The Axel Patents A Case Study in University Technology Transfer

The Axel Patents: A Case Study in University Technology Transfer C Alessandra Colaianni, B.A Center for Genome Ethics, Law & Policy Institute for Genome Sciences & Policy P.O Box 90141 Duke University North Building, Research Drive Durham, NC 27708-0141 (919) 668-2616 alessandra.colaianni@duke.edu Acknowledgements: This work was supported in part by the Center for Public Genomics, Duke University, under grant P50-HG003391 from the National Human Genome Research Institute and the US Department of Energy This work was also supported by the Institute for Genome Sciences and Policy Summer Fellowship I thank Robert Cook-Deegan and Bhaven Sampat for their support and help, Dick Nelson and Michael Cleare for their input and openness, and Dr Michael Wigler, Dr Saul Silverstein, and Dr Paul Marks for their courtesy and wealth of information during interviews September 26, 2007 The Axel Patents: A Case Study in University Technology Transfer September 26, 2007 Abstract: The Axel Patents are among the most lucrative university patents in history, earning $790 million in royalty revenues for Columbia University This paper tells the story of the Axel Patents, from the initial scientific discovery, through the decision to patent, to the non-exclusive licensing strategies Columbia used to spread the technology, the measures Columbia took to extend the life of the patents, and the controversy that erupted when another patent was issued in 2002 Columbia plowed most of the revenues back into research, including Richard Axel’s work that earned him a Nobel Prize Columbia’s aggressive pursuit of extended patent duration, however, also led it to considerable legal expenditures that have proven fruitless to date, and brought criticism for behavior unbecoming a nonprofit academic institution Keywords: Biotechnology, History, Intellectual Property Background: On February 25, 1980, at Columbia University, three scientists (Dr Michael Wigler, Dr Saul Silverstein, and Dr Richard Axel) filed a patent application claiming a biological discovery that was to change the pharmaceutical world profoundly Cotransformation, as they named their discovery, harnessed mammalian cells’ power to translate and fold proteins made from inserted genes Dr Axel was an Assistant Professor in the Institute for Cancer Research and the Department of Pathology, and Dr Silverstein was an Assistant Professor in Columbia’s Microbiology department Michael Wigler had transferred into Columbia’s Ph.D program in Microbiology after his third year at medical school, and was doing a rotation in Silverstein’s lab.2 The initial idea for cotransformation is credited to Wigler, who “…had come to the conclusion that we weren’t going to make progress in animal cells unless we could manipulate the genetic content of the animal cell.” As such, the cotransformation method is sometimes called the Wigler Method Cotransformation refers to manipulating the genetic content of a eukaryotic cell (a cell with a defined nucleus) by adding two genes: one, a marker gene, is used to detect whether the foreign DNA has been successfully taken up and expressed The marker gene serves as a screening tool The other gene can encode any protein to be studied or produced A bacterial analog of cotransformation, recombinant DNA, was developed and patented in the early 1970s by Herbert Boyer (UCSF) and Stanley Cohen (Stanford) It allowed scientists to “cut and splice” bacterial DNA It was a powerful biotechnological tool used with great success in molecular biology labs and pharmaceutical companies, and widely used in research and production of biologics to this day For researchers attempting to produce functional proteins from eukaryotic cells, however, recombinant DNA posed problems Some proteins required cellular “processing,” which bacterial cells did not perform When genes encoding those proteins are inserted into nucleated cells, they produce a fully functional protein The Wigler Method provided a way to introduce genes into nucleated cells Earlier attempts at transforming eukaryotic cells had been thwarted by low transformation efficiency—few cells took up the foreign DNA (Szybalska and Szybalski 1962) Wigler’s method reduced this problem: by using a high concentration of the protein-producing DNA and a low concentration of the marker DNA, it was more likely that the protein-producing DNA would be taken up in cells expressing the marker When the DNA became incorporated in the host’s chromosomal DNA, it created a stable, self-replicating line of cells The process allowed the incorporation of any known gene, prokaryotic or eukaryotic, into any mammalian cell The Wigler technology turned mammalian cells into protein-producing machines, a much more efficient way to produce a target protein than slow, expensive, and laborious synthesis reactions that yielded paltry results Proteins produced by microbes are not usually exported from their place of translation within the cell into the cell’s medium, because bacteria are single-celled organisms that use the protein within their own membranes Eukaryotic cells, by contrast, are themselves a