Researchers may recall a legal battle that erupted in the late 1990s between Elan Pharmaceuticals, Inc., headquartered in Dublin, Ireland, and the Mayo Foundation for Medical Education and Research. Elan sued the Minnesota-based nonprofit, alleging that its use and distribution of Tg2576 mice infringed two company patents on transgenic animals expressing amyloid precursor protein (APP) with the Swedish mutation. Mayo made a counterclaim that Elan’s patents were invalid, touching off a protracted legal seesaw that included a U.S. District Court’s dismissal of the case, Elan’s appeal of the ruling, and an eventual agreement that restored the use of the transgenic models and other AD research tools by both parties in 2004 (see ARF related news story).

Though this five-year court drama appeared to end on a promising note, a controversial U.S. patent that helped fuel those proceedings continues to stir up trouble even today. Issued in 1995, this patent covers certain genetic sequences of human APP with the Swedish mutation (APPswe), i.e., nucleotide substitutions that change the lysine at codon 670 and methionine at codon 671, and that cause early-onset familial AD. In 1996, the Mayo Foundation secured a license for this and related patents when it began breeding and distributing Karen Hsiao Ashe’s Tg2576 mice, which overexpress APPswe (Hsiao et al., 1996). The license agreement helped convince a district court judge in San Francisco nearly a decade ago that Elan’s patents on APPswe mice were invalid since they covered technology anticipated by the earlier APPswe patent Mayo had been allowed to use.

This patent was issued to the Alzheimer’s Institute of America (AIA), based in Kansas City, Kansas, and is set to expire in 2012. The patent lists just one inventor—Michael Mullan, who heads the Roskamp Institute and Archer Pharmaceuticals, both in Sarasota, Florida. As a doctoral student in John Hardy’s lab at Imperial College, London, who finished his dissertation at the University of South Florida, Tampa, Mullan was part of the collaboration that discovered the APP Swedish mutation (Mullan et al., 1992).

Now in its final years of life, this AIA patent, along with several others Mullan was granted and sold to AIA, is back at the center of heated litigation. In a lawsuit [.pdf] filed in February and amended in March 2010 in the Northern District of California, AIA is suing Elan and six other parties for infringement of patents on APPswe and its use in mice, cells, and other research tools. The other defendants include Eli Lilly and Company, Indianapolis, Indiana; AnaSpec, Inc., Fremont, California; Immuno-Biological Laboratories, Inc., Minneapolis, Minnesota; Phoenix Pharmaceuticals, Inc., Burlingame, California; American Peptide Company, Inc., Sunnyvale, California; and The Jackson Laboratory, Bar Harbor, Maine. AIA alleges that Elan and Lilly have used AIA-patented technology in their AD research and drug discovery efforts. The lawsuit cites several company-owned U.S. patents (e.g., Elan’s 7,553,831 and 7,514,408; Lilly’s 7,585,885) that describe the use of assays, cell lines, and animal models including the APP Swedish mutation. The other named companies face infringement charges related to their sale of APPswe-containing peptide sequences and other reagents.

Last summer, AIA filed a lawsuit in the Northern District of California with similar charges of APPswe patent infringement. The defendants in that suit are the Oklahoma Medical Research Foundation (OMRF), a nonprofit research institution based in Oklahoma City, and CoMentis, a South San Francisco biotech company trying to develop a BACE inhibitor (see ARF related conference story; ClinicalTrials.gov). OMRF general counsel Adam Cohen told ARF the case has since been moved to Oklahoma, where it is pending in federal court.

Even a nonprofit AD mouse repository has been dragged into the latest lawsuit filed this year. Along with its charges against the pharmaceutical and biotech companies, AIA is suing The Jackson Laboratory, Bar Harbor, Maine, for use and sale of 22 transgenic strains carrying the APPswe mutation. “It's sad this is happening,” David Einhorn, Jackson’s house counsel, told ARF. “We’re a nonprofit distributing mice to academic and nonprofit institutions for research use in an effort to cure this devastating disease.”

In a phone interview, Einhorn and Mike Sasner, manager of Jackson’s AD model repository, emphasized that despite the pending litigation, distribution of mouse models will continue as usual. “We are confident The Jackson Laboratory does not infringe any valid patent claim asserted by AIA. We have a commitment to the research community to make these mice available. We’re not going to change anything we’re doing. We’re continuing to distribute the mice we have,” Einhorn said. “But I’m concerned that, moving forward, people may be less willing to donate mice to our repository, or even to use AD mice because of the fear of being drawn into litigation.”

