Dexmedetomidine – USA

On Jan 09, 2020, Federal Circuit affirmed district court’s decision & found Precedex® premix patent invalid as inherently obvious.

Hospira is NDA holder for Precedex® (dexmedetomidine), used as a sedative in intensive medical care. Fresenius Kabi filed ANDA seeking approval for generic ready-to-use dexmedetomidine product. Hospira sued Fresenius for infringement of five patents and eventually dropped all but two claims, one of which was claim 6 of the US 8,648,106 patent which is dependant on claim 1.

Claim 1 is the only independent claim in the ’106 patent:

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.

Previously district court found that claim 6 of US’106 patent is invalid as obvious. Specifically, court held that prior arts disclosed exact embodiment of the current claimed formulation. Prior arts disclosed every limitation except “2% limitation”. Court said that this limitation is inherent when one practises the embodiment & thus claims are obvious. You can read the detailed discussion previously “reported here”.

Federal Ciruit decision:

Hospira appealed from the district court’s judgment mainly on 2 grounds. 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.

With respect to first point, Hospira argued that 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. And those samples were manufactured using the particular manufacturing process described in Example 5 of the ’106 patent. Federal Circuit said that district court did not err in relying on data obtained after the priority date of the ’106 patent in its inherency analysis. 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. See Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co., 878 F.3d 1336, 1345 (Fed. Cir. 2018) (allowing “non-prior art data” to be used to support inherency). The later evidence is not itself prior art; it only helps to elucidate what the prior art consisted of. 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. Furthermore, the unclaimed manufacturing variables in Example 5 do not, as a matter of law, preclude a finding of inherency in this case. Claim 6 is directed to a composition of 4 µg/mL dexmedetomidine disposed in a sealed glass container.  Claim 6 is not a method claim, it is not a product-by-process claim, and there are no limitations in claim 6 regarding the manufacturing process by which the recited 4 µg/mL dexmedetomidine composition must be prepared. Importing such limitations from Example 5 into the claim, as Hospira seeks to do, would be improper.

Now since district court did not err, the question here is that whether the about 2% limitation was necessarily present in the 4 µg/mL preferred embodiment. At trial Fresenius evidence included data from more than 20 samples of the 4 µg/mL preferred embodiment, every one of which met the about 2% limitation. The evidence also included expert testimony that concentration does not affect the stability of dexmedetomidine, which demonstrates that dexmedetomidine is a very stable drug. Federal Circuit said that Hospira’s arguments on appeal cannot change the trial record, which included more than 20 samples that all met the about 2% limitation.

With respect to second point, Hospira argued that the district court applied the “reasonable expectation of success” standard in its inherency analysis rather than “necessarily present” standard. Federal Circuit sided with district court & said that its inherency analysis was correct. Court further said that the district court engaged in a thorough and extensive analysis of the stability data in the record to reach its factual finding that the about 2% limitation was necessarily present in the prior art. But the district court then engaged in 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. The court thus conflated the standards for inherency and reasonable expectation of success. However, that was harmless error that did not infect its inherency analysis and findings. See Vanderbilt Univ. v. ICOS Corp., 601 F.3d 1297, 1308 (Fed. Cir. 2010). If a property of a composition is in fact inherent, there is no question of a reasonable expectation of success in achieving it. The claimed dexmedetomidine formulation already is, as the evidence in this case shows, possessed of the about 2% limitation. Thus district court’s factual findings were not clearly erroneous.

With respect to legal question of whether those findings support obviousness conclusion, Federal Circuit said that it is well-settled that the inclusion of an inherent, but undisclosed, property of a composition does not render a claim to the composition nonobvious. A patent can be invalid based on inherency when the patent itself makes clear that a limitation is “not an additional requirement imposed by the claims . . . , but rather a property necessarily present.” In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009); see also Persion Pharm. LLC v. Alvogen Malta Operations Ltd., Case No. 18-2361, slip op. at 13 (Fed. Cir. Dec. 27, 2019). Here, the ’106 patent itself states that the invention was based on “the discovery that dexmedetomidine prepared in a premixed formulation . . . remains stable and active after prolonged storage.” Claim 6 does not recite any manufacturing limitations that are related to stability or an added component that enhances stability; it simply recites a composition, with a “wherein” clause that describes the stability of that recited composition, a result that was inherent in the prior art.