UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`BUTAMAXTM ADVANCED BIOFUELS LLC
`Petitioner
`
`V.
`
`GEVO, INC.
`Patent Owner
`
`CASE IPR: Unassigned
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`8,273,565 B2 UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80,
`42.100-.123
`
`Mail Stop "PA TENT BOARD"
`
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION
`
`. 1
`
`OVERVIEW ................................................................................................... 1
`
`III. MANDATORY NOTICES ............................................................................3
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))................................5
`
`V.
`
`VI.
`
`PROCEDURAL STATEMENTS...................................................................6
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.104(b)) .........................................6
`
`A. Person of ordinary skill in the art and state of the art.............................6
`1. Established biochemical principles of iron regulation ......................7
`2. Established biochemical principles of fermentation products made
`from glucose in yeast.......................................................................10
`B. (cid:9) The’565 patent......................................................................................13
`C. (cid:9) Claim construction................................................................................13
`D. Identification of challenge (37 C.F.R. § 42.104(b)) .............................14
`1. Ground 1: claim 5 is anticipated by Flint ........................................15
`2. Ground 2: claim 10 would have been obvious over Flint in view of
`Valadi...............................................................................................23
`(a) Valadi discloses inactivation of GPD......................................24
`(b) Valadi demonstrates that deleting GPD results in increased
`levels of ethanol, a downstream product of pyruvate..............24
`3. Ground 3: claim 10 would have been obvious over Anthony in view
`of Puig, Ojeda and Valadi................................................................27
`4. Ground 4: claim 10 would have been obvious over Flint in view of
`Dundon.............................................................................................33
`(a) Dundon discloses inactivation of GPD....................................34
`(b) Dundon demonstrates that deleting GPD results in increased
`levels of lactic acid, a downstream product of pyruvate .........34
`5. Ground 5: claim 10 would have been obvious over Anthony in view
`
`11
`
`

`

`. 37
`
`of Puig, Ojeda and Dundon (cid:9)
`6. The art does not teach away from modifying a yeast containing
`recombinantly overexpressed DHAD .............................................. 39
`7. Gevo’s alleged unexpected results do not rebut the prima facie
`obviousness established herein........................................................43
`(a) Increased activity of recombinant overexpressed DFIAD in
`yeast lacking GRX3 and/or GRX4 would have been
`expected...................................................................................44
`(a) Gevo’s proffered evidence of unexpected results is not
`reasonably commensurate with the scope of the claims..........47
`
`II.
`
`THERE IS A REASONABLE LIKELIHOOD THAT PETITIONER WILL
`PREVAIL WITH RESPECT TO AT LEAST ONE OF THE
`CHALLENGED CLAIMS ...........................................................................49
`
`III.
`
`CONCLUSION.............................................................................................
`
`50
`
`111
`
`

`

`1 I. INTRODUCTION
`
`2 (cid:9)
`
`BUTAMAXTM ADVANCED BIOFUELS LLC’s ("Petitioner") Petition for Inter
`
`3 Partes Review ("Petition") seeks cancellation of claims 5 and 10 of U.S. Patent
`
`4 No. 8,273,565 ("the ’565 patent") (BMX1001).
`
`5
`
`6 (cid:9)
`
`7
`
`II. OVERVIEW
`
`on March 4, 2014, the Patent Trial and Appeal Board
`
`("Board") instituted
`
`inter partes review ("IPR") of claims 1-9 and 11-19 of the ’565 patent. In its
`
`8 decision on institution, the Board found that the ’565 patent claims are not
`
`9 supported by the limited disclosure in the provisional applications to which the
`
`10
`
`11 (cid:9)
`
`’565 patent claims priority benefit. Case 1PR2013-00539, Paper 9 at pp. 13-16
`
`(Mar. 4, 2014). The Board also found that it is reasonably likely that claims 1-4, 6-
`
`12 8, and 11-19 are anticipated (id. at pp. 16-18) and that claims 1-9 and 11-19 would
`
`13 have been obvious over the prior art (id. at pp. 19-27).
`
`14 (cid:9)
`
`15
`
`In its decision on institution, the Board concluded that Petitioner "has not
`
`demonstrated a reasonable likelihood it will prevail on the ground that claim
`
`5 is
`
`16 unpatentable as anticipated by Flint" because "Paragraph 0118 of the Flint ’333
`
`17 provisional, however, does not [incorporate by reference U.S. Patent Application
`
`18 Publication No. 2010/0197519 ("the ’519 publication")]." Id. at p. 18. But, as
`
`19 explained in detail below, Paragraph 0118 of the Flint ’333 provisional does
`
`20 incorporate the ’519 publication by reference, albeit by reference to its application
`
`1
`
`

