NEW KALORAMA INFORMATION! The World … FROM KALORAMA INFORMATION! The World Market for Molecular Diagnostics 5th Edition Authored by Shara Rosen • 850+ Pages of Market

NEW FROM KALORAMA INFORMATION!

The World Market for Molecular Diagnostics 5th Edition

http://www.kaloramainformation.com/Molecular-Diagnostics-Edition-7295219/

Authored by Shara Rosen

• 850+ Pages of Market Coverage • Market Estimates and Forecasts: Cancer, Infectious Disease, Blood

Screening, Molecular Coagulation Tests, Prenatal and Inherited Disease • Global Coverage (US, EU, Japan, China, ROW) • Test Markets for Specific Diseases and Procedures (Hepatitis, HIV, HAI,

Respiratory, Organism ID, TB, ISH testing, HPV, Microarrays and Others) • Latest Reimbursement, LDT, Regulatory, and Tech Trends • Over 200 Company Profiles Featuring: Revenue Performance, Products,

Partnerships

OVER 200 Company Profiles The Intense Competitor Focus In This Report Includes:

What Major Diagnostic Companies are Doing In Molecular DX

Abbott Diagnostics Alere

ARKRAY Beckman Coulter Inc./Danaher Becton, Dickinson and Company

bioMérieux Inc. Bio‐Rad Laboratories Inc. Gen‐Probe Inc./Hologic

Hologic, Inc. Instrumentation Laboratory Ortho Clinical Diagnostics

QIAGEN N.V. Roche Diagnostics

Siemens Healthcare Diagnostics Sysmex Corporation

Thermo Fisher Scientific Inc.

Status of Molecular Diagnostic Focused Companies Alacris Theranostics GmbH

Astra Biotech GmbH Autogenomics Inc.

Biocartis SA Biofortuna Ltd.

Biotype Diagnostic GmbH BlueGnome DiaGenic ASA DiagnoCure

ELITech Group EraGen Biosciences Inc.

Genetic Technologies Limited GenMark Diagnostics Inc.

Helicos BioSciences IRIS International, Inc. Luminex Corporation

Meridian Bioscience, Inc. Nanosphere, Inc.

Sony DADC Biosciences TrimGen Genetic Technology

TrovaGene, Inc.

New Innovators To Watch! Ahram Biosystems, Inc. Allegro Diagnostics Corp. Amoy Diagnostics Co. Ltd.

Anagnostics Bioanalysis GmbH

Applied BioCode, Inc. ArcticDx Inc.

Ariosa Diagnostics Axela Inc.

BioHelix Corporation BioNanomatrix/ BioNano Genomics

BJS Biotechnologies DiagCor Bioscience Inc. Ltd. DxTerity Diagnostics Inc.

Epistem plc Exiqon A/S Exonhit

GeneNews Limited Genome Diagnostics BV

Genomica S.A.U. Genorama Ltd. GnuBIO, Inc.

Great Basin Corporation Health Discovery Corporation

IncellDx, Inc. Insight Genetics IntegenX Inc.

Linkage Biosciences, Inc. Med BioGene, Inc.

Multiplicom NABsys, Inc.

Nanostring Technologies, Inc. NIPD Genetics Ltd OptiGene Ltd

Orion Genomics Oxford Gene Technology

PrimeraDx Rheonix Inc.

Skyline Diagnostics B.V. Spartan Bioscience Inc. Stratos Genomics Inc. VolitionRx Limited

WaferGen Biosystems, Inc.

And Many Other Companies…

http://www.kaloramainformation.com/Molecular-Diagnostics-Edition-7295219/

World Market for Molecular Diagnostics

5th

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THE WORLD MARKET FOR MOLECULAR DIAGNOSTICS, 5TH EDITION

A KALORAMA INFORMATION MARKET INTELLIGENCE REPORT

The World Market for Molecular Diagnostics has been prepared by Kalorama Information. We serve business and industrial clients in the United States and abroad with a complete line of information services and research publications.

Kalorama Information Market Intelligence Reports are specifically designed to aid the action-oriented executive by providing a thorough presentation of essential data and concise analysis.

Author: Shara Rosen Publication Date: January 2013

Copyright © 2013 Kalorama Information

Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited.

T A B L E O F C O N T E N T S

CHAPTER ONE: EXECUTIVE SUMMARY ..........................................................1 Introduction ......................................................................................................................... 1

Scope and Methodology ...................................................................................................... 4

Size and Growth of the Market ......................................................................................... 7

Market Trends .................................................................................................................. 11

CHAPTER TWO: INTRODUCTION .....................................................................15 Background ....................................................................................................................... 15

Developments since 2000 ............................................................................................... 16 New Platforms ................................................................................................................ 18 Test Quality Control ....................................................................................................... 24

Building a Strong Future .................................................................................................. 27 The Service Industry Makes Gains ................................................................................. 27 The $1000 Genome ......................................................................................................... 30 Information Technology and “Apps” ............................................................................. 32 Miniaturization and Multiplexed Assays ........................................................................ 35 Integrated Sample–to-Results Testing ............................................................................ 37 Mass Spectrometry ......................................................................................................... 38

Tests and Technologies in 2012 ........................................................................................ 42

CHAPTER THREE: THE COMMERCIALIZATION CONUNDRUM .............49 Background ....................................................................................................................... 49

Commercialization of Molecular Tests ........................................................................... 51

Regulatory Issues and Molecular Assays ........................................................................ 54

Patent Litigation Abounds ............................................................................................... 57 Consumer, Payer and Physician Acceptance .................................................................. 61 Clinical Molecular Test Reimbursement Coding in The U.S. ........................................ 64

CHAPTER FOUR: SEQUENCING – HYPE AND REALITY ............................69 Background ....................................................................................................................... 69

Companies and Technologies ......................................................................................... 71 PCR Not Ready To Take the Back Seat ......................................................................... 80 Pathogen sequencing ...................................................................................................... 86 Prenatal Fetal Chromosomal Analysis ............................................................................ 87

CHAPTER FIVE: MARKET ANALYSIS: WORLD MARKETS .......................91 Background ....................................................................................................................... 91

Market Estimate and Forecast by Region ...................................................................... 92



The United States .............................................................................................................. 97 RUO/IUO Issues ............................................................................................................. 98 The Patient Protection and Affordable Care Act ............................................................ 98 Accountable Care Organizations .................................................................................. 100

Europe .............................................................................................................................. 101 IVD Directive Update ................................................................................................... 105

China ................................................................................................................................ 107

India ................................................................................................................................. 110

CHAPTER SIX: THE MARKET FOR BLOOD MARKERS IN CANCER .....113 Overview .......................................................................................................................... 113

Methylation Patterns ..................................................................................................... 113 Other Tests .................................................................................................................... 114

Blood Molecular Test Market and Forecasts ............................................................... 115 LDTs ............................................................................................................................. 115 Radiotherapy Testing .................................................................................................... 116

CHAPTER SEVEN: THE MARKET FOR MOLECULAR ASSAYS IN HEMATOLOGY......................................................................................................121

Flow Cytometry ............................................................................................................... 122

CHAPTER EIGHT: THE MARKET FOR MOLECULAR ASSAYS IN COAGULATION AND CARDIAC CARE ...........................................................127

Thrombophilia SNPs ...................................................................................................... 127 MTHFR ........................................................................................................................ 128 Factor V ........................................................................................................................ 128 CYP4V2 ........................................................................................................................ 128 Market and Forecast ..................................................................................................... 129 Coagulation Molecular Research Projects .................................................................... 129

Pharmacodiagnostics ...................................................................................................... 130 Market for PGx testing ................................................................................................. 133 Plavix Testing ............................................................................................................... 134

CHAPTER NINE: HISTOLOGY AND CYTOLOGY ........................................137 Overview .......................................................................................................................... 137

in situ hybridization ........................................................................................................ 140

HPV Testing .................................................................................................................... 144 Tissue Microarrays ....................................................................................................... 148 Circulating Tumor Cells ............................................................................................... 150 Chromosome Analysis .................................................................................................. 155 Pharmacodiagnostic Histology ..................................................................................... 158



CHAPTER TEN: MICROBIOLOGY AND VIROLOGY ..................................165 Overview .......................................................................................................................... 165

Microbiology Market and Forecast ............................................................................... 166 Role of ID Testing in the Molecular Diagnostics Market ............................................. 167 Markets for Specific Infectious Disease Tests .............................................................. 168

Genome Sequencing ........................................................................................................ 170 Roche, Illumina and Life .............................................................................................. 171 Other Systems ............................................................................................................... 171

Mass Spectrometry ......................................................................................................... 173 Major Companies .......................................................................................................... 174 Market Estimate ............................................................................................................ 175

Blood Culture .................................................................................................................. 176 HIV ............................................................................................................................... 179 Market and Forecast ..................................................................................................... 179

Hepatitis ........................................................................................................................... 182 Market and Forecast ..................................................................................................... 182 Sexually Transmitted Diseases (STDs) ........................................................................ 184 Hospital Acquired Infections (HAIs) ............................................................................ 187 Market and Forecast ..................................................................................................... 190 Respiratory Tract Infections ......................................................................................... 191

Tuberculosis ..................................................................................................................... 195 Market and Forecast ..................................................................................................... 196

Fungal Infections ............................................................................................................. 200

CHAPTER ELEVEN: THE MARKET FOR MOLECULAR ASSAYS IN BLOOD TRANSFUSION MEDICINE .................................................................................203

Blood Pathogen Screening .............................................................................................. 204 Market and Forecast ..................................................................................................... 204

Blood Typing ................................................................................................................... 208 Molecular Blood Typing ............................................................................................... 211

CHAPTER TWELVE: THE MARKET FOR MOLECULAR ASSAYS IN ORGAN TRANSPLANT MANAGEMENT .........................................................................213

HLA Typing ..................................................................................................................... 213 Stem Therapy Matching ............................................................................................... 214 HLA Market and Forecast ............................................................................................ 216



CHAPTER THIRTEEN: THE MARKET FOR MOLECULAR ASSAYS IN PRENATAL AND NEONATAL TESTING .........................................................219

Overview .......................................................................................................................... 219

Market and Forecast ....................................................................................................... 221

FISH testing ..................................................................................................................... 222 Other Developments ..................................................................................................... 224

Neonatal Testing .............................................................................................................. 230

CHAPTER FOURTEEN: THE MARKET FOR MOLECULAR ASSAYS FOR INHERITED DISEASES ........................................................................................233

Arthritis ........................................................................................................................... 239

Gastrointestinal Conditions ........................................................................................... 241

Diabetes ............................................................................................................................ 242

Cardiovascular Disease................................................................................................... 246

Alzheimer’s Disease ........................................................................................................ 249

Parkinson’s Disease ........................................................................................................ 251

Psychiatric Disorders ...................................................................................................... 253

Autism .............................................................................................................................. 259

CHAPTER FIFTEEN: CONCLUSIONS AND STRATEGIC IMPLICATIONS – 2012 AND BEYOND ................................................................................................261

Expectations and Realities .............................................................................................. 261

Four Issues That Will Impact Market Success ............................................................. 263

CHAPTER SIXTEEN: COMPETITIVE ANALYSIS .........................................265 Companies and Vendors to Watch ................................................................................ 265

Acquisitions, Alliances and Collaborations .................................................................. 272

Looking Beyond Borders ................................................................................................ 277

CHAPTER SEVENTEEN: COMPANY PROFILES: TOP TIER IVD COMPANIES’ MOLECULAR BUSINESSES .....................................................279

Abbott Diagnostics .......................................................................................................... 280 Recent Revenue History ............................................................................................... 280 HLA .............................................................................................................................. 281 Molecular Histology ..................................................................................................... 281 Companion Tests .......................................................................................................... 282



Molecular Diagnostics .................................................................................................. 283 Infectious Diseases - Molecular .................................................................................... 286 IntelligentMDx Alliance ............................................................................................... 287 PLEX-ID ....................................................................................................................... 288

Alere ................................................................................................................................. 290 Recent Revenue History ............................................................................................... 290 ARKRAY ..................................................................................................................... 293

Beckman Coulter Inc./Danaher ......................... ........................................................... 294 Recent Revenue History ............................................................................................... 294 Instrumentation ............................................................................................................. 295

Becton, Dickinson and Company (BD) ......................................................................... 297 Recent Revenue History ............................................................................................... 297 The BD MAX Enterprise .............................................................................................. 298 Viper System ................................................................................................................ 300 Molecular Microbiology ............................................................................................... 300 BD GeneOhm ............................................................................................................... 301 Histology ...................................................................................................................... 301 Oncology, etc. ............................................................................................................... 302

bioMérieux Inc. ............................................................................................................... 304 Recent Revenue History ............................................................................................... 304 Molecular Oncology ..................................................................................................... 305 The Biocartis Program .................................................................................................. 306 Molecular Microbiology ............................................................................................... 307 NucliSENS .................................................................................................................... 307 Product Development ................................................................................................... 308

Bio-Rad Laboratories Inc. .............................................................................................. 309 Recent Revenue History ............................................................................................... 309

Gen-Probe Inc. ................................................................................................................ 311 Recent Revenue History ............................................................................................... 311 Product development .................................................................................................... 312 Expansion ..................................................................................................................... 313 Prostate Cancer ............................................................................................................. 314 STDs ............................................................................................................................. 315 Panther System ............................................................................................................. 315 HPV .............................................................................................................................. 316 Transplant/HLA testing ................................................................................................ 317 Infectious Diseases ....................................................................................................... 318 Blood Bank ................................................................................................................... 318

Hologic, Inc. ..................................................................................................................... 320 Recent Revenue History ............................................................................................... 320

Instrumentation Laboratory (IL) .................................................................................. 323 Recent Revenue History ............................................................................................... 323

Ortho Clinical Diagnostics ............................................................................................. 324 Recent Revenue History ............................................................................................... 324



QIAGEN N.V. .................................................................................................................. 325 Recent Revenue History ............................................................................................... 325 Market Expansion ......................................................................................................... 327 Histology ...................................................................................................................... 329 Infectious diseases ........................................................................................................ 329 Rotor-Gene ................................................................................................................... 330 Oncology/Personalized Medicine ................................................................................. 331 TB ................................................................................................................................. 334 HPV .............................................................................................................................. 335 HLA .............................................................................................................................. 336 Automation for the Future ............................................................................................ 336 Women’s Health ........................................................................................................... 337 Point of Care ................................................................................................................. 338 Sequencing .................................................................................................................... 340

