`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`PO. Box 1450
`Alexandria, Virginia 22313—1450
`www.uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`95/001,870
`
`'
`
`01/10/2012
`
`8017376
`
`ATTORNEY DOCKET NO.—_
`2888.075REX2
`2288
`
`03/23/2012
`
`58249
`COOLEYLLP
`
`7590
`
`ATTN: Patent Group
`Suite 1100
`777 _ 6th Street, NW
`WASHINGTON, DC 20001
`
`.
`
`RAILEY, JOHNNY r
`
`-
`
`ART UNTT
`3991
`
`PAPERNUMBER
`
`MAIL DATE
`
`‘ DELIVERY MODE
`
`03/23/2012 -
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period fer reply, if any, is set in the attached communication.
`
`PTOL-90A (Rev. 04/07)
`
`BUTAMAX 1 0 1 6
`
`

`

`91w"
`
`.“-'\
`
`
`‘5.“a 2
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Commissionerfor Patents
`United States Patenl and Trademark Office
`PO. Box1450
`Alexandria. VA 22313-1450
`WWO.”
`
`DO NOT USE IN PALM PRINTER
`
`(THIRD PARTY REQUESTER'S CORRESPONDENCE ADDRESS)
`
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
`1100 NEW YORK AVENUE, N.W.
`WASHINGTON, DC 20005
`
`Transmittal of Communication to Third Party Requester
`Inter Partes Reexamination
`
`
`REEXAMINATION CONTROL NUMBER 95/001 870.
`
`
`
`PATENT NUMBER 8 017 376. -
`
`TECHNOLOGY CENTER 3999.
`
`ART UNIT 3991.
`
`Enclosed is a copy of the latest communicatibn from the United States Patent and
`Trademark Office in the above-identified reexamination proceeding. 37 CFR 1.903.
`
`Prior to the filing of a Notice of Appeal, each time the patent owner responds to this
`communication, the third party requester of the inter partes reexamination may once file
`written comments within a period of 30 days from the date of service of the patent owner's
`response. This 30-day time period is statutory (35 U.S.C. 314(b)(2)), and, as such, it cannot
`be extended. See also 37 CFR 1.947.
`
`If an ex parte reexamination has been merged with the inter partes reexamination, no
`responsive submission by any ex parte third party requester is permitted.
`
`All correspondence relating to this inter partes reexamination proceeding should be
`directed to the Central Reexamination Unit at the mail, FAX, or hand-carry addresses
`given at the end of the communication enclosed with this transmittal.
`
`PTOL-207O (Rev.07-04)
`
`

`

`
`
`Control No.
`
`Patent Under Reexamination
`
`
`
`
`
`ORDER GRANTING/DENYING
`
`REQUEST FOR INTER PARTES
`
`
`
`95/001,870
`Examiner.
`
`8017376
`Art Unit
`
`
`
`
`
`
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address. --
`
`
`
`
`
`
`
`
`
`
`
`The request for inter partes reexamination has been considered. Identification of the claims, the
`references relied on, and the rationale supporting the determination are attached.
`
`1. E] The request for inter partes reexamination is GRANTED.
`
`[Z An Office action is attached with this order.
`
`
` [Z PTO-892
`
` Attachment(s):
`g PTO/SB/08
`EIOther:
`
`
`
`
`[:I An Office action will follow in due course.
`
`
`
`2. [:l The request for inter partes reexamination is DENIED.
`
`
`This decision is not appealable. 35 U.S.C. 312(c). Requester may seek review of a denial by petition
`to the Director of the USPTO within ONE MONTH from the mailing date hereof. 37 CFR 1.927.
`EXTENSIONS OF TIME ONLY UNDER 37 CFR 1.183. In due course, a refund under 37 CFR 1.26(c)
`will be made to requester.
`
`
`
`All correspondence relating to this inter partes reexamination proceeding should be directed to the
`Central Reexamination Unit at the mail, FAX, or hand-carry addresses given at the end of this
`Order.