Truth be told, Jackson has had to fight for submissions of these mice to its AD repository for years. “All along, academic institutions have been reluctant to provide us their mice. It’s nothing new,” Einhorn said. This is unfortunate and ironic, as Jackson created its AD repository in the year 2000 to make it easier for researchers to share and obtain mouse models that were at the time quite scarce. When publicly funded scientists create new strains, they have an obligation under U.S. government rules to make the mice available to other researchers. However, maintaining and distributing mice is time-consuming and expensive, and detracts from the lab’s scientific pursuits. Having Jackson Lab as a centralized distribution center would thus seem a win-win not only to the lab submitting the mouse, but also to research groups who receive the animals from a center that maintains some 5,000 strains under standardized care procedures.

That is how the scientists see it, but some of their institutions have felt hamstrung, or at least confused, by the complex patent landscape surrounding research tools involving APPswe. As such, patents or pending patent litigation have impeded AD research for much of the past decade by making it hard to obtain key AD mouse models or to make new ones. At a 2003 workshop in Boston, university technology transfer officers, pharmaceutical companies, and research service providers met with the National Institutes of Health to discuss these very issues (see ARF related news story).

“The universities are understandably concerned about being sued,” Einhorn said. “In at least one instance, we understand that submission of an APPswe strain was delayed because the technology transfer office at the investigator’s institution received a patent threat from AIA demanding a substantial license fee.” Reluctant to meet those demands, Einhorn said, the institution “took some years, and some courage, to decide to send us the mice.”

When asked about the situation via e-mail, the scientist who created that APPswe mouse and 13 others in Jackson’s AD repository declined comment. Alzforum contacted all defendants named in the 2009 and 2010 AIA lawsuits for comment. An Elan media representative said Elan believes AIA’s claims are “meritless” and will “defend [its] interests in federal court in the Northern District of California.” The other defendants ignored calls or declined comment. Similarly, 11 academic scientists in the U.S. and Europe who otherwise contribute to Alzforum begged off from speaking about the lawsuits brought by AIA. Off the record, several deplored the litigation’s chilling effect on tool sharing, collaboration, and research progress in the AD field.

Another investigator who has donated strains to the JAX collection wrote ARF saying he “(doesn’t) really know much about AIA or the lawsuit and would feel uncomfortable saying much given the ongoing litigation.” This scientist also did not want to be named. In an e-mail, Sasner noted, “most scientists avoid or ignore the legal complications and let their tech transfer offices deal with them,” and hence said it was believable that the investigator knew little about the AIA. “I personally still don’t know much about the AIA,” Sasner wrote.

So what is the AIA? According to its website, AIA is a “leading not-for-profit research and development institution,” (accessed 16 June 2010). Also, according to the website, “for more than 20 years, AIA has been conducting groundbreaking Alzheimer’s research.” The website offers no description or examples of said research beyond a single sentence mentioning that “world-renowned scientists” led by Mullan “have played a major role in single-handedly discovering the technology known as the ‘Swedish mutation.’”

When asked about AIA by phone and by e-mail, Mullan wrote to ARF saying he has “no idea” whether the institution funds external research programs and whom it employs. He declined to discuss AIA and furthermore wrote that he prefers not to talk by phone “as lawsuits are underway and I am a witness in one case.”

On the phone with ARF, Lars Lannfelt of Sweden’s Uppsala University said that on 28 September 2009, he was in Stockholm to give witness testimony at a deposition for this lawsuit. “I was in a room all day with Mike Mullan, Ronald Sexton, and with lawyers from AIA and from the Mayo Clinic, who had flown in from the States for this occasion. It was very interesting,” Lannfelt said.

A website with information on businesses lists Sexton and Marjorie Curran as AIA officers. Sexton’s office is mentioned on the answering machine connected to the Florida phone number on AIA’s contact page.

Lee Marshall is a patent attorney in the St. Louis, Missouri, branch of Bryan Cave LLP, which is representing AIA in the current lawsuit. Marshall also declined to speak about AIA’s ownership, employees, or directors. He cited “reports of one of the defendants engaging former CIA agents to approach witnesses.” (This story on Law.com refers to a different legal matter.) Pfizer is one of the defendants charged with APPswe patent infringement in a separate lawsuit [.pdf] filed by AIA last June. Pfizer had no comment on the matter after repeated phone calls and e-mails to its media office.

Marshall did tell ARF via e-mail that AIA receives revenues from licensing of APPswe patents and has sponsored Mullan’s research at the Roskamp Institute and at Archer Pharmaceuticals. (As for federal funding, the NIH grants tracking site RePORT lists one grant, in the amount of $270,015, going to Mullan in 2009. Recent Roskamp papers have cited support from the Department of Defense, two VA Merit awards, and the Alzheimer’s Association to institute scientists.)

