A hunch on that CRISPR patent battle as it heats up

CRISPR patent dispute

Adapted from NIH image

Who really invented CRISPR?

If it was many people and labs, who did it first and who deserves the credit?

When things like Nobel Prizes and Patents get decided on CRISPR-Cas9, who will be for lack of a better way of putting it, the winners and the losers?

It’s not a trivial question and despite what some argue that CRISPR shouldn’t be patented at all, someone will get the decisive patent and the fight to see who prevails in the CRISPR patent battle is getting more intense. For more background in what’s at stake on CRISPR and human gene editing, check out my new book GMO Sapiens.

The signs suggest that there cannot really be a kumbaya approach to credit for things CRISPR even if there were multiple key contributors. For Nobel Prizes, there are only 3 lots. For patents, in many cases even if they are scads of patents related to one thing as seems certain for CRISPR-Cas9-related technology, often only one patent dominates.

The patent situation on CRISPR has really become a battle between the UC system (disclaimer, I’m a UC employee) and the Broad Institute.

I am not going to choose sides or predict the outcome, but I do have a hunch and that is that despite all the different complicated, but important details and potential maneuvers now emerging this week in this patent dispute, what it will all boil down to in the end is just one thing.

The lab notebooks.

What is in the lab notebooks of the various parties involved, how conclusive is this material, and what are the dates on those notebooks?

Patent expert weighs in on CRISPR dispute between UC & Broad

CRISPR dispute patent

Adapted from NIH CRISPR-Cas9 image

The patent dispute on CRISPR between UC/Jennifer Doudna and The Broad/Feng Zhang has been the subject of major attention including in a recent piece on Stanford Center for Law & Biosciences Blog. There is a lot of confusion over this important CRISPR dispute so I turned to a patent expert for their take on this via an interview below.

The interview with this anonymous expert provides some helpful, informed assessments on the CRISPR patent dispute including fresh perspectives. This person has different views than those expressed in other media outlets and in some instances from those in that recent piece on the Stanford Law/Bioethics Blog.

(1) Are there elements to this patent situation that most people are overlooking?

Answer: Probably the most important thing that people are overlooking is the scope of the claimed subject material of the Doudna patent application (and also the Zhang patents in question); only Cas9 is claimed. The claims do not cover other nucleases that could work with CRISPR (such as Zhang’s recently published Cpf1, which is “smaller and easier to program than Cas9”) and thus would not exclude someone from using other nucleases. Therefore, I think that even if the Doudna patent is issued and the Zhang patents are pulled, the Doudna patent would still not exclude someone from using CRISPR/Cpf1 (or CRISPR with other non-Cas9 nucleases that may be eventually discovered or engineered). Similarly, the current Zhang patents also would not exclude someone from using CRISPR with non-Cas9 nucleases, although I assume that Zhang and the Broad Institute will now also be applying for patent coverage for Cpf1. Indeed, the Broad Institute’s press release for the discovery of Cpf1 mentioned that “The Broad Institute and MIT plan to offer non-exclusive licenses to enable commercial tool and service providers to add this enzyme to their CRISPR pipeline and services” and “We see much more to come, even beyond Cpf1 and Cas9, with other enzymes that may be repurposed for further genome editing advances.” Interestingly, this means that if the Doudna patent is issued and the Zhang CRISPR/Cas9 patents are pulled, Zhang and the Broad Institute (and their licensees) will still be able to use CRISPR/Cpf1, whereas if the Doudna patent application is rejected and the Zhang CRISPR/Cas9 patents are left intact and Zhang then patents CRISPR/Cpf1, then Zhang and the Broad Institute could potentially control the entire current CRISPR intellectual property landscape (at least until someone finds or engineers yet another CRISPR-compatible nuclease). Of course, I should also point out that all of this is assuming that there will be no settlement between the UC and the Broad Institute in the current interference proceeding; some kind of settlement could still happen. These aspects regarding the actual scope of the patent claims have been largely ignored by most media reports and were not mentioned in the Stanford Law blog. Therefore, although the outcome of the CRISPR/Cas9 patent battle is indeed important as this is the first wave of patents for this technology, it is important to keep things in perspective, and some assertions from the Stanford Law blog such as “needless to say, this is a monumental event for patent attorneys, molecular biologists, the PTO, and the world” and “the biotech patent dispute of this century” feel to me somewhat overstated.