`

`I serial number. This evidence establishes a reasonable likelihood that Flint
`
`2
`
`3 (cid:9)
`
`4
`
`5
`
`anticipates claim 5.
`
`The Board did not institute IPR for claim 10 because Petitioner allegedly (i)
`
`"has not directed us to any disclosure of an inactivated GPD" and (ii) "has not
`
`pointed to any disclosure in Overkamp or otherwise explained why one of
`
`6 ordinary skill would have reasoned that deleting GPD would result in increased
`
`7
`
`levels of pyruvate available for use in isobutanol production."
`
`Id. at p. 28. But, as
`
`8 explained in detail below and supported by the accompanying declaration of Dr.
`
`9 Dennis J. Thiele, ("Thiele Dec." BMX1002), the prior art described inactivating
`
`10 GPD. And, in view of the prior art, a person of ordinary skill in the art ("POSA")
`
`11
`
`had a reason, and the know-how, to arrive at the recombinant yeast of claim 10
`
`12 with a reasonable expectation of success. This is because the prior art presented
`
`13 herein teaches inactivating GPD so as to increase production of products made
`
`14
`
`from pyruvate. Thus, motivating a POSA to inactivate GPD when expressing a
`
`15 recombinant pathway for making isobutanol from pyruvate.
`
`16 (cid:9)
`
`This Petition squarely addresses the alleged deficiencies identified by the
`
`17 Board making it reasonably likely that Petitioner will prevail with respect to each
`
`18 of claims 5 and 10 in view of the Grounds presented in this Petition.
`
`2
`
`

`

`1 LII. MANDATORY NOTICES
`
`2 (cid:9)
`
`Real party-in-interest (37 C.F.R. § 42.8(b)(1)): BuTAMAxTM ADVANCED
`
`3 BIOFUELS LLC ("Petitioner") is the real party-in-interest.
`
`4 (cid:9)
`
`5
`
`Related matters (37 C.F.R. § 42.8(b)(2)): Administrative Matters: U.S.
`
`Patent No. 8,273,565 issued from U.S. Patent Appi. No. 13/246,693, filed
`
`6 September 27, 2011. The ’693 application is a division of U.S. Patent Appi. No.
`
`7 13/228,342, filed September 8, 2011, now U.S. Patent No. 8,071,358; and of U.S.
`
`8 Patent Appi. No. 12/953,884, filed November 24, 2010, now U.S. Patent No.
`
`9 8,017,376. The ’376 patent is currently under Inter Partes Reexamination as
`
`10 Control No. 95/001,870 (BMX1016).
`
`11 (cid:9)
`
`On August 30, 2013, Butamax filed a Petition for IPR requesting review of
`
`12 claims 1-19 of the ’565 patent. 1 The Board instituted IPR of claims 1-9 and 11-19
`
`13 on February 4, 2014. Case 1PR2013-00539, Paper 9 (Mar. 4, 2014).
`
`14 (cid:9)
`
`Judicial Matters: Patent Owner, Gevo Inc., asserted the ’376 patent against
`
`15 Butamax in Gevo, Inc. v. ButamaxTM Advanced Biofuels LLC, et al., No. 11-
`
`16 54(SLR)(D. Del. Aug. 11, 2011). Final judgment was entered on August 8, 2013
`
`Patent Owner, Gevo Inc., did not file a Patent Owner Preliminary Response in
`
`IPR20 13-00539, and, to date, has not disputed any of the arguments that Petitioner
`
`presented in that proceeding.
`
`3
`
`

`

`I in that case. Gevo asserted the ’565 patent against Butamax in Gevo, Inc. v.
`
`2 ButamaxTM Advanced Biofuels LLC, et al., No.
`
`12-1202(SLR)(D. Del. Sept. 25,
`
`3 2012). In addition, Butamax filed for declaratory judgment of invalidity of the
`
`4 ’565 patent in ButamaxTM Advanced Biofuels LLC, et al. v. Gevo, Inc., No. 12-
`
`5
`
`1201(SLR)(D. Del. Sept. 25, 2012). Gevo moved to voluntarily dismiss with
`
`6 prejudice all claims by Gevo against Butamax and DuPont in the 12-1202 and 12-
`
`7
`
`1201 actions on August 7, 2013. On the same day, Butamax moved to voluntarily
`
`8 dismiss without prejudice all claims, defenses and counterclaims of Butamax and
`
`9 DuPont against Gevo in the 12-1202 and 12-1201 actions. The court closed both
`
`10 actions on August 9, 2013.
`
`11 (cid:9)
`
`Designation of lead and back-up counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead Counsel
`Deborah A. Sterling (Reg. No. 62,732)
`STERNE, KESSLER, GOLDSTEIN & Fox
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8501 (telephone)
`202.371.2540 (facsimile)
`dsterlin-PTAB @skgf. corn
`
`Back-Up Counsel
`Peter A. Jackman (Reg. No. 45,986)
`STERNE, KESSLER, GOLDSTEIN & Fox
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8582 (telephone)
`202.371.2540 (facsimile)
`pjackman-PTAB@skgf.com
`
`Notice of service (37 C.F.R. § 42.8(b)(4)): Please direct all correspondence
`
`12
`
`13 (cid:9)
`
`14 to lead counsel at the above address. Petitioner consents to email service at:
`
`15 dsterlin-PTAB@skgf.com and pjackman-PTAB@skgf.com .
`
`rd
`
`

