Court Opinion

ID: 1034626
Source: CourtListenerOpinion
Date Created: 2013-07-22 21:10:45.509071+00
Date Added: 2024-06-11T09:57:36.749454
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                ______________________

   NOVOZYMES A/S, AND NOVOZYMES NORTH
             AMERICA, INC.,
            Plaintiffs-Appellants,

                          v.

DUPONT NUTRITION BIOSCIENCES APS (former-
 ly Danisco A/S), GENENCOR INTERNATIONAL
    WISCONSIN, INC., DANISCO US INC., AND
              DANISCO USA INC.,
               Defendants-Appellees.
              ______________________

                      2012-1433
                ______________________

   Appeal from the United States District Court for the
Western District of Wisconsin in No. 10-CV-0251, Senior
Judge Barbara B. Crabb.
                ______________________

                Decided: July 22, 2013
                ______________________

     DAVID K. TELLEKSON, Fenwick & West, LLP, of Seat-
tle, Washington, argued for plaintiffs-appellants. With
him on the brief were VIRGINIA K. DEMARCHI, MELANIE L.
MAYER, JEFFREY V. LASKER, and EWA M. DAVISON. Of
counsel was BRIAN D. BUCKLEY.
2           NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES

    CHARLES E. LIPSEY, Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP, of Reston, Virginia, argued for
defendants-appellees. With him on the brief were
HOWARD W. LEVINE and LILLIAN M. ROBINSON, of Wash-
ington, DC; JENNIFER S. SWAN, of Palo Alto, California.
Of counsel on the brief were TRACEY B. DAVIES, Gibson
Dunn & Crutcher, LLP, of Dallas, Texas; and MICHAEL A.
VALEK, Vinson & Elkins, LLP, of Austin, Texas.
                ______________________

 Before RADER, Chief Judge, SCHALL and BRYSON, Circuit
                        Judges.
    Opinion for the court filed by Circuit Judge SCHALL.
      Dissenting opinion filed by Chief Judge RADER.
SCHALL, Circuit Judge.
    Plaintiffs-Appellants Novozymes A/S and Novozymes
North America, Inc. (collectively, “Novozymes”) and
Defendants-Appellees DuPont Nutrition Biosciences APS,
Genencor International Wisconsin, Inc., Danisco US Inc.,
and Danisco USA Inc. (collectively, “DuPont”) are compet-
itors in the market for enzyme preparations used in a
variety of commercial applications, including ethanol
production. On May 11, 2010, Novozymes brought suit
against DuPont in the Western District of Wisconsin,
alleging infringement of its U.S. Patent No. 7,713,723 (the
“’723 patent”). The ’723 patent claims particular modified
enzymes that exhibit improved function and stability
under certain conditions. DuPont defended on grounds of
noninfringement and invalidity and filed counterclaims
seeking a declaratory judgment that the claims of the ’723
patent are invalid for failing to satisfy the enablement
and written description requirements of 35 U.S.C. § 112.
    As litigation progressed, the parties filed several mo-
tions for summary judgment. In pertinent part, the
district court granted summary judgment in favor of
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          3
Novozymes on the issue of infringement and denied
DuPont’s motion for summary judgment of invalidity
under the written description and enablement require-
ments. The case then went to trial before a jury, which
concluded that the ’723 patent’s claims are not invalid on
enablement or written description grounds and which
awarded infringement damages to Novozymes exceeding
$18 million.     The district court, however, granted
DuPont’s post-trial motion for judgment as a matter of
law that the claims of the ’723 patent are invalid under
§ 112 for failure to satisfy the written description re-
quirement.
    Novozymes now appeals from the district court’s final
judgment of invalidity. For the reasons set forth below,
we affirm.
                       BACKGROUND
                I. Alpha-Amylase Enzymes
    The ’723 patent, entitled “Alpha-Amylase Mutants
with Altered Properties,” relates to recombinant enzyme
technology. Enzymes are proteins that catalyze biochemi-
cal reactions, that is, they facilitate molecular processes
that either would not occur or would occur much more
slowly in the enzyme’s absence. Living cells produce
different enzymes to carry out a vast array of metabolic
functions. For example, one enzyme might help to join
the molecular building blocks needed to make a new DNA
molecule, while another might break a complex molecule,
such as a carbohydrate, into useful constituent parts.
    Like all proteins, enzymes are composed of amino acid
molecules linked together to form a continuous chain. An
enzyme’s primary structure is defined by the sequence of
amino acid molecules in the chain; in general, each indi-
vidual position in the amino acid sequence can consist of
any one of twenty amino acids normally found in nature.
In addition, the linear amino acid chains of different
4          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
enzymes will bend, fold, and loop onto themselves to
assume characteristic three-dimensional conformations.
Both the primary amino acid sequence and the three-
dimensional structure affect an enzyme’s ultimate func-
tional properties.
    Alpha-amylases constitute a class of enzymes synthe-
sized by a variety of organisms—from bacteria to fungi to
humans—that break down large molecules known as
polysaccharides. Polysaccharides, such as starch and
glycogen, are defined as long-chain polymers made of
repeating simple sugar molecules like glucose, among
others. Alpha-amylases sever the bonds between adjacent
sugars in a polysaccharide to yield single or short-chain
simple sugars that can provide energy or be used as
building blocks for other cellular processes. On average,
alpha-amylase enzymes comprise approximately 500
amino acids.
    Beyond a widespread role in natural systems, alpha-
amylases also have important commercial applications in
detergent formulations, sugar refining, and ethanol
production, among other uses. Of particular note, many
alpha-amylases derived from bacteria of the genus Bacil-
lus exhibit exceptional enzymatic activity, which has
made those bacterial enzymes attractive for commercial
use. One such product is a preparation of alpha-amylase
derived from B. licheniformis (“BLA”) that Novozymes
markets under the name Termamyl™.
        II. Novozymes’s 2000 Patent Application
     Many of the most common commercial or industrial
applications for alpha-amylase enzymes involve harsh
conditions, including high temperatures and/or high
acidity. Exposure to such conditions progressively desta-
bilizes and deactivates natural Bacillus alpha-amylase
enzymes, degrading the performance of the associated
enzyme-based products or processes over time. In the late
1990s, Novozymes sought to improve the acid tolerance
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          5
and heat tolerance (“thermostability”) of Bacillus alpha-
amylases used in commercial processes.
    Traditionally, the solution had been to add excess cal-
cium to commercial alpha-amylase formulations intended
for use under extreme temperature or pH conditions.
While concentrated calcium is effective for stabilizing
alpha-amylases to preserve their enzymatic activity, it
represents an added cost and often imposes undesirable
effects on industrial equipment. Thus, Novozymes’s aim
was to modify a naturally occurring “parent” Bacillus
alpha-amylase to produce an enzyme having improved
stability and thus more durable activity under harsh
conditions, even without calcium supplementation.
     Enzymes can often be altered at one or more positions
along their amino acid chain without destroying their
function. Changes (known as “mutations”) in a parent
enzyme can include deleting one or more amino acids,
adding one or more amino acids, or substituting the
original amino acid with one of the nineteen other possi-
bilities at any given position in the sequence. An enzyme
that has one or more mutations relative to its natural
parent sequence is referred to as a “variant.” The effects
of any given mutation or combination of mutations in a
variant can differ depending on the position(s) modified
and the specific mutation implemented at each position.
Some mutations may have no discernible effect on enzyme
function, some may lead to varying degrees of instability
or functional impairment, and some may actually improve
enzyme activity or impart other desirable properties, such
as improved stability at high temperatures.
    Novozymes pursued two parallel strategies in at-
tempting to identify promising mutation sites among the
approximately 500 amino acids that make up a Bacillus
alpha-amylase polypeptide: rational protein design and
random mutagenesis. Rational protein design involves
making functional inferences from the amino acid se-
6          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
quence and three-dimensional shape of a protein to pre-
dict which positions may influence a property of interest,
such as thermostability, enzymatic activity, or calcium
binding.     In contrast, random mutagenesis involves
making random mutations in a parent enzyme and then
screening the resulting variants to identify those that
exhibit the desired functional effects. Using rational
protein design and random mutagenesis, Novozymes
identified thirty-three Bacillus alpha-amylase amino acid
positions as targets for mutation in attempting to create
alpha-amylase variants with enhanced stability. Of those
thirty-three positions, seventeen were predicted using
rational protein design techniques, while sixteen were
identified via random mutagenesis experiments.
     With that information in hand, Novozymes filed U.S.
Provisional Patent Application No. 60/249,104 on Novem-
ber 16, 2000 (the “2000 application”), relating to Bacillus
alpha-amylase variants with enhanced stability. 1 The
2000 application disclosed seven potential parent en-
zymes, including an alpha-amylase isolated from BLA
bacteria that Novozymes was already using in its Ter-
mamyl™ product, and another alpha-amylase produced
by B. stearothermophilus (“BSG”). See ’723 patent col. 3
ll. 1–38. The 2000 application also disclosed the thirty-
three separate amino acid positions along the alpha-
amylase chain that Novozymes identified as promising
mutation targets using rational protein design or random
mutagenesis. In addition, the specification indicated that
one or more of those sites might be altered in any of the
seven disclosed parent alpha-amylases by deletion, addi-

