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Who Owns CRISPR?

Update: see also this post at Xconomy for a look at this issue.
CRISPR/Cas9 is an excellent technique for gene manipulation. Its discovery is absolutely going to be the subject of a Nobel prize; I think it’s pretty much of a lock. But at the moment, there’s a vicious legal fight going on over who owns the right to it. Technology Review has a good overview here.
I’m glad that they’ve gone to the trouble, because I wouldn’t want to summarize it myself. I last wrote about this here, and things have not gotten any less tangled. There are conflicting patent claims, multiple startup companies, and all sorts of cross-licensing tangles. To add to the confusion, the technology is still evolving, and may well evolve past some of the existing claims:

Few researchers are now willing to discuss the patent fight. Lawsuits are certain and they worry anything they say will be used against them. “The technology has brought a lot of excitement, and there is a lot of pressure, too. What are we going to do? What kind of company do we want?” Charpentier says. “It all sounds very confusing for an outsider, and it’s also quite confusing as an insider.”
Academic labs aren’t waiting for the patent claims to get sorted out. Instead, they are racing to assemble very large engineering teams to perfect and improve the genome-editing technique. On the Boston campus of Harvard’s medical school, for instance, George Church, a specialist in genomics technology, says he now has 30 people in his lab working on it.
Because of all the new research, Zhang says, the importance of any patent, including his own, isn’t entirely clear. “It’s one important piece, but I don’t really pay attention to patents,” he says. “What the final form of this technology is that changes people’s lives may be very different.”

At the moment, Feng Zhang and the Broad Institute have what appears to be the first and widest patent coverage. But some key claims of the patent seem to be based on the idea that extending the technique to human cells was an inventive step, and not everyone in the field buys that at all – saying, on the contrary, that the way the technique just seems to work on everything from bacteria on up is one of its distinguishing features. So all this looks very likely to end up in court, or at least most of the way to court until the various parties can work out some sort of settlement.
I expect that to be the way this situation resolves, actually, but clarity isn’t going to be available for a while yet. What will drive the whole process will be which CRISPR variants show the most medical promise, and that is yet to shake out. In the meantime, research in the area is going so quickly that it’s hard to keep up – certainly on a far different time scale than the patent system.

32 comments on “Who Owns CRISPR?”

  1. Anonymous says:

    Kinda fun to see these academics scramble around trying to grab dollar bills. Like those old game shows where they put the sap in the glass booth with wind blowing and dollars flying around and they have to grab as much a they can in 1 minute.
    Still a long shot that crispr will work in humans as a therapeutic approach. that being said, even ex vivo uses would be impactful-ex vivo genome editing already demonstrated by carl june.

  2. Boo says:

    “I don’t really pay attention to patents”

  3. Anonymous says:

    In my view it’s a huge fight over … nothing! Whilst CRISPR is undoubtedly a very flexible and powerful tool in vitro, there are very few diseases that could potentially be treated with this technology. Essentially, it is limited to rare genetic recessively inherited loss-of-function diseases of the blood, eye and liver, due to issues with poor bioavailability and incomplete efficacy. And that’s assuming they can fix the specificity issue.

  4. Barry says:

    if/when the patents are adjudicated, the challenge will be to show that the extension to humans was non-obvious to one skilled in the art. Since CRISPr works in all other organisms tested, and since humans are organisms, the answer seems to be that it was not non-obvious and that therefore the patent is invalid–unless the presiding judge is a Creationist.

  5. Anonymous says:

    #3:
    Hilarious to see the VCs however using the ‘promise’ to raise large sums of money. What are the chances the money raised will in the end go to in-licensing a small molecule…

  6. Anonymous says:

    … Or paying for patent lawyers.

  7. Imaging guy says:

    A very recent article about CRISPR patent fight
    “Who owns CRISPR-Cas9 in Europe?”, Nature Biotechnology 32,1194–1196(2014), doi:10.1038/nbt.3086

  8. anonymous says:

    When the smoke clears and the way things are going, I predict that China, will eventually own this patent!

