1. Regeneron Pharmaceuticals – Its history, science and technology
BIOMAN Conference
July 30, 2009

2. Regeneron at the start
Founded in by Len Schelifer, MD, PhD, Professor of Neurology, Cornell Medical School
Four original employees
Expertise in neuroscience
Cutting edge research in neurotropins (CNTF, BDNF, NGF, NT-3)
Commited to the discovery, development and commercialization of drug products for the treatment on unmet medical conditions
Initial therapeutic target was treatment of neurodegenerative disease (ALS or Lou Gehrig’s disease)

3. Regeneron Historical Ups and Downs 1989 - 1999
Rens Mfg site acquired for CNTF
Merck toll mfg agree
ment
Axokine collab. w/
P&G
BOD
formed
REGN goes public
BDNF collab. w/ Sumitomo
New HQ in Tarrytown
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
CNTF fails in PIII

4. Regeneron Historical Milestones 2000 - present
IL-1 Trap collab. w/ Novartis begins
VEGF Trap collab. w/ Aventis begins
VEGF Trap –Eye collab w/ Bayer
IL-1 Trap appoved in US for CAPS
Sanofi collab. expanded
to mAbs
Trap molecules begin to emerge
First
2 x 10 kL mfg suite on line
Second 2x10 kL mfg suite on line
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
BDNF dropped
Axokine poor PIII outcome
IL-1 Trap RA PII
released
Novartis
withdraws
Merck contract ends

5. Regeneron Evolution and Growth
Historical
Current
Therapeutic Areas
Neurogenerative disease
VelocImmune turn-key approach:
CAPS
Cancer
Gout
Eye disease
Arthritis
Pain
Drug Candidates
Neurotrophic factors
Cytokine traps
Monoclonal Antibodies & Fusion Proteins
Production Systems
Bacterial fermentation
misfolded proteins
inclusion bodies
Mammalian cell culture (CHO)
fully folded, functional proteins
post-translational modifications
secreted into cell culture fluid
Production Scale
300 L bioreactor
0.3 m diameter columns
10,000 L bioreactor
1.4 m diameter column
IND filings
3 in 10 years
2 – 3 per year

6. Therapeutic Proteins Today
Arcalyst, Rilonacept (IL-1 Trap) Approved
Aflibercept (VEGF Trap) Phase III
REGN88 (IL-6R antibody) Phase II
REGN421 (DLL4 antibody) Phase I
REGN475 (NGF antibody) Phase I
REGN668 (IL-4R antibody) IND Sept
REGN727/728 (PCSK9 antibody) IND Oct

7. Regeneron Today
Broad clinical development portfolio across all development stages provides multiple “shots on goal”
Three Phase 3 programs to yield initial data in 2010
Potential multiple product launches in next few years
Nearly 1,000 employees working in a science-driven, entrepreneurial culture
Rensselaer facility among the leaders in antibody production capacity

8. Regeneron Keys to Success
Commitment to cutting edge science and enabling technologies
Neurotrophins, cytokines, angiogenesis, receptor chemistry and signaling
Cytokine and growth factor Traps
VelociSuite technologies
Fully integrated biopharmaceutical enterprise
World reknown Board of Directors members - 3 nobel laureates as well as seasoned pharmaceutical professionals
Attract and secure investment and favorable corporate collaborations

9. Collaboration Agreements
Oncology
Eye Disease
Antibodies
Inflammation
sanofi-aventis
Bayer HealthCare –
Upfront/milestone payments
$130MM
$95MM
$85MM
Development costs paid by partner *
100%
~50%
~100%**
Profit split — Regeneron share US
50%
Japan
~35% royalty
35-45%
ROW
Milestones remaining
Regulatory
$400MM
$90MM
Sales
$135MM
$250MM
* 50% repayment from profits ** plus $475MM of research funding over 5 years 9 9 9 9 9

10. Trap Technology 10 10 10 10 10 10

11. First Generation Heterodimeric TRAP (subpicomolar affinity)
Traps: Based on Discovery that Some Receptors Must “Heterodimerize” for High-affinity
Ectodomain
Cytodomain
Factor
Conventional Receptor: Receptors “Homo-Dimerize” +
Many Receptors: Require “Heterodimerization”
Kd = 5 nM
Kd ~ pM R1 R2
Conventional “Homodimeric” Soluble Decoy Receptor (e.g. Enbrel for TNF)
Receptor
Ectodomains
Fc Constant (Dimerization & Half-life)
First Generation Heterodimeric TRAP
(subpicomolar affinity) 11