    1   The written descriptions of the 2000 application
and the ’723 patent are nearly identical. For convenience,
we will cite portions of the ’723 patent when referencing
identical, corresponding disclosures in the 2000 applica-
tion.
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES           7
tion, or substitution. See id. col. 7 ll. 36–57. The 2000
application further indicated that the disclosed variants
would exhibit improved stability at “high temperatures
(i.e., 70-120°C.) and/or extreme pH (i.e., low or high pH,
i.e., pH 4-6 or pH 8-11), in particular at free (i.e., un-
bound, therefore in solution) calcium concentrations below
60 ppm.” See id. col. 16 ll. 42–47.
     Given the number of parent enzymes (7), the number
of target positions in each of those parent enzymes (33),
and the number of possible mutations at each of those
target positions (at least 40), 2 the disclosure in the 2000
application spans a potentially wide range of alpha-
amylase variants. For example, one of the seventeen
positions identified by rational protein design was posi-
tion 239, occupied by the amino acid serine (abbreviated
as “S”) in the disclosed parent alpha-amylase proteins.
Many mutations would be possible at position 239, such
as an enumerated variant that would require replacing
the original serine with the amino acid tryptophan (ab-
breviated as “W”)—a substitution mutation that can be
expressed as “S239W.” See id. col. 8 l. 12. The 2000
application includes pages of similar exemplary substitu-
tions, presented alone and in double, triple, or larger
combinations, but the application does not state that any
one of the thirty-three disclosed mutations sites is pre-
ferred over any other and does not state whether single or
combined mutations are preferred. See id. col. 8 l. 25 –
col. 16 l. 37.
    Finally, the 2000 application provided two examples
with empirical data confirming the enhanced stability of