`

`I IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`
`2 (cid:9)
`
`Petitioner certifies that (1) the ’565 patent is available for IPR; and (2)
`
`3 Petitioner is not barred or estopped from requesting IPR of any claim of the ’565
`
`4 patent on the grounds identified in this Petition.
`
`5 (cid:9)
`
`In Case 1PR2013-00539, the Board held that Butamax’s dismissal without
`
`6 prejudice of its District Court Action nullifies the effect of Petitioner’s request for
`
`7 declaratory judgment of invalidity. Paper 9 at p. 7 ("Accordingly, Butamax’s
`
`8 complaint in the First District Court Action does not invoke the statutory bar of §
`
`9 3 15(a).")). So the present IPR is not barred in view of Petitioner’s dismissed
`
`10 request for declaratory judgment of invalidity.
`
`11 (cid:9)
`
`And, while Gevo served Butamax with its first complaint alleging
`
`12 infringement of the ’565 patent more than one year ago, the normal statutory one-
`
`13 year bar under 35 U.S.C. § 3 15(b) does not apply here because (1) the Board has
`
`14 already instituted an inter partes review trial on this patent on a timely first
`
`15
`
`Petition for IPR filed by Butamax (Case No. 1PR2013-00539), and (2) Butamax
`
`16 accompanies this Petition with a motion for joinder under 35 U.S.C. § 3 15(c). See
`
`17
`
`35 U.S.C. § 315(b)(final sentence); 37 C.F.R. § 42.122(b); see also, e.g., Ariosa
`
`18 Diagnostics v. Isis Innovation, Ltd., Case 1PR2013-00250, Paper 24 (Sept. 3,
`
`19 (cid:9)
`
`2013).
`
`5
`
`

`

`I V.
`
`PROCEDURAL STATEMENTS
`
`2 (cid:9)
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a).
`
`3 Concurrently filed are a (i) Power of Attorney under 37 C.F.R. § 42.10(b); (ii) an
`
`4 Exhibit List under § 42.63(e); and (iii) a Motion for Joinder with Case 1PR2013-
`
`5
`
`00539 under 35 U.S.C. § 315(c). The required fee is paid through online credit
`
`6 card payment. The U.S. Patent and Trademark Office ("USPTO") is authorized to
`
`7
`
`charge any fee deficiency, or credit any overpayment, to Deposit Acct. No. 19-
`
`8 0036.
`
`9 VI. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.104(b))
`10 (cid:9)
`
`11 (cid:9)
`
`Petitioner respectfully requests IPR under 35 U.S.C. §§ 311-319 and 37
`
`12 C.F.R. § § 42.1-.80 and 42.100-42.123, and the cancellation of claims 5 and 10 of
`
`13
`
`the ’565 patent as unpatentable under 35 U.S.C. §§ 102 and 103, respectively, as
`
`14 set forth herein.
`
`15 (cid:9)
`
`16 (cid:9)
`
`A. (cid:9)
`
`Person of ordinary skill in the art and state of the art
`
`A POSA is presumed to be aware of all pertinent art, thinks along
`
`17 conventional wisdom in the art, and is a person of ordinary creativity. With
`
`18 respect to the ’565 patent, a POSA typically would have a Ph.D. in the life
`
`19 sciences or a similar related discipline, and have familiarity, training, and
`
`20 experience in molecular biology, microbial genetics, and microbial metabolism.
`
`21 Alternatively, a POSA typically would have at least a scientific background such
`
`mo
`
`

`

`I (cid:9)
`
`as a Bachelor’s degree in the life sciences (e.g., biology, microbiology, molecular
`
`2 biology or biochemistry) or a similar related discipline, and have substantial
`
`3 familiarity, training, and experience in molecular biology, microbial genetics and
`
`4 microbial metabolism.
`
`5 (cid:9)
`
`6 (cid:9)
`
`7
`
`8 (cid:9)
`
`9 (cid:9)
`
`Prior to November 24, 2010 (cid:9)
`
`the earliest date to which the claims are
`
`entitled benefit (cid:9)
`
`a POSA understood the following biochemical principles
`
`regarding (i) iron regulation and (ii) fermentation products made from glycerol in
`
`yeast.
`
`1. (cid:9)
`
`Established biochemical principles of iron regulation
`
`10 (cid:9)
`
`Iron-sulfur (Fe-S) clusters are cofactors of proteins that perform a number
`
`11 of biological roles. DHAD is an Fe-S cofactor enzyme
`
`(i.e., an Fe-S protein),
`
`12 meaning that it requires this cofactor for activity. Thus, controlling Fe uptake and
`
`13 Fe-S cluster formation is necessary for the cellular functioning of DHAD.
`
`14 BMX1002at{67.
`
`15 (cid:9)
`
`Iron regulation in the model organism Saccharomyces cerevisiae is, to some
`
`16 extent, regulated at the level of transcription via the iron responsive transcriptional
`
`17 activators Afti and Aft2. See Rutherford, J.C., et al., J. Biol. Chem.,
`
`18
`
`278(30):27636-27643 (2003) (BMX1019) and BMX1002 at ¶69. Afti shuttles
`
`19 between the nucleus in iron-deficient cells (low iron) and the cytoplasm in iron-
`
`20 replete cells (high iron). See BMX1019 at p. 27636. A complex composed of
`
`7
`
`

