DSM IP Assets, B.V. et al v. Lallemand Specialties, Inc. et al

Filing 167

ORDER construing claims; granting 58 plaintiffs' motion for partial summary judgment on defendants' anticipation defense; denying 61 defendants' motion for summary judgment as to indefiniteness. Plaintiffs are granted summary judgment on this defense. The parties' cross-requests for summary judgment on noninfringement are denied. Signed by District Judge William M. Conley on 3/22/2018. (arw)

IN THE UNITED STATES DISTRICT COURT
FOR THE WESTERN DISTRICT OF WISCONSIN
DSM IP ASSETS, B.V. & DSM BIO-BASED
PRODUCTS & SERVICES, B.V.,
Plaintiffs and Counter-Defendants
OPINION & ORDER
v.
16-cv-497-wmc
LALLEMAND SPECIALTIES, INC. &
MASCOMA LLC,
Defendants and Counterclaimants.
In this lawsuit, plaintiffs DSM IP Assets, B.V. and DSM Bio-Based Products & Services
B.V. (collectively “DSM”) claim that Lallemand Specialties, Inc. and Mascoma LLC
(collectively “Lallemand”) are infringing U.S. Patent No. 8,795,998 (the “’998 patent”).
Before the court are the parties’ cross motions for claims construction and summary judgment,
with plaintiffs seeking summary judgment on defendants’ anticipation defense, and defendants
seeking summary judgment on their indefiniteness defense and plaintiffs’ claim of
infringement. (See dkts. ##59, 72, 64.) The court held an “expert colloquy” on Friday March
16, 2018, at which the parties’ experts made brief presentations and were guided through a
discussion with the court’s neutral expert (see dkt. #144) regarding proposed claim
constructions (dkt. #151) and the issues before the court at summary judgment, followed by
cross-examination by the parties’ counsel. Having considered the parties’ extensive written
submissions, expert reports and colloquy presentations, along with additional argument of
counsel and the record as a whole, the court will now issue its final claims constructions, grant
plaintiffs summary judgment on anticipation and indefiniteness, and deny defendants’ motion
for summary judgment on infringement.

UNDISPUTED FACTS1
A. Parties
Plaintiffs are Netherlands corporations that have their registered places of business in
The Netherlands. DSM Bio-Based Products & Services is a “pioneer” “in biomass conversion”
and develops “bioconversion technologies” for the “biofuels industry.”
Business,

DSM,

2017 Review of

http://annualreport.dsm.com/ar2017/en_US/7-3-innovation-

center.html#H4794108691 (last visited Mar. 13, 2018). DSM IP Assets, B.V. is the holding
company for DSM’s intellectual property. Lallemand is a Minnesota corporation that has its
principal place of business in Milwaukee, Wisconsin, while Mascoma is a Delaware LLC, with
its principal place of business in Lebanon, New Hampshire. Lallemand “specializ[es] in the
development, production, and marketing of yeasts and bacteria,” while Mascoma is “a leader
in

advanced

bioconversion

products.”

See

At

a

Glance,

Lallemand,

http://www.lallemand.com/about-us/at-a-glance/ (last visited Mar. 13, 2018); Overview,
Mascoma, http://www.mascoma.com/about-us/overview/ (last visited Mar. 13, 2018).

B. Enzymatic Activity
A chemical agent that increases the rate of reaction without being consumed by the
reaction is a catalyst. Enzymes are the most common biological catalysts. The rate at which a

The following facts are material and undisputed for purposes of summary judgment except where
specifically noted.
1

2

reaction produces its end product is the rate of catalysis.2 (Defs.’ Resp. to Pls.’ PFOF (dkt.
#80) ¶ 21.)

The rate of catalysis of an enzymatic reaction can be impacted by various

conditions, including “changes in the concentration of substrate, enzyme, and/or other
molecules that can bind to enzymes, pH, and temperature, and other cellular mechanisms.”
(Id. ¶ 22.) For instance, increasing the concentration of substrate increases the reaction rate of
an enzyme-catalyzed reaction until it reaches the saturation level.
Cells modify specific enzyme activity based on the cell’s production needs through
allosteric regulation, covalent modification of enzyme structure, and inhibition.

A cell’s

production of enzymes involves the expression of genes and then translation into an active
enzyme. While genetic expression produces enzymes, their activity is not solely dependent on
expression. After an enzyme is produced, it can be modified by chemical reactions such as
thiolation, methylation, phosphorylation, and acetylation. Enzymes can also be impacted by
temperature and pH. For instance, each enzyme has a specific pH at which it operates most
efficiently; the optimal pH depends on ionizable amino acid residues. The enzyme can become
denatured by a change away from its optimal pH due to changes in the amino acids’ ionization
states. As for temperatures, from 0˚C to approximately 40˚C, enzymatic reaction rates tend
to double for every 10˚C increase in temperature, but at some point increasing temperature
causes denaturation of enzymes, decreasing the reaction rate. (See Pls.’ Reply to Defs.’ Resp.
to Pls.’ PFOF (dkt. #92) ¶¶ 25-26, 28-30, 87-90.)

Defendant Lallemand does not dispute that the rate of catalysis is the rate at which the product
of the reaction is formed, although it disputes that the Russell text cited by plaintiff DSM equates
enzymatic activity to the rate of catalysis. (Defs.’ Resp. to Pls.’ PFOF (dkt. #80) ¶ 21.) For reasons
discussed in this opinion, the court views the definitions as equivalent, except that “enzymatic
activity” in the patent could also be measured as the rate at which the substrate of the reaction is
consumed.
2

3

The Nomenclature Committee of the International Union of Biochemistry and
Molecular Biology assigns “EC” numbers, which categorize enzymes based on the reactions
they catalyze. For example, one of the principle enzymes at issue here is categorized as “EC
1.2.1.10,” which refers to the catalysis of the conversion of acetyl-Coenzyme A to acetaldehyde;
an enzyme that performs this task is also referred to as NAD+-dependent acetylating
acetaldehyde dehydrogenase activity.

C. Ethanol Production
The largest industrial biotechnology fermentation process is ethanol production. The
parties agree that Saccharomyces cerevisiae, a species of yeast, produces ethanol by fermenting
glucose obtained from raw material, like corn, as illustrated here:3
In the production of ethanol, the NADH created
by the conversion of glyceraldehyde-3-phosphate
to pyruvate is used in the creation of ethanol
from acetaldehyde.

Where redox imbalance

exists (i.e., where there is excess NADH), cell
growth and ethanol production are impeded.
Thus, yeast cells also produce glycerol to
consume unused NADH as the main pathway for
intracellular redox balance.

In that reaction,

dihydroxyacetone phosphate (“DHAP”) is reduced to glycerol-3-phosphate (“G-3-P”) via

(See Pls.’ Resp. to Defs.’ PFOF (dkt. #75) ¶ 17 (citing Stephanopoulos Infringement Rpt. (dkt.
#47) ¶ 16).) Among other simplifications, the actual reaction between glucose and pyruvate is
simplified in this diagram. For a more detailed depiction of the reaction, see Glycolysis, Wikipedia,
https://en.wikipedia.org/wiki/Glycolysis (last visited Mar. 22, 2018).
3

4

NAD+-dependent glycerol-3-phosphate dehydrogenase (“GPD”), which involves oxidizing
NADH into NAD+.4 The G-3-P is hydrolyzed creating glycerol and inorganic phosphate by
glycerol 3-phosphate phosphatase (“GPP”).5
Importantly, glycerol is considered a waste byproduct of ethanol production because it
uses some of the glucose that could go toward additional ethanol production. This is no small
problem because in industrial-scale ethanol production, glycerol production can decrease
ethanol yield by millions of gallons. At the colloquy, the experts agreed that for a yeast cell
under anaerobic conditions, eliminating GPD2 would decrease -- but not eliminate -- glycerol
production compared to a yeast cell with GPD2, all other things being equal.

D. The ’998 Patent
1. Overview and Prosecution History
The ’998 patent, entitled “Fermentative Glycerol-Free Ethanol Production,” was filed
July 18, 2011 and issued on August 5, 2014. The listed inventors are Jacobus Thomas Pronk,
Antonius Jeroen Adriaan Van Maris, and Victor Gabriel Guadalupe Medina. The only assignee
listed is Technische Universiteit Delft.
In response to an Office Action, the patent applicants explained that the invention
“provides a yeast cell that actually grows preferentially in the presence of acetate,” which was
unique because the prior art did not suggest modifying a yeast cell to make it a net consumer

There are two forms of the catalyst, GPD: GPD1 and GPD2, both of which trigger the same
reaction in glycerol synthesis and are functionally equivalent (meaning they catalyze the same
reaction at the same rate). Yeast cells express GPD1 when under osmotic stress to increase glycerol
production; GPD2 is expressed under anaerobic conditions. GPD is needed for the conversion of
DHAP to G-3-P.
4

Just like GPD, the catalyst GPP has two isoforms: GPP1 and GPP2. GPP1 is expressed under
conditions of anaerobic stress, while GPP2 is expressed under osmotic stress.
5

5

of acetate so that it could use “acetate as an electron acceptor to reoxidize NADH,” thereby
reducing the necessity of glycerol synthesis. (May 2, 2013 Amend. & Resp. to Office Action
(dkt. #62-12) 8.) These features, the applicants argued, distinguished the claimed invention
from Valadi’s work by taking “advantage of the presence of acetate,” while “the Valadi yeast
still generates the undesired acetate contaminant as a product of its metabolism.” (Id.) Unlike
Valadi, which diminished the NADH-dependent glycerol synthesis, the claimed invention
consumed acetate and supplied NAD+-dependent acetylating acetaldehyde dehydrogenase -an alternate NAD+ generation pathway. (Id. at 10.) Further, the applicant explained that
Sonderegger, as is recognized by the Examiner, is focused on the
phosphoketolase circuit that is an alternate route for pentosebased metabolism. The phosphoketolase pathway generates
acetyl phosphate and thus it is necessary to employ both
phosphotransacetylase as well as acetyl acetaldehyde
dehydrogenase to generate NAD+. This approach is dependent
on a pentose metabolism pathway, unlike the present invention,
and it depends on acetate generated by the metabolism of xylose,
and does not address the presence of acetate from external
sources.
(Id. at 8.) The examiner found this explanation “persuasive” for claim 7, which became term
4 in claim 1. (See Aug. 1, 2013 Office Action (dkt. #47-74) 49); Oct. 30, 2013 Amend. (dkt.
#47-75) 3-6; Not. Allowability (dkt. #47-75) 17-18.)6
2. Objectives and Specifications
a. The Claimed Yeast Cells
The patent at issue discloses transgenic yeast cells that reduce or completely lack

The parties agree that the appropriate timeframe for construction of the patent is July 24, 2009,
but dispute four terms, all found in claim 1, as laid out and discussed in this court’s earlier order
proposing claims construction (Proposed Claim Constructions (dkt. #151)), as well as the final
claims constructions discussed infra.
6

6

“enzymatic activity needed for the NADH-dependent glycerol synthesis” as compared to wildtype yeast cells. (’998 Patent (dkt. #1-1) 2 (Abstract).) Specifically, the yeast cells either
reduce or eliminate the activity of GPD or GPP. (See id. at 40 (67:20-28).) The cells also
contain acetylating acetaldehyde dehydrogenase activity (EC 1.2.1.10), alcohol dehydrogenase
(EC 1.1.1.1) and acetyl-Coenzyme A synthetase (EC 6.2.1.1), permitting the conversion of
NADH to NAD+, which provides a metabolic pathway that complements the deletion of
glycerol synthesis. Thus, the patent provides two methods of reducing NADH-dependent
glycerol synthesis.
The claimed transgenic yeast cells convert acetate or acetic acid into ethanol through
three different, enzymatic reactions using acetyl-CoA synthetase (EC 6.2.1.1), aadh (EC
1.2.1.10), or alcohol dehydrogenase (EC 1.1.1.1):7

The patent specifies aldehyde/alcohol dehydrogenase enzyme (“AdhE”) as a
“bifunctional protein” that performs EC 1.2.1.10 activity from Escherichia coli, Staphylococcus
aureaus and Piromyces sp.E2. A bifunctional protein is one that catalyzes two reactions.

