A scientist describes how she decided that a legal fight would advance science
(A statement issued in response to this commentary is provided below)
At 9 p.m. on 9 August, 2001, US President George W. Bush announced the first opportunity to obtain federal funding for experiments on human embryonic stem cells (ES cells). Because funding was limited to lines already established at that time, Bush's executive order is perceived to be a constraint on this research. In fact, more restrictive decisions have already been made by another US government agency.
On 1 December, 1998, the US Patent and Trademark Office (USPTO) issued a patent that covers all primate (including human) embryonic stem (ES) cells. This patent, entitled 'Primate Embryonic Stem Cells' (Patent 5,843,780), was followed on 13 March, 2001 by a second (Patent 6,200,806) with the same title, but limited to human ES cells. Unlike a scientific publication, which encourages other scientists to reproduce a researcher's work, a patent has the force of law to exclude others from working with the patented invention or material. In this case, the patents are quite broad. Through a “composition of matter” claim, the patents would cover even human ES cells that were not derived through James Thomson's method, on whose work the patent is founded.
I was already working on deriving human ES cell lines, as were several of my colleagues in the field, when I learned about the patents, and I began to worry about what impact this monopoly would have. My concern about the patents grew as it became clear that the patent holder intended to exploit its monopoly, charging for licences to use human ES cells. I started seriously researching patents and came across an article1 about Dan Ravicher, an attorney who had founded the Public Patent Foundation in New York to challenge patents that threatened the public interest. I called him for advice, and within a month he had become my teacher and partner in the challenge to the patents that we brought in the summer of 2006 (refs 2–4).
The effects of a patent on research depend on the motives of the patent holder: the owner of a patent can sell it, mandate the terms under which it is licenced, or simply deny everyone else the chance to use the technology. In this case, the owner of the ES cell patents is the Madison-based Wisconsin Alumni Research Foundation (WARF), a technology-licencing organization associated with the University of Wisconsin, with US$1.6 billion in assets, that also holds patents for vitamin D and warfarin, a blood-thinning drug marketed in the United States as Coumadin. WARF requires a licence from every academic investigator who uses human ES cells in the US, thus restricting collaboration even within the same institution, and demands large licencing fees and royalty payments from companies that wish to use human ES cells for reagent or drug development5.
The 1998 patent (5,843,780) was based on monkey ES cells derived around 1994 by James Thomson at the Wisconsin Regional Primate Center (now the Wisconsin National Primate Research Center). The second patent was a “divisional” patent that claimed only human, not all primate ES cells.
These two patents and a third issued on 18 April, 2006 (7,029,913) form the basis for WARF's monopoly on human ES cells in the United States (Table 1). Under the law, WARF can exclude everyone else in the country (or anywhere the patents are enforced) from making, using, selling, offering for sale or importing any cells that fall under the patent claims. The broadest of these claims “composition of matter” of primate ES cells. The 1998 patent reads as follows:
We claim: 1. A purified preparation of primate embryonic stem cells which (i) is capable of proliferation in an in vitro culture for over one year, (ii) maintains a karyotype in which all the chromosomes characteristic of the primate species are present and not noticeably altered through prolonged culture, (iii) maintains the potential to differentiate into derivatives of endoderm, mesoderm and ectoderm tissues throughout the culture, and (iv) will not differentiate when cultured on a fibroblast feeder layer.
The research that formed the basis of the 1998 patent was supported by a grant from the US National Institutes of Health (NIH) to John Hearns, the director of the Primate Center. This is important, because it means the government automatically has a licence to this patent as well as rights to force broad licencing terms if deemed necessary in the public interest. (The government has never exercised these “march-in rights” for biological patents.) The patent issued in 2001 excluded the NIH-supported work, as the claims were only for work on human ES cells supported privately by the biotechnology company Geron, based in Menlo Park, California.
Anyone who believes that a patent should not have been issued can ask the patent office to re-examine a patent. The patent office will agree to do this only if there is a reason to believe that it was not able to consider all of the information available at the time the patent was in its first examination. After a few months of Dan teaching me about patent law and me teaching him about ES cells, we set out to make the case to the USPTO that these patents should never have been awarded.
But the spirit of scientific inquiry often requires us to venture beyond our areas of expertise, and I think that scientists have an obligation not only to perform research but to make sure that our research can benefit the society that supports it.
To issue a patent, examiners must determine that a process, machine, material or other 'invention' is novel, useful and non-obvious. Of these, 'obviousness' is the most difficult decision to make. Patent examiners generally look for 'prior art', that is, publications that singly or in combination contain all features of the invention being considered. Next, the examiner considers whether “one of ordinary skill in the art” at the time of the application would have found the ideas underlying the invention obvious.
