BUTAMAX ADVANCED BIOFUELS LLCv.GEVO, INC.

Patent Trial and Appeal Board

Mar 3, 2015

13246693 (P.T.A.B. Mar. 3, 2015)

Trials@uspto.gov Paper No. 33
571.272.7822 Filed: March 3, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

BUTAMAX
TM
ADVANCED BIOFUELS LLC,
Petitioner,

v.

GEVO, INC.,
Patent Owner.
____________

Case IPR2013-00539
Patent 8,273,565 B2
____________

Before RAMA G. ELLURU, CHRISTOPHER L. CRUMBLEY, and
KERRY BEGLEY, Administrative Patent Judges.

BEGLEY, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

Butamax
TM
Advanced Biofuels LLC (“Petitioner”) filed a Petition
requesting inter partes review of claims 1–19 of U.S. Patent No. 8,273,565
B2 (Ex. 1001, “the ’565 patent”). Paper 4 (“Pet.”). Pursuant to 35 U.S.C.
§ 314(a), we determined the Petition showed a reasonable likelihood that
Petitioner would prevail in establishing the unpatentability of claims 1–9 and
11–19 of the ’565 patent, and instituted an inter partes review of these
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claims on certain asserted grounds of unpatentability. Paper 9 (“Inst. Dec.”).
We, however, did not institute review of claim 10 of the ’565 patent,
because we determined the Petition did not show a reasonable likelihood that
Petitioner would prevail in establishing the claim to be unpatentable. Id. at
27–29.
Patent Owner Gevo, Inc. (“Patent Owner”) then filed a Patent Owner
Response. Paper 19 (“PO Resp.”). Petitioner filed a Reply to Patent
Owner’s Response. Paper 21 (“Reply”).
An oral hearing was held on October 28, 2014, pursuant to a request
by Petitioner. Paper 32 (“Tr.”); Petitioner Butamax’s Request for Oral
Argument (Paper 23); Order – Trial Hearing (Paper 24), at 1. During the
oral hearing, Petitioner presented argument; Patent Owner rested on its
arguments in the Patent Owner Response. Tr. 40:3–13; see id. at 39:7–
42:18; Order – Conduct of the Proceeding (Paper 25).
We issue this Final Written Decision pursuant to 35 U.S.C. § 318(a)
and 37 C.F.R. § 42.73. For the reasons that follow, we determine Petitioner
has shown by a preponderance of the evidence that claims 1–9 and 11–19 of
the ’565 patent are unpatentable.
I. BACKGROUND
A. THE ’565 PATENT
The ’565 patent, titled “Methods of Increasing Dihydroxy Acid
Dehydratase Activity to Improve Production of Fuels, Chemicals, and
Amino Acids,” is directed to recombinant yeast microorganisms with
increased activity of dihydroxy acid dehydratase (“DHAD”). Ex. 1001,
[57], 1:29–2:25. DHAD is an enzyme that catalyzes steps in various
biosynthetic pathways that produce metabolites, such as isobutanol, a
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common fuel additive. Id. at [57], 1:46–66, Fig. 1. Increased DHAD
activity is favorable for producing these metabolites. Id. at 1:65–2:20,
24:31–33. The patent also discloses methods of producing such metabolites
by cultivating the disclosed recombinant microorganisms in a culture
medium containing a carbon source feedstock. Id. at [57], 8:55–63.
The specification of the ’565 patent discloses recombinant
microorganisms with increased DHAD activity resulting from alterations in
the regulation, expression, or activity of either or both the GRX3 and GRX4
genes, which encode the proteins monothiol glutaredoxin-3 (“Grx3”) and
monothiol glutaredoxin-4 (“Grx4”), respectively. Id. at 24:36–50; see id. at
23:30–57, 24:1–30. For example, in one embodiment, the Grx3 protein, the
Grx4 protein, or both the Grx3 and Grx4 proteins are “deleted or
attenuated.” Id. at 24:9–11. The specification also discloses recombinant
microorganisms with improved DHAD activity resulting from
overexpression of either or both the transcriptional activator genes AFT1 and
AFT2, which encode activator of ferrous transport (“Aft”) proteins, Aft1 and
Aft2, respectively. Id. at 2:9–25, 4:14–26, 15:49–54. The DHAD in these
embodiments may be localized in either the cytosol or the mitochondria of
the microorganisms. Id. at 3:30–46, 16:33–34, 24:36–45. Further, the
recombinant microorganisms may be one of various disclosed yeast genera
and species, including Saccharomyces cerevisiae. See id. at 7:49–8:54.
B. ILLUSTRATIVE CLAIM
Claim 1, the only independent claim of the ’565 patent, is illustrative
of the challenged claims:
1. A recombinant yeast microorganism comprising a
recombinantly overexpressed polynucleotide encoding a
dihydroxy acid dehydratase (DHAD),
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wherein said recombinant yeast microorganism is
engineered to comprise at least one inactivated monothiol
glutaredoxin selected from the group consisting of
monothiol glutaredoxin-3 (GRX3) and monothiol
glutaredoxin-4 (GRX4),
and wherein said inactivated monothiol glutaredoxin results
from the deletion of one or more nucleotides of an
endogenous gene encoding said monothiol glutaredoxin, the
insertion of one or more nucleotides into an endogenous
gene encoding said monothiol glutaredoxin, or combinations
thereof.
Id. at 91:15–26 (line breaks added).
C. INSTITUTED GROUNDS OF UNPATENTABILITY
We instituted inter partes review of the ’565 patent on the following
grounds of unpatentability asserted in the Petition. Inst. Dec. 29.
Claim[s] Basis Reference[s]
1–4, 6–8, and 11–19 § 102(e) Flint
1–4, 6–8, 11, 13, 14,
and 16–19
§ 103(a) Anthony, Puig, and Ojeda
5 § 103(a) Anthony, Puig, Ojeda, and Li
9 § 103(a) Anthony, Puig, Ojeda, and van Maris
These instituted grounds rely on the following prior art references:
Anthony US 2010/0081179 A1 Apr. 1, 2010 Ex. 1005
Li US 2009/0163376 A1 June 25, 2009 Ex. 1015
Flint WO 2011/103300 A2 Aug. 25, 2011 Ex. 1003

Antonius J. A. van Maris et al., Directed Evolution of Pyruvate
Decarboxylase-Negative Saccharomyces cerevisiae, Yielding a C2-
Independent, Glucose-Tolerant, and Pyruvate-Hyperproducing Yeast, 70
APPLIED & ENVTL. MICROBIOLOGY 159 (2004). (Ex. 1008, “van Maris.”)

Sergi Puig et al., Coordinated Remodeling of Cellular Metabolism During
Iron Deficiency Through Targeted mRNA Degradation, 120 CELL 99 (2005).
(Ex. 1006, “Puig.”)

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Luis Ojeda et al., Role of Glutaredoxin-3 and Glutaredoxin-4 in the Iron
Regulation of the Aft1 Transcriptional Activator in Saccharomyces
cerevisiae, 281 J. BIOLOGICAL CHEMISTRY 17661 (2006). (Ex. 1007,
“Ojeda.”)
II. ANALYSIS
A. LEVEL OF ORDINARY SKILL IN THE ART
We begin our analysis by addressing the level of ordinary skill in the
art, which is relevant to the governing standards we apply in the remainder
of our analysis. Petitioner proposes a standard for one of ordinary skill in
the art. Pet. 6; see Ex. 1002 (Decl. of Dennis J. Thiele, Ph.D.) ¶ 17. Patent
Owner has not contested this proposal or proffered an alternative standard.
We adopt Petitioner’s proposed standard and, therefore, determine that one
of ordinary skill in the art would have had either: (1) “a Ph.D. in the life
sciences or a similar related discipline, and . . . familiarity, training, and
experience in molecular biology, microbial genetics and/or microbial
metabolism,” or (2) “a scientific background such as a Bachelor’s degree in
the life sciences (e.g., biology, microbiology, molecular biology or
biochemistry) or a similar related discipline, and . . . substantial familiarity,
training, and experience in molecular biology, microbial genetics and/or
microbial metabolism.” Pet. 6; see Ex. 1002 ¶ 17.
B. CLAIM INTERPRETATION
We next address the meaning of the claims. The Board interprets
claims using the “broadest reasonable construction in light of the
specification of the patent in which [they] appear[].” 37 C.F.R. § 42.100(b);
see In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 WL 448667, at
*5–*8 (Fed. Cir. Feb. 4, 2015). We presume a claim term carries its
“ordinary and customary meaning,” which is “the meaning that the term
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would have to a person of ordinary skill in the art in question” at the time of
the invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
2007). This presumption, however, is rebutted when the patentee acts as a
lexicographer by giving the term a particular meaning in the specification
with “reasonable clarity, deliberateness, and precision.” In re Paulsen, 30
F.3d 1475, 1480 (Fed. Cir. 1994).
1. “INACTIVATED”
Petitioner asserts that “inactivated,” as used in the following limitation
of claim 1, “said recombinant yeast microorganism is engineered to
comprise at least one inactivated monothiol glutaredoxin selected from the
group consisting of monothiol glutaredoxin-3 (GRX3) and monothiol
glutaredoxin-4 (GRX4),” Ex. 1001, 91:17–21 (emphasis added), “should be
construed to mean that the GRX3 and/or GRX4 protein lacks all activity and
excludes GRX3 and/or GRX4 proteins having reduced, attenuated or partial
activities.” Pet. 7. Petitioner supports its argument with statements in an
Examiner-Initiated Interview Summary in the prosecution history of the
’565 patent in which Patent Owner “noted that the meaning of ‘inactivate’ is
to render inactive so that GRX3 and GRX4 protein have no activity thereof,”
and the Patent Examiner “agree[d].” Id. at 7; Ex. 1012, Examiner-Initiated
Interview Summary (May 17, 2012). Patent Owner has not responded to
Petitioner’s assertions regarding the meaning of “inactivated” or proposed a
construction for the term. See generally PO Resp.
The plain and ordinary meaning of “inactivated” is having destroyed
biologic activity; chemically or biologically inert; non-functional. See
Ex. 3005 (The American Heritage Medical Dictionary 402 (Rev. ed. 2007))
(defining “inactivate” as “[t]o render nonfunctional”); Ex. 3006 (Stedman’s
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Medical Dictionary 959 (28th ed., Lippincott Williams & Wilkins 2006))
(defining “inactivate” as “[t]o destroy the biologic activity or the effects of
an agent or substance”); Ex. 3007 (Merriam-Webster’s Collegiate
Dictionary 584 (10th ed. 2000)) (defining “inactivate” as “to make inactive,”
and “inactive” as “chemically” or “biologically inert”); Ex. 3008 (Dictionary
of Science and Technology 1092 (Christopher Morris, ed. 1992)) (defining
“inactivate” as “to render inactive; destroy the activity of”). This customary
meaning, thus, requires a lack of all activity or functionality.
The usage of “inactivated” and related terms in the specification of the
’565 patent neither elucidates the meaning of the term nor indicates any
deviation from its ordinary and customary meaning. Dependent claims 9
and 10 recite the term “inactivate” in a manner similar to “inactivated” in
claim 1: “said recombinant yeast microorganism is further engineered to
inactivate one or more endogenous pyruvate decarboxylase (PDC)”
(claim 9) and “glycerol-3-phosphate dehydrogenase (GPD)” (claim 10).
Ex. 1001, 91:58–65 (emphasis added). These claims, therefore, offer no
further clarity regarding the meaning of the term. Likewise, references to
the term in other portions of the specification do not define or otherwise
explicate its meaning. Upon review of the record, we are not persuaded that
the inventors of the ’565 patent acted as their own lexicographer to alter the
ordinary and customary meaning of the term “inactivated.”
Accordingly, to the extent Petitioner’s proposed construction of
“inactivated” requires a “lack[ of] all activity,” we conclude that it is
consistent with the plain and ordinary meaning of the term as well as its
usage in the ’565 patent specification. Pet. 7. We, however, reject the
remainder of Petitioner’s proffered construction, “exclud[ing] GRX3 and/or
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GRX4 proteins having reduced, attenuated or partial activities,” because it is
directed to the scope of claim 1, rather than the meaning of the term
“inactivated.” Id.
For these reasons, we construed “inactivated” to mean lacking all
activity or functionality in our Decision to Institute. Inst. Dec. 8–10.
Neither party has challenged this construction. See generally PO Resp.;
Reply. Having considered whether this construction should be changed in
light of the evidence introduced during trial, we are not persuaded any
modification is necessary. Therefore, we maintain our construction of
“inactivated” as lacking all activity or functionality.
2. OTHER CLAIM TERMS
Petitioner also proposes a construction for the final limitation of claim
1, asserting that the recited inserted or deleted nucleotides could not occur in
“regulatory regions associated with the endogenous genes.” Pet. 8–11. In
our Decision to Institute, we determined that we need not address
Petitioner’s proposed construction, because whether the inserted or deleted
nucleotides can occur in regulatory regions does not impact Petitioner’s
asserted grounds of unpatentability. Inst. Dec. 10–11. Neither party has
challenged this determination. See Reply 1; see generally PO Resp. Having
considered the issue in light of the evidence adduced during trial, we are not
persuaded that any modification of our determination is necessary.
1

