The Broad Institute Scores Another Victory in Its Battle with the University of California over the Patenting of CRIPSR

Abstract

Biotechnology Law ReportVol. 41, No. 3 The Holman ReportFree AccessThe Broad Institute Scores Another Victory in Its Battle with the University of California over the Patenting of CRIPSRBy Christopher M. HolmanBy Christopher M. Holman*Christopher M. Holman, Professor of Law, University of Missouri-Kansas City School of Law; Senior Scholar, Center for the Protection of Intellectual Property, Antonin Scalia Law School, George Mason University; and Executive Editor, Biotechnology Law Report.Search for more papers by this authorPublished Online:15 Jun 2022https://doi.org/10.1089/blr.2022.29272.cmhAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In 2015, Science magazine named CRISPR gene editing technology its “Breakthrough of the Year,” and for good reason.1 CRISPR represents a transformative advance in the ability of biotechnologists to edit genes and genomes in both humans and nonhuman organisms with potentially broad application to medicine, diagnostics, basic research, and agriculture. The Royal Swedish Academy of Sciences awarded the 2020 Nobel Prize in Chemistry 2020 to Emmanuelle Charpentier Max Planck Unit for the Science of Pathogens and Jennifer A. Doudna, University of California, Berkeley2 In a 2019 Holman Report entitled A Fractured International Response to CRISPR-Enabled Gene Editing of Agricultural Products, I delved into one particularly interesting application of CRISPR, gene editing in the context of agriculture, and more particularly the regulation of genetically engineered (GE) crops and other agricultural plants produced using a sequence-specific gene editing technology such as CRISPR.3In the present I article, I report on recent developments in the battle for US patent rights in CRISPR technology that has pitted Doudna and Charpentier and their respective institutions, the University of California and the University of Vienna, (referred to collectively in this article as “UC”)4 against the Broad Institute, Inc., Massachusetts Institute of Technology, and the President and Fellows of Harvard College, (referred to collectively in this article as “Broad”). The battleground has been the US Patent and Trademark Office (PTO) and the Court of Appeals of the Federal Circuit, where the two parties have been involved in two high-profile patent interferences.While Doudna and Charpentier have received the lion's share of the acclaim for the development of CRISPR technology, they have not fared as well at the PTO. There have been two patent interferences between UC and Broad that have been decided by the Patent Trial and Appeal Board (the “Board”). In the first decision, UC attempted to knock out Broad patents and patent applications directed towards the use of CRISPR in eukaryotes, claiming that UC had priority for that technology based upon its patents and patent applications claiming the use of CRISPR generally, i.e., not limited to eukaryotes, or any particular environment. In fact, UC's patents were based on the disclosure of the successful use of CRISPR in in vitro systems, not in eukaryotes, and the Board dismissed the interference based on a finding of no interference-in-fact. Essentially, the Board found that the use of a CRISPR gene-editing system, unconstrained to any particular environment, e.g., in vitro or in a prokaryotic, was a patentably distinct invention from a system capable of accomplishing CRISPR-mediated gene editing in a eukaryote, essentially because the development of a method to use CRISPR for gene-editing in a non-eukaryotic context would not render obvious to one of skill in the art a CRISPR system operative in eukaryotes.5 On appeal, the Federal Circuit affirmed the board's decision.6More recently, in what I will refer to as the second interference, the Board has issued a decision once again finding in favor of Broad, this one addressing the merits of the priority dispute.7 In this case, the subject matter of the interference is a method of using a CRISPR system in eukaryotes, involving patents and patent applications of both parties reciting embodiments of that subject matter. Broad was the senior party in the interference, having the earlier effective filing date, and was able to push that date back even further by establishing an earlier actual reduction to practice. UC, on the other hand, failed to marshal the necessary evidence to convince the Board that it had conceived and/or actually reduced the invention to practice prior to the priority date established by Broad.In this installment of the Holman Report, I will begin with a brief introduction to the law of patent interferences, focusing on the issues that were relevant in the two CRISPR interferences. I will then provide a brief introduction to CRISPR and the CRISPR technology. Next, I will summarize the reported decisions in the two interferences, focusing on the Federal Circuit decision for the first interference, and the PTAB decision for the second (since the Federal Circuit has yet to decide any appeal of that decision). The article concludes with a discussion of the implications of the decisions.Patent InterferencesThe patent interference proceeding is a holdover from US patent law as it existed prior to changes made by the America Invents Act (AIA).8 Under pre-AIA 35 U.S.C. § 102(g), if two parties claim patentably indistinct subject matter, a patent may only be awarded to the first inventor. Section 3(n)(2) of the AIA provides a timing provision relating to the changes wrought by the AIA. Under this section, the interference proceeding “shall apply to