Navigate the Alnylam $ALNY Notes Pages

• Introduction (valuation, milestones, pipeline, general commentary)
• RNAi Background (science, delivery technologies, patents, litigation)
• ALN-TTR (lead 5x15 program for transthyretin amyloidosis)
• 5x15 Programs (details on 5x15 strategy and info on additional preclinical programs)
• Partnered Programs (partnered clinical and preclinical assets falling outside the 5x15 focus area)
• Alliances and Licensing (RNAi platform deals and other licensing agreements with pharma companies)

About RNAi Technology

• “RNAi is a natural biological pathway that occurs within cells and can be harnessed to selectively silence the activity of specific genes.”
  
• 5/25/11 webcast: The time is now for RNAi because

1) delivery breakthroughs 
2) growing human experience; safety and predictable PK including systemic therapy 
3) human RNAi proof of mechanism (derisking event for overall technology)

• “The discovery of RNAi first occurred in plants and worms in 1998, and two of the scientists who made this discovery, Dr. Andrew Fire and Dr. Craig Mello, received the 2006 Nobel Prize for Physiology or Medicine.”
• “Beginning in 1999, our scientific founders described and provided evidence that the RNAi mechanism occurs in mammalian cells and that its immediate trigger is a type of molecule known as an siRNA. They showed that laboratory-synthesized siRNAs could be introduced into the cell and suppress production of specific target proteins by cleaving and degrading the messenger RNA, or mRNA, of the specific gene that encodes that specific protein”
• “Our product platform provides a capability for a systematic approach to identifying RNAi therapeutic product candidates through sequence selection, potency selection, stabilization by chemical modification, improvement of biodistribution and cellular uptake by various chemical conjugates and formulations.”
• "The scientific evidence to support the feasibility of developing drugs based on these discoveries is both preliminary and limited. Skepticism as to the feasibility of developing RNAi therapeutics has been expressed in scientific literature. For example, there are potential challenges to achieving safe RNAi therapeutics based on the so-called off-target effects and activation of the interferon response"

9/2011 stifel nicolaus webcast

RNAi Delivery Advances and Challenges

• “Key to the therapeutic application of siRNAs is the ability to successfully deliver siRNAs to target tissues and achieve cellular uptake of the siRNA into the inside of the cell where the RNAi machinery, called RNA-induced silencing complex, or RISC, is active. In some tissues, including the respiratory tract and central nervous system, the direct RNAi delivery approach, which employs the direct or local application of siRNAs, achieves cellular uptake and gene knockdown.”
  
• “For other tissues, such as the liver, systemic RNAi delivery has been employed, where tissue access comes via intravenous or subcutaneous injection of the siRNA into the bloodstream and where cellular uptake can be achieved by formulation with other biomaterials, such as LNPs, or the conjugation of the siRNA with other molecules, such as small chemical groups.
• “Since delivery of RNAi therapeutics remains a major objective of our research activities, we also look to form collaboration and licensing arrangements with other companies and academic institutions to gain access to delivery technologies. For example, we have entered into agreements with Tekmira, the Massachusetts Institute of Technology, or MIT, The University of British Columbia, or UBC, and AlCana Technologies, Inc., or AlCana, among others, to focus on various delivery strategies. We have also entered into license agreements with Isis, Max Planck Innovation GmbH (formerly known as Garching Innovation GmbH), or Max Planck Innovation, Tekmira, MIT, Cancer Research Technology Limited, or CRT, Whitehead Institute for Biomedical Research, or Whitehead, Stanford University, or Stanford, UTSW, as well as a number of other entities, to obtain rights to intellectual property in the field of RNAi.”
  
• 5/25/11 webcast notes: 

1. significant improvement in the dose level needed to achieve target KD in animals. Have LNP collaboration w/ Alcana. 
   
2. New microfluidics technology (collaboration with Precision Nanosystems)- smaller LNP particle size- now can deliver to targets other than liver
   
3. new conjugate delivery technology: Takes advantage of hepatocyte asialoglycoprotein receptor (ASGPR)...facilitates sub-cutaneous vs IV infusion administration. Single dose, get silencing for weeks
   
4. Smaller particles- what other tissues would they reach? Current version is 70-90nm...similar physiologically to chylomicrons. Newer 20 nm resembles HDL- distribute into all stereogenic organs in body
   
5. Subcutaneous delivery program is advancing faster than would have thought and rapidly..but no date given for entering clinic
   

• “First generation” delivery technology was developed by Tekmira, "second generation SNALP technology is involved in legal dispute as to how much claim Tekmira has to the technology - click for update 10/2011.
  
