CRISPR-cas9 gene editing technology (“CRISPR”) provides a cheap, efficient and easy way to precisely modify genetic information. It has been described as the biggest game changer to hit biology since the Nobel prize winning invention of the polymerase chain reaction (PCR). CRISPR is also the subject of highly contentious patent battles in both the US and Europe, primarily between the Broad Institute and the University of California (UC), Berkeley. These battles continue to rage. Meanwhile, the promise of CRISPR as a revolutionary technology in biomedicine has been reaffirmed by a recent article reporting the genetic engineering of human embryos using CRISPR. Here we provide an update on the CRISPR patent disputes in the US and Europe and report on the recent scientific advances relating to CRISPR.
We recently reported the ruling by the U.S. Patent Trial and Appeal Board (PTAB) in favour of the Broad Institute regarding its granted CRISPR patents. The issue under consideration was whether the use of CRISPR in eukaryotic cells (e.g. plant and animal cells) by the Broad Institute was non-obvious in view of UC Berkeley’s previous use of CRISPR in bacteria. The PTAB ruled that the Broad Institute’s contested granted US patents did claim patentably distinct subject-matter over UC Berkeley’s pending US patent application to CRISPR. UC Berkeley has now filed an appeal to the U.S. Court of Appeal of the Federal Circuit, seeking to reverse the decision of the PTAB, arguing that the PTAB ignored key evidence that six other labs had achieved eukaryotic editing before the Broad Institute filed the contested patent (the full appellate brief can be seen here). The Broad Institute’s submissions in response to the appeal are due in October 2017.
In Europe, as we have previously reported, the Broad Institute has nine patents granted by the EPO relating to CRISPR. UC Berkeley’s European application relating to CRISPR was recently granted, and a notice of opposition has now been filed. We await the substantiation of the grounds of opposition. The text of the granted patent can be seen here.
Meanwhile, an article in Nature this month by Ma et al. reported the first use of CRISPR to successfully genetically engineer human embryos. Previous attempts at gene editing primate embryos using CRISPR produced genetically mosaic embryos containing an undesirable mixture of genetically engineered and wild-type cells. In these studies, CRISPR components were injected into a fertilised human egg cell (zygote). During embryonic development, the single zygote cell rapidly undergoes DNA replication and cell division to form a population of embryonic cells. DNA replication doubles the number of copies of a gene in the zygote before cell division, and thereby the number of successful gene editing events required to avoid heterogeneity. To reduce the risk of producing genetically mosaic embryos, Ma et al. therefore injected a human egg cell simultaneously with CRISPR components and sperm (as opposed to injecting CRISPR into the zygote after fertilisation with sperm) (See Figure 3a of Ma et al.). The authors hypothesised that this would enable gene editing to occur before the onset of DNA replication and cell division by the zygote. Ma et al. reported efficient production of genetically homogenous human embryos using this method. Importantly, full genome sequencing also confirmed the high target specificity of the gene editing relative to previous reports, potentially due to the use of recombinant Cas9 protein instead of transfection with a cas9 expression vector. This and other proof-of-principle studies further clear the way for the development of therapeutics to eliminate heritable mutations, while highlighting the potential need for an update of the ethical and legal framework governing such work.
Purely academic research is excluded from the list of acts constituting patent infringement in Europe and the US. However, there is concern that clinical translation of the technology may be stalled by the protracted ownership and validity disputes. The field is potentially further restricted by the sheer number of organisations possessing patents related to CRISPR, and the cumbersome licensing arrangements that this may necessitate for companies wishing to commercialise CRISPR technologies. In light of these concerns, the Broad Institute recently announced their wish to participate in a joint licensing pool with other parties, under which the various CRISPR rights will be available as a single non-exclusive license. However, concerns remain as to whether non-exclusive licensing will provide companies with sufficient commercial opportunity to justify the research development costs relating to CRISPR technologies.
We continue to follow with interest the CRISPR patent disputes in Europe and the US, as well as the progress of academic research directed at CRISPR therapeutics.
This article is for general information only. Its content is not a statement of the law on any subject and does not constitute advice. Please contact Reddie & Grose LLP for advice before taking any action in reliance on it.