Butamax™ Advanced Biofuels LLC v. Gevo, Inc. (931 F. Supp. 2d 589, 2013)

United States District Court for the District of Delaware 2013-03-19

Citations

Full opinion text

MEMORANDUM OPINION

SUE L. ROBINSON, District Judge.

I. INTRODUCTION

On January 14, 2011, plaintiff ButamaxTM Advanced Biofuels LLC (“Butamax”) filed suit in this district against defendant Gevo, Inc. (“Gevo”) alleging infringement of U.S. Patent No. 7,851,188 (“the '188 patent”). (D.I. 1) The '188 patent discloses and claims “a recombinant microorganism having an engineered isobutanol biosynthetic pathway” that “may be used for the commercial production of isobutanol.” ('188 patent, 2:3-6) Gevo answered the complaint on March 25, 2011. (D.I. 10) On August 11, 2011, Butamax filed an amended complaint, alleging that Gevo also infringed U.S. Patent No. 7,993,-889 (“the '889 patent”). (D.I. 41) The '889 patent was filed as a divisional application from the '188 patent and claims a method for isobutanol production using recombinant microorganisms with an engineered biosynthetic pathway. ('889 patent, 2:3-6)

Gevo answered the amended complaint on September 13, 2011 and counterclaimed against Butamax and E.I. DuPont De Nemours and Company (“DuPont”) alleging infringement of U.S. Patent Nos. 8,017,375 (“the '375 patent”) and 8,017,376 (“the '376 patent”), also related to the production of isobutanol from recombinant microorganisms. (D.I. 52) Butamax and DuPont answered the counterclaims on November 18, 2011 and counter-counterclaimed against Gevo seeking a declaratory judgment on non-infringement and invalidity of the '375 patent and the '376 patent. (D.I. 117) On December 9, 2011, Gevo answered the counter-counterclaims. (D.I. 130) On February 24, 2012, Butamax and DuPont filed a motion to sever Gevo’s counterclaims, which was granted. (D.I. 213, D.I. 371) On June 21, 2012, upon the grant of its timely motion to amend, Butamax and DuPont amended its answer to the counterclaims and the counter-counterclaims adding affirmative defenses and counter-counterclaims of inequitable conduct. (D.I. 372) Gevo’s untimely motion, filed June 29, 2012, seeking to amend its answer and counterclaims to include an affirmative defense and counterclaim of inequitable conduct was denied. (D.I. 388; D.I. 693)

On September 22, 2011, Butamax filed a motion for preliminary injunction which sought to enjoin Gevo from infringing the '889 patent. (D.I. 61) After an evidentiary hearing on the matter, March 1-2, 2012, the court denied Butamax’s motion for preliminary injunction on June 19, 2012, 868 F.Supp.2d 359 (D.Del.2012). (D.I. 370) On June 25, 2012, Butamax appealed this decision. (D.I. 376) On December 26, 2012, the Federal Circuit affirmed this court’s denial of the preliminary injunction. Butamax Advanced Biofuels LLC v. Gevo, Inc., 486 Fed.Appx. 883 (Fed.Cir.2012).

Presently before the court are several motions for summary judgment: Butamax’s summary judgment motion of infringement of the '188 and '889 patents (D.I. 595) and cross-motion of no invalidity of the '889 patent (D.I. 622), as well as Gevo’s motions for summary judgment of invalidity and non-infringement of the '188 and '889 patents. (D.I. 598; D.I. 610) Butamax and DuPont also filed a motion to exclude testimony by Gevo’s experts with respect to the '188 patent and '376 patent. (D.I. 640) The court herein addresses this motion as it relates to the '188 patent and reserves its decision as it relates to the '376 patent. The court has jurisdiction pursuant to 28 U.S.C. §§ 1331 and 1338(a).

II. BACKGROUND

A. The Parties

Butamax is a limited liability corporation organized and existing under the laws of the State of Delaware, with its principal place of business in Wilmington, Delaware. (D.I. 41 at ¶ 1) Butamax develops methods of making biofuels such as biobutanol, a product which may be used as a fuel or as a feed-stock chemical in the production of various plastics, fibers and other products. (Id.) In particular, Butamax has developed a biological method of producing isobutanol, a type of biobutanol. (Id.)

Gevo is a corporation organized and existing under the laws of the State of Delaware, with its principal place of business in Englewood, Colorado. (D.I. 52 at 5 ¶ 1) Gevo is also involved in the commercial-scale production of isobutanol using biological methods. (Id. at ¶ 11; D.I. 154 at 3)

DuPont is a corporation organized and existing under the laws of the State of Delaware, with its principle place of business in Wilmington, Delaware. (D.I. 470 at 9 ¶ 2) DuPont is engaged in research and development relating to the production of isobutanol. (Id. at 1 ¶ 5)

B. Technology

Isobutanol is an industrial chemical that may be blended with gasoline-based fuels as an alternative to ethanol, the current dominant biofuel in gasoline blends. ('889 patent, 6:38-40) Isobutanol is preferred over ethanol because it has a higher energy content and is less corrosive. ('889 patent, 6:33-40) Butamax proposes a method of producing isobutanol using genetically-engineered yeast microorganisms that promises to facilitate the transition to renewable transportation fuels and reduce greenhouse gas emissions. (D.I. 41 at ¶ 1)

This improved method for producing isobutanol is achieved by introducing engineered deoxyribonucleic acid (“DNA”) into microorganisms in order to stimulate isobutanol production. (Id. at ¶ 12; '889 patent, 17:9-19) Microorganisms such as yeast and bacteria are capable of producing isobutanol through a five-step pathway consisting of the following five chemical conversions: (1) pyruvate to acetolactate; (2) acetolactate to 2,3-dihydroxyisovalerate; (3) 2,3-dihydroxyisovalerate to a-ketoisovalerate; (4) a-ketoisovalerate to isobutyraldehyde; and (5) isobutyraldehyde to isobutanol. (D.I. 41 at ¶ 12; '889 patent, 325:19-30) The engineered DNA constructs encode enzymes that catalyze, or increase the chemical reaction rate, of the five steps in the isobutanol biosynthesis pathway. (D.I. 41 at ¶ 12; '889 patent, 325:32-42) Introducing these enzyme-coding DNA constructs into the microorganism stimulates the biosynthetic pathway and increases overall isobutanol production. (D.I. 41 at ¶ 12; '889 patent, 44:28-32)

