CHAPTER 17.23 Specific IP Issues with Molecular Pharming: Case Study of Plant-Derived Vaccines AnAtole KrAttiger, Research Professor, the Biodesign Institute at Arizona State University, Chair, bioDevelopments-International Institute; and Adjunct Professor, Cornell University, U.S.A. ricHArd t. MahoneY, Director, Vaccine Access, Pediatric Dengue Vaccine Initiative, International Vaccine Institute, Republic of Korea ABSTRACT clinical evaluation including human serum pro- The public sector is making substantially increased invest- teins (epidermal growth factor), monoclonal anti- ments in health technology innovation through public/ bodies, such as antigenic peptides for rabies virus, private partnerships to bring improved health technolo- gies to underserved people in developing countries. These tuberculosis and HIV, antibodies to treat cancer, product-development partnerships, however, face a com- cardiovascular diseases, gastric lipase in the fight mon problem: how to manage intellectual property (IP). against cystic fibrosis, and hepatitis B antibodies, Such management involves many issues. In relation to and a range of vaccines.1 Recombinant protein a case study, presented in this chapter, of plant-derived hepatitis B virus vaccine, the challenges involve obtaining drugs are one of the fastest growing segments of freedom to operate, securing new intellectual property, the pharmaceutical industry, currently generat- and deploying intellectual property to developing coun- ing over US$20 billion in annual revenues. They tries. We conclude that while challenges abound, the IP are the so-called third generation of recombinant issues are fairly clear and can be addressed with straight- plant products.2 forward IP management approaches. The cost of manag- ing the intellectual property is expected to be minimal on From a global perspective, plant-derived vac- the price of the finished vaccine. In the medium term, cines represent an attractive mode of production an IP protection strategy might offset costs and generate to address diseases of the poor and to stimulate modest income. Most important for the partnerships is manufacturing in developing countries.3 Over to develop a clear, transparent IP policy, with emphasis on the licensing principles, so that products can be made the last decade, the concept of plant-derived vac- available to developing countries at affordable prices. cines has grown more sophisticated and many re- search partnerships have emerged that involve ad- vanced research centers in developing countries. Several potential characteristics of plant-derived 1. Introduction vaccines could make them particularly attractive The goal of molecular pharming is to develop for controlling infectious diseases in developing valuable new drugs and vaccines for significant countries. diseases in developed and developing countries. • The vaccines would be orally active, thus A number of substances have already been pro- eliminating the need for injection and the duced in plants and include flavors, nutraceu- associated cost and safety concerns. ticals, biodegradable plastics, and metabolites. • Oral activity is associated with the ability From a health perspective, plants have been of plant-derived vaccines to evoke mucosal engineered to produce therapeutic proteins for immunity, which is valuable for a number Krattiger A and R Mahoney. 2007. Specific IP Issues with Molecular Pharming: Case Study of Plant-Derived Vaccines. In Intellectual Property Management in Health and Agricultural Innovation: A Handbook of Best Practices (eds. A Krattiger, RT Mahoney, L Nelsen, et al.). MIHR: Oxford, U.K., and PIPRA: Davis, U.S.A. Available online at www.ipHandbook.org. © 2007. A Krattiger and R Mahoney. Sharing the Art of IP Management: Photocopying and distribution through the Inter- net for noncommercial purposes is permitted and encouraged. HANDBOOK OF BEST PRACTICES | 1809 KRATTIGER & MAHONEY of infections that are transmitted through words, the cost per dose to deliver in a developing the mucosa. country immunization program and the percent • Plant-derived oral vaccines should be heat savings that could be enjoyed over the effective stable, thus largely eliminating the need for cost using plant-derived vaccines). The results are a cold chain for these vaccines. summarized in Table 1. It shows that the potential • It might be possible to make multi-antigen economic benefits of plant-derived vaccines justify vaccines either by multiple gene splicing or the establishment of a comprehensive program to by mixing various plant-derived vaccines. bring one or more products to the market soon. • A very important potential aspect of plant- It is not surprising therefore that govern- derived vaccines is that developing countries