Just last week the Federal Circuit affirmed the dismissal of a declaratory judgment in a patent case involving a biosimilar product. I found this case interesting for two reasons: (1) because the Court punted and failed to address the key question of whether a developer of a biosimilar must go through the complex patent infringement adjudication requirements of the Biologics Price Competition and Innovation Act (BPCIA) and (2) perhaps more interestingly, because the facts of the case suggest the FDA may be requiring full-blown Phase III human clinical trials for the approval of a biosimilar product. See Sandoz Inc. v. Amgen Inc., 2014-1693 (Fed. Cir. December 5, 2014).

For those of you not familiar with biosimilars, here is a one-paragraph primer. A biosimilar is a follow-on version of an original biological (large molecule) drug, analogous to a generic being a low-cost version of an original small molecule drug. In 1984, Congress passed the Drug Price Competition and Patent Restoration Act (commonly known as “Hatch-Waxman”) to bring low-cost prescription drug products to consumers, while balancing the competing interests of the branded pharmaceutical industry and generic drug manufacturers. Hatch-Waxman provided a unique statutory link between the patent and regulatory systems and set up a complex framework for adjudicating patent challenges by generic drug manufacturers. In 2010, the BPCIA created a similar framework for the approval and marketing of the generic equivalent of a biological drug, and for any ensuing patent challenges. This new regulatory pathway is just getting off the ground. To date, no biosimilar product has been approved for sale in the US. The first such products are expected to hit the market in 2015.

Getting back to our case, in 2013 Sandoz brought suit against Amgen and Hoffman-La Roche seeking a declaratory judgment that two patents owned by Hoffman-La Roche and exclusively licensed to Amgen are invalid, unenforceable, and would not be infringed. At issue are US Patent Nos. 8,063,182 and 8,163,522, which Amgen has identified as covering Enbrel®, its biologic product for treating rheumatoid arthritis. Sandoz is currently conducting a Phase III clinical trial in anticipation of filing for approval of a biosimilar copy and had not at the time it brought suit filed an application for approval of its product under the provisions of the BPCIA.

The District Court for the Northern District of California dismissed the case, determining no controversy existed between the parties and that the suit was barred by the adjudication provisions of the BPCIA. On appeal, the Federal Circuit affirmed, stating that “Sandoz did not allege an injury of sufficient immediacy and reality to create subject matter jurisdiction.” The Court went on to state that “[w]e do not address the district court’s interpretation of the BPCIA”, thereby leaving us to speculate how the Court will deal with future biosimilar litigation.

To market its biosimilar version of Enbrel®, Sandoz needs regulatory approval. In 2010, Sandoz initiated discussions with the FDA on its development plan for its biosimilar product. Even though the BPCIA established an abbreviated regulatory approval process for such a biosimilar, Sandoz eventually announced in 2013 that it had commenced a large-scale Phase III clinical trial for its product. In fact, this announcement by Sandoz was made on the very same day it brought suit for declaratory judgment against Amgen.

Must suit be brought in accordance with the BPCIA?

As stated above, in its reasons for affirming the District Court’s dismissal of the suit for a declaratory judgment, the Court failed to address whether such a controversy must be brought within the framework set up by the BPCIA. Rather, the Court focused on whether there was a controversy based on the immediacy and reality of the situation. In its analysis, the Court determined that any dispute about patent infringement between Sandoz and Amgen was subject to too many uncertainties – e.g., Sandoz’s Phase III clinical trial might not turn out as expected, or Sandoz could change the form of the biologic drug active, or that Sandoz might even abandon its plans to file for approval at all. However, the Court did state that it would “not [at this time] address Sandoz’s ability to seek a declaratory judgment if and when it files an FDA application under the BPCIA.” Therefore, the question of whether a biosimilar developer can attempt to get an early read on a patent infringement question via a declaratory judgment will have to wait for another day – or at least until the Federal Circuit takes on a case in which the biosimilar developer has already filed its application for approval under the BPCIA.

Is the FDA now requiring Phase III clinical trial data for a biosimilar?

Even though it has long been appreciated that the development and testing requirements for a follow-on biologic would be more stringent than for a generic copy of a small molecule drug, this recent case now suggests that the FDA may be requiring a much more stringent development plan than many had originally thought.

For example, generic copies of small molecule drugs do not need to be identical to their reference drug products. The key pharmacokinetic parameters for small molecule generics need only be within the range of a 90% confidence interval of 80-125% compared to the reference drug. Yes, it is recognized that biologics and their biosimilar copies are far more complex, and consequently more difficult to manufacture and purify than their small molecule counterparts. However, based on the background from this patent case, it seems that the testing requirements for a biosimilar may be nearly as stringent as for the original biologic. In its opinion the Court discussed Sandoz’s ongoing Phase III clinical trial and stating that “the FDA effectively required the trial” [emphasis added]. The Court added that “the biosimilarity approval standard is new . . . the FDA has not yet applied the new standard to complete its review of and approve any product under the BPCIA . . . [and that] [p]erhaps the FDA is exercising a caution that will prove excessive over time.” The Court then ends it speculation with the retraction “[b]ut we have no basis for saying so.”

Therefore, what exactly is the FDA requiring for approval of a biosimilar drug product? Is the approval bar being set excessively high? We will have to see what develops as the first biosimilars are expected to receive approval in 2015.


– Anthony D. Sabatelli, PhD, JD
Check out Anthony’s bio page


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