Ex Parte Steele et al

Patent Trials and Appeals Board

Feb 26, 2019

13964548 - (D) (P.T.A.B. Feb. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/964,548 08/12/2013 James L. Steele
72088 7590 02/28/2019
WISCONSIN ALUMNI RESEARCH FOUNDATION
C/0 BOYLE FREDRICKSON S.C
840 North Plankinton A venue
Milwaukee, WI 53203
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
Pl30023US02 [3152.058] 2435
EXAMINER
EKSTROM, RICHARD C
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
02/28/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
docketing@boylefred.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JAMES L. STEELE and JEFF R. BROADBENT
Appeal2017-009827
Application 13/964,548 1
Technology Center 1600
Before DEMETRA J. MILLS, RICHARD M. LEBOVITZ, and
DAVID COTTA, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims 1-11, 15-20, 22, and 23 for obviousness. We have jurisdiction
under 35 U.S.C. § 6(b).
We affirm.
1 According to Appellants, the real parties in interest are Wisconsin Alumni
Research Foundation and Utah State University. App. Br. 3.
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Application 13/964,548
STATEMENT OF CASE
The following claim is representative for purposes of this decision.
1. An engineered bacterium for producing ethanol from
one or more carbohydrates, made by a process comprising
introducing into a Lactobacillus casei bacterium one or more
exogenous genes encoding a pyruvate decarboxylase and one or
more exogenous genes encoding an alcohol dehydrogenase II,
each of which is operably linked to a L. casei promoter that is
highly expressed in the stationary phase;
whereby the resulting engineered bacterium produces
more ethanol than a wild-type Lactobacillus casei bacterium.
Claims Appendix ( emphasis added).
Cited References
Respell
Schmitz
Benfey
Lee
US 6,280,986 B 1
US 2006/0117401 Al
US 2009/0271894 Al
US 2010/0330639 Al
Aug. 28, 2001
June 1, 2006
Oct. 29, 2009
Dec. 30, 2010
R. Shane Gold et al., Cloning and Expression of the
Zymomonas mobilis "Production of Ethanol" Genes in
Lactobacillus casei, Current Microbiology, 33 :256-260 (1996)
(hereinafter "Gold").
Rosa Viana et al., Pleiotropic effects of lactate dehydrogenase
inactivation in Lactobacillus casei, Research in Microbiology,
156:641---649 (2005) (hereinafter "Viana").
Hui Cai et al., Genotypic and phenotypic characterization of
Lactobacillus casei strains isolated from different ecological
niches suggests frequent recombination and niche specificity,
Microbiology, 153 :2655-2665 (2007) (hereinafter "Cai").
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Application 13/964,548
Hui Cai et al., Genome Sequence and Comparative Genome
Analysis of Lactobacillus casei: Insights into Their Niche-
Associated Evolution, Genome Biology and Evolution, 1 :239--
257 (2009) (hereinafter "Cai 09").
Grounds of Rejection
3-11.
1. Claims 1, 2, 4--11, 15-20, 22, and 23 are rejected under pre-AIA
35 U.S.C. 103(a) as being unpatentable over Respell in view of
Gold, Cai 09, and Cai; and Lee or Schmitz.
2. Claims 1-11, 15-20, 22, and 23 are rejected under pre-AIA 35
U.S.C. 103(a) as being unpatentable over Respell in view of Gold,
Cai 09, Cai, and Benfey; and Lee or Schmitz and Viana.
FINDINGS OF FACT
The Examiner's findings of fact are set forth in the Answer at pages
1. Respell describes recombinant bacteria which are
transformed with heterologous DNA coding for alcohol
dehydrogenase and pyruvate decarboxylase, and which produce
ethanol (abstract). The bacteria also have mutations which inactivate
lactate dehydrogenase and pyruvate formate lyase ( column 3, lines
34--50).
2. Respell describes that the alcohol dehydrogenase and
pyruvate decarboxylase 11 genes are derived from Zymomonas
mobilis and are included in a vector which includes the PET operon.