C. The Patents

The '188 patent, entitled “Fermentive Production of Four Carbon Alcohols,” was filed on October 25, 2006 and issued on December 14, 2010. It claims priority from provisional application No. 60/730,290 which was filed on October 26, 2005. The '889 patent was filed on January 23, 2008 and issued on August 9, 2011. The '889 patent is a divisional application of the '188 patent. Both the '889 patent and the '188 patent are assigned to Butamax. (D.I. 41 at ¶¶ 6, 9)

The specifications of the '188 and '889 patents admit that isobutanol may be chemically synthesized from starting materials derived from petrochemicals, but this method of synthesis is expensive and bad for the environment. ('889 patent, 1:33-35; '188 patent, 1:33-35) The inventors assert that using yeast or other comparable microorganisms to produce isobutanol would reduce greenhouse gas emissions and, therefore, would be a desirable alternative to chemical synthesis. ('889 patent, 1:36-38; '188 patent, 1:36-38)

Yeast naturally produce low levels of isobutanol as a by-product of fermentation. ('889 patent, 1:39-49; '188 patent, 1:39-49) More specifically, isobutanol is produced from the catabolism, or metabolic breakdown, of the amino acid L-valine. ('889 patent, 1:39-49; '188 patent, 1:39-49) However, use of L-valine on an industrial scale as a feed-stock for yeast fermentation is prohibitively expensive. ('889 patent, 1:57-59; 188 patent, 1:57-59) The inventors claim a more cost-efficient method of producing isobutanol directly from pyruvate, a product of sugar digestion, in lieu of L-valine. ('889 patent, 325:15-23; 188 patent, 335:20-23) The transformation of pyruvate to isobutanol is achieved through one of four multi-step biosynthetic pathways. ('889 patent, 11:40-43; 188 patent, 12:1-4)

In the claimed biosynthetic pathway, all of the necessary reaction substrates are components of “well-characterized pathways” that are naturally present in yeast. ('889 patent, 11:57-61; 188 patent, 12:19-21) The inventors assert that stimulating this pathway through the introduction of DNA constructs coding for one or more enzymes specific to pathway steps yields increased isobutanol production. ('889 patent, 17:9-19, 44:28-32; '188 patent, 19:45-55, 49:46-51) Although the enzymes are introduced via genetic manipulation, the enzymes also exist in yeast or other microorganisms as naturally-occurring components of the “well-characterized” enzymatic pathways. ('889 patent, 11:58-12:32; '188 patent, 12:19-60)

Independent claim 1 of the '889 patent, reproduced below, describes the preferred biosynthetic pathway and identifies which enzymes catalyze each step of the claimed pathway:

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-dihydroxyisoval-erate (pathway step b);

in. 2,3-dihydroxyisovalerate to a-ketoisovalerate (pathway step c);

iv. a-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 dehydralase 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.

('889 patent, 325:15-44) Independent claim 1 of the '188 patent, reproduced below, is directed at the recombinant microbial host cell:

1. A recombinant microbial host cell comprising heterologous DNA molecules encoding polypeptides that catalyze substrate to product conversions for each step below:

i) pyruvate to acetolactate;

ii) acetolactate to 2,3-dihydroxyisovaler-ate;

iii) 2,3-dihydroxyisovalerate to a-ketoisovalerate;

iv) a-ketoisovalerate to isobutyraldehyde;

wherein said microbial host cell produces isobutanol; and wherein

a) the polypeptide that catalyzes a substrate to product conversion of pyruvate

. to acetolactate is acetolactate synthase having the EC number 2.2.1.6;

b) the polypeptide that catalyzes a substrate to product conversion of acetolactate to 2,3-dihydroxyisovalerate is acetohydroxy acid isomeroreductase having the EC number 1.1.1.86;

c) the polypeptide that catalyzes a substrate to product conversion of 2,3-dihy-droxyisovalerate to a-ketoisovalerate is aeetohydroxy acid dehydralase having the EC number 4.2.1.9;

d) the polypeptide that catalyzes a substrate to product conversion of a-ketoisovalerate to isobutyraldehyde is branched-chain a-keto acid decarboxylase having the EC number 4.1.1.72.

('188 patent, 335:19-44) Butamax alleges that Gevo’s lead strains infringe certain claims of the '188 patent. (D.I. 41 ¶¶ 17-20) Butamax further alleges that Gevo’s processes infringe certain claims of the '889 patent. (D.I. 41 ¶¶ 21-23)

III. CLAIM; CONSTRUCTION

A. Legal Principles

Claim construction is a matter of law. Phillips v. AWH Corp., 415 F.3d 1303, 1330 (Fed.Cir.2005) (en banc). Claim construction focuses on intrinsic evidence — the claims, specification and prosecution history — because intrinsic evidence is “the most significant source of the legally operative meaning of disputed claim language.” Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed.Cir.1996); Markman v. Westview Instruments, Inc., 52 F.3d 967, 979 (Fed.Cir.1995) (en banc), aff'd, 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996). Claims must be interpreted from the perspective of one of ordinary skill in the relevant art at the time of the invention. Phillips, 415 F.3d at 1313.

Claim construction starts with the claims, id. at 1312, and remains centered on the words of the claims throughout. Interactive Gift Express, Inc. v. Compuserve, Inc., 256 F.3d 1323, 1331 (Fed.Cir. 2001). In the absence of an express intent to impart different meaning to claim terms, the terms are presumed to have their ordinary meaning. Id. Claims, however, must be read in view of the specification and prosecution history. Indeed, the specification is often “the single best guide to the meaning of a disputed term.” Phillips, 415 F.3d at 1315.

B. “Acetohydroxy Acid Isomeroreductase Enzyme”

The above identified enzyme is recited in the engineered isobutanol biosynthetic pathway (“the pathway”) claimed by Butamax. The patentees of the '188 and '889 patents offered a definition of this enzyme, inter alia, “to be used for the interpretation of the claims and the specification,” to wit:

The terms “acetohydroxy acid isomeroreductase” and “acetohydroxy acid reduetoisomerace” are used interchangeably herein to refer to an enzyme that catalyzes the conversion of acetolactate to 2,3-dihydroxyisovalerate using NADPH (reduced nicotinamide adenine dinucleotide phosphate) as an electron donor. Preferred acetohydroxy acid isomeroreductases are known by the EC number 1.1.1.86 and sequences are available from a vast array of microorganisms ____

('188 patent, 7:12-13, 35-42; '889 patent, 6:52-53, 7:8-15) Despite being a defined term, the parties dispute how persons of skill in the art would interpret the language used by the patentees, more specifically, whether those of skill in the art would include within the scope of this definition enzymes that use either NADH or NADPH or both as a cofactor in the recited catalytic conversion.

