# United States **Court of Appeals**  **for the Federal Circuit**

______________________ BUTAMAX(TM) ADVANCED BIOFUELS LLC, Plaintiff

- Appellant,

v.

GEVO, INC., Defendant - Appellee.

______________________

2013

- 1342

______________________ Appeal from the United States District Court for the District of Delaware in No. 11

- CV

- 0054, Judge Sue L. Robinson.

______________________ Decided: February 18 , 2014

______________________

L EORA B EN -A MI , Kirkland & Ellis, LLP, of New York, New York, argued for plaintiff

- appellant. With her on the brief were T HOMAS F. F LEMING , C HRISTOPHER T. J AGOE , and P ETER B. S ILVERMAN

.

M ICHELLE S. R HYU , Cooley, LLP, of Palo Alto, Califo rnia, argued for defendant

- appellee. With her on the brief were S TEPHEN C. N EAL , B ENJAMIN G. D AMSTEDT , D ANIEL J. K NAUSS , of Palo Alto, California; and J AMES P. B ROGAN , of Broomfield, Colorado

.

______________________BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 2

Before R ADER , Chief Judge, L INN , and W ALLACH , Circuit Judges.

L INN , Circuit Judge

. Butamax TM Advanced Biofuel s LLC (“Butamax”) owns U.S. Pat. No. 7,851,188 (“’188 patent”) and No. 7,993,889 (“’889 patent”) (collectively, the “patents

- in

- suit”) and appeal s a final judgment entered against it following the district court’s 1) claim construction and denial of But amax’s motion for summary judgment of literal infring ement of the asserted claims of the ’188 and ’889 patents by Gevo, Inc. (“Gevo”) , 2) grant of Gevo’s motion for su mmary judgment of no n infringement under the doctrine of equivalents of the asserted claims of the ’188 and ’889 patents , 3) grant of Gevo’s motion for summary judg ment of invalidity of claims 12 and 13 of the ’889 patent for lack of written description, and 4) judgment of invalidity of claims 12 and 13 of the ’889 patent for lack of enablement. Opinion, Butamax TM Advanced Biofuels LLC v. Gevo, Inc.

, No. 11

- 54

- SLR, 2013 WL 3914467 (D. Del. March 19, 2013) (“ Opinion ”). Bec ause the district court erred in its claim construction, this court vacates the district court’s denial of Butamax’s motion for summary judgment of infringement and its grant of Gevo’s motion of noni nfringement under the doctrine of equivalents. Because
t he district court failed to recognize the existence of genuine issues of material fact on Gevo’s motion for summary judgment of invalidity as to claims 1 2 and 13 of the ’889 patent, this court reverses the district court’s grant of that motion. Finally, t his court reverses the grant of summary judgment of invalidity for lack of en ablement because that judgment appears to have been a scrivener’s error.BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 3

I. B ACKGROUND
A. The ’188 Patent
The ’188 patent covers a recombinant microbial host cell that uses a particular biosynthetic pathway to pr oduce isobutanol, which is useful as a fuel or fuel additive. Opinion at *3

. The claimed bio synthetic pathway co mprises essentially five steps. See ’188 Patent f ig. 1.
Claim 1 of the ’188 patent recites the first four steps : 1. A recombinant microbial host cell compri sing heterologous DNA molecules encoding pol ypeptides that catalyze substrate to product conversions for each step below:
i) pyruvate to acetolactate;
ii) acetolactate to 2,3

- dihydroxyisovalerate;

iii ) 2,3

- dihydroxyisovalerate to α

ketoisovalerate; and
iv) α

- ketoisovalerate to isobutyraldehyde;
wherein said microbial host cell produces is obutanol; and wherein a) the polypeptide that catalyzes a substrate to product conversion of pyruvate to acetolacta te 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 iso meroreductase having the EC number 1.1.1.86;
c) the polypeptid e that catalyzes a substrate to product conversion of 2,3

- dihydroxyisovalerate to

α

- ketoisovalerate is acetohydroxy acid dehydr atase having the EC number 4.2.1.9;BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 4

d) the polypeptide that catalyzes a substrate to product conversion of α

- ketoisovalerate to i sobutyraldehyde is branched

- chain α

- keto acid d ecarboxylase having the EC number 4.1.1.72.

’188 Patent col. 335 ll . 21

– 44 (emphasis added). In the fifth step, i sobutyraldehyde is converted into isobutanol. See ’188 Patent col. 336 ll . 43

– 48 (dependent claim 18, reciting a method for producing isobutanol from the recombinant microbial host cell of claim 1).
Claim 15 depends from claim 1 and recites “[a] host cell according to claim 1 wherein the acetohydroxy acid isomeroreductase has an amino acid sequence selected from the group consisting of SEQ ID NO: 43 , SEQ ID NO: 181 , SEQ ID NO: 183, and S EQ ID NO:185

. ” ’188 Patent col. 336 ll. 33

– 36. SEQ ID NO:183 is a sequenc e of Methanococcus

. This appeal primarily concerns step (ii): the conve rsion of acetolactate (“AL”) to 2,3

- dihydroxyisovalerate (“DHIV”) , catalyzed by the polypeptide enzyme acetoh ydroxy acid isomeroreductase (also known as keto