Roche Diagnostics ........................................................................................................... 342 Recent Revenue History ............................................................................................... 342 Miscellaneous ............................................................................................................... 344 Viral Load ..................................................................................................................... 345 STDs ............................................................................................................................. 346 Companion Tests .......................................................................................................... 347 Sample Preparation ....................................................................................................... 350 Tissue Diagnostics ........................................................................................................ 350 Blood Bank ................................................................................................................... 351 Sequencing .................................................................................................................... 352 Microarrays ................................................................................................................... 354

Siemens Healthcare Diagnostics .................................................................................... 355 Recent Revenue History ............................................................................................... 355 Histology ...................................................................................................................... 356 Molecular ...................................................................................................................... 356 Sequencing .................................................................................................................... 357 Companion Tests .......................................................................................................... 358

Sysmex Corporation ....................................................................................................... 359 Recent Revenue History ............................................................................................... 359

Thermo Fisher Scientific Inc. ......................................................................................... 361 Recent Revenue History ............................................................................................... 361 Allergy .......................................................................................................................... 363

CHAPTER EIGHTEEN: COMPANY PROFILES: MAJOR MOLECULAR TEST COMPANIES ...........................................................................................................365

Affymetrix, Inc. ............................................................................................................... 366 Histology ...................................................................................................................... 369 Whole Genome Analysis .............................................................................................. 371

Agilent Technologies Inc. ............................................................................................... 373 Research Products ......................................................................................................... 375



Asuragen, Inc. .................................................................................................................. 377 Oncology ...................................................................................................................... 377 Inherited Diseases ......................................................................................................... 380 Controls ........................................................................................................................ 381 Sample Collection ......................................................................................................... 381 Sequencing .................................................................................................................... 382

Beijing Genome Institute (BGI) ..................................................................................... 384 BGI Projects.................................................................................................................. 385

BioFire Diagnostics, Inc. ................................................................................................. 387 Respiratory Panel .......................................................................................................... 388 Environmental Testing .................................................................................................. 390

Caliper Life Sciences ....................................................................................................... 391 Clinical Diagnostics ...................................................................................................... 391 Sequencing .................................................................................................................... 393 Life Sciences ................................................................................................................. 395

Celera Diagnostics ........................................................................................................... 396

Cepheid ............................................................................................................................ 399 Market Expansion ......................................................................................................... 400 HAI ............................................................................................................................... 401 Personalized Medicine .................................................................................................. 402 TB ................................................................................................................................. 403 Infectious Diseases ....................................................................................................... 404

Eiken Chemical Co., Ltd ................................................................................................ 404

Enzo Biochem Inc. .......................................................................................................... 408 ColonSentry .................................................................................................................. 409 Alliances ....................................................................................................................... 410 IP Protection ................................................................................................................. 411

Epigenomics AG .............................................................................................................. 412

Fluidigm Corporation ..................................................................................................... 415 Prenatal ......................................................................................................................... 417

Illumina Inc. .................................................................................................................... 419 BeadXpress ................................................................................................................... 420 Sequencing .................................................................................................................... 422 Cytogenetics ................................................................................................................. 423 Sample Prep .................................................................................................................. 424 PCR ............................................................................................................................... 424 CLIA Lab Service ......................................................................................................... 425

Ipsogen SA ....................................................................................................................... 426

Life Technologies ............................................................................................................ 429 Ion Torrent Systems ...................................................................................................... 432 Personalized Medicine .................................................................................................. 434 PCR ............................................................................................................................... 436 Arrays ........................................................................................................................... 437



IVD Company Deals ..................................................................................................... 437 Life and Quidel develop diagnostics on the 7500 Fast Dx ........................................... 439 Sepsis ............................................................................................................................ 440 HIV ............................................................................................................................... 440 Informatics .................................................................................................................... 441 International Presence ................................................................................................... 441

Novartis Diagnostics ....................................................................................................... 443 Blood Bank ................................................................................................................... 443 International Programs .................................................................................................. 445 Blood Typing ................................................................................................................ 446 Molecular IVDs ............................................................................................................ 446 Companion Tests .......................................................................................................... 447

PerkinElmer, Inc. ............................................................................................................ 449 Prenatal and Neonatal Screening .................................................................................. 450 Personalized Medicine .................................................................................................. 452 Molecular and Sequencing Diagnostics ........................................................................ 453 Test Services ................................................................................................................. 454 Human Health Research ............................................................................................... 455

RainDance Technologies, Inc. ........................................................................................ 456 Product Development ................................................................................................... 457

Seegene, Inc. .................................................................................................................... 461 Instrumentation ............................................................................................................. 464

Transgenomic, Inc. .......................................................................................................... 465 Lab Services.................................................................................................................. 466 Diagnostic Tools Division ............................................................................................ 468 CTCs ............................................................................................................................. 470 Sequencing .................................................................................................................... 471

CHAPTER NINETEEN: MARKET PARTICIPANTS...................................................................................473

Alacris Theranostics GmbH ........................................................................................... 473

Astra Biotech GmbH ...................................................................................................... 474

Autogenomics Inc. ........................................................................................................... 476

Biocartis SA ..................................................................................................................... 477

Biofortuna Ltd. ................................................................................................................ 480

Biotype Diagnostic GmbH .............................................................................................. 481

BlueGnome ...................................................................................................................... 482

DiaGenic ASA .................................................................................................................. 485

DiagnoCure ...................................................................................................................... 487

ELITech Group ............................................................................................................... 488

EraGen Biosciences Inc. ................................................................................................. 490



Genetic Technologies Limited ........................................................................................ 491

Victoria, Australia ........................................................................................................... 491

www.gtglabs.com ............................................................................................................. 491

GenMark Diagnostics Inc. .............................................................................................. 492

Helicos BioSciences ......................................................................................................... 494

IRIS International, Inc. .................................................................................................. 495 Cytology ....................................................................................................................... 497

Luminex Corporation ..................................................................................................... 497 IVD Expansion ............................................................................................................. 499 Cystic Fibrosis .............................................................................................................. 501 MAGPIX Multiplexing ................................................................................................. 502

Meridian Bioscience, Inc. ............................................................................................... 502 Bioline .......................................................................................................................... 504

Nanosphere, Inc. .............................................................................................................. 505 Infectious Diseases ....................................................................................................... 507 Hospital Acquired Infections ........................................................................................ 507

Sony DADC Biosciences ................................................................................................. 509 Cell Sorting ................................................................................................................... 510 Mass Spectrometry ....................................................................................................... 511

TrimGen Genetic Technology ........................................................................................ 512

TrovaGene, Inc. ............................................................................................................... 513 Prenatal ......................................................................................................................... 515

CHAPTER TWENTY: PROMISING COMPANIES ..........................................517 Ahram Biosystems, Inc. .................................................................................................. 517

Allegro Diagnostics Corp................................................................................................ 518

Amoy Diagnostics Co. Ltd. ............................................................................................. 519

Anagnostics Bioanalysis GmbH ..................................................................................... 520 Sample Preparation ....................................................................................................... 522

Applied BioCode, Inc. ..................................................................................................... 522

ArcticDx Inc. ................................................................................................................... 524

Ariosa Diagnostics ........................................................................................................... 526

Axela Inc. ......................................................................................................................... 526

BioHelix Corporation ..................................................................................................... 528

BioNanomatrix/ BioNano Genomics ............................................................................. 530

BJS Biotechnologies ........................................................................................................ 531

DiagCor Bioscience Inc. Ltd. ......................................................................................... 532



DxTerity Diagnostics Inc. ............................................................................................... 533

Epistem plc ...................................................................................................................... 534

Exiqon A/S ....................................................................................................................... 535

Exonhit ............................................................................................................................. 536

GeneNews Limited .......................................................................................................... 537

Genome Diagnostics BV (GenDx) .................................................................................. 539

Genomica S.A.U. ............................................................................................................. 540

Genorama Ltd. ................................................................................................................ 541

Great Basin Corporation ................................................................................................ 543

Health Discovery Corporation (HDC) .......................................................................... 544

IncellDx, Inc. .................................................................................................................... 545

Insight Genetics ............................................................................................................... 547

IntegenX Inc. ................................................................................................................... 549 Sample Transport .......................................................................................................... 551

Linkage Biosciences, Inc. ................................................................................................ 551

Med BioGene, Inc. (MBI) ............................................................................................... 552

Multiplicom ..................................................................................................................... 554

NABsys, Inc. .................................................................................................................... 555

Nanostring Technologies, Inc. ........................................................................................ 556

NIPD Genetics Ltd .......................................................................................................... 558

OptiGene Ltd ................................................................................................................... 559

Orion Genomics .............................................................................................................. 561

Oxford Gene Technology (OGT) ................................................................................... 562

PrimeraDx ....................................................................................................................... 564

Rheonix Inc. ..................................................................................................................... 565

Skyline Diagnostics B.V. ................................................................................................. 567

Spartan Bioscience Inc. .................................................................................................. 569

Stratos Genomics Inc. ..................................................................................................... 571

VolitionRx Limited ......................................................................................................... 572

WaferGen Biosystems, Inc. ............................................................................................ 573



CHAPTER TWENTY ONE: MOLECULAR NEWCOMERS ...........................575 DiaSorin S.p.A. ................................................................................................................ 575

Fujirebio Diagnostics, Inc. .............................................................................................. 577

GE Healthcare ................................................................................................................. 579 Cell Imaging ................................................................................................................. 581 Molecular Sequencing .................................................................................................. 582

Phadia AB ........................................................................................................................ 583

Quidel Corporation ......................................................................................................... 585 Alliances ....................................................................................................................... 587

Randox Laboratories Ltd. .............................................................................................. 588

TOSOH Corporation ...................................................................................................... 589

Transasia Bio-Medicals Ltd. .......................................................................................... 590

CHAPTER TWENTY TWO: TEST PLATFORM INNOVATIONS ................593 Advanced Liquid Logic, Inc. (ALL) .............................................................................. 593

Aquila Diagnostic Systems ............................................................................................. 595

Canon U.S. Life Sciences (CLS) ..................................................................................... 595

DNA Medicine Institute (DMI) ...................................................................................... 596

Espira, Inc. ....................................................................................................................... 597

Genia Technologies Inc. .................................................................................................. 598

Genisphere ....................................................................................................................... 599

Lumora Ltd. .................................................................................................................... 600

Michigan State University .............................................................................................. 601

NobleGen Biosciences ..................................................................................................... 602

Oxford Nanopore Technologies Ltd. ............................................................................. 603

QuantuMDx Group Limited .......................................................................................... 603

SensiQ Technologies, Inc. ............................................................................................... 605

Thermal Gradient, Inc. ................................................................................................... 606

Vela Diagnostics (VelaDx) .............................................................................................. 606

CHAPTER TWENTY THREE: SAMPLE PREPARATION SUPPLIERS ......609 Arcxis Biotechnologies .................................................................................................... 609

Argylla Technologies LLC ............................................................................................. 610

Biomatrica, Inc. ............................................................................................................... 611

Fluoresentric, Inc. ........................................................................................................... 614



New England Biolabs, Inc. (NEB) .................................................................................. 615

NorDiag ............................................................................................................................ 616

Norgen Biotek Corp. ....................................................................................................... 617

Phthisis Diagnostics ........................................................................................................ 618

PreAnalytiX GmbH ........................................................................................................ 619

QIAGEN N.V. .................................................................................................................. 620

Streck ............................................................................................................................... 622

ZyGEM Corp. Ltd. ......................................................................................................... 623

CHAPTER TWENTY FOUR: COMPANY PROFILES: INFORMATION TECHNOLOGY SPECIALISTS ...........................................................................625

Access Genetics ................................................................................................................ 625

CLC bio ............................................................................................................................ 626

CollabRx, Inc. .................................................................................................................. 629

Definiens ........................................................................................................................... 632

DNA Direct ...................................................................................................................... 634

DIYGenomics .................................................................................................................. 634

GenoSpace, LLC ............................................................................................................. 637

HolGenTech Inc. ............................................................................................................. 637

Ingenuity Systems ........................................................................................................... 640

MediSapiens Ltd. ............................................................................................................ 642

NextBio ............................................................................................................................. 643

Personalis ......................................................................................................................... 643

Portable Genomics .......................................................................................................... 644

Sciclips .............................................................................................................................. 645

Selventa ............................................................................................................................ 646

Sophic Systems Alliance ................................................................................................. 647

Wellpoint Inc. .................................................................................................................. 647

CHAPTER TWENTY FIVE: MICROBIOLOGY SPECIALISTS ..................649 Advanced Biological Laboratories (ABL) ..................................................................... 649

AdvanDx, Inc. .................................................................................................................. 651

Akonni Biosystems Inc. .................................................................................................. 653 Sample Preparation ....................................................................................................... 654 Test Systems ................................................................................................................. 655



Biomagnetics Diagnostics Corporation ......................................................................... 658

BlackBio S.L. ................................................................................................................... 660

Bruker BioSciences Corporation ................................................................................... 660

CapitalBio Corporation .................................................................................................. 663

Ceeram S.A.S. .................................................................................................................. 666

Cooperative Diagnostics, LLC ....................................................................................... 667

Curetis AG ....................................................................................................................... 668

Enigma Diagnostics Limited .......................................................................................... 669

Focus Diagnostics, Inc. ................................................................................................... 672

GenoID Ltd. ..................................................................................................................... 674

Great Basin Scientific, Inc. ............................................................................................. 675

Hain Lifescience GmbH.................................................................................................. 676

HiberGene Diagnostics Ltd ............................................................................................ 678

Ibis Biosciences ................................................................................................................ 679

iCubate Incorporated ..................................................................................................... 680

Immunexpress Group ..................................................................................................... 681

InDevR ............................................................................................................................. 682

Ingen Biosciences SA ...................................................................................................... 683

Intelligent Medical Devices, Inc. (IMDx) ...................................................................... 684

IQuum Inc. ....................................................................................................................... 686

Miacom Diagnostics GmbH ........................................................................................... 687

MicroPhage, Inc. ............................................................................................................. 688

Mobidiag Ltd ................................................................................................................... 690

Molecular Detection Inc. (MDI) .................................................................................... 690

Molzym GmbH & Co. KG ............................................................................................. 692

Myconostica ..................................................................................................................... 693

nanoMR Inc. .................................................................................................................... 694

NetBio ............................................................................................................................... 696

PathGEN Dx Pte. Ltd. .................................................................................................... 696

PathoGene ........................................................................................................................ 697

Pathogenica ...................................................................................................................... 698

SIRS-Lab ......................................................................................................................... 701

T2 Biosystems .................................................................................................................. 702



CHAPTER TWENTY SIX: BLOOD BANK SPECIALISTS .............................705 AbSorber AB ................................................................................................................... 705

AXO Science .................................................................................................................... 706

GMS Biotech .................................................................................................................... 707