Butamax suggests that a broad construction is most consistent with the intrinsic evidence and skill in the art, namely, “an enzyme that is structurally similar to acetohydroxy acid isomeroreductase or ketol acid reductoisomerase [“KARI”] enzymes[*] known by the EC number 1.1.1.86[ ] and that converts acetolactate to 2,3-dihydroxyisovalerate.” (D.I. 492 at 9) Under this construction, to determine whether an enzyme literally meets the claim term, a skilled artisan would: (1) compare the enzyme’s amino acid sequence to the sequences of known KARI enzymes having EC number 1.1.1.86 (D.I. 492 at 10; D.I. 494 at ¶ 45); and (2) test the enzyme for activity using a standard KARI assay, e.g., the assay described in a 1969 reference by Arfin & Umbarger (D.I. 492 at 10; D.I. 495 at ¶¶ 41-43). According to Butamax, “[t]his two prong analysis, consistent with the intrinsic evidence, allows a skilled artisan to come to a conclusion that an enzyme literally meets the KARI claim element.” (D.I. 492 at 10) With respect to the characterization in the specification relating to cofactor NADPH, Butamax explains that, because it was well known in 2005 and 2006 that KARI enzymes can use either NADPH or NADH as an electron donor (D.I. 494 at ¶ 36), a construction limited to enzymes that will use solely NADPH is inappropriate without strong evidence of a clear intent to redefine the term narrowly, or an unambiguous disavowal of the full scope of the claim term.

Gevo’s proposed construction is more narrow, that is, “an enzyme which catalyzes the conversion of acetolactate to 2,3-dihydroxyisovalerate and that is solely NADPH-dependent (as opposed to NADH-dependent or NADH and NADPHdependent), having the EC number 1.1.1.86.” (D.I. 535 at 7) According to Gevo, its construction is most consistent with the intrinsic record, given that the patentees specifically included within its definition of “acetoydroxy acid isomeroreductase,” EC nomenclature and the use of NADPH as an electron donor, and clearly knew how to describe the use of both NADH and NADPH as cofactors, as they did elsewhere in the specification. (D.I. 535)

1. Intrinsic record

a. Prosecution history

Claims 1, 4-8, 15-31 and 38 of the '188 patent were rejected by the examiner as failing to comply with the written description requirement, 35 U.S.C. § 112, first paragraph. (D.I. 508 at BJA 1482) It was the examiner’s position that, while the specification described a genus of polypeptides catalyzing the reactions described in the pathway, the specification did not describe “any structural features, amino acid sequences, and/or biological functions that are commonly possessed by members of each claimed genus.” (Id. at BJA1484) The specification also failed to disclose “a representative number of species of each claimed genus, which includes many members with widely differing structural, chemical, and biological functions. There is no recognized correlation between any structure and catalytic activity of conversion of the substrates to products as recited in parts i)-v).” (Id.)

The patentees responded by amending claim 1 “to an isobutanol producing host cell comprising at least one nucleic acid molecule that encodes the enzymes listed in claim 1 as now further limited to those enzymes possessing a specific Enzyme Commission (EC) number to the fourth level. It is well known in the art that the Enzyme Commission numbering system categorizes enzymes based on the reactions they are able to perform. An enzyme classed with an EC number to the fourth level is discretely and specifically classified on the basis of its function.” (Id. at BJA1653 (emphasis added)) The patentees further disclosed a method that was “able to discriminate between enzymes assigned to different EC numbers exhibiting distinct functions,” thus “indicating a correlation between structural elements of enzyme binding pockets and their functional classification by EC number.” (Id. at BJA1654) In sum, the patentees submitted that “the specific guidance relating to the structure and physiochemical properties of enzymes that may be used in the invention [were] provided in the EC number of each enzyme.” (Id. at BJA1656)

The examiner also rejected the application on enablement grounds. In this regard, the patentees responded that “[a] patent need not teach, and preferably omits, what is well known in the art ... Thus a claim is enabled if the specification in combination with what is well known in the art permits the skilled person to make and use the invention without undue experimentation.” (Id. at BJA1701-2) To illustrate their point, the patentees referred the examiner to a publicly available database and explained that, “[u]sing the BRENDA database, the skilled person, searching for the EC number for[, e.g.,] acetolactate synthase ... would find corresponding enzymes catalyzing the conversion of pyruvate to acetolactate from 39 organisms. These polypeptides and the genes encoding them can be obtained from the recited organisms by methods well known in the art and without any excessive screening or additional guidance and used in the present invention.” (Id. at BJA1702)

The '188 patent ultimately issued on December 14, 2010. As noted by the patentees in the prosecution history, claim 1 was amended to “limit the enzyme terms to their corresponding EC numbers.” (Id. at BJA1652)

b. Specification

In addition to defining the enzymes of the pathway by their known EC numbers, the patentees added cofactor information to some of the definitions, including the one in dispute. For example, in defining the term “branched-chain alcohol dehydrogenase,” the patentees instructed that “[preferred branched-chain alcohol dehydrogenases are known by the EC number 1.1.1.265, but may also be classified under other alcohol dehydrogenases (specifically, EC 1.1.1.1 or 1.1.1.2),” and then noted that “[t]hese enzymes utilize NADH ... and/or NADPH as electron donor.” (’188 patent, 8:9-16; '889 patent, 7:49-56) Likewise, in defining the term “acylating aldehyde dehydrogenase,” the patentees referred to an enzyme that “catalyzes the conversion of isobutyryl-CcA to isobutyraldehyde, using either NADH or NADPH as electron donor,” with “preferred” enzymes “known by the EC numbers 1.2.1.10 and 1.2.1.57.” ('188 patent, 8:44-48; '889 patent, 8:17-21) In addition, in defining the term “valine dehydrogenase,” the patentees referred “to an enzyme that catalyzes the conversion of a-ketoisovalerate to L-valine using NAD(P)H as electron donor,” instructing that “preferred” enzymes “are known by the EC numbers 1.4.1.8 and 1.4.1.9.” ('188 patent, 9:9-11; '889 patent, 8:49-51) Finally, the patentees defined the term “branched-chain keto acid dehydrogenase” as “an enzyme that catalyzes the conversion of a-ketoisovalerate to isobutyryl-CoA (isobutrl-coenzyme A), using NAD + (nicotinamide adenine dinucleotide) as electron acceptor,” instructing that “preferred” enzymes are “known by the EC number 1.2.44.” ('188 patent, 8:25-29; '889 patent, 7:65-8:3)

