Juno Therapeutics, Inc. v. Kite Pharma, Inc. (Fed. Cir. 2021)

By Kevin E. Noonan --

Dominating the entering gallery of the Impressionists exhibit at the Art Institute of Chicago is Georges Seurat's A Sunday on La Grande Jatte (see below).  Painted in the pointillist style, the work comprises millions of individual paint dots reminiscent of photos taken with late 20th Century technology made up of hundreds of individual photographs.  Both these examples of "from many, one" come to mind when considering the Federal Circuit's opinion today in Juno Therapeutics, Inc. v. Kite Pharma, Inc., wherein the Court overturned a jury's factual determination that Kite had not shown by clear and convincing evidence that the asserted claims were invalid for failure to satisfy the written description requirement of 35 U.S.C. § 112(a).  As a consequence, the Court also vacated a $1.2 billion judgment to Juno Therapeutics.

The case arose over Juno's allegations that Kite infringed claims 3, 5, 9, and 11 of U.S. Patent No. 7,446,190 by "the use, sale, offer for sale, or importation of [Kite's] YESCARTA®" product; claim 1 is representative (although the opinion is directed to grounds of invalidation for all asserted claims):

1.  A nucleic acid polymer encoding a chimeric T cell receptor, said chimeric T cell receptor comprising
    (a) a zeta chain portion comprising the intracellular domain of human CD3 ζ chain,
    (b) a costimulatory signaling region, and
    (c) a binding element that specifically interacts with a selected target, wherein the costimulatory signaling region comprises the amino acid sequence encoded by SEQ ID NO:6.

As explained in the opinion, the invention is related to so-called "CAR-T" anticancer therapy, wherein a chimeric targeted receptor (CAR) directed to T cells is used to stimulate a patient's immune response against tumor cells.  The components include the intracellular domain of human CD3 ζ, "a signaling domain that, when the T cell binds to an antigen, is activated to create an initial immune response."  This is linked to a costimulatory signaling region, which has a specific amino acid sequence (SEQ ID NO: 6) that is part of naturally occurring CD28 expressed in T cells.  Stimulation of this sequence enhances an immune response by, inter alia, causing T cells to multiply.  The final portion is a specific binding element that binds to an antigen expressed by a target cell such as a tumor.  A nucleic acid encoding CAR is introduced into a patient's T cells after isolation from the patient and then returned, wherein these altered T cells specifically bind to the tumor cell, causing multiplication of these tumor-specific T cells and resulting in tumor cell death.

A species of the specific binding element at issue in this case is a single chain antibody variable fragment or scFv, produced by linking together antigen-binding portions of the heavy and light chain of an antibody's variable region to form the binding element.  Important to the Court's decision, "[e]ach variable region has a unique amino acid sequence that can dictate whether and how an antibody, and thus an scFv, binds to a target."  The '190 patent specification discloses only two such svFvs, one that binds CD19 (a protein expressed on the cell surface of diffuse large B-cell lymphoma cells) and one that binds to PSMA, an antigen that is expressed at the cell surface of prostate cancer cells.  The specification does not disclose the amino acid sequence of either of these scFvs.

A jury determined that Kite had not shown by clear and convincing evidence that Juno's asserted claims were invalid under the written description requirement of § 112(a) and the District Court denied Kite's motion for judgment as a matter of law directed at overturning this verdict.  This appeal followed.

The Federal Circuit reversed in an opinion by Chief Judge Moore, joined by Judges Prost and O'Malley.  While the opinion is based on several Federal Circuit opinions rendered in this century, the fundamental (doctrinal) basis for the decision is the Court's opinion in Regents of the Univ. of Cal. v. Eli Lilly & Co.:

A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials.

119 F.3d 1559, 1568 (Fed. Cir. 1997) (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)).  (It will be recalled that this decision stemmed from a time when isolating a gene was if not herculean then at least a daunting experimental task, fraught with unpredictability with regard to the similarity between a gene isolated from one organism (in the Lilly case, the gene encoding rat insulin) compared with another (human insulin).  The Court prudently ruled it improvident to hold that a party should be able to claim the undiscovered nucleic acid based on success in discovering a different one.  This factual predicate has not existed for almost a generation.)

