Tecan Group AG · SIX:TECN

Tecan — 3rd Tecan Symposium, Salzburg 2010

66 slides from Tecan's conference presentation, Oct 7, 2010

1. Slide 1: Molecular Testing and the Changing Face of Medicine

   Molecular Testing and the Changing Face of Medicine A Quick Walk through the Park James K. Fleming, PhD, FACB Vice President and Director Department of Science and Technology Laboratory Corporation of America Elon, North Carolina USA 3rd Tecan Symposium, Salzburg October 7, 2010

2. Slide 2: A Sinuous Walk Through the Park

   2 A Sinuous Walk Through the Park

3. Slide 3: 3

   3

4. Slide 4: The Beginning

   4 The Beginning

5. Slide 5: History of Molecular Testing

   5 History of Molecular Testing 1953 – Jim Watson and Francis Crick publish the structure of DNA (Nobel Prize 1962) 1957 – Kornberg identifies DNA polymerase which requires an initiation primer (Nobel Prize 1959)

6. Slide 6: History of Molecular Testing

   6 History of Molecular Testing 1960 – Khorana discovers the Genetic Code (Noble Prize 1968) 1969 – Brock isolates Thermus aquaticus from a hot spring in Yellowstone National Park

7. Slide 7: History of Molecular Testing

   7 History of Molecular Testing 1970 – DNA polymerase is isolated from E. coli 1971 – Kleppe and Khorana theorize that 2 primer system could lead to replication of a specific segment of DNA, but publish no data 1976 – DNA polymerase is isolated from T. aquaticus (Taq)

8. Slide 8: History of Molecular Testing

   8 History of Molecular Testing 1977 – Sanger reports a method of sequencing DNA (Nobel Prize 1980)

9. Slide 9: History of Molecular Testing

   9 History of Molecular Testing Between 1953 and 1980, these researchers set the stage for the next level of discovery by providing all the components needed to perform PCR  (4 Nobel awards) Structure Primers Polymerase Replication Sequencing

10. Slide 10: History of Molecular Testing

    10 History of Molecular Testing 1983 Kary Mullis at Cetus modified the amplification process by bracketing a desired sequence of the DNA strand with 2 primers using thermocycling  Then used DNA polymerase to make infinite copies

11. Slide 11: History of Molecular Testing

    11 History of Molecular Testing  Problem: DNA polymerase was thermal labile  1985 – 1st PCR publication appears in Science 1986 Cetus files PCR patents  Mullis uses Taq polymerase  First forensic use of PCR for HLA‐DQA 1988 Perkin Elmer launches first automated thermal cycler  Science prints

12. Slide 12: History of Molecular Testing

    12 History of Molecular Testing 1989 – Star Trek: The Next Generation. The ships doctor is aging rapidly by a virus and is cured when her pre‐infection DNA isolated from a strand of her hair is found in her room. PCR hits mainstream media

13. Slide 13: History of Molecular Testing

    13 History of Molecular Testing 1990‐ Fist forensic PCR kit for HLA‐DQA 1991– Roche secures world wide rights for PCR patents from Cetus for $300M US 1992 – Roche Molecular Diagnostics is founded  Launch Amplicor HIV‐1 Monitor x‐US 1993 – Launch of the 1st commercial kit in US for Chlamydia tra

14. Slide 14: History of Molecular Testing

    14 History of Molecular Testing  Roche also launches the first multiplex Amplicor CT/NG PCR 2000 – Roche launches Linear Array CF test 2001 – Roche patents real time PCR devise 2001 ‐ 2010

15. Slide 15: Molecular Testing

    Molecular Testing 15 Genetic Abnormalities  Oncology  Neurology  Prenatal  Coagulation  Pharmacodiagnostics  Tissue typing  Endocrine  Connective Tissue  Hematology  Renal  Transfusion Medicine

16. Slide 16: Molecular Testing

    16 Molecular Testing Infectious Organisms  Bacterial • Mycobacteria  Viral  Rickettsial  Fungi

17. Slide 17: Molecular Techniques

    17 Molecular Techniques PCR Non‐PCR Amplification  bDNA  TMA  SDA  LiPA  NASBA ISH Sequencing

18. Slide 18: Other Molecular Platforms

    18 Other Molecular Platforms Microarray Laser Capture Microdissection Tissue Arrays Amplification coupled LC/MS Microfluidics Invader

