CHAPTER 17.23

Specific IP Issues with Molecular Pharming: Case Study of -Derived 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, 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 ), monoclonal anti- ments in 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, to treat cancer, product-development partnerships, however, face a com- cardiovascular , gastric in the fight mon problem: how to manage intellectual property (IP). against , and antibodies, Such management involves many issues. In relation to and a range of vaccines.1 Recombinant 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 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 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 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. (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 -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 . 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 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 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 vaccines build on many distinct areas of innova- are always associated with a high level of tion, including: uncertainty, for a number of reasons, in- • Engineering of proteins and specific anti- cluding the large number of patents that gens (including immunogens and specific may exist, the numerous jurisdictions encoding antigenic proteins). Many (countries) in which the patents have been patents in this area are the same as those or have not been filed, and the varying that apply to vaccine production through practices of patent offices. A blocking pat- conventional means. ent may exist and might be voided in key • Antigen production and accumulation in markets only through long and costly legal plants (including the expression of foreign battles. The value of an FTO assessment is genes and the optimization of genes). The that it provides a good sense of the IP is- technologies associated specifically with sues relevant for any development project, the expression of antigenic determinants which helps minimize costly, unforeseen in plants are the subject of several issued problems. patents.

HANDBOOK OF BEST PRACTICES | 1811 KRATTIGER & MAHONEY

• Genetic transformation of plants (includ- of vaccines may require access to a number of pat- ing vectors for use in plant transforma- ents, which may be difficult to obtain. tion, transformation protocols, molecular Despite the complexity, the task is manage- toolkits, and various equipment). Basic able. Corporations typically manage their intel- plant transformation technologies have lectual property in a strategic manner. This entails, been under development for more than among others, significant in- and out-licensing 20 years. The procedures commonly in activities to obtain FTO as part of an integral use today are covered by a range of issued element in their product development strategy. and pending patents. Virtually all of the In contrast, public institutions are generally less groups that have been involved in plant- experienced with FTO procedures. A better un- derived vaccine activities have utilized the derstanding of IP management will allow these -mediated approach to plant institutions to take advantage of the flexibilities transformation. in IP systems. In the United States, for example, • Selectable marker systems (that allow for groups can undertake research without a license the identification of plant cells that have on patented technologies if the goal is to generate successfully taken up the DNA, and com- data for the regulatory requirements of the U.S. prising the gene expression systems), such Food and Drug Administration (FDA). as kanamycin (nptII), mannose-phosphate- While a patent thicket exists for plant-derived 6-isomerase, among others. vaccines in industrialized countries, very few of • Transcription regulatory elements (to en- these patents have been filed in developing coun- sure that the introduced genes are expressed tries. The absence of many patents in developing in plants), including promoters (constitui- countries simplifies matters significantly with tive and/or specific), and transcrip- respect to humanitarian use and also facilitates tion terminators (terminator nucleotide commercial applications in developing countries. sequences), which are quite often NOS or It does not, however, reduce the overall need for rubisco E9 terminator sequences. IP management in order to obtain FTO. • Sub-cellular targeting systems (used to There are several models of humanitarian- “guide” the transcribed products into spe- use licensing where patent rights are effectively cific cellular organs), such as rubisco sub- pooled. One example is the approach used by units and plastid signal sequences the developers of the biotech containing pro- • Related technologies (such as adjuvants, Vitamin A, called “.” The developers and product formulation and immuno- of Golden Rice encountered many of the FTO modulatory technologies). issues that face developers of plant-derived vac- • Bioprocess engineering for extraction and cines. An FTO assessment revealed that Golden processing. Rice was related to over 70 patent applications and issued patents, most notably in the United An additional complication is that most States and Europe, and that patent applications plant-derived vaccine projects are developed were owned by over a dozen institutions. Few through the collaborative efforts of a range of re- patents were applied for or issued in developing search institutions, including private companies countries. However, because the material was and academic institutions. Materials often change developed in Europe, it could not be transferred hands periodically during the development pro- for use in developing countries without proper gram, possibly in conformity with material trans- licenses. There were a few reasons for this, not fer agreements that stipulate certain restrictions. the least of which was that several material trans- Research agreements must be developed for all of fer agreements were limited to research use only. these collaborative efforts. The agreements must Thanks to the publicity surrounding Golden Rice address what will happen if such inventions are and the seriousness of vitamin A deficiency in de- developed jointly. Further, nasal administration veloping countries, these patent constraints were

