The Federal Circuit published a precedential decision on September 1, 2021 regarding the unenforceability of a pharmaceutical patent due to inequitable conduct.1 In Belcher Pharmaceuticals LLC v. Hospira, Inc., the Court (Judges Reyna, Taranto, and Stoll) affirmed the decision of the U.S. District Court for the District of Delaware (Judge Leonard P. Stark) that U.S. Patent No. 9,283,197 (“the ’197 patent”) was unenforceable due to inequitable conduct. Essentially the Belcher employee supervising patent prosecution failed to disclose prior art to the PTO that was directly relevant to certain claim limitations, while attempting to excuse that lapse based on his understanding of the claims. In particular, he believed that the prior art was irrelevant because that art required “overages” in the amount of active ingredient (i.e., an additional amount of an active ingredient or excipient compared to what is described in the product’s label), but he was mistaken because the claims only required particular concentrations of active, rather than “overages.”
The ’197 Patent
Belcher’s ’197 patent is directed to an injectable liquid formulation having a concentration of 1.0 – 1.06 mg/mL L-epinephrine, a pH between 2.8 and 3.3, and certain specified percentages of degradation products (D-epinephrine, formed by racemization) and adrenalone (formed by oxidation) over a shelf-life of at least 12-months.2
Claims 6 and 7 of the ’197 patent, which were the only claims asserted against Hospira, are reproduced below:
6. An injectable liquid pharmaceutical formulation of L-epinephrine sterile solution; said liquid pharmaceutical formulation having a pH between 2.8 and 3.3; said injectable liquid pharmaceutical formulation compounded in an aqueous solution as 1.0 to 1.06 mg/mL L-epinephrine, and further including a tonicity agent; said liquid pharmaceutical formulation including no more than about 6% D-epinephrine and no more than about 0.5% adrenalone at release, and no more than about 12% D-epinephrine and no more than about 0.5% adrenalone over a shelf-life of at least 12 months.
7. The said injectable liquid pharmaceutical formulation of claim 6 further having a concentration of 1 mg per mL L-epinephrine.
Prosecution of the ’197 Patent
During prosecution of the ’197 patent, the examiner rejected the claims as obvious over Canadian Patent Application No. 2002643 A (“Helenek”) in view of additional references.3 Helenek taught, amongst other things, a 1 mg/mL epinephrine injection at a pH between 2.2 to 5.0, and was made in an oxygen free environment to prevent oxidation of epinephrine.4 In response, Belcher successfully argued secondary considerations of non-obviousness in that the claimed range of a pH of 2.8 to 3.3 was unexpectantly found to be critical to reduce L-epinephrine racemization.5 On allowing the claims, the examiner noted that the cited art failed to render the claims unpatentable “in view of Applicant’s demonstration of criticality of a pH range between 2.8 and 3.3” and the prior art was silent that the claimed pH range would result in racemization and impurities as in the present invention.6
The District Court Decision
The district court held that the ’197 patent was unenforceable due to inequitable conduct because three pieces of prior art, which were improperly held by a Mr. Rubin, disclosed two aspects of the asserted claims: (1) the allegedly critical pH range, and (2) the claimed impurity levels.7 Although Mr. Rubin was not a patent professional or an inventor, he was in charge of Belcher’s NDA as well as the drafting and prosecution of the ’197 patent as he had a pertinent technical background with a biology degree (summa cum laude) and a master’s degree in biochemistry and molecular biology.8 The court found that the withheld information was “but-for” material to patentability of the ’197 patent and was known to Mr. Rubin and in fact was discussed by him in Belcher’s NDA.9 Indeed, during prosecution, Mr. Rubin was responsible for the argument that the claimed pH range of 2.8 to 3.3 was a “critical” innovation and that it “unexpectedly” reduced racemization, whereas discussion of the withheld prior art in Belcher’s NDA showed that information was already known.10
Belcher argued that Mr. Rubin did not have an intent to mislead the examiner because the withheld prior art required “overages” of 10-15%, and Mr. Rubin testified that he believed that the claim limitation “1.0 – 1.06” mg/ml L-epinephrine meant there could be no more than a 6% overage. The trial court did not credit that explanation because the patent claimed epinephrine concentrations rather than “overages.”11
The three references that Mr. Rubin withheld from the PTO examiner were (1) Sintetica SA’s marketed L-epinephrine product (“Sintetica’s Product”), (2) JHP Pharmaceuticals, LLC, marketed epinephrine product (“ADRENALIN”), and (3) an article by Stepensky12 titled Long-term Stability Study of L-adrenaline Injections: Kinetics of Sulfonation and Racemization Pathways of Drug Degradation (“Stepensky”).13 Sintetica manufactured epinephrine formulations since the 1930’s and in the 2000’s developed formulations free of preservatives and sulfites that have been found to cause side effects.14 Sintetica’s Product contained 1 mg/mL of L-epinephrine with a 15% overage that was preservative and sulfite-free, and had a pH in the range of 2.8 to 3.3.15 Sintetica’s Product was described in Belcher’s NDA and Belcher provided data to the FDA from four Sintetica batches showing a pH of 3.1-3.2, undetectable levels of the oxidation impurity (adrenalone), and epinephrine overages of 10-15%.16 Mr. Rubin was involved in drafting the NDA and knew that the concentration of L-epinephrine and the pH range in Sintetica’s Product overlapped the pending claims of the ’197 patent, but failed to disclose this information to the PTO examiner.