(See Defs.’ Reply to Pls.’ Resp. to Defs.’ PFOF (dkt. #95) ¶ 39 (citing Winge Infringement Report
(dkt. #51) ¶ 19).)
7

7

b. Blomberg Assay & HPLC Analysis
At the heart of defendants’ request for summary judgment on indefiniteness is the
Blomberg assay. In the section titled Enzyme Activity Assays, the patent details that “Glycerol3-phosphate dehydrogenase activities were assayed in cell extracts at 30˚ C. as described
previously (Blomberg and Adler (1989), J. Bacteriol. 171:1087-1092.[)]” (’998 Patent (dkt.
#1-1) 16 (20:37-40.).) The Blomberg assay is used to measure GPD activity through the
measurement of substrate consumption. At the colloquy, the experts agreed that the Blomberg
assay relies on the measurement of NADH. The parties agree that it can be used to measure
GPD1 activity, but disagree whether it can be used to measure GPD2 activity.
Lallemand attempted to test the GPD2 activity of the accused products by removing
EDTA from the Blomberg assay buffer solution.8 In his role as a retained expert for this case,
Professor Winge directed Lallemand to make three modifications to the assay, which he
believed would stabilize GPD2: (1) maintain the pH at 7.5, (2) provide magnesium, and
(3) provide a reductor for GPD2’s cystines. The parties disagree about the scientific validity
of these modifications, and Winge acknowledged at the colloquy that there were no published
scientific articles or studies supporting his modifications to the Blomberg assay to stabilize the
GPD2 activity, nor did he run any regression analyses to try to confirm his opinion.
In the section titled Metabolite Analysis, the patent describes how “[s]upernatant
obtained by centrifugation of culture samples was analyzed for glucose, acetic acid, succinic
acid, lactic acid, glycerol and ethanol via HPLC analysis.” (Id. at 16 (19:65-67); see also id.
19:67-20:19 (describing HPLC analysis with a Waters Alliance 2690 HPLC).) The parties

The parties agree that EDTA is often found in enzyme buffer solutions due to its general ability
to stabilize enzymes.
8

8

agree that HPLC analysis can be used to measure the rate at which glycerol is produced during
fermentation and that it is disclosed in the patent.

At the colloquy, Winge opined that

measuring the glycerol production was inappropriate because there was not a direct correlation
between concentrations of GPD and glycerol. However, he also agreed that current technology
did not support more accurate means for testing, like carbon tracking in vivo. Moreover, the
experts agreed at the colloquy that so far there is no way to currently measure GPP activity or
G-3-P production because the GPP enzymatic reaction (EC 3.1.3.21) converting G-3-P to
glycerol happens so quickly.

E. Sun Patent
Lallemand asserts that the ’998 patent was anticipated by International Publication No.
WO 2009/111672, which the parties refer to as “Sun,” after the lead inventor, Jun Sun. The
Sun patent discloses “a non-naturally occurring microbial organism that includes one or more
gene disruptions occurring in genes encoding enzymes that couple long-chain alcohols (LCA)
production to growth of the non-naturally occurring microbial organism.” (Sun Patent (dkt.
#55-2) 4 (2:23-26).) Specifically, the microorganisms are designed to create LCA using “a
malonyl-CoA-independent fatty acid synthesis (FAS) pathway and an acyl-reduction pathway.”
(Id. (2:6-7); see also id. at 116 (114:2-5).) Sun explains that “some embodiments” contain “one
or more gene disruptions in the eukaryotic organism encoding an enzyme,” such as “a glycerol3-phospate dehydrogenase shuttle[ or] an external NADH dehydrogenase.” (Id. at 61-62
(59:24-60:3).) The cells “disrupt[] . . . the glycerol-3-phosphate dehydrogenase shuttle.” (Id.
at 63 (61:26-28); id. at 64 (62:13-14) (“In some embodiments, the ethanol-specific alcohol
dehydrogenases is disrupted to prevent ethanol formation.”).) Further, some embodiments

9

detail “a non-naturally occurring eukaryotic organism [that] uses a heterologous acetaldehyde
dehydrogenase (acetylating).” (Id. at 69 (67:15-16).) Sun specifies “exemplary bacteria” and
“[e]xemplary yeasts or fungi” that can be chosen to be the “[h]ost microbial organism[],”
including Saccharomyces cerevisiae. (Id. at 32-33 (30:27-31:2).)
As defendants’ expert, Professor Winge compared the claim elements of the ’998 patent
with the disclosures in Sun. His analysis can be summarized as follows:9
Label
Required Element
Transgenic yeast cells comprising one or more
[a]
recombinant heterologous, nucleic acid sequences
encoding a protein with NAD+-dependent acetylating
acetaldehyde dehydrogenase activity (EC 1.2.1.10)
[b]
wherein said cells lack enzymatic activity needed for
the NADH dependent glycerol synthesis, or said cells
have a reduced enzymatic activity with respect to the
NADH-dependent glycerol synthesis compared to a
corresponding wild-type yeast cell, and
wherein said cells are free of NAD-dependent glycerol
[c]
3-phosphate dehydrogenase activity or have reduced
NAD-dependent glycerol 3-phosphate dehydrogenase
activity compared to corresponding wild-type cells,
and/or
wherein the cells are either free of glycerol phosphate
[d]
phosphatase activity or have reduced glycerol
phosphate phosphatase activity compared to
corresponding wild-type cells, and
[e]
which comprise a genomic mutation in at least one
gene selected from the group consisting of GPD1,
GPD2, GPP1 and GPP2, and
[f]
wherein said cells further comprise one or more
nucleic acid sequences encoding an acetyl-Coenzyme
A synthetase activity (EC 6.2.1.1) and
one or more nucleic acid sequences encoding NAD+[g]
dependent alcohol dehydrogenase activity (EC
1.1.1.1).

Sun References
2:23-24; 30:27-31:2;
59:24-60:11; 67:15-25

59:24-60:11;
61:1-62:2;
62:3-22; 65:23-27; 68:5-30

59:24-60:11;
61:1-62:2;
62:3-22; 65:23-27; 68:5-30

59:24-60:11;
61:1-62:2;
62:3-22; 65:23-27; 68:5-30

59:24-60:11;
61:1-62:2;
62:3-22; 65:23-27; 68:5-30
61:1-62:2; 62:3-22; 114:29
61:1-62:2; 62:3-22; 114:29

(See Pls.’ Reply to Defs.’ Resp. to Pls.’ PFOF (dkt. #92) ¶¶ 119-22, 124-27, 129-31, 133-39, 14143, 146-57.)
9

10

[h]

[i]

The cells of claim 1 are Saccharomycetaceae,
Kluyveromyces, Pichia, Zygosaccharomyces, or
Brettanomyces.
The cells of claim 1, wherein at least one said
mutation is a complete deletion of said gene in
comparison to the corresponding wild-type yeast gene

30:27-31:2

59:24-60:11;
61:1-62:2;
62:3-22; 65:23-27; 68:5-30

Plaintiffs dispute that Sun discloses genetic modifications to the genes encoding GPD
or GPP.10 Plaintiffs also dispute whether: (1) Sun discloses a single embodiment with all the
limitations of the asserted claims; and (2) Sun would have led a person of ordinary skill in the
art to combine its teachings to create yeast cells for reducing the production of glycerol and
increasing production of ethanol as disclosed in the ’998 patent.

F. Accused Products
Defendants apparently offer for sale two genetically modified yeast cells, TFY+ and
YP3, that are designed to reduce the production of glycerol. Both products contain nucleic
acid sequences that encode an NAD+-dependent alcohol dehydrogenase activity (EC 1.1.1.1).
TFY+ uses a transgenic S. cerevisiae to produce ethanol through the fermentation of partially
or totally liquefied grains. Lallemand explains that TFY+ increases the production of ethanol
by: (1) reducing glycerol production; (2) improving yeast’s tolerance of industrial fermentation
conditions; and (3) reducing the need for glucoamylase (an enzyme that converts starch into
glucose). The parties agree that glycerol production is reduced but not entirely eliminated, and

Defendants characterize this dispute as follows: “DSM does not dispute that Sun discloses each
and every limitation of the Asserted Claims,” rather DSM disputes whether Sun discloses the
combination of all the elements. (Defs.’ Opp’n (dkt. #77) 27 & n.16.) At the expert colloquy, the
anticipation discussion centered on an embodiment on pages 65-67 and in Figure 18 of Sun. There
is no dispute that the embodiment discussed at those pages of Sun and referenced in Figure 18 does
not include GPD/GPP gene modification for the purpose of reducing glycerol production in the
making of ethanol.
10

11

that TFY+ also contains glycoamylase from S. fibuligera. Thus, the parties agree that the first
and third methods of boosting ethanol production are present in the accused products, while
DSM contends that Lallemand has not proven that the second method is present.
The parties also agree that the yeast cells of TFY+ lack the GPD2 gene and are modified
with genes from Bifidobacterium adolescentis, which “provide pyruvate formate lyase activating
enzyme (pflA), pyruvate formate lyase (pflB), and the bifunctional acetaldehyde-CoA/alcohol
dehydrogenase AdhE.” (Defs.’ Reply to Pls.’ Resp. to Defs.’ PFOF (dkt. #95) ¶ 49.) Thus,
TFY+ converts pyruvate to ethanol and oxidizes NADH to NAD+.

Internal Lallemand

documents refer to TFY+ as strain M8841. Plaintiffs contend that Lallemand also sells strain
M10156 as TFY+ to one customer.
Derived from TFY+, YP3 contains the same modifications.

