -1.113608349 9.441580738 1.43E-05 0.012763184 229934 at -1.146000763 9.629181433 1.67E-05 0.013799705 244190 at THAP5 -1.235324953 3.96404755 1.70E-05 0.013885917 1556346 at COTL1 -1.23259647 9.131189047 1.97E-05 0.01563098 215111 s at TSC22D1 -1.115773148 9.642583368 2.19E-05 0.016510136 235274 at -1.142519223 7.012670757 2.86E-05 0.020344359 1558782 a at -1.13456131 8.05846686 3.69E-05 0.024635148 _ _ 201147 s at TIMP3 -1.069861862 11.50473352 5.32E-05 0.031621345 224559 at MALAT1 -1.221208621 9.943150851 7.51E-05 0.039950998 210592 s at SAT1 -1.20105501 9.927587911 8.05E-05 0.042336898 The gene with the highest fold change among those upregulated by Polimunol relative to Copaxone was CYP1B1 (adj p < 1.5e-10), a member of the cytochrome P450 superfamily of enzymes. All four present probesets for this gene in this study showed similar results, as exemplified in Table 13. As shown in Fig. 25a, CYP1B1 is significantly upregulated by Polimunol stimulation in human THP-1 monocyte cell line compared to Copaxone stimulation at 6 hours. A second example is shown in Table 13 and Fig. 25b, a probeset for GPR68 which was also upregulated by Polimunol relative to Copaxone (adj p < 1.5e-5). Two probesets for the DOC1 gene were significantly upregulated by Polimunol relative to Copaxone, as shown in Table 13.
One of the probesets downregulated by Polimunol relative to Copaxone was ADRB2, the gene encoding the beta-2 adrenergic receptor. As shown in Figure 26, ADRB2 is significantly downregulated by Polimunol stimulation in human THP-1 monocyte cell line compared to Copaxone stimulation at 6 hours.

Discussion - Example 9 Copaxone treatment was compared with treatment with the purported generic Polimunol (manufactured by Synthon), as well as a mannitol control. More than 80% of the pathways that enriched among top upregulated genes in the previous study were also enriched among top upregulated genes in the current study. The results show concordance with the earlier study and confirm the gene expression patterns associated with Copaxone treatment of human monocytes - i.e. the complex, yet consistent mode of action of Copaxone in this immunological cell type.
As an example at the individual gene level, IL1RN was significantly upregulated (adjusted p 2.8e-10), consistent with the previous study described in Example 1. This gene encodes for the protein IL-lra, which inhibits the activities of pro-inflammatory cytokines IL-la and IL-lb.
Overall, the results demonstrated that the effects of the complex biological mechanism of Copaxone observed in prior studies were mechanistically consistent with the effects observed in this study, corroborating the validity of this approach for studying glatiramoid functionality in treatment paradigms.
The study also identified significant differences between Copaxone and Synthon's Polimunol. The results show that 27 highest-confidence probesets, representing 21 distinct genes, differed significantly by adjusted p value in expression between the two treatments (14 probesets downregulated, 13 upregulated by Polimunol relative to Copaxone).
The gene with the highest fold change among those upregulated by Polimunol relative to Copaxone was CYP1B1 (adj p < 1.5e-10), a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism.
A second example is a probeset for GPR68 which was also upregulated by Polimunol relative to Copaxone (adj p < 1.5e-5). After traumatic brain injury, cerebral cortical astrocytes abundantly expressed GPR68, suggesting a role in reactive astrogliosis.

Two probesets for the DOC1 gene were significantly upregulated by Polimunol relative to Copaxone. DOC1 is also known as CDK2A21, or cyclin-dependent kinase 2 associated protein 1. DOC1 has been implicated as a locus for susceptibility to MS. (International Multiple Sclerosis Genetics Consortium (IMSGC), Genes Immun., 2010).
One of the probesets downregulated by Polimunol relative to Copaxone was ADRB2, the gene encoding the beta-2 adrenergic receptor. Agonists for this receptor have been reported to affect antigen cross-presentation by dendritic cells (Herve et al, J Immunol, 2013), alter cytokine secretion in human PBMC (Hilbert et al, Plos One, 2013), and change the proportions of myeloid cells in mouse brain under TNFa treatment (Laureys et al, J Neuroinflammation, 2014). In addition, signaling via this receptor in FOXP3+ regulatory T cells has been shown to enhance the suppressive function of these cells (Guereschi et al, Eur J Immunol, 2013). This functionality coupled with the observed expression levels of ADRB2 in Figure 26 warrants further investigation.
These initial studies show clear and significant differences between Polimunol and Copaxone in terms of impact on genomic profiling, including expression of genes with relevance for safety. Follow-on experiments are currently underway in both THP-1 cells and other model systems to further elucidate the differences identified to date.
Substantial differences between Polimunol and Copaxone were also identified using physicochemical methods and biological methods.
Therefore, the gene expression differences described here, albeit subtle in terms of fold change, may represent chronic treatment effects that could have a clinically significant impact, and warrant further investigation in the interest of keeping MS patients safe.
Example 10 Differences in gene expression induced by Polimunol versus branded GA
in mouse splenocyte gene expression studies Immunological cells, particularly T cells, are critical to the antigenic mechanism of action of Copaxone, thus post-treatment gene expression modulation needs to examine such relevant cell types, including lymphocytes.
As one approach to modeling these effects, a splenocyte system was utilized, in which mice were first immunized with either Copaxone or Polimunol, and then sacrificed, having the splenocytes stimulated ex-vivo with Copaxone , Polimunol, or medium. This model was used to simulate switching between medications compared with consistent use of one medicine or the other. A total of 157 samples were tested, and gene expression was measured using the Mouse Genome 430 2.0 Affymetrix chip.
Some similarities are observed between the genes modulated by Copaxonee in a mouse splenocyte model and in a human monocyte (THP-1) model: a prior study indicated that 1,378 genes were modulated by Copaxone in both systems, while another 6,691 were modulated only in splenocytes and another 2,121 were modulated only in THP-1 cells (MSBoston Joint ACTRIMS-ECTRIMS 2014 Meeting, P282). These findings indicate that the majority of the impact of glatiramoids is cell type and tissue specific, including different interactions with lymphocytes versus antigen presenting cells, and thus several different immunologically relevant model systems are required to study the various implications of treatment with this NBCD.
Copaxone-modulated genes Mechanism of Action(MoA) Analyzing splenocytes from mice immunized by Copaxone and later activated with Copaxonee, 16,647 probesets were significantly modulated relative to medium (8,342 upregulated and 8,305 downregulated). The fact that over one third of the total probesets expressed in this tissue (i.e. 22,524 probesets called present on the chip) are significantly downregulated, and similarly over one third significantly upregulated, by Copaxone treatment demonstrates the complexity of Copaxone's mechanism of action in this model system.
Copaxone treatment upregulated key anti-inflammatory cytokines 1110 and 114 (adj p < 2.3e-24 and 5.1e-35, respectively; Figure 27a-b) as well as markers of regulatory T cells, Foxp3 and Gpr83 (adj p < 3.4e-23 for Foxp3; adj p < 4.2e-33 and 9.0e-31 for the two Gpr83 probesets;
Figure 27c-d). Copaxone downregulated pro-inflammatory cytokines, such as 1112a (adjusted p < 8.3e-31; Figure 27e). Consistently similar effects were observed for both immunization conditions (p values given above correspond to Copaxone immunization, and are within the same order of magnitude for immunization by Polimunol).

Copaxone-modulated pathways After imposing a conservative fold change filter of IFCI 2, probesets are upregulated by Copaxone relative to medium (in Copaxone -immunized mice), and these probesets enrich for 76 pathways.
These pathways include relevant aspects of Copaxone's mechanism of action such as the cytokine-cytokine receptor interaction pathway identified previously in the THP-1 study for Copaxone mechanism of action (as well as differences observed with Polimunol). Similarly, 485 downregulated probesets are detected, which enrich for 56 pathways. Both the upregulated and downregulated pathways are depicted in Figure 28. The full list of pathways entiched among top probesets modulated by Copaxone relative to medium is provided in Table 15.

