Ex Parte Palsson

Patent Trial and Appeal Board

Jun 10, 2013

09923870 (P.T.A.B. Jun. 10, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
09/923,870 08/06/2001 Bernhard Palsson 012956-0003-999 1729
20583 7590 06/11/2013
JONES DAY
222 EAST 41ST ST
NEW YORK, NY 10017
EXAMINER
NEGIN, RUSSELL SCOTT
ART UNIT PAPER NUMBER
1631
MAIL DATE DELIVERY MODE
06/11/2013 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte BERNHARD PALSSON
__________

Appeal 2011-010818
Application 09/923,870
Technology Center 1600
__________

Before DEMETRA J. MILLS, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, 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 for obviousness and obviousness-type double patenting. We have
jurisdiction under 35 U.S.C. § 6(b).
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STATEMENT OF CASE
This invention relates to constructing metabolic
genotypes and genome specific stoichiometric matrices from
genome annotation data. The functions of the metabolic genes
in the target organism are determined by homology searches
against databases of genes from similar organisms. Once a
potential function is assigned to each metabolic gene of the
largest organism[, t]he resulting data is analyzed. In one
embodiment, each gene is subjected to a flux balance analysis
to assess the effects of genetic deletions on the ability of the
target organism to produce essential biomolecules necessary for
its growth.

(Oct. 29, 2007, Spec. 4.)
Claims 49-52, 56-60, 64, and 68-83 are pending. Claims 49 and 57
are representative.
49. A method performed in a computer of simulating a metabolic
capability of an in silica strain of a microbe, comprising:
obtaining a plurality of DNA sequences comprising most metabolic
genes in a genome of the microbe to produce an in silico representation of a
microbe;
determining open reading frames of genes of unknown function in the
microbe in said plurality of DNA sequences;
assigning a potential function to proteins encoded by said open
reading by determining the homology of said open reading frames to gene
sequences encoding proteins of known function in a different organism;
determining which of said open reading frames potentially correspond
to metabolic genes by determining if the assigned function of said proteins is
involved in cellular metabolism;
determining substrates, products and stoichiometry of the reaction for
each of the gene products of said metabolic genes having an assigned
potential function;
producing a genome specific stoichiometric matrix of said microbe
produced by incorporating said substrates, products and stoichiometry into a
stoichiometric matrix;
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determining a metabolic demand corresponding to a biomass
composition of said microbe;
calculating uptake rates of metabolites of said microbe;
combining said metabolic demands and said uptake rates with said
stoichiometric matrix to produce an in silico representation of said microbe;
incorporating a general linear programming problem to produce an in
silico strain of said microbe;
performing a flux balance analysis on said in silico strain, and
providing a visual output to a user of said analysis that simulates a
metabolic capability of said strain predictive of said microbe's phenotype.

57. A method performed in a computer for simulating a metabolic
capability of an in silico strain of a microbe, comprising:
a) providing a nucleotide sequence of a potential metabolic gene in
the microbe;
b) determining substrates, products and stoichiometry of the reaction
for the gene product of said potential metabolic gene, wherein said gene
product having an unknown function in the microbe is assigned a potential
function by determining homology of said nucleotide sequence to gene
sequences encoding gene products of known function in a different
organism;
c) repeating steps a) and b) for most potential metabolic genes of said
microbe to produce an in silico representation;
d) producing a genome specific stoichiometric matrix produced by
incorporating said substrates, products and stoichiometry of the potential
metabolic gene products in said microbe into a stoichiometric matrix;
e) determining a metabolic demand corresponding to a biomass
composition of said microbe;
f) calculating uptake rates of metabolites of said microbe;
g) combining said metabolic demands and said uptake rates with said
stoichiometric matrix to produce an in silico representation of said microbe;
h) incorporating a general linear programming problem to produce an
in silico strain of said microbe;
i) performing a flux balance analysis on said in silico strain; and
j) providing a visual output to a user of said analysis that simulates a
metabolic capability of said strain predictive of said microbe's phenotype.

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Cited References

F. Kunst and K. Devine, The project of sequencing the entire Bacillus
subtilis genome, 142 RES. MICROBIOL. 905-912 (1991).

J. Pramanik and J. D. Keasling, Stoichiometric Model of Escherichia coli
Metabolism: Incorporation of Growth-Rate Dependent Biomass
Composition and Mechanistic Energy Requirements, 56 BIOTECHNOL.
BIOENG. 398-421 (1997).

Blattner et al., The Complete Genome Sequence of Escherichia coli K-12,
277 SCIENCE 1453-1462 (1997).

Liangzhi Xie and Daniel I. C. V., Integrated approaches to the design of
media and feeding strategies for fed-batch cultures of animal cells, 15
TIBTECH 109-113 (1997).

