Why UC Berkeley deserves the main CRISPR patent

crispr nihSome months back a USPTO court issued a ruling that most interpreted as meaning the Broad Institute had won the so-called ‘CRISPR patent battle’ in the U.S. and that UC Berkeley, Jennifer Doudna, and Emmanuelle Charpentier had lost. Now this week Berkeley has appealed that ruling. It seems the odds are against Berkeley prevailing in its appeal, but frankly Berkeley deserves the main CRISPR patent and Broad doesn’t. Interestingly, the European Patent Office apparently agrees with this view and disagrees with the USPTO. Update: note that the Berkeley patent application itself also mentions eukaryotic use.

At the heart of the original decision that favored the Broad was an illogical argument by the USPTO court. They said that the research of Doudna and Charpentier did not make the work that the Broad later patented based on the work of Feng Zhang obvious. In my view Doudna and Charpentier’s work in fact did render Zhang’s later work a totally obvious next step.

Why?

A hypothetical scenario can help to illustrate this.

Let’s say a colleague tells me something along the lines of “Hey, I found this novel nuclease we are calling ‘DUH1’ that cuts DNA in a nifty new way in a prokaryote and in a test tube” and they publish that. Of course, after that many people are going to want to try DUH1 in eukaryotes. Duh, it’s a no-brainer, right? It’s therefore bizarre that the USPTO would think the step to try CRISPR in eukaryotes was not obvious after Doudna & colleagues groundbreaking work.

Flip it around too and imagine that the hypothetical colleague who discovered DUH1 only reported that it worked in vivo and then someone else was allowed to patent that DUH1 could be used in vitro on plasmid DNA in a tube. Does that make any sense? Someone else could patent the in vitro use of DUH1 over the inventor who discovered DUH1 first and reported how it worked in vivo? Even if was a bit of a challenge to get DUH1 to work in vitro, I don’t think that makes sense.

Back to the real CRISPR world, does the in vivo to in vitro or in vitro to in vivo or prokaryote to eukaryote “directionality” of the research flow matter for a patent? I’m not sure, but in theory it shouldn’t in this case as the next steps were obvious. How obvious?

If you read Doudna and Charpentier’s seminal Science paper, the abstract concludes with a statement for all the world suggesting the use of CRISPR-Cas9 for genomic editing in general and I took that to mean in eukaryotes too:

“Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.”

and the paper itself ends:

“We propose an alternative methodology based on RNA-programmed Cas9 that could offer considerable potential for gene-targeting and genome-editing applications.”

You’re telling me that these statements were meant to be restricted to only prokaryotes or DNA in a tube? Really? Nope.

Strangely the patent court apparently felt that Doudna’s public statements about it being a challenge to get CRISPR to work in eukaryotes was a big deal in rendering their decision, but again technical difficulty does not equate to an idea being non-obvious. For sure kudos to Zhang, who was technically speaking quite adept to get the CRISPR-Cas9 system to work well in eukaryotes quickly, but even if the Broad ironed out key technical kinks in getting CRISPR-Cas9 to work well inside eukaryotic cells that still doesn’t justify them having the main CRISPR patent. It’s just not conceptually or technically different enough from the earlier Doudna and Charpentier work. To me it’s not even a close call, but USPTO got it totally wrong.

Another exercise reinforces my argument. Can anyone imagine Zhang publishing his first CRISPR work (which by the way cites and heavily relies on the works of Doudna and Charpentier) if he didn’t have those earlier key papers of Doudna and Charpentier to build on moving forward? No way. Could Doudna and/or Charpentier and others have gotten CRISPR to work in eukaryotes without Zhang? Yes and almost certainly it was already inevitable before Zhang even published his key Science paper.

For all these reasons, Berkeley deserves the main patent based on simple common sense, but whether things will turn out that way longer term seems far less clear.

Some may say that no one should get to patent CRISPR, but these days that’s probably a naive perspective. For more on the history of patenting (or lack thereof) of nucleases and in particular restriction enzymes, this is an interesting read. 

Does Word Cloud of Lander’s Heroes of CRISPR Text Suggest Bias?

Lander Heroes of CRISPR word cloud

Eric Lander’s recent piece in Cell on The Heroes of CRISPR has sparked strong reactions that are mostly critical and have argued that the article is biased. I’m going to weigh in with my own thoughts at some point later, but I thought it would be interesting to try a word cloud-based text mining of the Lander piece. See above.

