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As CRISPR-Cas9 Technology Sets to Take Off, Uncertainty Swirls Around IP Landscape

NEW YORK (GenomeWeb) – As the CRISPR-Cas9 gene editing technology sets to take off, the patent landscape surrounding the method has quickly become muddled with stakeholders seeking a claim to what some are calling a foundational technology.

In April, the US Patent and Trademark Office issued the first patent, No. 8,697,359, for the CRISPR-Cas9 system to the Broad Institute, granting it intellectual property rights over a technology that, through its rapid adoption in the biotech space, is setting off what could be a scramble for IP rights over the technology and its applications and muddying the implications for both researchers and industry players using the technology.

"At the end of the day, the [CRISPR-Cas9] landscape is still very much in developmental stages," Chelsea Loughran, an IP lawyer with the law firm Wolf Greenfield told GenomeWeb Daily News recently. "Just because the Broad got this patent, it definitely doesn't foreclose other entities from getting patents in slightly different spaces, and I think a lot of the IP landscape has yet to play out."

CRISPRs — short for clustered regularly interspaced short palindromic repeats — are DNA loci containing short repetitions of base sequences. Though CRISPR sequences were first observed nearly 30 years ago, the CRISPR Cas system has been used for gene editing for only about two years. In that short time, though, it has gained wide acceptance in a number of biotech applications.

According to Feng Zhang, a core member of the Broad and the inventor listed on the '359 patent, all gene editing tools cut DNA. The advantage of CRISPR-Cas9 is that it offers a "significantly easier" method of reprogramming RNA to recognize a new DNA sequence.

Two other widely used gene editing technologies, TALEN and zinc fingers, work through protein DNA recognition, while CRISPR-Cas9 recognizes DNA through an RNA sequence that Watson-Crick base pairs with a target DNA, Zhang said. Cas9 is an enzyme that originally evolved in bacterial cells, "and in bacterial cells, it uses RNA to … target DNA, so we engineered it so that it can target human DNA," Zhang told GWDN. He and his colleagues described their method in Science in February 2013.

While there are other types of CRISPR technologies, the form of the technology based on Cas9 enzymes, called type II CRISPR, lends itself to biotech applications because of its simplicity, according to Zhang. The single enzyme Cas9 mediates DNA cleavage and targeting, while in other CRISPR systems, that targeting is achieved through a group of enzymes, making them more difficult to use.

Types I and III CRISPR, which have been used primarily for researching biological systems, also mediate bio-immunity inside bacterial cells and have the same effect as Type II, but because they do so through a group of enzymes, "that makes it more complicated to engineer," Zhang said.

Additionally, he said that potential applications of CRISPR-Cas9 are wide ranging, and "using the Cas9 system, we can now basically engineer any organism we want by modifying its own genome."

For example, the technology can be used to engineer better crops for agricultural or biomaterial applications. It can also be used to engineer biofuels "to optimize organisms so that you can increase the yields," and to design plants that are drought-resistant, Zhang said.

Currently, he and his colleagues are pursuing multiple research paths with the technology, such as the generation of new model systems for biological research, including cellular models of human diseases. They also plan to use the technology to develop new animal models, such as mouse models. And they are using CRISPR-Cas9 for genetic screens in order "to better understand the function of genes," and to study gene regulation to better understand the genome.

The most exciting possible use of CRISPR-Cas9, perhaps, is in the area of therapeutic development.

"For a monogenic recessive disorder due to loss-of-function mutations (such as cystic fibrosis, sickle-cell anemia, or Duchenne muscular dystrophy) Cas9 may be used to correct the causative mutation," Zhang and colleagues wrote in a review article published this month in Cell. "This has many advantages over traditional methods of gene augmentation that deliver functional genetic copies via viral vector-mediated overexpression — particularly that the newly functional gene is expressed in its natural context."

Two other studies also published this month underscore the potential far-reaching implications of the CRISPR-Cas9 technology in the therapeutic space. In Proceedings of the National Academy of Sciences researchers described a method based on CRISPR-Cas9 to engineer induced pluripotent stem cells to create HIV-resistant white blood cells, an approach that the scientists said "can be applied in the future toward the functional cure of HIV infection."

And in Circulation Research, researchers said they used CRISPR-Cas9 to alter the function of the liver gene PCSK9. The method, they said, could eventually be used to reduce blood cholesterol and prevent heart disease in humans.

The financial stake around the CRISPR-Cas9 technology could be enormous. No dollar figure on the size of the market for the technology exists, but since late 2013, two firms have been launched to leverage CRISPR-Cas9 for therapeutic development, suggesting the technology's market opportunity. Last November, Editas Medicine, which Zhang co-founded, was launched with a $43 million Series A investment round. Then, in April, shortly after the '359 patent was issued, Swiss biopharma firm CRISPR Therapeutics launched with a $25 million Series A investment to leverage CRISPR-Cas9 technology developed by Emmanuelle Charpentier, a professor at the Hannover Medical School in Germany.

In the meantime, numerous firms, including Thermo Fisher Scientific's Life Technologies, Sigma-Aldrich, and Origene offer products based on the CRISPR-Cas9 system, and in late May, Taconic launched a CRISPR gene editing technology for mouse and rat models after securing a license from the Broad for Zhang's technology.

Most recently, Horizon Discovery licensed Zhang's technology, following a similar deal in May with ERS Genomics for Charpentier's technology.