Scientists familiar with AIA and its litigation told ARF that AIA has “done no scientific research” and describe it as an organization that supports Mullan and Sexton, his financial backer. Nature reported in a 2000 news story that shortly after Mullan arrived at the University of South Florida, Tampa, in 1992, he sold his APPswe patent rights to AIA, “a company set up by Kansas venture capitalist Ron Sexton, who had been funding Mullan’s work.” Marshall confirmed that AIA was incorporated in Florida in 1992, but also has a Kansas office.

If AIA has influenced science in any tangible fashion, it may well have been through its litigation, which dates back to the earlier part of the decade. In 2003, the year Mullan left the University of South Florida in Tampa amid an unrelated controversy (see St. Petersburg Times story), AIA sued the Mayo Foundation and Salt Lake City, Utah-based Myriad Pharmaceuticals in the District of Kansas for using APPswe-expressing cell lines. These cells, AIA argued, were not covered under the 1996 license Mayo obtained from AIA. Mayo then sued AIA in 2005 in an attempt to move jurisdiction to Florida to resolve the licensing dispute, and the cases were consolidated into a single suit in Florida. There, an arbitrator concluded that Mayo was not allowed to use the APPswe cell lines under the licensing agreement with AIA, and that AIA was not entitled to additional money for benefits Mayo received through third-party agreements. “This meant the AIA’s claims of infringement were still alive…and re-opened the case in federal court in late 2008,” said Sara Cotton, a patent lawyer at the Twin Cities, Minnesota, office of Fish and Richardson, which is representing Mayo in the case.

Both Mayo and Myriad “believe they do not infringe AIA’s patents (U.S. Patents 5,455,169 and 5,795,963),” Cotton noted in an e-mail to ARF. The companies contend that the AIA patents are “invalid because they are obvious, anticipated, indefinite, lack utility, are not enabled, fail to satisfy the written description requirement, and were procured through inequitable conduct,” she wrote.

Among other considerations, Mayo and Myriad cite improper inventorship as a prime reason AIA’s patents are invalid. The APPswe patents list Mullan as the sole inventor despite significant intellectual contribution from other scientists. Bengt Winblad and Lars Lannfelt of the Karolinska Institute, Stockholm (Lannfelt has since moved), co-identified the APPswe mutation in an extended Swedish family and are senior authors on the scientific paper (Mullan et al., 1992). According to Mayo’s and Myriad’s attorneys, Mullan knew Winblad and Lannfelt were claiming they should be co-inventors while the APPswe patent applications were still pending, yet failed to disclose this dispute to the U.S. Patent and Trademark Office.

Here is how Lannfelt recalled this period in a conversation with ARF: “In January of 1992, Bengt Winblad recruited me to work with families with inherited genetic diseases his group was assembling. I had experience with neurogenetics. I focused on two families from 300 kilometers north of Stockholm and started investigating them. But with just myself and a technician, we were underpowered, so I visited John Hardy in London the next month. John had published the London APP mutation the year before [Goate et al., 1991]. We decided to collaborate, but then John moved to Tampa and asked me to send my families’ DNA to Mike Mullan from his lab, who was already in Tampa. I did the clinical characterization of the families. For sequencing, we decided to divide up the gene. Mike would sequence exon 16, I exon 17. In April or May the mutation showed up in exon 16. Mike was first and I last author on the paper that came out in Nature Genetics in August of that year. This was fair. It was a good collaboration and I have never regretted it. Then Mike told me he was going to take out a patent and said you can only have one name on it. This was untrue. But in 1992, I knew nothing about patenting mutations.” When asked who contributed more to the discovery, Lannfelt said, “I would have found the mutation without Mullan, though later. He would never have found it without us.”

“Patents can certainly be held invalid if there was a failure to name correct inventors,” said Edward Reines, a Silicon Valley patent attorney at the firm Weil, Gotshal & Manges, which is not involved in the pending AIA litigation. He noted, however, that it is “not unusual at all” for patents to have a single inventor. Furthermore, inventorship claims can be hard to prove and are easily corrected (i.e., by adding the new inventors), all of which presents a “disfavor for the defense,” he said in a recent phone interview.

In the end, inventorship disputes may be trumped by a federal judge’s recent decision to invalidate patents on two different genes (BRCA1 and BRCA2), which are linked to breast and ovarian cancer. Last May, the American Civil Liberties Union (ACLU) filed a lawsuit that challenged the validity of Myriad Genetics’ exclusive license to the genetic sequences of BRCA1 and BRCA2. On 29 March 2010—less than a year later—a U.S. district court judge sided with the ACLU and ruled the BRCA1 and BRCA2 patents had been “improperly granted.” (See New York Times story.) Myriad Genetics is expected to appeal the ruling. (Myriad Pharmaceuticals is a spin-off of Myriad Genetics, and both are parties in the ongoing AIA lawsuit.)