Grounds of Rejection
Claims 49-52, 56-60, and 68-83 are rejected under 35 U.S.C. § 103(a)
as being unpatentable over Pramanik in view of Blattner and Kunst.
Claim 64 is rejected under 35 U.S.C. § 103(a) as being unpatentable
over Pramanik in view of Blattner, Kunst and Xie.
Claims 49-52, 56-60 and 64 are provisionally rejected on the ground
of nonstatutory obviousness-type double patenting as being unpatentable
over claims 26- 28, 30, 32, 35-36, and 39-41 of copending Application No.
11/980,199.

FINDINGS OF FACT
The Examiner’s findings of fact are set forth in the Answer at pages 4-
11. The following facts are highlighted.
1. Figures 1 and 2 of the 2007 Specification are reproduced below.
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“Figure 1 is a flow diagram illustrating one procedure for creating
metabolic genotypes from genomic sequence data for any organism.” (Spec.
5.)
2. Figure 2 of the Specification is reproduced below.

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“Figure 2 is a flow diagram illustrating one procedure for producing
in silico microbial strains from the metabolic genotypes created by the
method of Figure 1, along with additional biochemical and microbiological
data.” (Spec. 5.)
3. The Specification on page 4 states that
Pramanik, et al. produced a metabolic model of metabolism for
E. coli based on biochemical information rather than genomic
data since the metabolic genes and related reactions for E. coli
had already been well studied and characterized. Thus, this
method is inapplicable to determining a metabolic model for
organisms for which little or no biochemical information on
metabolic enzymes and genes is known.

Discussion
Claims 49-52, 56-60, and 68-83 are rejected under 35 U.S.C. § 103(a)
as being unpatentable over Pramanik in view of Blattner and Kunst. Claim
64 is rejected under 35 U.S.C. § 103(a) as being unpatentable over Pramanik
in view of Blattner, Kunst and Xie.

ISSUE
The Examiner finds that
Pramanik et al. studies many metabolic reactions that take place
within E. coli (i.e. see the list in Appendix A on pages 411-
417). Equations 1 and 2 on page 399 denote the flux model
metabolism via a mass balance on E. coli wherein the matrix S
is a matrix of stoichiometric coefficients relevant to the
equations.

(Ans. 5.)

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The Examiner finds that Pramanik teaches the claimed method steps
except
Pramanik et al. does not teach obtaining a plurality of DNA
sequences comprising most of the metabolic genes in a genome,
determining open reading frames of these genes, assigning
functions to the proteins encoded by the open reading frames,
and determining which of said open reading frames correspond
to metabolic genes. Additionally, Pramanik et al. does not
teach determining open reading frames of genes having an
unknown function and assigning a function to their encoded
products based on homology to proteins in a different organism.

(Ans. 6.) The Examiner relies on Blattner and Kunst to make up for the
deficiencies of Pramanik. (Id. at 6-7.)
The Examiner concludes that
It would have been obvious to someone of ordinary skill
in the art at the time of the instant invention to modify the
stoichiometric model of E. coli metabolism as taught by
Pramanik et al. by use of the complete genome sequence of
Blattner et al. wherein the motivation would have been that by
knowledge of the full genome of E[.] coli, not only can
metabolism be further analyzed, but also knowledge of the
entire sequence of E. coli enables global approaches to
understanding biological function in living cells and has led to
new ways of looking at the evolutionary history of bacteria. …
It would have been further obvious to modify the stoichiometric
model of E. coli metabolism as taught by Pramanik et al. and
the complete E. coli genome structure in Blattner et al. by use
of the comparison of E. coli and B. substilis metabolism genes
and proteins to determine function of unknown proteins as in
Kunst et al. wherein the motivation would have been that such
homology comparisons allow for an analysis of the differences
in evolution between the two different, but related, organisms to
result in improvement in industrial applications.

(Id. at 8-9.)
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Appellant argues that
1) There is no motivation to combine the cited references (App. Br.
15, Reply Br. 6).
2) There is no reasonable expectation of success in practicing the
claimed method steps based on the cited references (App. Br. 19,
Reply Br. 9).
3) Appellant’s Declaration evidence rebuts any prima facie case of
obviousness as they evidence skepticism on the basis of persons of
ordinary skill in the art, evidence lack of an expectation of success
and show unexpected results. (App. Br. 22-23, Reply Br. 11.)

The dispositive issue with respect to each of the cited obviousness
rejections is: Does the combination of Pramanik, Blattner and Kunst support
the Examiner’s conclusion that the claimed invention is obvious?

PRINCIPLES OF LAW
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993) (citations omitted). In order to determine whether a prima facie
case of obviousness has been established, we consider the factors set forth in
Graham v. John Deere Co., 383 U.S. 1, 17 (1966): (1) the scope and content
of the prior art; (2) the differences between the prior art and the claims at
issue; (3) the level of ordinary skill in the relevant art; and (4) objective
evidence of nonobviousness, if present.
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While the analysis under 35 U.S.C. § 103 allows flexibility in
determining whether a claimed invention would have been obvious, KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), it still requires showing
that “there was an apparent reason to combine the known elements in the
fashion claimed by the patent at issue.” Id. “We must still be careful not to
allow hindsight reconstruction of references to reach the claimed invention
without any explanation as to how or why the references would be combined
to produce the claimed invention.” Innogenetics, N.V. v. Abbott Labs., 512
F.3d 1363, 1374 n.3 (Fed. Cir. 2008).
Our case law makes clear that the best defense against
the subtle but powerful attraction of a hindsight-based
obviousness analysis is rigorous application of the requirement
for a showing of the teaching or motivation to combine prior art
references. . . . Combining prior art references without
evidence of such a suggestion, teaching, or motivation simply
takes the inventor‟s disclosure as a blueprint for piecing
together the prior art to defeat patentability—the essence of
hindsight.