1812 | HANDBOOK OF BEST PRACTICES CHAPTER 17.23

resolved in only a few months. The public and (1) achieve freedom to operate, (2) capitalize on private organizations that held relevant patents new inventions, and (3) achieve the highest possi- made them available at no cost to the inventor, ble level of accessibility and affordability in devel- who, in turn, granted one single license for all oping countries. The relevant IP includes patents, the necessary intellectual property to develop- trademarks, know-how/trade secrets, plant variety ing country institutions. Golden Rice serves as a protection (PVP), and tangible property (such as useful model of how to approach the owners or research materials obtained through agreements). assignees of proprietary technologies for royalty- For practical purposes, we consider IP manage- free access for humanitarian uses. ment at three different levels: One important difference between nutrition- • incoming third-party intellectual property ally enhanced rice and plant-derived vaccines is • newly generated intellectual property, and that the vectors and gene-expression components • outlicensed intellectual property used to produce Golden Rice were assembled without advance consideration of intellectual 2.2.1 Third-party intellectual property property and FTO. Thus, the way forward with Third-party intellectual property considerations plant-derived vaccines should proceed more relate to tangible and intangible property and the smoothly than it did with Golden Rice with re- relevant contractual obligations. spect to IP issues. Preliminary analysis and con- Tangible property. The components of tan- tinued review of the IP landscape, however, are gible property typically comprise plants, genes, essential elements in the development of plant- vectors, and the conditions under which such derived vaccines. While it is relatively easy to put material property was obtained. In most cases, the different pieces into place, managing the pro- public germplasm or varieties are available (in- cess, in tandem with scientific advancements and cluding corn, tomatoes, and ). Whereas the development of the product, remains a major scientists in public research institutions typically challenge. prefer to obtain such materials from colleagues, Based on a preliminary review of a specific the resulting material transfer restrictions should plant-derived vaccine against hepatitis B virus, not be underestimated. In the private sector, it it was concluded that (1) the IP issues are fairly would be more typical to have genes synthesized, clear, although additional FTO analysis will be which avoids the material transfer restrictions on required to address specific cases, (2) the issues the genes. can be addressed with straightforward IP man- Other tangible property issues involve the agement approaches, and (3) the impact on the machinery required for bioprocesses. cost of finished vaccine is expected to be mini- Intangible property. The intangible property mal. If a great deal of the work is conducted in aspects are often more complex. Among the rea- developing countries, the IP management issues sons for this complexity is that intangible prop- will be significantly simplified, since a number erty takes many forms, including utility patents, of the relevant patents may not have been filed trademarks, trade secrets/know-how, plant va- in developing countries and thus the need for li- riety protection/plant breeders’ rights and plant censes would be reduced significantly (unless the patents (including utility patents on plants). products are exported to countries where a patent • Utility patents. Much of the third-party thicket existed). intellectual property will be in the form of utility patents. A detailed FTO opinion will 2.2 Types of intellectual property and material be based on the specific antigen, process, property rights associated with plant- and market in which the products are to derived vaccines be sold. In countries where certain patents Increasingly, IP rights influence every stage of vac- are not issued, licenses will not be required cine development. In this section, the specific as- either for the production or the sale of such pects of IP management are considered as tools to vaccines.

