Do You Have A License?: Products Licensed for PCR in Research Applications

Date: June 8, 1998 Author: Shane BeckLicensed Research Reagent Companies, Thermal Cyclers, Taq Polymerase Catalog Prices F or those of you who regularly read LabConsumer, this article may be something other than what you are used to seeing. The topic of polymerase chain reaction (PCR) licensing is one that, as LabConsumer gathered information from an increasing number of people with numerous points of view, it became more and more difficult to sort out. With a topic as hot as this, and with litigation currently ongoing, it is important to keep in mind that LabConsumer is not providing legal advice in this article and that each researcher's situation is unique. Detailed licensing information can be obtained by contacting Roche and Perkin-Elmer. Biotechnology is a somewhat unique field in that in the course of their daily chores, scientists may perform processes that are protected by patents. With regard to processes, several biological patents have been issued to protect these processes, including the polymerase chain reaction. License and patent fees paid to companies and universities help to recover costs incurred in the development of this technology and maintain the research and development stream for future technologies. United States patent law dates back to colonial America with the first patent laws enacted shortly after the drafting of the Constitution. Since that time, millions of U.S. patents have been issued, granting each inventor or creator the right to control the rights of others to make, use, or sell his or her invention for a certain period of time. These patents are categorized by class, and currently, hundreds of different classes of patents exist in the United States. Moving from Class 2 (apparel) down to Class 43 (fishing, trapping, and vermin destroying) to Class 135 (tent, canopy, umbrella, or cane), one eventually makes his or her way to Class 435 (chemistry: molecular biology and microbiology), where some of the most important patents protecting intellectual property rights relating to biotechnology are included. In the early 1980s, the notion of the polymerase chain reaction entered Kary Mullis's mind during a famous California nighttime ride. This revolutionary method that changed the course of science earned this employee of Cetus Corporation the Nobel Prize in chemistry in 1993. Two patents issued to Cetus Corporation in July 1987, 4,683,195 and 4,683,202 (referred to as the '195 and '202 patents, respectively), cover the processes of amplifying, detecting, and cloning nucleic acid sequences. Patent 4,683,202 covers PCR as we know it, and in the patent, Kary Mullis is credited as the inventor of this process. Patent 4,683,195, issued to Cetus on the same day as the previous patent, covers not only nucleic acid amplification but also downstream applications of PCR. For research, PCR reagents and thermal cyclers were commercialized through a partnership between Cetus and Perkin-Elmer in the late 1980s. In 1989, Roche acquired the rights to all of the in vitro diagnostic applications of PCR from Cetus Corporation and in 1991 went on to acquire the PCR business and all of the patents as well. Following this acquisition in 1991, the remainder of Cetus Corporation was purchased by Chiron for about $600 million. At this time, Roche had not only the PCR patents but also patents covering native and recombinant Taq polymerase and PCR using thermostable polymerases. Additional patents have been issued to Roche and Perkin-Elmer since then. How does a company become a licensed supplier of research reagents? While gathering information for this article, LabConsumer staff spoke with representatives of both licensed and unlicensed suppliers of PCR enzymes, and many wished to remain anonymous when discussing the subject of PCR licensing. In most cases, companies wishing to manufacture Roche-patented enzymes and to sell thermostable enzymes that pass along the right to do PCR for research meet with Roche, agree to the up-front and royalty fees, and agree to various labeling and compliance issues. To date, two dozen companies worldwide have obtained the appropriate license rights from Roche to sell licensed research reagents. In looking at available licensed enzymes and kits in the United States, LabConsumer found that almost every thermostable polymerase is represented, including Taq, Tth, Pwo, Tfl, and Pfu, as well as several specialty enzymes. At least eighteen companies in the United States sell licensed DNA polymerases and kits for PCR. Some companies that sell licensed reagents in Europe and Asia, such as DNAmp Ltd., Enzyme Technologies, Finnzymes OY, and TaKaRa Shuzo Co. Ltd., have distributors in the United States that offer these products as well. As for thermal cyclers carrying the "authorized for PCR" sticker, researchers can turn to several companies in the United States that provide cyclers with