Spring 2009
Induced Pluripotent Stem Cell Intellectual Property and Commercialization Update By David Resnick and Teresa Hopkins Recent developments relating to induced pluripotent stem cell IP are summarized below for your information. Induced pluripotent stem cells (iPS cells) are a type of pluripotent stem cell artificially derived by reprogramming a somatic cell. iPS cells are morphologically similar to embryonic stem cells and are capable of differentiating into a variety of different somatic cell types. This technology allows researchers to obtain pluripotent stem cells for use in a research setting. iPS cells may also have therapeutic uses for the treatment of disease without the need for stem cells derived from an embryonic source. Inventor: Shinya Yamanaka Dr. Yamanaka is credited with discovering iPS cells and is a leader in the field. An international patent application and a European patent application were recently published and a Japanese patent relating to the technology, has been issued to Dr. Yamanaka. In addition, Dr. Yamanaka has established a company entitled iPS Academia Japan Inc., with the stated intention of making his technology freely available to non-profit organizations and institutions. The patent filings and activities of IPS Academie Japan, Inc. are summarized below. 1. European Patent application “Nuclear Reprogramming Factor” EFA 08-37 01970446/EP-A1 Inventor: Yamanaka, Shinya Date Filed: 2006-12-06 Patent Priority Information: JP, 2005359537, 2005-12-13 The claims relate to the use of three reprogramming factors for reprogramming of somatic cells to a pluripotent state: an Oct family gene, a Klf family gene and a Myc family gene. An additional reprogramming factor from the Sox family is optional but not necessary for production of iPS cells. In addition, Dr. Yamanaka claims the use of a cytokine, such as bFGF, or SCF, with the Myc gene product or as a replacement for the Myc family gene. Also described in the application is a method for producing an induced pluripotent stem cell by introducing the aforementioned factors to a somatic cell, which in one embodiment is a
human cell. This application also has composition claims directed to an induced pluripotent stem cell obtained by this method. Further composition claims relate to a somatic cell derived by inducing differentiation of the induced pluripotent stem cell produced by introducing the reprogramming factors. 2. PCT/JP2006/324881 “Nuclear Reprogramming Factor” Inventor: Yamanaka, Shinya This PCT application is published in Japanese, however we suspect that the scope of the claims recited in the European application is similar to the claims in the PCT application. The English abstract for this application is as follows. Abstract: Disclosed is a means for inducing the reprogramming of a differentiated cell without using any embryo or ES cell and establish an inducible pluripotent stem cell having similar pluripotency and growing ability to those of an ES cell in a simple manner and with good reproductivity. As the means, a nuclear reprogramming factor for a somatic cell is provided, which comprise products of the following three genes: an Oct family gene; a Klf family gene; and a Myc family gene. We note that this application has entered the National Phase in Australia (AU), Egypt (EG), Europe (EU) and Japan (JP). 3. Japanese patent (2008-131577) Granted: Sept 2, 2008 Inventor: Yamanka, Shinya Expires: December 6, 2026 Dr. Yamanaka and Kyoto University opted to use a fast-track system available in Japan for the most basic claim, which covers the “method” of using four reprogramming factors to produce an iPS cell. The cell can be from any species, and will likely encompass the use of human cells. The English translation of the claim states: “A method for producing an induced pluripotent stem cell from a somatic cell, comprising the step of introducing the following four kinds of genes into the somatic cell: Oct3/4, Klf4, c-Myc and Sox2.” According to the translated version of Dr. Yamanaka’s company website, this is a divisional of the parent application and claims production of an iPS cell from a somatic cell by introducing Oct3/4, Klf4, c-MYC and Sox2. The website alludes to some coverage for the cell compositions in Japan. Because this is a divisional, there is likely another application currently undergoing prosecution in Japan. 4. iPS Academia Japan Inc. http://ips-cell.net Dr. Yamanaka and colleagues have formed a company based on the intellectual property relating to induced pluripotent stem cells that they have attained in Japan and also that which is currently under prosecution in various countries.