If the ACLU ruling is upheld, it could call into question the validity of patents covering thousands of other human genes, including the AIA patents at the center of pending litigation. “It’s going to create uncertainty in the law for the next year,” Reines said of the ACLU decision. “It presents issues that the appeals court will have to address.”

Confused already? It gets more convoluted. Reines noted that the appellate ruling could, in turn, be influenced by the Bilski case, for which a Supreme Court decision is expected in June 2010. The Bilski case addresses the patentability of a financial hedging scheme and, more broadly, what is considered patentable subject matter. The Bilski decision “has serious potential to affect [all patents], but it’s very likely to affect the process patent claims,” Reines said. “My guess is that in the long run, the gene patents are not going to survive, but the therapeutic or diagnostic patents will.”

The ACLU ruling may ultimately affect the standing of the AIA patents on APPswe; however, it primarily concerned the validity of gene patents for human testing in genetic diseases. On this separate issue, a special supplement of Genetics in Medicine, the Journal of The American College of Medical Genetics, just appeared. It is freely available online. One article in this supplement, by Robert Cook-Deegan at Duke University’s Center for Genome Ethics, Law and Policy in Durham, North Carolina, reviews the patent situation of all AD genes with regard to human testing, including APP, presenilin-1 and -2, and ApoE.

Thus far, it seems Mullan and others have found ways to capitalize on the U.S. patent law system. “When you have literally hundreds of patents out there, some overlapping, on pieces of naturally occurring human DNA…it’s a failure in the sense that so many patents have been granted over basically the same subject matter,” Einhorn told ARF, noting the universities are often wary for this reason. “How could anybody trying to exercise due diligence do so when you have overlapping claims? You could enter into a license with one party and still get sued by three others on patents that never should have been issued,” he said. “Unfortunately, what people do as a result is say, ‘Who needs the aggravation? There’s no simple solution. Let’s not even bother.’ The search for a cure for Alzheimer’s is the ultimate victim here.”

David Morgan of the University of South Florida, Tampa, a noted AD researcher who is not involved in the AIA lawsuits, agrees that a flawed patent law system is the real story here. “The lawyers are going to make money no matter what happens. Whether AIA wins or loses, there are lawyers everywhere who benefit. There’s no productive value in what they’re doing,” Morgan said. According to another scientist who refused identification due to involvement in the pending AIA suits, “this has got to be one of the nastiest things that has happened in the AD field.” Nevertheless, this person said Mullan “legitimately got these patents. I don’t fault the guy for insuring his intellectual property is safeguarded. The issue is how much is legitimate policing of IP and how much is disregard for scientific progress.”

Einhorn points out a certain irony in the AIA litigation, which charges 10 parties in three suits filed this year and last summer. “It is counterproductive for them to be suing The Jackson Laboratory,” he said. “If they really are interested in making money from the patent, they should want the mice to be used by the research world. Only then, with this basic research as a foundation, is there any hope for developing therapeutics and products. If nobody can get the mice, then you won’t get the therapeutics.” Einhorn notes that AIA is suing The Jackson Laboratory for 22 APPswe transgenic lines—“less than one half of 1 percent of the mouse strains we have. But now we have to deal with an expensive lawsuit.” Marshall, one of AIA’s attorneys, refused to comment on this issue, saying “it is generally not AIA's policy to comment about pending litigation.”

AIA is not alone in pursuing broad patent claims on AD mutations. Last fall, Elan got a patent approved in Europe for transgenic mice carrying any APP mutation associated with early-onset AD. As it took the company nearly 18 years to gain approval, this patent expires in less than two years. In the meantime, some companies have stopped drug development studies with APP mice carrying Arctic and Swedish mutations. Elan had no comment on how, if at all, its recently issued European patent might influence U.S. legal proceedings.

Lost in the AD patent landscape? Wait, here’s one last twist. Frank LaFerla, University of California, Irvine, told ARF that submission of his triple-transgenic (3xTg AD) strain to The Jackson Lab was held up not up by AIA’s APPswe patents and associated litigation. Rather, his institution worried about submitting mice to JAX because of a Xenogen patent on the microinjection process for making any transgenic model. “Eventually, the Xenogen patent expired,” LaFerla said. “In the meantime, we distributed the mice ourselves at great cost.”

As for the ongoing AIA lawsuits, progress is unpredictable and slow going, but this is not unusual. “The way these things play out is not days or months, but years,” said Cohen of OMRF. “We’re still in a very, very early phase of litigation.” The suit involving OMRF and CoMentis is in a cumbersome period known as discovery, in which attorneys gather documents and witnesses from the named parties to make information available to the plaintiffs. Even for this lawsuit filed last summer, Cohen said, “there is no reasonable time when I could predict it will be over.”—Esther Landhuis and Gabrielle Strobel.