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Is CRISPR-Cas9 a Controversial Technology?

In June 2012, University of California (UC), Berkeley professor and Howard Hughes Medical Institute investigator Jennifer Doudna and Umea University professor Emmanuelle Charpentier (now at the Max Planck Institute for Infection Biology) and their research team, which included Martin Jinek from UC and Krzysztof Chylinski from the University of Vienna, published an article in the journal of Science that first revealed what has been described as the scientific breakthrough of the century. This international team of researchers determined how a bacterial immune system known as CRISPR-Cas9 is able to cut DNA, and then engineered CRISPR-Cas9 to be used as a powerful gene editing technology.

 

CRISPR-Cas9 system is a special scissors that cut DNA “threads.” CRISPR-Cas immunity is a natural process occurring in bacteria and archaea. CRISPR-Cas prevents bacteriophage infection, conjugation and natural transformation by degrading foreign nucleic acids that enter the cell. In nature, bacteria use these scissors to cut the DNA threads of invading viruses. Doudna and Charpentier team came out with the technology to use these scissors to cut any DNA thread of choice to make repairs or modifications to the complex structures such as human genome.  The naturally occurring CRISPR-Cas9 system consists of three parts namely, the scissors part involved in cutting the DNA thread, two-pieced “homing beacon” portion which can direct the scissors to the targeted DNA thread. The two pieces of the homing beacon should come together prior to the homing in on of the natural CRISPR-Cas9 system that eventually cuts a targeted thread. Here, Doudna and Charpentier team came out with a one-piece homing beacon, a path breaking technology having enormous potential and application in various fields. The studies included making various modifications to the natural components of the system, and even included studies where two separate RNA components from the natural system were combined into a single molecule, thereby simplifying the system and making it easier to employ. This work demonstrated that engineered CRISPR-Cas9 can be used for gene editing.

Publication of the Doudna-Charpentier team’s seminal paper, CRISPR-Cas9 gene editing has revolutionized biological research including medicine and agriculture in the sense that  CRISPR-Cas9 technology can edit the genetic information of any organism  including human cells, accurately and efficiently, to come out with disease free crops, genetic therapies for diseases like sickle cell anaemia, thalassemia and many more genetic diseases, increasing the yields in crops, treatment of cancer, controlling mosquito populations etc. University of California, along with the University of Vienna, has reserved the right to allow research organizations and Universities to exploit their technology in the interest of the general public.

 

When the European Patent Office (EPO) s announced its intention to grant a broad patent for the revolutionary CRISPR-Cas9 gene-editing technology by Jennifer Doudna, Emmanuelle Charpentier and their teams as the CRISPR-Cas9 inventors, and recognized that the original patent application covers a wide range of cell types, including human cells,” to the University of California, the University of Vienna and Emmanuelle Charpentier, it really opened a Pandora’s box. This decision by the EPO raked up the present issue as the patent is issued for broad claims almost in any environment ,( European Patent Office to grant UC a broad patent on CRISPR-Cas9 (By Robert Sanders, Media relations | MARCH 28, 2017)  and the applications included treatment of various human diseases, as well as veterinary, agricultural and other biotech applications despite  the objections from third parties, including the Broad Institute, a joint research institute of Harvard University and the Massachusetts Institute of Technology. The EPO’s notice of intent to issue the patent, as well as the UK Intellectual Property Office’s grant of two similarly broad patents, are precedents for Doudna and Charpentier to receive wide-ranging patents in many countries, since EPO and UK decisions serve as  guidance in granting patents in their respective countries.

 

The UC patent application to the EPO was substantially the same as the UC patent application filed in the United States. In the U.S., UC claims covering the use of single-guide CRISPR-Cas9 technology in any setting were found to be allowable by the U.S. Patent & Trademark Office, and were placed in an interference with patents owned by the Broad Institute that cover use of the technology in eukaryotic cells.

