Case Name: Vifor Fresenius Medical Care Renal Pharma Ltd. v Teva Pharms. United States, Inc., Civ. N. 18-390 (MN), 2022 WL 3562555 (D. Del. 18 August 2022) (Noreika, J.)
Pharmaceutical product and patent(s) in overalls: Velphoro® (sucroferric oxyhydroxide); US Patent No. 9,561,251 (“the ‘251 patent”)
Nature of the case and problem(s) presented: Vifor is suing Teva after Teva filed an ANDA to market a generic version of Velphoro before the ‘251 patent expires. Teva denied infringement and argued that all of the claims made were invalid. The court presided over a four-day bench trial and ruled: that Teva’s ANDA product infringed the ‘251 patent and that the ‘251 patent was not invalid.
Why Vifor prevailed: Teva first argued that its ANDA product did not violate the limitation of the claim, “in which iron oxyhydroxide is essentially non-bioabsorbable.” The court interpreted “essentially non-bioabsorbable” to mean that “following oral administration, iron oxyhydroxide is not absorbed by the human body in a clinically significant amount.” Teva argued that in vivo testing was required to demonstrate a violation of this limitation and that bioequivalence alone was not sufficient. But Teva’s label doesn’t just show bioequivalence. Teva has told the FDA that the iron oxyhydroxide formulated in its ANDA product is not absorbed in clinically significant amounts following oral administration. The proposed label includes data from a clinical study showing that iron absorption was “pretty low and insignificant” when measured using radiolabelled sucroferric oxyhydroxide. The fact that these claims were copied from Velphoro’s package insert doesn’t matter, however, because Teva seeks approval to market a product with these attributes. In addition, Teva’s drug and product development reports also state that iron “is not available in a soluble form to be absorbed into the body.” [gastrointestinal tract].” Therefore, Teva’s ANDA product would satisfy this limitation.
The next limitation in the context of the infringement was “having an iron release rate of less than 2.5% w/w”. The court interpreted this limitation as “the release of iron measured in water at a pH of 3 according to chapter 2.9.3 of the European Pharmacopoeia using standard dissolution equipment and parameters as described in the monograph, where the iron content is analyzed by titration after 2 hours, in which the amount of dissolved iron after 2 hours is less than 2.5%.At the trial, the Vifor expert testified that he tested six tablets.The iron release rate was measured at a pH ranging from 3.22 to 3.28 in the six tablets of Teva’s ANDA product, with an average pH of 3.25.Teva disputed these results on the grounds that they were not conducted “at a pH of 3” and that the Vifor expert never tested Teva’s product at an initial pH of 3 because he adjusted the pH to 2.31 before adding the ANDA product tablets to the test medium.Given Federal Circuit jurisprudence, the construction of the court “to a pH of 3” encompasses a pH range of 2.5 to 3.4 using basic rounding. If more precision were required, a POSA would expect to see further significant digits stated explicitly, such as “3.0”, not “3”. Regarding the pH adjustment, the Vifor expert explained that EP 2.9.3 is a dissolution test but, before the dissolution started, disintegration of the tablets occurred and this affected the pH of the medium. To account for this, the Vifor expert adjusted the pH before adding the tablets so that the pH with the tablets was 3 during dissolution and when iron release was measured as required.
The court then addressed Teva’s disability defenses. Each of the asserted claims calls for a “pharmaceutical composition” with “at least 500 mg” of iron oxyhydroxide “per pharmaceutical form”. Teva has failed to demonstrate that the claimed “dosage form” of “at least 500 mg” would have been obvious for a POSA at the time of invention in light of the ‘442 prior art patent. The ‘442 patent describes a “daily dose of the absorbents according to the invention is, for example, 1 to 3 g, preferably about 1.5 g of iron”. The ‘442 patent does not teach how the daily dose would be administered (i.e., as a single dosage form or across multiple dosage forms) or whether the daily dose would be different for the phosphate binders given in the ‘442 patent examples. Teva’s argument that the general knowledge of a POSA would fill in the blanks was also rejected. “Even if the Court were satisfied that a POSA would understand that the ‘daily dose of … 1.5 g of iron’ of the ‘442’ patent would be administered as three 500 mg doses, the defendant still has to demonstrate with clear and convincing evidence that each 500 mg dose would be packaged in a single “dosage form”.
Reference to Hergesell’s prior art, in combination with the ‘442 patent, did not yet make the patent in question apparent. According to Teva, Hergesell “confirmed the general practice of administering the phosphate binder 3 times a day with meals.” The court was not convinced. Hergesell did not refer to formulations of iron oxyhydroxide comprising sucrose. Therefore, a POSA would not look to Hergesell’s teachings regarding dosages in their analysis of the obviousness of Example 1 of the ‘442 patent. Hergesell only teaches “a constant dose of 3 × 2.5 g of stabilized polynuclear iron hydroxide … supplied as a powder in pre-weighed sachets”. Therefore, a POSA would not understand how much powder was in each sachet (i.e., 10 sachets containing 250 mg with each 2.5 g dose, or one sachet containing 2.5 g) or how much iron oxyhydroxide would be included per 2.5 g.
The court also ruled that Velphoro filled a long-felt but unmet need and enjoyed some commercial success, both of which lend further support to the non-obviousness finding.