1
The Petition also argues that claim 1 encompasses at least the yeast genera
and species recited in dependent claims 17 and 18, and at least DHAD
localized in either the cytosol or the mitochondria, as recited in dependent
claims 11 and 12, respectively. Pet. 9–10. Although we agreed with
Petitioner in our Decision to Institute, this interpretation is not necessary to
our final decision. See Inst. Dec. 11–12; Pet. 24–25; infra n.5.
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C. INSTITUTED GROUNDS OF UNPATENTABILITY
We turn to the merits of the instituted grounds of unpatentability.
1. ANTICIPATION BY FLINT — CLAIMS 1–4, 6–8, AND 11–19
We begin with the instituted ground asserting that claims 1–4, 6–8,
and 11–19 of the ’565 patent are unpatentable under 35 U.S.C. § 102(e)
2
as
anticipated by Flint. Pet. 12–29; Inst. Dec. 12–18, 29. Flint, PCT
Application No. WO 2011/103300 A2, was filed on February 17, 2011, and
claims priority to U.S. Provisional Application No. 61/305,333 (“’333
provisional” or “Flint ’333 provisional”), filed on February 17, 2010.
Ex. 1003, [10], [22], [30], [43]. Therefore, Flint’s earliest claimed effective
filing date is February 17, 2010.
The ’565 patent was filed on September 27, 2011 as a divisional of
U.S. Application Serial Nos. 13/228,342, filed September 8, 2011, and
12/953,884, filed November 24, 2010. Ex. 1001, [22], [62], 1:9–12. The
’565 patent further claims priority to two provisional applications: U.S.
Provisional Application Serial Nos. 61/350,209 (“’209 provisional”), filed
June 1, 2010, and 61/263,952 (“’952 provisional”), filed November 24,
2009. Id. at [60], 1:12–17.
Thus, Flint—with the benefit of the filing date of the ’333 Flint
provisional (February 17, 2010)—is prior art to the ’565 patent under
§ 102(e) unless the ’565 patent is entitled to the benefit of the filing date of
the ’952 provisional (November 24, 2009). See 35 U.S.C. § 102(e); Pet. 12.

2
The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
Stat. 284 (2011), revised 35 U.S.C. §§ 102–103, effective March 16, 2013.
Because the ’565 patent has an effective filing date before March 16, 2013,
our references and citations to §§ 102–103 in this decision are to their pre-
AIA version.
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Accordingly, in addition to arguing that Flint and the ’333 provisional
disclose each limitation of claims 1–4, 6–8, and 11–19 of the ’565 patent,
the Petition further contends that the ’565 patent claims are not entitled to
the benefit of the filing date of either the ’952 provisional or the
’209 provisional, because neither provides written description support for
claim 1, the sole independent claim, of the ’565 patent. Pet. 12–29.
In the Response, Patent Owner disputes Petitioner’s assertion that
Flint is prior art to the ’565 patent, arguing that the ’565 patent is entitled to
the benefit of the filing date of the ’952 provisional, because both the ’952
and ’209 provisionals provide written description support for the ’565 patent
claims. PO Resp. 2–3, 5–15. Patent Owner, however, does not contest that
Flint and the ’333 provisional disclose each limitation of claims 1–4, 6–8,
and 11–19 of the ’565 patent. See id. at 2–3, 15.
We consider first whether Flint is prior art to the ’565 patent, then
whether Flint’s disclosure is anticipatory.
a. PRIOR ART STATUS OF FLINT
In this inter partes review, Petitioner has the burden of persuasion to
establish unpatentability—including “all issues relating to the status of
[Flint] as prior art,” Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1576–78
(Fed. Cir. 1996)—by a “preponderance of the evidence,” 35 U.S.C. § 316(e).
This burden of persuasion remains with Petitioner, while the burden of
production—the burden to come forward with evidence—shifts between the
parties. See Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327–
29 (Fed. Cir. 2008); Mahurkar, 79 F.3d at 1576–77; Corning Inc. v. DSM IP
Assets B.V., Case IPR2013-00053, slip op. at 6–8 (PTAB May 1, 2014)
(Paper 66) (“[T]hough the patent owner bears the burden of production in
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antedating a reference, the burden of persuasion to prove unpatentability . . .
remains with the petitioner.”). Now, “with all of the evidence from both
sides before [us]”—the burden of production having shifted back and forth
between the parties—Petitioner bears the ultimate burden of persuasion to
establish by a preponderance of the evidence that Flint is prior art to the
’565 patent, including that the ’565 patent is not entitled to the benefit of the
earlier filing date of the ’952 provisional. Tech. Licensing, 545 F.3d at
1327–29; Mahurkar, 79 F.3d at 1578. We determine that Petitioner has met
its burden, as we explain below.
i. Written Description Support for the ’565 Patent Claims in the
’952 and ’209 Provisionals
Petitioner argues that claim 1 of the ’565 patent, along with its
dependent claims, is not entitled to the benefit of the filing date of either the
’952 or ’209 provisional based on a lack of written description support for
the following limitations of the claim:
wherein said recombinant yeast microorganism is
engineered to comprise at least one inactivated monothiol
glutaredoxin selected from the group consisting of
monothiol glutaredoxin-3 (GRX3) and monothiol
glutaredoxin-4 (GRX4),
and wherein said inactivated monothiol glutaredoxin results
from the deletion of one or more nucleotides of an
endogenous gene encoding said monothiol glutaredoxin, the
insertion of one or more nucleotides into an endogenous
gene encoding said monothiol glutaredoxin, or combinations
thereof.
Pet. 12–24; Ex. 1001, 91:15–26. Petitioner, with supporting testimony from
its expert, Dr. Dennis J. Thiele, asserts that the provisionals describe, at best,
only complete deletion of endogenous GRX3 and GRX4 genes. Pet. 17–24;
Ex. 1002 ¶¶ 29–49. According to Petitioner, neither provisional provides
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precise definitions—such as the type, location, or size—of the insertions,
deletions, or insertion and deletions of nucleotides in these genes that would
result in “inactivated” Grx3 and Grx4 proteins. Pet. 17–24; Ex. 1002 ¶¶ 29–
49. Petitioner, therefore, urges that the “’952 and ’209 provisional
applications fail to describe adequately the full scope of the broadly claimed
deletions, insertions, or combinations of deletions and insertions in the
endogenous GRX3 and GRX4 genes” encompassed by claim 1 of the
’565 patent. Pet. 20. In response, Patent Owner “directs [our] attention” to
a list of disclosures in the ’952 and ’209 provisionals, which Patent Owner
argues demonstrates that the inventors were in possession of the full scope
of claimed insertions and deletions of nucleotides in the GRX3 and GRX4
genes as of the filing date of each provisional. PO Resp. 7–15. Patent
Owner also argues that one of ordinary skill would have been familiar with
gene deletions and insertions as techniques for “inactivating a gene” and,
thus, Petitioner’s arguments overlook that it is not necessary to disclose in
detail what was well known in the art. Id. at 13–15.
A claim in a later-filed patent application is entitled to the benefit of
the filing date of an earlier-filed provisional application only if the
provisional application, and all applications in the chain leading back to the
provisional application, satisfy the written description requirement of
35 U.S.C. § 112 for the invention claimed in the later-filed application. New
Railhead Mfg., L.L.C. v. Vermeer Mfg. Co., 298 F.3d 1290, 1294–97 (Fed.
Cir. 2002); see 35 U.S.C. §§ 119(e)(1), 120; Hollmer v. Harari, 681 F.3d
1351, 1355 (Fed. Cir. 2012). This requirement prevents an inventor from
“overreaching” in a later-filed application as to the scope of what was
invented at the time of the earlier-filed application by requiring that the
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invention be described in “such detail that . . . future claims can be
determined to be encompassed within the . . . original creation.” Vas-Cath
Inc. v. Mahurkar, 935 F.2d 1555, 1561 (Fed. Cir. 1991). Specifically, to
satisfy the written description requirement, the disclosure of the earlier-filed
application must “reasonably convey[]” to one of ordinary skill in the art
that, as of the filing date sought, “the inventor had possession” of the subject
matter now claimed. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336,
1351–52 (Fed. Cir. 2010); Vas-Cath, 935 F.2d at 1563–64. The test for
written description, therefore, requires “an objective inquiry into the four
corners of the specification from the perspective of a person of ordinary skill
in the art” to determine whether the specification “show[s] that the inventor
[had] actually invented,” or possessed, each feature now included as a claim
limitation. Ariad Pharm., 598 F.3d at 1351; see New Railhead Mfg., 298
F.3d at 1295.
The Federal Circuit has established specific requirements for written
description of genus claims, i.e., claims encompassing two or more
embodiments, that “use functional language to define the[ir] boundaries.”
Ariad Pharm., 598 F.3d at 1349–50; see Billups-Rothenberg, Inc. v.
Associated Reg’l & Univ. Pathologists, Inc., 642 F.3d 1031, 1037 (Fed. Cir.
2011). Claim 1 of the ’565 patent is a functionally-defined genus claim
because it recites the function, or desired or useful result, of “inactivat[ion]”
of “at least one” Grx3 and Grx4 proteins, and further recites that this
inactivation “results from” any one of a number of different means:
“deletion of one or more nucleotides of an endogenous gene encoding” the
protein, “insertion of one or more nucleotides into an endogenous gene
encoding” the protein, or “combinations thereof.” Ex. 1001, 91:15–26; see
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Tr. 8:6–7, 11:3–4; Billups-Rothenberg, 642 F.3d at 1037; Ariad Pharm., 598
F.3d at 1349–50. We, therefore, must determine whether the ’952 and
’209 provisionals meet the governing standards for written description
support of this genus claim.
Evaluating written description support for genus claims presents the
issue of whether the disclosure in the specification demonstrates that the
inventor had possession of species sufficient to support a claim to the totality
of the functionally-defined genus. Carnegie Mellon Univ. v. Hoffman-La
Roche Inc., 541 F.3d 1115, 1126 (Fed. Cir. 2008); Ariad Pharm., 598 F.3d at
1349–50. To meet the written description requirement for such claims, the
specification must disclose either: (1) “a representative number of species
falling within the scope of the genus,” “precise[ly] defin[ed], such as by
structure, formula, chemical name, physical properties, or other properties,”
or (2) “structural features common to the members of the genus.” Ariad
Pharm., 598 F.3d at 1350; Carnegie Mellon, 541 F.3d at 1122–26; Regents
of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566–69 (Fed. Cir.
1997). A functionally-defined genus claim also can “meet the written
description requirement if a reasonable structure-function correlation is
established, whether by the inventor as described in the specification or
known in the art at the time of the filing date.” AbbVie Deutschland GmbH
& Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1301 (Fed. Cir. 2014);
see Ariad Pharm., 598 F.3d at 1350. These standards are premised on the
basic principle that one of ordinary skill in the art “must be able to ‘visualize
or recognize the identity of the members of the genus’” upon reviewing the
disclosure. Carnegie Mellon, 541 F.3d at 1124 (quoting Eli Lilly, 119 F.3d
at 1569); see Ariad Pharm., 598 F.3d at 1350.
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Here, the disclosures of the ’952 and ’209 provisionals cited by the
parties as relevant to claim 1 of the ’565 patent divide into two categories.
One category includes disclosures regarding inserting or deleting nucleotides
of genes—not specific to the GRX3 or GRX4 gene. Ex. 1010 ¶¶ 67–68, 213,
229, 258–264, 268; Ex. 1011 ¶¶ 73–74, 244, 260, 289–295, 299; see Pet.
20–23; PO Resp. 7–12; Reply 2–4. For example, the ’952 and ’209
provisionals define “engineer” to include “inserting a polynucleotide and/or
polypeptide heterologous to the microorganism and mutating a
polynucleotide and/or polypeptide native to the microorganism.” Ex. 1010
¶ 67; Ex. 1011 ¶ 73 (emphases added). The provisionals, in turn, define
“mutation,” to include, for example, “deletions, or insertions of single or
multiple residues in a polynucleotide,” or “an insertion, or a deletion of part
or all of a gene.” Ex. 1010 ¶ 68; Ex. 1011 ¶ 74 (emphases added). The
provisionals explain that “an engineered or modified microorganism can also
include alteration, disruption, deletion, or knocking-out of a gene or
polynucleotide.” Ex. 1010 ¶ 213; Ex. 1011 ¶ 244 (emphasis added). The
provisionals further refer to “known deletion techniques” and include a
section, titled “Genetic insertions and deletions,” which references known
techniques to “introduce” or “integrat[e]” genes or “nucleic acid
molecule[s]” into yeast and to “remove[]” such “introduced marker genes.”
Ex. 1010 ¶¶ 258–263, 268; Ex. 1011 ¶¶ 289–294, 299.
The other category includes disclosures specifically referring to
deleting, attenuating, or reducing either or both the GRX3 and GRX4 genes.
Ex. 1010 ¶¶ 28, 154–58, claim 56; Ex. 1011 ¶¶ 31, 178, 180–82, claim 56;
see Pet. 17–24; PO Resp. 7–12; Reply 2–4. For example, the
’952 provisional states that the disclosed recombinant microorganism “may
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be engineered to delete and/or attenuate one or more genes selected from the
group consisting of GRX3 and GRX4, or homologs thereof.” Ex. 1010 ¶ 28.
The later-filed ’209 provisional adds that these genes may be reduced,
specifically disclosing that the microorganism “may be engineered to delete,
reduce, and/or attenuate” either or both the GRX3 and GRX4 genes.
Ex. 1011 ¶ 31.
Petitioner, with supporting testimony from Dr. Thiele, takes the
position that one of ordinary skill in the art would understand these
disclosures in the ’952 and ’209 provisionals regarding reduction and
attenuation of the GRX3 and GRX4 genes to accomplish “less than complete
inactivation” of the corresponding protein. Pet. 17–18; Ex. 1002 ¶ 29.
Patent Owner does not dispute this testimony or otherwise address the
meaning of reduction or attenuation to a person of ordinary skill in the art.
See PO Resp. 5–15; Reply 2. We credit Dr. Thiele’s testimony on this point
and, therefore, find that the Grx3 and Grx4 proteins in yeast engineered to
reduce or attenuate either or both GRX3 and GRX4 genes would not be
“inactivated” within the meaning of claim 1 of the ’565 patent. Ex. 1002
¶¶ 29–30; see supra Section II.B.1. Accordingly, the disclosed reduced or
attenuated GRX3 and GRX4 genes do not fall within the scope of claim 1 of
the ’565 patent, and do not provide written description support for the claim.
As to the disclosures in the ’952 and ’209 provisionals regarding
deletion of the GRX3 and GRX4 genes, Petitioner argues that one of ordinary
skill would understand the disclosures directed to deleting either or both the
GRX3 and GRX4 genes “to only encompass, at best, a complete deletion of
the GRX3 and/or GRX4 genes.” Pet. 18–19; Ex. 1002 ¶ 31. Patent Owner
contests Petitioner’s interpretation, citing to the disclosures in the
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provisionals regarding “a deletion of part or all of a gene.” PO Resp. 9–10,
13–14 (emphasis omitted); see Ex. 1010 ¶ 68; Ex. 1011 ¶ 74. We agree with
Patent Owner. Petitioner’s proposed interpretation takes an overly narrow
view of the relevant disclosures that is unjustified in light of other statements
in each provisional. In each, the disclosures that microorganisms may be
“engineered to delete” either or both GRX3 and GRX4 genes (Ex. 1010
¶¶ 28, 158; Ex. 1011 ¶¶ 31, 182 (emphasis added)) ties to the definitions of
“engineer,” which “includes . . . mutati[ons]” (Ex. 1010 ¶ 67; Ex. 1011
¶ 73), and “mutation,” which includes “deletions, or insertions of single or
multiple residues in a polynucleotide,” or “an insertion, or a deletion of part
or all of a gene” (Ex. 1010 ¶ 68; Ex. 1011 ¶ 74). Therefore, based on the
express language of the provisionals, we find that one of ordinary skill in the
art would understand the references to deleting either or both the GRX3 and
GRX4 genes to refer to deleting “all or part” of these genes—more
specifically, both complete gene deletion (deletion of all nucleotides of the
gene) and partial gene deletion (deletion of only a subset of nucleotides of
the gene). Even so, however, the disclosures of the ’952 and ’209
provisionals fall short of the required standards for written description, for
the reasons we explain below.
First, the disclosures in the ’952 and ’209 provisionals do not disclose
a representative number of species falling within the scope of the claimed
genus and, thus, fail to show that the inventors had “conceived and described
sufficient representative species encompassing the breadth of the genus” of
insertions, deletions, and combinations of insertions and deletions in either
or both the GRX3 or GRX4 genes that inactivate the corresponding protein.
AbbVie, 759 F.3d at 1300. Starting with deletions, the ’952 and
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’209 provisionals do reference both complete and partial deletion of the
GRX3 and GRX4 genes, as we noted above. Complete deletion of the GRX3
or GRX4 genes results in non-expression of the corresponding protein,
making the protein “inactive,” as recited in claim 1. See Ex. 1002 ¶¶ 31–32.
Based on the disclosures in the ’952 and ’209 provisionals regarding
“eliminat[ion]” of genes according to “known deletion techniques” and
specifically regarding “delet[ion]” of either or both GRX3 and GRX4 genes,
together with Petitioner’s acknowledgement that complete deletion of the
GRX3 and GRX4 genes was known in the art when the provisionals were
filed, we find that the provisionals sufficiently disclose species involving
complete deletion of the GRX3 gene, the GRX4 gene, and the GRX3 and
GRX4 genes, which fall within the scope of claim 1. See Ex. 1010 ¶¶ 28,
154–158, 268; Ex. 1011 ¶¶ 31, 178–182, 299; Ex. 1002 ¶¶ 31–32, 37, 40–
41; Tr. 10:15–17; see also Butamax(TM) Advanced Biofuels LLC v. Gevo,
Inc., 746 F.3d 1302, 1314–15 (Fed. Cir. 2014) (explaining that patentee may
rely upon information well known in the art for purposes of satisfying
written description requirement).
Unlike complete deletion of the GRX3 and GRX4 genes, the
references to partial deletion of the GRX3 and GRX4 genes in the
provisionals do not “precise[ly] defin[e]” a species falling within the scope
of the claimed genus.
3
Ariad Pharm., 598 F.3d at 1350; see Univ. of
Rochester v. G.D. Searle & Co., 358 F.3d 916, 927 (Fed. Cir. 2004); Eli

