Chapter 1 - Who Owns CRISPR-Cas9?

    16/09/2018

    The past few years has seen CRISPR/Cas9 emerge as the driving force that could revolutionize gene therapy, precision medicine and many other biological problems.  It has been heralded as the technology that could cure anything from cystic fibrosis to muscular dystrophy to HIV. It also promises to revolutionize agriculture, reduce infectious diseases and save global animal extinction. The implications of this technology are so huge that Science magazine dedicated a special edition to it in 2015 as breakthrough of the year.  The biotech world as well as Wall Street are now invested in some tantalizingly opportunities that this technology can bring.  With the start of the first clinical trials utilizing the CRISPR system this year, many investors are in an uproar over its commercial applications.  Furthermore, one only has to look to Hollywood and bingeable TV such as Rampage, Luke Cage and C.R.I.S.P.R. (I kid you not!) to know that it has entered the mainstream consciousness of our society.

    Rampage, the Hollywood movie starring D.T.R.Johnson and CRISPR-imaginary monsters:

    Yet the real action movie fight for CRISPR has been going on behind the scenes in a long drawn-out court battle between two rival academic institutions, the Broad Institute in Cambridge Massachusetts and the University of California at Berkeley.  The fight centers around who owns the patents rights to CRISPR/Cas9 gene-editing.  With so much at stake, it is little wonder this patent litigation battle has become “the most heated ever between two educational institutions” according to New York law expert Jacob Sherkow.

    Two main scientists on either side of the CRISPR battle, Jennifer Doudna (left) and Feng Zhang (right):

     

    Here is a brief background:

    CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, or segments of DNA used by bacteria to cut out unwanted invading DNA from phages (viruses that invade bacteria).  Cas9 (CRISPR associated protein 9) is a protein which aids the function of CRISPR to cut out undesirable foreign genes.  A few years ago it was found that CRISPR-Cas9 could be engineered to edit the entire genomes of a panoply of organisms from bacteria all the way to mammals and humans, thus potentially curing many genetic diseases.  As with any discovery many teams of scientists worked to uncover mechanisms CRISPR-Cas system.

    In April 2014, a broad U.S. patent was awarded to Feng Zhang, a scientist at the MIT-Harvard Broad Institute who claims to have discovered the effectiveness of CRISPR-Cas9 on gene editing in human cells.  Zhang filed his patent with a priority date of Dec 2012.  Just a few months later, a Breakthrough Prize was awarded to Jennifer Doudna and Emmanuelle Charpentier from UC Berkeley and Vienna, Austria, for their contribution to the discovery of CRISPR.  Doudna and Charpentier filed a patent with a priority date of May 25, 2012, which includes 155 claims, encompassing numerous applications of the system for a variety of cell types.

    The Takeaway:

    The biggest difference between the two patents was that Doudna’s involved modifying just prokaryotic cells while Zhang’s included the use of CRISPR on eukaryotic cells in vivo, enabled him to potentially apply it in human trials.  Although the Broad patent was filed a few months later than the UC patent, the Broad patent was awarded first based on the “First to File” system and on Zhang’s expedited review payment. In early 2016, UC Berkeley requested that a patent interference be initiated claiming that the Doudna / Charpentier team invented CRISPR first. In February 2017 the USPTO Appeals Board rejected this claim. Furthermore, the board concluded that Zhang’s work in eukaryotic and mammalian cells was not an “obvious extension” of Doudna’s work so he had no “reasonable expectation” of success. This decision meant that the Broad Institute patent remained valid and the UC Berkeley team had to file their case with the US Court of Appeals for the Federal Circuit.  This week, as of September 10th, the Federal Circuit court awarded the pivotal intellectual property to the Broad team and upheld the previous decision from the USPTO. It looks like the Broad Institute team have won the overall court battle and things are coming to a close.

    Three Main issues with the CRISPR patent dispute:

    At the time of the original patent dispute in 2014, several challenges arose.  Firstly, Doudna and Charpentier argued that they filed the patent documents for CRISPR before Zhang because they had an earlier priority date but Zhang was awarded the patent first.  Zhang was awarded the broad patent because he had a laboratory notebook demonstrating his group was doing CRISPR genome editing in human cells before anyone else and also because he paid for an expedited patent review.  Patent lawyers have disputed over the nuances of “First to file” ever since the America Invents Act was signed in 2011.  Thus, the obscurity of the definition contributed to the argument right at the beginning.

    Secondly, hundreds of patents which make use of the CRISPR-Cas9 technology have now been filed by leading scientists around the world.  If the patents filed by Zhang are broad enough this could land many scientists with patent infringements if CRISPR-Cas9 were licensed.  In June this year, the USPTO granted Doudna and the UC team a reprieve by awarding them two of the original CRISPR-Cas9 patents (patent 1 and patent 2) they had filed for editing short nucleotide regions of genomes.  Unfortunately these may have little commercial value.

