UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`BUTAMAXTM ADVANCED BIOFUELS LLC
`
`Petitioner
`
`V.
`
`GEVO, INC.
`
`Patent Owner
`
`Case No. IPR2013-00539
`
`US. Patent No. 8,273,565
`
`PATENT OWNER’S RESPONSE TO PETITION FOR INTER PARTES
`
`REVIEW OF US. PATENT NO. 8,273,565
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`
`US. Patent and Trademark Office
`
`PO. BOX 1450
`
`Alexandria, VA 223 13—1450
`
`
`
`

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`Case No: IPR2013-00539
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`US. Pat. No. 8,273,565
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`Table of Contents
`
`I.
`
`INTRODUCTION.......................................................................................... 1
`
`A.
`
`B.
`
`Procedural Background ....................................................................... 1
`
`Summary of Gevo’s Response............. ................................................ 2
`
`II.
`
`ARGUMENT ................................................................................................. 5
`
`A.
`
`Ground 1: The ‘5 65 patent is entitled to a November 24, 2009
`and June 01, 2010 priority dates and consequently Flint is not
`prior art................................................................................................. 5
`
`i.
`
`ii.
`
`iii.
`
`U.S. Prov. App. No. 61/263,952 —— Filed 11/24/2009 ................ 6
`
`U.S. Prov. App. No. 61/350,209 — Filed 06/01/2010 .............. 10
`
`The skilled artisan’s understanding of the priority
`disclosures ............................................................................... 13
`
`iv.
`
`Ground 1 fails as Flint is not prior art ..................................... 15
`
`B.
`
`Ground 2: Claims 1-4, 6- 8, and 11- 19 are not rendered obvious
`by Anthony, Puig, and Ojeda ............................................................. 15
`
`i.
`
`ii.
`
`iii.
`
`Anthony contains no teaching or suggestion that GRX3
`and/or GRX4 should be inactivated ........................................ 15
`
`The combination of Anthony and Puig teaches against an
`“overexpressed” DHAD as claimed, as Puig teaches the
`downregulation of DHAD ....................................................... 16
`
`Ojeda teaches away from the present claims of the ‘5 65
`patent ....................................................................................... 20
`
`C.
`
`D.
`
`Ground 3: Claim 5 is not rendered obvious by Anthony, Puig,
`Ojeda, and Li ...................................................................................... 22
`
`Ground 4: Claim 9 is not rendered obvious by Anthony, Puig,
`Ojeda, and van Maris ......................................................................... 22
`
`E.
`
`Ground 5: The Board ruled that claim 10 is not obvious over
`
`Anthony, Puig, Ojeda, and Overkamp ............................................... 23
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`F.
`
`Petitioner’s party admission as to the unexpected ability of
`GRX3 deletion to increase DHAD activity supports the
`patentability of Gevo’s claims ........................................................... 23
`
`III.
`
`CONCLUSION ............................................................................................ 26
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`Case No: IPR2013—00539
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`US. Pat. No. 8,273,565
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`I.
`
`INTRODUCTION
`
`A.
`
`Procedural Background
`
`US. Patent No. 8,273,565 (Ex. 1001; “the ‘565 patent”),
`
`issued on
`
`September 25, 2012, from US. Application No.
`
`l3/246,693, filed on September
`
`27, 2011. The ‘565 patent claims priority as a Divisional Application from US.
`
`Application No. 13/228,342, filed on September 08, 2011, which issued as US.
`
`Pat. No. 8,071,358, on December 06, 2011, and which claims priority as a
`
`Divisional Application from U. S. Application No. 12/953,884, filed on November
`
`24, 2010, which issued as US. Pat. No. 8,017,376, on September 13, 2011, and
`
`which claims priority to US. Provisional Application No. 61/263,952, filed on
`
`November 24, 2009, and US. Provisional Application No. 61/350,209, filed on
`
`June 01, 2010 (“the ‘952 application and ‘209 application,” respectively).
`
`Consequently,
`
`the earliest priority date claimed in the ‘565 patent
`
`is
`
`November 24, 2009.
`
`Petitioner BUTAMAXTM ADVANCED BIOFUELS LLC (“Petitioner”)
`
`filed a petition for Inter Partes Review of the ‘565 patent on August 30, 2013
`
`(“Petition,” Ex. 4).
