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Published online 18 June 2008 | Nature 453, 962-963 (2008) | doi:10.1038/453962a
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Japan ramps up patent effort to keep iPS lead
United States in race to commercialize pluripotent stem cells.
As the battle to create therapeutic stem-cell lines intensifies, Japan is waking up to the fact that the United States could steal a march on it by being the first to commercialize induced pluripotent stem (iPS) cell technology.
Shinya Yamanaka and his colleagues at Kyoto University pioneered the creation of iPS cells, and the technology is seen as something of a national industry — albeit one in its extreme infancy.
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On the patentability of iPS discovery---------A Correspondence critical on the politics of the iPS promise was published in Nature Biotechnology 1.Now, without too much repetition of what I have stated in the previous criticisms on the iPS research (http://im1.biz/Cloning.htm), I wish to touch base on the issue of intellectual property and the patentability of the iPS discovery.A Chinese physician named Rong-xiang Xu has pioneered a successive treatment for burn patients 2 and discovered a way to activate pre-exiting stem cell (he called as "regenerative stem cell") with chemical compositions 3, 4. His achievements not only identified a non-carcinogenic way of activating stem cells in adult tissues but also proved the clinical value of stem cell activation for regenerative medicine. Unfortunately, his discovery has been ignored by the western stem cell researchers even though his burn treatment medicine has been sold world-wide (http://en.mebo.com).If iPS technology will go to the direction of virus-free and chemical-based approach, then I believe the first road block that it has to go through is the patents already possessed by Xu 3, 4. The "913" patent 5 assigned to the Wisconsin Alumni Research Foundation (WARF) actually present no threat to iPS technology because it specifically covers the claims for embryonic stem (ES) cells which iPS cells are not, no matter how similar or even "indistinguishable" they are claimed to be with ES cells. As a matter of fact, the claims for the "913" patent 5 specifically emphasizes that the cells (protected by the patent) are negative for the SSEA-1 marker. However, as shown in recent studies 6, 7, the level of SSEA-1 actually increases over the alleged "induction" process which "generates" iPS cells.Besides those real or imagined "threats" of the prior "arts", the patentability of iPS technique actually will rest on whether the magic claims of "induction" and "reprogramming" can be proved. So far, as criticized mainly by me earlier and just publicly acknowledged by Yamanaka recently, "the cell origins and molecular mechanisms of iPS cell induction remain elusive" 8. Then how could a patent be granted to an application with invalid scientific claims?If retraction is held with a universal standard of purging untrue claims from scientific literature, many earlier publications on iPS cells should be retracted because they are severe misrepresentations 9-14 if not some total lies 15, 16. -------------Shi V. Liu (SVL@logibio.com; http://im1.biz)------------References1. Gottweis, H. & Minger, S. iPS cells and the politics of promise. Nat Biotechnol 26, 271-272 (2008).2. Xu, R.-X. Burns Regenerative Medicine and Therapy. (Karger, Basel; 2004).3. Xu, R.-X. Physiological tissue repair and functional organ regeneration by cultivation of regenerative stem cells in vivo and in situ. US Patent 6991813 B2 (2006).4. Xu, R.-X. Method and composition for repairing and promoting regeneration of mucosal tissue in the gastrointestinal tract. US Patent 6685971 B2 (2004).5. Thomson, J.A. Primate embryonic stem cells. US patent 7029913 B2 (2006).6. Brambrink, T. et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2, 151-159 (2008).7. Stadtfeld, M., Maherali, N., Breault, D. & Hochedlinger, K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2, 1-11 (2008).8. Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science AOP Februay 14, 2008, DOI 10.1126/science.1154884 (2007).9. Liu, S.V. iPS cells: stem cells induced from terminally differentiated cells or just pre-existing stem cells being detected? Logical Biology 7, 63-65 (2007).10. Liu, S.V. Are iPS cells really indistinguishable from ES cells? Logical Biology 7, 66-68 (2007).11. Liu, S.V. IPS cells are man-made cancer cells. Logical Biology 8, 16-18 (2008).12. Liu, S.V. IPS cells versus ES cells. Science Under consideration (2008).13. Liu, S.V. Understanding the "reprogramming" process in "inducing" iPS cells. Logical Biology 8, 19-22 (2008).14. Liu, S.V. Sequential reprogramming into iPS cells or sequential differentiation of isolated pre-existing stem cells. Logical Biology 8, 27-29 (2008).15. Liu, S.V. Can Yamanaka explain his contradictory statements? Logical Biology 8, 13-15 (2008).16. Liu, S.V. A simple experiment to verify the 'direct reprogramming' claim on iPS cell 'induction'. Logical Biology 8, 23-24 (2008).
