Epinephrine – USA

On March 31, 2020, Delaware district court found epinephrine composition patent invalid & not infringed by Hospira’s 505(b)2 product.

This is a Hatch-Waxman litigation, where Plaintiff (Belcher Pharmaceuticals, LLC) sued Defendant (Hospira, Inc.) for filing NDA with USFDA to market Epinephrine Injection. Belcher is the holder of NDA No. 205029, which was approved by FDA on July 29, 2015 for a 1 mg/mL injectable l-epinephrine formulation with 1 mL of solution contained in a 2 mL ampule. Hospira’s NDA seeks FDA approval of a 0.1 mg/mL injectable l-epinephrine formulation.

Background:

Belcher’s NDA was a paper NDA, means “literature-only” based submission. It was essentially based on Sintetica’s early pharmaceutical preparations of epinephrine, which was preservative and sulphites free, had pHs of 2.8-3.3, and included 15% more epinephrine (i.e., an “overage”) than “the theoretical value to compensate the activity loss during manufacturing and storage.” As part of its NDA, Belcher sought to replace the “old” in-process pH of 2.8-3.3 with a “new” in-process pH of 2.4-2.6, and use an overage of 10-15%. But during review, FDA asked Belcher to evaluate the effect of an in-process pH of 2.4 to 2.6 on racemization of epinephrine. Belcher’s regulatory consultants – INC Research – recommended that Belcher use the in-process pH of 2.8-3.3 presented in the original NDA and Sintetica batch data, since any changes in the process from the process used to obtain the batch data would delay approval. Thus, Belcher submitted its response to the FDA, stating, they have refocused their studies on determining the effect of the in-process pH of 2.8-3.3 and not pH of 2.4 to 2.6. The FDA ultimately approved Belcher’s epinephrine product with a pH of 2.8-3.3.

During litigation, Plaintiff specifically asserted infringement of claims 6 & 7 of US 9,283,197 patent which is expiring in Aug. 2034. The patent is related to more potent and less toxic formulations of epinephrine.  The asserted claims are as follows:

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.

Belcher alleged that Hospira’s bioequivalent product infringes US’197 patent under the doctrine of equivalents. Hospira contends that it does not infringe the ’197 Patent and, further, that the Patent is invalid and/or unenforceable. In June 2019, the Court held a two-day bench trial.

Infringement: Doctrine of Equivalents

The parties agreed that only one claim limitation is at issue and, thus, “the only dispute is whether Hospira’s [0.1 mg/mL] NDA Product is equivalent to a formulation ‘compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine.’” Belcher argued the two are equivalent because both are intended to use low (0-6%) overages and to deliver the same total amount (1 mg) of epinephrine to a patient (Hospira's product contains 10 ml solution). Hospira responds that the claims are directed to concentrations, not overages or amounts, and the concentrations of the claim and the Hospira NDA Product are, indisputably, not equivalent. Court agreed with Hospira.

Central to the parties’ dispute is whether the Court, in applying DOE, should look to the claimed concentration itself, or the intended purpose of that concentration. Court said that the all-elements rule mandates that the Court look only at the claimed concentration – “compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine” – and not the intended overage, amount, or use of the formulation as a whole, as none of those features are claimed. The disputed claim limitation is directed to concentration, so to prove infringement Belcher was required to prove that the accused product practices the claimed concentration, either literally or by equivalents. Having failed to do so, the Court cannot find infringement.

Invalidity:

Hospira sought to invalidate claims 6 and 7 of the ’197 Patent on three independent bases: (1) the prior art anticipates the claims; (2) the prior art renders the claims obvious; and (3) the Patent fails to list all of the correct inventors. (4) Hospira also argued that the ’197 Patent is unenforceable based on inequitable conduct.

Anticipation:

Hospira argued the ’197 Patent is invalid based on two pieces of anticipatory prior art: (1) JHP’s Adrenalin Product; and (2) Hospira’s Ampul Product. Court said that neither JHP’s Adrenalin Product nor Hospira’s Ampul Product anticipates the claimed invention, as neither teaches a “formulation compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine”. The Court construed this limitation as a product-by-process limitation, which means that, “for validity purposes, the ‘invention’ . . . is the product.” Medicines Co. v. Hospira, Inc., 827 F.3d 1363, 1374 (Fed. Cir. 2016). Hospira argued there are no structural differences between the claimed invention and JHP’s Adrenalin Product or Hospira’s Ampul Product, as all constitute a 1 mg/mL epinephrine product according to the USP. Court, however said that to anticipate the claimed invention, the prior art must have a post-compounding l-epinephrine concentration between 1.0 and 1.06 mg/mL. This does not mean at any time after compounding (like Hospira’s Ampul Product, which arguably had 1.002-1.01 mg/mL l-epinephrine at testing, but some time relatively immediately thereafter. The prior arts products have higher post-compounding overages and concentrations (e.g., 1.095-1.134 mg/mL for JHP’s Adrenalin Product and approximately 1.1 mg/mL for Hospira’s Ampul Product) than the claimed invention. Thus, this structural difference precludes a finding of anticipation.