A variety of promoters may be used to direct expression of the alcohol
dehydrogenase and pyruvate decarboxylase genes (column 5, lines 9-
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26). Bacteria suitable for use include those described in US Patent
No. 5,842,846 (column 5, lines 32-34), whose contents have been
incorporated by reference into Respell ( column 2, lines 64--66); the
suitable bacteria include those of the genus Lactobacillus, although
Lactobacillus casei is not explicitly mentioned (US Patent No.
5,842,846 at column 9, lines 48-59).
3. Respell also does not explicitly describe the L-lactate
dehydrogenase 1 gene, L-lactate dehydrogenase 2 gene, D-lactate
dehydrogenase gene, or particular promoters from Lactobacillus casei
including a GroEL or DnaK promoter from Lactobacillus casei.
4. Gold describes engineering Lactobacillus casei strain
686 by incorporating pyruvate decarboxylase and alcohol
dehydrogenase genes, which resulted in increased ethanol production
(abstract; Table 2). The pyruvate decarboxylase and alcohol
dehydrogenase genes were derived from Zymomonas mobilis and
were incorporated into expression vectors containing the PET operon
(abstract; Figure 2). One of the expression vectors contained a
promoter and ribosome binding site from Lactococcus
lactis (abstract).
5. Cai 09 describes an analysis of the genome sequence of
Lactobacillus casei. The genome of Lactobacillus casei ATCC334
was used as the basis for the analysis ( abstract; page 241 under
"Characterization of ATCC 334 Genome").
6. Cai describes a genotypic and phenotypic
characterization of Lactobacillus casei strains, including
Lactobacillus casei strain 12A. Ans. 4.
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7. Lee describes the GroEL promoter for use in controlling
the expression of ethanol-production-pathway enzymes (paragraph
71).
8. Schmitz describes the DnaK promoter for use in
controlling the expression ofheterologous genes (paragraph 115).
PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the
evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F .2d 1422, 1427
(Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings
before the Office).
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
"Reading a list and selecting a known compound to meet known
requirements is no more ingenious than selecting the last piece to put into
the last opening in a jig-saw puzzle. It is not invention." Sinclair & Carroll
Co. v. Interchemical Corp., 325 U.S. 327, 335 (1945); see also, Merck &
Co. Inc. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989)
("Disclos[ ure of] a multitude of effective combinations does not render any
particular formulation less obvious").
The burden of demonstrating unexpected results rests on the party
asserting them, and "it is not enough to show that results are obtained which
differ from those obtained in the prior art; that difference must be shown to
be an unexpected difference." In re Klosak, 455 F.2d 1077, 1080 (CCPA
1972). "Unexpected results must be established by factual evidence. Mere
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argument or conclusory statements in the specification does not suffice." In
re DeBlauwe, 736 F.2d 699, 705 (Fed. Cir. 1984). "[W]hen unexpected
results are used as evidence of nonobviousness, the results must be shown to
be unexpected compared with the closest prior art." In re Baxter-Travenol
Labs., 952 F.2d 388,392 (Fed. Cir. 1991).
Obviousness Rejection
The Examiner concludes that
It would have been obvious to one of ordinary skill in the
art at the time the invention was made to have introduced the
genetic modifications taught by Respell et al. into Lactobacillus
casei strain 12A because Respell et al. teaches that the genus
Lactobacillus, and thus any species of Lactobacillus, is suitable
for such genetic modifications for making a recombinant
bacterium to produce ethanol, Gold et al. have shown that
Lactobacillis casei in particular is a suitable species for
incorporation of genetic modifications for allowing ethanol
production and Cai et al.-2007 disclose that strain 12A is an
available strain of Lactobacillus casei. With regard to the
Lactobacillus casei GroEL or DnaK promoter, the use of such
promoters in Lactobacillus casei for ethanol production would
have been obvious because Respell et al. teach that a variety of
promoters may be used to direct expression of the alcohol
dehydrogenase and pyruvate decarboxylase genes in a
recombinant host cell, Gold et al. show the applicability of
using an endogenous promoter from a lactic acid bacteria for
directing the synthesis of an "ethanol production" gene, Lee and
Schmitz et al. describe the GroEL promoter and DnaK
promoter, respectively, as promoters applicable for regulating
the expression of heterologous genes, and Cai et al.-2009
provide the appropriate sequence information to identify a
GroEL or DnaK promoter from Lactobacillus casei.
