Success with iPSCs

By Elie Dolgin Success with iPSCs The nascent science still has many stumbling blocks to step over before companies can reap the rewards of reprogramming. iPS cells Courtesy of California Institute for Regenerative Medicine A decade ago, the United States granted a series of patents that some say changed the embryonic stem cell (ESC) field forever. The Wisconsin Alumni Research Foundation (WARF) received three broad patent

Elie Dolgin
Jul 1, 2009

Success with iPSCs

The nascent science still has many stumbling blocks to step over before companies can reap the rewards of reprogramming.

iPS cells
Courtesy of California Institute for Regenerative Medicine

A decade ago, the United States granted a series of patents that some say changed the embryonic stem cell (ESC) field forever. The Wisconsin Alumni Research Foundation (WARF) received three broad patents related to a method for isolating human ESCs that was developed by James Thomson at the University of Wisconsin–Madison. These patents, which effectively covered all ESC lines regardless of who made them or how they are generated, were so far reaching, many critics argued, that they effectively put a stranglehold on the ESC field. Indeed, only one company—Menlo Park, Calif.–based Geron Corp.—has ever received approval from the US Food and Drug Administration to test ESC-derived products in the clinic. Companies working with ESCs "are walking on very...

Not so for the field of reprogrammed embryonic-like stem cells known as induced pluripotent stem cells (iPSCs), which are created by turning the developmental clock back on adult or other specialized cell types through the use of viruses, plasmids, transposons, or other reprogramming factors. Now, "the pendulum has swung at the patent office toward very narrow patents" across most of biology and chemistry, says David Resnick, a patent lawyer with Nixon Peabody in Boston, Mass. "It's extremely difficult to get a broad patent right now." That means that no single company should obtain the same de facto monopoly over iPSCs the way WARF has for ESCs.

In the past year, more than 20 applications directly relating to iPSCs and another 50 or so involving iPSC culture methods or other indirect uses of the reprogrammed cells have been published worldwide, around half of these in the US alone. Many more patent applications have also been filed since then, notes Resnick.

IPSCs can also be tailor-made to match particular disease, ethnic, or other genetic profiles, and these cells do not require embryos—a continued source of debate. Together, all this suggests that the iPSC industry could prove much more fruitful than the ESC commercialization landscape. And because there are so many methods for obtaining iPSCs, "you have the opportunity for companies to spring up that will compete against each other to ultimately get to the same place," says M. William Lensch, a senior scientist who studies iPSCs at Children's Hospital Boston and the Harvard Medical School. "At the end of the day, the one that produces the best results and is the quickest and cheapest is the one you're going to go with, and at this point it's anyone's guess" which company will reap the most rewards. But first, they must overcome the hurdles facing everyone as a young field strives to define itself in a wide-open space.

Induced Income

"The best and first application for [iPSCs] is really to change the paradigm of drug discovery," says John Walker, chief executive of iZumi Bio, a South San Francisco–based biotech company focused on using reprogrammed skin cells from patients to screen for new drug compounds to treat neurodegenerative diseases, such as spinal muscular atrophy, amyotrophic lateral sclerosis, and Parkinson's disease. "It replicates the in vivo system for your drug discovery system," says Walker. "This is really new biology… that puts the patient at the front of the drug discovery process."

iZumi was founded in 2007 by two venture capital firms based on three patents from Bayer Yakuhin, a Japanese subsidiary of the German chemical giant Bayer AG. In addition to these patents, iZumi has expanded its reach to include nonexclusive partnerships with Kyoto University's Shinya Yamanaka, aimed at developing new methods for deriving high-quality iPSC lines, and with the University of California at San Francisco's Gladstone Institute, primarily focused on developing cardiovascular therapies. Within 5 years, the company expects to have two compounds in clinical trials.

Wisconsin-based Cellular Dynamics International (CDI), which Thomson cofounded with two other UW-Madison scientists in 2005, is targeting a different market. Currently, the company sells ESC-derived heart cells to a select few large pharmaceutical companies for drug screening and predictive toxicology assays, but CDI is rapidly transitioning toward selling iPSC-based technologies, based on patents licensed from WARF and developed in-house. "We can now provide individual biology, disease models, retrospective analysis, and ethnic diversity to a portfolio where only one product would have existed" if they had stuck with only using ESCs, says Chris Kendrick-Parker, CDI's chief commercial officer, in an email.