3
We note that even if the ’952 and ’209 provisionals described both
complete and partial deletion of the GRX3 and GRX4 genes to inactivate the
respective protein, we still would find that the provisionals do not disclose a
representative number of species falling within the scope of the genus,
because neither provisional discloses insertions, or insertions and deletions
of nucleotides, falling within the scope of claim 1, as we explain below.
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Lilly, 119 F.3d at 1566–69. In contrast to complete gene deletion, not all
partial deletions of a gene result in inactivation of the corresponding protein.
See, e.g., Ex. 1002 ¶¶ 31, 46; Tr. 8:6–13, 10:3–12. Yet, as Dr. Thiele
explains, “other than . . . deletion of the entire gene,” the disclosures in the
’952 and ’209 provisionals “do not provide any description of the type,
location, or size of a deletion in . . . an endogenous GRX3 and/or GRX4
gene that would result in an inactive protein.” Ex. 1002 ¶ 41; see id. ¶¶ 32,
37, 39–40.
Similar to partial deletion of the GRX3 or GRX4 genes, the ’952 and
’209 provisionals also lack disclosures regarding the remaining scope of the
claimed genus. In particular, the provisionals do not include any disclosure
regarding insertions of one or more nucleotides into the GRX3 or GRX4
genes that would inactivate the corresponding protein. See id. ¶ 42.
Likewise absent is any disclosure regarding a combination of insertions and
deletions of one or more nucleotides in the GRX3 or GRX4 genes that would
result in an inactivated protein. See id. ¶¶ 43–44.
Based on the analysis above, the only species falling within the scope
of claim 1 that is defined with any precision in the disclosures of the ’952
and ’209 provisionals is complete deletion of either or both the GRX3 and
GRX4 genes. With this exception, the ’952 and ’209 provisionals make no
reference to which of a multitude of nucleotides can be inserted, deleted, or
inserted and deleted in the GRX3 and GRX4 genes, or the locations where
such alterations can be made, to effect the recited function of inactivating
either or both the Grx3 and Grx4 proteins. See Tr. 10:3–12. Nor do the
provisionals reference that these alterations were known in the art. Generic
disclosures referring to known means to insert or delete nucleotides—not
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specific to the GRX3 or GRX4 genes—are insufficient. See Ex. 1002 ¶¶ 39–
40; Ex. 1010 ¶¶ 67–68, 213, 229, 258–264, 268; Ex. 1011 ¶¶ 73–74, 244,
260, 289–295, 299; see, e.g., Univ. of Rochester, 358 F.3d at 927 (holding
that specification disclosing, inter alia, tests for screening compounds to
identify those that selectively inhibit enzyme lacked written description
support for claimed methods involving administering such compounds
because it “does not disclose just which peptides, polynucleotides, and small
organic molecules have the desired characteristic”) (quotations and citation
omitted). Indeed, other than references to deleting the GRX3 and GRX4
genes, the disclosures do not refer to any goal, purpose, or intention to
inactivate, in any form, Grx3 and Grx4 proteins, making it unclear that
inactivation of these proteins by anything other than complete deletion of the
corresponding gene was even a “wish or plan,” much less in the inventors’
possession. Eli Lilly, 119 F.3d at 1566–67.
The disclosed species—limited to complete deletion of either or both
the GRX3 and GRX4 genes—do not represent adequately the full scope of
the genus recited in claim 1, which also extends to inactivated proteins
resulting from deleting less than all nucleotides, inserting one or more
nucleotides, and combinations of deleting and inserting nucleotides in either
or both genes. As the Federal Circuit explained in AbbVie Deutschland
GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299–300 (Fed.
Cir. 2014), “analogizing the genus to a plot of land,” the “disclosed species
only abide in a corner” of the plot or the genus—leaving undisclosed the
remainder of the vast genus, claiming a variety of alterations to the GRX3
and GRX4 genes that inactivate the respective protein. The disclosed
species, therefore, do “not describe[] the genus sufficiently to show that the
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inventor[s] invented, or had possession of” the wide breadth of the genus.
AbbVie, 759 F.3d at 1299–300.
In addition, the disclosures do not meet the alternative means of
satisfying the written description requirement. The ’952 and ’209
provisionals do not disclose any structural features common to members of
the recited genus. See Ex. 1002 ¶ 38. Similarly, there is no disclosed
correlation between the structure of endogenous GRX3 or GRX4 genes with
one or more inserted, deleted, or inserted and deleted nucleotides and a
resulting function of inactivating the respective protein. See id. ¶¶ 47–48.
Nor does “the record here . . . indicate such an established correlation.”
AbbVie, 759 F.3d at 1301; see Tr. 8:6–9, 8:22–24, 11:1–14. This lack of any
disclosed common structural features, and known or disclosed structure-
function correlation, was not disputed in this case. See generally PO Resp.
In sum, we are persuaded that one of ordinary skill in the art, upon
reading either the ’952 provisional or ’209 provisional, would not be able to
“visualize or recognize” members of the claimed genus with the exception of
complete deletion of either or both the GRX3 and GRX4 genes. See
Ex. 1002 ¶ 47. The evidence in this record demonstrates that the
provisionals do not reasonably convey to one of ordinary skill in the art that,
at the time of filing, the inventors possessed the scope of the genus later
recited in claim 1 of the ’565 patent. See id. ¶ 49. Patent Owner’s
conclusory, unsupported attorney argument asserting the contrary is not
persuasive. See PO Resp. 7–13; Reply 2–4.
We note that even if the disclosures in the ’952 and ’209 provisionals
would have rendered obvious, or enabled one of ordinary skill to make and
use, the full scope of the claimed genus, the disclosures still would be
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insufficient to satisfy the written description requirement. See Novozymes
A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir.
2013); Ariad Pharm., 598 F.3d at 1352, 1356; Eli Lilly, 119 F.3d at 1567.
The written description issue we consider here does not address whether
claim 1 of the ’565 patent is “an obvious variant of that which is disclosed”
in the provisionals. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1571–72
(Fed. Cir. 1997) (holding that “a description which renders obvious the
invention” does not satisfy the written description requirement because
“[o]ne shows that one is in possession of the invention by describing the
invention, with all its claimed limitations, not that which makes it obvious”)
(emphasis, quotations, and citations omitted). Nor do we address whether
“one of ordinary skill in the art presented with the [provisionals] would have
been enabled” to determine, without undue experimentation, nucleotides to
insert, delete, or insert and delete in order to inactivate the Grx3 and Grx4
proteins. Novozymes, 723 F.3d at 1350; see Tr. 9:5–14, 10:21–11:5.
Finally, we are not persuaded by Patent Owner’s contention that
Petitioner’s arguments contradict Federal Circuit precedent holding that the
written description requirement does not require disclosure of what was well
known in the art, because one of ordinary skill would have known various
methods for “inactivating a gene, including: gene deletions (including partial
gene deletions) and gene insertions.” PO Resp. 13–15; see Tr. 41:9–42:8.
We recognize that “[b]ecause the specification is viewed from the
perspective of one of skill, . . . a patentee may rely on information that is
well-known in the art for purposes of meeting the written description
requirement.” Butamax(TM), 746 F.3d at 1314–15 (citation and quotation
omitted)). Yet, Patent Owner merely restates that general techniques for
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deleting or inserting nucleotides in a gene to inactivate the corresponding
protein were known in the art—which is not disputed in this case. See Tr.
9:5–14, 10:13–11:5; Pet. 20–21; Ex. 1002 ¶¶ 38–39. Patent Owner’s
argument is not specific to knowledge of the inventors, or persons of
ordinary skill in the art, with respect to the particular subject matter recited
in claim 1—alterations to the GRX3 and GRX4 genes to inactivate their
respective proteins. See PO Resp. 13–15 (lacking any reference to the GRX3
gene, GRX4 gene, Grx3 protein, or Grx4 protein).
In contrast to the cases on which Patent Owner’s argument relies,
there is no evidence in this case that, with the exception of complete deletion
of either or both the GRX3 and GRX4 genes, the particular subject matter
recited in the relevant limitation of claim 1 was known in the art, or that one
of ordinary skill would have understood from the disclosures in the ’952 and
’209 provisionals that the inventors had possession of this subject matter.
See Capon v. Eshhar, 418 F.3d 1349, 1350–52, 1354–61 (Fed. Cir. 2005)
(reversing decision that specifications of patent and application claiming
chimeric DNA did not meet written description requirement where both
parties presented testimony from “expert witnesses” and “scientific
literature” demonstrating that “nucleotide sequence of claimed DNA . . .
[wa]s already known in the field”); Vas-Cath, 935 F.2d at 1557, 1561–67
(reversing summary judgment determination of insufficient written
description where expert declaration explained that drawing in application
conveyed to one of ordinary skill in the art that inventor had possession of
“claimed range,” and plaintiffs “submitted no technical evidence to refute
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[expert]’s conclusions”).
4
Here, Patent Owner did not put forward the
testimony of any expert, or anyone of ordinary skill in the art. In addition,
Patent Owner did not take the opportunity to depose Dr. Thiele, Petitioner’s
expert. Patent Owner also has not submitted any relevant prior art
references.
In sum, Petitioner presented comprehensive and persuasive expert
testimony and supporting analysis that the disclosures in the ’952 and
’209 provisionals would not have conveyed to one of ordinary skill in the art
that the inventors possessed the claimed scope of alterations to the GRX3
and GRX4 genes. Ex. 1002 ¶¶ 29–49; Pet. 13–24. In response, Patent
Owner has presented no evidence—only attorney argument—regarding what
one of ordinary skill in the art would have known and understood the
disclosures to convey at the time of filing. Patent Owner’s imprecise
attorney argument does not refute Petitioner’s detailed showing, with
evidentiary support.
We find Petitioner has shown by a preponderance of the evidence that
the ’952 and ’209 provisionals do not provide written description support for
independent claim 1 of the ’565 patent.
5
Thus, the provisionals also do not