Claim 1 of the '188 patent includes the EC nomenclature for the enzymes of the pathway; claim 1 of the '889 patent does not. ('188 patent, 335:21-45; '889 patent, 325:16-42) Dependent claim 14 of the '889 patent refers to the method of claim 1, with the further limitation that “one or more enzymes of said engineered isobutanol biosynthetic pathway uses NADH as an electron donor.” ('889 patent, 326:37-39)

2. Extrinsic evidence

The term “cofactor” is generally understood to refer to an organic molecule that is required for certain enzymatically catalyzed reactions to proceed. Cofactors bind to enzymes as substrates of the enzymes that rely on them and are converted to products of the enzymatic reaction after it is completed. NADH and NADPH are two important and distinct cofactors that are also substrates. These cofactors act as electron donors and, in their oxidized forms (NAD+ and NADP+), as electron acceptors, respectively, in oxidation or reduction reactions. Enzymes that depend on them for catalytic activity are frequently termed NADH- or NADPH-dependent. (D.I. 537 at ¶¶ 8, 9)

NADH and NADPH have distinct chemical structures, with NADPH containing an additional phosphate group. This extra phosphate group allows NADPH “to be recognized selectively by the enzymes involved in biosynthesis;” thus, “‘despite their close chemical resemblance,’ NADH and NADPH are ‘not metabolically interchangeable.’” (Id. at ¶¶ 4, 12 (citations omitted)) To put the point another way, “[t]he difference between NADH and NADPH is trivial in chemical terms, but it is crucial for their distinctive functions.” (Id. at ¶ 11 (citation omitted))

“As of October 26, 2005, all natural KARI enzymes were known to be NADPH-dependent.” (D.I. 537 at IT 40) Although “the limits of biology virtually guarantee that all KARI enzymes will have at least some ancillary activity with both cofactors,” a person of ordinary skill in the art would understand that an enzyme that “uses NADPH” or that “uses NADH” is “NADPH-dependent” or “NADH-dependent”, respectively. (Id. at ¶ 58)

The EC enzyme classification system was developed in the 1950s to provide international standards of nomenclature. According to the “second general principle” of the EC classification system, “enzymes are principally classified and named according to the reaction they catalyse. The chemical reaction catalysed is the specific property that distinguishes one enzyme from another, and it is logical to use it as the basis for the classification and naming of enzymes.” (D.I. 496, ex. A at 5) Relevant to the dispute at bar is Rule 18 of the EC nomenclature, which states that, “[f]or oxidoreduetases using NAD+ or NADP + , the coenzyme should always be named as the acceptor[] ... Where the enzyme can use either coenzyme, this should be indicated by writing NAD(P) +.” (D.I. 496, ex. A at 18) Although some enzymes are classified based on their co-factor selectivity, no unique EC numbers have been assigned to EC 1.1.1.86 to reflect this feature.

Examining EC 1.1.1.86, the chemical reaction that distinguishes this class of enzymes is described as “(R )-2,3-dihy-droxy-3-methylbutanoate + NADP + = 0S')-2-hydroxy-2-methyl-3-oxobutanoate + NADPH + H + .” (D.I. 496, ex. C) The IUBMB Enzyme Nomenclature also includes four references and links to other databases. With respect to the listed references: (1) Arfin & Umbarger, which describes a standard assay to identify a KARI enzyme in an environment where AL and NADPH are present (id, ex. E; D.I. 492 at 10-11); (2) Hill, which studied the synthesis, configuration and enzymatic specificity of intermediates involved in the biosynthesis of isoleucine and valine, notes that “[a]ssays were performed by measuring the rate at which NADPH was oxidized, as described previously by Arfin & Umbarger” (D.I. 496, ex. F at 175-76,181); (3) Kiritani, which sought to characterize the reductoisomerase involved in the isoleucine-valine pathway of Neurospora crassa, includes the observation that “NADPH is required for enzymatic activity, and NADH does not substitute” (D.I. 496, ex. G at 2047-48); and (4) Satyanarayana, which studied the properties of a reductoisomerase involved in the synthesis of valine and isoleucine in plants, used TPNH, and states that no a-keto-|3-hydroxy acids could be detected when “TPNH was omitted from the standard assay mixture” (id., ex. H at 380-81, 387).

In looking at the enzyme entries for EC I. 1.1.86 found in the listed databases, one finds the following: (1) the ExPASy database entry describes the reaction catalyzed as one using NADPH (D.I. 497, ex. FF); (2) the KEGG database entry describes the reaction, the substrate, and the product in relation to NADPH or NADP + (id., ex. GG); (3) the PDB database entry describes reactions involving NADPH and NADP(+) (id., ex. HH); and (4) the BRENDA database entry likewise describes the reaction in relation to NADPH (id., ex. D at 1).

Unlike the other databases identified in the IUBMB Enzyme Nomenclature, the BRENDA database includes information about specific activity, substrates, products, and organisms, with commentaries and multiple references to literature. In the 43 pages of information contained on the BRENDA database for EC 1.1.1.86, NADH is mentioned in only 16 entries, all of which refer to one or more of only five literature references. (Id., ex. D at 13-14, 22, 25, 28, 39-40) The five literature references are: (1) Arfin & Umbarger (reference 639169), as described above; (2) Kiritani (reference 639171), as described above; (3) Dumas (1989) (reference 639176), which includes the observation that “[t]he enzyme also utilized NADH as electron donor,” but describes the reaction as an “NADPH-dependent reduction” and goes on to analyze how the enzyme was regulated by the NADPH/NADP + ratio (D.I. 497, ex. AA at 971, 974-975); (4) Dumas (1992) (reference 639176), which reiterates the earlier observation that “the over-expressed enzyme was able to use NADH as an electron donor,” nevertheless, “the plant enzyme displays a very high selectivity for NADPH” (D.I. 538, ex. X at 870, 873); and (5) Rane (reference 639183), which started with the stated goal of “identifying] the positively charged amino acid(s) that confer NADPH specificity on KARI,” and found that by altering four amino acids and constructing a “quadruplet mutant,” “the specificity constants for NADH and NADPH are almost exactly reversed in the mutant relative to the wild type,” i.e., the “mutant was changed from being a NADPH-specifie dehydrogenase into a NADH specific enzyme” (D.I. 497, ex. BB).