Additional comments on iPS patenting ----- Acutally two publications in Nature Biotechnology addressed the issue of patenting iPS discovery and the intellectual property battle in the stem cell research field 1, 2. A focus has been whether the Wisconsin Alumni Research Foundation (WARF) patents will represent some road blocks for the iPS patenting. However, the WARF patents really do not present such a threat because they claim intellectual property protection for only human EMBRYONIC stem (ES) cells. iPS cells are distinct from ES cells 3, 4 and are true ADULT cells 5. In contrast two patents describing compositions and methods of promoting cell growth, tissue repair and organ regeneration in postal natal patients 6, 7 may be more relevant prior arts. These patents clearly indicated the activation and proliferation of some stem cells, defined as "regenerative stem cell", with chemical compositions. They also represent successful therapeutic cloning because they demonstrated the beneficial clinical effects with regenerated tissue/organs that have to be clonally derived from some stem cells 8. The present iPS cells all contain oncogenic factors and are associated with tumor development 9. It is said that future iPS cells may be made using simple chemicals as the inducers. If this is the way for the iPS cells then I wish Xu's prior patents 6, 7 should not be ignored any more in cross examination. Let me quote the first independent claim from Xu's US patent 6991813 B2 6: "A method for regenerating skin with normal physiological structure at a wound site of the skin in a mammal comprising: Administering in vivo to said mammal at the site of the wound a composition comprising ...". Thus, any future iPS patent application must face the novelty test and proven not obvious beyond any doubt in front of Xu's patents 6, 7 which in my view have presented some obvious and successful cases for achieving induction of stem cells into real therapeutic cloning 8. As a matter of fact, whether or not the current iPS discovery is patentable will depend on whether or not its central claim – the induction of pluripotent stem cells from normal differentiated cells can be validated 10. Currently, this is still a hotly debated issue (http://im1.biz/Cloning.htm). Even Yamanaka's research group have confessed that "the cell origins and molecular mechanisms of iPS cell induction remain elusive." 9 -------- Shi V. Liu (SVL@logibio.com; http://im1.biz) ------ References 1.Gottweis, H. & Minger, S. iPS cells and the politics of promise. Nat Biotechnol 26, 271-272 (2008). 2.Vrtovec, K.T. & Scott, C.T. Patenting plutipotence: the next battle for stem cell intellectual property. Nat Biotechnol 26, 393-395 (2008). 3.Liu, S.V. IPS cells versus ES cells. Logical Biology 8, 47-48 (2008). 4.Liu, S.V. Are iPS cells really indistinguishable from ES cells? Logical Biology 7, 66-68 (2007). 5.Liu, S.V. Embryonic stem cells versus adult stem cells: Similarities and differences. Logical Biology 7, 87-90 (2007). 6.Xu, R.-X. Physiological tissue repair and functional organ regeneration by cultivation of regenerative stem cells in vivo and in situ. US Patent 6991813 B2 (2006). 7.Xu, R.-X. Method and composition for repairing and promoting regeneration of mucosal tissue in the gastrointestinal tract. US Patent 6685971 B2 (2004). 8.Xu, R.-X. Burns Regenerative Medicine and Therapy. (Karger, Basel; 2004). 9.Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science AOP Februay 14, 2008, DOI 10.1126/science.1154884 (2008). 10.Liu, S.V. iPS cells: stem cells induced from terminally differentiated cells or just pre-existing stem cells being detected? Logical Biology 7, 63-65 (2007).
iPS: From a fruitless national project to a money-sucking national industry???? This News pointed out the (so far at least) fruitless nature of the iPS national project in Japan in comparing with the continuing moving of an US iPS bandwagon. However, people SHOULD think hard why could this happen or be open-minded to read publications collected at http://im1.biz/Cloning.htm.//// Yamanaka's last report on iPS came out as an advanced epub quickly after its submission. However, four months have passed the formal print version has still not come out. Why???? Nature pointed out in March that Yamanaka made some "minor" mistakes (in his Science paper). However, what are these mistakes? Could Nature be more specific about it so that the public can have their own assessment whether the mistakes are "minor" or major.//// If Yamanaka cannot prove his earlier claim made in his patent application that they generated iPS cells from differentiated adult cells, then the patent application would loss its legitimacy by itself. If Yamanaka and others cannot get rid of the tumorigenicity of iPS cells, then the hope for therapeutic use and for regenerative medicine will remain as the hype.///// Shi V. Liu (SVL@logibio.com; http://im1.biz; http://blog.sina.com.cn/im1)