ment- and foundation-funded molecular pharm- could launch and carry forward their devel- ing represents a new generation of public sector opment and ultimately their production. initiatives that seek to rectify a widely acknowl- • Plant-derived vaccines could be produced edged imbalance: a lack of investment in R&D on a very large scale and at very low cost, for health technologies for the poor. Since the perhaps as little as a few cents per dose. private sector is, by definition, profit driven, it cannot, on its own, address this imbalance be- Indeed, a multi-disciplinary team led by cause of the need to make a competitive return on Charles Arntzen4 recently carried out detailed investment, which the market for the poor does calculations of the comparative costs of the not provide. production of vaccines by traditional methods and The public sector is now making substan- by plants. The chapter here is an extension of that tially increased investments in health technology report. In that study (as indeed in this chapter), innovation through public/private partnerships. hepatitis B vaccine (HBV) was used as a model. These product-development partnerships face a The cost-of-production study computed the costs common problem: how to manage intellectual for facilities in the United States, Korea, and India property (IP). This is no small challenge. IP man- capable of producing 75 million doses per year. agement is a complex field in which learning, un- The “effective cost” was also computed (in other derstanding, and using best practices is essential. Table 1. Comparison of Production and effective Cost for Three Countries and Two Presentations Korea or India United States Korea India Plant-derived Plant-derived Plant-derived Yeast-derived single-dose 10-dose single- 10-dose single- 10-dose 10-dose vials packet packet dose packet dose packet packet packet Cost $0.27 $0.15 $0.06 $0.09 $0.04 $0.075 $0.03 Effective Cost $0.42 $0.16 $0.08 $0.10 $0.05 $0.08 $0.04 % savings 62% 81% 76% 88% 81% 90% for plant- derived vaccine against yeast-derived for effective cost Source: Arntzen et al., 2006.5 1810 | HANDBOOK OF BEST PRACTICES CHAPTER 17.23 IP management involves many issues, includ- 3. Deploying intellectual property. Public ing patenting, the protection of confidential sector groups are often dedicated to achiev- information, and the formation of cooperative ing social goals, such as developing safe R&D programs. For any area where many orga- and effective health technologies to address nizational actors converge, there are three primary disease. Further, these groups would like to challenges to IP management: see these products made widely available 1. Securing new intellectual property. New at affordable prices to all levels of society. research initiatives will naturally develop To accomplish these ends, public sector new intellectual property. It is essential groups should use humanitarian licensing to public sector goals that this intellectual practices. For example, if a group helps property be identified and secured, either to develop a new monoclonal antibody by filing the appropriate patent applica- against the rabies virus, it could license the tions or by obtaining licenses from patent technology to companies in Europe and holders. If, for example, one group devel- the U.S., but the group could also reserve ops a method for promoting the synthesis the right to license companies in develop- of an antigen, and another group develops ing countries under different terms. These a technique for purifying the antigen from countries may enjoy some advantages, such plant material, it is essential to be able to as lower costs of production. Licensing to bring together both intellectual proper- companies in developing countries could ties for developing the final product. This also help to make the product available to IP challenge can be largely overcome by the poor at prices near the marginal cost of undertaking an inventory of the existing production. intellectual property of key groups. To ac- complish this work there must be access to technical experts who can identify the spe- 2. Specific InTellectuAl pRoperty cific ways the intellectual property can be ISSueS with plAnT-derived useful for product development. pHARmaceuticalS 2. Freedom to operate (FTO). If a molecular pharming initiative is to achieve its goals, 2.1 Background the partnership will need to undertake a As with most biotechnology products, the IP thorough Freedom-to-Operate review to situation in plant-derived vaccines is complex. provide a clear picture about which pat- Managing IP and tangible property presents add- ents do, may, and do not stand in the way ed challenges and expense because plant-derived of developing products. These assessments