The ultimate goal, every company admits, is to transplant iPSCs into patients for clinical therapies. However, "transplantation therapy is far away," says Rudolf Jaenisch, a leading iPSC researcher at the Whitehead Institute in Cambridge, Mass. "But for some cell types"—particularly blood cells, bone marrow, and insulin-producing cells—"it might be closer than others." Even so, companies that develop the core scientific capabilities to enable the use and application of iPSCs should be "well positioned to support and capitalize on… future potential clinical applications of these exciting new cell types," says Steven Munevar, president and CEO of Munevar & Associates, a life sciences development and commercialization company, in an email.

"It's sort of the wild west. Everyone is just racing to develop their own technologies and it'll have to be sorted out later on."
—David Resnick

Several supply companies, however, are happy just to be enablers of the new technology. Big suppliers, including Invitrogen and Thermo Fisher (in partnership with Athens, Ga.–based ArunA Biomedical), are now offering "kits" tailored to perform cellular reprogramming. More specialized providers are also getting into the iPSC game. For example, Addgene, a nonprofit plasmid supplier in Cambridge, Mass., has distributed more than 6,000 reprogramming vectors to around 1,000 laboratories in the past 3 years alone. "We hand them the materials and then they're on their own," says Melina Fan, Addgene's executive director.

"It's a land grab at this time," says Enal Razvi, a biotechnology analyst with Select Biosciences, a UK-based company that tracks life sciences market trends. "Investors are putting in small amounts of money to play a larger hand. They want to have a say at the table if and when iPSCs become a mainstay." As a result, small biotechs are scooping up intellectual property left and right from academic researchers as well as tinkering with internal methods, which are also being patented, in the hopes of taking an early dominant position.

The IP of iPSCs

Another one of these companies is San Diego–based Fate Therapeutics, which started in late 2007 and now counts Jaenisch and Scripps's Sheng Ding among its scientific leadership. In April, the company announced a partnership with Stemgent, a stem cell reagent company with dual headquarters in Boston and San Diego, to provide iPSC technologies and iPSC-derived mature cells to biotechnology and pharmaceutical companies for toxicity testing and primary drug screening. Currently, Fate is "sustainable but not profitable," says company president and CEO Paul Grayson, but within 3 to 7 years he hopes to have the company's first therapeutic target on the market, likely relating to blood disorders.

"It's sort of the wild west," says Resnick, whose clients include Children's Hospital Boston, the Massachusetts General Hospital, and the Harvard Stem Cell Institute. "Everyone is just racing to develop their own technologies and it'll have to be sorted out later on." But without clear guidelines from the Patent Office about what technological advances count as nonobvious, it may "create fights down the line that deter final commercial application," warns Ken Taymor, executive director of the Berkeley Center for Law, Business, and the Economy in California. "The field is still too young, and that's where the danger lies."

Taymor applauds any company with a "business plan that's not entirely dependent on patent exclusivity." By establishing multiple partnerships, he says, the loss of any one patent shouldn't topple any of these companies. This is also sound business strategy, adds Munevar. "A diverse pipeline that considers multiple application strategies... [can] provide near-term revenues streams which would support future activities," like therapeutics.

Loring urges iPSC companies to form a "patent pool," a strategy that could save patentees and licensees time and money by sharing intellectual property. It has worked in the software industry, she notes, and "I think that it may be realistic for iPS cells, too." Indeed, the idea has been bandied about at several meetings of the California Institute for Regenerative Medicine and elsewhere. "It has to dawn on those individual [companies] that they don't hold all the pieces of the puzzle," Loring says.

Biotech companies realize that intellectual property can only take them so far. "What will truly be important and differentiate us will be to deliver high-quality products to our customers that serve their needs," says CDI's Kendrick-Parker. Fate's Grayson agrees that profiting from iPSCs will take more than just novel patents. "It's going to be those elements of experience and the best technology that will lead to the best company," he says. n

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