`
`US. Patent and Trademark Office
`PTOL-2063 (08/06)
`
`Paper No. 20120316
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 2
`
`Decision Granting Inter Partes Reexamination
`The Third Party Request filed on 10 January 2012 for inter partes reexamination asserts that
`
`there is a reasonable likelihood that the requester will prevail with respect to claims 1-20 of United States
`Patent Number 8,017,376 32 to Dundon et al.
`'
`
`The current Request has been assigned Control Number 95/001,870.
`
`Procedural Posture
`
`Patented claims - US. Patent 7,851,188 32
`
`The patent consists of claims 1-20, all of which are under reexamination.
`
`Documents Cited in the Inter Partes Reexamination Request
`
`1.
`
`W0 2011/ 103300 A2. Flint et al., inventors. Published 25 August 2011. International Filing Date
`
`17 February 2011, claims benefit of provisional US. application Serial No. 61/305,333 [filed 17
`
`February 2010]. [“the ‘300 publication"]
`
`2.
`
`US 2011/0076733 A1. Urano et al., inventors. Published 31 March 2011. Filed 12 August 2010,
`
`claims benefit of provisional U.S. application Serial No. 61/272,058 [filed 12 August 2009] and
`
`benefit of provisional U.S. application Serial No. 61/272,059 [filed 12 August 2009]. [“the ‘733
`
`' publication”]
`
`3.
`
`US 2010/0081179 A1. Anthony et al., inventors. Published 1 April 2010. Filed 29 September
`
`2009, claims benefit of provisional U.S. application Serial No. 61/ 100,801 [filed 29 September
`
`2008] and benefit of provisional U.S. application Serial No. 61/ 100,806 [filed 29 September
`
`4.
`
`5.
`
`6.
`
`2008]. [“the ‘179 publication”]
`
`Puig eta/., (2005). Cell 120:99-110. [“Puig”]
`
`Rutherford et al., (2003). The Journal of Biological Chemistry 278(30):27636-27643.
`
`[“Rutherford 2003”]
`
`US 2009/0163376 A1. Li et al., inventors. Published 25 June 2009. Filed 18 December 2008,
`
`claims benefit of provisional U.S. application Serial No. 61/015,346 [filed 20 December 2007] and
`
`benefit of provisional US. application Serial No. 61/ 109,297 [filed 29 October 2008]. [“the ‘376
`
`publication”]
`
`7.
`
`Conde e Silva et al., (September 2009). Genetics 183(1):93-106. [“Conde e Silva”]
`
`

`

`
`
`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 3
`
`Reasonable Likelihood to Prevail (RLP) on the Issue of Patentability
`
`The claims for which reexamination is requested will be utilized to show whether the above-cited
`
`references, taken together with the explanation provided by the requester are found to establish, or not
`
`to establish, that there is a reasonable likelihood that the requester will prevail with respect to at least
`
`one of the patent claims.
`
`Identification of Every Claim for Which Reexamination is Requested
`
`References 1-7 cited above are discussed in the Request and asserted to render unpatentable
`
`claims 1-20 of United States Patent Number 8,017,376 32. Pages 66-138 of the Request include
`
`explanations that seek to establish a reasonable likelihood that the requestor will prevail with respect to
`
`at least one of the patent claims in light of references 1-7 cited above, in the proposed combinations. The
`
`explanations in the Request are addressed below under subheadings designating each numbered Issue:
`
`Issue #1 - the ‘300 publication
`
`Whether it has been shown that there is a reasonable likelihood that the requester would prevail
`
`with respect to claims 1-15 and 17—20 as set forth at pages 66-90 of the Request, these claims
`
`challenged as being anticipated by the ‘300 publication.
`
`Issue #2 — the ‘733 publication
`
`‘ Whether it has been shown that there is a reasonable likelihood that the requester would prevail
`with respect to claims 1-9, 11, 13 and 18-20 as set forth at pages 91-105 of the Request, these claims
`
`challenged as being anticipated by the ‘733 publication.