Word clouds indicate which words are used the most by the relative size of the letters of the words. Common words such as “the”, “experiment”, etc. are filtered out to reduce noise. In this case I also filtered out “CRISPR” and “Cas” because they were too big in the cloud making it hard to see the rest.

The names of scientists that show up in the upper cloud are almost all men including Mojica, Zhang, Marraffini, Siksnys, and Horvath. Dr. Charpentier is the only woman whose name makes it into this cloud and with fewer mentions than most of the others.

Making the word cloud settings a bit less stringent now allows (see at the bottom of the post) for the word “Doudna” as in Dr. Jennifer Doudna to appear and “Church” too as in Dr. George Church and Barrangou, but as relatively smaller words meaning not used as often as the others. Note that in this second cloud I removed “genome” and “sequence” as they disrupted the cloud since they were so big.

The number of uses of a particular scientist’s name in a piece overall relative to others could be interpreted to reflect the author’s level of importance given to that scientist. Here are the numbers of times names were used in the piece according to the word cloud tool I used:

  1. Mojica 23
  2. Zhang 15
  3. Marraffini 13
  4. Charpentier 11
  5. Siksnys 10
  6. Horvath 9
  7. Doudna 8
  8. Church 8
  9. Barrangou 8

What do you think of the Lander piece? The strong reaction to it?

What about the word cloud and text mining approach to analyzing papers? Do these Heroes of CRISPR clouds reflect possible bias or just the random nature of words and names used in writing?

Lander cloud 2

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.

Cool biomed blogs you may not heard of: a drugmonkey, a med student, #CRISPR, & more

Science blogging is somewhat of a communal exercise. At least, it should be and cool biomed blogs are a great community.

One of the most invigorating aspects of blogging is finding new blogs that are worthwhile and edgy.

The NodeBelow I list some of my recommendations for blogs that you might not be familiar with, but that you should definitely check out.

DrugMonkey Blog. A go-to source for perspectives and a reality check on NIH funding, careers, and sometimes a bit about drug science. Whoever DrugMonkey is, s/he is awesome. @drugmonkeyblog

Innovative Genomics Initiative (IGI) Blog. The IGI is Berkeley’s fantastic gene editing and genomics group that includes Jennifer Doudna and Jacob Corn. Jacob writes the IGI blog and his posts are definitely worth reading including many insights on CRISPR. @igisci 

The Node. Love stem cells and developmental biology? Then you’ll love The Node (symbol above), the timely web offering of news in this arena that feels very much like a blog from the folks who bring us the wonderful journal Development@the_Node 

Nerds Eye View Blog. UC Davis Medical Student Fiona Scott (pictured)Fiona Scott is funny and irreverent as she writes this edgy blog about medical school and more. Many of you will enjoy this site. @Nerdseyeview22

STAT. While STAT is not a blog, it is my vote for the best new biomedical science news outlet of 2015. It has a stellar group of science writers who also seem to have some of the best insider sources. You’ll often read about cool new developments here first. @statnews 

New #CRISPR updates: Editas to go public, patent issues, dragons & more

CRISPR dragon

Dragon image from Wikipedia

A lot has been going on in the CRISPR world. Here are some key CRISPR updates.

Editas has filed the paperwork on the road to going public as a company. Such an IPO, should it come to fruition, could raise billions of dollars. Will the other CRISPR companies like Caribou and CRISPR Therapeutics follow suit? Simplistically, it seems like the first CRISPR IPO could get the lion’s share of investor money, but then there’s the patent thing hanging over all of this (see below)

Patent dispute rolls on. Jacob Sherkow over at the Stanford Law Blog dug into recent developments in the CRISPR patent battle. One big thing is the interference proceeding. A patent person I recently communicated with on this topic has some different views than Sherkow on much of this. I’m hoping to blog about that soon.

CRISPR on the news. If you missed it, Jennifer Doudna and I were interviewed by Gwen Ifill on the PBS News Hour last week (see below).

A BBC piece came out that was the subject of quite a bit of discussion on Twitter about whether CRISPR could be used to make a dragon. The item mentioned an article by Hank Greely and Alta Charo on CRISPR Critters (animals made using CRISPR) that had referenced the possibility of making a dragon. I tweeted that that was unlikely but that making a unicorn (adding a horn genetically to horses) was relatively more plausible.

A lively discussion followed including Carl Zimmer, Leonid Kruglyak, and Matthew Herper.