Recently I was approached by Sophia Frentz from the University of Melbourne and writer for Lateral (a science communication zine), for my opinions regarding some key questions over the current CRISPR patent battle between UC Berkeley/University of Vienna (Profs. Jennifer Doudna and Emmanuelle Charpentier) and the Broad Institute/Harvard/MIT (Prof. Feng Zhang). I supplied Sophia with the answers to her queries before the news broke today that the US Patent and Trademark Office judges ruled in favour of Zhang and his patents.
This was the results of an interference proceeding that was instigated by UC Berkeley to have Zhang’s patent thrown out for lack of inventive step/ or for obviousness. Despite me answering the questions prior to this news, I believe my thoughts are worth putting out there. So below are the questions and answers, and I of course am happy to hear others thoughts.
– Do you think the application of CRISPR to eukaryotes was obvious? Why?
I believe it was obvious for several reasons, firstly because of the fact that Doudna and Charpentier had already alluded to the use of CRISPR in eukaryotes in their patent claims (patent US 20140068797 A1). Their patent had a priority filing date of May, 2012, contrasted to the priority date of the Zhang patent of December 2012. Doudna and Charpentier’s patent says under claim 40 “The genetically modified cell of claim 38, wherein the cell is selected from the group consisting of: an archaeal cell, a bacterial cell, a eukaryotic cell, a eukaryotic single-cell organism, a somatic cell, a germ cell, a stem cell, a plant cell, an algal cell, an animal cell, in invertebrate cell, a vertebrate cell, a fish cell, a frog cell, a bird cell, a mammalian cell, a pig cell, a cow cell, a goat cell, a sheep cell, a rodent cell, a rat cell, a mouse cell, a non-human primate cell, and a human cell”. This is in addition to listing eukaryotic cells in various other claims in that patent (claim 43, 70, 95, 101, 104, 130 and 131).
Secondly, patent US 20140068797 A1 was not the first CRISPR patent applied for that mentioned its utility for eukaryotic gene editing. For example, patent WO2013098244A1, titled “Modified cascade ribonucleoproteins and uses thereof” was filed by Wageningen Universiteit in 2011. In this patent’s description the following is stated “In any of the methods of the invention as described above, the cell which is subjected to the method may be a prokaryote. Similarly, the cell may be a eukaryotic cell… The invention allows a variety of possibilities to physically alter DNA of prokaryotic or eukaryotic hosts at a specified genomic locus, or change expression patterns of a gene at a given locus”. There is also a patent on CRISPR with a priority filing date of 2008 (US20160319260A1)!
Now I know what one might say in opposition to what I have stated above; “ah, but the priority filing dates are not the dates when the patents were published and able to be viewed by anyone”. Well yes, that is true. However, what I strongly think the above patents demonstrate are that scientists were indeed thinking that CRISPR could be used for eukaryotic cells since 2008 (hence why they listed this precise bit of information in the patents), and I would also reasonably think that they would be communicating this with each other when visiting or at conferences. Now I also understand that patent attorney’s tend to draft patents with broad claims, but if the use of CRISPR for eukaryotic gene editing was not at all obvious, it stands to reason that at least one of the scientists who were listed as inventor on the patents would have objected to this being listed in the description or claims of the patent they were on.
Onto my second reason that I think the use of CRISPR/Cas9 in eukaryotic gene editing was obvious; it comes down to a quick and dirty test I used when the patent battle started but before its current levels of infamy. What I would do is ask bright undergraduate and masters students in the molecular biology discipline (who had not heard of CRISPR) what they thought was the next logical step/s for CRISPR/Cas9 is after explaining where it was found, what it did and how it worked. Every time I had students telling me they would try utilize it in human or animal cells. Now you could of course make the argument that perhaps I unconsciously led them to that answer since I was biased towards it, and that would be a fair call most likely. However, keep in mind that these students often knew that other gene editing techniques such as TALENs and Zinc-finger nucleases were not only first found in prokaryotes, but adapted for use in eukaryotic cells. This is a third reason why I think it is obvious to someone trained in the art of molecular biology (this is importantly what “obviousness” means in patent law). If CRISPR/Cas9 was found in a eukaryotes, then I might be leaning more on the opposite view since typically, getting a eukaryotic enzyme to work in a prokaryote is tougher than the opposite. And note, that to be potentially granted a patent you have to merely file first, not invent first (except in the USA before March 16th, 2013, which is where the majority of the headache of this current case comes from).