Table 15: Pathways enriched among top probesets modulated by Copaxone relative to medium in splenocytes from mice immunized with Copaxone (Pathways enriched among top upregulated probesets listed first followed by pathways enriched among top downregulated probesets).
uftwy Tenn Coed Naito Fold Enrichm Beniarrtini G01E148 ME ALL 011:1005123-cookine activity 20 424E14 9.93177158 2.11E-11 KEGG PATHWAY mmu04060:00tokirre-cytokine reoeptor interaction 29 116E-13 1.15544371 2.36E-11 GOTERM CC ALL G00005576"extracellular region 44 2.62E-13 336241762 5.65E-11 GOTERM CC_AU. G0.0005615-eitracellular space 26 2.29E-12 5.71196261 2.47E-10 GOTERM CC ALL G00044421-metracellular region part 29 5.96E-1.2 4040013694 4.29E-10 G0TE144 BP AU. GO:0006955-Immune response 34 1.04E-11 399299275 1.665-011 KEGG PATHWAY mmu041130118-5TATs2gna8n9 pathway 22 2631-10 524077519 1.672-06 GOMM BP AU- G01002.376-irronune system process 42 2.40-09 276516571 1.98E-06 GOTERM BP ALL G09016126-sterol Wray, tholi-process 10 637E09 15.1694577 3.49E-05 GOTERM CC ALL G000091197--ecterrial side of plasma membrane 17 335E-GCITERM BP AU. 010006299.iisoprenoid biosynthetic process 8 5.51E-01 04159059 2.8005 GOTER94 BP AU. 0011016129-stero1 metabolic proems 12 1.93E-GOTERM CC AU- G011009966..tell surface 19 9.95E-07 401671563 4.30E05 GOIERM SP AU. G011006698-,steroid biosynthetic process 11 1.64E-07 9.31334149 435E-05 GOTERM SP All. 000006686=chotederol biosynthetic process 8 3.93E-07 153241362 7.83E05 G0TEP11_64 ALL G00050396-response to stimulus 55 3.63E-KEGS PATHWAY mmu00900Terpericsid backbone biosynthesis 7 6.27E-06 12.8270722 0.00026558 KEGS PATHWAY mmu001003tenaid biosynthesis 7 toa-as 11.9101527 000033672 GOTER14_64 ALL G00006202stero1d metabolic process 13 2.19E06 35008331 000035349 GOIIIRM BP ALL G00001203-dtolestenal metabolic process 111 2.70-06 8.09037746 0,00035191 GOTERM SP ALL 0C1001111264-pos2tive regulation of cell proliferation 11 2.13E-06 3.99585716 0.00037779 GOTERM SP ALL G00005737-isoprenoid metabefic process 3 2.40-06 12.1355662 0.00031277 GOTERM tip AIL GO:00331311-positive regulation of peptidsli-serine phosphorylation 5 2.66E-06 344066986 0.00036457 GOTERM BP AU. G011050730-regulation of per:idyl-tyrosine phosphoryistion 9 3.40-06 9.36172249 00011657 GOTERM MF ALL 0000051112=Vvoeptor birding 24 2.03E-06 113177103 0.00092312 GOTERM BP ALL 000042323Me9ulation ofphosphorylation 19 634E-06 331130595 0.00069403 GOTERM SP AU. 0010001932 ii.ulation of protein amino acid phosphoryilation 12 1,11E-05 5.39358497 ozonant 0011164 SP ALL GO51351174uregulation of phosphorus metabolic process 19 1.22.505 335789938 0.00114199 001149469 445. G0101.9220megulation of phosphate metabolic process 19 1221-05 3.35789938 000114199 GOTERM BP ALL GCk00066100o1d biosynthetic process 16 2.07E-05 13779411 0.00173115 =UM SP ALL O0.0050731"-posithre regsilation of pepddyi-tyrosine phosphorylation 7 2011-05 11 1814145 0.00177599 GOTERM BP ALL Gaooann-legulation of cell proliferation 24 2571-05 268024775 0.00204526 GOTERM BP ALL G120001934-pasitive regulation of protein Wale acid phosphorylation 8 296E-05 8.56621202 0.00204813 GOTERM BP ALL 0000/0740-positive regulation of protein Line cascade 10 2.75E-05 6.1706261/ 0.0020109 GOTERM SP ALL G00010627-regulatito of protein kinase cascade 13 2.92E-05 4.45497247 0.00210856 GOTIPM SP All. 000033135 4,,,ulation of peptidyl-serine phosphorylation 5 148E-05 22.754180 0.00231024 GOTERM BP ALL G00042327-oositive. regulation of phosphoryiation 8 4.38E-05 80037746 0.00279017 001E14E4 69 442. GC10045937-positive regulation of pelioututte metabolic process 5.28E05 717171861 0.00323223 GOTERM BP AU. G00010562'padtive regulasiors of phosphorus metabolic process 8 5.211-435 7.1717101 0.0023223 GOMM BE An G11.0046522-ssositive regulation of cellular process 41 0.00014045 113826926 000825294 GOTERM 1P AM G010051152-defense response 18 0.0003494 10617471 0 n04461171 GOTERM SP ALL GO-000662941pid metabolic process 26 0.0009818 2.24305674 0.01041917 01711511 0P ALL 000006065-alco9rol metabolic process 11 GOTERM BP ALL G011051251positiye regulation of lymphocyte actitotion 10 00037211 443914129 0.01819122 GOTERM BP ALL 000031399'regulation of protein modification process 12 0.00036131 3.70237613 0.01839868 GOTERM SP 411 00110618219`ce6 death 24 0.00038531 214041222 0_01845504 GOTERM SP MIL 0111017609-apoptosis 23 0.00341493 22/161871 0.01925699 GOTERM BP ALL 000016265-deadt 24 0.00019622 2.2009003 00200039 001E144 1160 ALL G00002696positive regulation of leukemias activation 10 0170114578 4.33413078 002013394 GOTERM BP ALL 00110125121-programmed ce1 death 23 0.0004.6402 2.2631191 002032637 001E144_04, AVL G00002694-vegulation of Setskocyte activation 12 0.0005166 335187303 0.0203666 GOTERM BP ALL 0201150867`positive regulation of cell activation 10 00ce803242 4,23333704 0.021347943 GOTERM_BP ALL 000043110.positive regulation of MARIE cascade 6 0.00049453 8.73760766 002052261 GOTERM BP AU. 00310099471sositive regulation of signal transduction 11 000048296 3.28609402 0.0205057 GOTERM BP ALL 001460863-re5ulation of cell activation 12 0.00059269 3.49504306 0.02223545 G01E104 SP ALL 00003101-"positive regulation of pnwein modification process 8 0.0006867 5.29551979 0.02512736 GOTERM BP ALL 010010647-pasitive regulation of cell communication 11 0.0007012 170806967 0.02511163 aCITERM BP ALL 02.01151042.negative regulation of secretion 5 000616246 113770933 0.02664025 GOTERM SP AU. 011104115611-^embryonic organ desselaprnent 10 0.00080674 400073611 0.02756213 GOMM BP ALL GOOC110604-positive regulation of macromolecule metabolic process 23 000065001 2.1637056 0.028411/2 GOTERM BP AU. G0.00485111-pasinve regulation of biological process 42 0.009007 166566595 0_0288702 GOMM MF ALL 0000167139"oxiciorechartase activity, acting on paired donors, with incorporate 9 000629343 5.1901528 0.0239092 GOTERM BP ALL 01.0044255`ceitular lipid metabolic process 20 00000925 2.32630662 002906335 GOTERM MF AU. G04. 042379-thernokinereceptorizinding 5 000035759 9.32723112 0-02919116 GOTERM MF All 000004812-tranorserobrariereceptor son' ity 13 0.00042544 264547303 aannioaz GOTERM &IF AU. 00.001.9955.cyto4ine besting 9 000013429 1544109437 0.0300733 GOMM BP AIL 00.0346833etegative rep/dation of hormone secretion 4 00010187 GOTERM MF ALL 00:0006009"thernokine activity 6 0.00015529 GOTERIM BP ALL G011042130=co6clarketanernetaboeicprocess 20 000120964 2.25333013 0.0364004 GOTERB4 BP 41.1 13C10116053-organic acid biosynthetic process 10 0.00113661 GOTERM_BP ALL 000046394-corbairy6c acid biosynthetic process 10 0.00113661 1,79236443 0.03540669 GOTERM BP ALL G04051249negtilstionallyrrep4',ocytesoidation 11 0001313104 3.422552 0.0386639 KEGG_PATHWAY mms03320.Autoimmuine thyroid disease 7 000172331 s_nasseas 0.04286406 GCITERM BP ALL 004009611-nesponsetowouncfing 14 {wawa 2.77007489 0.04438422 GOTERM 13P ALL 50.0006954"in6antenatOnf response 11 000158927 3.3372927 0.04502272 GCRE1914 BP AUõ 004050364"Vegulation of B cell anaiotion 7 aocusassz 5.42227425 0,04550354 Category Tenn Count Psalm fold Enriden Beniarrini GOTERM CC All G0-0044425-1e015r35e part 167 3.13E-15 153662801 7.90E-13 GOTERM OC AU. GO:0044774-intrin5c to membrane 140 8_73E-15 GOTERM CC AU. 000311021-integral to membrane 135 3.09E-14 3.78531827 2_61E-12 GOTERM MP AIL G0-0004872-receptor activity 59 6.67E-15 GOTERM OC_ALI. GO:0016020-rnernbrane 172 3.65E-12 2.50486701 2.32E-10 GOTERM MP ALL G00004871-sig91a4 transducer activity 63 1.622-12 2.59629647 3_77E-10 GOTERM ALL 000060089-mo195ular transducer activity 63 1.62E-12 GOTERM BP ALL 00.17006955-irnmure response 40 634E-13 3.77617866 1.06E-09 GaTERm MP AU. 0000134888-transrnernis63ne receptor activity 33 3_17E-11 3.96796312 4.91E-09 Gomm BP AU. G0.00023781itsoune system process 53 7.56E-12 2.80481986 6.14E-09 GOTERMI_CC_ALL 00-0009986-ce11 surface 27 221E-10 4.47916667 1.07E-02 GOTERM CC AU. 00:0005886-pl33ina membrane 83 1.643e-09 1.91580807 6.79E-08 Gcrream OC ALL G01.3005576-extraoe4btar region 42 1.02E-08 2.66843972 3.93E-07 GOTERM MP Au. GOn040746"tarbotrtdrate binding 21 1.71E-08 4.5484065 1.99E-06 GOMM CC AU. 00.0044421-extracelkslar region part 26 1.42E-07 3.40521443 4.51E-06 KEGG PATHWAY ITHnU0464034efflatOPOletiC ce2 rineage 14 150E-07 5.976938134 2.75E-05 GOTEEM_BP_Aa 00.13009605tespanse to external stimulus 33 7_98E-08 GOTERM OC ALL G0:0009197-external side of plasma membrane 16 1848-06 4.04135338 520E-05 GOMM" BP ALL G0:13050896-response tostirmatts 77 2352-07 175912148 3.302-05 GOTERM BP ALL 000007166-cell surface receptor Raked signal transduction 43 233E-07 2.3390549 0.00010269 GOTERM EP ALL G0200096.11-response to wounding 22 9.96E-07 3_49912207 0.00026984 GOMM an All 900002682 -regulation of Marone system process 25 1.50E-06 107409502 0.00037039 GOTERM CC ALL 000005615-ettracelkiar space 19 3.75E-05 3279544 0.00044365 GOTEMA BP All G07.0002684-positive regulation of immune system process 19 4.74E-05 3.58736973 0.00096165 GOTERM BP AU. 0000485114-positive regulation of response to stinefus 17 5.63E-06 3.91741369 00010166 GOTERM BP AU. 010-0006952-defestse response 23 8.45E-06 196521518 0.00137227 GOTERM IMF ALL 00:0065529r-8ug3r binding 13 1022-05 45322231 0.00178054 GOTERM BP ALL 000050778pos18ive regulation Of immune response 14 3.562-05 43526743 0.00230833 GOTERM OC ALL 000044459-plasma membrane part 46 0_007/1625 1.79088802 0.00268093 GOTERM BP ALL 0013050776-regtiation of immune response 16 5.03E-05 3_46849003 0.00679349 GOTERIVI MP ALL 00:0005539-glyorisaniarroglycan bindrig .3 0.00012123 547497355 0.00935183 GOTERM BP ALL 00:0007155Tel! adhesion 20 0.000113998 2.74792344 0.0135546 GOTERM_BP ALL 00r0022610-biokigivii adhesion 20 0.00319998 2.74792344 00136546 GOTERM BP AU. 000007626-loosrnotory behavior 14 0.0001342 3.56274243 0.01545668 GOTERM_MP ALL G00008201-heparin Um:Eng 7 0_0002.4088 757520244 0.01587561 GOTERM MF ALL 00.0001871-p3ttern binding 8 040029954 5.99356677 0.01725253 GOTERM 0000307.47-polysacc.baride binding 8 0_00029954 5.99355677 0.01725258 GOTERM BP ALL G013006909-phagacytosis 3 0.0001.7473 99 51934.198 0.01759075 GOTERM BP ALL G0:0032501-rmiticeliular organismal process 77 0.00017032 147960251 0.01828376 GCMERM_BP ALL 000006954-inffarnmatory response 14 0.03020677 141429427 0.01957233 GOTERM 51. ALL G0:0047.330-ta31s 10 0.00977742 4.77077133 0.01992284 GOTERM BP ALL G013006935-thernotaiis 10 0.00922296 4.72022333 0.01992284 GCTIVIM CC ALL G00005578-proteinaceous extracellular matrix 9 1300971761 4.19921875 0.117c4587 GOTERM BP ALL GC1.0077126-G-protein coupled receptor protein signaling pathway 17 0_00035255 2.79500364 0.02970748 GOTERM MF AIL G0230131664-0-protrin-coupled receptor binding 7 0.00063894 6.39157706 0.03248313 GOTERM MF ALL 00:00138009-thernokine activity 6 0.00072678 7.96871945 0.03324267 GOTERM BP ALL 000008037-7611 recognition 5 040044777 877961539 0.03406274 GOTERM BP AU. G0110509001euk0cyte Mention 7 000343774 6.878c7974 01,03494g42 GOTERM MF ALL 00:0042379-chentokine receptor hinting 6 0_00290307 7.52225339 043747238 GOTERM IMF ALL 000004930'G-pro1ein coupled receptor activity 12 0.0010892 3-24651533 0.03823098 GOTERM BP ALL G00043583-7egulation of response to stimulus 19 0.000539112 2.50469508 0.03909905 GOTERM Witt/ 000060326-ce11 thernonutis 6 000057152 836153846 0.03958565 GOTERM BP All G013030595-letilexyte chernotaxis 6 0.00057152 3.36153846 0.03958565 GOTERM MF AU_ GOV, 0051W-receptor binding 21 0-00105337 2.23938465 0.04001704 GOTERM CC ALL Grroanau-extlautlfular rnatrix 9 040218595 183928571 0.04155565 GOTERM BP AU. G0:0007155-sign31 transduction 51 0.00074467 1.58750273 0.04913342 V/02016)(004250 Copaxone MoA discussion More than two thirds of the probesets expressed in the spleen were significantly modulated by Copaxone treatment, and the top modulated probesets in either direction were enriched for many relevant pathways, including immune response and cytokine-cytokine receptor interaction pathways. Key anti-inflammatory cytokines, such as 1110 and 114, and regulatory T cell markers, such as Foxp3 and Gpr83, are upregulated by Copaxone , while pro-inflammatory cytokines, such as 1112a, is downregulated by Copaxone treatment in this model system, consistent with induction of a Thl to Th2 shift. Thus, these studies help to illustrate the complexity of Copaxone's mechanism of action (impacting thousands of genes in over 100 different pathways), and provide validation of the experimental system Polimunol and Copaxone comparison: differentially expressed genes, under Copaxone immunization When splenocytes from Copaxone _ immunized mice were activated with Polimunol and compared to activation by Copaxone (as reported in the prior section), controlling for mannitol control, 223 probesets were found to be differentially expressed (208 were upregulated, 15 were downregulated). The top 25 upregulated probesets by Polimunol versus Copaxone are reported in Table 16, and include many interferon-induced genes as will be further discussed in the pathway enrichment section below. The 15 downregulated probesets by Polimunol versus Copaxone are reported in Table 17.
Polimunol and Copaxone comparison: differentially expressed genes, under Polimunol immunization When splenocytes from Polimunol-immunized mice were activated with Copaxone versus Polimunol, 431 probesets were found to be differentially expressed when both were corrected for medium (301 were upregulated, 130 were downregulated). The top 25 upregulated probesets by Polimunol versus Copaxone are reported in Table 18 and consistently with the reciprocal study design (prior paragraph) include many interferon induced genes, and the top 25 downregulated probesets by Polimunol versus Copaxone are reported in Table 19.
Table 16: Top 25 probesets upregulated by Polimunol versus Copaxone in splenocytes from Copaxone -immunized mice 3111111111111111111,-L-4 ' i 142155t V Ili 777 ifi 'cl ib7-77-7777-71ii4i7-7, 67.6iL15?' 1 3.62g-- :i 1451905 a_at Mxl 1.75 2.21E714 4.98E-10 114217998 at ; Tpr3 a. 11.19 li33B-14 1.140E--.09 _ If1202b ///
1457666_s at L0C100044068 1.49 1.25E-13 1.41E-09 142029214, , Oas11 1.46 12-05ge,13 _ 149E-09 1418293 at Ifit2 1.38 2.24E-13 1.69E-09 1423-555' ai 1.1fi44 ' 1,62 , 2.85E-13 .1...k14g,. .-99. _ 1425917,rat , 1fi441 ., _ 1.63 4.06E-12 2.29E-08 14.15*-90,-4 at , It1441. ;1,65 j 1.40Fell 1 i 7t03.7.-0-g:"-1456164.,_at_ AW011738 , 1.20 2.32E-11 9.03E-08 11,1-0.1.4.54 at . Air3it. _ j las_ 1240E 11J 9,0E70 1449455 at Hck 1.16 4.06E-11 1.33E-07 G.t1634-0 /// reilth //1,1 14487:75_at_ ;i_,gcno$02473 1121 J 4-.10E41 1-33E-07 1438868 at Phfl ld _ 1.25 4.42E-11 1.33E-07 14284V V-at 1 Tg1,3 a : 1,25 j5.25*õ."41. i 11.41E707 1434401 at Zcchc2 1.16 5.31E-11 1.41E-07 14181-iti _ 11,4_--11/1, _ : 139 1.1,10E-10 ' 2.71E-07 1450027 at Sdc3 1.25 1.14E-10 2.71E-07 1435pt itt__ .iliy_hinl .1 L19.: ,_ _ 212E-10 i 4,79E-07 1436120_at Setdb2 1.16 2.43E-10 5.21E-07 1451.* 4 4.t, IIIPPA 1. i2 - !I00E:4 Q. 104E-07 1424921 at Bst2 1.23 3.99E-10 7:83E-07 _ õ ... .
141940 at J .. 1M04 1.44 5.104.9. , ' ''.t.70.--C,17 1438037 at Herc6 1.27 6.06E-10 1.09E-06 1419026! at , gaxx 1.21,. 0,74Z-1Q. r'.11,4:--(10-.
Table 17: 15 probesets downregulated by Polimunol versus Copaxonee in splenocytes from Copaxonee -immunized mice 111111111111. ' , .
1454757_s_at !1f12711 i -1.15 1,92E-08 I .57g,05 1415837 at Klk 1 -1.41 4.55E-08 3.16E-05 1452956_a _at 11112711 -1,14 j1.80E-07, _19.56E-05 i 1448107 x at Klkl -1.34 2.21E-07 0.000114521 1439771 s_at . - D13ERTD608E__ 4.25_ J2,71E-Q7 0,00013591 _ 1415823_at Scd2 -1.35 3.68E-06 0.001275671 ,4 1442544_14 _ õI Ighra _ _ -1.17 .,, 5.89E-06, .,.. _J0.00191673_8_ 1415824 at , Scd2 -1.31 2.36E-05 0.006376176 -1=-..............-1415822 ' I Scd2 1-1.28 43E-05 0,008489827 1429100_at Ccdc711 -1.08 3.68E-05 0.008965532 l427J Ighm -117 _ A 0.1E-P5I -A Q_t.010,874062. _ 1449325_at Fads2 -1.16 0.000104782 0.022291363 1-',1' ;""4",-"0 'rn 1416188 at I Gm2a 1 -1,Q8 i 0,09,919982.4 .10t02,3255296 1424567_at Tspart2 -1.13 0.00016899 0.033873925 14A6,13,1At 1,Sigaec1, _ : -1.12 19.09.02163.91:
,,_, , Q44241044 . A
Table 18: Top 25 probesets upregulated by Polimunol versus Copaxone in splenocytes from Polimunol -immunized mice 1434441_at_ ZICchc2 , 1.17 1,7_4E714 , 1..96E0 _ _ ' 1417932Tat 1118 1.26 8.67E-14, 1.96E-09 14:57i/35 at ,i AN-1)7873 11147.' i 14E42 1421551_s_at Ifi202b 1.43 1:86E712 2.10E-08 14 W599 s_at A Ms4a6d ; 1.38 1548E-12 5.04E-08 ' 1456164_at AW011738 1.21 1.21E-11 9.11E-08 1 If12021) ///

