Dexmedetomidine – USA

On Dec 17, an Illinois federal judge invalidated two patents covering a “ready-to-use” version of Hospira Inc.’s sedation drug Precedex.

Background:

Hospira is the owner of brand Precedex® (100 µg/mL, approved in 1999) & new product, known as Precedex Premix (4 µg/mL, approved in 2013 & 2014 in different strengths).  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 (Precedex Premix, is the subject of the patents-in-suit). Fresenius Kabi notified Hospira that it had filed an ANDA with the FDA, seeking approval to market its own proposed dexmedetomidine products prior to the expiry of Hospira’s patents [U.S. Patent Nos. 8,242,158 (07/04/2032), 8,338,470 (07/04/2032), 8,455,527 (07/04/2032), and 8,648,106 (07/04/2032)]. Hospira filed suit a month later, alleging patent infringement. In 2017, Hospira obtained a fifth patent covering the same dexmedetomidine product—U.S. Patent No. 9,616,049 (07/04/2032)—and filed a second complaint of patent infringement. Following the court’s claim construction order in Nov. 2017, the parties jointly agreed to limit the number of patent claims asserted in both actions. Since then, Hospira has dropped all but claim 6 of the ’106 Patent and claim 8 of the ’049 Patent. Fresenius Kabi has stipulated that its proposed product would infringe those claims, but maintains its challenges to their validity. The court held a five-day bench trial on the issue of the validity of these claims on July 16, 2018 through July 20, 2018.

Independent claim 1 and dependent claim 6 of the ’106 Patent read as follows:

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.

Independent claim 1 and dependent claim 8 of the ’049 Patent read as follows:

1. A ready to use liquid pharmaceutical composition for parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.005 to about 50 μg/mL disposed within a sealed glass container, wherein the liquid pharmaceutical composition has a pH of about 2 to about 10.

8. 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.

Prior arts include among other things mainly, US 4,910,214 (discloses use of dexmedetomidine as a sedative), Precedex Concentrate label (as discussed above), Dexdomitor-2002 (EU approved ready-to-use, 500 μg/mL product), articles by John Fanikos (RTU drug formulations & preparations in general), James G. Cain (premixed syringes of dexmedetomidine, 10 mL with 4 mcg/mL) & Gregory A. Sacha (Glass Storage Containers). All these references were published or otherwise available before Jan 4, 2012.

Court’s analysis:

Fresenius Kabi argued that claim 6 of the ’106 Patent and claim 8 of the ’049 Patent are invalid as obvious under 35 U.S.C. § 103(a). Fresenius Kabi specifically argued that a POSA would have been motivated to combine the disclosures in Precedex Concentrate, Fanikos, the CSHP Guidelines, Cain, Remington, and Sacha 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. According to Fresenius Kabi, the prior art expressly disclosed these claim limitations. Fresenius relied on doctrine of inherency argument for claim limitation “no more than about 2%” loss in concentration at five months.”  In its post-trial brief, Hospira did not specifically rebut most of the contentions, but it disputed the “about 2%” limitation of the ’106 Patent. Hospira’s key arguments for non-obviousness are that Fresenius Kabi has failed to prove by clear and convincing evidence (1) the inherency of the “about 2%” limitation and (2) that a POSA would have been motivated to combine the prior art teachings with a reasonable expectation of success.

1. Ready-to-Use, Sealed Glass Container with 4 μg/mL Dexmedetomidine HCl:

Precedex Concentrate has been on the market since 1999. Its label discloses the exact contents of its formulation, including that it contains no preservatives, additives, or chemical stabilizers. A named co-inventor of the ’106 Patent, Dr. Roychowdhury, admitted that the label taught her the formulation and that there is “no difference between the formulations of the further diluted Precedex concentrate versus the Precedex Premix product.” Hospira’s corporate representative, Dr. Tata-Venkata, gave similar testimony. The Precedex Concentrate label also discloses that the formulation must be diluted to 4 μg/mL before being administered to humans and sets forth the steps to perform the dilution. Drs. Roychowdhury and Cedergen testified they knew from the label that their goal was to make a 4 μg/mL formulation. For these reasons, the court concluded that the Precedex Concentrate label disclosed how to make the 4 μg/mL formulation. The court also concluded that Precedex Concentrate disclosed a glass container as a storage material for dexmedetomidine HCl. In addition, the court concluded that Precedex Concentrate disclosed the use of a coated rubber stopper to seal the Type I glass vial.

