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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.
• 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
agrobacterium-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 tissue 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 rice containing pro-
• Related technologies (such as adjuvants, Vitamin A, called “Golden Rice.” 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
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 tobacco). 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.
• 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 crop 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, cotton, 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.
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. afk3@cornell.edu
the creation of a quality seal for all plant-derived
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. rmahoney@pdvi.org 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
drought tolerance), 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