In connection with the argument posed by Butamax that the specification “lists ‘preferred’ KARIs, denoted by EC 1.1.1.86, that have significant activity with NADH,” (D.I. 492 at 11 (emphasis added)), the one KARI enzyme identified in this regard is the Methanococcus maripaludis KARI (’188 patent, 7:46Al7; '889 patent, 7:19-20) and the analysis of such KARI enzyme in a single reference, R. Xing. & W. Whitman, Characterization of Enzymes of the Branched-Chain Amino Acid Biosynthetic Pathway in Methanococcus spp, 173(6) J. Bacteriology 2086-2092 (1991). (D.I. 496, ex. K; see D.I. 492 at 11; D.I. 493 at ¶ 34; D.I. 494 at ¶¶ 39^0; D.I. 495 at ¶ 48) The authors of the reference observe that, “[w]hile the eubacterial and eucaryotic AAlRs are NADPH specific, NADH supported 60% of the methanococcal activity obtained with NADPH.” (D.I. 496, ex. K at 2089) There is neither a reference nor data noted to support this assertion.

3. Analysis

The court starts with the premise that the claims and specification of a patent serve a public notice function, and that patentees who choose to provide definitions should be especially mindful of being their own lexicographers. See, e.g., Johnson & Johnston Associates Inc. v. R.E. Service Co., Inc., 285 F.3d 1046, 1052 (Fed. Cir.2002) (citing Mahn v. Harwood, 112 U.S. 354, 361, 5 S.Ct. 174, 28 L.Ed. 665 (1884)) (claims give notice to the public of the scope of the patent); In re Paulsen, 30 F.3d 1475, 1480 (Fed.Cir.1994) (patentee choosing to define terms must do so “with reasonable clarity, deliberateness, and precision”). In this case, the patentees choose to define the KARI enzyme not only by reference to its EC classification, but by its “use” of NADPH. Having reviewed the scientific literature referenced through the patent’s definitional language, the court finds the expert opinions proffered by Gevo (and, therefore, Gevo’s proposed construction) to be more consistent with the intrinsic record.

In this regard, the scientific references almost exclusively characterize KARI enzymes as NADPH-dependent. Of the two references relied on by Butamax to support the use of NADH by KARI enzymes, one (Xing) included a single conclusory sentence with no data or other literature references to support it, and the other (Rane) described having to construct a “quadruplet mutant” in order to change a KARI enzyme from being NADPH-dependent to being NADH-dependent.

Even if the court were to accept the proposition that those of skill in the art recognized in 2005 that the KARI enzyme known by EC number 1.1.1.86 could use NADH and/or NADPH as an electron donor, consistent with Butamax’s position in this dispute, the question remains why the patentees choose then to include more limiting language in their definition. Butamax responds by arguing that NADPH was simply a known tool for identifying a KARI enzyme (referencing the Arfin & Umbarger standard assay), and co-factor usage was not meant to be a limiting physiochemical property of the enzyme.

The court declines, however, to make superfluous the patentees’ description of the very reaction that is the defining characteristic of the KARI enzyme. In light of the record, the patentees’ definition of “aeethydroxy acid isomeroreductase enzyme” simply reflects the state of the art, that is, that the KARI enzyme known by the EC number 1.1.1.86 was generally understood to be NADPH-dependent. That dependent claim 14 of the '889 patent calls out use of NADH is of no moment in this analysis, given that more than one of the enzymes of the claimed pathway were defined by the patentees as using NADH as an electron donor. ('889 patent, 7:54-56, 7:67-8:1, 8:19, 51)

4. Conclusion

For the reasons stated above, the court concludes that a person of ordinary skill in the art would understand “acetohydroxy acid isomeroreductase” to be “an enzyme known by the EC number 1.1.1.86 that catalyzes the conversion of acetolactate to 2,3-dihydroxyisovalerate and is NADPHdependent.”

C. Other Terms of the '889 Patent

1. “[A] recombinant yeast micoorganism expressing an engineered isobutanol biosynthetic pathway”

The court construes this term to mean “a recombinant yeast microorganism that is genetically transformed such that it expresses the five enzymes that form the biosynthetic pathway described hereafter for the production of isobutanol, wherein one or more of those enzymes is recombinantly expressed.”

Butamax does not contend that all five enzymes in the “engineered isobutanol biosynthetic pathway” must be recombinantly expressed and Gevo asserts that “the patent contemplates engineered pathways where only one or more of the enzymes are recombinantly expressed.” (D.I. 492 at 26; D.I. 535 at 27) The court’s construction resolves any ambiguity in this regards. According to Butamax, “[t]he parties’ only apparent substantive dispute regarding this term is whether it should be construed to require carbon flow through pathway steps a-e recited later in the claim.” (D.I. 552 at 12) Gevo argues that Butamax’s construction is ambiguous and that “the patent recites several different pathways for isobutanol production.” (D.I. 535 at 28) The court finds that the remaining language of the claim resolves this dispute. In other words, the entire phrase “a recombinant yeast micoorganism expressing an engineered isobutanol biosynthetic pathway ... wherein said pathway comprises the following substrate to product conversions” instructs that the “engineered isobutanol biosynthetic pathway” is in fact the pathway described in the following steps a-e. ('889 patent, 325:19-22 (emphasis added))

2. “([Pjathway step a); ... (pathway step b); ...,” etc.

The court construes this term to mean “the pathway steps a-e are contiguous steps such that the product of step a is the substrate for step b; the product of step b is the substrate for step c; etc.” The court recognizes that the term “comprising” recited in the introductory language “raises a presumption that the list of elements is nonexclusive.” Dippin’ Dots, Inc. v. Mosey, 476 F.3d 1337, 1343 (Fed.Cir.2007). However, the court agrees with Butamax that the intrinsic evidence demonstrates the patentees’ intent that the addition of intermediate steps to the preferred claim 1 pathway forms a different pathway that is outside the scope of the claim and that the claim’s use of “comprising” reflects that the claimed pathway can be used as part of a larger process, and additional steps might be performed before or after without avoiding infringement. (D.I. 492 at 28-29) This construction is not inconsistent with Dippin’ Dots, wherein the Federal Circuit declares that the enumerated steps “must ... all be practiced as recited in the claim for a process to infringe.” Id.

3. “The microorganism produces isobutanol as a single product”

The parties agree that any fermentation process produces more than one single product. (D.I. 552 at 15) Butamax reasons that one skilled in the art would understand this term to mean producing “predominantly one product.” (D.I. 552 at 15) This reasoning is consistent with distinguishing the production of isobutanol as a primary product with production of byproducts or as part of a mixture. The court construes this term to mean “[t]he microorganism produces isobutanol without substantial amounts of other fermentation products.”

