Plant Cell Rep
DOI 10.1007/s00299-016-1988-9
REVIEW
Genome editing: intellectual property and product development
in plant biotechnology
Helga Schinkel1 • Stefan Schillberg1
Received: 12 February 2016 / Accepted: 18 April 2016
Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Genome editing is a revolutionary technology in
molecular biology. While scientists are fascinated with the
unlimited possibilities provided by directed and controlled
changes in DNA in eukaryotes and have eagerly adopted
such tools for their own experiments, an understanding of
the intellectual property (IP) implications involved in
bringing genome editing-derived products to market is often
lacking. Due to the ingenuity of genome editing, the time
between new product conception and its actual existence can
be relatively short; therefore knowledge about IP of the
various genome editing methods is relevant. This point must
be regarded in a national framework as patents are instituted
nationally. Therefore, when designing scientific work that
could lead to a product, it is worthwhile to consider the
different methods used for genome editing not only for their
scientific merits but also for their compatibility with a
speedy and reliable launch into the desired market.
Keywords CRISPR/Cas9
Oligonucleotide-directed
mutagenesis
Patent landscape
TALE-nucleases
Zinc
finger nucleases
Introduction
Genome editing has revolutionized the manipulation of
DNA in eukaryotic organisms allowing the precise muta-
genesis of single base pairs as well as the deletion,
Communicated by T. Cardi.
& Stefan Schillberg
stefan.schillberg@ime.fraunhofer.de
1 oligonucleotides to change or remove single nucleotides
Department of Plant Biotechnology, Fraunhofer Institute for
Molecular Biology and Applied Ecology IME,
Forckenbeckstrasse 6, 52074 Aachen, Germany
introduction or replacement of large DNA fragments. The
most common editing techniques include oligonucleotide-
directed mutagenesis (ODM) (Sauer et al. 2016), the use of
zinc finger nucleases (Petolino 2015), transcription acti-
vator-like effector nucleases (TALENs) and clustered
regulatory interspaced short palindromic repeats
(CRISPR)/Cas9 (Pu et al. 2015). All four techniques are
used for numerous applications (Hsu et al. 2014; Cardi and
Stewart 2016), though due to its operational simplicity and
flexibility the CRISPR/Cas9 system is the favorite system
for most approaches. This is also reflected in the field of
plant biology and biotechnology; most published studies
exploit the CRISPR/Cas9 system to study gene function or
to introduce novel traits into crops during gene function
studies (Bortesi and Fischer 2015; Xiong et al. 2015;
Lombardo et al. 2016). Whereas for many academic
approaches the choice of genome editing technique is
based on the availability of tools and expertise, more
applied or even commercial applications must consider the
IP and license implications of the chosen technique to
allow for sustainable business development. Importantly,
all of the genome editing methods commonly used today
are patented; however, the IP situation is rather straight-
forward for some methods but less so for others.
The patent landscape and development
of commercial plant products
Oligonucleotide-directed mutagenesis
Oligonucleotide-directed mutagenesis (ODM) uses short
within the genome (Sauer et al. 2016), and this is part of
the Rapid Trait Development System of the Californian
123

company CibusTM (http://www.cibus.com). This technol-
ogy is protected by several patents (Arntzen et al. 1998;
Walther et al. 2000; Beetham et al. 2000a, b, 2002, 2014,
2015), and no one seems to dispute the claims of this IP.
The IP of the company is protecting various aspects of the
ODM technology and patents have been granted in the
USA, Australia, some members of the European Commu-
nity, Japan and China. CibusTM has produced sulfonylurea
herbicide-tolerant canola, which was launched in the Uni-
ted States in 2015. According to the company the modified
canola plants will be available in Canada in 2017 and will
launch in other major global markets after 2018. This case
demonstrates the capacity of ODM with respect to the
precise editing of genes and the commercialization of the
corresponding plant products. In this respect, the ODM
approach is clearly ahead of other genome editing
approaches in the field of plant biotechnology. CibusTM is
currently developing further modified crops using the
ODM technology, including glyphosate-tolerant flax, her-
bicide-tolerant rice and potato plants resistant to the plant
pathogen Phytophthora infestans.