- acid reductoisomerase, or “KARI” ) “having the EC number 1.1.1.86.” K ARI assists reaction s by rear ranging (i.e., isomerizing) a reagent and also by “ reducing” (the process of adding electrons) this rearranged molecule. To acco mplish the reduction, KARI needs a source for the added electrons. This electron source is known as the “cofactor ” or “coenzyme.” Two such cofactors are NADH (nicotin amide adenine dinucleotide + hydrogen) and NADPH (nicotinamide adenine dinucleotide phosphate + hydr ogen).
The ’188 patent’s specification provides “defin itions . . . to be used for the i nterpretation of the claims ,” including a definition of KARI:

a n enzyme that catalyzes the conversion of acet olactate to 2,3

- dihydroxyisovalerate using NADPHBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 5

(reduced nicotinamide adenine dinucleotide pho sphate) as an electron donor. Preferred acetoh ydroxy acid isomeroreductases are known by the EC number 1.1.1.86 and sequences are available from a vast array of m icroorganisms, including b ut not limited to . . . Methanococcus maripal udis

. . . . ’188 Patent col. 7 ll . 35

– 47.

EC number 1.1.1.86, referenced in both this d efinition and claim 1, is an E nzyme C ommission number for an enzyme known by the names KARI, “acetohydroxy acid isomeroreduc tase,” and several other names

. The EC enzyme classification system was developed in the 1950s to standardize enzyme nomenclature. Opinion at * 15. Notably, Rule 18 of the EC system states that “[f]or oxidoreductases using NAD + or NADP + [the oxidized states of NADH and NADPH, respectively] , the coenzyme should always be named as the acceptor” unless a certain exception applies, which is irrelevant here. Id. However, it also appears common to assign different EC numbers to the same enzyme , where the difference between the numbers is the identity of the cofactor named

. Id. at 15

n. 8. EC num ber 1.1.1.86 names only NAD P + as an acce ptor , and neither party calls atten tion to another EC number for KARI naming any other cofactor as an acce ptor. Butamax alleges that Gevo infringes claim 1 of the ’188 patent and claims 2

– 4, 13

– 15, 17, and 36 depen dent therefrom, as well as claim 18 and claims 19

– 25, and 34

– 35 dependent therefrom.

B. The ’889 Patent
The ’889 patent issued from a divisional of the appl ication from which the ’188 patent issued. The patents’ specifications largely are identical , each for example including the KARI definition quoted above

. See ’889BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 6

Patent col. 7 ll . 8

– 20. The ’889 patent focuses on a met hod of producing isobutanol from a recombinant yeast microorganism that expresses the five

- step biosynthetic pathway described above

. Claim 1 of the ’889 patent states:

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 α

ketoisoval erate (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 e nzyme; b) the substrate to product conversion of step (ii) is performed by an acetohydroxy acid isomer oreductase enzyme;BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 7

c) the substrate to product conversion of step (iii) is performed by an acetohydroxy acid deh ydratase enzyme; d) the substrate to product convers ion 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 e nzyme; whereby isobutanol is produced.

’889 Patent col. 325 ll . 14

– 43. As with the ’188 patent, the

p rimary issue with the ’889 patent on appeal involves step (ii): the conversion of AL to DHIV using acetohydroxy acid isomeroreductase enzyme, i.e., KARI. Unlike claim 1 of the ’188 patent, claim 1 of the ’889 patent does not refer to any EC classificatio n number. Butamax alleges that Gevo has infringed claim 1 of the ’889 patent and claims 2

– 14 and 16

– 19 dependent therefrom.
C. The Parties and Previous Proceedings Butamax was formed in 2009 as a joint venture b etween E.I. du Pont de Nemours and Co. (“ Du Pont”) and BP Biofu el s North America LLC

. The applications that led to the patents

- in

- suit are part of Du Pont’s previous research and development into isobutanol production

. The patents

- in

- suit have been assigned to Butamax.

Gevo was incorporated i n 2005 as Methanotech, Inc. and likewise pursues isobutanol production. Gevo uses mutant KARI enzymes that when using NADH as a cofactor exhibit significantly lower K m (Michaelis

- Menten constant) for the AL

- to

- DHIV conversion than when using NAD P H as a c ofac tor. This indicat es that the reaction rate with Gevo’s mutant enzymes is much faster with NADH than with NADPH.BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 8

On January 14, 2011 , Butamax sued Gevo in the di strict court and on September 22, 2011

, moved for a pr eliminary injunction predicated on the ’889 patent. The di strict court construed the KARI term as “an enzyme th at is solely NADPH

- dependent” and denied the motion. Butamax(TM) Advanced Biofuels LLC v. Gevo, Inc.

, 486 F. App’ x 883 (Fed. Cir. 2012) . This c ourt affirmed the denial of the preliminary injunction

. Id. However, this court noted that the district court’s construction of the KARI term was “very questionable” and asked the district court “to reconsider its construction when it holds the Markman h earing.” Id.