   2    According to the 2000 application, the possible
mutations at any amino acid position would include a
single deletion, a substitution with any of the 19 other
amino acids, and a single downstream addition of any of
the 20 amino acids. See ’723 patent col. 7 ll. 45–52.
8           NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
selected variants harboring mutations at the sixteen
positions that were identified through random mutagene-
sis. See id. col. 25 l. 1 – col. 26 l. 65. No such data were
disclosed regarding the activity or thermostability of any
of the seventeen positions that had been identified
through rational protein design, however. Indeed, later
experiments revealed that some of the seventeen predict-
ed positions did not yield any thermostable variants, and
even for many of those that did, only a minority of substi-
tutions actually had the desired effect. For example, no
substitutions at predicted positions 179 or 180 actually
led to increased thermostability, and thirteen of the
nineteen possible substitutions at position 239 proved
similarly ineffective, including the disclosed S239W
mutation.
    Novozymes filed its first non-provisional patent appli-
cation claiming priority from the 2000 application on July
31, 2001. After the examiner issued a restriction re-
quirement directing Novozymes to elect a single disclosed
species, i.e., a single specific parent alpha-amylase with a
single specific amino acid substitution, Novozymes elected
a BLA parent modified at position 49. In addition, Novo-
zymes filed a continuation application on July 29, 2003,
electing a BLA parent modified at position 170. Neither
of those applications resulted in an issued patent.
    III. DuPont’s Accused Products and the ’723 Patent
    In 2006, while Novozymes’s patent prosecution efforts
remained ongoing, DuPont began work to develop an
alpha-amylase having increased stability at high temper-
atures and low calcium concentrations for use in corn
ethanol production. Starting from a BSG parent enzyme
that corresponded to one of its own existing alpha-
amylase products, DuPont produced approximately 1,500
alpha-amylase variants with substitutions covering 150 of
the 515 amino acid positions in the parent BSG enzyme.
Of those 150 positions, six also appeared in the list of
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          9
thirty-three candidate positions disclosed in Novozymes’s
2000 application. DuPont then screened its panel of 1,500
variants for increased thermostability under low-calcium
conditions and identified a variant substituted at position
239 as the best performer. As described, position 239 was
also among the thirty-three positions disclosed in Novo-
zymes’s 2000 application, though the particular substitu-
tion DuPont chose—replacing serine 239 with glutamine
(“Q”), denoted “S239Q”—was not. In November 2008,
DuPont filed a patent application and developed a new
thermostable alpha-amylase product based on the BSG
S239Q variant. DuPont’s patent application issued as
U.S. Patent No. 7,541,026 in June 2009.
    Upon learning that DuPont had introduced a thermo-
stable BSG alpha-amylase variant substituted at position
239, Novozymes filed a new continuation application on
December 22, 2009, (the “2009 application”) that claimed
priority from its original 2000 application. The written
descriptions of the 2009 application and the 2000 applica-
tion were nearly identical, but Novozymes for the first
time sought claims drawn specifically to BSG alpha-
amylase variants substituted at position 239. The ’723
patent issued from the 2009 application on May 11, 2010,
with seventeen claims. Claim 1 is representative:
   1. An isolated variant of a parent alpha-amylase,
   wherein:
   (a) the variant has at least 90% sequence identity
       to SEQ ID NO: 6 [BSG alpha-amylase],
   (b) the variant comprises a substitution of serine
        at position 239 relative to the parent alpha-
        amylase, using the amino acid sequence of
        SEQ ID NO: 8 [BLA alpha-amylase] for de-
        termining position numbering, and
   (c) the variant has increased thermostability rela-
        tive to the parent alpha-amylase, wherein
10          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
         thermostability is determined at pH 4.5, 90°
         C. and 5 ppm calcium and has alpha-amylase
         activity.
’723 patent col. 87 ll. 40–51 (emphasis added). Like claim
1, all claims of the ’723 patent require an alpha-amylase
variant with at least the following three features: (1) a
parent sequence having at least 90% homology with BSG
alpha-amylase; (2) a substitution at position S239; and
(3) increased thermostability at 90°C, pH 4.5, and 5 ppm
calcium. Each of those limitations can be found at points
within the underlying 2000 application, but, outside of the
’723 patent’s claims, Novozymes never presented them
together in any particular embodiment and did not high-
light the BSG parent or position 239 among the other
disclosed options.
              IV. District Court Proceedings
    On May 11, 2010, the same day the ’723 patent is-
sued, Novozymes filed a complaint in the Western District
of Wisconsin accusing DuPont of infringing claims 1–5, 8–
13, and 15–16 of the ’723 patent. DuPont’s answer in-
cluded noninfringement and invalidity defenses, as well
as counterclaims for invalidity under the enablement and
written description requirements of § 112, ¶ 1. 3 Shortly
thereafter, the district court denied Novozymes’s motion
for a preliminary injunction, in part because, in its view,
DuPont’s written description challenge had raised a
substantial question regarding the validity of the ’723
patent’s claims. Novozymes A/S v. Danisco A/S, No. 10-
cv-251, 2010 WL 3783682, at *5 (W.D. Wis. Sept. 24,

     3  Paragraph 1 of 35 U.S.C. § 112 was replaced with
newly designated § 112(a) when § 4(c) of the Leahy-Smith
America Invents Act (“AIA”), Pub. L. No. 112-29, took
effect on September 16, 2012. Because this case was filed
before that date, we will refer to the pre-AIA version of
§ 112.
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES           11
2010) (“[A] substantial question remains whether [the]
’723 patent will survive defendants’ challenge to the
patent’s validity.”).
     On February 4, 2011, the district court denied
DuPont’s motion for summary judgment that the ’723
patent was invalid for lack of written description. Novo-
zymes A/S v. Danisco A/S, No. 10-cv-251 (W.D. Wis. Feb.
4, 2011), ECF No. 185 (“Written Description Summary
Judgment Order”). The district court indicated that it
“still [had] doubts that the specification of the ’723 patent
provides an adequate written description for the claims,”
id. at 2, but the court concluded that the parties’ conflict-
ing positions reflected at least a genuine issue of material
fact. The district court later granted summary judgment
in favor of Novozymes on the issue of infringement, hold-
ing that DuPont’s products literally infringed the asserted
claims of the ’723 patent. Novozymes A/S v. Danisco
A/S, No. 10-cv-251, slip op. at 4–30 (W.D. Wis. July 7,
2011), ECF No. 399.
     The case then went to trial before a jury. DuPont
maintained its validity challenges, asserting that the
claimed subject matter was neither enabled nor sufficient-
ly described in the 2000 application. At the trial’s conclu-
sion, the jury was provided a special verdict form that
asked whether DuPont had “proven by clear and convinc-
ing evidence that any one or more of the [’723 patent’s]
claims are invalid because the application filed on No-
vember 16, 2000 . . . does not contain an adequate written
description,” and, similarly, whether DuPont had estab-
lished that the claims were not enabled. The jury an-
swered “No” as to each claim. The jury further concluded
that DuPont’s adjudged infringement was willful and
awarded Novozymes $18,219,500 in damages. According-
ly, the district court entered judgment for Novozymes on
October 27, 2011.
12          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
     After the entry of judgment, Novozymes sought a
permanent injunction, fees, enhanced damages, and pre-
and post-judgment interest, while DuPont filed motions
for judgment as a matter of law on various issues, includ-
ing willfulness, damages, and invalidity for lack of ena-
blement and written description. In an order dated May
4, 2012, the district court granted DuPont’s motion for
judgment as a matter of law under Federal Rule of Civil
Procedure 50(b), holding that the claims of the ’723 patent
were invalid under § 112 for lack of adequate written
description in the 2000 application. Novozymes A/S v.
Danisco A/S, No. 10-cv-251 (W.D. Wis. May 4, 2012), ECF
No. 966 (“JMOL Order”).
    Addressing the written description requirement, the
district court stated that “[t]he concern is that a patentee
may attempt to use later filed claims, relying on more
recently discovered data, to expand the scope of his inven-
tion or to complete an idea.” Id. at 6 (citing Billups-
Rothenberg, Inc. v. Associated Reg’l & Univ. Pathologists,
Inc., 642 F.3d 1031, 1036 (Fed. Cir. 2011)). Turning to
the ’723 patent, the court noted that the 2000 application
disclosed a potentially enormous number of alpha-
amylase variants, encompassing all possible combinations
among the seven disclosed parent enzymes, the thirty-
three disclosed positions for mutation, the numerous
different mutations possible at each position, and the
various possible combinations of individual mutations.
The court also noted that the 2000 application did not
point out the specific variants later claimed in the ’723
patent. Id. at 6–7.
    In its analysis, the district court analyzed precedents
in which patent claims had been held invalid due to an
underlying written description that set forth a broad,
generic group of structures without specifically identify-
ing the later-claimed species among many possible op-
tions. Id. at 9–12 (citing Boston Scientific Corp. v.
Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011);
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          13
Billups-Rothenberg, 642 F.3d at 1036; Centocor Ortho
Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir.
2011); Univ. of Rochester v. G.D. Searle & Co., 358 F.3d
916 (Fed. Cir. 2004); Purdue Pharma L.P. v. Faulding
Inc., 230 F.3d 1320 (Fed. Cir. 2000); In re Ruschig, 379
F.2d 990 (CCPA 1967)). Acknowledging that the ’723
patent was “superficially different” from the patents at
issue in those cases, in that the 2000 application express-
ly named the individual limitations recited in the claims,
id. at 9–10, the district court nonetheless concluded that
“there is no meaningful difference between identifying a
generic group in which a limitation of a claim may be
found (as in many of the prior cases) and individually
listing each member of that group without directing the
reader to a particular member (as in the ’723 patent).” Id.
at 11. In the district court’s view, the problem in either
situation was that “the specification failed to inform the
reader which member of that group was the right one.”
Id. Accordingly, because “[t]he actual inventive work of
producing a [working variant] was left for subsequent
inventors to complete,” the district court held that the
2000 application provided insufficient written description
for the claims of the ’723 patent and that those claims
were therefore invalid under § 112. Id. at 17–18 (altera-
tions in original) (quoting Centocor, 636 F.3d at 1353)
(internal quotation marks omitted).
    The district court thus granted DuPont’s motion for
judgment as a matter of law. JMOL Order, slip op. at 19.
On May 11, 2012, the court entered an amended judg-
ment in favor of DuPont, holding the claims of the ’723
patent invalid for lack of sufficient written description
under § 112, ¶ 1. 4

