Publications: ISAAA Briefs

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Executive Summary

List of Tables, Figures and Appendices

1. Background and Introduction

1.1 Rice Consumption and Vitamin A Deficiency in Asia

1.2 Biotechnology Research and the Development of ifpro-Vitamin A Ricel. (GoldenRice^TM)

1.3 The Institutional Context of GoldenRice^TM

2. Objectives, Limitations and Methodology of the Freedom-to-Operate Review

2.1 Objectives and Purpose

2.2 Limitations

2.3 Methodology

3. Biotechnology Product Management: The Role of Freedom-to-Operate Reviews

3.1 Why Biotechnology Product Management is Important

3.2 What is a Freedom-to-Operate Review and How is it Done ?

4. Deconstruction of the GoldenRice^TM Product

4.1 Overview

4.2 Movement of Tangible Property

4.3 Intellectual Property Analysis: Deconstruction of the Components

4.3.1 Plant/Seed Source

4.3.2 Gene Constructs (cloning vectors)

4.3.2.1 The plant transformation vector, pBin19Hpc

4.3.2.2 The plant transformation vector, pZPsc

4.3.2.3 The plant transformation vector, pZLcyH

4.3.3 Transformation vectors, techniques, and plant regeneration

4.4 Discussion of Special Cases

4.4.1 The nptII gene

4.4.2 Method of Plant Transformation

4.4.3 Overlapping Patent Claims in Carotenoid Biosynthetic Option Genes

4.4.4 Interpreting Patent Claims: From Greater to Lesser Uncertainty.

4.4.5 Pea Rubisco Small Subunit Transit Peptide.

5. IP Management Implications

5.1 Introduction

5.2 Potentially Applicable Patents (or IP) to the Current Form of GoldenRice^TM

5.3 Product vs. Process vs. Use Claims

5.4 The Important Distinction between IP and TP

5.5 IP Management Options or Strategies

5.5.1 OPTION 1: Invent Around Current Patents

5.5.2 OPTION 2: Re-design Constructs

5.5.3 OPTION 3: IP/TP Owners to Relinquish Claims

5.5.4 OPTION 4: Ignore all IP and TP

5.5.5 OPTION 5: Seek Licenses for all IP and TP

5.5.6 OPTION 6: Mix of all Options (1 to 5)

5.6 Practical Considerations on Where the Final Product is Developed

6. Conclusions: Implementing IP/TP Management Systems

6.1 Major Options on the Management of IP associated with GoldenRice^TM

6.1.1 Complete and Regular Updates to the FTO

6.1.2 Strategic Science Plan

6.1.3 Strategic Distribution Plan

6.1.4 Cost/Benefit Analysis

6.2 Outlook

 References

 Acknowledgements

 Appendices

Introduction

Rice is a staple food for millions of people, predominantly in Asia, but lacks essential nutritional components such as Vitamin A. This is very important for over 180 million children and women of child bearing age who suffer from Vitamin A deficiency in Asia alone. For this reason, an improvement was made under an effort led by Profs. Ingo Potrykus and Peter Beyer by inserting several genes into rice to produce an improved product called "GoldenRice^TM". (on the trademark, see Note on Trademark and Domain Names below). Because GoldenRice^TM has the potential to be easily integrated into the farming systems of the world's poorer regions, the advent of GoldenRice^TM promises to go a long way towards solving Asia's Vitamin A deficiency problem in an effective, inexpensive, and sustainable way.

Objectives, Limitations and Definitions

As a result of the increasing complexity of the intellectual property (IP) framework under which the international agricultural development community operates, the Rockefeller Foundation funded an ISAAA project to conduct a selective Freedom-To- Operate (FTO) analysis of GoldenRiceTM with the objectives of:

1. reviewing the IP and Technical Property (TP; or tangible property) components associated with GoldenRice^TM;

2. providing institutions interested in distributing GoldenRice^TM with the information needed to develop strategic options for handling the proprietary science embedded in the product; and

3. developing possible alternative strategies on how the IP/TP constraints could be managed effectively.

Any FTO opinion is a risk management opinion and its results vary on a country-by- country basis. It is a dynamic opinion; never a definitive answer. Hence the present document serves as an analytical framework that can serve as the basis of a legal FTO review. While it contains information on ownership and statutory protection issues, it is not intended to be a final legal opinion.

In addition, this report is not aimed at commenting on any institution's current IP/TP strategy, but on providing relevant information to make sound policy and strategy decisions. Neither is this study intended to promulgate any particular approach about how to overcome the IP and TP challenges while dealing with the proprietary science of agriculture and plant breeding.

