Mapping CRISPR-Cas9 public and commercial innovation using The Lens institutional toolkit

CRISPR-Cas9 is a revolutionary technology because it is precise, fast and easy to implement, cheap and components are readily accessible. This versatility means that the technology can deliver a timely end product and can be used by many stakeholders. In plant cells, the technology can be applied to knockout genes by using CRISPR–Cas nucleases that can alter coding gene regions or regulatory elements, alter precisely a genome by base editing to delete or regulate gene expression, edit precisely a genome by homology-directed repair mechanism (cellular DNA), or regulate transcriptional machinery by using dead Cas proteins to recruit regulators to the promoter region of a gene. All these applications can be for: 1) Research use (Non commercial), 2) Uses related product components for the technology itself (reagents, equipment, toolkits, vectors etc), and 3) Uses related to the development and sale of derived end products based on this technology. In this contribution, we present a prototype report that can engage the community in open, inclusive and collaborative innovation mapping. Using the open data at the Lens.org platform and other relevant sources, we tracked, analyzed, organized, and assembled contextual and bridged patent and scholarly knowledge about CRISPR-Cas9 and with the assistance of a new Lens institutional capability, The Lens Report Builder, currently in beta release, mapped the public and commercial innovation pathways of the technology. When scaled, this capability will also enable coordinated editing and curation by credentialed experts to inform policy makers, businesses and private or public investment.


Introduction
The idea of introducing a precise genetic change at any position within a living genome with minimal disturbance to the system is a thrilling scientific discovery. And if the technology is simple, efficient, accessible, and versatille, then its potential applications are almost limitless.
At Lens.org, we were excited to bring the contextual knowledge about CRISPR-Cas9 (scholarly, patent, human, institutional and biological), user annotations and third party content into the one place, Lens Reports, to begin the process of building maps -at various resolutions-for the innovation trajectories of this technology, mainly in the agriculture/food space and highlighting trends, blockers, or enablers across its fields of use.
Since the technological potential was articulated in the scientific literature back in 2012, there have been more than 25,000 scholarly works published on the CRISPR-Cas9 topic and over 20,000 patents filed across the globe. Enabling not only patent professionals, but also researchers, investors, policymakers, and the public to interrogate and navigate such knowledge by providing a toolkit for those trying to solve problems or help guide precise partnerships, will accelerate outcomes.
In the overview section of this report, we introduce CRISPR-Cas9 technology, which Emmanuelle Charpentier and Jennifer Doudna share the Nobel prize in Chemistry for developing, and its potential impact on the industry, intellectual property and technology transfer issues that are arising, and we offer some guidance along with some strategies for monitoring or tracking patent battles. In the scholarly analysis section, we describe the timeline of the scientific progress made in the research discipline, main scholars and their institutions driving the scientific discoveries, and compare the research outputs from China to those from the USA. This analysis is followed by a patent analysis that covers specifically the CRISPR-Cas9 system rather than the broad CRISPR technologies. We present a few patent search strategies to enable users to find information based on their interest and the issues that they are trying to address. We use dynamic Lens patent collections to highlight the most up to date information on where these filings are, who are the key applicants, and-using patent classification codes-the technology sector to which they belong. Then, we complement such analysis with a manual drawing of the licensing network across all fields of use as we were able to get information so far, and highlight the key owners of patent rights based on licensing information and press releases available online. In the last section, we perform some comparative analyses with another published broader CRISPR patent landscape and show various trends based on various technology sectors. All the data presented in the report are then made available in the Data sources section and can be linked to, cloned, and shared with others. The draft report is a prototype of Lens.org that is being developed at present, and we are providing examples for the larger community to seek their feedback on the usefulness of such a toolbox in their own workplace and to engage them in building a more transparent innovation ecosystem.

Overview
Why is CRISPR-Cas9 a revolutionary technology? CRISPR-Cas9 is a revolutionary technology because it is precise, fast and easy to implement, cheap, and uses components readily accessible. This versatility means that the technology can deliver a timely end product and can be used by many stakeholders.
In plant cells, the technology can be applied to knock out genes by using CRISPR-Cas nucleases that can alter coding gene regions or regulatory elements, alter precisely a genome by base editing to delete or regulate gene expression, edit precisely a genome by homology-directed repair mechanisms (cellular DNA), or regulate transcriptional machinery by using dead Cas proteins to recruit regulators to the promoter region of a gene (https://www.nature.com/articles/ s41477-019-0461-5). All these applications can be for: Giant agriculture companies such as DuPont Pioneer, Monsanto (merged with Bayer), BASF and Syngenta seem to be the early licensees and in most cases, they licensed different CRISPR technologies from the various IP holders, gaining access to the latest research tools available (Fig. 1). The category of applications identified so far includes: Human Health (20) Animals (3) Agriculture (15), and Technical improvement (22) Licensing agreements varied from research collaborations, partnerships, simple commercial use, to joint ventures, acquisitions and mergers.