Grifols, S.A. ..................................................................................................................... 708

Immucor, Inc. .................................................................................................................. 710

Progenika Inc. ................................................................................................................. 711

CHAPTER TWENTY SEVEN: COMPANIES SPECILAIZING IN CIRCULATING TUMOR CELLS ........................................................................715

ApoCell, Inc. .................................................................................................................... 715

Biocept, Inc. ..................................................................................................................... 717

Clearbridge BioMedics ................................................................................................... 719

Cynvenio Biosystems, Inc. .............................................................................................. 720

On-Q-ity ........................................................................................................................... 721

RareCyte, Inc. .................................................................................................................. 723

ScreenCell ........................................................................................................................ 723

Veridex, LLC ................................................................................................................... 725

CHAPTER TWENTY EIGHT: COMPANY PROFILES: HISTOLOGY SPECIALISTS .........................................................................................................729

Advanced Cell Diagnostics ............................................................................................. 729

Biocare Medical, LLC .................................................................................................... 732

ChipDX, LLC .................................................................................................................. 733

Cymogen Dx, LLC .......................................................................................................... 734

Dako A/S .......................................................................................................................... 736 Alliances ....................................................................................................................... 738 Companion Diagnostics ................................................................................................ 739

Horizon Discovery Ltd.................................................................................................... 741

HTG Molecular Diagnostics ........................................................................................... 742 Automation ................................................................................................................... 744

Mitomics Inc. ................................................................................................................... 745

Norchip............................................................................................................................. 746



CHAPTER TWENTY NINE: COMPANY PROFILES: SELECTED TEST SERVICE PROVIDERS .........................................................................................753

23andMe ........................................................................................................................... 753

Agendia BV ...................................................................................................................... 756 Market Expansion ......................................................................................................... 758 Product News ................................................................................................................ 758

AltheaDx Diagnostics, Inc. ............................................................................................. 760

Ambry Genetics ............................................................................................................... 762

Aria Diagnostics, Inc. (formerly Ariosa Diagnostics) ................................................. 763

ARUP Laboratories ........................................................................................................ 764

AssureRx Health, Inc. ..................................................................................................... 766

Avesthagen Limited ........................................................................................................ 767

Bio-Reference Laboratories, Inc. (BRLI) ..................................................................... 767

bioTheranostics ............................................................................................................... 771

Bostwick Laboratories .................................................................................................... 773

CardioDx, Inc. ................................................................................................................. 774

Caris Life Sciences .......................................................................................................... 777

Castle Biosciences Inc. .................................................................................................... 779

CBLPath .......................................................................................................................... 780

Chronix Biomedical Inc. ................................................................................................. 781

Clarient Inc. ..................................................................................................................... 783

CombiMatrix Molecular Diagnostics, Inc. ................................................................... 787

Complete Genomics ........................................................................................................ 789

Crescendo Bioscience, Inc. ............................................................................................. 793

deCode genetics ehf ......................................................................................................... 794 Gene Variants ............................................................................................................... 796

DermaGenoma, Inc. ........................................................................................................ 798

Diagnósticos da América (DASA) .................................................................................. 799

Diatherix Laboratories Inc. ............................................................................................ 800

EXACT Sciences Corporation ....................................................................................... 801

Exosome Diagnostics ....................................................................................................... 803

Genelex Corporation ...................................................................................................... 806

Genetadi Biotech SL ....................................................................................................... 807

Genomic Health, Inc. ...................................................................................................... 808 Service Spin off ............................................................................................................ 811



Expansion ..................................................................................................................... 811 Sequencing .................................................................................................................... 812 Information Technology ............................................................................................... 813

Genoptix Medical Laboratory ....................................................................................... 814

GenoVive LLC ................................................................................................................ 815

Inostics GmbH ................................................................................................................. 817

IntegraGen SA ................................................................................................................. 818

Interleukin Genetics, Inc. ............................................................................................... 820

Knome, Inc. ...................................................................................................................... 822

Lab21 Limited ................................................................................................................. 824 Services ......................................................................................................................... 825 Products Division .......................................................................................................... 826 Expansion ..................................................................................................................... 827

Laboratory Corporation of America Holdings (LabCorp) ......................................... 829

LifeCodexx AG ................................................................................................................ 833

Lineagen Inc. ................................................................................................................... 834

Lumigenix ........................................................................................................................ 835

Mayo Medical Laboratories ........................................................................................... 836

MDxHealth SA (formerly Oncomethylome Sciences) ................................................. 838

Medical Diagnostic Laboratories L.L.C. (MDL) .......................................................... 840

Myriad Genetics, Inc....................................................................................................... 842 Alliances ....................................................................................................................... 843 Test Information ........................................................................................................... 845 Patent Issues.................................................................................................................. 846

Natera Inc. ....................................................................................................................... 848

Navigenics ........................................................................................................................ 849

NewGene .......................................................................................................................... 850

Pathway Genomics .......................................................................................................... 851

Pathwork Diagnostics ..................................................................................................... 853

PGXL Laboratories ........................................................................................................ 855

Precision Therapeutics ................................................................................................... 856

Prometheus Laboratories Inc. ....................................................................................... 859 Patent Issues.................................................................................................................. 861

Quest Diagnostics ............................................................................................................ 862 Information Technology ............................................................................................... 866

Ridge Diagnostics, Inc. ................................................................................................... 866

Rosetta Genomics Ltd. .................................................................................................... 867



Rules-Based Medicine, Inc. (RBM) ............................................................................... 871

Sequenom Inc. ................................................................................................................. 872 Sequenom Center for Molecular Medicine ................................................................... 874 Market Expansion ......................................................................................................... 875 Prenatal Patent .............................................................................................................. 876 Genetic Analysis Products ............................................................................................ 877

Sequenta, Inc. .................................................................................................................. 878

Signal Genetics ................................................................................................................ 879

Sonic Healthcare ............................................................................................................. 881

SureGene, LLC ............................................................................................................... 882

Veracyte. Inc. ................................................................................................................... 883

Verinata Health, Inc. ...................................................................................................... 885

XDx Inc. – Expression Diagnostics ................................................................................ 887



L I S T O F E X H I B I T S

CHAPTER ONE: EXECUTIVE SUMMARY Table 1-1: Common Next Generation Molecular Test Traits ......................................... 2

Table 1-2: Selected salient developments for now and the future .................................. 3

Table 1-3: Exchange Rate Fluctuations, 2009-2012 ......................................................... 4

Table 1-4: Molecular Diagnostics Market by Type (Microbiology/Virology, Histology, Blood Screening, Prenatal, Coagulation, Inherited Diseases, Tissue Typing, Cancer Markers, Pharmacodiagnostics, CTCs) ............................................................................ 9

CHAPTER TWO: INTRODUCTION

Table 2-1: Common Next Generation Molecular Test Traits ....................................... 16

Table 2-2: Selected Salient Developments for Now and The Future ............................ 18

Table 2-3: Key Molecular Technologies .......................................................................... 20

Table 2-4 Selected Nucleic Acid Testing Platforms, 2009-2012 .................................... 22

Table 2-5: Selected Sample Preparation Tools, 2012 ..................................................... 26

Table 2-6: Revenues For A Selection of Molecular Test Service Labs ......................... 28

Table 2-7: Selected Company-sponsored Labs, 2012 ..................................................... 30

Table 2-8: Selected open-source variant annotation software ...................................... 33

Table 2-9: Selected Information Technology Innovations in Molecular Testing ........ 34

Table 2-10: Selected App Products .................................................................................. 35

Table 2-11: Selected Molecular Test Miniaturization Innovations .............................. 36

Table 2-12: Selected Sample-to-Result Innovations ....................................................... 38

Table 2-13: Selected Mass Specrometry Clinical Lab Applications ............................. 42

Table 2-14: Worldwide Molecular Test Sales by Type,2017 (Microbiology/ Virology, Histology, Blood Screening, Prenatal, Coagulation, Inherited Diseases, Tissue Typing, Cancer Markers, Pharmacodiagnostics, CTCs) .................. 43

Table 2-15: Key Molecular Test Applications and Technologies ................................. 44

Table 2-16: Selected Reference Lab and IVD Company Collaborations ..................... 46

CHAPTER FOUR: SEQUENCING – HYPE AND REALITY

Table 4-1: Major Sequencing Platforms ......................................................................... 75

Table 4-2: Selected Innovations in Sequencing .............................................................. 77



Table 4-3: Selected Sequencing Informatics Tools ........................................................ 79

Table 4-4: Selected PCR Testing Platforms, 2009-2012 ................................................ 84

Table 4-5: Selected Sequencing-Based Cancer Reagents .............................................. 86

CHAPTER FIVE: MARKET ANALYSIS: WORLD MARKETS Table 5-1: Market Penetration Of Clinical Molecular Diagnostics, by Geographic Area (N. America, W. Europe, Japan, China, ROW), 2012-2017 .......................................... 94

Table 5-2: Key Drivers for Healthcare in India ........................................................... 112

CHAPTER SIX: THE MARKET FOR BLOOD MARKERS IN CANCER

Table 6-1: Selected Cancer Markers, 2012 ................................................................... 118

CHAPTER SEVEN: THE MARKET FOR MOLECULAR ASSAYS IN HEMATOLOGY

Table 7-1: Selected Innovations in Molecular Hematology ......................................... 125

CHAPTER EIGHT: THE MARKET FOR MOLECULAR ASSAYS IN COAGULATION AND CARDIAC CARE

Table 8-1: Selected Molecular Pharmacodiagnostics for Anticoagulant Drug Testing, 2012 .......................................................................................................... 135

CHAPTER NINE: HISTOLOGY AND CYTOLOGY

Table 9-1: Worldwide Molecular Histology/Cytology Sales, 2012-2017 (in situ hybridization, HPV, Tissue Microarrays) .................................................................... 139

Table 9-2: Selected Molecular Histology Innovations, 2012 ....................................... 143

Table 9-3: Selected HPV Test Innovations ................................................................... 147

Table 9-4: Selected Tissue Microarray Products, 2008-2010 ...................................... 150

Table 9-5: Selected Innovations in CTC Technology ................................................... 154

Table 9-6: Selected Flow Cytometry Innovations ........................................................ 155

Table 9-7: Selected companies involved in chromosomal analysis of cancer cells .... 157

Table 9-8: Major Pharmacodiagnostic Markers .......................................................... 160

Table 9-9: Selected Pharmacodiagnostic Histology Tests ........................................... 163

CHAPTER TEN: MICROBIOLOGY AND VIROLOGY

Table 10-1: Molecular Test Sales, Microbiolog/Virology, 2012-2017 (HIV, Hepatitis, GC/Chlamydia, HAI, Respiratory, Organism ID, Mycobacteria, TB, Blood Culture, Others) .................................................................................................. 168



Table 10-2: Selected Next Generation Sequencing Platforms ..................................... 172

Table 10-3: Selected Advanced Microbiology Platforms ............................................ 176

Table 10-4: Selected Advanced Techniques for Positive Blood Cultures .................. 179

Table 10-5: Selected New Molecular STD Assays, 2012 .............................................. 186

Table 10-6: Selected Molecular HAI Test Innovations, 2012 ...................................... 191

Table 10-7: Selected Molecular Tests for Respiratory Tract Infections .................... 195

Table 10-8: Selected Molecular Tests for TB ............................................................... 200

Table 10-9: Selected Molecular Tests for Fungal Infections ....................................... 201

CHAPTER TWELVE: THE MARKET FOR MOLECULAR ASSAYS IN ORGAN TRANSPLANT MANAGEMENT

Table 12-1: Selected HLA Typing Tests, 2012 .............................................................. 218

CHAPTER THIRTEEN: THE MARKET FOR MOLECULAR ASSAYS IN PRENATAL AND NEONATAL TESTING

Table 13-1: Developments in Molecular Prenatal Testing, 2012 ................................ 230

CHAPTER FOURTEEN: THE MARKET FOR MOLECULAR ASSAYS FOR INHERITED DISEASES

Table 14-1: Most Frequently Requested Genetic Tests ............................................... 234

Table 14-2: Selected Single Gene Disorders ................................................................. 236

Table 14-3: Selected Molecular Tests for Inherited Diseases, 2012 ............................ 238

Selected Molecular Tests for Inherited Diseases, 2012 ................................................ 239

Table 14-4: Selected Innovations in Genetic Tests for CVD ....................................... 249

Table 14-5: Selected Personalized Tests For CNS Diseases & Psychiatric Disorders ......................................................................................................................... 258

CHAPTER SIXTEEN: COMPETITIVE ANALYSIS Table 16-1: Estimated Molecular Test Revenues of Selected IVD Vendors, 2009-2012 ......................................................................................................... 267

Table 16-2: Selected Acquisitions in Molecular Diagnostics ....................................... 274

Table 16-3: Selected Collaborations and Licensing and Distribution Alliances ....... 276

Table 16-4: Selected Market Expansion Activity ......................................................... 278



C H A P T E R O N E

Executive Summary

INTRODUCTION

The 60th anniversary of the discovery of DNA will be celebrated in 2013. On April 25, 1953 the journal Nature published the discovery of the double helix structure of DNA by James Watson and Francis Crick. Similar to many other scientific innovations, no one at that time realized that this might turn out to be one of the most significant discoveries of our time. Now virtually every segment of clinical laboratory medicine has been touched by research in genetics.

The first generation of molecular testing tools includes basic, time consuming and labor intensive techniques such as the Southern blot, DNA probes, pulsed field gel electrophoresis and capillary electrophoresis. These techniques are still used however their influence in the evolution of molecular testing has been overshadowed by the power of PCR and other amplification techniques, sequencing, mass spectroscopy, microarrays and biochips.

The full development of PCR by F. Hoffmann La Roche, Basel, Switzerland ushered in the second generation of molecular testing tools. These were first used for medical research and now play an essential role diagnostic medicine and in patient care.

In 1991, Cetus sold the PCR intellectual property to F. Hoffmann-La Roche Ltd. for $300 million. This proved to be the major building block of modern molecular testing. This is partly due to the flexibility of the technology but mostly due to Roche’s

One: Executive Summary 2



liberal licensing strategy that has resulted in more than 400 licensees - companies and organizations.

PCR has become the most widely used method for amplifying DNA. More importantly it was the catalyst for the beginning of modern molecular testing. PCR and automated sequencing instrumentation are the tools used by the Human Genome Project and Celera Genomics Corp. (Rockville, MD) to produce the draft sequence of the human genome that was published in 2000. These tools have also been used to sequence the genome of many other animals, pathogens and non-pathogenic organisms.

