Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Among unresolved issues are gene patentability, patent protection vs. open access, and the effect of patent reform.

The biotechnology world was rocked a year ago this month, when J. Craig Venter, Ph.D., reported that he led a team of 17 researchers at his namesake institute in completing the second of three key steps toward creating a fully synthetic organism. The team created the largest man-made DNA structure by synthesizing and assembling the 582,970 base pair genome of the Mycoplasma genitalium.

Scientists and even politicians debated the ethics of the research and of the broader goal of creating artificial life. Soon after Dr. Venter’s announcement, President Obama directed the Presidential Commission for the Study of Bioethical Issues to assess the field of synthetic biology. Last December, the 13-member panel recommended coordination of federal agencies involved in oversight, product licensing, and funding.

Even before Dr. Venter’s work, though, biologists, bioethicists, and others have been trying to streamline synthetic biology. One of the goals is to standardize synthetic biology parts and devices. Commenting on intellectual property, Drew Endy, Ph.D., assistant professor, bioengineering with Stanford University’s Department of Bioengineering, stated during a testimony before Congress last year, “As our capacity to engineer biology increases, so does the number and combinations of uses of genetic functions that will be deployed. Such novel uses and combinations are typically protected via patents.

“However, via synthetic biology, we are already experiencing situations in which the cost and time required to use a patent-based approach does not match the scale or pace of work.” As a result, much is still in the air when it comes to intellectual property issues in synthetic biology, added Arti K. Rai, member, Duke Institute for Genome Science and Policy, and Elvin R. Latty, professor of law at Duke Law School.

“If and when standardization is realized, then we could see the same sorts of IP issues that we see in information technology regarding standards—strategic behavior in disclosing IP to the standard-setting organization, et cetera,” Rai told GEN. “Right now—i.e., absent standardization—I am not sure I see a set of issues distinct from those that face biological research more generally.”

Syn Bio IP Law Expected to Follow Biotech

Stephen A. Bent, a partner with the law firm Foley & Lardner, agreed. Since synthetic bio involves synthesis and assembly of cells or organisms, it is not likely to upend years of IP law developed since the early days of biotechnology, he told GEN.

“To some extent, we are talking about an elaboration of things that went before,” Bent noted. “This is biotechnology revolution 2.0, so I’m not sure that there’s so much of a demarcation of 1.0 and 2.0 that we’re talking about a different paradigm for IP protection. That seems unlikely.”

Among issues that arose and were settled during biotech’s first generation from the 1970s through the 1990s was the rejection of overly broad claims intended to cover large areas of research. “During biotech 1.0, we were trying to use words to describe the engineering of biological systems we didn’t build ourselves and didn’t really know a lot about, in the same way that people used them to describe devices during the industrial revolution. That was the problem.”

Courts, Bent said, addressed that problem by rejecting sweeping claims seeking patent protection beyond inventors’ limited application of manipulating DNA in one plant or animal, for example, toward all forms of genetic tinkering. As a result, biotech inventors had to narrow their claims and corresponding descriptions to protect their intellectual property.

Bent expects that focus on narrow claims to continue under synthetic biology, since the work being done and the IP resulting from that work are more extensive than what was carried out in biotech’s first generation.

“The whole notion of synthetic biology is something of a hyperbole. We’re still a long ways away from building multicellular organs, maybe a century or more. So we’re doing more extensive rebuilding, re-engineering of biological systems.

“We acknowledge that it’s more far-ranging than ‘Hey I’ve got this gene. Let’s see if I can express it in every background I can think of,’” Bent said. “We know more about these systems. We’re going to engineer them in a more extensive manner, the way Venter and his crew did with those bacterial cells.”

Impact of Myriad Case

Other professionals also predict that IP creation for synthetic biology is likely to develop along the lines established for the broader field of biotechnology over the past three decades. But at least some of those lines may be rewritten in the near future, since a current court case threatens to limit patentability of individual genes.

In 1980, the U.S. Supreme Court established the patentability of manipulated genes. Now, a case working its way through the U.S. Court of Appeals for the Federal Circuit threatens to end patentability for individual genes. The appellate court last month heard an appeal in the case of The Association for Molecular Pathology et. al. v. U.S. Patent & Trademark Office et. al., which focuses on the validity of patents issued to Myriad Genetics and the University of Utah for BRCA1 and BRCA2, breast cancer gene mutations.

