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List of Tables and Figures

Executive Summary

Chapter 1 Introduction to RNAi
Chapter 2 RNAi in Infectious Disease
Chapter 3 RNAi in Cancer
Chapter 4 RNAi in Inflammatory and Other Diseases
Chapter 5 RNAi Companies: Technologies and Therapies
Chapter 6 Market Trends and Opportunities

Chapter 1 Introduction to RNAi

  1.0 Executive summary
  1.1 Introduction
  1.2 Antisense technology
     1.2.1 Antisense oligonucleotides
     1.2.2 Ribozymes and DNAzymes
  1.3 Discovery of natural RNAi activated by dsRNA
     1.3.1 Mechanisms of RNAi stimulated by dsRNA
       1.3.1.1 Approaches to activate RNAi in mammals 
  1.4 Discovery of micro-RNAs
  1.5 The potential for RNAi-based therapeutics
     1.5.1 The promise of siRNA therapeutics
     1.5.2 The promise of miRNA therapeutics
  1.6 Optimizing siRNA design
     1.6.1 On- and off-target activity
     1.6.2 Immune system reactivity
     1.6.3 Improving siRNA stability
  1.7 Optimizing siRNA delivery
     1.7.1 Naked siRNA
     1.7.2 Liposomes and lipoplexes
     1.7.3 Polymer carriers/nanoparticles
     1.7.4 Conjugates
  1.8 Optimizing shRNA delivery

Chapter 2  RNAi in Infectious Disease

  2.0 Executive summary
  2.1 Introduction
  2.2 Respiratory viral infections
     2.2.1 RSV virus
       2.2.1.1 Clinical and biological features
       2.2.1.2 Design of RNAi therapeutics
       2.2.1.3 RNAi therapeutics in development
     2.2.2 Influenza virus
       2.2.2.1 Clinical and biological features
       2.2.2.2 Design of RNAi therapeutics
       2.2.2.3 RNAi therapeutics in development
     2.2.3 SARS
       2.2.3.1 RNAi therapeutics in development
  2.3 Chronic viral infections
     2.3.1 Hepatitis viruses
       2.3.1.1 Clinical and biological features
       2.3.1.2 Design of RNAi therapeutics
       2.3.1.3 RNAi drugs in development
     2.3.2 HIV virus
       2.3.2.1 Clinical and biological features
       2.3.2.2 Design of RNAi therapeutics
       2.3.2.3 RNAi drugs in development
     2.3.3 HPV
     2.3.4 HSV
  2.4 Viral hemorrhagic fever and Ebola
  2.5 Malaria

Chapter 3  RNAi in Cancer

  3.0 Executive summary
  3.1 Introduction
  3.2 Cancer types
  3.3 Treatment of cancer
  3.4 Approaches to RNAi in cancer therapy
     3.4.1 Approaches to RNAi delivery
  3.5 Targeting microRNAs
  3.6 RNAi therapeutics in development
     3.6.1 Agents directed at established targets
     3.6.2 Agents directed at novel targets
     3.6.3 Agents directed at multiple targets
     3.6.4 Agents directed at unspecified targets
     3.6.5 microRNAs
     3.6.6 DNAi therapeutics

Chapter 4  RNAi in Inflammatory and Other Diseases

  4.0 Executive summary
  4.1 Introduction
  4.2 Inflammation/immune dysfunction
     4.2.1 Current therapies
     4.2.2 Allergies and respiratory diseases
       4.2.2.1 RNAi therapeutics in development
     4.2.3 Age-related macular degeneration
       4.2.3.1 RNAi therapeutics in development
     4.2.4 Other inflammatory conditions
       4.2.4.1 RNAi therapeutics in development
     4.2.5 Acute Renal Failure
       4.2.5.1 RNAi therapeutics in development
  4.3 CNS diseases
     4.3.1 Huntington's disease
       4.3.1.1 RNAi therapeutics in development
     4.3.2 Parkinson's disease
       4.3.2.1 RNAi therapeutics in development
     4.3.3 Other CNS conditions
  4.4 Cardiology and metabolism
     4.4.1 Cardiovascular disease
       4.4.1.1 RNAi agents in development
     4.4.2 Type 2 diabetes
       4.4.2.1 RNAi agents in development
     4.4.3 Non-alcoholic steatohepatitis
  4.5 Other indications