Ans. 4.
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Appellants contend that the Examiner's rejection should be reversed
because:
(a) the Office has not adequately explained why the skilled
artisan reviewing the cited documents would choose to use an
L. casei promoter that is active in the stationary phase in the
Respell system to obtain the claimed invention; (b) the cited
documents disclose a very large number of potential promoters,
with no guidance that would lead the skilled artisan to use an L.
casei promoter that is active in the stationary phase in the
Respell system to obtain the claimed invention; and ( c) the
evidence of record[] suggests that the use of an L. casei
promoter that is highly expressed in the stationary facilitates an
increase in ethanol production that would not have been
expected, based on the cited documents or on what was known
in the art at the time of filing.
App. Br. 12.
Appellants further argue that
the Office's stated reasons as to why the skilled artisan would
operably link an L. casei promoter that is highly expressed in
the stationary phase to the two recited exogenous genes to
obtain the claimed invention are mere conclusory statements
that the elements are disclosed in the cited combination of
documents and thus can be combined, not a reasoned
explanation supported by facts or evidence as to why the skilled
artisan would choose to use the recited promoters, as required
under the law.
App. Br. 13.
More specifically, Appellants argue that
First, the Office does not even address any alleged motivation
to use L. casei promoters that are highly expressed in the
stationary phase, except to note that GroEL and DnaK promoter
are "within the scope of' such promoters (see final Office
Action, p. 6, last paragraph through top of p. 7). Second,
regarding the motivation to specifically use L. casei GroEL or
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L. casei DnaK promoters, the Office states that the use of such
promoters would have been obvious "because Respell et al.
teach that a variety of promoters may be used to direct
expression of the alcohol dehydrogenase and pyruvate
decarboxylase genes in a recombinant host cell, Gold et al.,
show the applicability of using an endogenous promoter from a
lactic acid bacteria for directing the synthesis of an 'ethanol
production' gene, Lee and Schmitz et al. describe the GroEL
promoter and DnaK promoter, respectively as promoters
applicable to the expression of heterologous genes ... " (see
final Office Action, p.4, last four lines through top of p. 5,
emphasis added).
App. Br. 13-14 (emphasis omitted).
With respect to Lee, Appellants argue that
Lee discloses, among many other promoters, light- and heat-
responsive GroE promoters (including GroEL) from sixteen
different oxyphotobacteria of the genera Synechocystis,
Synechococcus, Anaboena, Thermocynechococcus, and
Prochlorococcus. Lee teaches that these specific
oxyphotobacteria promoters are inducible by heat and/or light.
Lee's disclosure clearly excludes the GroEL promoter from
non-oxyphotobacteria (such as Lactobacillus), as such
promoters are not light-sensitive. Accordingly, the cited section
of Lee does not provide any guidance directing the skilled
artisan to use an L. casei GroEL promoter to drive exogenous
pyruvate decarboxylase and alcohol dehydrogenase II gene
expression in an engineered L. Casei ethanologen, as recited in
the rejected claims.
App. Br. 15.
Appellants rely on two Declarations of Dr. Steele to support
unexpected results.
ANALYSIS
Appellants do not argue individual claims separately in the Appeal
Brief with arguments other than those presented for claim 1, therefore we
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select claim 1 as a representative claim for purposes of this appeal. We
agree with the Examiner's fact finding, statement of the rejection, and
responses to Appellants' arguments as set forth in the Answer. We find that
the Examiner has provided evidence to support a prima facie case of
obviousness. We provide the following additional comment to the
Examiner's argument set forth in the Final Rejection and the Answer.
