IP Law Daily Patent claim regarding stability of ready-to-use sedative product was invalid as obvious
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Thursday, January 9, 2020

Patent claim regarding stability of ready-to-use sedative product was invalid as obvious

By Thomas Long, J.D.

Key claim limitation on stability of the drug under prolonged storage was "inherent" in the prior art, and a district court did not improperly rely on non-prior-art information in reaching that conclusion.

The U.S. Court of Appeals for the Federal Circuit has affirmed a district court’s conclusion that a challenged claim of a patent covering a pre-diluted, ready-to-use form of dexmedetomidine, the active ingredient of the sedative drug Precedex Premix, was invalid as obvious. The district court did not err by relying on non-prior art information in determining that the claim limitation "exhibit no more than about 2% decrease in the concentration of dexmedetomidine" was inherent in the patent’s preferred embodiment. An "unnecessary analysis" by the district court as to whether product labels and industry guidance for stability testing would enable a person of ordinary skill to have had a reasonable expectation of successfully achieving that claim limitation was harmless error, in the appellate court’s view, and did not affect the district court’s obviousness finding, which was supported by ample evidence (Hospira, Inc. v. Fresenius Kabi USA, LLC, January 9, 2020, Lourie, A.).

Hospira, Inc., manufactures pharmaceuticals and medical supplies. One of Hospira’s products is a chemical compound known as dexmedetomidine, which Hospira sells to health care providers under the brand name Precedex, a sedative. Hospira marketed a ready-to-use product, called Precedex Premix, which was a diluted version of a product, known as Precedex Concentrate. Precedex Concentrate was formulated at 100 micrograms per milliliter (µg/mL) and must be diluted with saline to a concentration of 4 µg/mL before being administered to patients. Precedex Premix had the same formulation and the same package configuration as Precedex Concentrate but was pre-diluted with saline to a 4 µg/mL concentration.

Hospira accused Fresenius Kabi USA—an Illinois-based subsidiary of a German pharmaceutical manufacturer that had sought FDA approval of a generic version of Precedex Premix—of infringing several patents covering the Precedex Premix product. Hospira sued for infringement of five patents and eventually dropped all but two claims, one of which was claim 6 of U.S. Patent 8,648,106 ("the ’106 patent"). Fresenius stipulated to infringement of claim 6, and the district court held a bench trial on its validity. The district court concluded that Fresenius established by clear and convincing evidence that claim 6 was invalid as obvious, and Hospira appealed.

The ’106 patent. The ’106 patent was entitled "Dexmedetomidine Premix Formulation" and was directed to pharmaceutical compositions comprising dexmedetomidine (or a pharmaceutically acceptable salt of dexmedetomidine) formulated as a liquid for parenteral administration to a patient, "wherein the composition is disposed within a sealed container as a premixture." Hospira summarized the invention claimed in the ’106 patent as "premixed pharmaceutical compositions of dexmedetomidine, or a pharmaceutically acceptable salt thereof, that are formulated for administration to a patient, without the need to reconstitute or dilute the composition prior to administration." The ’106 patent purportedly addressed shortcomings in the prior art, including the expense, inconvenience, delay, and risk of contamination or overdose involved in use of the older products. The patent stated that the invention was based on the discovery that premixed and diluted dexmedetomidine remained stable and active after prolonged storage.

Independent claim 1 of the ’106 patent disclosed:

1. A ready to use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof disposed within a sealed glass container, wherein the liquid pharmaceutical composition when stored in the glass container for at least five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine.

Dependent claim 6—the claim at issue on appeal—disclosed:

6. The ready to use liquid pharmaceutical composition of claim 1, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 4 µg/mL.

The district court construed the disputed term "ready to use" to mean "formulated to be suitable for administration to a patient without dilution or reconstitution," and it determined that no construction was required for the disputed term "sealed glass container."

District court proceedings. The only dispute between the parties concerned whether 4 µg/mL dexmedetomidine HCl—when stored at room temperature in a Type I glass vial, sealed with a coated rubber stopper—will always "exhibit no more than about 2% decrease in the concentration of dexmedetomidine" at five months (the "about 2%" limitation in claim 6).

Fresenius contended that a ready-to-use, sealed glass container with 4 µg/mL dexmedetomidine HCl was disclosed two combinations of references and that a POSA would have been motivated to combine the disclosed limitations to create a ready-to-use 4 µg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial, sealed with a coated rubber stopper. The district court agreed, noting that the Precedex Concentrate label disclosed how to make the 4 µg/mL formulation and that Precedex Concentrate disclosed a glass container as a storage material for dexmedetomidine HCl, and the use of a coated rubber stopper to seal the container. Moreover, "a POSA would have known from his or her experience in the pharmaceutical industry that glass, and specifically Type I glass, was a suitable storage material for the drug," the district court said.