Chapter 5 RNAi Companies: Technologies and Therapies

  5.0 Executive summary
  5.1 Alnylam Pharmaceuticals Inc
     5.1.1 Company description
     5.1.2 RNAi-related technology
     5.1.3 Candidate RNAi therapeutics
     5.1.4 RNAi-related agreements
  5.2 Ambrilia Biopharma Inc
     5.2.1 Company description
     5.2.2 RNAi-related technology
     5.2.3 Candidate RNAi therapeutics
  5.3 Angioblast Systems Inc
     5.3.1 Company description
     5.3.2 RNAi-related technology
     5.3.3 Candidate RNAi therapeutics
  5.4 AVI BioPharma Inc
     5.4.1 Company description
     5.4.2 Exon Skipping Pre-RNA Interference
     5.4.3 Technology (ESPRIT)
     5.4.4 RNA splicing-related agreements
  5.5 Benitec Ltd
     5.5.1 Company description
     5.5.2 RNAi-related technology
     5.5.3 Candidate RNAi therapeutics
     5.5.4 RNAi-related agreements
  5.6 BioCancell Therapeutics Inc
     5.6.1 Company description
     5.6.2 Candidate RNAi therapeutics
     5.6.3 RNAi-related agreements
  5.7 Calando Pharmaceuticals Inc
     5.7.1 Company description
     5.7.2 RNAi-related technology
     5.7.3 Candidate RNAi therapeutics
     5.7.4 RNAi-related agreements
  5.8 Cequent Pharmaceuticals Inc
     5.8.1 Company description
     5.8.2 RNAi-related technology
     5.8.3 Candidate RNAi therapeutics
  5.9 Dicerna Pharmaceuticals Inc
     5.9.1 Company description
     5.9.2 RNAi-related technology
     5.9.3 Candidate RNAi therapeutics
  5.10 Generex Biotechnology Corp
     5.10.1 Company description
     5.10.2 RNAi-related technology
     5.10.3 Candidate RNAi therapeutics
     5.10.4 RNAi-related agreements
  5.11 Genesis Research and Development Corp
     5.11.1 Company description
     5.11.2 RNAi-related technology
     5.11.3 Candidate RNAi therapeutics
  5.12 Green Cross Corp
     5.12.1 Company description
     5.12.2 Candidate RNAi therapeutics
  5.13 Gruenenthal Group
     5.13.1 Company description
     5.13.2 RNAi-related technology
     5.13.3 Candidate RNAi therapeutics
  5.14 Intradigm Corp
     5.14.1 Company description
     5.14.2 RNAi-related technology
     5.14.3 Candidate RNAi therapeutics
     5.14.4 RNAi-related agreements
  5.15 Isis Pharmaceuticals Inc
     5.15.1 Company description
     5.15.2 RNAi-related agreements
  5.16 Lorus Therapeutics Inc
     5.16.1 Company description
     5.16.2 Candidate RNAi therapeutics
  5.17 MDRNA Inc
     5.17.1 Company description
     5.17.2 RNAi-related technology
     5.17.3 Candidate RNAi therapeutics
     5.17.4 RNAi-related agreements
  5.18 Merck & Co Inc
     5.18.1 Company description
     5.18.2 RNAi-related technology
     5.18.3 Candidate RNAi therapeutics
     5.18.4 RNAi-related agreements
  5.19 Nucleonics Inc
     5.19.1 Company description
     5.19.2 RNAi-related technology
     5.19.3 Candidate RNAi therapeutics