19. Slide 19: Top Molecular Companies

    19 Top Molecular Companies Abbott Cepheid Qiagen Agilent Dako Roche BD Genomic Health Siemens Beckman Coulter GenProbe Sysmex bioMerieux Genzyme Ventana Celera Ortho Plus 130 additional companies providing molecular diagnostics from AdnaGen, AG to Zila, Inc

20. Slide 20: The Impact on Medicine

    20 The Impact on Medicine

21. Slide 21: HIV: The Beginning

    21 HIV: The Beginning The 1st Culprits Chimpanzee SIVcpz HIV-1 Sooty Mangabey SIVsm HIV-2

22. Slide 22: HIV: The Beginning

    22 HIV: The Beginning The 2nd Culprits Contaminated Needle Theory Hunter Theory

23. Slide 23: HIV: The Beginning

    23 HIV: The Beginning Oral Polio Vaccine Theory Conspiracy Theory

24. Slide 24: HIV: The Beginning

    24 HIV: The Beginning Earliest Evidence  1959 – plasma from adult male living the Congo  1960 – lymph node of adult female living in Congo  1969 – tissue of dead teenager living in St Louis  1976 – tissue sample Norwegian sailor  1979 – Gay men in US and Sweden and heterosexuals in Tanzania an

25. Slide 25: PCR and HIV

    25 PCR and HIV June 1981 – Brief report in MMWR of unusual pmeumocystis carinii pneumonia among “5 gay, otherwise healthy men” from LA.  PCP almost always seen in immunocompromised patients  The 5 men had no significant medical history July 1981 – 45 more cases isolated in LA, SF, NY  Some deve

26. Slide 26: PCR and HIV

    26 PCR and HIV 1984 – 4000 cases in the US including • hemophiliacs • infants born to HIV infected mothers • Men who have sex with men • The disease now called AIDS  French researchers discover a retrovirus  NIH announces that a vaccine will be ready in 2 years

27. Slide 27: HIV: The Beginning

    27 HIV: The Beginning Early developers of HIV tests were faced with an unmet clinical need for testing viral infectious diseases  Need to detect low antibody levels  Need early detection  Need to follow viral concentration in host

28. Slide 28: PCR and HIV

    28 PCR and HIV 1985 – 1st HIV antibody test became available (ELISA) 1986 – Switzerland begins testing blood products 1987 – ATZ (zidovudine) becomes 1st anti‐HIV drug at a dose of 100mg q4h ‐24 hours per day  Western Blot testing begins 1988 – Deaths in US at 4,855

29. Slide 29: PCR and HIV

    29 PCR and HIV 1989 – Deaths in US at 14,544  Reverse transcriptase inhibiters released 1992 – First rapid test for HIV antibody released  Deaths in US at 23,411 1994 – HIV ability to mutate have made vaccine development difficult and risky 1995 – Roche launches HIV‐1 PCR quant

30. Slide 30: HIV and PCR

    30 HIV and PCR 1996‐ Era of HAART begins (3 drugs recommended)  Deaths in US at 21,399  Estimated 22M infected WW with 6.4M deaths 1999 – NIH pledges to develop a vaccine within the next 10 years  HIV ‐1 ultra sensitive PCR test launched  Deaths in US at 17,741

31. Slide 31: PCR and HIV

    31 PCR and HIV 1999 – Monogram launches anti‐retroviral susceptibility testing  Tropism for CCR5 or CXCR5 for CCR5 agonists  Phenotypic and genotypic susceptibility • non‐nucleoside reverse transcriptase inhibitors • nucleoside reverse transcriptase inhibitors • protease inhibitors • Integrase •

32. Slide 32: PCR and HIV

    32 PCR and HIV 2002 – Roche HIV‐1 v1.5 PCR screen for blood and blood products launched in Italy 2007 – 2.7 M have been infected in US and 2.0M have died  HIV‐1 RT viral load launched by Roche and Abbott (Abbott claims greater detection of subtypes) 2010 – Roche releases v2 of HIV‐1 RT PCR with

33. Slide 33: HIV and Changes in Medicine

    33 HIV and Changes in Medicine Several influencing factors  PCR • Drug discovery • Patient diagnosis • Patient monitoring • Selective patient treatment  Pharmaceuticals and HAART  Education HAART has decreased death rate by 80% and increased life expectancy by 20 years

34. Slide 34: HIV and Changes in Medicine

    34 HIV and Changes in Medicine In 1985  Median time of progression to AIDS – 9 to 10 y  Median survival time – 9.2 months In 2010  Survival time has increased by 4 to 12 y

