CUSTOM-EDITED DNA: LEGAL LIMITS ON THE PATENTABILITY OF CRISPR-CAS9'S THERAPEUTIC APPLICATIONS.

• Author: Chauvin, Noah C.

TABLE OF CONTENTS INTRODUCTION 299 I. SCIENTIFIC BACKGROUND 303 A. What is CRISPR-Cas 9? 304 B. Therapeutic Applications 308 1. Viral Infections 308 2. Bacterial Infections 310 3. Editing Somatic Cells 311 4. Editing Germline Cells 312 II. LEGAL LANDSCAPE 313 A. General Requirements for Patentability 313 B The America Invents Act Regime 315 C. The Law as Applied to Human Biology 316 1. Fetuses 316 2. DNA 317 3. Stem Cells 319 D. Scholarly Perspectives on the Patentability of CRISPR-Cas9 320 III. ARE CRISPR-CAS9 THERAPIES PATENTABLE? 321 A. Where Patent Protection Will Apply 322 1. Treating Viral Infections 322 2. Treating Bacterial Infections 325 B. Where Patent Protection Will Not Apply 325 1. Editing Somatic Cells 326 2. Editing Germline Cells 327 IV. COUNTERARGUMENTS 329 A. CRISPR-Cas9 Should Not Be Patentable at All 329 B. Patents Have Issued on Some CRISPR-Based Therapies 330 C. Some Somatic Cell Editing Should Be Patentable CONCLUSION 331 331 INTRODUCTION

Imagine a future where large corporations use CRISPR, a genetic editing tool, to modify almost every living thing. (1) Perfectly manicured lawns are comprised of genetically-modified grasses, people adore their genetically-modified pets, and parents select only the best traits to be carried by their genetically-modified children. (2) This is a future T. Coraghassen Boyle recently imagined in a short story in The New Yorker. (3) In Boyle's story, genetic editing is supposed to lead to perfect happiness by removing all flaws from the natural world. (4) The only catch is that the new, genetically perfect world feels wholly unnatural to some of the people living in it. (5)

The dystopian future envisioned in Boyle's story is fast becoming scientifically possible. (6) (Whether it is ethically desirable is an entirely separate matter. (7)) CRISPR-Cas9, short for "Clustered Regularly Interspaced Short Palindromic Repeats" and "CRISPR-associated protein 9" is a genetic-editing technology that allows scientists to edit DNA with a remarkable degree of accuracy. (8) It is an advance on other genetic-editing technologies, which had limited programmability and, in turn, often caused off-target effects (edits to segments of DNA that the researcher was not trying to impact). (9) Scientists continuously find new, creative uses of CRISPR-Cas9, (10) and the technology is increasingly in the public eye. (11) The FDA recently issued a press release warning consumers that the sale of "do it yourself" CRISPR kits is against the law due to safety concerns about CRISPR-Cas9-mediated gene therapies. (12) Chinese scientists reported in October of 2016 that they had injected a lung cancer patient with cells modified by CRISPR-Cas9, (13) scientists at Oregon Health & Science University reported in August of 2017 that they had made CRISPR-mediated repairs to non-viable human embryos, (14) and human trials of a CRISPR-based treatment for a blood disorder will begin in Europe in 2018. (15)

Most of the legal scholarship on CRISPR-Cas9 has focused on the patent dispute between the University of California and The Broad Institute, (16) on how the use of CRISPR should be regulated, (17) or on the ethical concerns about how CRISPR should be used. (18) Legal scholarship has not yet addressed the question that this Note seeks to answer: are therapeutic applications of CRISPR-Cas9 patentable? Previous articles have examined the patentability of the processes required to make CRISPR-Cas9 and transcribe it into other organisms, but have not examined the patentability of CRISPR-Cas9 systems in the context of providing medical care by editing viral, bacterial, or human DNA. (19)

It is not clear that these CRISPR-Cas9 applications would qualify as patentable subject matter under the traditional tests for patentability. (20) This issue is further complicated because federal law prevents patents from issuing "on a claim directed to or encompassing a human organism," and it is not obvious whether CRISPR-Cas9 systems cross that line. (21) The legislative history of the Act suggests that Congress designed this provision to prevent "human embryos and fetuses" from being patented. (22) However, the law's authors did intend that "genes, stem[] cells, [and] animals with human genes" would remain patentable. (23) This suggests that researchers seeking to create scalable CRISPR-Cas9 treatments for a broad range of human ailments will have to do more than simply convince the FDA that their therapy is safe (24) : they will also likely have to litigate the question of whether their treatment is patentable subject matter under current federal law.