`

`I Grx3/Grx4/Fral/Fra2 and the proteins Aftl/Aft2 is localized in the cytosol in high
`
`2 iron conditions. See Li, H., et al., Biochem., 48:9569-9581 (2009) (BMX1020)
`
`3 and BMX1002 at ¶69. In low iron conditions, Afti translocates to the nucleus. See
`
`4 BMX1020 at p. 9569. Cells lacking Grx3 and/or Grx4 see an increased activation
`
`5
`
`of Aft proteins, and cells lacking both Grx3 and Grx4 show increased levels of
`
`6 expression of a group of dozens of genes collectively referred to as the "iron
`
`7 regulon." See Ojeda, I Biol. Chem. 281(26):17661-17669 (2006) (BMX1007);
`
`8 and BMX 1002 at ¶69.
`
`9 (cid:9)
`
`In the nucleus, Afti activates transcription by binding to a conserved
`
`10 promoter sequence in the genes in the iron regulon. Id.; see Figure A below. The
`
`11 iron regulon includes a series of genes with products that function in the
`
`12 regulation of Fe-S cluster availability. See e.g., BMX1006, Suppl. Table S2;
`
`13 BMX 1O19, pp. 27636-9, Tables land II, and Fig. 1; and BMX 1002 at T70.
`
`

`

`Hfl ro (cid:9)
`
`Fra 1/2 (cid:9)
`
`I (cid:9)
`
`complex
`
`I
`
`Low Iror,
`All 112 (cid:9)
`-
`activaon, ( Aflh/Th
`complex
`dasowbon
`
`Cth2(Tis11)
`
`execn(cid:216)ary won regulon genes
`
`Fe uptake
`Fe-S cksstec fonnatkxilassembty
`
`/\\
`
`exemplary Fe-S cster protests
`
`1
`
`cytosOl (cid:9)
`
`nucleus
`
`2 FIGURE A - Regulation of Aft 1/2 and the iron regulon in high iron and low iron
`
`3 (cid:9)
`
`4
`
`5
`
`conditions.
`
`Importantly, Afti and Aft2 were known to transcriptionally activate
`
`cysteine-three-histidine-2 (Cth2; aka TIS1 1), a member of the iron regulon.
`
`6 BMX1006, pp. 99-100; BMX1002 at ¶72. The CTH2 gene, in turn, encodes an
`
`7 mRNA binding protein that binds to and accelerates the decay of mRNAs
`
`8 encoding a group of proteins that include numerous endogenous Fe-S cluster-
`
`9
`
`requiring proteins, such as DHAD (which is encoded by the ILV3 gene).
`
`10 BMX1006 at Table 1, pp. 107-108; and BMX1002 at ¶72. The decay of
`
`11 endogenous Fe-S cluster proteins would reduce competition for Fe-S clusters for a
`
`12 recombinantly overexpressed protein. BMX 1002 at ¶72. Deletion of Grx3 and/or
`
`(cid:9)
`(cid:9)
`

`

`I Grx4 would result in an increase in Afti activity and an increase in Cth2
`
`2 expression, thereby accelerating the decay of endogenous Fe-S cluster proteins.
`
`Id.
`
`3 This would increase Fe-S sulfur cluster availability for recombinantly
`
`4 overexpressed Fe-S proteins, such as overexpressed DHAD. Id.
`
`5 (cid:9)
`
`Because overexpressed DHAD would have a need for additional available
`
`6 Fe-S clusters, Anthony et at., U.S. Appl. Pubi. 2010/0081179 ("Anthony")
`
`7 (BMX 1005) suggested increasing Fe-S cluster availability in yeast engineered to
`
`8 overexpress DHAD, and in yeast comprising an engineered isobutanol
`
`9 biosynthetic pathway. BMX1005 at ¶[0006]. The significance of this teaching
`
`10 would not have been lost on a POSA, as industry and academia focused a great
`
`11 deal of attention toward identifying recombinant approaches to increase the
`
`12 specific activity of DHAD. BMX 1002 at ¶73.
`
`13 (cid:9)
`14 (cid:9)
`
`15 (cid:9)
`
`2. (cid:9)
`
`Established biochemical principles of fermentation products
`made from glucose in yeast
`
`By November 24, 2010, yeast had been used as biocatalysts in a number of
`
`16 industrial fermentation processes. These fermentations produced, for example,
`
`17 ethanol, lactic acid (also known as "lactate"), and isobutanol, each of which are
`
`18 made through native (ethanol) or recombinant (lactic acid and isobutanol)
`
`19 metabolic pathways that utilize pyruvate. See BMX 1005, BMX1O15, BMX 1O18,
`
`20 BMX1027, and BMX1028. Pyruvate is made from glucose. BMX1026 at pp.
`
`10
`
`