`
`On March 04, 2014, the Board issued a Decision instituting Inter Partes
`
`Review of the ‘5 65 patent (EX. 9).
`
`Pursuant to 35 U.S.C. § 316(a)(8) and 37 C.F.R. § 42.120, the Patent Owner
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`GEVO, INC. (“Gevo”) hereby responds to Grounds 1—5 of the Petition.
`
`B.
`
`Summary of Gevo’s Response
`
`Gevo has developed and patented a novel and non-obvious recombinant
`
`microorganism comprising
`
`a
`
`recombinantly
`
`overexpressed polynucleotide
`
`encoding a dihydroxy acid dehydratase (DHAD) and engineered to comprise at
`
`least one inactivated endogenous gene encoding a monothiol glutaredoxin selected
`
`from the group consisting of monothiol glutaredoxin-3 (GRX3) and monothiol
`
`glutaredoxin—4 (GRX4).
`
`Petitioner has presented argumentation asserting that the ‘565 patent is not
`
`entitled to its earliest priority date of November 24, 2009. Based upon Petitioner’s
`
`as-of—yet unrefuted assertions, the Board has preliminarily adopted the position that
`
`the ‘565 patent is entitled to an earliest priority date of November 24, 2010.
`
`Decision Instituting Inter Partes Review, at pgs. 15-16 (EX. 9).
`
`Consequently, the reference of Flint (EX. 1003) cited by the Petitioner, is
`
`tentatively deemed by the Board to be prior art under 35 U.S.C. § 102(6). Id.
`
`Gevo respectfully disagrees with the Board’s tentative conclusions regarding
`
`the priority date entitled to the ‘5 65 patent.
`
`The ‘565 patent is entitled to a priority date of November 24, 2009. One of
`
`ordinary skill in the art would understand from the disclosure of the two parent
`
`provisional
`
`applications
`
`that Gevo was
`
`in possession of a recombinant
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`microorganism as recited in claim 1 of the ‘565 patent.
`
`Thus, Flint is not prior art to the ‘5 65 patent and the Petitioner’s Ground of
`
`Rejection l is rendered moot.
`
`As Flint is not prior art against the ‘565 patent, the whole of Petitioner’s
`
`argumentation relies upon the teachings and asserted combination of Anthony (Ex.
`
`1005), Puig (EX. 1006), and Ojeda (Ex. 1007).
`
`However, one of skill in the art would not have been motivated to combine
`
`the aforementioned references, as Anthony and Puig provide no teaching or
`
`suggestion to choose endogenous GRX3 and/or GRX4 proteins for inactivation.
`
`Further, Puig teaches the downregulation of DHAD in contravention of the
`
`recited claim language of an “overexpressed” DHAD.
`
`The Petitioner has provided no evidence that Cth2 would bind to
`
`endogenous DHAD mRNA and not also bind the exogenous DHAD mRNA. The
`
`statements in the Petition regarding the 3’-untranslated regions of the DHAD
`
`mRNA being different between endogenous and exogenous DHAD mRNA may
`
`well be true; however, this does not necessarily mean that Cth2 would not still be
`
`capable of binding a 3’-untranslated mRNA of exogenous DHAD if such
`
`exogenous DHAD contained said region. See Petition, at pgs. 45—46 (EX. 4); see
`
`also, Declaration of Dr. Thiele, 1111 102—105 (Ex. 1002).
`
`Yet further, Oj eda teaches that many Fe-S proteins are either not affected by,
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`or have their activities decreased by, GRX3 and/or GRX4 inactivation. The recited
`
`“overexpressed” DHAD of the ‘565 patent is a Fe-S protein.
`
`
`For example, Ojeda teaches that GRX3 or GRX4 depletion in yeast does not
`
`impact the enzymatic activity of several Fe-S proteins including aconitase, sulfite
`
`reductase, and isopropylmalate isomerase (Leul). See Ojeda, at pg. 17667, Col. 1
`
`(Ex. 1007).
`
`Ojeda also taught
`
`that
`
`the double mutants lacking GRX3 and GRX4
`
`decreased the enzymatic activity of several Fe—S proteins.
