Case Name: Vifor Fresenius Medical Care Renal Pharma Ltd. v. Teva Pharms. USA, Inc., Civ. No. 18-390 (MN), 2022 WL 3562555 (D. Del. Aug. 18, 2022) (Noreika, J.)
Drug Product and Patent(s)-in-Suit: Velphoro® (sucroferric oxyhydroxide); U.S. Patent No. 9,561,251 (“the ’251 patent”)
Nature of the Case and Issue(s) Presented: Vifor sued Teva after Teva filed an ANDA to market a generic version of Velphoro prior to the expiration of the ’251 patent. Teva denied infringement and argued that all asserted claims were invalid. The court presided over a four-day bench trial and found: 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 infringe the claim limitation, “wherein the iron oxy-hydroxide is essentially non-bioabsorbable.” The court construed “essentially non-bioabsorbable” to mean “upon oral administration, the iron oxyhydroxide is not absorbed by the human body in a clinically significant amount.” Teva argued that proving infringement of this limitation required in vivo testing and that bioequivalence alone was not sufficient. But Teva’s label does more than show bioequivalence. Teva represented to the FDA that, upon oral administration, the iron oxyhydroxide formulated in its ANDA product is not absorbed in clinically significant amounts. Its proposed label includes data from a clinical trial showing that iron uptake was “quite low and insignificant” when measured using radio-labeled sucroferric oxyhydroxide. That these statements were copied from the Velphoro package insert was of no moment, however, because Teva seeks approval to market a product having these attributes. Moreover, Teva’s pharmaceutical and product development reports also stated that the iron is “not available in soluble form to be absorbed in the [gastrointestinal tract].” Therefore, Teva’s ANDA product would meet this limitation.
The next limitation in the infringement context was “having an iron release rate of below 2.5% w/w.” The court construed this limitation to mean “the iron release measured in water at a pH of 3 according to European Pharmacopeia chapter 2.9.3 using standard dissolution equipment and parameters as described in the monograph, where iron content is analyzed by titration after 2 hours, wherein the quantity of iron dissolved after 2 hours is less than 2.5%.” At trial, Vifor’s expert testified to testing six tablets. The iron release rate was measured at a pH that ranged from 3.22 to 3.28 across the six tablets of Teva’s ANDA product, with an average pH of 3.25. Teva contested these results on the grounds that they were not conducted “at a pH of 3” and that Vifor’s expert never tested Teva’s product at a starting pH of 3 because he adjusted the pH to 2.31 prior to adding the ANDA product tablets to the test medium. Given Federal Circuit case law, the court’s construction “at a pH of 3” comprises a pH range of between 2.5 to 3.4 using basic rounding. If greater precision were required, a POSA would expect to see additional significant figures explicitly stated, i.e. “3.0,” not “3.” Regarding the pH adjustment, Vifor’s expert explained that EP 2.9.3 is a dissolution test but, before dissolution began, disintegration of the tablets occurred and that affected the pH of the media. To account for this, Vifor’s expert adjusted the pH prior to the addition of tablets so that the pH with tablets would be 3 during dissolution and when iron release was measured as required.
The court then addressed Teva’s invalidity defenses. Each of the asserted claims requires a “pharmaceutical composition” with “at least 500 mg” of iron oxy-hydroxide “per dosage form.” Teva failed to prove that the claimed “dosage form” of “at least 500 mg” would have been obvious to a POSA at the time of the invention in view of the prior art ’442 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 provided in the examples of the ’442 patent. Teva’s argument that a POSA’s general knowledge would fill in the blanks was also rejected. “Even if the Court were convinced that a POSA would have understood that the ’442 patent’s ‘daily dose of ... 1.5 g of iron’ would be administered as three 500 mg doses, Defendant still must show by clear and convincing evidence that each 500 mg dose would be packaged in a single ‘dosage form.’”
The Hergesell prior art reference, in combination with the ‘’442 patent, still did not render the patent-in-suit obvious. According to Teva, Hergesell “confirmed the general practice of administering phosphate binder 3 times per day with meals.” The court was not convinced. Hergesell did not refer to iron oxy-hydroxide formulations comprising saccharose. Therefore, a POSA would not look to the teachings of Hergesell regarding dosages in their obviousness analysis of Example 1 of the ’442 patent. Hergesell only teaches “a constant dose of 3 × 2.5 g stabilized polynuclear iron hydroxide ... provided as a powder in pre-weighed sachets.” Thus, a POSA would not understand how much powder was contained in each sachet (i.e., 10 sachets including 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 further found that Velphoro satisfied a long-felt but unmet need and has enjoyed some measure of commercial success, both of which provide further support the finding of non-obviousness.