12. Antibody Structure
Conventional “Homodimeric” Soluble Decoy Receptor (e.g. Enbrel for TNF)
Cytokine/Interleukin
Cytokine/Interleukin
Heavy Chain
Fc Constant (Dimerization & Half-life)
Light Chain
Variable Regions (Binding)
Receptor
Ectodomains
Fc Constant (Dimerization & Half-life)
First Generation Heterodimeric Interleukin-1 Trap
(subpicomolar affinity)
“Single-Chain” Interleukin-1 Trap
(sub-picomolar affinity)
Receptor 1
(IL1 AcP)
Ectodomain
Last December an article published in Nature Medicine described the development of the Cytokine Trap technology and the general approach for incorporating the 2 necessary receptor components into a single Trap that binds a cytokine or growth factor very tightly.
Receptor 1
(IL1 AcP)
Ectodomain
Receptor 2
(IL1 R1)
Ectodomain
Receptor 2
(IL1 R1)
Ectodomain
Fc Constant (Dimerization & Half-life)
Fc Constant (Dimerization & Half-life) 12

13. Regeneron’s Traps: Proprietary & Turnkey Solutions for Blocking Well-Validated Cytokine & Growth Factor Targets
Advantages
Allow targeting of extremely well-validated cytokines & growth factors
Can target multiple ligands for same receptor (e.g., IL1a & b, VEGF & PLGF)
All human components
Long circulating half-life in humans
In each case, Traps are most potent blockers described for their targets (often by fold)
Prior to development of VelocImmune technology, much more efficient and higher affinity than conventional human antibody approaches
2 Receptor’s
Binding Regions
… fused to…
IgG Fc region
Regeneron Traps 13

14. ARCALYST® (rilonacept) Approved and Launched in 2008
ARCALYST® (rilonacept) is approved for treatment of Cryopyrin-Associated Periodic Syndromes (CAPS)*
Rare, inherited, auto-inflammatory diseases
Approved for adults and children age 12 and older
Patients with CAPS experience ongoing lifelong symptoms
Intermittent, debilitating exacerbations or flares can be triggered at any time by exposure to cooling temperatures
Symptoms include rash, fever/chills, joint pain, eye redness/pain and fatigue
Patients often adopt a compromised lifestyle *

15. Aflibercept (VEGF Trap)15 15 15 15 15 15

16. Aflibercept Differentiation
Figure 1. Structure of VEGF Trap
Bevacizumab
Humanized MAb
~160,000 MW
Kd = pM
Only blocks primate VEGF-A
Forms Immune Complex with VEGF-A
Aflibercept
All human amino acid sequences
~110,000 MW
Kd = 0.5 pM (tighter than natural receptors)
Blocks all mammalian VEGF-A, as well as PlGF and VEGF-B
Binds VEGF isoforms as monomer without Immune Complex formation
Check on our current t1/2
Change color of box 16 16

17. VEGF Trap-Eye 17 17 17 17 17 17

18. Change in Visual Acuity (letters)
VEGF Trap – Eye Extension Study: Durable Responses in Visual Acuity to 18 Months (all 5 dose groups combined, n=117)
Results Announced May 2009
PRN dosing
2mg
Fixed-dosing
PRN-dosing phase
+8.4 letters*
Change in Visual Acuity (letters)
+7.3 letters*
+7.1 letters*
*P < vs. baseline 3
Month 12 18 18 18

19. Nine Phase 3 Trials Currently Underway
Initial Phase 3 data coming in 2010

20. VelociSuite of Technologies

21. VelociSuite of Technologies: Target Identification and Validation
VelociGene®
VelociMouse™
High-throughput generation of almost any desired genetic alteration in mouse embryonic stem cells
High-throughput generation of mouse models directly from embryonic stem cells containing genetically altered target genes
Together, used to identify and validate drug targets:
Rapidly replaces gene with reporter to see where gene is active
Shows the result of deleting or adding extra copies of genes
Allows direct testing in mammalian models of whether the gene product is an important target in a disease setting and for therapeutic intervention
Selected to play major role in NIH Knockout Mouse Project 21 21

22. Rapid generation of high-quality, fully human antibodies
VelociSuite of Technologies: Human Antibody Generation and Manufacturing
VelociMab™
High-throughput antibody screening and selection and high-expression, manufacturing cell line development
VelocImmune®
Rapid generation of high-quality, fully human antibodies
Genetically humanized over 6 megabases of mouse immune genome
VelocImmune mice mount a robust immune response and generate antibodies as efficiently as normal mice
Antibodies with most desirable characteristics selected and extracted from B cells
Antibodies cloned into high-expression manufacturing cell lines, suitable for clinical and commercial use
human heavy chain Vs Ds Js
mouse constants and controlling regions
human kappa chain Vs Js
mouse constant and controlling regions 22 22