In 2003 the Human Genome Project published the identification of all the building blocks in the human DNA. In all, since 2003, research has linked nearly 100 DNA variants to as many as 40 common diseases and traits.

We now are in the full evolution of the third generation of molecular testing or the “next generation” of a number of molecular test solutions. These have had several common effects on molecular diagnostics that are leading to a further expansion of clinical lab testing possibilities:

Table 1-1

Common Next Generation Molecular Test Traits

• Reduced test time to hours versus days • More test data leads to a better understanding of disease processes • Easier to use and thus found in more clinical labs • Automated sample to answer test procedures • A variety instrument choices – from high throughput systems to table top low

volume options • Data analysis algorithms incorporated in testing system

Source: Kalorama Information

In the glow of the completion of the Human Genome Project, many industry

experts predicted that many diseases would be diagnosed using molecular tests by 2005 and 2010 at the latest. Also the techniques developed for the project would be transferred to testing in routine clinical labs. At this time molecular testing is making a valuable contribution to clinical diagnostics on many fronts, but is far from the expected panacea. Molecular testing has made a huge contribution to cancer diagnosis and therapy




management. In infectious disease diagnostics DNA-based tests allow the detection of difficult to culture pathogenic bacteria or viruses and to uncover the epidemiology of infections. The analysis of mutations of known human genes is used to diagnose common disorders, inherited diseases, or different types of cancer and can indicate the prognosis of malignant diseases. But the routine and substantial use of molecular tests is yet to be realized. Part of the process of speading the presence of molecular testing is linked to technological parameters needed to facilitate the democratization of the genre from elite and large laboratories to testing sites in small venues and in those with limited resources.

So what are the most salient developments for now and the future of molecular diagnostics (not in order of importance):

Table 1-2

Selected salient developments for now and the future

• User-friendly platforms for use in low volume and resource limited labs • Market cleared validated tests for analytes other than the first wave of molecular

tests for traditional STDs and coagulation factors • Market cleared validated tests on sample-to-result platforms for infectious

diseases, oncology, autoimmune diseases, psychosocial conditions, neurological diseases and others

• Quality control products and assurance programs • Room temperature transport of samples • Information technology for data analysis and probability results reporting • mHealth options for the interpretation of test results performed in routine clinical

labs • Clinical studies to demonstrate the clinical utility of molecular tests • Partnerships with pharmaceutical companies to demonstrate the efficacy of

companion diagnostics • Realistic pricing and reimbursement for molecular tests • Democratization of valuable infectious disease and other molecular tests to far

flung labs everywhere





Table 1-4

Worldwide Molecular Test Sales, 2012-2017

(Sales $ millions)

Segment Sales % Sales % 2012 Mkt 2017 Mkt CAGR Microbiology/Virology Histology Blood Screening Prenatal Coagulation Inherited diseases Tissue Typing Cancer Markers Pharmacodiagnostics CTCs TOTAL


This market estimate covers market authorized assays and reagents. In-lab

developed tests, which account for a large portion of this IVD segment are not included. It is beyond the scope of this report to estimate the market for these in-lab developed tests. However, with the increased market penetration of molecular assays, demand will decrease the cost of commercialized kits and the need for standardization will make commercial kits more attractive, especially for small labs.

Overall, clinical molecular testing remains a phenomenon of the developed world. At least 80% of the molecular assays performed are concentrated in the developed world—North America and Western Europe. Recently molecular test companies and laboratories have established partnerships in the the top seven emerging markets: Brazil, Russia, India, China, South Korea, Mexico and Turkey. As market growth in the U.S. has started to reach a steady state of some 5% annual growth, these emerging markets offer opportunities for growth and market expansion.

Two: Introduction 42



Table 2-13

Selected Mass Specrometry Clinical Lab Applications

Company Location Area Details StatusbioMérieux France micro VITEK MS, ID/AST on Shimadzu mass spec CE Bio-Rad Laboratories U.S. instr with Bruker products for Bio-Rad's SELDI

platform dev

Bruker Biosciences U.S. histo MALDI Molecular Imager, mass spec from tissue

mkt

Bruker Biosciences U.S. micro MALDI Biotyper CE Bruker Biosciences U.S. micro MALDI SepsiTyper CE Intrinsic Bioprpbes/Thermo Fisher

U.S. immuno beta-2- microglobulin, cystatin C, RBP, MASSAY platform

mkt

KIESTRA Lab Automation

Netherlands automation MalditofA, automatic colony picker with Bruker

dev

Ortho Clinical Diagnostics U.S. diabetes Intrinsic Bioprobes diabetes markers dev PerkinElmer Inc. U.S. mol PE's exact mass TOF with Abbott's PLEX-ID dev SensiGen LLC U.S. mol AttoSense mass spec molecular assays dev Sequenom U.S. histo PCR-MS AttoSense HPV dev Sequenom U.S. mol MassARRAY Compact 96 system rsch Sequenom U.S. mol MassARRAY Analyzer 4 RUO Sequenom U.S. prenatal SensiGene Fetal RHD Genotyping test srvc Sequenom U.S. prenatal MaterniT21, a noninvasive Down Syndrome srvc Sequenom U.S. mol late stage age-related macular degeneration srvc Thermo Fisher U.S. ID/AST ID/AST on Bruker biotyper dev Vermillion Inc. U.S. card peripheral artery disease markers, mass spec dev

Source: Kalorama Information, company reports

TESTS AND TECHNOLOGIES IN 2012

The clinical market for molecular assays can be segmented in ten main categories of tests that include: blood screening, cancer markers, coagulation, CTCs, histology, inherited diseases, microbiology/virology, pharmacodiagnostics, prenatal and tissue typing.

The 2012 market for molecular-based assays, worldwide is estimated at $5,297 million. The market will grow 8% annually and will reach $7,630 million in 2017 worldwide (see Table 2-14).

Four: Sequencing 78



Table 4-2 (cont.)

Selected Innovations in Sequencing

Company Location Area Details StatusIllumina U.S. instr HiSeq 2000 RUO Illumina U.S. array iScanSQ, microarray RUO Illumina U.S. histo TruSeq Amplicon - Cancer Panel, MiSeq RUO Illumina U.S. instr MiSeq table top RUO Illumina U.S. sample Nextera XT DNA Sample Preparation RUO Illumina U.S. genome $19,500, individual genome sequencing

service srvc

Illumina U.S. test RapidTrack Whole Genome Sequencing srvc InteGenX U.S. inf dis Apollo 100 System, Sample-to-Sequence dev Intelligent Bio-Systems U.S. instr DNA sequencing system, biochip $250 dev Life Technologies U.S. instr 3500 series, electrophoresis gene sequencing CE Life Technologies U.S. instr SOLiD Sequencing Systems RUO Linkage Biosciences U.S. celiac LinkSēq, HLA-B5701, Celiac Disease RUO Linkage Biosciences U.S. prenatal LinkSēq HLA product line RUO Linkage Biosciences U.S. PGx LinkSēq, HLA-DQ Novartis' osteoarthritis Rx RUO Medical Diagnostic Lab U.S. vaginosis vaginosis PCR panels srvc Microchip Biotechnologies

U.S. smpl prep

sample preparation, pyrosequencing biochip dev

Multiplicom Belgium breast BRCA MASTR Dx, seq reagent CE NanoString U.S. RNA nCounter miRNA Expression, RUO NobleGen Biosciences U.S. instr Optipore DNA sequencing platform, nano

sequencing dev

Olink Genomics Sweden smpl prep Selector Technology, sequencing samples dev Oxford Nanopore Tech UK instr label-free nanopore sequencing dev Pacific Biosciences U.S. instr Single Molecule Real Time (SMRT), chip dev PathoGenetix U.S. micro Genome Sequence Scanning (GSS) dev Pathogenica U.S. test DxSeq, Cloud DNA sequencing RUO Promega Corporation U.S. instr Maxwell 16, DNA/RNA sequencing CE Qiagen Netherlands cancer Intelligent Bio-Systems, sequencing, cancer dev Qiagen Netherlands sample sample preparation instruments dev Quantalife U.S. micro Droplet Digital PCR system, flow RUO RainDance Technologies U.S. histo DeepSeq, digital sequencing, FFPE tissue

samples RUO

RainDance Technologies U.S. autism Syndromic Autism 62-Gene Panel RUO RainDance Technologies U.S. arthritis RainDance HLASeq Research Screening

Panel RUO

RainDance Technologies U.S. cancer Cancer Hotspot Panel RUO Roche Diagnostics U.S. SNP bench-top GS Junior System RUO Roche Diagnostics U.S. leukemia GS GType TET2/CBL/KRAS RUO Rubicon Genomics U.S. instr PicoPlex-NGS WGA (whole genome

amplification) RUO



C H A P T E R S E V E N

The Market For Molecular Assays In Hematology

Hematology is the study of peripheral blood and bone marrow cells in order to diagnose various diseases of the blood including leukemias, anemia and autoimmune diseases. Historically, diagnosing blood diseases and disorders has included a three-pronged approach: the complete blood count (CBC), blood chemistries and microscopic investigation.

The basis of hematology testing is the complete blood count (CBC) that provides information on blood components: hemoglobin, hematocrit, red blood cells, white blood cells, reticulocytes, platelets. The CBC is run as part of the normal work up in an annual health exam and for every inpatient. With the CBC, all major cell lines, platelet numbers as well as signs of anemia and malignancy can be investigated.

The Coulter Counter revolutionized the CBC by standardizing the analysis of blood cells. By the mid 1980's just about every hematology lab, worldwide, had a Coulter Counter of one type or another and with varying degrees of automation. Now this same principle could invigorate the hematology lab.

Cell sorting by the Coulter Principle is the basis of all hematology analyzers. It is also the basis of flow cytometry. Flow cytometry is not commonly used in the clinical laboratory, it is primarily a research-based tool used for blood cancer cell analysis and for CD counting for HIV patients.

Seven: Hematology 122



High-end hematology analyzers and flow cytometers have more in common than ever before. With the technological enhancements found in most high-end hematology analyzers such as laser optics and the ability to perform multiple stain analysis, these instruments have become clinical flow cytometers. Each of the major hematology analyzer companies markets a model with advanced flow cytometry enhancements.

Thus, routine hematology labs that have these more technology sophisticated hematology analyzers are now equipped to offer flow cytometry-based assays on a routine hematology lab analyzer. This is important, because these analyzers are perfectly placed to respond to some of the major trends at play in molecular diagnostics. As medical research increases physicians' understanding of cell biology, morphology, and function, more and more blood-based molecular assays will come to market in many areas—cancer, diabetes, cardiac diseases, prenatal analysis and others. New hematology analyzers will have the ability to perform these tests.

One possibility is to move new generation molecular tests into the routine lab. The most appropriate would be circulating tumor cell analyses. High-end hematology analyzers are ubiquitous in every large clinical and reference lab. Further they already can detect very rare blood cells for anemias and blood cancers from the general mix of circulating blood cells.

The traditional classifications of lymphoma and leukemia are based purely on morphology, but the latest classifications, such as the Revised European-American Classification of Lymphoid Neoplasms (REAL classification) and the World Health Organization Classification of Lymphoid Neoplasms (WHO classification), require a deeper look at these cancer cells including molecular cytogenetic analysis. This has become necessary because new therapeutics target these molecular mutations. The techniques use include flow cytometry, immunophenotyping and karyotyping that may also help predict the prognosis of disease.

FLOW CYTOMETRY

Flow cytometry (flow) is a technique for counting and examining microscopic particles, such as cells and microspheres, by suspending them in a stream of fluid and passing them by an electronic counting apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical characteristics of up to thousands of particles per




second. Flow cytometry is routinely used in the diagnosis of blood cancers and HIV testing. Based on these features, flow cytometry-based tests are moving into urinalysis, prenatal testing and live cell analysis (CTCs), mostly for tumor cells.

The goal is to detect abnormal cells present in body fluids—blood, bone marrow, urine, saliva, etc. early in the disease. For early diagnosis of leukemias and for detecting therapeutic relapse, sensitive, high throughput assays which can detect one cancer cell in the presence of at least 1,000 non-cancerous cells are needed.

Until recently flow cytometry has been used exclusively for the analysis of blood based or liquid tumors and CD4/CD8 counts in HIV/AIDS diagnosis. The primary advantage of flow cytometry compared with other cell screening methods is the ability to rapidly screen large numbers of single cells and to identify rare sub-populations in a large number of cells. Further, with the appropriately labeled antibodies of molecular probes, flow cytometry can analyze multiple features of individual cells.

Flow cytometry is being extensively used in the analysis of hematological malignancies. Flow cytometry also has the potential to monitor residual disease in solid tumor patients through the detection of rare circulating tumor cells in the peripheral blood or bone marrow.

For example, Sequenta Inc. (San Francisco, CA) has developed an assay that is capable of measuring the antigen receptor sequences of the millions of white blood cells that are found in circulation. Proprietary multiplex PCR assays have been developed that allow recombined lymphocyte DNA from blood and tissue to be amplified and sequenced. These sequences can be used with proprietary informatics to reconstruct full DNA and protein sequences from T and B cells. The assays allow all of the several million lymphocytes found in up to 10mL of blood to be measured and quantitated.

Biocept’s (San Diego, CA) OncoCEE-BR provides cell enumeration and diagnostic biomarker analyses for HER2. Competitive CTC tests rely on the expression of the epithelial cell adhesion (EpCAM) molecule and cytokeratins for CTC capture, detection and enumeration. This approach may exclude CTCs that have undergone intrinsic modifications of their phenotype, such as the epithelial-to-mesenchymal transition (EMT), thought to be critical for metastasis.

On-Q-ity (Waltham, MA) is developing diagnostics to determine optimal treatment choice for cancer patients at each stage of the treatment cycle - from the first




therapy choice to monitoring for recurrence. The company's circulating tumor cell (CTC) technology and predictive biomarker platform allows for the analysis of tumor tissue samples as well as the capture of rare tumors cells that are circulating in a cancer patient's blood. Those cells are then monitored for molecular changes that are characteristic of therapy response. This combination enables minimally invasive real-time data on a patient's status - allowing treatment adjustments before changes are visible with any other technology.

May 2010, IncellDx (Menlo Park, CA) announced a supply agreement with Accuri Cytometers, Inc. (Ann Arbor, MI) that combines IncellDx’s HPV OncoTect E6, E7 mRNA test with the capabilities available from the Accuri C6 Flow Cytometer technology. The combination provides quantification of the over expression of E6/E7 mRNA in each cell, as well as the total proportion of cells that are over expressing.