`
`Issue #3 - the ‘179 publication taken in view of Puig
`
`Whether it has been shown that there is a reasonable likelihood that the requester would prevail
`
`with respect to claims 1-4, 6-11 and 17-20 as set forth at pages 105-128 of the Request, these claims
`
`challenged as being obvious over the ‘179 publication taken in view of Puig.
`
`Issue #4 - the ‘179 publication taken in view of Puig and further in view of the ‘376
`
`publication
`
`Whether it has been shown that there is a reasonable likelihood that the requester would prevail
`
`with respect to claim 5 as set forth at pages 128-130 of the Request, this claim challenged as being
`
`obvious over the ‘179 publication taken in view of Puig and further in view of the ‘376 publication.
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 4
`
`Issue #5 - the ‘179 publication taken in view of Puig and further in view of Conde e Silva
`
`Whether it has been shown that there is a reasonable likelihood that the requester would prevail
`
`with respect to claims 12 and 13 as set forth at pages 130-134 of the Request, these claims challenged
`
`as being obvious over the ‘179 publication taken in view of Puig and further in view of Conde e Silva.
`
`Issue #6 - the ‘179 publication taken in view of Puig and further in view of Rutherford 2003
`
`Whether it has been shown that there is a reasonable likelihood that the requester would prevail
`
`with respect to claims 14-16 as set forth at pages 134-138 of the Request, these claims challenged as
`
`being obvious over the ‘179 publication taken in view of Puig and further in view of Rutherford 2003.
`
`In order to determine the applicability of the art cited, the priority benefit of claims 1-20 is
`
`determined as detailed hereinbelow:
`
`Priority
`
`The application Serial No. 12/953,884 [published as US 2011/0183393 A1] that issued as U.S.
`
`Patent 8,017,376 52 was filed on 24 November 2010 and claims benefit of provisional US. application
`
`Serial No. 61/263,952 [filed 24 October 2009] and provisional US. application Serial No. 61/350,209
`
`[filed 1 June 2010].
`
`In the Request at Section VII, pages 26-52, arguments are provided regarding granting of
`
`priority benefit to the two provisional applications: US. application Serial No. 61/263,952 [“the ‘952
`
`application”] and Serial No. 61/350,209 [“the ‘209 application”]. In considering these arguments,
`
`MPEP 2163, section II.A.3.(b) is instructive (emphasis added):
`
`New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit
`(b)
`of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, or 365(c)
`
`The examiner has the initial burden of presenting evidence or reasoning to explain why
`persons skilled in the art would not recognize in the original disclosure a description of the
`invention defined by the claims. See Wertheim, 541 F.2d at 263, 191 USPQ at 97 (“[T]he PTO
`has the initial burden of presenting evidence or reasons why persons skilled in the art would not
`recognize in the disclosure a description of the invention defined by the claims”). However, when
`filing an amendment an applicant should show support in the original disclosure for new or
`amended claims. See MPEP § 714.02 and § 2163.06 (“Applicant should * * * specifically point out
`the support for any amendments made to the disclosure").
`
`To comply with the written description requirement of 35 U.S.C. 112, para. 1, or to be
`entitled to an earlier priorig date or filing date under 35 U.S.C. 119, 120I or 365(c)I each claim
`limitation must be expresslyI implicitly. or inherently supmrted in the originally filed disclosure.