(2) Do the recent developments chronicled on the Stanford Law Blog favor Doudna’s patent claim?

Answer: The recent developments chronicled in the Stanford Law blog simply amount to the initiation of the interference proceeding, which I think that people have been expecting for a while, perhaps ever since the Zhang patents were issued and it was known that the Doudna application was still under examination. The USPTO’s decision to actually institute the interference proceeding means that the USPTO supports the Doudna team’s position that the scope of the inventions claimed by Doudna and Zhang overlaps and that the claims are in conflict. This is a step forward for Doudna’s team because it opens up the possibility that the Doudna patent could be issued and that the Zhang patents could be pulled. However, the initiation of the interference proceeding itself does not favor or disfavor Doudna’s patent claim; indeed, the entire purpose of having the interference proceeding is to determine whether or not Doudna’s patent claims can be allowed, and as the Stanford Law blog pointed out, decisions to institute interference proceedings are largely pro forma. Basically, we still have no idea who will come out on top, except that it should be whoever can show that they invented CRISPR/Cas9 first.

Regarding the reporting in the Stanford Law blog, though, I disagree with trying to draw a difference between Zhang and Doudna with regard to the modification of eukaryotic cells; Doudna specifically recites it in the originally filed claims (see, e.g., original claim 95), not to mention discussing it in the originally filed specification. Genome editing of human cells is explicitly presented in Doudna’s Example 2, and in vivo genome editing in mice is described in Example 7. Thus, the argument that Doudna did not contemplate eukaryotic applications and the suggestion that Zhang’s claims might thus somehow be more worthy, valuable, or patentable (on this basis) is incorrect. Furthermore, it should be noted that patent claims allow the patent owner to exclude someone else from practicing the invention; they do not give the owner a right to practice what is claimed. Therefore, even if hypothetically Doudna had not explicitly contemplated eukaryotic applications (which is not the case), the broader scope of the resulting claims (which would basically cover any genomic editing by CRISPR/Cas9, not just in eukaryotic cells) might even be considered to make the Doudna patent more (and not less) valuable than the Zhang patent.

Despite disagreeing with some elements of its analysis of the actual patents, I do however think that the Stanford Law blog did a great job of describing what happens in interference proceedings, which are mysterious even to many patent practitioners.

(3) What could be the deciding factor in this patent dispute?

Answer: Because the application was filed under the first-to-invent rule, I think that in the end that it will come down to establishing the actual date of invention on both sides, i.e., at what point both sides achieved what they are claiming. If Doudna has lab data showing that she invented CRISPR/Cas9 before Zhang, then her patent should be allowed and Zhang’s patents should be pulled. If Zhang instead has lab data showing that he invented CRISPR/Cas9 first, then his patents should stand and Doudna’s application should be rejected.

However, Doudna’s team could also go after Zhang’s patents or vice versa by attacking the patentability of the claims themselves under the written description and enablement requirements, i.e., by saying that the invention is not described sufficiently to indicate that Doudna/Zhang was actually in possession of the claimed matter at the time of filing/invention or to enable one of ordinary skill in the art to actually practice the invention. The outcome would be to invalidate Zhang’s patents or reject Doudna’s application on that basis. It should be noted, though, that the enablement and written description aspects were already considered to not be an issue by the examiners for both Zhang’s patents and Doudna’s application. The patentability of the claims over the prior art could also potentially be made an issue, although similar to the enablement and written description aspects, the examiners already found Zhang’s patents and Doudna’s application to be clear of any prior art, and any prior art that one side further attempts to apply would probably also apply to the other side in terms of date, as the dates of invention and the claimed subject material seem to be so similar.

Another possibility is that if the claims of either Doudna’s application or Zhang’s patents, or both, could be amended so that the claimed material no longer overlaps, then Zhang could keep his patents and Doudna’s patent could still be issued. However, given that they are both claiming the same fundamental CRISPR/Cas9 technology, I think that this is unlikely. Still another possibility is that some other kind of settlement could be reached, although it seems as though they have already been trying to settle without success, and as the Stanford Law blog rightly notes, settlement is discouraged in interference proceedings. Thus, I predict that in the end it will probably amount to who has the earliest lab records to determine whether Doudna’s application is issued and Zhang’s patents are pulled or whether Doudna’s application is rejected and Zhang keeps his patents (unless there is a settlement of some kind).