IV. STANDARDS OF REVIEW

A. Summary Judgment

“The court shall grant summary judgment if the movant shows that there is no genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law.” Fed.R.Civ.P. 56(a). The moving party bears the burden of demonstrating the absence of a genuine issue of material fact. Matsushita Elec. Indus. Co. v. Zenith Radio Corp., 475 U.S. 574, 586 n. 10, 106 S.Ct. 1348, 89 L.Ed.2d 538 (1986). A party asserting that a fact cannot be — or, alternatively, is — genuinely disputed must support the assertion either by citing to “particular parts of materials in the record, including depositions, documents, electronically stored information, affidavits or declarations, stipulations (including those made for the purposes of the motions only), admissions, interrogatory answers, or other materials,” or by “showing that the materials cited do not establish the absence or presence of a genuine dispute, or that an adverse party cannot produce admissible evidence to support the fact.” Fed.R.Civ.P. 56(c)(1)(A) & (B). If the moving party has carried its burden, the nonmovant must then “come forward with specific facts showing that there is a genuine issue for trial.” Matsushita, 475 U.S. at 587, 106 S.Ct. 1348 (internal quotation marks omitted). The court will “draw all reasonable inferences in favor of the nonmoving party, and it may not make credibility determinations or weigh the evidence.” Reeves v. Sanderson Plumbing Prods., Inc., 530 U.S. 133, 150, 120 S.Ct. 2097, 147 L.Ed.2d 105 (2000).

To defeat a motion for summary judgment, the non-moving party must “do more than simply show that there is some metaphysical doubt as to the material facts.” Matsushita, 475 U.S. at 586-87, 106 S.Ct. 1348; see also Podobnik v. U.S. Postal Service, 409 F.3d 584, 594 (3d Cir. 2005) (stating party opposing summary judgment “must present more than just bare assertions, conclusory allegations or suspicions to show the existence of a genuine issue”) (internal quotation marks omitted). Although the “mere existence of some alleged factual dispute between the parties will not defeat an otherwise properly supported motion for summary judgment,” a factual dispute is genuine where “the evidence is such that a reasonable jury could return a verdict for the nonmoving party.” Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 247-48, 106 S.Ct. 2505, 91 L.Ed.2d 202 (1986). “If the evidence is merely colorable, or is not significantly probative, summary judgment may be granted.” Id. at 249-50, 106 S.Ct. 2505 (internal citations omitted); see also Celotex Corp. v. Catrett, 477 U.S. 317, 322, 106 S.Ct. 2548, 91 L.Ed.2d 265 (1986) (stating entry of summary judgment is mandated “against a party who fails to make a showing sufficient to establish the existence of an element essential to that party’s case, and on which that party will bear the burden of proof at trial”).

B. Infringement

A patent is infringed when a person “without authority makes, uses or sells any patented invention, within the United States ... during the term of the patent.” 35 U.S.C. § 271(a). A two-step analysis is employed in making an infringement determination. See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir.1995). First, the court must construe the asserted claims to ascertain their meaning and scope. See id. Construction of the claims is a question of law subject to de novo review. See Cybor Corp. v. FAS Techs., 138 F.3d 1448, 1454 (Fed.Cir.1998). The trier of fact must then compare the properly construed claims with the accused infringing product. See Markman, 52 F.3d at 976. This second step is a question of fact. See Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed.Cir.1998).

“Direct infringement requires a party to perform each and every step or element of a claimed method or product.” BMC Res., Inc. v. Paymentech, L.P., 498 F.3d 1373, 1378 (Fed.Cir.2007), overruled on other grounds by 692 F.3d 1301 (Fed. Cir.2012). “If any claim limitation is absent from the accused device, there is no literal infringement as a matter of law.” Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241, 1247 (Fed.Cir.2000). If an accused product does not infringe an independent claim, it also does not infringe any claim depending thereon. See Wahpeton Canvas Co. v. Frontier, Inc., 870 F.2d 1546, 1553 (Fed.Cir.1989). However, “[o]ne may infringe an independent claim and not infringe a claim dependent on that claim.” Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 1359 (Fed.Cir.2007) (quoting Wahpeton Canvas, 870 F.2d at 1552) (internal quotations omitted). A product that does not literally infringe a patent claim may still infringe under the doctrine of equivalents if the differences between an individual limitation of the claimed invention and an element of the accused product are insubstantial. See Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S. 17, 24, 117 S.Ct. 1040, 137 L.Ed.2d 146 (1997). The patent owner has the burden of proving infringement and must meet its burden by a preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed.Cir.1988) (citations omitted).

When an accused infringer moves for summary judgment of non-infringement, such relief may be granted only if one or more limitations of the claim in question does not read on an element of the accused product, either literally or under the doctrine of equivalents. See Chimie v. PPG Indus., Inc., 402 F.3d 1371, 1376 (Fed.Cir.2005); see also TechSearch, L.L.C. v. Intel Corp., 286 F.3d 1360, 1369 (Fed.Cir.2002) (“Summary judgment of noninfringement is ... appropriate where the patent owner’s proof is deficient in meeting an essential part of the legal standard for infringement, because such failure will render all other facts immaterial.”). Thus, summary judgment of non-infringement can only be granted if, after viewing the facts in the light most favorable to the non-movant, there is no genuine issue as to whether the accused product is covered by the claims (as construed by the court). See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1304 (Fed.Cir. 1999).

For there to be infringement under the doctrine of equivalents, the accused product or process must embody every limitation of a claim, either literally or by an equivalent. Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S. 17, 41, 117 S.Ct. 1040, 137 L.Ed.2d 146 (1997). An element is equivalent if the differences between the element and the claim limitation are “insubstantial.” Zelinski v. Brunswick Corp., 185 F.3d 1311, 1316 (Fed.Cir.1999). One test used to determine “insubstantiality” is whether the element performs substantially the same function in substantially the same way to obtain substantially the same result as the claim limitation. See Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605, 608, 70 S.Ct. 854, 94 L.Ed. 1097 (1950). This test is commonly referred to as the “function-way-result” test. The mere showing that an accused device is equivalent overall to the claimed invention is insufficient to establish infringement under the doctrine of equivalents. The patent owner has the burden of proving infringement under the doctrine of equivalents and must meet its burden by a preponderance of the evidence. See Smith-Kline Diagnostics, Inc. v. Helena Lab. Corp., 859 F.2d 878, 889 (Fed.Cir.1988) (citations omitted).