It was created to

overexpress Stl1, a native glycerol transport protein. The parties disagree about the purpose of
this overexpression: Lallemand contends that “[t]he purpose of Stl1 in TFY+ is to attenuate
Gpd1 function by increasing the intracellular concentration of glycerol,” while DSM contends
that Lallemand’s R&D documents show instead that the Stl1 glycerol transport protein’s
overexpression in YP3 “downregulates Gpd1 via feedback inhibition.” (Id. ¶ 60.) The parties
agree that this modification decreases the amount of extracellular glycerol and helps the yeast
remain osmotically balanced under stressful conditions. Internal Lallemand documents refer
to YP3 as strain 12156.
Additionally, the parties agree that a number of Lallemand’s documents refer to
“downregulat[ion],” including “of the gpd1/gpd2 genes.” (See Defs.’ Resp. to Pls.’ Addl. PFOF
¶¶ 31-32; LAL00041342 (dkt. #47-48) 1; International Patent Publication No. WO
2012/138942 (dkt. #47-47) ¶ 150.) However, they disagree about what that means.

12

G. Person of Ordinary Skill in the Art
Finally, in the summary judgment briefing, the parties dispute what would qualify a
person to be one of ordinary skill in the art, although that dispute does not appear to be
material to their motions. Regardless, at the colloquy, the parties’ experts agreed that in order
for one to practice the patent, they would need a master’s level understanding of biochemistry,
or biological or mechanical engineering.

They also agree that that person would require

familiarity with the use of multiple enzymes in biochemical reactions, as well as background
processes, and would have experience with metabolic flux. Therefore, the court finds that this
is a reasonable floor for one with sufficient skill in the art to practice the invention, and that
such an individual would understand the basic elements of the claims well enough to know
when to consult others with the necessary specific expertise to implement some of the actual
steps for industrial scale ethanol production through the use of modified yeast cells.

OPINION
FINAL CLAIMS CONSTRUCTION
As explained at the time of the court’s earlier, proposed constructions, “‘the claims of a
patent define the invention to which the patentee is entitled the right to exclude.’” Phillips v.
v. AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) (en banc) (quoting Innova/Pure Water,
Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111, 1115 (Fed. Cir. 2004)). For this reason,
the right to exclude “begins and ends . . . with the actual words of the claim.” Renishaw PLC v.
Marposs Societa’ Per Azioni, 158 F.3d 1243, 1248 (Fed. Cir. 1998).

The goal of claims

construction “is to give claim terms the meaning understood by a person of ordinary skill in
the art at the time of invention.” Mass. Inst. of Tech. v. Shire Pharms., Inc., 839 F.3d 1111, 1118

13

(Fed. Cir. 2016) [hereinafter MIT] (citing Phillips, 415 F.3d at 1312-14). While this includes
“a heavy presumption that claim terms are to be given their ordinary and customary meaning,”
id. at 1118 (quoting Aventis Pharm. Inc. v. Amino Chems. Ltd., 715 F.3d 1363, 1373 (Fed. Cir.
2013)), this “meaning” is based on the understanding of a person of ordinary skill in the art
after reading the entire patent, id. (quoting Phillips, 415 F.3d at 1321). See also Renishaw, 158
F.3d at 1250 (“Ultimately, the interpretation to be given a term can only be determined and
confirmed with a full understanding of what the inventors actually invented and intended to
envelop with the claim.” (citing Markman v. Westview Instruments, Inc., 517 U.S. 370, 389
(1996))).
For patent claims in highly specialized fields of study, like that at issue here,
“determining the ordinary and customary meaning of the claim requires examination of terms
that have a particular meaning in a field of art,” yet are “not immediately apparent,” which
requires the court to examine intrinsic and extrinsic evidence “‘concerning the relevant
scientific principles, the meaning of technical terms, and the state of the art.’” Phillips, 415
F.3d at 1314 (quoting Innova, 381 F.3d at 1116).11 Similarly, while the “ordinary meaning”
inquiry remains “an objective baseline from which to begin claim interpretation,” id. at 1313
(citing Innova, 381 F.3d at 1116), where a patent fails to explicitly define a disputed or arguably
ambiguous term, the court may look to the patent as a whole, including its prosecution history,
to determine that term’s meaning, Wi-LAN USA, Inc. v. Apple Inc., 830 F.3d 1374, 1387 (Fed.
Cir. 2016) (citing Phillips, 415 F.3d at 1315). See also Renishaw, 158 F.3d at 1248 (“The
intrinsic evidence, and, in some cases, the extrinsic evidence, can shed light on the meaning of

Intrinsic evidence includes the patent itself and the file history, while extrinsic evidence includes
evidence like expert testimony, dictionaries, inventor testimony, technical treatises and articles, or
evidence of prior art. See Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1584 (Fed. Cir. 1996).
11

14

the terms recited in a claim, either by confirming the ordinary meaning of the claim terms or
by providing special meaning for claim terms.” (citing Vitronics, 90 F.3d at 1583)). Still, claims
construction is viewed as a question of law, Wi-LAN, 830 F.3d at 1381, reserved only for the
court, Teva Pharms. USA, Inc. v. Sandoz, Inc., 135 S.Ct. 831, 835 (2015).
Here, the parties dispute the proper construction of four terms, all found in claim 1.
(See Joint Statement on Claims Construction (dkt. #44) 2-3; ’998 Patent (dkt. #1-1) 40
(67:12-37).)12 Plaintiffs claim that all four of their proposed constructions are faithful to the
terms’ “[p]lain and ordinary meaning[s],” although even they put a gloss on certain terms,
while defendants claim that some terms require further construction to be consistent with the
claimed invention and prosecution history. (Joint Statement on Claims Construction (dkt.
#44) 2-3.) With emphasis on the terms in dispute, Claim 1 specifies:
1. Transgenic yeast cells comprising one or more recombinant
heterologous, nucleic acid sequences encoding a protein with
NAD+-dependent acetylating acetaldehyde dehydrogenase
activity (EC 1.2.1.10),
wherein said cells lack enzymatic activity needed for the NADHdependent glycerol synthesis, or
said cells have a reduced enzymatic activity with respect to the
NADH-dependent glycerol synthesis
compared to a corresponding wild-type yeast cell, and
wherein said cells are free of NAD-dependent glycerol 3phosphate dehydrogenase activity or have reduced NADdependent glycerol 3-phosphate dehydrogenase activity
compared to corresponding wild-type cells, and/or
wherein the cells are either free of glycerol phosphate phosphatase
activity or have reduced glycerol phosphate phosphatase activity
compared to corresponding wild-type cells, and
which comprise a genomic mutation in at least one gene selected
from the group consisting of GPD2, GPD2, GPP1 and GPP2, and
wherein said cells further comprise one or more nucleic acid
sequences encoding an acetyl-Coenzyme A synthetase activity
As noted during the expert colloquy, the parties appear to disagree about the meaning of some
aspects of other phrases, like “corresponding wild yeast cells” that is addressed below and, therefore,
may yet require a further construction before consideration by the trier of fact at trial.
12

15

(EC 6.2.1.1) and one or more nucleic acid sequences encoding
NAD+-dependent alcohol dehydrogenase activity (EC 1.1.1.1).
(’998 Patent (dkt. 1-1) 40 (67:12-37) (emphasis added).) The court addresses each of the four
disputed terms below.
Term 1
“one or more recombinant heterologous, nucleic acid sequences encoding a protein with
NAD+-dependent acetylating acetaldehyde dehydrogenase activity (EC 1.2.1.10)”
DSM’s Proposed Construction

Lallemand’s Proposed Construction

“one or more recombinant heterologous, “a recombinant heterologous, nucleic acid
nucleic acid sequences that encode a protein encoding an NAD+-dependent acetylating
having
NAD+-dependent
acetylating acetaldehyde dehydrogenase enzyme”
acetaldehyde dehydrogenase activity (EC
1.2.1.10)”
Plaintiff DSM proposes changing “nucleic acid sequences encoding a protein with
NAD+-dependent acetylating acetaldehyde dehydrogenase activity” to “nucleic acid sequences
that encode a protein having NAD+-dependent acetylating acetaldehyde dehydrogenase
activity.”

In contrast, defendant Lallemand proposes: (a) limiting the cells to having a

“recombinant heterologous, nucleic acid” instead of the possibility of one or more “recombinant
heterologous[] nucleic acid sequences” and (b) encompassing an “NAD+-dependent
acetylating acetaldehyde dehydrogenase enzyme” instead of “a protein with NAD+-dependent
acetylating acetaldehyde dehydrogenase activity (EC 1.2.1.10).”
Plaintiffs explain that EC numbers classify enzymes based on the reaction they catalyze,
which means that “EC 1.2.1.10” is reserved for proteins that catalyze the conversion of acetylCoenzyme A to acetaldehyde. (Pls.’ Opening Br. (dkt. #59) 15.) In response, defendants
argue that the claim specifies a protein that has “NAD+-dependent acetylating acetaldehyde
dehydrogenase activity” -- a particular enzymatic activity. (Defs.’ Opp’n (dkt. #77) 26-27.)

16

Plaintiffs characterize this dispute as a question whether AdhE and other bifunctional
acetylating acetaldehyde dehydrogenase enzymes are included, adding that because the patent
identifies AdhE it would be improper to exclude a preferred embodiment. (Pls.’ Reply (dkt.
#97) 8-9.)
The court will not adopt either side’s proposed construction, having determined that
the plain and ordinary meaning of this term is indeed appropriate. As an initial matter, the
court sees no reason to limit the term to a single “recombinant heterologous[] nucleic acid,”
where the term specifies “one or more . . . sequences.” As to plaintiffs’ proposal to change the
word “encoding” to “that encode,” the court is unconvinced that there is a meaningful
difference. And importantly, if there is a difference, there is no basis to depart from the claim’s
actual syntax.
The court also rejects defendants’ proposed change of “NAD+-dependent acetylating
acetaldehyde dehydrogenase activity (EC 1.2.1.10)” to “NAD+-dependent acetylating
acetaldehyde dehydrogenase enzyme.”

