The Case of Conception in CRISPR
The magic key to life is real—and its proprietary interest is currently being disputed in the court of law.
CRISPR-Cas9 is a naturally-occurring immune-system-like mechanism in microbes that utilizes a genome editing process to recognize and protect from foreign invaders [1]. In August of 2012, researchers Jennifer Doudna and Emmanuelle Charpentier of the University of California, Berkeley and the University of Vienna, respectively, published a co-authored Science article, detailing their success in utilizing CRISPR-Cas9 to induce controlled genetic modification in prokaryotic organisms; they (the University of California, Berkeley, the University of Vienna, and Charpentier--collectively known as “CVC”) then submitted a provisional patent application. Their work inspired Feng Zhang at the Broad Institute (the Massachusetts Institute of Technology and Harvard University’s collaborative research center; known as “Broad”), who successfully implemented CRISPR-Cas9 in eukaryotic organisms. Broad eventually submitted their own patent application for the CRISPR-Cas9 in eukaryotes under accelerated review, which was approved and awarded before CVC’s. After a 10-year dispute involving two patent interference proceedings filed by CVC against Broad, the patent—specific to employing CRISPR-Cas9 technology in eukaryotes—had been decidedly awarded to Broad. However, CVC filed an appeal on the decision in 2022. The appeal invokes various offensive arguments and accusations, from proposing different definitions of the term “guide RNA” (which was vital to the Broad team’s accuracy in genetic modification) to accusing the Patent Trial and Appeal Board of violating the Administrative Procedures Act. Ultimately, the ruling of this appeal will hinge on the dichotomy between theoretical conception of a patented technology’s potential applications and its actual reduction to practice, and thus, that will be the focal point of this article. The outcome of this case will set a significant precedent for impending patent disputes concerning the emergence and improvement of revolutionary biotechnologies as the world enters an era marked by advancements like artificial intelligence driving drug discovery. However, CVC’s appeal is weakened by the fact that a generic idea without any tangible inventive work cannot sensically be patentable for two reasons. Firstly, conception, specifically as it was defined by CVC, should not be patentable and does not have a genuine precedent of intellectual property protection. Secondly, their conception was not complete nor thorough enough to induce Zhang’s success alone; Zhang and his team at the Broad Institute had to substantially alter CVC’s initial concept to achieve success. Thus, it appears that CVC’s appeal is not valid, and the Broad Institute’s patent for use of CRISPR/Cas9 technology in eukaryotic cells must be affirmed.
CVC’s legal team posited a twofold argument in their recent appeal. Firstly, CVC claimed that, according to the Broad brief, Zhang had done functionally nothing to contribute to the count (a patentably distinct claim or invention) regarding implementation of CRISPR-Cas9 in eukaryotic environments. Allegedly, his collaborator and distinguished microbiologist, Luciano Marraffini, had exposed their research design to Zhang, to which Zhang adhered precisely unto success [2]. Further, CVC claimed that the Patent Trial and Appeal Board exhibited an overreliance on precedent set in Cooper v. Goldfarb, which made “reduction to practice”—the process of a conceived invention becoming real—a focal metric for patent interference proceedings [3]. Rather, CVC provided countless cases, such as Applegate v. Scherer (where disclosure of a complete conception leads to successful reduction to practice by a separate party, the patent must be awarded to the conceivers) and Acromed Corp. v. Sofamor Danek Group, Inc. (which established that joint inventors must make substantial contributions) to support an alternate basis for the ruling of this interference: that conception of an idea is enough to make said idea patentable. They posit that they should be granted the patent if their research design could be successfully executed and reduced to practice, “regardless of whether the inventor [CVC] succeeds [4].” CVC also cited cases like Sewall v. Walters (where complete conception induces a successful reduction to practice, the reduction to practice is not enough to prove neither joint inventorship nor sole inventorship) and Burroughs Wellcome Co. v. Barr Laboratories, Inc. (which determined that a “definite and permanent” conception must have been presented by the party claiming interference for the issued patent to be invalidated) to push that the conception of their idea was sufficiently "definite and permanent" that "one of ordinary skill in the art could construct the apparatus without unduly extensive research or experimentation [5]."
