Suing for Alzheimer’s Mouse

Are patents the protectors of innovation or repressors of research?  - Why the academic community can’t make up its mind  

In February 2010, the Alzheimer's Institute of America (AIA) filed lawsuits against several research institutes, one of which was the Jackson Laboratory, for alleged infringement of their patented Alzheimer’s mouse. These unfortunate rodents are engineered to carry a mutant form of the gene for human amyloid precursor protein in their genetic code, a characteristic that guarantees the mice will develop Alzheimer’s disease symptoms. This makes them particularly useful models for studying the development and prevention of the disease in humans. The Jackson Laboratory is a non-profit institute that is funded by the National Institute for Health (NIH) to produce these mice and distribute them to the research community. Herein lies the problem – by distributing the mice (and allegedly making a profit from them, according to AIA), the Jackson Laboratory is infringing AIA’s exclusive right to make and sell their patented invention (35 U.S.C. 271).

Photo: Rama

Both sides accept that these mice are vital to Alzheimer’s research. According to judge Elizabeth Laporte for the US District Court of Northern California, AIA has not disputed Jackson's claim that "prolonging the litigation in this case would harm Jackson and the public by extending the chilling effect of the litigation on mice research on Alzheimer's disease".

An interesting facet to this whole case is how reflective it is of academic science’s love-hate relationship with patents.

In April, we (or maybe just those of us who follow patent news) heard the outrage from the academic community at the European Court of Justice’s Advocate General’s opinion regarding the patentability of human embryonic stem cells (hESC). As explained in an earlier post, the AG found that inventions that used hESC were contrary to ordré public and morality, and as such, unpatentable under European Law. This was unacceptable to much of the academic community. Thirteen prominent academics implored the ECJ to rule against the AG’s opinion in a letter to Nature. If stem cell inventions were ruled unpatentable, the academics argued, stem cell research in Europe would be severely disadvantaged. Selling and licensing patented technology to large pharmaceutical companies gives university and small and medium enterprises an indispensable funding source. Without such funding, the future of stem cell research and potential cures for the millions suffering diseases such as Parkinson’s, would be severely threatened. Being able to patent research is essential.

Yet in the states, a very similar rhetoric is being used to support a completely incompatible point. Researchers are arguing that by enforcing their patent, the AIA is threatening research and essential funding for the development of therapies for a devastating disease. The Jackson Lab has the advantage that Alzheimer’s is an incredibly emotive issue – blocking Alzheimer’s therapies arguably has a lot more sympathy than blocking stem cell research. So much so, that the NIH has come to the rescue, granting the Jackson lab government sanction to use the patent (the US government has the power to commandeer any US patent for it’s own use - within reason). Not being too keen on attempting to sue the US federal government, the AIA dropped their case against the Jackson Laboratory. But not, however, against the other defendants.

To the outside observer, there does seem to be some inconsistency in the academic communities’ approach to patents. Rudolf Tanzi, a researcher studying Alzheimer's disease at the Massachusetts General Hospital in Charlestown, taking to Nature News remarked “I think you need to respect people's intellectual property, but the impact on field if the mice were not freely available would be devastating.” However this same argument could equally be applied to any patented stem-cell inventions. For example, the stem-cell patent in dispute in Europe refers to neural precursor cells produced from hESC – surely if these were not freely available it would be devastating on any field researching potential therapies for neurodegenerative diseases, for example Parkinson's, and indeed, Alzheimer’s.

(Interestingly, the application to patent the original transgenic mouse, Harvard University’s “Oncomouse”, provoked similar ethical opposition as has arisen to the patenting of stem cells. If “Oncomouse”, genetically programmed to get cancer, had been ruled unpatentable due to ethical considerations, AIA’s “Alzheimer’s mouse” would be freely available to use.)

The problem is that the arguments on both sides are convincing. (Note that I am referring to the value of the patenting tools of scientific research per se, not any morality issues relating the use of transgenic mice or stem cells.) Arguably, these patents do the job they are intended for – that is to promote scientific advancement by encouraging investment in research. The potential loss of this investment is driving the scientific outrage at the Advocate General’s opinion on stem cells in Europe. However, any exclusive rights to a technology are bound also to produce some blocking effects, especially if the owner of those rights sets a high price to use the technology, as AIA has presumably done.* Personally, I have my own opinion on whether the current patent system is a Good or a Bad thing with regards to medical research, but this would be a much longer (and much rantier) post. However, which side of the fence you are on as a scientist, seems to depend on where you are with your research – i.e. at a patenting stage or an exploiting stage. I just wonder if the laboratories that purchased Jackson Lab’s mice are planning on patenting any of the cures they develop. I would bet that they probably are.

*Outside of medicine, the case may be more clear-cut. For example, in engineering, patents are probably a good thing. In other fields, such as computer programming, the blocking effect seems to dominate (as discussed in This American Life’s brilliant episode “When Patents Attack!”).

Patent Pain for Stem Cell Research

Confused how Greenpeace managed to call out Europe’s highest court to break-up the stem-cell party? 