   4    Having invalidated the claims of the ’723 patent
for lack of adequate written description, the district court
dismissed the parties’ other post-trial motions, including
14          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
    Novozymes filed a timely notice of appeal on May 29,
2012.    We have jurisdiction pursuant to 28 U.S.C.
§ 1295(a)(1).
                        DISCUSSION
                   I. Standard of Review
    When reviewing a district court’s grant of judgment
as a matter of law, we apply the law of the governing
regional circuit. Uniloc USA, Inc. v. Microsoft Corp., 632
F.3d 1292, 1301 (Fed. Cir. 2011). “The Seventh Circuit
reviews a district court’s grant of a JMOL motion without
deference, while viewing all the evidence in the light most
favorable to the nonmoving party.” Trading Techs. Int’l v.
eSpeed, Inc., 595 F.3d 1340, 1357 (Fed. Cir 2010) (citing
Harper v. Albert, 400 F.3d 1052, 1061 (7th Cir. 2005)).
Judgment as a matter of law “is proper when ‘a party has
been fully heard on an issue and there is no legally suffi-
cient evidentiary basis for a reasonable jury to find for
that party on that issue.’” Harper, 400 F.3d at 1061
(quoting Fed. R. Civ. P. 50(a)(1)).
                    II. Issues Presented
         A. The Written Description Requirement
     The written description requirement is set forth in the
first paragraph of 35 U.S.C. § 112. Ariad Pharm., Inc. v.
Eli Lilly & Co., 598 F.3d 1336, 1343–45 (Fed. Cir. 2010)
(en banc). In pertinent part, § 112 provides that:
     The specification shall contain a written descrip-
     tion of the invention, and of the manner and pro-
     cess of making and using it, in such full, clear,
     concise, and exact terms as to enable any person
     skilled in the art to which it pertains, or with
     which it is most nearly connected, to make and

