Why CRISPR may define pre- and post-AIA changes
Polymerase chain reaction (PCR) revolutionised the ability of researchers to modify DNA strands and study gene action, gene mutations, and sequence the genomes of many organisms to learn more about ourselves at a molecular level. The ‘Queen et al patents’ helped pioneer human monoclonal antibody technology.
Clustered regularly interspaced short palindromic repeat (CRISPR)-based technology may be another landmark biotechnology invention. It may open the doors for exploring not only gene transcription but also how humans can modulate gene transcription. It promises to help us explain what is ‘junk’ DNA (regions of DNA that are non-coding, but may or may not have code instructions) and whether it is really junk? More than 98% of the human genome is believed to be ‘junk”’ non-coding DNA. CRISPR, as a tool, may help to shed light on the junk DNA universe.
What is CRISPR?
CRISPR, usually tied to CRISPR-associated protein 9 (Cas9), is a tool that scientists can use to test hypotheses on regions of non-coding DNA. With that tool, drugs can be developed for modulating the transcription of genes. The transcription of a gene is the first step for producing a protein. Loosely put, proteins can signal cells to perform different tasks through various mechanisms. Therefore, having a tool to edit the genome to elucidate biological mechanisms will be important for uncovering causes and mechanisms of action in diseases, as well as perhaps eventually finding drugs to treat such disease.
CRISPR, like PCR, will be a tool—not a treatment. PCR was used to isolate and elucidate genes associated with diseases such as BRCA1 (one of the genes having known mutations linked to various types of breast and ovarian cancer), or genes that encode proteins useful for the treatment of disease, such as interferon, erythropoietin, and so on.
Who developed CRISPR?
CRISPR is just beginning its patent scrum. As with all landmark inventions (eg, identification of the HIV), there is controversy about who developed the idea first and who has patent rights to it. The first patent for CRISPR was issued to the Broad Institute and Massachusetts Institute of Technology (MIT)—US patent number 8,697,359; first inventor Feng Zhang). However, Jennifer Doudna and Emmanuelle Charpentier allege to have filed an application (serial number 13/842,859) before the Broad Institute’s patent that covers CRISPR.
Applications filed later can be frequently granted ahead of earlier-filed applications, especially today when applicants use a patent prosecution highway, or as with Zhang’s application, a fast-track request. The US Patent and Trademark Office (USPTO) did know about the Doudna application when examining Zhang’s application, as Doudna’s seemed to have been considered as prior art.
Who are the other players in the CRISPR scrum?
Players are piling into the scrum, even though there is a lot of debate over who will get the ball: Doudna or Zhang, and each of their respective licensees. Doudna and Charpentier filed their application on behalf of the University of California. Editas Medicine was co-founded by Zhang and allegedly has rights to the patent, which currently lists the Broad Institute and MIT as assignees. CRISPR Therapeutics was co-founded by Charpentier. Intellia Therapeutics was co-founded by Doudna’s Caribou Biosciences. Another player allegedly is Horizon Discovery, which allegedly has licensed Zhang’s patent and Charpentier’s intellectual property. Taconic also allegedly has a licence to Zhang’s patent. These are just the players for the purported ‘ball’ at the bottom of the scrum.
As of September 2015, there were 60 applications published on the USPTO system with the term ‘CRISPR’ in the abstract. Many applications belong to Zhang and the Broad Institute, but other entities include the University of Massachusetts, The Rockefeller University, Agence Nationale de Securite Sanitaire de I’Alimentation, de I’Environnement et du Travail, Maisons-Alfort Paris, Bundesinstiful für Risikobewertung, Board of Regents of the University of Minnesota, Fred Hutchinson Cancer Research Center, Regeneron Pharmaceuticals, DuPont Nutrition Biosciences ApS, Penn State Research Foundation, Sage Labs, Larix Bioscience, Wageningen University and Research Centre, Agilent Technologies, The General Hospital Corporation, System Biosciences, University of Georgia Research Foundation, and the Pasteur Institute, as well as various individuals.
Additionally, Zhang’s patent is tied to US government support and therefore the US government has potential march-in rights to the invention. The topics and titles appear to have implications for prokaryotic, eukaryotic, and plant CRISPR manipulation, impacting potentially industrial enzymes, plants, and animals. And this scrum is only likely to get deeper.
What is the legal future of CRISPR?
The technology will help to define pre- and post-America Invents Act (AIA) legislative changes. Why?