• 7/2011: ALNY and MIT announce publication re "lipidoid" technology for systemic RNAi delivery - click here for PR.
• 7/2011: ALNY and MIT announce publication re "core-shell nanoparticles" for systemic RNAi delivery - click here for PR.
• 9/2011: data presentations on delivery advances - click for PR - click for abstracts

      Click to download slide deck on GalNac delivery technology (siRNA-carbohydrate complexes)
    Click to download slide deck on next generation LNP delivery technology

• 10/2011: announced 2 papers published on delivery advances.

Intellectual Property (IP) License Agreements and Disputes

• Tuschl II patents exclusively licensed to ALNY for therapeutic applications (see table listing key patent families below)
  
• "We believe that no other company possesses a portfolio of such broad and exclusive rights to the patents and patent applications required for the commercialization of RNAi therapeutics. Our intellectual property estate for RNAi therapeutics includes over 1,800 active cases and over 700 granted or issued patents, of which over 300 are issued or granted in the United States, the EU and Japan. Given the importance of our intellectual property portfolio to our business operations, we intend to vigorously enforce our rights and defend against challenges that have arisen or may arise in this area."
• ALNY has amassed an IP estate covering:

1. Fundamental aspects of the structure and uses of siRNAs, including their use as therapeutics, and RNAi-related mechanisms;
   
2. Chemical modifications to siRNAs that improve their suitability for therapeutic and other uses;
   
3. siRNAs directed to specific targets as treatments for particular diseases;
   
4. Delivery technologies, such as in the field of cationic liposomes; and
   
5. All aspects of our specific development candidates.
   

• "In December 2002, we entered into a co-exclusive license with Max Planck Innovation for the worldwide rights to use and sublicense certain patented technology to develop and commercialize therapeutic products and related applications. We also obtained the rights to use, without the right to sublicense, the technology for all diagnostic uses other than for the purposes of therapeutic monitoring. In consideration for the rights to license this technology, we issued to Max Planck Innovation 723,240 shares of Series B redeemable convertible preferred stock with a fair value of $1.8 million. We were also given the right to acquire the remaining 50% exclusive rights, which right we exercised upon our acquisition of Ribopharma AG in July 2003. In consideration for the remaining rights to this technology, we issued Max Planck Innovation an additional 158,605 shares of Series B redeemable convertible preferred stock with a fair value of $0.4 million. The 881,845 shares of Series B redeemable convertible preferred stock held by Max Planck Innovation converted into 464,128 shares of common stock upon the closing of our initial public offering in June 2004. In June 2005, we entered into an amendment to our agreement with Max Planck Innovation that secured our exclusivity to use and sublicense certain patented technology to develop and commercialize therapeutic products and related applications. In connection with this amendment, we issued 270,000 shares of our common stock, which were valued at $2.1 million, to Max Planck Innovation and certain of its affiliated entities. We are not obligated to pay any development or sales milestone payments to Max Planck Innovation, however, we will be required to pay Max Planck Innovation future single-digit royalties on net sales of all therapeutic and prophylactic products developed with the technology, if any. Our agreements with Max Planck Innovation generally remain in effect until the expiration of the last-to-expire patent licensed thereunder. We estimate that the principal issued patents covered under the Max Planck Innovation agreements will expire both in and outside the United States during 2021, subject to any potential patent term extensions, restoration and/or supplemental protection certificates extending such term extensions in countries where such extensions may become available. We may terminate the agreements without cause with six months' prior notice to Max Planck Innovation, and Max Planck Innovation may terminate the agreements in the event that we materially breach our obligations thereunder. Max Planck Innovation also has the right to terminate the agreements in the event that we, independently or through a third party, attack the validity of any of the licensed patents"
• "In May 2007, we entered into an agreement with the David H. Koch Institute for Integrative Cancer Research at MIT, under which we are sponsoring an exclusive five-year research program focused on the delivery of RNAi therapeutics. In December 2009, we and MIT announced the publication of new data in the journal PNAS describing further advancements in the discovery and development of LNPs based on novel "lipidoid" formulations for the systemic delivery of RNAi therapeutics. Lipidoids are lipid-like materials discovered for the delivery of RNAi therapeutics, and were originally described by us and our collaborators at MIT. Lipidoid formulations represent one of several approaches we are pursuing for systemic delivery of RNAi therapeutics."
  