     5.19.4 RNAi-related agreements
  5.20 Opko Health Inc
     5.20.1 Company description
     5.20.2 Candidate RNAi therapeutics
     5.20.3 RNAi-related agreements
  5.21 ProNAi Therapeutics Inc
     5.21.1 Company description
     5.21.2 RNAi-related technology
     5.21.3 Candidate DNAi therapeutics
     5.21.4 DNAi-related agreements
  5.22 Quark Pharmaceuticals Inc
     5.22.1 Company description
     5.22.2 RNAi-related technology
     5.22.3 Candidate RNAi therapeutics
     5.22.4 RNAi-related agreements
  5.23 Regulus Therapeutics LLC
     5.23.1 Company description
     5.23.2 miRNA-related technology
     5.23.3 Candidate miRNA therapeutics
     5.23.4 RNAi-related agreements
  5.24 Rosetta Genomics Ltd
     5.24.1 Company description
     5.24.2 miRNA-related technology
     5.24.3 Candidate miRNA therapeutics
     5.24.4 miRNA-related agreements
  5.25 RXi Pharmaceuticals Corp
     5.25.1 Company description
     5.25.2 RNAi-related technology
     5.25.3 Candidate RNAi therapeutics
     5.25.4 RNAi-related agreements
  5.26 Santaris Pharma A/S
     5.26.1 Company description
     5.26.2 RNAi-related technology
     5.26.3 Candidate miRNA therapeutics
     5.26.4 RNAi-related agreements
  5.27 Senesco Technologies Inc
     5.27.1 Company description
     5.27.2 Candidate RNAi therapeutics
  5.28 Senetek plc
     5.28.1 Company description
     5.28.2 Candidate RNAi therapeutics
     5.28.3 RNAi-related agreements
  5.29 Silence Therapeutics plc
     5.29.1 Company description
     5.29.2 RNAi-related technology
     5.29.3 Candidate RNAi therapeutics
     5.29.4 RNAi-related agreements
  5.30 Sirnaomics Inc
     5.30.1 Company description
     5.30.2 RNAi-related technology
     5.30.3 Candidate RNAi therapeutics
     5.30.4 RNAi-related agreements
  5.31 siRNAsense AS
     5.31.1 Company description
     5.31.2 Candidate RNAi therapeutics
     5.31.3 RNAi-related agreements
  5.32 Stelic Institute & Co
     5.32.1 Company description
     5.32.2 Candidate RNAi therapeutics
     5.32.3 RNAi-related agreements
  5.33 Targeted Genetics Corp
     5.33.1 Company description
     5.33.2 RNAi-related technology
     5.33.3 Candidate RNAi therapeutics
     5.33.4 RNAi-related agreements
  5.34 Tekmira Pharmaceuticals Corp
     5.34.1 Company description
     5.34.2 RNAi-related technology
     5.34.3 Candidate RNAi therapeutics
     5.34.4 RNAi-related agreements
  5.35 ToleroTech Inc
     5.35.1 Company description
     5.35.2 RNAi-related technology
     5.35.3 Candidate RNAi therapeutics
  5.36 Topigen Pharmaceuticals Inc
     5.36.1 Company description
     5.36.2 RNAi-related technology
     5.36.3 Candidate RNAi therapeutics
  5.37 TransDerm Inc
     5.37.1 Company description
     5.37.2 RNAi-related technology
     5.37.3 Candidate RNAi therapeutics

