Novozymes v. DuOont Nutrition Biosciences APS

• Decision Date: 23 October 2013
• Docket Number: No. 2012–1433.,2012–1433.
• Citation: 723 F.3d 1336
• Parties: NOVOZYMES A/S, and Novozymes North America, Inc., Plaintiffs–Appellants, v. DuPONT NUTRITION BIOSCIENCES APS (formerly Danisco A/S), Genencor International Wisconsin, Inc., Danisco U.S. Inc., and Danisco USA Inc., Defendants–Appellees.
• Court: U.S. Court of Appeals — Federal Circuit

723 F.3d 1336

NOVOZYMES A/S, and Novozymes North America, Inc., Plaintiffs–Appellants,

v.DuPONT NUTRITION BIOSCIENCES APS (formerly Danisco A/S), Genencor International Wisconsin, Inc., Danisco U.S. Inc., and Danisco USA Inc., Defendants–Appellees.

No. 2012–1433.

United States Court of Appeals, Federal Circuit.

July 22, 2013.

Rehearing En Banc Denied Oct. 23, 2013.^*

David K. Tellekson, Fenwick & West, LLP, of Seattle, WA, argued for plaintiffs-appellants. With him on the brief were Virginia K. DeMarchi, Melanie L. Mayer, Jeffrey V. Lasker, and Ewa M. Davison. Of counsel was Brian D. Buckley.

Charles E. Lipsey, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, of Reston, VA, argued for defendants-appellees. With him on the brief were Howard W. Levine and Lillian M. Robinson, of Washington, DC; Jennifer S. Swan, of Palo Alto, CA. Of counsel on the brief were Tracey B. Davies, Gibson Dunn & Crutcher, LLP, of Dallas, TX; and Michael A. Valek, Vinson & Elkins, LLP, of Austin, TX.

Before RADER, Chief Judge, SCHALL and BRYSON, Circuit Judges.

Opinion for the court filed by Circuit Judge SCHALL.

Dissenting opinion filed by Chief Judge RADER.

SCHALL, Circuit Judge.

Plaintiffs–Appellants Novozymes A/S and Novozymes North America, Inc. (collectively,“Novozymes”) and Defendants–Appellees DuPont Nutrition Biosciences APS, Genencor International Wisconsin, Inc., Danisco U.S. Inc., and Danisco USA Inc. (collectively, “DuPont”) are competitors in the market for enzyme preparations used in a variety of commercial applications, including ethanol production. On May 11, 2010, Novozymes brought suit against DuPont in the Western District of Wisconsin, alleging infringement of its U.S. Patent No. 7,713,723 (the “'723 patent”). The '23 patent claims particular modified enzymes that exhibit improved function and stability under certain conditions. DuPont defended on grounds of noninfringement and invalidity and filed counterclaims seeking a declaratory judgment that the claims of the '23 patent are invalid for failing to satisfy the enablement and written description requirements of 35 U.S.C. § 112.

As litigation progressed, the parties filed several motions for summary judgment. In pertinent part, the district court granted summary judgment in favor of Novozymes on the issue of infringement and denied DuPont's motion for summary judgment of invalidity under the written description and enablement requirements. The case then went to trial before a jury, which concluded that the '23 patent's claims are not invalid on enablement or written description grounds and which awarded infringement damages to Novozymes exceeding $18 million. The district court, however, granted DuPont's post-trial motion for judgment as a matter of law that the claims of the '23 patent are invalid under § 112 for failure to satisfy the written description requirement.

Novozymes now appeals from the district court's final judgment of invalidity. For the reasons set forth below, we affirm.

Background

I. Alpha–Amylase Enzymes

The '23 patent, entitled “Alpha–Amylase Mutants with Altered Properties,” relates to recombinant enzyme technology. Enzymes are proteins that catalyze biochemical reactions, that is, they facilitate molecular processes that either would not occur or would occur much more slowly in the enzyme's absence. Living cells produce different enzymes to carry out a vast array of metabolic functions. For example, one enzyme might help to join the molecular building blocks needed to make a new DNA molecule, while another might break a complex molecule, such as a carbohydrate, into useful constituent parts.

Like all proteins, enzymes are composed of amino acid molecules linked together to form a continuous chain. An enzyme's primary structure is defined by the sequence of amino acid molecules in the chain; in general, each individual position in the amino acid sequence can consist of any one of twenty amino acids normally found in nature. In addition, the linear amino acid chains of different enzymes will bend, fold, and loop onto themselves to assume characteristic three-dimensional confirmations. Both the primary amino acid sequence and the three-dimensional structure affect an enzyme's ultimate functional properties.