The world market for flow cytometry (not exclusively for molecular cell analysis) is estimated at $1,100 million in 2012, and with 2% annual growth will reach $1,200 by 2017. Two companies dominate the flow cytometry industry. BD Biosciences and Beckman Coulter together hold 87% of the flow market. BD is the clear leader with product sales of $825 million in 2012. BD continues to update its systems and test kits to maintain complete dominance of this market.

It is beyond the scope of this report to estimate the market for molecular tests in hematology with certainty. Circulating tumor cell testing is covered in Chapter 6. Table 7-1 presents a selection of CTC and flow cytometry innovations for molecular hematology.




Table 7-1

Selected Innovations in Molecular Hematology

Company Location Area Details Status Accuri Cytometers U.S. flow IncellDx’s HPV OncoTect E6, E7 mRNA mkt Accuri Cytometers U.S. flow eBioscience flow reagents mkt Affymetrix U.S. CTC ScreenCell CTC with Affymetrix platforms RUO Affymetrix U.S. CTC QuantiGene ViewRNA ISH Cell Assays, CTC RUO ApoCell, Inc. U.S. CTC CTC in hepatocellular carcinoma dev Atossa Genetics U.S. CTC ArgusCYTE Breast Health srvc Beckman Coulter/Danaher

U.S. flow CD cells for Transgene’s anticancer drugTG4010

Beckman Coulter/Danaher

U.S. flow Solastra antibodies, hematolymphoid neoplasia CE



C H A P T E R E I G H T

The Market for Molecular Assays in Coagulation and Cardiac Care

Hemostasis (coagulation) is a complex process in which multiple enzymes and proteins regulate blood flow and clot formation. Coagulation (clot formation), fibrinolysis and platelet aggregation are a part of this process. Fibrinolysis is a normal body process that keeps naturally occurring blood clots from growing and causing problems.

Coagulation factors have been implicated as independent factors in the development of myocardial infarction, stroke and deep vein thrombosis in some patients. With the increasing incidence of cardiovascular diseases, this discovery has brought what was a rather lackluster discipline into the limelight. The intensive investigation of coagulation processes has uncovered a number of other conditions in which coagulation factors are implicated, such as: post surgical bleeding due to the use of aspirin or Plavix, spontaneous abortion and pregnancy problems.

THROMBOPHILIA SNPS

Research into the cardiac disease continuum has pointed to an increasing important role of genetics in the evolution of hypercoagulopathies. More and more evidence has been collected that illustrate the use of genetic procoagulation and thrombolytic markers in assessing risk for CVD. In addition to the traditional

Eight: Coagulation 128



coagulation cascade factors several related molecular markers have grown in importance. These tests include thrombophilia molecular assays Factor V Leiden, Factor II Prothrombin, and MTHFR along with pharmacodiagnostic tests for anticoagulant dosing.

MTHFR

The thrombophilia markers have established definitive links to treatable diseases and have become part of the standard of care for various coagulation related diseases. 5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in the metabolism of folate, a cofactor that is essential for normal homocysteine metabolism. Individuals with MTHFR mutations can suffer from hyperhomocysteinemia, a condition that drastically increases risk for coronary heart disease and stroke. Hyperhomocysteinemia during pregnancy may cause neural tube defects such as spina bifida.

Factor V

Factor V is a cofactor in blood coagulation, regulated by the Protein C system. The Factor V Leiden mutation results in hypercoagulability, and is the leading genetic cause of venous thrombosis. Factor II Prothrombin, is a key protein in the blood coagulation system. Mutations in the gene that codes for Factor II are indicative of significant increase in risk for clotting disorders. These conditions are commonly treated with blood thinners such as coumadin (warfarin), which has lead to the commercialization of a number of tests for warfarin sensitivity.

These genes have been implicated in diseases that are more common than generally realized. One in one thousand individuals develop deep vein thrombosis (DVT) or pulmonary embolism (PE) annually. These conditions are caused by acquired and genetic risk factors including: age, hospitalization, cancer, surgery, pregnancy, hormone therapy, and air travel.

CYP4V2

There is ongoing research for other genetic implications. Thrombosis is a multicausal disease due to multiple risk factors. Generic studies have revealed that the CYP4V2 gene variant, which is present in over 50% of the population, was found to increase risk of DVT 1.5 fold. In contrast, Factor V Leiden and Factor II (prothrombin) are present in only 1-8% of the population, although carriers of these variants have been

Eight: Coagulation 129



found to have higher levels of risk for DVT. This suggests that tests for the CYP4V2 gene mutation may be added to Factor V Leiden and Factor II in identifying high-risk individuals.

Market and Forecast

The thrombophilia SNPs - Factor V Leiden, Factor II Prothrombin, MTHFR - have become part of the molecular test establishment. The market for this group of tests is estimated at $145 million in 2012, with 4% annual growth, will reach $180 million in 2017.

These tests are used most often in Europe where they were first launched by Behring (now part of Siemens). In the U.S., they have been a harder sell. June 2009 a report from the U.S. Agency for Healthcare Research and Quality (AHRQ) stated that their review of available scientific literature indicated there is not enough evidence to conclude that genetic testing for the two gene mutations in adults with a history of blood clots helps prevent deep vein thrombosis or improves other patient outcomes.

The researchers also said they found no benefit to genetic testing of family members of patients who have at least one of the two gene mutations as well as a history of deep vein thrombosis. The researchers concluded: “While genetic testing shows great promise to improve treatment and prevent disease, this report clearly shows that we need more research and evidence to achieve its full potential. But people can help reduce their likelihood of developing a blood clot by talking with their doctor about precautions." The study appeared in the June 17, 2009 issue of the Journal of the American Medical Association.

Coagulation Molecular Research Projects

The link between coagulation factors and cardiac disease has lead to a number of molecular research projects. For example, researchers at Universities of Leicester, (Leicester, UK) and Cambridge (Cambridge, UK) reported that an analysis of genome-wide platelet RNA expression data can identify people at risk of developing potentially fatal blood clots that can lead to heart attack. They suggest that this discovery of novel genes regulating platelets will help our understanding of what makes these cells more sticky in some people than in others and could provide potential therapeutic targets for treatment of cardiovascular disease. They identified 63 genes in which transcript levels



C H A P T E R N I N E

Histology and Cytology

OVERVIEW

Histology and cytology is the study of tissue and cells respectively (hereafter referred to as histology). Fluids such as cervical, sputum and joint and bits of tissue that have been biopsied or surgically removed are processed, placed on glass slides, and stained to characterize targeted cellular constructions, tissue morphology and cell components. The stained slides are read by technologists using microscopy. Pathologists read slides with suspicious or aberrant cells. The tests are used primarily to test tissue for cancer and cervical fluid for sexually transmitted diseases and HPV.

In situ hybridization and more specifically fluorescent in situ hybridization (FISH) techniques use DNA probes to detect pathogens and molecular structures in cells. More recently flow cytometry techniques allow professionals to select targeted cells that can be further analyzed with PCR, sequencing and mass spectrometry.

The result so far has been gene patterns that help distinguish cell and tumor attributes that demonstrate their virulence for disease progression and sensitivity to specific therapeutics. FISH along with a growing population of cancer patients have increased the number of histology analyses performed.

Further, developments in cytology and cervical cancer diagnosis fuel a continuous stream of innovation. For at least the past twenty years molecular analysis of tissue biopsies involves some form if in situ hybridization. Bit by bit, PCR, microarrays and sequencing techniques are making their way into routine tissue analysis, especially for difficult to manage cases.

Nine: Histology/Cytology 138



The reader is reminded that many of these new technologies - arrays, DNA patterns, mass spectrometry, sequencing, circulating tumor cells, plasma DNA and tissue-based pharmacodiagnostic tests are just emerging. Most are used in a research mode for very special cases. The traditional route to market and hopefully routine testing is a long process of quality control and test validation.

For the past few years, many new tests have jumped the FDA and CE Mark regulatory processes for commercialization and are offered as services by reference laboratories and authorized laboratories set up by the company that developed the test. These test services dominate the market for new histological and molecular tests for cancer and other diseases. This is discussed more fully in chapter eight.

It may be seen as queue jumping but it really makes sense. Only a few hospital labs have the expertise to run and interpret many of the new histology tests. Companies and labs that offer these tests services are capitalizing on their knowledge to introduce novel and important tests. The success of these test services is attracting more and more players.

In situ hybridization (ISH) allows pathologists and researchers to view specific molecular structures in fixed tissues, body fluids, and cells. These histopathology technologies are the backbone of cancer testing; in fact it is estimated that formalin fixed paraffin embedded (FFPE) tissue samples make up almost 90% of the tests that are performed on cancer patients.

Histology and cytology testing are a phenomenon of the developed world, therefore at least 85% of the world market for histology/cytology products is held by N. America, Japan, Western Europe and Latin America.

Nine: Histology/Cytology 139



Table 9-1 presents a forecast for the molecular histology market.

Table 9-1

Worldwide Molecular Histology/Cytology Sales, 2012-2017

(Sales $ million)

Sales % Sales % CAGR 2012 Mkt 2017 Mkt in situ hybridization HPV Tissue Microarrays TOTAL


The world market for molecular histology has been estimated at $1,040 million in 2012. With increasing demand for cancer diagnostics and pharmacodiagnostics the market will see 10% annual growth to reach $1,690 million in 2017. Traditional in situ hybridization analysis contributes most to this growth.

The growing number of cancer patients is a major factor, but a number of technological advancements also contribute to the growth. Sample preparation of histology samples has always been fairly automated, but companies have invested to improve upon this with new faster tissue fixatives and systems that improve nucleic acid extraction from tissue samples. Of note is new instrumentation to automate RNA detection in fixed tissues. This is important for advanced tissue-based pharmacodiagnostic testing.

Sequencing DNA extracted from FFPE tissue is challenging due to crosslinking that occurs because of the fixing process and because the DNA is highly fragmented. Because most clinical samples are stored and banked using FFPE, however, there is a huge interest in using these specimens for clinical next-generation sequencing research, particularly in cancer research and patient management.

This growing market has attracted many new entrants and competition has intensified. Most recently life science companies Agilent Technologies (acquired Dako)



C H A P T E R T E N

Microbiology and Virology

OVERVIEW

The goal of microbiology and virology testing (further referred to as microbiology) is to detect pathogens in humans and determine a course of antimicrobial treatment that is the most appropriate for the patient. Amazing as every other laboratory segment moves toward individualized therapy, this has always been the state-of-the-art in microbiology testing. Microbiology tests are super time sensitive tests—an infection detected and treated early can sometime make a difference between life and death or severe morbidity.

The world of microbiology in all its facets has become one of the most dynamic IVD segments. Events in recent years such as the SARS outbreak; threat of TB and influenza epidemics; HIV and STD’s uncontrolled march across continents; and the heavy cost of hospital acquired infections have shown healthcare professionals that one can never remain complacent.

The net result is that microbiology, faced with the added weight of current and emerging pathogens, has had to join the crowd and look for cost effective solutions. An important part of the new toolbox is molecular tests that allow for rapid and highly specific identification of viruses, bacteria, fungi and parasites. The most sophisticated of these tests can drill down to individual species and can detect the source of epidemics and the genetic variations that may confer resistance to therapeutics.

The tests use many different technologies including: nucleic acid amplification, sequencing, mass spectrometry, flow cytometry, FISH, line probe assays and next

Ten: Microbiology/Virology 166



generation sequencing. However nucleic acid amplification technologies such as PCR, TMA, bDNA and NASBA are used in the vast majority of tests.

Nucleic acid testing is further referred to as DNA testing so as to differentiate this from NAT (nucleic acid testing) in blood transfusion management (Chapter 11). DNA tests have decreased test turnaround times from as long as a week to days and in other cases from days to hours.

Infectious diseases, primarily sexually transmitted diseases (STDs), tuberculosis, HIV and hepatitis are the number one public health problem worldwide. In addition globalization of the world's food supply and increased world travel has introduced viruses, parasites and bacteria from emerging countries to the developed world. Hospitals have become hotbeds of infections that have made their way into the community and then back again. Lastly, and by far not the least pressing micro problem, is emerging pathogens and increasingly therapy resistant microorganisms.

MICROBIOLOGY MARKET AND FORECAST

Several years ago Kalorama suggested it is quite likely that by 2010 at the latest most immunoassays for infectious diseases would have been replaced by nucleic acid test procedures for primarily TB, HIV, chlamydia, gonorrhea and hepatitis. This is not the case, though molecular tests for microbiology have made incredible market gains. The 2000 world market for nucleic acid tests for microbiology was estimated at $650 million, $1,680 million in 2007 and $2,375 million in 2010 and $2,787 million in 2012.

The recent mobilization of molecular test manufacturers to introduce completely automated and user-friendly tests for MRSA, and respiratory disease pathogens illustrates that there is a huge potential for molecular tests.

This is one test segment where lab-developed tests play a small but important role in molecular microbiology. Test services for HIV viral load and tropism refine the drug cocktail that people with AIDS receive and new formulations of the drugs make them more easily tolerated. These actions work to mediate the issue of HIV drug resistance. An elite group of hospital and reference labs had begun offering molecular test services for at least 30 gene-based diseases and hard to culture bacteria and viruses.




Many larger microbiology labs may have a Cepheid (Sunnyvale, CA) GeneXpert System. Cepheid reported that as of October 2012, 3,614 GeneXpert systems had been placed, worldwide.

Also FDA cleared and CE Mark assays have been launched for the Roche Lightcycler 2.0, Stratagene Mx3000 series platforms and Life Technologies’ Applied Biosystems ABI 7500. These are the most common real-time PCR instruments found in clinical molecular labs. Kalorama estimates that there are approximately 3000 hospitals, worldwide, that have the sophistication to run molecular tests using these instruments.

Until recently only U.S. labs with CLIA high complexity accreditation could run molecular tests for infectious diseases. However several instruments and specific tests have been reclassified as CLIA moderate. This opens an opportunity for just about any routine laboratory to run molecular tests for infectious diseases. Nanosphere’s Verigene RVNATSP test, Becton Dickinson’s BD MAX System and Grp B Strep tests and Cepheid’s GeneExpert System are now classified as CLIA moderate.

Role of ID Testing in the Molecular Diagnostics Market

Molecular tests for infectious diseases make up the largest portion of molecular testing with at least 50% of the market for molecular tests and will remain so for the next 5 years due to advancements molecular tests for hospital acquired infections, respiratory viruses, viral load testing for HIV and hepatitis and increased research in microorganism genotyping related to molecular variation. Many labs are beginning to transfer critical tests such as fungi (e.g. aspergillis, candida), MRSA, VRE, and nosocomial infections from culture to molecular platforms. Therefore important growth is seen organism ID for bacterial detection and antimicrobial resistance—MRSA, VRE, and others—that will grow 18% annually from 2012 to 2017.