With respect to the Examiner's prima facie case of obviousness, Gold
describes that the production of ethanol in lactobacillus casei was well
known in the art at the time of the invention. Gold Abstract. Respell
describes recombinant bacteria that are transformed with heterologous DNA
coding for alcohol dehydrogenase and pyruvate decarboxylase, and that
produce ethanol (abstract). Ans. 3. Respell describes that it was well
known in the art at the time of the invention that a variety of promoters may
be used to direct expression of the alcohol dehydrogenase and pyruvate
decarboxylase genes (column 5, lines 9-26). Ans. 3. Lee describes that it
was well known in the art at the time of the invention to use the GroEL
promoter in controlling the expression of ethanol-production-pathway
enzymes (paragraph 71 ). Ans. 4. Schmitz describe the DnaK promoter for
use in controlling the expression of heterologous genes (paragraph 115).
Ans. 4.
We agree with the Examiner that it would have been prima facie
obvious at the time of the invention to use well known bacteria (Gold) and
promoters known for use in the production of ethanol (Lee, Respell) in a
single engineered bacterium for the production of ethanol using a pyruvate
decarboxylase and one or more exogenous genes encoding an alcohol
dehydrogenase II.
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We are not persuaded by Appellants' arguments, and evidence of
unexpected results provided in the Specification and discussed in the two
Declarations of Dr. Steele.
Respell discloses, generally, that a variety of equivalent promoters
can be used to produce alcohol dehydrogenase from a variety of bacteria.
Lee describes that it was well known in the art at the time of the invention to
use the GroEL promoter in controlling the expression of ethanol-production-
pathway enzymes (paragraph [0071 ]). It would have been obvious to one of
ordinary skill in the art at the time of the invention to select from promoters
well known in the production of ethanol, and that ethanol could be produced
using any of the disclosed promoters.
The issue then becomes whether the Appellants have rebutted the
Examiner's prima facie case of obviousness with evidence of unexpected
results using promoters which are "highly expressed in the stationary phase,"
as claimed. We find no definition of what is meant by the term "highly
expressed in the stationary phase" in the Specification. The term 'high" is a
relative term. We interpret the term "high" in this phrase to mean, "situated
or passing above the normal level, surface, base of measurement, or
elevation. "2 Thus, the term "high or highly" expressed alone does not
necessarily meet the legal criteria for unexpected results as high expression
can be just above the normal level of expression. The burden of
demonstrating unexpected results rests on the party asserting them, and "it is
not enough to show that results are obtained which differ from those
obtained in the prior art; that difference must be shown to be an unexpected
ps://www.merriam-webster.com/ dictionary/high
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difference." In re Klosak, 455 F.2d at 1080. "Mere improvement in
properties does not always suffice to show unexpected results." In re Soni,
54 F.3d 746, 751 (Fed. Cir. 1995). Moreover, it has been long held that
"even though applicant's modification results in great improvement and
utility over the prior art, it may still not be patentable if the modification was
within the capabilities of one skilled in the art, unless the claimed ranges
'produce a new and unexpected result which is different in kind and not
merely in degree from the results of the prior art." In re Huang, 100 F.3d
135, 139 (Fed. Cir. 1996) (quoting In re Aller, 220 F.2d 454, 456 (1955),
and citing In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990)).
"The evidence presented to rebut a prima facie case of obviousness
must be commensurate in scope with the claims to which it pertains." In re
Dill, 604 F.2d 1356, 1361, 202 USPQ 805, 808 (CCPA 1979). "It is well
established that the objective evidence of nonobviousness must be
commensurate in scope with the claims." In re Lindner, 457 F.2d 506, 508
( CCP A 1972 ). "Commensurate in scope" means that the evidence provides a
reasonable basis for concluding that the untested embodiments encompassed
by the claims would behave in the same manner as the tested
embodiment(s). See In re Lindner, 457 F.2d 506, 508 (CCPA 1972).