4
Patent Owner also cites Hybritech Inc. v. Monoclonal Antibodies, Inc., 802
F.2d 1367, 1384 (Fed. Cir. 1986), which involves enablement, not written
description. Nonetheless, we note that there was evidence in that case that
the “monoclonal antibodies used in the invention were known in the art.” Id.
5
We note that we are not persuaded by Petitioner’s two other theories of
lack of written description in the provisionals for claims 12 and 18 and, thus,
claim 1 and other dependent claims. Pet. 24–25. The argument for each
theory is conclusory and not supported sufficiently. E.g., Ex. 1011 ¶¶ 232–
239 (“Mitochondrially Localized DHAD”). Also, neither case Petitioner
cited in the hearing stands for the proposition that if a feature in a dependent
claim (e.g., a species (claim 18), location (claim 12)) lacks written
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meet the written description requirement for claims 2–4, 6–8, and 11–19,
which depend from claim 1. Accordingly, these claims are not entitled to
the benefit of the filing date of either provisional, and have an effective
filing date no earlier than November 24, 2010, making Flint—with the
benefit of the effective filing date of the Flint ’333 provisional, February 17,
2010, see infra Section II.C.1.b—prior art under § 102(e).
b. FLINT’S ANTICIPATORY DISCLOSURE
We now address the anticipatory disclosure of Flint. Patent Owner
does not dispute that Flint is entitled to the benefit of the filing date of the
’333 provisional or that Flint discloses the limitations of the ’565 patent
claims. See PO Resp. 2–3, 15. As we outline below, Petitioner has shown
by a preponderance of the evidence that Flint, and the ’333 provisional,
disclose each limitation of claims 1–4, 6–8, and 11–19 of the ’565 patent
and, thus, that Flint is entitled to the benefit of the filing date of the
’333 provisional for the relevant disclosures.
i. Flint
Flint and the ’333 provisional disclose “increased specific activity of
[DHAD]” in recombinant yeast cells of various genera and species.
Ex. 1003, [57], ¶¶ 3, 12, 25, 103–116, 129; Ex. 1004 ¶¶ 1, 11, 24, 98–111

description, the independent claim and other dependent claims—that do not
recite that feature—also lack support even if the specification describes other
such features (e.g., other species, locations). ICU Med., Inc. v. Alaris Med.
Sys., Inc., 558 F.3d 1368, 1372–79 (Fed. Cir. 2009) (specification described
“only medical valves with spikes”); The Gentry Gallery, Inc. v. The Berkline
Corp., 134 F.3d 1473, 1478–80 (Fed. Cir. 1998) (specification identified
console “as the only possible location for the controls”); Tr. 12:19–14:22.
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(pp. 39–44).
6
The applications explain that the specific activity of DHAD in
these recombinant yeast cells is increased by “delet[ing], mutat[ing],
express[ing], up-regulat[ing], or down-regulat[ing]” Fe-S cluster genes,
including the GRX3 and GRX4 genes. Ex. 1003 ¶ 123, Table 8; Ex. 1004
¶ 163, Table 8; see Ex. 1003 ¶¶ 240–242; Ex. 1004 ¶¶ 154–155. Both
applications also discuss methods of making isobutanol by providing a
recombinant host cell and putting the cell in contact with a fermentable
carbon source substrate. Ex. 1003 ¶ 16; Ex. 1004 ¶ 15.
ii. Flint’s Disclosure of Claims 1–4, 6–8, and 11–19
Flint and the ’333 provisional disclose the subject matter recited in
claim 1. See Pet.26–27; Ex. 1002, 27–30. Specifically, the disclosure in
each application that DHAD may be overexpressed by “over-express[ing]
the recombinant polynucleotide” in a “recombinant host cell” meets the first
limitation of the claim, “[a] recombinant yeast microorganism comprising a
recombinantly overexpressed polynucleotide encoding . . . DHAD.”
Ex. 1003 ¶¶ 3, 113; Ex. 1004 ¶¶ 1, 108 (p. 43); see Ex. 1003 ¶¶ 9, 103–116,
229–233; Ex. 1004 ¶¶ 8, 98–111 (pp. 39–44), 144–148. Flint and the ’333
provisional disclose the remaining limitations of claim 1, regarding
inactivated Grx3 and Grx4 proteins resulting from insertions, deletions, or
insertions and deletions in the corresponding endogenous gene, based on the
discussion in each application of “delet[ion]” of Fe-S cluster genes—
particularly the GRX3 and GRX4 genes. Ex. 1003 ¶¶ 123, 237–242, Tables
8, 10; Ex. 1004 ¶¶ 152–155, 163, Tables 8, 10. Deleting the GRX3 or GRX4