part of more complex organisms that require cell-to-cell communication Thus, they have hormones, receptors, transporters, and other cellular machinery to facilitate export of the proteins that they produce Eukaryotic proteins are often secreted from the cell in which they are produced, for transport to other locations within the organism The Wigler Method allowed production of such proteins (Fox 1983) The Wigler Method: Wigler approached Silverstein with the idea of inserting a purified copy of the tk gene (which codes for a metabolic protein necessary for cell survival called thymidine kinase) from the Herpes Simplex Virus genome into mammalian cells which lacked their own copy of the gene The cells would then be grown on a medium that inhibits the de novo synthesis of thymidine so that the only cells to survive would be those who had taken up the viral gene Cell published the original paper in May 1977 (Wigler et al 1977) By 1979, the Axel group realized they could pair a selective marker (as they had done in 1977 with thymidine kinase) with a gene that could not be readily selected, using a process which they called cotransformation They cultured cells with a large amount of the non-selective gene and a small amount of the thymidine kinase gene, which increased the likelihood that the cells would take up both genes together, if they took up any DNA at all (see Figure 1) The cells were then grown on a selective medium as they were in the 1977 experiments, and probes were used to confirm that the non-selective gene had in fact been incorporated into the host cell’s chromosomes The abstract of a 1979 Cell paper showed the breathtaking power of the new technology: “This cotransformation system should allow the introduction and stable integration of virtually any defined gene into cultured cells” (Wigler et al 1979) Figure 1: Cotransformation schematic This image is from the original patent application (US 4399216), entitled “Process for Inserting DNA into Eucaryotic Cells and for Producing Proteinaceous Materials.” Citation trends of these two seminal cotransformation papers show how influential they were Figure 2A shows citations of the 1977 paper “Transfer of Purified Herpes Virus Thymidine Kinase Gene to Cultured Mouse Cells.” Figure 2B shows the citation trends for the 1979 Cell paper, “Transformation of Mammalian Cells with Genes from Procaryotes and Eucaryotes.” Figure 2C combines citations to the 1979 and 1977 papers A B C Figure 2: These citation graphs show that cotransformation was being cited approximately 175 times per year at its peak, compared to a Cell Journal Impact Factor (reported by ISI Citation Research) of 39 and 36 in 1998 and 1999, respectively (Journal Citation Report 2007) Citation trends tend to taper off between fifteen and twenty years after initial publication, when the method either is replaced by a more advanced one or it becomes common knowledge A few caveats must be taken into consideration when interpreting the graph: accuracy of the data, typographical errors or other mistakes in citation, and intention of citation—whether the lab is actually using the process or simply describing the process in a background section The Axel Patent: According to Dr Wigler, the initial idea to patent the discovery came from Dr Richard Axel, and it struck Wigler “as a rather odd thing to do… it seemed like a long shot, but it wasn’t any effort on our part, since the patents were based on manuscripts that we had prepared.” Aside from the trouble applying for and being granted a patent, the scientists had no guarantee that the work would pay off: “We all agreed on the scientific importance of what we had done Whether this thing would become useful or not—we’re all very objective people, and I think we all would have said ‘Yeah, there’s some probability of being useful, but there’s no certainty.’ It was not clear at the time whether bacteria would be useful for producing all proteins, all medicinal proteins And it was clearly a possibility that they were not, in which case this would be a better method… but there wasn’t a guarantee that it would be valuable.” Even after the first patent issued, Silverstein wasn’t sure that it would be valuable: “When it was issued, everybody said ‘Gee that’s terrific,’ and I pointed out to them, ‘Yeah, it’s terrific if we get somebody to actually license it.’”6 The inventors informed Paul A Marks, then the Vice President of the Health Sciences at Columbia, of their decision to patent Their decision to go to Marks was most likely because Columbia did not have a technology transfer office at the time As Marks recalled in an interview, “I don’t think the Columbia University industrial licensing group was very sophisticated, and they were not encouraging or enthusiastic about going forward to try to get a patent on this work.” Marks then went to the provost, Michael I Sovern, who referred the inventors to Cooper-Dunham, where attorney John White (who had received his BS in chemical engineering, MA in chemical biology, and MPh in biophysical chemistry from Columbia) handled the patent prosecution The major involvement of the scientists was in the initial drafting