Thursday, January 11, 2018

The Cas Against CRISPR

The realization that some diseases have genetic etiologies long inspired the hope that "correcting" mutant DNA sequences in patients could cure their diseases.  Recent progress in gene therapy has made this tantalizing possibility seem achievable, and precise and efficient gene editing methods using tools like CRISPR-Cas9 have accelerated progress considerably.  However, an important preprint article, entitled "Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans", published by Charlesworth et al. on bioRχiv, has now cast a shadow on the efficacy of CRISPR-Cas9 in humans.  The Matt Porteus' research team, based at Stanford Medical School, appear to have discovered an immune response to CRISPR-Cas9:
The most widely used homologs of the Cas9 protein are derived from the bacteria Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). Based on the fact that these two bacterial species cause infections in the human population at high frequencies, we looked for the presence of pre-existing adaptive immune responses to their respective Cas9 homologs, SaCas9 (S. aureus homolog of Cas9) and SpCas9 (S. pyogenes homolog of Cas9)...[Our results] demonstrate[s] that there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials. [Italics added for Linnaean emphasis.]
If humans, and, presumably, other mammals, possess potent immune responses to the Cas protein component of this powerful gene editing system, the therapeutic prospects for CRISPR-Cas9 may dim considerably beyond applications in isolated cells or tissues or patients having immature or suppressed immune responses.  After many more than two steps forward, therapeutic gene editing may be about to take at least one substantial step backward.

Sunday, December 31, 2017

A New Gene Therapy Vision

Vertebrates see by converting photons into electrical signals in the retina, which, in turn are interpreted by the brain into visual depictions of the environment.  Part of this phototransduction system relies on an enzyme called retinoid isomerohydrolase (or retinal pigment epithelium-specific 65 kDa protein ("RPE65")) to convert all-trans-retinyl esters into 11-cis-retinol in the smooth endoplasmic reticulum.  Healthy functioning of retinal pigment epithelium ("RPE"), a thin layer of cells that nurtures the retina, can become impaired when both RPE65 genes contain mutations that prevent normal enzymatic function.  In patients with Confirmed Biallelic RPE65 Mutation-associated Retinal Dystrophy, this can lead to poor vision or even blindness.

The Food and Drug Adminstration ("FDA") announced, on December 19, 2017, its approval of a gene therapy method developed to improve, or even restore, healthy RPE65 enzyme function by introducing wild-type copies of RPE65 genes directly into RPE tissue.  The method involves surgical delivery of RPE65 genes incorporated into adeno-associated viruses.  Spark Therapeutics, the company marketing this gene therapy, calls its "drug" voretigene neparvovec-rzyl (brand-named LUXTURNA).

As the FDA announced, LUXTURNA "is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene."  In the FDA press release, FDA Commissioner, Scott Gottlieb, waxed enthusiastic, suggesting that
this milestone reinforces the potential of this breakthrough approach in treating a wide-range of challenging diseases. The culmination of decades of research has resulted in three gene therapy approvals this year for patients with serious and rare diseases. I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses[.]
After previous fatal missteps (e.g., see here), gene therapy is finally seeing the light of day.

Thursday, October 26, 2017

The True North Strong IP?

On October 26, 2017, Television Ontario ("TVO") broadcast a fascinating, wide-ranging discussion about intellectual property in Canada and other countries.  Here it is.

Wednesday, September 27, 2017

Amaizing Syngenta Settlement

I appeared on Bloomberg Radio on September 27, 2017, to discuss the ~$1,400,000,000 settlement reached between Syngenta and farmers allegedly harmed by the agrobiotechnology firm's decision to sell genetically-modified corn in the United States, which subsequently caused China to ban U.S. corn imports.  You may listen to the story here.

Monday, September 25, 2017

CRISPR Becomes Clearer

Recently, The Hastings Center invited me to write an article discussing current legal, policy, and ethical issues surrounding the gene editing revolution triggered by CRISPR-Cas9.  The result, "CRISPR Becomes Clearer", was published on September 20, 2017, in The Hastings Center Report, Volume 47, Issue 5 (September/October 2017).