2
It appears that Dr. Yamanaka would like the iPS cell technology to be freely available to the public, and as such, a translated version of his website indicates that non-profit organizations can, in principle, use the technology free of charge under a non-exclusive license. However, profit organizations are offered a non-exclusive license for new research and development for a “proper and reasonable price”. iPS Academia Japan, Inc. recently attended the BioJapan2008 conference, which describes the company as follows. “iPS Academia Japan Inc. is the new company established in Kyoto on June 25, 2008. The company is to contribute to the healthcare through the transfer of the research outcomes and technology relating to the induced pluripotent stem (iPS) cells, which have been developed by Prof. Shinya Yamanaka, Kyoto University and other researchers. The company will mainly manage the patents and other intellectual properties relating to the iPS cells, and grant to any corporations, universities and research institutes certain rights to utilize such intellectual properties worldwide for a while. Availing this opportunity, we would like to discuss and seek any chance to collaborate with you.” Inventor: James A. Thomson (WARF) Dr. Thomson is also a leader in the iPS field and is credited with being the first person to successfully produce iPS cells without using c-Myc. Dr. Thomson has many patent applications currently under prosecution, however only one published application relates directly to induced pluripotent stem cell production. 1. US2008/0233610 “Somatic Cell Reprogramming” Filed: March 21, 2008 Priority: Provisional application no. 60/919,687 filed on Mar. 23, 2007; provisional application no. 60/974,980 filed on Sept 25, 2007; and provisional application no. 60/989,058 filed on Nov 19, 2007. This US utility application claims a method for reprogramming primate somatic cells without the use of c-Myc and Klf4, as well as composition type claims to induced pluripotent stem cells produced by this method. The reprogramming factors currently claimed include Oct-4, Sox2, Nanog and Lin28. Dr. Thomson’s application also claims the use of only two reprogramming factors (Oct-4 and Sox2) for the successful reprogramming of primate somatic cells. 2. Cellular Dynamics International (CDI) Dr. Thomson is one of the scientific co-founders of a company called Cellular Dynamics International (http://www.cellular-dynamics.com/) in Madison, WI. The company website states that “Cellular Dynamics provides drug screening and toxicity testing products based on breakthrough induced pluripotent stem (iPS) cell technology”.
3
CDI entered into an agreement with Roche Palo Alto in March 2008 in order to test candidate drug compounds for cardiotoxicity. Commercialization of iPS Cell Technology iZumi Bio iZumi Bio is an iPS start-up company based in San Francisco, CA (www.izumibio.com). The company website states “We are using the power of induced pluripotent stem cells to transform drug discovery and regenerative medicine. The company is financially funded by Kleiner Perkins Caufield and Byers, and Highland Capital Partners. Nature news reports that “The magazine Nikkei Biotechnology and Business reports that iZumi has been collecting “iPS cell patents from all over the world” and has already licensed ES- and iPS cell-related patents from Harvard University and the Massachusetts Institute of Technology (MIT) in Cambridge.” In addition, iZumi Bio has entered into a scientific collaboration with the Gladstone Institute of Cardiovascular Disease and its director Dr. Deepak Srivastava. iZumi Bio, Inc., announced in August 2008 that John T. Dimos, Ph.D., will join its team of scientists translating induced pluripotent stem (iPS) cell research from the bench to the bedside to achieve patient benefits. Dimos’ previous work has demonstrated the potential for iPSderived cells in regenerative medicine. Fate Therapeutics http://www.fatetherapeutics.com/index.php Fate Therapeutics was founded in 2007 and collaborates with scientists from cities known for innovative research including Boston, San Francisco, San Diego and Seattle. The company was founded by top stem cell scientists at Harvard University, The Scripps Research Institute, the University of Washington, Stanford University, and the Whitehead Institute for Biomedical Research. The company is involved in research that will lead to safe, efficient and reproducible methods to differentiate iPS cells into specific cell types to yield personalized cell replacement therapies and new ways to modulate cell fate that may be applicable to activating adult stem cells in the body to treat disease. Fate Therapeutics has a licensing agreement with the Whitehead Institute. In December 2008, one of Fate’s collaborating scientists published a paper in Cell-Stem Cell indicating that rat and human iPS cells can be produced using a method that combines genetic reprogramming and chemical inhibitors (Li, W. et al., (2008) Cell-Stem Cell 4(1):1619). In February 2009, Fate Therapeutics announced the addition of Dr. Rudolf Jaenisch, a pioneer in the field of iPS cells, to the founding scientific team of the company. According to XConomy San Diego (March 13, 2009) Fate Therapeutics “plans to begin its first clinical trial in the next several weeks involving patients with blood cancer or other disorders who are getting stem cell transplants.” Stem Cell Technologies http://www.stemcelltechnologiesi.com/about_us.html Stem Cell Technologies i (SCTi) was established by Dr Susan Lim to conduct research into Adult Stem Cells. Dr Susan Lim holds both surgical degrees and a doctorate (PhD) in basic science (transplantation immunology), and is the Chairman and Chief Executive Officer. 4