35. Slide 35: AIDS Diagnoses and Deaths of Adults and Adolescents

    AIDS Diagnoses and Deaths of Adults and Adolescents with AIDS, 1985-2007— United States and 90- Dependent Areas Diagnoses =@Deaths (in “ £ & wu mo) mo} c © wv 7] “ °o = 122) po mo] rr f°] ) = 1985] 1986] 1987] 1988] 1989] 1990] 1991] 1992] 1993 | 1994] 1995] 1996] 1997] 1998] 1999] 2000] 2001| 2002]

36. Slide 36: Adults and Adolescents Living with an AIDS Diagnosis

    Adults and Adolescents Living with an AIDS Diagnosis, by Sex, 1993-2007—United States and Dependent Areas NO ND o wo o (in thousands) rn) Females “a < 3° “ he Q a i) (} = = o o 1993] | 1995| 1996| 19971 1998] 1999| 2000 | 2001] 20021 2003| 2004] 2005 | 2006| 2007] Year of diagnosis Note. All display

37. Slide 37: Median Age at Death due to HIV Disease

    Median Age at Death due to HIV Disease United States, 1987-2006 = - © ® Q — © ® D < e = a] ® = LJ LJ LJ LJ Ly q qT q ! i LJ LJ ! I T q i 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pc st3¥ice, ty : 2 (4 Note: For comparison with data for 1999 a

38. Slide 38: Estimated Numbers of AIDS Cases, Deaths, and Persons Living with AIDS

    Estimated Numbers of AIDS Cases, Deaths, and Persons Living with AIDS, 1985-—2007—United States and Dependent Areas ” & 5 Oo {00} UG Ze © § nos oo AS Se OF (eo) fe} ra “| A Cases Deaths @ Prevalence i<—— 1993 definition implementation 500 450 400 + 350 10]0) + 250 Prevalence thousands) + 200 in ( 15

39. Slide 39: But Not Globally

    39 But Not Globally 95% of new HIV infections arise in lower to middle income nations <1% of sexually active people of Africa’s urban population has been tested. Over 33M people are currently infected  31M adults  15.7 women (50%)  2.1M children

40. Slide 40: But Not Globally

    40 But Not Globally  25M have died from AIDS since 1981  More than ½ of all those who are infected are less than 25 yo • Will likely die before they are 35  AIDS deaths in 2008 – 2M WW  WHO estimates only 5.2M receiving treatment

41. Slide 41: Companion Diagnostics in 2010 Anti-retrovirals

    Companion Diagnostics in 2010 41 Anti‐retrovirals NRTI NNRTI PI Integrase FI Zidovudine Nevirapine Saquinavir Raltegravir Enfuvirtide Didanosine Delavirdine Ritonavir Zalcitabine Efavirenz Indinavir Stavudine Etravirine Nelfinavir Lamivudine Atazanavir Abacavir Fosamprenavir Tenofovir Tipranavir 6 d

42. Slide 42: PCR and HIV

    42 PCR and HIV Medical science can help  It has the means and ability to increase the quality of life Global economics, governments and education remain barriers PCR has changed the practice of medicine for a pernicious and deleterious disease  But its influence is limited.

43. Slide 43: 43

    43

44. Slide 44: Molecular Testing and Controversy

    44 Molecular Testing and Controversy The Case of MRSA  2007 CMS issued a directive that the agency would no longer pay for complications arising from hospital acquired conditions if that condition was not present at time of admission. Hospitals immediately sought a molecular solution for methicil

45. Slide 45: Molecular Testing and Controversy

    45 Molecular Testing and Controversy CMS decided to delay its rule MRSA molecular screening interest precipitously dropped in US  In preference to Remel’s selective media  Lower cost Doesn’t eliminate the need for rapid detection Does set up a mechanism for substandard treatment and patient cr

46. Slide 46: Molecular Testing and Controversy

    46 Molecular Testing and Controversy Direct to Consumer Testing  Posed scientific, ethical, and moral dilemmas for the US  Can have our entire genome scanned for $1000‐ $3000  Is there a benefit?  Or should we selectively genotype specific disease causing regions of our DNA  The genotype is ac

47. Slide 47: Molecular Testing and Controversy

    47 Molecular Testing and Controversy  Interpretation may vary from one company to another  Is it beneficial to know if one has a predisposition to heart disease or diabetes – much debate • Could lead to undue stress, anxiety, needless decisions  Genetic information should be considered with other