2. The “About 2%” Limitation:

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. Hospira contended that Fresenius Kabi has not established inherency because it has failed “to exclude the possibility that the combination could be prepared in a way that would fail the limitation.” Court while disagreeing with Hospira, said that Fresenius Kabi need not to prove that every possible embodiment of claim 6 necessarily meets the “about 2%” limitation, that is not the law. Rather, to prove that a claim covering multiple alternative embodiments is invalid, a defendant need only prove that one of the embodiments is invalid (In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1281 (Fed. Cir. 2015). Having disposed of Hospira’s threshold arguments, the court held that all stability data in the record for the 4 μg/mL preferred embodiment shows that there was “no more than about 2%” loss in the tested samples at five months. The data includes stability test results disclosed in the patent, eighteen batch configurations of Precedex Premix in upright and inverted storage, measurements from three batches of Precedex Premix and three batches of Fresenius Kabi’s ready-to-use product. Significantly, this data shows not only that samples from the 4 μg/mL preferred embodiment necessarily lost no more than about two percent of their concentration at five months, but also that many samples lost less than two percent.

Hospira contended that Fresenius Kabi cannot rely on any of the data for the 4 μg/mL preferred embodiment because it is either Hospira’s own development work for the patents-in-suit or is copied from it. But court disagreed & said that in this case, 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. Analyzing data from this prior art combination in order to confirm that a property is in fact inherent is not an application of hindsight, even if the data comes from the inventors. Hospira next argued that even if Fresenius Kabi can rely on this data, the data does not prove inherency by clear and convincing evidence. In support of this argument, Hospira submits that Fresenius Kabi ignored that Hospira’s development work revealed a 2.3 percent loss in concentration after five months. As Fresenius Kabi points out, this argument is puzzling because that data supports the only example in the patent of the “about 2%” limitation. And as previously discussed, named co-inventor of the ’106 Patent, Dr. Roychowdhury, testified that 2.3 percent is “within” two percent. Hospira’s argument that its own development work precludes a finding of inherency is unpersuasive.

The court said that it is aware that in Amneal, in which Hospira has asserted claim 6 of the ’106 Patent against another defendant, the Delaware court determined that the defendant failed to establish inherency of the “about 2%” limitation. The Amneal court faulted the defendant for “offering no expert testimony regarding the scientific principles underlying its inherency argument, and relying on just two examples of stability data covering the claimed 4 μg/mL dexmedetomidine concentration.” The record before this court is different. As referenced above, Fresenius Kabi has offered far more than two examples of stability data for the 4 μg/mL preferred embodiment, all of which show that the drug lost no more than two percent of its concentration at five months. Additionally, unlike in the defendant in Amneal, Fresenius Kabi has offered expert testimony regarding the chemical properties of dexmedetomidine.

Reasonable expectation of success:

Fresenius Kabi argued that a POSA would have had a reasonable expectation of success for developing a ready-to-use, sealed glass container with 4 μg/mL dexmedetomidine HCl. Setting aside the “about 2%” limitation, the court found 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 Fresenius Kabi must also prove that a POSA would have had a reasonable expectation of success concerning the “about 2%” limitation is not entirely clear to the court. Because claimed inherent property “added nothing of patentable consequence” to a formulation expressly disclosed in the prior art, without addressing reasonable expectation of success regarding the inherent property. But to the extent such a burden exists, the court concludes Fresenius Kabi has met it. Therefore, the court concluded that there is clear and convincing evidence that a POSA would have had a reasonable expectation of success in meeting the “about 2%” limitation 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 labels.

Like claim 6 of the ’106 Patent, claim 8 of the ’049 Patent covers a ready-to-use, sealed glass container with 4 μg/mL dexmedetomidine HCl. The court has already concluded for purposes of claim 6 of the ’106 Patent that the prior art discloses each of these limitations; a POSA would have been motivated to combine the disclosures; and a POSA would have had a reasonable expectation of success in doing so. That conclusion applies equally to claim 8 of the ’049 Patent. Thus, court finally concluded that Fresenius Kabi has proven by clear and convincing evidence that claim 6 of the ’106 Patent and claim 8 of the ’049 Patent are invalid as obvious.