`When an explicit limitation in a claim “is not present in the written description whose benefit is
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 5
`
`sought it must be shown that a person of ordinary skill would have understood, at the time the
`patent application was filed, that the description requires that limitation.” Hyatt v. Boone, 146
`F.3d 1348, 1353, 47 USPQ2d 1128, 1131 (Fed. Cir. 1998). See also In re Wright, 866 F.2d 422,
`425, 9 USPQ2d 1649, 1651 (Fed. Cir. 1989) (Original specification for method of forming images
`using photosensitive microcapsules which describes removal of microcapsules from surface and
`warns that capsules not be disturbed prior to formation of image, unequivocally teaches absence
`of permanently fixed microcapsules and supports amended language of claims requiring that
`microcapsules be “not permanently fixed” to underlying surface, and therefore meets description
`requirement of 35 U.S.C. 112.); In re Robins, 429 F.2d 452, 456-57, 166 USPQ 552, 555 (CCPA
`1970) (“[W]here no explicit description of a generic invention is to be found in the specification[,]
`mention of representative compounds may provide an implicit description upon which to base
`generic claim language”); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a
`subgenus is not necessarily implicitly described by a genus encompassing it and a species upon
`which it reads); In re Robertson, 169 F.3d 743, 745, 49 USPQ2d 1949, 1950-51 (Fed. Cir. 1999)
`(“To establish inherency, the extrinsic evidence must make clear that the missing descriptive
`matter is necessarily present in the thing described in the reference, and that it would be so
`recognized by persons of ordinary skill. Inherency, however, may not be established by
`probabilities or possibilities. The mere fact that a certain thing may result from a given set of
`circumstances is not sufficient."’) (citations omitted). Furthermore, each claim must include all
`elements which applicant has described as essential. See, e.g., Johnson Worldwide Associates
`Inc. v. Zebco Corp., 175 F.3d at 993, 50 USPQ2d at 1613; Gentry Gallery, Inc. v. Berkline Corp.,
`134 F.3d at 1479, 45 USPQ2d at 1503; Tronzo v. Biomet, 156 F.3d at 1159, 47 USPQ2d at 1833.
`
`If the originally filed disclosure does not provide support for each claim limitation, or if
`an element which applicant describes as essential or critical is not claimed, a new or amended
`claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description, g
`in the case of a claim for priority under 35 U.S.C. 119, 120, or 365(c), the claim for prioriy must
`be denied.
`
`Therefore, a claim limitation not "expressly, implicitly, or inherently supported in the originally filed
`
`disclosure" means that the claim under consideration should be either rejected as lacking adequate
`
`written description under 35 U.S.C. 112, para. 1, or’denied benefit of an earlier priority date. For claims
`
`lacking such support in the originally filed disclosure, the denial of benefit of an earlier priority date is an
`
`alternative to the rejection of the claims under 35 U.S.C. 112, para. 1. This is an important point because
`
`as noted in MPEP 2616, inter partes reexamination involves considerations of prior art patents or printed
`
`publications only:
`
`Questions relating to grounds of rejection other than those based on prior art patents or printed
`publications should not be included in the request and will not be considered by the examiner if
`included. Examples of such questions that will not be considered are questions as to public use,
`on sale, conduct, and compliance of the claims with 35 U.S.C. 112.
`
`The arguments presented in the Request at pages 26-52 regarding the benefit of priority will be
`
`considered insofar as the patented claim limitations are "expressly, implicitly, or inherently supported in
`
`the originally filed disclosure." Arguments regarding written description under 35 U.S.C. 112, para. 1, will
`
`not be addressed for the patented claims.
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`The ‘952 application and the '209 application
`
`Page 5
`
`The ‘952 application is drawn to recombinant microorganisms that express "cytosolically active
`
`dihydroxyacid dehydratase (DHAD)." See The Summary of the Invention at page 4, particularly paragraph
`
`[0008]. The microorganism is typically various genera and species of yeast capable of producing
`
`isobutanol. See paragraphs [0045] through [0054]. Paragraphs [0097] through [0099] note that the
`
`recombinant expression of the DHAD localized in the cytosol is a critical feature for the biosynthesis of
`
`isobutanol. “Cytosolically active" and "cytosolically localized" DHAD are explicitly required in the invention
`
`as disclosed in this application. In this regard, the entire text of the priority document limits the
`
`recombinant expression of the DHAD to cytosolic localization of DHAD and ways to achieve this. See
`
`paragraphs [00100] through [00113]. Paragraphs [00108] and [00109] note that 5‘. cefewS/ae DHAD is
`
`“normally targeted to the mitochondria" but removal of the N-terminus of the native protein disrupts the
`
`mitochondrial targeting sequence. See also paragraph [00122] wherein concerns of altering the DHAD
`
`from a mitochondrially-localized protein to a cytosollically-localized protein are raised. Clearly, the
`
`essential point of the invention of the ‘952 application is using recombinant means to express the DHAD
`
`protein localized in the cytosol instead of in the mitochondria. In order to enhance the cytosolic DHAD
`
`activity, the cytosolic levels of iron can be increased by the recombinant expression of two transcription
`
`factors, Atf1 and Atf2, which activate iron uptake gene expression. See paragraphs [00149] through
`[00159]. Therefore the yeast microorganism would recombinantly express both cytosolically localized
`DHAD and Alt proteins. The recombinant expression of DHAD localized in the mitochondria as a means of
`
`enhancing DHAD activity is neither desired nor described by this priority document. The ‘209 application
`
`contains essentially the same disclosure as the '952 application.