  9. anonymous says:

    #1 made me chuckle but who can blame them or the VCs.
    The same situation presented itself with siRNA with lots of licensing revenue and exits well before any clinical application.

  10. Bryan says:

    #3
    Medical applications are not the only applications for CRISPR. For example, CRISPR makes modifying plants much easier, and plant biotechnology is no small market (just ask Monsanto).

  11. Anonymous says:

    @10: And who is going to know if CRISPR is used (without permission) by Monsanto in their private labs? Even if the patents are granted they are going to be impossible to police and enforce.

  12. Anonymous says:

    Correct me if I’m wrong, but isn’t the whole CRISPR story ‘obvious’ to someone skilled in the art? Zinc finger nucleases and TALENs were known long before that, Cas9 is just another nuclease, otherwise the principle is the same. CRISPR only happens to be more suitable for genome editing.

  13. Anonymous says:

    30 people in one lab working on it? what a waste

  14. artkqtarks says:

    #12
    Feng Zhang with George Church had worked on TALENs to do genome editing. So, they were able to move pretty quickly to demonstrate that the CRISPR/Cas9 system can be used for genome editing (Cong et al. (Zhang lab) and Mali et al. (Church lab) were published back to back in Science in January, 2013.) I guess that was the advantage they had over someone like Doudna and Charpentier.
    But CRISPR was relatively new. The nuclease activity of Cas9 was not demonstrated until 2012 (Jinek et al. (from the collaboration of Doudna and Charpentier labs) published in Science and an independent study by Gasiunas et al. published in PNAS). Perhaps the nuclease activity could be anticipated from previous studies. (For example Garneau et al. Nature (2010).)
    Anyway, there were contributions from many groups. But I see Feng Zhang as the guy who is at the forefront of the technology development.

  15. Anonymous says:

    I just don’t see how heterologously expressing a protein of previously demonstrated function is patentable. if there is a vote, its got to be to those who discovered the nuclease in the first place.

  16. DN says:

    #3, it will have broad applicability to every disease influenced by blood-borne hormones. You can “simply” edit in a tetracycline-sensitive hormone expressor and turn an oral drug into the circulating hormone of your choice. Disposal works too. Too much leukokine 47 causing rheumatoid arthritis? Have the liver excrete the disposal protease.

    Liver viruses will be a big target. Cas9 evolved as an anti-DNA defense, after all, so creating a subpopulation of virus resistant hepatocytes should be straightforward. Ditto for HIV resistant hemapoietic stem cells.

  17. DN says:

    #3, it will have broad applicability to every disease influenced by blood-borne hormones. You can “simply” edit in a tetracycline-sensitive hormone expressor and turn an oral drug into the circulating hormone of your choice. Disposal works too. Too much leukokine 47 causing rheumatoid arthritis? Have the liver excrete the disposal protease.

    Liver viruses will be a big target. Cas9 evolved as an anti-DNA defense, after all, so creating a subpopulation of virus resistant hepatocytes should be straightforward. Ditto for HIV resistant hemapoietic stem cells.

  18. Anonymous says:

    @17: So you are saying it is better to inject tetracycline each time to induce expression of a hormone (added with genetic engineering) than it is to inject the hormone itself? Get real, we have enough problems with antibiotic resistance as it is. And what’s the benefit, if you still have to inject each time?

  19. Anonymous says:

    Trust me, CRISPR is going nowhere, except as a tool for scientists to burn more money. Same as siRNA.

  20. artkqtarks says:

    As someone who works in an academic lab, I don’t really care about the patents. The CRISPR/Cas9 system has already been enormously useful for me and my colleagues. And I am appreciative of Feng Zhang for making the reagents available quickly, providing useful information on his web site, and answering questions. He has shown openness that I admire. This patent battle makes me a little sad. I am a fan of Jennifer Doudna’s work, too.
    Derek says this is a lock to be the subject of a Nobel Prize, but I’m not so sure. I don’t know how you can choose the winners, even though that’s what the Breakthrough Prize did.