The doctrine of equivalents is limited by the doctrine of prosecution history estoppel. In Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd., 535 U.S. 722, 122 S.Ct. 1831, 152 L.Ed.2d 944 (2002), the Supreme Court stated:

Prosecution history estoppel ensures that the doctrine of equivalents remains tied to its underlying purpose. Where the original application once embraced the purported equivalent but the patentee narrowed his claims to obtain the patent or to protect its validity, the patentee cannot assert that he lacked the words to describe the subject matter in question. The doctrine of equivalents is premised on language’s inability to capture the essence of innovation, but a prior application describing the precise element at issue undercuts that premise. In that instance the prosecution history has established that the inventor turned his attention to the subject matter in question, knew the words for both the broader and narrower claim, and affirmatively chose the latter.

Id. at 734-735, 122 S.Ct. 1831. In other words, the prosecution history of a patent, as the public record of the patent proceedings, serves the important function of identifying the boundaries of the patentee’s property rights. Once a patentee has narrowed the scope of a patent claim as a condition of receiving a patent, the patentee may not recapture the subject matter surrendered. In order for prosecution history estoppel to apply, however, there must be a deliberate and express surrender of subject matter. See Southwall Tech., Inc. v. Cardinal IG Co., 54 F.3d 1570, 1580 (Fed.Cir.1995).

Once a court has determined that prosecution history estoppel applies, it must determine the scope of the estoppel. See id. at 1580. This requires an objective examination into the reason for and nature of the surrendered subject matter. Id.; see also Augustine Med., Inc. v. Gaymar Indus., Inc., 181 F.3d 1291, 1299 (Fed.Cir. 1999). If one of ordinary skill in the art would consider the accused product to be surrendered subject matter, then the doctrine of equivalents cannot be used to claim infringement by the accused product; i.e., prosecution history estoppel necessarily applies. Augustine Med., 181 F.3d at 1298. In addition, a “patentee may not assert coverage of a ‘trivial’ variation of the distinguished prior art feature as an equivalent.” Id. at 1299 (quoting Litton Sys., Inc. v. Honeywell, Inc., 140 F.3d 1449, 1454 (Fed.Cir.1998)).

C. Invalidity

1. Anticipation

An anticipation inquiry involves two steps. First, the court must construe the claims of the patent in suit as a matter of law. Key Pharms. v. Hercon Labs. Corp., 161 F.3d 709, 714 (Fed.Cir.1998). Second, the finder of fact must compare the construed claims against the prior art. Id. A finding of anticipation will invalidate the patent. Applied Med. Res. Corp. v. U.S. Surgical Corp., 147 F.3d 1374, 1378 (Fed. Cir.1998).

Under 35 U.S.C. § 102(b), “[a] person shall be entitled to a patent unless the invention was patented or described in a printed publication in this or a foreign country ... more than one year prior to the date of the application for patent in the United States.” The Federal Circuit has stated that “[t]here must be no difference between the claimed invention and the referenced disclosure, as viewed by a person of ordinary skill in the field of the invention.” Scripps Clinic & Research Found, v. Genentech, Inc., 927 F.2d 1565, 1576 (Fed.Cir.1991). In determining whether a patented invention is explicitly anticipated, the claims are read in the context of the patent specification in which they arise and in which the invention is described. Glaverbel Societe Anonyme v. Northlake Mktg. & Supply, Inc., 45 F.3d 1550, 1554 (Fed. Cir.1995). The prosecution history and the prior art may be consulted if needed to impart clarity or to avoid ambiguity in ascertaining whether the invention is novel or was previously known in the art. Id. The prior art need not be ipsissimis verbis (i.e., use identical words as those recited in the claims) to be anticipating. Structural Rubber Prods. Co. v. Park Rubber Co., 749 F.2d 707, 716 (Fed.Cir.1984).

A prior art reference also may anticipate without explicitly disclosing a feature of the claimed invention if that missing characteristic is inherently present in the single anticipating reference. Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1268 (Fed.Cir.1991). The Federal Circuit has explained that an inherent limitation is one that is necessarily present and not one that may be established by probabilities or possibilities. Id. That is, “[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient.” Id. The Federal Circuit also has observed that “[i]nherency operates to anticipate entire inventions as well as single limitations within an invention.” Schering Corp. v. Geneva Pharms. Inc., 339 F.3d 1373, 1380 (Fed.Cir.2003). Moreover, recognition of an inherent limitation by a person of ordinary skill in the art before the critical date is not required to establish inherent anticipation. Id. at 1377.

2. Obviousness

“A patent may not be obtained ... if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.” 35 U.S.C. § 103(a). Obviousness is a question of law, which depends on underlying factual inquiries.

Under § 103, the scope and content of the prior art are to be determined; differences between the prior art and the claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background the obviousness or nonobviousness of the subject matter is determined. Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented.

KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (quoting Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)).

“[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 550 U.S. at 418, 127 S.Ct. 1727. Likewise, a defendant asserting obviousness in view of a combination of references has the burden to show that a person of ordinary skill in the relevant field had a reason to combine the elements in the manner claimed. Id. at 418-19, 127 S.Ct. 1727. The Supreme Court has emphasized the need for courts to value “common sense” over “rigid preventative rules” in determining whether a motivation to combine existed. Id. at 419-20, 127 S.Ct. 1727. “[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.” Id. at 420, 127 S.Ct. 1727. In addition to showing that a person of ordinary skill in the art would have had reason to attempt to make the composition or device, or carry out the claimed process, a defendant must also demonstrate that “such a person would have had a reasonable expectation of success in doing so.” PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed.Cir.2007).

A combination of prior art elements may have been “obvious to try” where there existed “a design need or market pressure to solve a problem and there [were] a finite number of identified, predictable solutions” to it, and the pursuit of the “known options within [a person of ordinary skill in the art’s] technical grasp” leads to the anticipated success. Id. at 421, 127 S.Ct. 1727. In this circumstance, “the fact that a combination was obvious to try might show that it was obvious under § 103.” Id. Federal Circuit precedent has also established that “[structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds,” and that particular types of structural similarity can give rise to a case of prima facie obviousness. Genetics Institute, LLC v. Novartis Vaccines and Diagnostics, Inc., 655 F.3d 1291, 1312 (Fed.Cir.2011) (citing In re Deuel, 51 F.3d 1552, 1558 (Fed.Cir.1995)).

A court is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a “check against hindsight bias.” See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed.Cir.2012). “Such secondary considerations as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented.” Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966).

