IP Law Daily Methods of purifying antibodies and proteins were unpatentable for anticipation or obviousness
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Friday, January 10, 2020

Methods of purifying antibodies and proteins were unpatentable for anticipation or obviousness

By Thomas Long, J.D.

Overlap in temperature ranges disclosed by the challenged claims and the prior art established that the claimed range was anticipated or obvious, rendering the claims invalid.

Substantial evidence supported a finding of the Patent Trial and Appeal Board that challenged claims of a patent for methods of purifying certain antibodies and other proteins were invalid for anticipation or obviousness in light of prior art, the U.S. Court of Appeals for the Federal Circuit has held in a split decision. A temperature range taught by a prior art reference overlapped with the temperature range disclosed in the challenged claims, which set forth a prima facie case of anticipation that the patent owner failed to rebut by proving that the claimed range was "critical" to the patented methods. Circuit Judge Pauline Newman dissented, arguing that the prior art did not establish that the claimed methods were anticipated or obvious because the cited references did not even suggest that the patented methods would be successful if attempted (Genentech, Inc. v. Hospira, Inc., January 10, 2020, Chen, R.).

Patent at issue. Genentech, Inc., owned U.S. Patent 7,807,799 ("the ’799 patent"), which was directed to methods of purifying antibodies and other proteins containing a CH2/CH3 region from impurities by protein A affinity chromatography. Protein A affinity chromatography is a standard purification technique employed in the processing of therapeutic proteins, especially antibodies, which involves "using protein A ... immobilized on a solid phase." The invention of the ’799 patent "concerns a method for reducing leaching of protein A ... by reducing [the] temperature" of the "composition that is subjected to protein A affinity chromatography." According to the specification, "Preferably, .. the temperature of the composition is reduced below room temperature, for instance in the range from about 3°C to about 20°C, e.g. from about 10°C to about 18°C." The patent states, "The temperature of the composition may be reduced prior to and/or during protein A affinity chromatography." A preferred embodiment involves "lowering the temperature of the harvested cell culture fluid (HCCF) which is subjected to chromatography."

Review proceedings. Hospira, Inc., sought inter partes review (IPR) of claims 1–3 and 5–11 of the ’799 patent. The Board instituted trial on all eight grounds of unpatentability, all of which relied on two prior art references: (1) International Patent Application Publication WO 95/22389 A1, J.A. 508–54 ("WO ’389") and (2) van Sommeren et al., 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), J.A. 555–74 ("van Sommeren"). The Board determined that the challenged claims were unpatentable as anticipated by WO ’389 or rendered obvious by WO ’389 alone or in combination with other prior art. The Board also construed the claim term "about 18°C," and based on that claim construction, it concluded that all the challenged claims were unpatentable as anticipated by van Sommeren or rendered obvious by van Sommeren alone or in combination with other prior art references. Genentech appealed. The USPTO intervened to defend against one of Genentech’s arguments—that institution of IPR was unconstitutional because the ’799 patent issued before the enactment of the America Invents Act (AIA).

Anticipation by WO ’389. WO ’389 taught a method for purifying certain antibodies of the IgG class, which are proteins comprising the CH2/CH3 region, including a step wherein HCCF is subject to protein A affinity chromatography. WO ’389 taught that "all steps are carried out at room temperature (18–25°C)," whereas claim 1 of the ’799 patent "subjecting a composition ... to protein A affinity chromatography at a temperature in the range from about 10°C to about 18°C." These temperature ranges overlapped, particularly since Genentech’s proposed construction for "about 18°C" embraced temperatures up to 19 degrees.

"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," the court explained. The patentee can rebut this prima facie case of anticipation by establishing that the claimed range is critical to the operability of the claimed invention. The Board found that Genentech failed to establish that the claimed temperature range of "about 10°C to about 18°C" was critical to performing protein A chromatography, and Genentech did not challenge the Board’s finding as to criticality.