In addition, Mr. Rubin admitted at trial that he possessed the label for an epinephrine product called ADRENALIN prior to and during prosecution of the ’197 patent.17 Mr. Rubin knew that ADRENALIN contained 1 mg/mL of epinephrine at a pH of 2.2 to 5.0.18 Also, testing of three lots of ADRENALIN purchased by Belcher showed that product had a pH range of 2.8 to 3.3, no more than 0.5% of the adrenalone impurity, and less than 6% D-epinephrine at release.19 These values were within the ranges provide for in claim 6 of the ’197 patent. As such, Mr. Rubin knew that the concentrations of epinephrine, adrenalone, and the pH range in ADRENALIN were identical to the pending claims of the ’197 patent, but failed to disclose this information to the PTO examiner.
Mr. Rubin also admitted at trial that he did not disclose Stepensky to the examiner, even though he knew about it prior to the filing of the ’197 patent. Stepensky disclosed an epinephrine bitartrate formulation having a pH of 3.25 to 3.70, and less than 6% of the D-isomer after two years of storage. Yet, he had emailed and quoted it to Belcher’s FDA consultant and cited it to the FDA twice during the FDA approval process for its drug product.20
Despite his representations to the FDA, Mr. Rubin argued to the examiner in support of secondary indicia of non-obviousness that the claimed range of pH 2.8 to 3.3 was “critical” to the claims and which “unexpectedly” reduced racemization. However, Belcher’s NDA showed that the optimum pH range for the composition was 2.4 to 2.6, which was outside of the claimed range (i.e., 2.8 to 3.3) that was argued to the examiner to support secondary indicia of non-obviousness. Furthermore, the marketed product ADRENALIN had a pH range of 2.8 to 3.3 such that Belcher’s alleged critical improvement was known by Belcher to be in the public domain.21
The Federal Circuit Decision
Citing Therasense, the Court explained that prior art is “but-for” material information if the examiner would not have allowed a claim had it been aware of the undisclosed prior art.22 Furthermore, “[T]he standard for establishing but-for materiality in the inequitable conduct context only requires a preponderance of the evidence, ‘giv[ing] claims their broadest reasonable construction.’”23 In the district court, Mr. Rubin was found to have committed inequitable conduct even under a clear and convincing standard.24 As such, ADRENALIN was “necessarily material to patentability” under the district court’s higher standard of clear and convincing evidence.25
The intent element in inequitable conduct cases is usually the more difficult element to prove under a clear and convincing standard.26 Intent requires that the patent applicant “knew of the reference, knew that it was material, and made a deliberate decision to withhold it,” and the intent must be specific to deceive the PTO and “must be the single most reasonable inference able to be drawn from the evidence.”27 Belcher’s argument that Mr. Rubin’s belief about the withheld references got no traction with the Court.28 The Court agreed that Mr. Rubin’s testimony was implausible and lacked credibility given Mr. Rubin’s prior knowledge of the withheld references, his central role in both FDA approval and patent prosecution, and his arguments to the PTO examiner about the criticality of the pH range of 2.8 to 3.3, despite knowing that the Sintetica’s Product used the same range. The Court found that the single most reasonable inference was that Mr. Rubin possessed the specific intent to deceive the PTO by withholding the three disclosures.29
In summary, inequitable conduct was shown by clear and convincing evidence when Belcher’s Mr. Rubin withheld three documents that were material to patentability of the ’179 patent. The Court found that the single most reasonable inference was that Mr. Rubin possessed the specific intent to deceive the PTO by not only withholding the three disclosures, but by giving implausible testimony at trial, having a posture that lacked credibility, having detailed knowledge about the NDA and patent prosecution, and making statements during prosecution regarding the criticality of the pH range to overcome obviousness that were contrary to the data in the NDA.