each claim of an application for patent, and any patent issued thereon, for which the amendments made by this section also apply, … if such application or patent contains or contained at any time … a claim to an invention having an effective filing date [before March 16, 2013]; or a specific reference under section 120, 121, or 365(c) of title 35, United States Code, to any patent or application that contains or contained at any time such a claim.” In a recent decision, the PTAB found it proper to declare an interference between a patent application with a priority date before March 16, 2013, the AIA implementation date, and a patent with a priority date after March 16, 2013.9It bears noting that the patent claims at issue in the recently decided CRISPR interference have effective filing dates, based on the filing of provisional applications, in December 2012 (Broad) and January 2013 (UC). If the effective filing dates were only a few months later, the patent interference proceeding would not have been available for UC to challenge Broad's presumptive priority by means of a patent interference. Notably, unless the Federal Circuit overturns the PTAB decision on appeal, the outcome in this case would appear to be the same as it would have been if the parties' effective filing dates were post-AIA. In other words, the change in the law would not have changed the outcome, but could have saved a lot of time and money that were expended over the course of these interferences.Whether an interference occurs is determined by comparing the involved claims.10 The PTAB applies a two-way test to determine whether the claims are patentably distinct, asking whether “the subject matter of a claim of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and vice versa.”11 If the two-way test is not met, no interference-in-fact exists. As discussed below, this is what happened in the first CRISPR interference.Under pre-AIA 35 U.S.C. § 102(g), priority of invention goes to the first party to reduce an invention to practice unless the other party can show that it was the first to conceive of the invention and that it exercised reasonable diligence in later reducing that invention to practice. The senior party, i.e., the party with the earliest effective filing date, is presumed to have invented the subject matter of the interference count (i.e., the disputed subject matter) before the junior party. However, the junior party can overcome the presumption against it by presenting arguments and evidence of dates of conception and reduction to practice prior to its filing date, so long as it can convince the PTAB that this evidence and argument overcomes the presumption in favor the senior party. When evaluating the testimony of an inventor, the PTAB looks to corroborative, independent evidence to safeguard against inventors who might otherwise “be tempted to remember facts favorable to their case.”12An actual reduction to practice requires proving that the inventors constructed an embodiment of the count, meeting all its limitations, and that they determined the invention would work for its intended purpose.13Conception requires a “formation in the mind of the inventor, of a definite and permanent idea of the complete and operative invention, as it is hereafter to be applied in practice.”14 “An idea is definite and permanent when the inventor has a specific, settled idea, a particular solution to the problem at hand, not just a general goal or research plan he hopes to pursue.”15The inventor need not know that the invention will work in order for conception to be complete, because determining it works is part of reduction to practice.16 Even when the invention is in an uncertain or experimental art, where the inventor cannot reasonably believe an idea will be operable until some result supports that conclusion, “[a]n inventor's belief that his invention will work or his reasons for choosing a particular approach are irrelevant to conception.”17 Thus, the court is not to base a determination of conception on facts regarding the state of the art or the inventor's beliefs of what will happen, but on the facts of how specific and settled the inventor's ideas were at the time asserted.Under facts “where results at each step do not follow as anticipated, but are achieved empirically by what amounts to trial and error” there has not been a complete conception.18 “Conception is complete only when the idea is so clearly defined in the inventor's mind that only ordinary skill would be necessary to reduce the invention to practice, without extensive research or experimentation.”19 Similarly, a conception may not be complete “if the subsequent course of experimentation, especially experimental failures, reveals uncertainty that so undermines the specificity of the inventor's idea that it is not yet a definite and permanent reflection of the complete invention as it will be used in practice.”20 “When a research plan requires extensive research before the inventor can have a reasonable expectation that the limitations of the count will actually be met, complete conception has not occurred.”21In such cases it is the factual uncertainty about whether the idea was complete in the mind of the inventor, rather than a generalized uncertainty surrounding experimental sciences or a specific field of art, that undermines conception.22 For example, under the facts of Hitzeman it was not the general state of the art, but statements made by the inventor during prosecution and subsequent publications that revealed he had not conceived of the complete subject matter of the count and considered it not to have been reasonably expected by one of