`
`Claims 1—8 and 10-20 are given benefit only of the filing date of 24 November 2010 for the
`
`application Serial No. 12/953,884. Claims 1-8 and 10-20 are not entitled to the benefit of the two
`provisional applications: US. application Serial No. 61/263,952 [“the ‘952 application”] and Serial No.
`61/350,209 [“the ‘209 application”]. As noted, the prior provisional applications do not describe the
`
`recombinant expression of DHAD localized in the mitochondria as a means of enhancing DHAD activity.
`
`Claim 1 is an independent claim that does not specify the location for the recombinantly expressed
`
`DHAD. However, dependent claim 10 explicitly claims DHAD localized in the mitochondria. (Dependent
`
`claim 9 explicitly claims DHAD localized in the cytosol.) Therefore, the breadth of claim 1 includes both
`cytosolic as well as mitochondrial localization of DHAD expressed by recombinant means. All claims 2-8
`
`and 10-20 that depend from claim 1 embrace mitochondrial localization of DHAD expressed by
`
`recombinant means and similarly lack support in the originally filed priority applications.
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 7
`
`Claim 9 is given benefit of the earliest filing date of 24 October 2009 for the provisional
`
`application Serial No. 61/263,952. Claim 9 is drawn to DHAD expressed by recombinant means and
`
`localized in the cytosol. This claim is therefore granted benefit of both priority applications.
`
`Claim 13 contains numerous SEQ ID Nos. that are not found in any of the priority documents.
`
`See the Request at pages 36-37 wherein the SEQ ID Nos. are discussed. The two proteins SEQ ID No. 2
`and SEQ ID No. 4 of claim 13 correspond to the .S'. cerevisiae Aftl and Aft2 proteins, and these two
`
`sequences first appear only in the later '209 application at page 129, Table 13-4 as SEQ ID No. 56 and
`
`SEQ ID No. 58. See the sequence listings at pages 175-176 of the ‘209 application. These two protein
`
`sequences are NOT found in the earlier priority document, the ‘952 application. See page 71, Table 2 of
`
`the ‘952 application where there is no listing of any Aft proteins at all. In fact, the text of the '952
`
`application in paragraphs [00149] through [00159] does not provide for any source of information where
`
`the protein sequences for the Aft proteins could be found in the prior art. Note that the references
`
`described in this section of the application lack any journal citations, only the author and date, e.g.
`
`(Yamaguchi-Iwai et al., 1995) as found in paragraph [00150]. This omission was corrected in the later
`
`filed '209 application. See page 38, paragraph [00159] of the ‘209 application wherein the Yamaguchi-
`
`Iwai et al. reference is given a specific journal citation. Therefore, the two proteins SEQ ID No. 2 and
`
`SEQ ID No. 4 of claim 13 that correspond to the 5. cerestiae Aft1 and Aft2 proteins have support to the
`
`later filed ‘209 application but the other sequences of claim 13 are denied priority benefit of both
`
`provisional applications. Therefore, Claim 13 asa whole is denied priority benefit of both provisional
`
`applications.