As plaintiffs point out, the Enzyme Commission

number -- the EC number -- is a unique four-digit number which describes the chemical reaction
catalyzed. Specifically, the first digit identifies one of six classes; “the second and third digits
describe the type of reaction catalyzed”; and “the fourth digit is employed to distinguish
between enzymes of the same function on the basis of the actual substrate in the reaction
catalyzed.” Douglas S. Clark & Harvey W. Blanch, Biochemical Engineering 1 (2d. ed. 1997).
The enzyme identified by “EC 1.2.1.10” is “acetaldehyde dehydrogenase (acetylating).”
Information on EC 1.2.1.10 -- acetaldehyde dehydrogenase (acetylating), BRENDA,
https://www.brenda-enzymes.org/enzyme.php?ecno=1.2.1.10 (last visited Mar. 1, 2018).
Replacing “activity” with “enzyme” would appear to change the claim’s meaning since it is the

17

activity -- not the enzyme that performs the activity -- that is at the heart of this portion of the
claim term and, indeed, the invention itself. Thus, this term simply means “one or more
recombinant heterologous, nucleic acid sequences encoding a protein with NAD+-dependent
acetylating acetaldehyde dehydrogenase activity (EC 1.2.1.10).” (See ’998 Patent (dkt. 1-1)
40 (67:12-15).)
Term 2
“said cells . . . have reduced NAD-dependent glycerol 3-phosphate dehydrogenase activity
[GPD] compared to corresponding wild-type cells”
DSM’s Proposed Construction

Lallemand’s Proposed Construction

“the cells exhibit a reduction in the rate of
the reaction catalyzed by GPD in the
enzymatic production of glycerol compared
to the corresponding wild-type yeast cells”

“the cells include modifications to one or
more genes encoding GPD activity such that
GPD is expressed considerably less than in
the wild-type yeast cell or such that one or
more genes encode GPD with reduced
activity”

Term 3
“said cells have a reduced enzymatic activity with respect to the NADH-dependent glycerol
synthesis compared to corresponding wild-type cells”
DSM’s Proposed Construction

Lallemand’s Proposed Construction

“the cells exhibit a reduction in the rate of “the cells include modifications to one or
enzymatic production of glycerol compared more genes encoding one or more enzymes
to the corresponding wild-type yeast cell”
needed for NADH-dependent glycerol
synthesis such that one or more enzymes are
expressed considerably less than in the wildtype yeast cell or such that one or more genes
encode a polypeptide with reduced activity”
The parties discuss the second and third terms together, and the court will follow suit,
while actually construing the terms in dispute individually. DSM argues that “enzymatic
activity” is defined by enzymology and metabolic engineering as “the enzyme-catalyzed rate of

18

product conversion under a given set of conditions, usually measured as the concentration
change (substrate consumption or product formation) per unit time,” which is usually
expressed “in terms of units based upon the rate of the reaction that the enzyme promotes.”
(Pls.’ Opening Br. (dkt. #59) 18.) According to plaintiffs, therefore, “‘enzymatic activity’ is
synonymous with the rate of the enzyme-catalyzed reaction, with an increased enzymatic
activity corresponding to an increased reaction rate (due to lower activation energy) and a
reduced enzymatic activity corresponding to a reduced reaction rate (due to a higher activation
energy).” (Id. at 19.) Thus, plaintiffs argue that both “reduced enzymatic activity terms”
should be construed to mean: “(1) the cells exhibit a reduction in the rate of enzymatic
production of glycerol compared to corresponding wild-type yeast cells; and (2) the cells exhibit
a reduction in the rate of the reaction catalyzed by GPD in the enzymatic production of glycerol
compared to the corresponding wild-type yeast cells.” (Id.)
Defendants counter that plaintiffs’ proposed constructions would render any reduction
in glycerol production an infringement, but that unreasonably and unnecessarily simplifies the
claims. Lallemand further argues that DSM’s reading must be rejected for three additional
reasons: (1) inappropriately including “enzymatic production of glycerol” in both terms would
make one superfluous; (2) intrinsic evidence establishes that “enzymatic activity” refers to the
amount of enzyme expressed making it improper to equate enzymatic activity with the rate of
substrate consumption or product formation; and (3) no extrinsic evidence requires a different
meaning for “enzymatic activity.” (Defs.’ Opp’n (dkt. #77) 7-8.)
In reply, plaintiffs first point out that their construction does not make one term
superfluous because a reduction in enzymatic activity could be achieved under Claim 1 by
deleting GPP activity -- without necessarily impacting the GPD-catalyzed reaction at all. (Pls.’

19

Reply (dkt. #97) 12.) Secondly, plaintiffs explain that enzymatic activity cannot mean the
“amount of enzyme” because enzymatic activity is dependent on other factors, such as
temperature, pH, and substrate concentration. (Id. at 26.) Plaintiffs also argue that the
structural requirement of genetic modification comes from a different term, and it need not
(and should not) be read into terms 2 and 3, especially because the specification contemplates
other methods. (Id. at 13-14; Pls.’ Opening Br. (dkt. #59) 19-20.) Third, plaintiffs argue that
defendants’ proposed construction would actually exclude the embodiment introducing a
separate metabolic pathway to compete with the NADH-glycerol synthesis pathway. (Pls.’
Reply (dkt. #97) 15-16.)
Finally, defendants likewise emphasize that their proposed constructions of terms 2 and
3 differ from plaintiffs’ in two ways: (1) the meaning of “enzymatic activity”; and (2) the
structural requirements necessary for a “reduction.” (Defs.’ Opening Br. (dkt. #64) 15.) As
to the meaning of “enzymatic activity,” Lallemand proposes construing it as a measure of the
expression or availability of GPD in the cell, while DSM construes it as a measurement of the
rate of the GPD-catalyzed reaction. As to the structural requirements necessary to measure “a
reduction,” Lallemand proposes tying the reduction to the genetic modification, while DSM
does not.
As an initial matter, “activity” is a noun that refers here to a metabolic process, whose
“rate” would normally be understood by one skilled in the art to be measured by the change in
moles of a substrate converted or of its converted product per unit of time. Here, GPD (an
enzyme) catalyzes the conversion of dihydroxyacetone phosphate (“DHAP”) to glycerol-3phosphate (“G-3-P”), so that “activity” is measured by the change in DHAP or the change in

20

G-3-P over time.13 Stated another way, the rate of activity may be calculated by a rate law,
often written with an equation first postulated by Michaelis and Menten14 as follows:
(𝑘 𝑐𝑎𝑡 )(𝐸0 )(𝑠𝑢𝑏𝑠𝑡𝑟𝑎𝑡𝑒)
.
𝐾 𝑚 +(𝑠𝑢𝑏𝑠𝑡𝑟𝑎𝑡𝑒)

𝑚𝑜𝑙
𝑠

=

In this rate law, kcat refers to the rate constant that describes the maximum

rate of enzymatic reaction -- when the enzyme is saturated with substrate (i.e., when the rate
is no longer dependent on substrate concentration); E0 refers to the abundance of the enzyme;
and substrate is the amount of the substance on which the enzyme acts; Km refers to the enzyme
saturation constant (i.e., the concentration of the substrate where the rate is ½ (k cat). The
characteristic enzyme constants, kcat and Km can be changed through modification of the
enzyme itself,15 such that the maximum rate of reaction is altered and/or its saturation point is
altered, while E0 can be altered through genetic modification or mutation, as suggested by the
patent-in-suit to prevent or change the production of the enzyme.
Turning to term 2, the plain language simply provides that the patented cells have
reduced GPD activity as compared to wild-type cells. Contrary to defendants’ proposal, this
language does not limit the reduction in the rate of activity to a genetic modification removing
or reducing production of GPD; indeed, term 2 does not specify the means by which the

The conversion of DHAP to G-3-P generally involves a 1:1 reaction ratio so the rate of change in
either the concentration of DHAP or the concentration of G-3-P divided by the amount of time
should provide an approximately equal measure of activity. This reaction can be displayed as:
DHAP → G-3-P
13

𝐺𝑃𝐷

See Kenneth A. Johnson & Roger S. Goody, The Original Michaelis Constant: Translation of the 1913
Michaelis-Menten
Paper,
50
Biochemistry
8264
(2011),
https://pubs.acs.org/doi/abs/10.1021/bi201284u.
14

The catalytic constant may be altered by the environmental conditions of the activity, such as
pH and temperature, but here those conditions are presumably held constant.
15

21

reduction in

𝑚𝑜𝑙
𝑠

is achieved.16 Thus, the language of this term permits a change in kcat, Km, E0

or substrate.
Accordingly, plaintiffs’ proposal specifying that the cells “exhibit a reduction in the rate
of the reaction catalyzed by GPD” is a clarification of the “have reduced NAD-dependent
glycerol 3-phosphate dehydrogenase activity [GPD]” language found in the term.

In its

proposed claim construction, the court indicated that plaintiffs’ addition of “enzymatic
production of glycerol” further clarified that the claim term is talking about GPD’s function in
the production of glycerol. However, following the expert colloquy, the court recognizes that
a more accurate clarification of the role of GPD would be to specify that NADH-dependent
GPD catalyzes the reaction of DHAP to glycerol-3-phosphate. As such, the court will construe
term 2, as “said cells exhibit a reduction in the rate of the reaction catalyzed by NADHdependent GPD in the enzymatic production of glycerol 3-phosphate compared to the
corresponding wild-type yeast cells.”
For similar reasons, plaintiffs’ proposed construction of term 3 is closer to the mark
than defendants’. Term 3 specifies that the patented cells have decreased metabolic activity
regarding the NADH-dependent glycerol synthesis as compared to wild-type cells. As with

In fact, genetic modification is required by a different term. (’998 Patent (dkt. #1-1) at 40
(67:30-32 (“which comprise a genomic mutation in at least one gene selected from the group
consisting of GPD1, GPD2, GPP1, and GPP2”)); id. (68:39-41 (“The cells of claim 1, wherein at
least one said mutation is a complete deletion of said gene in comparison to the corresponding wildtype yeast gene.”)).) Reading the genetic modification requirement into this term would make the
later term superfluous. See WiLAN, 830 F.3d at 1391 (noting the “presumption that differently
worded claims cover different claim scope,” stemming from “the legal canon of construction against
superfluity” such that “[a] construction that would cause two differently worded claims to cover
exactly the same claim scope would render one of the claims superfluous, so [courts] apply a
presumption against such constructions”).
16

22

term 2, term 3 does not require genetic modification.17 Accordingly, plaintiffs’ proposed
language -- “exhibit a reduction in the rate” -- provides appropriate clarification. However, the
term’s construction should maintain a specific reference to the “NADH-dependent glycerol
synthesis.” Thus, term 3 will be construed to mean “said cells exhibit a reduction in the rate
of NADH-dependent glycerol production compared to the corresponding wild-type yeast cell.”
Term 4
“wherein said cells further comprise one or more nucleic acid sequences encoding an acetylCoenzyme A synthetase activity (EC 6.2.1.1) and one or more nucleic acid sequences
encoding NAD+-dependent alcohol dehydrogenase activity (EC 1.1.1.1)”
DSM’s Proposed Construction

Lallemand’s Proposed Construction

“the cells comprise (i) one or more nucleic
acid sequences that encode an acetylCoenzyme A synthetase activity and (ii) one
or more nucleic acid sequences that encode
an
NAD+-dependent
dehydrogenase
activity”

“wherein said cells further comprise one or
more nucleic acid sequences encoding an
acetyl-Coenzyme A synthetase activity and
one or more nucleic acid sequences encoding
NAD+-dependent alcohol dehydrogenase
activity, whereby the cells are net consumers
of acetate/acetic acid such that the cells can
reoxidize NADH by the reduction of
acetate/acetic acid to ethanol via NADHdependent reactions in place of glycerol
synthesis and whereby the cells grow
preferentially in the presence of acetate”

The parties basically agree on the substance of DSM’s proposed construction.18 The
dispute arises from Lallemand’s three additional limitations: (1) “the cells are net consumers
of acetate/acetic acid”; (2) “the cells can reoxidize NADH by the reduction of acetate/acetic

17

See supra, note 16.