process; both Wigler and Silverstein confirmed that their role was negligible after the initial draft was completed Silverstein recalled, “I remember the hours spent with John White, who was the lead attorney at that time on this series of patents… he asked us lots of good questions, and we had to figure out answers.”8 On February 25, 1980, the patent application was filed The claims in the application, which included any cell transformed via the method of cotransformation, were progressive for the time, given that they predated the landmark Supreme Court decision in Diamond v Chakrabarty by about four months Diamond v Chakrabarty was a watershed for biotechnology patenting, because the Supreme Court made clear that living organisms could be patented, arguing that patents applied to “… anything under the sun, that is made by man.”9 Another important event that month was the Bayh-Dole Act, which Congress passed on December 12, 1980 The Act was meant to clear the way for nonprofit institutions and small businesses to get title to inventions made using federal funds, an effort to resolve the contentious debate “over the propriety of transferring to private entities the title to inventions developed via public subsidy” (Dudzinski 2004) Columbia applied for the first Axel patent ten months before BayhDole was enacted Interestingly, the patent may not have been crucial in facilitating technology transfer, in the sense of being necessary for commercial use Skilled researchers at universities and biotechnology companies alike could replicate cotransformation based on scientific papers alone, and had in all likelihood begun to so by the time the patent application was filed (Mowery et al 2004) In a September 2, 1983, Science article, author Jeffrey Fox noted that “the procedures developed by Axel and his colleagues are being used extensively in basic research” (Fox 1983) The main effect of the patent was that Columbia got a slice of the pie when commercial use met with success Because Bayh-Dole had not yet been passed, the NIH could still take title to the patents, or decide not to allow the patent at all Columbia University had to ask permission of the NIH for the title to any potential patents (Mowery et al 2004) Columbia sent a letter to NIH on April 4, 1980, six weeks after it filed the patent application, asking for permission to patent, to take title of the patent, and to have the right to license the technology exclusively On February 24, 1981, NIH wrote back to Columbia giving title, but denying the request for an exclusive license unless Columbia could demonstrate that nonexclusive licensing was not viable (Miller 1981) The NIH also required that Columbia provide copies of any licensing agreements to the Department of Health and Human Services (HHS), as well as a detailed annual report “…regarding the development and commercial use that is being made and is intended to be made of the invention, including the amounts and source of money expended in such development and such other data and information as the HHS may specify After the first commercial sale of any product embodying the invention, such report shall specify the date of the first commercial sale and shall include information relating to gross sales by licensees, and gross royalties received by the University” (Miller, 1981) NIH also specified that the any potential licenses must “include adequate safeguards against unreasonable royalties and repressive practices” (Miller 1981) While Columbia did request an exclusive license, this was by no means the only option they were considering Paul Marks noted that the exclusive license was just one option of many, and Columbia’s attitude was that it would not hurt to ask In retrospect, Marks commented, “I think it’s very fortunate for a number of reasons that we didn’t succeed because I don’t think we fully anticipated the sort of impact that this discovery would have on drug development.” 10 In 1982, Columbia formed the Office of Science and Technology Development (OSTD), which took over the administration of the patent application (Mowery et al 2004) The office has since gone through two name changes, and is now called the Science and Technology Ventures Office The first of five patents was granted a year later, on August 16, 1983 (U.S patent number 10 laboratory reagent… that the process has been patented just doesn’t seem right” (Mowery et al 2005) However, as Columbia never tried to license the technology to research institutions, Barbosa’s implicit fear went unrealized In the beginning, Columbia’s licensing strategy was to identify firms that were already using the technology, and advise them to take a license To this, “… Columbia licensing personnel examined the patents, end products, and scientific publications of industrial firms… and informed these firms that if they were using the cotransformation process to produce proteins, they must pay royalties to Columbia” (Mowery et al 2005) The OSTD made it clear that if infringing companies did not comply, they would face legal action Columbia also recognized, as Stanford University did with the Cohen-Boyer patents, that they could not charge an exorbitant