Tracking CRISPR patent battles
The long-running patent battle between the CRISPR team at the University of California (UC) and that at the Broad institute over who was the first to invent uses of the original CRISPR system in eukaryotic cells continues to rage. While in Europe the UC team leads, in the USA, the Broad institute leads. The current status of the intellectual property rights decisions can be searched by entering this string in the Lens: author.display_name:(''Jon Cohen'') AND (CRISPR). Automatic updates can be set up by saving the string in your work area and requesting alert notifications. Scholarly works addressing intellectual property and technology transfer challenges and opportunities of CRISPR-Cas9 system, can be found in this dynamic collection, CRISPR Cas9: IP & Tech transfer that is based on this search query: (title:(''CRISPR Cas9'') OR abstract:(''CRISPR Cas9'') OR fulltext:(''CRISPR Cas9'')) AND ((title:(''Intellectual property'') OR abstract: (''Intellectual property'') OR fulltext:(''Intellectual property'')) OR (title:(''IP landscape'') OR abstract:(''IP landscape'') OR fulltext:(''IP landscape''))) and which has been manually edited to select what we thought are the most relevant works (Fig. 2). Others are welcome to edit the search, modify it and share it. In this report, we analyze various sets of patent searches related to the technology, and compare findings from a recent landscaping exercise, with results in the Lens enabling the user to access these datasets from Lens.org for further analyses.

CRISPR Cas9 Scholarly works analysis
Who is investing in CRISPR Cas9 research ? Identifying which countries are contributing to CRISPR-Cas9 technology allows different actors in the innovation system to find each other, to better understand the capabilities each brings, to find and share opportunities to collaborate and formulate more productive partnerships, to minimize duplicated efforts, unnecessary intellectual property risks, and guide ongoing decisions on forward trajectories. To create a search strategy, an initial scouting was done of various keywords and concepts around that technology and after a few preliminary searches, this simple broad search was developed: title:CRISPR-Cas9 OR Fig. 2 Top affiliated Institutions with scholarly works addressing Intellectual property and technology transfer issues regarding the CRISPR-Cas9 technology (a), and when the scholarly works collection was first filtered by Field of Study, we show the groupings of these affiliated institution by that field (b). Readers can explore further the dynamic collection in the Lens at https:// link.lens.org/YoTUeNdu3oh and follow the dynamic mapping in the online report at https://link.lens.org/Wca170NGgqg abstract:CRISPR-Cas9 OR keyword:CRISPR-Cas9 OR field_of_study:CRISPR-Cas9 OR title:cas9 OR abstract:cas9 OR keyword:cas9 OR field_of_study:-cas9 OR (title:(CRISPR) OR abstract:(CRISPR) OR keyword:(CRISPR) OR field_of_study:(CRISPR)). This resulted in a dynamic parent collection: CRISPR Cas9: Broad. To narrow it further to the CRISPR Cas9 system, The search results were filtered using the ''Field of Study'' facet: CRISPR and Cas9, and a sub collection named: CRISPR Cas9: Field Of Study CRISPR ? Cas9 was developed, which was then used to do the preliminary analyses.
Which scientific works are perceived most important?
Importance of scholarly works here is tracked based on the cited scholarly works in the patent and scholarly literature. We list below the top three publications based on the number of their unique citing patents or citing scholarly works using CRISPR Cas9: Field Of Study CRISPR ? Cas9 collection.
Top scholarly works based on either unique citing patents or scholarly work counts:  Who is doing the research at these institutions?
The most active authors are displayed based on the institutional affiliation recorded in the scholarly work results set and may include collaborating institutions (Fig. 5).