6
Certain paragraph numbers in Exhibit 1004, the Flint ’333 provisional,
repeat. Therefore, we include page numbers, in addition to paragraph
numbers, as necessary.
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gene results in inactivation of the respective protein, as recited in claim 1.
Ex. 1002 ¶ 57.
The additional limitations of claims 2–4 and 6–8, reciting an
“isobutanol producing metabolic pathway” with enzymes catalyzing steps of
the pathway, also are found in Flint and the ’333 provisional. See Pet. 27;
Ex. 1002, 30–35. Specifically, both applications discuss an “isobutanol
biosynthetic pathway,” as recited in claim 2, that includes the conversion of:
(a) “pyruvate to acetolactate,” as catalyzed by “acetolactate synthase”
(claim 3); (b) “acetolactate to 2,3-dihydroxyisovalerate,” as catalyzed by
“acetohydroxy acid isomeroreductase,” which Dr. Thiele explains is a ketol-
acid reductoisomerase (claim 4); (c) “2,3-dihydroxyisovalerate to α-
ketoisovalerate,” as catalyzed by DHAD; (d) “α-ketoisovalerate to
isobutyraldehyde,” as catalyzed by “branched-chain α-keto acid
decarboxylase,” which Dr. Thiele explains is a 2-keto acid decarboxylase
(claim 6), and (e) “isobutyraldehyde to isobutanol,” as catalyzed by a
branched-chain alcohol dehydrogenase (claim 7). Ex. 1003 ¶¶ 138–145; Ex.
1004 ¶¶ 111–118 (pp. 60–61). In addition, Flint and the ’333 application
incorporate by reference U.S. Patent Application Publication No.
2007/0092957 A1, which discloses branched-chain alcohol dehydrogenases
utilizing NADH, thereby disclosing the additional limitation of claim 8 that
the “alcohol dehydrogenase” of step (e) be “NADH-dependent.” Ex. 1003
¶¶ 143–145; Ex. 1004 ¶¶ 116–118 (p. 61); Ex. 1018 ¶ 88; Ex. 1002, 34–35;
see Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 1382 n.3 (Fed.
Cir. 2007) (explaining that “material [that] is incorporated by reference” in a
prior art reference “may . . . be considered for purposes of anticipation”).
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Flint and the ’333 provisional also disclose that the DHAD may be in
the locations in recombinant yeast and from the bacterium recited in
claims 11–14. See Pet. 27–28; Ex. 1002, 35–36. Specifically, Flint and the
’333 provisional explain that in some embodiments, the DHAD is
“expressed in the cytosol,” as recited in claim 11. Ex. 1003 ¶¶ 13, 25, 118;
Ex. 1004 ¶¶ 12, 24, 113 (p. 45). In addition, the DHAD in Flint and the
’333 provisional is expressed in the mitochondria—as recited in claim 12.
See Ex. 1003 ¶ 6; Ex. 1004 ¶ 4; Ex. 1002, 35; Tr. 5:10–6:2. In particular,
Flint and the ’333 provisional explain that DHAD natively is located in the
mitochondria, and do not refer to removing the mitochondrial targeting
sequence for DHAD that directs its transport to the mitochondria. Ex. 1003
¶ 6; Ex. 1004 ¶ 4; Ex. 1002, 35; Tr. 5:10–6:2; see generally Exs. 1003, 1004.
Likewise, both applications explain that the DHAD may be from
“Lactococccus lactis” and “S. mutans,” i.e., Streptococcus mutans, thereby
disclosing the additional limitations of claims 13 and 14, respectively. Ex.
1003 ¶¶ 97, 99, 229–233, Table 4b; Ex. 1004 ¶¶ 93–94, 144–148, Table 4b.
In addition, Flint and the ’333 provisional disclose the additional
limitations of claims 15 and 16 that the yeast recited in claim 1 is “further
engineered to comprise increased expression of one or more polynucleotides
encoding one or more . . . Aft[] proteins” and “to express one or more
polynucleotides encoding one or more constitutively active . . . Aft[]
proteins,” respectively. See Pet. 27–28; Ex. 1002, 36–38. Specifically, Flint
and the ’333 provisional discuss “upregulat[ing]” the AFT1 and AFT2 gene,
as well as AFT1 and AFT2 being “co-expressed” with DHAD. Ex. 1003
¶¶ 123, 130, Table 8; Ex. 1004 ¶¶ 103 (p. 57), 163; Table 8. The
applications also disclose “expression” of the “constitutive mutant[s],”
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“AFT1 L99A, AFT1 L102A, AFT1 C291F, AFT1 C293F.” Ex. 1003
¶¶ 130, 246; Ex 1004 ¶¶ 103, 158; see Ex. 1003 ¶¶ 243–246; Ex. 1004
¶¶ 156–161.
Flint and the ’333 provisional also explain that the disclosed
recombinant yeast microorganism may be the yeast genera and species
recited in claims 17 and 18. See Pet. 28; Ex. 1002, 38–39. Specifically,
both applications state that the yeast strain used in the disclosed invention
can be one of the following genera recited in claim 17, Saccharomyces,
Schizosaccharomyces, Hansenula, Candida, Kluyveromyces, Yarrowia,
Issatchenkia, and Pichia, and one of the following species recited in
claim 18, Saccharomyces cerevisiae, Kluyveromyces thermotolerans,
Candida glabrata, Pichia stipitis, and Yarrowia lipolytica. Ex. 1003 ¶¶ 12,
25, 108, 129; Ex. 1004 ¶¶ 11, 24, 103 (p. 40).
Finally, Flint and the ’333 provisional disclose the “method of
producing isobutanol” recited in claim 19. See Pet. 28–29; Ex. 1002, 39–40.
In particular, the applications disclose “methods of making isobutanol” by
putting the disclosed recombinant host cell in contact with a “fermentable
carbon substrate in a fermentation medium,” with “carbon substrates,” and
“recovering” the isobutanol. Ex. 1003 ¶¶ 16, 150; Ex. 1004 ¶¶ 15, 121; see
Ex. 1003 ¶¶ 159, 163; Ex. 1004 ¶¶ 130, 134; Ex. 1002, 39–40.
Accordingly, the disclosures of both Flint and the ’333 provisional
encompass claims 1–4, 6–8, and 11–19 of the ’565 patent.
c. CONCLUSION
In conclusion, having considered the arguments and evidence of
record, we find Petitioner has shown by a preponderance of the evidence that
claims 1–4, 6–8, and 11–19 of the ’565 patent are anticipated by Flint.
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2. OBVIOUSNESS GROUNDS
We turn to the instituted obviousness grounds, which allege that
claims 1–9, 11, 13, 14, and 16–19 would have been obvious as of November
24, 2009, the earliest claimed effective filing date of the ’565 patent. Inst.
Dec. 19–29; Pet. 29–47; see Pet. 30 (explaining knowledge in the art “[a]s of
the earliest asserted priority date of November 24, 2009”); Ex. 1002 ¶¶ 66,
80 (“[a]s of November 24, 2009”).
7
We start by addressing the prior art
status of the relevant references. Petitioner asserts, and Patent Owner does
not dispute, that Anthony, Puig, Ojeda, Li, and van Maris are prior art to the
’565 patent, regardless of whether the patent is entitled to the benefit of the
filing date of the ’952 or ’209 provisionals. See Pet. 29–30 & n.5, 47–48 &
n.8. We agree. See Inst. Dec. 19.
We consider each of the instituted obviousness grounds in turn.
a. ANTHONY, PUIG, AND OJEDA — CLAIMS 1–4, 6–8, 11, 13, 14, AND 16–19
We first address the instituted ground challenging claims 1–4, 6–8,
11, 13, 14, and 16–19 of the ’565 patent as unpatentable under 35 U.S.C.
§ 103 over Anthony, Puig, and Ojeda. Pet. 29–47.
i. Independent Claim 1
We focus our discussion on independent claim 1, the center of the
parties’ dispute. Petitioner argues that based on the combined teachings of
Anthony, Puig, and Ojeda, it would have been obvious to a person of
ordinary skill in the art to delete the GRX3 gene, the GRX4 gene, or both the

