The battle over clustered regularly interspaced short palindromic repeat (CRISPR) technology between Feng Zhang and the Broad Institute at the Massachusetts Institute of Technology on the one side and Jennifer Doudna, Emmanuelle Charpentier, Krzysztof Chylinski, the University of California Berkeley (UC Berkeley) and the University of Vienna on the other concluded on February 15 2017. The US Patent Trial and Appeal Board (PTAB) maintained the validity of the Broad Institute’s patents and dismissed UC Berkeley's charges. It held that there was no question of an interference battle because the parties’ claims were distinct and covered different patentable subject matter. But was the matter really settled?
An interference battle broke out in January 2016 between UC Berkeley, which had submitted patent applications using CRISPR-Cas9, and the Broad Institute, which had filed its own patents after Berkeley’s, but had had them granted first.
In February 2017, after a long battle, the PTAB granted UC Berkeley’s patent for using the CRISPR-Cas9 system in any living cell (from bacteria to blue whales) and the Broad Institute’s patent relating to the use of CRISPR gene editing technology in eukaryotic cells. The PTAB’s decision heavily depended on statements by Doudna, who had not expected successful results in eukaryotic cells at the time of the inventions. In light of her statements, the PTAB found that Zhang’s claimed technology had not been obvious. The conclusion shook UC Berkeley inventors as the technology is estimated to be worth billions – CRISPR-Cas9 is considered a major technical discovery.
In spite of this ruling, the battle was far from over. The episode took an interesting turn when the European Patent Office (EPO) reached a conflicting decision to that of the PTAB and announced its intention to grant a broad patent to UC Berkeley that would cover the use of the CRISPR technology in all cell types. 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, was a win-win situation for UC Berkeley, as many countries look to the EPO and UK decisions for guidance in granting patents. In April 2017 the university brought the case to a US federal appellate court with the certainty that Doudna and Charpentier were the pioneer engineers to use this technology in all cell types.
Broad Institute and UC Berkeley
Future investors in this technology should consider the fate of these companies’ patents in different jurisdictions. The data for US Patent 8,697,359 B1 and UC Berkeley application US 13/842,859 were extracted from Questel orbit (which provides information of family members from the FamPat database) and each family members’ legal status was checked to find out the status in different countries Questel orbit )
The following insight was extracted from the Broad Institute’s patent data:
- Five applications were filed in the United States: three were granted (US 8,697,359 B1, US 8,771,945 B1 and US 8,945,839 B2), one is pending with the examiner for response from the applicant (US 2015184139 A1) and one is under examination (US 20160281072 A1).
- Two applications were filed in jurisdictions covered by the EPO: one was granted but has been opposed by Schlich attorneys (EP 2764103 B1) and the other is under examination (EP 2998400 A1).
- Two applications were filed in Australia: one was granted (AU 2013359238 A1) and the other remains unexamined (AU 2016244244 A1).
- Two applications were filed in China: both are under examination (CN 106170549 A and CN 106480080 A).
- Two applications were filed and granted in Hong Kong (HK 1201290 A1 and HK 1216259 A1).
- Two applications were filed in Japan and is under examination (JP 2016500262 A and JP 2016171817 A).
- One application was filed in Brazil in June 2015 and remains pending (BR 112015013785 A1).
- One application was filed in Canada in June 2015 and remains pending (CA 2894688 A1).
- One application was filed and granted in Denmark (DK 2764103 T).
- One application was filed and granted in Spain (ES 2552535 T3).
- One application was filed and is under examination in South Korea (KR 20150107739 A).
- One application was filed and granted in Portugal (PT 2764103 E).
The following insight was extracted from UC Berkeley’s patent data:
- Nine applications were filed in the United States: one was involved in a court appeal (US 2014068797 A1), four were abandoned (US 2016046961 A1, US 2016060654 A1, US 2016060653 A1 and US 2016068864 A1) and four face non-final rejections (US 2016130608 A1, US 2016130609 A1, US 2016138008 A1 and US 2017051310 A1).
- One application was filed and granted in an EPO jurisdiction.
- One application was filed and is under examination in Australia (AU 2013266968 A1).
- One application was filed and is under examination in China (CN 104854241 A).
- Three applications were filed and granted in Hong Kong (HK 1204003 A1, HK 1207107 A1 and HK 1211978 A1).
