Thursday, March 19, 2015

Judge Robinson rules on "summary judgment" motions in infringement case of Butamax against Gevo; two year anniversary.

The decision of Judge Robinson of D. Del. of 19 March 2013 (two years ago; 931 F. Supp. 2d 589) begins:

On January 14, 2011, plaintiff Butamax™ 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)
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 outcome is a bit complex:

1. Butamax's summary judgment motion of infringement of the '188 and '889 patents. (D.I. 595) is denied.

2. Gevo's motion for summary judgment on non-infringement of the '188 and '889 patents (D.I. 610) is granted in part and denied in part. The motion is granted as to no infringement under the doctrine of equivalents.

3. Gevo's motion for summary judgment of invalidity (D.I. 598) is granted in part and denied in part. The motion is granted as the invalidity of claim 12 and 13 of the '889 patent for lack of written description and enablement.

Yes, no infringement under the doctrine of equivalents BUT literal infringement is left open [!]

AND, one recalls "how" the CAFC handled this decision in Feb. 2014 (746 F.3d 1302 ):

Because 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 noninfringement under the doctrine of equivalents. Because the 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 12 and 13 of the '889 patent, this court reverses the district court's grant of that motion. Finally, this court reverses the grant of summary judgment of invalidity for lack of enablement because that judgment appears to have been a scrivener's error.

As to issues involving NADH/NADPH, Robinson had noted:

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 1 known by the EC number 2 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 (D.I. 492 at 10; [p. 599] 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 3 (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 [**14] 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 4), 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.

footnote 4: Dr. Rabinowitz, one of Butamax's experts, avers that,

[w]here the only cofactor in the environment is NADPH, such as in the Arfin & Umbarger assay, a KARI will use that cofactor exclusively because [**15] it is the only one present. Likewise, in a system where the only cofactor in the environment is NADH, that cofactor will be used exclusively. In environments like living yeast cells, both cofactors are present in varying concentrations. Therefore, in such an environment, after each catalytic cycle, when the enzyme needs to bind another cofactor molecule, it will bind either NADPH or NADH. Which cofactor becomes bound at any one instance is random, but statistically both the concentration of the cofactor and the Km for the cofactor will determine the aggregate cofactor binding.


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 NADPH-dependent), having the EC number" (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 [**16] cofactors, as they did elsewhere in the specification. (D.I. 535)

Footnote 6 is relevant to Teva v. Sandoz analysis, which may be of some interest in the remand of the Gevo infringement case against Butamax:

The court recognizes that extrinsic evidence generally is not considered in the claim construction exercise. Under the circumstances at bar, however, where the parties are disputing how those of skill in the art would interpret the definition provided by the patentees, the court finds it instructive, if not imperative, to consider expert testimony and the scientific literature referenced in the patent to illuminate the disputed language.

Relevant to NADH/NADPH:

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 ¶ 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 oxidoreductases using NAD+ or NADP+, the coenzyme should always be named as the acceptor 7 . . . Where the enzyme can use either coenzyme, this should be indicated by writing NAD(P)+." [p. 602] (D.I. 496, ex. A at 18) Although some enzymes are classified based on their cofactor selectivity, 8 no unique EC numbers have been assigned to EC to reflect this feature.

The analysis by Judge Robinson:

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, [p. 604] 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 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, 15 the patentees' definition of "acethydroxy acid isomeroreductase enzyme" simply reflects the state of the art, that is, that the KARI enzyme known by the EC number 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)

The bottom line, Judge Robinson adopts the Gevo position on claim construction:

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 that catalyzes the conversion of acetolactate to 2,3-dihydroxyisovalerate and is NADPH-dependent."