At the Markman hearing, the district court construed the term as “an enzyme known by the EC number 1.1.1.86 that catalyzes the conversion of acetolactate to 2,3

- dihydroxyisovalerate and is NADPH

- dependent.” Opi nion at * 21. Additionally, a dopting Butamax’s proposed construction, the district court construed the ’889 patent’s term “pathway step (a); . . . pathway step (b); . . . pathway step (c); . . . pathway step (d); . . . pathway step (e)” to mean “the pathway steps a

- e are contiguous st eps 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.” Id. at * 22.
At the district court, Butamax moved for summary judgment of infringement of the patents

- in

- suit and for a judgment of no invalidity of the ’889 patent. Opinion at

* 2. Gevo moved for summary judgment of invalidity and

non

- infringement. Id. In a memorandum opinion, the district cour t denied Butamax’s motion for summar y judgment of infringement. The district court granted Gevo’s motion for summary judgment of non infringement as it related to the doctrine of equivalents, but otherwise denied the motion. Each o f Butamax’s motion of no invalidity and Gevo’s motion for invalidity was granted by the district court with respect to some claims and denied with respect to others. Relevant to this appeal, the di s-BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 9

trict court granted Gevo’s invalidity motion and denied Butamax’s motion of no in validity with respect to claims 12 and 13 of the ’889 patent , find ing the claims lacking in written description support

. Opinion at * 52

– 53

. The district court issued an order reflect ing the memorandum opinion and also holding claims 12 and 13 the ’889 pa tent invalid for lack of enablement , a ground not raised in the motions of the parties

. Butamax appeals the claim construction of the KARI term, the denial of Butamax’s motion for summary jud gment of literal infringement, the grant of Gevo’s motion for s ummary judgment of non infringement under the doctrine of equivalents, the grant of Gevo’s motion for summary judgment of invalidity of claims 12 and 13 of the ’889 patent for inadequate written descrip tion , and the order also holding those same claims invalid for lack of enablement. This court has jurisdiction under 28 U.S.C. § 1295(a)(1).

II. D ISCUSSION
A. Standards of Review

“We review claim construction de novo. ” Thorner v. Sony Computer Entm ’ t Am. LLC , 669 F.3d 1362, 1365 (Fed. Cir. 2012)

. Summary judgment is granted “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). “This c ourt reviews the di strict court’s grant or denial of summary judgment under the law of the regional circuit.” Lexion Med., LLC v. Northgate Techs., Inc., 641 F.3d 1352, 1358 (Fed. Cir. 2011). The Third Circuit “review[s] an order granting summary judgment de novo, applying the same standard used by the Distr ict Court.” Azur v. Chase Bank, USA, Nat ’l Ass’ n, 601 F.3d 212, 216 (3d Cir. 2010) (quotation omitted).BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 10

“[A] determination of infringement, both literal and under the doctrine of equivalents, is a question of fact.” Lockheed Martin Corp. v. Space Sys./Loral, Inc. , 324 F.3d 1308 , 1318 (Fed. Cir. 2003) . “ Summary judgment on the issue of infringement is proper when no reasonable jury could find that every limitation recited in a properly construed claim either is or is not found in the accused device either literally or under the doctrine of equiv alents.” PC Connector Solutions LLC v. SmartDisk Corp.

, 406 F.3d 1359, 1364 (Fed. Cir. 2005).

B. Claim Construction
The primary dispute between the parties concerns whether the claimed KARI must be “NADPH

- dependent.” 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 data bases. It concluded that in the “state of the a rt
, ” the “KARI enzyme known by the EC number 1.1.1.86 was generally understood to be NADPH

dependent.” Opinion at * 20. This decision is premised in large part on the district court’s conclusion that the patentees acted as their own lexicographers in defi ning KARI by reference to EC number 1. 1.1.86 and the e nzyme’s “use” of NADPH rather than use of NADH or both NADPH and NADH. Id. at * 19

– 20. The district court therefore construed the KARI term as “an enzyme known by the EC number 1.1.1.86 that catalyzes the conversion of acetolactate to 2,3

- dihydroxyisovalerate and is NADPH

- dependent.” Id. at * 21. Butamax argues that the district court erred because KARI’s plain meaning merely refers to an enzyme cataly zing the AL to DHIV conversion and because the pat entees did not expressly relinquish any of that claim scope in the specification or the prosecution history. Butamax co ntends that the patent ees in defining KARI did not clearly

express an intent to redefine KARI to be NAD PH-BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 11

dependent. In support, Butamax points to the other claims, the embodiments provided in the specification s , and extrinsic evidence including contemporary scientific literature, a database referenced in EC number 1.1.1.86
, and Gevo’s use of EC number 1.1.1.86 to describe its own

e nzymes. Gevo disagrees, arguing that the district court co nstrued the term correctly. Gevo contends that the specifications’ definition of KARI demonstrates that the patentees did clearly express a n intent to specify KARI as NADPH

- dependent , and points to other aspects of the specification s as well as the prosecution histor ies in support. Gevo further contends that extrinsic evidence, such as EC number 1.1.1.86 and its references, the EC rules, and Butamax’s internal documents and subsequent patent appl ications indicate tha t the claimed KARI must be NAD PH- dependent.
Generally, claim terms are:
given their ordinary and customary meaning as understood by a person of ordinary skill in the art when read in the context of the specification and prosecution his tory. There are only two exce ptions to this general rule: 1) when a patentee sets out a definition and acts as his own lexicographer, or 2) when the patentee disavows the full scope of a claim term either in the specification or during prosecution.