fee for the licenses Instead, they charged a rate of $30,000 in the hopes that companies would choose to take out a license rather than challenge the validity of the patent in court To encourage companies to sign up early, Columbia took another lesson from Stanford’s handling of the Cohen-Boyer patents, and offered reduced license fees to firms that took a license before June 1, 1984 (Sampat, 2000) The “early bird” terms were $20,000 annually, with royalty rates of 1.5% of sales for finished products, 3% of sales for bulk products, 12% of sales for basic genetic research products, and 15% of cost savings from process improvements The standard terms were $30,000 annually and royalties of 3%, 6%, 15%, and 18% for the categories listed above Ten firms did so, and Columbia continued to identify potential users and advise more companies to take a license until at least the 1990s As inventor Dr Saul Silverstein put it in an interview, “They [Columbia] were fairly aggressive at pursuing some of the companies who we knew were making pharmacologically active drugs that would require using this technology.” 16 All in all, 34 firms licensed the cotransformation technology Ten companies signed up for the special early deal, and twenty-four signed up under the regular license agreement (Sampat, 2000) 14 Columbia’s threats of litigation were not idle—in 2000, Columbia brought action against the company Roche Diagnostics (formerly Boehringer Mannheim) for patent infringement in a complicated case also involving the therapeutic protein erythropoietin (EPO) Columbia alleged that some of GI’s old EPO was shipped to Roche in 1985, allowing Roche an upper hand in the production of EPO which earned them more than $1.5 billion in drug sales.17 Judge Nancy Gertner ultimately awarded Columbia $1.2 million in damages from Roche Over the Axel patents’ 17-year term, Columbia earned $790 million in royalties 18 Year-byyear data were not available from Columbia’s office of Science and Technology Ventures, but we can say with reasonable certainty that most of the royalty revenues were earned in the last few years of the patent’s life, when derivative products had hit the market and were generating royalty-relevant revenue for the licensees Columbia’s current policy regarding profit sharing is as follows: 20% of the gross income is deducted for expenses, and the remainder is divided between the inventor, the inventor’s research activities, and the university However, because the patent application came before Bayh-Dole, Columbia was obligated to follow the royalty-sharing scheme outlined in the NIH letter they received denying their request for an exclusive license (Miller 1981) According to that letter, the inventors would share 50% of the first $3,000; 25% of the income between $3,000 and $13,000; and 15% of the income exceeding $13,000 The remaining royalty income, after deducting expenses, would “be utilized for the support of educational and research pursuits” (Miller 1981) Following this policy, the three inventors would have divided approximately $118.5 million for personal use An unnamed fourth person also receives a share of the personal-use profits, according to Silverstein, but it is unclear what percentage the fourth person receives.19 After deducting 20% of the remainder for expenses, approximately $537.2 million would remain for use in the inventors’ laboratories and general university funds It is unclear how the rest of the royalty income was divided between the inventors’ laboratories and the university 15 Expiration and Controversy: On August 16, 2000, the first three Axel patents (‘216, ‘665, and ‘017) were set to expire Columbia’s administrators spoke of an imminent drop in the university’s revenue “‘In the near future, our revenues are likely to drop sharply,’ warned Jonathan Cole, then Columbia's provost, in an October 2000 internal document” (Wysocki 2004) In an effort to keep the revenue stream alive, Columbia began to take measures to extend the patent’s term In March of 2000, Columbia turned to Senator Judd Gregg, R-N.Y., a Columbia alumnus, to insert language into a bill granting them a 15-month extension on the three patents that would expire later that year (Rosenberg 2000) If the bill went through, Columbia would be able to continue collecting royalties for another 15 months, which could yield approximately another $125 million in royalties The effort caused a significant backlash because it became public Gregg and Columbia received “a storm of criticism from drug manufacturers, consumer groups, and members of Congress, including Senator Edward M Kennedy” (Rosenberg 2000) Henry A Waxman, coauthor of the Hatch-Waxman Act, which was cited as a rationale for the patent extension, “insist[ed] that Columbia and Gregg [were] misinterpreting the law” (Rosenberg 2000) Waxman felt that Gregg’s proposal “ha[d] nothing to with the original intent of the act… On the contrary, it [ran] counter to what we accomplished” (Rosenberg 2000) Despite opposition from the press, Columbia officials stood by their decision to try to extend the life of the patent Michael Crow, then Columbia’s executive vice-provost (and a professor