CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a region in the genome of most archea and of
about a half of all bacteria, playing a role in a cellular defense system
against viruses. The region integrates samples of the invading viral DNA, to be
later used for the virus recognition and destruction. Adjacent to the CRISPR
region, there is CAS region (Crisper Associated System or Crisper ASsociated) coding for nucleases for cleaving the viral DNA. A nucleoprotein complex derived
from CAS and CRISPR, comprising said nuclease and usually two RNA molecules, is
able to find the foreign DNA complementary to said samples and neutralize it by
cleaving. The system is now popularly utilized in a genome editing technology
known as CRISPR-Cas9 which enables to modify genes in any organism much more
quickly and simply than the previous techniques such as ZFN and TALEN. Jennifer
Doudna (California University in Berkeley, born 1964) and Emmanuelle Charpentier (Max Planck Institute for Infection Biology, born 1968)
re-engineered bacterial components into a simple system comprising one RNA
segment and protein Cas9; the RNA guides (gRNA) the cleaving enzyme Cas9 to any
complementary DNA and cuts it in both strands; the free ends enable to modify
the DNA as wished (using HDR, NHEJ, etc.).
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Doudna and Charpentier published their work in Science in August 2012.
An explosion of CRISPR published works followed, firstly
scientific publications and later patent applications, utilizing CRISPR-Cas9
for modifying human cell cultures, yeast, mice, monkeys, and human embryos.
Commercially available CRISPR-Cas9 systems and working
protocols quickly appeared (Sigma Aldrich, Nature Protocols, etc.), and
"democratization of gene editing occurred". The potential of
CRISPR-Cas9 was immense. Doudna started her company Caribou Biosciences already
in 2011, and with Charpentier they filed a provisional patent application in
May 2012. In 2015, U.S. teams announced using CRISPR in creating a
"mutagenic chain reaction" that was able to stop the mosquito
susceptibility to host malaria, and they even made modifications rendering female
mosquitoes infertile, thereby possibly wiping out the whole population. Wiping
out human subgroups can be easily envisaged. Doudna and Charpentier became
famous overnight. In November 2014 they received the $3 million Breakthrough
Prize, competing against the Nobel (4-10 times more money), created by the Internet
billionaires including Yuri Milner (Internet), Mark Zuckerberg (Facebook),
Sergey Brin (Google), and Jack Ma (Alibaba), etc.
Time Magazine named them among 100 most influential people in
2015. When Doudna studied, she already had been supervised by two Nobelists,
Szostak (telomeres) and Cech (catalytic RNA). From 2013 on, also the two women,
Doudna and Charpentier, were expected to get a Nobel Prize. Her famous
University of California in Berkeley, of course, supported the publicity. Although
the University is generally known more for its hippies history of the Sixties,
the California University in Berkeley, as well as the Lawrence Berkeley
National Laboratory connected to the University, have surely achieved great
successes. Look at the elements in the Mendeleev Table, Am (americium), Cf
(californium), Bk (berkelium), Lw (lawrencium), Sg (seaborgium), and other, created
there, Lawrence and Seaborg being the directors of the National Laboratory and
Nobel prize winners as well. Nobelists are indeed appreciated in the Berkeley
university, and inside the university where at nine the morning nobody can find
a free parking lot, they even have the most precious valuable – a reserved parking
place for every Nobel prize winner.
Natural sciences are supported in Berkeley, and famous is
the Lawrence Hall of Science for children and adults located at a charming site
on the hills between the University and the Laboratory, from which a wonderful
view of the whole city of Berkeley can be enjoyed, with the bridges of San
Francisco and the Pacific in the background. Look at a climbing toy in the
shape of the DNA molecule at this site; my grandson Dan climbs it and makes a DAN
AND DNA complex.
The Doudna’s US provisional patent application proceeded to
an international application PCT as is usual, and slowly also to national patent
applications in other countries. It came as a shock and caused consternation,
when on 15 April 2014 a US patent was granted on CRISPR/Cas9 technology, US
8697359, to a 32-year old inventor Feng Zhang working in Broad Institute and
MIT, Cambridge, Massachusetts.
Although generally unknown, the young scientist (born 1982, linked
to Stanford, Harvard, and MIT) had been among the most hyperactive and successful ones in
the wave following Doudna’s 2012 publication. He coauthored a 2013 Science
publication describing the use of CRISPR-Cas9 in Eukaryotic cells, as well as tens
quickly filed US provisional patent applications. In 2013 Zhang cofounded
Editas
Medicine together with Church and Doudna, but Doudna broke off after the
Zhang’s patent had been granted. Her rights in her own pending patent have been
licensed to Intellia. In the meantime, Charpentier cofounded a startup CRISPR
Therapeutics in Basel, Switzerland, selling her rights in the patent
application to them. Other companies have since been formed. The companies raised hundreds of millions of dollars to
turn CRISPR into cures for incurable diseases.
Granting a patent to Zhang was totally unexpected. Firstly,
from filing the provisional to the grant took only 1 year and 4 months.