(4) There have been some suggestions that the original UC attorneys were outplayed by those at the Broad. What do you think?

Answer: I don’t really think so. The strategies used are different, but it is difficult to say that one is better than the other. The Broad Institute attorneys opted for the fast track to ensure early granting and as a result had to limit what they were claiming (hence the limiting of the claims to eukaryotic cells) and submit relatively few claims. The UC attorneys submitted lots of claims with a broader scope and more coverage, but then had to deal with the longer conventional prosecution process. I think that one could argue, though, that in the end the pathway used wouldn’t make a much of a difference with regard to total patent coverage that could eventually be obtained, as subsequent applications with broader claims could be filed to increase coverage in the case of Zhang, or an interference proceeding can be requested if the patent prosecution process takes too long and someone else patents the invention first in the case of Doudna.

Furthermore, I think that the question of whether or not the UC’s original attorneys were outplayed by the Broad’s may not even be relevant because the outcome of this patent dispute will likely not depend on whose patents were issued first or on whose patent claims initially had a broader scope. For example, if Doudna’s attorneys had instead filed a fast-track application where the patent was granted before Zhang’s but Zhang believed that he had invented CRISPR/Cas9 before Doudna, then Zhang could have requested the interference proceeding and we would still basically be where we are today. Rather, I think that the quality of the initial attorneys and what they did will only impact the interference proceedings if written description or enablement issues come up, because the resolution of such issues would depend on how solidly the patents/patent applications were written. I think that the arguments made by the currently litigating attorneys will have a greater impact, but the greatest impact will probably come from the dates in the lab records.

(5) What about the “mysterious third party” in this patent situation?

Answer: It could be anyone. However, a couple of things to note:

(a) Whoever it is used a solo attorney (not a firm) who doesn’t seem to do much (if any) life science/biotech work, so I am guessing that (like the Yamanaka patent challenge) they are not serious and are not major players in the field.

(b) The attorney is based out of the San Francisco Bay Area, so I think that whoever it is probably is from the Bay Area, too. I think that it’s highly unlikely that someone from Boston, New York, DC, or another major city (or another country, for that matter) would turn to a local solo non-biotech practitioner who is not from their own locality for this. A look at the patent applications handled by the former firm of the attorney confirms that almost all are from Bay Area inventors. However, another possibility would be if the third party is a friend or relative of the attorney.

(c) Most importantly, the “prior art” cited in both 3rd party submissions was largely filed or published after Doudna’s effective filing date, and thus well after her presumed invention date; the only documents that predate her filing/invention date only generally describe the CRISPR/Cas system as it exists naturally in bacterial cells, which would not render obvious what Doudna did in turning it into a bioengineering tool by including the targeting RNA and activator RNA and then using it in other cell types. Therefore, none of the documents are actually applicable as prior art, and so it is really unclear why the “mysterious third party” would have thought that filing these submissions would affect the granting of Doudna’s patent. The examiner working on this thought the same thing, as she did not consider a single one of the references supplied by the third party to be applicable to reject Doudna’s application.

(d) Furthermore, some of the documents in the 3rd party submission (for example, WO2013141680, which is the main patent application cited) were even already disclosed in the information disclosure statements originally filed with Doudna’s application- so the USPTO had already even been informed about some of these documents by Doudna’s own team. Therefore, I think that the “mysterious third party” submissions were never really an issue, although the fact that someone was actively trying to prevent Doudna’s patent from being issued is indeed interesting.

A Conversation with Jennifer Doudna on Cas9 and Human Germline Gene Editing

Jennifer DoudnaI’m doing a series of interviews with leaders in the field on human germline modification. The first interview in this series was with George Church.

Today is the second in this series and is a conversation I had with Dr. Jennifer Doudna, a pioneer in CRISPR-Cas9 technology.

Doudna is a Professor in MCB and Chemistry as well as Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences at UC Berkeley. She is also an HHMI Investigator.