of science and technology policy in Columbia’s School of International and Public Affairs) noted, “We are the only university that has come forth and raised our hand about remedying the patent policy situation and we are getting whacked pretty hard” (Rosenberg 2000) He defended the measures that the University was taking to protect its source of income by pointing to the fact that much of the money went back into research: 16 “…The three inventors split 20 percent of the royalties, he said, so each reaps millions annually The rest - minus some administrative costs - goes to research ‘It's not like we're taking the money and buying hotels’” (Fram 2000) Richard Axel went on to earn a Nobel Prize in 2004 for his study of the molecular neurobiology of olfaction (Axel 2004) In his Nobel Lecture, Axel acknowledged the Howard Hughes Medical Institute, U.S National Institutes of Health, and the Mathers Foundation for funding this work While patent royalties were not explicitly cited, some of this Nobel-quality research may have derived from his or Columbia’s patent royalties In May, Senator Gregg tried unsuccessfully to insert a 350-word clause into an agricultural spending bill that would grant Columbia’s request; he repeated the attempt in June, trying this time to get the amendment into a military spending bill (Rosenberg 2000) After both of these attempts failed, Gregg gave up In retrospect, legal scholars reflected that if the extension had become law, it would have established a dangerous precedent (Dudzinski 2004) After the bill failed to pass in Congress, Columbia stated that there was not a “next step in this patent extension story… there’s just no way to go back after it expires” (Dudzinski 2004) The university, however, was still pursuing the divisional applications filed on June 7, 1995 On September 24, 2002, two years after the expiration of the original Axel patents, Columbia’s persistence paid off: US Patent 6,455,275 (hereafter ‘275) was issued The patents claims were similar to the prior Axel patents (Ravicher 2004), but because there was no terminal disclaimer on this patent, Columbia legally had the right to enforce royalties on the cotransformation technology until 2019 Columbia sent letters to licensees alerting them to this fact Licensees who thought they paid their last royalty payment two years before were nonplussed They reacted strongly: in 2003, Genentech, Immunex, Amgen, Biogen, Genzyme, Abbot, Wyeth, Genetics Institute LLC, Johnson and Johnson, Serono, Baxter, and Ares all filed suit against Columbia for double patenting, asking the judge to find the ‘275 patent invalid and 17 unenforceable (Dudzinski 2004) Thomas Bucknum, then-executive vice president of Biogen, said, “It's the same invention, and that's why we decided we just wouldn't pay” (Wysocki 2004) In court, Columbia was represented by eight lawyers, prompting Judge Mark L Wolf to say, “I thought Columbia was a nonprofit organization who couldn’t afford this litigation” (Wysocki, 2004) Judge Wolf’s conclusion was that: “The timing of its [the ‘275 patent] issuance strongly suggests that Columbia deliberately delayed obtaining a patent that it always intended to secure in order to make it effective just as the other Axel patents expired and thus increase its commercial value by maximizing the period in which the public would have to pay Columbia royalties for the use of the Axel patents.”20 The press got hold of the story, and began to liken Columbia to “an aggressive U.S corporation” (Wysocki 2004), accusing them of “submarine patenting” (Marshall 2003) Dan Ravicher also took aim at Columbia’s new patent Ravicher is a patent attorney and founder of PubPat, a non-profit organization that seeks to “protect the public from the harms caused by wrongly issued patents and unsound patent policy” (Ravicher 2004) In February 2004, PubPat filed a request for re-examination ex parte of the ‘275 patent, asserting that “none of Axel et al.’s four patents are patentably distinct from one another,” and that the ‘275 patent had been issued only after numerous rejections for double patenting and seven years of “unreasonable and unexplainable delay on the part of Axel et al and changes in the personnel examining the application” (Ravicher 2004) The request for re-examination was granted Faced with these lawsuits and re-examination requests, Columbia signed a covenant not to sue, effectively relinquishing their right to enforce the ‘275 patent On October 12, 2004, they agreed not to sue not just the plaintiffs involved in the lawsuits, but any potential plaintiff They maintained that the ‘275 patent was valid, however: “In granting this covenant to plaintiffs, Columbia in no way concedes plaintiffs’ allegations that the ‘275 patent is invalid, unenforceable, or not infringed To the contrary, Columbia categorically rejects 18 all such claims by plaintiffs” (Attorneys for the Trustees of Columbia University in the City of New York, 2004) This claim is undermined by the March 15, 2007, Final Rejection decision, resulting from the re-examination proceedings [need ref] Columbia’s final continuation application (application 477, 159) of the original Axel patent application, filed on June 7, 1995, is still being prosecuted and may therefore result in the issuance of a patent Dan Ravicher, founder of PubPat, wrote, “To my knowledge, they are still pursuing [the second application] vigorously, as they are a reissue of the ‘275 patent.” 