Belcher Pharm., LLC v. Hospira, Inc.

11 F.4th 1345

BELCHER PHARMACEUTICALS, LLC, Plaintiff-Appellant

v.HOSPIRA, INC., Defendant-Appellee

2020-1799

United States Court of Appeals, Federal Circuit.

Decided: September 1, 2021

Peter Mccreery Lancaster, Dorsey & Whitney LLP, Minneapolis, MN, argued for plaintiff-appellant. Also represented by Kenneth Levitt.

Matthew S. Freimuth, Willkie Farr & Gallagher LLP, New York, NY, argued for defendant-appellee. Also represented by Devon Wesley Edwards, Thomas J. Meloro.

Before Reyna, Taranto, and Stoll, Circuit Judges.

Reyna, Circuit Judge.

This is an appeal from a decision of the U.S. District Court for the District of Delaware that U.S. Patent No. 9,283,197, which Appellant Belcher Pharmaceuticals, LLC asserted against Appellee Hospira, Inc. in a patent infringement suit under the Hatch-Waxman Act, is unenforceable for inequitable conduct. The district court concluded that Belcher's Chief Science Officer engaged in inequitable conduct by withholding material information from the U.S. Patent and Trademark Office during prosecution of the ’197 patent with the requisite deceptive intent. For the reasons below, we affirm.

BACKGROUND

Epinephrine

Epinephrine (also called adrenaline) is a hormone as well as a grandfathered drug product that has been on the market since approximately 1938 and used for a variety of medical purposes. It has long been understood that epinephrine degrades in two ways pertinent to this appeal: racemization and oxidation. Racemization involves a change in the arrangement of a molecule around a "chiral center," such that levorotatory epinephrine ("l-epinephrine"), the more potent isomer, converts to dextrorotatory epinephrine ("d-epinephrine"), the less potent isomer. Oxidation involves a change in a compound's chemical composition due to reaction with oxygen or other oxidizing agents. Oxidation of l-epinephrine yields adrenalone, which is deemed an impurity in l-epinephrine drug products.

A handbook for pharmacists published in 1986 explained that, in l-epinephrine solutions, there is an inverse relationship between racemization and pH and a proportional relationship between oxidation and pH. See KENNETH A. CONNORS ET AL., CHEMICAL STABILITY OF PHARMACEUTICALS: A HANDBOOK FOR PHARMACISTS 438–47 (John Wiley & Sons 2d. ed. 1986) [hereinafter Connors] (J.A. 1335–46). In other words, when an epinephrine solution becomes more acidic (i.e., pH decreases), racemization increases and oxidation decreases, and when the solution becomes more basic (i.e., pH increases), oxidation increases and racemization decreases. Id. Accordingly, Connors taught that "there is an optimum pH at which racemization and oxidation can be balanced to minimize loss of intact drug by these two routes; this is approximately pH 3.0-3.8." Id. at 441.

Belcher's NDA

On November 30, 2012, Belcher Pharmaceuticals, LLC ("Belcher") submitted New Drug Application ("NDA") No. 205029 for a 1 mg/mL injectable l-epinephrine formulation. J.A. 1559, 1562. The NDA was literature-based, meaning that Belcher did not perform any clinical or nonclinical studies on its epinephrine formulation to support its application. J.A. 1560. The NDA described the development of Belcher's formulation. It first discussed Swiss company Sintetica SA's ("Sintetica") "original formulation" of 1 mg/mL injectable l-epinephrine, which Sintetica developed in the 1930s and registered in Switzerland in 1947. J.A. 1564–65. The formulation included sodium metabisulphite as an antioxidant preservative and about a 10 percent overage¹ of epinephrine to ward off activity loss, and it had a pH range of 2.2 to 4.0. J.A. 1565–66. The manufacturing process involved a continuous flow of nitrogen gas to remove oxygen and thereby enhance stability. J.A. 1566.

According to the NDA, in the early 2000s, market demand shifted to epinephrine formulations that did not include "preservatives and sulfites," which had been found to cause side effects. J.A. 1566. The NDA explained that "[t]he switch was very simple" and involved increasing the sodium chloride concentration and increasing the epinephrine overage from 10 percent to 15 percent. J.A. 1566–67. The NDA described the new composition as having a pH range of 2.8 to 3.3. J.A. 1567. Given the removal of the sulfite antioxidant, "careful attention was paid to the nitrogen purge during the whole process" to maximize stability in the absence of the antioxidant. Id.

Belcher's NDA named as reference product Sintetica's preservative- and sulfite-free 1 mg/mL epinephrine formulation manufactured for the U.S. market by American Regent Laboratories, Inc. J.A. 1575. Belcher submitted data from four batches of the reference product, made from November 2002 to April 2003, for validation of the product's stability. J.A. 1578–82. This data showed that the batches included overages of 10 to 15 percent and maintained, over a 24-month period, a pH range of 3.1 to 3.3, and undetectable levels of the impurity adrenalone. J.A. 1578–82. According to Belcher, this data met U.S. Pharmacopeia ("USP") specifications, including the requirement for a pH between 2.2 and 5.0. J.A. 1578; see also J.A. 1595.

