Muddied waters: the CRISPR IP landscape in Europe
The continuing interference proceedings in the US concerning clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 systems for gene-editing of eukaryotes have received much media attention. Coverage focuses on two groups: one led by Feng Zhang of the Broad Institute of Harvard University and the Massachusetts Institute of Technology, and the other by Jennifer Doudna of the University of California, Berkeley and Emmanuelle Charpentier of the Helmholtz Centre for Infection Research. The commentary focuses on a potential winner-takes-all scenario.
However, the situation in Europe, where both groups’ patent applications will be examined under a first-to-file system, has received much less media attention. The question remains, which of these two groups will have the underlying rights to CRISPR/Cas9 in Europe? Or will filings by other applicants during this period lead to a more complex early CRISPR/cas9 landscape in Europe?
European legislation
The content of patent applications which enter Europe and are filed before, yet published after, the filing of a specific European patent application (application X) can be cited for novelty against application X for the content filed before application X, according to article 54(3) of the European Patent Convention (EPC).
In a rapidly evolving area of technology, where a plethora of interwoven priority applications are made in a short time period, a number of article 54(3) EPC applications may be cited against a specific European patent application. This would confuse the CRISPR IP landscape and make the maintenance of an earliest possible priority date essential to obtain the widest patentable scope.
In Table 1, we delve into the CRISPR landscape for gene-editing of eukaryotes in Europe by referring to the filings from March 2012 to December 2013 by the six key groups working in this field.
Table 1: CRISPR patent filings in Europe from March 2012 to December 2013
Date | Application number | Applicant |
Mar 20, 2012 | US 61/613,373 | Vilnius University |
Apr 17, 2012 | US 61/625,420 | Vilnius University |
May 25, 2012 | US 61/652,086 | Regents of the University of California |
Oct 19, 2012 | US 61/716,256 | Regents of the University of California |
Oct 23, 2012 | US 61/717,324 | ToolGen |
Dec 6, 2012 | US 61/734,256 | Sigma-Aldrich |
Dec 12, 2012 | US 61/736,527 | Broad |
Dec 17, 2012 | US 61/738,355 | Harvard College |
Jan 2, 2013 | US 61/748,427 | Broad |
Jan 28, 2013 | US 61/757,640 | Regents of the University of California |
Jan 29, 2013 | US 61/757,972 | Broad |
Jan 30, 2013 | US 61/758,624 | Sigma-Aldrich |
Jan 30, 2013 | US 61/758,468 | Broad |
Feb 5, 2013 | US 61/761,046 | Sigma-Aldrich |
Feb 15, 2013 | US 61/765,576 | Regents of the University of California |
Feb 25, 2013 | US 61/769,046 | Broad |
Mar 13, 2013 | US 61/779,169 | Harvard College |
Mar 15, 2013 | PCT/US2013/032589 | Regents of the University of California |
Mar 15, 2013 | US 61/794,422 | Sigma-Aldrich |
Mar 15, 2013 | US 61/791,409 | Broad |
Mar 15, 2013 | US 61/802,174 | Broad |
Mar 20, 2013 | PCT/US2013/033106 | Vilnius University |
Mar 20, 2013 | US 61/803,599 | ToolGen |
Mar 28, 2013 | US 61/806,375 | Broad |
Apr 20, 2013 | US 61/814,263 | Broad |
May 6, 2013 | US 61/819,803 | Broad |
May 28, 2013 | US 61/828,130 | Broad |
Jun 17, 2013 | US 61/835,931 | Broad |
Jun 17, 2013 | US 61/836,127 | |
Jun 20, 2013 | US 61/837,481 | ToolGen |
Sep 23, 2013 | PCT/KR2013/009488 | ToolGen |
Sep 26, 2013 | WO 2013/142578 | Vilnius University |
Dec 5, 2013 | PCT/US2013/073307 | Sigma-Aldrich |
Dec 12, 2013 | PCT/US2013/074611 | Broad |
Dec 12, 2013 | PCT/US2013/074667 |
|
Dec 12, 2013 | PCT/US2013/074691 | |
Dec 12, 2013 | PCT/US2013/074736 | |
Dec 12, 2013 | PCT/US2013/074743 | |
Dec 12, 2013 | PCT/US2013/074790 | |
Dec 12, 2013 | PCT/US2013/074800 | |
Dec 12, 2013 | PCT/US2013/074812 | |
Dec 12, 2013 | PCT/US2013/074819 | |
Dec 12, 2013 | PCT/US2013/074825 | |
Dec 16, 2013 | PCT/US2013/075317 | Harvard College |
Figure 1: Priority and filing dates for European CRISPR applications
Figure 1 illustrates the interwoven nature of the priority and filing dates of Vilnius University (in black), UC Berkeley (in green), ToolGen (in purple), Sigma-Aldrich (in red), Broad (in blue) and Harvard College (in yellow). Each circle represents a priority filing or the application as filed for each group. While they are not to timescale, the circles are aligned to show the interplay between the filing of the groups, with the earliest filings on the left and the latest on the right. As can be seen from Figure 1, the CRISPR IP landscape is more complex than is generally reported in the media.