`
`Id.
`
`(“Aconitase
`
`activity...was decreased in the double null strain (Fig. 10A)”; As with aconitase,‘
`
`enzymatic activities of the cytosolic Fe-S enzymes sulfite reductase and Leul are
`
`“depressed in the double null strain”).
`
`Thus, a skilled artisan would interpret Oj eda as teaching that many members
`
`of the Fe-S protein family are either not
`
`impacted by GRX3 and/or GRX4
`
`inactivation or are negatively impacted.
`
`Based upon the results of Ojeda, a skilled artisan would not have had a
`
`reasonable expectation that disruption or deletion of an endogenous GRX3 and/or
`
`GRX4 gene would result in increased DHAD activity and consequently isobutanol
`
`production.
`
`There is no teaching or suggestion from Anthony or Puig that would
`
`overcome such a strong teaching away from Oj eda and motivate a skilled artisan to
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`disregard Oj eda’s teaching away and pursue the creation of recombinant yeast with
`
`an inactivated GRX3 and/or GRX4 with a reasonable expectation that such yeast
`
`would yield increased isobutanol.
`
`Thus, for at least these reasons, Petitioner has failed to demonstrate that the
`
`claimed invention is obvious as alleged in Ground 2 of the Petition.
`
`As the secondary art cited in Grounds 3—4 is insufficient to overcome the
`
`teaching away presented by Puig and Ojeda, these Grounds of rejection also fail.
`
`Gevo acknowledges that the Board was not persuaded by Petitioner’s
`
`Ground 5 of rejection and consequently the Inter Partes Review trial was not
`
`instituted upon claim 10.
`
`For at
`
`least
`
`the aforementioned reasons and those to follow, Gevo
`
`respectfully submits to the Board that Grounds 1-4 should be rejected, and claims
`
`1-9 and 11-19 of the ‘565 patent should be affirmed as novel and non—obvious.
`
`VII.
`
`ARGUMENT
`
`A.
`
`Ground 1: The ‘565 patent is entitled to a November 24, 2009 and June
`01, 2010 priority dates and consequently Flint is not prior art
`
`Gevo respectfully submits that the Board’s tentative conclusion that the ‘5 65
`
`patent is not entitled to its earliest priority date is in error. The below citations from
`
`the disclosures of the ‘952 and ‘209 provisional applications will demonstrate that
`
`a skilled artisan would understand that Gevo was indeed in possession of
`
`recombinant yeast as claimed in the ‘5 65 patent, as of November 24, 2009.
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`i.
`
`U.S. Prov. App. No. 61/263,952 — Filed 11/24/2009
`
`In the request for Inter Partes Review, Petitioner repeatedly indicates that
`
`the ‘952 and ‘209 provisional applications have minimal disclosure regarding
`
`inactivation of GRX3 and/or GRX4 and insists that the priority documents “are
`
`noticeably directed to expression and overexpression of GRX3 and/or GRX4.”
`
`Petition, pgs. 13-14 (Ex. 4). The Petitioner even counts the number of experiments
`
`relating to overexpression of the GRX3 and/or GRX4 genes and argues that the
`
`number of experiments relating to increased expression of these genes indicates
`
`that “Applicants considered increasing GRX3 and GRX4 expression to be the
`
`focus of any change in GRX3 and GRX4 activity, and not deletion or
`
`‘inactivation.”’ Id. at 14.
`
`Gevo respectfully disagrees with Petitioner’s unfounded conjecture and
`
`mischaracterization of what the company “considered...to be the focus” of its
`
`experimental and research endeavors in 2009 and 2010. Id.
`
`Actually, “despite Petitioner’s hand waving around the issue, the United
`
`States allows patent applicants to recite more than one embodiment in patent
`
`applications. Applicants should not be punished for reciting multiple embodiments
`
`of an invention in an application. There is no authority supporting Petitioner’s
`
`argument that a negative inference should be drawn against Gevo’s possession of
`
`the inactivated GRX3 and/or GRX4 recombinant yeast embodiment simply
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`because other embodiments were also described.
`
`Gevo respectfully directs the Board’s attention to the following disclosure
`
`from the ‘952 application (EX. 1010),
`
`illustrating that
`
`the company was in
`
`possession of a recombinant yeast embodiment comprising an inactivated GRX3
`
`and/or GRX4 as claimed in the ‘565 patent, as of November 24, 2009.