1457666 s_at , L9C100044068 11,44 '5.09E-11 2.73E-07 1449591_at Casp4 1.11 6.06E-11 2.73E-07 1440865. at ;Ifitm6 ; 1,23 : 7.78E4 t j 3.19E-07 1438004_at Papd7 1.19 9.92E-11 3.44E-07 1426721__at _i Tiparp i1.12 - ]1800 5.815_797 1426716_at Tdrd7, 1.21 2.85E-10 8.56E-07 1419598 at Ils'n.4a¾a i 133 _ I 799.--10' 12:17i-0-6 1420796 at Ahrr 1.47 1.38E-09 3.45E-06 143.60 Lat jlta.d2 , 1.5. 11.6E-09_ 1:46747.00,.-_, 1421008,at , Rsad2 1.40 _ 2.22E-09 _ 4.77E-06 _ 14_2I'Vi.9-4 It-s-4047 ' -153 I 2.,_04709 ' '150;7i_4"i.
1418293_at Ifit2 1.42 2.58E-09 5.07E-06 , 1427192 ' at I S_IfrO : 142 12.8-6E:09 1 i:3- 0,46 1453939_x_at Gm9706 1.28 3.33E-09 6.02E-06 142,7/47 a at L,cn2,, i 1,";21.-__ 13.$4E:097 16,14E-06-1447851_x_at AtplOa 1.16 4.58E709 ,. 7.37E-06 1450322_8_at _ _j Slfn3 /1/ Slfri4 , 11..38 _,15:2-00 ._ 1 8.17Z-1)6_ 1438148_at. . Cxcl3 , 1.68 6.34E-09 9.54E706 1-4199,5_4 41, _ ,'; ,--1Nbc- 1 . 1179 :1 11 1..Q.;08 1144-05_ 1 Table 19: Top 25 probesets downregulated by Polimunol versus Copaxone in splenocytes from Polimunol-immunized mice . , 716cci71f I, -64- :3.576E:11 :r 27.11E-6-1451461a.,at Aldoc_ -1.60 3.75E-11 2.11E-07 1454757.j at I112711 -1745 19.'61E77711 344E-07 1442544 at Ighm_ -1.29 8:19E-10 2.17E-06 145295 a at 12:70. -113 . 1..48.-69.
1417679 at Gfi 1 -1.23 4.10E-09 6.85E-06 1417864 at Pgkl -119 866E-09 16E-O5 1429100_at Ccdc711 -1.12 1.45E-08 1.99E-05 1435686 s at 'Kowa. - 43E 08 di433-5 1451385 at Fam162a -1.17 1.15E-07 0.000102062 1417034_2g_ ITtaPPO4 -148 11.33E-07 0,009.111102 1435659_a_at Tpi1 -1.37 1.69E-07 0.000128996 14157797,07577at _ CEtSP -1,13 j2.32E-q7 _ 0.000164 67 _ 1450081_x_at ,Gpil -1.13 3.06E-07 0.000206058 4,9 , 1437481 4- X at Gpil -1.11 l4447 0.0013287936 1418709at Cox7a1 -1.31 4.64E-07 0.000298801 147772_1a a'rhpr 1-123 14,84E1:07 0.%10307264 1439435_x_at Pgkl -1.16 5.64E-07 0.000334169 143440_x_at iPgit -65 1744470 10-:96640 1417308_at Pkm -1.14 1.00E-06 0.000518315 141.'5911'4 41 'TP1.1 l.3j /..013g^g6õ 41,-6455'366-1424714_at Aldoc -1.32 1:23E-06 _ 0.000599143 _ 1418649_at 'Eght3, 1Q,00_06i6123 1452927 x_at Tpil -1.29 1.34E-06 0.000631391 145775787 ...,11cPCL5 = 4.14 11,86E-06 0.0007_89W
It is important to note that for either immunization (Copaxone or Polimunol) , 1118 and its receptor Ill8rl are downregulated (and inhibitor Ill8bp is upregulated) by both of the activation treatments, Copaxone and Polimunol. 1118 is downregulated significantly less by Polimunol than by Copaxone (differential expression FDR p < 9e-6 (FC
1.20) with Copaxone immunization and FDR p < 2e-9 (FC 1.2 6 ) for Polimunol immunization) . Downregulation of both 1118 and Marl expression upon Copaxone treatment was also reported in an earlier splenocyte study of similar design (Bakshi et al, 2 0 1 3) . Boxplots of 1118 expression are shown in Figure 29.
The probesets significantly entiched among top probesets modulated by Copaxone relative to medium is provided in Table 20.