ordinary skill in the art.23 The Hitzeman court found that claiming the result of a biological process with “no more than a hope, or wish,” that the process would be performed, when it had never before been achieved, was insufficient to establish conception.24Crispr SystemsCRISPR is a phenomenon that occurs naturally in bacteria, and essentially functions as a bacterial immune system that is capable of remembering and responding to viral attackers. Its mechanism of action involves double-stranded cleavage of DNA at a specific sequence, and it is this ability to selectively cleave DNA that has been repurposed for gene-editing and other associated applications in biotechnology. A key component of CRISPR is the CRISPR-associated (Cas) nuclease, which binds and cuts DNA. While multiple Cas nuclease have been identified, the CRISPR system at issue in the patent interference employs Cas9.More particularly, the patent claims at issue in these interferences relate to the use of a CRISPR-Cas9 system for the targeted cutting of DNA molecules.25 The system includes three components: (1) a “crRNA”; (2) a “tracrRNA”; and (3) the Cas9 protein. The crRNA is an RNA molecule with a variable portion that targets a particular DNA sequence. The nucleotides that make up the variable portion complement and hybridize with the target sequence in the DNA. Another portion of the crRNA consists of nucleotides that complement and bind to a portion of the tracrRNA. The Cas9 protein interacts with the crRNA and tracrRNA and cuts both strands of DNA at the target location. CRISPR-Cas systems occur naturally in prokaryotes such as bacteria, but have not been found to naturally exist in eukaryotes, such as plants and animals.The inventions at issue in these interferences involve CRISPR systems engineered to be better adapted for targeted genome editing in the hands of biotechnologists. One of the key innovations in this regard was the recognition that the crRNA and tracrRNA could be fused into a single RNA molecule, sometimes referred to as a “single guide RNA,” “sgRNA,” or “chimeric RNA.” In the terminology used by Broad in its patents, the single guide or chimeric fused RNA comprises a “guide sequence” fused to a “tracr sequence.” In UC's terminology, a “single molecule DNA-targeting RNA” comprises a “targeter-RNA” (i.e., a “crRNA”) fused to an “activator-RNA” (i.e., a “tracrRNA”). Under both parties' terminology, the fused RNA hybridizes to the targeted DNA to achieve specific cutting of the targeted DNA sequence.In August 2012, UC researchers published an article demonstrating that the isolated elements of the CRISPR-Cas9 system could be used in a non-cellular (i.e., in vitro) experimental environment.26 In February 2013, Broad researchers published their own article describing the use of CRISPR-Cas9 in a human cell line.27 It is undisputed that the UC article did not report the results of experiments using CRISPR-Cas9 in a eukaryotic cell.The First InterferenceThe first interference was declared by the PTAB and involved UC's Application No. 13/842,859 and the claims of twelve patents and one application owned by Broad.28The UC application's claims were directed towards a method of cleaving a nucleic acid by means of a CRISPR system comprising a single molecule DNA-targeting RNA that itself comprises a targeter-RNA that hybridizes with a target sequence and an activator-RNA. The claims are not limited to particular cell type or environment. Claim 165 of the '859 application is representative: 165. A method of cleaving a nucleic acid comprisingcontacting a target DNA molecule having a target sequence with an engineered and/or non-naturally-occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)— CRISPR associated (Cas) (CRISPR-Cas) system comprisinga) a Cas9 protein; andb) a single molecule DNA-targeting RNA comprisingi) a targeter-RNA that hybridizes with the target sequence, andii) an activator-RNA that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment,wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides,wherein the single molecule DNA-targeting RNA forms a complex with the Cas9 protein,whereby the single molecule DNA-targeting RNA targets the target.The claims in Broad's patents and application recite methods of using a CRISPR system to alter the expression of a gene product in a eukaryotic cell wherein the Cas9 protein and the guide RNA do not naturally occur together.29 The crucial distinction between the Broad and UC claims is that the Broad claims are limited to use in eukaryotic cells. Claim 1 of U.S. Patent No. 8,697,359 is representative: 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 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)—CRISPR associated (Cas) (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 hybridizes with the target sequence, andb) 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 the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together.After institution of the interference Broad moved to terminate the interference, arguing that its claims are patentably distinct from UC's claims because a person of ordinary skill in the art would not have had a reasonable expectation that the CRISPR-Cas9 system would work successfully in a eukaryotic cell. The Board determined there was no interference-in-fact because, given the differences between eukaryotic and prokaryotic systems, a person of ordinary skill in the art would not have had a reasonable expectation of success in applying the CRISPR-Cas9 system in eukaryotes.30 It followed that UC's claims to the use of CRISPR-Cas9 did not render obvious Broad's claims to its use in eukaryotes, and thus the inventions