`
`0 Paragraph [0028]: “[T]he microorganism may be engineered to delete
`
`and/or attenuate one or more genes selected from the group consisting of
`
`GRX3 and GRX4, or homologs thereof.” (emphasis added).
`
`0 Paragraph [0067]: “The term ‘engineer’ refers to any manipulation of a
`
`microorganism that results in a detectable change in the microorganism,
`
`wherein the manipulation includes but
`
`is not
`
`limited to inserting a
`
`polynucleotide and/or polypeptide heterologous to the microorganism
`
`and mutating a polynucleotide and/or polypeptide native to the
`
`microorganism.” (emphasis added).
`
`0 Paragraph [0068]: “The term ‘mutation’ as used herein indicates any
`
`modification of a nucleic acid and/or polypeptide which results in an
`
`altered nucleic acid or polypeptide. Mutations include, for example,
`
`point mutations, deletions, or insertions of single or multiple residues
`
`in a polynucleotide, which includes alterations arising within a protein-
`
`encoding region. . .A genetic alteration may be a mutation of any type.
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`For instance, the mutation may constitute a point mutation, a frame-shift
`
`mutation, an insertion, or a deletion of part or all of a gene.”
`
`(emphasis added).
`
`0 Paragraph [00154]: “[D]eletion or attenuation of the genes...GRX3
`
`and/or GRX4 alone or in combination will modulate the amount and
`
`availability of iron in the yeast cytosol or mitochondria.”
`
`0 Paragraph [00156]: “In another embodiment, er3, er4, or er3 and
`
`er4 are deleted or attenuated.”
`
`0 Paragraph [00213]: “[A]n engineered or modified microorganism gap
`
`also include alteration, disruption, deletion or knocking-out of a gene
`
`or polynucleotide to alter the cellular physiology and biochemistry of
`
`the microorganism.” (emphasis added).
`
`Thus, disruption means the insertion of one or more polynucleotides,
`
`knocking-out means the insertion of one or more polynucleotides (1'. e., through the
`
`use of a knock-out cassette), and as noted above in paragraph [0068], deletion
`
`means deletion of part or all of a gene.
`
`0 Paragraph [00229]: “The microorganism_ can comprise a reduction in
`
`expression, disruption or knockout of a gene found in the wild-type
`
`organism. . .”. (emphasis added).
`
`0 Techniques for genetic insertions and deletions in yeast are described at
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`paragraphs [00258]—[00263] under the heading “Genetic Insertions and
`
`deletions.” These techniques would have been well within the
`
`understanding of one skilled in the art and are routine, well-recognized
`
`procedures performed by individuals practicing in the
`
`field of
`
`recombinant microorganisms.
`
`0 Paragraph [00264]: “Many different methods can be used to make yeast
`
`having reduced enzymatic activity. For example, a yeast cell can be
`
`engineered to have a disrupted enzyme-encoding locus using common
`
`mutagenesis or knock-out technology.” Knock-out technologies rely on
`
`the insertion of one or more nucleotides as a means of disrupting protein
`
`activity.
`
`Thus, Gevo respectfully submits that the Board’s characterization of the
`
`priority document’s disclosures as not describing “inactivated GRX3 or GRX4
`
`proteins resulting from inserted nucleotides...’
`
`is erroneous,
`
`as
`
`the
`
`‘952
`
`9
`
`application clearly illustrates that Gevo was in possession of such an embodiment.
`
`Decision Instituting Inter Partes Review, at pg. 15 (EX. 9). Moreover, Gevo
`
`respectfully submits that the Board’s characterization of the priority document’s
`
`disclosures as not describing “inactivated GRX3 or GRX4 proteins resulting from
`
`partial deletion” is erroneous, as the ‘952 application clearly illustrates that Gevo
`
`was in possession of embodiments resulting in the deletion of one or more
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`nucleotides of endogenous GRX3 and/or GRX4 nucleotides. See, e. g, paragraph
`
`[0074] referencing “a deletion of part or all of a gene.”