There are two slight differences: (1) plaintiffs modify “encoding” to “that encode,” while
defendants use “encoding” as found in the disputed term; and (2) plaintiffs remove the “alcohol”
from the “NAD+-dependent alcohol dehydrogenase activity,” while defendants keep it in,
consistent with the disputed term. (The addition of the romanettes in plaintiffs’ proposal is nonsubstantive and improves readability.)
18

23

acid to ethanol via NADH-dependent reactions in place of glycerol synthesis”; and (3) “the
cells grow preferentially in the presence of acetate.” Defendants argue that their additions are
based on the patent applicants’ statements to distinguish the invention from the prior art.
(Defs.’ Opp’n (dkt. #77) 18.) Specifically, defendants base the first addition on the patent
applicants’ statement that “[t]here is no suggestion to modify a yeast cell in order to make it a
net consumer of acetate”; the second addition is based on a statement that the invention “is
capable of using acetate as an electron acceptor to reoxidize NADH and therefore avoids or
reduces the need for glycerol synthesis”; and the third addition is based on a statement that
“[t]he invention provides a yeast cell that actually grows preferentially in the presence of
acetate.” (Id. at 24.)
Plaintiffs argue that defendants have failed to meet the “high standard” of establishing
prosecution disclaimer. (Pls.’ Opening Br. (dkt. #59) 24-25 (citing MIT, 839 F.3d at 1119).)
As to the first two additions, in particular, plaintiffs argue that the ability of the cells to use
the acetate in the production of ethanol instead of glycerol is a “further advantage,” not a
disclaimer. (Id. at 25-26.) Further, DSM argues that “Lallemand’s argument is scientifically
flawed” because the proposed “functional acetate limitations are not even commensurate in
scope with the functions of the nucleic acid sequences specifically recited in the disputed claim
term.” (Pls.’ Reply (dkt. #97) 25-26.)19 As to the remaining addition, plaintiffs argue that the
patentees noted that the patented cell grew preferentially with acetate, but that that statement
was not a limitation required by the claims; rather it was prompted by a Lallemand corporate

Specifically, DSM argues that a yeast cell with only (EC 6.2.1.1) and alcohol dehydrogenase
activity (EC 1.1.1.1) (as specified in the term itself) cannot convert acetate to ethanol and that the
claimed cell’s ability to “consume acetate and create ethanol stems from the acetyl-Coenzyme A
synthetase and alcohol dehydrogenase activities in combination with the claimed acetylating
acetaldehyde dehydrogenase activity.” (Pls.’ Reply (dkt. #97) 25.)
19

24

representative’s admission that the accused products consume acetate. (Pls.’ Opening Br. (dkt.
#59) 26-27.) Plaintiffs also argue that defendants’ construction defines the claimed cells “in
terms of how they might be used,” even though the claims do not contain that requirement.
(Pls.’ Reply (dkt. #97) 26.)
A patent’s prosecution history sheds light on how the inventor and the Patent and
Trademark Office conceptualized the patent.

Phillips, 415 F.3d at 1317.

Prosecution

disclaimer is a doctrine that prevents “patentees from recapturing through claim interpretation
specific meanings disclaimed during prosecution.” MIT, 839 F.3d at 1119 (quoting Omega
Eng’g, Inc. v. Raytek Corp., 334 F.3d 1314, 1323 (Fed. Cir. 2003)). However, the doctrine only
applies where the patentees’ disavowal is “both clear and unmistakable.” Id. (quoting 3M
Innovative Props. Co. v. Tredegar Corp., 725 F.3d 1315, 1325 (Fed. Cir. 2013)). Anything short
of “clear and unmistakable,” which must be proved by the party attempting to invoke
prosecution disclaimer, does not warrant application of the doctrine. Id.
Having reviewed the prosecution history, the court concludes that defendants have not
met this “high standard.” See id. at 1120. In short, did the patentees stress that acetate was
beneficial? Yes. Did they say that it was critical for the invention? No. The invention teaches
away from prior art by making use of a formerly disfavored metabolite. Specifically, the
patentees argued that one of ordinary skill in the art would not realize the benefits of
production or presence of acetate since Sonderegger was trying to reduce acetate production and
the common understanding at the time of the invention was that the presence of acetate would
be a detriment. Valadi, on the other hand, determined that “glycerol formation could be
reduced even further” by altering the genes encoding GPD2, but recognized that precisely
“[h]ow the redox balance in the gpd2∆ mutant is accomplished is not known.” (See H. Valadi

25

et al., Improved Ethanol Production by Glycerol-3-phosphate dehydrogenase mutants of Saccharomyces
cerevisiae, 50 Applied Microbiology Biotechnology 434, 438 (1998) (dkt. #47-4) 5.) In
hindsight, perhaps, someone with exceptional skill in the art would have realized that
combining Sonderegger and Valadi would make the presence of acetate beneficial, but that
does not make the invention obvious.
Further, these additions are not scientifically necessary. Claim 1 provides for a yeast
cell that has three modifications: (1) a genetic modification to reduce the production of GPD
and/or GPP; (2) the addition of alcohol dehydrogenase (EC 1.1.1.1) and acetyl-Coenzyme A
synthetase (EC 6.2.1.1); and (3) the addition of acetylating acetaldehyde dehydrogenase
activity (EC 1.2.1.10). Without the second modification, the yeast cells would not be able to
function adequately because the only modification would have been to delete GPD or GPP,
meaning that the cells would not be able to use glycerol production to achieve redox balance,
thereby stymying the production of ethanol. In the invention, acetate is catalyzed to become
acetyl-CoA, which in turn permits the acetylating acetaldehyde dehydrogenase activity to
produce ethanol, via alcohol dehydrogenase. Thus, term 4 provides the clarification of acetate
as the basis for the redox reaction, making defendants’ additional limitations unnecessary. At
minimum, defendants have not proven the patentees’ disavowal clearly and unmistakably.
Thus, the court construes this term to mean “the cells comprise (i) one or more nucleic
acid sequences encoding an acetyl-Coenzyme A synthetase activity (EC 6.2.1.1) and (ii) one
or more nucleic acid sequences encoding an NAD+-dependent alcohol dehydrogenase activity
(EC 1.1.1.1).”

26

SUMMARY JUDGMENT
Summary judgment is appropriate where there are “no genuine dispute[s] as to any
material fact[s] 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 showing that the facts material to the motion are
not in dispute. Celotex Corp. v. Catrett, 477 U.S. 317, 323 (1986); see also Conroy v. Reebok
Internat’l, Ltd., 14 F.3d 1570, 1575 (Fed. Cir. 1994) (“The moving party, however, need not
produce evidence showing the absence of a genuine issue of material fact but rather may
discharge its burden by showing the district court that there is an absence of evidence to
support the nonmoving party’s case.” (internal citations omitted)).
Where it has the burden of proof, the nonmoving party may not avoid summary
judgment merely by showing that some facts are in dispute; rather, it must establish that one
or more factual disputes might affect the ultimate outcome of the suit under governing law.
Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 247-48 (1986). Although the court must “take
all facts and reasonable inferences in the light most favorable to” the nonmoving party, Helman
v. Duhaime, 742 F.3d 760, 761 (7th Cir. 2014), the nonmoving party with the burden of proof
must still come forward with enough evidence to support a reasonable jury verdict in its favor,
Delta Consulting Grp., Inc. v. R. Randle Constr., Inc., 554 F.3d 1133, 1137 (7th Cir. 2009).
Summary judgment is “not a dress rehearsal or practice run,” but the “put up or shut up
moment” in which a proponent of facts must show what evidence it has to convince a trier of
fact to accept its version of events. Nichols v. Nat’l Union Fire Ins. Co. of Pittsburgh, PA, 509 F.
Supp. 2d 752, 760 (W.D. Wis. 2007) (quoting Schacht v. Wis. Dep’t of Corr., 175 F.3d 497,
504 (7th Cir. 1999)).
Here, plaintiffs seek summary judgment on defendants’ anticipation defense (Pls.’ Mot.

27

Judicial Construction & Partial Summ. J. (dkt. #58) 3), and Defendants seek summary
judgment of invalidity on the basis of indefiniteness and no willful infringement. (Defs.’ Mot.
Summ. J. (dkt. #61) 1.)20

I. Anticipation
Because it is the strongest, the court will begin with plaintiffs’ motion for summary
judgment on defendants’ anticipation defense. Evaluating a claim of anticipation involves a
two-step inquiry. The first step requires proper construction of the meaning and scope of the
claims. Power Mosfet Techs., L.L.C. v. Siemens AG, 378 F.3d 1396, 1406 (Fed. Cir. 2004). “The
second step in the analysis requires a comparison of the properly construed term to the prior
art[.]” Id. To demonstrate anticipation, “the proponent must show ‘that the four corners of a
single, prior art document describe every element of the claimed invention.’” Net MoneyIN,
Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008) (quoting Xerox Corp. v. 3Com Corp.,
458 F.3d 1310, 1322 (Fed. Cir. 2006)). Importantly, “[b]ecause the hallmark of anticipation
is prior invention, the prior art reference . . . must not only disclose all elements of the claim
within the four corners of the document, but must also disclose those elements ‘arranged as in
the claim.’” Id. (quoting Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983)).
This means that the prior art must detail all the limitations “arranged or combined in the same
way as in the claim.” Id. at 1370. Thus, “it is not enough that the prior art reference discloses
part of the claimed invention, which an ordinary artisan might supplement to make the whole,
or that it includes multiple, distinct teachings that the artisan might somehow combine to

DSM did not affirmatively move for summary judgment of infringement, but requests it in its
opposition. (Pls.’ Opp’n (dkt. #74) 36.)
20

28

achieve the claimed invention.” Id. at 1371.21
As defendants emphasize, “[h]owever, a reference can anticipate a claim even if it d[oes]
not expressly spell out all the limitations arranged or combined as in the claim, if a person of
skill in the art, reading the reference, would at once envisage the claimed arrangement or
combination.” Blue Calypso, LLC v. Groupon, Inc., 815 F.3d. 1331, 1341 (Fed. Cir. 2016) (first
alteration added) (internal citations and quotation marks omitted); id. at 1344 (“[A] reference
may still anticipate if that reference teaches that the disclosed components or functionalities
may be combined and one of skill in the art would be able to implement the combination.”
(internal citations omitted)); see also Purdue Pharma, 811 F.3d at 1351 (“A single prior art
reference may anticipate without disclosing a feature of the claimed invention if such feature
is necessarily present, or inherent, in that reference.” (internal citation omitted)). Although
anticipation is ultimately a question of fact, “it may be decided on summary judgment if the
record reveals no genuine dispute of material fact.” Leggett & Platt, Inc. v. VUTEk, Inc., 537
F.3d 1349, 1352 (Fed. Cir. 2008) (quoting Golden Bridge Tech., Inc. v. Nokia, Inc., 527 F.3d
1318, 1321 (Fed. Cir. 2008)). Specifically, summary judgment on anticipation is appropriate
if no reasonable jury could find that the patent was anticipated. See Telemac Cellular Corp. v.
Topp Telecom, Inc., 247 F.3d 1316, 1327 (Fed. Cir. 2001) (explaining summary judgment of

DSM relies on In re Arkley, 455 F.2d 586, 587 (C.C.P.A 1972), for the proposition that in order
for a prior art reference to anticipate an invention, it “must clearly and unequivocally disclose the
claimed compound or direct those skilled in the art to the compound without any need for picking,
choosing, and combining various disclosures not directly related to each other by the teachings of
the cited reference” -- that all elements must be contained within a single embodiment. However,
Arkley was not intended by the Court of Customs and Patent Appeals to alter the test for
anticipation. See In re Schaumann, 572 F.2d 312, 317 (C.C.P.A. 1978) (Arkley “should not be
interpreted as establishing a new test for determining whether an invention has been described in
a reference within the meaning of 35 U.S.C. s 102.”). Arkley instead requires the disclosures in the
prior art be “directly related” to prevent “impermissible picking and choosing.” Purdue Pharma L.P.
v. Epic Pharma, LLC, 811 F.3d 1345, 1358-59 (Fed. Cir. 2016) (citing Arkley, 455 F.2d at 587).
21

29

anticipation for the defendant “is proper if no reasonable jury could find that the patent is not
anticipated”).

