The CRISPR Battle Through the Lens of International Patent Harmonization

“In the end, the Federal Circuit faces a momentous decision: Affirm the PTAB’s status as an apparent international outlier—thereby denying the Nobel Prize winners—or reverse the PTAB, which can be equally challenging.”

CRISPROn Tuesday, May 7, the U.S. Court of Appeals for the Federal Circuit will hear argument in a long-awaited appeal addressing the inventorship of the Nobel Prize-winning CRISPR technology. The case is the latest in a continuing legal battle between two groups of innovators, each asserting patent rights to key aspects of the groundbreaking technology.

The facts on appeal are numerous, and the issues nuanced, covering questions of conception, reduction to practice, and written description (as well as cross-appeal issues). This article’s purpose is not to reiterate each side’s various legal positions, but to explore a narrower issue intertwined with the global CRISPR patent disputes: considerations of patent harmonization and the thus-far inconsistent patent outcomes.

The CRISPR Wars

“CRISPR” is an acronym for “Clustered Regularly Interspaced Short Palindromic Repeats.”  As many readers know, CRISPR technology enables precision gene editing. The technology’s potential benefits are enormous, some of which are already being realized with the FDA’s approval of CRISPR-based therapies late last year.

Competing patents and applications have been awarded and filed in the United States and across the globe. On one side are Jennifer Doudna and Emmanuelle Charpentier (the two Nobel Prize winners), along with their research institutions, collectively known as the CVC appellants. On the other side are Feng Zhang and his colleagues at the Broad institute, MIT, and Harvard, collectively known as the Broad cross-appellants.

A basic aspect of the pending dispute is who first invented (to a satisfactory degree, under patent law) a CRISPR system that could work in eukaryotic cells. Recall from high school biology that prokaryotic cells do not have a nucleus, but eukaryotic cells do. The former are generally earlier on the evolutionary scale and thus less complex, but the two types of cells nonetheless have many common systems and features.

CVC filed its patent application describing the CRISPR-Cas9 complex and claiming its use in eukaryotic cells earlier than Broad, but Broad filed a patent application with experimental results in eukaryotes earlier than CVC. CVC also asserted an earlier invention date (through conception and reduction to practice). The case to be argued this week at the Federal Circuit concerns the Patent Trial and Appeal Board’s (PTAB’s) interference decision, which awarded priority of the invention’s use in eukaryotic cells to Broad. (Note that this is not the first CRISPR dispute to reach the Federal Circuit).

CVC’s CRISPR patents are being challenged in multiple patent tribunals, in the United States, Europe, Japan, and China. Intriguingly, the PTAB is the only patent office thus far to rule against CVC’s patents for the eukaryotic CRISPR system. As described below, the challenges in the other three fora have generally been in CVC’s favor.

The disparate outcomes may offer the Federal Circuit a reason to account for harmonization considerations when it hears oral argument. While harmonization is not front-and-center of the appeal—and was not expressly briefed by the parties—the Court may still want to ask why the PTAB was the apparent outlier as the only adjudicator thus far to rule against the Nobel Prize winners.

Harmonization Across Nations Can Improve Biotechnology Innovation

Harmonization of patent laws advances goals of incentivizing and enabling innovation, especially in the areas of potentially lifesaving, life-altering technologies. For instance, in August 2011, then-Director Kappos outlined the importance of patent law harmonization:

“Harmonization—the alignment of laws and procedures among intellectual property (IP) systems to ensure consistency and clarity of rights for the world’s innovators—is a prerequisite to maximizing the development and dissemination of innovation and thereby improving quality of life for all the world’s people.”

David J. Kappos, The Time Is Now, Landslide 16-17 (July/Aug. 2011).

The America Invents Act (AIA) was another effort to harmonize U.S. patent law with the law of other nations. As the USPTO stated: “The [AIA] paves the way for greater patent harmonization-the alignment of laws and procedures among intellectual property systems to ensure consistency and clarity of rights for the world’s innovators.”  U.S. Patent and Trademark Office, Harmonization: The Time is Now (last modified Oct. 31, 2019).

Before the AIA, the “IP5” was advancing harmonization efforts. Founded in 2007, the IP5 includes the European Patent Office (EPO), U.S. Patent and Trademark Office (USPTO), the Japan Patent Office (JPO), the Korean Intellectual Property Office (KIPO), and the National Intellectual Property Administration of the People’s Republic of China (CNIPA), the five largest patent offices in the world.

Even earlier, the biotechnology industry was identified as an area where global harmonization efforts are important considerations. See, e.g., National Research Council, Global Dimensions of Intellectual Property Rights in Science and Technology 319 (1993).

The Non-Harmonized CRISPR Results

With a broad consensus for harmonizing patent law to better enable innovation, an intriguing aspect of the ongoing CRISPR litigation is how the PTAB reached a different decision compared to the other patent offices. While there should be no expectation of identicality among the disputes, one must wonder how the PTAB reached a decision at odds with the decisions in the EPO, Japan, and China.

