In pursuing the most efficient production of a drug material (i.e., the active pharmaceutical ingredient in a drug product) exhibiting optimal potency for the therapeutic endpoint of interest, chemists and drug companies explore strategies for removing or minimizing impurities in that drug material that do not contribute to such potency. For example, where a drug material consists of a racemic mixture of enantiomers, one may wish to explore whether the activity of the drug in fact resides with a single enantiomer within the racemic mixture. When formulating an argument regarding the patentability over the prior art (or lack thereof) of a patent claim directed to an isolated component of a prior art mixture, it is worthwhile to step back and consider from which analytical framework it will likely be most advantageous to present one’s argument, taking into consideration potentially applicable Federal Circuit case law. For example, one might analyze the issue by viewing the purified drug material as a species; i.e., relative to the genus/racemic mixture. It is also conceivable that one might liken the purified drug material to a range within a larger range and apply a burden-shifting framework such as that which the Federal Circuit applied in Galderma. See Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731 (Fed. Cir. 2013). In short, arguments could be made for applying several different potential modes of analysis. It is, therefore, worthwhile to examine how the Federal Circuit has dealt with obviousness and anticipation challenges to patent claims directed to an isolated component of a prior art mixture.
As a general rule, disclosure of a drug material comprised of a mixture of components, without more, does not render obvious a specific component of that mixture. See, e.g., In re May, 574 F.2d 1082, 1090 (CCPA 1978); Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1084 (Fed. Cir. 2008). The Federal Circuit has held that, if the prior art discloses a drug material comprised of a mixture of compounds and the activity of the drug material is known to reside with one particular component of the prior art mixture/drug material, or if the prior art provides reason to believe this is so, then there will generally be found to be motivation to purify the mixture and isolate the active component even without an express teaching to this effect. Aventis Pharma Deutschland GmbH v. Lupin Ltd., 499 F.3d 1293, 1301 (Fed. Cir. 2007) (“Requiring an explicit teaching to purify the 5(S) stereoisomer from a mixture in which it is the active ingredient is precisely the sort of rigid application of the TSM test that was criticized in KSR.”); see also Spectrum Pharms., Inc. v. Sandoz Inc., 802 F.3d 1334 (Fed. Cir. 2015). In such instances, isolation of the purified component will be prima facie obvious even without an express teaching in the prior art to isolate the component. Aventis Pharma Deutschland, 499 F.3d at 1301. The Federal Circuit has explained that “[o]rdinarily, one expects a concentrated or purified ingredient to retain the same properties it exhibited in a mixture, and for those properties to be amplified when the ingredient is concentrated or purified; isolation of interesting compounds is a mainstay of the chemist’s art. If it is known how to perform such an isolation, doing so is likely the product not of innovation but of ordinary skill and common sense.” Id. at 1302 (internal quotations omitted). As noted in Spectrum, “[a] physician would not likely want to administer a contaminant or a less pure material to a patient if one could use a pure material. Thus, there is always in such cases a motivation to aim for obtaining a pure, resolved material.” Spectrum Pharms., 802 F.3d at 1334-35.
The above Federal Circuit guidance, however, concerns instances where the component of interest is known to exist within the prior art mixture and is known to be responsible for the beneficial physical, chemical, and/or biological properties of the mixture, or the prior art provides reason to believe this is so. The Federal Circuit has recognized, however, that “[i]t may not be known that the purified component is present in or an active ingredient of the mixture,” and where this is the case, the court has held that “[s]uch a purified compound is not always prima facie obvious over the mixture.” Aventis Pharma Deutschland, 499 F.3d at 1301. In such instances, courts will default back to an analysis of the structural similarities/differences between the claimed component and the other component(s) of the prior art drug material known to exhibit the desired properties in assessing obviousness. Id. at 1302. The Federal Circuit engaged in such an analysis in Aventis. On this issue, the court reasoned as follows:
The record suggests that when Dr. Smith synthesized SCH 31925, she understood that the 5(S) form of Ramipril was the mixture’s therapeutically active ingredient. Even if she did not, however, the prior art provides a sufficient reason to look to the 5(S) configuration. The SCH31925 composition contained only the 5(S) and SSSSR stereoisomers of ramipril. Importantly, the forms differ by the configuration of only one carbon atom, and that atom is not one of the “bridgehead” carbons.
Id. at 1302.