Thorne r , 669 F.3d at 1365 (citation omitted). “ To act as its own lexicographer, a patentee must ‘ clearly set forth a defini tion of the disputed claim term’ other than it s plain and ordinary meaning.” Id. at 1365 ( quoting CCS Fitness, Inc. v. Brunswick Corp.

, 288 F.3d 1359, 1366 (Fed. Cir. 2002) ). “ It is not enough for a patentee to simply disclose a single embodiment or use a word in the same manner in all embodiments, the patentee must ‘ clearly express an intent ’ to redefine the term. ” Id. ( citing Helmsder fer v.BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 12

Bobrick Washroom Equip., Inc.

, 527 F.3d 1379, 1381 (Fed. Cir. 2008) ).
i. KARI’s Ordinary Meaning The initial inquiry is whether the plain meaning of KARI in dicates that the enzyme is NAD PH- dependent

. While t he district court found that “the scientific refe rences almo st exclusively characterize KARI enzymes as NADPH

- dependent

, ” Opinion at * 19 , there is nothing in the record to indicate that persons of ordinary skill in the art in 2005 understood the plain meaning to be limited to dependence on NADPH as a cofactor. Gevo conceded as much at the district court, acknowledging that under KARI’s plain meaning, the enzyme converts AL to DHIV “using NADH or NADPH as a cofactor.” See Joint Appe ndix (“ J.A. ”) 10240

. We agree that the plain meaning of KARI itsel f i mposes no limitation on the cofactor or source of electrons for the AL to DHIV conversion. The question then b ecomes whether the asserted claims are limited, as Gevo contends, to the use of NADPH only based principally on the “explicit defini tion” set forth in the patents

- in

- suit. See J.A. 10241.

ii. The Specifications and Claims

a. The Patentees’ Definition of KARI
The patents provide definitions of several terms, no ting that “[t]he following definitions and abbreviations are to be used for the interpretation of the cl aims and specification.” ’188 Patent col. 7 ll . 12

– 14. 1 As described above, the patents subsequently define KARI as:

1 Because the specifications of the patents

- in

- suit largely are identical, the court for brevity will cite only to the ’188 patent.BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 13

an enzyme that catalyzes the conversion of acet olactate to 2,3

- dihydroxyisovalerate using NADPH (reduced nicotinamide adenine dinucleotide pho sphate) as an electron donor. Preferred acetoh ydroxy acid isomeroreductases are known by the EC number 1.1.1.86 and sequences are available from a vast array of m icroorganisms, in cluding but not limited to . . . Methanoc occus maripal udis

. . . . ’188 Patent col. 7 ll . 35

– 47. It cannot be disputed that the patentees offered a de finition of KARI. It is disputed, however, whether this definition “clearly expresses an intent” to redefine KARI in a way that differs from the plain and ordinary meaning identified above and, if so, the extent of any such diffe rence

. Gevo contends that the phrase “using NAD P H . . . as an electron donor” is a clear expression of the paten tees’ intent to exclude KARI that are not “NADPH

dependent .”
Butamax disagrees and asserts that the fact that an enzyme can catalyze the conversion of AL to DHIV “using NADPH” does not, on its own, indicate that the enzyme
cannot also use other cofactors, such as NADH, to cat alyze that conversion.

Gevo argues that Butamax’s interpretation reads out an important aspect of the patentees’ definition of KARI because all KARI are capable of using NADPH as a cofa ctor. T hus , Gevo argues it would have been completely unnecessary for the patents to have referred to “u sing NADPH” in the first instance. Gevo also argues that the phrase “using NADPH” must be understood in light of other aspects of the specifications. Gevo first contends that the specifications use the term “use (s) NADPH” interch angeably with the phrase “NADPH

- dependent.” Gevo points to this passage:BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 14

[A]lcohol dehyd rogenase VI (ADH6) and Ypr1p . . . use NADPH as electron donor. An NADPH

dependent reductase, YqhD, .

. . has also been r ecently identified in E. coli

. . . .

’ 188 P aten t col. 1 2 ll

. 50

– 60

. Th e patent s further describe ADH6 as “NADPH

- dependent cinnamyl alcohol dehydr ogenase.” Id. at col. 4 ll . 60

– 62. However, “[i] t is not enough for a patentee to simply disclose a single embod iment or use a word in the same manner in all embod iments.” Thor ner , 669 F.3d at 1365. We agree with Butamax and find no reason to co nstrict the phrase “using NADPH” to mean “only use NADPH” or “NADPH

- dependent.” We also disagree with Gevo’s argument that such an interpretation reads out an important part of the pat entees’ definition. The patents’ definition at least excludes as -yet- undiscovered KARI enzymes that could catalyze the conversion of AL to DHIV without using NADPH at all. Moreover, the description of specific types of KARI as NADPH

- dependent does not cl early express an intent to redefine all KARI “using NADPH” as KARI that must be NADPH

- dependent.
Next, Gevo points to the patents’ description s of other enzymes that use or utilize either NAD + or “NADH . . . and/or NADPH” as an electron donor. Id. at co l. 8 ll . 14