DuPont’s parallel motion for judgment as a matter of law
on the issue of enablement.
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          15
    use the same, and shall set forth the best mode
    contemplated by the inventor of carrying out his
    invention.
35 U.S.C. § 112, ¶ 1 (2006).
    To satisfy the written description requirement, “the
applicant must ‘convey with reasonable clarity to those
skilled in the art that, as of the filing date sought, he or
she was in possession of the invention,’ and demonstrate
that by disclosure in the specification of the patent.”
Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541
F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v.
Mahurkar, 935 F.2d 1555, 1563–64 (Fed. Cir. 1991)).
Accordingly, claims added during prosecution must find
support sufficient to satisfy § 112 in the written descrip-
tion of the original priority application.        See, e.g.,
Anascape, Ltd. v. Nintendo of Am., Inc., 601 F.3d 1333,
1335 (Fed. Cir. 2010). Assessing “possession as shown in
the disclosure” requires “an objective inquiry into the four
corners of the specification.” Ariad, 598 F.3d at 1351.
Ultimately, “the specification must describe an invention
understandable to [a] skilled artisan and show that the
inventor actually invented the invention claimed.” Id. A
“mere wish or plan” for obtaining the claimed invention
does not satisfy the written description requirement.
Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d
1559, 1566 (Fed. Cir. 1997). The written description
inquiry presents an issue of fact. Ariad, 598 F.3d at 1351.
                B. The Parties’ Contentions
    To begin, Novozymes argues that the level of skill in
the art of alpha-amylase biotechnology is very high and
that, at the time that the 2000 application was filed, a
person of ordinary skill in that art would have recognized
the field as well developed and predictable. Specifically,
Novozymes contends that alpha-amylases have been
studied since 1833 and that, by the time it filed the 2000
application, the amino acid sequences and three-
16         NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
dimensional structures of many alpha-amylases had been
solved, methods for introducing mutations into alpha-
amylase proteins and measuring the resulting variants’
enzymatic activity were well known, and the use of alpha-
amylase structure-function relationships in designing
variants was commonplace and effective. Novozymes
further argues that the key to deriving functional alpha-
amylase variants lies in finding the right position to
mutate rather than the specific mutation(s) made at that
position.
    In that context, Novozymes asserts that sufficient ev-
idence supported the jury’s validity determination, em-
phasizing that the 2000 application expressly discloses
each limitation of the asserted claims, namely (1) a parent
BSG alpha-amylase; (2) a substitution at the S239 posi-
tion; and (3) increased thermostability at 90°C, pH 4.5,
and 5 ppm calcium. In Novozymes’s view, a person of
ordinary skill in the art thus would have understood the
2000 application as clearly describing the claimed inven-
tion. Moreover, Novozymes argues that the district court
revisited factual issues without applying the deferential
standard demanded by Rule 50(b). In particular, Novo-
zymes complains that the district court discounted its
experts’ testimony indicating that a person of ordinary
skill in the art would have had no difficulty deriving the
claimed invention from the disclosure of the 2000 applica-
tion.
     In addition, Novozymes distinguishes Boston Scien-
tific and like cases on the grounds that those cases con-
cerned complex, unpredictable technologies and involved
written descriptions that lacked express disclosure of the
claimed subject matter. Relying on Snitzer v. Etzel, 465
F.2d 899 (CCPA 1972), Novozymes argues that the 2000
application’s written description is not deficient simply
because it discloses unclaimed inventions and inoperative
species. Novozymes also points to Union Oil Co. of Cali-
fornia v. Atlantic Richfield Co., 208 F.3d 989 (Fed. Cir.
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          17
2000), as illustrating that the level of ordinary skill and
predictability in an art inform the written description
inquiry. According to Novozymes, Union Oil demon-
strates that a disclosure is not lacking merely because it
relies on the understanding of an ordinarily skilled read-
er.
    For its part, DuPont defends the district court’s judg-
ment, arguing that the written description requirement
precludes premature claims to a research plan and re-
quires the disclosure of an actual invention. According to
DuPont, Novozymes disclosed in its 2000 application no
more than a theory or a laundry list of potential solutions,
while DuPont performed the hard, inventive work of
actually deriving a useful variant of BSG alpha-amylase.
    Citing In re Ruschig, 379 F.2d 990 (CCPA 1967),
DuPont argues that where a patentee adds claims during
prosecution that, as here, were not included in the origi-
nal priority application, courts require a detailed descrip-
tion and identification of the later-claimed invention in
the original disclosure, particularly where the specifica-
tion discloses numerous possibilities with scant guidance
on which to select. In this case, DuPont points out that
the 2000 application fails to disclose a single alpha-
amylase variant substituted at position 239 that actually
exhibits increased thermostability, noting that the only
disclosed substitution at that position (S239W) disclosed
in the 2000 application does not work as required by the
’723 patent’s claims. DuPont also asserts that the 2000
application’s undifferentiated disclosure was no more
than an “invitation to experiment” that failed to provide
guidance toward the later-claimed solution.
    Additionally, DuPont discounts Union Oil as conflat-
ing the written description requirement with “enablement
reasoning,” an approach that it claims is no longer viable
in view of Ariad. DuPont also distinguishes Union Oil on
the ground that the disclosure in that case taught exactly
18         NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
how to make compositions with the claimed properties,
while the disclosure of the 2000 application offers no
insight as to how any given mutation at any of the dis-
closed amino acid positions would affect the functional
properties of a resulting variant.
    Finally, DuPont accuses Novozymes and its experts of
relying on hindsight to work backward from the claims of
the ’723 patent, filed in 2009, to show that, given
knowledge of the claimed invention, each limitation could
be retroactively derived from the disclosure of the 2000
application.
                       III. Analysis
                        A. Holding
     In view of the record before us, including the disclo-
sure of the 2000 application, we hold that no reasonable
jury could find that the claims of the ’723 patent meet the
written description requirement of § 112, ¶ 1, and that the
district court therefore correctly entered judgment as a
matter of law invalidating those claims. In contrast to the
claims—which narrowly recite specific alpha-amylase
variants that result from mutating a particular parent
enzyme at a single amino acid position to yield distinctive
functional properties—the supporting disclosure of the
2000 application provides only generalized guidance
listing several variables that might, in some combination,
lead to a useful result. Taking the claims as a whole
rather than as the sum of their individual limitations,
nothing in the 2000 application indicates that Novozymes
then possessed what it now claims. Finally, the testimony
of Novozymes’s experts does not overcome the fundamen-
tal deficiencies of the 2000 application’s written descrip-
tion.
                   B. Legal Framework
    Numerous prior decisions addressing the written de-
scription requirement guide our analysis in this case. We
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES          19
have consistently held that, to satisfy § 112, a patent’s
written description “must ‘clearly allow persons of ordi-
nary skill in the art to recognize that [the inventor] in-
vented what is claimed.’” Ariad, 598 F.3d at 1351
(alteration in original) (quoting Vas-Cath, 935 F.2d at
1563). A “mere wish or plan” to obtain the claimed inven-
tion is not sufficient. Regents of the Univ. of Cal., 119
F.3d at 1566.
     We have often applied those fundamental concepts to
hold claims invalid in cases where a patent’s written
description disclosed certain subject matter in terms of a
broad genus but its claims specified a particular sub-
genus or species contained therein. For example, in
Ruschig, our predecessor court affirmed the holding of the
Patent Office Board of Appeals that a claim to a specific
drug molecule, added after filing, lacked sufficient de-
scription in the underlying application, which disclosed
only a generic structure that could yield the claimed
molecule given the proper selections at several variable
positions. 379 F.2d at 993–94. In that case, the applica-
tion’s undifferentiated description was deficient because it
failed to provide sufficient “blaze marks” to guide a reader
through the forest of disclosed possibilities toward the
claimed compound, which resided among the myriad
others that also could have been made. Id. at 994–95.
     We have reached similar conclusions in subsequent
cases. For example, the claims at issue in Boston Scien-
tific required drug-eluting stents incorporating a particu-
lar drug or a “macrocyclic triene analog” of that drug. 647
F.3d at 1367. The supporting written description dis-
closed a broad genus of “analogs” and made passing
reference to the term “macrocyclic triene” but failed to
describe or identify any member of the claimed sub-genus
of macrocyclic triene analogs. Id. Because “nothing in the
[disclosure] indicate[d] that the claimed triene analogs
might be of special interest,” and because the disclosure
did not identify any such analogs or any reliable means
20          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
for divining one, we held that the written description
failed to demonstrate that the inventors were in posses-
sion of the claimed invention. Id. at 1367–69. In Purdue
Pharma, the disputed claims recited an extended-release
drug formulation requiring a certain ratio between the
drug’s maximum blood concentration and its concentra-
tion at twenty-four hours after administration. 230 F.3d
at 1323. The supporting disclosure included seven exam-
ples, two of which could be shown to meet the claimed
ratio limitation by piecing together the disclosed data, but
“neither the text accompanying the examples, nor the
data, nor anything else in the specification in any way
emphasize[d] the [claimed] ratio.” Id. at 1326. According-
ly, we upheld the district court’s conclusion that “one of
ordinary skill in the art would not be directed to the
[claimed] ratio as an aspect of the invention.” Id. Finally,
in University of Rochester, we affirmed a summary judg-
ment of invalidity for lack of written description because
the claimed methods required administering a drug
having a certain, selective activity, but the specification
did not disclose any suitable drugs, and none were known
in the art at the time of filing. 358 F.3d at 927. At most,
the specification provided screening assays for identifying
suitable drug candidates. Id. We therefore held that the
claims failed the written description requirement. We
stated that the disclosure represented no more than a
“wish or plan for obtaining the claimed chemical inven-
tion” and did “not provide any guidance that would steer
the skilled practitioner toward compounds that can be
used to carry out the claimed methods.” Id. at 927, 929.
    On the other hand, in some cases, broad or generic
disclosures can adequately describe particular constituent
species. Thus, in Snitzer, our predecessor court held that
claims requiring a specific laser-active ytterbium ion had
been adequately described in an accompanying disclosure
naming that ion among a group of fourteen individually
enumerated ions that were described as useful separately
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES           21
or in various combinations. The written description
challenge in that case cast the disclosure as speculative
and misleading because several of the fourteen disclosed
ions had proven to be inoperative. 465 F.2d at 902. The
court nonetheless held that the literal description of the
ytterbium ion provided adequate support for claiming
that species, whether or not a larger group containing
several inoperative species was also disclosed. Id. The
court similarly held that certain species claims had been
adequately described in In re Driscoll, 562 F.2d 1245
(CCPA 1977). In that case, the disputed claim recited a
chemical compound having a specific substituent at one of
several variable positions. Id. at 1246. The disclosure
listed a number of possible structures that could be incor-
porated at the position in question, including one option
that ultimately appeared in the claims. Id. at 1249.
Again, the court held that the written description was
sufficient because the particular claimed compound had
been individually described as one of several possibilities.
Id. at 1250.
    In addition, in Union Oil, we affirmed a district
court’s finding that claims to gasoline compositions capa-
ble of reducing tailpipe emissions had adequate written
description support. 208 F.3d at 996–1001. Rather than
reciting a recipe of specific ingredients, the claims in that
case defined the claimed gasoline compositions in terms of
various chemical and physical properties. Id. at 992. The
supporting specification disclosed that the properties
recited in the claims correlated with emission levels, but
the specification did not set forth specific compositions
that would achieve those properties. Id. at 998–99. The
record in the case, however, demonstrated that ordinarily
skilled petroleum refiners would immediately appreciate
that the qualitative chemical properties recited in the
claims translated to specific, manifest compositions that
would yield those properties. In other words, given the
target properties, anyone having ordinary skill in the art
22          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
of petroleum refining would have been able to envision
and readily produce a composition having those character-
istics. The written description thus showed that “the
inventors possessed the claimed invention at the time of
filing in the assessment of those of ordinary skill in the
petroleum refining art.” Id. at 999.
                   C. The Present Case
     Turning to the case at hand, the question before us is
whether the 2000 application demonstrates to one of
ordinary skill in the art that, by the application’s filing
date, Novozymes had invented the particular alpha-
amylase variants that Novozymes claimed almost a
decade later in the ’723 patent. We conclude that it does
not. 5
     As described, claim 1 of the ’723 patent recites an al-
pha-amylase variant that (1) has at least 90% sequence
identity to BSG alpha-amylase, (2) includes an amino acid
substitution at serine 239, and (3) has increased thermo-
stability at pH 4.5, 90°C, and 5 ppm calcium. ’723 patent
col. 87 ll. 40–50. Novozymes is correct that each of those