`

`1
`
`527-544. However, glucose also serves as a substrate for a competing pathway in
`
`2 yeast that leads to the production of glycerol. See Figure B below.
`
`glucose
`
`fructose- i ,6-bisphosphate
`
`Dihydroxyacetone phosphate <_> glyceraldehyde-3 -phosphate
`
`4,
`
`pyruvate
`
`S I (cid:9)
`
`glycerol-3 -phosphate (cid:9)
`
`3
`
`glycerol (cid:9)
`
`ethanol (cid:9)
`
`isobutanol lactic acid
`
`4 FIGURE B - Relevant Portions of Pathways for Yeast Fermentation Products
`
`5 Made from Glucose. BMX1005 at ¶24 and Figure 1; BMX1027 at p. 434; and
`
`6 BMX1026 at pp. 527-544.
`
`7 (cid:9)
`
`As evidenced in Figure B, glucose can be used to produce either glycerol-3-
`
`8 phosphate (which is used to produce glycerol) or pyruvate (which is used to
`
`9 produce, e.g., ethanol or lactic acid, and, in certain recombinant host cells, lactic
`
`10 acid or isobutanol). BMX1026 at pp. 527-44, BMX1027 at p. 434, and BMX1002
`
`11 at ¶J74 and 75. Therefore, glycerol production consumes glucose that could
`
`12 otherwise be used to produce pyruvate and downstream products made from
`
`13
`
`pyruvate. BMX 1002 at ¶75. Glycerol-3 -phosphate dehydrogenase (GPD, also
`
`14 referred to as GPI-ID) is a key enzyme in the conversion of glucose to glycerol.
`
`11
`
`

`

`I BMX1027 at p. 434, BMX1024 at p. 783, and BMX 1002 at ¶77. Therefore, yeast
`
`2 lacking GPD produce less glycerol. BMX1024 at p. 791 and Table 1; BMX1027
`
`3 at pp. 434 and 436; BMX1028 at p. 36; and BMX1002 at ¶77. By converting
`
`4 DHAP to G3P in the glucose to glycerol pathway, GPD enzymes reduce the
`
`5
`
`availability of pyruvate 2 and downstream products made from pyruvate.
`
`6 BMX1027 at p. 437, BMX1028 at p.36, and BMX 1002 at ¶78. A POSA interested
`
`7
`
`in engineering yeast to express recombinant pathways for producing downstream
`
`8 products derived from pyruvate (such as ethanol and lactic acid) would have
`
`9 known that the action of GPD enzymes negatively affects the ability of
`
`10 microorganisms to produce ethanol and lactic acid. BMX 1002 at ¶78.
`
`2 Pyruvate is a short-lived intermediate in native ethanol, and recombinant lactic
`
`acid, and isobutanol producing pathways. Therefore, a POSA would not
`
`necessarily expect to see a build-up of pyruvate in yeast lacking GPD. Instead, a
`
`POSA would understand that extra pyruvate produced in the absence of GPD
`
`could rapidly be converted to downstream products of pyruvate, resulting in an
`
`increased accumulation of the downstream products. BMX 1002 at ¶74.
`
`12
`
`