– 16 , 25

– 29. Gevo contends that the patentees knew how to describe enzymes that used NADH or both NADH and NADPH and that the patentees instead chose to de fine KARI as using only NADPH.
Butamax counters that the patents’ description s of other enzymes “using” or “utilizing” various cofactors merely is a reference to particular EC numbers or the assays for the enzyme s in question. For example, But amax contends that the standard assay for KARI is the Arfin

- Umbarger assay, which “uses” NADPH to measure KARI activity by monitoring the consumption of NADPH in the presence of acetolactate and the enzyme in que s-BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 15

tion. Appellant’s Br. 14. The patents’ Example 2 expres sly teaches to measure KARI activity “using the method described by Arfin and Um barger,” ’188 P atent col. 33 ll

. 45

– 47. Example 10 teaches using the same method. Id. at col. 39 ll . 4

– 5. Butamax also argues that t he patents’ reference to “using NADPH ” merely matches the descri ption of the enzyme in EC number 1.1.1.86, which notes th e use of NADP + but is silent as to NAD + or NADH. Butamax notes that the other enzymes in question from the specifications have multiple EC numbers

— each referring to NADH, NADPH, or both NADH and NADPH

— and/or have multiple different assays for their identi fication

— each assay using a different cofactor. Thus, Butamax argues that t he patentees merely referred the other cofactors where appropriate . Appellant’s Br. 45. We agree with Butamax that the references to other

enzymes as either using NAD + or using NADH and/or NADPH do not imply that the patentees intended to limit KARI’s use of NADH. The paten tees’ description of KARI merely corresponds with the Arfin

- Umbarger assay and the description of KARI in EC Number 1.1.1.86.

b. Reference to EC Number 1.1.1 .86 in Claim 1
The ’188 patent’s claim 1 explicitly states that the e nzyme in question is “acetohydroxy acid isomeroreductase having the EC number 1.1. 1.86.” ’188 P atent c ol. 335 ll

. 33

– 36. As described above, EC number 1.1.1.86 identifies NADP + as the c ofactor, but does not itself mention NAD + or NADH. See Appellee’s Br. 45. The EC rules provide that for an enzyme “using” both NADH and NADPH, the entry should “always” name both cofactors. Gevo co ntends that this confirms that a person of ordinary skil l in the art understood KARI having EC number 1.1.1.86 to be NADPH

- dependent.
It must first be appreciated that the EC nomenclature was drafted to categorize naturally

- occurring enzymes and that new EC numbers generally are not created forBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 16

modified forms of enzymes that might rely on different cofactors. See J.A. 17810

– 11. The nomenclature is also not necessarily complete. In 2005, for example, it was known that some KARI, such as KARI from at least some species of Methanococcus , can use either cofactor effectiv ely. Significantly, Methanococcus was explicitly recited in Butamax’s own definition as a preferred KARI and recited in dependent claim 15 . ’188 P atent col. 7 ll. 40

– 47. Butamax points to additional evidence showing persons of skill in the art would have understood that EC number 1.1.1.86 enzymes need not be NADPH

- dependent. T he EC number 1.1.1.86 entry contains a link to the BRENDA database (Br aunchschweig E n zyme Database), which contains a reference to a mutated KARI en zyme in which NADH “can substitute for NADP H.” Appellant’s Br. 16. The district court discounted this lone reference because it was the only reference out of many indicating that NADH could be substituted and because the specific
enzyme in question was a “quadruplet m utant.” Opinion
at * 19

– 20.
However, even a single reference to mutant KARI u nder EC number 1.1.1.86 is particularly important here because the accused enzymes also are mutants. Butamax points to evidence that Gevo in approximately 2008

— prior to the lit igation

— described its own mutant enzymes by reference to EC number 1.1.1.86. See, e.g., Appellant’s Br. 25; J.A. 9804. And of course Gevo contends that its enzymes are not NADPH

- dependent. Th ough th is ev idence identified by Butamax did not exist until years after the patents

- in

- suits were filed in 2005

, t he BRENDA entry for EC number 1.1.1.86 referred to a mutant KARI that was not NADPH

- dependent and was known prior to 2005 , and Gevo years later indicated that EC number 1.1.1.86 sti ll “would ha ve been the best way [they] knew how” to describe its own mutant enzyme. Appellant’s Br. 25 (citing testimony of Gevo’s former Executive Vice President of Technology). See e.g., ASM Am. , Inc. v.BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 17

Genus, Inc.

