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. 

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.

A role for nationalism in science?

we're #1One of the rewarding things about being a scientist is the opportunity to connect and even collaborate with other scientists around the world., but at the same time there is nationalism in science too.  Some nations, perhaps most of them, and some scientists feel a sense of competition against others at least some of the time.

In fact science is very competitive whether it is the colleague just down the hall in some instances or somewhere else on the same campus, same city, state, or country. But when competition in science pits one country against another, things can go to a whole other level. In times of war or even in peace but when countries are adversarial there might be good reasons for science to be woven into a sense of nationalism or at least national self-preservation. Who in American for instance would have wanted Germany to make an atomic bomb first?

Today in most countries we are not openly at war with other countries, but there are still nation-focused threads to science. For instance, in the stem cell field’s area focused on clinical translation there is a growing narrative thread that America must be more competitive with Japan or risk falling behind.

From talking to some colleagues in Japan they likewise have indicated a sense in Japan of wanting to be the #1 leader in stem cells. China is also very competitive on the stem cell front. The UK wants to lead the world it seems in certain reproductive technologies such as 3-person IVF and in other ways including certain areas of stem cell work. Is this kind of competition based on national identity healthy? Toxic? More complicated than such binary ways of thinking?

Does it matter than Japan has a strong and dominant IP position over IPS cells, while arguably many companies in the US do not? Or that pharma companies in Japan recently bought a few notable stem cell biotechs? Does it make a difference to the world that the US is poised to have almost complete control of the IP on CRISPR?

At the same time we need to also keep in mind that there are thousands of collaborations going on between scientists in these and countless other countries too. What if these collaborating scientists’ countries are from a broader perspective fierce competitors with each other? Do individual scientists need to think about that? Worry about it? Embrace it?

I believe collaboration makes science better and it should transcend national boundaries so I’m not a big fan of nationalism in science. What do you think?

CRISPR Update: Patents, Embryos, & IPOs, oh my

It’s been a busy few weeks for the CRISPR arena so I’ve made a CRISPR Update. I’ve listed below links to some commentaries and key developments.Joanne Manaster

 

Fun Video interview on Read Science! with Joanne Manaster on my new book on CRISPR in humans, GMO Sapiens.

CRISPR: Pursuit of profit poisons collaborationNature piece by Jacob Sherkow

HIV Fights Off CRISPR Gene-Editing Attack. HIV adapts when CRISPR attacks.

2nd group CRISPR’s human embryos and things don’t go well. More Indels than precise gene edits, mosaicism and more.

CRISPR biotech Intellia strikes licensing deal with Regeneron, readies IPO. It’s interesting that there are these CRISPR IPO’s when the CRISPR patent situation remains entirely up in the air.

George Church versus Marcy Darnovksy on human modification in the WSJ

CRISPR/Cas9 Used to Create Knockout Chickens. Bock bock adoodle moo

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?