These beautiful dancing fronds are a bundle of human neurons. These cells have not been taken from a brain; instead they have been grown from human embryonic stem-cells. With the capability to turn into any type of cell, human embryonic stem-cells (hESC) have the potential to cure the incurable, from the degenerative diseases of old age, to broken spinal chords. But research into hESC has provoked ethical debate, with religious groups, and organisations such as Greenpeace, being longstanding opponents of their use. Image: Nissim Benvenisty

Way back in 1997, the German Patent Office received an application for a patent from a Dr. Oliver Brüstle. The application was for neural precursor cells that could be used in the treatment of neural defects, and a method for making these cells from pluripotent stem-cells. Dr (now Professor) Brüstle was granted his patent, and he duly put his invention to work developing a new treatment for Parkinson’s Disease.  But now, 14 years after he originally filed his application, the subject matter of Professor Brüstle’s patent is being scrutinized by Europe’s highest court, with implications for the whole stem-cell research field in Europe.

As reported last week in the Guardian, the European Court of Justice (ECJ) will soon rule on whether inventions that use human embryonic stem cells (hESC) in any capacity can be patented under European Law. The Advocate General (a sort of Yoda-of-the-court figure, who provides a legal assessment of the problem before the court makes its judgement) has already given his opinion, and to the dismay of the stem-cell research community, has come out against allowing inventions such as Prof. Brüstle’s, to be patented. But why has this issue arisen now? And if the court does follow it’s Advocate General, will it really lead to the devastation of stem-cell therapies, as supporters of the technology claim?

Following the grant of Brüstle’s original patent, Greenpeace (as it frequently does when it unearths a patent that is not to it’s tastes) took proceedings to the German patents court, alleging that under both German and European Law the patent was invalid. The significant piece of European legislation can be found in the 1998 Biotechnology Directive: 

Article 6

(1)Inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality; …

(2) On the basis of paragraph 1, the following, in particular, shall be considered unpatentable:

 …

(c) uses of human embryos for industrial or commercial purposes

Greenpeace argued that because Brüstle relied on pluripotent stem-cells (a type of hESC) to make his neural precursor cells, the invention involved the commercial use of embryos, and was therefore unpatentable according to the Biotechnology Directive. Brüstle obviously disagreed, and the case worked its way up to a higher court, the Bundesgerichtshof. On examining the facts, the Bundesgerichtshof felt a legal brick wall had been reached, and so referred three questions pursuant to hESC and European Law to the ECJ for clarification.

The most pertinent of these questions, currently under deliberation at the ECJ, is the third one. If an invention, which doesn’t actually involve the destruction of embryos per se, but none-the-less specifies ingredients (e.g. pluripotent stem-cells) that can only be obtained through the destruction of embryos, does the invention fall within the scope of Art 6(2)(c) of the Biotechnology Directive? The Advocate General, Judge Yves Bot, was of the opinion that such inventions do use “human embryos for industrial or commercial purposes”, and thus, being contrary to ordre public and morality, cannot be patented.

Despite the dramatic language, a declaration of being “contrary to morality” does not mean such technology is rendered illegal.  A patent does not give you permission to use a particular invention; instead it gives you the right to exclude others from using it. So, if this judgement introduces no legal barrier to using stem-cell technology (in fact, it does quite the opposite, as patents are exclusionary in nature), what is all the fuss about?

Predictably, it is about money. The thirteen stem-cell academics, who wrote to Nature to protest at the Advocate General’s opinion, put the problem as such.  Without the promise of patent protection for stem-cell inventions, who will invest in the development of stem-cell therapies? Universities do not possess the resources to take treatments from the lab to the market, and so rely on assigning or licensing their inventions to big pharmaceutical companies. In the absence of legally guaranteed monopolies, what motivation will these companies have for sponsoring university research or funding expensive clinical trials to allow European stem-cell therapies to reach the marketplace? Instead Pharma companies will take their investments and research grants overseas – the US, for example, following the departure of George W., is as a much more stem-cell research friendly place. In contrast to what the Guardian reports, this is not so much a problem of stem-cell treatments being threatened, but a problem of stem-cell research moving elsewhere.

In their letter, the academics argue that an in vitro fertilised egg is not an embryo, a position which was neatly contradicted by Judge Yves Bot, at least from a legal perspective. But the academics also make a rather more compelling point; in actual fact, sourcing pluripotent hESC no longer requires the routine destruction of embryos. Cell lines (cells that are propagated in a Petri dish ad infinitum) are well established, and as a result, pluripotent stem-cells are available through international cell banks. They can be ordered online. This facet of the stem-cell conundrum does not appear to have been touched upon by the Advocate General. In fact, in paragraph 114 of his judgement (case C-34/10), Bot states the opposite, reasoning that for every additional number of cases of disease treated with stem-cell therapies, a proportional number of embryos would have to be created and destroyed. This, it appears, is simply not the case.

It is unusual for the ECJ not to follow the advice of its Advocate General, but not impossible. It will be interesting to see whether the outrage of the scientific community, and the concerns that have been raised regarding European research interests, have any impact. It will be particularly interesting to see whether the matter of established cell-lines, which seems to have been overlooked in the Advocate General’s statement, will be addressed at all. Can the ECJ come to a judgement that is more lenient on stem-cell inventions than that advised by Judge Yves Bot? 

Watch this vacuole.

(A postscript. Greenpeace has been fighting Mr Brüstle’s patent for many years now, and this case will now return to German courts. Lawyers are expensive. If you love the planet and want to donate to an organisation that fights Earth’s corner, please, please reconsider before donating to Greenpeace. There are many other groups that do a marvellous job of caring for the planet, campaigning against climate change and preserving endangered species, without wasting your hard-earned cash on lengthy lawsuits.)