23. Why Fully Human Antibodies? Evolution of Technologies
Murine
(0% Human)
Chimeric
(66% Human)
Humanized
( % Human)
Fully Human
(100% Human)
Immunogenicity
Human Antibody Platforms
Phage-Display
AstraZeneca (Cambridge Antibody Technology)
Several companies using technology
Transgenic Mouse
Amgen Inc. (Abgenics, Inc.)
Medarex Inc. / Kirin Pharma, Ltd.
Regeneron VelocImmune Mouse
Broad-based collaboration with Sanofi-aventis
Licensed to AstraZeneca and Astellas Pharma 23

24. Selection of Antibody Candidates
Early screening steps focus on:
binding affinity
blocking
diversity
Final screening steps focus on:
protein expression/purification
protein characterization/quality
in vivo properties 24

25. Regeneron Cell Line Technologies
FASTR System (Flow cytometry based Autologous Secretion Trap)
High-copy system for high-level expression
Inducible Fc capture protein on cell surface to utilize FACS-based sorting (96-well format)
Perfect for commercial cell lines
EESYR System (Enhanced Expression and StabilitY Region)
Provides a common site of integration
High efficiency integration of single copy heavy & light chain
Perfect for head-to-head comparisons
Perfect for providing a speed-to-clinic cell line 25

26. Selecting High Producing Cells Using Fluorescence Associated Cell Sorting (FACS)
Droplet Generator
Detector 
Electrical Wire
Computer + -
Laser
Empty Droplet
Cells In
Key Advantages - Speed and Throughput
Individually examines 20,000 cells per second
Up to 100 million transfected cells examined
Can directly single-cell sort - eliminates subcloning step 26

27. Value of VelocImmune™ Mouse Validated By Multiple Relationships
Corporate Licenses
Academic Licenses
sanofi-aventis Collaboration
AstraZeneca/Cambridge Antibody Technology (February 2007)
Astellas Pharma (March 2007)
Columbia University (September 2008)
The University of Texas Southwestern Medical Center (March 2009)
Broad profit-sharing program to discover, develop and commercialize human antibodies (November 2007)
3 antibodies now in clinical trials
Terms of corporate licenses: $20mm/year for up to 6 years (minimum 4 years). Mid-single-digit royalty on antibody sales.
Terms of academic licenses: Regeneron has exclusive option to license antibodies for development and commercialization 27 27 27 27

28. Regeneron is a Fully-integrated Biopharmaceutical Company

29. Regeneron Manufacturing

30. State-of-the-Art Manufacturing Facility

31. Process Area 3 – 1 x 1600 L Bioreactor
CONFIDENTIAL
Process Area 3 – 1 x 1600 L Bioreactor
Primarily for PI/II Supply
Ten years of operating experience
3 Traps
7 mAbs
Flexible Process Design 31 31

32. Process Area 1 – 2 x 3000 L Bioreactor
CONFIDENTIAL
Process Area 1 – 2 x 3000 L Bioreactor
Primarily for PII/III Supply
New facility realized in 14 months (!)
Focus on characterizing and understanding the process 32 32

33. Red Mill Process Area CONFIDENTIAL
Our final scale in our Red Mill facility is our L Bioreactor Production Suite. In this suite we have two L production bioreactors, which are primarily intended for Phase III and commercial production, but can also be used to support large Phase II needs. This suite has undergone a PAI from the FDA in 2007 and MHRA as recently as last month for rilonacept and is also used to produce aflibercept.
Currently we are in the midst of a rilonacept campaign. Purification of batch #1 was performed last week, we are in the production bioreactor for our second batch and seed train expansion for our third batch. Seven batches are scheduled for this campaign which should take us through late may, when we will perform a “rolling changeover” and start a 6 batch aflibercept campaign immediately thereafter.
Engineering and Procurement activities for RM2 in-progress??
Pics
To operate each of these suites, we have a manufacturing department with approximately 55 FTEs. The staffing for each area is very dynamic and responsive to manufacturing needs. We have a strong emphasis on cross training for each unit operation. On a given day an operator may be expanding a seed train in Red Mill, the next day they may be formulating drug substance in PA1. This approach gives us maximum flexibility. The manufacturing group works very closely with PAS for “on the floor” technical support. PAS is also responsible for the transfer of processes from PD group in TT. We also work closely with QA for the generation of manufacturing documents and compliance with procedures, as well as QC for our analytical needs.
Questions? 33 33

34. Currently Doubling Manufacturing Capacity

35. IL-6R Antibody Formulated Drug Substance Manufacturing Upstream Operations, 3,000L Production Scale
Thaw of
the MCB
500ml Flask
2L Wavebag
20L Wavebag
200L Wavebag
1,000L Bioreactor
3,000L Bioreactor
Low pH Hold
Protein A
Harvest Pool
Depth and Polish Filtration
Centrifugation

