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. 

Live blogging Future of Genome Medicine: great talks by Feng Zhang & others

What is the future of Genome Medicine?

The meeting by that same name that I’m at down here in La Jolla is all about tackling this question and the line up of speakers today on the first day is amazing. I’m speaking about IPS cells as a basis for personalized medicine tomorrow morning so that’s exciting.

As time permits I’m going to try to do a bit of stream of consciousness live blogging of the event so here goes. Don’t expect everything to be a full sentence…

Today got started with a cool presentation on diagnosing brain pathogens by deep sequencing, which is a remarkable technology. The first case presented was on a patient with a tap worm in the brain that could only be diagnosed via genomics.

Feng Zhang talk

CRISPR innovator Feng Zhang next discussed genome editing.

He started by talking about harvesting research tools from natural diversity. They asked, “Are there other CRISPR effectors that remain to be discovered?” They computationally looked for the answer and found a long list of candidates. They found for instance Cpf1, C2c1-c3. They felt C2c2 was more interesting and is a guided RNase. Upon recognition of the target, the enzyme becomes activated but becomes a non-specific RNase at that point. Naturally targets phage via immunity and PCD. How can C2c2 be useful? Sherlock method for diagnostics of biological pathogens. Using a guide that “looks for” target sequence using a degradation-activated reporter based on targeting pathogen RNAs. Example of Zika.  Sensitive to aM level in experiments. I wonder: could the same be done with CRISPR for pathogen DNA? He also briefly mentioned natural system of genome rearrangement in organisms such as one particular ciliate.

Ante “Bill” Lundberg, CSO of CRISPR Therapeutics, spoke next on CRISPR Therapeutics for Sickle Cell and B-thalassemia, both diseases of B-globin. The dramatic increase in characterized disease-causing genes lays the foundation for genomic medicine. A key question, once you edit cells in the body? What will work efficiently for delivery? Not everything can be done on cells outside the body. Goal is to get fetal hemoglobin elevation. They gene edited patient CD34+ HSCs as their therapeutic modulation. He also discussed safety considerations including off-target editing and unintended consequences of on-target editing. The rigorously probe for these including in animals. They get about 90% editing in the lab and strikingly very similar level at clinical scale, which is impressive. IND studies are underway.

He also talked about the National Academies report released this Valentine’s Day on non-heritable and heritable human gene editing. More discussion is needed going forward by all of us, he said. His own personal view is one of caution on germline editing and only rare applications are imagined plus PGD is an existing option. “Treat the patient, not the germline”.

Great session to start the conference.

7 cool recent CRISPR articles

CRISPR Model Jacob Corn

CRISPR Model from Jacob Corn

So everyone is buzzing about the CRISPR patent court decision (which BTW I think was flawed but that’s for another post), but the research roars on at warp speed.

Here are 7 recent CRISPR articles that caught my attention.

What are your favorite recent CRISPR papers?

Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration. Do you think the term “genome surgery” is appropriate?

Efficient CRISPR/Cas9-assisted gene targeting enables rapid and precise genetic manipulation of mammalian neural stem cells. CRISPR on the brain.

Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. CRISPR pre-clinical promise.

The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia. CRISPR vs. cancer.

Expanding the CRISPR Toolbox: Targeting RNA with Cas13b. CRISPR systems continue to evolve.

CRISPR/Cas9-AAV Mediated Knock-in at NRL Locus in Human Embryonic Stem Cells. CRISPR’ing ES cells.

Interspecies Chimerism with Mammalian Pluripotent Stem Cells. I blogged on this one here and did an opinion piece at WaPo here.

Where are all the new CRISPR human embryo papers?

Last year I heard from several sources that there somewhere between 3-5 unpublished manuscripts reporting the use of CRISPR gene targeting in human embryos being shopped around at various journals in addition to the one that had been published. Since that time we’ve seen a grand total of one additional paper reporting on CRISPR of human embryos.

So what gives?

Were the sources wrong?

I don’t think so and I believe there are additional labs pursuing research on the use of CRISPR in human embryos.

Depending on the context, the oversight, and the training of those involved, there may be nothing wrong with these studies at all. In fact, they could be positive and teach us a lot if the teams are careful. However, CRISPR’ing human embryos without a good rationale and appropriate oversight is unwise. I also cannot imagine supporting use of CRISPR with the intent to make a modified new human being for many years to come if ever. You can learn more about the history of genetic modification and my views as well as those of CRISPR leaders in my new book, GMO Sapiens.

So where are all the CRISPR human embryo papers? I can think of a few main reasons why we haven’t seen more so far.

embryo human

Wikimedia Photo

Editors as gatekeepers? One possible reason we haven’t seen more CRISPR’d human embryo papers is that journal editors are reluctant to publish them and are acting as essentially gatekeepers for this kind of work. If true, what are the potential risks or benefits of such a de facto filtering system and what is the basis by which the editors are making such decisions?

Outcomes of first 2 pubs discouraged more? Another possibility is that other research teams have been discouraged by the first two papers reporting CRISPR use in human embryos. I can see at least two levels at which those considering working and publishing in this area might be reluctant to proceed because of the first two papers. On the one hand, both papers reported technical challenges with this research, which was discouraging. On the other hand, both papers were heavily criticized by some.

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Nature Biotechnology looking at NgAgo paper amidst reproducibility concerns

When potentially game changing new technologies are reported such as NgAgo gene editing, both scientists and the public get excited, but especially if such new reports stem from a single paper it is wise to take a cautious approach for a while. The key question is whether the new findings will turn out to be reproducible.

With the case of NgAgo specifically, the Nature Biotechnology paper reporting potentially very desirable gene editing properties, drew a lot of interest. See archived blog posts on NgAgo here.

NgAgo China newspaper

Snapshot of part of China Daily article. Photo Credit Dr. Robert Geller

However, recently many within the scientific community have reported consistent difficulties in getting NgAgo to function as reported. Gaetan Burgio did a guest post here presenting 7 figures of data that together paint a picture of NgAgo not functioning at all like CRISPR.

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