Appellants rely on two Declarations of Dr. Steele to support
unexpected results associated with use of promoters which are highly
expressed in the stationary phase for the production of ethanol. We agree
with the Examiner and find the Declarations of Dr. Steele insufficient to
rebut the Examiner's prima facie case of obviousness.
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The Examiner finds that
(1) Paragraph 5 of the 1.132 Declaration presents evidence
showing that the L. casei uspAC2 promoter increases its expression
activity during the stationary phase while the L. casei GroEL and
DnaK promoters remain active, but lose expression activity, in the
stationary phase as shown by expression of the glyceraldehyde
phosphate dehydrogenase gene. Paragraph 6 states "to determine if
increased stationary phase expression activity results in increased
ethanol production in our engineered Lactobacillus, L. casei pgm,
groEL, dnaK and uspAC2 promoters were placed in front of the pPET
expression cassette described in the application .... The resulting
expression cassettes were introduced into L. casei 12A L'iL-ldh". The
results from the experiment are shown in paragraph 8 and Table 1,
however, ethanol production is only described for Lactobacillus
engineered with expression cassettes comprising the pgm and uspAC2
promoters, with the uspAC2 promoter resulting in a significantly
higher production of ethanol. No results for ethanol production are
described for Lactobacillus engineered with expression cassettes
comprising the groEL or dnaK promoters.
(2) Consequently the Declaration evidence is unconvincing as
showing unexpected results with regard to ethanol production for
engineered Lactobacillus comprising the broad recitation of a "L.
casei promoter that is highly expressed in the stationary phase". The
evidence for enhanced ethanol production by the engineered
Lactobacillus comprising the single species of a uspAC2 promoter is
not regarded as sufficient to establish unexpected results for the
generic recitation of a "L. casei promoter that is highly expressed in
the stationary phase", i.e., a showing of unexpected results
commensurate in scope with the claims has not been made.
Ans. 12-13 (emphasis omitted). Even ifwe were to agree with Appellants
that they have shown unexpected results with respect to ethanol production
using the uspAC2 promoter, which is highly expressed in the stationary
phase, the claims are not so limited, as they broadly encompass all L. casei
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promoters which are highly expressed in the stationary phase. Indeed, we
have not een been directed to a definition in the Specification to a definition
of "highly expressed." Thus, Appellants' results presented in the Steele
Declarations are not commensurate in scope with broad scope of claimed
promoters. Nor is there any indication presented in the Specification that
unexpected results were allegedly produced using the uspAC2 promotor or
that unexpected results can be extended to other promoters which highly
express in the stationary phase. The uspAC2 promoter is not specifically
mentioned at all in the Specification, as filed.
Finally, Appellants do not provide comparative results with the closest
prior art, for example, the organisms and promoters of Gold or Lee to show
unexpected results.
With respect to Appellants' argument regarding the motivation in the
art to select promoters which are highly expressed in the stationary phase,
we find that one of ordinary skill in the art would have expected each of the
promoters mentioned in the cited references to provide some level of ethanol
production. Appellants, at best, have shown increased expression using a
promoter not disclosed in the Specification, uspAC2. Appellants have not
persuasively demonstrated that one of ordinary skill in the art would not
have expected this increased expression. Moreover, as discussed above, this
increased expression is not commensurate with pending claim scope which
encompasses all L. casei promoters that highly express in the stationary
phase.
Appellants provide no separate argument for rejection 2 set forth in
the grounds of rejection above, other than the arguments presented for
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rejection 1. App. Br. 26. Rejection 2 is affirmed for the same reasons as
rejection 1.
CONCLUSION OF LAW
The cited references, and the preponderance of the evidence, support
the Examiner's obviousness rejections of claims 1-11, 15-20, 22, and 23,
which are affirmed for the reasons of record.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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