CAFC Affirms Lack of Enablement Ruling Due to Gaps in Specification Requiring Undue Experimentation

The U.S. Court of Appeals for the Federal Circuit (CAFC), in a precedential decision, on Thursday affirmed a district court ruling that found certain claims of Wyeth LLC’s two patents for methods of cancer treatment invalid for lack of enablement.

Wyeth sued AstraZeneca Pharmaceuticals in September 2021, alleging that AstraZeneca induced infringement of its U.S. Patents 10,603,314 and 10,596,162 “based on marketing, distribution, and sales of its irreversible EGFR inhibitor Tagrisso (osimertinib).”

The court construed several claim terms and said the claimed methods involve “administering daily a ‘unit dosage’ of an irreversible EGFR inhibitor that covalently binds to a specific part of the enzyme.” It also determined that the specification  “expressly define[d]” a “unit dos[age],” and adopted that definition: “physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluents; i.e., carrier, or vehicle.”

A jury ultimately determined that AstraZeneca induced infringement of the claims, that the claims were not invalid, and awarded Wyeth $107,500,000 in damages. But AstraZeneca renewed its motion for judgment as a matter of law (JMOL that the claims were invalid and that no reasonable jury could have found otherwise. The district court agreed with AstraZeneca’s argument that the claims were not enabled because “identifying the unit dosage for even just a single compound is highly unpredictable and involves [a] tremendous amount of work and experimentation” and AstraZeneca had “presented unrebutted evidence that some disclosed dosage levels would be toxic, including doses required to achieve a therapeutic effect in patients,” among other arguments.

The court therefore granted AstraZeneca’s motion for JMOL, explaining that “the asserted patents ‘provide[d] ‘only a starting point, a direction for future research’ that place[d] the burden on a [skilled artisan] to conduct ‘an iterative, trial-and-error approach to practice the claimed invention.’”

On appeal, Wyeth argued that the district court “improperly changed its construction of the term ‘unit dosage’ post-verdict by imposing additional clinical safety and efficacy requirements,” as well as that its grant of JMOL fails independently, on the evidence.

Wyeth said the district court “improperly imported clinical safety and efficacy requirements into the claims because, in its view, the claims require only that the ‘unit dosage’ provide the therapeutic effect of ‘inhibiting EGFR and killing cancer cells’ full stop.” But, while it conceded the claims do not require clinical safety or efficacy standards, the Federal Circuit noted that other relevant claim terms require the claimed “unit dosage” must be “administer[ed] daily” to a human “patient,” for example. Under the district court’s adopted definition of “unit dosage,” the claims “plainly require the daily administration of a unit dosage to a patient to achieve a therapeutic effect in treating g/e-resistant NSCLC, not merely the identification of compounds capable of inhibiting EGFR activity in vitro,” said the opinion. The CAFC added that the district court specified that there are no Food and Drug Administration (FDA)-type limitations in the claims, but that it also noted that “does not necessarily mean that the claims therefore provide no meaningful limitations on dosing.”

The CAFC added that the district court’s “elaboration” on its construction post-verdict also did not constitute an improper amendment of the construction, as it was “permissible to ‘clarif[y] what was inherent in the construction.’”

Turning to enablement, the CAFC disagreed with Wyeth that “AstraZeneca failed to prove by clear and convincing evidence that the asserted claims require undue experimentation to determine a non-toxic or non-fatal unit dosage for daily administration to a patient.”

Writing for the court, Judge Lourie explained that the specification leaves it entirely up to the skilled artisan to determine the claimed “unit dosage.”

“While the knowledge of one of ordinary skill may play an important role in enablement, it may not provide the only means to enable these specific claim limitations,” Lourie wrote.

The specification fails to provide working examples of the unit dosage calculated and the three compounds provided as examples of preferred embodiments did not suffice because “the specification describes in vitro experimentation without any further description of (1) how to extrapolate in vivo dosing from those in vitro results or (2) any other teachings sufficient to allow a skilled artisan to calculate a ‘unit dosage’ as claimed.”

Ultimately, said the CAFC, those “in vitro data alone are insufficient to enable these claims.”

Wyeth pointed to the patents’ disclosure of certain studies and clinical experience as evidence that “skilled artisans would have understood that irreversible inhibitors could be administered safely and could have determined appropriate dosages without concern that patients would die,” but the CAFC said that sidesteps the issue of “whether the specification teaches how to determine the claimed therapeutically effective daily ‘unit dosage’ for the claimed compounds.”

Furthermore, while the specification does recite dosage ranges, “they are qualified as ‘general,’… and ‘projected,’…ranges, and the specification provides no further explanation of how those ranges were derived, how a skilled artisan would select among them for a given compound, or how they relate to the claimed unit dosage calculated to produce a therapeutic effect in a patient.” The skilled artisan is left to fill the gaps via “undue experimentation,” said the CAFC.

AstraZeneca also provided unrebutted evidence, and Wyeth’s own experts agreed, that the therapeutically-effective dosage levels for the compounds disclosed in the specification “far exceed the maximum tolerated dose in humans.”

“Such testimony reinforces the lack of guidance provided by the specification,” said the CAFC.

Ultimately, the opinion explained that, despite the common practice of claiming a range of doses without clinical data, these particular patents leave too much up to the skilled artisan:

“We recognize that it is accepted practice in patent law for one to be able to claim a method of treatment disclosing a range of doses to be administered, without showing actual clinical data, and leaving it to the FDA to ensure that approved products are safe and effective… The problem with these patents is that, perhaps because of close prior art, their claims are limited to dosage forms to be administered to patients, yet they disclosed only a broad range of doses some of which were shown to be toxic, and they disclosed no actual dosages for any compound within the scope of the claims, thereby leaving it to a practitioner of the claims to perform undue experimentation.”

The district court’s grant of JMOL of invalidity was thus affirmed.