Chapter 6  Market Trends and Opportunities

  6.0 Executive summary
  6.1 Validating RNAi in the clinic
  6.2 From first-in-class to best-in-class
  6.3 Exploring alternatives to siRNAs
  6.4 Overcoming delivery challenges
  6.5 Moving beyond "druggable" targets
  6.6 Intellectual property considerationsô
     6.6.1 Introduction to RNAi patents
     6.6.2 Fire and Mello Patent
     6.6.3 Tuschl Patents
     6.6.4 Kreutzer-Limmer Patents
     6.6.5 Benitec patents
     6.6.6 Crooke / RNAi modification patents
     6.6.7 Glover patent
     6.6.8 RNAi target patents
     6.6.9 miRNA patents
     6.6.10 Effect of patents on infringing R&D
  6.7 Patent survey results
  6.8 Market value considerations
     6.8.1 Commercial prospects
     6.8.2 Summary of key indications
     6.8.3 Forecasts
       6.8.3.1 Wet AMD:  bevasiranib and others
       6.8.3.2 RSV infection:  ALN-RSV01
       6.8.3.3 Acute renal failure:  AKTi-5
       6.8.3.4 The RNAi bottom line

Appendix 1 Abbreviations and acronyms
Appendix 2 Index
Appendix 3 Research Methodology

List of Figures

Figure 6.1:  RNAi by development stage
Figure 6.2:  RNAi by origin of material
Figure 6.3:  RNAi USPTO Patents: Therapy Area
Figure 6.4:  RNAi WIPO Patents: Therapy Area
Figure 6.5:  RNAi USPTO Patents: Patent Focus
Figure 6.6:  RNAi WIPO Patents: Patent Focus

List of Tables

Table 1.1:  RNAi Oligonucleotide Indications - Infectious Disease
Table 1.2:  RNAi Oligonucleotide Indications - Cancer
Table 1.3:  RNAi Oligonucleotide Indications - Cancer (continued)
Table 1.4:  RNAi Oligonucleotide Indications - Cancer (continued)
Table 1.5:  RNAi Oligonucleotide Indications - Miscellaneous Disorders
Table 1.6:  RNAi Oligonucleotide Indications - CNS
Table 1.7:  RNAi Oligonucleotide Indications - Inflammation/Immune Disorders
Table 1.8:  RNAi Oligonucleotide Indications - Inflammation/Immune Disorders (continued)
Table 1.9:  RNAi Oligonucleotide Indications - Cardiology, Metabolism
Table 5.10:  Financial Details, year ending Dec 2007, (US$m): Alnylam Pharmaceuticals Inc
Table 5.11:  Financial Details, year ending Dec 2007, (Can$m): Ambrilia Biopharma Inc
Table 5.12:  Financial Details, year ending Dec 2007, (US$m): AVI BioPharma Inc
Table 5.13:  Financial Details, year ending Jun 2007, (Aus$m): Benitec Ltd
Table 5.14:  Financial Details, year ending Dec 2006, (NISm): BioCancell Therapeutics Inc
Table 5.15:  Financial Details, year ending July 2007, (US$m): Generex Biotechnology Corp
Table 5.16:  Financial Details, year ending Dec 2007, (NZ$m): Genesis Research and Development Corp
Table 5.17:  Financial Details, year ending Dec 2006, (Ym): Green Cross Corp
Table 5.18:  Financial Details, year ending Dec 2007, (US$m): Isis Pharmaceuticals Inc
Table 5.19:  Financial Details, year ending May 2007, (Can$m): Lorus Therapeutics Inc
Table 5.20:  Financial Details, year ending Dec 2007, (US$m): MDRNA Inc
Table 5.21:  Financial Details, year ending Dec 2007, (US$m): Merck & Co Inc
Table 5.22:  Financial Details, year ending Dec 2007, (US$m): Opko Health Inc
Table 5.23:  Financial details, year ending Dec 2007, (US$m): Rosetta Genomics Ltd
Table 5.24:  Financial details, year ending Dec 2007, (US$m): RXi Pharmaceuticals Corp
Table 5.25:  Financial details, year ending Jun 2007, (US$m): Senesco Technologies Inc
Table 5.26:  Financial details, year ending Dec 2007, (US$m): Senetek plc
Table 5.27:  Financial details, year ending Dec 2007, (£m): Silence Therapeutics plc
Table 5.28:  Financial details, year ending Dec 2007, (US$m): Targeted Genetics Corp
Table 5.29:  Financial details, year ending Dec 2007, (Can$m): Tekmira Pharmaceuticals Corp
Table 6.30:  Common RNAi/Antisense Targets
Table 6.31:  Common RNAi/Antisense Targets (Contd.)
Table 6.32:  Targets of Antisense Oligonucleotides but not RNAis
Table 6.33:  WIPO RNAi Patents: Filing and Publication Dates
Table 6.34:  USPTO RNAi Patents: Filing and Publication Dates
Table 6.35:  WIPO RNAi Patents: Top Assignees
Table 6.36:  WIPO RNAi Patents: Top Assignees (Contd.)
Table 6.37:  WIPO RNAi Patents: Top Assignees (Contd.)
Table 6.38:  USPTO RNAi Patents: Top Assignees
Table 6.39:  Leading RNAi Oligonucleotide Originators
Table 6.40:  Key data: Forecasts for wet AMD, RSV therapy and acute renal failure ($m), 2012