On appeal, Genentech argued that WO ’389’s statement that "[a]ll steps are carried out at room temperature (18–25°C)" referred only to the temperature of the laboratory where each step was performed, and not to the temperature of the HCCF composition applied to the chromatography column. According to Genentech, this statement could not refer to the temperature of the HCCF composition because WO ’389 disclosed some "steps" being carried out where the composition was cold or frozen. Genentech contended that even if the laboratory was at "room temperature (18–25°C)," the HCCF composition need not have been. Hospira responded that WO ’389 used the term, "room temperature (18–25°C)," to describe the temperature for conducting protein A affinity chromatography, and all the components involved in that process, including the composition to be purified, and it introduced expert testimony to support its contention.

In the appellate court’s view, substantial evidence supported the Board’s finding that the HCCF subject to protein A affinity chromatography in WO ’389 was within the claimed temperature range of claim 1. In the Board’s view, it would have been redundant to specifically call out the temperature of the HCCF during protein A affinity chromatography in light of WO ’389’s blanket statement to carry out all steps at "18–25°C." To the extent that the parties’ experts disagreed, the Board did not act unreasonably by choosing to credit Hospira’s expert over Genentech’s. Nor was the result contrary to case law, the court said, turning away Genentech’s citation of a case holding that a reference missing a limitation cannot anticipate, because, in the court’s opinion, there was no "missing limitation" in the instant case.

Obviousness based on WO ’389. As with anticipation, Genentech challenged the Board’s determination that WO ’389’s disclosed temperature range rendered the claimed temperature range obvious. If the relevant comparison between a disputed claim limitation and the prior art pertained to a range of overlapping values, explained the court, even a slight overlap in range established a prima facie case of obviousness. Again, Genentech did not dispute that it failed to establish criticality for the claimed temperature range that would rebut the prima facie case. Genentech also could rebut the prima facie case of obviousness by showing temperature was not recognized as "result-effective" in the prior art. The Board found that a skilled artisan would have recognized that the temperature for conducting protein A affinity chromatography was a result-effective variable because prior art at the time of the invention recognized that leaching was affected by temperature. The Federal Circuit held that substantial evidence supported the Board’s conclusion that it would have been routine experimentation to explore the temperature dependence of protein A leaching.

Invalidity based on van Sommeren. The court said that because it had determined that the Board did not err in concluding that all of the challenged claims were unpatentable on grounds based on WO ’389, it did not need to reach the arguments involving van Sommeren.

Retroactive application of IPR. Finally, the court rejected Genentech’s contention that retro-active application of IPR to a patent issued prior to passage of the AIA constituted a violation of the Fifth Amendment’s Takings Clause. The court recently addressed this issue in Celgene Corp. v. Peter, 931 F.3d 1342, 1356–63 (Fed. Cir. 2019), and in that case, the court reasoned that IPRs did not differ from the pre-AIA review mechanisms significantly enough, substantively or procedurally, to effectuate a taking. The court held that application of IPR to Genentech’s patent, on grounds that were available for USPTO reconsideration when the patent was issued and under the same burden of proof, did not create a constitutional issue.

Conclusion. Accordingly, the Board’s decision invalidating the challenged claims was affirmed.

Dissenting opinion. Circuit Judge Pauline Newman dissented, asserting that no prior art showed the claimed method or suggested that it might be successful. "The court presents a hindsight determination that this apparently simple solution to a difficult problem is anticipated and obvious," Judge Newman wrote, "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." According to Judge Newman, experts for both sides agreed that the prior art did not show or suggest that the claimed temperature range would produce the favorable results that were achieved.

This case is No. 2018-1933.

Attorneys: Thomas S. Fletcher (Williams & Connolly LLP) for Genentech, Inc. Thomas J. Meloro (Willkie Farr & Gallagher LLP) for Hospira, Inc.

Companies: Genentech, Inc.; Hospira, Inc.

MainStory: TopStory Patent FedCirNews

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