, 401 F .3d 1340, 1347 (Fed. Cir. 20 05) (concluding that extrinsic evidence that post

- dated the patent filing date nonetheless was helpful in determining how a person of ordinary skill in the art would have understood the claim term at the time it was filed).
For the foregoing reasons , the C ourt cannot conclude that the reference to EC number 1.1.1.86 is an expression of a clear intent to redefine KARI to be NADPH

dependent

. c. Preferred Embodiments and Dependent Claims
Other aspects of the patent s raise further doubt of
any express intent to redefine KARI in the limited way adopted by the district court. As above, t he patents specifically list “ Methanococcus maripaludis

. . . SEQ I D NO: 183 ” as a source organism for the preferred KARI. ’188 patent at col. 7 ll. 35

– 47. Moreover, d epen dent claim 15 of the ’188 patent claims that KARI. ’188 P atent c ol. 336 ll . 33

– 36. Butamax contends that it would be wrong to conclude that KARI from this organism are NADPH

- dependent , pointing to evidence that at least

some Methanococcus KARI are “able t o ut ilize NADH as well as NADPH ” and have “broad specificity for NADPH and N ADH.” Further, Butamax notes that “ NADH su pported 60% of the methanococcal activity obtained with NADPH.” See R. Xing & W. Whitman, Characterization of Enzymes of the Branched

- Chain Amino Acid Biosy nthetic Pathway in Methanococcus spp, 173(6) J. Bacterio logy 2086

– 92 (1991 ) (“Xing”)

. The district court discounted Xing because it provided no references or data to support these findings. Opinion
at * 19 (noting that Xing “included a si ngle conclusory sentence with no data or other literature references to support it”). However, Xing’s accuracy is not in dispute. Indeed, Gevo’s 2007 Pat. App. No. 61/016,483 cites to Xing for this very proposition. Gevo does note that the patents iden tify the KARI of Methanococcus maripaludis whileBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 18

Xing examined the KARI of Methanococcus aeolicus

, a different species of Methanococcus . However, there is no genuine dispute that Methanococcus maripaludis exhibit s similar characteristics. See Appellant’s Reply Br. 9.

The district court’s claim construction , without justification, exclude s a preferred embodiment, which in this case also is the subject of dependent claim 15, and this court “normally do[es] not interpret claim terms in a way tha t excludes embodiments disclosed in the specification.” Oatey Co. v. IPS Corp ., 514 F.3d 1271, 1276 (Fed. Cir. 2008).
iii. Prosecution History Gevo also contends that the prosecution history evin ces an express intent to redefine KARI to be NADPH

depend ent

. The Patent Office separately rejected But amax’s claims for lack of enablement and for lack of wri tten description , and Gevo contends that the patentees’ responses demonstrated that the claimed KARI are NADPH

- dependent.
In the application leading to t he ’188 patent, the P atent Office rejected for inadequate written description a then

- pending claim which stated: A recombinant microbial host cell comprising at least one DNA molecule encoding a polypeptide that catalyzes a substrate to product conversion selected from the group consisting of:
i) pyruvate to acetolactate (pathway step a)
ii) acetolactate to 2,3

- dihydroxyisQvalerate (pathway step b)
iii) 2,3

- dihydroxyisovalerate to a

ketoisovaler ate (pathway step c)
iv) a

- ketoisovalerate to isobutyraldehyde, (pathway step d), andBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

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v) isobutyraldehyde to isobutanol; (pathway step e)

wherein the at least one DNA molecule is he terologous to said microbial host cell and wherein said microbial host cell produces isobutanol.

J.A. 6906. The Patent Office concluded that “[o]ne skilled in the art would require additional guidance, such as information regarding the specific identity and structure of the polypeptides that catalyze[] ” t he conversions in the cl aim. J.A. 6927. The patentees responded, amending the claim to refer to the EC numbers of the various e nzymes, submitt ing a copy of the EC nomenclature rules, and pointing to the specific examples of the enzymes in the specification (including SEQ ID No: 183

— Methanococcus maripaludis

— as an example of KARI). J.A. 7095. The Patent Office concluded that this sufficiently described the claimed inventions but concluded that the claim lacked enablement for its full scope

. J.A. 7117. The patentees disagreed, contending that the EC numbers, together with the level of ordinary skill in the art ( including knowledge reflected in the BRENDA dat abase ) did enable skilled artisans to identify appropriate enzymes, and the examiner eventually wi thdrew the rejection. J.A. 7209, 7251. In the application leading to the ’889 patent, a then

pending claim similarly was rejected for lack of enabl ement. J.A. 7572

– 73. The patentees again amended, this time naming the enzymes used in each claimed ste p without referring to any EC numbers. J.A. 7585. The patentees argued that “[t]he specific enzymes that cat alyze the steps of the pat hway recited in the claims are described in the application in an abundance of detail,” and went on to discuss Table 2 a s a particular example. J.A. 7583.

In the prosecution history, the patentees defended their claims by referring the Patent Office to the ECBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

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numbers and the examples of the enzymes provided in the specifications. For the reasons stated above, these refe rences do not clearly express an intent by the patentees to

re define KARI to be NADPH

- dependent

. Indeed, the patentees specifically named Methanococcus maripaludis KARI as an example during the prosecution history, a KARI that appears to “use” NADH.