Chapter 1 Introduction

• This chapter traces the development of antisense technologies beginning with antisense DNA-like oligonucleotides and advancing to next-generation RNA agents which trigger RNA inhibition (RNAi).

• The discovery of the natural RNAi mechanism for sequence-specific gene silencing launched a new era in antisense technology. Compared to antisense oligonucleotides, RNAi offers greatly improved potency, specificity, and a catalytic mode of action.

• Mechanisms of RNAi stimulated by double stranded RNA (dsRNA) and approaches developed to activate RNAi in mammals using synthetic short inhibitory RNAs (siRNA) are reviewed. Another option is the use of short hairpin RNA (shRNA) constructs.

• The discovery of micro-RNAs, naturally occurring functional RNAs which regulate the expression of broad networks of genes, defined a new strategy to target multiple points on disease pathways.

• Potential advantages of siRNA therapeutics over small molecule drugs are described as well as ongoing methods to optimize siRNA design for therapeutic use.

• Optimization of on- and off-target activity of siRNAS makes use of algorithms developed to find siRNA target sites that exhibit high target-specific activity and minimal off-target activity.

• Long dsRNA is known to activate the immune response in mammals. Chemical modifications of the siRNA molecule and improved delivery methods may prevent activation of the immune response.

• The stability of siRNAs in serum-containing environments can be improved by chemical modifications of the siRNA molecule and other approaches.

• Approaches to optimizing delivery of siRNA drugs are under active investigation, and include: use of naked siRNA; use of delivery vehicles (lipid-based or polymer nanoparticles); or conjugation to a targeting molecule. Advantages and challenges presented by these approaches are discussed.

• The construction and delivery of shRNA constructs (which use viral or plasmid vectors) also needs to be optimized.

Chapter 2 RNAi in Infectious Disease

• In the infectious disease field, therapeutic RNAi is mainly being applied to viruses. RNAi-based approaches target virally encoded proteins, but may also target cellular receptors used by viruses to gain entry into host cells.

• Many of the viruses targeted with RNAi have RNA genomes characterized by high mutability rates which may lead to treatment resistance. siRNAs are therefore being designed against conserved domains of viral proteins.

• Twenty RNAi therapies under commercial development are discussed in detail in this chapter. One product is in Phase II trials, three are in Phase I trials, and the rest are in preclinical development.

• Multiple features of respiratory viral infections have contributed to treatment difficulties with traditional approaches, but siRNAs promise to become effective antiviral agents.

• Respiratory syncytial virus (RSV) poses a particular threat to children worldwide. Anti-RSV RNAi approaches use naked siRNA administered intranasally. In 2008 Alnylam achieved human proof-of-concept with its siRNA agent which showed statistically significant anti-viral efficacy in a Phase II clinical trial.

• Influenza viruses are a major cause of life-threatening respiratory tract disease. RNAi has been shown to be effective in suppressing influenza virus replication in vivo and a number of RNAi agents are under development. Another virus targeted by RNAi is the highly lethal SARS virus.

• Several viruses pose a serious global health threat due to their chronic nature. These include human hepatitis viruses B and C (HBV, HCV) and human immunodeficiency virus 1 (HIV-1).