Table 20: Top probesets significantly differentially expressed between Polimunol and Copaxoneg treatment (corrected for medium control) in splenocytes from Copaxoneg-immunized mice.
Probeset Gene raw.FC AveExpr t P. Value adj.P.Val B
1421551 s_a 1f1202b 1.47550912 9.16666894 10.5600946 6.69E-15 3.02E-10 22.5317107 1451905 a_z Mx1 1.75432592 8.47709648 10.2249021 2.21E-14 4.98E-10 21.4748998 1421998 at Tor3a 1.2928856 9.17160227 9.82507613 9_33E-14 1.40E-09 20.1932231 1457666_s_a 16202b /hr LC 149450011 8.60997589 9.74469879 1.25E-13 141E-09 19.9328881 1424339 at Dash 1_46319835 9.8248556 9_60829293 2.05E-13 1.69E-09 19.489091 1418293_at Ifit2 138359824 10.906172 9.5837092 2.248-13 169E-09 19.4088447 1423555 a i1644 1.62258196 9.94187992 9.51838876 2.85E-13 1.84E-09 19.1952407 1425917 at 16441 1.6309207 8.85125178 8.79871072 4.06E-12 229E-08 16.8068255 1421596_s_a16441 1.62779642 8.55050842 8.4667453 1.40E-11 7.03E-08 15.6855236 1456164_at AW011738 119734234 6.98570845 8.33256611 2.32E-11 9.03E-08 15.2292395 1450454 at Tor3a 1.25024933 8.74969803 8.32329605 2.40E-11 9.03E-08 15.1976556 , 1449455_at lick 1.1582816 10.9515022 3.13380999 4.06E-11 1.33E-07 14.7215139 1448775 at Gm163401/j 1.20618615 11.6014591 8.1770987 4.16E-11 1.33E-07 14.6985633 143886E1 at PhIlld 1.2483759 10.329053 8.16092351 4.42E-11 1.33E-07 14.6432337 1428660 s_aTor3a 1.248966 10.5033156 8.11568562 5.25E-11 1.41E-07 14.488379 1434401 at Zcchc2 1.15603797 10.8249905 8.1125305 5.31E-11 141E-07 14.4775726 1418191 at Usp18 1.38861948 11.5218281 7.91969756 1.10E-10 2.718-07 13.8156858 1450027 at Sdc3 1.25031078 10.4588938 7.9099888 1.148-10 2_71E-07 13.7822905 1435331_at Pyhin1 1.19292098 12.437413 7.74536994 2.12E-10 4_79E-07 13.2151145 1436120_at Setdb2 1.15959289 10.4269299 7.71019806 2.43E-10 5.21E-07 13.0937189 1451330_a_lInpp5b 1.12122817 10.7773832 7.65452165 3.00E-10 6.14E-07 12.90141 1424921_at Bst2 1.22915197 11.6875461 7.57865435 3.99E-10 7.83E-07 12.6390995 1419603 at 16204 1.43740773 7.15143963 7.51082104 5.16E-10 9.70E-07 12_4043263 1438037_at Herc6 1.27135334 10.4464057 7.46845772 6.06E-10 1.09606 122576026 1419026 at Daxx 1.20586588 12_032791 7.44071108 6.74E-10 1.17E-06 12.1614627 1451567 a EGm16340 hri 1.14843448 12_2623403 7.42376782 7_18E-10 1.20E-06 12.1027407 1426716 at Tdrd7 1.17546145 9.81553185 7.38758714 8.24E-10 1.33E-06 119773091 1426774 at Parp12 1.23323427 10_568.185 7.32082974 106E-09 1.606-06 117457533 1426276_at Ifihl 1.25213306 10.3259786 7.3202472 1.06E-09 1.608-06 11.7437321 1435665_at Trirn30d 1_25197418 9.71194292 7.26872528 1.29E-09 188E-06 11.5649255 1431591_s _a Gm9706/1/ I 1.32351255 11_382458 7.17864536 1.82E-09 2.56E-06 11.2521346 1435330 at Pyhinl 1.20956064 9.18347439 7.12657207 2.22E-09 3.03E-06 11_0712364 1438716 at Trim30d 1.23305159 7.93829998 7.11825503 2.29E-09 3.03E-06 11.0423392 1421008 at Rsad2 1.40087837 7.80703835 7.0280384 3.22E-09 4.15E-06 10.7288224 1421571_4 _z Ly6c1 //,/ Ly6 1.12684658 13_613752 6.99594752 3.64E-09 4.56E-06 10.6172805 1435792_at Csprsf//Gm 1.187456 9_75936346 6.97563188 3.93E-09 4.76E-06 10.5466635 1423754 at Ifitrn3 1.19002363 12.4964655 6.96462013 4.10E-09 4_76E-06 10.5083857 1457035_at A1607873 1.33928347 5.46136565 6.96314834 4.12E-09 4.76E-06 10.5032697 1453939_x_EGm9706 1.28772667 8_70376747 6.95300697 4.28E-09 4.83E-06 10.468017 1420671_x_a Isils4a4c 1.11351765 13.1959702 6.9122537 5.00E-09 5.50E-06 10.326351 1426721 s_aTiparp 1.12038515 10.8883102 6.87404388 5.77E-09 6.20E-06 10.1935268 1427059__at Tmern1846 1.19049436 9.2053589 6.80169576 7.60E-09 7.97E-06 9.94204892 1453196_a_z OasI2 1.34151303 10.6174821 6.77476842 8.41E-09 8.62E-06 9.84846205 1452231_x ENIndal 120215669 12.1489677 635397715 9_10E-09 9_12E-06 9.77620711 1417932_at 1118 1.2024199 8.58526778 6.73898284 9.63E-09 9.44E-06 9.72410174 1420796_at Ahrr 135482305 6.39700067 6.68881415 1.16E-08 1.12E-05 9.54979119 1426906_at Mndal 122985583 12_0834069 6.68154198 120E-08 1.12E-05 952452794 1417244_a ;2167 129690765 11.8707637 6.66482592 1.28E-08 1.17E-05 9.46646104 1456494 a_arim30a /1/1 124228874 10.5953269 166073405 129E-08 117E-05 9.45224793 1445897 s a tf135 1.09502194 13.2112571 6.64901185 1.35E-08 1.20E-05 9.41153295 1418115_5 a Tor1a1p2 1_09066644 11.3826254 6.63787659 1.41E-08 1.22E-05 9.37285954 1426670_at Agrn 1.16650332 8_38464727 6.61334752 1_55E-08 1.32E-05 928767938 1450783_at IfIti 1.31370421 11.6154892 6.57611523 1.78E-08 1.49E-05 9.15841659 1436058_at Rsad2 144054736 10.0892795 632152657 2..19E-08 1_76E-05 8.96897228 1460603_at Samd9I 1.09852241 13.0008563 6.48452217 2.52E-08 1.99E-05 8.84061078 1450484_a_a Crnpk2 1.4069656 9.18452824 6.47037709 2_66E-08 2.06E-05 8.79155778 1452349_x_2 if1205/1/Mn /20045125 732773058 6_46703491 239E-08 2_06E-05 1435529_at Gm14446 1.28471375 11.9844626 6.46256796 2.74E-08 2.06E-05 8.76448031 1455581_x 8Gm20559 113805761 11.6732978 6_44922028 238E-08 2_09E-05 8.71820419 1451860_a_4Trim30a 1.18244967 122537452 6.36625749 3.94E-08 2.82E-05 8.43075121 1436562_at Ddx58 1.14667035 11.473735 6.36165042 4.00E-08 2.82E-05 8.41479807 1448380_at Lgals3bp 1.16298116 112244145 630367575 4.98E-08 3_40E-05 821414149 1449025 at Ifit3 1.3414478 11.8181697 630015076 5.056-08 3_40E-05 8.20194708 1452087 at Epstil 1.11549904 11.2912312 6_24845347 113E-08 4.01E-05 8_02318829 1421009_at Rsad2 1.51117184 7.74253963 6.2035856 7.26E-08 4.64E-05 7.86817911 1443698 at )(af1 1.18282113 119302802 6_20178329 7.30E-08 4.646-05 7.86195528 1442130 at Hsh2d 1_1709592 10.2697537 6_16886582 8.27E-08 5_18E-05 7.7483219 1459151 x Elf135 1.10594094 11.6543585 6_131E15928 9.50E-08 5.87E-05 7.62066485 1436172_at Gm20559 1.1493816 113396111 6_07854249 1_16E-07 7.05E-05 7.43692632 1448575_at 117r 1.09825437 11.0940999 6.07547051 1.17E-07 7.05E-05 7.4263466 1452160 at Tiparp 1_11979242 9.76721315 106904538 1.206-07 7_136-05 7_40422136 1451050 at Nt5c3 116150561 10.6183063 6.05166841 128E-07 7.51E-05 7.34439991 1431095_3 a Herc6 1.19901119 10.4733187 6_04385458 1.32E-07 7.63E-05 7.31750846 142.3681_at Ftsjd2 /// Rrr 1.09083446 10.9815969 6.03834145 1.35E-07 7.686-05 7.3002584 1449143_at Rtp4 124304662 7.42935297 6.02.268936 1.43E-07 8.05E-05 7.24469409 1437636_at Pydc4 1.33382761 8.19945237 6_01217359 1.49E-07 827E-05 7.20853136 1450495_a_8 KIrkl 1_14444626 9.11777277 199801423 1_57E-07 8_59E-05 7.15985406 1450276_a aScin 1.26600893 8.7352575 5.99419456 159E-07 839E-05 7.14672584 1427091_at znfx1 1.16622599 9.5503153 5.99232677 1.60E-07 8.59E-05 7.1403067 1432026 a_a Herc6 1.2332518 9.6340896 5.91285077 2_15E-07 0.00011289 6.86746993 1451777 at Ddx60 1.2572541 9.17655647 5.89999373 2.26E-07 0.00011573 6.82339016 1451655_at Slfn8 1_16818125 11.8030813 5.85259478 2.69E-07 0.00013591 6_6610318 1423071_x a6720475.119F 1.12577119 8.9545691 5.84322799 2.79E-07 0.00013788 6.62897522 1450241_a_8 Evi2a 111124373 11.3075457 5.84097845 2_81E-07 0.00013788 6.62127789 1421217 a_a Egals9 1.11289495 12.0356748 5.83616937 2.86E-07 0.00013886 6.60482433 1424775_at Oasla 1_26381284 10.9682776 5_82921661 2.94E-07 0.00014098 6.58104095 1447851_x_8 Atp10a 1.13412363 9.35/t/039 5.81806601 3_06E-07 0_0001454 6.54290906 1451426 at Dhx58 1.27494236 10.5332943 539964551 3.28E-07 0.00015407 6.47994653 1452013_at AtplOa 1.16582075 7_25191599 534981475 3.95E-07 0.00018343 6.30981665 1438004_at Papd7 1.15866963 8.7651013 532747713 4.29E-07 0.00019722 6.23364804 1453757 at Herc6 1.25111898 9.09811412 5.64424695 5.83E-07 0.00026558 5.95039163 1456890 at Ddx58 1/0405595 8.33433728 163983971 5.93E-07 0.00026723 5_93541754 1416697_4 Dpp4 1.1097733 9.72105276 5.63576616 6.01E-07 0.00026859 5.92157948 1422006_at Eif2ak2 1.23465729 9.21616067 5_61858421 6.41E-07 0.00028336 5.86323608 1424617_at fi35 1.10413772 12_2660487 5_60315363 6.78E-07 0.00029704- 5.8108739 1426278_at 1112712a 1.13356673 13.6135311 5.55624326 8.06E-07 0.00034964 5.65189199 1452676_a _a L0C1005051 1.11295467 9.74168879 533659908 8.67E-07 0.00037225 5.58541026 1451852_at Tcsty3 1.22404052 6.8712238 552210287 9.14E-07 0.00038891 5.53638704 1449366_at Mmp8 1.22832664 9.31371883 550428037 9.76E-07 0.00041133 5_47615784 1425405_a Adar 1.10728732 11.4786191 5A8996899 1.03E-06 0.0004295 5_42782879 1429570 at Mild 1.20072042 8.28523783 5.48602776 1.04E-06 0.00043175 5.4145249 1456288 at 51fn5 1.32340243 939871024 5.47997663 1.07E-06 0.00043564 5.3941035 1417961_a_eTrim30a 1.17912824 12.8108758 5.47899844 1.07E-06 0.00043504 5.39080284 14.14105_at Pydc4 132066484 5_20069324 5_43876125 1.24E-06 0.0004952 5.25516142 1435454_a_a Hellz2 1.13249361 17 5204465 5_43239671 127E-06 0.00050243 5/3372972 1430530 s a Nrnrall 1.17435967 9.31355989 5.37375224 1.57E-06 0.00061706 5.03656379 1438148 at Cxd3 1.69044193 7.09902456 5_35135811 1.71E-06 0.00065812 496142512 1422141_s_a Csprs /1/ Gm 1.19436756 7.71681771 5.33738357 1.80E-06 0.00068662 4.91458012 1418116_at Torlaip2 1.08075944 103447031 5_32686698 1.87E-06 0.00070743 4.87934914 1425065_at Oas2 1.28607157 10.4532534 5.32376691 1.89E-06 0.0007095 4.86896748 1436778 at Cybb 1.1006634 12.2766584 5.29025539 2_13E-06 0.00079482 4.75685109 1428346 at Trafdl 1.15659445 11.2650229 128308824 2_19E-06 0.0008091 4.73289875 1440522_at Chic1 1_11707615 8.8938542 5_26963652 2.30E-06 0.00084269 4.68796879 1418580_4 Rtp4 1.16283443 12_43898 5.25438045 2.43E-06 0.00086346 4_637052.34 1425374 at Oas3 1.32020993 10.3330288 5.23952375 2.56E-06 0.00092489 4.58751022 1435840 x_a 80147527 1.21647215 7.14546794 5.20034393 2.95E-06 0.00104904. 