Just to try and balance some of the pictures painted by the Landhuis/Strobel story: I'm referred to as being "a doctoral student in John Hardy's lab". (In passing, is the inference that being a doctoral student is an intellectually inferior position?). I was also a fully qualified medical physician seeing patients including those in the families where the first FAD APP mutations were found. I was also the group's linkage expert during those years of the discovery of the APP mutations. I had my own peer-reviewed funding which I brought to the department. I was a co-inventor on the London APP mutations as consensually agreed by the other members of the team, including Hardy, at that time due to my contributions, mostly of linkage analysis which confirmed the presence of mutations in the APP gene. The resulting patents had value and were licensed. Certain team members, including Hardy, benefited financially from the commercial licensing of those patents. I am clearly not a lawyer but it's my understanding that there is no intention nor was there ever any intention that academic...  Read more

Just to try and balance some of the pictures painted by the Landhuis/Strobel story: I'm referred to as being "a doctoral student in John Hardy's lab". (In passing, is the inference that being a doctoral student is an intellectually inferior position?). I was also a fully qualified medical physician seeing patients including those in the families where the first FAD APP mutations were found. I was also the group's linkage expert during those years of the discovery of the APP mutations. I had my own peer-reviewed funding which I brought to the department. I was a co-inventor on the London APP mutations as consensually agreed by the other members of the team, including Hardy, at that time due to my contributions, mostly of linkage analysis which confirmed the presence of mutations in the APP gene. The resulting patents had value and were licensed. Certain team members, including Hardy, benefited financially from the commercial licensing of those patents. I am clearly not a lawyer but it's my understanding that there is no intention nor was there ever any intention that academic institutions and academics should not have free access to the Swedish mutation. Clearly, there would be no controversy if this mutation was not widely regarded as an important model for AD and, as such, I do not know of any case where academics are being sued or are being threatened to be sued for academic use of the Swedish mutation. My understanding is quite the opposite, that its use is highly encouraged where appropriate - it certainly is by me. I think the issues arise when the mutation has been deliberately exploited in for-profit programs. Then under US law (and law in most other countries) if patents are not licensed but are infringed the owner of the patent has the right to act against that infringing party. This is why Elan sued Mayo, AIA and has sued others. In infringement lawsuits, one of the defendant’s positions is to try and invalidate a patent and one of the ways they can do that is to claim that the inventorship is incompletely attributed. Hence the new Lannfelt story. Ultimately, juries will decide whether they believe him or not. It is a sad fact of life that if, as academics, we become inventors on important patents then we might expect that we may end up in court on either side of lawsuits. Such lawsuits can become very nasty very quickly - lawyers want to win. An academic life without patents might be nice but it's very likely to be true that any efficacious treatments for AD will be very extensively patented. Perhaps some courses on navigating the world of intellectual property might be useful to many researchers?

View all comments by Michael Mullan

Dr. Mullan comments in reply to this article that academics are not being sued for use of the Swedish mutation and, just the opposite, are highly encouraged to use the mutation. That statement hardly comports with the fact that The Jackson Laboratory, a nonprofit, is being sued by his organization despite the fact that the mouse strains that are the subject of the lawsuit are made available by the Jackson Lab to only academic and nonprofit institutions for research purposes only.

View all comments by Michael Sasner

Due to the pending litigation in which AIA is unfortunately involved, AIA originally refused to comment when this forum contacted it. Having now seen the resulting article, AIA must respond to correct many of the misstatements and misconceptions reported.

First, AIA has always encouraged academic research using the Swedish mutation. For example, AIA worked with Mayo to ensure that the Tg2576 mice containing the Swedish mutation were widely available to academic researchers. In fact, there are dozens and dozens of academic institutions that are using the Swedish mutation for non-commercial purposes and have never been bothered about it, much less brought to court.

Second, the uses of the Swedish mutation employed by the companies mentioned in the article are categorically different because they are commercial uses. When companies sell products containing the Swedish mutation (such as Jackson Labs' sale of Swedish mutation containing mice) or where the Swedish mutation has been deliberately exploited in for-profit ventures (such as OMRF's use of the Swedish mutation...  Read more

Due to the pending litigation in which AIA is unfortunately involved, AIA originally refused to comment when this forum contacted it. Having now seen the resulting article, AIA must respond to correct many of the misstatements and misconceptions reported.

First, AIA has always encouraged academic research using the Swedish mutation. For example, AIA worked with Mayo to ensure that the Tg2576 mice containing the Swedish mutation were widely available to academic researchers. In fact, there are dozens and dozens of academic institutions that are using the Swedish mutation for non-commercial purposes and have never been bothered about it, much less brought to court.