The panel agreed with Kite's contention that "the '190 patent discloses neither representative species nor common structural features of the claimed scFv genus to identify which scFvs would function as claimed," because:

[T]he claims cover an enormous number (millions of billions) of scFv candidates, only a fraction of which satisfy the functional binding limitation for any given target, and that the written description does not meet the written description requirement for this functional binding limitation [and] the scFv field is unpredictable since an scFv's binding ability depends on a variety of factors.

The opinion assesses the failure to satisfy the written description requirement for dependent claims 3 and 9, which the Court properly identifies as "[t]he broadest asserted claims."  These claims recite scFv binding elements that "specifically interact[] with a selected target."  The specification discloses that "[t]he target . . . can be any target of clinical interest to which it would be desirable to induce a T cell response" (emphasis in opinion), or as the opinion paraphrases "any scFv for binding any target."  (Rarely has a validity kiss of death been stated in fewer words.)  The opinion states in this context that the written description "fails to provide a representative sample of species within, or defining characteristics for, that expansive genus," i.e., utterly fails to satisfy the Eli Lilly test for satisfying the written description requirement.

The opinion then explicates the degree to which the '190 patent specification is deficient in its disclosure, being limited to two examples of this "expansive genus."  In particular, the specification designates the targets merely by their "alphanumeric designations" (i.e., providing no sequence information), while noting elsewhere that this feature is not dispositive.  The panel rejects Juno's argument that this disclosure constitutes a representative number of species of the scFv genus, if only because "there is no limit as to the particular target" encompassed by claims 3 and 9, asserting "the patent needed to demonstrate to a skilled artisan that the inventors possessed and disclosed in their filing the particular species of scFvs that would bind to a representative number of targets."

The panel was not convinced that the expert testimony Juno adduced to counter Kite's invalidity allegations was sufficient (again, disregarding factual determinations by a jury having the conventional opportunity to judge demeanor, believability, and other aspects of testimony usually kept somewhat sacrosanct within the province of the jury).  Yet the opinion is careful to distinguish its decision here from the Court's opinion in Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005), based on the error by the Board of Patent Appeals and Interference in that case to require an applicant to recite in its specification sequences "already known in the prior art."  The opinion adheres to the requirement set forth in Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), that the purpose of the written description requirement is to "lead a person of ordinary skill in the art to understand that the inventors possessed the entire scope of the claimed invention," something that the Court held Juno's specification did not do.  And the Court further rejected Juno's contention that the fact that scFvs were generally known was sufficient (this being essentially an argument sounding in enablement rather written description jurisprudence).  The Court sets forth the impossible standard they impose:

To satisfy written description, however, the inventors needed to convey that they possessed the claimed invention, which encompasses all scFvs, known and unknown, as part of the claimed CAR that bind to a selected target.  Even accepting that scFvs were known and that they were known to bind, the specification provides no means of distinguishing which scFvs will bind to which targets.

The opinion then turns to the alternative Lilly basis for satisfying the written description requirement, disclosure of common structural features, and finds the '190 specification similarly wanting.  While acknowledging that scFvs have "structural commonalities," the differences in amino acid sequences are what determine different specificities to different antigens, and thus the '190 specification "fails to disclose a way to distinguish those scFvs capable of binding from scFvs incapable of binding those targets" (emphasis in opinion).  This situation is reminiscent for the Court with the (frankly very much different) circumstances in the Ariad case, because the '190 patent is claiming a "problem to be solved while claiming all solutions to it . . . cover[ing] any compound later actually invented and determined to fall within the claim's functional boundaries."

The opinion then asserts as a basis of its recent (and philosophical twin) opinion in Idenix Pharms. LLC v. Gilead Scis. Inc., 941 F.3d 1149, 1164 (Fed. Cir. 2019), as well as the more distant (but more antibody-related) decision in AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1301–02 (Fed. Cir. 2014), for the broader principle that functional similarities are not enough to satisfy the written description requirement absent "an established correlation between the structure and the claimed function."