“Evidence of invalidity must be clear as well as convincing.”

Schumer v.

Laboratory Computer Sys., Inc., 308 F.3d 1304, 1315 (Fed. Cir. 2002). As such, “[t]ypically,
testimony concerning anticipation must be testimony from one skilled in the art and must
identify each claim element, state the witnesses’ interpretation of the claim element, and
explain in detail how each claim element is disclosed in the prior art reference.” Id. Conclusory
statements by experts -- or attorneys -- are insufficient. See id. at 1315-16.
Defendants assert that International Patent Publication No. WO 2009/111672 (“Sun”)
anticipated the invention. (See Pls.’ Mot. Judicial Construction & Partial Summ. J. (dkt. #58)
3.) At summary judgment, plaintiffs begin by arguing that the microorganisms described in
Sun are distinguishable from those of the present invention, which is certainly true as a matter
of fact. Sun organisms create long chain alcohols, to the detriment of ethanol production, and
rely on the “the incorporation of a malonyl-CoA-independent fatty acid synthesis pathway and
an acyl-reduction pathway.” (Pls.’ Opening Br. (dkt. #59) 29.) Plaintiffs argue that defendants
fail to provide enough evidence showing that Sun disclosed the invention, choosing instead to
improperly “pick[] and choose[] beneficial excerpts from Sun in order to stitch together various
elements of the Asserted Claims.” (Id.) In particular, plaintiffs accuse defense expert, Professor
Winge, of “improperly treat[ing] the Asserted Claims ‘as mere catalogs of separate parts, in
disregard to the part-to-part relationships set forth in the claims and that give the claims their
meaning,’” while failing to identify a single embodiment containing all necessary claim
elements, such that there is no clear and convincing evidence of anticipation. (Id. at 31-32
(quoting Therasence, Inc. v. Becton, Dickinson & Co., 593 F.3d 1325, 1332 (Fed. Cir. 2010)).)
Plaintiffs also argue that: (1) “Sun does not disclose each element arranged into a

30

transgenic yeast cell as in the Asserted Claims” because “the only embodiments of Sun
purportedly meeting elements [f] and [g] of the Asserted Claims are missing other required
elements”; (2) defendants fail to “identify any disclosure in Sun that would have led a person
of ordinary skill in the art to combine its various teachings to achieve the Asserted Claims”; (3)
defendants fail to “explain why a person of ordinary skill in the art would have selected
particular teachings from the various embodiments of Sun and combined them to achieve the
Asserted Claims”; and (4) Sun “does not disclose any transgenic yeast cells having all of the
elements arranged in the Asserted Claims.” (Id. at 35-36.) As to the last, plaintiffs point out
that Sun fails to disclose a preferred example with a genetic modification to GPD or GPP genes,
much less for the purpose of eliminating or reducing glycerol production in the biological
manufacture of ethanol. (Id. at 36.)
In response, defendants argue that plaintiffs’ attempt to distinguish between the
microorganisms disclosed in Sun and those disclosed in the ’998 patent is “unavailing” because
the cells disclosed in the ’998 patent “can include additional structures and functions beyond
those listed”; more specifically, Claim 1 is a “comprising” term, making the different use of Sun
organisms “irrelevant.” (Defs.’ Opp’n (dkt. #77) 30-31.) The bulk of defendants’ opposition
to plaintiffs’ motion, however, is based on the argument that a single embodiment in Sun,
found on pages 65–67 and shown in figure 18, discloses all necessary claims limitations. (See

31

id. at 31-39.)22
In reply, plaintiffs point out that defendants’ expert, Professor Winge, does not rely on
that embodiment. Thus, defendants are left with nothing more than attorney argument,
despite specialized, scientific expertise being necessary to establish anticipation by clear and
convincing evidence. (See Pls.’ Reply (dkt. #97) at 34-35.)23 Additionally plaintiffs argue that:
(1) Figure 18 fails to “disclose any disruption to the glycerol-3-phosphate shuttle”; (2) “there
is no evidence that Sun would have led a person of ordinary skill in the art to modify Figure
18 to include” that disruption; (3) anticipation cannot be established based on a person of
ordinary skill’s ability to “modify Figure 18 to include a disruption to the glycerol-3-phosphate
dehydrogenase shuttle”; and (4) defendants have presented no evidence showing that Sun
would have directed a person skilled in the art “to combine acetylating acetaldehyde
dehydrogenase activity with a disruption to the gpd1 and/or gpd2 genes other than Dr. Winge’s
conclusory expert report.” (Id. at 35-38.) The court agrees.
To begin, while the embodiment on pages 65-67 and shown in Figure 18 was arguably
relied on by Winge, it is discussed in the most oblique, superficial manner imaginable. (See

Defendants note that “[o]ther embodiments of Sun also arguably disclose each of the limitations
of the Asserted Claims” but that “in the interest of brevity these other embodiments will not be
addressed” because the embodiment on pages 65-67 “is sufficient.” (Defs.’ Opp’n (dkt. #77) 31
n.19.) Defendants purport to “reserve the right to use any and all other anticipating embodiments
of Sun at trial, however, should the need arise.” (Id.) This being the “put up or shut up” time for
such arguments, the court simply disagrees, although defendants could move for reconsideration if
they truly believe that some other embodiment addresses the court’s concerns and they have a good
excuse for not advancing that embodiment on summary judgment.
22

Plaintiffs also argue that defendants failed to disclose this anticipation theory before summary
judgment, depriving plaintiffs of an opportunity to obtain and present expert opinion in reply.
(Pls.’ Reply (dkt. #97) 35.) On this point, the court is less sympathetic, particularly given the
expanded deadlines to disclose expert opinions and the subsequently adjusted expert schedule
accommodating the ill-health of plaintiffs’ original liability expert.
23

32

Pls.’ Opening Br. (dkt. #59) 33 (reflecting Winge’s reliance on Sun disclosures at 65:23-27
and 67:15-25); Sun Patent (dkt. #55-2) 69 (67:18) (stating that “such embodiments” are
“shown in Figure 18”).) Even if this is enough for defendants to rely on Figure 18 to assert
disclosure of all the asserted claim elements, it is not enough to save defendants’ anticipation
defense because: (1) the elements are not arranged in the same way as in the ’998 patent; and
(2) there is no evidence that a person of ordinary skill in the art would assemble the elements
scattered about Sun into the invention claimed in the ’998 patent, particularly in light of no
expert opinion that one skilled in the art would have done so based on Sun alone.
Sun is a remarkably broad patent, generally directed towards the production of
dodeconol, and the embodiment relied on by defendants is buried almost sixty pages into the
“Detailed Description of the Invention.”24

At least arguably, this “disclosure” generally

suggests “gene[] disruptions includ[ing] those encoding” YDL022W (GPD1) and YOL059W
(GPD2), among numerous other enzymes (see Sun Patent (dkt. #55-2) 67 (65:23-26)), and
the addition of acylating acetaldehyde dehydrogenase (id. 149 (Figure 18)) for redox, but these
elements are certainly not arranged as in the ’998 patent. To the contrary, the acylating
acetaldehyde dehydrogenase in Sun is introduced into the mitochondrion for production of
dodecanol, instead of aiding redox for ethanol production in the cytosol. (Id.; see also id. at 8
(6:16-17) (“Figure 18 shows the formation of dodecanol in the mitochondrion by adding the
mitochondrial acylating acetaldehyde dehydrogenase.”).)
Even if a reasonable jury could conclude that one skilled in the art would realize that
acylating acetaldehyde dehydrogenase could be added to the cytosol instead, there is also no

This assumes that Sun truly discloses a single embodiment at pages 65-67 and Figure 18, which
itself is uncertain.
24

33

reference to glycerol reduction. Finally, nothing suggests combining the acylating acetaldehyde
dehydrogenase and the genetic disruptions for the purpose of more efficient production of
ethanol. (See id. at 149 (Figure 18).) Thus, the elements are not arranged in the same fashion
as in the ’998 patent.
Tellingly, defendants’ expert, Professor Winge, does not offer a valid opinion on
anticipation. Instead, he expressly operated on the erroneous assumption “that a claim is
invalid as anticipated if each and every limitation as set forth in the claim is described, expressly
or inherently, in a single prior art reference.” (Winge Invalidity Rpt. (dkt. #52) ¶ 42.) As
discussed above, it is not enough that the prior art discloses all the elements, it must disclose
them as arranged or combined in the claim, Net MoneyIN, 545 F.3d at 1369-70, or one skilled
in the art must immediately derive the claim from reading the prior reference. Blue Calypso,
815 F.3d. at 1341. Winge opines that all the claimed elements are present in Sun, but not
that one skilled in the art would read this embodiment and “at once envisage” the ’998 patent,
nor do defendants offer any other evidence that would permit a reasonable lay jury to so find.
Id.; see also In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (“An assertion of what seems to
follow from common experience is just attorney argument and not the kind of factual evidence
that is required to rebut a prima facie case of obviousness”); Carrier Corp. v. Goodman Global,
Inc., 64 F. Supp. 3d 602, 616 (D. Del. 2014) (finding attorney argument insufficient “to meet
the burden of persuasion on invalidity at the summary judgment motion stage” for a patent
that “involves complex technology”). Therefore, plaintiffs are entitled to summary judgment
on this defense.

