For our human practices, we decided to look at how intellectual property, biotechnology companies, and synthetic biology intersect in order to understand the development of products from academia to industry. With recent landmark decisions by the US Supreme Court regarding DNA sequence patents, we wanted to know how the patent landscape looks in synthetic biology and taking products from the academic sphere to the biotechnology world, given that open-source technologies is lauded by the community, as shown in the BioBrick movement. In addition, since we are working with yeast, a commonly engineered organism used in the biotechnology industry, we were curious as to what steps we as the Duke iGEM team would have to take to get our product to market. We look at how patents have come to prominence and helped many companies start their thriving businesses, but also how patents have been detrimental to the community of scientists. In order to prevent a closed community of synthetic biologists, we suggest a few things to allow for more open-access research to reach the biotechnology industry.

History of Intellectual Property in Synthetic Biology

Gene patents date back to 1976, when Stanford and the University of California filed a patent application for recombinant DNA technologies. Two years later, under the Institutional Patent Agreement, universities were granted the right to own all inventions arising from research as long as they complied with physical and biological containment standards in NIH guidelines and allowed the government to receive a free non-exclusive license to use the results. Opposing arguments claimed that since research is publicly funded, it should therefore be property of the US government.

The Human Genome Project initiated the debate of whether DNA is patentable or not. Since DNA sequences are discoveries and not inventions, they would appear to not be patentable or copyrightable. In 1991, Craig Venter learned of a method to identify short cDNA sequences called ESTs (expressed sequence tags), which were coined by Anthony Kerlavage. Using this EST method, Venter was able to rapidly identify all mRNAs in a cell, and applied for patents of 337 partial cDNA sequences of unknown function. This was seen as a movement towards a cDNA arms race- the exact opposite of the collaboration and cooperativity that was expected from the Human Genome Project. While the goal of the NIH is rapid dissemination of products to be used to treat disease, this move directly contradicts the easy and fair access that it claims to support. Venter’s push to patent cDNA sequences would have granted him access to the entire coding sequence, complementary sequence, allelic sequence, and ultimately, the encoded proteins from a cDNA, although this was unknown to him at the time. The patent was ultimately rejected, creating a precedent for the future of synthetic biology.

Current

More recently, a series of Supreme Court cases have brought the world of synthetic biology to the public eye.  

More recently, a series of Supreme Court cases have brought the world of synthetic biology to the public eye. Sangamo Biosciences Inc., a clinical stage biopharmaceutical company, holds the vast majority of zinc finger intellectual property. Purchasing zinc fingers from Sangamo rings up a hefty price of $15,000 or more for a single functioning zinc finger nuclease, which only work in pairs. Using purchased zinc fingers, it is impossible to do open source research due to licensing and high costs. Sangamo’s monopoly over the zinc finger industry prompted the synthetic biology community to develop an open source alternative so that research would not be hindered.

In June 2013, the Supreme Court unanimously decided that genes are not patent eligible after Myriad Genetics claimed the rights to two isolated genes that greatly increase the risk of ovarian and breast cancer when mutated. This decision ruled that genomic DNA is a product of nature and cannot be patented solely because it is isolated. However, cDNA, or DNA with the introns removed, remains patent-eligible.

Benefits of a patent for a biotech industry vs. copyrights and trademarks

The broad use of the term “intellectual property” has blurred the lines between patents, copyrights, and trademarks, all of which carry important distinguishing features when considering their uses in synthetic biology. By definition, copyrights apply to a work of art, while patents cover inventions and methods. Trademarks, which are less common in the synthetic biology industry, essentially label a certain researcher’s creation. By putting a “watermark sequence” on a product, such as when Craig Venter put his name and those of the authors into the DNA sequence of their synthetic cell, the manufacturer has claimed exclusive control over that product, protecting the credibility and quality of its source. However, trademarks do not protect an idea, and allow other researchers to produce similar, or even identical, products, thus reducing the chances for a monopolistic industry. Therefore, in an effort to maintain control over a product, researchers are less likely to use trademarks over copyrights or patents. One major topic of discussion is whether to treat synthetic biology as a copyrightable or patentable entity. Arguments have been made to pull emerging synthetic biology to follow in the footsteps of either the software industry or biotechnology. To be copyrightable, engineered products such as proteins and DNA must be deemed as “original works of art or expression”. This qualification has been made in the software industry for code and programs, which are copyrightable. However, methods are not copyrightable, allowing for protocols to be adapted and used in the building of new synthetic parts. In addition, copyrights do not carry much enforceability.