Accor dingly, the court does not consider t he prosec ution history to warrant any limitation of the claimed KARI as being NADPH

- dependent

. iv. Extrinsic Evidence
Gevo also relies on extrinsic evidence to support its arguments. EC number 1.1.1.86 was discussed above. Gevo further points to Butamax’s internal documents and subsequent patent applications. For example, based on its research, Butamax filed a patent application in 2008 which stated that “discovery of a KARI enzyme that can use NADH a s a cofactor as opposed to NADPH woul d be an advance in the art.” J.A. 8794. Gevo contends that this application and the related evidence demonstrate that Butamax itself recognized that the earlier- filed patents

- in

- suit did not encompass KARI that use NA DH. However, as discussed above, the ordinary meaning of KARI is not cofactor dependent, and this subsequent extrinsic evidence does not clearly express an intent at the time of the invention to redefine KARI to use one cofactor over another

. The subseque nt discovery of the beneficial results obtained by the use of NADH does not support the conclusion that it was understood to be excluded as a cofactor at the ti m e the patents

- in

- suit were filed.

v

. Claim C onstruction For all of the foregoing reasons, t he term “acetoh ydroxy acid reductoisomerase” is construed as “ an enzyme, whether naturally occurring or otherwise, known by theBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 21

EC number 1.1.1.86 that catalyzes the conversion of acetolactate to 2,3

- dihydroxyisovalerate .”
C. Infringement

Butamax contends that this court, under the more a ccurate claim construction, should reverse the district court’s ruling that denied Butamax’s motion for summary judgment of literal infringement. Gevo disagrees, co ntending that 1) there remains a dispute concerning the

“ contiguous” pathway term and 2) there remains a di spute as to the accused enzymes ’ “use” of NADPH.

T he continuous pathway term relates only to the ’889 patent and does not present a genuine issue of material fact on this record. Butamax provided expert te stimony, and Gevo failed to present any contention, interrogatory, or expert testimony challenging Butamax’s contention that the limitation was met.
As to the dispute over whether Gevo’s enzymes use detectable levels of NADPH, Gevo argues on appeal that there is a distinction between in vivo and in vitro use that gives rise to a genuine issue of material dispute. Howe ver, Gevo does not appear to have argued at any point before the district court that the construc tion of KARI requires focusing on use of a specific cofactor in vivo as opposed to in vitro

. T his court declines to consider what appears to be a new claim construction argument raised for the first time on appeal

. Gevo further contends that Butamax’s in vitro testing of Gevo’s enzymes, showing them to use NADPH, may be unreliable. Appellee’s Br. 61. Gevo’ s argument however, is not that the results of the testing were inaccurate, but rather that a person of ordinary skill in the art would not draw the same conclusions from the experiments as the conclusions drawn by Butamax’s expert. Whether Gevo’s argument s create a genuine issue of material fact underBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 22

the claim constr uction set forth in this opinion is best left to the district court on remand.
The court accordingly vacates the district court’s d enial of Butamax’s motion for summary judgment of infringement of claims 1, 2

– 4, 13

– 15, 17

– 25, and 34

– 36 of the ’188 patent and claims 1, 2

– 14, and 16

– 19 of the ’889 patent and directs the district court to reconsider the question un der this court’s new claim construction.

D . Invalidity

i. Written Description of Claims 12 and 13 of the ’889 Patent
Claim 12 of the ’889 patent states:
12. The recombinant yeast microorganism of claim 1 wherein the said microorganism further co mprises inactivated genes thereby reducing yield loss from competing pathways for carbon flow.
Claim 13 of the ’889 patent states:
13. The recombinant yeast microorganism of claim 12, wherein said inactivated genes reduce p yruvate decarboxylase activity.

The district court found that both claims were inad equate ly described and thus invalid because the specific ation does not sufficiently describe how to inactivate genes to disable the competing synthetic pathway

. When determining whether a specification co nta ins adequate written description, one must make an “objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art.” [Citation.] Because the specification is viewed from the perspective of one of skill, in some circumstances, a patentee may rely on information that is “well

- known inBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 23

the art” for purposes of meeting the written d escription requirement. Boston Scientific Corp. v. Johnson & Johnson

, 647 F .3d 1353, 1366 (Fed. Cir. 2011) (citation omi tted)

. The district court concluded that while the patent’s specification “may be interpreted as identifying both the [ ] problem and the solution, it does not even begin to describe how to put into practice the solution.” Opinion at

* 52. Butamax disag rees, but its evidence in support of its arguments is weak. First, Butamax contends that the patent does teach how to deactivate the pathway in question. In support, Butamax cites to multiple aspects of the specification, but each describes only a desire to deactivat e the genes rather than how to actually do it. See, e.g., ’889 Patent col. 1 ll. 63

– 65 (“[t]here is a need

. . . for an environmentally responsible, cost

- effective process for the production of isobutanol as a single product”), col. 16 ll. 55

– 57 (“[t]he microbial host has to be manipulated in order to inactivate competing pathways for carbon flow by deleting various genes”), col. 12 ll. 12

– 17 (“[t]o prevent misdirection of pyruvate away from isobutanol produ ction, a decarboxylase with decrease d affinity for pyruvate is desired ”) (all emphasis added).
Next, Butamax contends that irrespective of what is explicitly taught in the specification itself, it was well

known in the art how to deactivate the genes that express the pathway. Butamax points to the testimony of Gevo’s own experts, Dr. Stephanopolous and Dr. Kirsch, conten ding that they agreed that it was “conventional” in 2005 t o deacti vate the pathway . However, the expert testimony on which Butamax relies merely agrees that, in light of the specification, it would have been understood that such deactivation was desirable. See, e.g., Appellant’s Br. 68 (Dr. Stephanopolous agreeing that “the concept” of dea ctivating the pathway was conventional by 20 05, that it was “nothing new” to “want to get rid of competing pat h-BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 24

ways,” that the patents “tell you [you] want to delete” the competing pathway, and that the patent “tells you you’r e knocking out” that pathway); s ee also, e.g., Appellant’s Br. 69 (Dr. Kir sch agreeing that the patents teach that “you
want to knock out” the competing pathway) (emphasis added).