`
`The aforementioned disclosure illustrates that as of November 24, 2009,
`
`Gevo was in possession of the recombinant yeast as claimed in the ‘565 patent.
`
`Specifically,
`
`it
`
`is clear
`
`from the foregoing that
`
`the ‘952 application
`
`adequately disclosed recombinant yeast comprising “inactivated” GRX3 and/or
`
`GRX4.
`
`ii.
`
`U.S. Prov. App. No. 61/350,209 — Filed 06/01/2010
`
`Gevo respectfully directs the Board’s attention to the following disclosure
`
`from the ‘209 application (EX. 1011), illustrating that the company was also in
`
`possession of a recombinant yeast embodiment comprising an inactivated GRX3
`
`and/or GRX4 as claimed in the ‘565 patent, as of June 01, 2010.
`
`0 Paragraph [0073]: “The term ‘engineer’ refers to any manipulation of a
`
`microorganism that results in a detectable change in the microorganism,
`
`wherein the manipulation includes but
`
`is not
`
`limited to inserting a
`
`polynucleotide and/or polypeptide heterologous to the microorganism
`and mutating a polynucleotide and/or polypeptide native to the
`
`microorganism.” (emphasis added).
`
`0 Paragraph [0074]: “The term ‘mutation’ as used herein indicates any
`
`modification of a nucleic acid and/or polypeptide Which results in an
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`altered nucleic acid or polypeptide. Mutations include, for example,
`
`point mutations, deletions, or insertions of single or multiple residues
`
`in a polynucleotide, which includes alterations arising Within a protein-
`
`encoding region. . .A genetic alteration may be a mutation of any type.
`
`For instance, the mutation may constitute a point mutation, a frame—shift
`
`mutation, an insertion, or deletion of part or all of a gene.” (emphasis
`
`added).
`
`0 Paragraph [00178]: “[D]eletion or attenutation of the genes GRX3 and/or
`
`GRX4 will modulate the amount and availability of iron in the yeast
`
`cytosol or mitochondria.”
`
`0 Paragraph [00180]: “In another embodiment, er3, er4, or er3 and
`
`er4 are deleted or attenuated.”
`
`0 Paragraph [00181]: “[D]eletion or attenuation of the genes GRX3 and/or
`
`GRX4 will increase the amount of iron Within the yeast cells.”
`
`0 Paragraph [00244]: “[A]n engineered or modified microorganism m
`
`also include alteration, disruption, deletion or knocking-out of a gene
`
`or polynucleotide to alter the cellular physiology and biochemistry of
`
`the microorganism.” (emphasis added).
`
`Thus, disruption means the insertion of one or more polynucleotides,
`
`knocking—out means the insertion of one or more polynucleotides (216., through
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`the use of a knock-out cassette), and as noted above in paragraph [0074],
`
`deletion means deletion of part or all of a gene.
`
`0 Paragraph [00260]: “The microorganism can comprise a reduction in
`
`expression, disruption or knockout of a gene found in the Wild-type
`
`organism. . .”. (emphasis added).
`
`0 Techniques for Genetic Insertions and Deletions in Yeast are described at
`
`paragraphs [00289]-[00294] under the heading “Genetic insertions and
`
`deletions.” These techniques would have been well Within the
`
`understanding of one skilled in the art and are routine, well-recognized
`
`procedures performed by individuals practicing in the
`
`field of
`
`recombinant microorganisms.
`
`0 Paragraph [00295]: “Many different methods can be used to make yeast
`
`having reduced enzymatic activity. For example, a yeast cell can be
`
`engineered to have a disrupted enzyme-encoding locus using common
`
`mutagenesis or knock-out technology.” Knock-out technologies rely on
`
`the insertion of one or more nucleotides as a means of disrupting protein
`
`activity.
`
`Thus, Gevo respectfully submits that the Board’s characterization of the
`
`priority document’s disclosures as not describing “inactivated GRX3 or GRX4
`
`proteins resulting from inserted nucleotides...’
`
`is erroneous, as
`
`the
`
`‘209
`
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`application clearly illustrates that Gevo was in possession of such an embodiment.
