NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 4 APRIL 2006 411 The paths around stem cell intellectual property Kenneth S Taymor, Christopher Thomas Scott & Henry T Greely Can new approaches for deriving human stem cells circumnavigate existing patents that dominate embryonic stem cell intellectual property? I n November 1998, James Thomson, of the University of Wisconsin in Madison, Wisconsin, reported the first derivation of human embryonic stem (hES) cell lines 1 . Less than two years earlier, Ian Wilmut (then at Roslin Institute, Edinburgh, UK) had electrified the world by announcing the birth of Dolly, the first mammal cloned from an adult donor cell 2 . Taken together the two discoveries promised the possibility of making hES cell lines carefully tailored to match a particular donor. Many expected, and continue to expect, these discov- eries to transform biomedical sciences. But with the discoveries came patents. Thomson’s work was the subject of two impor- tant patents 3 , owned by the Wisconsin Alumni Research Foundation (WARF); patents on Wilmut’s work were assigned to Roslin Institute and then to Geron (Menlo Park, CA, USA) when that firm acquired Roslin 4 . Concerns have been raised that the breadth of the patents’ claims encompass all hES cell and downstream thera- peutic and diagnostic products, regardless of the stem cell derivation process employed 5 . Both WARF—through its affiliate, WiCell Research Foundation (WiCell)—and Geron will permit other institutions or firms to use these patents under individually negotiated materials transfer agreements (MTAs) 6 . Those MTAs, however, require the researchers to make an initial cash payment and prohibit commer- cial research without an additional license. The commercial licenses require sharing profits with WiCell or Geron. These ‘reach-through’ rights are often cited as impediments to a free and clear research environment, constraining the ability of stem cell research to move forward 5 . Since Thomson’s and Wilmut’s initial work, researchers have explored refinements, varia- tions and entirely new ways to produce stem cell lines. Here, we explore these new methods and the effect they have on understanding the scope of the existing US patents. We first ana- lyze the claims of Thomson’s patents on hES cell lines and Wilmut’s somatic cell nuclear transfer (SCNT) patents and then describe emerging technologies for creating useful pluripotent cells. Although we offer no definitive legal opinions, we find that some new methods and the stem cells they create may be outside the scope of the Thomson and Wilmut patent claims. This has important implications for understanding the application, scope and constraints of the hES cell patent landscape. The core hES cell patents The two key Thomson patents, issued in 1998 and 2001, will expire in the United States in 2015, 20 years from the earliest date of filing. Geron, which funded Thomson’s work, has an exclu- sive license to use the Thomson patents for three important therapeutic and diagnostic areas: the use of embryonic cell lines to make neural, car- diac and insulin-producing cells. Any researcher seeking to use the patents for research in those areas would need a license from Geron. The key Thomson patents claim both the composition of stem cells and cell lines them- selves as well as the process used to create them. A key composition claimed in the Thomson pat- ents is pluripotent hES cells with four significant characteristics: the cells (i) proliferate in vitro for over one year; (ii) maintain a stable, euploid chromosome karyotype; (iii) have the poten- tial to differentiate into the three germ layers, endoderm, mesoderm and ectoderm; and (iv) are inhibited from differentiation when cultured on fibroblast feeder layers. Any ‘pluripotent hES cells’ with these four characteristics fall within that claim. Additional compositions claimed include hES cells with the ability to differentiate spontaneously to extra-embryonic tissues (the trophoblast) and hES cells with certain specific markers. The Thomson Process claim describes creat- ing hES cells by (i) growing a human embryo to the blastocyst stage, (ii) removing cells of the inner cell mass (ICM), (iii) plating them on embryonic fibroblasts, (iv) dissociating the mass, (v) replating the dissociated cells on embryonic feeder cells, (vi) selecting colonies with compact morphologies and cells with high nucleus-to- cytoplasm ratios and prominent nucleoli, and (vii) culturing the cells of the selected colonies to obtain a stem cell line. Thomson claims any cell lines created by this process regardless of whether the cell line has the characteristics that he described in his patents (See Figure 1). The Wilmut patents on SCNT Wilmut and his collaborators patented their original work in nonhuman mammalian SCNT in several countries, including the United States 4 . The US patent, originally assigned to the Roslin Institute, was transferred to Geron, and will expire in 2016. Wilmut claims several variations on a process for transferring a donor nucleus into a recipient cell of the same species includ- ing activation after nuclear transfer, incubation of the SCNT product, and transferring and developing the blastocyst in utero. The recipi- ent cell may be an enucleated oocyte, zygote or cell extracted after cleavage. The patent describes several methods of enucleation, including physi- cal (aspiration) and noninvasive (irradiation with ultraviolet light). The Wilmut patents address nonhuman uses of SCNT for the production of animals, not stem cells. Their relevance in hES cell research, however, may be significant because the series of techniques that they describe are one likely means of producing hES cells by SCNT. In addi- tion, commercialization of SCNT-derived hES cells is likely to require use of SCNT animal models and testing. Kenneth Taymor, Christopher Thomas Scott and Henry T Greely are at the Stanford University Program on Stem Cells in Society, Stanford University, 701 Welch Road, Palo Alto, California 94304, USA. e-mail: ktaymor@stanford.edu PATENTS © 2006 Nature Publishing Group http://www.nature.com/naturebiotechnology