CVC’s appeal makes a bold claim: that conception is sufficient for claiming rights to a patent. However, CVC’s appeal seems to manipulate the ruling of the numerous cases it sets forth to suggest that they had a sufficiently-developed conception of the process of implementing CRISPR-Cas9 in eukaryotic cells. CVC relies heavily on a precedent set in Applegate v. Scherer, claiming that it supports the idea of a conception being patentable. Close examination of the written ruling of the Patent Trial and Appeal Board reveals that CVC appears to have misappropriated this case. Towards the very end of the ruling, the Board clarifies that the ruling of Applegate v. Scherer is specific to situations in which the reduction to practice is “no more than [an] exercise [of] ordinary skill [6].” However, it has been decisively clarified in both prior interference proceedings that the implementation of CRISPR-Cas9 in eukaryotes was a task far beyond the capability of a person of ordinary skill in the art (a metric elucidated in Graham v. John Deere Co. as whether an invention or improvement upon an existing invention “would have been obvious…to a person having ordinary skill in the art to which said subject matter pertains”), and even beyond the capabilities of most skilled artisans, including those at the University of California, Berkeley and the University of Vienna [7]. Similar misappropriation takes place with many of the other cases that CVC sets forth in their appeal, such as *Burroughs Wellcome Co. v. Barr Laboratories, Inc. *Since none of these rulings are congruent with CVC’s current situation, they fail to contradict or invalidate the precedent of Cooper v. Goldfarb being followed by the Patent Trial and Appeal Board in this dispute.
One key aspect of CVC’s appeal to note is that it relies on the argument that their disclosure was thorough and precise enough to single-handedly induce successful experimentation at the Broad Institute and elsewhere. CVC positions cases like Acromed Corp. v. Sofamor Danek Group, Inc. and Sinclair & Carroll Co. v. Interchemical Corp. as exemplary in this dispute, making the claim that Broad’s contributions to the CRISPR-Cas9 technology were not inventive [8], substantially conceptual, nor fundamentally instrumental [9] to their success. Conversely, in a statement by the Patent Trial and Appeal Board throughout the initial interference proceeding processes, “the CVC inventors’ experimental failures reveal uncertainty undermining a definite and permanent idea of an sgRNA CRISPR-Cas9 system that edits or cleaves DNA [10].” This clarification by the Board preemptively attacks one of CVC’s key appeal points by highlighting CVC’s ambiguous and indefinite plans as to approaching the task of employing CRISPR-Cas9 in eukaryotic environments. CVC’s conception was incomplete, which means their attempts to minimize Broad’s conceptual work fall flat and references to cases like Sewall v. Walters and Acromed Corp. v. Sofamor Danek Group, Inc. are also misappropriated. This quote also provides an interpretation for Burroughs Wellcome Co. v. Barr Laboratories, Inc., which CVC attempted to invoke in their appeal. As clarified by the Patent Trial and Appeal Board, CVC’s conception was not definite; it was vague and admittedly uncertain, which required substantial contribution by the Broad team to actually reduce the CRISPR-Cas9 technology to practice in eukaryotes. Thus, even under the Burroughs precedent, CVC’s conception cannot be patentable. Furthermore, this quote by the Patent Trial and Appeal Board alludes to the research article published by Zhang’s team at the Broad Institute that detailed their successes in implementing CRISPR-Cas9 in eukaryotic environments, which outlines the specific ways in which they altered the structure of the sgRNA to increase accuracy in gene-editing efforts [11]. These crucial structural changes and implementation strategies were not outlined by the CVC team; their Invention Disclosure Form does not mention any specifics of implementation and relies on assumptions that strategies employed in other genome-editing softwares will be operable within the CRISPR-Cas9 system [12]. Since there was no definite conception of the processes of utilizing CRISPR-Cas9 to edit genes in eukaryotic environments with the success and precision employed by the Broad team, CVC cannot claim complete conception. Even within CVC’s internal communications, there is express doubt in their research design (“...this will be fabulous if it works,”) and recognition by Doudna and other team members that successful implementation of CRISPR-Cas9 technology in eukaryotic cells would be a “profound discovery,” which emphasizes the speculative nature of CVC’s conception [13].
Since CVC’s proposed precedents do not fully encompass the nuances of this dispute, the case should retain the precedent chosen by the Patent Trial and Appeal Board in the first two interference proceedings, Cooper v. Goldfarb, which is strikingly similar to the case at hand. Cooper v. Goldfarb was a case related to implementing expanded polytetrafluoroethylene (a synthetic polymer used as a non-stick coating; commonly known as PTFE or Teflon) as an artificial vascular graft to replace or repair damaged blood vessels. Cooper had conceived the invention earlier than Goldfarb, but Goldfarb was the first to successfully implant the graft in a living organism. The court determined that unless the conceiver is able to provide some kind of evidence that the invention works for its “intended purpose,” the patent must be awarded to that party that is able to reduce the invention to practice in its intended environment [14]. Evidently, Cooper v. Goldfarb is the most relevant precedent to the CRISPR dispute, as both cases are centered around biotechnologies that may shape the future of healthcare. PTFE is one of the most reliable surgical implant materials as it is non-reactive and human bodies do not reject it, which are key reasons many implants fail and induce infection, blood clot formation, strokes, and aneurysms. CRISPR-Cas9’s practical significance lies in its potential to correct debilitating genetic mutations such as sickle cell anemia and cystic fibrosis; it is unparalleled as a tool that will allow medical professionals to alter the human genome in any way they desire [15]. With both technologies, ensuring they are operable within the biological environments in which they are posited to work is crucial to being able to reap their life-changing benefits, which is the ultimate goal of all invention. A patent cannot be awarded to the person who merely conceived the idea since their thought process alone could not have induced the monumentous, tangible impact that resulted from the subsequent reduction to practice. Thus, within this context, Cooper v. Goldfarb is an appropriate precedent to rely upon and the ruling must be affirmed in favor of Broad.