Tuesday, July 25, 2017


The Office of the United States Trade Representative ("USTR") published its "Summary of Objectives for the NAFTA Renegotiation" on July 17, 2017.  Among its musings is a section devoted to intellectual property.  Here are the intellectual property "objectives":

Intellectual Property: 
- Promote adequate and effective protection of intellectual property rights, including through
the following:
  • Ensure accelerated and full implementation of the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), particularly with respect to meeting enforcement obligations under TRIPS.
  • Ensure provisions governing intellectual property rights reflect a standard of protection similar to that found in U.S. law.
  • Provide strong protection and enforcement for new and emerging technologies and new methods of transmitting and distributing products embodying intellectual property,including in a manner that facilitates legitimate digital trade.
  • Prevent or eliminate discrimination with respect to matters affecting the availability, acquisition, scope, maintenance, use, and enforcement of intellectual property rights.
  • Ensure standards of protection and enforcement that keep pace with technological developments, and in particular ensure that rightholders have the legal and technological means to control the use of their works through the Internet and other global communication media, and to prevent the unauthorized use of their works.
  • Provide strong standards enforcement of intellectual property rights, including by requiring accessible, expeditious, and effective civil, administrative, and criminal enforcement mechanisms.
  • Prevent or eliminate government involvement in the violation of intellectual property rights, including cybertheft and piracy.
- Secure fair, equitable, and nondiscriminatory market access opportunities for United States persons that rely upon intellectual property protection. 
- Respect the Declaration on the TRIPS Agreement and Public Health, adopted by the World Trade Organization at the Fourth Ministerial Conference at Doha, Qatar on November 14, 2001, and to ensure that trade agreements foster innovation and promote access to medicines. 
- Prevent the undermining of market access for U.S. products through the improper use of a country’s system for protecting or recognizing geographical indications, including failing to ensure transparency and procedural fairness and protecting generic terms.

Among the issues that apparently pique the interest of the USTR are several that may be quite challenging to address.  A few are discussed below.

One is to "[e]nsure provisions governing intellectual property rights reflect a standard of protection similar to that found in U.S. law."  If U.S. intellectual property ("IP") law were fixed and static, this might be relatively straight-forward, encroachments on national sovereignty notwithstanding.  However, U.S. IP law has evolved at a brisk pace over the last decade, with the United States Supreme Court (the "Supremes") overturning long-standing lower court precedents in areas such as availability of injunctive relief, exhaustion doctrine, patentable subject matter, and nonobviousness.  This raises the question of whether Canada and Mexico should be expected continually to change their IP laws to reflect the fluid evolution of U.S. IP laws?

Another is to "Provide strong protection and enforcement for new and emerging technologies..."  Do "new and emerging technologies" include software, DNA, or methods of medical diagnosis or treatment?  If so, will the U.S. Congress statutorily reverse the Supremes' recent decisions in Alice Corporation v. CLS Bank International (2104), Association for Molecular Pathology v. Myriad Genetics (2013), and Mayo Collaborative Services v. Prometheus Laboratories (2012), which rendered inventions in these fields largely unpatentable subject matter?

Questions also arise regarding how the Doha Declaration and "ensur[ing] that trade agreements foster innovation and promote access to medicine" might affect biopharmaceutical patents, and how new NAFTA provisions might attempt to "Prevent the undermining of market access for U.S. products" that, presumably, are described by their sellers using geographical indications registered by others.

An especially intriguing objective is to "Provide strong standards enforcement of intellectual property rights, including by requiring accessible, expeditious, and effective...criminal enforcement mechanisms."  Does this mean that "criminal enforcement mechanisms" must be available not only in copyright, trademark, and trade secrecy law, where they already exist, to some extent, in the U.S., but also extended to patent law, where U.S. law currently lacks such remedies?

As discussed earlier on Lexvivo, the AstraZeneca Canada v. Apotex (2017) decision, in which the Supreme Court of Canada/La Cour Suprême du Canada annulled the "promise doctrine", may help to mollify U.S. demands for Canadian IP conformity.  However, the opaque wording of the USTR's "Summary of Objectives for the NAFTA Renegotiation" introduces considerable uncertainty as to what an acceptable agreement on IP issues would be.