48. Slide 48: Molecular Testing and Controversy

    48 Molecular Testing and Controversy  Part of problem • Genetic information frequently incomplete Unlike Huntington’s or CF  Heart Disease, Diabetes, Cancer, • Genetics are complex No single genes May be tens of genes that have correlative mutations yet to be discovered Interpretations provide ris

49. Slide 49: Molecular Testing and Controversy

    49 Molecular Testing and Controversy  Negative Test does not mean your free of risk or disease  Environmental Factors  Population bias  All pose caveats and limitations that change the clinical significance of the mutations detected

50. Slide 50: Who Owns Our Genes

    50 Who Owns Our Genes ~25,000 protein encoding genes 20% of genes are patented US Patent Office has received more that 3M gene Round Worm applications over past 20 ~20,000 genes years 40,00 patents held on gene segments

51. Slide 51: Who Owns Our Genes

    51 Who Owns Our Genes 1906 – Adrenalin was patented  Patent was challenged and US Supreme Court ruled that the substance was “isolated and purified” and that constituted an invention regardless of it’s source 1923 – Insulin was patented  1980 – Diamond v Chakrabarty  GE engineer who developed a

52. Slide 52: Who Owns Our Genes

    52 Who Owns Our Genes  Patent challenge resulted in the US Supreme Court ruling that GE patent was valid • The organism was man made therefore it was an invention Supreme Court ruling led to liberal interpretation of the rulings by the Patent Office and began applying the rulings to genetic materi

53. Slide 53: Who Owns Our Genes

    53 Who Owns Our Genes March 29, 2010  ACLU v Myriad Genetics • Myriad holds patents for several genes in the BRCA family • Mutations of BRCA incur susceptibility to breast and ovarian cancer • Myriad also has property rights to the diagnostic test which is sold for $3000 US

54. Slide 54: Who Owns Our Genes

    54 Who Owns Our Genes ACLU argued that the gene patents stifled research, innovation and limited testing options Attorney Generals Office argued that the Patent Office was interpreting court rulings and Congressional law Federal Court invalidated 7 Myriad IP patent for BRCA Myriad vowed to appea

55. Slide 55: Cartoon on breast cancer genes

    Whey re our breast Cancer % genes —we idenhfied then. —¢ It's kind of you fe let uS have the disease LabCorp

56. Slide 56: The Prospects

    56 The Prospects

57. Slide 57: The Future

    57 The Future Do gene patents stifle research?  Do companies sit on patents that could led to new therapies in lieu of working on blockbuster genes that could result in lucrative returns  Or will loss of gene patents disincentivize companies from active pharmacodiagnostic research  Will invalida

58. Slide 58: The Future

    58 The Future Will other countries see court action due to less conscientious molecular laboratories Will professional organizations rally to the cause and self police through stricter laboratory operating guidelines and certification programs

59. Slide 59: The Future

    59 The Future  Will governmental agencies pass laws governing molecular diagnostic practices for the protection of the consumer  Many states in US have laws banning the use of genetic testing to determine insurability

60. Slide 60: The Near Future from LabCorp's Perspective

    60 The Near Future from LabCorp’s Perspective Increased decentralization of molecular testing  Molecular testing equipment is becoming more black box  No longer a central laboratory test • CT/NG • HPV • HIV • HBV • HCV

61. Slide 61: The Near Future from LabCorp's Perspective

    61 The Near Future from LabCorp’s Perspective Alternate Sample Types

62. Slide 62: The Near Future from LabCorp's Perspective

    62 The Near Future from LabCorp’s Perspective Microfluidics PCR coupled technology  Multiplexing for Infectious Organisms

63. Slide 63: The Near Future from LabCorp's Perspective

    63 The Near Future from LabCorp’s Perspective Single cell PCR Circulating Tumor Cells Increased microarray applications for  clinical trials  R&D  diagnostics

64. Slide 64: The Future from LabCorp's Perspective

    64 The Future from LabCorp’s Perspective  Changing role for molecular biologists • Directors rather than bench technologists  Expanded role of DNA evidence in pretrial and post conviction cases

65. Slide 65: The Future ?

    65 The Future ?

66. Slide 66: The Break!

    66 The Break!

Tecan Group — 3rd Tecan Symposium, Salzburg 2010 on 6ix