Second, the uses of the Swedish mutation employed by the companies mentioned in the article are categorically different because they are commercial uses. When companies sell products containing the Swedish mutation (such as Jackson Labs' sale of Swedish mutation containing mice) or where the Swedish mutation has been deliberately exploited in for-profit ventures (such as OMRF's use of the Swedish mutation and subsequent spin off of CoMentis, Inc.) or where large pharmaceutical companies (such as Elan and Pfizer) engage in massive drug discovery and development programs using the technology, then AIA is entitled to a license and to share in the potential revenue. AIA made licenses to many of these companies available, and the companies decided to use the technology without a license anyway. When that happens, AIA has no choice but to seek a resolution in court.

Third, the defense of incorrect inventorship is an old tactic pursued by infringers in many patent cases. This case is no different. In this case, Dr. Lannfelt has come up with a new story, despite the fact that he conceded long ago that he was not an inventor on these patents. Dr. Lannfelt's new story is at odds with contemporaneous correspondence from March 1992 (the same month the original patent application was filed) that specifically states that Dr. Lannfelt examined the data and (incorrectly) decided that amyloid was not the gene containing the mutation and that the mutation was actually discovered by Dr. Mullan. Ultimately, however, the issue of inventorship -- like all the other issues in the article -- will be decided in court, not in the media. That is how it should be.

View all comments by Brian Sexton

The report by Esther Landhuis and Gabrielle Strobel reflects the inherent intellectual and financial turbulence that evolves when advancing technology interfaces with the patent system and commercial system.

First, let’s examine the patent issues. It is critical to understand the patent process, whereby a government-based patent officer is required to review patent material put forth by inventors. The officer has a limited amount of time to devote to an individual patent. In the 1990s, in the same period when the disputed patent was granted, I talked to such an officer, who told me that the time spent on an individual patent should average out to about 20 hours. This time allotment is complicated because the patent officers cover a broad range of material, such as the field of “biotechnology,” which can range from degeneration to inflammation to cancer to agriculture. Thus, some of the time must be spent in education. This specific number of hours and breadth of subjects might have changed over time, but the fact remains that officers have limited time to spend on any given...  Read more

The report by Esther Landhuis and Gabrielle Strobel reflects the inherent intellectual and financial turbulence that evolves when advancing technology interfaces with the patent system and commercial system.

First, let’s examine the patent issues. It is critical to understand the patent process, whereby a government-based patent officer is required to review patent material put forth by inventors. The officer has a limited amount of time to devote to an individual patent. In the 1990s, in the same period when the disputed patent was granted, I talked to such an officer, who told me that the time spent on an individual patent should average out to about 20 hours. This time allotment is complicated because the patent officers cover a broad range of material, such as the field of “biotechnology,” which can range from degeneration to inflammation to cancer to agriculture. Thus, some of the time must be spent in education. This specific number of hours and breadth of subjects might have changed over time, but the fact remains that officers have limited time to spend on any given patent. Meanwhile, the inventors have hired highly skilled lawyers to push their case. There is little room in the process for other parties to contest the patent or claims until after it is granted and made public. The result is that patent officers are often convinced to grant patents or claims that are flawed. These flaws are corrected through a cumbersome process of litigation that has chilling effects on scientific advancement because of the financial risks incurred by the litigation process.

It is clear that one of the flaws in this patent process was the issue of inventorship. I would suggest that history indicates that Mike Mullan was unlikely to be the sole inventor because the other contributors have had a far larger impact on the Alzheimer’s research field and a far stronger record of discovery and inventorship than Mullan before and after the APPswe identification. It seems likely that Mullan played an important role but was not the sole inventor. However, it would be very difficult for a patent officer who is not familiar with the field to catch this nuance. Hence, a flawed claim.

Second, let’s examine technology. Patents are granted for 20 years. During that time, technology evolves, and what might have seemed like a reasonable claim in 1992 rapidly becomes superseded. Genetic technology is a prime example. Originally, identifying a genetic mutation was a seminal event and represented a large amount of work. Now, sequencing is routine. The advancing technology does not diminish the value of identifying the Swedish mutation, but from a commercial standpoint means that the process associated with the original identification of the Swedish mutation rapidly evolved to reflect a scientific process that was less unique. The evolving patent law as evidenced by the recent BRCA1/2 rulings reflects this evolution.

