By Michael Rebagliati
In addition to the cited sources, the author would like to thank a family member with far more scientific knowledge, Michael R. Rebagliati, Ph.D., for his essential scientific edits, commentary and analysis.
Right now, a new gene-editing technology called CRISPR-Cas9 is spreading throughout the scientific and business communities and into the public consciousness. The scientific implications are vast because CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is not just one scientific invention with one purpose. Rather, it is a natural process that has been harnessed and redirected into a gene-editing technique that is (relatively) easy to use. Moreover, its high efficiency means that scientists can use it to edit the genetic code of any gene in many kinds of organisms. Think Industrial Revolution for genetic engineering.
CRISPR-Cas9 is an ingenious, bacterial immune system that has evolved to help many kinds of bacteria resist viral infections or the effects of simple genetic elements like plasmid DNAs. During an initial viral infection, viruses will try to hijack bacterial cells’ reproductive capabilities by injecting their viral DNA into the cells. Usually, where the viruses succeed, the bacteria die. However, a small fraction of the infected bacteria resist the infection and survive. These bacteria retain a memory of the infecting virus: Using a mechanism that scientists do not fully understand, these bacteria use their Cas (CRISPR-associated) enzymes to choose and insert small fragments of the viral DNA into “storage regions” on the bacterial genome, which are found in the CRISPR sequences.
Then, if there is another viral infection of that type, the bacterial cell will essentially use its stored viral DNA to form a specialized “virus hunting” complex that targets and cuts up viral DNA that matches the stored viral DNA. Stated otherwise, “Cas9 cuts the DNA like scissors,” and specialized RNAs, produced from the CRISPR region(s) of the bacterial genome, tell Cas9 where (viral DNA) and where not (bacterial DNA) to cut. Thus, the more attacks a bacterial cell survives, the more targeting data it will have available in future attacks and the more viral strains from which it will be immune. Basically, what doesn’t kill you makes you stronger.
Moreover, scientists have learned to do some hijacking of their own by manually directing the CRISPR-Cas9 defense system and applying it in new cellular environments. By doing this, scientists can use the same process in other types of cells, such as human embryos, to target DNA other than viral DNA. More specifically, scientists have learned how to reprogram the CRISPR-Cas9 immunity mechanism for two different purposes:
1) They can target and cut any specific gene of interest, which usually results in sequence changes that inactivate the gene; or
2) They can replace a specific portion of a gene with new genetic information. Here, scientists can replace a defective, mutated portion of a gene with the correct, normal bit of DNA sequence. This would cure the defective gene and cure the associated genetic disease.
Both of these purposes rely on synthetic CRISPR RNAs to target a specific region of the gene of interest. Essentially, each of these designer CRISPR RNAs recognizes its matching sequence in the gene of interest. In this manner, the CRISPR RNA-associated Cas “scissors” are brought to the target gene. As with viral DNA, Cas9 then cuts the target DNA to inactivate or disrupt that gene; or, with some additional molecular trickery, Cas9 cuts the target DNA to replace a specific stretch of DNA sequence with a desired new DNA sequence.
As you might imagine, this scientific advance has many commercial and clinical applications. However, a massive patent dispute threatens to complicate these applications. The dispute is between two groups of distinguished CRISPR researchers and their associated academic institutions. On one side is “UC” (a party comprising the University of California, Jennifer Doudna, University of Vienna, and Emmanuelle Charpentier), and on the other side is the “Broad Institute” (a party comprising the Broad Institute, Feng Zhang, MIT, and Harvard).
The parties’ dispute centers on the distinction between learning to direct manually the CRISPR-Cas9 system and learning to apply that harnessed technology in a new cellular environment. UC filed the first patent application in this saga when it filed a patent with a priority date of May 25, 2012, which claimed isolation and control of CRISPR in its native prokaryotic cellular environment. Seven months later, on December 12, 2012, Broad Institute filed several patents showing that CRISPR could be used in animal, plant, and human cells (eukaryotic cellular environments). However, Broad Institute paid an extra fee to accelerate the patent examination process and thus received its patents before UC.
Almost immediately after the USPTO awarded Broad Institute’s patents, UC filed a patent interference claim, arguing that Broad Institute’s patents should be invalidated since UC had been the “first-to-invent” a modified CRISPR system. UC argued that it was the first to invent because it was the first to publish a proof of concept, and it argued that extending this proof of concept to other cellular environments was not a significantly distinct step. Broad Institute countered that its claims were distinct and not drawn to the same invention. In particular, Broad Institute argued that its claims more conclusively demonstrated that the CRISPR-Cas9 system could work in eukaryotic cellular environments.
On February 15, 2017, the Patent Trial and Appeal Board (PTAB) held in favor of Broad Institute, ruling that there was no interference-in-fact. This decision does not bar UC from obtaining its patent for demonstrating that CRISPR can be manipulated in prokaryotic environments. However, it does uphold Broad Institute’s patents on the (likely more valuable) eukaryotic applications of CRISPR manipulation.
PTAB reasoned that even if UC’s claims were prior art, they would not have rendered Broad Institute’s claims obvious and invalid. The test PTAB used for assessing obviousness was whether, by a preponderance of the evidence, a person of ordinary skill in the art would have had a reasonable expectation of success in using the knowledge of UC’s patent to extend CRISPR-Cas9 to eukaryotic cells.
Ultimately, PTAB gave great weight to the contemporaneous statements of scientists familiar with the UC research and held for Broad Institute. PTAB viewed those contemporaneous statements as suggesting a motivation to try to extend the new technique to eukaryotic environments as opposed to a reasonable expectation of success in doing so.
Nevertheless, this legal battle continues. In April, UC appealed the decision to the Federal Circuit Court of Appeals. In the interim, tech companies and other universities hoping to build on this ground-breaking research may find themselves in precarious positions. Ultimately, it may be necessary to negotiate licensing arrangements with both sides. Whichever side wins the patent battle, the CRISPR dispute reminds us that while it is exciting to recognize the potential of new scientific advances, it can be difficult to discern who deserves the credit for those advances.