Last year Justice Robert W. Sweet of the U.S. District Court for the Southern District of New York surprised biotech industry observers when he declared the patents invalid, as sought by the association and its attorneys from the American Civil Liberties Union and Public Patent Foundation.

“The continuing debate over the patentabilty of isolated genes is relevant to synthetic biology,” Baskut Tuncak, staff attorney for the Center for International Environmental Law (CIEL), told GEN with respect to the Myriad case. “However, the questions of patentability raised by synthetic biology are much broader in scope, as the subject matter would presumably include raw materials and/or assembled systems that have no counterparts in the natural world.”

Role of Open-Access

Rai recalled the patent history of custom-engineered zinc finger proteins (ZFPs) capable of binding virtually any DNA sequence of interest. A single company, Sangamo, consolidated the majority of relevant patents generated from the research, raising questions of whether any company’s monopoly control over a research platform will ultimately help or hinder its optimal development. Rai with three co-authors explored these issues in a 2009 Nature Biotechnology article.

According to the article, academic scientists said they routinely used patented technologies owned by Sangamo without securing a license, under the apparent expectation that Sangamo will refrain from suing academics. Rai and co-authors discussed how the scientists they interviewed wanted to collaborate with Sangamo only to find the company would not disclose its proprietary technologies and was highly selective in its choice of collaborators.

Sangamo’s actions prompted ZFP researchers J. Keith Joung and Dan Voytas to create the Zinc Finger Consortium, with a commitment to develop resources, software, and other tools for engineering zinc fingers and for performing robust, user-friendly genome engineering that is publicly available to the academic scientific community.

Consortium members have developed Zinc Finger Targeter (ZiFiT), one of several web-based tools for identifying potential ZFP target sites in DNA sequences. Another openly available tool is Zinc Finger Tools, developed by Carlos Barbas’ research team at the Scripps Research Institute, allowing for DNA sequences to be searched for contiguous or separated target sites.

“Because of problems with patent disclosure, patents may effectively be posing a barrier to academic research in this field,” Rai and his co-authors concluded. “Second, resolving deficiencies in patent disclosure could mitigate the problem of academic access to physical materials and know-how, perhaps even obviating the need to develop open-science alternatives.”

Tuncak of CIEL said another challenge to open-innovation strategies and platforms was “the sluggish pace at which patent offices identify, react, and classify emerging technological fields.”

While the consortium and the BioBricks Foundation have made strides in keeping synthetic bio research open, Tuncak said, “the ever expanding patent-oriented practices of universities and small, medium, and large corporate research laboratories still make the challenges that result from inaccurate classification of patents a problem for researchers, entrepreneurs, and investors.”

Consequences of America Invents Act

Bent said the development of IP ownership rules for synthetic bio are not likely to be impacted by the expected overhaul of the U.S. patent law, unless the measure undercuts the longstanding one-year grace period given to inventors to file patent applications. Current law protects inventors for a year from describing their invention in a printed publication, making public use of the invention, or offering the invention for sale. The America Invents Act, which is making its way through the U.S. House of Representatives, would narrow the grace period to one year from disclosure, a term undefined in the bill.

“So much of the synthetic biology work right now is done at the academic level, and it’s the academics who are major beneficiaries of the U.S. grace period. And if that gets impaired, they will suffer accordingly, and that will have an indirect, but real, impact on synthetic biology,” Bent said.

The grace period change is among common provisions of the America Invents Act that passed the U.S. Senate in March and is now before the House. An amended version of the House measure, House Bill 1249, cleared the House Judiciary Committee by a 32–3 vote. The legislation has since advanced to the floor of the House.

Tuncak said smaller companies engaged in synthetic bio may also be challenged by provisions of America Invents that allow third-party challenges to new patents through inter partes review. “The proposed reform is intended to improve the quality of patents issued, in particular the proposal to have increased interaction with third parties before issuance of patents might help with the issue of classification of inventions. But this still requires considerable time and money, especially for small-to-medium enterprises, to effectively monitor and engage in this process,” Tuncak said.

Even if the House and Senate agree to a patent-reform measure, the outlook for resolving the intellectual property issues pertaining to synthetic biology remains cloudy. Courts have reopened the issue of gene patentability, while companies and universities investing millions of dollars into research are likely to continue patenting their discoveries rather than joining scientists in developing more open-access tools and data.

Alex Philippidis is senior news editor at Mary Ann Liebert, Inc., and Genetic Engineering & Biotechnology News.

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