The increasing problem of antibiotic resistant organisms has lead to the development of a new class of microbiology tests based on molecular analyses for the identification and the determination of treatment susceptibility. Despite the overwhelming need for molecular-based antibiotic resistance tests, few commercially available test kits have come to market. Microbiologists using in-lab developed PCR-based tests perform the vast majority of molecular analyses. Many established molecular labs even produce their own nucleotide probes.




Markets for Specific Infectious Disease Tests

A number of genotyping tests have come to market for HPV, influenza, HIV, and hepatitis. These tests are used to further analyze viral load and to characterize the sensitivity status of viruses to targeted therapies. As this area of molecular diagnostics advances, these tests will contribute significant growth to the molecular segment in developed countries. Many of these tests are now provided as services in reference and company sponsored labs. Table 10-1 presents a forecast for molecular tests for microbiology/virology. ($ millions)

Table 10-1

Molecular Test Sales, Microbiolog/Virology, 2012-2017

Test 2012 % 2017 % Sales Mkt Sales Mkt

HIV Hepatitis GC/Chlamydia HAI Respiratory Organism ID Mycobacteria, TB Blood Culture Others Total


Respiratory = RSV, Strep A, FLU HIV = all HIV diagnostics, genotyping and drug resistance Hepatitis = all HIV diagnostics, genotyping and drug resistance Other = Grp B Strep, EBV, HSV, CMV, West Nile, fungi, and others

The world market for molecular microbiology tests is estimated at million in 2012 and with annual growth of will reach million in 2017. Approximately % of this market is held in the U.S. and Europe. Approximately of this market is held in the U.S. and Europe. In 2012 approximately of the market



C H A P T E R T H I R T E E N

The Market for Molecular Assays in Prenatal and Neonatal Testing

OVERVIEW

Testing of genetic material can be performed on blood as a parental screening tool to assess whether would be parents have an autosomal or X-linked recessive gene that, when combined in a child, can produce a serious disorder in that child. This is called carrier screening. Prenatal genetic testing is also performed while a fetus is still in utero and considered to be at risk. It is also used to analyze embryos before implantation in in vitro fertilization (IVF), so as to insure that disease free embryos are implanted. Finally genetic testing can be performed on newborns to screen for a wide number of gene-based diseases.

This test segment has become very hot in the past few years or so; partly because the test technologies are becoming more user-friendly using arrays and sequencing. Blood and saliva offer non-invasive sample options. Developments in the genetic basis of disease has increased the number of diseases that can be screened with molecular testing. The National Center for Genomic Resource (NCGR, www.ncgr.org) has suggested that test panels cover gene abnormalities for 448 genetic diseases that include a mix of autosomal recessive and X-linked recessive disorders.

There has also been growing consumer demand. People are marrying and having children later in life. They are more informed about the possible transmission of all types

Thirteen: Prenatal and Neonatal 220



of diseases to their children. Carrier and prenatal screening allow them to them to limit this possibility. In addition, more couples must resort to IVF in order to have children. Here too, they expect pre-IVF testing to limit the birth of children with gene-based diseases.

Consumer demand has also been supported by medical guidelines and screening programs supported by payer groups. In 2007, the American College of Obstetricians and Gynecologists began recommending that every pregnant woman, regardless of age, be offered a choice of tests for Down syndrome. Previously, the focus had been on women older than 35 because the chance of having a child with Down syndrome increases with age. But even before the recommendation, the number of pregnant women receiving prenatal tests has been increasing over the past five to 10 years. This is not without controversy as pro-life groups fear that the testing leads to the termination of many pregnancies.

November 2009, The National Library of Medicine (NLM) published a Newborn Screening Coding and Terminology Guide (http://newbornscreeningcodes.nlm.nih.gov) in order to promote efficient electronic exchange of standard newborn-screening data and enable more effective use of newborn-screening test results in assessing child health. The website is designed to help states move toward the use of common terminology and coding standards, a key step in enabling electronic exchange of laboratory-test information. The site covers more than 100 conditions, and lists the terminologies and codes used for each. It also identifies the tests that may be used in screening for each condition.

Parental carrier and prenatal genetic screening is rapidly advancing in the U.S. and has now become mandatory for nearly 90% of newborn babies in the U.S. Many of the states, which require genetic screening do not screen for all genetic disorders however, two new federal bills have been introduced that would mandate more genetic screening.

In addition, the European Commission (EC), the European Parliament (EP) and the Council of Europe have issued ethical and legal guidelines for genetic diseases screening.

Molecular techniques for newborn screening are also growing. September 2010, the American College of Medical Genetics (www.ACMG.net) recommended replacing

Thirteen: Prenatal and Neonatal 221



karyotyping with chromosomal microarrays as first-line postnatal test. Some geneticists who use arrays hope the new guidelines will prompt other labs to adopt the technology and compel insurance firms to reimburse for the tests.

Guidelines suggest that every U.S. newborn be tested for 29 rare but devastating genetic diseases, using paper heel-prick blood samples. Most states have adopted the recommendations, and U.S. statistics indicate that the testing has found some 5,000 babies a year with disorders including: sickle cell anemia, maple syrup urine disease, and Pompe, Fabry, Gaucher, Niemann-Pick and Krabbe diseases.

MARKET AND FORECAST

The global market for parental carrier and prenatal and neonatal screening is estimated at $180 million in 2012. With 8% annual growth, the market will increase to $260 million in 2017. Kalorama estimates FISH assays account for $72 million (40%) of the market for prenatal screening in 2012. More advanced technologies are used primarily by test service providers. This estimate applies to commercial kits used for chromosomal analysis including all technologies. The lure of an estimated $1 billion services market has attracted a number of competitors. Most labs use lab-developed tests. Table 13-1 presents a selection of developments in molecular prenatal testing in 2012.

An average of 4,200,000 children are born in the U.S. every year, 350,000 in Canada, 7,300,000 in the EU, 16 million in China and 1,200,000 in Japan. It is estimated that approximately 700,000 amniocentesis procedures are performed in N. America and W. Europe each year.

It is estimated that there are an average of 150,000 IVF cycles performed in the U.S. with another 650,000 cycles performed outside the U.S. Approximately 6% of these cycles include preimplantation genetic diagnosis (embryo screening) including aneuploidy screening for the purpose of improving implantation rates, decreasing miscarriages, and preventing birth defects.

The basis of prenatal screening is an analysis of the 23 pairs of chromosomes that every human being has. Using a variety of techniques a cytogeneticist examines the number, shape and staining pattern of these chromosomes to detect extra chromosomes, missing chromosomes, or rearranged chromosomes.



C H A P T E R F O U R T E E N

The Market for Molecular Assays for Inherited Diseases

Single nucleotide polymorphism (SNP) analysis of tissue, blood, urine and saliva is the main technique used for gene mutations for inherited diseases. SNPs are DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered. Many SNPs have no effect on cell function, but scientists believe others could predispose people to disease or influence their response to a drug. Although more than 99% of human DNA sequences are the same, variations in DNA sequence can have a major impact on how humans respond to disease; environmental factors such as bacteria, viruses, toxins, and chemicals; and drugs and other therapies. This makes SNPs valuable for biomedical research and for developing pharmaceutical products or medical diagnostics. SNPs are also evolutionarily stable—not changing much from generation to generation—making them easier to follow in population studies.

At approximately 30,000 genes for the human genome and with an estimated diagnostic significance of about 5%, the eventual commercialization of 1,500 gene-based tests can be expected. This is a huge market opportunity set to revitalize the market for molecular tests for inherited diseases including autoimmune disorders, diabetes, psychiatric conditions, neurological diseases and cardiac disease.

The market for molecular tests for inherited diseases involves two test segments – tests for thrombophilia molecular assays (Chapter 8) and genetic tests for inherited diseases and those for which there is ongoing research to discover the inherited aspects of

Fourteen: Inherited Diseases 234



the disease. Table 14-1 presents a list of the most frequently requested genetic tests. Just about all of these tests are offered as test services by large hospital and reference labs.

Table 14-1

Most Frequently Requested Genetic Tests

• AML • Apolipoprotein E genotyping • ASPA—Canavan disease • CML • Cystic Fibrosis • Duchenne muscular dystrophy • Familial adenomatous polyposis coli (APC) • Gaucher’s disease • Hemachomatosis • Hemophilia A • Huntington’s disease • Lymphomas • Multiple Sclerosis • Myotonic dystrophy • Neurofibromatosis (NF-1) • Prader Willi/Angelman • Sickle Cell anemia • Spinal muscular atrophy • Thalassemia (alpha and beta)


Genomic research is opening the possibility of genetic marker tests for number of

diseases not usually diagnosed with molecular tests, including cardiac diseases, diabetes, autism, neurological disorders, psychiatreic conditions, arthritis, disorders of the gastrointestinal tract, Crohn’s disease, and others. This area of medicine is in the early phase of development. Various markers for disease stratification but many of the studies are small and retrospective in nature. They do not provide conclusive arguments for the clinical utility of these markers.

However, while the clinical translation of genomic data has resulted in accepted diagnosis and treatment paradigms for cancer patients, this is not the case for many



C H A P T E R F I F T E E N

Conclusions and Strategic Implications – 2012 and beyond

For the next few years a constant stream of commercially available test kits for the newest molecular targets will be coming to market. Yet for the next generation of molecular test segments, infectious diseases and oncology, as well as emerging tests segments it appears that test services from large hospital and private and company-sponsored laboratories prevail. This limits the growth potential of the market for commercial products, except a few laboratories have chosen to submit their tests for market clearance. This expands their distribution to their partner labs and other potential test service providers.

EXPECTATIONS AND REALITIES

It was expected that by 2015-2020 molecular assays would have increased market penetration at the expense of incumbent immunoassays techniques. The expectation is that cost effective commercial kits will be available for many assays previously run with home-brew reagents. Molecular tests have made great gains with infectious diseases but in-lab developed molecular tests still dominate other test segments and the demand for many tests is too low to warrant the commercialization of market cleared test kits

Molecular assays and lab tests in general hold the key to outcomes research for the new generation of biotherapeutics. These face the threat of poor market penetration unless they can prove to payer groups that they will improve patient outcome and will be cost



C H A P T E R S I X T E E N

Competitive Analysis

COMPANIES AND VENDORS TO WATCH

The past ten years or so have seen sales of molecular tests increase almost five fold, and the number of companies and tests has literally exploded. Some 350 companies are actively involved in molecular diagnostics. This is not surprising; given there are molecular applications in just about every segment of the IVD industry. Yet as shown below, the market is still controlled by one company and only a handful of companies can boast significant success.

Company revenues include sales of commercial market cleared molecular tests and ASR reagents in all segement of the IVD market. It is beyond the scope of this report to segment company sales by test segment with certainty.

The major players in the 2012 market were Roche Diagnostics and Qiagen with 46% and 21% of the market respectively. Qiagen has emerged as a major force in molecular diagnostic innovation. The vast majority of the remaining 33% of the market was held by other players including: Abbott Diagnostics, Becton Dickinson, Gen-Probe, Siemens Healthcare, and bioMérieux.

In 2012, fourteen companies control at least 85% of the market for molecular tests. Even with the dynamic growth predicted for this industry, not all of the minor companies will be successful in their business pursuits. Given that most of these companies have product sales of less than $10 million, they will be hard pressed to make a real go of it.

Roche is the undisputed market leader with a broad product portfolio, which includes molecular diagnostic tests for oncology, virology, microbiology, and blood

Sixteen: Companies to Watch 266



screening. The company’s molecular test revenues are bolstered by the continued dominance of its Ventana Medical histology business.

Qiagen has a major player, its transformation from a molecular sample-preparation technology manufacturer to be the number two molecular test company. Some 48% of its revenues are now generated by molecular assays.

Becton Dickinson’s GenOhm acqusition has begun to bear fruit and its investment in the BD Max has helped increase the company’s market share.

Similarly, Abbott Diagnostics continued release of tests for the m2000 has helped the company advance in the market for molecular assay.

Gen-Probe’s growth rate has outpaced the industry average based on the company’s leadership in chlamydia and gonorrhea (CT/NG) testing.

Similarly Cepheid leads the market for hospital acquired infection testing, Hologic/Digene continues to expand its share of the market for HPV testing and Luminex’s respiratory diseases tests are gaining market traction. Table 16-1 presents product sales data for selected molecular test companies in 2009 to 2012.




Table 16-1

Estimated Molecular Test Revenues of Selected IVD Vendors, 2009-2012

Company Location 2009 2010 2011 2012 CAGR Roche Diagnostics Qiagen Becton Dickinson Novartis Abbott Gen-Probe/Hologic Dako/Agilent Cepheid Siemens Healthcare Ventana Medical/Roche Hologic/Digene bioMérieux Luminex Seegene


The reader will note that while the major IVD players still play a significant role in

the expansion of the market for molecular tests, but in some cases growth in their product sales is slowing down. This is especially evident in molecular product sales, which have now slowed to less than % compared to % in the early 2000s.

Companies such as have product sales far below that of market leader , but their marketing and alliance efforts have resulted in significant market gains. A short review of selected companies and their potential is found below. The reader will note the current absence from the molecular space of r. Further have not managed to fully exploit their investments in molecular products.

Roche Diagnostics, Basel, Switzerland - Roche has led the market and continues

to dominate. In spite of a slow down in product sales, the company has product sales almost twice the nearest competitor. Roche is the undisputed leader in clinical molecular diagnostics. Virology is Roche Molecular Diagnostics’ largest segment by sales.




April 2012, Illumina announced the availability of its MyGenome application for the iPad, available for download on the App Store for $0.99. According to Illumina: “The MyGenome app is an exciting educational tool that enables consumers to learn how much we already understand about variation in the human genome, served up in a graphically accessible format. This first version of the app provides a glimpse of what we think could become a clinical tool for use by physicians with their patients to improve understanding and communication of genetic data.”

ACQUISITIONS, ALLIANCES AND COLLABORATIONS

A number of totally disparate phenomena have come together to advance molecular diagnostics. Human genome research is finding links between a person’s genome and several lifestyle situations such as nutrition, dieting, skin conditions and other essentially non-medical conditions. This has attracted consumer product companies such as Proctor & Gamble and Nestlé to develop products and services based on IVD technologies.

Decreases in life science grants has encouraged companies active in this space to migrate their technologies for clinical applications. The result is the entry of companies such as Caliper Life Sciences, Illumina, Affymetrix and Life Technologies to the diagnostics market with products and test services.