HANDBOOK OF BEST PRACTICES | 1813 KRATTIGER & MAHONEY

• Plant variety protection/plant breeders’ licensing fees vary widely—from as high as 20% rights, plant patents (United States only) of sales prices for newly introduced vaccines, to and utility patents on plants (mainly United as low of 2% for haemophilius influenzae type B. States). Depending on which is being However, this comparison of royalty rates does not used, different types of intellectual prop- help much when it comes to plant-derived vac- erty may apply. For example, it is becom- cines, since the total royalties of all in-licensed IP ing increasingly common for companies will depend on the type of product, the number and universities alike to seek utility patents of patents, and type of market. Manufacturing on inbreds and hybrids of corn, and for va- costs per vaccine can be reduced by economies of rieties of soybeans, , fruit trees, and scale/increased production, but, in such cases, roy- ornamental plants. If such protected ma- alty fees are unlikely to be affected since they are terial were used, a license may need to be generally fixed percentages of the sale price of each obtained to use the plant or export it for dose. production in other countries. Similarly, In terms of possible royalty rates for the hepa- with the advent of new PVP regulations titis B model that has been mentioned in this chap- (under the 1991 UPOV [International ter, it is perhaps premature to speculate on royalty Union for the Protection of New Varieties ranges and licensing terms, since such speculation of Plants] treaty), a variety with PVP could may influence the type of deal that could be ob- not be used to produce plant-derived vac- tained. Nevertheless, it seems that reasonable roy- cines within the duration of the certificate’s alty rates in aggregate would add no more than 1% validity, because inserting one gene or a set to 5% to the estimated total production costs. of genes would make it an “essentially de- Finally, in addition to the costs related to in- rived” or protected line.6 licensed IP, IP-management-related expenditures However, many of the IP problems de- will be incurred during the R&D phase. These in- scribed here can be avoided if appropriate clude expenditures for FTO opinions, which will strategies are pursued from the outset. This need to be commissioned well ahead of produc- could, for example, entail the use of public tion. Typical FTOs cost $20,000 to $100,000, germplasm instead of proprietary varieties. depending on the complexity of the technology. Such a step may not be a feasible nor cost effective since some newer varieties might be the highest yielding or provide the high- 3. detailed analysis for Hepatitis B est regeneration efficiency during genetic virus vaccine modification work. • Trade secrets/know-how. Some of the critical 3.1 Research steps of bioprocesses lie in the know-how Since the decision of the Supreme Court of the or trade secrets. Know-how refers to the United States on Merck v. Integra Life Sciences in knowledge of how something is produced, 2005,7 analysts contend that, with the broadened and not the specific components that con- definition by the Supreme Court of the Hatch- stitute a product. Know-how can be li- Waxman Act8 as it relates to data exclusivity, censed through appropriate confidentiality research in preparation of FDA approval is ex- or secrecy agreements. Requirements for li- empt from the requirement for research licenses. censing, however, vary widely from country Although this broad conclusion has not been to country and certain information may not tested within specific circumstances in the lower be legally protected in many jurisdictions. courts, it is reasonable to assume for hepatitis B that there are no IP constraints during the re- Cost implications. Traditionally, in-licensed search phase, until clinical trials are complete and, intellectual property has considerable impact on possibly, the submission of an investigational new the cost and pricing of vaccines. Estimates of the drug (IND) application to the FDA.

1814 | HANDBOOK OF BEST PRACTICES CHAPTER 17.23

3.2 IP components authors that cover all transgenic corn, tomato, or tobacco. There might be some differences in agro- 3.2.1 Patents related to the hepatitis B bacterium-related patents depending on whether vaccine (HBV) a monocotyledoneous or dicotyledoneous plant Many of the existing patents related to HBV are is used. These differences, however, will not ma- unlikely to be relevant for a number of reasons. terially affect the conclusions related to the key First, several surface antigens are either in the licensing requirements. public domain or their patents are limited to parenteral9 administration, rather than oral de- 3.2.3 Broad plant-made livery, or the claims do not cover their produc- pharmaceutical patents tion in plants. In addition, the patent issued in Three of the most often cited patents related to 1989 to Merck & Co, and the 1986 Chiron pat- plant-made pharmaceuticals for oral administra- ent for the first recombinant vaccine (hepatitis tion are the Curtiss-Cardineau patents (U.S. pat- B), will have expired by the time a plant-derived ents No. 5,654,184, 5,679,880 and 5,686,079), vaccine reaches the market. Furthermore, these assigned to Washington University in St. Louis, patents seem to be limited to the production but now owned by Dow. However, all claims of of virus-like particles in yeast only. A full FTO the three patents are limited to oral administration assessment will nevertheless be required to pro- of “transgenic plants” or of “transgenic plant tis- vide clearer answers and reveal other intellectual sue.” It is unclear whether the Curtiss-Cardineau property related to the specific methods of pro- patent would cover the oral administration of an- duction envisaged here. tigens “extracted” from plant tissue.