The opinion then turns to asserted claims 5 and 11, which recite the further limitations that the scFv bind to CD19.  This limitation does nothing to satisfy the written description requirement, the panel stating that while there are "four or five" scFvs that bind to CD19 known in the prior art, "the universe of possible sequences for scFvs is in the range of 'millions of billions'" according to Kite.  This is enough, accompanied with the total lack of any disclosure (such as "exemplary amino acid sequence") for the panel to determine that the '190 specification lacks disclosure of any general structural characteristics and thus would not be considered by the skilled artisan to show possession of the invention having the scope claimed.  The panel expressly rejects both expert and inventor testimony to the contrary, characterizing some of it as "circular reasoning" with regard to testimony that the witness was not aware of any functional CD19-specific svFv that was not functional in the CAR-T context.  At most, the panel was willing to concede that the "invention" was the "backbone" comprising the combination of the intracellular domain of human CD3 ζ and the costimulatory sequence identified by SEQ ID NO: 6.  But, of course, satisfaction of the written description requirement for these claims requires all components of the claimed invention to be sufficiently disclosed, and the deficiencies in disclosure of the svFv portions was enough to invalidate all asserted claims.

To continue the artistic analogy, the situation with all antibody-related claims (and in truth a great many chemical claims; see Idenix) is that there are sufficiently large combinatorial universes of species that only a vanishingly small number of them are (or practically can be) disclosed in a specification, like only dozens of the millions of paint dots making up Seurat's masterpiece.  Under these conditions, the painting would be rendered as something perhaps more akin to Jackson Pollack's work, and the picture produced thereby lacking entirely the characteristics that have made it a masterpiece.  Returning to patent law, the scope of claims relating to antibodies (and soon perhaps more mundane chemical species) will likely be limited to a "what you see (i.e., disclose expressly) is what you get (patented)" model, which will no doubt (by reducing valid claim scope) allow copyists to piggyback on others' inventions to make their own competing species of valuable therapeutic agents.  This will likely increase the universe of potential commercial embodiments for antibody-related inventions; whether first mover advantages will be enough to make advantageous commercialization by inventors and their companies is another question.

Juno Therapeutics, Inc. v. Kite Pharma, Inc. (Fed. Cir. 2021)
Panel:  Chief Judge Moore and Circuit Judges Prost and O'Malley
Opinion by Chief Judge Moore

Comments

[skeptical]

I am somewhat surprised that no one (yet) has offered up the 'solution' to the underlying "uncertainty" (based on the art being a so-called unpredictable art), that with AI, the degree of unpredictability more approaches the vanishingly small levels more often associated with the computing arts.

(not that such avoids OTHER potential issues)

[Greg DeLassus]

“[T]he scope of claims relating to antibodies (and soon perhaps more mundane chemical species) will likely be limited to… what you… disclose expressly…, which will… allow copyists to piggyback on others' inventions to make their own competing species of valuable therapeutic agents.”

That depends on FDA law. If the FDA insists on strict molecular identity of a candidate for biosimilar approval, then even a narrow “picture” claim will prevent generic competition. If the FDA takes a more loosy-goosey view of what counts as “biosimilar,” however, then this stricter standard for patent enforceability will—as you say—make generic competition much more vigorous.

I have asked dozens of FDA lawyers by now how they read the law and regulations around “biosimilarity” on this point. Is strict molecular identity necessary (as it would be for a bioequivalence analysis) or not? They all tell me the same thing—no one knows yet. We will have to wait for a biosimilar candidate to bring this question into live contention.

[Kevin E Noonan]

Greg; agreed unless competitors are willing to file independent BLAs which, according to how lucrative the market is, may not be out of the question. Particularly if FDA takes the stringent position on amino acid sequence.

Thanks for the comment

[Disappointed]

Mr. Noonan's analogy to pointilism and abstract expressionism is particularly apt, but he is too kind. The panel's result was correct, no doubt. But the opinion is so randomly pixelated with unequivocal contradictions and bizarre syllogisms that practitioners are left no better off in predicting the outcome of written description questions in biopharmaceutical claims. The lost opportunity to clarify the Court's written description jurisprudence is now almost characteristic. Unnecessary commentary in this opinion assures that sophisticated (in the Greek sense) lawyers will use this decision to support precisely the opposite of its apparent holding. How sad. A proper treatment of this opinion would take many pages. But I won't add to the muck. I'll remain optimistic that the future might bring light, even if through a glass darkly, to the written description problem in biological practice.

