United States: Biotech Patent Dispute Between Academics That Is Far From Academic

Last Updated: January 9 2017
Article by Allen M. Sokal

On December 6, 2016, the parties to the complex and soon-to-be departed world of patent interferences orally argued their positions on motions in what has been described as the "biotech trial of the century" and as "the biggest biotech patent case in memory."[1] The parties' oral arguments mirrored their motions, the most important of which rest on whether the senior party's invention of the gene-editing system CRISPR-Cas9 in bacteria (i.e. prokaryotic cells) rendered obvious the use of the system in higher organisms (i.e. eukaryotic cells), such as those of humans. The groundbreaking system "has the potential to treat serious human genetic disorders and create designer crops that resist drought and pathogens"[2] and to reap billions for the victor. The PTAB's decisions on motions might terminate the interference without a priority phase. In any event, absent a settlement between the academic contestants like that between the Pasteur Institute and the National Cancer Institute over who first discovered the cause of AIDS,[3] a higher authority than the PTAB will probably provide the final decision in this monumental dispute.

The administrative patent judge managing the interference, Deborah Katz, has a Ph.D. in molecular biology, which should serve her well in this highly technical contest. The junior party, the Broad Institute of Massachusetts Institute of Technology and the president and fellows of Harvard College, has 12 patents and one allowed application involved in the interference, all claiming systems for gene editing in eukaryotes. The senior party, the University of California and the University of Vienna, requested the interference based on an application claiming only the system for gene editing in prokaryotes, though disclosing use of the system also in eukaryotes. The sole count in the interference as declared reads as follows:

A method, in a eukaryotic cell, of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising:

contacting, in a eukaryotic cell, 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 comprising:

  1. a DNA-targeting RNA comprising

    1. a targeter-RNA or guide sequence that hybridizes with the target sequence, and
    2. an activator-RNA or tracr sequence that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment,

    and

  2. a Cas9 protein,
  3. wherein the DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated.

Judge Katz designated all of the parties' claims as corresponding to the count.

The key pending motions include:

  1. Broad's motion for no interference-in-fact (Broad substantive motion 2); and
  2. UC's motion to substitute Count 1 with proposed Count 2 (UC substantive motion 3).

Broad maintained in its motion for no interference-in-fact that its claims to using the system in eukaryotic cells are separately patentable over UC's claims, which are not limited to any environment. Broad argued that in the 2012 time frame, its involved claims were directed to unpredictable technology such that a person of ordinary skill would not have had a reasonable expectation that the claimed CRISPR-Cas9 system would have successfully cleaved or edited the nuclear DNA of a eukaryotic cell. Broad relied heavily on an admission by one of UC's inventors that development of a CRISPR system for use in eukaryotic cells would be a "profound discovery." Based on prior failures, Broad argued, "one of skill in the art would not have had a reasonable expectation of success in obtaining successful functioning of a CRISPR-Cas9 system in eukaryotes."

UC countered that shortly after its inventors first published their work on Type-II CRISPR-Cas9 system in Jinek et al., 337 SCIENCE 816-821 (2012) (Jinek 2012), in prokaryotic cells, an independent group filed a patent application before Broad filed its first provisional application on December 12, 2012, and several independent groups, either before Broad filed its first provisional application or at about the same time, drafted manuscripts, all citing UC's publication as motivation and confirming the use of UC's Type-II CRISPR-Cas system in eukaryotic cells. Both Broad and the independent groups, UC argued, were able to quickly do so because they used well-known conventional techniques that had been routinely used to adapt other prokaryotic systems to eukaryotic cells. For example, since prokaryotic cells do not have nuclei, one of the independent groups tagged NLS (nuclear localization signal) sequences to Cas9 and also codon-optimized it to successfully move the Cas9 enzyme into the nuclei of eukaryotic cells. UC cited as exemplary a provisional application filed by Dr. Kim et al. in October 2012 that stated that UC's "seminal" paper raised the possibility of using the system for genome editing in cells and organisms and that confirmed that it "could recognize and cleave the target DNA sequence in cultured human cells." Broad relied on a letter that Dr. Kim sent to the UC inventors noting that his group had been developing its genome-editing technology for a "few months" after reading UC's paper. And UC relied on a number of earlier successful uses of prokaryotic DNA-targeting proteins in eukaryotic cells. Such evidence, UC argued, established the requisite expectation of success in eukaryotic cells. Moreover, UC relied on the disclosure in Jinek 2012 before Broad filed its first provisional application of "the potential to exploit the system for RNA-programmable genome editing" and "the exciting possibility of developing a simple and versatile RNA-directed system to generate dsDNA breaks for genome targeting and editing." As to admissions by UC's inventors tending to show unobviousness, UC argued that they were irrelevant because obviousness must be determined from the viewpoint of one of ordinary skill in the art, not an inventor, and the inventors made other positive, forward-looking statements before Broad filed its first provisional application.