4.45705855 1459913_4 Tnfsf10 1_10617704 8.60982005 5_19467099 3_02E-06 0.00106241 4_43819454 1418346_at ins% 1.1375775 8.67983728 5_17515611 3.24E-06 0.00113118 4.3733569 1440299_at Mb21d1 1.08850433 8.80638297 5.10764055 4.13E-06 0.0014208 4_14959418 1452306 at Zfyye26 1.08114798 10.6819271 5.09739051 4.28E-06 0.00146298 4.11570542 1425008 a iGm16340M 1.14711446 8.2805057 5.07062975 4.71E-06 0.00159849 4.02733237 1426971_at Uha7 1_0921264 115979875 5_05902098 4.91E-06 0.00165404 3_98904342 1427102_at 511-n4 1.4307997 10.9094731 5.02506971 5.55E-06 0.00184054 3.87722913 1447272_s_a AtplOa 1.16573994 8_48146745 5_00861675 5.89E-06 0.00191674 3.82313389 1452161_at Tiparp 1.12341519 9.30889526 5.00763194 5.91E-06 0.00191674 3.81989785 1419668 at Sgcb 111311815 8.08482712 4_99202128 6.25E-06 0.00201223 3.7686309 1452973_at Ppmlk 1.06538857 10_5472337 4_97566869 6.62E-06 0.00211808 3_71498595 1440866_at Eif2ak2 1.27644426 8.72230965 4.96189632 6.96E-06 0.00220906 3.66985249 1425225_at Fcgr4 1.15148701 7_97090773 4_94964494 7.27E-06 0.00229151 162973994 1428843_4 5-Mar 1.06276216 11.9004332 4.89939887 8.69E-06 0.00270208 3.46559327 1455500_4 Rnf213 1.18104388 12_9664015 4.8925931 8.90E-06 0.00273916 3_44340567 1450322_5 a Slfri3 Sfin 1.32138137 734711588 4.8916997 833E-06 0.00273916 3.4404939 1419569_a_2 rsg20 1.21173809 11.9296506 426452698 9.83E-06 0.00299161 3.35202465 1451161 Emrl 1.18065879 9.48930222 4.86302162 9.88E-06 0.00299161 3.3471287 1452348_s_alf1204 /// If12 1.22015123 10.6929234 4.85654465 1.01E-05 0.00304061 3.32606974 1451564_at Parp14 1.13986145 12.0654567 4.85172709 133E-05 0.00307242 3.31041282 1418244 at Naa20 1.08893101 11_1644701 4.76808963 138E-05 0.00407322 3.03951865 1436899 at Zufsp 1.09784747 111470022 4.74873354 1.48E-05 0.00433173 2.97708107 1419599 s_a N154a6d 1.33981893 8.57140996 4.74664377 1.49E-05 0.0043355 2.97034589 1443621_at Xafl. 1.16509294 7.24967566 4_74194912 151E-05 0.00437932 2.95521955 1436472_at SlfrI9 1.11910501 8.38309804 4.73923193 1.53E-05 0.00439313 2.94646731 1453562_a_z Nmrall 1.15341413 9_19098832 4.73002801 1.58E-05 0.00450863 2.91683543 1454809 at Ncoa7 1.09311088 10.3983869 47257237 1.60E-05 0.00454843 2.90298546 1436779 at Cvbb 1.0941996 11.6457179 4.7126236 1.68E-05 0.00473241 2.86086374 1426970_a_8 Llba7 1.07523655 12.3984639 438910631 1823-05 0_00510655 2.78536262 1434139 at Parpll 1.09338753 10.840668 4.6805127 1.88E-05 0.00522983 2.75781068 1452178_at Parp10 //./ PI 1.10641059 11.7358548 4_66046456 2.01E-05 0.00552329 2.6936131 1417516 at Ddit3 1.07723921 9.94848573 4.66039944 2.02E-05 0.00552329 2.69340478 1459973_x_ Dpja4 1.14507385 7.63353457 4.65962457 2.02E-05 0.00552329 2.69092573 1422140 at Gm7609 116864971 839169472 4_63609019 2_19E-05 0.00595944 231571222 1417685_at Ankfyi 1.06791545 11.0934338 4.61168057 2.39E-05 0.00E40602 2.53850302 1423627 at Nciol 1_16457475 6_67427154 4.59518149 2_53E-05 0.00674846 2_48534355 1451755_a_a Apobecl 1.07861266 9.62528811 4.56307937 2.83E-05 0.00749855 2.38337634 1430700 a_a P1a2g7 1.18443125 10,1013856 4_56135068 234E-05 0.00749945 2_37789398 1438948_x Cfspo 1.10391642 113941786 4.5571403 239E-05 0.0075653 236454478 -1450291_s _a Ms4a4c 1.12154489 12_4861899 4.55455972 231E-05 0.00758904 2.35636554 1419879 s_a Trim25 1.09549971 12.1244381 4.5525076 2.93E-05 0.00759918 2.34986266 1428615_at t.par6 1_07528364 9.93379264 434743285 2.98E-05 0.00768686 2.33378681 1416695 at Tspo 1.0780893 124808237 434588597 3.00E-05 0.00768686 2.32888813 1424857_a Trim34a 1_11791554 10.7165118 433973664 3_06E-05 0.00780763 2_30947175 1446457_at 0dx58 1.16007779 8_02122625 433347715 3.13E-05 0.00793348 228961716 1442640 at - 1_2168656 9.07831829 4.51929521 3.29E-05 0.00828496 2.24479093 1449078_at St3gaI6 1.09165835 10.7727541 4.51684697 3.32E-05 0.0083088 2.23705863 1449591_at Casp4 110948228 11.1338558 4.50971919 140E-05 0_00846848 2_2145572 1418030 at Slco3a1 108661497 934424904 449526041 337E-05 0.00880366 2_16895999 1416871_at Adam8 1.1193914 9.62857594 4.48900903 3.65E-05 0.00894624 2.14926531 1454668 at Ubr4 112814814 11_184894 4.48414411 3.71E-05 0.0089994 2.1339469 1442201_at 1.1432126 9.81756401 4_47986246 3.77E-05 0.00908403 2.12047102 1436032 at - 121380001 11_1380493 4.47297003 3.86E-05 0.00925232 2.09878995 1454169_a_a Epstil 1.12897335 10_1539562 445618995 4.09E-05 0.00974916 2,04606725 1434601_at Amigo2 113289174 9.38089015 4.42595648 433E-05 0.01075628 1.95129594 1448576 at 117r 1.10438001 935743301 4.3992231 4.96E-05 0.01166251 1.86773693 1421550_a_8Thm34a LI/ 1 1.12211108 9.72957463 4.39764723 4.99E-05 0.01166465 1.86281845 1415713_a_a Ddx24 1.06449185 11_5232541 4.37956906 5.31E-05 0.01234241 180645151 1419667_at Sgcb 1.12646472 8.33509646 434873052 5.90E-05 0.01363746 1_71054358 1455227 at Ncehl 1.08446292 9.91489676 4.34099563 6.05E-05 0.01392902 1.68653707 1418612_at Wig 1.09272571 12.96439 4.32568503 6.38E-05 0.01459714 1.63907653 1452318_a_a Hspalb 1.19057538 7.25960902 4_30400323 6.86E-05 0.01562991 1.57200028 1427127_x_z Hspalb 1.21832745 7.30468517 4.29624366 704E-05 0.01588217 1.54803323 1419598 at Ms4a6d 1.30010562 8.68960331 4.29561853 7.06E-05 0.01588217 1.54610327 1448303_at Gpnmb 1.22944041 8.9049785 4.29482104 7.086-05 0.01588217 1.54364139 1435660 at L00664787 1.08388982 8.74033836 4.29173015 7.15E-05 0.01596949 1.5341017 1422511_a_z Ogfr 1.07234468 /2.3938197 4.24109747 8.48E-05 0.01875548 137829561 1437176_at NIrc5 1.07682641 12.3735454 4.23387901 839E-05 0.01912232 1.35615536 1436633_at Gm11772 1.14601474 4.72784952 4_22090965 9.08E-05 0.01980988 1.316422 1451082_at Ftsjd2/1/Rn= 1.06640728 113628274 4.2204656 9.09E-05 0.01980988 1.31506267 1425974_a_z Trim25 1.08480215 11.7657133 4.20895728 9.45E-05 0.02049028 1.27985683 1417876_at Fcgrl 1.2323332 7.0806629 4.19894373 9.77E-05 0.0210878 1.24926191 1457069_at Asec3 1.11288948 9.43740297 4_19582127 9.876-05 0.02120788 123972903 1429831 at Pik3ap1 1.06680759 12.4737143 4.1806008 0.0001039 0.0222095 1.19331067 1449538 a iGcntl 1.11915617 8.47448492 4.14722631 000011614 0.02447684 109181994 1422005_at Eif2ak2 1.19563857 9.53538322 4.12771094 0_00012393 0.02599698 1.03266263 1449875_s_a H2-T10///H 1.04842787 12.8867189 4.11331035 0.00013 0.02714397 0.98909995 1418722 at Ngp 1.11092189 12.7881149 4.10510418 0_00013359 0.02776429 0_96431022 1426133_a_a Mitdl 1_10636222 10.1667831 4.07764709 0.00014629 0.03009875 0.88154944 1424354 at Tmem140 1.11754478 9.34810202 4_07577197 0.0001472 0.03009875 0.87590785 1423052_at A,-f4 1.05369833 12.3484921 4_06902312 0.00015052 0.03046771 0.85561388 1456251 x iTspo 1.1023499 11.1159008 4.06877418 0.00015065 0.03046771 0.85486562 1423986 a z Shisa5 1.04210813 14.2786011 4.03888346 0.00016625 0.03347242 0_76519512 1428378 at Zt3hav1 1.08752006 10.7288018 4.02875397 0.00017188 0.0343001 0_73488508 1420401_a_z Ramp3 1.12512462 9.98404572 4_00377593 0.00018656 0.0370668 0.66031463 1460657_at Wntl0a 1.12684061 835987776 3_98317991 0.00019958 0.03947847 0.5990/024 1424444 a z1600014C101 1.09898446 11.5959589 3.98018984 0.00020154 0,03969221 0_59012418 1428494 at Asb2 1.13292232 8.24932226 3.95719355 0.00021725 0.04241625 0.52190117 1439814 at Atp8b4 1.11510444 9.33960673 3.95146957 0.00022134 0.04302868 0_50195269 1429588_at 2810474019 1.05637397 11.2428969 3_93455457 0.00023387 0.04526887 0.4549451 1433617_s_a B4galt5 1.11846333 10.5599476 3_92169381 0_00024385 004679878 0_41700096 1431296_at Gpr15 1_14301562 6.60205175 3.9193265 0.00024573 0.04695995 0.41002381 Pmbeset Gene raw.FC AveExpr t P.Value adj.P.Val B
1454757 s aI112711 -1.1515249 12.2428344 -6_5569053 1.926-08 137E-05 9.09173948 1415837_at Klk1 -1.4082454 7.5804401 -6.3275656 4_55E-08 3_16E-05 8.29680484 1452956 a_ilf12711 -1.1424326 10.7927481 -5.9606126 1.80E-07 9.56E-05 7.03136178 1448107 x Kai -1.3445567 7.49119412 -5.9058876 2_2_1E-07 0.00011452 6.84359495 1439771_s _a D13ERTD608 -1.2546842 8.86787505 -5.8507689 2.71E-07 0.00013591 6.65478212 1415823 at Scd2 -1.3537166 102235672 -5.1396945 3.68E-06 0.00127567 4.25571056 1442544_at Ighm -1.1737796 9_42424035 -5.0083987 539E-06 0.00191674 3.82241733 1415E124 at Scd2 -1.3093243 10.9433795 -4.6149411 2.366-05 0.00637618 2.54825457 1415822 at Scii2 -1_2780512 11.8313256 -4.5073901 3.43E-05 0.00848983 220720796 1429100_at Ccdc711 -1.0849357 10.7147161 -4.4868075 3.68E-05 0.00896553 2.14233223 1427756_x_z Ighm -1.1707153 9.14115987 -4.4212385 4.61E-05 0.01087406 1.93653267 1449325_at Fads2 -11644392 8_52583689 -4.1780844 0.00010478 0.02229136 1.18564443 1416188 at Gm2a -1.0836296 10.9313169 -4.163994 0.00010983 0.02325521 1.1427593 1424567 at Tspan2 -1.1339633 9.59951853 -4.0339051 0.00016899 0.03387392 0.75029377 1436131_at Siglech -1.1248775 7.91450702 -3.9583983 0.0002164 0.04241625 0.52546999 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims

What is claimed:

1. A process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a);
and c) i) determining the level of expression of at least one gene selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6; ii) determining the level of expression of at least one gene selected from the group consisting of BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA, wherein if IL1B, IL10, or MMP9 is the at least one gene selected in paxt (c)(ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the level of expression of at least one gene selected from the group consisting of C130RF31, C140RF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, L0C100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7; iv) determining the level of expression of at least one gene selected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOXO3B, HSD11B1, HSPD1P6, LOC387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27, SOD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7; v) determining the level of expression of at least one gene selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C130RF31, C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL411, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1; vi) determining the level of expression of at least one gene selected from the group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566; vii) determining the level of expression of at least one gene selected from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP564O0823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IF144, IFNGR1, IGFBP3, IL2RG, IL4I1, IL1ORA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LOC51334, LOC201895, LOC284262, LOC51334, LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSU1, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGAll, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1;
viii) determining the level of expression of at least one gene selected from the group consisting of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFIl, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LOC642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1; ix) determining the level of expression of at least one gene selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP; x) determining the level of expression of at least one gene selected from the group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1; xi) determining the level of expression of at least one gene selected from the group consisting of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068, LOC100862473, Mxl, Oasl1, Phfl1d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2; xii) determining the level of expression of at least one gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2; xiii) determining the level of expression of at least one gene selected from the group consisting of Ahrr, AI607873, Atp10a, AW011738, Casp44, Cxcl3, Gm9706, Ifi202b, Ifit2, Ifitm6, I118, Lcn2, LOC100044068, Ms4a6d, Mx1, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2; xiv) determining the level of expression of at least one gene selected from the group consisting of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3, Fam162a, Gfi1, Gpil, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm, Tpil, and Trappc6a; xv) determining the level of expression of at least one gene selected from the group consisting of 1600014C10Rik, 2810474019Rik, 6720475J19Rik, Adam8, Adar, Agrn, Ahrr, AI607873, Amigo2, Ankfyl, Apobec1, Arf4, Asb2, Ascc3, Atp10a, Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chic1, Cmpk2, Csprs, Cxcl3, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emr1, Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772, Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-T10, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspalb, Ifi202b, Ifi203, Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifih1, Ifit1, Ifit2, Ifit3, Ifitm3, 1118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lgals3bp, Lgals9, LOC100041903, LOC100044068, LOC100503923, LOC100505160, LOC100862473, L00664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitd1, Mlkl, Mmp8, Mnda, Mndal, Ms4a4c, Ms4a6d, Mxl, Naa20, Nceh1, Ncoa7, Ngp, Nlrc5, Nmral1, Nqol, Nt5c3, Oasla, Oas2, Oas3, Oasl1, Oas12, Ogfr, Papd7, Parp10, Parpl1, Parp12, Parp14, Phflld, Pik3apl, P1a2g7, Plec, Pnptl, Ppmlk, Pydc4, Pyhinl, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1õ Slfn1, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9, St3ga16, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10, Torlaip2, Tor3a, Trafd1, Trim25, Trim30a , Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wntl0a, Xaf1, Xaf1, Zc3hav1, Zcchc2, Zfyve26, Znfx1, and Zufsp;
xvi) determining the level of expression of at least one gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2; xvii) determining the level of expression of at least one gene selected from the group consisting of CCl2, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL411, MSC, NQ01, PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF; xviii) determining the level of expression of at least one gene selected from the group consisting of BCL2, CACNA2D3, C130RF18, C200RF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049, L00645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1, and TDRD7; xix) determining the level of expression of at least one gene selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57, ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6VOC, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35, C13ORF31, C14ORF43, C15ORF39, C17ORF32, C19ORF58, C1ORF122, C1ORF144, C1ORF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88, CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A, CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1Aõ CHST11, CIDEC, CKB, CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1, DDB1, DGAT2, DKFZP68601327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489, FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, ID2, IER5, IFI30, IFNGR1, IFNGR2, IGFBP3, IL1ORA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, IL411, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, LOC113179, LOC338758, LOC440934, LOC54103, LOC644242 , LOC648998 , LOC650429, LOC650446, LOC651816, LOC653524, LOC653361, LOC653840, LOC653361, LOC653506, LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQ01, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU, PLAUR, PLEKH01, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4, PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSP03, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, 5LC25A20, SLC2A1, SLC2A6, SLC37A2, SLC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG, ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697; xx) determining the level of expression of at least one gene selected from the group consisting of ABHD14B, ACTN1, ACY1L2, ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE, BSPRY, BTBD14A, C130RF18, C130RF18, C140RF106, C1SORF41, C160RF73, C1ORF121, C1ORF63, ClQBP, C1S, C20ORF103, C20ORF112, C20ORF12, C3ORF14, C5ORF13, C60RF147, C70RF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2, CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274, LOC220594, LOC254559, LOC284702, LOC28SO84, LOC285758, LOC340061, LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456, LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, M54A7, MSRB3, MT1E, MT1H, MT1M, MTBP, MTHFD1,MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG, SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4, SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1, ST3GAL3, STAR , STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1, TMEM14A
TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2, VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92; xxi) determining the level of expression of at least one gene selected from the group consisting of CCL2, CCL5, CXCL10, IL1RN, and MMP9; xxii) determining the level of expression of at least one gene selected from the group consisting of CCL5, CXCL10, and MMP9; xxiii) determining the level of expression of at least one gene selected from the group consisting of IL10 and CCL2; xxiv) determining the level of expression of at least one gene selected from the group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10;
xxv) determining the level of expression of at least one gene selected from the group consisting of MMP9, CCL2, CCL5, CXCL1, and IL1B; xxvi) determining the level of expression of at least one gene selected from the group consisting of MMP9, CXCL10, CCL2, and CCL5; xxix) determining the level of expression of at least one gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF; or xxx) determining the level of expression of at least one gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).

2. The process of claim 1, wherein step (c) comprises i) determining the level of expression of at least one gene selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6; ii) determining the level of expression of at least one gene selected from the group consisting of C13ORF31, C14ORF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, LOC100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7; or vi) determining the level of expression of at least one gene selected from the group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, wherein all genes ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6f CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6, are selected for determining the level of expression, or wherein all genes ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6, are selected for determining the level of expression, and wherein in step (c)(i), if IL10 is the at least one gene selected in part(c) (i), then selecting at least a second different gene from the group of (c)(i) other than IL10, or wherein in step (c)(ii), if CARD15, CCL2, CCL5, CD14, IL10, THBD, or NFKBIA is the at least one of gene is selected in part (c)(ii), then selecting at least a second different gene from the group of (c)(i) or c(ii) other than CARD15, CCL2, CCL5, CD14, IL10, THBD, or NFKBIA, and wherein if two or more genes are selected in step (c), then the second or additional gene selected is different from the other selected gene or genes.

3. The process of claim 1 or 2 comprising the step of (c) (vii) or (c) (viii), wherein the level of expression is determined for all genes identified in Table 5 or Table 12 to be involved in one or more than one pathway, at least one pathway, two or more pathways, three or more pathways, four or more pathways, five or more pathways, six pathways; or wherein the level of expression is determined for at least one gene which is involved in only one pathway set forth in Table 5 or Table 12; or wherein the level of expression is determined for at least two genes, at least three genes, at least four genes, at least five genes, or at least six genes identified in Table 5 or Table 12 to be involved in the same pathway.

4. The process of any one of claims 1-3 comprising the step of (c) (v) or (c)(vi), wherein the level of expression is determined for all genes identified in Table 6 to be involved in one or more than one pathway, at least one pathway, two or more pathways, three or more pathways, four or more pathways, five or more pathways, six or more pathways, or at least one gene which is involved in only one pathway set forth in Table 6; or wherein the level of expression is determined for at least two genes, at least three genes, at least four genes, at least five genes, or at least six genes identified in Table 6 to be involved in the same pathway.

5. The process of any one of claims 1-4, wherein contacting the mammalian cells in step (b) comprises i) administering to a mammal a predetermined amount of glatiramer acetate related drug substance or drug product of step (a), or ii) incubating the cells with an amount of the glatiramer acetate related drug substance or drug product of step (a), or a combination thereof;
or i) administering to a mammal a predetermined amount of glatiramer acetate related drug substance or drug product of step (a), and ii) obtaining cells from the mammal at one or more predetermined time points; and wherein step (c) comprises determining the level of expression of at least one gene selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a), wherein the mammal is human and the cells are peripheral mononuclear blood cells, or wherein the predetermined time point is 0, 1, 2, or 3 months;
or wherein contacting the mammalian cells in step (b) comprises incubating monocytic cell line cells with an amount of the glatiramer acetate related drug substance or drug product of step (a), thereby characterizing the glatiramer acetate related drug substance or drug product of step a), thereby characterizing the glatiramer acetate related drug substance or drug product of step (a);
wherein contacting the mammalian cells in step (b) comprises incubating monocytic cell line cells with an amount of glatiramer acetate related drug substance or drug product of step (a), thereby characterizing the glatiramer acetate related drug substance or drug product of step (a) thereby characterizing the glatiramer acetate related drug substance or drug product of step (a);
wherein the mammalian cells are THP-1 cells; or wherein contacting the mammalian cells in step (b) comprises i) immunizing a mammal with a predetermined amount of glatiramer acetate related drug substance or drug product, ii) preparing a culture of cells from the mammal of step i) at one or more predetermined time points after immunization, and iii) incubating cells from the culture of cells obtained from the mammal with an amount of the glatiramer acetate related drug substance or drug product of step (a), thereby characterizing the glatiramer acetate related drug substance or drug product of step (a);
wherein the glatiramer acetate related drug substance or drug product of step (iii) is the same glatiramer acetate related drug substance or drug product of step (i), wherein the glatiramer acetate related drug substance or drug product of step (iii) is a different glatiramer acetate related drug substance or drug product of step (i), wherein the incubation is for about 24 hours, for about 12 hours, or for about 6 hours, wherein the predetermined time point after immunization is 3 days, wherein the contacting of step (b) is in a cell culture, wherein the culture is a primary culture, wherein the contacting of step (b) is in a mammal, wherein the mammal is a rodent or human, wherein the glatiramer acetate related drug substance or drug product is other than glatiramer acetate drug substance or drug product, wherein the cell is of a type i) selected from the group of cell types consisting of FoxP3+ T cells, regulatory T cells, natural killer T cells, T helper 2 cells, CD8+ T cells, CD4+ T cells, B
cells, macrophage cells, monocyte cells, eosinophils, dendritic cells, granulocytes, megakaryocytes, and myeloid progenitors;
ii) selected from the group of cell types identified in Table 9; iii) selected from the group of cell types identified in Table 10; or iv) selected from the group of cell types identified in Table 11.

6. A process for discriminating between glatiramer acetate related drug substances or drug products comprising the steps of:
a) characterizing two or more glatiramer acetate related drug substances or drug products according to the process of any one of claims 1-5 to obtain characteristics of each of the glatiramer acetate related drug substances or drug products; and b) comparing the characteristics of the glatiramer acetate related drug substances or drug products obtained in step a), thereby discriminating between glatiramer acetate related drug substances or drug products.

7. The process of any one of claims 1-6, wherein the mammal is a rodent or human, and wherein the level of expression is determined in hematological cells;
wherein the level of expression is determined in splenocytes, or wherein the level of expression is determined in monocytes, and wherein the monocytes are THP-1;

wherein the level of expression is determined in peripheral blood mononuclear cells, and wherein the peripheral blood mononuclear cells are from a human; or wherein the human has previously been treated with a glatiramer acetate related drug substance or drug product, wherein the human is a naive, wherein the human is a glatiramoid naive human, or wherein the human is afflicted with RRMS; or wherein the rodent is a mouse, wherein the mouse is a female (SJL X BALB/C) F1 mouse, wherein the mouse is about 8 to 12 weeks old; or wherein the primary culture is a culture of spleen cells, wherein the primary culture is a culture of lymph node cells, wherein the primary culture of spleen cells is prepared about 3 days after immunization; or wherein the glatiramer acetate related drug substance is a glatiramoid or wherein the glatiramer acetate related drug product comprises a glatiramoid, or wherein the glatiramer acetate related drug substance is a glatiramoid other than glatiramer acetate drug substance, or wherein the glatiramer acetate related drug product comprises a glatiramoid other than glatiramer acetate drug substance.

8. A process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting a first group of mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a);
c) contacting a second group of mammalian cells of the same type with an amount of a reference standard; and d) determining a set of genes differentially expressed by the first group after the contacting of step (b) relative to genes expressed by the second group after the contacting of step (c), thereby characterizing the glatiramer acetate related drug substance or drug product of step a), wherein the cells are THP-1 cells, wherein the reference standard is glatiramer acetate related drug substance or drug product, wherein the reference standard is mannitol, or wherein the reference standard is medium, wherein the determining step (d) comprises comparing the expression of genes expressed by the first group to the expression of genes expressed by the second group, or wherein the determining step (d) comprises comparing the expression of genes by the first group of cells and by the second group of cells to expression of the genes by the same type of cells exposed to mannitol or medium.

9. A process for discriminating between glatiramer acetate related drug substances or drug products comprising the step of characterizing two or more glatiramer acetate related drug substances or drug products according to the process of any one of claims 1-8 to obtain characteristics of each of the glatiramer acetate related drug substances or drug products; and comparing the characteristics of the glatiramer acetate related drug substances or drug products, thereby discriminating between glatiramer acetate related drug substances or drug products.