Zinc finger nucleases
The patent situation is similarly clear-cut for zinc finger
nucleases (ZFN) that exploit zinc fingers for binding to
specific sequences and FokI nuclease activity for cutting
DNA strands. The IP for ZFN belongs to Sangamo BioS-
ciences, and because this company has been working on the
technology for over 10 years their IP portfolio is consider-
able (Scott 2005). Sangamo BioSciences is using their ZFN
technology primarily for developing therapeutics, e.g., for
metastatic melanoma, beta-thalassemia and sickle cell dis-
ease (Beane et al. 2015; Hoban et al. 2015). Sangamo
BioSciences licensed the technology to Dow AgroSciences
for the development of commercial products concerning
agricultural crops, industrial products and plant-derived
biopharmaceuticals in 2008 (http://investor.sangamo.com/
releasedetail.cfm?releaseid=317375). At the same time Dow
AgroSciences also became responsible for giving subli-
censes for ZFN use in plant-derived products under the
trademark EXZACTTM Precision Technology (http://www.
exzactprecisiontechnology.com). Although the potency of
the ZFN technology to edit plant genes or to introduce new
genes into plant cells has been demonstrated (Ainley et al.
2013; Schneider et al. 2016), no plant product developed
with ZFN has entered the market. However, this also applies
for the two following genome editing techniques.
Transcription activator-like effector nucleases
Another well-known genome editing method that has been
widely used in research is transcription activator-like effector
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Plant Cell Rep
nucleases (TALENs). This technology also uses the nuclease
activity of the restriction enzyme FokI for DNA cleaving but
relies upon the TALE domains for binding to specific DNA
fragments. Patents for TALENs are owned by the University
of Minnesota and the Iowa State University Research Foun-
dation, which gave exclusive rights to their use to the Min-
nesota-based Cellectis Plant Sciences Inc. in January 2011
(http://www.cellectis.com/en/content/cellectis-acquires-
exclusive-license-tal-effector-patents-university-minnesota-
0). The company changed its name to Calyxt,1 Inc. in May
2015 but is still responsible for giving sublicenses for
TALEN use in plants. The IP for TALEN is based on one
patent family (Voytas et al. 2012), of which patents have
been granted in the USA and in the European Community.
However, the situation is more complex, as the information
about how to design the DNA-binding domain that assures
the specificity of TALEN is protected by a different patent
(Bonas et al. 2010). This patent and its family are now in the
hands of the Two Blades Foundation, an organization that
‘‘supports the development of durable disease resistances in
crop plants and their deployment in agriculture’’ (http://
2blades.org/). They have a cross-license agreement with
Cellectis (http://www.cellectis.com/en/content/cellectis-
plant-sciences-and-two-blades-foundation-announce-execu
tion-cross-license-0), which allows the Two Blades Foun-
dation to use the TALEN technology for non-profit
humanitarian efforts, while Cellectis gets the license to use
the technology for commercial use in certain specified crop
plants. From this, it seems that Cellectis is the key player in
regard to IP connected to TALEN, an opinion that is shared
by the Boston consulting group among others (Boglioli and
Richard 2015).
Cellectis exploits the TALEN technology to develop
healthier crops, e.g., high oleic soybean and cold storable
potato (Clasen et al. 2016), and for both modified plants,
first field trials were completed at the end of 2015.
CRISPR/Cas9
The last genome editing method, CRISPR, discussed here
is also the newest, most applied and most controversial in
regard to its IP situation. In this system, DNA is cleaved by
Cas9, and the Cas9 protein is guided by a CRISPR RNA to
the target DNA. There are two research groups that both
claim the invention of the technology and have both
applied for patents, not for covering exactly the same
points but with enough overlap to give rise to legal dispute.
The scientists who first applied for a patent were Jennifer
Doudna of the University of California, Berkeley, and
1
The name Cellectis is used in this publication because nearly all
documents that are cited are older than May 2015 and therefore still
use the ‘‘old’’ name Cellectis instead of the ‘‘new’’ name Calyxt.
Plant Cell Rep
Emmanuelle Charpentier, currently at the Max Planck
Institute for Infection Biology in Berlin, Germany. They
applied for a patent in May 2012 (Jinek et al. 2013) and
published their results a short time later (Jinek et al. 2012).
The competing party is Feng Zhang from the Mas-
sachusetts Institute of Technology and the Broad Institute,
Inc. He filed a patent in December 2012 (Zhang 2013) and
asked for a fast-track application. This was approved, and
his patent was granted in the USA in April 2014. He also
published his data, which are closer to an actual application
in eukaryotes, in the magazine Science in February 2013
(Cong et al. 2013). This scenario means that a patent that
was applied for later was granted first, which makes a legal
battle self-evident, especially in regard to the expected
value of IP for CRISPR/Cas9.