21 If the reissue does occur, many of the plaintiffs from the earlier double patenting case have indicated that they will challenge the validity of such a patent.22 Concluding Remarks: Columbia’s decision to file divisional and continuation applications on the same invention for fifteen years is a good example of a wider trend Numerous patent applicants have used this tactic, and it is not without consequence Mark Lemley details some of the potential problems with continuation applications: “First, at a minimum, continuation practice introduces substantial delay and uncertainty into the lives of a patentee’s competitors, who cannot know whether a patent application is pending in most circumstances Second, the structure of the PTO suggests that continuations may well succeed in “wearing down” the examiner, so that the applicant obtains a broad patent not because he deserves one, but because the examiner has neither incentive nor will to hold out any longer Third, continuation practice can be—and has been—used strategically to gain advantages over competitors by waiting to see what product the competitor will make, and then drafting patent claims specifically designed to cover that product Finally, some patentees have used continuation practice to delay the issuance of their patent precisely in order to surprise a mature industry, a process known as ‘submarine patenting’” (Lemley and Moore 2004) 19 Lemley’s second and fourth points are applicable to the Axel patents Had more stringent USPTO restrictions against continuation applications been in effect, Columbia would never have been able to obtain the ‘275 patent, and much of the controversy surrounding the Axel patents could have been avoided Why would an institution like Columbia fight so hard for a patent extension and new patents beyond the term of the originals? One answer is patent royalties, shown in Table In a ranking of the top 18 hospitals and universities by how much of their research and development money derived from royalty revenues, Columbia was tied at second place with the Sloan-Kettering Institute for Cancer Research: 41% of Columbia’s research expenditures came from patent royalties It could be argued, from these data, that Columbia’s dependency on royalty-based research funding made it work hard to maintain the revenue stream This is indicative of a problem: if universities depend on patent revenue, the may be more vigorous, taking extreme measures in pursuit of patent royalties The problem with this “winner’s curse” is that most patent royalties come from “blockbuster” patents like the CohenBoyer and Axel patents, which are few and far between Furthermore, the harder universities push the industry to continue paying patent royalties, the more likely it is that they will incur ill will, bad reputations, and even steep legal fees in court battles Table 1: Percentage of total R+D funding accounted for by licensing revenue for top 18 US and Canadian institutions Data compiled by Bhaven Sampat, Columbia University, using FY2002 licensing revenue data from the Association of University Technology Managers Institution Rank Licensing Revenue/ Institution Name City of Hope National Total R+D Expenditures Medical Ctr & Beckman Institution Type Hospital/Research Research Inst Sloan Kettering Inst for 42% 41% 20 Institute Hospital/Research Cancer Res Columbia Univ New York Univ Florida State Univ Univ de Sherbrooke St Elizabeth's Medical Ctr of 35% 34% 32% University University Canadian Hospital/Research Boston Wake Forest Univ Univ of Rochester Brigham Young Univ Emory Univ Tulane Univ TRIUMF 23% 17% 16% 14% 12% 11% 11% Institute University University University University University Canadian Hospital/Research 15 16 Children's Hospital Boston Michigan State Univ The Salk Inst for Biological 11% 10% Institute University Hospital/Research 17 18 Studies Stanford Univ Univ of Florida 9% 9% 9% Institute University University 10 11 12 13 14 41% Institute University The cost of litigation in the Columbia case was undoubtedly substantial Although the university earned nearly $800 million from the patents, they spent a significant amount of time and money on legal fees after being sued by eight of their licensees Many of the costs accrued after the original patents expired Furthermore, the legal fees involved in pursuing the ‘275 patent—which earned few if any royalties, because Columbia signed a covenant not to sue—were likely significant, as were the legal fees involved in defending the university against the eight litigants The costs to the innovation system as a whole also include the expenditures by those litigants It is difficult to estimate the cost of pursuing a patent application for almost twenty-two years, but it would certainly be considerable The money that paid for that legal assistance must be subtracted from the previously earned Axel royalties, according to