are patentably distinct.On appeal, the Federal Circuit affirmed, finding the PTAB's underlying factual findings to be supported by substantial evidence, and that the PTAB had not erred in concluding that Broad's claims would not have been obvious over UC's claims.31 In reaching this decision, the court noted that in determining whether the claims involved in an interference are patentably distinct, the PTAB applies a two-way test that asks whether “the subject matter of a claim of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and vice versa.”32 If the two-way test is not met, no interference-in-fact exists.When an interference-in-fact turns on whether one set of claims renders obvious the subject matter of another set of claims, the Federal Circuit reviews the Board's ultimate conclusion of obviousness de novo, and the underlying factual findings for substantial evidence. In this case, the outcome was driven entirely by the substantial evidence standard. The PTAB found a person of ordinary skill in the art would not have had a reasonable expectation of success in applying the CRISPR-Cas9 system in eukaryotic cells, and given the mixture of evidence in the record, the Federal Circuit held that substantial evidence supported the PTAB's finding that there was not a reasonable expectation of success.Among the substantial evidence cited by the Federal Circuit as supporting the Board's finding that there would not have been a reasonable expectation of success was the testimony of Broad's expert Dr. Paul Simons describing the differences between prokaryotic systems and eukaryotic systems that rendered the application of the CRISPR-Cas9 system in eukaryotic cells unpredictable. He explained that the function of the CRISPR-Cas9 system is dependent on the proper folding of the Cas9 protein, and that folding is particularly important for the CRISPR-Cas9 system because of the conformational changes the Cas9 protein undergoes in performing its function. He further explained that differences in cellular conditions can cause differences in protein folding, and elaborated on some of the differences between prokaryotic and eukaryotic cellular conditions that would make the functionality of CRISPR-Cas9 in eukaryotes unpredictable. These included: intracellular temperature, the concentration of various ions, pH, and the presence of other molecules that may be present in one type of cell, but not the other.Dr. Simons identified additional concerns involving the CRISPR-Cas9 system, which he testified would have caused a skilled artisan not to have a reasonable expectation that it would work in eukaryotic cells. The CRISPR-Cas9 system relies on two RNA components, crRNA and tracrRNA. Eukaryotic cells contain a number of molecules, known as ribonucleases, which are not present in prokaryotic cells, that cut up RNA molecules. Eukaryotic cells also contain systems that degrade double-stranded RNA. The CRISPR-Cas9 system contains a section of double-stranded RNA where the crRNA binds with the tracrRNA, adding additional uncertainty. Dr. Simons suggested a person of ordinary skill in the art would have been concerned that the CRISPR-Cas9 system could result in an excessive number of double-stranded DNA breaks given factors such as the greater size of the human genome compared to typical bacterial genome and the frequency with which similar DNA sequences appear in the human genome.In a contemporaneous article published September 2012, UC's own expert witness Dr. Dana Carroll recognized many of the same issues identified by Broad's expert that could arise in attempting to apply the CRISPR-Cas9 system in eukaryotic cells. These included the possibility that CRISPR-Cas9 might be degraded by nucleases in eukaryotic cells and that toxicity could result from its use in eukaryotic cells. He also noted potential problems arising from the fact that, unlike prokaryotic DNA, eukaryotic DNA exists in a chromatin complex, in which the DNA is wrapped around protein structures. He stated in this contemporaneous article that “[t]here is no guarantee that Cas9 will work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in that context.” He further noted that the efficacy of prior systems relying on gene editing through base pairing “remains discouragingly low in most cases.”The PTAB was also presented evidence of statements by the UC inventors acknowledging doubts and frustrations about engineering CRISPR-Cas9 systems to function in eukaryotic cells while noting the significance of Broad's success in this regard. Dr. Doudna, for example, acknowledged the “huge bottleneck” in making genetic modifications in animals and humans, and after the publication of the initial UC research, she stated “[o]ur 2012 paper was a big success, but there was a problem. We weren't sure if CRISPR/Cas9 would work in eukaryotes.”