7
Because Petitioner has argued and established obviousness as of
November 24, 2009, the earliest claimed effective filing date of the
’565 patent, our obviousness determination is not contingent on our
determination that the ’565 patent is entitled to an effective filing date no
earlier than November 24, 2010. See supra Section II.C.1.a.i.
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GRX3 and the GRX4 gene, thereby inactivating the respective protein or
proteins, in a recombinant yeast recombinantly overexpressing DHAD. See
id. at 34–39; Ex. 1002 ¶¶ 73–81. For the reasons explained below, we
conclude Petitioner has shown by a preponderance of the evidence that
claim 1 would have been obvious because, based on the knowledge of one of
ordinary skill in the art and the teachings of Anthony, Puig, and Ojeda, it
would have been obvious to inactivate both the Grx3 and Grx4 proteins by
deletion of their respective genes in a recombinant yeast overexpressing
DHAD. Because this conclusion is sufficient to render claim 1 obvious, we
need not and do not reach the issue of whether it would have been obvious to
delete only either the GRX3 gene or the GRX4 gene. See KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 419 (2006) (“If the claim extends to what is
obvious, it is invalid under § 103.”); Allergan, Inc. v. Apotex Inc., 754 F.3d
952, 963 (Fed. Cir. 2014) (holding that party challenging patent “had the
burden of showing that any compounds within the broad genus claimed by
the . . . patent . . . were obvious at the time of the invention”).
(a) The Prior Art’s Teaching of the Claim Limitations
Turning to the prior art’s teachings, Petitioner argues that Anthony
teaches the first limitation of claim 1, which recites: “[a] recombinant yeast
microorganism comprising a recombinantly overexpressed polynucleotide
encoding a dihydroxy acid dehydratase (DHAD).” Ex. 1001, 91:15–17; Pet.
35; Ex. 1002 ¶ 75. Patent Owner does not counter this assertion. See PO
Resp. 15–16; see generally id. We agree with Petitioner and find that
Anthony’s disclosure of a “recombinant yeast cell[] engineered” to increase
activity of an expressed heterologous DHAD protein teaches this limitation.
Ex. 1005 ¶¶ 38, 74–75; see id. ¶¶ 6, 13; Ex. 1002 ¶ 75.
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Petitioner relies on Ojeda for the remaining limitations of claim 1.
See Pet. 39; Ex. 1002 ¶ 81. Patent Owner does not contest that Ojeda
teaches or suggests the limitations. See PO Resp. 20–22; see generally id.
We find that Ojeda teaches the remaining limitations based on its disclosure
of yeast in which both Grx3 and Grx4 proteins are inactivated as a result of
deletion of their respective genes. See Ex. 1007, 17662, Table 1 (explaining
∆grx3∆grx4 yeast strains, in addition to ∆grx3 and ∆grx4 yeast strains, used
in the disclosed study); id. at 17663, Fig. 1 (discussing “lack[]” or “absence
of Grx3 and Grx4 proteins” in ∆grx3∆grx4 yeast cells, as well as absence of
Grx3 protein in ∆grx3 yeast cells and Grx4 protein in ∆grx4 yeast cells).
(b) Reason to Combine
Petitioner argues that one of ordinary skill would have had reason to
combine these teachings of Anthony and Ojeda, along with the teachings of
a third reference, Puig, to reach the recombinant yeast recited in claim 1.
See Pet. 34–39; Ex. 1002 ¶¶ 66–81. Patent Owner disputes this assertion.
See PO Resp. 15–22.
To start, Petitioner has established that Anthony, Puig, and Ojeda are
in the same field with interrelated teachings, given that each of the
references relates to altered expression of Fe-S cluster proteins in yeast,
specifically Saccharomyces cerevisiae. See Pet 34–39; Ex. 1002 ¶¶ 74–81;
Ex. 1005, [57], ¶¶ 38, 74–76; Ex. 1006, 99, 101; Ex. 1007, 17661, 17667.
Likewise, Petitioner, with supporting testimony from Dr. Thiele, has shown
that one of ordinary skill in the art would have wanted to increase the
specific activity of one Fe-S cluster protein, DHAD—a goal on which both
“industry and academia focused a great deal of attention.” Pet. 34, 38;
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Ex. 1002 ¶¶ 72, 80. With this goal in mind, we turn to the teachings of
Anthony, Puig, and Ojeda.
(1) Anthony
Anthony, as the parties agree, explains a reason for the focus on
increased DHAD activity, namely that increased activity of DHAD—which
catalyzes a step in biosynthetic pathways producing isobutanol—increases
isobutanol production in yeast containing such a pathway. Ex. 1005, [57],
¶¶ 3, 38, 112–119; Ex. 1002 ¶ 75; Pet 35; PO Resp. 15. Further, Anthony
discloses that increased activity of expressed heterologous Fe-S cluster
proteins, including DHAD, results from “reduced expression” of at least one
endogenous Fe-S cluster protein—a teaching the parties also agree upon.
Ex. 1005, [57], ¶¶ 13, 38, 74–77; Ex. 1002 ¶¶ 75–77; Pet. 35; PO Resp. 15.
In particular, Anthony reports that heterologous DHAD expression improved
with inactivation of either the endogenous gene encoding DHAD (ILV3), or
isopropylmalate isomerase (or dehydratase) (LEU1). Ex. 1005 ¶ 74.
Anthony discloses other exemplary endogenous Fe-S cluster proteins, along
with their encoding genes, that may be targets for reduced expression, such
as aconitase (ACO1), lipoate synthase (LIPS), succinate dehydrogenase
(SDH2), ubiquinol-cytochrome-c reductase (RIP1), and ABC protein Rli1
(RLI1). Id. ¶¶ 9, 77; Ex. 1002 ¶ 79; Pet. 36. Anthony’s disclosure also
includes exemplary ways to reduce expression of such Fe-S cluster proteins,
including “gene disruption, deletion or inactivation.” Ex. 1005 ¶ 53; see id.
¶¶ 77–97; Ex. 1002 ¶ 77; Pet. 36.
We credit and are persuaded by Dr. Thiele’s testimony that one of
ordinary skill in the art, reading Anthony with the goal of increasing
isobutanol production by increasing DHAD activity, would have considered
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alternative, known means to reduce expression of endogenous Fe-S proteins
other than these exemplary techniques disclosed in Anthony. Ex. 1002
¶¶ 77–78, 80; Pet. 36–37. Dr. Thiele explains that a reason for considering
alternative techniques is that one of ordinary skill would have understood
that individually deleting genes encoding Fe-S proteins, as disclosed in
Anthony, “would have potentially negative implications on cell growth and
yield.” Ex. 1002 ¶ 78; Pet. 37.
(2) Puig
Puig teaches one such alternative technique for reducing the
expression of endogenous Fe-S cluster proteins. Specifically, Puig discloses
that the Cth2 protein in yeast downregulates specific mRNAs of certain
genes encoding Fe-S cluster proteins—including many Fe-S cluster proteins
Anthony explicitly lists as targets for reduced expression, such as the ILV3
gene encoding DHAD, as well as the LEU1, ACO1, LIPS, SDH2, RIP1, and
RLI1 genes. Ex. 1006, 99, 101, 107, Table 1; see Ex. 1005 ¶¶ 9, 77;
Ex. 1002 ¶ 79; Pet. 37, 45; PO Resp. 17–19. Puig explains that this
downregulation occurs because the Cth2 protein binds to, and targets for
degradation, AU-rich elements (“AREs”) in the three-prime untranslated
region (“3’UTR”) of specific mRNAs. Ex. 1006, 99, 104, 107; Ex. 1002
¶ 102; Reply 10. Puig also lists putative AREs of genes downregulated by
the Cth2 protein, including the ILV3 gene. Ex. 1006, Table 1; Reply 10.
In addition, as Petitioner and Patent Owner agree, Puig explains that it
was known in the art that Aft1 and Aft2 induce expression of the iron
regulon, a collection of genes, including the CTH2 gene that encodes the
Cth2 protein. Ex. 1006, 99 (“[C]ells utilize . . . Aft1 and Aft2 to induce
expression of the so-called iron regulon . . . .”); id. at 100–01, Fig. 2;
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Ex. 1002 ¶¶ 69, 79–80; Pet. 37; PO Rep. 16–19 (“On its face, Puig teaches
that Aft1 and Aft2 . . induce expression of the iron regulon, including
Cth2.”); see also Ex. 1007, 17661 (“Aft1 and Aft2 . . . induce expression of
more than 20 genes that are referred to as the iron regulon . . . .”); id. at
17663, Table 2 (identifying the CTH2 gene as an “iron regulon gene[]”).
Petitioner, with supporting testimony from Dr. Thiele, has established
that one of ordinary skill would understand that Puig’s teaching regarding
the Cth2 protein downregulating genes encoding Fe-S cluster proteins is
directed to endogenous Fe-S cluster proteins encoded by endogenous
genes—not recombinant Fe-S cluster proteins encoded by a recombinant
gene using well-known techniques for recombinant protein expression.
Ex. 1002 ¶¶ 80, 100–105; Pet. 38, 45–47; Reply 7–10. As Dr. Thiele
explains, in “standard techniques for recombinant protein expression,” a
recombinant Fe-S cluster protein is “encoded by an mRNA that lacks an
endogenous 3’-untranslated region”—which Puig discloses is the location at
which the Cth2 protein targets and binds mRNA. Ex. 1002 ¶ 103; Ex. 1006,
99, 104, 107; see Ex. 1006, 109 (discussing cloning a gene “sequence with
no 3’UTR”). Accordingly, one of ordinary skill would have understood that
the Cth2 protein would not downregulate recombinant Fe-S cluster genes
lacking the 3’UTR to which the Cth2 protein binds and targets for
degradation. Ex. 1002 ¶¶ 80, 103. As a result, one of ordinary skill would
have expected that expression of the Cth2 protein would lower levels and
activity of endogenous Fe-S cluster proteins—encoded by endogenous
mRNAs with the 3’UTR that the Cth2 protein degrades—but would increase
levels and activity of recombinant Fe-S cluster proteins—encoded by
recombinant mRNAs lacking the 3’UTR that the Cth2 protein degrades—as
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a result of less competition with endogenous Fe-S cluster proteins for Fe-S
binding. Id. ¶¶ 80, 102–104. In sum, one of ordinary skill would have
recognized that Cth2 protein expression would be a means to increase the
number and activity of recombinant Fe-S cluster proteins, including DHAD.
Id. ¶¶ 80, 102–104.
Accordingly, based on the teachings of Anthony and Puig, one of
ordinary skill in the art would have been motivated to recombinantly express
DHAD, encoded by mRNA lacking the 3’UTR, and to induce expression of
the Cth2 protein, including by activating Aft1 and Aft2. See Ex. 1002
¶¶ 77–80; Pet. 38–39; Reply 7–8.
(3) Ojeda
Ojeda, in turn, reports data confirming that iron regulon genes—
including CTH2—are “fully induced” and show “constitutive expression” in
yeast as a result of the “absence of Grx3 and Grx4 proteins” when their
respective genes are deleted. Ex. 1007, 17661–63, Table 1; id. at 17662
(“The induced expression of iron regulon genes . . . was due to the absence
of Grx3 and Grx4 . . . .”); id. at Table 2 (listing data for “iron regulon
genes”—including CTH2—“document[ing] that the iron regulon genes are
induced in ∆grx3∆grx4 cells”); id. at 17667–68 (“[T]he iron regulon genes
are . . . fully induced in the absence of both [Grx3 and Grx4] proteins.”);
Pet. 39; Ex. 1002 ¶ 81. In addition, Ojeda’s data show that Aft1 is “fully” or
“constitutively active” in yeast lacking the Grx3 and Grx4 proteins, and
suggest corresponding activity for Aft2. Ex. 1007, Fig. 1 (“Aft1 is . . . fully
activated in cells lacking both glutaredoxins.”); id. at 17663, 17664
(“[D]epletion of Grx3 and Grx4 resulted in constitutive Aft1 activity . . . .”);
Pet. 39; Ex. 1002 ¶ 81.
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(4) Combination of Anthony, Puig, and Ojeda
Based on the teachings of Anthony, Puig, and Ojeda and the
knowledge in the art discussed above, we conclude Petitioner has
demonstrated that one of ordinary skill would have been motivated to create
the yeast recited in claim 1, and would have had a reasonable expectation of
success in doing so, by inactivating Grx3 and Grx4 proteins through deletion
of the endogenous GRX3 and GRX4 genes—as taught by Ojeda—in a yeast
recombinantly overexpressing DHAD—as taught by Anthony. Specifically,
one of ordinary skill, wanting to increase DHAD activity and ultimately
isobutanol production, would have had reason to combine Anthony’s
teaching that in recombinant yeast, increased activity of expressed
heterologous DHAD results from reduced expression of one or more
endogenous Fe-S cluster proteins; with Puig’s teaching that reduced
expression of certain genes encoding endogenous Fe-S cluster proteins is
caused by the Cth2 protein, whose expression is induced by Aft1 and Aft2;
and Ojeda’s teaching that the CTH2 gene is induced, and Aft is activated, in
cells lacking the Grx3 and Grx4 protein as a result of gene deletion. See
Ex. 1002 ¶ 81; Pet. 39; Reply 8. Given these “interrelated teachings” of
Anthony, Puig, and Ojeda and the “background knowledge” and motivations
of one of ordinary skill in the art, we determine that there was sound reason,
with “rational underpinning,” to combine elements known in the art in the
manner recited in claim 1. See KSR, 550 U.S. at 418.
We, therefore, disagree with Patent Owner’s assertion that Petitioner
“impermissibly forecasts” that one of ordinary skill would have considered
alternative means to reduce expression of endogenous Fe-S cluster proteins
beyond that disclosed in Anthony, and that Petitioner has not proffered a
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“salient rationale” to look to Ojeda to cure the failure of both Anthony and
Puig to disclose inactivated Grx3 and Grx4 proteins. PO Resp. 16, 20.
Patent Owner’s attorney argument provides no reliable evidence to dispute
Petitioner’s proposed combination, which is supported by the interrelated
teachings of the references as well as the testimony of Dr. Thiele.
Patent Owner’s other arguments disputing the combination of
Anthony, Puig, and Ojeda also are not convincing. Patent Owner contends
that Anthony does not provide sufficient direction regarding which
endogenous Fe-S cluster protein’s expression should be reduced to increase
the activity of DHAD, and neither Anthony nor Puig teaches or suggests
inactivating Grx3 or Grx4 proteins. Id. at 15–17. This attack on Anthony
and Puig individually, however, does not support Patent Owner’s
nonobviousness arguments because Ojeda—not Anthony or Puig—provides
the relevant teaching regarding inactivating Grx3 and Grx4 proteins, as we
found above. See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986)
(“Non-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references.”); Reply 5–8; see also Banner Eng’g Corp. v.
Tri-Tronics Co., Nos. 93-1115, 93-1116, 93-1158, 1993 WL 432383, at *3
(Fed. Cir. Oct. 27, 1993) (holding that a party’s “attack on the prior art—
reference by reference—[wa]s not persuasive” because in assessing
obviousness, “references are read not in isolation but for what they fairly
teach in combination”). Further, we are not persuaded by Patent Owner’s
more general argument that Anthony lacks direction as to which endogenous
Fe-S cluster protein should be targeted for reduced expression to increase
DHAD activity. See PO Resp. 16. As discussed above, Anthony provides a
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list of exemplary Fe-S cluster proteins that may be targets for reduced
expression and specifically reports that heterologous DHAD expression
improved with reduced expression of either of two specific endogenous
genes: (1) the ILV3 gene encoding DHAD, or (2) the LEU1 gene encoding
isopropylmalate isomerase (or dehydratase). Ex. 1005 ¶¶ 74–77; Reply 6–7.
(c) Alleged Teaching Away
Patent Owner also counters Petitioner’s obviousness arguments by
asserting that both Puig and Ojeda teach away from overexpression of
DHAD and inactivation of either or both the Grx3 and Grx4 proteins, as
recited in claim 1. PO Resp. 16–22. Specifically, as to Puig, Patent Owner
agrees with Petitioner that Puig discloses that the Cth2 protein, whose
expression is induced by activated Aft, downregulates genes encoding Fe-S
cluster proteins. Id. at 16–19. According to Patent Owner, however,
because heterologous DHAD is an Fe-S cluster protein and Puig does not
provide any teaching distinguishing the binding of the Cth2 protein to
endogenous versus heterologous DHAD mRNA, Puig teaches one of
ordinary skill that induced expression of the Cth2 protein decreases the
production of heterologous DHAD. Id. Patent Owner further argues that we
should disregard Dr. Thiele’s opinion that one of ordinary skill, reading
Puig, would have understood that the Cth2 protein would degrade
endogenous DHAD—but not recombinant DHAD expressed using standard
techniques—because Dr. Thiele does not cite scientific literature or data for
this point, which is “contrary to the plain teachings of Puig.” Id. at 19; see
id. at 17–18. Instead, according to Patent Owner, “the teachings of Puig
must be taken on their face.” Id. at 19.
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Similarly, Patent Owner argues that Ojeda “explicitly teaches away”
from deriving the yeast recited in claim 1 based on the following statements.
Id. at 20. First, Ojeda explains that the enzymatic activity of aconitase,
sulfite reductase, and isopropylmalate isomerase was “decreased” or
“depressed” in yeast lacking both the Grx3 and Grx4 proteins, but was
“normal” or “wild type” in yeast lacking either the Grx3 or Grx4 protein.
Ex. 1007, 17667; see PO Resp. 20. Second, Ojeda reports that other Fe-S
cluster enzymes similarly were “unaffected” in yeast lacking either the Grx3
or the Grx4 protein. Ex. 1007, 17668; PO Resp. 20–21. Patent Owner
argues that one of ordinary skill would have expected that inactivating either
or both the Grx3 and Grx4 proteins would impact the activity of DHAD, an
Fe-S cluster enzyme, in a manner similar to the Fe-S cluster enzymes
reported in Ojeda and, therefore, would have been dissuaded from doing so.
See PO Resp. 20–21.
In reply, Petitioner argues that Patent Owner’s teaching away
argument—supported only by attorney argument—“fundamentally
misunderstands and misapplies the knowledge and routine practice of a
skilled practitioner in the field of eukaryotic recombinant gene expression,”
particularly with respect to endogenous versus recombinant Fe-S cluster
proteins. Reply 12; see id. at 8; Ex. 1002 ¶¶ 101, 105; Pet. 45. Petitioner
reiterates Dr. Thiele’s opinion and argues that it is substantiated by the prior
art, including Puig, as well as the knowledge and common practice in the
field. Reply 9–10. Further, Petitioner asserts that Patent Owner’s attempt to
limit the knowledge of one of ordinary skill to “the four corners of a
reference” is contrary to Supreme Court precedent in KSR. Id. at 10–11.
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We first note that Puig and Ojeda are each silent as to whether the
Fe-S cluster genes and proteins being discussed are endogenous or
recombinant. See generally Ex. 1006; Ex. 1007. Therefore, Petitioner’s
position, with supporting testimony from Dr. Thiele, that one of ordinary
skill would understand Puig and Ojeda to be referring to endogenous Fe-S
cluster genes and proteins and would know that recombinant Fe-S cluster
genes and proteins, encoded using standard techniques for recombinant
protein expression, would behave differently is not “contrary to the plain
teachings” of the references—as Patent Owner contends. PO Resp. 19.
Instead, Dr. Thiele’s testimony merely explains how one of ordinary skill in
the art would understand and interpret the teachings of the references. See
Ex. 1002 ¶¶ 80, 100–105; Reply 9–13.
Further, we agree with Petitioner that Patent Owner’s suggestion to
take the references “on their face” is contrary to controlling precedent. PO
Resp. 16–22; see Reply 10–11. The Supreme Court, in KSR, “required an
analysis that reads the prior art in context, taking account of . . . ‘the
background knowledge possessed by a person having ordinary skill in the
art,’ and ‘the inferences and creative steps that a person of ordinary skill in
the art would employ.’” Randall Mfg. v. Rea, 733 F.3d 1355, 1362 (Fed.
Cir. 2013) (quoting KSR, 550 U.S. at 418); see KSR, 550 U.S. at 417–19.
Indeed, KSR held that “the knowledge of such a [person of ordinary skill in
the art] is part of the store of public knowledge that must be consulted when
considering whether a claimed invention would have been obvious.”
Randall Mfg., 733 F.3d at 1362 (emphasis added). Therefore, we consider,
as we must, the background knowledge possessed by one of ordinary skill in
the art reading Puig and Ojeda.
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Dr. Thiele explained the background knowledge of one of ordinary
skill in detail in his declaration. Patent Owner asks us to reject Dr. Thiele’s
opinion, yet offers no legal precedent to support its argument and no
evidence—only attorney argument—as to how one of ordinary skill would
understand the references. See PO Resp. 16–22. We decline to do so,
because we conclude that the prior art of record is consistent with and
supports Dr. Thiele’s testimony. Further, Patent Owner’s proposed view of
the references, in which one of ordinary skill would not distinguish
endogenous and recombinant Fe-S cluster protein expression, lacks support
in the record and takes an improperly narrow view of the knowledge of one
of ordinary skill in the art.
We credit and are persuaded by Dr. Thiele’s testimony that one of
ordinary skill would have understood Puig’s teaching regarding Fe-S cluster
genes being downregulated by the Cth2 protein, and Ojeda’s teaching
regarding the activity of Fe-S cluster enzymes being decreased or unaffected
by inactivation of either or both Grx3 and Grx4 proteins, to be directed to
endogenous Fe-S cluster proteins encoded by endogenous genes. Ex. 1002
¶¶ 80, 102–105. As Dr. Thiele explains, one of ordinary skill would have
understood that, using standard techniques for recombinant protein
expression, recombinant Fe-S proteins encoded by recombinant mRNA
lacking the 3’UTR—which Puig teaches is what Cth2 binds to and
degrades—would not be downregulated by induced expression of the Cth2
protein, including through the means taught by Ojeda, namely inactivating
the Grx3 and Grx4 proteins. Ex. 1002 ¶¶ 80, 103; Pet. 38, 46; Reply 7;
Ex. 1006, 99, 104, 107. Thus, one of ordinary skill in the art would have
expected that such induced expression of Cth2 would result in lower levels
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and activity of endogenous Fe-S cluster proteins—encoded by endogenous
mRNAs with the 3’UTR that the Cth2 protein degrades—but greater levels
and activity of recombinant Fe-S cluster proteins—encoded by recombinant
mRNAs lacking the 3’UTR that the Cth2 protein degrades—with less
competition from endogenous Fe-S cluster proteins for Fe-S binding.
Ex. 1002 ¶¶ 80–81, 102–104; see Pet. 38, 45–47; Ex. 1007, 17661–63, Table
1–2. In other words, Ojeda’s disclosure regarding decreased activity of Fe-S
cluster enzymes in yeast lacking Grx3 and Grx4 proteins would have been
entirely expected for endogenous Fe-S cluster enzymes, yet the opposite
effect would have been expected for recombinant Fe-S cluster enzymes.
Ex. 1002 ¶¶ 100–105; see Pet. 43–47; Reply 12–13. Thus, neither Puig’s
nor Ojeda’s disclosures regarding reduced expression of Fe-S cluster genes
and proteins would have dissuaded one of ordinary skill from inactivating
the Grx3 and Grx4 proteins in yeast recombinantly overexpressing DHAD.
Ex. 1002 ¶¶ 80, 100–105.
Dr. Thiele’s position is consistent with and supported by the evidence
of record.
8
As Petitioner points out, Puig discloses that the means by which
the Cth2 protein downregulates mRNAs of Fe-S cluster genes is by binding
to AREs within the 3’UTR. Ex. 1006, 101, 104, 107, Table 1. Thus, as Puig

