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In CRISPR Patent Interference, Parties Argue Over What to Argue About

NEW YORK (GenomeWeb) – It's still early and a lot could change, but the details in the fight over the intellectual property rights for CRISPR are officially beginning to emerge. The lawyers representing either side — the University of California and the Broad Institute — have shown which strategies they're likely to pursue, and the referees in the fight are beginning to decide what kind of tactics they will allow.

On March 17, judges from the US Patent Trial and Appeal Board (PTAB) issued rulings on a number of motions put forward by lawyers for UC — the senior party in the case based on their unawarded patent application's earlier filing date — and the Broad, which holds more than a dozen patents related to CRISPR, including the keystone Patent No. 8,697,359 (the '359 patent).

Both UC and the Broad have thus far laid out so-called "threshold" issues, potential knockout punches that would essentially end the interference before it begins. Broad, which has been awarded a dozen patents related to CRISPR besides the '359 patent, argued that because it specifies a method of using CRIPSR in eukaryotic cells, there isn't actually anything to discuss.

UC is saying just the opposite: Broad's patent claims, especially its later patents, are actually unpatentable, because Broad can't show that it fully conceived of the idea before UC submitted its patent application.

Moreover, UC is separately arguing to both narrow and widen the playing field, so that it might specifically get a patent for the single-stranded guide RNA (sgRNA) or that it be awarded a patent to cover any use outside of a prokaryotic cell whether that's in vitro or in a eukaryotic cell.

So which is it? "Like with everything else in patent law, and this case in particular, the answer is complicated," Jacob Sherkow, a professor at New York Law School and a frequent commentator on the CRISPR patent interference, told GenomeWeb.

"The battlefield is still being drawn," he said.

The judges have ruled that Broad will be able to argue its case that there is no interference; however, they punted on whether they would allow UC to argue its threshold issue.

While the judges denied a number of other interesting proposals sent by the parties, they deferred on several more questions and allowed a number of arguments that could totally reshape the CRISPR IP landscape.

"The way it's set up today makes it look like it's going to be an all or nothing decision," Sherkow said. But that very well could change.

When the PTAB declared the patent interference proceedings in January, it set forth an important passage known as the count (Document No. 1, "Notice to Declare Interference"), which Sherkow describes as the hypothetical patent claim set up to encompass everything on either side's patent or patent application. If the patent interference continues, this is essentially what the resulting patent will cover.

The count encompasses a lot including any use of CRISPR/Cas9 in a eukaryotic cell to cut or edit the genome as well as modulate gene expression, and using any DNA targeting strategy where a crisprRNA "hybridizes" to a tracerRNA sequence.

The wording appears to cover CRISPR/Cas9 guided by either sgRNAs or two-component targeting systems, which could quash any hope of skirting patents by using separate crispr- and tracrRNAs, Sherkow said, but it might not cover the use of Cpf1, another CRISPR-based, RNA-guided, DNA-cutting technology Zhang has discovered and developed.

Broad's opening salvo is to argue that there's really nothing to fight about. By developing and patenting the use of CRISPR in eukaryotic cells, Feng Zhang has invented something above and beyond what UC's Jennifer Doudna and Emmanuelle Charpentier, who is now at Max Planck Institute for Infection Biology,  claimed to have invented, the institute claims. The court has granted  Broad the opportunity to make this argument.

Should that fail, the Broad has several backup arguments. A straightforward one is that Zhang actually invented CRISPR first. It could make several other arguments as well, depending on how things play out, like claiming its other patents aren't governed by the count.

But that all assumes the parties are arguing over the count as it stands now.

One of UC's strategies is to press the PTAB to change the count from how it's currently stated into one of several alternatives. At the moment, the count would cover any guide RNA, whether the crispr- and tracrRNA sequences were fused to each other in a chimeric sgRNA or simply hybridized to each other. One of UC's proposals is to change the count so it refers specifically to an sgRNA, which they argue is a separately patentable invention.

Then again, different alternative counts proposed by UC might be a ploy to make it a winner-take-all fight, Sherkow said, but on a playing field tilted more in UC's favor.

Another of UC's alternative counts would change the existing count so that it covers any application outside a prokaryotic cell, as Doudna and Charpentier were able to demonstrate CRISPR/Cas9 in vitro in 2012.

"My guess is that they are doing this to ensure that they capture the largest degree of Zhang's technology," Sherkow said. "They want to make this an all or nothing decision. That's one strategy of doing this if you're in the senior party's seat."

The judges will allow UC the chance to argue for a reworded count, but UC will have to decide which alternative count it wants to propose. UC may also opt to propose two counts, if it thinks there are two separately patentable inventions wrapped up in the current count.

What UC decides here could have a large impact on the future IP landscape. If the case proceeds on two counts — both the sgRNA and the method itself of CRISPR — the judges could potentially split the CRISPR baby. If this came to pass, Sherkow said companies operating in the space might need two separate licenses if they wanted to use sgRNAs, which are easier to work with.  "Even with one count, the court could still split things if it adopts Broad's 'no interference in fact' motion on some of its claims," he said.

One of the more interesting rulings was that the judges weren't willing to let UC accuse Broad and Zhang of malfeasance. At least, not yet.

In one of the more inflammatory arguments from either side, UC said Broad had obtained the '359 patent "through inequitable conduct with respect to the filing of certain declarations."

Spelled out in UC's list of proposed motions submitted March 3, UC said, "Zhang never demonstrated in his supporting documents that he was in possession of any claimed methods that made use of tracrRNA. Because the omission of essential subject matter in [Zhang's] supporting documents would have been readily evident to a person of ordinary skill in the art, it is believed that Broad withheld or misrepresented material information with the intent to deceive the USPTO, contributing to the issuance of Broad's involved patents."In other words, UC is claiming Broad lied about the timeline of when and how Zhang got CRISPR/Cas9 genome editing to work..

The judges said that it would be premature to consider this argument at this time, because they had yet to establish the relationship between tracrRNA, the interfering claims, and proof of priority. While Charpentier (but not Doudna) first described tracrRNA and showed its importance in a 2011 paper published in Nature, "Whether or not tracrRNA is an essential element of the interfering subject matter will likely be apparent from the priority proofs," the judges wrote. "UC may request authorization to file its motion after the conclusion of the priority phase of the interference."

Zhang and Broad will hope that question never comes to bear. If Broad can win the argument that there's actually nothing to any of the interference claims, the process will be over before it truly begins.

But beyond that, it's almost impossible to predict how the fight will turn out. Any number of permutations and combinations of arguments could wind up going forward. What the early judgments show is that it's far too early to begin keeping score.

In the bigger picture, Sherkow stressed that the patent interference is really only suitable to address whether there is a conflict between the two parties. "It is not a referendum on the scientific priority of the dispute, it's not a referendum on the merits of [Broad's] patents," he said.

"It's not even a referendum on whether CRISPR should be patented at all," he said.