`
`Decision Instituting Inter Partes Review, at pg. 15 (EX. 9). Moreover, Gevo
`
`respectfully submits that the Board’s characterization of the priority document’s
`
`disclosures as not describing “inactivated GRX3 or GRX4 proteins resulting from
`
`partial deletion” is erroneous, as the ‘209 application clearly illustrates that Gevo
`
`was in possession of embodiments resulting in the deletion of one or more
`
`nucleotides of endogenous GRX3 and/or GRX4 nucleotides. See, e. g, paragraph
`
`[0074] referencing “a deletion of part or all of a gene.”
`
`The aforementioned disclosure illustrates that as of June 01, 2010, Gevo was
`
`in possession of the recombinant yeast as claimed in the ‘565 patent. Specifically,
`
`it
`
`is clear from the foregoing that the ‘209 application adequately disclosed
`
`recombinant yeast comprising “inactivated” GRX3 and/or GRX4.
`
`iii.
`
`The
`
`skilled
`
`artisan’s understanding of
`
`the priority
`
`disclosures
`
`Based on the teachings of the ‘952 and ‘209 provisional applications, the
`
`skilled artisan would plainly recognize that engineering a gene to delete and/or
`
`attenuate activity could include deletion of part or all of a gene, as well as insertion
`
`of one or more residues into a polynucleotide to disrupt activity.
`
`A skilled artisan would understand, at the time of the ‘952 and ‘209
`
`applications filing, that there are various mechanisms for inactivating a gene,
`
`including: gene deletions (including partial gene deletions) and gene insertions
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`(i.e., through the use of gene disruption cassettes, etc.).
`
`Consequently, based upon the level of skill in the art and art—recognized
`
`recombinant protocols, a skilled artisan would appreciate that gene deletions can
`
`mean gene disruptions and/or gene deletions.
`
`Gevo respectfully submits
`
`that Petitioner’s characterization of what
`
`allegedly must be disclosed in the priority applications, in order to show possession
`
`of a recombinant yeast as claimed in the ‘565 patent, disregards the basic patent
`
`law tenant that what is conventional or well known to one of ordinary skill in the
`
`art need not be disclosed in detail. See Hybritech Inc. v. Monoclonal Antibodies,
`
`Inc., 802 F.2d 1367, 1384 (Fed. Cir. 1986), cert. denied, 480 U.S. 947 (1987); See
`
`also Capon v. Eshhar, 418 F.3d 1349, 1357, (Fed. Cir. 2005) (“The ‘written
`
`description’ requirement must be applied in the context of the particular invention
`
`and the state of the knowledge....As each field evolves, the balance also evolves
`
`between what is known and what is added by each inventive contribution”).
`
`Consequently, if a skilled artisan would have understood the inventor to be
`
`in possession of the claimed invention at the time of filing, even if every nuance of
`
`the claims is not explicitly described in the specification,
`
`then the adequate
`
`description requirement is met. See, e. g, Vas-Cath, Inc. v. Mahurkar, 935 F.2d
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`1555, 1563 (Fed. Cir. 1991).
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`Thus, from the standpoint of one of skill in the art at the time the priority
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`applications were filed, it is apparent that Gevo had possession of the full scope of
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`recombinant yeast as claimed in the ‘565 patent, as of November 24, 2009 and
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`June 01,2010.
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`iv.
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`Ground 1 fails as Flint is not prior art
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`Gevo therefore respectfully submits that Petitioner’s Ground 1 of rejection
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`fails, as the ‘565 patent is entitled to a priority date of November 24, 2009 and
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`therefore Flint
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`(EX. 1003) is not available as prior art to support a 35 U.S.C. §
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`102(e) rejection.
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`For at least the aforementioned reasons, Gevo respectfully requests that the
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`Board reject Ground 1 of the Petition.
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`B.
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`Ground 2: Claims 1-4, 6—8, and 11-19 are not rendered obvious by
`Anthony, Puig, and Ojeda
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`i.
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`Anthony contains no teaching or suggestion that GRX3
`and/or GRX4 should be inactivated
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`Anthony (Ex. 1005) teaches that increased DHAD activity causes increased
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`‘ production of isobutanol. Decision Instituting Inter Partes Review, at pg. 20 (Ex.
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`9). However, there is no suggestion from Anthony that one should inactivate
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`GRX3 and/or GRX4 to increase the activity of DHAD and thereby increase
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`isobutanol production.