Columbia’s policies regarding legal fees related to university patents 21 To conclude, the Axel patents were very successful: they were nonexclusively licensed to a large number of companies, and a number of highly valuable derivative products were developed as a result of the initial invention (Table 2) However, because Columbia became dependent on the royalty revenues from the Axel patents, it was willing to attempt a congressional patent extension, which many judged unbefitting a nonprofit research institution These tactics harmed Columbia both in terms of their public reputation and financially, because they had to pay to fight eight companies suing them in 2003 Other university technology licensing programs might take a lesson from Columbia, learning to be cautious in how far they go to preserve patent royalties after an initial patent term has expired Interview Methods: The author conducted three interviews in the summer and fall of 2005 during the preparation of this paper Interviews with Dr Saul Silverstein, Dr Michael Wigler, and Dr Paul S Marks were on the record and were recorded using a standard tape recorder Interviewees gave oral consent to a prepared informed consent statement (appendix 1) All three interviewees were given the opportunity to respond to their statements and points attributed to them; two made minor comments which were honored by the author, and one did not respond The interviews were conducted Duke University IRB protocol 1277 Drs Silverstein and Wigler were chosen as interviewees because they are listed as inventors on the co-transformation patents; Dr Richard Axel did not respond to repeated requests for interviews Dr Paul A Marks was chosen based on the interview with Dr Silverstein, because it became apparent that Dr Marks had played a significant administrative role in the early life of the patent Table 2: Commercial Drugs Using Cotransformation Technology Drug names and manufacturers (Dudzinski 2004); target diseases (Drugs.com 2007) Generic Name Brand Name Disease 22 Manufacturer Adalimumab Agalsidase beta Alefacept Alteplase Humira Fabrazyme Amevive Activase and Cathflo Rheumatoid Arthritis Fabry Disease Psoriasis Heart Attacks and Abbott Genzyme Biogen Idec Genentech Bevacizumab Chorionic Activase Avastin Ovidrel Stroke Colon, Rectal Cancer Puberty induction, Genentech Serono Gonadotropin alfa Darbepoetin alfa Dornase alfa Efalizumab Epoetin alfa Etanercept Aranesp Pulmozyme Raptiva Epogen, Procrit Enbrel Fertility Anemia Cystic Fibrosis Psoriasis Anemia Arthritis Amgen Genentech Genentech Amgen, J&J Immunex (now Factor VIII Factor VIII Factor VIII Factor IX Follitropin alfa Ibritumomab Tiuxetan Advate Recombinate ReFacto BeneFix Gonal-f Zevalin Hemophilia A Hemophilia A Hemophilia A Hemophilia B Reproductive Health Non-Hodgkins Amgen) Baxter Baxter Wyeth Wyeth Serono Biogen Idec Imiglucerase Interferon beta-1a Cerezyme Avonex Lymphoma Gaucher Disease Multiple Sclerosis Genzyme Biogen Idec Interferon beta-1a Rebif (MS) Multiple Sclerosis Serono Laronidase Aldurazyme (MS) Mucopolysaccharidosis Genzyme Omalizumab Rituximab Xolair Rituxan (MPSI) Asthma Non-Hodgkins Genentech Genentech Somatropin Tenecteplase Serostim TNKase Lymphoma Growth Hormone Acute Myocardial Serono Genentech Thyrotropin alfa Trastuzumab Thyrogen Herceptin Infarction Thyroid Cancer Breast Cancer Genzyme Genentech 23 References: Attorneys for the Trustees of Columbia University in the City of New York “Columbia University’s Amended and Restated Covenant Not to Sue Plaintiffs for Infringement of the ‘275 Patent.” Available at http://www.pubpat.org/assets/files/ColumbiaCotransformation/Axel_275_Covenant_Not_to_Sue.pdf (accessed September 25, 2007) Axel, R “Scents and Sensibility: A Molecular Logic of Olfactory Perception.” Nobel Lecture, December 8, 2004 Available at: http://nobelprize.org/nobel_prizes/medicine/laureates/2004/axellecture.pdf (accessed September 25, 2007) 24 Dudzinski, DM Columbia, Cotransformation, Commercialization & Controversy: The Axel Patent Litigation Harvard Journal of Law and Technology 17(2): 584-618 “Drugs.com: Prescription Drug Information, Side Effects & Interactions,” Available at www.drugs.com Accessed 6/26/2007 Fox, J 1983 Columbia awarded biotechnology patent Science 221(4614): 933 Fram, A 2000 Alumnus senator Gregg helps Columbia seek lucrative patent extension Associated Press: Washington Dateline Journal Citation Reports ISI Web of Knowledge Available at http://portal.isiknowledge.com/portal.cgi/jcr?Init=Yes&SID=4CjCc8hJNKhaFIleeAi (accessed September 25, 2007) Lemley, M and Moore, K 2004 Ending Abuse of Patent Continuations Boston University Law Review 84: 63-117 Available at http://papers.ssrn.com/sol3/papers.cfm?abstract_id=462404 (accessed September 25, 2007) Marshall, E 2003 Depth Charges Aimed at Columbia’s ‘Submarine Patent’ Science 301(5632) :448 Miller, C 1981 Letter from Charles Miller, Department of Health & Human Services, to Paul A Marks, Vice President for Health Sciences, dated February 24, 1981 25 Mowery, D., Nelson, R., Sampat, B., Ziedonis, A 2004 Ivory Tower and Industrial Innovation: University-Industry Technology Transfer Before and After the Bayh-Dole