A Claimed Range May be Anticipated and/or Obviousness When the Lower Limit of the Range of the Reference Abuts the Upper limit of the Disputed Claim Range
| January 31, 2020
Genentech, Inc., v. Hospira, Inc.
Prost, Newman and Chen. Opinion by Chen; Dissenting opinion by Newman.
Summary
At an inter partes review (IPR) proceeding, the Board held that a reference that discloses a range where the lower limit of said range abuts the upper limit of the disputed claim range was sufficient to render the disputed patent invalid for anticipation and obviousness. The Majority Opinion of the CAFC affirmed the holding of anticipation and obviousness. The Dissenting Opinion held that there was insufficient evidence to establish anticipation, the wrong reasoning was used to establish obviousness and the findings of Board and the Majority Opinion were based on hindsight.
Details
Background
Protein A affinity chromatography is a purification method, wherein “a composition comprising a mixture of the target antibody and undesired impurities often present in harvested cell culture fluid (HCCF) is placed into the chromatography column…. The target antibody binds to protein A, which is covalently bound to the chromatography column resin, while the impurities and rest of the composition pass through the column…. Next, the antibody of interest is removed from the chromatography column….” Id. at 3. A known problem of protein A affinity chromatography is leaching, wherein protein A detaches from the column and contaminates the purified antibody solution. Thus, further purification steps of the antibody solution retrieved from the column are necessary. Patent 7,807,799 (hereinafter “‘799”), owned by Genentech, addresses the known problem of protein A leaching, with regards to antibodies and other proteins that comprises a CH2/CH3 region. By reducing the temperature of the composition that is subjected to chromatography, leaching can be prevented and/or minimized to an acceptable level of impurity for commercial purposes. Claim 1, herein presented below, is the representative claim.
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.
See Patent ‘799, Col. 35, Lines 44-47.
IPR
Hospira sought an inter partes review (IPR) of claims 1-3 and 5-11 of Patent ‘799. The Board instituted a trial of unpatentability and held that WO95/22389 (hereinafter “WO ‘389) anticipated and WO ‘389, both solely and in combination with secondary references, rendered obvious all of the challenged claims.
WO ‘389 discloses a method for purifying similar antibodies by a protein A affinity chromatography step and then a washing step, comprising washing with at least three column volumes of buffer. WO ‘389 discloses that “[a]ll steps are carried out at room temperature (18-25oC).” Id. at 6.
The Board held that WO ‘389 overlaps the claimed range of “about 10oC to about 18oC”, regardless of the claim construction of “about 18oC”. Further, the Board held that Genentech failed to establish the criticality of the claimed range to the operability of the claimed invention and thus did not overcome the prima facie case of anticipation. Also, the Board held that the claimed temperature range was in reference to the temperature of the composition both prior to and/or during chromatography. The Board held that the disclosed temperature range (18-25oC) of WO ‘389 applied to all components of the purification process and that the temperature of the HCCF composition both prior to and during chromatography were within said range.
Genentech appealed the Board’s holding of unpatentable due to anticipation and obviousness over WO ‘389. Of note, in the Appeal, Genentech did not challenge the Board’s holding that criticality of the claimed temperature range was not established.
CAFC
Anticipation
Genentech argued that the meaning of “all steps are carried out at room temperature (18-25oC)” is applicable only to the temperature of the laboratory and is not applicable to the temperature of the HCCF composition. Genentech asserted that 1) WO ‘389 discloses “steps” where the HCCF composition was cold or frozen, 2) Genentech’s expert and Hospira’s expert testified that typically HCCF coming from a bioreactor, are at a temperature of 37oC, 3) both experts testified WO ‘389 is silent regarding how long HCCF was held prior to chromatography and 4) Genentech’s expert testified that a skilled artisan in industrial processing would perform chromatography of the HCCF as soon as possible, i.e. without waiting for the HCCF to cool to room temperature, unless there were explicit instructions to do so. Id. at 8. Hospira argued that the explicit disclosure of “room temperature (18-25oC)” is with regards to the temperature of performing chromatography and all the components of said purification process, including the HCCF composition. Hospira noted that WO ‘389 disclosed specific temperatures for when the composition was not at room temperature. Further, Hospira’s expert testified that a skilled artisan would perform experiments at “ambient temperature with all materials equilibrated in order to obtain robust scientific data.” Id. at 9. The CAFC affirmed the Board and held that there was substantial evidence that the HCCF composition was within the claimed temperature of “about 10oC to about 18oC.” The CAFC agreed with the Board’s findings that 1) the statement “[a]ll steps are carried out at room temperature (18-25oC)” was a blanket statement and thus, specifying the temperature of HCCF during chromatography is redundant, 2) it disagreed with Genentech’s expert because said opinion was based upon large-scale industrially standards, and 3) it agreed with Hospira’s expert that a skilled artisan would not use HCCF at 37oC in a chromatography column and then report that all steps were performed at room temperature because the warm HCCF would raise the temperature of the entire system. Id. at 10. Lastly, the CAFC disagreed with Genentech’s argument that there was no anticipation because there was a missing limitation in WO ‘389 and agreed with the Board’s finding that WO ‘389 discloses a composition that is at the claimed temperature of “about 10oC to about 18oC” either prior to or during chromatography. (Nidec Motor Corp. v. Zhongshan Board Ocean Motor Co., cited by Genentech, holds that a reference missing a limitation cannot anticipate even if a skilled artisan would ‘at once envisage’ the missing limitation. 851 F.3d 1270, 1274–75 (Fed. Cir. 2017).” Id. at 10.)