Doudna’s ‘859 application was filed on March 15, 2013. It claims benefit to four priority applications, with the earliest priority date being May 25, 2012, making it a pre-AIA application. Zhang’s patent issued on April 15, 2014. According to the Patent Application Information Retrieval, it has a filing date of October 15, 2013. It claims benefit of five provisional applications, three of which have pre-AIA filing dates and two of which have post-AIA dates. The earliest provisional date is December 12, 2012. This makes Zhang’s application likely to be a post-AIA application or possibly a transitional application.
“One legal issue to be resolved will be how a pre-AIA application and a potentially post-AIA application go through a possible interference proceeding together.”
Shortly before the Zhang patent issued, on April 13, 2015, Doudna et al filed papers requesting an interference against Zhang’s patent. So, one legal issue to be resolved will be how a pre-AIA application and a potentially post-AIA application go through a possible interference proceeding together. Technically, applications filed after March 16, 2013 are post-AIA and are no longer subject to interference statutes and rules. Therefore, an interference may or may not even be possible. As of September, the claims in the Doudna application are still in prosecution and have not been allowed. Until they are allowed, they cannot advance into any interference proceeding.
On June 1, 2015, someone (perhaps Zhang et al) filed a third-party submission at the USPTO under 37 CFR 1.290 that was nearly 100 pages in length and contained 22 prior art references. The 1.290 pre-issuance submission is a new procedure instituted under the AIA. It allows parties, which can remain unidentified, to only provide prior art (under section 102 and 103 of the US Code) and show how the art applies, although without providing any legal conclusions. Its use is gaining popularity in the US.
Additionally, as Zhang’s is a post-AIA application, it can be subject to a post-grant review (PGR) as well as an inter partes review under the statutes effective for it. And, given we do not know who filed the 1.290 submission, perhaps some of that art in the Doudna application constitutes prior art to Zhang’s patent as well.
As the number of patent owners and licensees increases, the freedom to use CRISPR in research and its practical applications will have to be assessed in a similar fashion to how US attorneys approached using the PCR technology of Kary Mullis, the Nobel Prize-winning biochemist. Parties will have to wind their way through the licensees, licences, patents, pending applications, and prior art to find the open field that they can play in. Finding and maintaining that open field will be no trivial (cheap) task.
Perhaps chief scientific officers and chief IP officers should be sitting down now with their research groups asking:
(1) Will we need this technology?
(2) How would we implement the technology?
(3) What products/innovations could we expect to result from it?
(4) What space do we need to achieve those goals?
(5) Can we get early filings in now, even if they are just place-holders, to protect our space in a particular disease or treatment field?
(6) Should we have quarterly assessments of where CRISPR has evolved?
The IP and business units should perhaps also include in their strategic planning the cost of legal assessments for using the technology and innovations developed through its use.
Is CRISPR patent-eligible?
Some in the scientific community have already cried foul and that no-one should ‘own’ CRISPR, as it is found in nature. It will be interesting to see whether CRISPR will be the target of patent eligibility allegations in the US under section 101. Sadly, the US, which developed the patent system copied round the world, is rapidly becoming one of the most anti-patent nations in the world through patent-destroying exceptions instituted by the Supreme Court.
The ‘359 patent recites a method claim. Method claims have been the types of claims most vulnerable to attack under the US Supreme Court decisions of Mayo v Prometheus and Alice v CLS Bank. The first claim in the ‘359 patent reads as follows:
1. A method of altering expression of at least one gene product comprising introducing into a eukaryotic cell containing and expressing a DNA molecule having a target sequence and encoding the gene product an engineered, non-naturally occurring CRISPR-Cas system comprising one or more vectors comprising:
a) A first regulatory element operable in a eukaryotic cell operably linked to at least one nucleotide sequence encoding a CRISPR-Cas system guide RNA that hybridises with the target sequence; and
b) A second regulatory element operable in a eukaryotic cell operably linked to a nucleotide sequence encoding a type-II Cas9 protein, wherein components a) and b) are located on same or different vectors of the system, whereby the guide RNA targets the target sequence and the Cas9 protein cleaves the DNA molecule, whereby expression of at least one gene product is altered; and wherein the Cas9 protein and the guide RNA do not naturally occur together.
Whether, for example, the final ‘wherein’ clause indicating that the Cas9 protein and the guide RNA do not naturally occur together is sufficient to overcome future attacks under section 101 remains to be seen, given the current state of obfuscated eligibility in which we reside. CRISPR will not only define science, but will help define post-AIA law.
Mercedes Meyer is a partner at and co-chair of the life sciences IP group at Drinker Biddle & Reath in Washington, DC. She can be contacted at: mercedes.meyer@dbr.com