     5  Novozymes expends considerable effort emphasiz-
ing that the district court submitted the written descrip-
tion issue—an issue of fact—to the jury, which then found
the claims not invalid. Novozymes thus appears to sug-
gest that it was inherently inappropriate for the district
court to overturn a jury verdict concerning the written
description requirement. But a verdict on written de-
scription is no more immune from review than any other
factual issue, and we have in past cases held that the
entry of judgment as a matter of law on written descrip-
tion grounds was appropriate. See, e.g., Centocor, 636
F.3d at 1353 (holding claims invalid for inadequate writ-
ten description and reversing the denial of a post-verdict
motion for judgment as a matter of law); Ariad, 598 F.3d
at 1340 (same).
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES            23
individual limitations is expressly stated in the disclosure
of the 2000 application. Specifically, the 2000 application
(1) lists BSG as one of seven disclosed parent alpha-
amylase enzymes, see ’723 patent col. 3 ll. 1–50;
(2) includes amino acid position 239 among a group of
thirty-three positions that could be mutated to produce a
variant alpha-amylase, see id. col. 7 ll. 36–58; and
(3) states that the disclosed alpha-amylase variants
should function at high temperatures (“especially 85-95°
C”), low pH (“especially 4.5-5”), and at low calcium con-
centrations (“especially 5 ppm calcium”), see id. col. 7 l. 6–
32; col. 16 ll. 42–47.
     The 2000 application, however, contains no disclosure
of any variant that actually satisfies the claims, nor is
there anything to suggest that Novozymes actually pos-
sessed such a variant at the time of filing. First, the bulk
of the specification focuses on using BLA (Termamyl™)
alpha-amylase, rather than BSG alpha-amylase, as the
parent enzyme. BLA alpha-amylase is described as the
“preferred” parent in the 2000 application, see ’723 patent
col. 5 ll. 21–26, and appears in the two disclosed working
examples. 6 BLA alpha-amylase, though, shares only
65.4% sequence identity with BSG alpha-amylase—i.e.,
less than the 90% identity required by the claims. Id.
col. 3 ll. 6–20 (Table 1). In addition, amino acid position
239 is disclosed in the 2000 application as only one among
a list of thirty-three positions that could be altered by