The decision of who owns the IP for CRISPR/Cas9 in
the USA is further complicated by the fact that at the time
when both patent applications were made the US patent
system still worked as a ‘‘first-to-invent’’ patent priority
regime (they have changed since March 2013 to the more
common and easier to handle ‘‘first-inventor-to-file’’ patent
priority regime). This system now makes it necessary to
examine circumstance in detail, i.e., screening laboratory
notebooks to determine who was indeed the first inventor,
regardless of the time of filing (Summerfield 2015; Muhuri
2015). Indeed, the representatives of the Doudna party
have issued an ‘‘interference proceeding’’ in December
2015 to determine the priority issue of Doudna’s and
Zhang’s patent portfolios (Sherkow 2015; Ledford 2016).
Nevertheless, it is expected that the legal dispute in the
USA will take 3–5 years before a final decision is made.
However, this decision will only be valid for the USA;
other nations might resolve this IP conflict with a different
outcome. In the European Community, IP regimes differ
from those in the USA, e.g., the practice of ‘‘third-party
observations’’ to direct the attention of the European Patent
Office towards prior art in connection with a strong
emphasis on novelty leads to deviating conclusions in
regard to patentability (Kupecz 2014). Still, it is anticipated
that it will take years until the patent issue on CRISPR/
Cas9 is resolved in Europe as well. Similar challenges will
also present themselves in regard to follow-up patents on
CRISPR/Cas9-related inventions so that a license that is
attained now might end up worthless, as the patent will not
be ultimately granted due to a lack of novelty or IP rights
granted to another party.
Keeping all that in mind, it is astonishing (or may require
insider knowledge that the authors of this article do not pos-
sess) that a number of licenses on CRISPR/Cas9 have been
issued, e.g., by CRISPR Therapeutics, a Switzerland-based
company founded by Emmanuelle Charpentier to Vertex
Pharmaceuticals Inc. (http://www.european-biotechnology-
news.com/news/news/2015-04/crispr-licensing-deal.html)
and to Bayer (Nature Biotechnology, News 2016, http://
crisprtx.com/news-events/news-events-press-releases-2015-
12-21.php).
Even though Vertex Pharmaceuticals is a US company,
they seem to have trust in Charpentier and Doudna to hold
IP rights in the end; otherwise, it is difficult to believe why
they paid USD $105 million up-front for a license. Addi-
tionally, Bayer is investing USD $335 million in a long-
term alliance with CRISPR Therapeutics. On the other
hand, the Broad Institute, assignee to the Zhang patent on
CRISPR/Cas9, has signed license agreements with GE
Healthcare Life Sciences and Sigma-Aldrich (Philippidis
2014).
Interestingly, DuPont Pioneer received an exclusive
license for the guided Cas9 genome editing technology
from Vilnius University in June 2015 (Grushkin 2016,
http://www.pioneer.com/home/site/about/news-media/news-
releases/template.CONTENT/guid.BAED75F2-4190-04E9-
6549-0AA417910776). The group of Virginijus Siksnys
from Vilnius University filed their patent application in
March 2013 with a priority date in March 2012 (Siksnys
et al. 2013) and therefore might be the third competitor for
the IP rights. However, DuPont also formed an alliance with
the California company Caribou Biosciences Inc., which
was co-founded by Jennifer Doudna to exploit the CRISPR/
Cas9 technology for agricultural applications.
Conclusions and future perspectives
Genome editing is increasingly used to improve economi-
cally important crops (Cardi and Stewart 2016; Wolt et al.
2016). Whereas basic research is less restricted through IP
rights, generation of a commercial crop product with the
help of genome editing requires a license from the owner of
the relevant IP. As it is not clear who will be the owner of
the IP of CRISPR/Cas9 in the end, it is worthwhile con-
sidering alternative genome editing techniques (as descri-
bed above) where IP ownership is decided. Obviously, a
clear patent situation supports accelerated commercial
implementation as in the case of the first launched crop, the
sulfonylurea-tolerant SU Canola plant generated through
the ODM technology by CIBUSTM.
Finally, it has to be considered that the IP landscape for
genome editing will develop further by optimizing the
current technologies and making new inventions. For
example, a key component of the CRISPR/Cas9 system is
the Cas9 protein responsible for DNA cleavage. In
September 2015, the group of Feng Zhang reported the
discovery of a DNA-cutting enzyme called Cpf1 with
features distinct from Cas9 that may make it even easier to
edit genomes because it does not require the tracrRNA
needed by the CRISPR/Cas9 system (Zetsche et al. 2015).
123

A corresponding patent application has been filed, which
may give Zhang’s lab its own incontestable IP rights.
Compliance with ethical standards
Conflict of interest Authors HS and SS have received grants from
Dow AgroSciences for research on zinc finger nucleases.
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