Last week, the Federal Circuit affirmed invalidation of claims to methods for reducing Protein A leaching in affinity column chromatographic methods important inter alia in purifying monoclonal antibodies, in Genentech, Inc. v. Hospira, Inc. In doing so, the panel majority (over a dissent by Judge Newman) illustrated anew the importance of the deference the U.S. Patent and Trademark Office (and particularly the Patent Trial and Appeal Board) is due under the Administrative Procedures Act, and how that deference can be outcome determinative under the right circumstances.
The case arose before the PTAB in an inter partes review (IPR) of U.S. Patent No. 7,807,799, which claimed methods for purifying antibodies comprising a CH2/CH3 region using Protein A affinity chromatography. The claimed methods are directed to an improvement wherein the amount of Protein A contaminant in the antibody eluate is minimized (substantially to zero). The opinion characterized the claimed method as a "standard purification technique," relying on high affinity, reversible binding to CH2/CH3 regions, which methods were capable of "reducing leaching of protein A . . . by reducing [the] temperature" of the "composition that is subjected to protein A affinity chromatography." The inventors found that leaching can be minimized by performing chromatography at temperatures between 10-18°C (the specification also disclosing a broader range of 3-20°C). Claim 1 of the '799 patent is representative:
A method of purifying a protein which comprises CH2/CH3 region, comprising subjecting a composition comprising said protein to protein A affinity chromatography at a temperature in the range from about 10°C to about 18°C.
The primary references asserted by Hospira in its IPR was International Publication No. WO 95/22389 and a scientific reference contributed by van Sommeren and colleagues to a treatise entitled Effects of Temperature, Flow Rate and Composition of Binding Buffer on Adsorption of Mouse Monoclonal IgG1 Antibodies to Protein A Sepharose 4 Fast Flow, 22 PREPARATIVE BIOCHEMISTRY 135 (1992), as well as other secondary references that were applied in combination with the '389 PCT publication for the Board's obviousness determinations. The '389 PCT publication disclosed Protein A purification of antibodies performed at room temperature, defined as 18-25°C, which overlapped with the '799's temperature range of from about 10°C to about 18°C. The Board held all claims in IPR (1-3 and 5-11) to be anticipated by the '389 PCT publication or obvious in light of the '389 PCT publication or the van Sommeren reference as primary reference, in combination with other secondary references. Genentech appealed and also challenged the constitutionality of applying IPRs retroactively in view of the '799 patents priority date; the Federal government intervened to address this issue on appeal.
The Federal Circuit affirmed, in an opinion by Judge Chen joined by Chief Judge Prost; Judge Newman dissented. Regarding the Board's anticipation decision, the Federal Circuit relied on the overlap of the temperature ranges, on the basis that the method disclosed in the '389 PCT publication was directed to purifying antibodies comprising the CH2/CH3 region and included a Protein A purification step performed at room temperature, defined in the specification as the range of 18-25°C. The Federal Circuit's opinion states that "[a] prior art reference that discloses an overlapping but different range than the claimed range can be anticipatory, even where the prior art range only partially or slightly overlaps with the claimed range," citing Ineos USA LLC v. Berry Plastics Corp., 783 F.3d 865, 870–71 (Fed. Cir. 2015). The question that a court must answer, according to the opinion, is "whether the patentee has established that the claimed range is critical to the operability of the claimed invention," citing Ineos and E.I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1008 (Fed. Cir. 2018). The Board found that Genentech had not carried this burden and (curiously, perhaps) Genentech did not challenge this finding on appeal.