    6    One of the few differences between the written de-
scription of the 2000 application and that of the later-filed
’723 patent is that the 2000 application names only BLA
alpha-amylase as a “preferred” parent enzyme, while
language was added to the ’723 patent denoting BSG
alpha-amylase as another “preferred” option. ’723 patent
col. 21 ll. 47–50; see also Appellants’ Br. 37 n.7 (acknowl-
edging that “[t]he November 2000 Application does not
refer to BSG variants as preferred”).
24         NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
deletion, insertion, or substitution, either alone or in
combination. See id. col. 7 ll. 35–52. And while the bulk
of the disclosure concerns substitutions, the only specifi-
cally described substitution at position 239 is S239W, see
id. col. 8 l. 12, which the parties agree does not confer
increased thermostability in alpha-amylase enzymes and
thus would fall outside of the claims.
     Nevertheless, the 2000 application’s written descrip-
tion might superficially appear to differ from those exem-
plified in cases like Ruschig and Boston Scientific, where
undifferentiated generic disclosures provided no descrip-
tion regarding the particulars of a claimed species, and to
more closely resemble the written description in Snitzer
or Driscoll, where claims to a specific member of a more
broadly disclosed group were upheld because the claimed
species had been literally described. In particular, BSG
alpha-amylase, amino acid position 239, and improved
thermostability—all recited as limitations in the claims of
the ’723 patent—are literally described in the disclosure
of the 2000 application.
     On closer examination, however, such analogies fall
flat. While the 2000 application provides formal textual
support for each individual limitation recited in the
claims of the ’723 patent, it nowhere describes the actual
functioning, thermostable alpha-amylase variants that
those limitations together define. Taking each claim—as
we must—as an integrated whole rather than as a collec-
tion of independent limitations, one searches the 2000
application in vain for the disclosure of even a single
species that falls within the claims or for any “blaze
marks” that would lead an ordinarily skilled investigator
toward such a species among a slew of competing possibil-
ities. “Working backward from a knowledge of [the
claims], that is by hindsight,” Novozymes seeks to derive
written description support from an amalgam of disclo-
sures plucked selectively from the 2000 application.
Ruschig, 379 F.2d at 995. Indeed, Novozymes’ expert, Dr.
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES           25
Arnold, in effect admitted that her testimony suffered
from this flaw when she “point[ed] to [a] part of the claim”
and told the judge she was “going back and finding if
there’s a written description for that” in the specification.
With such an approach “it is all very clear what route one
would travel through the forest of the specification to
arrive at [the claimed invention].” Ruschig, 379 F.2d at
995. However, viewing the matter from the proper van-
tage point “of one with no foreknowledge of the specific
compound,” we agree with the district court that the
particular variants claimed in the ’723 patent lack mean-
ingful support in the written description of the 2000
application. Id.
    Furthermore, while the disclosure of an inoperative
embodiment like the S239W substitution is not necessari-
ly invalidating, see Snitzer, 465 F.2d at 902, the 2000
application lacks any indication that Novozymes had
invented any thermostable alpha-amylase variants sub-
stituted at amino acid position 239 by the time of filing,
much less one specifically produced from a BSG parent.
The specification does provide examples showing that
Novozymes had tested and verified at least some thermo-
stable variants for the sixteen amino acid positions identi-
fied by random mutagenesis, but nothing in the 2000
application demonstrates that it had verified whether any
of the remaining seventeen positions predicted by rational
protein design (including position 239) actually yielded a
thermostable variant. In fact, the 2000 application’s
limited disclosure compels the opposite conclusion—if
Novozymes had possessed a working variant substituted
at position 239, it surely would have disclosed that substi-
tution instead of, or at least along with, the non-
functional S239W substitution in the several pages of the
2000 application devoted to listing exemplary substitu-
tions. See ’723 patent col. 7 l. 40 – col. 16 l. 37.
    In this way, the present case is also distinguishable
from Union Oil, upon which Novozymes relies. Union Oil
26          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
involved claims to gasoline compositions capable of reduc-
ing tailpipe emissions, and the claims defined the compo-
sitions in terms of various chemical and physical
properties. There, the patentee described relationships
linking certain chemical and physical properties of gaso-
line compositions to the compositions’ emissions profiles.
In doing so, the patentee relied on the knowledge of those
skilled in the relevant art to extrapolate the undisclosed,
but claimed, compositions from their recited properties.
In that case, the record indicated that a recitation of
particular physical and chemical properties of a gasoline
composition necessarily conveyed simultaneous posses-
sion of the actual recipe for making that composition
because of the recognized level of standardization and
predictability in mixing various petroleum stocks to
achieve particular properties in the resulting gasoline
products. See Union Oil, 208 F.3d at 999.
     In contrast, one of ordinary skill in the art reading the
2000 application would have understood that Novozymes
had only predicted that at least some mutations at posi-
tion 239 would yield variants with increased thermosta-
bility, not that it possessed or had definitively identified
any mutations that would do so. The parties’ experts
agreed that one could not know which, if any, individual
substitutions at any of the seventeen sites selected by
rational protein design would yield increased thermosta-
bility without actually making and testing the variants.
In fact, DuPont’s later empirical work showed that only
six of the nineteen possible substitutions at position 239
actually conferred increased thermostability. Novozymes
nonetheless maintains that one of ordinary skill in the art
directed to position 239 would have known how to test
every possible variant at that position and thus would
have found the claimed variants as a matter of course.
That argument misses the point, however. The question
before us is not whether one of ordinary skill in the art
presented with the 2000 application would have been
NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES            27
enabled to take those final steps, but whether the 2000
application “discloses the [variants] to him, specifically, as
something appellants actually invented.” Ruschig, 379
F.2d at 995.
    In this case, to actually possess the variant enzymes
claimed in the ’723 patent would have required Novo-
zymes to confirm its predictions by actually making and
testing individual variants or at least identifying sub-
classes of variants that could be expected to possess the
claimed properties, which it did not do before filing the
2000 application. At best, the 2000 application describes
a roadmap for producing candidate alpha-amylase vari-
ants and then determining which might exhibit enhanced
thermostability. A patent, however, “is not a reward for
the search, but compensation for its successful conclu-
sion.” Ariad, 598 F.3d at 1353 (quoting University of
Rochester, 358 F.3d at 930 n.10). For that reason, the
written description requirement prohibits a patentee from
“leaving it to the . . . industry to complete an unfinished
invention.” Id.
    In our view, this case is very analogous to University
of Rochester, where the patent specification failed to
disclose any compounds that could be used in the claimed
methods, which required administering a drug having a
certain selective activity (inhibiting PGHS-2 activity in a
human host). 7 We stated: “[T]he ’850 patent does not
disclose just which peptides, polynucleotides, and small
organic molecules have the desired characteristic of
selectively inhibiting PGHS-2. Without such disclosure,
the claimed methods cannot be said to have been de-

    7   PGHS-2, also known as COX-2, is an enzyme pro-
duced by human cells in response to certain inflammatory
stimuli. PGHS-2 is believed to play an important role in
the inflammation associated with diseases such as arthri-
tis. University of Rochester, 358 F.3d at 917.
28          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
scribed.” 358 F.3d at 927 (citation and internal quotation
marks omitted).
    In sum, we agree with the district court that no rea-
sonable jury could conclude that the 2000 application
provides adequate written description to support the
later-filed claims of the ’723 patent.
                       CONCLUSION
    We have considered Novozymes’s remaining argu-
ments and find them unpersuasive. Accordingly, we
conclude that the claims of the ’723 patent are invalid for
failure to satisfy the written description requirement of
§ 112, ¶ 1. We therefore affirm the district court’s entry of
judgment as a matter of law on that basis.
                       AFFIRMED
                            COSTS
     No costs.
  United States Court of Appeals
      for the Federal Circuit
                  ______________________

    NOVOZYMES A/S, AND NOVOZYMES NORTH
              AMERICA, INC.,
            Plaintiffs-Appellants,

                             v.