Obviousness
The Board, citing the secondary references, determined that the temperature at which chromatography is performed is a result-effective variable and that when temperature is lowered, leaching is reduced. Thus, a skilled artisan would have been motivated to optimize temperature. Genentech argued that there was no reason or motivation to optimize the temperature because “the desire to reduce protein A leaching applies only to the large-scale, industrial purification of therapeutic antibodies for clinical applications…[and] that chilling HCCF for largescale, industrial processes would have been inconvenient, costly, and impractical.” Id. at 13. Hospira argued that a skilled artisan in non‑clinical applications would have been motivated to reduce leaching because leaching damages chromatography columns. The CAFC held that the Board was correct in holding that neither the ‘799 patent nor WO ‘389 are limited to large-scale industrial applications. The CAFC affirmed the Boards’ finding that temperature is a “result-effective variable” and that it would have been routine experimentation for a skilled artisan to optimize the temperature to reduce protein A leaching.
Dissent
Newman dissented and asserted that affirming the holding of invalidity for anticipation and obviousness was an error because none of the prior art shows or suggest the claimed method. Id. at 9. According to Newman, the determination by the Board and the CAFC is based on hindsight. Newman noted that the “retrospective simplicity of the solution apparently led the Board to find it obvious to them, despite the undisputed testimony that no reference suggests this solution to the contamination problem here encountered, as the experts for both sides acknowledged.” Id. at 3. Newman noted that the ‘799 patent disclosed in detail the complexities with regards to obtaining and purifying antibodies, the many factors to consider when performing chromatography, the problems associated with the leaching of protein A, and explained their discovery of the cause of said leaching and their solution to said problem. At the Board, Genentech argued the advantages of their claimed method, i.e. prevent leaching of protein A in protein A affinity chromatography, in contrast to the need to perform additional purification chromatography to remove protein A, as in WO ‘389. Both experts agreed that the reference to room temperature (18-25oC) was in reference to the ambient temperature and was not in reference to the chilled material in the column. “Nonetheless, the PTAB and now my colleagues hold that this ‘room temperature’ range anticipates the ‘799 patent’s chilled range of 10oC-18oC, ignoring the significantly different results in the recited ranges.” Id. at 6.
According to Newman, mere abutment of the 18oC is not anticipation. “Anticipation requires that the same invention, including all claim limitations, was previously described. Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 851 F.3d 1270, 1274– 75 (Fed. Cir. 2017). The “anticipating reference must describe the entirety of the claimed subject matter.” Id. at 7. Newman holds that the affirmation of anticipation fails to consider the “absence of identify of these ranges” (18-25oC vs. about 10oC-about 18oC), fails to consider “the different results at the lower range” and fails to consider “the significance of the purity of the eluted antibody.” Id. at 8 Regarding obviousness, Newman holds that there is no evidence that it was known or suggested that cooling the HCCF composition either prior to or during chromatography would minimize or prevent leaching of the protein A in the purified antibody solution. According to Newman, “the question is not whether it would have been easy to cool the material to the 10ºC–18ºC 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 antibody with leached protein A.” Id. at 9. That is, even if it is possible to modify the temperature, Newman asserts that there is no reason or motivation to optimize the temperature to prevent leaching of protein A.
Takeaway
- If possible, establish the criticality of a claimed range. One is encouraged to rebut a prima facie case of anticipation or obviousness by establishing that the claimed range is critical to the operability of the claimed invention.
- If there is an overlap of a disputed claim range and the range disclosed in the prior art, but the results are different, this may be evidence of the criticality of the range.
