History of Device Development: Past, Present and Future 1

MY CONFLICTS OF INTEREST ARE

Approaches to Establish Funding Angel Venture Corporate 2

Angel

Venture

Corporate

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

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

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

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

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

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

Funding Stages Company Stage Concept Company Sales / Profits Liquidity Product Devt and Commercialization 6 Funding Type Seed Stage (Series A) Startup (Series B) Expansion (Series C) Mezzanine (Series D) IPO or Merger RISK Higher Lower $$$ VALUE $$$ Lower Higher

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

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

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

Intense Competition Intellectual Property Capital Requirement Engineering Regulatory Environment 9

Intense Competition

Intellectual Property

Capital Requirement

Engineering

Regulatory Environment

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

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

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

Rigor of randomized clinical trials Clinical adoption Ease of use Learning curves 12

Rigor of randomized clinical trials

Clinical adoption

Ease of use

Learning curves

Goals of Startups Balancing 13

Understanding of the Opportunity 14 Very high Moderate - high Importance of Expense Control Lower Higher Likely Exit Value Shorter Longer Adoption Curve Novel Idea IP protection Customer willingness to change/adopt Technical/Clinical Market adoption timeliness Longer Higher Experienced team Laser focus Most Important for Success Execution timeliness and quality Competition Biggest Risks Shorter Time to Liquidity Lower Investment Dollars Needed Iterative Idea

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

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

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004 2005 2006 16

History of Interventional Cardiology 1977

Coronary Angioplasty (PTCA) Andreas Gruntzig

History of Interventional Cardiology 1977 1984

Directional Coronary Atherectomy (DCA) John Simpson

History of Interventional Cardiology 1977 1984 1988

Rotational Atherectomy (PTCRA) David Auth

History of Interventional Cardiology 1977 1984 1988 1989

Coronary Stenting Julio Palmaz

History of Interventional Cardiology 1977 1984 1988 1989 1997

In- Stent Restenosis

Brachytherapy

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000

Drug Eluting Stents

Event-Free Survival at Two Years following procedure Freedom from events (%) Days after initial procedure 92% 76%

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

.

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002

Percutaneous Treatment of Carotid Artery Stenosis

Percutaneous Aortic Valve Therapy Alain Cribier

Percutaneous Valve Therapy Edwards LifeSciences

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

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003

Percutaneous “Mitral” Valve Repair Coronary Sinus Annuloplasty Edge-to-Edge Repair

Coronary Sinus Annuloplasty

Edge-to-Edge Repair

Coronary Sinus Annuloplasty Edwards LifeScience Handle Sliding Knob Location of Implant (Internal) Distal Anchor Proximal Anchor Bridge

Mitral Valve Edge-to-Edge Repair

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004

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

500,000 strokes per year

AHA estimates that 15 – 20% of strokes/year are related to AF

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

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

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

Left Atrial Appendage Closure

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004 2005

The Next Frontier in Coronary Stenting

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

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

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

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

Chronic Total Occlusion (CTO) .

History of Interventional Cardiology 1977 1984 1988 1989 1997 1999 2000 2002 2003 2004 2005 2006

Why Degradable Stents? 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

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

Bioabsorbable Stent Design . Core: Polymer A Undercoat: Polymer B Topcoat: Polymer B Drug Layer: Polymer B + Sirolimus Coating Layers

Multi-Layer, Combination Drug Delivery

Biodegradable Stents Could also be the ideal vehicle for several other applications: non-obstructive vulnerable plaque, gene transfer for infract repair and angiogenesis…..

Could also be the ideal vehicle for several other applications: non-obstructive vulnerable plaque, gene transfer for infract repair and angiogenesis…..

“ Biodegradable Stents: They Do Their Job and Disappear” Ron Waksman

“ Biodegradable Stents:

They Do Their Job and Disappear”

Ron Waksman

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