The USPTO receives hundreds of thousands of patent applications each year. A successful application is examined for an average of two years, during which time overworked examiners can devote an average of only 18 hours to each patent application. Patent attorneys do not have such constraints on their time, so in the sense that obtaining a patent is a debate between lawyer and examiner, the lawyer has the advantage. After months of investigation, we came to understand the events that led to the issuance of these patents.
We scrutinized the patents themselves as well as the 'file wrappers', the documents exchanged between the USPTO and the applicant6. For the primate ES cell patents, the patent history was a stack of paper about 10 centimeters high. Most consisted of badly photocopied scientific manuscripts, patents and other dated material such as newspaper clippings. By sifting through this pile, I learned that the USPTO rejected the first patent application on primate ESCs that WARF submitted, and that the patent that did get issued had squeaked through because of an administrative oversight.
A primate ES cell patent application was first submitted by WARF in January 1995, but failed to convince the patent examiner that the work was patentable, and this application was finally abandoned in December 1997. However, in January 1996, WARF submitted the same patent application a second time. In effect, WARF had two copies of the same patent in prosecution at the same time. A lawyer friend of mine tells me this not that unusual. Applicants who fear they have been assigned to a tough examiner can resubmit the patent to get a different one.
The file wrapper shows that this second attempt was more successful. The examiner this time criticized WARF for double patenting during the period that both applications were live, and WARF abandoned its first submission. If the appeal on the first patent application hadn't been turned down, WARF would likely have withdrawn the second submission, and so obtained an earlier filing date, which creates earlier 'prior art' and so provides a stronger position for intellectual property.
Among the interesting items in the file is an undated page from Thomson's lab notebook, used as evidence that he derived monkey ES cells before a newspaper article announcing their success in 1994. More importantly, the file contains a letter from the director of the patent examiners' group, written after the examiner had approved the patent. This letter, dated 18 November, 1998, requests the patent printing office to delay issuing the patent so it could be further examined. However, the letter did not arrive in the printing office in time, and the patent was issued on 1 December, 1998. This patent remains in effect until 2016, 20 years after its filing, and the later patents will stretch some of WARF's claims even longer. WARF has tried to get the same patent issued in multiple countries and failed. Other countries have not even allowed patenting of human ES cells.
On 17 July, 2006, three of us — Dan and I, and John Simpson of the Foundation for Taxpayer and Consumer Rights in Santa Monica, California — requested that three “Primate Embryonic Stem Cell” patents be re-examined on the grounds that the claims were obvious. We cited several publications from the 1980s that described the precise recipe for ES cell derivation that Thomson used, and I wrote a declaration explaining that I thought that using the published methods for mouse ES cell derivation was an obvious approach for primate ES cells. On 30 March, 2007, the USPTO completed its re-examination and soundly rejected all of the claims in all three challenged patents. The examiners even came up with additional evidence of obviousness that we had not provided8. The rejection does not mean the end of the patents, however, because WARF is appealing the decision, and the patents remain in force until WARF exhausts its appeals or decides to let the PTO's decision stand.
In WARF's official response to the rejections, it included a declaration from Colin Stewart, a stem-cell researcher at the Institute of Medical Biology in Singapore, who argued that he did not think the approach was obvious. WARF also used the publicity surrounding Thomson's publications as an argument that his work was patentable. We responded by obtaining declarations from three other stem-cell scientists stating that the successful derivation of primate ES cells depended on availability of resources, not novel ideas.
We were surprised when WARF responded with a press release saying, correctly, that I and the other scientists also have patents. This isn't relevant to the validity of the WARF patents, and seems to be an attempt to undermine our credibility. Our patents, like Thomson's, are assigned to companies or to our universities, and we have little control over how they are enforced. We are not challenging Thomson; we're challenging the patent owner, WARF.
It's important to remember that the patents remain in force until the challenge is resolved, but we think that our challenge is already having a positive effect. In January 2007, WARF changed their licencing policy for academics, allowing them more freedom to share human ES cell lines, and to accept funding from companies for their research. Still, only a few companies have taken licences because they feel that WARF is demanding unreasonable licencing and royalty terms. Geron, because of their investment in Thomson's research, retains an exclusive licence for therapeutic use of neural, pancreatic and cardiac derivatives of human ES cells.
