By Joseph Arshawsky, J.D.
Following a bench trial, the federal district court in Chicago has ruled that Fresenius Kabi USA, LLC proved by clear and convincing evidence that claim 6 of U.S. Patent No. 8,648,106 ("the ‘106 patent") and claim 8 of U.S. Patent No. 9,616,049 ("the ‘049 patent"), both covering Hospira’s sedative drug Precedex Premix, were invalid as obvious (Hospira, Inc. v. Fresenius Kabi USA, LLC, December 17, 2018, Pallmeyer, R.).
Plaintiff 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. The new product, known as Precedex Premix, is a ready-to-use, diluted version of a Hospira product that has been on the market since 1999. That product, known as Precedex Concentrate, is 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 has the same formulation and the same package configuration as Precedex Concentrate but is 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. Following claim construction, Hospira dropped most infringement contentions, but continued to assert that Fresenius Kabi’s ANDA product infringed claim 6 of the ’106 Patent and claim 8 of the ’049 Patent. Fresenius Kabi stipulated that its proposed product would infringe both claims, but challenged their validity. In July, 2018, the court held a five-day bench trial on the issue of the validity. The court concluded that Fresenius Kabi established by clear and convincing evidence that both claims were invalid as obvious.
The patents-in-suit. Hospira summarized the invention claimed in the ’106 and ’049 Patents 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 and ’049 Patents cover the same basic subject matter—the medication itself—and share a title: "Dexmedetomidine Premix Formulation." The patents share a common specification. Independent claim 1 and dependent claim 6 of the ‘106 patent read as follows, illustrating the claim:
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.
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 court previously construed the disputed term "ready to use" to mean "formulated to be suitable for administration to a patient without dilution or reconstitution," and determined that no construction was required for the disputed term "sealed glass container."
Prior art. The relevant prior art included U.S. Patent No. 4,910,214 (issued in March 1990 and expired in July 2013) claiming dexmedetomidine as a sedative, Abbott Laboratories’ Precedex Concentrate (on the market since 1999), Dexdomitor (a ready-to-use, 500 µg/mL dexmedetomidine HCl formulation, for veterinary use), 2011 Guidelines published by the Canadian Society of Hospital Pharmacists (CSHP), a 2011 article by John Fanikos, a 2007 article by James G. Cain, a 2010 article by Gregory A Sascha, and a scientific treatise (REMINGTON: THE SCIENCE OF PRACTICE AND PHARMACY (21st ed. 2006) ("Remington"). The references were published or otherwise available before the patents’ January 4, 2012, priority date.
The "about 2% limitation" of the ’106 patent. A major point of contention between Fresenius Kabi and Hospira was 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). Hospira’s case for non-obviousness depended largely on the argument that a 4 μg/mL formulation stored under these conditions will not always meet that limitation. At trial, Fresenius Kabi and Hospira offered testimony from expert and fact witnesses regarding the "about 2%" limitation, and they also offered expert testimony regarding the chemical structure of dexmedetomidine.
Obviousness. Hospira did not challenge Fresenius Kabi’s contention that claim 8 of the ’049 Patent is invalid as obvious, but the parties disputed whether claim 6 of the ’106 Patent is invalid as obvious. Fresenius Kabi asserted that the prior art expressly disclosed a ready-to-use, sealed glass container with 4 µg/mL dexmedetomidine HCl claim limitation. Fresenius Kabi acknowledged that the prior art did not expressly disclose this limitation, but relied on the doctrine of inherency to supply it.
Fresenius Kabi 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 court agreed. The court noted 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 court said. Thus, a POSA would have been motivated to combine his or her knowledge of the industry with the teachings from Precedex Concentrate to create a ready-to-use dexmedetomidine HCl product packaged in a Type I glass container, sealed with a coated rubber stopper.
Because the prior art did not explicitly disclose the "about 2%" limitation of claim 6, Fresenius Kabi relied on the doctrine of inherency to supply it. In a separate case, the federal district court in Wilmington, Delaware, found that the defendant, Amneal Pharaceuticals, LLC, failed to establish inherence of the "about 2%" limitation. However, the record in this case was different. The court concluded that Fresenius Kabi established by clear and convincing evidence that the "about 2%" limitation is 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 Kabi was allowed to rely for inherency purposes on stability data that comprises or is derived from Hospira’s development work.
The court agreed with Fresenius Kabi that a POSA would have had a reasonable expectation of success from combining a 4 µg/mL dexmedetomidine formulation with a Type I glass vial, sealed with a coated rubber stopper. Whether a POSA would have had a reasonable expectation of success concerning the "about 2%" limitation was not as clear, but Fresenius Kabi marshaled enough evidence at trial to support such an inference. For example, a POSA’s knowledge of dexmedetomidine’s chemical structure would have supported a reasonable expectation that it would lose very little concentration at five months. In addition, the Dexdomitor and Precedex Concentrate products had two-year shelf lives.
Thus, 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 court concluded that a POSA would have had a reasonable expectation of success in meeting the "about 2%" limitation. Hospira did not present any significant evidence of secondary considerations to alter the court’s conclusion. Claim 8 of the ’049 Patent covers the same composition having "a pH of about 2 to about 10." For completeness, the court also held that Fresenius Kabi proved by clear and convincing evidence that claim 8 of the ’106 Patent is invalid as obvious.
This case is No. 1:16-cv-00651.
Attorneys: Bradford P. Lyerla (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 IllinoisNews
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