Analysis of patents related to CRISPR-Cas9 technology field
This analysis targets the CRISPR-Cas9 system, rather than the broad CRISPR-based gene editing. For a comparative analysis of the latter please see the next section.
To build on the early patent landscape by Egelie et al., 2016 and capture inventions that claim the CRISPR-Cas9 system including any of its components, we used this simple search strategy that highlights relevant keywords in the patent claims: claims:CRISPR OR claims:Cas9 OR claims:gRNAs OR claims:(''RNAs guided'') OR claims:(''guided RNAs'') OR claims:sgRNAs OR claims:(''CRISPR cas9''). Search results captured 7,980 Patents (3,835 Families) on October 9, 2020 which were then used to create the dynamic collection, CRISPR Cas9: Claims.
This collection was then expanded by simple patent family (CRISPR Cas9: Claims-Expanded) to capture all filings around the world and determine geographical distribution of potential patent rights, should patent applications be issued.
An alternative/complementary search strategy was also tried by narrowing the search to just the keyword ''CRISPR Cas9'' in the claims, or by combining it with a search for a CPC classification code C12N2310/20* taking into consideration the use of examiner-classified code for CRISPRs which may reveal new patents. The resulting search string used in the Lens: claims:(CRISPR cas9) OR classification_cpc: (C12N2310/20*).
Both search results were saved into dynamic collections: (1) CRISPR Cas9: only in claims, and (2) CRISPR Cas9: claims & CPC code. Both results show that the majority of documents are patent applications and most filings have been recent, indicating that the technology is still in its early stage of development. For a more detailed mapping and landscaping, readers may want to try various search strategies in the Lens, edit or combine various queries and using the various Lens tools, distill these into a set of patents which can then be saved into a dynamic collection for further analysis/ tracking, and manual inspection. Universities seem to be leading the patenting race but are they also participating in product development? Fig. 6 displays the top inventors and applicants based on Lens dynamic collection: CRISPR Cas9: Claims (https://link.lens.org/LLl1Aea0RVb).
Where are these patents filed?
Analysis of the Lens dynamic collection, CRISPR Cas9: Claims expanded by patent family, showed that global filings accelerated post-2013. The majority of the top 100 patents were international filings (WO) and were cited by other patents. Forward patent citations ranged from 1 to more than 300 (Fig. 7). Further analysis reveals that international filings are almost on par with US publications. Readers can explore further the graphs from Figs. 7, 8 and 9 and the corresponding collection in the Lens and create their own customized dashboard.
What are the main technology fields of use covered ?
Here, we display the technology fields of use based on The Cooperative Patent Classification (CPC) which is a joint effort between the United States Patent and Trademark Office (USPTO) and the European Patent Office (EPO) to harmonize their existing classification systems (Fig. 9). These codes are generally assigned by patent examiners to reveal the nature and field of use of the claimed invention in a patent and readers can look up the verbose meaning of the codes in the Lens Classification Explorer when viewing this graph in the Lens.

Which patents are the most important?
Importance can be measured by the size of the simple patent family, a value, mainly perceived by patent applicants upon increasing the filings of their patent applications, considered to be the same inventions, across various jurisdictions. Also, importance can be evaluated by whether the patent was recognized and cited by other patents, i.e.the number of forward patent citations. As an example, here are the top two patents based on each of the two metrics.  Who has IP rights to Agricultural applications using CRISPR technology? Exclusive and non-exclusive worldwide licenses have been granted to the major agriculture companies and structural re-organizations of some of these companies have been observed since 2017. For example, BASF signed agreements with Bayer in 2017 and 2018 to buy its global vegetable seeds business, mainly operating under the brand NunhemsÒ. Bayer and Monsanto have merged and although integration is taking place, the two companies will be operating as two separate legal entities in many countries for several years. Moreover, the spinoff of DuPont Pioneer, DuPont Crop Protection and Dow AgroSciences, Corteva Agriscience TM has become independent and publicly traded company since June 1, 2019 (Fig. 10).

What trends other published CRISPR patent landscapes show?
Martin-Laffon et al.,2019 reported a manually curated ''per technical categories'' related inventions list (Fig. 11), with a total of 2072 patent families considered as CRISPR gene editing patents (from 2002 up to 31 December 2017 as a priority date). We extracted the published patent publication keys from that list and created an overall Lens patent collection that encompasses all categories and separate collections for each technical category (Table 1). As the published data was based on early patent filings (patents with the earliest priority data number), we used either the extracted documents list for each technical category to show geographical distribution and applicants based on the earliest filed patent documents or the expanded by simple patent family documents to capture all subsequent filings that are published. The analyses show a slight shift in the most active jurisdictions and applicants in some of the categories over time suggesting increased patenting activities across various jurisdictions following early filings (Figs. 12, 13,  and 14). Similarly, applicants' proportions also shifted with time. To view the criteria the authors used to select patents please see the supplementary note in their publication at https://static-content.springer. com/esm/art%3A10.1038%2Fs41587-019-0138-7/ MediaObjects/41587_2019_138_MOESM1_ESM. pdf     • Collections (one patent per family) for Economic Co-operation and Development (OECD) for the invitation to present an earlier version of this work at the conference ''Control and Access: Intellectual Property and CRISPR-Cas Gene Editing for Innovation in Crop Agriculture'' that was organized and hosted by Colorado State University on the 24th-25th of October 2019 at the Keystone Policy Center in Keystone, Colorado, USA. Thanks also to Jacob Sherkow for sharing some of the licensing information presented in this review.
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