DUPONT NUTRITION BIOSCIENCES APS (former-
              ly Danisco A/S),
GENENCOR INTERNATIONAL WISCONSIN, INC.,
  DANISCO US INC., AND DANISCO USA INC.,
            Defendants-Appellees.
           ______________________

                        2012-1433
                  ______________________

   Appeal from the United States District Court for the
Western District of Wisconsin in No. 10-CV-0251, Senior
Judge Barbara B. Crabb.
                ______________________

RADER, Chief Judge, dissenting.
    Although a separate written description requirement,
and the vague notion of “possession” that it embodies, still
troubles me, see Ariad Pharm., Inc. v. Eli Lilly and Co.,
598 F.3d 1336, 1361 (Fed. Cir. 2010) (Rader, J., dissent-
ing-in-part and concurring-in-part), I write today to ask
the court instead to give full attention to the rules that it
has created. The written description inquiry is a question
of fact. Ariad, 598 F.3d at 1351. In this case, a jury
found—in its role as a finder of fact—that the specifica-
2           NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
tion of U.S. Patent No. 7,713,723 (the ’723 patent) satis-
fies the written description requirement. In my judgment,
substantial evidence supports the jury’s verdict, which
deserves significant deference. Therefore, I would re-
spectfully suggest that our written description rules urge
reversing the district court’s post-verdict grant of judg-
ment.
                              I.
    The written description analysis requires an “objec-
tive inquiry into the four corners of the specification from
the perspective of a person of ordinary skill in the art.”
Ariad at 1351. In this field of technology, the level of skill
is high. A skilled artisan would possess an advanced
degree and have experience in sophisticated protein
design and engineering techniques. See J.A. 11242–43.
The jury found as a matter of fact that a skilled artisan
would know to substitute an amino acid as the invention
suggests. Indeed, the patent identifies thirty-three posi-
tions for beneficial mutation on a Termamyl-like alpha-
amylase. In this field, the highly skilled artisan would
find that disclosure more than adequate to direct the
substitution of an amino acid at one of those positions.
The jury made that finding. Substantial evidence sup-
ports that finding.
    The specification of the ’723 patent discusses variants
of Termamyl-like alpha-amylases with altered stability at
“high temperature and/or low pH conditions, in particular
at low calcium concentrations.” ’723 patent col. 1 ll. 30–
33. The specification includes listings for seven different
parent alpha-amylases (including both BSG and BLA),
and explains that variants can be made “comprising an
alteration at one or more positions . . . selected from the
group of [thirty-three positions].” Id. col. 7 ll. 36–43. The
specification teaches that any amino acid can be substi-
tuted at those positions. Id. col. 2 ll. 21–30; see also J.A.
10256–57.
 NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES           3
    The specification also discloses two working examples,
which used random mutagenesis to identify sixteen
positions at which substitutions led to increased thermo-
stability at pH 4.5, 90 ° C and 5 ppm calcium (the claimed
conditions). ’723 patent col. 25–26. The examples all use
BLA as the parent alpha-amylase. Dr. Arnold testified
that the specification fully discloses the tests for deter-
mining activity and thermostability at the claimed condi-
tions. See J.A. 11248 (discussing disclosure in the ’723
patent relating to assays). She also noted that these
procedures were well-known in this field. Id.
     The jury heard expert testimony that “finding the po-
sition where you can make a beneficial mutation is, in
fact, the inventive step,” and that once those positions are
known, the procedure for making the substitutions was
routine and well known, as was the process for determin-
ing which substitutions would result in the desired prop-
erties. See J.A. 11228–48. Novozymes also presented
expert testimony to support its assertion that, while the
specification explains that each alteration may be a
deletion, insertion, or substitution of an amino acid, or a
combination of these, a skilled artisan reading the specifi-
cation would have focused on substitutions. See J.A.
11263–70. Making and testing all nineteen amino acid
substitutions at one position was routine and would only
take one week. J.A. 11251. In other words, a team of ten
scientists could test all thirty-three positions with relative
ease.
    The court states: “the 2000 application disclosed a po-
tentially enormous number of alpha-amylase variants,
encompassing all possible combinations among the seven
disclosed parent enzymes, the thirty-three disclosed
positions for mutations possible at each position, and the
various possible combinations of individual muta-
tions. . . .” Majority Op. at 12. This conclusion overstates
the problem in a way that appeals to a lay audience but is
routine to this field. Novozymes offered expert testimony
4          NOVOZYMES A/S   v. DUPONT NUTRITION BIOSCIENCES
that this calculation, while mathematically correct, is
unrealistic because skilled artisans would not blindly try
random combinations. J.A. 10935–36; see also Snitzer v.
Etzel, 465 F.2d 899, 903 (CCPA 1972) (concluding appel-
lee’s reliance on a theoretical calculation of billions of
possible combinations was “hopelessly exaggerated” when
the specification directed persons of skill in the art to
fourteen ions that could be used “in various combina-
tions”). This court might also have credited the patentee
with reducing the original 500 total amino acid positions
down to a mere thirty-three. J.A. 10936.
                            II.
    In conclusion, the jury received expert testimony,
heard from skilled protein engineers, reviewed visual aids
and publication excerpts, and examined the patent docu-
ment as guided by those skilled in the art, over an eight
day trial. The jury was given a special verdict form
asking whether DuPont had proven by clear and convinc-
ing evidence that the claims at issue were invalid for lack
of written description. J.A. 216. The jury answered in
favor of Novozymes, and substantial evidence supports
this determination. Therefore, I would reverse the grant
of judgment as a matter of law and reinstate the jury’s
verdict.