- One application was filed and is under examination in Japan (JP 2015523856 A).
- One application was filed in Brazil in March 2015 and is under examination (BR 112014029441 A1).
- One application was filed in Canada in October 2014 and is under examination (CA 2872241 A1).
- One application was filed and is under examination in South Korea (KR 20150016588 A).
- Three applications were filed in the United Kingdom: two were granted (GB 2537000 B and GB 2518764 B) and one is under examination.
- Three utility model applications were filed and granted in Germany (DE 202013012240 U1, DE 202013012241 U1 and DE 202013012242 U1).
- Two applications were filed in Singapore: one was granted (SG 11201407702 XA) and the other is under examination (SG 10201701800 YA).
- One application was filed and is under examination in Chile (CL 2014003208 A1).
- Single applications were filed, but remain unexamined, in the following jurisdictions:
- Costa Rica (CR 20140538 A);
- the Eurasian Patent Organisation (EA 201401319 A1);
- India (IN 2995/KOLNP/2014 A);
- Mexico (MX 2014014477 A);
- Peru (PE 03362015 A1);
- Philippines (PH 12014502574 A1); and
- Vietnam (VN 43181 A).
Worth fighting for?
The global market for CRISPR technology is predicted to grow to $2.3 billion by 2022. With considerable sums of money at stake from licensing, the question remains as to who will receive the royalties from CRISPR patents. With the Broad Institute and UC Berkeley claiming different aspects of the technology in different countries, any company which utilises CRISPR to develop new therapies will be charged large amounts by both institutions. In reality, not everyone is lucky in making deals. “It’s a bit frustrating that the patent office has done it this way”, says Eric Rhodes, CEO of ERS Genomics, which licenses UC Berkeley’s CRISPR technology to other companies for non-human therapeutic uses. “A lot of people were hoping they would make a decision to go with one group or another.” ERS Genomics’ charges range from $10,000 for small start-ups to $1 million for large pharmaceutical firms. Such a decision would likely generate more lawsuits further down the line, and the commercial costs are too high for many smaller biotech companies.
Power and responsibility: a battle fought within
The attenuated battle between the Broad Institute and UC Berkeley has not prevented researchers from all over the globe from using CRISPR technology, which is being applied in the following areas:
- plant and animal research;
- curing and preventing congenital diseases;
- isolating and removing HIV in immune cells;
- human bioengineering (sparking a biomedical race between the United States and China); and
- reducing the spread of cancer.
The first CRISPR trial within a human body took place in May 2017 (in contrast with the usual CRISPR method of extracting cells and re-injecting them into an affected area). Twenty further trials were lined up for 2017 and 2018.
As the world awaits the fate of a new CRISPR trial to eliminate the human papillomavirus by targeting cells within the human body, many fear that the technology is too nascent and may have unexpected consequences. Experiments on mice have determined that CRISPR gene-editing techniques could result in hundreds of unintended and potentially dangerous DNA mutations. Such doubts have led to the fall of both investor confidence in the biotech sector and stock prices in genome-editing companies. Whether further research supports or challenges it, there is a long way to go before this technology can be applied in human gene therapy.
Even if one of the major players wins the patent battle or each decide to develop the technology independently, uncertainties with regard to the ethical and safety considerations for investors still exist.
India has been quietly observing the battle from a distance, but has yet to address the issue at an international level. Further, it has declined support for the trials of CRISPR-Cas9 technology to edit the human germline: “Our main concern is that this technology should not be used for human enhancement” (Indian Council of Medical Research director general Dr Soumya Swaminathan). Meanwhile, several countries, including China, the United States, the United Kingdom and a few other European countries will meet in China later in 2017 to take forward discussions on genome editing. There is no clarity on India’s participation. As ethical concerns are more important in India than in many other countries, strict laws regulating this technology would be required.
The following questions surrounding CRISPR technology must be addressed before further action is taken:
- Who does the technology belong to?
- How safe is the technology when it is used to cure human diseases?
- Can the technology be overused?
- How will countries that privilege male babies (eg, India) regulate the technology to prevent its misuse?
With regard to licensing, the technology remains too new to stake a claim on. Therefore, investors must weigh their decisions carefully.
This article first appeared in IAM. For further information please visit www.IAM-media.com.