In re Dembiczak, 175 F.3d 994, 999 (Fed. Cir. 1999).
Under § 103, “there must be some articulated reasoning with some
rational underpinning to support the legal conclusion of obviousness.” KSR,
at 418. See also, In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006).
“„It is impermissible within the framework of section 103 to pick and
choose from any one reference only so much of it as will support a given
position, to the exclusion of other parts necessary to the full appreciation of
what such reference fairly suggests to one of ordinary skill in the art.‟” In re
Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986) (quoting In re Wesslau, 353
F.2d 238, 241 (CCPA 1965)).
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ANALYSIS
We do not find that the Examiner has provided sufficient evidence to
support a prima facie case of obviousness on the record before us. In
particular, Appellant argues that there is no motivation or other rationale to
combine the cited references to arrive at the claimed invention. (App. Br.
14.) Appellant argues that they have requested that “the Examiner articulate
the reason to combine a stoichiometric matrix element with substrates,
products and stoichiometry of reactions from metabolic proteins having a
potential function assigned by determining the homology of genes of
unknown function to gene sequences encoding proteins of known function.”
(Reply Br. 4.)
The Examiner, in response, has taken the position that
by expanding the metabolic pathways of Pramanik et al. to the
genome of E. coli as (such as studied in Blattner et al.), the
combination of studies leads to new ways of examining the
evolutionary history of bacteria. … By understanding
similarities and differences in evolution of bacteria, genes with
unknown functions may be assigned function based on
homology with genes of known function in different organisms
(as in Kunst et al.) which results in a better understood genome
of the original organism leading to improvement in industrial
applications of this organism.

(Ans. 12-13.)

We find that Appellant has the better argument. While Blattner and
Kunst together may involve assigning function to unknown genes based on
homology of genes with known function, what is missing from the
Examiner’s analysis is a reason why genes of unknown function generally
would be relevant or useful in constructing metabolic genotypes and genome
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specific stoichiometric matrices from genome annotation data, or where the
functions of the metabolic genes in the target organism are determined by
homology searches against databases of genes from similar organisms.
Pramanik’s metabolic studies were based on 153 reversible and 147
irreversible known reactions and 289 known metabolites. (Page 400, col. 2.)
The Examiner has not pointed to any disclosure in the cited references which
provides motivation for using genes of unknown function [e.g., deletion
mutants] in studies which computer simulate a metabolic capability of an in
silico strain of a microbe and determine the unknown or deletion mutant
gene’s effect on cellular metabolism. It would therefore appear that the
Examiner has used Appellant’s Specification as a template for combining
the cited references to arrive at the claimed invention. Combining prior art
references without evidence of a rationale or suggestion, teaching, or
motivation simply takes the inventor’s disclosure as a blueprint for piecing
together the prior art to defeat patentability—the essence of hindsight. In re
Dembiczak, 175 F.3d at 999.
Moreover, even if the Examiner had presented a prima facie case of
obviousness, we do not find that the Examiner has properly considered and
addressed Appellant’s Declaration evidence of lack of an expectation of
success or unexpected results. The obviousness rejections are reversed.

Double Patenting Rejection
Claims 49-52, 56-60 and 64 are provisionally rejected on the ground
of nonstatutory obviousness-type double patenting as being unpatentable
over claims 26- 28, 30, 32, 35-36, and 39-41 of copending Application No.
11/980,199.
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Appellant
submits that the provisional double patenting rejection is not in
issue in the instant appeal and Appellant is not required to
respond to this provisional ground of rejection. Per Appellant's
response of record and consistent with M.P.E.P. § 804(1)(B),
should the subject application be deemed in condition for
allowance prior to application serial no. 11/980,199, Appellant
requests that this provisional rejection be withdrawn in this
earlier filed application and permit it to proceed to issuance
without the need of a terminal disclaimer.

(Reply Br. 14.)
Both applications serial no. 11/980,199 and the pending application
claim continuity to the same application 09/243,022, filed Feb. 2, 1999.
Therefore the pending application was not filed earlier than application
serial no. 11/980,199.
Appellant does not address the merits of the obviousness-type double
patenting rejection (Ans. 17) and therefore it is summarily affirmed.

CONCLUSION OF LAW
The cited references do not support the Examiner’s obviousness
rejections which are reversed. The obviousness-type double patenting
rejection is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED-IN-PART

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