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`Anthony’s teaching to increase the activity of a heterologous Fe—S cluster
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`protein, such as DHAD, by “reduced expression” of an endogenous Fe-S cluster
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`protein,
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`is at best a generalized teaching of a hypothesized mechanism for
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`achieving increased Fe-S protein activity. This generalized scheme is noticeably
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`devoid of any reference or indication that GRX3 and/or GRX4 should be
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`inactivated.
`
`The Petitioner’s statement
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`tha
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`“a POSA would have understood that
`
`individually deleting the genes of the multitude of Fe-S proteins disclosed in
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`Anthony was only one available option, which would have potentially negative
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`implications on cell growth and yield,” is telling. Petition, at pg. 37 (EX. 4). That
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`is,
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`the Petitioner has identified one of the key problems with utilizing the
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`generalized teachings of Anthony. There is a lack of direction provided by
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`Anthony, as to which endogenous Fe-S cluster protein’s expression should be
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`reduced in order to increase the activity of DHAD.
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`More particularly, there is no indication from Anthony that GRX3 and/or
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`GRX4 expression should be reduced, in order to increase the activity of DHAD.
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`In light of this fact, Petitioner impermissibly forecasts the conclusion that a
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`person of ordinary skill in the art would have “considered alternative approaches”
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`such as those taught by Puig. Id.
`
`ii.
`
`The combination of Anthony and Puig teaches against an
`“overexpressed” DHAD as claimed, as Puig teaches the
`downregulation of DHAD
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`Puig (EX. 1006) teaches that Aftl and Aft2 are iron-responsive transcription
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`factors that induce expression of the iron regulon (including Cth2), and that Cth2 is
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`responsible for down—regulating Fe-S cluster genes.
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`Still noticeably absent from these two references is any indication that
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`GRX3 and/or GRX4 should be chosen ‘1 to be inactivated in order to increase the
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`function of DHAD.
`
`Equally as troubling, is the fact that Puig teaches against the overexpression
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`of DHAD. The claims of the ‘565 patent require that the host cell comprise a
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`recombinantly “overexpressed” DHAD.
`
`The recombinantly overexpressed DHAD, as recited in the ‘565 patent’s
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`claims, increases metabolic flux through an isobutanol pathway. The combination
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`of Anthony and Puig proposed by Petitioner defeats this purpose, as DHAD (a Fe-
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`S cluster protein) would purportedly be downregulated based upon the teachings of
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`Puig.
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`That
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`is, Puig teaches that Cth2 is induced by activated Aft. Cth2 is
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`responsible for downregulating Fe-S cluster genes, of which the heterologously
`
`expressed DHAD is one such example. Thus, Puig teaches the skilled artisan to
`
`increase the production of Cth2 that in turn decreases the production of DHAD. ‘
`
`Petitioner argues that “Puig teaches that Cth2 targets endogenous DHAD
`
`mRNA for degradation” and thus, because of this targeted action against
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`endogenous DHAD, Cth2 production would be beneficial
`
`for reducing the
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`competition for Fe-S clusters from the heterologous DHAD. Petition, at pg. 38.
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`(Ex. 4) (emphasis in original).
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`However, Puig does not provide a teaching that distinguishes between Cth2
`
`binding to a heterologous DHAD mRNA and an endogenous DHAD mRNA. Puig
`
`merely teaches that Cth2 will mediate the downregulation of Fe-S cluster proteins.
`
`Petitioner also cites to a statement in the Declaration of Dr. Dennis Thiele
`
`that “Puig teaches that Cth2 targets endogenous DHAD mRNA for degradation,”
`
`and that a skilled artisan would be motivated to “construct DHAD expression
`
`systems that do not express mRNA containing the endogenous Cth2-mRNA
`
`binding sequence in order to increase DHAD production.” Declaration of Dr.
`Thiele, at pg. 50, 1] 80 (EX. 1002)..
`
`There is no explicit disclosure from Puig indicating that Cth2 would not
`
`target the mRNA of the claimed “overexpressed” exogenous DHAD.