Take the EPO oppositions. There, the Opposition Division made several conclusions recognizing that perfect predictability is not required when describing and claiming pioneering and groundbreaking technology. In one decision, the Opposition Division expressly concluded that CVC’s patent “enables Cas9-mediated and sgRNA-directed cleavage of DNA in cells including eukaryotic cells.”  In doing so, the Opposition Division noted that “[e]nablement is met when it is plausible that cleavage can be achieved at all i.e. irrespective of its efficiency” and that “[e]fficiency of the system however is not to be confounded with the plausibility of it being realisable.” See, e.g., ’811 Opp. at 25, ¶ 36.1.2.20.

In another decision, the Opposition Division was also persuaded by “[t]he fact that shortly after the date of filing of [CVC’s patent application],” “different scientific groups were able to implement the CRISPR/Cas system in eukaryotic cells.” That fact was, according to the Opposition Division, “further proof that there was no undue burden involved.”

In contrast, the PTAB appears to have considered the same or similar evidence but concluded that the CVC group had not done enough to establish priority to its earliest-filed patent application. As one example, the PTAB found CVC’s patent application “did not disclose specific instructions or conditions necessary for CRISPR-Cas9 activity in a eukaryotic cell, or indicate that no specific instructions or conditions were necessary.”

Beyond the EPO decision, CVC has prevailed in disputes in China and Japan. As reported in April of this year, “China’s patent and trademark office has upheld a key patent within the portfolio of CRISPR/Cas9 intellectual property belonging to [CVC].”  China’s decision follows the December 2023 decision by the Japan Patent Office, which upheld a CVC-filed patent also with eukaryotic CRISPR claims.

How Will the Federal Circuit Address Harmonization Concerns?

There are, of course, many more relevant facts than the few highlighted here. Furthermore, the decisions in Europe, China, and Japan are subject to appeal and thus not final. Those decisions nonetheless underscore that the PTAB, thus far, is the outlier in how it views the CRISPR inventorship dispute—which sets the stage for some intriguing questions on appeal.

First, why is the PTAB standing alone? It’s possible that differences in evidence are to explain, although that seems unlikely to be a dispositive basis. Both sides have some of the best patent attorneys and litigators involved in the various disputes, and the key evidence appears very similar.

Perhaps the differential outcomes flow from the increasingly stringent written-description and enablement requirements under 35 U.S.C. § 112. It is no secret that recent decisions of the Supreme Court (Amgen v. Sanofi) and the Federal Circuit (e.g., Juno v. Kite) have intensified § 112 standards. Perhaps the inconsistent CRISPR outcomes are manifestations of an increasing chasm between U.S. enablement and written-description law and the analogous requirements under European, Chinese, and Japanese patent law.

Another question is how much of a role, if any, should harmonization and global innovation-incentivizing concerns play in the Federal Circuit’s decision-making. At the end, the patent system’s goal is to enable and incentivize innovation, and the court’s decisions should always apply that gloss to its decision-making. To be sure, global harmonization cannot be the controlling factor, but a discerning eye must examine the PTAB’s decision in light of the other major patent offices’ different conclusions.

In the end, the Federal Circuit faces a momentous decision: Affirm the PTAB’s status as an apparent international outlier—thereby denying the Nobel Prize winners—or reverse the PTAB, which can be equally challenging. The authors here take no stance on the “correct” outcome. We write mainly to highlight how this appeal has even broader implications beyond the significance of the groundbreaking technology.

Image Source: Deposit Photos
Author: vchalup2
Image ID: 147081781 

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Join the Discussion

8 comments so far. Add my comment.

  • [Avatar for Lab Jedor]
    Lab Jedor
    May 8, 2024 03:32 pm

    Ha, ha. Patent law is a completely abstract construct and there is no law of nature or some other fundamental requirement to go with “first to file.” The USA elected to go with first-to-invent in a prior version of patent protection. And yes, I liked that. I find it more reasonably protective of the interest of inventors, especially when combined with a one- year grace period. We had it in the USA. Now it is gone, under the requirement of “Harmonization.”

    I do not like the European Patent system. But the EU has to do what it thinks is best for the EU. And we have to do what we think is best for our inventors. Admittedly we currently do a lousy job, partially because of harmonization. And I really don’t want our patent system to be like the European one.

    The Framers wanted to promote innovation as articulated in our Constitution. And protecting “first-to-invent” is not an illogical consequence of that. In fact it is a very good rule that greatly benefitted the transition of the USA into an industrial powerhouse, as it allowed inventors to start businesses against established companies.

    I personally know that first-to-invent with a one year grace period is better for me, as an inventor. And the whole AIA in many regards (not only the first to file) has been a disaster.