Alpha-amylases constitute a class of enzymes synthesized by a variety of organisms—from bacteria to fungi to humans—that break down large molecules known as polysaccharides. Polysaccharides, such as starch and glycogen, are defined as long-chain polymers made of repeating simple sugar molecules like glucose, among others. Alpha-amylases sever the bonds between adjacent sugars in a polysaccharide to yield single or short-chain simple sugars that can provide energy or be used as building blocks for other cellular processes.On average, alpha-amylase enzymes comprise approximately 500 amino acids.

Beyond a widespread role in natural systems, alpha-amylases also have important commercial applications in detergent formulations, sugar refining, and ethanol production, among other uses. Of particular note, many alpha-amylases derived from bacteria of the genus Bacillus exhibit exceptional enzymatic activity, which has made those bacterial enzymes attractive for commercial use. One such product is a preparation of alpha-amylase derived from B. licheniformis (“BLA”) that Novozymes markets under the name Termamyl0.

II. Novozymes's 2000 Patent Application

Many of the most common commercial or industrial applications for alpha-amylase enzymes involve harsh conditions, including high temperatures and/or high acidity. Exposure to such conditions progressively destabilizes and deactivates natural Bacillus alpha-amylase enzymes, degrading the performance of the associated enzyme-based products or processes over time. In the late 1990s, Novozymes sought to improve the acid tolerance and heat tolerance (“thermostability”) of Bacillus alpha-amylases used in commercial processes.

Traditionally, the solution had been to add excess calcium to commercial alpha-amylase formulations intended for use under extreme temperature or pH conditions. While concentrated calcium is effective for stabilizing alpha-amylases to preserve their enzymatic activity, it represents an added cost and often imposes undesirable effects on industrial equipment. Thus, Novozymes's aim was to modify a naturally occurring “parent” Bacillus alpha-amylase to produce an enzyme having improved stability and thus more durable activity under harsh conditions, even without calcium supplementation.

Enzymes can often be altered at one or more positions along their amino acid chain without destroying their function. Changes (known as “mutations”) in a parent enzyme can include deleting one or more amino acids, adding one or more amino acids, or substituting the original amino acid with one of the nineteen other possibilities at any given position in the sequence. An enzyme that has one or more mutations relative to its natural parent sequence is referred to as a “variant.” The effects of any given mutation or combination of mutations in a variant can differ depending on the position(s) modified and the specific mutation implemented at each position. Some mutations may have no discernible effect on enzyme function, some may lead to varying degrees of instability or functional impairment, and some may actually improve enzyme activity or impart other desirable properties, such as improved stability at high temperatures.

Novozymes pursued two parallel strategies in attempting to identify promising mutation sites among the approximately 500 amino acids that make up a Bacillus alpha-amylase polypeptide: rational protein design and random mutagenesis. Rational protein design involves making functional inferences from the amino acid sequence and three-dimensional shape of a protein to predict which positions may influence a property of interest, such as thermostability, enzymatic activity, or calcium binding. In contrast, random mutagenesis involves making random mutations in a parent enzyme and then screening the resulting variants to identify those that exhibit the desired functional effects. Using rational protein design and random mutagenesis, Novozymes identified thirty-three Bacillus alpha-amylase amino acid positions as targets for mutation in attempting to create alpha-amylase variants with enhanced stability. Of those thirty-three positions, seventeen were predicted using rational protein design techniques, while sixteen were identified via random mutagenesis experiments.

With that information in hand, Novozymes filed U.S. Provisional Patent Application No. 60/249,104 on November 16, 2000 (the “2000 application”), relating to Bacillus alpha-amylase variants with enhanced stability.¹ The 2000 application disclosed seven potential parent enzymes, including an alpha-amylase isolated from BLA bacteria that Novozymes was already using in its Termamyl0 product, and another alpha-amylase produced by B. stearothermophilus (“BSG”). See '23 patent col. 3 ll. 1–38. The 2000 application also disclosed the thirty-three separate amino acid positions along the alpha-amylase chain that Novozymes identified as promising mutation targets using rational protein design or random mutagenesis. In addition, the specification indicated that one or more of those sites might be altered in any of the seven disclosed parent alpha-amylases by deletion, addition, or substitution. See id. col. 7 ll. 36–57. The 2000 application further indicated that the disclosed variants would exhibit improved stability at “high temperatures (i.e., 70–120°C.) and/or extreme pH (i.e., low or high pH, i.e., pH 4–6 or pH 8–11), in particular at free (i.e., unbound, therefore in solution) calcium concentrations below 60 ppm.” See id. col. 16 ll. 42–47.

Given the number of parent enzymes (7), the number of target positions in each of those parent enzymes (33), and the number of possible mutations at each of those target positions ...