Secondly, Zhang claimed the use of CRISPR-Cas9 in eukaryotes, which was seen by
many as a particular use of Doudna’s general technology. Doudna expected in her
earlier work that the technique would work in all cells as well as in bacteria,
but according to Zhang this was a mere conjecture and he was supposedly the
first to show that it really works, concluding that his work was an act of surprising
action – an invention. But the fact, that many scientists quickly managed to
get CRISPR technique to work in eukaryotic cells, together with excellent reproducibility
of the method in different organisms, might have suggested that CRISPR would have
worked in all cells. As there is no patent opposition procedure in the U.S. (in
contrast to Europe), Doudna decided to challenge the Zhang's patent by
utilizing the interference process – a procedure in patent examination having existed only in the U.S., and having been abolished with the passage of the Leahy-Smith America
Invents Act in 2011 by Congress. In case of two independent inventors competing
for a patent, the U.S. patent law traditionally used to give priority rights
according to a first-to-invent system and not a first-to-file system; the interference
proceedings used to decide who was the first to conceive the invention and to
reduce it to practice, regardless who filed the application as first. The Leahy-Smith
Act set 16 March 2013 as the last filing date of a patent application which can
utilize the interference proceedings. Doudna’s provisional patent application was
filed on 25 May 2012 and her PCT application on 15 March 2013 – interestingly one
day before the last day.
The patent dispute over the Gene Editing Technology between the
Broad Institute Inc. vs. The Regents of the University of California was seen
as one of the biggest litigations in the biotech history, and in any case it
was probably the last important interference case in history. Zhang’s
application was filed half a year after the Doudna’s application, but it was
prosecuted quicker thanks to Zhang’s attorneys who filed Petition to Make
Special, enabled when the patented subject is related to environmental quality,
recombinant DNA, superconductivity materials, HIV, cancer, countering
terrorism, and others. In the meantime, Doudna’s attorneys added amendments to
the patent application to cover the use in human cells; in September 2015 an
Official Action (OA) raised a number of rejections of the claims; in October
the applicants’ attorneys conducted an interview with the examiner, untypically
participated by four examiners, showing that the USPTO was aware of the
importance of this case; in November a response to the OA was filed, and on 23
December 2015 the USPTO issued a notice of indicating that all of Doudna’s
claims were in condition for allowance. Instead of taking a patent, Doudna et al. filed a request
for Interference in January 2016, and it was granted. The three-judge panel should determine the
priority of invention between the disputing parties, as well as the patentability of both inventions.
The burden of proof to establish earlier inventorship lied with Zhang (junior
party). The junior party won in about 43% of cases in the US patent history. It
had to be shown that the inventor had proceeded to reduce the invention to
practice without further inventive activity and with sufficient diligence,
usually demonstrated by detailed and dated laboratory notebooks. Doudna’s team demonstrated
the mechanism only in bacterial cells but claimed all types of cells in the US
patent application, and examiners accepted Doudna’s claims as allowable. Zhang’s
claims were limited to the use of the CRISPR-Cas9 in eukaryotic cells, and Zhang’s
examiners acknowledged that the extension to eukaryotic cells was not obvious. During
the oral hearing on 6 December 2016, UC Berkeley’s lawyer argued that Zhang’s accomplishments
in eukaryotes were an obvious extrapolation of Doudna and Charpentier’s work,
and the Broad’s lawyer argued that Zhang’s achievement was inventive and not obvious.
Moreover, in order to show he was "first to invent" the use of
CRISPR-Cas in human cells, Zhang supplied lab notebooks, as was usual in the
interference cases; the notes allegedly showed he had the technique ready before
Doudna and Charpentier published their results or filed their patent
application. Generally, it was expected that Doudna’s team would prevail in the
interference proceedings.
For many surprisingly, on 15 February 2017 the US patent
office (USPTO) ruled on a patent interference case brought by University of
California with respect to patents issued to the Broad Institute, and found
that the Zhang’s patent was distinct from the Doudna’s invention, the two
techniques not competing and being separately patentable. The USPTO thus pronounced
a judgment of “no interference-in-fact”, stating that the Broad Institute had rebutted
the presumption of interference by showing the claims of the two parties are
drawn to distinctly patentable subject matter, so that the parties do not claim
the same invention. With billions of dollars in the air, the Patent Office was
afraid to deliver a verdict, which would be fateful for any one of the two
parties. The ruling left Zhang with his patent and Doudna merely with her
application. On April 12, 2017, the University of California-Berkeley filed
notice of appeal with the US Court of Appeals for the Federal Circuit in
Washington, DC, challenging the February ruling.
On May 10, 2017, Doudna et al. got a patent in Europe in
this patent family. As of June 2017, Zhang had about 27 patents, Doudna and Charpentier about 6. Many questions have been raised. How does it come that Zhang is the only inventor of the granted US patent, when many co-workers probably
participated in the work? How was it possible to grant patents (in several
countries) to two parties who claim the same invention or whose inventions
overlap? Was Doudna’s decision to go to the interference procedure not a tactical
mistake, as the US patent office is now afraid to grant a patent to her before
the appeal is decided, and she remains with empty hands (in the U.S.) for the time being? Can
Doudna and Charpentier get a Nobel Prize when they got the Breakthrough Prize?
Can Zhang get Nobel Prize, when he seemed to be only second after Doudna? The
most important question is, to whom should the investors of billions of dollars
pay for the license when utilizing the invention?
It can be noted that beside Cas9, there are Cas1 and Cas2
and many other systems in the innumerable bacteria and archea, which may replace
the patented systems, and the gene editing technologies of tomorrow might do
without the techniques patented in the disputed patents.
The appeal result is keenly expected.
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