`
`Claims 18 and 19 are drawn to a list of alternative yeast genera and species embodiments,
`
`respectively. Each embodiment must be "expressly, implicitly, or inherently supported in the originally
`
`filed disclosure." Like biomolecules that have distinct characteristics, specifically claimed microorganisms
`
`must be expressly supported in the priority documents. Claims 18 and 19 represent a collection of distinct
`
`species under a generic label of "yeast" microorganisms. Each genus and species of yeast is distinct and
`
`must have explicit support in the priority applications in order to be granted priority benefit. See MPEP
`
`2163 II.A.3.(a)(i). Claim 18 includes the genus Issatchenk/‘a that is not found in either of the priority
`
`applications. Claim 19 includes Debaromyces caison/i, Pichia casti/lae, Candida xestobil; Issatchenkia
`
`oriental/Ls, Issatchenkia occidental/s and Issatchenkia scutu/ata that are not explicitly taught in either of
`
`the priority applications. The identifying characteristics of these distinct species are not implied or
`
`inherent in the priority applications. See the Request at pages 38-39.
`
`Claims 1-8 and 10-20 are given benefit only of the filing date of 24 November 2010 for the
`
`application Serial No. 12/953,884.
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 8
`
`Claim 9 is given benefit of the earliest filing date of 24 October 2009 for the provisional
`
`application Serial No. 61/263,952.
`
`Issue #1
`
`W0 2011/ 103300 A2. [“the ‘300 publication"] is granted benefit of provisional US. application
`
`Serial No. 61/305,333 [filed 17 February 2010].
`
`With respect to claims 1-8, 10-15 and 17-20, the Examiner agre_es that there is a reasonable
`
`likelihood that the requester would prevail against these claims for being anticipated by the ‘300
`
`publication as evidenced by the accompanying Office Action rejecting these claims.
`
`With respect to claim 9, the Examiner does not agree that there is a reasonable likelihood that
`
`the requester's challenge would prevail. Claim 9 is drawn to DHAD expressed by recombinant means and
`
`localized in the cytosol. This claim is granted benefit of both priority applications and therefore the ‘300
`
`publication is not prior art against this claim.
`
`Issue #2
`
`US 2011/0076733 A1. [“the ‘733 publication”] is NOT granted benefit of provisional US.
`
`application Serial No. 61/272,058 [filed 12 August 2009] and NOT granted benefit of provisional US.
`
`application Serial No. 61/272,059 [filed 12 August 2009]. Neither of the priority documents teaches
`
`introduction of polynucleotides expressing one or more of the Aft proteins into S. cereV/s/ae or any other
`
`host microorganism. The filing date of the ‘733 publication is 12 August 2010.
`
`With respect to claims 1-8, 11, 13 and 18-20, the Examinerm that there is a reasonable
`
`likelihood that the requester would prevail against these claims for being anticipated by the ‘733
`
`publication as evidenced by the accompanying Office Action rejecting these claims.
`
`With respect to claim 9, the Examiner does not agree that there is a reasonable likelihood that
`
`the requester's challenge would prevail. Claim 9 is drawn to DHAD expressed by recombinant means and
`
`localized in the cytosol. This claim is granted benefit of both priority applications and therefore the ‘733
`
`publication is not prior art against this claim.
`
`Issue #3
`
`The Examiner does not agree that there is a reasonable likelihood that the requester would
`
`prevail with respect to claims 1-4, 6-11 and 17-20 challenged as being obvious over the ‘179 publication
`
`taken in view of Puig.
`
`

`

`Application/Control Number: 95/001,870
`
`Art Unit: 3991
`
`Page 9
`
`US 2010/0081179 Al [“the ‘179 publication”] qualifies as prior art under 35 U.S.C. 103, based
`
`upon a 102(e) filing date of 29 September 2009.
