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BIOTECH BUZZ Industrial Biotechnology Subcommittee February 2015 Contributor: Judith Roesler Butamax™ Advanced Biofuels LLC v. Gevo, Inc., Certiorari Summary Disposition, 13-1286, January 26, 2015, 574 U.S. ___ (2015) Summary On January 26, 2015, the Supreme Court granted the petition for a writ of certiorari in Butamax Advanced Biofuels LLC v. Gevo Inc. (“Butamax”) and remanded the case for further consideration in light of Teva Pharmaceuticals USA, Inc., v. Sandoz., Inc., 574 U.S. ___ (2015) (“Teva Pharmaceuticals”). At issue was the review of claim construction de novo by the Court of Appeals for the Federal Circuit (the “CAFC”) in February 2014 as compared to the “clear error” standard of review recently set forth by the Supreme Court in Teva on January 20, 2015. Background Butamax is a joint venture between E.I. DuPont de Nemours and Co. and BP Biofuels North America LLC formed in 2009 with the goal of producing renewable fuel technologies. Gevo is also active in renewable fuel technologies. Both Butamax and Gevo are engaged in the production of isobutanol through biosynthesis using plant materials. Isobutanol has a high energy content and can be blended with fossil fuel. The patents-in-suit, U.S. Patent Nos. 7,851,188 (“the ‘188 Patent”) and 7,993,889 (the ‘889 Patent”) are assigned to Butamax. The ‘889 Patent is a divisional of the ‘188 Patent. Claim 1 of the ‘188 Patent is directed to a recombinant microbial host cell comprising heterologous DNA molecules encoding polypeptides that catalyze substrate to product conversions, with the conversions recited in four steps and the polypeptides for each conversion also recited. The enzymes set forth in Claim 1 of the ‘188 Patent include, among other things, the EC (Enzyme Commission) number for each recited polypeptide. Claim 1 of the ‘889 Patent is directed to a method for producing isobutanol from a recombinant yeast microorganism expressing an engineered isobutanol biosynthetic pathway, with the conversions and the enzymes utilized for five conversion steps included in the claim language. The enzymes set forth in Claim 1 of the ‘889 Patent do not include an EC number. Butamax sued Gevo on January 14, 2011 and later moved for a preliminary injunction based upon the ‘889 Patent. One of the issues appealed to the United States Court of Appeals, Federal Circuit (“Federal Circuit”) concerns claim construction for one of the recited steps of the biosynthetic pathway in the ‘889 Patent. Although the EC number was not recited in Claim 1 of the ‘889 Patent nor was any dependence on a coenzyme such as NADPH or NADP recited in the claim, the district court construed the claim as “an enzyme known by the EC number 1.1.1.86 that catalyzes the conversion of acetolactate to 2,3-dihydroxyisovalerate and is solely NADPH-dependent.” Federal Circuit Decision (Case No. 2013-1342; Decided February 18, 2014) Butamax appealed the final judgment entered against it following the district court’s decisions on a number of motions and the district court’s claim construction. The Federal Circuit accepted the appeal and reviewed claim construction de novo. On February 18, 2014, the Federal Circuit (before Chief Judge Rader, Linn and Wallach, Circuit Judges) found that the district court erred in its claim construction and vacated the district court’s denial of Butamax’s motion for summary judgment of infringement of the ‘188 Patent and the ‘889 Patent and its grant of Gevo’s motion of noninfringement under the doctrine of equivalents. In response, Gevo filed a petition for a Writ of Certiorari with the Supreme Court to vacate the decision of the Federal Circuit. Supreme Court Certiorari Summary Disposition (Case No. 13-1286; Decided January 26, 2015) In light of the decision in Teva Pharmaceuticals, the Butamax case was remanded to the Federal Circuit for further consideration on January 26, 2015. In Teva Pharmaceuticals, the Supreme Court held that when reviewing a district court’s resolution of subsidiary factual matters made in the course of its construction of a patent claim, the Federal Circuit must apply a “clear error,” not a de novo, standard of review. Discussion The primary claim construction dispute before the Federal Circuit in Butamax concerns whether the enzyme recited in step (ii) of the patent claims must be “NADPHdependent.” The enzyme in question is the enzyme polypeptide enzyme acetohydroxy acid isomeroreductase (also known as “KARI”). To accomplish the conversion, KARI requires a cofactor as an electron source. Two such cofactors are NADH and NADPH. According to the district court record, Gevo uses mutant KARI enzymes that when using NADH as a cofactor exhibit significantly lower Km (Michaelis-Menten constant) for the conversion of acetolactate to 2,3-dihydroyisovalerate in their isobutanol process. Claim 1 of the ‘889 Patent is reproduced below. 