. She also explained that she had “many frustrations” in getting CRISPR-Cas9 to work in human cells, and that she thought success in doing so would be “a profound discovery.” Evidence in the record also suggested her colleagues recognized the significance of Broad's development. When a colleague contacted Dr. Doudna to inform her of Broad's success he stated, “I hope you're sitting down,” “CRISPR is turning out to be absolutely spectacular in [Broad researcher] George Church's hands.” The Board viewed this evidence as indicating that an ordinarily skilled artisan would have lacked a reasonable expectation of success.The Board also considered evidence regarding the development of other gene editing systems. It found several of these were not particularly informative in assessing the reasonable expectation of success with respect to CRISPR-Cas9. Specifically, it found that the prior art TALEN and zinc finger nuclease (“ZFN”) systems were not analogous to CRISPR-Cas9 because they have their origins in eukaryotic domains and that the adaptability of small prokaryotic protein systems like Cre would not have informed the expectation of success for the larger CRISPR-Cas9 complex. Broad presented evidence regarding three other systems derived from prokaryotes that had been adapted for use in eukaryotes: riboswitches, ribozyme systems, and group II introns. The Board found that in each instance there was either limited efficacy or the technology required a specific strategy to adapt it for use in eukaryotic cells. Broad presented expert testimony that only a few riboswitches had been successfully adapted to work in eukaryotes, and a prior art article explained that differences in RNA folding in vivo versus in a cellular environment may prevent the riboswitches from working. Based on expert testimony and an earlier publication, the Board found that although some success was achieved using ribozyme systems, “that success required a specific strategy developed particularly for ribozymes.” As to group II introns, there was evidence before the Board that despite 16 years of experimental efforts and the development of a specific strategy to increase the likelihood of success for that system, their use in eukaryotes remained limited.The Federal Circuit acknowledged that UC had expended substantial time and effort to convince the court that substantial evidence supports the view that a person of ordinary skill would have had a reasonable expectation of success in implementing the CRISPR-Cas9 system in eukaryotes, stating: There is certainly evidence in the record that could support this position. The prior art contained a number of techniques that had been used for adapting prokaryotic systems for use in eukaryotic cells, obstacles adopting other prokaryotic systems had been overcome, and Dr. Carroll suggested using those techniques to implement CRISPR-Cas9 in eukaryotes. However, as an appellate body it is not the role of the Federal Circuit to reweigh the evidence.Subsequent to an affirmance of that decision by the Federal Circuit, at least some of UC's involved applications were issued as patents with claims to a method of cleaving DNA with a CRISPR-Cas9 system having a single RNA component, without restriction to the environment.33The Second InterferenceThe second interference was instituted with respect to claims “directed to a CRISPR-Cas9 system having a single RNA component, which along with the protein Cas9, can cleave a DNA molecule to alter gene expression or modulate transcription of a targeted gene in a eukaryotic environment.”34 The PTAB found the existence of an interference-in-fact and proceeded to determine the priority dispute under 35 U.S.C. § 102(g) on its merits.The interference count at issue (Count 1, a so-called “McKelvey count”)35 recited Broad patent 8,697,359, claim 18 or UC application 15/981,807, claim 156.Broad patent 8,697,359, claim 18 recites: The CRISPR-Cas system of claim 15, wherein the guide RNAs comprise a guide sequence fused to a tracr sequence.Broad patent 8,697,359, claim 15 recites: An engineered, programmable, non-naturally occurring Type II CRISPR-Cas system comprising a Cas9 protein and at least one guide RNA that targets and hybridizes to a target sequence of a DNA molecule in a eukaryotic cell, wherein the DNA molecule encodes and the eukaryotic cell expresses at least one gene product and the Cas9 protein cleaves the DNA molecules, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together.UC application 15/981,807, claim 156 recites: A eukaryotic cell comprising a target DNA molecule and an engineered and/or non-naturally occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-—CRISPR associated (Cas) (CRISPR-Cas) system comprising a) a Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding said Cas9 protein; and b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA-targeting RNA; wherein the single molecule DNA-targeting RNA comprises: i) a targeter-RNA that is capable of hybridizing with a target sequence in the target DNA molecule, and ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment,wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides; andwherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said system is capable of cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule.Broad was accorded benefit of the filing of date 12 December 2012 of its provisional application 61/736,527. UC, as junior party, was accorded benefit of the filing date 28 January 2013 of its provisional application 61/757,640.Broad was able to prove actual reduction to practiceBroad was able to establish a priority date of 5 October 2012 by proving an actual reduction to practice of the claimed invention prior to that date. The primary evidence of this actual reduction to practice was a manuscript submitted to Science magazine on 5 October 2012, entitled “CRISPR-Assisted Mammalian Genome Engineering,” and naming as authors several Broad inventors, including Le Cong and Feng Zhang. The PTAB found that the manuscript memorialized experiments that were done by the inventors prior to 5 October 2012 which demonstrated that the invention worked and included all of the limitations of the claimed invention.Broad successfully argued that Dr. Zhang's decision to prepare the manuscript for submission to the journal, which would then undergo extensive peer-review, indicated that he recognized and appreciated that his results demonstrated successful use of a chimeric RNA CRISPR system to