3.2.2 Plant transformation and antigen 3.2.4 Bioprocess facility production in plants Many aspects of a bioprocess facility (which is A preferred method of production for the HBV required for the extraction, purification and pro- is through stable lines produced through agrobac- cessing of the vaccine) are covered by the very terium-mediated transformation. The IP thicket broad U.S. patent No. 6,617,435 B2 and U.S. related to agrobacterium is relatively complex and application No. 2004/0166026 A1 and, possibly, still evolving; at least one of the interference pro- patents that are continuations, divisionals, for- ceedings of agrobacterium-related patents filed eign counterparts, reissues, reexaminations, and prior to March 1995 is still ongoing, and no de- continuations-in-part of known patents. The for- tails on possible claims have been made public.10 mer is assigned to the now-defunct Large Scale However, based on counterpart patents issued in (LSB) Corp. in Vacaville, California; the Eurpoe, it is fair to assume that at least one li- latter, if issued, also would be assigned to the suc- cense could be required from either or cessors of LSB Corp.11 Since much of this bio- (since they, or companies they acquired, process facility design would draw on the trade are presumed to have filed patents for agrobac- secrets and know-how of LSB Corp., a license terium-mediated transformation prior to March from LSB Corp. or its successor would be highly 1995). desirable. The currently used plasmid is a derivative of the antigen pBin19 and may be covered by 3.2.5 Cost implications Monsanto patents. The promoter that drives the Production of plant-derived hepatitis B vaccines gene expression (CaMV 35S) and the selectable through plant transformation and antigen pro- marker that allows for the selection of transformed duction in plants is expected to require a num- cells (nptII) are both covered by Monsanto pat- ber of licenses. These should be obtainable, es- ents. Other patents may also cover the applica- pecially because the proof of concept has already tions; these will be identified during an FTO. been demonstrated and confidence built into However, broad patents are not known to these the technology. In aggregate, licenses for HBV

HANDBOOK OF BEST PRACTICES | 1815 KRATTIGER & MAHONEY

technology, plant transformation and broad vaccines that are made using the processes out- molecular pharming patents, the total royalties lined in this chapter. Such trademarks could be should not add more than 1% to 3% to the cost valuable and would afford a level of quality assur- of production. This estimate is based on common ance and control not otherwise available. industry licensing practices. Bioprocess patents are in a different catego- 3.3.4 Cost implications ry because know-how is important for the con- Obtaining IP protection through utility patents, struction and operations of bioprocess facilities. and trademarks incurrs legal and government Nevertheless, favorable terms for a license that filing fees (especially if trademarks are pursued in would not exceed 1% to 3% of the cost of pro- multiple countries). (Trade secret protection, on duction could likely be obtained. the other hand, costs nothing.) There will also be expenses related to ongoing licensing negotiations. 3.3 New intellectual property Nonetheless, the added cost for the protection of new intellectual property will undoubtedly be 3.3.1 Utility patents small compared to overall production costs. The During the development of plant-derived vac- expenses would likely add no more than US$10- cines, certain new inventions will emerge that 100,000 per year to the cost of production. In might be patentable. Aside from the typical in- time these costs can be recovered, and the IP may ventions related to antigens, plant transforma- even lead to a modest royalty stream if licensed. tion systems, and related technologies, innovative business models and production processes might also be developed. Care should be taken in mak- 4. Conclusions ing decisions about whether or not the inventions The chapter’s survey of intellectual and material should be patented, kept as trade secrets, or made property issues was based on a cursory FTO re- public and consideration given especially to the view. We attempted to highlight key issues and es- best ways to make the plant-derived vaccine avail- timated the possible costs associated with the res- able at affordable prices to the neediest countries olution of these. As the current research emphasis in the developing world. This goal is more likely evolves into a product development program with to be achieved if a certain level of control over the more downstream considerations, a detailed FTO vaccine is retained. will be required leading to in- and out-licensing of intellectual property. To successfully move the 3.3.2 Trade secrets/know-how candidate vaccine through the various stages from Many critical aspects of the operations of biopro- research to commercialization will also require the cessing facilities are valuable knowledge. In some development of a global access strategy to reach jurisdictions, this knowledge can be protected developing country markets.12 For this, various under trade secret law. It is customary for any components will need to be integrated, includ- pharmaceutical production plant to keep its stan- ing regulatory aspects, manufacturing, access to dard operating procedures as trade secrets, given markets/distribution, and trade. IP management the considerable time and resources involved in then essentially becomes nothing but a useful tool fine tuning operations. By extension, employees for reinforcing the vaccine development and de- of such plants will need to be informed of pro- ployment/marketing strategy. n cedures for keeping information confidential and should have related clauses in their employment contracts. Anatole Krattiger, Research Professor, the Biodesign Institute at Arizona State University, Chair, bioDevel- opments-International Institute; and Adjunct Professor, 3.3.3 Trademarks Cornell University, PO Box 26, Interlaken, NY 14847, One expense that might be worth considering is U.S.A. [email protected] the creation of a quality seal for all plant-derived