Now, I will say that if there was a creative step needed to utilize CRISPR/Cas9 in Eukaryotes, then that would be patentable/non obvious (unless perhaps it was already covered in another section of the original patent). Now in light of the fact that Zhang’s group was not the first to try and patent CRISPR tech, I would say that the inventive step should be a reasonable one, but from what I can tell from reading the patent, it was using a codon-optimized sequence (this should be obvious to an undergrad molecular biologist), and regulatory elements (which I guess one could make arguments around, but with the weight of the rest of my argument, I feel this is hair-splitting at best).
– Could this interference/patent challenge happen in Europe? Why/not? (From what I can tell – it shouldn’t?)
In Europe there isn’t really an equivalent process to interference (which results from the first to invent rather than first to file system in the US), but an entitlement dispute, where there is an argument about who owns the inventions, is possible. However, the inventorship issue has resulted in potential problems with entitlement to priority (whether the applicant was the same entity in view of the removal of an inventor etc.), and this is being fought about at the EPO in the opposition process – you can see this on the EPO register. When I was on a study visit to the EPO headquarters in Munich to learn about biotech patent law and examination in Europe, I actually got to spend the day with the patent examiner at the EPO in Munich who is dealing with the third-party opposition filings for the CRISPR/Cas9 case (sadly he of course was not allowed to discuss the case). But depending on the follow up to the ruling today in the US (Doudna and Charpentier may file an appeal), it may or may not proceed; that is a decision for the clients to make. My gut feeling says it probably would go ahead given the size of the European market, but they would have to do a cost-benefit analysis.
In a little more detail:
The European Patent Office has been making the argument that Doudna and Charpentier’s provisional application did not actually describe the invention properly due to the absence of what they deem to be key DNA sequences (PAM sequences). However, as Doudna and Charpentier have noted, these should be common knowledge due to being essential for native CRISPR in bacteria. The EPO though, does not see it this way, claiming an expert in genome engineering may not be up to date with this information (I personally disagree). If this decision stands (UC Berekely is contesting it) and the EPO rejects the 2012 patent from the UC Berkely team, they would have to use a later date.
On the other side of the coin, more patents for CRISPR tech have been filed from the Broad Institute via the EPO and 7 have been granted in Europe. However, and here is the fun part, all are being contested under opposition proceedings. The key reason is quite hair-splitting; the initial EPO filing by the Broad Institute listed a co-inventor that wasn’t named on later versions of the application. This is a lesson in understanding the nuances of IP law in different places, because this is allowed in the US, but not in Europe. It may well result in the initial Broad filing on these new patents to be revoked.
[I would like to thank my friend Douglas Drysdale, a patent attorney at HGF in Scotland for his clarification on my original thoughts on the European side of the patent battle].
– Can you comment on the potential applications of CRISPR?
There are numerous important prospective applications of not only what the aforementioned CRISPR patents would cover, but on the swathe of related patents that have since been filed. The first application I personally saw was when the Cowman lab at the Walter and Eliza Hall Institute (my main doctoral supervisor is Prof. Alan Cowman) used the technique to speed up the production of transgeneic malaria parasites, which had been notoriously known to be difficult to swiftly genetically manipulate. I have also seen CRISPR used for making other transgenic animals to assist in faster research.
Outside of the research applications, you obviously have human health potential, which is where the real money-spinner is. Being able to cut out a detrimental or defective gene and replace it with a good copy is extremely attractive. Two clinical trials using CRISPR-Cas9 for targeted cancer therapies have already been approved in China and the US. To save me reinventing the wheel, I would recommend reading Doudna and Charpentier’s 2016 Nature Biotechnology Reviews article titled “Applications of CRISPR technologies in research and beyond”. Being realistic; due to regulatory hurdles, we most likely will not see the real wide-spread power of CRISPR and CRISPR-related advances for human health until near the end of the patent’s life, if not well after. Companies need to get comfortably well-established, gain both investor and prospective customer trust and support, and be able to quell public fears over the technology. I would argue this is a lot tougher than the actual science. As an aside, competing CRISPR companies have been cross-licensing IP with each other as a prophylactic against any outcome over the CRISPR/Cas9 dispute, which is shear genius (well, probably more like obvious pragmatism). This will help facilitate the real-world applications of the technology regardless of how the patent dispute goes (where the real winners are the IP lawyers). This is exactly why I disregard people ignorantly claiming patents prevent innovation; in reality the opposite is true.
*Declaration of interest: I have no potential conflicts of interest other than to say I did a summer school program in entrepreneurship with MIT, and am considering investing in Editas and watching what happens with Caribou Biosciences Ltd.