Despite the rising clamour, WARF is vowing to hang on to the patents at all costs. At the beginning of October, it filed amendments with the USPTO in an effort to strengthen its case that the patented discoveries differ from prior art. Dan, John and I, along with an increasing number of scientists, ethicists, and lawyers, will continue to maintain that the work is unpatentable. Notably, a Nobel Prize was awarded this year to the three scientists who actually did invent ES cell technology (see Nature 449, 642; 2007). Early in the 1980s, Martin Evans, Mario Capecchi and Oliver Smithies developed the technology that all of us, including Thomson, have used to derive ES cell lines ever since.
I do not get paid for our work on this challenge. I did not set out to become an expert in patent law, and it is still very much outside my comfort zone. I'd rather be spending my time learning more about the molecular interactions that make human ES cells pluripotent. But the spirit of scientific inquiry often requires us to venture beyond our areas of expertise, and I think that scientists have an obligation not only to perform research but to make sure that our research can benefit the society that supports it.
Response from WARF to Dr. Jeanne Loring's Commentary, A Patent Challenge for Human Embryonic Stem Cell Research , published in Nature Reports Stem Cells
November 5, 2007
WARF, the Wisconsin Alumni Research Foundation, continues to be perplexed by the misguided motivations of the challengers to our stem cell patents and deeply concerned about the misinformation they continue to promote about the goals and operations of our non-profit organization.
Since our founding in 1925 as the world's first university-based technology transfer organization, WARF's mission has been to patent, license and advance University of Wisconsin-Madison discoveries to the commercial market for the benefit of the university, its inventors and the world. Every year we gift the university millions of dollars, earned from our licensing and investment activities, to fund further scientific research. WARF is well respected among our peers for our leadership, expertise, ethics and innovation.
Along with our non-profit affiliate, the WiCell Research Institute, WARF is committed to advancing human embryonic stem cell research. WARF protects and advances stem cell research; we do not restrict it.
WARF established WiCell (www.wicell.org) in 1999 to:
conduct stem cell research and establish research protocols
provide cell lines, research tools and training to scientists worldwide
offer educational outreach programs to researchers, area schools and the public
Since 1999, our affiliate, the WiCell Research Institute, has provided free human embryonic stem cell licenses to more than 500 researchers in 25 countries and 40 states. Academic researchers never have been charged for these licenses; they are required only as a method for meeting information obligations stipulated by the National Institutes of Health.
The NIH Registry Lines available through the National Stem Cell Bank (www.nationalstemcellbank.org), which is hosted at WiCell, are priced at an affordable $500 per two vials, which contain approximately six million cells capable of establishing multiple new colonies. No restrictions are placed upon academic scientists using WARF cell lines and methodologies who patent or publish their own research, and they need no approval from WARF to do so.
WiCell provides an ongoing schedule of stem cell training classes and workshops customized for participants ranging from youth to non-technical adults to lab technicians to top researchers. Since 2002, WiCell has trained nearly 600 individuals in stem cell technologies and methodologies.
WARF continues to believe that Dr. James Thomson's breakthrough discoveries were, and are, patentable. We are confident that ultimately our patents will be upheld.
Response from Jeanne Loring to WARF's response
November 7, 2007
I have a great deal of respect for WARF's long history of commercializing research performed at the University of Wisconsin. But this time they have taken the wrong approach. While the cost for academics for each hESC line has been reduced from $5000 to $500, this change was not because of good will, but because WARF's stem cell organization, WiCell, has a contract with the NIH that more than compensates for their expenses in providing the cells. It's important to understand that training courses, NIH grants, distribution agreements, charity, and publicity have NOTHING to do with the validity of a patent. This is a legal issue about what is patentable and what is not, not a popularity contest.
Kintisch, E. A 'Robin Hood' declares war on lucrative U.S. patents. Science 309, 1319 (2005).
Loring, J. F. & Campbell, C. Science and law. Intellectual property and human embryonic stem cell research. Science 311, 1716–1717 (2006).
Kintisch, E. Groups challenge key stem cell patents. Science 313, 281 (2006).
Somers, T. Foundation's stem cell patents impede research, scientists say. San Diego Union Tribune 30 July (2006).
Regalado, A. & Hamilton, D. P. How a university's patents may limit stem-cell research. The Wall Street Journal 18 July (2006).
All patent-challenge documents are available from the Public Patent Foundation website: http://www.pubpat.org Official correspondence and documents (called File Wrappers) are available at http://portal.uspto.gov/external/portal/pair
Kaplan, K. U.S. invalidates three human stem cell patents. Los Angeles Times 3 April, 2007.
Check, E. Patenting the obvious? Nature 447, 16–17 (2007).
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Loring, J. A patent challenge for human embryonic stem cell research. Nat Rep Stem Cells (2007). https://doi.org/10.1038/stemcells.2007.113