Of the six groups’ patent applications, only Vilnius University’s was published during the time period illustrated. Therefore, only this patent application could be cited for inventive step, and then only if Sigma-Aldrich, Broad or Harvard College were not entitled to any of their priority dates.
In the third party observations (TPOs) and oppositions filed against each of the six groups’ applications, much focus is placed on priority as well as disclosures in journals, as these will determine which of the other group’s filings are relevant for the analysis of novelty.
Each claim is given an effective date based on when the claimed subject matter was first disclosed. All earlier European patent applications that have validly entered Europe will be citeable for novelty against the claims. Referring to Figure 1, the ten blue circles piled up on the right of the diagram indicate ten Patent Cooperation Treaty (PCT) patent applications filed by Broad which claim the priority of the preceding blue circles.
Hypothetically, even if a European patent application based on one of these PCT patent applications were acknowledged as having the earliest priority date of December 12, 2012, the contents of the first two Vilnius University priority documents, the first two UC Berkeley priority documents, the first ToolGen priority document, and the first Sigma-Aldrich priority document will be citeable for novelty against the subject matter of the Broad patent application.
Vilnius University
Vilnius University has a pending European patent application (EP 2 828 386) which has TPOs filed against it.
The international preliminary report on patentability (IPRP) considers most of the claims to lack novelty and the remaining claims to lack an inventive step over a journal article. No analysis of priority was conducted in the international phase, but the IPRP noted the significance of this determination due to a number of intervening publications of relevance to the claims.
“It is likely that maintaining priority will be a key issue in determining the scope of the subject matter that Sigma-Aldrich may ultimately obtain.”
Since entry into Europe, new substantial claim amendments have been filed to methods of introducing site-specific modifications (eg, in mammalian cells) and to Cas9-crRNA complexes where the crRNA comprises engineered sequences. These amendments do not appear to have a strict literal basis in the application as filed. On filing the amendments, no comments on priority were filed. It will be interesting to see how the European Patent Office (EPO) responds, as it appears that the issuance of an examination report is imminent.
At this stage, it is unclear whether Vilnius University will be successful in obtaining any rights to the underlying CRISPR/cas9 system.
UC Berkeley
UC Berkeley has a pending European patent application (EP 2 800 811) claiming the benefit of the priority documents recited in Table 1. Six sets of TPOs have been filed against the application.
A corresponding UK patent, GB 2 518 764, was granted on February 2, 2016.
The first two priority documents filed, US 61/652,086 and US 61/716.256, disclosed two molecules (chimera A and chimera B) and no data showed gene-editing in eukaryotes.
Initially, the UK examiner considered that UC Berkeley was only entitled to claim priority from the third priority document (filed on January 28, 2013) because: 1) there was no mention of a protospacer adjacent motif (PAM) sequence and, without this, the vast majority of the claimed constructs would not work; and 2) successful cleavage in eukaryotic cells requires a sequence element (which was not even hinted at).
Therefore, the examiner considered it an undue burden to work the invention across the claimed scope. UC Berkeley overcame these objections by filing various documents to establish that a PAM motif was common general knowledge, and by submitting a declaration in response to the allegations that the chimera A and chimera B would not work in eukaryotes. In response, Broad filed TPOs, but the application was granted the following day.
The European search opinion has issued in Europe, and the EPO currently considers the UC Berkeley application to be entitled to the second priority date (October 19, 2012). Broad has subsequently filed TPOs in an attempt to persuade the EPO that EP 2 800 811 is not entitled to the second priority date, although these refer to the UK examination report which UC Berkeley has subsequently been able to overcome.