`
`The ‘179 publication teaches recombinant yeast expressing enhanced dihydroxy-acid dehydratase
`
`(DHAD) activity. DHAD is an Fe-S cluster protein and it is expressed from a heterologous gene introduced
`
`into the yeast host cell. See paragraphs [0003], [0009] and [0015]. The Fe—S cluster proteins are those
`apoprotein enzymes that require available Fe-S clusters for function. See paragraph [0005]. Reducing the
`
`expression of endogenous Fe-S cluster proteins provides more Fe-S clusters available to heterologous Fe—
`
`S cluster proteins expressed in recombinant yeast cells. See paragraph [0006] and paragraphs [0074]
`
`through [0079]. Thereby, activity of the heterologous Fe-S protein is increased in the host cell. See
`
`paragraphs [0111] and [0112]. Heterologous DHAD protein is expressed lacking the mitochondrial
`
`targeting signal. See page 10, paragraph [0098]. As the endogenous DHAD is normally expressed and
`
`localized in the mitochondria, the heterologous DHAD remains in the cytosol where it participates in the
`
`biosynthetic pathways localized in the cytosol. Specifically, the DHAD catalyzes the conversion of 2,3-
`
`dihydroxyisovalerate to oc—ketoisovalerate, a common step in the multiple isobutanol biosynthetic
`
`pathways. See paragraph [0003] and paragraphs [0111] through [0128]. Increased activity of the
`
`heterologous DHAD results in increased production of isobutanol in the cytosol. See particularly the
`
`paragraphs [0111] and [0112]. The ‘179 publication describes “reduced expression” of an endogenous
`
`protein in terms of diminished activity of the protein (using antisense technology) or "gene disruption,
`
`deletion or inactivation." See paragraph [0053]. Deleting genes encoding endogenous Fe-S cluster
`
`proteins causes the increased activity of heterologous DHAD in recombinant yeast. See paragraphs
`
`[0006] through [0009] and paragraphs [0074] through [0079]. See also Example 1 at page 15,
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`paragraph [0151] through paragraph [0156]. The host yeast strain BY4743(Aleu1) has a deleted LEU1
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`gene. See paragraph [0156]. It is transformed with a heterologous ILV3 gene encoding DHAD. The
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`dehydratase activity of the heterologous DHAD in transformed yeast BY4743(Aleu1), having the LEU1
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`gene deletion, is higher than in the transformed yeast parent strain BY4743 that retains the LEU1 gene.
`Example 3 shows that deletion of the endogenous ILV3 gene encoding endogenous DHAD causes
`increased activity of the heterologous DHAD. Other than "gene disruption, deletion or inactivation," the
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`‘179 publication suggests no other way in which the expression of endogenous Fe-S cluster proteins is
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`reduced to cause increased activity of the heterologous DHAD expressed in the host cell.
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`The Request has cited the reference to Puig in combination with the ‘179 publication as rendering
`obvious claims 1-4, 6-11 and 17-20 of the United States Patent Number 8,017,376 B2. The Puig
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`reference is a study in 5. cerev/s/ae that shows under conditions of Fe deficiency, the Cch protein
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`specifically downregulates mRNAs encoding proteins that participate in many Fe-dependent processes.
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`The Cch protein binds to these mRNAs in the 3’ untranslated region and targets the mRNAs for
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`

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`Application/Control Number: 95/001,870
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`Art Unit: 3991
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`Page 10
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`degradation. This is a “mechanism that mediates global post transcriptional control of multiple
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`components of Fe—dependent pathways to respond in a concerted fashion to Fe deficiency.” See the
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`abstract and page 99, second column, last paragraph under the "Introduction." The degradation of
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`specific mRNA molecules under Fe deficiency thus facilitates the utilization of limited available Fe for
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`normal growth.” In short, there is less competition for the limited Fe, making it available for use by other
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`processes in the cell. At page 100, second column, Puig notes that the th2 protein contains two putative
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`Aft1-Aft2 binding sites that cooperate in the activation of CTH2 by Fe starvation. Based on this
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`information, at page 109 of the Request a proposed rejection is made:
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`...a person of ordinary skill in the art would have had reason to reduce the expression of
`endogenous Fe-S cluster proteins such as Leu1 and DHAD, by overexpressing polynucleotides
`encoding one or more Aft proteins in order to, among other things, activate Cch-mediated
`degradation of the mRNA encoding endogenous Fe-S sulfur cluster proteins demonstrated in the
`'179 publication to, when deleted, result in increased heterologous DHAD activity.