`

`I (cid:9)
`
`2 (cid:9)
`
`3
`
`4
`
`5
`
`B. (cid:9)
`
`The ’565 patent
`
`Against this backdrop, the ’565 patent issued on September 25, 2012. The
`
`’565 patent asserts its earliest priority claim to November 24, 2009, but the Board
`
`has found that the ’565 patent claims are not entitled to claim the benefit of a filing
`
`date earlier than November 24, 2010. Case 1PR2013-00539, Paper 9 at p. 16 (Mar.
`
`6 4, 2014). According to the USPTO’s electronic-assignment records, Gevo owns
`
`7
`
`8
`
`9
`
`the ’565 patent by assignment. The ’565 patent specification is generally directed
`
`towards "recombinant microorganisms comprising one or more dihydroxyacid
`
`dehydratase (DHAD)-requiring biosynthetic pathways and methods of using said
`
`10 recombinant microorganisms to produce beneficial metabolites derived from said
`
`11 DHAD-requiring biosynthetic pathways." BMX 1001, Abstract.
`
`12 (cid:9)
`
`13 (cid:9)
`
`14
`
`15
`
`C. (cid:9)
`
`Claim construction
`
`In its decision on institution in Case 1PR2012-00539, the Board construed
`
`the following terms and phrases of the ’565 patent claims: (i) "inactivated," (ii) the
`
`yeast genera and species of claims 1-16 and 19, and (iii) the localization of
`
`16 DFIAD. Case 1PR2013-00539, Paper 9 at pp. 8-12 (Mar. 4, 2014). Petitioner
`
`17
`
`18
`
`19
`
`agrees with the Board’s conclusions on how those terms should be construed.
`
`Petitioner posits that any remaining terms of claims 5 and 10 are plain on their
`
`face, require no specific construction, and are to be given their broadest reasonable
`
`20 interpretation, as understood by a POSA in view of the ’565 patent’s specification.
`
`13
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`I (cid:9)
`
`2 (cid:9)
`
`3 (cid:9)
`
`4
`
`5
`
`See 37 C.F.R. § 42.100(b).
`
`D. (cid:9)
`
`Identification of challenge (37 C.F.R. § 42.104(b))
`
`IPR of claims 5 and 10 of the ’565 patent is requested on the grounds for
`
`unpatentability listed in the table below. Per 37 C.F.R. § 42.6(d), copies of the
`
`references are filed herewith. In support of the proposed grounds for
`
`6 unpatentability, this Petition is accompanied by the declaration of Dr. Dennis J.
`
`7 Thiele (BMX1002), an expert in the fields of molecular biology, microbial
`
`8 genetics, and microbial metabolism, which explains what the art would have
`
`9 conveyed to a POSA.
`
`Ground
`
`Claim
`
`35 U.S.C.
`
`Index of References
`
`1
`
`2
`
`3
`
`4
`
`5
`
`5
`
`10
`
`10
`
`10
`
`10
`
`§ 102(e)
`
`§ 103(a)
`
`§ 103(a)
`
`Flint (BMX1003)
`
`Flint (BMX1003) and Valadi (BMX1027)
`
`Anthony (BMX 1005) in view of Puig
`(BMX 1006), Ojeda (BMX 1007), and
`Valadi (BMX1 027)
`
`g 103’a1
`
`Flint (BMX 1003) and Dundon
`(BMX1O28)
`
`§ 103(a)
`
`Anthony (BMX 1005) in view of Puig
`(BMX 1006), Ojeda (BMX 1007), and
`Dundon (BMX 1028)
`
`10 (cid:9)
`
`While the combined references in Grounds 2-5 disclose all the limitations of
`
`11 claim 10 of the ’565 patent, the proposed grounds are non-cumulative as each
`
`12 primary and secondary reference relied upon teaches different limitations found in
`
`14
`
`

`

`I (cid:9)
`
`claim 10 of the ’565 patent. Further, it is reasonably likely the Petitioner will
`
`2 prevail in challenging the patentability of claim 10 on the basis of each ground.
`
`3 (cid:9)
`
`4 (cid:9)
`
`5
`
`1. (cid:9)
`
`Ground 1: claim 5 is anticipated by Flint
`
`In its first Petition for IPR, Butamax asserted that the
`
`’565 patent claims are
`
`not entitled to claim priority benefit prior to November 24, 2010. Case 1PR2013-
`
`6 00539, Paper 3, at pp. 12-25 (Aug. 30, 2013). The Board agreed. Id. Paper 9, at
`
`7
`
`pp. 15-16 (Mar. 4, 2014). According to the Board, the ’565 patent claims are not
`
`8 entitled to claim priority benefit prior to November 24, 2010 because:
`
`9 (cid:9)
`
`10 (cid:9)
`
`11 (cid:9)
`
`12 (cid:9)
`
`13 (cid:9)
`
`14 (cid:9)
`
`15 (cid:9)
`
`16 (cid:9)
`
`17 (cid:9)
`
`18 (cid:9)
`
`19 (cid:9)
`
`20 (cid:9)
`
`21 (cid:9)
`
`22 (cid:9)
`
`23 (cid:9)
`
`24 (cid:9)
`
`the ’952 and ’209 provisionals would not convey, with reasonable
`
`clarity, to one of ordinary skill that the inventors had invented or
`
`were in possession of yeast with inactivated GRX3 or GRX4
`
`proteins resulting from insertions, deletions, or combinations of
`
`insertions and deletions of nucleotides of the corresponding gene-
`
`with the exception of complete gene deletion. See Centocor Ortho
`
`Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011)
`
`("To satisfy the written description requirement, the [specification]
`
`must convey with reasonable clarity to those skilled in the art that, as
`
`of the filing date sought, [the inventor] was in possession of the
`
`invention, and . . . show that the inventor actually invented the
`
`invention claimed.") (internal quotations omitted). Thus, we are
`
`persuaded that the provisionals do not provide written description
`
`support for claim 1 and its dependent claims 2-19 and that the claims
`
`are not entitled to priority to these applications, making the effective
`
`filing date of the ’565 patent no earlier than November 24, 2010.
`
`15
`
`