You can read more about the Doudna lab’s research here. She is not only an internationally respected researcher, but also continues to lead efforts to catalyze discussion on the potential future applications of CRISPR-Cas9 technology including dialogue on possible future work in the human germline.

An initial meeting was held earlier this year in Napa that led to a recent commentary piece in Science. Other views have been published as well including Lanphier, et al. in Nature and I have put out there my own perspectives with a roadmap I call the ABCD plan.

I followed up on the Napa meeting in today’s interview with Doudna and also touched on other important issues related to CRISPR-Cas9 technology.

What specifically sparked the Napa meeting? Did you help to start the ball rolling?

Doudna: The Napa meeting was organized by myself and my colleagues at the Innovative Genomics Initiative. We had ethical concerns regarding potential applications of genome editing because CRISPR-Cas9 is widely adapted and so simple. We felt it was important to convene a meeting of stakeholders.

At that time did the organizers know about the rumors of papers potentially in review that might report genetic modification of human embryos?

Doudna: I wasn’t aware of that work coming up, the possible papers in press on embryo editing. We knew, however, that that type of work was possible. We hoped that before it would appear in a publication we’d be able to pull together a consensus point of view through this meeting. We didn’t go in with a preconceived notion, but we felt that scientists should be discussing this, and it should be open and transparent.

How did the meeting go? Were there some areas of disagreement?

Doudna: It actually went fairly smoothly. There was definitely very animated discussion. This is a topic that people can feel emotion about. It is pretty profound if you talk about clinical applications that could change human evolution. There were different points of view, but not hugely different. I didn’t hear anybody at either extreme saying things like “We should edit people tomorrow!” or “We have to get rid of this technology.” It was more focused on questions such as “What kind of safety or regulatory matters should be discussed?” It was only a one-day meeting so there wasn’t a lot of time to get into other issues such as gene editing triggering a biological chain reaction where a dominant change could spread through a whole population.

Will there be another Asilomar meeting like the one in the 1970s?

Doudna: That’s the goal. We would like to convene a larger meeting. We want broad, international representation. That meeting will probably happen later this year. A number of groups have expressed interest. The aim would be to have representatives of the various stakeholders. Some of the top scientific advisory groups. Governmental groups. Funding agencies.

George Church seems to have a more open view on application of this technology.

Doudna: Any group of people will have a diversity of opinions. It’s the kind of topic that each of us comes to with our own set of beliefs and level of comfort with making changes to the DNA of an organism. That’s one of the reasons to get together. I found that Napa meeting to be extremely interesting and stimulating. George was not there in person, but he had a lot of input. I certainly learned a lot.

Should there be a “pause” on clinical applications? How would that work? I don’t think I saw the word “pause” in the Science piece.

Doudna: We decided not to use the word “moratorium” because some people view that as policing. How do you police it? That may be hard or impossible. Rather, we were suggesting that the community decide together about the technology. There’s this incredible potential to help, and yet also risks. It’s a great technology and we should be excited about it. It is incredibly enabling. It enables a lot of new biology that would have been otherwise difficult or impossible. At the same time, because it is powerful and straightforward, it means it also enables clinical and other applications that might be problematic. We, meaning the scientific community, have to proceed in a way that is considered.

We can’t dictate what is happening in every part of the world. It would be presumptuous to ask for a moratorium worldwide. To be more realistic, we strongly encourage scientists to not use it for this clinical kind of purpose at this time. Let’s make sure we are doing the appropriate research before employing it in ways that could be harmful (or helpful for that matter). The recommendation is for a clinical pause. Research should proceed. Then this provides data to evaluate clinical potential and risks.

Can you imagine a future point at which you’d support the use of gene editing in humans in a heritable manner? If so, how do we get to that point from where things are today? What do we need to learn first?

Doudna: We need to learn how efficiently it works. What’s the best way to deliver it safely and efficiently? Not only efficiency, but also what are the off-target levels? How do we minimize that? What would be a safe level if any of off-targets? I’d like to see basic research like what happens to the DNA in germ cells or pre-germ cells when a double-stranded break occurs? What is the repair process like in those specific cells? Those answers would be interesting from a basic science perspective as well as informing future potential clinical applications.