  21. bioUK says:

    Politics, greed and money will win through in the end, leaving a trail of bodies in it’s wake. Science will be the last thing on anyones mind in the gold rush. Reminds me of the PCR situation back when Roche tried to stop everyone using it without a licence from them.

  22. Anonymous says:

    #20. Easy: Doudna, Carpentier and maybe one more…done. paper trail is clear.

  23. artkqtarks says:

    #22
    Despite what #15 said, I think the actual demonstration of gene editing using CRISPR was hugely important. And that was published by Zhang and Church at the same time. It’s hard to pick one of the two. But the Nobel Prize can only be shared by up to three people.
    Also, should we ignore the Gasiunas et al. PNAS paper because it came from an obscure lab from Lithuania? FWIW the paper was submitted earlier than the Doudna/Charpentier paper. I don’t know the field enough to know which group actually did it earlier.
    If you ask me my favorite paper in the CRISPR field, that would be a prophetic paper published by Eugene Koonin’s group in 2006, even though it has nothing to do with gene editing. They were able to guess what CRISPR does from bioinformatic analysis.
    http://www.biologydirect.com/content/1/1/7

  24. Anonymous says:

    #4, #15, in fact Doudna is on record saying that she could not get CRISPR to work in human cells, in an interview from Jan 2014:
    “…Doudna experienced “many frustrations” getting CRISPR to work in human cells. But she knew if she succeeded, CRISPR would be “a profound discovery” — and maybe even a powerful gene therapy technique.
    “I hope you’re sitting down,” an excited colleague told Doudna in an unexpected phone call. “CRISPR is turning out to be absolutely spectacular in [Harvard geneticist] George Church’s hands.” He had even gotten it to work in human cells. Thrilled, Doudna immediately contacted Church. They shared their results, and both published studies in January 2013 showing that CRISPR can cut, delete and replace genes in human cells.”
    http://www.ozy.com/rising-stars-and-provocateurs/jennifer-doudna-crispr-code-killer/4690

  25. Anonymous says:

    It is not uncommon to experience technical issues when expressing proteins in different hosts- proteolysis, codon usage, promoter, etc. was it merely 30 postdocs grinding on different constructs or was there truly something nonobvious for the breakthrough? I stand by the comment- solving heteologous expression issues for a protein of known function is simply nonpatentable. Ayone skilled in the art would be able to do it (and many were trying at the time with less firepower however)

  26. tangent says:

    That Koonin 2006 paper is impressive — was some of this floating around at the time, or was this pretty much novel? Granted, they had published a different hypothesis earlier, so you want a multiple-trials correction, but still.

  27. Anonymous says:

    Bolotin 2005 has a much fuller story than the Koonin 2006 paper. Bolotin also discovered Cas9, although called Cas5 in that paper.
    http://www.ncbi.nlm.nih.gov/m/pubmed/16079334/

  28. artkqtarks says:

    #27
    I hadn’t read this paper. It’s certainly earlier. Thanks!

  29. Anonymous says:

    #28, it would also be worthwhile to look at the work from the obscure Lithunian lab you mentioned especially their Sapranauskas 2011 paper. It shows harnessing of Cas9 for DNA cleavage in bacterial cells.

  30. joe miano says:

    Folks, the application of CRISPR is not non-nonobvious. The Nobel will go to those who defined its beautiful process in bacteria and archaea.

  31. anon says:

    See US Patents 8,945,839; 8,932,814; 8,906,616; 8,895,308; 8,889,418; 8,889,356; 8,871,445; 8,865,406; 8,795,965; 8,771,945 and 8,697,359; allowed US applications 14/226,274 and 14/105,017: issued EP 2771468; accepted EPA 14170383.5; and pending US 13/842,859, EP 2800811, and US 14/318,933

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