• "In January 2007, we obtained an exclusive worldwide license to the liposomal delivery formulation technology of Tekmira for the discovery, development and commercialization of LNP formulations for the delivery of RNAi therapeutics and a non-exclusive worldwide license to certain liposomal delivery formulation technology of Protiva Biotherapeutics Inc., or Protiva, for the discovery, development and commercialization of certain LNP formulations for the delivery of RNAi therapeutics. In May 2008, Tekmira acquired Protiva. In connection with this acquisition, we entered into new agreements with Tekmira and Protiva, which provide us access to key existing and future technology and intellectual property for the systemic delivery of RNAi therapeutics with liposomal delivery technologies. Under these agreements, we continue to have exclusive rights to the Semple (U.S. Patent No. 6,858,225) and Wheeler (U.S. Patent Nos. 5,976,567 and 6,815,432) patents for RNAi, which we believe are critical for the use of LNP delivery technology. Under our agreements with Tekmira and Protiva, Tekmira and Protiva are eligible to receive up to an aggregate of $16.0 million in milestone payments for each RNAi therapeutic formulated using Tekmira's or Protiva's liposomal delivery formulation technologies, together with single-digit royalty payments on annual product sales. In each of 2009 and 2010, we paid $0.5 million in milestone payments to Tekmira under these license agreements. We charge these milestone payments to research and development expense." (ALN-VSP is covered by this agreement…what about others candidates?)
• "Under our agreements with Tekmira and Protiva, we also granted Tekmira and Protiva three exclusive and five non-exclusive licenses under our InterfeRx program to develop and commercialize RNAi therapeutics directed to up to eight gene targets in which we have no direct strategic interest, including the targets apolipoprotein B and polo-like kinase 1, or PLK1, and a recently granted license in connection with Tekmira's research program directed towards the Ebola virus. We are eligible to receive up to an aggregate of $8.5 million in milestone payments for each RNAi therapeutic directed to four of these targets, together with single-digit royalties on annual sales of RNAi therapeutic products directed to all of these targets, if any. In addition, under our agreement with Protiva, we have the right to "opt-in" to the Tekmira research program directed to PLK1 and contribute 50% of product development costs and share equally in any future product revenues. We have until the start of a Phase II clinical trial in this PLK1 research program to exercise our opt-in right. In connection with Tekmira's acquisition of Protiva, in May 2008, we made an equity investment of $5.0 million in Tekmira, purchasing 2,083,333 shares of Tekmira common stock at a price of $2.40 per share, which represented a premium of $1.00 per share. In November 2010, Tekmira effected a one-for-five reverse stock split, after which we own 416,666 shares of Tekmira common stock."
• "In July 2009, we and Tekmira agreed to a new research collaboration with scientists at UBC and AlCana focused on the discovery of novel lipids for use in LNPs for the systemic delivery of RNAi therapeutics. We are funding the collaborative research over a two-year period, and the work is being conducted by our scientists together with scientists at UBC and AlCana. We will receive exclusive rights to all new inventions relating to the delivery of oligonucleotides and other nucleic acid constructs, as well as sole rights to sublicense any resulting intellectual property to our current and future collaborators. Tekmira will receive rights to use new inventions for its own RNAi therapeutic programs that are licensed under our InterfeRx program. We are pursuing additional approaches for delivery that include other LNP formulations, mimetic lipoprotein particles and siRNA conjugation strategies, among others. In addition, we have other RNAi therapeutic delivery collaborations and intend to continue to collaborate with government, academic and corporate third parties to evaluate and gain access to different delivery technologies."
• "The Fire and Mello patent owned by the Carnegie Institution covers the use of dsRNAs to induce RNAi. The Carnegie Institution has made this patent broadly available for licensing and we, like many companies, have taken a non-exclusive license to the patent for therapeutic purposes. We believe, however, that the claims of the Fire and Mello patent do not cover the structural features of dsRNAs that are important for the biological activity of siRNAs in mammalian cells. We believe that these specific features are the subjects of the Crooke, Kreutzer-Limmer, Glover and Tuschl II patents and patent applications for which we have secured exclusive rights"
• 1/2012 - Alnylam files counter lawsuit alleging patent infringement against Tekmira - click to read complaint.

source: 2010 10k