In February, 2017, the U.S. Patent Trial and Appeal Board ruled that although a team led by UC- Berkeley structural biologist Jennifer Doudna had first laid claim to the use of CRISPR to cut DNA in a test tube, the use of the method on human cells by molecular biologist Feng Zhang’s team at the Broad is a advancement . In its February ruling, the PTAB terminated the interference between the UC application and Broad patents, determining that the claims of the two parties did not constitute the same invention and, accordingly, the PTAB could not determine which party first invented the use of the technology in eukaryotic cells.

 

According to UC general counsel and vice president for legal affairs Charles F. Robinson, PTAB has committed several legal errors including disregarding Supreme Court and Federal Circuit precedent. The University of California argued before the United States Court of Appeals for the Federal Circuit to overturn the February, 2017 ruling of the Patent Trial and Appeal Board (PTAB) and reinstate the interference regarding the patent rights for CRISPR-Cas9.

But lawyers argued that after the Doudna-Charpentier invention, use of CRISPR-Cas9 in plant and animal cells was obvious, and therefore the Broad patent interference should be reinstated since it was able to use conventional, off-the-shelf tools to employ CRISPR-Cas9 to cleave DNA in eukaryotic cells. Finally the University of California announced that the United States Patent and Trademark Office has granted patent number 10,000,772 covering the use of CRISPR-Cas9 gene editing with formats that will be particularly useful in developing human therapeutics and improvements in food security. (Doudna-Charpentier team awarded U.S. patent for CRISPR-Cas9Public Affairs, UC Berkeley | JUNE 19, 2018)

 

The decision from the European Patent Office (EPO) has put the Broad Institute in Cambridge, Massachusetts, on shaky ground with its intellectual property claims to the gene-editing tool CRISPR. EPO revoked a patent granted to the Broad for fundamental aspects of the technology, since those earliest U.S. filings included an inventor, microbiologist Luciano Marraffini of the Rockefeller University, New York City, who was not listed on the European filing. Disagreement between Rockefeller and the Broad over Marraffini’s role in key CRISPR inventions led to a bizarre dispute, creating conflicting, identical patents with different authors,( The Scientist reported in 2016) and one of several of its patents  is facing opposition in Europe(Broad Institute takes a hit in European CRISPR patent struggle, Kelly Servick, Jan. 18, 2018, 3:30 PM) Marraffini’s exclusion from the European filing resulted in a situation wherein Broad can’t claim the “priority date” of the earliest U.S. patents, and therefore can’t claim in Europe to the technologies described.

Though Broad  plans to appeal the decision, the chances are “slim,”  as per Catherine Coombes, a patent attorney with HGF Limited in York, U.K.. The CRISPR landscape is very complex in Europe since there is every possibility to have lots of overlapping rights”

(Posted in: BiologyEuropeHealth)Business Wire, 13 February 2018,https://www.businesswire.com/news/home/20180212006461/en/Issued-U.S.-Patents-Granted-Cellectis-CRISPR-T-Cells

Though it is a path breaking research, Doudna et al came out with the invention using stem cells but they claimed all most every cell line and in any environment. This has even been accepted by the EPO by way of granting very broader claims . Is it not against the spirit of the patenting process? More over it might prove detrimental and against the morality when employed on human germ cell lines. The path breaking technology should be helping the human kind globally but it should not give monopoly to a few persons for ever. So far the claims made by the UC have not been tested in all the conditions.  And here goes the extract that substantiates my views:

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.( “But a recent study reveals a mess of missing and moved chromosome parts in the wake of deploying the famed “molecular scissors.”, single-base mutations popped up The assaults could kill a cell or send it on a pathway to cancer. Instead of using the cancer cells of past studies that can have altered DNA repair and chromosomes, the researchers targeted a well-studied gene in stem cells from mice and human retinal cells “immortalized” to divide. Both are “surrogates for various clinical editing applications.” ( https://phys.org/news/2018-08-crispr-gene-doomed-therapy-clinic.html#jCp)

 

 

 

 

 

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