Proprietary Property, or proprietary science, as used throughout this document, is comprised of: ·

• IP or Intellectual Property, which has been taken to mean, without limitation, intellectual property rights, including patent rights, plant variety protection certificates, unpublished patent applications, and any inventions, improvements, and/or discoveries that may or may not be legally protectable, including all know-how, trade secrets, research plans and priorities, research results and related reports, statistical models and computer programs and related reports, and market interests and product ideas; and ·

• TP or Technical Property, which has been taken to mean, without limitation, tangible property such as computer software, germplasm and the biological materials and derivatives thereof, and related information.

Under the product deconstruction process of GoldenRice^TM, we reviewed plant/seed source; gene constructs (TP and IP) of cloning vectors pBin19hpc, pZPsC and pZLcyH; transformation, plant regeneration, and other techniques; and DNA amplification technologies.

Technical Property

At least fifteen TP components went into the three different genetic constructs; many of which were acquired by ETH-Zürich under Material Transfer Agreements or by use licenses. Some of this complexity stems from the product being a multi-transformant, in which three genes/enzymes (phytoene synthase, phytoene desaturase, and lycopene cyclase) were introduced in the carotenoid biosynthetic pathway (Figure 1 shows the flow chart of the elements that went into one of the three constructs or plasmids). This required three transformation vectors and the application and use of many other processes and components. For reasons related to the confidentiality embedded in these agreements, we are not providing details of these agreements nor our interpretation of them in this published version of the FTO. Determining what entity has the right to grant licenses or sub-licenses is a relatively tedious process, one which continually evolves as companies re-structure, sell or assign patents, or grant licenses with or without the right to sub-license. Hence at this stage we only identified the patents according to the original assignee and have not determined which entity would have to be approached for licensing the various components.

Intellectual Property

Depending on the country where the current form of GoldenRice^TM would be used we identified between zero and 44 patents which applied to the product. In the USA and most countries of the European Union, around 40 patents apply. In the 10 top rice producing countries, many fewer patents apply, namely: China (11), India (5), Indonesia (6), Bangladesh (0), Vietnam (9), Thailand (0), Myanmar (0), Japan (21), the Philippines (1) and Brazil (10). Similarly, in  the top ten rice importing countries, relatively few patents apply: Iran (0), Brazil (10), Nigeria (0), the Philippines (1), Iraq (0), Saudi Arabia (0), Malaysia (0), South Africa (5), Japan (21) and Côte d'Ivoire (10).

Recognizing that patent claims may be granted for different kinds of inventions, claims may be worded to cover products per se, products-by- process, uses, or processes. Whereas the first three types of claims generally extend to the products that embed the new discoveries, "process" claims or claims for the claimed technical procedures do not extend to the products that are produced by the claimed processes. What is of great importance for "process" claims is the country in which the process is applied. If the product is made in a country where those "process" claims have not been issued, then a license for such claimed processes are not required.

A total of 26 of the approximately 70 patents identified in this study contain primarily process claims thus reducing somewhat the number of applicable patents which could inhibit FTO in a given country. A detailed analysis on a country-by-country basis may reduce the complexity of the IP landscape.

Discussion on Alternative IP/TP Management Strategies

Transfer and use of GoldenRice^TM , depending on the country in which it is to be deployed, would, at a minimum, require agreements from a dozen or so entities (public and private) for the TP transfer and use. In addition, again depending on the country of use, between zero and 40 licenses for IP rights would be required, from a dozen or so entities. In total, negotiations with 12 to 20 entities might be required, again depending on the country of release. Noteworthy is that if a regional or international organization, such as the International Rice Research Institute (IRRI), wishes to obtain FTO, say for national use in all developing countries in Asia, licenses for around 30-40 patents would need to be obtained (in addition to the resolution of TP).

All in all, the widespread release of the current version of GoldenRice^TM  will require significant licensing activity if it is to legitimately become available to the world, either commercially or for humanitarian purposes.

We identify and discuss the advantages and disadvantages of six alternative strategies on how to gain FTO for GoldenRice^TM , namely:

1. Invent around current patents: Research alternative ways to develop pro- Vitamin A rice, generating new inventions. This option, which is a science and research based approach, leads to less reliance on other institution's patents but is likely to be very costly and time consuming (if at all feasible). It would arguably not constitute a wise use of development funds.

2. Re-design constructs: Re-design each construct to reduce number of applicable patents, whenever possible synthesize own genes to reduce reliance on TP of others. This strategy, which is a product development based approach, is a likely one as it may be necessary for scientific reasons to re-design the product. It is an effective way to reduce other institution's IP and particularly efficient if an FTO analysis is done prior to initiation of the research. This approach would almost certainly be the approach favored by any company as the TP issues are potentially the most difficult ones to resolve.

