The US Court of Appeals for the Federal Circuit held that data obtained after an asserted patent’s priority date may be used to demonstrate what is “necessarily present” in a prior art embodiment. Although the district court conflated the standards for inherency and reasonable expectation of success, the Federal Circuit determined that it was harmless error.

In Hospira, Inc. v. Fresenius Kabi USA, LLC,[1] plaintiff Hospira, Inc. (Hospira) filed suit against Fresenius Kabi USA LLC (Fresenius) alleging infringement of five patents.[2] Hospira ultimately dropped all but two claims, one of which was claim 6 of US Patent No. 8,648,106 (the ‘106 Patent), and Fresenius stipulated to infringement of this claim.[3]

Claim 6 of the ‘106 Patent depends from independent claim 1, each of which is reproduced below:

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.[4]

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 held a bench trial on Fresenius’s defense that claim 6 is invalid as obvious over the prior art combinations of Precedex Concentrate (Abbott Laboratories’ 100 μg/mL dexmedetomidine hydrochloride formulation approved in 1999) and Dexdomitor (a “ready-to-use 500 μg/mL formulation of dexmedetomidine hydrochloride” authorized for use by the European Medicines Evaluation Agency).[5]

In assessing invalidity, the district court “focused on one allegedly obvious embodiment of claim 6, namely, ‘a ready-to-use, sealed glass container—made from Type I glass and a coated rubber stopper—with 4 μg/mL dexmedetomidine HCl,’ which the court referred to as the ‘4 μg/mL preferred embodiment.’”[6] The district court held that this 4 μg/mL preferred embodiment was expressly taught by the prior art.[7]

The dispute thus centered on whether this 4 μg/mL preferred embodiment disclosed the requirement that “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” (the about 2% limitation).[8]

Although the prior art did not expressly disclose the “about 2%” limitation,” the district court ultimately concluded that Fresenius had proven by clear and convincing evidence that the “about 2% limitation” is “inherent in a 4 μg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial sealed with a coated rubber stopper, and stored at room temperature for five months.”[9] In so concluding, the district court relied on fact and expert testimony about stability data for more than 20 tested samples of 4 μg/mL dexmedetomidine hydrochloride, including 18 batch configurations in the Precedex Premix New Drug Application and three samples from Fresenius’s ANDA.[10] All samples met the “about 2% limitation.”[11]

The district court also relied on the testimony from Fresenius’s expert that the concentration of dexmedetomidine does not affect stability.[12] After concluding that the limitation was inherent, the district court further considered whether a person of ordinary skill in the art (POSITA) “would have had a reasonable expectation of success in achieving the “about 2% limitation” from combining the other limitations disclosed in the prior art.”[13]

Based on its factual findings, the district court concluded that claim 6 of the ‘106 Patent is invalid as obvious.[14]

DECISION

On appeal, Hospira challenged the district court’s conclusion that claim 6 of the ‘106 Patent is invalid as obvious based on its conclusion that the “about 2% limitation” was inherent to the prior art.[15] In particular, Hospira argued (1) 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,” and (2) “the court applied a lower ‘reasonable expectation of success standard’ rather than the higher ‘necessarily present’ standard to the inherency question.”[16]

1. Consideration of Non-Prior Art Embodiments in Inherency Analysis

Hospira first argued that the district court “erred in its application of the inherency doctrine by considering the inherent properties of non-prior art embodiments” since every tested sample of the 4 μg/mL preferred embodiment in the record was not prior art—i.e., data obtained after the patent’s priority date.[1] The Federal Circuit disagreed, noting that “[e]xtrinsic 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.”[2] As the Federal Circuit explained, “[t]he later evidence is not itself prior art; it only helps to elucidate what the prior art consisted of,” and, therefore, the district court did not err in relying on non-prior art data as evidence of the inherent stability of the 4 μg/mL preferred embodiment.[3]

Hospira further argued:

…[E]ach of those [tested] samples was manufactured using the particular manufacturing process described in Example 5 of the ‘106 patent, and thus the stability data from those samples cannot suffice to prove that all samples of the allegedly obvious combination—a formulation of the 4 μg/mL preferred embodiment which may or may not have been prepared using the manufacturing process of Example 5—would “necessarily” meet the about 2% limitation.[4]

The Federal Circuit disagreed, holding that “the unclaimed manufacturing variables in Example 5 do not, as a matter of law, preclude a finding of inherency in this case.”[5] Specifically, claim 6 is directed to a composition of 4 μg/mL dexmedetomidine disposed in a sealed glass container and is not a method claim or a product-by-process claim. Thus, “[i]mporting such limitations from Example 5 into the claim, as Hospira seeks to do, would be improper,” and the “district court did not misapply the law of inherency by considering the samples in the record without regard to the process by which those samples were prepared.”[6]

With these issues resolved, the Federal Circuit turned to the district court’s factual finding that the “about 2% limitation” was “necessarily present” in the 4 μg/mL preferred embodiment.[7] The Federal Circuit noted that “it was not clearly erroneous for the district court to find that the about 2% limitation was necessarily present in the prior art” where the trial record included (1) more than 20 samples that all met the “about 2% limitation,” and (2) testimonial and statistical evidence that dexmedetomidine is a very stable drug at any concentration.[8]

2. ‘Necessarily Present’ Standard

The Federal Circuit next considered Hospira’s argument that the district court applied a lower “reasonable expectation of success standard” instead of the higher “necessarily present” standard to the inherency question.[9] According to Hospira, the district court erred in considering whether a POSITA would have had a reasonable expectation of success in achieving the “about 2% limitation” from combining other limitations disclosed in the prior art based on his or her understanding of dexmedetomidine’s chemical properties.[10] But the Federal Circuit disagreed and determined that the district court’s inherency analysis was correct.[11]

According to the Federal Circuit, the district court’s analysis consisted of two steps: (1) first “engag[ing] 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”; and (2) then “engag[ing] in unnecessary analysis in evaluating whether dexmedetomidine’s chemical properties, label information for Precedex Concentrate and Dexdomitor, and industry guidance for stability testing would enable a POSITA to have had a reasonable expectation of successfully achieving the about 2% limitation.”[12]

Despite determining that this two-step analysis “conflated the standards for inherency and reasonable expectation of success,” the court deemed it harmless error.[13] The court explained that there is “no question of a reasonable expectation of success” in achieving a property of a composition if that property is in fact inherent.[14] As to this case specifically, the evidence showed that the dexmedetomidine formulation already possessed the “about 2% limitation,” and the district court’s additional analysis was gratuitous.[15]

CONCLUSION

The Federal Circuit’s opinion reminds practitioners that non-prior art extrinsic evidence may be used in an inherency analysis to demonstrate what is necessarily present in a prior art embodiment and may “help[] to elucidate what the prior art consisted of.”[32] The decision also confirms that the standard for inherency remains whether the prior art necessarily, or inevitably, includes the unstated characteristic or property. If that characteristic or property necessarily exists, there is no need to question whether a POSITA would have a reasonable expectation of success in achieving it.