In reply, Broad argued that Jinek 2012's spurring others to adapt CRISPR to eukaryotes, because of the huge award if success were achieved, evidenced only motivation and a mere possibility of success, not a reasonable expectation of success. Broad further argued that prior successes with four prokaryotic proteins in eukaryotic cells did not provide a reasonable expectation of success, because "there are thousands of different types of prokaryotic proteins," and differences between those four proteins and Cas9 would have discouraged adaptation of the claimed system to eukaryotic cells. And Broad emphasized that none of those instances involved an RNA component and that UC's experts admitted that that was a "major difference." Finally, Broad relied on a history of failed attempts to adapt prokaryotic protein-RNA complexes to eukaryotes. As an example, Broad argued that after 16 years of attempts, researchers had succeeded in showing Group II introns to function in eukaryotic cells only by microinjection into an embryonic cell that had its magnesium level artificially increased. According to Broad, the literature in 2012 uniformly characterized that and other prokaryotic systems including RNA, citing as examples CRISPR systems, as failures. As to the later successes by others, Broad argued that they do not demonstrate the existence of an expectation of success before the successful experiments, and they were achieved by extraordinarily skilled persons, not those of ordinary skill in the art.

Both parties argued similarly well and made similar arguments regarding UC's motion to substitute Count 1 with proposed Count 2. Indeed, UC's motion is in part the mirror image of Broad's motion.

That part stems from UC's argument that the limitation of Count 1 to eukaryotes, which none of UC's designated claims recites, is not separately patentable (i.e. would have been obvious in view of UC's claims). Count 1, UC argued, unfairly would prevent UC from relying on proofs within the scope of its designated claims because of the limitation to eukaryotes. In connection with that limitation, omitted from proposed Count 2, UC's arguments are virtually identical to its arguments in opposition to Broad's motion for no interference-in-fact, with one notable exception. UC noted that if, contrary to UC's position, practicing the invention in eukaryotes is separately patentable, while none of UC's claims recites that limitation and all of Broad's claims do, there is no interference-in-fact and the PTAB should not have declared an interference. On the other hand, if practicing the invention in eukaryotes is not separately patentable, as implied by the declaration of the interference, then the count should not be limited to that environment.

UC's proposed Count 2, however, includes an additional limitation that UC contended is separately patentable, namely replacing the limitation of Count 1 generically permitting the DNA-targeting RNA to comprise one or more molecules with a requirement for a single-molecule DNA-targeting RNA, to which UC further contends all involved claims of both parties are directed. UC argued that proposed Count 2 is fair to Broad because it does not exclude its eukaryotic proofs, and Count 2 appropriately requires a single-molecule DNA-targeting RNA because both parties' claims are so limited and it is separately patentable.

Thus, proposed Count 2 reads as follows:

A method of cleaving or editing a target DNA molecule or modulating transcription of at least one gene encoded thereon, the method comprising:

contacting 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 comprising:

  1. a single-molecule DNA-targeting RNA or guide RNA comprising

    1. a targeter-RNA that hybridizes with the target sequence, and
    2. an activator-RNA, or a trans-activating CRISPR RNA (tracrRNA), that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein binding segment, and
  2. a Cas9 protein,

wherein i) and ii) are covalently linked to one another, and

wherein a) forms a complex with b), thereby targeting the Cas9 protein to the target DNA molecule, whereby said target DNA molecule is cleaved or edited or transcription of at least one gene encoded by the target DNA molecule is modulated.

Proposed Count 2 substantively differs from Count 1 by omitting the restriction to eukaryotic cells and by limiting the DNA-targeting RNA to a single molecule as a result of covalent linking of the targeter-RNA and activator-RNA or tracrRNA. The proposed count also alternatively identifies the DNA-targeting RNA as a "guide RNA" because that is the terminology used in Broad's claims that UC interprets to mean an RNA comprising both the guide sequence and the tracr sequence.