“Because patents are presumed to be valid, see 35 U.S.C. § 282, an alleged infringer seeking to invalidate a patent on obviousness grounds must establish its obviousness by facts supported by clear and convincing evidence.” Kao Corp. v. Unilever U.S., Inc., 441 F.3d 963, 968 (Fed. Cir.2006) (citation omitted). In conjunction with this burden, the Federal Circuit has explained that,

[w]hen no prior art other than that which was considered by the PTO examiner is relied on by the attacker, he has the added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job, which includes one or more examiners who are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art and whose duty it is to issue only valid patents.

PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed.Cir.2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1359 (Fed.Cir.1984)).

3. Written description a. Indefiniteness

The definiteness requirement is rooted in § 112, ¶2, which provides that “the specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.” “A determination of claim indefiniteness is a legal conclusion that is drawn from the court’s performance of its duty as the construer of patent claims.” Personalized Media Comm., LLC v. Int’l Trade Com’n, 161 F.3d 696, 705 (Fed.Cir.1998).

Determining whether a claim is definite requires an analysis of whether one skilled in the art would understand the bounds of the claim when read in light of the specification ... If the claims read in light of the specification reasonably apprise those skilled in the art of the scope of the invention, § 112 demands no more.

Id. (citing Miles Lab., Inc. v. Shandon, Inc., 997 F.2d 870, 875 (Fed.Cir.1993)).

b. Enablement and written description

The statutory basis for the enablement and written description requirements, § 112 ¶ 1, provides in relevant part:

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same....

“The enablement requirement is met where one skilled in the art, having read the specification, could practice the invention without ‘undue experimentation.’ ” Streck, Inc. v. Research & Diagnostic Systems, Inc., 665 F.3d 1269, 1288 (Fed.Cir. 2012) (citation omitted). “While every aspect of a generic claim certainly need not have been carried out by the inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed.Cir.1997). The specification need not teach what is well known in the art. Id. (citing Hybritech v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed.Cir. 1986)). A reasonable amount of experimentation may be required, so long as such experimentation is not “undue.” ALZA Corp. v. Andrx Pharms., Inc., 603 F.3d 935, 940 (Fed.Cir.2010).

“Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” Martek Biosciences Corp. v. Nutrinova, Inc., 579 F.3d 1363, 1378 (Fed. Cir.2009) (citing In re Wands, 858 F.2d 731, 737 (Fed.Cir.1988)). The Federal Circuit has provided several factors that may be utilized in determining whether a disclosure would require undue experimentation: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance disclosed in the patent; (3) the presence or absence of working examples in the patent; (4) the nature of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability of the art; and (8) the breadth of the claims. In re Wands, 858 F.2d at 737. These factors are sometimes referred to as the “Wands factors.” A court need not consider every one of the Wands factors in its analysis, rather, a court is only required to consider those factors relevant to the facts of the case. See Streck, Inc., 665 F.3d at 1288 (citing Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927 F.2d 1200, 1213 (Fed.Cir.1991)).

The enablement requirement is a question of law based on underlying factual inquiries. See Green Edge Enters., LLC v. Rubber Mulch Etc., LLC, 620 F.3d 1287, 1298-99 (Fed.Cir.2010) (citation omitted); Wands, 858 F.2d at 737. Enablement is determined as of the filing date of the patent application. In re '318 Patent Infringement Litigation, 583 F.3d 1317, 1323 (Fed.Cir.2009) (citation omitted). The burden is on one challenging validity to show, by clear and convincing evidence, that the specification is not enabling. See Streck, Inc., 665 F.3d at 1288 (citation omitted).

A patent must also contain a written description of the invention. 35 U.S.C. § 112, ¶ 1. The written description requirement is separate and distinct from the enablement requirement. See Ariad Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed.Cir.2010). It ensures that “the patentee had possession of the claimed invention at the time of the application, i.e., that the patentee invented what is claimed.” LizardTech, Inc. v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1344-45 (Fed.Cir.2005). The Federal Circuit has stated that the relevant inquiry— “possession as shown in the disclosure” — is an “objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art. Based on that inquiry, the specification must describe an invention understandable to that skilled artisan and show that the inventor actually invented the invention claimed.” Ariad, 598 F.3d at 1351.

This inquiry is a question of fact: “the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.” Id. (citation omitted). In this regard, Gevo must provide clear and convincing evidence that persons skilled in the art would not recognize in the disclosure a description of the claimed invention. See PowerOasis, Inc. v. T-Mobile USA Inc., 522 F.3d 1299, 1306-07 (Fed.Cir.2008) (citation omitted). While compliance with the written description requirement is a question of fact, the issue is “amenable to summary judgment in cases where no reasonable fact finder could return a verdict for the non-moving party.” Id. at 1307 (citing Invitrogen Corp. v. Clontech Labs., Inc., 429 F.3d 1052, 1072-73 (Fed.Cir.2005)).

V. DISCUSSION

A. infringement

The court starts its infringement analysis of claim 1 of both patents-in-suit with the term “acetohydroxy acid isomeroreductase,” construed by the court as “NADPH-dependent.” Butamax contends that Gevo’s lead strains are similar to KARIs having E.C. number 1.1.1.86 and catalyze the AL to DHIV conversion. (D.I. 596 at 18, 20) Butamax makes the following usage arguments in light of its alternative claim construction, which includes “using NADPH as an electron donor.” (D.I. 596 at 31; D.I. 648 at 30) Gevo’s lead strains “use NADPH at values similar to or greater than several wild-type KARIs from other bacteria.” (D.I. 596 at 20 (emphasis omitted); D.I. 648 at 30) For instance, the patents-in-suit identify a specific activity of 0.026 units/mg with an enzyme having KARI activity. (D.I. 648 at 30 (citing '889 patent, 35:2-9 and '188 patent, 39:5-10)) Butamax then compares this specific activity to several values disclosed in Gevo’s patents and published data, concluding that the data “prove[s the] activity with NADPH exceeds the 0.026 units/mg disclosed in the Butamax patents.” (D.I. 648 at 30 (emphasis omitted)) Butamax asserts “that P2D1A1 and SE26E6 have statistically significant activity with NADPH, which follows a dose response,” based on its expert’s experiments. (D.I. 596 at 21) Butamax further argues that Gevo’s KARI enzymes “can use NADH or NADPH, as they have roughly equivalent specific activity with use of either cofactor.” (D.I. 648 at 31) To support this statement, Butamax cites to Gevo’s published data showing a 6 to 1 and 8 to 1 preference for NADH to NADPH for SE26E6 and P2D1A1 strains, respectively, determined using specific activities. (D.I. 648 at 31) Butamax concludes that this difference is not enough to define Gevo’s KARIs as