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`The Requester further cites the declaration provided in the Request by Dennis J. Thiele, at pages
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`69-71, paragraphs 99-104 to support their arguments. See particularly paragraph 103 in the declaration
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`which argues that a "person of ordinary skill in the art, using common sense and ordinary creativity”
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`would combine the teachings of the ‘179 publication and Puig to arrive at the claimed invention. This is
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`not found persuasive. It is an extreme stretch of the imagination to argue that under the general desire
`of wanting to reduce expression of at least one endogenous Fe-S cluster protein (as provided by the ‘179
`publication at paragraph [0006]) that the skilled artisan would take the teachings of Puig under
`cohsideration. The ‘179 publication only provides for reduced expression by means of "gene disruption,
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`deletion or inactivation." See paragraph [0053]. The examples provided in the ‘179 publication all
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`describe chromosomal deletion of genes encoding Fe—S cluster proteins. The requester is proposing a
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`totally unrelated means of gene regulation never suggested, imagined or contemplated by the '179
`publication: posttranscriptional regulation, or the degradation of mRNAs that encode proteins involved in
`Fe—dependent processes, in order to free up limited Fe for other cellular uses. The claims of the ‘376
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`patent require the recombinant overexpression of polynucleotides encoding Aft proteins. The Request
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`uses essentially the following line of reasoning to argue that the claim limitations are met by the
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`combined teachings of the ‘179 publication and Puig:
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`a) the skilled artisan would want to introduce polynucleotides overexpressing the Aft proteins into
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`a yeast host cell in order to activate the Cch protein;
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`b) the activated Cch protein will perform the targeted degradation of mRNA encoding proteins
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`involved in Fe-dependent processes; and
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`c) the reduced production of proteins involved in Fe—dependent processes will now free up Fe for
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`use by other cellular processes; therefore
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`

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`Application/Control Number: 95/001,870
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`Art Unit: 3991
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`Page 11
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`d) the free Fe is now available for use by the overexpressed heterologous DHAD apoenzyme.
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`This line of reasoning appears to be hindsight reconstruction to arrive at the claims in the '376
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`patent. Puig provides no gene sequences encoding the Alt proteins, nor does it provide guidance or
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`direction for delivery of such genes to a host yeast cell. Further, the skilled artisan could take from the
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`teachings of Puig that overexpressing the Cch protein would be a more direct route than introducing a
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`gene encoding the Alt protein. See the last paragraph in the Discussion in Puig at page 108:
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`A single regulatory protein, Cch, controls the coordinated response of multiple Fe-dependent
`metabolic pathways to Fe deficiency by targeting specific mRNA molecules for degradation. This
`mechanism of regulation represents a functional “posttranscriptional Fe regulon” that optimizes
`the utilization of limited available Fe.
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`Consequently, the skilled artisan would, not have been drawn to combine the teachings of the
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`‘179 publication with Puig as argued in the Request to arrive at the invention as found in claims 1-4, 6-11
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`and 17-20 in the ‘376 patent.
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`Issue #4
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`The Examiner does not agree that there is a reasonable likelihood that the requester would
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`prevail with respect to claim 5 challenged as being obvious over the ‘179 publication taken in view of Puig
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`and further in view of the ‘376 publication.
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`The ‘179 publication and Puig do not teach that the ketol-acid reductoisomerase is an NADH-
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`dependent ketol-acid reductoisomerase. The ‘376 publication teaches that the KARI (ketol-acid
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`reductoisomerase; also called acetohydroxy acid isomeroreductase) that enhance isobutanol production
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`has a preference for NADH as opposed to NADPH. However, for the reasons as set forth under Ground
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`#3, the skilled artisan would not have been drawn to combine the teachings of the ‘179 publication with
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`Puig as argued in the Request. The teachings of the ‘376 publication do not cure the deficiencies of the
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`teachings of the ‘179 publication taken in view of Puig. Therefore, the skilled artisan would not have been
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`drawn to combine the teachings of the ‘179 publication w