Third, let’s examine commerce from two angles. First commerce and academia. The OMRF is a not-for-profit institution, as is my institution, Boston University. However, both institutions have a keen desire to develop technology and spin it off towards some sort of commercialization. This interest in commercialization, which I personally find to be really exciting, blurs the boundaries between academia and commerce. The Supreme Court noted this in a recent ruling that academic institutions (I think Duke was the target) can also have commercial interests. This intersection between academia and commerce is vital for the nation’s economies. Our academic institutions are also critical sources of intellectual and technological innovation in America and need to be protected. However, the reality is that the OMRF has a dual interest (even if they do spin off all commercial interests to a secondary party), and such dual interests open up these institutions to the realities of commercial life. The good comes with the bad.

Commerce also needs to be examined from the corporate angle. Note that a business corporation in Kansas purchased rights to the patent. Corporations have one purpose and only one purpose, which is to make money. The welfare of the people (e.g., officers and employees), the ideas, the country, the environment (intellectual or natural) are all secondary to the primary mission of the corporation, which is...to make money. Many people in our country feel that on aggregate this profit motive will benefit society. This is true, but corporations, particularly publicly held corporations, act with a very short time frame for their vision. This short temporal horizon means that any individual corporation might act in a way that has a long-term chilling or harmful effect on society. This is true for the scientific environment, as we see in the case of the APPswe patent. This is also true in the cases of financial issues, as we saw with the banking debacle recently. This is also true in the case of global warming or environmental protection, where the short-term profit motive logically trumps any long-term interest in social or global issues. I personally believe that it is false to assume that the commercial sector will always act in a manner that benefits society in the long term. In these cases, we need government intervention to protect the academic and, yes, commercial entities in a way that fosters innovation (which is the actual goal of the patent system). Similarly, we need government intervention to protect us against other catastrophes—financial or natural.

I do not know all of the details of this story. However, based on this outstanding Alzforum article, it is disingenuous of Mike Mullan or those affiliated with AIA to claim that they are making strong efforts to foster scientific research. This is clearly not the case. The goal of the AIA corporation is to make money for the corporation, regardless of other damages, and Mike Mullan directly benefits from this goal. Of course, for them to say otherwise would damage their position in any litigation, so their response is what we should expect.

Conclusion: I return to my original statement. This case reflects the intellectual and financial turbulence that evolves when advancing technology interfaces with the patent system and commercial system. It is painful, and the inefficiency of the system has a chilling effect on academic innovation. Unfortunately, the U.S. system lacks a mechanism to efficiently and cheaply correct flaws in a patent process. I would love to present a quick solution, but I don’t see it.

View all comments by Benjamin Wolozin

Mullan appears to misunderstand the architecture of modern biological science. Without the contributions by Glenner, Masters, Beyreuther, Van Broeckhoven, Hardy, Winblad, Lannfelt, and many others, the Swedish mutations would not have been identified. Without the efforts by Selkoe, Younkin, and colleagues, their utility would not have been recognized. It is greedy and arrogant to try to exclusively possess this particular intellectual property, which in my view should be commonly shared by the entire research community. Incidentally, Mullan's having been a "fully qualified physician seeing patients" when he was a graduate student has nothing to do with science.

View all comments by Takaomi Saido

I read this news story with sadness. I regret the lack of investigators cooperating on the basis of mutual trust and a handshake. Of course, that is still possible among some, but these days commercial/monetary/legal issues are too often inserted to the detriment of science.

View all comments by Paul Coleman

This is an unpleasant situation that is hindering Alzheimer research and progress. Progressing the field is what we promise to the patients and the families. A mutation that segregates in an early-onset AD family is a major cause of grief to that family and a huge burden for them to carry. They agree generously to participate in research, often not directly benefitting themselves from the research but hoping their (grand)children and others will. They do not demand any financial return, although, in fact, they could use it given the economical cost of caring for young patients in their families. In fact, are they not the owners of the mutation that segregates in their family? Also, are the neurologists and geneticists who invest in diagnosing and sampling the families not contributors to progress of Alzheimer research? Is it really so that those who can handle a technology are the real inventors?

In the case of APP, we knew already that it was an Alzheimer gene as shown by the detection of the Dutch APP segregation and mutation in 1990 (  Read more

This is an unpleasant situation that is hindering Alzheimer research and progress. Progressing the field is what we promise to the patients and the families. A mutation that segregates in an early-onset AD family is a major cause of grief to that family and a huge burden for them to carry. They agree generously to participate in research, often not directly benefitting themselves from the research but hoping their (grand)children and others will. They do not demand any financial return, although, in fact, they could use it given the economical cost of caring for young patients in their families. In fact, are they not the owners of the mutation that segregates in their family? Also, are the neurologists and geneticists who invest in diagnosing and sampling the families not contributors to progress of Alzheimer research? Is it really so that those who can handle a technology are the real inventors?