10. In a process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug substance according to the process of any one of claims 1-8; and b) i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; iii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of C13ORF31, C14ORF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, LOC100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; iv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOXO3B, HSD11B1, HSPD1P6, LOC387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27, SOD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; v) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31, C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL411, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VP533A, and VSNL1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; vi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; vii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP564O0823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IFI44, IFNGR1, IGFBP3, IL2RG, IL4I1, IL10RA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LOC51334, LOC201895, LOC284262, LOC51334, LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSU1, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1, is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; viii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LO0642083, LO0648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1, is downregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions;
or ix) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; x) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068, LOC100862473, Mx1, Oas11, Phf11d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Ahrr, AI607873, Atp10a, AW011738, Casp44, Cxc13, Gm9706, Ifi202b, Ifit2, Ifitm6, I118, Lcn2, LOC100044068, Ms4a6d, Mx1, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3, Fam162a, Gfi1, Gpi1, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm, Tpi1, and Trappc6a is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of 1600014C10Rik, 2810474019Rik, 6720475J19Rik, Adam8, Adar, Agrn, Ahrr, AI607873, Amigo2, Ankfy1, Apobec1, Arf4, Asb2, Ascc3, Atp10a, Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chic1, Cmpk2, Csprs, Cxc13, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emr1, Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772, Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-T10, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspalb, Ifi202b, Ifi203, Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifih1, Ifit1, Ifit2, Ifit3, Ifitm3, I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lgals3bp, Lgals9, LOC100041903, LOC100044068, LOC100503923, LOC100505160, LOC100862473, L00664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitdl, Mlkl, Mmp8, Mnda, Mndal, Ms4a4c, Ms4a6d, Mx1, Naa20, Nceh1, Ncoa7, Ngp, Nlrc5, Nmra11, Nqo1, Nt5c3, Oasla, Oas2, Oas3, Oas11, Oas12, Ogfr, Papd7, Parp10, Parp11, Parp12, Parp14, Phflld, Pik3apl, P1a2g7, Plec, Pnptl, Ppmlk, Pydc4, Pyhin1, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1õ Slfn1, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9, St3ga16, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10, Torlaip2, Tor3a, Trafd1, Trim25, Trim30a , Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wnt10a, Xaf1, Xaf1, Zc3hav1, Zcchc2, Zfyve26, Znfx1, and Zufsp is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, 1fi2711, Ighm, K1k1, Scd2, Siglech, and Tspan2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCl2, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL4I1, MSC, NQO1, PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of BCL2, CACNA2D3, C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049, LOC645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1, and TDRD7 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57, ANXA2, APBBlIP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6V0C, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35, C13ORF31, C14ORF43, C15ORF39, C17ORF32, C19ORF58, C1ORF122, C1ORF144, C1ORF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88, CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A, CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1A,, CHST11, CIDEC, CKB, CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1, DDB1, DGAT2, DKFZP686O1327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489, FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, ID2, IER5, IFI30, IFNGR1, IFNGR2, IGFBP3, IL10RA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, 1L27RA, IL27RA, IL4I1, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, LOC113179, LOC338758, LOC440934, LOC54103, LOC644242 , LOC648998 , LOC650429, LOC650446, LOC651816, LOC653524, LOC653361, LOC653840, LOC653361, LOC653506, LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQO1, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU, PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4, PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSPO3, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6, SLC37A2, SLC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG, ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABHD14B, ACTN1, ACY1L2, ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE, BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41, C16ORF73, C1ORF121, C1ORF63, C1QBP, C1S, C20ORF103, C20ORF112, C20ORF12, C3ORF14, C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2, CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274, LOC220594, LOC254559, LOC284702, LOC285084, LOC285758, LOC340061, LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456, LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MTlE, MT1H, MT1M, MTBP, MTHFD1,MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG, SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4, SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1, ST3GAL3, STAR , STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1, TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2, VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCL2, CCL5, CXCL10, IL1RN, and MMP9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCL5, CXCL10, and MMP9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of IL10 and CCL2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of MMP9, CCL2, CCL5, CXCL1, and IL1B is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxvi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of MMP9, CXCL10, CCL2, and CCL5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABI2, ARPC4, CD84, CLU, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions;
or ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ABCF2, ACP6, AFG3L2, CHAF1A, COX11, LPHN1, NACA, OLAH, POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TSHZ1, TSPAN13, UBAP2, VDAC2, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, wherein in step (b)(i), if, one or more genes selected from the group consisting of ABI2, ARPC4, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, then including the batch of the glatiramer acetate related drug substance in the production of the drug product, wherein in step (b)(ii), if, one or more genes selected from the group consisting of ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, then including the batch of the glatiramer acetate related drug substance in the production of the drug product; or i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCL2, CCL5, MMP1, MMP9, CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD, NFKBIA, IL10, PRDM1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CISH and HSPD1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; iii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of CCl24, CCR1, CSF1R, CX3CR1, IL27, IFNGR1, IL2RG, and IL7R is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate drug related substance under the same conditions; iv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of PGRMC1 is upregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; v) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of MMP14 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; vi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of IL1RN is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; or vii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of IL1B is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions;
i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31, C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL4I1, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or i) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or ii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more genes selected from the group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions.

11. In a process for releasing a drug product comprising a glatiramer acetate related drug substance, which process involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug product according to the process of any one of claims 1-8; and b) i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions; ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, ILlB, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; iii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of C13ORF31, C14ORF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, LOC100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; iv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOXO3B, HSD11B1, HSPD1P6, LOC387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27, SOD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; v) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C130RF31, C50RF13, C50RF32, C90RF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL411, INADL, I5G20, ITGB5, KIAA1505, KYNU, LACTB, L0054103, L0C388344, L00652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; vi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ACTN4, BTBD14A, C140RF10, CISH, CLK1, CRLF3, FAM62A, FBX045, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, L00648342, MYB, NAPB, 0XCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; vii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP564O0823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IF144, IFNGR1, IGFBP3, IL2RG, IL411, IL10RA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LO051334, LOC201895, LOC284262, LO051334, LO0643424, LO0643834, LO0643847, LOC644242, LO0645238, LO0650429, LO0650446, LO0652543, LO0653610, LO0653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSU1, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKH01, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1, is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; viii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C10RF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LOC642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNP02, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1, is downregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions, ix) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; x) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; xi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068, LOC100862473, Mx1, Oas11, Phf11d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Ahrr, AI607873, Atp10a, AW011738, Casp44, Cxc13, Gm9706, Ifi202b, Ifit2, Ifitm6, 1118, Lcn2, LOC100044068, Ms4a6d, Mx1, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xiv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3, Fam162a, Gfil, Gpil, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm, Tpi1, and Trappc6a is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of 1600014C10Rik, 2810474019Rik, 6720475J19Rik, Adam8, Adar, Agrn, Ahrr, AI607873, Amigo2, Ankfy1, Apobec1, Arf4, Asb2, Ascc3, Atp10a, Atp8b4, AW011738, B4ga1t5, BC147527, Bst2, Casp4, Chic1, Cmpk2, Csprs, Cxc13, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emr1, Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772, Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-110, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspalb, Ifi202b, Ifi203, Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifih1, Ifit1, Ifit2, Ifit3, Ifitm3, I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lgals3bp, Lgals9, LOC100041903, LOC100044068, LOC100503923, LOC100505160, LOC100862473, L0C664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitd1, Mlk1, Mmp8, Mnda, Mnda1, Ms4a4c, Ms4a6d, Mx1, Naa20, Ncehl, Ncoa7, Ngp, Nlrc5, Nmra11, Nqo1, Nt5c3, Oas1a, Oas2, Oas3, Oas11, Oas12, Ogfr, Papd7, Parp10, Parp11, Parp12, Parp14, Phf11d, Pik3ap1, P1a2g7, Plec, Pnpt1, Ppm1k, Pydc4, Pyhin1, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1õ Slfn1, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9, St3ga16, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10, Torlaip2, Tor3a, Trafd1, Trim25, Trim30a , Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wnt10a, Xaf1, Xaf1, Zc3hav1, Zcchc2, Zfyve26, Znfx1, and Zufsp is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xvii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of CC12, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL4I1, MSC, NQO1, PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF
is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xviii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of BCL2, CACNA2D3, C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049, LOC645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1, and TDRD7 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xix) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57, ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6V0C, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35, C13ORF31, C14ORF43, C15ORF39, C170RF32, C19ORF58, C1ORF122, C1ORF144, C10RF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C60RF166, C90RF16, C90RF88, CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A, CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1Aõ CHST11, CIDEC, CKB, CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1, DDB1, DGAT2, DKFZP68601327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489, FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, ID2, IER5, IFI30, IFNGR1, IFNGR2, IGFBP3, IL10RA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, IL4I1, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, L0C113179, LOC338758, LOC440934, LOC54103, LOC644242 , LOC648998 , LOC650429, LOC650446, LOC651816, LOC653524, LOC653361, LOC653840, LOC653361, LOC653506, LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQO1, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU, PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4, PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSPO3, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6, SLC37A2, SLC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG, ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xx) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ABHD14B, ACTN1, ACY1L2, ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE, BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41, C16ORF73, C1ORF121, C1ORF63, ClQBP, C1S, C20ORF103, C20ORF112, C20ORF12, C3ORF14, C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2,.CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274, LOC220594, LOC254559, LOC284702, LOC285084, LOC285758, LOC340061, LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456, LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24, M54A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H, MT1M, MTBP, MTHFD1,MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG, SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4, SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1, ST3GAL3, STAR , STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1, TMEM14A
TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2, VLDLR, V2S35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, Z5T333, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of CCL2, CCL5, CXCL10, IL1RN, and MMP9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of CCL5, CXCL10, and MMP9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of IL10 and CCL2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxiv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of MMP9, CCL2, CCL5, CXCL1, and IL1B is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxvi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of MMP9, CXCL10, CCL2, and CCL5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; xxix) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions; or xxx) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug substance under the same conditions;
i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of ABI2, ARPC4, CD84, CLU, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions; or ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of ABCF2, ACP6, AFG3L2, CHAF1A, COX11, LPHN1, NACA, OLAH, POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9, TOMM40, ISHZ1, TSPAN13, UBAP2, VDAC2, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions, wherein in step (b)(i), if, one or more genes selected from the group consisting of ABI2, ARPC4, HFE, and IL10 is upregulated relative to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug product under the same conditions, then releasing the batch of the glatiramer acetate related drug product, wherein in step (b)(ii), if, one or more genes selected from the group consisting of ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1 is downregulated relative to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions, then releasing the batch of the glatiramer acetate related drug product;
i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of CCL2, CCL5, MMP1, MMP9, CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD, NFKBIA, IL10, PRDM1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of CISH and HSPD1 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; iii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one of more genes selected from the group consisting of CC124, CCR1, CSF1R, CX3CR1, IL27, IFNGR1, IL2RG, and IL7R
is not substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate drug related substance under the same conditions;
iv) releasing the batch of the glatiramer acetate related drug product if the level of expression of PGRMC1 is upregulated or substantially identical to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; v) releasing the batch of the glatiramer acetate related drug product if the level of expression of MMP14 is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions; vi) releasing the batch of the glatiramer acetate related drug product if the level of expression of IL1RN is upregulated to the level of expression by the same type of cells in the absence of the glatiramer acetate related drug substance under the same conditions; or vii) releasing the batch of the glatiramer acetate related drug product if the level of expression of IL1B is substantially identical to the level of expression by the same type of cells in the presence of glatiramer acetate drug substance under the same conditions;
i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31, C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL4I1, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, 50D2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VP533A, and V5NL1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; or ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFR514, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions;
or i) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions; or ii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more genes selected from the group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate drug product under the same conditions.

12. A glatiramer acetate related drug product produced by the process of any one of claims 1-11, wherein the glatiramer acetate related drug product is other than glatiramer acetate drug product;

which is capable of inducing a level of expression of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 that is not substantially identical to the level of expression of the genes induced in the same tpe of cells and under the same conditions in the absence of the glatiramer acetate related drug product, wherein the glatiramer acetate related drug product is capable of inducing a level of expression of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6, which is capable of upregulating genes ABI2, ARPC4, HFE, and IL10 relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product, and capable of downregulating genes ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1 relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product, or which is capable of inducing a level of expression of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP564O0823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IFI44, IFNGR1, IGFBP3, IL2RG, IL4I1, IL10RA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LOC51334, LOC201895, LOC284262, LOC51334, LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSU1, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, ZFP36L1, ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71,C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LOC642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1, that is not substantially identical to the level of expression of the genes induced in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product, which is capable of upregulating genes A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP564O0823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IFI44, IFNGR1, IGFBP3, IL2RG, IL4I1, IL10RA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LOC51334, LOC201895, LIC284262, LOC51334, LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSUl, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1, relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product, and capable of downregulating genes ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C1IRF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C2O0RD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LOC642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1 relative to the level of expression of the genes in the same type of cells and under the same conditions in the absence of the glatiramer acetate related drug product.