• Viral hepatitis has emerged as a major global public health problem. HCV genotype 1, the most prevalent variant, is the most difficult to treat. Several products - formulated siRNAs and vectors that carry siRNA or shRNA are under investigation, but delivery into hepatocytes presents a challenge.

• Pioneering companies are also targeting microRNA-122, a liver-specific microRNA used by HCV for its replication.

• HIV infection in humans is now pandemic. HIV latency and other factors present a significant challenge for developers of RNAi-based therapeutics. A Phase I study has been initiated by Benitec which uses genetically modified autologous hematopoietic stem cells to deliver anti-HIV RNAi.

• Other RNAi therapeutic programs are targeting Human papilloma virus (HPV), herpes simplex virus (HSV), viral hemorrhagic fever, Ebola virus and the protozoan Plasmodium (the cause of malaria).

Chapter 3 RNAi in Cancer

• Cancer has surpassed heart disease as the leading cause of death in the US. Solid tumors are much more common than blood-borne tumors. Cancer is characterized by uncontrolled cell growth.

• In recent years, a number of alternatives to cytotoxic-anticancer drugs have been introduced. One of the most active areas of cytostatic drug development has been in the field of angiogenesis inhibition.

• Cancer cells have different patterns of gene expression from normal cells. Many currently non-druggable genes are expressed in the multi-step process driving the development of cancers. Some of these genes are known to regulate responses to conventional chemotherapy drugs.

• Cancer cells also have different patterns of microRNA expression. MicroRNAs that are altered in cancers frequently regulate the expression of genes that are involved in the control of cellular proliferation. Choosing appropriate targets will be crucial for the successful therapeutic application of RNAi in cancer.

• RNAi agents will need to demonstrate metabolic stability and potency in vivo while maintaining an appropriate therapeutic index. Studies to date indicate that it is highly unlikely that non-formulated, non-modified RNAi compounds will be effective as therapeutics in oncology.

• In animal tumor models, delivery of siRNA (incorporated in lipoplexes or polymer nanoparticles) has been achieved following intravenous, intraperitoneal, and intratumoral administration. Targeted delivery has also been achieved in some cases through the use of targeting ligands.

• Of the 29 anticancer RNAi therapies discussed in this chapter, only two products are in Phase I trials; the rest are in preclinical development.

• RNAi therapeutics in commercial development include agents directed at established targets such as ribonucleotide reductase (RNR) and vascular endothelial growth factor (VEGF). In June 2008, Calando Pharmaceuticals' RNR-targeting siRNA became the first siRNA therapeutic to enter the clinic in oncology and the first targeted RNAi product to do so.

• Many RNAi therapeutics in commercial development target novel or proprietary proteins expressed by tumor cells. Some companies are developing multitargeted siRNA products; these may prove particularly useful when redundant oncogenic pathways are operative or drug resistance is expected.

Chapter 4 RNAi in Inflammatory and Other Diseases

• A number of RNAi agents (at least 22) are in development for the treatment of conditions involving pathological inflammation. Chronic inflammation contributes to a diverse range of conditions all sharing as a common denominator a disregulated, mostly overreacting immune response.

• Two inflammatory respiratory diseases stand out as increasing in frequency and being difficult to treat - asthma and chronic obstructive pulmonary disease (COPD).

• Since delivery of siRNAs to the lung by aerosol inhalation is relatively straightforward, a number of RNAi agents for the treatment of asthma and COPD are under investigation, directed mainly at established targets such as cytokines and their receptors. Other anti-inflammatory siRNAs are being developed for the treatment of allergies and atopic dermatitis.

• The delivery to the eye is readily accomplished by intravitreal injection of naked siRNA and the first wave of RNAi agents, now in advanced clinical trials, targeted wet age-related macular degeneration (AMD) and other eye conditions with inflammatory components.

• Three RNAi agents targeting wet AMD are in advanced clinical trials: one therapy is in Phase III trials and two are in Phase II trials. The most advanced siRNA drug candidate, Opko Health's bevasiranib, targets the proangiogenic factor VEGF.

