“ToolGen cracked its way into the global 'scissors' war Registered a patent quickly ahead of others for a technology which applies the CRISPR-Cas9 to eukaryotic cells"

26 Dec 2022
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Registered a patent quickly ahead of others for a technology which applies the CRISPR-Cas9 to eukaryotic cells

The purpose of genetic engineering technology is to artificially manipulate the gene sequence or expression, etc. of a living organism or a cell and induce a desired character accordingly. Some view genetic engineering technology as a challenge to the realm of god, but if religious or ethical issues are not discussed, the scope of its application can be infinite.

For example, in the past, a direct breeding process was required to improve the characters of crops or livestock, which needed considerable time and effort, and the effect was insignificant. However, with the innovative development of genetic engineering technology, it is now possible to artificially introduce desired genetic characters into living things through genetic manipulation. As kinds of genetically modified organisms (GMOs), ‘tomatoes that doesn’t go soft (Flavr Savr)', 'herbicide-resistant soybeans (Round-up Ready Soybean)', and 'pest-resistant corns (Bt maize)', etc. were produced on a commercial scale, and various types of disease-model animals including mice with cancer genes (Harvard mouse) were developed and are now used for disease research. In addition, various treatment methods using genetic engineering technology are presented for incurable diseases which are difficult to overcome including genetic diseases, AIDS, and cancers. That is to say, we can say that with the development of genetic engineering technology, the problems directly related to survival of human race beyond the quality of life of human being, including food problems and human health problems, have already been solved or have gotten a clue to be solved.

In this editorial, the patent dispute issue of CRISPR/Cas9, which is one of the technologies currently attracting the most attention in the field of genetic engineering, will be reviewed and the points to which attention should be paid from a standpoint of patent practician when in charge of patent business on such innovative technologies will be adressed.

◆What is the CRISPR/Cas9?

Gene manipulation by use of restriction enzymes has already been performed since the 1970s, but due to the nature of restriction enzymes which recognize short unit sequences, there was a limitation that the precise genetic manipulations such as direct editing of genes existing in cells were difficult.

From this background, the gene scissors technology which recognizes the target gene region directly and cleaves the DNA was truly innovative. After the first-generation gene scissors 'Zinc Finger nuclease' and the second-generation gene scissors 'TALLEN', the third-generation gene scissors 'CRISPR' was developed, and the CRISPR-Cas9 is most widely used as a genome editing tool.

Source: ToolGen website.

CRISPR gene scissors consist of a guide RNA combined to a target gene and a Cas9 protein which cleaves DNA. When DNA is cleaved (double strand break, DSB) by a Cas9 protein, there occurs some insertion/deletion (INDEL) in the base sequence of target DNA due to a formula error in the process of repairing the cleaved DNA (non-homologous end joining, NHEJ), and as a result, the function of target gene may be removed (knocked-out). In addition, a desired gene sequence can be inserted into the genome by homologous recombination (knock-in) together with the introduction of donor DNA.

In both cases of the first and second generation gene scissors, ZFN and TALLEN, the 'protein' plays the role of recognizing target DNA, so a corresponding protein must be created each time according to target gene. However, the design of such protein is not easy, it takes a lot of time and expenses to design and manufacture, and there are other problems like poor efficiency or difficult introduction into cells due to the large size of protein, etc. However, since CRISPR gene scissors recognize target DNA by 'guide RNA', there is no need to go through a separate protein design process. In addition, since RNA design is relatively simple, CRISPR gene scissors are evaluated as the most useful among gene scissors in terms of cost, convenience, and efficiency.

Such technology of CRISPR gene scissors has been recognized for its technological value, such as innovation of the year in 2015 selected by the Science Magazine and one of top 10 technologies in 2016 selected by the MIT Technology Review. According to the data announced by the Biotechnology Policy Research Center in 2019, the global CRISPR gene scissors market is expected to grow from USD 4.14 billion in 2019 to USD 7.12 billion in 2023. The potential of CRISPR gene scissors seems to be endless, not only as a research tool, but also in the improvement of crops or livestock, and further to the treatment of incurable diseases by use of gene editing.

◆ Status of CRISPR/Cas9 Patent Dispute

CRISPR technology was first filed by a joint research team of Professor Jennifer Doudna at the University of California, Berkeley, USA and Professor Emmanuelle Charpentier at the Max Planck Institute in Germany (hereinafter, UC Berkeley group). UC Berkeley group applied for a total of 4 provisional applications, starting with the first provisional application in the United States (May 25, 2012), and bundled them all together to file a US regular application and a PCT application (March 15, 2013).   