As to infringement:

In response, Gevo asserts that its strains are NADH-dependent and do not infringe Butamax's patents. (D.I. 611 at 34-39) Citing to the same set of published data as Butamax, but relying on kinetic data, 23 Gevo asserts that the SE26E6 "enzyme has a catalytic efficiency for NADH that is 172-fold higher than its catalytic efficiency for NADPH." (D.I. 611 at 38) Gevo maintains that its strains show some ancillary usage of NADPH, but disputes Butamax's characterization and testing of the usage of NADPH by its strains. (D.I. 611 at 47-48) To refute Dr. Brown's conclusions from his experiments, Gevo argues that Dr. Brown used different parameters to run the Arfin & Umbarger assay and engineered the parameters to "force the assay to produce his desired results." 24 (D.I. 611 at 47-48)

Footnote 23: Gevo supports the statement that its strains are NADH dependent with data and measurements "of Kcat/Km, referred to as the 'catalytic efficiency' of an enzyme." (D.I. 611 at 34-39; D.I. 612 at ¶¶ 49, 89) This measurement and the use of Km is present in many of the references cited by both parties. See, e.g., Carol Larroy et al., Characterization of the Saccharomyces cerevisiae YMR318C (ADH6) gene product as a broad specificity NADPH-dependent alcohol dehydrogenase: relevance in aldehyde reduction, 361(1) Biochemical J., 163 (2002) ("Larroy 2002"); Kiritani; Dumas (1992 and 1989); Xing; and, BRENDA database. Butamax's expert, Dr. Rabinowitz, used Km.

As to infringement under the doctrine of equivalents:

Gevo also moves for summary judgment of no infringement under the doctrine of equivalents, asserting that its NADH-dependent enzyme is not equivalent to an NADPH-dependent enzyme. (D.I. 610; D.I. 611 at 43-44) Butamax alleges that the doctrine of equivalents should apply because "the use of NADH as an electron donor is insubstantially different from the use of NADPH." (D.I 648 at 33) For the reasons discussed above in claim construction, the court does not agree that NADH and NADPH are insubstantially different. 26 See supra part III.B; Bicon, Inc. v. Straumann Co., 441 F.3d 945, 955-56 (Fed. Cir. 2006) (holding that a patented device claiming a particular part with a convex shape was not infringed under the doctrine of equivalents by a similar device using a part with a concave shape, even though the device could function with either a convex or concave portion); Novartis Pharm. Corp. v. Eon Labs Mfg., 363 F.3d 1306, 1312 (Fed. Cir. 2004) (affirming summary judgment of no infringement under the doctrine of equivalents because this would vitiate one of the claimed requirements of the patent); Zelinski v. Brunswick Corp., 185 F.3d 1311, 1317 (Fed. Cir. 1999) (finding that the district court's grant of summary judgment was proper where the only evidence on infringement under the doctrine of equivalents was a conclusory statement of plaintiff's expert). The court grants Gevo's summary judgment of no infringement under the doctrine of equivalents.

As to enablement, Judge Robinson noted: Enablement does not require an inventor to meet lofty standards for success in the commercial marketplace. Title 35 does not require that a patent disclosure enable one of ordinary skill in the art to make and use a perfected, commercially viable embodiment absent a claim limitation to that effect." CFMT, Inc. v. Yieldup Int'l Corp., 349 F.3d 1333, 1338 (Fed. Cir.2003); cf. Atlas Powder Co. v. E.I. du Pont De Nemours & Co., 750 F.2d 1569, 1577 (Fed. Cir.1984) (patentee's experiments designated as "failures" because they were "not optimal under all conditions" did not establish nonenablement; "such optimality is not required for a valid patent"). As Butamax did not claim a commercially viable product, it is of no consequence whether the patent enables such a product.

As to the expert of Gevo:

Butamax moves to exclude the testimony and reports of Gevo's expert, Dr. Stephanopoulos, on inherent anticipation of the '889 patent. (D.I. 641) Butamax contends that Dr. Stephanopoulos based his analysis on "the incorrect legal construct that inherent anticipation can be found when the prior art 'possibly' practices the claimed invention." (D.I. 641 at 2) Gevo argues that the "prior art reference need not practice the claims all the time under every conceivable condition." (D.I. 683 at 6) The court concludes that, at most, the standard for finding inherent anticipation was not eloquently articulated in Dr. Stephanopoulos' expert report. Reading the articulated standard as a whole, Dr. Stephanopoulos applied the correct standard. 37 (D.I. 683, ex. A at ¶ 18); Glaxo Group Ltd. v. Teva Pharms., Civ. No. 02-219, 2004 U.S. Dist. LEXIS 16750, 2004 WL 1875017, at *19 (D. Del. Aug. 20, 2004) ("Although inherent anticipation does not require the element to be present each and every time, it does require the result to be a necessary and inevitable consequence of practicing the invention claimed in the prior art under normal conditions.").


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