1. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Device Development: Past, Present and Future 1

2. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine MY CONFLICTS OF INTEREST ARE

3. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Approaches to Establish Funding Angel Venture Corporate 2

4. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Angel Funding Pros –Less Expensive –Industry Expertise –Provides Upstart to build value and more leverage Cons: –Hassle Factor –One/Two Round Only When does it make sense? –Less Cash intensive opportunities –Low regulatory hurdles –Fast-followers –First-timers putting an experienced executive team together 3

5. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Venture Funding Pros –Deep Pockets –Professional Expertise –Extensive Business Network Cons –More Expensive –Return / Liquidity Requirements –In-Depth Due Diligence When does it make sense? –Large Opportunities –Markets > $500 million –Cash and time intensive –First-timers unable to assemble a solid executive team together 4

6. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Corporate Funding Pros: –Less Expensive –Value Add –Credibility Cons: –Hidden Agenda/Special Rights –Questionable Follow-On Dollars –Exit Strategy Limited –Business Alignment When does it make sense? –Funding Needs beyond VC’s –Close to commercialization…looking for a commercial partner 5

7. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Funding Stages Company Stage Concept Company Sales / Profits Sales / Profits Liquidity Product Devt and Commercialization Funding Type Seed Stage (Series A) Startup (Series B) Expansion (Series C) Mezzanine (Series D) IPO or Merger RISK HigherLower $$$ VALUE $$$ LowerHigher 6

8. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Important Startup Rule #1 The more $$ you spend The more $$’s you have to raise The more of your opportunity you have to sell The less return you provide to investors… 7

9. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine The Team & The Company Management: – Do You Have a CEO? – Is He/She Qualified, Experienced as CEO? – Can They Raise Money? Team: – Functional Disciplines? – No-compromise on hiring great people? – Team Chemistry? Bottom Line: Risk in the team….COSTLY The timing of the right functional teams coming together ….CRITICAL TO SUCCESS 8

10. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Intense Competition Intellectual Property Capital Requirement Engineering Regulatory Environment 9

11. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Anatomy of a Start-up… IPO FDA Approval; Product Launch Distribution Agreement Hired CEO; Key management in place FDA submission Animal studies completed; Start clinical trials Prototype completed; Funds raised Patents Disclosed Time (years) Valuation ($) 10

12. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Timing is everything It is often, but not always best to be first Some markets change quickly; others very slowly New market development is expensive Window of Opportunity 11

13. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Rigor of randomized clinical trials Clinical adoption Ease of use Learning curves 12

14. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Goals of Startups Balancing 13

15. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Understanding of the Opportunity Novel IdeaIterative Idea Investment Dollars Needed HigherLower Time to Liquidity LongerShorter Biggest Risks Technical/Clinical Market adoption timeliness Execution timeliness and quality Competition Most Important for Success IP protection Customer willingness to change/adopt Experienced team Laser focus Adoption Curve LongerShorter Likely Exit Value HigherLower Importance of Expense Control Moderate - highVery high 14

16. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Golden Rules Device or procedure must be simple to apply an can be adopted by the average practitioner Invention addresses an otherwise unmet clinical need Device regulatory path is associated with a “reasonable” chance for success in an otherwise well defined study with a finite sample size

17. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004 2005 2006 16

18. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977

19. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Coronary Angioplasty (PTCA) Andreas Gruntzig

20. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984

21. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Directional Coronary Atherectomy (DCA) John Simpson

22. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988

23. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Rotational Atherectomy (PTCRA) David Auth

24. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989

25. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Coronary Stenting Julio Palmaz

26. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997

27. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine In- Stent Restenosis

28. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Brachytherapy

29. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000

30. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Drug Eluting Stents

31. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Event-Free Survival at Two Years following procedure Freedom from events (%) Days after initial procedure 92% 76%

32. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine ARTS I: Three-year outcome after Stenting vs. CABG for the Treatment of Multivessel Disease. 100 99 98 97 96 95 94 93 92 91 90 0 120 240 360 480 600 720 840 960 1080 1200 Days since randomization % Survival Stent CABG Van Domburg, et al., Circ. 2004:109, 1114-20

33. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine

34. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002

35. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Percutaneous Treatment of Carotid Artery Stenosis

36. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Percutaneous Aortic Valve Therapy Alain Cribier

37. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Percutaneous Valve Therapy Edwards LifeSciences

38. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Self-expanding Nitinol multi-level frame Porcine pericardium Tissue Valve Disposable Loading System Delivery Catheter 18 French 12 Fr body The CoreValve Revalving™ System Self-Expanding Support Frame

39. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine

40. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003

41. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Percutaneous “Mitral” Valve Repair Coronary Sinus Annuloplasty Edge-to-Edge Repair

42. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Coronary Sinus Annuloplasty Edwards LifeScience Handle Sliding Knob Location of Implant (Internal) Distal Anchor Proximal Anchor Bridge

43. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Mitral Valve Edge-to-Edge Repair

44. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004

45. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Atrial fibrillation is a major source of cardiogenic embolism-related stroke Source: Neurology, 1978; Stroke, 1985; European Heart Journal, 1987; Lancet, 1987 500,000 strokes per year AHA estimates that 15 – 20% of strokes/year are related to AF

46. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine WATCHMAN ® Device Frame: Nitinol (shape memory) –Contour shape accommodates most LAA anatomy –Barbs engage the LAA tissue Fabric Cap: Polyethyl terephthalate (PET) Fabric –Prevents harmful emboli from exiting during the healing process Barbs 160 µ PET fabric Device available in various sizes: –21, 24, 27, 30 and 33 mm (diameter) –Device diameter is measured across face of device –Device Length = Device Diameter

47. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Left Atrial Appendage Closure

48. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004 2005

49. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine The Next Frontier in Coronary Stenting

50. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Treating Bifurcation Lesions Limitations of Current DES –Stents are tubular structures not intended for Y-shaped anatomy –Side branch jailing –Limited ostial coverage (“Gaps”) –Technically demanding –Multiple layers of metal –Increasing risk of thrombosis –Myriad of Techniques Gap Multiple Layers

51. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine The TAXUS Petal TM Boston Scientific Coroporation Stent Advantages –Special stent feature to cover ostium of side branch (~2mm) –Reduces / eliminates side branch “gap” –May reduce frequency of 2nd stent –Placing 2nd stent, when necessary, is technically more straight forward Delivery System Advantages –Side Branch wire lumen aids in alignment at ostium –Side branch “pre-wired”, no need to re-access through stent –Final Petal size determined by post dilatation balloon

52. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Chronic Total Occlusion (CTO).

53. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004 2005 2006

54. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Why Degradable Stents? No late adverse events –Late thrombosis –Hypersensitivity reactions (chronic inflammation) –Stent fractures Does not restrict arterial remodeling Permits non-invasive imaging of artery Permits bypass surgery in future Degradable Stents

55. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Bioabsorbable Stent Design. Core: Polymer A Undercoat: Polymer B Topcoat: Polymer B Drug Layer: Polymer B + Sirolimus Coating Layers

56. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Multi-Layer, Combination Drug Delivery

57. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Biodegradable Stents Could also be the ideal vehicle for several other applications: non-obstructive vulnerable plaque, gene transfer for infract repair and angiogenesis…..

58. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine “Biodegradable Stents: They Do Their Job and Disappear” -Ron Waksman

59. Maurice Buchbinder, MD Foundation for Cardiovascular Medicine Future Opportunities in Interventional Cardiology Peripheral Vascularization -Claudication -Limb Salvage -Angiogenesis Structural Heart/ Stroke Prevention -PFO/ASD Closure -Left Atrial Appendage closure - Atrial Fib. Ablation Cerebral Revascularization -Carotid Stenting -Embolic Protection Devices -Acute Stroke Intervention Congestive Heart Failure -Resynchronization Therapy -Impulse Modulation -Implantable Pressure Regulators