Butamax also relies on extrinsic evidence purportedly teach ing how to deactivate the pathway. Butamax su bmitted the declaration of Alexander M. Kli banov, who opined that it would have been well

- known to a person of ordinary skill in the art how to deactivate the genes, citing to seven references that purportedly describe orga nisms with reduced or inactivated pyruvate decarboxylase activity . Appellant’s Br. 67 ; J.A. 3141 . The district c ourt does not appear to have address ed M r. Klibanov’s test imony or six of the references he cited. The seventh refe rence, D ickinson

, was addressed by the district court, which agreed that Dickinson discloses yeast wit h dea ctivated genes associated with pyruvate decarboxylase activity as described in claim 13. Opinion at * 53. Howe ver, the district court concluded that Dickinson was not appropriately incorporated by reference into the ’889 patent for this point and eve n if it had been, that Dicki nson effectively teaches away from claim 13 because in deac tivating those genes responsible for expressing the pathway

, isobutanol production was “virtually abolished.” Id.
Notwithstanding the short comings of the foregoing

, Butamax has identified sufficient evidence that at least
create s a genuine dispute of material fact. Gevo makes much of the fact that Dickinson, though cited in the ’889 patent, was not cited in connection with the deactivation of this pathway and was not incorporated by reference into the patent. Nonetheless, Dickinson’s teachings still reflect what was known in the art. See Falko

- Gunter Falkner v. Inglis

, 448 F.3d 1357, 1368 (Fed. Cir. 2006) (holding that where “accessible literature sources clearlyBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 25

pr ovided” a description of the teachings at issue, the written description requirement does not require their incorporation by reference). Dickinson does show that persons of ordinary skill in the art could deactivate the pathway in question , and though it appears that accor ding to Dickinson the claimed invention would not have worked particularly well (isobutanol production would be “virtually abolished” ), the evidence at least creates a genuine dispute as to whether a person of ordinary skill in the art wo uld have understood the patentees to have possessed the invention on some level (isobutanol produ ction would not necessarily have been completely abo lished). Further, Mr . Klibanov opined that deactivation of the genes associated with the pathway was well

- known in the art, and cited Dickinson as well as six other references in su pport. Gevo’s experts disagree with M r. Klibanov and his interpretation of th ese references, but this merely indicates the existence of a genuine dispute of material fact.
Though not addressed by the district court, Gevo rai ses an argument that there can be no genuine dispute of material fact because a subsequent Butamax patent application demonstrate s conclusively that the ’889 patent lacks an adequate written description of these claims . Butamax filed a continuation

- in

- part of the applications leading to the ’188 and ’889 patents, this time providing additional detail on the deactivation of certain genes. See U.S. Pat. App. No. 12/966, 333. The Patent Office concluded that th e ’889 patent wa s not

— on its own

— invalidating prior art to this application because the ’889 patent “do[es] not teach the disruption of endog enous pyruvate decarboxylase genes.” J.A. 17353. Howe ver, the issue here is not just whether the ’889 patent itself teaches the disruption such that the patent itself would be invalidating prior art on that point. T here is a genuine dispute with respect to whether in 2005 it was generally well- known in the art how to deactivate the genetic pat h-BUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , INC

. 26

way such that a person o f ordinary skill in the art reading the ’889 patent would understand the patentees to have possessed the invention claimed in claims 12 and 13.

For these reasons

, the district court’s grant of Ge vo’s motion for summary judgment of invalidity of claims 12 and 13 for lack of adequate written descript ion is reversed.

ii. Enablement of the ’889 Patent’s Claims 12 and 13

In its order, the district court summarily concluded that claims 12 and 13 were invalid for lack of enablement. However, its memorandum opinion does not reflect that judgment, nor did Gevo mov e for invalidity of those claims on this basis. On appeal, Gevo does not defend the jud gment. It thus appears that the judgment was a scriv ener’s error, and this court reverses the judgment that the claims are invalid for lack of enablement.

III. C ONCLUSION For the forgoing reasons, this court vacates the di strict court’s denial of Butamax’s motion for summary judgment of literal infringement of the asserted claims of the ’188 and ’889 patents and remands the question of infringement to the district court for reconsideration under the claim construction set forth herein

. Further, this court likewise vacates and remands the district court’ s grant of Ge vo’s motion for summary judgment of noninfringe ment under the doctrine of equivalents

. The court further reverses the district court’s grant of Gevo’s motion for summary judgment of invalidity for lack of written description of claims 12 and 13 of the ’889 patent and the district court’s order that those same claims are invalid for lack of enablement.

REVERSED

- IN

- PART, VACATED

- IN

- PART, AND REMANDEDBUTAMAX ( TM ) ADVANCED BIOFUELS v. GEVO , I NC

. 27

IV. C OSTS
Costs are awarded to Butamax.