    Thirdly, biotech patents that deal with genes and genetic engineering have often been contentious.   Intellectual property that use DNA technology which has already existed in bacteria for millennia and can seem “obvious” for many scientists who can now easily use it in their laboratories.  In a sense CRISPR was in fact “invented” by nature and not by any individual, so claiming a patent over the mechanism would be an act of god.  However, the courts have now clearly decided that the invention was not obvious and therefore is valid.

    Historically biotech patents have found different solutions to disputes.  For example, when small interfering RNAs (siRNA) and when polymerase chain reaction (PCR) were first discovered debates arose in the science community about whether people could use the technology without a license.   With the discovery of recombinant DNA, Stanford University was assigned the Cohen-Boyer patent which allowed Stanford to non-exclusively hold the patent, enabling non-profit research institutes to use the technology without a licence.  Stanford also developed a graduated royalty system with small companies to ensure some share of profits if companies used their technology effectively.  For the discovery of siRNA, MIT was awarded the “Tuschl” patent, which also granted nonexclusive licences to companies selling the technology and allowed academic scientists to work on the molecules with no licence.  Similarly, with the invention of the PCR, patents were adapted through a strategy known as “rational forbearance” to prevent researchers from being sued for patent infringement everytime they used the technology and to allow adaptive licences to be held by business partnerships. 

    Startups Galore

    Since the initial filing, all parties have founded startup biotech companies in the race to develop CRISPR as a viable clinical drug.  Zhang co-founded Editas Medicine with his lab director, George Church at Harvard. Jennifer Doudna was also a co-founder for Editas before she dropped out to found Caribou Biosciences and Intellia Therapeutics.  Charpentier is the founder of CRISPR Therapeutics but has now sold the rights for that company. Her co-founder Roger Novak now runs as President of the firm. CRISPR have teamed up with Vertex, the biotech company that came of age developing drugs for cystic fibrosis in a $100 million deal to develop its technologies for primarily for their pipeline.  Various CRISPR/Cas9 patents have since been filed in Europe and the rest of the world in preparation for commercial use by these firms.  In total, venture capitalists have now invested over a billion dollars in various CRISPR startups, with millions of dollars being paid to lawyers for the patent fight. What makes it interesting is that each CRISPR biotech has overlapping applications and many of the founding scientists hold stakes in rival companies.

    A diagram published in Science Magazine in 2017 showing how each researcher or licensee is connected to the major CRISPR startup companies and what applications they have in the pipeline.

    This year, Vertex and CRISPR Therapeutics have been given the go-ahead to launch the first CRISPR/Cas9 clinical trial to treat beta-Thalassemia in Europe.  The therapeutic candidate, CTX001, is designed to treat a deficiency in hemoglobin production by cutting the gene BCL11A that represses fetal hemoglobin production.  It is of note that the FDA has ordered a clinical hold on this trial in the US based on safety concerns with the IND filing. German hospitals, however have given it a green light to start by the European Medicines Agency.

    Given all of the hype around CRISPR-Cas9 it is important to bear in mind that research is still being done to develop our basic understanding for this molecular machine.  Already this year, two groups (here and here in Nature Medicine) have reported on the potentially worrying link between CRISPR and the cancer preventing gene, p53, which sent biotech investors into a panic and stock prices diving. Normally, p53 serves to prevent cancer formation by correcting genes that have been edited and changed, thus preventing malignant cell division.  It appears that CRISPR-Cas9 works best by targeting cells that lack the functional p53 and therefore selects for cells that develop cancer.  This has been a huge stumbling block for clinical trials using CRISPR-Cas9 thus far from progressing to a larger scale.

    Never the less there is optimism that CRISPR-Cas9 therapy could be engineered to work effectively once we gain a foothold of our scientific and mechanistic understanding.  In the meantime, I for one am going to advocate adding CRISPR biotech stocks to your investment portfolios.  There is money to be made in the new frontier of biology!

    Reference:

    Image: https://geneticliteracyproject.org/2018/08/06/what-is-crispr-and-why-should-you-care/

    Rampage Image: https://www.stanforddaily.com/2018/05/08/rampage-the-giant-monster-movie-is-a-colossal-failure/

    Shwerkow JS, Law, history and lessons in the CRISPR patent conflict, Nature.  Vol 33 (3): 256-257, 2015.

    Regalado A, Who Owns the Biggest Biotech Discovery of the Century? MIT Technology Review, Dec 4 2014.

    How the battle lines over CRISPR were drawn, Cohen S, Science, 2017: http://www.sciencemag.org/news/2017/02/how-battle-lines-over-crispr-were-drawn

    STAT News/Scientific American: https://www.scientificamerican.com/article/all-you-need-to-know-for-round-2-of-the-crispr-patent-fight/

    https://www.bereskinparr.com/doc/the-battle-to-control-crispr-ip-continues

    https://www.the-scientist.com/news-opinion/us-companies-launch-crispr-clinical-trial-64746

    https://endpts.com/fda-slaps-a-clinical-hold-on-sickle-cell-ind-filed-by-vertex-and-crispr-therapeutics/

    Pivotal CRISPR Patent Battle won by Broad: https://www.nature.com/articles/d41586-018-06656-y