    As cited by others and me in a co-pending post on this blog: “The real problem is the inability of patent owners to enforce their rights against infringers.”

  • [Avatar for Max Drei]
    Max Drei
    May 8, 2024 12:58 pm

    Four questions:

    1. Which patent system, First to Invent or First to File, better promotes the progress of the useful arts?

    2. How does anybody come to the conclusion that the patents clause of the US Constitution obliges The Congress to write a First to Invent patent statute?

    3. Is the AIA in conformity with the Constitution?

    4. Is there any evidence yet, that the transition to First to File is promoting the progress less effectively than the former First to Invent regime?

  • [Avatar for Max Drei]
    Max Drei
    May 8, 2024 12:51 pm

    Whoa there. Whoa. Do I see here an attempt to whip up a controversy when none is actually extant?

    In a battle over PTO priority dates between rival Applicants A and B , who says that the party that was First to Invent is inevitably the party that was first to file? What is so unsatisfactory when an interference awards the First to Invent win to Party A while at the same time the EPO awards to Party B the prize for being First to File? Being blunt: so what?

    International harmonisation first comes under threat when two leading jurisdictions differ in their conclusons which Party, as between A and B, who both rely on respective filings under the Patent Co-operation treaty, was first to file their respective application for patent protection. If I see it right, the later CRISPR filings at the USPTO were under the AIA. Forget interference practice! When any of these later filings get litigated, in the USA and in Europe, then for the first time we can talk about international harmony, or disharmony.

    Or not?

  • [Avatar for Lab Jedor]
    Lab Jedor
    May 6, 2024 11:08 pm

    A core issue here is the crazy “harmonization” sought by Congress to harmonize the previously innovation directed USA patent system with the expensive corporation focused European patent system, implemented by the AIA and further demolished by SCOTUS.

    We lost our reasonable “first-to-invent” system to the bureaucratic “gotcha” first-to-file system of the Europeans. If they want harmonization, let them harmonize with us.

    The CRISPR case exemplifies the dangers of the first-to-file. CVC was the first to invent and had reduced to practice despite earlier doubts and uncertainties by the inventors. And before Broad, but Broad was favored because of its date of filing.

    Strangely enough, the Europeans had it right in this case. And we, with our increasingly screwed up system and even though we “harmonized” have it wrong.

    Rather than pleading for “more harmonization” I vote with Anon for a system that works for us, in the context what the Framers intended.

  • [Avatar for JabberDabber7BIG]
    JabberDabber7BIG
    May 6, 2024 07:29 pm

    It seems to me that U.S. enablement jurisprudence has become increasingly hostile to inventions in the biochemical arts (e.g., inventions relating to antibodies, antibody fragments, methods of using antibodies to detect antigens and treat disease, among others). Courts can’t seem to get past the inherent unpredictability of the usual methods (even though such methods also harness that unpredictability in a systematic way). It’s true that there are significant combinatorial possibilities for how many different DNA sequences might encode a protein (or promote its production) or how many different amino acid sequences can yield an antibody that targets a particular antigen. This might astound judges, but it’s entirely normal and well known to those in the art. Most undergraduates in biochemistry learn about binding assays, microarrays, flow cytometry, antibody diversification by somatic hypermutation, protein crystal assays/screening, etc. Yet courts want a “roadmap” along with structures/examples across the entire range of what’s claimed. It’s a ridiculous (if not impossible) hurdle to clear in exchange for obtaining commercially relevant claim scope (yes, you can claim less, as multiple commentators have advised, but doing so will allow competitors access to a huge set of viable substitutes and make the R&D investment entirely unattractive ex ante).

    It seems unlikely that the Supreme Court will overrule Amgen (or its progeny at the Federal Circuit). A solution from Congress is even more unlikely. Maybe “secondary considerations” of enablement is the path forward (for now). Obviously not a panacea (see how well secondary considerations performs in the § 103 context), but it’s at least an acknowledgement of scientific/practical reality. The Opposition Division seems to have taken this approach by looking to what “different scientific groups [actually] were able to implement” without undue burden.

  • [Avatar for Anon]
    Anon
    May 6, 2024 05:01 pm

    Calls for “harmonization” are abhorrent.

    We simply do not have a “One World Order.”

    Rather – call for laws in the US to be true and proper renditions of US law. That is what should happen – nothing more, nothing less.

  • [Avatar for Pro Say]
    Pro Say
    May 6, 2024 04:10 pm

    “why the PTAB was the apparent outlier”

    Why? Wouldn’t be an innovation Death Squad if it wasn’t an outlier.

    These so-called “judges” should fire themselves for what they’re doing to America.

  • [Avatar for Kevin E Noonan]
    Kevin E Noonan
    May 6, 2024 02:27 pm

    The Court also has the option of sending the case back to the PTAB to consider the purported “derivation” argument which was not directly addressed.

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