8
In reaching this conclusion, we do not consider Exhibit 1025 (Joseph
Sambrook et al., Molecular Cloning: a Laboratory Manual (2d ed. 1989)),
which Petitioner submitted with its Reply. Exhibit 1025 is relevant to
Petitioner’s affirmative obviousness arguments presented in the Petition and
Dr. Thiele’s declaration, see Pet. 38; Ex. 1002 ¶ 80, and Petitioner gave no
reason why this evidence could not have been submitted with the Petition.
See Tr. 19:17–22:8; see generally Reply. Accordingly, we determine this
evidence is untimely and outside the proper scope of a reply. See 37 C.F.R.
§ 42.23(b); Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,767
(Aug. 14, 2012).
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states, “CTH2-dependent mRNA downregulation under low Fe conditions is
dependent on the presence of specific AREs located in the 3’UTR.” Id. at
104. In addition, Puig lists putative AREs in the 3’UTR for various Fe-S
cluster genes, including the ILV3 gene encoding DHAD. Id. at Table 1.
Significantly, Puig also expressly discusses cloning a gene “sequence with
no 3’UTR.” Id. at 109. These disclosures bolster Petitioner and Dr. Thiele’s
position that one of ordinary skill would know to, and be motivated to,
recombinantly express DHAD, encoded by mRNA lacking the 3’UTR, and
would appreciate that the resulting difference in the 3’UTR in mRNA would
prevent the Cth2 protein from downregulating recombinant DHAD. In
addition to Puig’s teachings, Anthony is directed to increased activity of
expressed heterologous Fe-S cluster proteins resulting from reduced
expression of endogenous Fe-S cluster proteins. See Ex. 1005 ¶¶ 38, 74. In
fact, Anthony specifically reports that heterologous DHAD expression
improved with inactivation of the endogenous gene encoding DHAD (ILV3).
Id. ¶ 74. Anthony’s teachings, therefore, further support Petitioner and
Dr. Thiele’s position that one of ordinary skill in the art would have
understood that endogenous and recombinant proteins behave differently.
In sum, the cited prior art, including Anthony and Puig, and
Dr. Thiele’s opinion demonstrate that one of ordinary skill, upon reading
Puig and Ojeda, would not have been “discouraged from following the path
set out in [Puig and Ojeda], or . . . led in a direction divergent from the path”
taken by the inventors of the ’565 patent. In re Mouttet, 686 F.3d 1322,
1333–34 (Fed. Cir. 2012) (quotations omitted); accord Ricoh Co. v. Quanta
Computer Inc., 550 F.3d 1325, 1332 (Fed. Cir. 2008). Patent Owner’s
argument that Puig and Ojeda teach away from deriving the yeast recited in
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claim 1 lacks factual and legal support, and is contrary to the evidence of
record. We find by a preponderance of the evidence that neither Puig nor
Ojeda teaches away from deriving the recombinant yeast recited in claim 1
in which DHAD is recombinantly overexpressed and both Grx3 and Grx4
proteins are inactivated by deletion of their respective genes.
(d) Purported Evidence of Secondary Considerations
In its final dispute of Petitioner’s obviousness arguments, Patent
Owner submits Exhibit 2001, U.S. Patent Application Publication No.
13/837,921 (“the ’921 application”), Petitioner’s pending patent application,
which claims priority to the Flint ’333 provisional. Ex. 2001, [21], [60].
Patent Owner directs our attention to paragraphs 290 and 291 of the ’921
application:
Surprisingly, DHAD specific activity in the
crude extract in strains with a deletion in either the
FRA2 or the GRX3 gene increased by 2- to 3-fold,
which was unexpected as many of the deletions
tested did not increase DHAD specific activity. . . .
Another unexpected finding is the effect of a
Grx3 deletion on DHAD activity. It has been
shown that Grx3 and Grx4 are equivalent in
function. While double mutations in both GRX3
and GRX4 genes resulted in drastic activation of
the Fe regulon, mutation in Grx4 alone confers
minimal phenotype (Pujol-Carrion, et al, J Cell
Sci. 119:4554-4564 (2006); Ojeda, et al, J Biol.
Chem. 281:17661-17669 (2006)). As shown in
Table 10 above, GRX3 deletion alone leads to
significant improvement in DHAD specific activity.
Id. ¶¶ 290–291 (emphases added); see PO Resp. 24–25. Patent Owner cites
dependent claims 65 and 71, which involve increased DHAD activity and
“at least one deletion, mutation or substitution in” one or a combination of
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several endogenous genes, including GRX3, respectively. Ex. 2001, 77; PO
Rep. 23–24. Patent Owner urges us to treat Petitioner’s representations in
the ’921 application as a “party admission” regarding “the unexpected
ability of GRX3 deletion to increase DHAD activity.” PO Resp. 23–25
(emphasis omitted). Thus, Patent Owner essentially asks us to treat these
representations as evidence of secondary considerations, specifically
unexpected results, to rebut Petitioner’s obviousness showing.
We, however, are not persuaded that the ’921 application has any
impact on this case for several reasons. We first note that Petitioner’s
statements in the ’921 application regarding the “unexpected” or
“surprising[]” effects on DHAD activity involve only deletions in the GRX3
gene. Ex. 2001 ¶¶ 290–291. Our conclusion that Petitioner has shown that
claim 1 would have been obvious rests on Petitioner’s showing that it would
have been obvious to inactivate both the Grx3 and Grx4 proteins, by deletion
of both the GRX3 and GRX4 genes. See supra Section II.C.2.a.i.
Accordingly, Petitioner’s statements and representations regarding GRX3
gene deletion alone do not contradict, and have no impact on, our
obviousness conclusion in this case.
Nor are we persuaded that the statements and claims in the ’921
application—when viewed in context—contradict Petitioner’s position in
this trial that one of ordinary skill would have known that deleting the GRX3
gene would increase DHAD activity. It is reasonable to interpret the
statements in paragraphs 290 and 291 of the ’921 application to mean that
what is “surprising[]” and “unexpected” is the extent of the increase in
DHAD activity, specifically that this activity was “significant[ly]
improve[d]” by “2-to3-fold,” not that DHAD activity increased at all.
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Ex. 2001 ¶¶ 290–291; Tr. 34:12–17. Patent Owner has not shown otherwise.
As to the claims of the ’921 application to which Patent Owner cites,
9