3. IP/TP owners to relinquish claims: All FTO issues for all GoldenRice^TM related activities, commercial or otherwise, are eliminated through public (or private) statements and related activities by the certified owners/assignees of each set of IP/TP rights for making, having made, using, having used, importing, exporting, selling, and having sold all GoldenRice^TM plants, plant parts, and all related products and processes. This humanitarian strategy focuses on public perception. Some companies (e.g. Zeneca and Monsanto) already publicly declared that they will make their technologies available for GoldenRice^TM. This will greatly simplify licensing negotiations although a royalty- free license may still need to be negotiated, at least for liability/indemnity reasons.

4. Ignore all IP and TP: All FTO issues for all GoldenRice^TM related activities, commercial or otherwise, are ignored, and research and product development as well as plans for general distribution proceed. This approach is a strategy that certainly has the lowest near-term costs but may lead to long terms costs, especially if a lawsuit ensues, and may lead to the longest delay in product dissemination.

5. Seek Licenses for all IP and TP: All FTO issues are resolved by the process of any party (individually or through consortia) acquiring an appropriate (commercial or other) license from the certified owners/assignees for each set of IP/TP rights for the GoldenRice^TM related activities that are of interest to the licensee. This license may be commercial in nature (a grant to make, have made, use, have used, import, export, sell, or have sold all GoldenRice^TM plants and plant parts and all related products and processes) or a more restrictive one as the licensee and licensor mutually determine to be required. This licensing approach is complex and costly, but may lead to stronger public- private relationships whereby corporations are also willing to transfer know-how and future biotechnology inventions. It is also the safest route and ensures good relations with IP owners (be they from the public or private sectors).

6. Mix of all Options (1 to 5): While research and development plans are made to optimize the product, re-design of constructs and acquisition on TP is planned to minimize IP and TP conflicts (OPTION 2); selected FTO issues are removed through public (or private) rescinding of rights by selected holders of certain IP/TP rights (OPTION 3); this i)moral high ground ld is used to leverage additional rights holders to either rescind their claims (OPTION 3) or to reduce their demands within the context of license negotiations (OPTION 5). In the end all remaining unrescinded IP/TP rights can be either licensed (OPTION 5) or ignored (OPTION 4). This strategy is again complex from the perspective of IP/TP management but seems to be the most pragmatic and realistic. It capitalizes on the upsides of most of the other options while reducing the risks of future complications.

Discussion on Risk Management Strategies

Developing a sound IP management strategy is, in many ways, primarily a matter of risk management. No one ever definitively knows who has rights to do what with all IP, because new patents are continually being issued, older patents expire and patent-related court settlements take place around the world. All that any organization can do is try to comply with the FTO opinions that they commission, establish protocols to defend (or proactively fight) themselves, and seek whatever licenses they believe that they need to reach their goals.

For international institutions, licensing issues are further clouded because their donors and clients are from many different nations. Thereby the statutory protection laws required for full FTO are as varied as their client list. This leaves such institutions, particularly the centers of the Consultative Group on International Agricultural Research (CGIAR) with the challenge as to whether or not to distribute improved germplasm with full FTO or to pass this responsibility for obtaining FTO along with their improved germplasm, on to the client nation with a caveat regarding these matters.

For the present FTO, we also had to make strategic decisions on how wide a net to cast in terms of listing certain patents where it is not entirely clear whether or not they apply to GoldenRice^TM, and whether or not to include patent applications or only issued patents. We opted to cast a wide net so as to provide those institutions who wish to further develop and distribute GoldenRice^TM with a broad base of information to make sound risk management decisions. ISAAA, through the Global IP/TT Initiative, can be assisting institutions in developing appropriate and pragmatic IP management options or strategies.

Conclusions

Regardless of which option discussed above or which scenario is chosen, there are a series of tasks that should be completed in order to adequately manage the IP/TP. These are:

1. Complete and regularly update the present FTO analysis, preferably on a country-by- country basis.
   
2. Develop a scientific strategic plan (who manages, what is to be done, which biotech and germplasm components are to be used, where is the research to be done, who is to do the research, what are the timelines for completion) for finalizing the current scientific initiative.
   
3. Draft and negotiate a strategic plan for distribution (who manages, what must be licensed, list of licensors/licensees, acceptable terms, timelines) of the finished product(s).
   
4. Complete a cost/benefit analysis for the preferred options. It will be for the developing countries, which wish to benefit from GoldenRice^TM and for the organizations whose mandate is to assist these countries to make choices on the best options to follow. The dominating consideration must be the impact of GoldenRice^TM on the health and well being of rice producing and consuming populations. These and related factors will condition the speed and configuration of the eventual broad release of GoldenRice^TM.

National Agricultural Research Services, once they obtain access to GoldenRice^TM, may still wish to conduct their own FTO review in order to confirm which IP issues and TP issues are covered in their country. This is particularly true if the recipient country foresees an export market for its GoldenRice^TM. Additionally, any country to which they export their GoldenRice^TM will likely present a different IP/ TP landscape.