Belcher's NDA also described the sterilization process and the "in[-]process pH" value. J.A. 1584–95. Belcher explained that lowering the in-process pH from a range of 2.8 to 3.3 (called "old") to a range of 2.4 to 2.6 (called "new"), when coupled with effective removal of oxygen using a nitrogen purge, "reinforces the manufacturing process robustness and reproducibility" and "reduces the impact of possible residues of oxygen in the solution." J.A. 1595.

On February 7, 2013, the U.S. Food and Drug Administration ("FDA") sent a letter to Belcher asking for certain additional information, including (i) "data that support evaluation of [the] drug product for potential racemization from manufacturing process conditions and over the shelf life," and (ii) clarification on whether the Sintetica batches on which Belcher relied for stability validation were manufactured in the same way as that proposed for marketing. J.A. 1483. Belcher forwarded the letter to Sintetica asking for assistance in responding to the FDA's requests. J.A. 1481.

Belcher responded to the FDA on March 8, 2013. Addressing the FDA's question on racemization, Belcher explained that "[r]acemization of the enantiomerically pure L-Epinephrine isomer in injectable formulations of epinephrine is a well-known process," citing literature authored by Fylligen² and Stepensky.³ J.A. 1430. Responding to the FDA's inquiry on manufacturing process for the stability validation batches, Belcher stated that the only difference between the relied-upon Sintetica batches and Belcher's proposed formulation "is related to the in[-]process pH" and that it "consider[ed] the in[-]process pH change to be a very minor change not requiring additional stability studies." J.A. 1432. Belcher also explained that the release specification of 2.2 to 5.0 "complies with [the] USP specification and stays unchanged between all the batches." Id.

The FDA responded on October 4, 2013, asking Belcher to evaluate the effect of an in-process pH range of 2.4 to 2.6 on racemization. Belcher Pharms., LLC v. Hospira, Inc. , 450 F. Supp. 3d 512, 524 (D. Del. 2020). On October 17, 2013, Belcher's regulatory consultants, INC Research, recommended that Belcher revert to the 2.8 to 3.3 pH range shown in the Sintetica batch data because deviating from that range would delay the FDA's approval. Id. ; see also J.A. 668–69 (Trial Tr. 138:5–139:11). Belcher followed that advice. In its response to the FDA, Belcher stated that it had "refocused [its] studies on determining the effect of the in-process pH of 2.8 - 3.3 on the formation of d-epinephrine during each step of the manufacturing process, which was used to manufacture the 3 primary stability batches ... provided in the NDA." J.A. 1464. Belcher accordingly requested approval of the drug proposed in the NDA "with the exception[ ] of changing the [in-process] pH from 2.4 - 2.6 back to the initial pH of 2.8 - 3.3." J.A. 1471. The FDA approved the NDA on July 29, 2015.

The ’197 Patent

On August 15, 2014, Jugal Taneja, Belcher's CEO, filed U.S. Patent Application No. 14/460,845 ("’845 application"), which issued as U.S. Patent No. 9,283,197 ("the ’197 patent"). J.A. 1003–27. The application was directed to certain epinephrine formulations and was entitled "More Potent and Less Toxic Formulations of Epinephrine and Methods of Medical Use." J.A. 1016, 1025–27. Mr. Taneja later assigned the application to Belcher.

The patent describes the problem of l-epinephrine's degradation and the resulting need for product overages and sulfite antioxidants, and it claims to provide an answer to this need. ’197 patent col. 2 ll. 50–59. According to the patent, an answer "seemed impossible" and "had never been accomplished before." Id. at col. 4 ll. 31–35. The patent similarly states that the idea of raising the in-process pH above the range of 2.2 to 2.6 "was contradictory to one skilled in the art" before the claimed invention. Id. at col. 4 ll. 41–47. But "[i]nadvertently," the patent states, "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, from 14% to 5%, respectively." Id. at col. 4 ll. 48–51. The inventor's alleged discovery of raising the pH "led to new methods of manufacturing sulfite-free, l-epinephrine solution with an in-process pH of 2.8 to 3.3, approximately 3.0, which was a nonobvious solution to the problem of racemization. Most importantly, with these new methods, overages could greatly be reduced." Id. at col. 4 ll. 55–59.

Claims 6 and 7 of the ’197 patent, which are at issue in this appeal, cover pharmaceutical epinephrine formulations having a pH between 2.8 and 3.3 and certain concentrations of l-epinephrine, d-epinephrine, and adrenalone at the time of release and 12 months later. These claims read as...