1. A method for producing isobutanol comprising; a. providing a fermentation media comprising carbon substrate; and b. contacting said media with a recombinant yeast microorganism expressing an engineered isobutanol biosynthetic pathway wherein said pathway comprises the following substrate to product conversions; i. pyruvate to acetolactate (pathway step a); ii. acetolactate to 2,3-dihydroxyisovalerate (pathway step b); iii. 2,3-dihydroxyisovalerate to .alpha.-ketoisovalerate (pathway step c); iv. α-ketoisovalerate to isobutyraldehyde (pathway step d); and v. isobutyraldehyde to isobutanol (pathway step e); and wherein a) the substrate to product conversion of step (i) is performed by an acetolactate synthase enzyme; b) the substrate to product conversion of step (ii) is performed by an acetohydroxy acid isomeroreductase enzyme; c) the substrate to product conversion of step (iii) is performed by an acetohydroxy acid dehydratase enzyme; d) the substrate to product conversion of step (iv) is performed by a decarboxylase enzyme; and e) the substrate to product conversion of step (v) is performed by an alcohol dehydrogenase enzyme; whereby isobutanol is produced. The district court considered the patents’ specifications, prosecution histories, and the extrinsic evidence such as expert testimony and the EC enzyme classification system and other enzyme databases. It concluded that in the “state of the art,” the KARI enzyme known by the EC number 1.1.1.86 was generally understood to be NADPH dependent. In reviewing the district court’s decision, the Federal Circuit considered (i) the plain meaning of KARI; (ii) the specification and claims; (iii) prosecution history; (iv) extrinsic evidence; and (v) claim construction, as summarized in brief below. (i) The Federal Circuit found that the plain meaning of KARI itself imposes no limitation on the cofactor for the conversion of acetolactate to 2,3dihydroxyisovalerate. (ii) In the specification, the patentee offered a definition of KARI but it is disputed whether the definition “clearly expresses an intent” to refine KARI in a way that differs from the plain and ordinary meaning. The specification indicated that the definitions were intended for interpretation of the claims and specification. The specification then went on to generally describe KARI as an enzyme that catalyzes the conversion of acetolactate to 2,3-dihydroxyislovaerate using NADPH as an electron donor. The Federal Circuit found that the use of the phase “using NADPH” in the specification did not mean “only use NADPH” or “NADPHdependent” as argued by Gevo. The Federal Circuit also found that the district court’s claim construction improperly excluded a preferred embodiment described in the specification where KARI from Methanococcus maripaludis SEQ ID NO: 183 is taught as “able to utilize NADH as well as NADPH.” (iii) The prosecution history showed the patentee defending against enablement rejections by referring the Patent Office to the EC numbers and examples of enzymes provided in the specifications. The Federal Circuit did not consider the statements to warrant any limitation of the claimed KARI as being NADPH-dependent. (iv) In considering extrinsic evidence, the Federal Circuit found that a subsequent patent filing by Butamax which taught a “discovery of a KARI enzyme that can use NADH as a cofactor as opposed to NADPH would be an advance in the art” was subsequent extrinsic evidence that did not clearly express an intent at the time of the invention to refine KARI to use one cofactor over another. (v) The Federal Circuit construed the term “acetohydroxy acid reductoisomerase” as “an enzyme, whether naturally occurring or otherwise, known by the EC number 1.1.1.86 that catalyzes the conversion of acetolactate to 2,3-dihyroxyiosvalerate. On remand, the Federal Circuit will be required to use the “clear error” standard of review in Butamax. Conclusion In Teva Pharmaceuticals, the Supreme Court explained how the “clear error” rule must be applied (Slip Op. Pp 11-14). The use of intrinsic evidence and extrinsic evidence by the district court impacts the standard of review. In those situations when the district court reviews only evidence intrinsic to the patent, the judge’s determination is solely a determination of law and thus the court of appeals will review that construction de novo. In those situations where the district court needs to consult extrinsic evidence in order to understand the meaning of a term during the relevant time period, and where those subsidiary facts are in dispute, courts will need to make subsidiary factual findings about the extrinsic evidence. To overturn the judge’s resolution of an underlying factual dispute, the appellant court must find that the judge, in respect to those factual findings, has made a “clear error.” In Butamax, for example, extrinsic evidence such as expert testimony and the EC enzyme classification system and other enzyme databases, will be reviewed with the “clear error” standard. It should be noted that the ultimate construction of the claim remains a legal conclusion that the appellate court can review de novo per the Supreme Court opinion in Teva Pharmaceuticals. (Pp 14). Nothing herein should be construed as legal advice or legal representation.