`

`1 (cid:9)
`
`2 (cid:9)
`
`Id. at pp. 15-16.
`
`PCT Appi. Publ. No. WO 2011/103300 A2 ("Flint") (BMX1003) was filed
`
`3 by another on February 17, 2011, published in English under Article 2 1(2) on
`
`4 August 25, 2011, designated the U.S., and claimed priority to U.S. Prov. Appl.
`
`5 No. 61/305,333 ("the ’333 application") (BMX1004), filed February 17, 2010.
`
`6 Thus, Flint qualifies as prior art to claim 5 of the ’565 patent under 35 U.S.C.
`
`7 § 102(e) as of the ’333 application’s February 17, 2010 filing date. Claim
`
`5
`
`8 depends from claims 1, 2, and 4; each of which the Board found reasonably likely
`
`9 to be anticipated by Flint. Case 1PR2013-00539, Paper 9 at pp. 16-18 (Mar. 4,
`
`10 2014). Flint also discloses the additional limitation of claim 5, thus anticipating
`
`11 (cid:9)
`
`that claim also. Because Flint anticipates claim 5, it is reasonably likely that
`
`12 Petitioner will prevail with regard to at least one challenged claim on the basis of
`
`13 Ground 1.
`
`14 (cid:9)
`
`is
`
`The following claim chart shows where Flint and its provisional describe
`
`every limitation of claim 5 (rewritten in independent form), arranged as claimed:
`
`’565 Disclosure (cid:9)
`5 (cid:9) of the (cid:9)
`(BMX 1003)
`independent
`in (cid:9)
`
`of (cid:9)
`
`’333
`of (cid:9)
`Flint Disclosure (cid:9)
`provisional (BMX 1004)
`
`Claim (cid:9)
`patent (cid:9)
`form
`
`A recombinant yeast
`microorganism
`comprising a
`recombinantly
`overexpressed
`polynucleotide encoding
`
`"For over-expression of "For over-expression of
`the
`the a (cid:9) DFIAD (cid:9) protein, (cid:9)
`a DHAD protein, (cid:9)
`DHAD gene ilvD from DHAD gene ilvD from
`ID S. mutans was used. .
`(SEQ (cid:9)
`S. (cid:9) mutans (cid:9)
`." (Example 1, ¶[0146])
`N0:167) was used . . . ."
`(Example 1, ¶[023 1])
`
`16
`
`

`

`’565
`5 (cid:9) of the (cid:9)
`in (cid:9)
`independent
`
`Disclosure (cid:9)
`(BMX 1003)
`
`of (cid:9)
`
`Flint
`
`t333
`of (cid:9)
`Disclosure (cid:9)
`provisional (BMX 1004)
`
`Claim (cid:9)
`patent (cid:9)
`form
`
`a dihydroxy acid
`dehydratase (DI-IAD),
`
`wherein said
`recombinant yeast
`microorganism is
`
`"Specifically, the present
`invention is related to a
`recombinant host cell, in
`particular a yeast cell,
`comprising a dihydroxy-
`acid dehydratase
`polypeptide. The
`invention is also related
`to a recombinant host
`cell having increased
`specific activity of the
`dihydroxy-acid
`dehydratase polypeptide
`as a result of increased
`expression of the
`polypeptide. . ."
`([[00O3])
`
`"Provided herein are
`recombinant host cells
`comprising at least one
`heterologous
`polynucleotide encoding
`a polypeptide having
`dihydroxy-acid
`dehydratase activity. . ."
`({[0009])
`
`"Specifically, the present
`invention is related to a
`recombinant host cell, in
`particular a yeast cell,
`comprising a dihydroxy -
`acid dehydratase
`polypeptide. The
`invention is also related
`to a recombinant host
`cell having increased
`specific activity of the
`dihydroxy-acid
`dehydratase polypeptide
`as a result of increased
`expression of the
`polypeptide. .
`(J[0001])
`
`"Provided herein are
`recombinant host cells
`comprising at least one
`heterologous
`polynucleotide encoding
`a polypeptide having
`dihydroxy-acid
`dehydratase activity...
`"(J[0008])
`
`See also section entitled
`"Over-Expression of
`DHAD Activity...
`(J[0098]-[00111])
`
`See also section entitled
`"Over-Expression of
`DHAD Activity ... ."
`(J[0103]-[01 16])
`DHAD
`DHAD "Surprisingly, (cid:9)
`"Surprisingly, (cid:9)
`in (cid:9)
`the
`the specific (cid:9) activity (cid:9)
`specific (cid:9) activity (cid:9)
`in (cid:9)
`crude extract in strains crude extract in strains
`
`
`
`17
`
`