36. Hydrophobic Interaction Transfer to Formulation Tank
IL-6R Antibody Formulated Drug Substance Manufacturing Downstream Operations, 3,000L Production Scale
Anion Exchange
Chromatography
Hydrophobic Interaction
Chromatography
Viral Clearance Filtration
Addition of concentrated
excipient buffer
< -20C
Freezing of
Formulated
Drug Substance
Filling of
1 L bottles
Transfer to Formulation Tank
Concentration and
Diafiltration

37. Regeneron Human Resources

38. IOPS Personnel Headcount Totals Group Personnel Total 271
CONFIDENTIAL
IOPS Personnel
Headcount Totals 8% 4%
Group
Personnel
Quality (QA, QC, Audit) 88
Facilities Operations (Maintenance, EH&S, Engineering) 44
Manufacturing (Internal and External) 70
Business Operations (Finance, Supply Chain, Warehouse) 35
Process & Analytical Sciences 21
Human Resources and Training 10
Administrative 3
Total
271
61%
25%
43%
18%
39% 38

39. Employee Profile Title Degree Major Yrs of Service Biotech Prod
Associate
AAS/BA/BS
Biology 4
Process
Specialist
BA/BS
Chemical
Engineering
2.3 QA
4.6 QC
Analyst
Chemistry;
5.8
Scientist
Biology;
Chemical Eng
3.6
Analytical
MA/PhD
Chemistry
6.9

40. BACK-UP SLIDES
BIOMAN 2009

41. A Look at the U.S. Biotech Industry
The biotech industry is a major growth area in the global healthcare market and due to developments in monoclonal antibodies, genomics and proteomics the biotech market has experienced great expansion since its emergence in the 1970s
To date, biotechnology has created more than 200 new therapies and vaccines, including products to treat cancer, diabetes, HIV/AIDS and autoimmune disorders
There are more than 400 biotech drug products and vaccines currently in clinical trials targeting more than 200 diseases
As of Dec. 31, 2006, there were 1,452 biotechnology companies in the United States, of which 336 were publicly held
Source: Biotechnology Industry Organization Guide, “Beyond Borders,“ Ernst & Young Biotechnology Report 2008

42. U.S. Biotech Industry Statistics
According to BioWorld, biotechnology attracted more than $24.8 billion in financing in 2007 and raised more than $100 billion in the five-year span of 2003–2007
The biosciences employed 1.2 million people in the U.S. in 2004 and generated an additional 5.8 million related jobs
Revenues of publicly traded biotechs grew 12% to $89.7 billion in The global industry’s net loss improved 53%, from US$3 billion in 2007 to US$1.4 billion in 2008
In 2008, the US publicly traded industry posted an aggregate net profit for the first time - US$0.4B
Source: Biotechnology Industry Organization Guide, “Beyond Borders,“ Ernst & Young Biotechnology Report 2008

43. U.S. Biotechnology Regions
There are 10 thriving clusters of life science industry in the U.S., helping to attract investment, talent and additional resources to specific geographic areas
Ranking of Clusters
by total number of companies
Biotech Bay
Genetown
Biotech Beach
Pharm Country
BIO NC
BIOMidwest
BIOCapital
BIO Forest
BIOCanada
SouthernPharm
US Device
The U.S. Biotechnology Regions map can be found on Biospace.com (

44. A Look at the Pharm Country Cluster
Regeneron belongs to “Pharm Country”
The U.S. Biotechnology Regions map can be found on Biospace.com (

45. New York State Biotechnology
In its 2009 annual report, the New York Biotechnology Association (NYBA) reported that:
In New York State, biopharmaceutical companies directly employed 55,446 workers and were responsible for a total of 130,464 jobs.
The industry generated $29.1 billion in total economic output in 2006 and New York State is responsible for nearly seven percent of all direct biopharmaceutical output nationally
New York last year was second in the nation with 5,053 clinical testing sites for potential new medicines 45

46. Growth of New York Biotechs Continues

47. Opt-in Rights to Novartis IL-1 Antibody Converted to Royalty
Regeneron had opt-in rights to canakinumab (Ilaris®, ACZ885) since 2003
Option to share in development, commercialization, and profits
Regeneron would pay upfront, milestones, and 45% of N. American development costs
Royalty agreement (June 2009)
Opt-in rights cancelled
Stepped royalty on worldwide sales in all indications
Initial 4% royalty, reaches 15% of total sales if sales >$1.5B
No Regeneron financial obligation
Canakinumab status
Approved in U.S. for CAPS treatment
In clinical trials for gout, COPD, type 2 diabetes, SJIA