Patentee doublethink in regulatory submissions and patent prosecution is inequitable conduct: Belcher v. Hospira (US)

The US Courts of Appeal of the Federal Circuit (CAFC) found in Belcher Pharmaceuticals v Hospira, Inc that a formulation patent was unenforceable in view of inequitable conduct, in the form of contradictory submissions to the patent office and the regulatory agency (FDA) by the patentee. The case serves to highlight the fine line that innovators sometimes must tread between a) demonstrating the unexpected advantages of drug dose or formulation, and b) convincing regulatory agencies of the obvious safety and efficacy of selected formulation or dose regime for a product, whilst simultaneously avoiding any cognitive dissonance or doublethink. 

Legal Background: Duty of disclosure and inequitable conduct

Patent applicants and attorneys prosecuting patent applications at the USPTO have a duty to disclose information that is material to the patentability of the intention (37 C.F.R. 1.56). The intentional failure to comply with the duty of disclosure is considered inequitable conduct. Crucially, a patent granted in the absence of compliance with the duty of disclosure is considered fraudulently obtained, and therefore unenforceable. Inequitable conduct has been called the "atomic bomb of patent law" (Aventis v. Amphastar (Fed. Cir. 2008)). 

Case law has established a two-pronged test for inequitable conduct, of intentionality and materiality (Therasense v. Beckton, Fed. Cir 2011). Inequitable conduct includes, for example, intentionally failing to disclose information to the USPTO that is material to the patentability of an application (see also Sanofi-Aventis v Hospira, IPKat). Inequitable conduct also includes intentionally presenting incorrect material facts to the USPTO

Case Background: Belcher v Hospira

The patent in Belcher v Hospira related to a formulation of L-epinephrine (L-adrenaline) (US 9,283,197), that was also the subject of a new drug application (NDA) before the FDA. Adrenaline is a very old drug that has been on the market since 1938, and has been used to treat a range of conditions from asthma to septic shock. L-adrenaline is the more potent chiral form of adrenaline. Hospira (a Pfizer subsidiary), in seeking FDA approval for their own L-adrenaline formulation submitted that Belcher's L-adrenaline formulation patent was unenforceable for inequitable conduct.

The Patent: Increasing formulation pH to improve stability was non-obvious

The patent in question purported to provide a more stable formulation of L-adrenaline. As with many drugs, the stability of L-adrenaline depends on formulation pH. At a low pH, L-adrenaline converts to the D-adrenaline isomer. At a high pH, L-adrenaline is prone to oxidation. Preservatives and antioxidants can be used to improve stability, however these can cause unwanted side effects.  

Belcher's patent application, filed in 2014, described the stability problem of L-adrenaline formulations. According to the patent, producing a stable L-adrenaline formulation "seemed impossible in a preservative-free, sulphite-free solution, and had never been accomplished before". The solution provided by the patent was a L-adrenaline formulation having a high pH (2.8-3.3). It was argued during patent prosecution that increasing the formulation of the low pH prior art formulations to 2.8 or above had the surprising effect of reducing degradation of L-adrenaline.  According to the patent application, a skilled person would believe that increasing the pH of L-adrenaline formulation would have the contrary effect of decreasing stability. As such, the patent application indicated, a formulation of pH of 2.8-3.3 would have been non-obvious to a skilled person.  

The USPTO was convinced, noting that "Applicant has demonstrated that pH range of between 2,8 and 3.3. is critical...[T]here is nothing in the prior art that would teach or suggest the...claimed pH range". The patent was granted with a claim to a formulation of pH 2.8-3.3.

The New Drug Application (NDA): Increasing formulation pH is a minor change with limited impact on stability

Prior to the filing of the patent, Belcher submitted a New Drug Application (NDA) for a L-adrenaline formulation. The formulation for which Belcher initially sought approval had a pH of 2.4 to 2.6 (i.e. lower than was subsequently claimed in their patent application).  To support the NDA, Belcher provided stability data from a reference product, in the form of a preservative-free L-adrenaline formulation having a high pH of 3.1-3.3. Belcher responded that the difference in pH between the reference product and a formulation with a lower pH was very minor, and thus did not require additional stability studies.  

Doublethink

The FDA, however, queried whether the stability data for the high pH reference product (pH 3.1-3.3) could be considered applicable to the lower pH formulation for which Belcher's sought approval (pH 2.4-2.6), The FDA particularly asked for more data relating to the low pH formulation. In order to avoid a delay to FDA approval, Belcher changed their NDA to a formulation with a higher pH of 2.8-3.3. The FDA approved the pH 2.8-3.3 formulation in 2015. 

Belcher's patent application for the pH 2.8-3.3 L-adrenaline formulation was filed during the NDA regulatory approval period. 

The Decision: Materiality and Intent

Therefore, on the one hand there were Belcher's submissions to the FDA that changes to the pH of L-adrenaline formulations, within the broad range of 2.4-3.3 would have only a minor effect on stability, and the associated stability data for the reference product. On the other hand, there were Belcher's arguments in its patent application that a skilled person would have considered a high pH formulation as highly detrimental to stability. 

Importantly, the Belcher's Chief Scientific Office (CSO), was involved both in the NDA and in patent prosecution. The CSO testified at trial that he was aware of the high pH prior art formulation and stability data that were submitted as a reference product as part of the NDA. The CSO also admitted being aware, before the filing date of the patent application, that another company (JHP) had already introduced a high pH (2.2-5.0) adrenaline formulation into the market. Belcher even performed stability tests on this formulation, and found it to be stable. 

In view of the behaviour by the CSO during regulatory submission and patent prosecution, the District Court found the Belcher patent unenforceable for inequitable conduct (IPKat). Particularly, the prior art was found material, in view of expert witness testimony that the claimed formulation was obvious in view of the prior art formulations and stability data, known to the CSO, and not disclosed to the USPTO.  Attempts by Belcher that the prior art was immaterial to the patentability of the formulation were rejected in view of counter-arguments made by Becher themselves during prosecution of the patent application that the pH of the claimed formulation was critical. The Federal Circuit (as a unanimous 3 judge panel) agreed with the District Court's analysis.  

The second prong of the inequitable conduct test, intent, was also found by both the District Court and the Federal Circuit to be satisfied. The CSO, it was concluded "performed an about-face and emphatically and repeatedly advanced the position that the 2.8 to 3.3 pH range was a “critical” innovation". With regards to citation of the material prior art the Federal Circuit found a plausible intent to deceive the patent office by the CSO, given the CSO's involvement in the NDA. 

Final thoughts

A decisive factor in Belcher v Hospira was the critical role played by a single employee, the CSO, in both the NDA and patent prosecution. The CSO was centrally involved in preparing responses to the USPTO Examiner and it was therefore difficult for Belcher to convince the Federal Circuit that the CSO would not recognise the materiality of the prior art documents that should have been submitted. The case in Belcher v Hospira could perhaps be considered an extreme example, given the apparent direct contradictory nature of submissions to the USPTO and FDA. However, the decision none-the-less highlights the potential pitfalls of combining the responsibility for IP and regulatory submissions, which may require different nuanced interpretations of complex data, for example with regards to dose selection for a clinical trial.