• One RNAi agent is in Phase II trials in renal failure. Other indications are beginning to be pursued by developers of RNAi therapies, but are yet to enter full-scle clinical trials.

• Delivery of RNAi into the CNS is difficult. Current initiatives in Huntington's disease and Parkinson's disease are exploring implantable infusion systems and direct injection into the brain.

• Hypercholesterolemia offers promising protein targets and a miRNA target for treatment. Liposomal delivery of siRNAs is a popular mode of delivery.

• Potential RNAi treatments for type 2 diabetes and non-alcoholic steatohepatitis are under investigation, as well as treatments aimed at a range of other conditions including cystic fibrosis, wound healing, and hirsutism.

Chapter 5 RNAi Companies: Technologies and Therapies

• 37 companies developing RNAi or related technologies and (in most cases) RNAi therapeutics are profiled.

• The companies profiled include 22 public and 15 private companies. Their headquarters are as follows: US (21 companies); Canada (6 companies); Israel (2 companies); and Germany, Norway, Denmark, UK, Australia, South Korea, New Zealand, Japan (one company/country).

• Each company profile contains full contact details, key financial data for 2007 (if available), and information (as appropriate) on: company's main activities; RNAi-related technology; candidate RNAi therapeutics; and RNAi-related agreements (collaborations and licensing from 2005 onwards).

• RNAi-related technologies include proprietary inhibitory molecules, approaches to RNAi therapy, chemical modifications, and vehicles for RNAi delivery.

• Candidate RNAi therapeutics listed in these profiles were discussed in more detail in Chapters 2-4 of this report (in the context of a particular therapy area) and are also listed in separate tables.

Chapter 6 Market Trends and Opportunities

• Human proof of concept has been produced in a Phase II clinical trial of an inhaled RNAi formulation. Validation of systemically delivered RNAi agents will require pharmacodynamic end points.

• siRNA agents are being subjected to lead optimization and proprietary modifications in order to obtain the best safety and efficacy profiles in patients and create best-in-class agents.

• Alternatives to siRNAs are being explored including improved shRNA constructs, microRNA therapeutics, and next-generation inhibitory agents and technologies.

• A single solution to the RNAi delivery problem is unlikely. Companies are staking out proprietary positions in lipid-based, nanotransporter-based, and other delivery technologies.

• RNAi will allow targeting of previously undruggable targets. Initially current targets of antisense oligonucleotides could be explored for the development of RNAi agents.

• The use of RNAi has been claimed in many patents, focusing at first on longer dsRNAs and converging upon 21-23 nucleotide long siRNAs/shRNAs. The strongest patent portfolios have been assembled by Alnylam Pharmaceuticals and Sirna Therapeutics.

• Apart from the Fire and Mello patent (which refers only to RNA molecules of 25 nucleotides or longer) most key patents in the field of RNAi therapeutic R&D are owned (i.e. invented or exclusively licensed) by Alnylam or Sirna, and sub-licensed to many small RNAi players. They include; Tuschl I/II, Kreutzer-Limmer I/II, Benitec, Crooke, Glover, and Hannon.

• In addition to RNAi technology, leading companies have been submitting applications covering specific RNAi (i.e. gene or disease) targets. For example, Sirna has sought cover for more than 250 mammalian and viral genes targeted by siRNA.

• Key patents in miRNA have been applied for by the Max Planck Institute, the Rockefeller University, University of Massachusetts Medical School, and Johns Hopkins University.

• For this report, we carried out a survey of RNAi-related patents and applications filed under the USPTO and WIPO systems. Sirna Therapeutics was shown to be the most prolific innovator. Infection and cancer stood out as the major therapy areas, with most other applications running at around 3-4%.

• Based on five Phase II/III RNAi agents identified by us (targeted at wet age-related macular degeneration, RSV infection, and acute renal failure), and taking into account current treatments and level of market satisfaction, we forecast a total RNAi therapy market of US$580m for 2012