`

`’565
`5 (cid:9) of the (cid:9)
`independent
`in (cid:9)
`
`Disclosure (cid:9)
`(BMX 1003)
`
`of (cid:9)
`
`Flint
`
`’333
`of (cid:9)
`Disclosure (cid:9)
`provisional (BMX 1004)
`
`Claim (cid:9)
`patent (cid:9)
`form
`
`with a deletion in either with a deletion in either
`engineered to comprise
`the FRA2 or the GRX3
`the FRA2 or the GRX3
`at least one inactivated
`gene increased by 2- to gene increased by 2- to
`monothiol glutaredoxin
`3-fold....... (Example 3-fold.... ... (Example
`selected from the group
`3, ¶[0154])
`3, ¶[0240J)
`consisting of monothiol
`glutaredoxin-3 (GRX3)
`"Fe uptake and
`"Fe uptake and
`and monothiol
`metabolism and/or Fe-S metabolism and/or Fe-S
`glutaredoxin-4 (GRX4),
`cluster biosynthesis
`cluster biosynthesis
`and wherein said
`genes, including, but not
`genes, including, but not
`inactivated monothiol
`limited to, those listed in
`limited to, those listed in
`glutaredoxin results from Tables 7, 8 or 9 can
`Tables 7, 8 and 9 can
`the deletion of one or
`potentially be deleted,
`potentially be deleted,
`more nucleotides of an
`mutated, expressed, up-
`mutated, expressed, up-
`endogenous gene
`regulated, or down-
`regulated, or down-
`encoding said monothiol
`regulated to increase the
`regulated to increase the
`glutaredoxin, the
`flux in an F e-S cluster
`flux in an Fe-S cluster
`insertion of one or more
`biosynthesis pathway
`biosynthesis pathway
`nucleotides into an
`and improve specific
`and improve specific
`endogenous gene
`activity of Fe-S cluster
`activity of Fe-S cluster
`encoding said monothiol
`requiring proteins such
`requiring proteins such
`glutaredoxin, or
`as DI-IAD." (J[0163])
`as DHAD." (J[0123])
`combinations thereof
`
`wherein said
`recombinant
`microorganism further
`comprises an isobutanol
`producing metabolic
`pathway, said isobutanol
`producing metabolic
`pathway comprising the
`following substrate to
`product conversions:
`
`Note: GRX3 and GRX4 Note: GRX3 and GRX4
`are both listed in Table 8
`are both listed in Table 8
`"As described in U.S.
`Patent Appi. Pubi. No.
`20070092957 Al, which
`is incorporated by
`reference herein, steps in
`an example isobutanol
`biosynthetic pathway
`include conversion of:
`- pyruvate to
`acetolactate (see Fig. 5,
`pathway step a therein),
`
`"As described in U.S.
`Patent Appl. Pubi. No.
`20070092957 Al, which
`is incorporated by
`reference herein, steps in
`an example isobutanol
`biosynthetic pathway
`include conversion of:
`- pyruvate to
`acetolactate (see Fig. 5,
`pathway step a therein),
`
`18
`
`

`

`5 (cid:9) of the (cid:9)
`’565
`in (cid:9)
`independent
`
`Disclosure (cid:9)
`(BMX 1003)
`
`of (cid:9)
`
`Flint
`
`’333
`of (cid:9)
`Disclosure (cid:9)
`provisional (BMIX 1004)
`
`Claim (cid:9)
`patent (cid:9)
`form
`
`(a) pyruvate to
`acetolactate;
`
`(b) acetolactate to 2,3-
`dihydroxyisovalerate;
`
`(c) 2,3-
`dihydroxyisovalerate to
`a-ketoisovalerate;
`
`(d) a-ketoisovalerate to
`isobutyraldehyde; and
`
`(e) isobutyraldehyde to
`isobutanol;
`
`and wherein said DHAD
`catalyzes the conversion
`of 2,3-
`dihydroxyisovalerate to
`a-ketoisovalerate
`
`wherein the enzyme that
`
`as catalyzed for example
`as catalyzed for example
`by acetolactate synthase,
`by acetolactate synthase,
`- acetolactate to 2,3-
`- acetolactate to 2,3-
`dihyd roxyisovale rate
`dihyd roxyisovale rate
`(see Fig. 5, pathway step
`(see Fig. 5, pathway step
`b therein) as catalyzed
`b therein) as catalyzed
`for example by
`for example by
`acetohydroxy acid
`acetohydroxy acid
`i someroreductase;
`isomeroreductase;
`
`
` 3- - 2 93-
`- 2 93-
`’ d i hydroxyisovalerate to dihydroxyisovalerate to
`a- keto isovale rate (see
`a- keto isovale rate (see
`Fig. 5, pathway step c
`Fig. 5, path