The company intends “to use iPS technology for generation of insulin-secreting cells and hepatocytes”. StemCells Inc. http://www.stemcellsinc.com/ The StemCells Inc. website recites: “ StemCells has exclusive or non-exclusive rights to a portfolio of patents and patent applications related to various stem and progenitor cells and methods of deriving and using them. These patents and patent applications relate to compositions of matter, methods of obtaining such cells, and methods for preparing, transplanting and utilizing such cells. Currently, StemCells’ U.S. patent portfolio in the stem cell therapy area includes forty-three issued U.S. patents. In addition, StemCells has foreign counterparts to many of the U.S. applications and patents, about one hundred thirty of which have been issued. Over one hundred additional patent applications are pending worldwide.” StemCells Inc. (Palo Alto, CA) has acquired stem cell technologies from Stem Cell Sciences (United Kingdom) relating to iPS cells for therapeutic and drug discovery applications. Embryome Sciences, Inc (Subsidiary of BioTime Inc) http://www.embryome.com/ Embryome Sciences Inc. has obtained a license for a portfolio of patents and patent applications from Advanced Cell Technology, Inc. (“ACT”) relating to induced pluripotent stem cells (“iPS”) and embryonic stem cell differentiation technology. The license is for the commercialization of products in human therapeutic and diagnostic product markets. The technology licensed by Embryome Sciences covers methods for the transformation of cells of the human body, such as skin cells, into an embryonic and pluripotent state. A press release by Embryome Sciences Inc. recites: “Sublicensed from ACT for all human therapeutic and diagnostic applications are US patent application numbers 10/032,191, titled “Methods for cloning mammals using reprogrammed donor chromatin or donor cells,” and 10/910,156, “Methods for altering cell fate.” These patent applications relate to technology to alter the state of a cell, such as a human skin cell, by exposing the cell’s DNA to the cytoplasm of another reprogramming cell with differing properties. In a second series of patent applications licensed nonexclusively from ACT for use in commercializing the previously-mentioned patents are technologies for the use of reprogramming cells that overexpress RNAs for the genes OCT4, SOX2, NANOG, cMYC, LIN28, and other factors known to be useful in iPS technology (PCT/US2006/030632), methods of resetting cell lifespan by extending the length of telomeres (10/790,640 and 11/079,930), the use of the cytoplasm of undifferentiated cells to reprogram human 5
cells (PCT/US2000/018063), the use of hemizygous HLA O- stem cells for blood and other cell banking (PCT/US2006/040985), methods of screening for differentiation agents (PCT/US02/26945), and stem cell-derived endothelial cells modified to disrupt tumor angiogenesis (11/228,549)”. Further details on intellectual property licensed by Embryone Sciences Inc. can be found on the company website at http://embryome.net/iprop.htm. The company has extensive licenses relating to iPS cell technology as evidenced by the statements on their website “Embryome Science’s proprietary vector-free technology modifies collateral cells with iPS transcription factors such as OCT4, NANOG, SOX2, LIN28, and others, and utilizes the resulting cytoplasm to reprogram the patient’s cells. The Company utilizes a series of patents filed beginning in 2000 as announced in the Company’s press release dated August 21, 2008. Embryome Sciences plans to collaborate with other companies in commercializing vector-free iPS technology for a host of therapeutic and diagnostic applications”. Unlicensed IP 1. Non-viral method for creating Induced Pluripotent Stem Cells Researchers at the University of Edinburgh and Mount Sinai Hospital in Toronto have developed a safer non-viral plasmid vector for generating induced pluripotent stem cells (iPS). The vector enables researchers to transfect in the four genes required for reprogramming of somatic cells in a single fragment. Once reprogramming is complete the genes can be removed. The technology developed by the research teams enables the reprogramming of adult cells through the introduction of the appropriate genes using a non-viral plasmid-based method, which can be removed once the pluripotent cells are generated. This non-viral reprogramming technology enables complete elimination of exogenous reprogramming factors and provides a safer method for producing iPS cells for drug screening, regenerative medicine and establishment of disease models. IP Status A UK priority patent (Reference 0813770.5) was filed on 28th July 2008 entitled “Reprogramming Cells”. A US provisional patent was filed on the 11th August 2008 entitled “Compositions, Methods and kits for reprogramming Somatic Cells”. The University of Edinburgh would like to hear from companies wishing to license this technology or collaborate in its future development eg companies interested in developing iPS tools and reagents. We will continue to keep you apprised of new developments as we become aware of them. We are happy to discuss these developments with you and look forward to your comments.
6
