Material Information Submitted to FDA but Withheld from PTO Gives Rise to Inequitable Conduct

By on September 16, 2021
Posted In Patents

The US Court of Appeals for the Federal Circuit found prior art submitted to the US Food and Drug Administration (FDA), yet withheld from the US Patent & Trademark Office (PTO) during prosecution of an asserted patent, sufficient evidence for a finding of inequitable conduct. Belcher Pharmaceuticals, LLC v. Hospira, Inc., Case No. 20-1799 (Fed. Cir. Sept. 1, 2021) (Reyna, J.)

The patent in issue relates to injectable formulations of l-epinephrine. Epinephrine is a hormone that has been on the market since approximately 1938 and is used for a variety of medical purposes. It is also known that l-epinephrine degrades into a more potent isomer known as d-epinephrine. L-epinephrine also degrades into an impurity known as adrenalone through a process called oxidation.

In 2012, Belcher first submitted a New Drug Application (NDA) for a 1 mg/mL injectable l-epinephrine formulation. The NDA was literature-based, meaning that Belcher did not perform any clinical or non-clinical studies on its epinephrine formulation to support its application. Among the materials submitted to the FDA was an article by Stepensky et al to support its statement that “racemization of the enantiomerically pure L-Epinephrine isomer in injectable formulations of epinephrine is a well-known process.” It also submitted data from Swiss pharmaceutical company Sintetica SA’s formulation that had a pH range of 3.1 – 3.3 and undetectable levels of adrenalone. Ultimately, Belcher pursued a formulation with a similar pH range of 2.8 – 3.3.

In 2014, Belcher filed a patent application that was ultimately issued as the asserted patent. The patent taught that increasing the in-process pH to 2.8 – 3.3 unexpectedly reduced the racemization of l-epinephrine to d-epinephrine at release by approximately two thirds. The asserted claims covered pharmaceutical epinephrine formulations having a pH between 2.8 – 3.3 and certain concentrations of l-epinephrine, d-epinephrine and adrenalone at the time of release and 12 months later.

The prosecution of the application involved a single office action in which the pending claims were rejected in view of Helenek. The examiner explained that Helenek taught 1 mg/ml of epinephrine injection that, among other things, had a pH range of 2.2 – 5.0. Belcher overcame this rejection by arguing that Helenek did not render obvious the claimed range of 2.8 – 3.3 because the claimed range was unexpectedly found to be critical to reduce racemization of l-epinephrine.

Hospiria also submitted an NDA seeking approval of an injectable l-epinephrine formulation, which included a certification under 21 U.S.C. § 355(b)(2)(A)(iv)(Paragraph IV) that the asserted patent’s claims were invalid, unenforceable and/or not infringed by Hospira’s NDA product. Belcher subsequently sued Hospira for patent infringement.

During trial, Darren Rubin, Belcher’s Chief Science Officer, testified that in his role at Belcher, he was involved in the drafting and development of the NDA and in the prosecution of the asserted patent—including drafting the claims and specification and responding to the examiner’s office action. Darren admitted he knew of Stepensky before the application was filed and that he possessed a label for a 1 mg/mL epinephrine product marked by a company named JHP. Belcher had sent the JPH product to Sintetica for testing, which showed that the JHP product had a pH within the range of 2.8 – 3.3. The district court found that the patent was unenforceable for inequitable conduct based on three pieces of information that Darren withheld from the PTO: JHP’s product, Sintetica’s product and Stepensky. Belcher appealed.

INEQUITABLE CONDUCT

At issue is whether Darren’s conduct amounts to inequitable conduct, which if proven, would render the asserted patent unenforceable. To prevail on an inequitable conduct defense, a defendant must establish both materiality of the withheld reference and the applicant’s intent to deceive the PTO.

Materiality. A prior art reference may constitute material information if the PTO would not have allowed a claim had it been aware of the undisclosed prior art. Here, the Federal Circuit found that the withheld information was material. For one, Belcher did not challenge the district court’s decision that the asserted claims were invalid as obvious based on JHP’s epinephrine product. The Court noted that if a claim is properly invalidated in district court based on the deliberately withheld reference, then that reference is necessarily material. Further, the Court rejected Belcher’s argument that the withheld art, including the JHP product, is immaterial because it was cumulative of Helenek’s disclosure. The Court noted that this argument was directly at odds with its own argument during prosecution that the claimed range was “critical” to the invention. The trial record later established that the JHP product had a pH within the alleged critical range of 2.8 – 3.3. Belcher’s alleged critical improvement over the prior art was therefore already within the public domain, just not before the examiner.

Intent. The Federal Circuit found no clear error in the district court’s finding of intent. First, the district court found Darren’s reasons for withholding the JHP product to be implausible and not credible. Darren claimed at trial that he withheld the references because he believed they were irrelevant because they differed from the asserted claims in certain respects—including their high overages. The Court rejected Rubin’s assertion of no deceptive intent, noting that his reasons for withholding directly undercut Belcher’s most important patentability argument. The district court also relied on other record evidence to support its finding of intent, including Darren’s prior knowledge of the JHP product, his central role in both the FDA approval and patent prosecution and his arguments to the examiner about the “criticality” of the 2.8 – 3.3 pH range despite knowing that Sintetica’s batches used the same range.

Amy MahanAmy Mahan
Amy Mahan focuses her practice on intellectual property matters in the life sciences, pharmaceutical and biotechnology sectors. She works on a variety of patent infringement litigation cases involving monoclonal antibody biologics, cell-based immunotherapies and small molecule drugs. Read Amy Mahan's full bio.

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