Because the prior art did not explicitly disclose the "about 2%" limitation of claim 6, Fresenius relied on the doctrine of inherency to supply it. The district court concluded that Fresenius established by clear and convincing evidence that the "about 2%" limitation was inherent in the 4 µg/mL preferred embodiment and that Hospira failed to disprove inherency. All stability data in the record for the 4 µg/mL preferred embodiment showed that there was "no more than about 2%" loss in the tested samples at five months. The court also found that the limitations alleged to have an inherent property when combined are explicitly disclosed in the prior art, and a POSA would have been motivated to combine them. Fresenius was allowed to rely for inherency purposes on stability data that comprised or was derived from Hospira’s development work. Based on the chemical properties of dexmedetomidine; evidence tending to show that dexmedetomidine’s concentration does not affect its stability; and the disclosures in the Precedex Concentrate and Dexdomitor label, the district court concluded that a POSA would have had a reasonable expectation of success in meeting the "about 2%" limitation.

Arguments on appeal. Hospira challenged the district court’s conclusion that claim 6 of the ’106 patent was invalid as obvious based on the inherency of the "about 2%" limitation. First, Hospira argued that the district court incorrectly considered the inherency of the about 2% limitation in non-prior art embodiments rather than the allegedly obvious prior art combination. Second, Hospira argued that the court applied a lower "reasonable expectation of success standard" rather than the higher "necessarily present" standard to the inherency question.

Inherency based on non-prior art embodiments. According to Hospira, every tested sample of the 4 µg/mL preferred embodiment in the record was either from Hospira’s NDA for Precedex Premix or from Fresenius’s ANDA for its ready-to-use product, none of which were in the prior art. Fresenius argued that it was irrelevant to the inherency analysis whether or not those samples were prior art. The Federal Circuit agreed with Fresenius that the district court did not err in relying on data obtained after the priority date of the ’106 patent in its inherency analysis, explaining that extrinsic evidence can be used to demonstrate what is "necessarily present" in a prior art embodiment even if the extrinsic evidence is not itself prior art. "Moreover, the work of the inventor or the patentee can be used as the evidence of inherency," said the court. "Therefore, it was not legally incorrect for the district court to rely on non-prior art data from Hospira’s NDA and Fresenius’s ANDA as evidence of the inherent stability of the 4 µg/mL preferred embodiment."

In addition, the appellate court held that the evidence supported the district the court’s factual finding that the "about 2%" limitation was necessarily present in the 4 µg/mL preferred embodiment. That evidence included data from more than 20 samples of the 4 µg/mL preferred embodiment, every one of which met the about 2% limitation, as well as expert testimony that concentration does not affect the stability of dexmedetomidine, demonstrating that dexmedetomidine is a very stable drug. "On that record, it was not clearly erroneous for the district court to find that the about 2% limitation was necessarily present in the prior art," the appellate court said.

Reasonable expectation of success. The Federal Circuit sided with Fresenius on the issue of whether the district court’s inherency analysis was correct. Although the district court engaged in what the appellate court called "unnecessary analysis" in evaluating whether the chemical properties of the dexmedetomidine molecule, the information in the Precedex Concentrate and Dexdomitor labels, and the industry guidance for stability testing would enable a person of ordinary skill to have had a reasonable expectation of successfully achieving the about 2% limitation—which conflated the standards for inherency and reasonable expectation of success—that was harmless error that did not infect the district court’s inherency analysis and findings. "If a property of a composition is in fact inherent, there is no question of a reasonable expectation of success in achieving it," the Federal Circuit said.

Obviousness. Finally, the appellate court concluded that the district court’s findings supported a conclusion that claim 6 would have been obvious. The ’106 patent itself stated that the invention was based on "the discovery that dexmedetomidine pre-pared in a premixed formulation ... remains stable and active after prolonged storage," the court noted. Claim 6 did not recite manufacturing limitations or an added component that enhanced stability, it simply recited a composition, with a "wherein" clause that described the stability of that recited composition. Because that result was inherent in the prior art, the Federal Circuit affirmed the district court’s decision that claim 6 was invalid for obviousness.

This case is Nos. 2019-1329 and 2019-1367.

Attorneys: Adam G. Unikowsky (Jenner & Block LLP) for Hospira, Inc. Imron T. Aly (Schiff Hardin LLP) for Fresenius Kabi USA LLC.

Companies: Hospira, Inc.; Fresenius Kabi USA LLC

MainStory: TopStory Patent FedCirNews

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