The Board also found that the '389 PCT publication taught that Protein A column chromatography was performed throughout at room temperature (18-25°C, i.e., the overlapping temperature range). Genentech attempted to challenge this interpretation on the ground that "room temperature" as disclosed in the '389 PCT publication was precisely that, the temperature of the room in which the chromatography was performed and not the temperature of the components, buffers, etc. used in the purification. Genentech based this argument in part on the temperature of the source material to be subjected to chromatography (i.e., antibody preparations from cells cultured at 37°C) in the absence of instructions in the '389 PCT publication to cool this material to "room temperature" and relied on testimony from its expert. Hospira's expert, on the contrary, argued that those of skill in the art would perform chromatography at "ambient" (room) temperature. The Federal Circuit majority held that "substantial evidence supports the Board's finding that the HCCF subject to protein A affinity chromatography in WO '389 is within the claimed temperature range of claim 1." The majority identified portions of Genentech's expert's testimony that it disagreed with (correctly, in the majority's view) and held that "to the extent the experts disagreed with one another, the Board reasonably chose to credit the testimony of [Hospira's expert] over the testimony of [Genentech's expert], another instance where the deference the Court is mandated to give fact questions to the Board under Dickinson v. Zurko was dispositive. The Federal Circuit majority also rejected Genentech's argument that the Board's decision was contrary to the Court's precedent (thus converting the issue to a question on law) and affirmed the Board's determination that Genentech's claims were invalid for anticipation by the disclosure in the '389 PCT publication.
Turning to the Board's decision that the claims were also obvious over the combination of the disclosure of the '389 PCT publication in combination with a variety of other prior art references, the panel majority relied on their precedent that "[i]f the relevant comparison between a disputed claim limitation and the prior art pertains to a range of overlap-ping values, 'we and our predecessor court have consistently held that even a slight overlap in range establishes a prima facie case of obviousness,'" citing In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). This has the effect of raising a presumption of obviousness, according to the opinion, thus shifting the burden on the patentee to rebut the presumption (which the Board held Genentech did not do and the panel majority affirmed). Genentech neither showed that the temperature range was critical to the invention nor that the prior art did not recognize temperature as being "result-effective" (two ways to achieve the required rebuttal). This latter stratagem was ineffective in the Board's view because the prior art understood Protein A leaching to be the result of proteolysis, and that proteolysis was affected by temperature. Moreover, according to the Court, "[t]he Board reasonably found that a skilled artisan would have been motivated to optimize the temperature given the teachings of the prior art, and that given the ease with which temperature can be varied, finding an optimal temperature range would have been nothing more than routine experimentation." The panel majority rejected Genentech's argument that the purported desire to reduce Protein A leaching was relevant only in large-scale, industrial applications of the technique, not at least because Genentech's claim was not limited to these circumstances.
Finally, the Board held that the objective indicia of nonobviousness did not change their conclusion that Genentech's claims were obvious, and the panel majority affirmed this determination.
The majority's opinion closes with the Court's rejection of Genentech's challenge that inter partes review are an unconstitutional violation of the Fifth Amendment (for reasons substantially identical to the Court's earlier opinion in Celgene Corp. v. Peter, 931 F.3d 1342, 1356–63 (Fed. Cir. 2019)), nor the Seventh Amendment nor Article III.
Judge Newman dissented, on the basis inter alia that the invention had actually solved a real world problem and that the majority's affirmance ignored the value the invention brought to the art. "The court presents a hindsight determination that this apparently simple solution to a difficult problem is anticipated and obvious, although it was not known or obvious to the scientists who were attempting to solve the problem of leaching contamination, and the experts for both sides agreed that the solution presented in the '799 patent was new to them," Judge Newman writes. She sees the complexities involved in arriving at this solution, and the failure in the art to disclose the solution rebuts, for the Judge the Board's invalidation on anticipation and obviousness grounds. On the merits, Judge Newman discounts the overlap at 18°C as supporting anticipation, because her understanding of the law would require the temperature range disclosed in the '389 PCT publication (18-25°C) to be the same as the claimed temperature range (10-18°C). And Judge Newman rejects the "optimization" basis for the Board's obviousness determination (and the majority's affirmance), stating that:
[T]he question is not whether it would have been easy to cool the material to the 10°C - 18°C range; the question is whether it would have been obvious to do so. Contrary to the Board's and the court's view, this is not a matter of optimizing a known procedure to obtain a known result; for it was not known that cooling the material for chromatography would avoid contamination of the purified protein with leached protein A.
Genentech, Inc. v. Hospira, Inc. (Fed. Cir. 2020)
Panel: Chief Judge Prost and Circuit Judges Newman and Chen
Opinion by Circuit Judge Chen; dissenting opinion by Circuit Judge Newman