Since, as noted above, the UC's arguments regarding whether the count should be limited to eukaryotes are virtually identical to its arguments regarding Broad's motion for no interference-in-fact, only UC's arguments regarding the single-molecule limitation require further discussion.[4] UC argued that the single-molecule DNA-targeting RNA for Cas9 is separately patentable because it has received praise and been widely adopted, while before the publication of Jinek 2012, one of ordinary skill in the art would not have believed that the DNA-targeting RNA could be a single molecule and still function with Cas9 to cleave DNA. UC introduced evidence of the praise and widespread adoption and evidence that such structural changes were known to cause problems with enzymatic functions in analogous systems. UC explained that it interpreted all of Broad's involved claims as reciting a single-molecule DNA-targeting RNA because "Junior Party's involved specifications state that the term 'guide RNA' can be used interchangeably to refer to the single-molecule DNA-targeting RNA." But UC further argued that any of Broad's claims that were not so construed would still correspond to the proposed count because the single-molecule DNA-targeting RNA of the proposed count would anticipate a generic guide RNA.

Broad vigorously disagreed that all of its involved claims recite a single-molecule DNA-targeting RNA, arguing that "guide RNA" has long been used in the art to encompass one or more molecules for guiding the RNA to the target and that the paragraph in UC's application is ambiguous and not a "clear disavowal" of the ordinary meaning. Broad therefore asserted that more than 330 of its involved claims include subject matter outside the scope of proposed Count 2 (although that leaves 55 claims within the scope of the proposed count) and that the proposed count "therefore fails to properly define the interfering subject matter."

Broad argued also that proposed Count 2 is unfair because it excludes Broad's earliest proofs, which use a two-molecule guide RNA. On the other hand, Broad argued that Count 1 is not unfair to UC even though it excludes UC's earliest proofs, because UC sought an interference with Broad's patent claims, all approximately 400 of which are limited to eukaryotic cells and were allowed based on the separate patentability of that limitation, and because UC canceled its claims reciting the eukaryotic environment to argue that none of its claims recites that limitation. "It is therefore fair," Broad argued, "that UC cannot rely on in vitro [prokaryotic] work to prove priority on this key invention." Of course, Broad, like UC, repeated its arguments about the patentability of the eukaryotic environment made in its motion for no interference-in-fact.

Broad also argued that proposed Count 2 should not be substituted for Count 1 because the proposed count is not patentable over the prior art. But Broad's argument appears to be that if the standard for patentability that UC argued in opposition to Broad's motion for no interference-in-fact, with which Broad disagrees, is correct, then proposed Count 2 as well as the eukaryotic environment would have been obvious in view of the prior art. But suppose the PTAB concludes that both counts present separately patentable inventions? Broad did not appear to address that possibility, which might lead to blocking patents, the invention of proposed Count 2 to UC and the invention of Count 1 to Broad.

In its reply, UC again repeated its arguments that the subject matter of Count 1 would have been obvious and that the count therefore is improperly limited to eukaryotes. But UC did not appear to repeat its unfairness argument or deny that it canceled its claims reciting the eukaryotic environment. UC did repeat its argument, however, that the subject matter of proposed Count 2 is separately patentable and claimed by both parties.

Although the parties filed other motions, such as motions for benefit of provisional applications, decisions on the two motions addressed in some detail above will probably determine whether the interference proceeds to a priority phase. If the use of the system in the eukaryotic environment is ultimately determined to have been obvious and not separately patentable, Broad might be left empty-handed and UC might have the exclusive right to this immensely important technology. But if the use of the system in the eukaryotic environment is separately patentable, Broad would likely be the big winner, possibly sharing the spoils with UC, depending on the outcome with respect to single-molecule DNA-targeting RNA. Stay tuned.

Footnotes

1 Jacob S. Sherkow, Biotech Trial of the Century Could Determine Who Owns CRISPR, https://www.technologyreview.com/s/603034/biotech-trial-of-the-century-could-determine-who-owns-crispr/ (Dec. 7, 2016). See also Emily Mullin, CRISPR Patent Outcome Won't Slow Innovation, https://www.technologyreview.com/s/603117/crispr-patent-outcome-wont-slow-innovation/ (Dec. 13, 2016).

2 Emily Mullin, CRISPR Patent Outcome Won't Slow Innovation, https://www.technologyreview.com/s/603117/crispr-patent-outcome-wont-slow-innovation/ (Dec. 13, 2016).

3 See, e.g., https://www.newscientist.com/article/dn14881-was-robert-gallo-robbed-of-the-nobel-prize/.

4 Indeed, if UC could have simply incorporated by reference its arguments regarding the motion for no interference-in-fact, it might have spared a small forest.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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