The final ruling of this dispute will set a major precedent in patent law that will be crucial as the age of technology reaches heights never seen before. As of now, though, Cooper v. Goldfarb provides the most parallels to the CRISPR dispute than any other, meaning the final ruling of this case will likely be consistent with the ruling of Cooper v. Goldfarb. As CVC seemed to have misappropriated many of the precedents it attempted to invoke and only further reinforced their lack of a complete conception and Broad’s claim to the patentability for the implementation of CRISPR-Cas9 in eukaryotic environments, there are few plausible arguments in their appeal, and the Patent Trial and Appeal Board is most likely to affirm their ruling in favor of the Broad Institute.
Bibliography
[1] Li, Tianxiang, Yanyan Yang, Hongzhao Qi, Weigang Cui, Lin Zhang, Xiuxiu Fu, Xiangqin He, Meixin Liu, Pei-feng Li, and Tao Yu. 2023. “CRISPR/Cas9 Therapeutics: Progress and Prospects.” Signal Transduction and Targeted Therapy 8, no. 36 (January). https://doi.org/10.1038/s41392-023-01309-7.
[2] Count means the Board’s description of the interfering subject matter that sets the scope of admissible proofs on priority. Where there is more than one count, each count must describe a patentably distinct invention (Code of Federal Regulations. Title 37, § 41.201).
[3] Cooper v. Goldfarb, 154 F.3d 1321 (Fed. Cir. 1998).
[4] Noonan, Kevin E. 2023. “CVC Files Response and Reply Brief in Interference No. 106,115 Appeal.” Patent Docs. https://www.patentdocs.org/2023/08/cvc-files-response-and-reply-brief-in-interference-no-106115-appeal.html.
[5] Sewall v. Walters, 21 F.3d 411, 415 (Fed. Cir. 1994); Burroughs Wellcome Co. v. Barr Laboratories, Inc., 828 F. Supp. 1200 (E.D.N.C. 1993).
[6] Vernon C. Applegate and John H. Howell, Appellants, v. Otto Scherer, Heinz Frensch and Gerhard Stähler, Appellees, 332 F.2d 571 (C.C.P.A. 1964).
[7] Graham v. John Deere Co., 383 U.S. 1 (1966).
[8] Acromed Corp. v. Sofamor Danek Group, Inc., 253 F.3d 1371.
[9] Sinclair & Carroll Co., Inc. v. Interchemical Corp., 325 U.S. 327 (1945).
[10] Noonan, Kevin E. 2022. “PTAB Holds for Broad in CRISPR Interference: The Reasoning.” Patent Docs. https://www.patentdocs.org/2022/03/ptab-holds-for-broad-in-crispr-interference-the-reasoning.html.
[11] Nishimasu, Hiroshi, F Ann Ran, Patrick D Hsu, Silvana Konermann, Soraya I Shehata, Naoshi Dohmae, Ryuichiro Ishitani, Feng Zhang, Osamu Nureki. 2014. “Crystal structure of Cas9 in complex with guide RNA and target DNA.” Cell 156, no. 5 (February): 935–949. https://doi.org/10.1016/j.cell.2014.02.001.
[12] Noonan, Kevin E. 2023. “CVC Files Response and Reply Brief in Interference No. 106,115 Appeal.” Patent Docs. https://www.patentdocs.org/2023/08/cvc-files-response-and-reply-brief-in-interference-no-106115-appeal.html.
[13] Noonan, Kevin E. 2022. “PTAB Holds for Broad in CRISPR Interference: The Reasoning.” Patent Docs. https://www.patentdocs.org/2022/03/ptab-holds-for-broad-in-crispr-interference-the-reasoning.html; University of California v. Broad Institute, Inc., No. 17-1907 (Fed. Cir. 2018).
[14] Cooper v. Goldfarb, 154 F.3d 1321 (Fed. Cir. 1998).
[15] Kotagama, Odatha W., Chanika D. Jayasinghe, Thelma Abeysinghe. 2019. “Era of Genomic Medicine: A Narrative Review on CRISPR Technology as a Potential Therapeutic Tool for Human Diseases.” BioMed Research International 2019, no. 1 (January). https://doi.org/10.1155/2019/1369682.