`
`Also, Dr. Thiele does not cite to any scientific literature that provides for the
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`Cth2-mRNA binding sequence that allegedly is only contained in the endogenous
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`DHAD mRNA and not the exogenous DHAD mRNA. Thus, Petitioner relies
`
`erroneously on statement of Dr. Thiele — not supported by any available art —— as a
`
`means of suggesting the skilled artisan would have been motivated to construct a
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`DHAD system not impacted by Cth2. The existence or feasibility of such a DHAD
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`system, however, is not provided by the Petitioner or Petitioner’s declarant.
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`In the absence of any indication from Puig itself that endogenous DHAD
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`mRNA would be targeted for downregulation while exogenous DHAD mRNA
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`would not be targeted, Gevo respectfiilly submits that Dr. Thiele would be required
`
`to either cite to relevant scientific literature supporting the position or provide
`
`independent scientific data that backs the assertion. Neither of those things has
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`been provided by Dr. Thiele or the Petitioner.
`
`Thus, Gevo respectfully submits to the Board that the teachings of Puig must
`
`be taken on their face and without speculation as to the unsupported conclusions
`
`and impermissible hindsight of Petitioner.
`
`On its face, Puig teaches that Aftl and Aft2 are iron-responsive transcription
`
`factors that induce expression of the iron regulon, including Cth2. Further, Puig
`
`teaches that Cch is responsible for downregulating Fe-S cluster genes. DHAD is
`
`an F6-8 cluster gene. Consequently, Puig teaches the downregulation of Fe—S
`
`cluster genes such as DHAD, in contravention of the claims of the ‘565 patent that
`
`recite an “overexpressed. . .DHAD.” Any argument contrary to the plain teachings
`
`of Puig must be supported by citation to relevant scientific literature or
`
`independent evidentiary data.
`
`Furthermore, even if Petitioner is correct that an exogenous DHAD mRNA
`
`will contain a 3’-untranslated region that is different from the 3’-untranslated
`
`mRNA region of endogenous DHAD, this fact alone does not necessarily mean
`
`that Cth2 will not still bind to the exogenous mRNA. See Petition, at pg. 45-46; see
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`also, Declaration of Dr. Thiele, M 102-105 (EX. 1002).
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`For at least the aforementioned reasons, Gevo respectfully requests that the
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`Board reject Ground 2 of the Petition.
`
`iii.
`
`Ojeda teaches away from the present claims of the ‘565
`patent
`
`The Petitioner does not provide a salient rationale as to Why a skilled artisan
`
`would look to Ojeda to cure the deficiencies of Anthony and Puig with respect’to
`
`inactivating GRX3 and/or GRX4.
`
`Assuming arguendo that a skilled artisan would look to Ojeda, the effort
`
`would be futile, as Ojeda explicitly teaches away from the claimed yeast. That is,
`
`Gevo respectfully submits to the Board that Ojeda plainly teaches away from the
`
`claims of the ‘565 patent.
`
`DHAD is a Fe-S protein. Concerning Fe—S proteins, Ojeda teaches that
`
`GRX3 or GRX4 depletion in yeast does not impact the enzymatic activity of a
`
`variety of Fe-S proteins including aconitase, sulfite reductase, and isopropylmalate
`
`isomerase (Leul). See Ojeda, at pg. 17667, Col. 1 (EX. 1007). Ojeda also teaches
`
`that the double mutants lacking GRX3 and GRX4 decreased the enzymatic
`
`activity of several Fe-S proteins. Id. (“Aconitase activity...was decreased in the
`
`double null strain (Fig. 10A)”; As with aconitase, enzymatic activities of the
`
`cytosolic Fe-S enzymes sulfite reductase and Leul are “depressed in the double
`
`null strain”).
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`Ojeda also “addressed whether er3 and er4 .
`
`.
`
`. contributed to Fe-S
`
`maturation” and observed that “in the absence of either er3 or er4 the activities
`
`of mitochondrial and cytosolic Fe-S clusters enzymes were unaffected.” Id, at pg.
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`17668, Col. 2 (emphasis added) (Ex. 1007).
`
`Applicants respectfully submit that these results, if anything, teach away
`
`from deriving a recombinant yeast that comprises an “inactivated” GRX3 and/or
`
`GRX4 gene, as claimed in the ‘565 patent.
`
`Indeed, based upon Ojeda’s results,