Obviousness:

Court said that the FDA historically approved (or permitted through grandfathering) the sale of epinephrine products that complied with the USP monograph, which set the upper limit on overages at 15%. At some point, however, the FDA began rejecting products that were otherwise USP-compliant, and demanded justifications for overages in accordance with ICH Guidelines. Due to the FDA’s enforcement of the ICH Guidelines, a POSA would have been motivated to minimize the overage in any epinephrine product in order to obtain FDA approval. A POSA would have known that reducing overages would not negatively impact other relevant properties, such as racemization rate or safety. Instead, as a POSA would know, reducing overages would predominantly impact shelf life, for there would be less epinephrine available to oxidize or racemize before reaching the 90% floor set by the USP.

Both JHP’s Adrenalin Product and Hospira’s Ampul Product had ample shelf life to spare. Therefore, it would have been obvious to minimize the approximately 10-15% overages of the Products, including to between 0 and 6%, while balancing allowable shelf life. That, in turn, means it would have been obvious to compound JHP’s Adrenalin Product or Hospira’s Ampul Product at 1.0-1.06 mg/mL to produce a 1 mg/mL product, in accordance with the ICH Guidelines. A POSA would have had a reasonable expectation of success in pursuing this obvious modification of one or both of the Products.

Improper Inventorship:

Court said that under 35 U.S.C. § 102(f), one cannot obtain a valid patent if “he did not himself invent the subject matter sought to be patented.”  “Determining ‘inventorship’ is nothing more than determining who conceived the subject matter at issue, whether that subject matter is recited in a claim in an application or in a count in an interference.” [Sewall v. Walters, 21 F.3d 411, 415 (Fed. Cir. 1994)]. Conception is a question of law premised on underlying factual findings.

In this case, Hospira argued that Mr. Taneja – the sole named inventor – “neither conceived of nor reduced to practice the alleged invention of the ’197 Patent,” as his sole contribution was to suggest a pH of between 2.8 and 3.3, which was known in the prior art. Court agreed with Hospira. Court said that the record is devoid of reliable corroborating evidence to support Mr. Taneja’s claim that he conceived of the pH range limitation and communicated it to Sintetica. Additionally, as Mr. Taneja himself testified, he was aware that “as early as 2003 Sintetica manufactured 1 milligram per milliliter epinephrine products having a pH in the range of 2.8 to 3.3,” so in fact even he recognized that he was not the first to conceive of using the claimed pH range in epinephrine formulations. Even if all of this were incorrect, and even taking Mr. Taneja’s testimony in the best possible light, all he had was a “hope, or wish” that his pH would be successful, which is insufficient to constitute conception. This conception requires more than “just a general goal or research plan,” and 6+requires a “definite and permanent idea of an operative invention, including every feature of the subject matter to be patented.” [In re VerHoef, 888 F.3d 1362, 1366 (Fed. Cir. 2018)].

Inequitable Conduct:

Court said that inequitable conduct is an equitable defense to patent infringement that, if proved, bars enforcement of a patent.” Therasense, Inc. v. Becton, Dickinson and Co., 649 F.3d 1276, 1285 (Fed. Cir. 2011). To prevail on a claim of inequitable conduct, the accused infringer must prove by clear and convincing evidence that the patentee: (1) “acted with the specific intent to deceive the PTO” and (2) made a material misrepresentation or omission. “In a case involving nondisclosure of information, clear and convincing evidence must show that the applicant made a deliberate decision to withhold a known material reference.” For a misrepresentation or omission to be “material,” it must be “but-for” material. That is, the accused infringer must prove that “the PTO would not have allowed a claim had it been aware of the undisclosed prior art.”

Court said that as Chief Scientific Officer of Belcher and an active participant in the prosecution of the ’197 Patent, Mr. Rubin owed a duty of candor and good faith to the Patent Office. Despite this duty, Rubin admitted that he withheld information from Belcher’s patent prosecution attorney and the Patent Office, including Stepensky, JHP’s Adrenalin Product, and the 2003 Sintetica Products, at least some of which the Court has found to be but-for material to patentability. Rubin testified that he withheld these references because he considered them (and others) irrelevant, as they were directed to formulations that contained preservatives, used epinephrine bitartrate base, or had “high” overages. But, the Court did not find Rubin’s testimony about why he did not disclose the prior art references to the PTO to be credible or plausible.

During prosecution, in non-final rejection the Examiner relied on Helenek, which taught an epinephrine formulation with a pH range of 2.2-5.0. In counter arguing Rubin and Belcher knew that pH would be critical to persuading the Examiner to approve the patent. Certainly by this point in the prosecution, Rubin and Belcher had an unambiguous duty to disclose any material information pertinent to the claimed pH, and not just prior art limited to preservative-free or low overage formulations. Yet Rubin approved the following response from Belcher: “Helenek et al. does not make obvious the Applicant’s pH range of 2.8 and 3.3, which was unexpectedly found to be critical by the Applicant to reduce the racemization of 1-epinephrine.” The statement that Belcher’s claimed pH was “unexpected” was false. At the time this statement was made, Rubin knew about Stepensky, the JHP Adrenalin Product, and the 2003 Sintetica Products, all of which taught a pH in the range of 2.8 to 3.3. The Examiner, not knowing of these references, accepted Belcher’s representations as true and was persuaded by them to approve the Patent.

Therefore, Court found US’197 patent unenforceable because of Inequitable Conduct.