a wide variety of formats, features, and functions. For some companies, the distinction of being a licensed supplier of research reagents and/or authorized thermal cyclers has faded as the field of licensed enzyme suppliers continues to grow and unlicensed companies continue to sell thermal cyclers and enzymes, with prices for unlicensed enzymes and instruments often lower than those for licensed products. Indeed, a quick comparison of prices for licensed Taq conveying PCR rights and unlicensed Taq from Promega (Madison, Wis.) shows researchers can potentially pay twice as much for licensed Taq polymerase. Speaking from another viewpoint, the president of one company that previously suppied unlicensed PCR enzymes explains why he didn't obtain the license rights from Roche. "We're a small company. We can't afford to give the small profit we make each year away." In addition, LabConsumer spoke to a representative from one chemical company that also recently stopped offering a particular Taq polymerase because it was not licensed. However, when asked about the decision to obtain a license to sell research reagents for PCR, a representative from one company that has obtained those rights explained, "If you want to go to the movies, you buy a ticket. If you want to play in this business, you buy a ticket." What does all of this mean for today's basic researcher performing PCR? Regardless of whether you perform one PCR a year or dozens of reactions at a time, Roche points out that, as with any patented method, permission is required from the patent holder to perform that method. The easiest way to receive permission for research, according to Hanna Fischer, director of licensing at Perkin-Elmer, "is by purchasing licensed reagents and authorized thermal cyclers." Where does Perkin-Elmer fit into this process? Roche, through its exclusive distributor, Perkin-Elmer, and its research reagent licensees, grants rights to use PCR for research when Roche-manufactured or Roche-licensed enzymes are used in conjunction with an authorized thermal cycler. Perkin-Elmer manufactured the first thermal cyclers authorized for PCR and also makes available these rights for competitors' thermal cyclers; these rights constitute the "up-front component" of the PCR license. If a researcher is using an "unauthorized" thermal cycler for PCR, he or she can contact Perkin-Elmer and purchase the appropriate authorization, and in most cases, apparatus rights. The "running-royalty component" of the PCR license may be obtained by purchasing PCR enzymes from one of the numerous manufacturers who have purchased license rights from Roche. Licensed Research Reagent Companies Outside of the U.S. Advanced Bioenzymes Angewandte Genetechnologie Systeme GmbH Appligene Oncor Biotech International Laboratoires Eurobio Nippon Gene Awady Technology Co. Ltd. Toyobo So who is using these products? It's difficult to gauge what percentage of researchers are using licensed and authorized products or feel they need to be using licensed products. A Perkin-Elmer advertisement in the April 24, 1998, issue of Science with the headline "Information About Perkin-Elmer's PCR Licensing Program" states, "Because PCR is patented, using PCR, even for research, requires a license. . . To make it easy for users to obtain the PCR rights they need, we not only offer PCR rights in a variety of ways directly to end users, we also have licensed many of our competitors to convey these rights with their products [instruments]." While several researchers LabConsumer contacted understand and appreciate the premise of protecting intellectual property through patents, not all felt it applied to their "basic research," and many didn't know if the enzymes they were using were licensed or not. One university spokesperson explained that there is a long-held popular contention that people conducting basic research at universities are exempt from patent compliance. Perkin-Elmer feels this view is being fostered by the manufacturers of unlicensed products. According to Roche, legal experts have found no basis in the law for a university exemption. This position is explained in detail in Chapters 9 and 10 in the following source (M.S. Frankel, A.H. Teich, The Genetic Frontier: Ethics, Law, and Policy, Washington, D.C., American Association for the Advancement of Science, 1994, pages 181-208). In the chapter titled "Intellectual Property and Genetic Testing", Kate Murashige notes, "There is no provision for compulsory licensing, available at least at some level in many other jurisdictions, wherein a patent owner, most commonly a patent owner who is not working the invention, may be forced to permit others to practice it in return for a royalty. There is also no statutory 'research exemption' in the United States, except for activities carried out in order to secure regulatory approval." Is there such a thing as "academic research"? LabConsumer spoke with the director of corporate