I feel uncomfortable imagining widespread gene editing use in humans now, but it is possible that there are going to be certain types of very specific applications that could be envisioned as beneficial in the future. I won’t be able to make a decision of the wisdom of such an approach until we have more data. What are the real risks? There is always a risk-versus-reward kind of consideration. In which cases is the risk worth the payoff?

Can you comment on the recent Nature piece by Lanphier, et al. from ARM and Sangamo? Did you read that they are opposed to any germline editing, even in vitro? What do you think of their view?

Doudna: They would not allow research. That’s one point of view. The challenge I see with that is first of all I don’t see how you would stop it. Secondly, even if everyone agrees with that, how do we move forward? If we don’t do the research, how do we make informed decisions on the potential for clinical use? If it is possible to permanently fix a genetic mutation that is responsible for a horrible disease, maybe there would be an argument; if we have the technology to fix it, maybe that’s a good thing to do. How do we know if we don’t do the research? To say that we are not going to do any research, it blocks the ability to inform.

We have recently seen the papers on Staph aureus Cas9 that is smaller and the NHEJ inhibitor w/Cas9. What’s it been like to see this technological innovation from you and your team take off so dramatically?

Doudna: It is an intense experience. It is very exciting. I was astounded this spring to wake up one morning with the realization that, “gosh just three years ago I hadn’t even written the paper yet.” Back then, three years ago, looking at the data we were thinking this was an incredibly exciting enzyme.

The pace at which this technology is being employed is so fast, and there are many different ways to use it; these are aspects that have been so fun about it. It has real legs. There are many different flavors of Cas9 that occur naturally. That’s all just been wonderful. It’s a very special and unique experience. I doubt that it will ever happen again for me in my career. Work that started off as a very basic science project with our collaborator Emmanuelle and seeing how it turned into this incredible technology.

What do we do if someone goes rogue?

Doudna: That’s one of the purposes of these meetings: to get out in front of that. I can’t guarantee that that might not happen. I can work to form a coalition to say, “here’s our considered view of the technology and here’s what we see as a prudent way to move forward with this”. That’s really the best that we can do. There’s no way to unlearn what is learned. We can’t put this technology to bed. If a person has basic knowledge of molecular biology they can do it. It’s not realistic to think we can block it. Same thing with regulations. To imagine that we could have international regulations, it’s just not realistic, and in any case, how do you enforce them? I wouldn’t feel comfortable hiding away in the lab. The better path is to try to be open and transparent and to educate people who want to understand it. It’s such a wonderful technology in many ways. Like any technology it has the potential to be used for good and not so good. We want to put out there the information that people would need to make an informed decision, to encourage appropriate research and discourage forging ahead with clinical applications that could be dangerous or raise ethical issues.

Do you anticipate that there will be papers this year on germline editing?

Doudna: I’ve read that article in MIT Tech Review indicating that they might be coming. I wouldn’t be shocked if they got published this year. We need to forge ahead with open discussions. I don’t know how people will respond to such papers if they come out. It depends on what’s been done.

Do you have any comments on the patent situation?

Doudna: I think any time there’s a new technology there are going to be multiple claims around it. Especially something that’s very broadly enabling. That’s something that’s probably par for the course. What I would love to see as a scientist is to see people helped with this technology and to see society helped. I would like to see this employed to do that. I would hope that the IP situation doesn’t impede that. I’m just speaking as a scientist or person. Not as a lawyer or a UC professor. These IP matters are in the hands of very capable people who handle this kind of stuff. I have to let them do their job and just continue to do my job.

Anything else you wanted to mention?

Doudna: It’s really important for people to appreciate that this technology grew out of a project to figure out how a basic process in biology worked. Many discoveries are made via basic science and working to understand a process. You can do careful work and obtain data that allow you to deduce something fundamental about nature. That was very much the origin of this system here. That’s something great to emphasize. There’s a tendency now in our country and Europe to emphasize “translational research.” Maybe there is not as much of an appreciation of basic science as there should be. That kind of research was critical with Cas9. A lot of non-scientists don’t understand the process. Scientists are just curious about the world and we’ve chosen particular kinds of questions. We are doing it for the purpose of understanding our world and life.