Complex IP picture

All this is happening even as the IP landscape around the technology has quickly become murky. The Broad may have received the first patent covering the CRISPR-Cas9 technology, but others may be forthcoming. In addition to Zhang, Editas' co-founders include University of California, Berkeley researcher Jennifer Doudna, and the school has filed an application with the USPTO for CRISPR-Cas9 technology that she and Charpentier invented.

Doudna and Charpentier are also listed as co-inventors on the CRISPR-Cas9 technology being leveraged by CRISPR Therapeutics.

Doudna referred a request for an interview to the university's technology transfer office, which declined to discuss its application, citing USPTO's ongoing review.

Similarly, Charpentier declined a request for comment and referred questions to CRISPR Therapeutics CEO Rodger Novak who, through a spokesman, also declined to comment. Novak told Gene Silencing News recently, though, that he does not believe that patent issues will hold back the field.

"Because of the broad applicability of this technology … there will be room for more than just one or two players," he said.

Regardless, Charpentier has made it clear that she believes that she is the inventor of the CRISPR-Cas9 technology. In a recent interview, she told UK publication The Independent, "The fundamental discovery comes from my laboratory and no one has told me that they have scooped me," she said. "Be certain that this discovery did not happen by chance. I have been thinking, defending, and carrying this study from Austria to Sweden and now Germany."

She added that she identified Cas9 while she was at Umea University in Sweden before she and Doudna co-authored a Science article on CRISP-Cas9 in August 2012. Editas "does not have access to the intellectual property of the patent where I'm the co-inventor," even though Doudna is one of Editas' founders, she told The Independent. "I made the decision to do something in Europe and I made the decision not to do something with Editas Medicine. I'm trying to remain true to myself," Charpentier said.

Zhang declined to comment about the technology described in the patent application filed by UC Berkeley based on Charpentier and Doudna's research, saying he was not familiar enough with it.

How the tangled IP landscape may affect the field is unclear, but in announcing his firm's deal with the Broad earlier this month, Horizon Discovery CEO Darrin Disley alluded to potential problems, saying the UK company is securing access to the widest range of CRISPR technology possible in order "to ensure that our customers and partners are secure in the knowledge that they have the freedom to pursue their research and commercial goals when they choose to work with us."

While the Broad is pursuing licensing deals with industry players for Zhang's CRISPR-Cas9 system, it is also making reagents for the method available through a non-profit called Addgene, which runs a repository offering plasmids to scientists in academia and non-profit organizations. The Broad is not charging Addgene for the reagents although Addgene charges a fee to researchers for the tools. Additionally, Zhang said that his lab has provided CRISPR-Cas9 plasmids directly to researchers for free.

As UC Berkeley awaits the USPTO's decision on its CRISPR-Cas9 application, IP lawyer Loughran said that whether a patent issued for the technology would duel with or complement the Broad's patent could determine how the CRISPR-Cas9 field evolves.

Loughran questioned whether the field would evolve in such a way that the different IP holders would fight with each other, or whether they would coalesce their IP "under some licensing curve" that will then be available to researchers. At the moment, there are clear issue claims and pending claims with no way of telling what will be complementary or competitive claims, she said.

Both the Broad and UC Berkeley are pursuing similar patent protection for CRISPR-Cas9 for basic genomic editing purposes, but as UC Berkeley's application goes through the USPTO review, the scope of its claims could be narrowed. The result is that what gets patented could be very different from what the university and its researchers sought, Loughran said.

"That is going to be the big question: Will it be possible for Berkeley to get claims issued that overlap with [the Broad's], and if they do, then how is that going to play out?" she added. "Will there be a dispute between those two entities regarding who invented the subject matter first?"

She also pointed out that numerous other CRISPR-related patent applications were filed prior to the issuance of the Broad's '359 patent — in some cases, several years before — but that the USPTO had yet to prosecute some of the applications. For example, Dupont's Danisco business, which focuses on food ingredients, has applications for the use of CRISPR technology for food products and dietary supplements going back to at least 2005.

Writing in The Bureau of National Affairs earlier this year, Loughran and her colleague Patricia Granahan noted that published patent applications and issued patents that do not directly relate to genomic editing may, nevertheless, be cited as prior art to later-filed pending patent applications. They noted Danisco's patent applications, as well as US Patent No. 8,546,553, issued to the University of Georgia Research Foundation and titled "Prokaryotic RNAi-like system and methods of use." That patent includes claims around an isolated polynucleotide comprising at least 23 nucleotides, a psiRNA-tag, and guide sequence.

While such patent applications and/or issuances were filed before it was determined that CRISPR-Cas9 could be used in gene editing, "you wonder what kind of claims [the filers will] ultimately get from" their patent applications now that the Broad has been issued the '359 patent, Loughran told GWDN.

And now that it's been demonstrated that the CRISPR-Cas9 system has use in therapeutic development, parties have started seeking IP protection for the technology around such purposes, including Sangamo Biosciences, for example, which has several patent applications with the World Intellectual Property Organization.

Last fall, just as the buzz around the technology was starting to build, Loughran started looking into the CRISPR-Cas9 IP space and found only a limited number of recent patent applications covering the technology. Since then, however, "the landscape has changed drastically and has drastically started to develop," she said, adding that she anticipates much of the same in the near term.

"Over the next eight to 10 months, I think we're going to have even more patent applications, potentially more patents issued, and hopefully, the outcome is positive for research and for technology in this area," Loughran said.

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