Regulus Announces U.S. Allowance of Fundamental microRNA Therapeutics Patent Application

Regulus Therapeutics Inc., founded by Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), and Isis Pharmaceuticals, Inc. (Nasdaq: ISIS), announced today that the United States Patent and Trademark Office (USPTO) has allowed a patent application within the ‘Esau’ patent family (US Application Serial No. 10/909,125). The Esau patent estate, which is owned exclusively by Regulus, represents one of the earliest filings in the microRNA intellectual property landscape, and is fundamental to the discovery, development, and commercialization of microRNA therapeutics.

"Regulus is advancing a new class of innovative medicines based on microRNAs. Indeed, microRNA therapeutics represent a new frontier of pharmaceutical research where an entire pathway of human disease can be targeted,” said Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus Therapeutics. "This Notice of Allowance is the first in the Esau series, and we expect many more patents covering microRNA therapeutics to issue from this important and early patent family.”

The currently allowed claims describe methods of inhibiting miR-122, a liver-specific microRNA that has been shown to facilitate replication of hepatitis C virus (HCV) infection (Jopling et al. (2005) Science 309, 1577-81). Specifically, the claims encompass methods of inhibiting miR-122 in a cell using a broad class of anti-miRs with sugar modifications at each nucleoside, such as 2’-MOE or bicyclic nucleic acid modifications, and with or without the addition of conjugate groups. Regulus holds exclusive rights to additional patents covering miR-122 antagonists and their use as HCV therapeutics, including the ‘Tuschl III’ patent claiming the sequences of miR-122 and its complement (U.S. Patent No. 7,232,806), and the Sarnow patent pertaining to the use of anti-miR-122 to inhibit HCV replication (US Patent No. 7,307,067).

"The Regulus miR-122 program is focused on developing a therapeutic oligonucleotide that antagonizes miR-122, a microRNA that has been shown to be essential for HCV replication,” said Peter Linsley, Chief Scientific Officer of Regulus Therapeutics. "We are very pleased by the decision of the USPTO to allow the current claims of the Esau ‘125 application, as it will strengthen our continued advancement of this important program.”

Following a Notice of Allowance, the process resulting in final issuance of a patent involves several administrative steps that are typically completed within a year.

About microRNAs

microRNAs are small, non-coding RNAs that regulate a large number of human genes; there are more than 700 microRNAs in the human genome that play a role in controlling expression of over one-third of all human genes. Abnormal expression and genetic mutation of microRNAs have been linked to numerous diseases including cancer, cardiovascular disease, metabolic disease, autoimmunity, and viral infection, among others. In 2005, Alnylam scientists and collaborators at The Rockefeller University were the first to describe antagomirs, which are part of a larger class of microRNA inhibitors known as anti-miRs (Krutzfeldt et al., (2005) Nature 438, 685-689). Anti-miRs were created to selectively inhibit microRNAs expressed in a broad range of tissues and to have pharmacological properties required for microRNA-based therapeutics. This research has created new drug discovery strategies focused on antagonizing microRNAs.

About Regulus Therapeutics Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery of innovative new medicines based on microRNAs. Regulus is targeting microRNAs as a new class of therapeutics by working with a broad network of academic collaborators and leveraging oligonucleotide drug discovery and development expertise from Alnylam Pharmaceuticals and ISIS Pharmaceuticals (Alnylam and Isis jointly formed Regulus in 2007). Regulus is advancing microRNA therapeutics towards the clinic in several areas including hepatitis C infection, cardiovascular disease and fibrosis, oncology, and immunology and inflammation. Regulus intellectual property estate contains both the fundamental and core patents in the field as well as over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In 2008, Regulus entered into a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. For more information, visit www.regulusrx.com.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world’s top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection and is partnered with Cubist and Kyowa Hakko Kirin. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including liver cancers, hypercholesterolemia, Huntington’s disease, and TTR amyloidosis. The company’s leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam established "RNAi 2010” in January 2008 which includes the company’s plan to significantly expand the scope of delivery solutions for RNAi therapeutics, have four or more programs in clinical development, and to form four or more new major business collaborations, all by the end of 2010. Alnylam and Isis are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA-based therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About Isis Pharmaceuticals, Inc.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world’s first antisense drug and has 19 drugs in development. Isis’ drug development programs are focused on treating cardiovascular, metabolic and severe neurodegenerative diseases and cancer. Isis’ partners are developing antisense drugs invented by Isis to treat a wide variety of diseases. Isis and Alnylam Pharmaceuticals are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development and commercialization of microRNA therapeutics. Isis also has made significant innovations beyond human therapeutics resulting in products that other companies, including Abbott, are commercializing. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of over 1,600 issued patents worldwide. Additional information about Isis is available at www.isispharm.com.

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’, Alnylam’s, and Isis’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus. Any statement describing Regulus’, Alnylam’s, and Isis’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as such parties’ goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such parties’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause their results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of the management of each such party, these statements are based only on facts and factors currently known by Regulus’, Alnylam’s, and Isis’ as the case may be. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2008, and their most recent quarterly reports on Form 10-Q which are on file with the SEC. Copies of these and other documents are available from Alnylam or Isis.

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