[Kevin E Noonan]

The problem, Disappointed, is that this IS the state of written description jurisprudence on the Court, one that is very unlikely to change (the Supreme Court will never take a written description case, if only because the exquisitely factual nature of the inquiry is outside their purview of rendering broad-brush interpretations of the proper scope of Congress's patent power). The only answer, as it always has been, is to determine ways to provide claims having proper scope while avoiding written description-based invalidity.

For antibody claims per se, as Greg noted above, this may be limited to therapeutic antibodies that rely on FDA regulations requiring identical amino acid sequences in biosimilars products (although the Federal Circuit's rejuvenated doctrine of equivalents decisions suggest that simple changes in amino acid sequence, like substituting all the valines for isoleucine or vice versa) might give some comfort. The scope problem can be limited (with regard to the "billions and billions" rhetoric) by defining antibodies by their CDRs, which provide somewhat less opportunity for mischief.

Another possibility is claiming the antigenic specificity as an inherent property (analogous to ways Sec 101 challenges may be avoided in diagnostic methods tied to particular treatments). In this case, for example, the claim could read:

1. A T cell or progeny thereof that specifically binds a tumor-specific antigen expressed at a tumor cell surface, the T cell having been genetically engineered to comprise a nucleic acid encoding a chimeric T cell receptor [or a polypeptide if that is more appropriate], said chimeric T cell receptor [or simply] comprising
(a) a zeta chain portion comprising the intracellular domain of human CD3 ζ chain, and
(b) a costimulatory signaling region,
wherein the costimulatory signaling region comprises the amino acid sequence encoded by SEQ ID NO:6.

There might be an issue with utility but that law is perhaps more certain than written description case law.

My point is that the "clever draftsperson" Justice Breyer warned against in Mayo is alive and well and always will be. Sometimes patent law reminds me of all those English rules from various cases that illustrate clever ways the nobles attempted to avoid having to pay taxes to the King; at other times, Whack-A-Mole.

But in any case I think this is how the cases will shake out, the Federal Circuit evincing no inclination to change the deleterious effects their decisions are having on innovation in the biotechnology space.

[skeptical]

Sadly, not only do I concur with the statement of, "My point is that the "clever draftsperson" Justice Breyer warned against in Mayo is alive and well and always will be" - but the broader point in a member of the Judicial Branch USING that statement as an excuse for the ultra vires usurping of the Constitutional delegation of authority to WRITE patent law will ALSO remain "alive and well" until enough people take note and rise the cry as to the mess created BY the Supreme Court and their fervent desire to keep their fingers in the wax nose of patent law.

The Supreme Court COULD remove themselves from their own created Gordian Knot (through the use of the Kavanaugh Scissors), but that just does not seem likely.

We are left then with waiting for someone in Congress with enough gumption to eradicate the mess created by the Court, reset eligibility (and with that, other collateral messes such as 112 and 103, not to mention reinvigorating the very nature of the patent right and that negative nature through restoration of injunctive remedy as a DE FACTO best restoration of an aggrieved patent holder), REMOVE the Supreme Court through jurisdiction stripping (seeing as patent cases do NOT fall to the original jurisdiction of the Supreme Court), and cap it off by eradicating and resetting a NON-whipped patent court to replace the very-whipped Court of Appeals for the Federal Circuit.

I fear that ONLY upon these events, will we put an end to the (current) endless circus, and once again place US Patent Law as the gold standard in protecting innovation.

[Greg DeLassus]

“… unless competitors are willing to file independent BLAs…”

Sure, that amounts to possible competition, but not the sort that should make a biological innovator lose much sleep. (1) A competitor who would file an independent BLA must do the clinical trials. That takes several years, during which the original innovator has the field exclusively. (2) The cost of the independent BLA also means that the new market entrants have serious capital costs to recoup (unlike a traditional generic), so their ability to undercut the original innovator’s price is fairly constrained.

In other words, this new state of §112[a) law is not a significant threat to biological innovation *if* the FDA insists on strict molecular identity for biosimilars. Whether FDA will do so, however is anyone’s guess.