Decision: Hospira, Inc. v. Fresenius KABI USA, LLC, Nos. 16-cv-651 and 17-cv-7903, 2018 WL 6621401 (N.D.Ill. Dec. 17, 2018))

This case provides an example of the use of inherency in an obviousness determination. That is, the Northern District Court of Illinois found that claim 6 of U.S. Pat. 8,648,106 (the ’106) patent would have been obvious based on a finding that the prior art inherently contained a certain property. But the authors suggest that inherency in the obviousness context should generally be very narrowly applied and that this case, based on its particular facts, is an exception to such narrow application.

Background:

The claims at issue in Hospira v Fresenius recite a product made from dexmedetomidine (dex) that Hospira sells as Precedex Premix. Precedex Premix is a ready-to-use diluted version of Hospira’s Precedix Concentrate, on the market since 1999. Fresenius, filing an an ANDA with the FDA to sell its own proposed dex products, challenged the ’106 patent.

After the district court’s claim construction order and prior to trial, Hospira dropped all but claim 6 of the ’106 patent. Fresenius stipulated that its proposed product would infringe claim 6 but asserted invalidity of claim 6, which depended from claim 1 and both are repeated herein:

Claim 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 ug/mL.

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.

Issue: The obviousness issue, centering on the claim limitation of “no more than about 2% decrease” in the concentration of dex, was articulated as follows:

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.

According to Hospira, the answer was “no” - a 4 μg/mL formulation stored under these conditions will not always meet that claim limitation.

Fresenius, however, proffered expert testimony that none of the data Hospira submitted with its NDA showed a loss of concentration of more than 2% at five months. Another Fresenius expert testified that “the stability data he analyzed for Precedex Concentrate (100 μg/mL and 200 μg/mL formulations) showed that dex experienced no more than two percent loss at five months.”

Outcome: While the district court found that all of the limitations of claim 6 were present in the prior art except for the “about 2%” limitation, the court found that one of ordinary skill in the art would have been motivated to modify the prior art to obtain a ready-to-use product and would have had a reasonable expectation of success in obtaining a product that met the “about 2%” limitation.

Here, the “about 2%” limitation was found 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, in view of stability data of record and expert testimony. Specifically, expert testimony showed that every sample tested lost no more than 2% concentration at five months. Furthermore, from a chemical properties’ perspective, expert testimony showed that dex was expected to be “rock stable” over “any long period of time.”

In support of its inherency conclusion, the district court found it significant that the “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.” “This information bolsters the court’s conclusion that the data concerning the 4 μg/mL preferred embodiment showed by clear and convincing evidence that the ‘about 2%’ limitation necessarily results from the combination of the prior art teaching of the embodiment, rather than something that probably or possibly results.”

The court discussed several inherency/obviousness decisions, including PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186 (Fed. Cir. 2014) (stating that in some circumstances, “inherency may supply a missing claim limitation in an obviousness analysis”); Millennium Pharm., Inc. v. Sandoz Inc., 862 F.3d 1356 (Fed. Cir. 2017); Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A., 865 F.3d 1348 (Fed. Cir. 2017); and Endo Pharm. Solutions, Inc. v. Custopharm Inc., 894 F.3d 1374 (Fed. Cir 2018). Below is a brief synopsis of those cases.

In Par Pharma., Inc. v. TWI Pharms., Inc., 773 F.3d 1186 (Fed. Cir. 2014), the district court held that claims directed to a method of treatment using nanoparticles of a megestrol formulation would have been obvious. The claims at issue recited that there was no substantial difference in maximum concentration achieved when the formulation was administered in a fed versus a fasted state. The Federal Circuit vacated the district court’s determination that the claimed food effect was inherent and that the claims therefore would have been obvious. As the court explained, inherency must be limited when applied to obviousness, and the limitation must be the “natural result” of the combination of prior art elements. Because the district court had not made any findings that the claimed food effect necessarily occurred, the court remanded for additional fact-finding.

In Millennium Pharms., Inc. v. Sandoz Inc., 862 F.3d 1356 (Fed. Cir. 2017), the district court held that claims to a new compound, the D-mannitol ester of bortezomib, would have been obvious despite evidence of unexpected results and unpredictability. The inventors had lyophilized bortezomib, a known compound, in the presence of mannitol. There was nothing in the prior art to indicate that the specific new compound would be created by this process, or that the new compound would have superior properties that would solve the stability problems associated with bortezomib. The district court nevertheless determined that the ester was a natural result of freeze drying the bortezomib with mannitol, meaning the ester was the inherent, or “inevitable,” result of the combination and that Millennium had conceded this fact. The Federal Circuit disagreed with this analysis and reversed the district court’s obviousness determination.

In Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A., 865 F.3d 1348 (Fed. Cir. 2017), the PTAB found that the stability and miscibility of the claimed mixture of HFO-1234yf and PAG were unexpected properties. But the PTAB nevertheless determined that they were inherent and that the claims to this mixture would have been obvious. The Federal Circuit reversed, holding that the PTAB should not have dismissed properties as merely inherent without further looking into their unpredictability and unexpectedness. Importantly, the court explained that “all properties of a composition are inherent,” and thus when considering the obviousness of a composition what matters is whether its properties are known and expected.

In Endo Pharm. Solutions, Inc. v. Custopharm Inc., 894 F.3d 1374 (Fed. Cir 2018), the claims related to Aveed®, a testosterone undecanoate (TU) intramuscular injection. Prior art references disclosed using a composition of 250 mg/ml TU in castor oil but not the use of it as a co-solvent. The district court held that the claims were not invalid; there was no inherent disclosure just because that is what the prior art used. The Federal Circuit affirmed. Custopharm did not show that a formulation was necessarily present and did not show that a POSA would necessarily have recognized that the art used benzyl benzoate as a co-solvent. Nor would the POSA have recognized the claimed ratio.

In Hospira, the court distinguished Millennium, where a finding of inherency was overturned by the Federal Circuit because it was based on a hindsight review of the inventor’s research, by explaining that:

In this case, unlike in Millennium Pharmaceuticals, 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, at 36-37.

The court also rejected another district court’s finding regarding the very same ’106 patent that another defendant failed to establish inherency of the “about 2%” limitation, noting that “[t]he record before this court is different.” (The other case is Hospira, Inc. v. Amneal Pharm., LLC,. 285 F.Supp.3d 776 (D. Del. 2018).

Prosecution Takeaway:

Hospira lost partly because Fresenius only had to show inherency of a single embodiment, not inherency of every possible embodiment. Fresenius met that burden, thus coming within the boundaries of Federal Circuit inherency/obviousness caselaw like In re Kao, 639 F.3d 1057 (Fed. Cir. 2011), where features are shown to be necessarily present in otherwise obvious subject matter, and there is no showing that those features are unexpected.

There remains a tension between inherency (which allows for later recognition) versus obviousness (in which hindsight is forbidden). Recognizing this tension, the Federal Circuit has repeatedly cautioned that the use of inherency must be “carefully circumscribed” in the context of obviousness. See, e.g., Honeywell, 865, F.3d at 1354 (“the use of inherency in the context of obviousness must be carefully circumscribed because ‘[t]hat which may be inherent is not necessarily known’ and that which is unknown cannot be obvious. In re Rijckaert, 9 F.3d 1531, 1534 (Fed. Cir. 1993) … (quoting In re Spormann, 363 F.2d 444, 448 (1966)).” It will be interesting to see if this case is appealed and if so, whether the Federal Circuit will agree with the district court that this case is distinguishable from Millennium and the other recent Federal Circuit decisions applying the doctrine of inherent obviousness narrowly.

Then again, the peculiar facts of this case might be enough for the Federal Circuit to sustain the decision on appeal, i.e., here, the judge accepted testimony that all of the formulations analyzed met the “not more than 2%” deterioration of dex and also found persuasive Fresenius expert’s testimony based on the chemical structure of dex, that dex would be expected to be “rock stable” for “any long period of time.”

If faced with an inherent obviousness argument during prosecution or before PTAB in an AIA post-grant proceeding, it could be helpful to remind the examiner/administrative law judge that the Federal Circuit has repeatedly stated that inherent obviousness is a narrow doctrine. And, particularly in an inter partes PTAB proceeding, it could be helpful to demonstrate that the petitioner either provided no evidence or that the evidence offered falls far short of the type of evidence found persuasive in Hospira v. Fresenius. In other words, inherent obviousness must satisfy strict standards. The inherent limitation(s) must necessarily be present in the combination of references, buttressed by a reasonable expectation of success. It is not enough to merely show that the limitation “possibly” or “probably” is present.

Moreover, inherent properties of a new combination can be patentable if those properties were not expected at the relevant time. If you are faced with an opponent, such as in an AIA post-grant proceeding, trying to use the principle of inherent obviousness to discount evidence of unexpected results, push back. Perhaps you can demonstrate that your facts are controlled by Honeywell, where the Federal Circuit explained, in rejecting inherent obviousness, that “[w]hat is important regarding properties that may be inherent, but unknown, is whether they are unexpected.” Honeywell., 865 F.3d at 1355.

As always when relying on expert declarations and crafting arguments before the USPTO (including the PTAB), parties must remember that the duty of disclosure applies. Selective disclosure of test results or intentional omissions or misrepresentations may lead to facing allegations of inequitable conduct in later litigation.

For example, one can imagine that in challenging an Examiner’s inherent obviousness rejection, the applicant should not make arguments that are inconsistent with evidence about the prior art, and what would necessarily result therefrom, that is in possession of any of the inventors. And this underscores the importance of making sure all inventors are properly named. If not, one can conceive making arguments inconsistent with evidence in possession of an unnamed inventor.