development of a life science company that has purchased license rights from Roche who commented that with regard to academics, "In the 1970s it was 'publish or perish'." However, he said, it seems that today that while the underlying premise is still 'publish or perish', it now includes checking to see if you've got something patentable before you publish, even if you do not intend to commercialize the product or process. On the other side of the fence, "Promega favors a broad interpretation of the experimental-use exception--that academic and nonprofit researchers have no need for licenses," explains Randy Dimond, vice president and chief technical officer of Promega. According to Promega, the experimental use doctrine "holds that it is not an act of infringement to make and use a patented invention if the use is limited to research or experimentation and the user does not profit from the experimental use." Dimond clarifies, "Roche, on the other hand, takes the position that experimental-use exception does not exist." Promega also contends that researchers employed by the U.S. government and governments of many other countries, including many of their contractors or grantees, do not need to obtain licenses to perform patented processes because of statutory government exemptions that are part of the patent statutes of many countries. Promega's position is explained in detail on their web site (www.promega.com). PCR and Taq patents have been challenged both in the United States and abroad. Roche and Promega have stood toe-to-toe for some time now, and the courtroom arguments are still in progress. With PCR comes a legal history too extensive to detail here. Preliminary shots were fired in August 1989, two years after the '195 and '202 patents were granted, when DuPont challenged the validity of the PCR patents. DuPont claimed the PCR process was discovered by MIT professor and Nobel laureate H. Gobind Khorana and his colleagues in the early 1970s. In 1991, a jury upheld both of Cetus's patents and rejected the claim that the work done at MIT anticipated PCR technology. In the fall of 1992, Roche filed a suit against Promega for breach of contract over Taq sales and infringement of the Taq patent and other PCR patents. Since then, Promega and Roche have been volleying back and forth in court over Roche's Taq patents. On March 6, 1998, a U.S. federal district court set a date of June 29, 1998, for a trial to establish whether the material omissions and misstatements already identified by the court were made intentionally by the patent applicants in obtaining the U.S. Patents as contended by Promega. The patent battles are not confined to the United States, either. On March 4, 1998, Becton Dickinson (Bedford, Mass.), Bioline (United Kingdom), New England BioLabs (Beverly, Mass.), and Promega filed oppositions to a recently issued themostable DNA polymerase patent with the European Patent Office. What are the implications for manufacturers selling unlicensed enzymes and thermal cyclers and for researchers using the same? The final outcome and coincidental ramifications are unclear at this time, but it is likely that the situation will be better understood when the dust settles from the courtroom patent disputes, whenever that may be. Roche has invested substantial time and resources to obtain these patents and develop the technologies, and claims its goal is for Promega to take a license so that Taq is properly (legally) manufactured and PCR research rights can be passed on to customers. According to a Roche spokesperson, "This would result in a more even playing field for research reagent manufacturers." LabConsumer began to wonder if scientists knew what licensed products are available today. Accompanying this article are three tables listing companies that have obtained license rights from Roche for selling research reagents for PCR and those companies that have obtained license rights from Perkin-Elmer to sell authorized thermal cyclers. What is the cost to a researcher to authorize an unauthorized thermal cycler? When asked, a Perkin-Elmer spokesperson was unwilling to specify a price range. Her response was that since there are numerous considerations that weigh into the equation, including applicable patents and the capacity and features of the instrument, each authorization must be considered on a case-by-case basis. Intellectual property is subject to much debate, and a topic that all researchers, industrial and academic alike, should contemplate. Additional patent and licensing information can be obtained by contacting Roche (510-814-2984) or Perkin-Elmer (650-638-5845 or www2.perkin-elmer.com/ab/pcrlicensefaq). Licensed Research Reagent Companies, Thermal Cyclers, Taq Polymerase Catalog Prices The author can be reached online at sbeck@the-scientist.com.

Do You Have A License?: Products Licensed for PCR in Research Applications

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