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18 February 2016EuropeCatherine Coombes

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


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