At the similar time, MIT Professor Feng Zhang's Broad Institute (a joint research institute between MIT and Harvard; hereafter, Broad Institute group) applied for regular patent of CRISPR technology in the United States (Oct. 15, 2013) based on 5 provisional US applications (first in Dec. 12, 2012).     Although the filing date was later than that of UC Berkeley group, Broad Institute group obtained a patent registration (April 15, 2014) in the United States for the first time in CRISPR technology through a track one request. 

UC Berkeley group had to do something. Patent disputes related to CRISPR technology began on a full scale as an application for interference proceeding is filed with the Patent Trial & Appeal Board (hereinafter, PTAB) (an interference proceeding is a procedure for determining the first inventor under the US Patent Act before it amendment, and it grants a patent right to the first inventor if the claims of both parties are not patently indistinguishable. Here, whether the claims are patently distinguishable is judged based on whether novelty and inventive step can be acknowledged when one invention is assumed as prior art).

In the United States, provisional applications from both groups and regular applications based on them are intertwined intricately.

In this case, PTAB determined that Broad Institute group's patent relates to <CRISPR technology in eukaryotic cells> and UC Berkeley group's patent relates to <CRISPR technology in prokaryotic cells>, and the two technologies do not conflict with each other. UC Berkeley group appealed to Court of Appeals for the Federal Circuit (hereinafter, CAFC) against PTAB's decision, but CAFC supported PTAB's decision and the case seemed to be settled with a victory for Broad Institute group.

However, recently, UC Berkeley group separately filed a continuation application for an invention in which CRISPR was applied to eukaryotic cells and filed a new interference proceeding for the registered patent of Broad Institute group, and the dispute is continued. Attention is focused on how the issue will develop as to whether UC Berkeley group can win the dispute and also obtain the rights to technology applied to eukaryotic cells, or whether Broad Institute group can successfully defend and maintain the registered patent.

On the other hand, ToolGen, a Korean company, filed a provisional patent application for technology of applying CRISPR gene scissors to eukaryotic cells earlier than Broad Institute group (Oct. 23, 2012), and obtained patent registration in Korea, Europe, and Japan based thereupon.   It is still under review in the United States, but considering that UC Berkeley group's <CRISPR technology in prokaryotic cells> and Broad Institute group's <CRISPR technology in eukaryotic cells> do not conflict in the interference proceeding, it is thought that there is a possibility that ToolGen, which has secured a faster priority date, will occupy an advantageous position compared to Broad Institute group.

However, as disputes are occurring simultaneously around the world, and because the possibility that UC Berkeley group will also obtain the rights to technology of applying CRISPR gene scissors to eukaryotic cells cannot be completely ruled out, who will be the final winner remains to be seen.

◆What a patent practician should be cautious of?

In a technology field where technological development is progressing rapidly and many researchers are interested, it is very important to preoccupy the filing date. In extreme cases, the patent right for original technology may be secured or, conversely, registration may not be achieved due to just one day difference. Therefore, a practician in charge of innovative technologies such as CRISPR gene scissors technology needs to recognize the importance of securing a fast filing date and actively utilize the provisional application system of the United States or the foreign language application system of Korea.

However, if the application is unreasonably proceeded by only considering the preoccupation of filing date, there also exists a risk that priority date may not be acknowledged up to the scope of claim desired by the applicant during the regular application or priority claim due to the poor specification of the earlier application. Therefore, it is necessary for a patent practician to determine whether the preoccupation of filing date is the most important issue in the invention in charge or whether the earlier application specification prepared scrupulously is required rather than the preoccupation of filing date.

In addition, although not discussed above, the European applications of Broad Institute group was not acknowledged its priority because some of the provisional applications in the United States which claimed priority did not meet the 'same applicant' requirement, and as a result, the European Patent Office's objection department denied the novelty of European application by determining the papers published one day before the filing date of the third provisional application for which priority was acknowledged as prior art literature (currently a complaint is under way). The patent itself is in danger of being blown away due to bibliographic data that may be treated as trivial matters. By letting the above case as a lesson, patent practicians should pay considerable attention not only to the preparation of application specification but also to the preparation of bibliographic data like applicants and inventors, etc. and should always be careful not to cause incidents like the above by clearly recognizing the differences in patent systems by country.

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