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!”).

Great Expectations - Or why I would rather read about Kate n’ Wills than Medical Miracles

JAB TO REVERSE ALZHIEMER’S - Breakthrough vaccine could be available within two years” announced the headline of last Saturday's Daily Mail A slow news day, one might conclude, if TDM was driven to fall back on such an up-beat, non-hysteria inducing headline.

Yet for anyone who has watched a loved one succumb to this brutal, incurable disease, this headline highjacks your attention. Alzheimer’s is a degenerative brain disease that progressively robs sufferers of their personality, their speech and finally their basic functions. It affects around half a million people in the UK alone. There are no effective treatments. An actual cure within two years is an unbelievable result - a proper old-fashioned miracle.

The hero jab of the article is bapineuzumab¹. As the Mail reports, its development is being funded by three of the biggest players on the Pharma scene - Pfizer, Johnson & Johnson and Elan Corporation - which is interpreted as indicative of bapineuzumab's impending blockbuster status.

TDM explains that bapineuzumab is currently in the phase III stage of testing, meaning that “it has passed initial safety hurdles and been shown to be effective”.² Hmm… no phase III data – was the phase II data really good enough to warrant such a proclamatory headline? A quick search on Google scholar reveals that the outcomes of phase II testing were inconclusive (see this phase II trial abstract and this review). In fact there is no requirement for a drug to have been shown to be definitively efficacious at phase II in order for it to enter phase III. If the backers (Pfizer etc) think there is a big enough market for the treatment, it may be worth the gamble taking the treatment to phase III, with the hope that with a larger sample size (1000s of patients as opposed to merely 100s), a statistically significant result will arise. In fact, this article is nothing more than speculation made on the basis that the bapineuzumab has made it into phase III and a quote from one doctor, Dr David Wilkinson, who, in fairness to him, talks only in maybes. As yet there is no data showing a positive effect of bapineuzumab on Alzheimer’s symptoms, never mind any evidence that it reverses the effects of the disease. Dr Ridley of the Alzheimer’s Society, also quoted in the article, puts it succinctly, "it’s too early to tell whether bapineuzumab could benefit people until the results of this trial are known". There is nothing in this article to justify the headline. 

While it is always relatively easy to Mail-bash on science articles, this does raise a wider point. How much of a disservice is done to science by “bigging it up”? i.e. predicting deliverables in 2, 4, 10 years time. Surely this doesn’t sit very well with the very reason research is carried out in the first place – to obtain an answer to an unknown. Furthermore, wrong predictions can only serve to undermine public and financial confidence in evidence based research. And who is really responsible? Is it the big bad media, who don’t know any better (although I suspect everyone who works at the DM did know better re: Saturday’s front page) or is it scientists themselves?

A key example of science “bigged-up” that leaps to mind is The Human Genome Project. Back in 2000, Bill Clinton made a speech announcing to the world that the first draft of the Human Genome was complete. Clinton proclaimed that this achievement would revolutionize medicine, yet last year, on the 10 year anniversary of the speech, the media was full of articles, such as this one from the New York Times, asking why had the HGP failed to live up to its promise. I find this an illogical conclusion - 10 years simply isn’t long enough time for treatments to appear. It typically takes around 15 years for a drug to move from the lab to the market, and that is after you have identified the appropriate target. Genetic diseases are complex, with many, for example cystic fibrosis, involving a myriad of contributory genes, all of which take time to identify. Yet before HGP, finding a human gene took months and was prohibitively expensive. Now a curious researcher can search for any sequence on a database. For free. Far from being a biological curio, the HGP has vastly accelerated and reduced the cost of research into the genetic causes of disease. This will translate it into tests and cures, but it will take more then 10 or 15 years, something that must have been known in 2000, even without the benefit of hindsight.

Regarding the HGP, it is clear that scientists themselves were complicit in the over-sell. Dr Francis S Collins, who predicted genetic tests within 10 years and cures within 15 years, is certainly a scientist. What was his motivation? Perhaps to try and justify the cost, or to ensure future grants? Or perhaps, simply because he was caught up in the moment. Obviously he never predicted the media’s reaction to the disappointment of the HGP a decade down the line. Either way it is a shame, because HGP is a substantial achievement of science and international cooperation, but this has been overshadowed by the initial over-sell.

Back to the Alzheimer’s story. I have little doubt that someday antibodies, or more likely cocktails of antibodies, are going to be invaluable in slowing or even quelling the rampaging effects of Alzheimer’s on the human brain.³ But within 2 years? It is impossible to know, but based on the phase II data for bapineuzumab, I would bet against it. This sort of reporting does nobody any favours. For the Daily Mail, it is after all, a reasonably boring headline – unless Alzheimer’s has directly effected a close family member, you are unlikely to care that much. Short of a “Vajazzling Gives You Cancer” headline, health stories just aren’t likely to compete with yet another headline about the impending bit of out-breeding the royal family is about to do. But importantly, it does science a huge disservice. By creating unjustified expectations, science and medicine can only fail, and thus public confidence in (and enthusiasm for spending on) vital evidence based research is reduced even further. Both scientists and the media have a duty to ensure that science is communicated responsibly, and that predictions, where they are made, are thoughtful and evidence based. Less punchy headlines are an inevitable result, but perhaps, until scientists can make p numbers sexy, science will just have to consent to being left off the front page.

A final comment, this one is directed just at the dirty feet of the Daily Mail. Above everything else, Saturday’s article struck me as an exceptionally exercise in cruelty. For someone who has just received a diagnosis of Alzheimer’s, whether critical enough to read on and understand, or not, that headline would have made their heart leap, and for no real reason.

1. For those who are interested, bapineuzumab is a monoclonal antibody, similar to the antibodies already produced by our bodies, except grown in industrial amounts using mouse cells. Antibodies are like hazard warning labels. They stick to anything in the body that shouldn’t be there, for example a virus or a cancer cell, signalling to the body’s immune cells to attack and dispose of the offending article. Bapineuzumab is an antibody that sticks to amyloid beta, the protein that forms tangled masses in the Alzheimer’s brain called plaques, presence of which during autopsy is the final definitive diagnosis of the disease. The theory behind the vaccine is this: bapineuzumab will stick to the amyloid beta plaques, causing to immune system to clear the amyloid deposits out of the brain, thus undoing the symptoms Alzheimer’s.  However, as explained in this excellent article, it is disputed whether amyloid tangles or plaques are a cause or a symptom of the disease. There are other candidates, including the tau protein, as well as smaller, soluble forms of amyloid beta, which theoretically bapineuzumab could work against as well.

2. Initial safety hurdles are phase I of testing, normally in healthy volunteers (although, with certain drugs that have the potential to cause harm, e.g. chemotherapies and certain Alzheimer drugs, such as bapineuzumab, phase I trial take place in disease sufferers). Phase II trials are small scale testing in people with the actual disease. Drugs that fail phase II often will not progress to phase III, the large scale trials required to get marketing authorization for a drug. 

3. Why? At university, I was lucky enough to be taught by a group researching Alzheimer’s and antibodies, and saw some brilliant data. Unfortunately the unlucky subjects of the experiments were fruit flies engineered to have Alzheimer’s-like symptoms, but none the less, it was enough to make me a believer in the potential of this stuff.