IP Law Daily Preliminary injunction against generic producer of lymphatic imaging dye affirmed
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Friday, May 19, 2017

Preliminary injunction against generic producer of lymphatic imaging dye affirmed

By Mark Engstrom, J.D.

The U.S. Court of Appeals for the Federal Circuit has affirmed a preliminary injunction prohibiting Indian drug maker Aurobindo Pharma Ltd. and two affiliates from making, using, selling, offering to sell, and importing a lymphatic imaging agent called isosulfan blue ("ISB"), which allegedly infringed three Apicore patents that were licensed to Mylan Institutional. Although the district court had erred in granting an injunction under two of the asserted patents, it correctly granted one under the third patent (Mylan Institutional LLC v. Aurobindo Pharma Ltd., May 19, 2017, Lourie, A.).

Lawsuit, invention. Apicore US and Mylan Institutional sued Aurobindo Pharma Ltd., Aurobindo Pharma USA Inc., and Auromedics Pharma LLC (collectively, "Aurobindo") for the infringement of U.S. Patent Nos. 7,622,992; 8,969,616; and 9,353,050. The patents disclosed a triarylmethane dye (ISB) for the mapping of lymph nodes. The ’992 and ’616 patents ("the process patents") were directed to a process for preparing ISB by reacting isoleuco acid with silver oxide in a polar solvent, followed by reaction with a sodium solution. The ’992 patent required 2.0–3.0 equivalents of silver oxide. The ’050 patent (the "purity patent") was directed to an ISB compound with a purity that exceeded 99.0 percent, as measured by high performance liquid chromatography (HPLC).

Around 1981, Hirsch Industries developed a one-percent injectable solution of ISB, which it commercialized under the trade name Lymphazurin. Hirsch’s successor-in-interest, Covidien Ltd., held the original new drug application (NDA) and was the sole supplier of Lymphazurin for 30 years.

In 2003, Apicore decided to develop an improved process for synthesizing ISB. In 2004, it partnered with Mylan’s predecessor, Synerx Pharma, to develop and market a generic version of Lymphazurin. In 2007, Apicore filed a patent application that ultimately led to the ’050 patent and the process patents. Based on the claimed process, Synerx filed an abbreviated new drug application (ANDA) for generic Lymphazurin, and the FDA approved the ANDA in 2010. By 2011, ISB sales were a significant portion of Apicore’s revenue, and in 2012, Covidien withdrew Lymphazurin from the market for "reasons other than safety or effectiveness." Mylan became the sole supplier of the one-percent ISB product until 2016, when Aurobindo entered the market.

Aurobindo sought FDA approval for a generic version of Lymphazurin and informed the FDA that it had studied a "number of patents" that described ISB manufacture, had selected Apicore’s ’992 patent, and had "considered the process" that was described therein "for the initial sample preparation" and the "optimization of the process." In addition, Aurobindo acknowledged that it was looking for a reagent "other than silver oxide."

Aurobindo eventually selected manganese dioxide, and its process resulted in ISB with a five to ten percent impurity that could not be removed by recrystallization. Aurobindo thus used a preparatory HPLC to achieve an ISB purity of greater than 99.5 percent. Mylan sued Aurobindo for patent infringement and sought a preliminary injunction, which was granted by that district court. Aurobindo appealed.

The process patents. The court had to determine whether the district court had erred in finding that Mylan was likely to succeed on the merits because Aurobindo "more likely than not" infringed the process patents under the doctrine of equivalents. In the appellate court’s view, the district court’s equivalence analysis was flawed because of the "sparse and confusing case law regarding equivalents," particularly the paucity of chemical equivalence case law and the difficulty of applying the legal concepts to the facts.

In evaluating the equivalence issue, the district court applied the function-way-result ("FWR") test, which determined whether the accused product performed "substantially the same function in substantially the same way to obtain the same result." The appellate court reviewed the district court’s decision in that light, and in doing so, concluded that the lower court’s analysis of the process claims under the FWR test was "flawed" because it was "unduly truncated and hence incomplete."