Several acquisition events are of particular interest. Life Technologies’ purchase of Ion Torrent places the company in the lead for research and clinical next generation sequencing. Amgen’s acqusition of genetic test pioneer deCode will help expand molecular companion tests for personalized medicine. bioMérieux has set its sites for expansion in emerging markets

Miniaturization of traditional immunoassay and molecular test technologies is maturing to the point where they may be ready for scale-up and then commercialization into products. Here electronics companies such as Sony, Samsung, Dell Computers and Intel Corp. have invested in clinical diagnostics ventures.

These exciting developments join expansion of molecular diagnostics by companies already involved in the IVD industry. Tables 16-2 provides a sample of the movement in the IVD industry related to acquisitions.




Intel Corporation (Washington, DC) made a $100 million investment in Pacific Bioscience's (Menlo Park, CA) SMRT chip, a single-molecule, real-time DNA sequencing platform that is expected to allow for the first time the observation of natural DNA synthesis by a DNA polymerase as it occurs. The company believes SMRT will lead to a transformation in the field of DNA sequencing that will facilitate sequencing of individual genomes as part of routine medical care.

Other electronics industry companies that have shown interest or made investment in genetics research include IBM, Motorola, and Texas Instruments.




Table 16-2

Selected Acquisitions in Molecular Diagnostics

Company Location Details AbSorber AB Stockholm, Sweden Olerup Inc., HLA organ transplant PCR Agilent Technologies

Santa Clara, CA Dako, leader IHC, FISH

Amgen Thousand Oaks, CA deCode Genetics Axela Biosensors, Inc.

Toronto, ON Xceed Molecular, Ziplex System for gene-expression analysis

Biocartis Netherlands Royal Philips Electronics’ automated DNA/RNA platform bioMérieux France RAS Lifesciences Pvt. Ltd, India 60% bioMérieux France Argene, molecular assays




the industry lies in the development of more sensitive, faster, user-friendly, IT capable devices for a host of new molecular markers. No company, big or small, owns all of the technology needed to develop these new tests and systems. They have to get the pieces they do not have from partners. This activity will go on for at least the next 5-10 years. Table 16-3 presents a sample of the collaborations and licensing and distribution alliances established in the past few years.




Table 16-3

Selected Collaborations and Licensing and Distribution Alliances

Company Location Action Details Abbott Diagnostics U.S. distr Biofortuna's freeze-dried SSPGo HLA-typing kits Affymetrix U.S. distr ScreenCell CTC product BD Diagnostics U.S. distr Epistem Genedrive TB Curetis AG Germany distr BioLine LLC, microbiology in Russia Gen-Probe Inc. U.S. distr SeCore HLA on Life Tech 3500 Dx Genetic Analyzer Novartis U.S. distr distribute Cepheid's Xpert BCR-ABL PerkinElmer U.S. distr Roche NimbleGen CGX microarray Qiagen Netherlands distr Cardinal Health for small labs Xcelris Labs India distr Epistem Genedrive TB Affymetrix U.S. license Siemens bDNA for in situ Becton Dickinson U.S. license Exiqon's LNA technology GenMark Diagnostics

UK license GE's microfluidic technology

Immunexpress Group

Australia license SeptiCyte Triage tests on Biocartis’ instr




LOOKING BEYOND BORDERS

The repercussions of the economic meltdown in N. America and Europe are still very obvious at this time. In an effort to maintain growth, IVD companies have begun to look to markets outside their home and traditional geographies. The major IVD companies have been active in Asia, Africa and Latin America for some time, now a host of smaller players are expanding east.

Qiagen reported that it has been increasing its market presence in emerging countries; the top seven emerging markets: Brazil, Russia, India, China, South Korea, Mexico and Turkey represent 12% of total QIAGEN sales in 2012.

Similarly, Roche Diagnostics continues to expand geographically with special emphasis on the top seven emerging countries: Brazil, Russia, India, China, South Korea, Mexico and Turkey. November 2010, Roche Diagnostics and CapitalBio (Beijing, China) formed a partnership targeting molecular diagnostic applications.

This trend is fuelled primarily by the anticipated increase in the uptake of IVDs in emerging markets that are expected to grow by 10%-20% compared to an average of 5% in mature markets. Table 16-4 present a selection of market expansion activities in molecular diagnostics.




Table 16-4

Selected Market Expansion Activity

Company Location Area Details Epigenomics AG Berlin,

Germany Middle East

Life Technologies Carlsbad, CA EMEA

Life Technologies Carlsbad, CA China Life Technologies Carlsbad, CA Japan Menarini Diagnostics Italy Europe

Novartis Diagnostics Emeryville,

CA China

Novartis Diagnostics Emeryville,

CA India

OptiGene Limited Horsham, UK PerkinElmer Inc. Boston, MA Egypt PerkinElmer Inc. Boston, MA China PerkinElmer Inc. Boston, MA India

Qiagen Netherlands China Qiagen Netherlands China Takara Bio Inc. Japan Japan Transasia/ Erba Mumbai, India




C H A P T E R S E V E N T E E N

Company Profiles: Top Tier IVD Companies’

Molecular Businesses

These top IVD companies are presented in alphabetical order. The profiles include

events related to their molecular test businesses that have occurred in the past few years. These profiles are not a comprehensive review or history of the companies selected to appear in the section.

Seventeen: Top Tier IVD Companies 280



ABBOTT DIAGNOSTICS Abbott Park, IL 60064

www.abbott.com RECENT REVENUE HISTORY: ($ MILLION)

2009 2010 2011 2012 (est) Total Dx $

Molecular $

Histology (Vysis)* $ * estimated Geographically, Abbott's molecular test sales were generated about

internationally and in the U.S. The company has a stake in chemistry, immunoassays, molecular assays, hematology, pharmacodiagnostics, and histology (Vysis).

In 2011 Abbott reported that more than systems have been placed in laboratories worldwide and that molecular diagnostics sales rose on the launch of new tests and the uptake of its Ibis PLEX-ID platform.

KEY COMMENT: In face of stiff competition from Gen-Probe, Roche and

Siemens, especially in the U.S., the company’s molecular test business growth has stalled. Abbott is making a huge effort to improve its test menu.

Abbott Laboratories is a global, diversified health care company active in

pharmaceuticals, nutritionals, devices and diagnostics. Abbott's diagnostic products strength is its sheer presence worldwide. The company has a direct presence in more than 130 countries and broad access to a variety of distribution channels, from consumer outlets to clinical laboratories. Abbott participates in several key diagnostic test segments: blood bank screening, molecular testing, immunoassays, hematology, clinical chemistry and blood glucose monitoring.

The following is a discussion of Abbott’s molecular test business developments. Abbott Molecular focuses on tests for the evaluation and management of cancer, prenatal disorders and other genetic diseases. The reader is reminded that Abbott was one of the first major IVD companies to be active in molecular histology. Abbott acquired upstart Downers Grove-based biotech company Vysis Inc. (Downers Grove, IL) in October 2001. Vysis’ FISH diagnostic tests were among the first to receive FDA market clearance.




HLA

April 2011, Biofortuna (UK) signed an exclusive distribution agreement with Abbott’s molecular diagnostics business, whereby Biofortuna will design, develop and manufacture a range of freeze-dried HLA-typing kits called SSPGo.

Abbott will obtain exclusive distribution rights in the U.S. and all global territories, except France, Spain, Portugal and the Benelux countries, once regulatory approvals are obtained. The agreement includes rights to distribute the SSPGo products, interpretation software Verdict, as well as kit updates and improvements.

The SSPGo product range is the first freeze-dried HLA-typing kit of its kind. The kits will be available to laboratories outside the U.S. to purchase and order through Abbott in June 2011. The kits are currently CE-marked and have been submitted for U.S. FDA approval.

Molecular Histology

Abbott Molecular markets FISH probes, offering a broad menu of tests for use in cancer diagnostics and genetic testing. The Vysis product line of genomic-based tests, includes the PathVysion HER-2 DNA probe kit and UroVysion that detects genetic changes in bladder cells for aiding in the diagnosis and monitoring of bladder cancer and for monitoring of bladder cancer recurrence. These tests form only a small part of Abbott’s IVD business, but the company is making an effort to increase its market presence.

April 2012, Abbott acquired an exclusive license from Stanford University for gene markers that could differentiate aggressive from nonaggressive prostate cancer. Abbott will develop a molecular assay based on its proprietary FISH technology to detect rearrangements of the ERG and ETV1 genes and measure loss of the PTEN gene. A study published in the British Journal of Cancer (January 2010) demonstrated the effects of ERG/ETV1 genetic aberrations and PTEN gene loss in determining prostate cancer prognosis.

Abbott's PathVysion test, the first FDA approved FISH-based companion diagnostic, detects amplification of the HER-2 gene and acts as an aid in identifying patients for Herceptin (trastuzumab) therapy for breast cancer.

Abbott reported that UroVysion is the first and only test approved by the FDA that uses DNA probes to identify up to four chromosomal abnormalities frequently associated with bladder cancer. UroVysion is based on Abbott's proprietary FISH technology.




October 2011, Abbott received FDA clearance to market the Vysis EGR1 FISH Probe Kit that helps establish the prognosis of patients with acute myeloid leukemia (AML). The kit detects the chromosomal deletion of the LSI EGR1 probe target in bone marrow, usually associated with an unfavorable prognosis for AML patients. The chromosomal deletion of the EGR1 probe target occurs on chromosome 5q and is approximately 209 kb in length, located at 5q31, and contains the complete EGR1 gene. The probe kit is intended for use in bone marrow specimens and is for use together with cytogenetics, other biomarkers, morphology, and other clinical information.

Companion Tests

Abbott has personalized medicine collaborations in place with a number of pharmaceutical companies, including Pfizer and GlaxoSmithKline. Abbott's portfolio of companion diagnostic tests includes the PathVysion HER-2 DNA Probe Kit and Abbott's Vysis ALK Break Apart FISH Probe kit that was approved in 2011 for use in identifying non-small cell lung cancer patients for XALKORI (crizotinib) treatment.

March 2012, Abbott announced that it will collaborate with Merck to evaluate the use of a FISH-based companion diagnostic test to aid in the development of a Merck investigational cancer therapy. Abbott will develop a test based on its proprietary FISH technology, intended to identify deletions of the TP53 gene in cancer patients. The Abbott FISH assay will be evaluated in clinical trials to help identify patients more likely to respond favorably to Merck's investigational cancer therapy.

August 2011, Abbott received FDA clearance to market the Vysis ALK Break Apart FISH Probes, a companion diagnostic test will help determine if a patient has the abnormal Anaplastic Lymphoma Kinase (ALK) gene before targeted chemotherapy is used. The qualitative test is used to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non-small-cell lung cancer (NSCLC) tissue specimens.

The test is designed to identify ALK-positive NSCLC patients for Pfizer's approved NSCLC therapy, XALKORI (crizotinib), an oral first-in-class ALK inhibitor. The Vysis ALK Break Apart FISH Probe Kit has been optimized only for identifying and quantifying rearrangements of the ALK gene from formalin-fixed, paraffin-embedded human NSCLC tissue specimens.

The Vysis ALK FISH test uses Abbott's fluorescence in situ hybridization (FISH) technology to detect rearrangements of the 2p23 chromosome of the ALK gene. These




ALERE Waltham, MA

www.alere.com RECENT REVENUE HISTORY: ($ MILLION) 2009 2010 2011 2012* Total Dx Molecular in development In 2011, N. America accounted for 63% of products sales, Europe 24%, Asia Pacific

8%, ROW 5%. KEY COMMENT: July 2010, Inverness Medical Innovations announced that it had

changed its name to Alere Inc. Alere is best known for its dominance of the market for POC immunoassays and women’s health and infectious disease testing.

Alere has begun developing its molecular testing business. August 2011, VitaPath

Genetics (Foster City, CA) and Alere announced that Alere has licensed worldwide marketing rights to VitaPath’s spina bifida risk assessment assay. The assay is a genetic test that identifies elevated risk in women of childbearing age for the common birth defect spina bifida, which can be prevented with high-dose folic acid under the care of a physician. In addition, Alere has licensed the right to develop with VitaPath additional product line extensions primarily focused in the area of fetal health.

Alere is also developing its own molecular testing platforms, specifically for infectious diseases. The base for Alere’s molecular platforms began with the acquisition of biochip maker Clondiag (Jena, Germany) in February 2006. The company is part of Alere GmbH in Germany. Clondiag has been developing a point-of-care HIV viral load test that can detect multiple HIV-1 and HIV-2 targets simultaneously using a real-time, microarray-based detection method called ArrayTube, which comprises custom biochips spotted with nucleic acid or protein probes in a standard laboratory microtube.

The Alere NAT Analyzer is designed for multiplexed nucleic acid measurements from whole blood samples, initially for HIV viral load monitoring but eventually for




detecting or monitoring other infectious diseases, such as hepatitis C. Alere expects to apply for the CE Mark by the end of 2012 and FDA clearance in 2013.

Alere's second platform in development, the iNAT, is a point-of-care platform that will be able to detect any DNA or RNA sequence from raw, unpurified samples with full multiplexing capabilities in less than 15 minutes. The iNAT, will use isothermal amplification technologies from two companies that Alere acquired in 2010: TwistDx and Ionian Technologies. The system is expected to provide low-cost molecular testing capabilities in physicians' offices and, eventually, the home, according to the company.

Alere announced that it has begun U.S. clinical trials for its first test on the iNAT platform, an assay for influenza that likely won't near the market until the 2013 respiratory disease season. Alere anticipates that the iNAT platform will use RPA and NEAR technologies in combination with Alere's patented lateral flow detection technology for rapid testing. The iNAT test pipeline includes tests for Strep A, respiratory syncytial virus, C. difficile, chlamydia, tuberculosis, and methicllin-resistant Staphylococcus aureus.

Alere acquired TwistDx (Cambridge, MA) in March 2010. TwistDx has developed the recombinase polymerase amplification (RPA) method, which uses a recombinase enzyme to pair oligonucleotide primers to a DNA template and a polymerase to synthesize daughter strands, resulting in exponential product accumulation. According to TwistDx RPA products can be detected in real-time using fluorescent probes or by end-point methods such as lateral flow strips or gel electrophoresis. This method directs DNA synthesis to defined points in sample DNA and, if the target sequence is present, DNA amplification is initiated without thermal cycling or chemical melting. The method works optimally at around 37° C and can specifically amplify DNA to detectable levels from just a few target copies within five to 10 minutes.