34

II. Indefiniteness
Defendants’ motion for summary judgment based on indefiniteness is a substantially
closer call. “[A] patent is invalid for indefiniteness if its claims, read in light of the specification
delineating the patent, and the prosecution history, fail to inform, with reasonable certainty,
those skilled in the art about the scope of the invention.” Nautilus, Inc. v. Biosig Instruments,
Inc., 134 S.Ct. 2120, 2124 (2014). While “[s]ome modicum of uncertainty” is expected, “a
patent must be precise enough to afford clear notice of what is claimed, thereby ‘apprais[ing]
the public of what is still open to them.’” Id. at 2128-29 (citations omitted). “Claim language
employing terms of degree” or relative terms is not indefinite “where it provide[s] enough
certainty to one of skill in the art when read in the context of the invention.” Interval Licensing
LLC v. AOL, Inc., 766 F.3d 1364, 1370 (Fed. Cir. 2014) (internal citations omitted); One-EWay, Inc. v. Internat’l Trade Comm’n, 859 F.3d 1059, 1063 (Fed. Cir. 2017) (citing Interval
Licensing, 766 F.3d at 1370); see also id. at 1067 (“While we note that ‘virtually’ is a term of
degree, one that slightly expands the scope of the term ‘free from interference,’ the inclusion
of ‘virtually’ in these claims does not render them indefinite.”). This requires that the baseline,
against which the comparison is made, be clear to those skilled in the art. Liberty Ammunition,
Inc. v. United States, 835 F.3d 1388, 1395 (Fed. Cir. 2016). On the other hand, because a
patent is presumed valid, defendants must prove invalidity by clear and convincing evidence.
See Microsoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 95 (2011); see also 35 U.S.C. § 282(a)-(b).
Sketching the invention’s scope is particularly important “where different approaches
to measurement are involved,” such that “‘[t]he claims, when read in light of the specification
and the prosecution history, must provide objective boundaries for those of skill in the art.’”
Dow Chem. Co. v. Nova Chems. Corp. (Canada), 803 F.3d 620, 630-31 (Fed. Cir. 2015) (quoting

35

Interval Licensing, 766 F.3d at 1371). This means that “the patent and prosecution history must
disclose a single known approach or establish that, where multiple known approaches exist, a
person having ordinary skill in the art would know which approach to select.” Id. at 630.
Accordingly, a patent is indefinite when:

(1) there are multiple ways of measuring a

characteristic; (2) the method selected “could affect whether or not a given product infringes
the claims”; and (3) the patent fails to inform a person of ordinary skill in the art of the
appropriate measure. Id. at 634; see id. at 635 (“[A] claim term is indefinite if it leave[s] the
skilled artisan to consult the unpredictable vagaries of any one person’s opinion.” (citations
and quotation marks omitted)); see also Teva Pharms. USA, Inc. v. Sandoz, Inc., 789 F.3d 1335,
1341 (Fed. Cir. 2015) (finding claim indefinite for failing to “convey with reasonable certainty
the measure of molecular weight to be used” where there were three possible ways to measure,
each calculated differently and resulting in a different measurement; “the claim on its face
offer[ed] no guidance on which measure of ‘molecular weight’ the claims cover[ed]”). Put
another way, a claim lacking “a sufficient objective boundary around [its term of degree]” is
indefinite. Liberty Ammunition, 835 F.3d at 1397. Like other forms of invalidity, indefiniteness
must be proven by clear and convincing evidence. One-E-Way, 859 F.3d at 1062.
Defendants argue that they are entitled to summary judgment because the claims are
indefinite. Specifically, defendants argue that to determine the scope of the term requiring
“reduced NAD-dependent glycerol 3-phosphate dehydrogenase activity [GPD] compared to
corresponding wild-type cells,” GPD activity must be measured, with the measurement being
one of degree. (Defs.’ Opening Br. (dkt. #64) 26.) Defendants further posit that the patent
only discloses one method of measuring GPD activity: the so-called Blomberg assay. (Id. at

36

27.)25 If correct, and the Blomberg assay is unable to measure GPD activity -- as asserted by
plaintiffs26 -- then the claim “must be indefinite for failing to provide any guidance on how to
determine the scope of the claim.” (Id.)
In particular, defendants argue that “a person of ordinary skill in the art would not be
able to determine from the intrinsic evidence how to measure GPD activity” and would be left
to their own devices to select the measuring method of their choice to determine if a yeast cell
has reduced GPD activity compared to wild-type cells. (Id. at 28.) Defendants also challenge
the relevance of Professor Stephanopoulos’s general opinion that “[b]ased on fundamental
principles of enzyme kinetics and metabolic engineering, a yeast cell that has been engineered
to eliminate expression of Gpd2 and that also reported exhibits a 30% reduction in glycerol
synthesis -- like the Accused products -- necessarily has reduced Gpd activity compared to the
corresponding wild-type strain.” (Id. at 28-29.)
To unpack these arguments, the court will begin with the Blomberg assay, which has
been the source of much confusion, and arguably obfuscation, from both sides in this lawsuit.
In fairness to defendants, the ’998 patent expressly discloses no preferred means for measuring
the claimed reduction of GPD or GPP enzymatic activity, unless it is by use of the Blomberg
assay. The defendants’ problem is that the patent does not support its use for purposes of

As is discussed in detail later in this section of the opinion, the patent states that “Glycerol-3phosphate dehydrogenase activities were assayed in cell extracts at 30˚ C. as described previously
(Blomberg and Adler (1989), J. Bacteriol. 171:1087-1092[)]. Reaction rates were proportional to
the amounts of cell extract added.” (’998 Patent (dkt. 1-1) 16 (20:37-40).)
25

To be more precise, plaintiffs contend that the Blomberg assay is unable to measure GPD2
activity accurately, not GPD1 activity. (See Pls.’ Opp’n (dkt. #74) 42 (“The Blomberg assay . . . is
suitable for measuring the relative production in Gpd1 activity in Examples 1 and 2 of the ’998
patent, both of which contain a deletion of the gpd1 gene. However, abundant scientific evidence
demonstrates that the Blomberg assay is not suitable for measuring Gpd2 activity because this
enzyme is not stable in the buffer solutions used for the assay.” (internal citation omitted)).)
26

37

determining whether there has been a reduction in “GPD activity compared to a corresponding
wild yeast cell.” Instead, the ’998 patent refers to the special use of Blomberg assays to detect
cell activity in vitro under the heading of “Enzyme Activity Assays” in a single paragraph in
Column 20, lines 20 to 45, which explains that:

(’998 Patent (dkt. #1-1) 16 (20:21-44).)
The experts agree that this column refers to a specific experiment conducted by the
patent’s inventors in which yeast cell extracts were prepared from batch cultures under
conditions specified from the Abbott assay of NAD+-dependent acetaldehyde dehydrogenase
(acetylating), in other words, the reaction using the AAD enzyme. (EC 1.2.1.10), which can

38

be depicted as:
𝐴𝐴𝐷
→

𝐴𝑐𝑒𝑡𝑦𝑙 − 𝐶𝑜𝐴

𝐴𝑐𝑒𝑡𝑎𝑙𝑑𝑒ℎ𝑦𝑑𝑒

𝑁𝐴𝐷𝐻 →𝑁𝐴𝐷+

The paragraph goes on to explain that “[f]or glycerol 3-phospate dehydrogenase (E.C. 1.1.1.8)
activity determination,” cell extracts were also prepared. This reaction can be depicted as:
𝐷𝐻𝐴𝑃

𝐺𝑃𝐷1/𝐺𝑃𝐷2
→

𝐺3𝑃

𝑁𝐴𝐷𝐻 → 𝑁𝐴𝐷 +
However, the use of either assay to measure the rate of enzymatic activity is highly doubtful,
nor is its use for that purpose taught by the ’998 patent.
Indeed, the parties’ experts agree that these assays were prepared for a batch culture of
yeast cells that were genetically modified to express no GPD1 and GPD2, the essential enzymes
for the production of glycerol-3-phospate, which in the presence of GPP1 or GPP2 is rapidly
converted to glycerol through E.C. 3.1.3.21.
𝐺3𝑃
↓ 𝐺𝑃𝑃1/𝐺𝑃𝑃2
𝐺𝑙𝑦𝑐𝑒𝑟𝑜𝑙
In fact, as reflected in the paragraph quoted above, the only stated information gleaned from
opening up and assaying the cells in vitro was to confirm that “Reaction rates were proportional
to the amounts of cell extract added,” likely referring both to the conversion of NADH to
NAD+ in the EC 1.1.1.8 enzymatic reaction detected in the Blomberg assay and the conversion
of NADH to NAD+ in the EC 1.2.1.10 enzymatic reaction found in the Abbot assay, which is
what the inventors sought to confirm and basic science predicts.

While measuring

proportionality, what neither method of assaying cell extracts measured was changes of rates of

39

enzymatic activity over time.
This is confirmed by the first two entries on Table 3 found in Col. 21 of the ’998 patent,
which purport to show the presence of glycerol-3-phospate dehydrogenase and acetaldehyde
dehydrogenase as determined by the presence of NADH in the Blomberg and Abbot assays of
the engineered yeast strain (IMZ132), in which no GPD1 or GPD2 was expressed as compared
to corresponding wild yeast strain (IME076) at a specific point in time. Similarly, Table 3
reflects amounts of biomass produced at a specific point in time for glycerol and ethanol from
substrates of glucose and acetate. To obtain the rate of the GPD activity in contrast, you have
to look to the output on these same substrates in in vivo batches as plotted over time on Figures
2A and B as described in Col. 3, lines 35-49 of the ’998 patent. These figures are reproduced
below:

40

That the Blomberg assay was not used to determine the rate of GPD enzymatic activity
in the patent-in-suit is hardly surprising. In fact, the only attempted use of the Blomberg assays
for this purpose in the record was by Lallemand, in 2011 and 2016, first to prove that its
product had reduced GPD activity, then in an attempt to prove that it did not. In 2011,
Lallemand’s use of the Blomberg assay purported to show that the cell extracts of a yeast strain
equivalent to TFY+ reduced GPD activity compared to the wild-type yeast cells, although
defendants now note that some results “were within the error margin of the data.” (Defs.’
Resp. to Pls.’ Add’l PFOF (dkt. #96) ¶ 34; see also LAL00196466 (dkt. #47-88); LAL00196467
(dkt. #47-89).) In June 2016, Lallemand’s testing using the Blomberg assay again purportedly
showed that TFY+ had reduced GPD activity compared to the wild type cells, which
defendants now explain was the result of “testing . . . performed at high protein concentration[]
levels, which can lead to GPD inactivation.” (Defs.’ Resp. to Pls.’ Add’l PFOF (dkt. #96) ¶
34; see also LAL00196486 (dkt. #47-99); LAL00196487 (dkt. #47-100).)

Finally, at

Professor Winge’s direction, Lallemand performed additional GPD activity assays, which now
purport to show that the accused products had greater GPD activity than the corresponding

41

wild-type yeast cells, although plaintiffs’ expert, Professor Stephanopoulos, found this testing
to be “scientifically invalid.” (See Defs.’ Reply to Pls.’ Resp. to Defs.’ PFOF (dkt. #95) ¶¶ 9293.)
As defendants’ own use of the Blomberg assay demonstrates and plaintiffs persuasively
argue, Professor Stephanopoulos has a point, particularly for use on the accused products,
which deleted only GPD2, an enzyme so unstable in the buffer solution that a Blomberg assay
is unlikely to reliably measure its activity. While Winge purports to correct for this instability,
by among other things removing EDTA from the buffer solution, there is no recognized
authority or peer reviewed study that supports this creative change in the Blomberg assay, nor
does he or defendants effectively dispute plaintiffs’ contention that this compound “(1) is
commonly used in buffers due to its ability to stabilize enzymes, and (2) was present in all the
assay buffers described in the scientific literature.” (Pls.’ Opening Br. (dkt. #59) 39-40.)
This then leaves one of ordinary skill in the art, and the trier of fact in this case, with
the only recognized measure of GPD activity (EC 1.1.1.8), which all the experts agree is the
rate of glycerol production (or the rate of reduction in the DHAP substrate), and the patent
certainly does not teach that the Blomberg assay would be preferable.