Aurobindo argued before the district court that the "function" prong of the FWR test was not met given the difference in oxidation strength between silver oxide and manganese dioxide. The district court did not address that argument, which in actuality related to the "way" component of the FWR test, but it found that silver oxide and manganese dioxide were "equivalent" without considering the "way" prong of the FWR test. In fact, the lower court "appeared to consider the relative oxidation strengths of silver oxide and manganese dioxide as a consideration for claim construction, rather than its equivalents analysis."

According to the Federal Circuit, either the district court did not address the "way" prong of the FWR analysis (having considered the relative oxidation strengths to be an issue for claim construction and rejecting Aurobindo’s arguments about oxidation strength because it had not argued for a narrow claim construction) or it performed a "way" analysis without considering critical factors under that prong—the relative oxidation strengths of silver oxide and manganese dioxide, as well as the use of an acid in the accused process. Either characterization constituted an error in the court’s equivalents analysis, the Federal Circuit concluded.

Because the district court had erred in its equivalents analysis under the FWR test, the Federal Circuit reversed that portion of the decision and directed the lower court to consider whether an evaluation of equivalence under the "substantial differences" test would be more appropriate. The substantial differences test determined whether an accused product or process was "substantially different" from the patented invention.

The ’050 patent. The court had to determine whether the district court had erred in finding that Aurobindo failed to raise a substantial question regarding the validity of the ’050 patent. Because Aurobindo did not appeal the finding that it "more likely than not" infringed the ’050 patent, the preliminary injunction premised on the ’050 patent would stand unless: (1) Aurobindo raised a substantial question regarding patent’s validity or (2) the district court erroneously found irreparable harm. The Federal Circuit concluded that the district court did not err in either respect.

Aurobindo identified no legal error in the district court’s analysis of the record evidence, the Federal Circuit noted. Instead, it argued that the court had erred in "misreading the factual content of the prior art." However, the teaching of the prior art was a question of fact that the appellate court reviewed with deference, especially at the preliminary injunction stage. It did not reweigh the evidence on appeal.

The Federal Circuit found no error in the district court’s analysis. Significantly, the appellate court had previously acknowledged that a purified compound was "not always prima facie obvious over the [prior art] mixture" if the process to arrive at that compound was itself of patentable weight. Further, if the prior art taught a mixture containing a compound but did not enable its purification, the purified form of the compound might not have been obvious over the prior art mixture.

In this case, the record clearly showed that, although ISB was known in the prior art, the path to arrive at ISB with a purity that exceeded 99.0 percent was not known before the relevant date of the ’050 patent. In fact, the record showed that, prior to the relevant date, a reliable source of high-purity ISB was so scarce that, at one point, Covidien was forced to notify its customers that it was "completely out of" Lymphazurin until it could find a new ISB supplier.

Finally, the Federal Circuit found no error in the district court’s finding that the ’050 patent was likely not invalid as indefinite. That finding was supported by substantial record evidence, the Federal Circuit explained, including the scientific literature and other patents that reported purity using the same "by HPLC" designation without providing specific HPLC parameters.

Ultimately, the appellate court concluded that the district court did not err in its legal analysis or its factual findings regarding the validity of the ’050 patent, particularly at the preliminary injunction stage of the litigation.

Irreparable harm. The district court did not err in concluding that Apicore would likely sustain a "substantial and immediate irreparable injury" in the absence of preliminary relief. According to the Federal Circuit, the district court made a reasoned factual determination that was supported by substantial record evidence.

Because the Federal Circuit found no error in the district court’s finding that Apicore would be irreparably harmed absent preliminary relief, and further found no error in the lower court’s finding that Aurobindo had not raised a substantial question of validity regarding the ’050 patent, the preliminary injunction premised on the ’050 patent was affirmed.

The case is No. 2017-1645.

Attorneys: Nicole W. Stafford (Wilson, Sonsini, Goodrich & Rosati, PC) for Mylan Institutional LLC. Joanna Garelick Goldstein (Sharma & DeYoung LLP) for Apicore US LLC. Sailesh K. Patel (Schiff Hardin LLP) for Aurobindo Pharma Ltd., Aurobindo Pharma USA Inc., and Auromedics Pharma LLC

Companies: Aurobindo Pharma Ltd.; Aurobindo Pharma USA Inc.; Auromedics Pharma LLC; Mylan Institutional LLC

MainStory: TopStory Patent FedCirNews

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