Act Stanford University Press Ravicher, D.B 2004 Ex-Parte Request for Reexamination of a Patent Under 37 C.F.R §1.510 Available at http://www.pubpat.org/assets/files/ColumbiaCotransformation/Axel_275_Reexam_Request.pdf (accessed September 25, 2007) Rosenberg, R 2000 Gregg Draws Ire Over Columbia Patent Move The Boston Globe: Metro/Region Sampat, B 2000 “Case Study #5: The Cotransformation Process.” Unpublished manuscript Szybalska, E.H., Szybalski, W “Genetics of Human Cell Lines, IV DNA-Mediated Heritable Transformation of a Biochemical Trait.” Proceedings of the National Academy of Sciences of the United States of America, Vol 48, No 12, 2026-2034 Wigler, M., Silverstein, S., Lee, L., Pellicer, A., Cheng, Y., and Axel, R 1977 Transfer of Purified Herpes Virus Thymidine Kinase Gene to Cultured Mouse Cells Cell 11:223-232 Wigler, M., Sweet, R., Sim, G.K., Wold, B., Pellicer, A., Lacy, E., Maniatis, T., Silverstein, S., and Axel, R 1979 Transformation of Mammalian Cells with Genes from Procaryotes and Eucaryotes Cell 16: 777-785 26 Wysocki Jr., B 2004 College Try: Columbia's Pursuit of Patent Riches Angers Companies In: The Wall Street Journal New York Endnotes: 27 Author’s interview with Dr Saul J Silverstein, Professor of Microbiology, Columbia University, 2005 Author’s interview with Dr Saul J Silverstein, Professor of Microbiology, Columbia University, 2005 Author’s interview with Dr Michael Wigler, Professor, Cold Spring Harbor Laboratory, 2005 Author’s interview with Dr Michael Wigler, Professor, Cold Spring Harbor Laboratory, 2005 Author’s interview with Dr Michael Wigler, Professor, Cold Spring Harbor Laboratory, 2005 Author’s interview with Dr Saul J Silverstein, Professor of Microbiology, Columbia University, 2005 Author’s interview with Dr Paul A Marks, Sloan-Kettering Institute, former Vice President for Health Sciences at Columbia University, 2005 Author’s interview with Dr Saul J Silverstein, Professor of Microbiology, Columbia University, 2005 Diamond v Chakrabarty, 447 U.S 303 (1980) 10 Author’s interview with Dr Paul A Marks, Sloan-Kettering Institute, former Vice President for Health Sciences at Columbia University, 2005 11 35 U.S.C 121 “Divisional Applications.” Appendix L Patent Laws Available at http://www.uspto.gov/web/offices/pac/mpep/documents/appxl_35_U_S_C_121.htm (accessed September 25, 2007) 12 35 U.S.C 120 “Benefit of earlier filing date in the United States.” Appendix L Patent Laws Available at http://www.uspto.gov/web/offices/pac/mpep/documents/appxl_35_U_S_C_120.htm (accessed September 25, 2007) 13 35 U.S.C 154 “Contents and Term of Patent, Provisional Rights.” Section 532(a)(1) of the Uruguay Round Agreements Act (Pub L 103-465, 108 Stat 4809 (1994)) amended 35 U.S.C 154; 35 U.S.C 120, 121, 365(c) Available at http://www.uspto.gov/web/offices/pac/mpep/documents/2700_2701.htm (accessed September 25, 2007) 14 Biogen Idec MA Inc., et al., Plaintiffs, v The Trustees of Columbia University in the City of New York, Defendant 332 F Supp 2d 286; 2004 U.S Dist LEXIS 16315 15 Columbia University was also granted thirteen international or world patents: WO8102426A1 (World); JP57500410T2; JP07095880A2; JP06030588B4; JP02736502B2 (Japan); HK0059992A (Hong Kong); EP0045809B1; EP0045809A1 (European Patent Office); DE3176369C0 (Germany); CA1179953A1 (Canada); AU7037881A1; AU0558061B2 (Australia); and AT0029042E (Austria) 16 Author’s interview with Dr Saul J Silverstein, Professor of Microbiology, Columbia University, 2005 17 Trustees of Columbia University in the City of New York, Plaintiff, v Roche Diagnostics GmbH, formerly known as Boehringer Mannheim GmbH, Defendant 150 F Supp 2d 191; 2001 U.S Dist LEXIS 6383 18 Personal Communication, Michael Cleare, former executive director of Columbia’s Science and Technology Ventures Office, to Richard R Nelson, Henry R Luce Professor of International Political Economy at Columbia University, and Bhaven Sampat, Assistant Professor of Health Policy and Management, Mailman School of Public Health, Columbia University; 2006 19 Author’s interview with Dr Saul J Silverstein, Professor of Microbiology, Columbia University, 2005 20 Biogen Idec MA Inc., et al., Plaintiffs, v The Trustees of Columbia University in the City of New York, Defendant 332 F Supp 2d 286; 2004 U.S Dist LEXIS 16315 21 Author’s communication with Daniel B Ravicher, president and executive director of the Public Patent foundation, 2005 22 Biogen Idec MA Inc., et al., Plaintiffs, v The Trustees of Columbia University in the City of New York, Defendant 332 F Supp 2d 286; 2004 U.S Dist LEXIS 16315 ... Name Disease 22 Manufacturer Adalimumab Agalsidase beta Alefacept Alteplase Humira Fabrazyme Amevive Activase and Cathflo Rheumatoid Arthritis Fabry Disease Psoriasis Heart Attacks and Abbott Genzyme... “unreasonable and unexplainable delay on the part of Axel et al and changes in the personnel examining the application” (Ravicher 2004) The request for re-examination was granted Faced with these lawsuits.. .The Axel Patents: A Case Study in University Technology Transfer September 26, 2007 Abstract: The Axel Patents are among the most lucrative university patents in history, earning $790