In the case of APP, we knew already that it was an Alzheimer gene as shown by the detection of the Dutch APP segregation and mutation in 1990 (Van Broeckhoven et al., 1990; Levy et al., 1990), and the London mutation APP mutation in 1991 (Goate et al., 1991). There are currently 32 different APP mutations known, and several of these have been modeled in mice and other model organisms. All are crucially important for Alzheimer research and are used by many researchers in the field, hoping to contribute to better insights in the disease process, leading in return to a better treatment for the patients.

View all comments by Christine Van Broeckhoven

I read this article and the commentaries with keen interest, since Alzheimer genetics was my original scientific field.

I have four observations.

1. Mullan raises the important point that scientists need some awareness of (and training to anticipate and manage) how complicated things can get in the mix of scientific and intellectual property concerns that permeate contemporary science. This is true. I strongly agree it's something that needs to be part of becoming a biomedical researcher these days.

At the same time, disputes like this are going to happen, even among the most sophisticated intellectual property (IP)-savvy researchers. Patents are a right to sue, and so legal conflict is part of the system for those who elect to secure patents; you don't get them if you don't intend to defend them.

2. One of the interesting ironies in the AD case study for the Secretary's Advisory Committee for Genetics Health and Society (mentioned in the story) was that Allen Roses secured ApoE patents not for commercial purposes, but to make sure the priority of discovery was...  Read more

I read this article and the commentaries with keen interest, since Alzheimer genetics was my original scientific field.

I have four observations.

1. Mullan raises the important point that scientists need some awareness of (and training to anticipate and manage) how complicated things can get in the mix of scientific and intellectual property concerns that permeate contemporary science. This is true. I strongly agree it's something that needs to be part of becoming a biomedical researcher these days.

At the same time, disputes like this are going to happen, even among the most sophisticated intellectual property (IP)-savvy researchers. Patents are a right to sue, and so legal conflict is part of the system for those who elect to secure patents; you don't get them if you don't intend to defend them.

2. One of the interesting ironies in the AD case study for the Secretary's Advisory Committee for Genetics Health and Society (mentioned in the story) was that Allen Roses secured ApoE patents not for commercial purposes, but to make sure the priority of discovery was clear (by using the formal patent application process). When the two of us who interviewed him asked, "So establishing priority of discovery was one reason you sought a patent?" he corrected us and said "It was the only reason we filed a patent application initially."

3. One way to avoid such disputes in the future would be to have collective agreements that secure (minimal) payments for use of research tools and reagents that have attached IP, such as transgenic mouse models of human disease. That is, some agreed pathway to get some minimal payments back to the institutions that hold patent rights (or other IP), but that do not rely on exclusive blocking rights and extensive litigation. If there are many more disputes like this, perhaps the system will create such mechanisms.

4. Given all the years of litigation, it is likely that the legal costs have outstripped any scientific value assessed in dollar terms in this case. The worldwide patent rights probably cost in the range of $50,000-$100,000; the litigation costs by now must surely be in the multiple millions if all the parties are included. Not to mention the aggravation and phone calls and e-mails and the opportunity costs of folks spending time on litigation instead of advancing science.

That really is too bad, and it's quite clear something did not go right in this case. The legal system is well situated to eventually deal with such problems—and it will do so here—but it's a hellishly expensive and protracted way to get there. It seems this has escalated beyond reason, and, I suspect, even at the end of a long legal trial, no one will be fully satisfied.

References:
Skeehan K, Heaney C, Cook-Deegan R. Impact of gene patents and licensing practices on access to genetic testing for Alzheimer’s disease. Peer-reviewed case study commissioned by the SACGHS. Republished in Genet Med. 2010 Apr;12(4 Suppl):S71-82. Abstract

Heaney C, Carbone J, Gold ER, Bubela T, Holman CM, Colaianni A, Lewis T, Cook-Deegan R. The perils of taking property too far. Stanf J Law Sci Policy. 2009 May;1:46-64. Abstract

Carbone J, Gold ER, Sampat B, Chandrasekharan S, Knowles L, Angrist M, and Cook-Deegan R. DNA patents and diagnostics: not a pretty picture. Nat Biotechnol. 2010 Aug;28(8):784-91. Abstract

View all comments by Robert Cook-Deegan