Regardless, the

difficulties and limitations of using the Blomberg assay as a substitute for this traditional
measurement of GPD activity, especially with respect to knocking out or reducing the amount
of GPD2 in an anaerobic batch of yeast cells for the production of ethanol, would be so
apparent that its use for that purpose is not credible, except perhaps by one searching for a way
to prove the commercial viability of this practice or to prove non-infringement. Moreover, the
only known method for measuring a change of GPP activity in the second chemical reaction (of
G-3-P to glycerol (E.C. 3.1.3.21)) is to plot the rate of glycerol production. As a result, the

42

patent not only offers no assay for measurement of GPP enzymatic activity, but all experts
agreed the reaction converting G-3-P to glycerol is nearly instantaneous, making any assay
measurement of that reaction unlikely if not impossible.
This is not to suggest that measuring GPD or GPP enzymatic activity by the rate of
glycerol production is ideal. The experts seem to agree that the best measure of that activity
would likely be some kind of carbon-based tracking in vivo, but acknowledge that no such test
has even been developed, much less tested to the point of consensus among experts in the field
of biochemistry and, therefore, known to one of ordinary skill in the art. In short, the only
recognized measurement of NAD-dependent GPD activity disclosed in the ’998 patent as
commonly understood by one of ordinary skill in the art is the rate of glycerol production.
In their reply brief and again during the expert colloquy, defendants nevertheless argue
that “[a]t no point does the ’998 patent describe measuring glycerol synthesis as a way to
measure GPD activity,” and the HPLC analysis referenced by plaintiffs is found in the
“Metabolite Analysis” section preceding the “Enzyme Activity Assays” section disclosing the
Blomberg assay. (Defs.’ Reply (dkt. #94) 23.) Additionally, defendants note that “[g]lycerol
is not the product of the reaction catalyzed by GPD; Glycerol-3-Phosphate is.” (Id. at 24.)
But for reasons already discussed, this is mainly sophistry. Given that measurement of the rate
of glycerol production is the only accepted scientific method for measuring GPD and GPP
activity, much less the only one known to someone of ordinary skill in the art of industrialscale yeast production of ethanol, the court is compelled to find that this is the proper method
to measure GPD or GPP activity, even if not quite the “gold standard” that plaintiffs’ expert
would make it out to be.
Having construed the proper measurement for GPD and GPP activity in claim 1, the

43

court turns to the defendants’ last remaining challenge under the Federal Circuit’s Dow Chemical
decision. First, as disclosed in the ’998 patent, and as agreed by the all experts during the
colloquy, a yeast cell entirely free of GPD or GPP will not produce glycerol, thereby satisfying
claim 1. Admittedly, there is still the question of what constitutes a “reduction” in GPD or
GPP activity, made more problematic by the aerobic (GPD1 and GPP1) and anaerobic (GPD2
and GPP2) forms of each. On the other hand, there is nothing inherently indefinite about the
requirement that there be “reduced” activity. In fact, as noted, the defendants claim just that
in their marketing materials to the ethanol-producing industry. Moreover, as the United States
Supreme Court explained in Nautilus, “[s]ome modicum of uncertainty” is allowed. 116 S.Ct.
at 2128. Unlike the issues confronting the Supreme Court in Nautilus or the Federal Circuit
in Dow Chemical, the requirement of a reduction is not clearly or convincingly indefinite.27 As
defendants have had an opportunity to respond to plaintiffs’ opposition, and because the court
has determined that the patent is not indefinite, summary judgment will be granted in
plaintiffs’ favor on this defense. See Fed. R. Civ. P. 56(f); Ellis v. DHL Express Inc. (USA), 633
F.3d 522, 529 (7th Cir. 2011).

III. Infringement
Because the required proof of infringement of the elements in claim 1 of the ’998 patent
are largely not in dispute, the resolution of defendants’ second basis for seeking summary

As discussed in the next section, this is not to minimize the burden on the plaintiffs to prove
infringement, since at minimum they must prove that a reduction in glycerol results from practicing
the ’998 patent “as compared to corresponding wild-type cells,” something that would likely only
be possible to determine by the accused infringer or at least with its cooperation. Of course, the
obvious resolution of the infringement dispute would be for the parties to agree to batch runs of
the accused products and corresponding wild-type cells, in consultation with the court’s neutral
expert witness if necessary.
27

44

judgment is much more straightforward.

A person infringes a patent when she “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). Analysis of patent infringement is a two-step process:
first, the scope of the claims are determined as a matter of law,
and second, the properly construed claims are compared to the
allegedly infringing device to determine, as a matter of fact,
whether all of the limitations of at least one claim are present,
either literally or by a substantial equivalent, in the accused
device.
Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1323 (Fed. Cir. 2002); see also Split Pivot,
Inc. v. Trek Bicycle Corp., 987 F. Supp. 2d 838, 876 (W.D. Wis. 2013) (explaining that following
claims construction, “the claim as properly construed must be compared to the accused device
or process”).
Whether an accused product infringes -- literally or by substantial equivalent -- is a
question of fact. Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed. Cir. 1998); TechSearch,
L.L.C. v. Intel Corp., 286 F.3d 1360, 1370-71 (Fed. Cir. 2002).

“Summary judgment is

appropriate when it is apparent that only one conclusion as to infringement could be reached
by a reasonable jury.” TechSearch, 286 F.3d at 1369 (citing ATD Corp. v. Lydall, Inc., 159 F.3d
534, 540 (Fed. Cir. 1998)). Accordingly, an accused infringer is entitled to summary judgment
of noninfringement “where the patent owner’s proof is deficient in meeting an essential part of
the legal standard for infringement, since such failure will render all other facts immaterial.”
Telemac Cellular Corp. v. Topp Telecom, Inc., 247 F.3d 1316, 1323 (Fed. Cir. 2001) (citing London
v. Carson Pirie Scott & Co., 946 F.2d 1534, 1537 (Fed. Cir. 1991)); see also Bai, 160 F.3d at
1353 (“[A] literal infringement issue is properly decided upon summary judgment when no
genuine issue of material fact exists, in particular, when no reasonable jury could find that every
limitation recited in the properly construed claim either is or is not found in the accused

45

device.” (internal citation omitted)). Concomitantly, the patent owner must provide more
than simply “general assertions of facts, general denials, and conclusory statements”; rather, it
“must point to an evidentiary conflict created on the record.” TechSearch, 286 F.3d at 1372.
Here, defendants maintain that the accused products do not have reduced NADdependent GPD activity compared to corresponding wild-type cells. (Defs.’ Opening Br. (dkt.
#64) 22-25.) Specifically, defendants argue that if the court adopted their proposed meaning
of “activity” -- that it is “the expression of GPD” -- they are entitled to summary judgment
because: (1) plaintiffs provide “conclusory expert opinions, and no evidence, that the accused
products exhibit decreased expression of [GPD] compared to wild-type yeast cells”; and (2)
defendants’ testing -- using the Blomberg enzyme activity assay described in the ’998 patent - “confirms that the accused products exhibit increased expression of [GPD] compared to wildtype yeast cells.” (Id. at 22-23 (emphasis in original).)
In their opposition brief, and again at the expert colloquy, plaintiffs argue that if the
court adopts their proposed constructions, there is no question that the accused products
infringe, such that it is entitled to summary judgment. (Pls.’ Opp’n (dkt. #74) 36.) Plaintiffs
further argue that they have put forward enough evidence to establish infringement and have
raised serious questions about the “validity, reliability, and credibility of [Lallemand’s GPD
activity assays].” (Id.) Professor Stephanopoulos’s expert opinion that “a yeast cell that has
been engineered to eliminate expression of Gpd2 and that also reportedly exhibits a 30%
reduction in glycerol synthesis -- like the Accused Products -- necessarily has reduced Gpd
activity compared to the corresponding wild-type strain” is not “conclusory,” as defendants
argue. Rather, it derives from “fundamental principles of enzyme kinetics and metabolic
engineering” and appears “confirmed by Lallemand’s own business records.”

46

(Id. at 37.)

Indeed, plaintiffs rely on Lallemand’s internal and advertising documents that appear to tout
TFY+ for:

(1) having a “[d]own-regulated glycerol pathway” with “down-regulation of

GPD1/GPD2”; and (2) reducing glycerol production “primarily by downregulating the
gpd1/gpd2 genes.” As plaintiffs note, Lallemand’s International Patent Publication defines
“downregulated” as “mean[ing] decreased in activity, e.g., decreased in enzymatic activity of
the enzyme as compared to activity in a native host organism.” (Id. at 37-38 (quoting WO
2012/138942).) At minimum, these seeming admissions make defendants’ denials ring hollow.
Ironically for plaintiffs, it appears most of the statements on which they rely are based
on the same dubious use of Blomberg assays that plaintiffs so persuasively attack. (Pls. Opp’n
(dkt. #74) 39-42.) Moreover, plaintiffs and their expert have done no testing of the accused
products to determine whether in fact they are free of any NAD-dependent GPD activity or,
at least, have reduced such activity compared to corresponding wild-type cells.
Even accounting for Professor Alper’s credible opinion that this would almost certainly
be true as a matter of basic science, he conceded at the expert colloquy at least the possibility
that a yeast cell that does not express GPD2 might be altered sufficiently so that glycerol
production might occur at a level approaching, if not exceeding, that of its corresponding wildtype cell. And defendants have produced some evidence to permit a reasonable jury to find
that the accused products have been sufficiently altered to make any reduction in glycerol
production unrelated to the elimination of GPD as compared to corresponding wild cells.
Of course, the opposite is also true. Indeed, on the facts provided at summary judgment
and in the experts’ opinions, there would appear to be a much greater likelihood that a
reasonable jury would find infringement. Indeed, Lallemand’s own document appears to show
that the elimination of GPD2 expression has sufficiently altered the GPD enzyme activity to

47

appreciably change glycerol production compared to conventional yeast cells:

(TransFerm Yield+ Marketing document (dkt. #47-56) 2.) Defendants may successfully argue
at trial that the accused products’ performance is no longer comparable to the “TransFerm
Yield+ Metabolism” set forth above, but they are certainly not entitled to summary judgment
on infringement. See TechSearch, L.L.C. v. Intel Corp., 286 F.3d 1360, 1370 (Fed. Cir. 2002)
(“Summary judgment is appropriate when it is apparent that only one conclusion as to
infringement could be reached by a reasonable jury.” (citing ATD Corp. v. Lydall, Inc., 159 F.3d
534, 540 (Fed. Cir. 1998))). Because of the factual disputes outlined above, neither are
plaintiffs.

ORDER
IT IS ORDERED that:
1) The disputed terms are construed as set forth above;
2) plaintiffs’ motion for partial summary judgment on defendants’ anticipation
defense (dkt. #58) is GRANTED;
3) defendants’ motion for summary judgment as to indefiniteness (dkt. #61) is
DENIED, and plaintiffs are GRANTED summary judgment on this defense; and

48

4) the parties’ cross-requests for summary judgment on noninfringement (dkt. ##61,
74) are DENIED.
Entered this 22nd day of March, 2018.
BY THE COURT:
/s/
__________________________________
WILLIAM M. CONLEY
District Judge

49