This Note seeks to answer that question, and concludes that while antibacterial and antiviral CRISPR-Cas9 treatments are patentable, treatments that edit somatic or germline cells are not. Part I will provide biological context, explaining what CRISPR-Cas9 is, how it differs from other genetic editing technologies, and how it may be used as a treatment for human illness in the future. Part II will provide legal context, explaining the current legal landscape for patents based on human biology. Part II will also provide a background on U.S. patent law, describe the patentability of embryos, DNA, and stem cells, and summarize some of the scholarship on the patentability of CRISPR-Cas9.

Part III will attempt some line-drawing. Are CRISPR-based treatments patentable? Are they too directed at a human organism to be patented? Does the answer change depending on the therapeutic use the DNA is put to? Part III will conclude that CRISPR-Cas9 systems used to treat viral or bacterial infections are patentable because they are analogous to non-biologic drugs, but CRISPR-Cas9 systems used to alter genetic mutations or for germline therapies are not patentable because they are directed at a human organism. Part IV considers and rejects some counterarguments to the normative framework outlined in Part III.

1. SCIENTIFIC BACKGROUND

   In order to be patentable, an invention must be, among other things, a "new and useful," (25) "novel []," (26) and "non-obvious" (27) thing or process. (28) To determine whether an invention meets these requirements, a patent examiner looks at the "prior art" (29)--the scientific background that undergirds the patent application. (30) Because the scientific background is useful not just for determining whether CRISPR-Cas9 is patentable, but also for defining precisely what it is, this Part will provide a basic introduction to CRISPR-Cas9 and its therapeutic applications.

   1. What is CRISPR-Cas9?

      Scientists have been using genome-editing technologies since 1994. (31) Genome-editing technologies "give scientists the ability to change an organism's DNA." (32) The three genome-editing technologies primarily in use today are zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR-Cas9. (33) Of these three, CRISPR-Cas9 has the greatest therapeutic potential because it is the most scalable--when compared to ZFNs and TALENs, CRISPR-Cas9 systems are cheap, easy to produce, efficient, and can easily be tailored to edit multiple genes at a single time. (34)

      CRISPR are short sequences of DNA that code for a guide RNA (gRNA) that is then paired with a CRISPR-associated (Cas) protein, an enzyme (36) that acts like a pair of molecular scissors and cleaves (36) target DNA at very specific locations in the genome. (37) The gRNA steers the Cas to the appropriate cutting site on the target DNA. (38)

      CRISPR-Cas9 originally evolved as an immune response in bacteria; it protected the bacteria from viral infection. (39) The bacteria would incorporate short sequences of DNA from viruses that had infected them into their own genetic code. (40) The bacteria could then use the incorporated viral DNA to create an "immune memory" that helped it recognize an infection from the same virus in the future. (41) The incorporated viral DNA would be used as a model for a gRNA. (42) That gRNA could then guide a Cas9 to the virus, in order to destroy it. (43) The gRNA would direct the Cas9 to the target site on the virus's DNA, where the Cas9 would create a double-strand break in the viral DNA, destroying it and ending the infection. (44)

      CRISPR-Cas9 was first discovered in 2000 by researchers in Spain, (45) but its genetic editing potential was not publicly recognized until 2012, when scientists at the University of California, Berkeley published a paper in the journal Science detailing the first complete catalogue of the CRISPR-Cas9 system as found in bacteria. (46) CRISPR-Cas9 is incredibly useful as a genetic editing tool because it is highly accurate. (47) Because the CRISPR-Cas9 gRNA is twenty nucleotides (48) long, and each nucleotide will pair exactly with a nucleotide on the target DNA, there is less than a one in one trillion chance that the Cas9 will cleave the DNA at the wrong site. (49) Cleaving DNA at only the intended target site is critical because any off-target editing (50) risks damaging functioning DNA and creating serious, potentially lethal side-effects. (61)

      CRISPR-Cas9's enormous therapeutic potential does not derive merely from the fact that it can damage DNA at very specific places. (52) This capacity by itself is not unique, or even necessarily very helpful. (53) After all, what frequently makes carcinogens carcinogenic is their ability to damage DNA. (54) CRISPR-Cas9 has enormous therapeutic potential because its highly specific cutting ability targets extremely specific sequences of DNA, and can be paired with processes that insert desirable DNA at the target site, creating the potential to replace a defective gene with a functioning one. (55) This means that CRISPR-Cas9 could serve as a cure to not just infectious diseases, but also inherited ones. (56)

      Recent research by scientists at Stanford University indicates that CRISPR-Cas9 in its current iteration may have limited effectiveness in treating human...