The other side of this spectrum pushes synthetic biology towards the biotechnology industry, with a race to patent both methods and products. A patent is issued by the government and confers to the applicant the exclusive rights to a method or product. To qualify for a patent, a method or product must be novel, non-obvious, and have utility. Determining the extent to which these qualifications cover has even been taken up in the Supreme Court. For biotech startups, investing in heftily priced patents allows researchers to accrue royalties by licensing their products. Patents encourage the commercialization and development of the industry by providing incentives for researchers.

Enforcement of patents and licensing in consideration of academia

Efforts have been made to create a balance between patents and open-source technologies regarding the respective users of new technologies. Intellectual property management must take into account private companies versus academic researchers, and all in between.

Open source is very effective in the software industry because of its modularity. Many people can contribute bits of code to a common domain so that others can utilize selected pieces to build new systems, which can then be integrated together. The same is true for synthetic biology. As new parts are characterized and submitted to the common domain, other researchers can build on these parts to create new systems. In our interviews with Arti Rai and Robert Cook-Deegan, we discussed the intrinsic and extrinsic motivations driving the open source model for synthetic biology. In the software industry, once developers create code to solve their specific problem, there is usually no reason to keep the information from being freely accessible. We also discussed the motivations driving the open source model for synthetic biology. It is interesting to note the different positions on the topic of access for academic versus commercial institutions. For academic institutions, it is clearly beneficial to maintain an open source registry modeled after the software industry so that parts can be freely shared between researchers. However, it can be argued that when these parts are taken up into the commercial sector, companies should pay appropriate royalties. Support for this argument stems from the fact that companies would then be commercializing parts that were publicly funded.

Sequence patents or methods patents

Craig Venter’s attempt to patent all cDNA sequences in the human brain exposed a possible threat to the future of synthetic biology commons. With the rapid design and building of TALEs, it would be possible for someone to synthesize all 16,777,216 combinations of 12 repeat variable diresidues (RVDs). Patenting all of these TALEs would effectively placing a lock on the industry. To avoid something of this nature, it is important to prevent methods patents in synthetic biology. Patent applications must have a clear written description of use and enablement. Patents would not be granted for parts without a known functionality.

   The zinc finger industry has been predominantly run by Sangamo Biosciences, accruing more than 40 design and methods patents on zinc fingers, the earliest of which ends in 2018. Even though the patents end soon, the scientific community cannot wait for the release of this information to further their research, and many researchers do not want to pay the large amounts to have custom built zinc finger proteins. Hence, many researchers such as Keith Joung, Dan Voytas, and Carlos Barbas developed open-source alternatives to Sangamo in order to advance in the field. Certainly, many of these open-source alternatives violated some aspect of the patents, but Sangamo has not pursued litigation against these academic institutions, largely because the alternative proteins are not as effective as Sangamo’s (Chandrasekharan et al., 2009). 


   With the initial growth of the TALE and CRISPR/Cas9 industry in 2009 and 2013, respectively, there has been an open-source movement from the inception, allowing for rapid growth and development of TALEs in biotechnology industry, as well as plant genetic engineering and biomedical applications. With the relative ease of designing and making TALEs and small guide RNA molecules for the CRISPR system, many groups that previously did not use these proteins are now using them in their research. We applaud the open access of TALEs and the CRISPR/Cas9 systems initiated by Dan Voytas and Feng Zhang, respectively, and encourage the future of synthetic protein research to follow the same approach to allow for the continued growth of synthetic biology. 

Guidelines and practice standards for the Biobrick community

It is important to note that there are many BioBrick parts in the registry that infringe on patents already. Most companies do not take action against academic institutions, but this can serve as an eye opener to the danger of upstream patent thickets. We fear that patent thickets can hinder the progression of synthetic biology tools into the biotechnology industry from academic institutions. Patent trolling has been a problem in some industries where the fear of litigation stops a group from pursuing research. This, while not as apparent in the zinc finger industry, has not been found with TALEs or CRISPR/Cas9, and we encourage this progress.

As the BioBrick community continues to expand, we urge contributors to maintain the registry as suggested below. We offer ideas for the development of the registry, and support the “9 Points” that many academic institutions have already adopted. “9 Points to Consider” was published in 2007 as the suggested standards for universities to follow when granting licenses to outside institutions and applying for patents that may limit research at other institutions. The “9 Points” emphasizes that the primary goal of research is to promote improvements for society, and warns against the use of patents which could hinder any advancement.

9 Points

1. Universities should reserve the right to practice licensed inventions, and to allow other nonprofit and governmental organizations to do so.
2. Exclusive licenses should be structured in a manner that encourages technology development and use.
3. Strive to minimize the licensing of ``future improvements.``
4. Universities should anticipate and help to manage technology transfer related conflicts of interest.
5. Ensure broad access to research tools.
6. Enforcement action should be carefully considered.
7. Be mindful of export regulations.
8. Be mindful of the implications of working with patent aggregators.
9. Consider including provisions that address unmet needs, such as those of neglected patient populations or geographic areas, giving particular attention to improved therapeutics, diagnostics and agricultural technologies for the developing world.