Alere acquired Ionian Technologies (San Diego, CA) in July 2010. The company has developed isothermal NEAR (nicking enzyme amplification reaction technology). NEAR technology is based on the rapid detection of any small DNA or RNA fragments generated directly from the target nucleic acid. According to Ionian, the NEAR Assay, provides “exquisite sensitivity coupled with rapid amplification speed. The NEAR Assay permits the amplification of DNA and RNA in approximately 5 minutes, with sensitivity and specificity equal to or better than PCR. The amplification products can be easily detected using a variety of methods that are compatible with point-of-care devices. Ionian's assay technology is therefore ideally suited for portable and handheld detectors and sensors,




where very rapid identification is required.” Ionian was developing rapid point of care assays for: Chlamydia & Gonorrhea, Influenza A & B, and tuberculosis.

In November 2009, Ionian Technologies and Roche Diagnostics entered into an agreement giving Roche exclusive manufacturing rights for certain (unnamed) applications of the NEAR technology. No further announcements have been made regarding this agreement.




ARKRAY Kyoto, Japan

www.arkray.co.jp/english RECENT REVENUE HISTORY: ($ MILLION) private, annual revenue estimated at approximately $ million in 2011, with

approximately 75% in Japan. KEY COMMENT: Arkray has a broad POC testing product portfolio in chemistry,

electrolyte analysis, immunology, blood cell count and blood gases. In Asia, Arkray owns 60% of the urine instruments and is the leading marketer of glucose meters in Japan. The company’s products are distributed in at least 80 countries. Its partner in the U.S. is IRIS International.

ARKRAY has been a pioneer for over 50 years in the field of automated analysis from

laboratory and point-of-care systems to home use patient self testing systems. ARKRAY developed the world's commercially successful portable blood glucose analyzer in the early 1970s and the world's first A1C analyzer in 1982.

ARKRAY has developed i-density IS-5310, an automated system to detect SNPs and mutations in human genes. ARKRAY released the i-densy IS-5310 in 2009 and it is currently used to support work carried out at research facilities in Japan. ARKRAY’s technology has the possibility of mutation detection from blood. With the i-densy IS-5310, the whole process from DNA extraction from biological samples such as blood, gene amplification through to determination of results is automated within a single device, all in approximately 80 minutes.

So far Arkray has demonstrated the ability of the i-densy IS-5310 to detect mutations in the EGFR gene that are associated with drug resistance with lung cancer drugs Gefitinib and Erlotinib.




BECKMAN COULTER INC./DANAHER Fullerton, CA

www.beckmancoulter.com RECENT REVENUE HISTORY: ($ MILLION)

: ($ million) * = estimated

2009 2010 2011 All diagnostics

The increase in 2010 revenues is mostly related to the purchase of Olympus Diagnostics at the end of 2009.

Geographically, Beckman Coulter's diagnostics sales were generated

KEY COMMENT: Beckman Coulter's strength is chemistries, immunoassays, flow

cytometry and hematology. With its strong presence in hematology, flow cytometry, life science molecular systems and immunoassay innovation, the company has significant potential to capitalize on the increased interest in molecular and personal medicine diagnostics, but has yet to do so. In the meantime Beckman Coulter has developed a presence in the market for genetic test services.

Beckman Coulter was acquired by Danaher Corporation in February 2011. The acquisition followed a number of setbacks. Beckman Coulter’s diagnostics revenues had been relatively flat for a number of years. Also Beckman Coulter had received a warning letter from FDA about violations the agency found at the Brea, CA facility. The agency inspected the facility between March 2010 and May 2011 in connection with quality control issues surrounding the company's AccuTnl troponin test kits that run on its Access and UniCel DxI immunoassay systems.

April 2009, Beckman Coulter acquired Clinical Data’s Cogenics division for

approximately $17 million. Cogenics provides genomic services and has operations in the U.S., U.K., Germany, and France. Then in August 2009, Beckman Coulter announced that it had formed Beckman Coulter Genomics (Danvers, MA), combining the operations of its Agencourt Bioscience business with Cogenics. For Beckman Coulter this is a return to the past, the company divested its laboratory services business in the 1980s and is now riding the trend to LDT services.

Cogenics provides genomics solutions for healthcare and life sciences industries. These solutions span the areas of current and next generation sequencing, gene expression,

Eighteen: Molecular Leaders 391



CALIPER LIFE SCIENCES Hopkinton, MA

www.caliperLS.com November 2011, Caliper was acquired by PerkinElmer Inc. for approximately $600

million in cash. RECENT REVENUE HISTORY: ($ MILLION): Total revenues ($ million) 2009 $ 2010 $ 2011 $ LabChip sales were $ million in 2009, $ million in 2010 and approximately

million in 2011. KEY COMMENT: Long-term, Caliper intends to combine its molecular diagnostics

competencies its multiplex tissue imaging technology to enter the emerging field of companion diagnostics.

Caliper Life Sciences is innovating new technology to bridge the gap between in vitro

assays and in vivo results, enabling researchers to translate those results into cures for human disease. Caliper's portfolio of offerings includes state-of-the-art microfluidics, lab automation & liquid handling, tissue microscopy, preclinical imaging technologies, and discovery & development outsourcing solutions.

Clinical Diagnostics

January 2011, Caliper launched the LabChip Dx system for use by clinical research laboratories developing molecular diagnostic tests. The LabChip Dx platform enables simultaneous analysis of up to ten different analytes in a single sample. It is also capable of analyzing large numbers of multiplex samples using minimal sample volume and avoids the need to further purify or dilute diagnostic PCR products. The new system includes specific identification, scoring and reporting software.

The LabChip Dx utilizes Caliper's microfluidics technology to perform high-resolution, electrophoretic separations for analyzing multiplex PCR products. The LabChip Dx is

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labeled "For Research Use Only." It has not been cleared or approved by the U.S. Food and Drug Administration.

July 2011, Caliper was awarded the CE Mark for the LabChip Dx instrument. The LabChip Dx was developed in collaboration with Seegene, Inc., with whom Caliper announced a strategic partnership in 2011.

The LabChip Dx system features diagnostic identification, scoring and reporting software. It is based on the same microfluidics technology that has become the standard electrophoretic separation platform in research, enabling high throughput, multiplexed, cost effective sample processing for discovery and validation of molecular and companion diagnostics. The platform can analyze large numbers of multiplex samples using minimal sample volume, provides automatic pipetting, and avoids the need to further purify or dilute diagnostic PCR products. The cost effective approach of Caliper's robust microfluidics platform explains its high rate of adoption among research laboratories around the world.

January 2011, Caliper and Seegene (Seoul, Korea) entered into a partnership to enable SeePlex multiplex diagnostic assays to run on Caliper's LabChip Dx platform. The LabChip Dx system, which includes specific diagnostic identification, scoring and reporting software was developed in collaboration with Seegene. Caliper's LabChip Dx platform and Seegene's complete line of multiplex diagnostic content will be marketed immediately; the companies will work together to implement specific content and platform technology-development efforts to expand the number of diagnostic tests available, which will be offered in a unique, co-branded product brochure.

March 2011, Caliper and HistoRx, Inc. (Branford, CT) formed a collaboration to provide integrated solutions for protein quantification of biomarkers in tissue. The companies will co-develop a new generation of tissue-based imaging and analysis solutions, based on immuno-fluorescence, that will deliver quantitative, and reproducible measurements of proteins in tissue samples. The collaboration will enable researchers to leverage the combined imaging and analysis power of Caliper's Vectra, an automated multiplexed tissue imaging platform, and AQUA technology, HistoRx's proprietary image analysis system, to provide an integrated platform to advance the identification and validation of new drug targets and improve assessment of drug response.

Under the agreement, Caliper will have exclusive worldwide distribution rights for the integrated product in the life sciences research market as the companies continue to explore additional collaborative opportunities in clinical research and diagnostics. The AQUA technology is complimentary to Caliper's inForm image analysis software, a flexible



C H A P T E R N I N E T E E N

Company Profiles: Market Participants

This section presents smaller companies that are either emerging or have yet to make significant market penetration or impact. The profiles include events that have occurred in the past few years, they are not a comprehensive review or history of the companies selected to appear in the section. (listed alphabetically)

ALACRIS THERANOSTICS GMBH Berlin, Germany www.alacris.de

RECENT REVENUE HISTORY: private KEY COMMENT: January 2011, QIAGEN acquired a strategic stake in Alacris

Theranostics GmbH, a company using proprietary technologies to develop individualized therapy approaches based upon a patient's genomic profile. QIAGEN gained an exclusive option to access all biomarkers emerging from this discovery program.

Alacris, founded by researchers at the Max Planck Institute for Molecular Genetics

(MPI-MG, Berlin, Germany) and Harvard Medical School (Cambridge, MA), uses a

Nineteen: Molecular Market Participants 474



proprietary modeling system developed at MPI-MG and exclusively licensed to Alacris Theranostics, as ModCell to analyze clinical sample data based on next-generation and other whole genome sequencing technologies.

Based on genome and transcriptome information obtained by next generation sequencing and including kinetic pathway information, mutation and drug databases the systems biology approach is providing a “Virtual Patient” model.

The Virtual Patient model can predict the effect of chemotherapeutic treatment and optimized combinatory treatment providing means for cancer patient stratification and for personalized medicine approaches.

A second major benefit of this system is the generation of “Virtual Clinical Trials”. Such trials permit the in silico analysis of known drugs or of drugs prior to be tested in real clinical trials identifying specific patient groups or particular genetic profiles and diseases that could be targeted by the drug.

ModCell allows users to identify and select from vast amounts of genetic data such markers that can prove useful to guide treatment decisions for patients. The technology can also be used to create marker subsets to stratify potential patient populations for R&D trials involving medicines in clinical development. These marker selections can be formatted into real-time PCR-based assays that QIAGEN can commercialize within its pharmaceutical development assay portfolio or its therascreen molecular diagnostics portfolio for use on its new QIAsymphony RGQ platform.

ASTRA BIOTECH GMBH Luckenwalde, Germany

www.astrabiotech.de RECENT REVENUE HISTORY: private KEY COMMENT: Astra Biotech offers a wide range of reagents and diagnostic kits

for detection of human hormones, genetic diseases, tumor markers and allergens. The product portfolio includes antibodies, antigens, recombinant products, conjugates, calibrators, microplates, ELISA kits, molecular test kits and microarrays.




Astra Biotech’s real-time PCR-based diagnostic kits are used to detect gene polymorphisms associated with diseases and individual sensitivities to specific drugs. The test kits simultaneously detect several and are validated on multiple commonly-used PCR instruments from leading biotechnology vendors.

The Thrombosis Kit detects polymorphisms in F5 and F2 genes encoding coagulations factors. Factor V is the cofactor for the transformation of prothrombin to thrombin. Factor II (Prothrombin) is one of the main components of the blood coagulation system. The kit contains a set of primers and fluorescent probes for amplification of the specific sequences of human F5 and F2 genes to predict the individual risk.

The Pharmaco-VKORC1 kit detects polymorphisms in the VKORC1 gene encoding the subunit of vitamin K epoxide reductase complex. VKORC1 is involved in the biosynthesis of the coagulation factors in the liver and is as well as target of oral anticoagulants. In case of polymorphism the expression level is changed. That might lead to an necessary adjustment of the drug dosage. The polymorphisms are detected by different fluorescent dyes.

The Pharmaco-CYP2C9 kit detects polymorphisms in the CYP2C9 gene. CYP2C9 is the isozyme of cytochrome P-450 and linked to the metabolism of oral anticoagulants as well as some diuretics and angiotensin II receptor blockers. The three widespread European variations of this gene lead to changed catalytic activity of this enzyme. The knowledge of occurrence of the polymorphisms helps to choose the exact medication and to avoid side effects.

Astra Biotech markets a microarray for simultaneous detection of 25 of the most common mutations causing cystic fibrosis in pan-European populations. Applications include CF newborn screening, prenatal diagnostics, carrier testing, and testing of couples with a personal or close family history of CF as recommended by the World Health Organization.

Astra Biotech offers a molecular test kit for osteoporosis kit for the determination of genes the genes of Collagen type 1 (COLIA1) and the vitamin D receptor (VDR) that have been associated with osteoporosis onset.




AUTOGENOMICS INC. Vista, CA

www.autogenomics.com RECENT REVENUE HISTORY: ($ MILLION): Private, for the past few years the

company’s revenues have hovered around $ million, 2011 revenues were $ million. In 2010, the company reported that this poor showing raises “substantial doubt about our

ability to continue as a going concern”, but the company continued to market its products. The company’s products have begun to gain acceptance.

For 2012, the company anticipates revenues of approximately $ million and so in

September 2012, AutoGenomics filed plans for an estimated initial public offering of up to $ million in common stock. It plans to use its IPO proceeds to expand its sales force, enhance its international distributor network, increase marketing and promotional activity and business development efforts.

KEY COMMENT: Autogenomics’ Infiniti system was FDA cleared in 2007 and the

company reports that it has some 50 tests on the market. The limited market penetration indicates just how competitive molecular test markets are.

AutoGenomics, Inc. has developed INFINITI, an automated, microarray based

multiplexing diagnostic platform that can be used to assess disease signatures with novel genomic and proteomic markers in the area of genetic disorders, infectious disease, cancer and pharmacogenetics manufactures and markets automated and integrated solution for the molecular diagnostics industry.

INFINITI automates the discrete processes of genetic testing performed by clinical laboratories. The INFINITI system consists of the INFINITI Analyzer and the consumable products used to run tests on its system, including the BioFilmChip Microarray and the Intellipac Reagent Management Module. It is designed to address in areas of infectious disease, cancer, genetic disorders, personalized medicine, cardiovascular disease/thrombophilia, women's health, newborn screening, and central nervous system disorders.

As of March 31, 2010, the company had an installed base of 151 INFINITI Analyzers in reference laboratories, hospital laboratories and specialty clinics in North America, Europe, Asia, the Middle East and South America.



C H A P T E R T W E N T Y - O N E

Company Profiles: Newcomers

In this section Kalorama presents a selection of IVD companies that have recently entered the market for molecular tests. The profiles include molecular testing events that have occurred in the past few years, they are not a comprehensive review or history of the companies selected to appear in the section. (listed alphabetically).

DIASORIN S.P.A. Saluggia Italy

www.diasorin.com May 2012, the DiaSorin Group acquired NorDiag ASA (Oslo, Norway), the molecular

business of the Nordiag Group. Nordiag’s molecular revenues are expected to be approximately $1.5 million in 2012.

RECENT REVENUE HISTORY: ($ MILLION): 2009 $ 2010 $ 2011 2012 $ 1 Euro = $1.39 Molecular product revenues (first year availability) in 2012 are estimated at $ million

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NEW KALORAMA INFORMATION! The World … FROM KALORAMA INFORMATION! The World Market for Molecular Diagnostics 5th Edition Authored by Shara Rosen • 850+ Pages of Market