If UK Berkeley maintains the priority date of October 19, 2012, the first priority documents of ToolGen Sigma-Aldrich and the first two priority documents of Broad are not citeable for novelty against the patent application, and perhaps more important, key journal publications will not be citeable. Therefore, UC Berkeley may obtain some valuable protection for CRISPR/Cas9. Accordingly, the determination of priority will be a key issue during the prosecution of EP 2 800 811.
ToolGen
ToolGen has a pending European patent application (EP 2 912 175) claiming an earliest priority date of October 23, 2012. After the initial two UC Berkeley priority filings, ToolGen was the next to file one.
The contents of UC Berkeley’s first two priority documents are citeable for novelty against ToolGen’s application. Currently, the claims on file in Europe focus on the presence of a Cas9 polypeptide having nuclear localisation signal (NLS) in the CRISPR/Cas9 system. The European search opinion raises issues of a lack of priority, as well as others raised by two sets of anonymous TPOs on file. If ToolGen maintains priority, the claimed subject matter would appear novel over the disclosures in the first two priority documents of UC Berkeley, as it does not appear that a nuclear localisation signal (NLS) is disclosed. Of course, patentability will also further depend on the contents of publications published before the effective date.
Thus, it is possible that ToolGen could obtain some protection for the CRISPR/Cas9 system.
Sigma-Aldrich
Sigma-Aldrich has a pending European patent application (EP 2 928 496) claiming an earliest priority date of December 6, 2012. The patent application entered Europe on June 29, 2015. Anonymous TPOs were filed at the EPO before the application had even entered Europe. Currently, the EPO has yet to issue a European search opinion on this subject matter.
The claimed subject matter relates to isolated endonucleases comprising at least one NLS, at least one nuclease domain and at least one domain that interacts with a guide RNA to target the endonuclease to a specific nucleotide sequence for cleavage, as well as methods of modifying chromosomal sequences in eukaryotic cells.
Most of the documents filed in the TPOs are article 54(3) citations. To obtain protection in Europe, the claims will need to be amended to be novel over at least the first two UC Berkeley applications and the ToolGen application (which discloses a NLS).
Further, the TPOs cite the Broad patent applications against the validity of the Sigma-Aldrich claims. It is likely that maintaining priority will be a key issue in determining the scope of the subject matter that Sigma-Aldrich may ultimately obtain.
Broad
Broad currently has six granted patents (including two which grant on March 9, 2016) and 13 patent applications pending in Europe. The nine-month opposition period has ended for the first two patents granted in Europe: nine parties have opposed EP 2 771 468 and seven parties have opposed EP 2 784 162. The opposition period for EP 2 764 103; EP 2 89 697; EP 2898 075; and EP 2 931 898 will expire on May 19, 2016, June 2 2016, December 9, 2016 and December 9, 2016, respectively. It is likely that these will be opposed.
The European patents entered Europe early and prosecution was accelerated. Accordingly, we note that EP 2 771 468 and EP 2 784 162 were granted before the contents of the earlier priority applications by ToolGen and Sigma-Aldrich became citeable for novelty under article 54(3) EPC. It will be interesting to see to what extent this may affect the claimed scope of the Broad patents in Europe.
Harvard College
Harvard College has a pending European patent application, EP 2 931 891, which entered Europe in July 2015 and claims an earliest priority date of December 17, 2012.
TPOs were filed a month before the European regional phase entry and cited the earlier patent applications by the other five groups. A European search opinion has yet to issue. However, the claims focus on methods of altering a eukaryotic cell, as opposed to claims covering CRISPR/Cas9.
We can also expect the determination of priority for all six groups to be relevant in establishing the patentability of the claimed subject matter of this patent application.
The interwoven nature of the priority documents of various parties in the rush to secure protection for the underlying CRISPR/Cas9 system for gene-editing has resulted in a highly contentious and somewhat murky IP landscape in Europe. It will only be when these patent applications have been granted or refused, and all oppositions and appeals have been heard, which could take several years, that a clear picture of who holds the underlying rights to CRISPR/Cas9 will emerge.
And yet, the use of CRISPR in gene-editing is still in its infancy, with new endonucleases such as Cpf1 emerging along with various improvements to the underlying systems. Thus, the IP landscape is likely to get much cloudier, leaving those seeking licences to use the technology confused.
Catherine Coombes is a senior patent attorney at HGF. She can be contacted at: ccoombes@hgf.com