1816 | HANDBOOK OF BEST PRACTICES CHAPTER 17.23

Richard T. Mahoney, Director, Vaccine Access, Pediatric to limit § 271(e)(1)’s exemption from infringement to Dengue Vaccine Initiative, International Vaccine Institute, submissions under particular statutory provisions that San Bongcheon-7dong, Kwanak-ku, Seoul 151-818, regulate drugs). This necessarily includes preclinical Republic of Korea. [email protected] studies of patented compounds that are appropriate for submission to the FDA in the regulatory process. There is simply no room in the statute for excluding 1 Arntzen C, B Dodet, R Hammond, A Karasev, M Rus- certain information from the exemption on the basis sell and S Plotkin. 2004. Plant-derived Vaccines and of the phase of research in which it is developed or the Antibodies: Potential and Limitations. Vaccine 23:1753- particular submission in which it could be included.” 1885. Refer to 545 U.S. 193, 125 S.Ct. 2372, Merck KGaA v. Integra Lifesciences I, Ltd., et al. No. 03-1237. Argued 20 April 2 The first generation products are the agronomic traits 2005. Decided 13 June 2005. (such as insect resistance, herbicide tolerance, and ), and the second generation are 8 The Hatch-Waxman Act introduced data exclusivity for nutritionally enhanced plants (including omega-3 medicines in 1984 and allowed for patent extensions fatty acid enrichment, vitamin A and E production, of up to five years to compensate for the loss of patent high oleic soybean oil, low saturate canola oil, and high life in meeting regulatory requirements. This came beta carotene oilseeds). with a trade-off: data exclusivity for pharmaceutical drugs and vaccines was reduced, allowing producers 3 ASU. 2006. Blueprint for the Development of Plant- of generic medicines to use the abbreviated new drug derived Vaccines for the Poor in Developing Countries. approval (ANDA) process of the U.S. Food and Drug Prepared by PROVACS-Production of Vaccines from Administration (FDA) to gain approval for generic Applied Crop Sciences, a Program of The Center for equivalents within six months. See also Derzko NM. Infectious Diseases and Vaccinology. The Biodesign 2005. The Impact of Reforms of the Hatch-Waxman Institute at Arizona State University: Tempe. Scheme on Orange Book Strategic Behavior and www.biodesign.asu.edu/centers/idv/projects/provacs. Pharmaceutical Innovation. IDEA 45:165–265. 4 Arntzen C, R Mahoney, A Elliott, B Holtz, A Krattiger, CK 9 In other words, administration of a vaccine by a Lee and S Slater. 2006. Plant-derived Vaccines: Cost of route that bypasses the gastrointestinal tract such Production. The Biodesign Institute at Arizona State as through the use of injections, patches, creams or University: Tempe. www.biodesign.asu.edu/centers/ sprays. idv/projects/provacs. 10 The filing date is important, since patents filed prior 5 Ibid. It is interesting to note that a sensitivity analysis to March 1995, once issued, would be valid for 17 years that reduced the yield of antigen in the plant by a from the date of issue (or 20 years from the filing factor of three was also conducted. This is equivalent date, whichever is longer) and may lead to so-called to increasing the required dose by a factor of three; all submarine patents that seem to appear from nowhere. other variables such as capital and labor costs have This is because any patent filed prior to March 1995 is little impact on final cost if they are varied within not published until issued. The rules changed as of reasonable ranges. This sensitivity analysis shows March 1995: Any non-provisional patent application that under worst-case conditions, the cost per dose of filed since then is published 18 months after filing. a product made in the US and prepared in a ten dose packet would rise to $0.09 from $0.06. 11 It is likely that Kentucky Bioprocessing has at least non- exclusive licenses to a number of LSB Corp.’s patents. 6 See, also in this Handbook, chapter 4.7 by M Blakney. 12 Mahoney RT, A Krattiger, JD Clemens and R Curtiss 7 Justice Scalia drafted the Court’s opinion. He wrote: III. 2007. The Introduction of New Vaccines into “As an initial matter, we think it apparent from the Developing Countries IV: Global Access Strategies. statutory text that 35 U.S.C. § 271(e)(1)’s exemption from Vaccine (in press). infringement extends to all uses of patented inventions that are reasonably related to the development and submission of any information under the FDCA. Cf. Eli Lilly, 496 U.S., at 665-669, 110 S.Ct. 2683 (declining

HANDBOOK OF BEST PRACTICES | 1817