Where it has been shown that the claimed component was known to exist in the prior art mixture and was known to be responsible for the beneficial properties of that mixture, the patentee can establish nonobviousness by showing that the isolated component exhibits unexpectedly superior properties relative to the prior art mixture. Aventis Pharma Deutschland, 499 F.3d at 1302; see also Sanofi-Synthelabo, 550 F.3d at 1089-90.
A patentee may also escape an obviousness finding based in whole or in part on the process used to isolate the desired component. For example, where the patentee has shown that the isolated component exhibits unexpected results, the fact that the process used to purify the prior art mixture would be a challenge for the person of ordinary skill in the art to carry out will further weigh in favor of a nonobviousness finding. Forest Labs., Inc. v. IVAX Pharms., Inc., 501 F.3d 1263, 1269 (Fed. Cir. 2007). Consistent with the foregoing, the Federal Circuit has held that where the process used to isolate the desired component from a prior art mixture is inventive, this may support a finding of nonobviousness of the component. Mylan Institutional LLC v. Aurobindo Pharma Ltd., 857 F.3d 858 (Fed. Cir. 2017); Aventis Pharma Deutschland, 499 F.3d at 1301.
Relatedly, the Federal Circuit has analyzed how enablement principles tie in to these sorts of obviousness analyses, understanding that the prior art need not, strictly speaking, enable the claimed subject matter as is necessary with anticipation. The Federal Circuit has held that even where the specific pieces of prior art relied upon do not enable one of ordinary skill in the art to isolate the desired component from the prior art mixture, the purified component will be held obvious where the “whole spectrum of prior art available before the invention was made would have enabled one of ordinary skill in the art to make and use the [purified] compound.” Spectrum Pharms., 802 F.3d at 1335-36 (citing Aventis Pharma Deutschland, 499 F.3d at 1301). Where the prior art as a whole does not enable purification of the desired component, however, the purified component may be nonobvious. Mylan Institutional, 857 F.3d at 871.
The above discussion concerns obviousness challenges to a patent claim directed to a purified component of a prior art mixture (for example, an enantiomer isolated from a racemic mixture); but what about where anticipation is argued? Under what circumstances will disclosure of a prior art mixture be viewed as constituting disclosure of a specific component of that mixture so as to anticipate a claim directed to that component?
The Federal Circuit has analyzed this issue as a genus-species issue. See e.g., Sanofi-Synthelabo, 550 F.3d at 1083-84. In Sanofi-Synthelabo the court re-affirmed the principle that “whether a generic disclosure necessarily anticipates everything within the genus … depends on the factual aspects of the specific disclosure and the particular products at issue.” Id. at 1083. More directly relevant to this discussion, the court held that “general statements that these compounds consist of enantiomers [do not] constitute an anticipating disclosure of the [specific claimed] enantiomer….” Id. at 1084. Similarly, the court held that “[t]he knowledge that enantiomers may be separated is not ‘anticipation’ of a specific enantiomer that has not been separated, identified and characterized.” Id. Along these same lines, a prior art reference disclosing a racemic mixture will not enable a later claim directed to a specific enantiomer, as is necessary for an anticipation finding, where it does not expressly teach how to separate out the desired enantiomer. Id. at 1085; see also Forest Labs., In, 501 F.3d at 1268-69.
Based on the governing Federal Circuit case law, where the patent claim at issue is directed to a specific component (such as a specific enantiomer) of a prior art mixture (such as a racemic drug material), it does not appear that there is anything to be gained by a patent challenger, from an anticipation standpoint, simply by virtue of the fact that the specific component inherently exists within that prior art mixture/composition. In other words, while a claim to such an isolated component may potentially be vulnerable to an anticipation attack, the anticipatory reference needs to specifically identify and characterize the component, and must teach how to isolate the component. Absent this sort of “slam dunk” scenario, a patent challenger’s success is likely to rise or fall with the merits of its obviousness argument(s). The critical factors in the obviousness analysis will likely be whether the claimed component was known to be responsible for the activity of the prior art mixture/composition; whether the process used to isolate the claimed component was challenging, or better yet still from the patentee’s perspective, whether the process was inventive; whether the prior art as a whole would have enabled one of ordinary skill in the art to isolate the claimed component; and whether the claimed component exhibits any unexpectedly superior properties relative to the prior art mixture/composition.