13. A process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a);
and c) determining the level of expression of at least one or more genes corresponding to probesets identified in Table 12, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).

14. A process or a product as defined herein, wherein the group of gene is represented by probesets of Table 12.

15. The process of any one of claim 1-14, further comprising i) determining the one or more proteins produced by each of the one of more genes selected in step c); and ii) determining protein level expression for each protein in step i), further comprising i) determining the one or more proteins produced by each of the one of more genes selected in step b);
and ii) determining protein level expression for each protein in step i), or further comprising determining the set of proteins produced by each gene of the set of genes in step d).

16. A process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a);
and c) xxii) determining the protein level expression of at least one protein selected from the group consisting of RANTES, IP-10, and MMP-9; xxiii) determining the protein level expression of at least one protein selected from the group consisting of IL10 and MCP-1; xxiv) determining the protein level expression of at least one protein selected from the group consisting of IFNg, TNFa, MIP-1a, IL-8, and IL-10;
xxv) determining the protein level expression of at least one protein selected from the group consisting of MMP-9, MCP-1, RANTES, Gro-a, and IL-1b; xxvi) determining the protein level expression of at least one protein selected from the group consisting of MMP-9, IP-10, MCP-1, and RANTES; xxvii) determining the protein level expression of at least one protein selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-.alpha., IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, and MIF; or xxviii) determining the protein level expression of at least one protein selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-.alpha., IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, MIF, IL-16, IL-6, TECK, IL-2, MIP-3b, CXCL2, MIG, and CXCL5, thereby characterizing the glatiramer acetate related drug substance or drug product of step a).

17. A process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
a) obtaining a batch of the glatiramer acetate related drug substance or drug product;
b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a);
and c) i) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, INFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, vAv3, VDAC2, and ZFAND6; ii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of B1RC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA, wherein if IL1B, IL10, or MMP9 is the at least one gene selected in part (c)(ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of C130RF31, C140RF10, C1ORF51, C10RF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, L0C100506233, MCM6, MMP1, MS4A4A, MISS1, PCMTD1, STK4, 5TX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7; iv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOX03B, HSD11B1, HSPD1P6, L0C387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27, SOD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7; v) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BIG1, CARD15, C1ORF21, C13ORF31, C5ORF13, C50RF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL411, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1, MISS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1; vi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ACTN4, BTBD14A, C140RF10, CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566; vii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP564O0823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IF144, IFNGR1, IGFBP3, IL2RG, IL4I1, IL1ORA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LOC51334, LOC201895, LOC284262, LOC51334, LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMRI1, MTSS1, MTSU1, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1;
viii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LO0642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, O5R2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1; ix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP; x) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ADRB2, COTL1, LOC285758, L00644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1; xi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of AW011738, Bst2, Daxx, Gml6340, Hck, Herc6, Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068, LOC100862473, Mxl, Oasll, Phflld, Oyhinl, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2; xii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klkl, Scd2, Siglech, and Tspan2; xiii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Ahrr, AI607873, Atpl0a, AW011738, Casp44, Cxc13, Gm9706, Ifi202b, Ifit2, Ifitm6, I118, Lcn2, LOC100044068, Ms4a6d, Mxl, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2; xiv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Aldoc, Casp6, Ccdc711, Cox7al, Egln3, Fam162a, Gfil, Gpil, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgkl, Pkm, Tpil, and Trappc6a; xv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of 1600014C1ORik, 2810474O19Rik, 6720475J19Rik, Adam8, Adar, Agrn, Ahrr, AI607873, Amigo2, Ankfyl, Apobecl, Arf4, Asb2, Ascc3, Atpl0a, Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chicl, Cmpk2, Csprs, Cxcl3, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emrl, Epstil, Evi2a, Fcgrl, Fcgr4, Ftsjd2, Gcntl, Gm11772, Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-T10, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspa1b, Ifi202b, Ifi203, Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifih1, Ifit1, Ifit2, Ifit3, Ifitm3, I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lgals3bp, Lgals9, LOC100041903, LOC100044068, LOC100503923, LOC100505160, LOC100862473, LOC664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitdl, Mlkl, Mmp8, Mnda, Mndal, Ms4a4c, Ms4a6d, Mx1, Naa20, Ncehl, Ncoa7, Ngp, Nlrc5, Nmral1, Nqol, Nt5c3, Oas1a, Oas2, Oas3, Oasl1, Oas12, Ogfr, Papd7, Parp10, Parpl1, Parp12, Parp14, Phfl1d, Pik3apl, P1a2g7, Plec, Pnptl, Ppmlk, Pydc4, Pyhinl, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1õ Slfnl, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9, St3ga16, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10, Torlaip2, Tor3a, Trafd1, Trim25, Trim30a , Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wntl0a, Xafl, Xafl, Zc3havl, Zcchc2, Zfyve26, Znfxl, and Zufsp;
xvi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klkl, Scd2, Siglech, and Tspan2; xvii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of CC12, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL411, MSC, NQ01, PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF; xviii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of BCL2, CACNA2D3, C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049, LOC645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1, and TDRD7; xix) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57, ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6VOC, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35, C13ORF31, C14ORF43, C15ORF39, C17ORF32, C19ORF58, C1ORF122, C1ORF144, C1ORF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88, CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A, CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1Aõ CHST11, CIDEC, CKB, CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1, DDB1, DGAT2, DKFZP686O1327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489, FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, ID2, IER5, IFI30, IFNGR1, IFNGR2, IGFBP3, IL1ORA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, IL411, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, K1TLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, LOC113179, LOC338758, LOC440934, LOC54103, LOC644242 , LOC648998 , LOC650429, LOC650446, LOC651816, LOC653524, LOC653361, LOC653840, LOC653361, LOC653506, LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQ01, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU, PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4, PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSP03, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, 5LC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6, SLC37A2, SLC39A8, 5LC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG, ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697; xx) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of ABHD14B, ACTN1, ACY1L2, ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE, BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41, C16ORF73, C1ORF121, C1ORF63, C1QBP, C1S, C20ORF103, C20ORF112, C20ORF12, C3ORF14, C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2, CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274, LOC220594, LOC254559, LOC284702, LOC285084, LOC285758, LOC340061, LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456, LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H, MT1M, MTBP, MTHFD1,MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG, SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4, SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1, ST3GAL3, STAR , STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1, TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2, VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92; xxi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of CCL2, CCL5, CXCL10, IL1RN, and MMP9; xxii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of CCL5, CXCL10, and MMP9; xxiii) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of IL10 and CCL2; xxiv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10; xxv) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of MMP9, CCL2, CCL5, CXCL1, and IL1B; xxvi) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of MMP9, CXCL10, CCL2, and CCL5; xxix) determining the protein level expression of at 1east one protein produced by a gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF; or xxx) determining the protein level expression of at least one protein produced by a gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5, thereby characterizing the glatiramer acetate related drug substance or drug product of step a), or wherein contacting the mammalian cells in step (b) comprises incubating monocytic cell line cells with an amount of the glatiramer acetate related drug substance or drug product of step (a); and wherein step (c) comprises xxii) determining the protein level expression of at least one protein selected from the group consisting of CCL5, CXCL10, and MMP9; xxiii) determining the protein level expression of at least one protein selected from the group consisting of IL10 and CCL2; xxiv) determining the protein level expression of at least one protein selected from the group consisting of IFNg, TNFa, MIP-1a (CCL3), IL-8 (CXCL8) and IL-10; xxv) determining the protein level expression of at least one protein selected from the group consisting of MMP-9, MCP-1 (CCL-2), RANTES (CCL5), Gro-a (CXCL1) and IL-lb; xxvi) determining the protein level expression of at least one protein selected from the group consisting of MMP-9, IP-10 (CXCL10), MCP-1 (CCL2) and RANTES (CCL5); xxvii) determining the protein level expression of at least one protein selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, and MIF; or xxviii) determining the protein level expression of at least one protein selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, MIF, IL-16, IL-6, TECK, IL-2, MIP-3b, CXCL2, MIG, and CXCL5, thereby characterizing the glatiramer acetate related drug substance or drug product of step (a), wherein the mammalian cells are THP-1 cells, wherein the incubation is for about 24 hours, or wherein contacting the mammalian cells in step (b) comprises i) immunizing a mammal with a predetermined amount of glatiramer acetate related drug substance or drug product, ii) preparing a culture of cells from the mammal of step i) at one or more predetermined time points after immunization, and iii) incubating cells from the culture of cells obtained from the mammal with an amount of the glatiramer acetate related drug substance or drug product of step (a), thereby characterizing the glatiramer acetate related drug substance or drug product of step (a), wherein the glatiramer acetate related drug substance or drug product of step (iii) is the same glatiramer acetate related drug substance or drug product of step (i), wherein the glatiramer acetate related drug substance or drug product of step (iii) is a different glatiramer acetate related drug substance or drug product of step (i), wherein the incubation is for about 24 hours, for about 12 hours, or for about 6 hours, wherein the predetermined time point after immunization is 3 days, wherein the contacting of step (b) is in a cell culture, wherein the culture is a primary culture, wherein the contacting of step (b) is in a mammal, wherein the mammal is a rodent or human, wherein the glatiramer acetate related drug substance or drug product is other than glatiramer acetate drug substance or drug product, or wherein the cell is of a type i) selected from the group of cell types consisting of FoxP3+ T cells, regulatory T cells, natural killer T cells, T helper 2 cells, CD8+ T cells, CD4+ T cells, B
cells, macrophage cells, monocyte cells, eosinophils, dendritic cells, granulocytes, megakaryocytes, and myeloid progenitors;
ii) selected from the group of cell types identified in Table 9; iii) selected from the group of cell types identified in Table 10; or iv) selected from the group of cell types identified in Table 11.

18. In a process for producing a drug product comprising a glatiramer acetate related drug substance which involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug substance according to the process of any one of claims 1-17; and b) xxii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of CCL5, CXCL10, and MMP9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions;
xxiii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of IL10 and is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions;
xxiv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of IFNg, TNFa, MIP-1a (CCL3), IL-8 (CXCL8) and IL-10 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxv) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of MMP-9, MCP-1 (CCL-2), RANTES (CCL5), Gro-a (CXCL1) and IL-1b is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions;

xxvi) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of MMP-9, IP-10 (CXCL10), MCP-1 (CCL2) and RANTES (CCL5) is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions; xxvii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, and MIF is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions;
or xxviii) including the batch of the glatiramer acetate related drug substance in the production of the drug product if the level of expression of one or more proteins selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, MIF, IL-16, IL-6, TECK, IL-2, MIP-3b, CXCL2, MIG, and CXCL5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug substance under the same conditions.

19. In a process for releasing a drug product comprising a glatiramer acetate related drug substance, which process involves an array of testing, the improvement comprising including in the array of testing the steps of:
a) characterizing the glatiramer acetate related drug product according to the process of any one of claims 1-18; and b) xxii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of CCL5, CXCL10, and MMP9 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxiii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of IL10 and CCL2 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; xxiv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of IFNg, TNFa, MIP-1a (CCL3), IL-8 (CXCL8) and IL-10 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions;
xxv) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of MMP-9, MCP-1 (CCL-2), RANTES (CCL5), Gro-a (CXCL1) and IL-1b is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions;
xxvi) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of MMP-9, IP-(CXCL10), MCP-1 (CCL2) and RANTES (CCL5) is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions;
xxvii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-lb, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, and MIF is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions; or xxviii) releasing the batch of the glatiramer acetate related drug product if the level of expression of one or more proteins selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a, MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, MIF, IL-16, IL-6, TECK, IL-2, MIP-3b, CXCL2, MIG, and CXCL5 is substantially identical to the level of expression by the same type of cells in the presence of the glatiramer acetate related drug product under the same conditions.

20. A process for discriminating between glatiramer acetate related drug substances or drug products comprising the steps of:
a) characterizing one or more glatiramer acetate related drug substances or drug products according to the process of any one of claims 1-19 to obtain characteristics of each of the glatiramer acetate related drug substances or drug products;
b) obtaining characteristics of a glatiramer acetate drug substance or drug product; and c) comparing the characteristics of the glatiramer acetate related drug substances or drug products obtained in steps a) and b), thereby discriminating between glatiramer acetate related drug substances or drug products.