Petitioner correctly points out in its Reply that claims 65 and 71 are separate
dependent claims. Reply 14; Ex. 2001, 77. Claim 71 relates to “at least one
deletion, mutation, or substitution” in an endogenous GRX3 gene, whereas
claim 65 involves DHAD activity. Ex. 2001, 77. Therefore, Patent Owner
has not directed us to any particular claim in the ’921 application that
contradicts Petitioner’s position in this case that it would have been obvious
to delete the GRX3 gene to increase DHAD activity.
Yet, even if we agreed with Patent Owner that the representations in
the ’921 application are contrary to Petitioner’s position in this case and are
evidence of unexpected results, this evidence would not save the claims of
the ’565 patent for two reasons. To rebut Petitioner’s obviousness showing,
evidence of secondary considerations, including unexpected results, “must
be reasonably commensurate with the scope of the claims.” In re Kao, 639
F.3d 1057, 1068 (Fed. Cir. 2011); see In re Harris, 409 F.3d 1339, 1344
(Fed. Cir. 2005) (holding showing of unexpected results insufficient because
“[e]ven assuming that the results were unexpected,” applicant failed “to
show results covering the scope of the claimed range”); Pet. 56–58. Here,
the purported evidence of unexpected results relates exclusively to deletions
in the GRX3 gene—not the GRX4 gene, or the GRX3 and GRX4 genes. See
Ex. 2001 ¶¶ 290–291; PO Resp. 23 (referring to the “unexpected ability of
GRX3 deletion to increase DHAD activity”) (emphasis added); id. at 25
(arguing that “Petitioner considers the increased DHAD activity brought

9
Petitioner clarified during the oral hearing that the claims in the ’921
application were amended after publication of Exhibit 2001. Tr. 31:3–13.
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about by inactivation of GRX3 to be an ‘unexpected finding’”) (emphasis
added). Accordingly, this purported evidence of unexpected results is not
reasonably commensurate with the scope of the genus recited in claim 1.
In sum, the ’921 application does not impact the obviousness of
claim 1.
(e) Conclusion
Based on our review of the arguments and evidence of record, we
conclude Petitioner has shown by a preponderance of the evidence that
claim 1 is unpatentable as obvious over Anthony, Puig, and Ojeda.
ii. Dependent Claims 2–4, 6–8, 11, 13, 14, and 16–19
Petitioner asserts that Anthony teaches or suggests the additional
limitations of dependent claims 2–4, 6–8, 11, 13, 14, and 17–19, and Puig
teaches or suggests the additional limitation of claim 16. See Pet. 34–43;
Ex. 1002 ¶¶ 82–92. Patent Owner does not dispute these assertions. See PO
Resp. 15–22. Based on our review of the arguments and evidence, we
determine that Petitioner has demonstrated that each of the additional
limitations recited in claims 2–4, 6–8, 11, 13, 14, and 17–19 are taught by
Anthony and the additional limitation of claim 16 is taught by Puig, for the
reasons set forth in the Petition as well as Dr. Thiele’s supporting
declaration. See Pet. 34–43; Ex. 1002 ¶¶ 82–92.
For these reasons, in addition to our reasoning outlined above
regarding the obviousness of claim 1, we conclude that Petitioner has shown
by a preponderance of the evidence that claim 2–4, 6–8, 11, 13, 14, and 16–
19 are unpatentable as obvious over Anthony, Puig, and Ojeda.
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b. ANTHONY, PUIG, OJEDA, AND LI — CLAIM 5
Next, we consider Petitioner’s assertion that claim 5 of the ’565 patent
is unpatentable under 35 U.S.C. § 103 as obvious over the combination of
Anthony, Puig, Ojeda, and Li. Pet. 47–49. In response to this asserted
ground of unpatentability, Patent Owner does not put forward any arguments
or evidence unique to the additional limitation of claim 5 or to the teachings
of Li, the additional reference Petitioner relies upon in this asserted ground.
See PO Resp. 22. Instead, Patent Owner relies on its challenges to
Petitioner’s contention that claim 1 would have been obvious over Anthony,
Puig, and Ojeda—which we have addressed and found unpersuasive above.
See id.; supra Section II.C.2.a.i.
Li discloses ketol–acid reductoisomerase (“KARI”) enzymes that
preferentially bind to the cofactor NADH instead of NADPH. Ex. 1015
¶¶ 2, 10–11. Li further discusses methods of producing such KARI enzymes
as well as methods of using these enzymes in recombinant yeast
microorganisms in the isobutanol biosynthetic pathway disclosed in
Anthony. Id. ¶¶ 11, 32–39, 126–144; see Ex. 1005 ¶¶ 112–119. Li explains
that using KARI enzymes that bind to NADPH, rather than NADH,
“enhance[s] the productivity of the isobutanol biosynthetic pathway by
capitalizing on the NADH produced by the existing glycolytic and other
metabolic pathways in most commonly used microbial cells.” Ex. 1015 ¶ 6.
Claim 5 of the ’565 patent depends from claim 4 and further requires
that the KARI of the recited recombinant yeast be “an NADH–dependent
ketol–acid reductoisomerase.” Ex. 1001, 91:45–49. We find that Li’s
disclosure of KARI enzymes that preferentially bind to the cofactor NADH,
instead of NADPH, teaches this additional limitation of claim 5. See
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Ex. 1015 ¶¶ 2, 10–11; Ex. 1002 ¶ 94. We also are persuaded by Dr. Thiele’s
opinion that one of ordinary skill would have had reason to combine this
teaching of Li with the teachings of Anthony, Puig, and Ojeda in a manner
that yields the recombinant yeast recited in claim 5, with a reasonable
expectation of success. Specifically, Dr. Thiele opines that one of ordinary
skill would look to combine the references, because Anthony and Li are
directed to recombinant yeast with the same isobutanol biosynthetic
pathway, and Li discloses the benefits of using KARI enzymes that bind to
the cofactor NADH for isobutanol production. See Ex. 1002 ¶¶ 93–94.
Accordingly, we conclude Petitioner has shown by a preponderance of
the evidence that claim 5 of the ’565 patent is unpatentable as obvious over
Anthony, Puig, Ojeda, and Li.
c. ANTHONY, PUIG, OJEDA, AND VAN MARIS — CLAIM 9
Finally, we address Petitioner’s assertion that claim 9 of the
’565 patent is unpatentable under 35 U.S.C. § 103(a) as obvious over
Anthony, Puig, Ojeda, and van Maris. Pet. 49–51. As with the instituted
ground of unpatentability challenging claim 5, Patent Owner has not
proffered any arguments or evidence specific to the additional limitation of
claim 9 or to the additional reference relied upon in this ground,
van Maris—again relying exclusively on its arguments that the combination
of Anthony, Puig, and Ojeda does not render independent claim 1 obvious.
See PO Resp. 22–23.
Van Maris discloses that in Saccharomyces cerevisiae yeast, deleting
the PDC1, PDC5, and PDC6 genes results in significantly decreased
production of ethanol, but increased production of pyruvate. Ex. 1008,
Abstract, 159, 163, Fig. 1, Table 2. Specifically, van Maris reports a
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theoretical yield of ethanol of less than 0.01 mmol in Saccharomyces
cerevisiae lacking the PDC genes. Id. at Table 2. Van Maris further
explains that these results occur because deleting the genes impairs a
pathway that converts pyruvate to ethanol. Id. at Fig. 1.
In claim 9 of the ’565 patent, which depends from claim 2, the yeast is
“further engineered to inactivate one or more endogenous pyruvate
decarboxylase (PDC).” Ex. 1001, 91:58–61. We find that van Maris’s
disclosure of deleting PDC1, PDC5, and PDC6 genes in yeast teaches this
additional limitation of claim 9. See Ex. 1008, Abstract, 159, 163, Fig. 1,
Table 2; Ex. 1002 ¶ 97. In addition, we credit and find persuasive
Dr. Thiele’s opinion that one of ordinary skill in the art would have
combined Anthony, Puig, Ojeda, and van Maris to reach the claimed
invention. Ex. 1002 ¶¶ 95–97. In particular, Dr. Thiele opines that Anthony
and van Maris involve yeast fermentation products with pyruvate as a
starting substrate. Id. ¶ 95; see Ex. 1005 ¶ 113. Further, van Maris’s
disclosure of decreased ethanol production in yeast lacking PDC would have
motivated one of ordinary skill, using the isobutanol pathway in Anthony
with pyruvate as a starting substrate, to delete PDC genes to direct pyruvate
away from ethanol production and towards isobutanol production. See
Ex. 1002 ¶¶ 95–97. We likewise find persuasive Dr. Thiele’s explanation
that one of ordinary skill would have had a reasonable expectation of
success in deleting PDC, because yeast strains lacking PDC activity were
available commercially before the earliest claimed effective filing date of the
’565 patent. Id. ¶ 97.
For these reasons, in addition to our reasoning outlined above
regarding the obviousness of claims 1 and 2, we conclude Petitioner has
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shown by a preponderance of the evidence that claim 9 would have been
obvious over Anthony, Puig, Ojeda, and van Maris.
III. CONCLUSION
In conclusion, Petitioner has shown by a preponderance of the
evidence that claims 1–9 and 11–19 of the ’565 patent are unpatentable.
Specifically, Petitioner has established that: (1) claims 1–4, 6–8, and 11–19
are anticipated by Flint; (2) claims 1–4, 6–8, 11, 13, 14, and 16–19 would
have been obvious over Anthony, Puig, and Ojeda; (3) claim 5 would have
been obvious over Anthony, Puig, Ojeda, and Li; and (4) claim 9 would
have been obvious over Anthony, Puig, Ojeda, and van Maris.
IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that Petitioner has shown by a preponderance of the
evidence that claims 1–9 and 11–19 of the ’565 patent are unpatentable; and
FURTHER ORDERED that, because this is a Final Written Decision,
the parties to the proceeding seeking judicial review of the decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.
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PETITIONER:
Deborah A. Sterling
Peter A. Jackman
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
dsterlin-PTAB@skgf.com
pjackman-PTAB@skgf.com

PATENT OWNER:
Erich E. Veitenheimer, Ph.D.
Chris Holly, Ph.D.
COOLEY LLP
eveitenheimer@cooley.com
IPR2013-00539@cooley.com