 We would also like to see the BioBrick registry become more accessible between shared systems. Since BioBrick parts only use four restriction sites, these limitations impose on the modularity desired in building compatible systems.  Open registries with fewer restrictions increase the diversity of standard parts that can be shared between systems.  Each category of parts, such as promoters, reporters, and genes, could be submitted on unique backbones for each part. In addition, it might also be possible to design BioBrick backbones with different restriction sites that might work better based on the system of interest. If, for example, there were four BioBrick plasmids, each with a different set of restriction sites, then if any insert interferes with one backbone, perhaps it will be compatible with another set. This still allows or the modularity of inserts while having more freedom in design. Finally, another option is to allow for the submission of any parts on any backbones, such as what AddGene does, although this does not allow for the modularity or standardization of parts. 

Taking the risk-Prize Funds

Prize funds can potentially serve the synthetic biology community to allow for academic innovations to reach the biotechnology market. In a prize funded project, researchers would receive funding on projects of particular need to the world, whether it be a therapy or drug, or some environmental cleanup tool, and if successful would receive prize money to take the product to industry with the intention of not patenting or obtaining exclusive licenses to the product. This has been outlined as a form of global justice in biotechnologies by Thomas Pogge and the Health Impact Fund in order to ensure that the world’s population benefits from tools developed by researchers. Such prize funds would allow smaller researchers with big synthetic biology inventions to take their products to market without having to compete against large companies with many patents to hold their stake. Many different funding groups, including the NIH, NSF, and governmental agencies could develop synthetic biology prize funds to tackle large-scale issues. This would allow the just distribution of products without the exorbitant prices allowed by holding exclusive rights of a product. This may seem to be more a matter of social justice, but still have high potential to spur innovation among academics and take the research to consumers.

Conclusion

After speaking with several professors, looking at the history of intellectual property in synthetic biology, and participating in the BioBrick community as iGEM members, we see the need to maintain open-source standards in the community. However, as groups operating under these principles take their products from the bench to the biotech world, they might face resistance when not having patent or IP rights, even though most academics do not see litigation involving patent infringements. One idea is to create prize funds that allow for smaller groups to innovate using synthetic biology and provide proper funding for the growth of their product while giving up patent rights and exclusivity. We encourage the continued open-source community of TALEs and CRISPR scientists in order to spur more innovation in this realm of synthetic biology. We also provide the Nine Points to Consider as a valuable set of guidelines for researchers and academic institutions to follow, especially with the BioBrick standards. The BioBricks and open-source synthetic biology is not mutually exclusive with the patent strongholds of the biotech industry; both can coexist but require an understanding of how to navigate the growth of academic research into real-world applications.

References

1. Belt, H van den: Synthetic biology, patenting, health and global justice. Syst Synth Biol. 2012.
2. Chandrasekharan S, Kumar S, Valley C, Rai A: Proprietary science, open science and the role of patent disclosure: the case of zinc-finger proteins. Nature 2009. 27: 140-144.
3. Cook-Deegan, Robert: Law and Science Collide Over Human Gene Patents. Science 2012. 338.
4. Cook-Deegan R, Heaney C: Patents in Genomics and Human Genetics. ARI 2010. 17: 1-36.
5. DeFrancesco, Laura: Move over ZFNs. Nature 2011. 29: 681-684.
6. Genome Patent Fight Erupts. Science. 245: 184-186.
7. Kumar S, Rai A. Synthetic Biology: The Intellectual Property Puzzle. Texas Law Review 85: 17 45-1768.
8. Ledford, Heidi: Bioengineers look beyond patents. Nature 2013. 499: 16-17.
9. Marshall, Eliot: Companies Rush to Patent DNA. Science 1997. 275:780-781.
10. Rai A, Boyle J: Synthetic biology: Caught between property rights, the public domain and the commons. PLoS Biol 2007. 5(3): e58. doi:10.1371/journal.pbio.0050058.
11. Rai A, Cook-Deegan R: Moving Beyond “Isolated” Gene Patents. Science 2013.
12. Scott C: The zinc finger nuclease monopoly. Nature 2005. 23: 915-923.
13. Universities can patent recombinant DNA results. Nature 1978. 272: 199.
14. Zinder N: Patenting cDNA 1993: efforts and happenings. Gene 1993. 135: 295-298.
15. Pogge, T. (2009), The Health Impact Fund and Its Justification by Appeal to Human Rights. Journal of Social Philosophy, 40: 542–569. doi: 10.1111/j.1467-9833.2009.01470.x