Ex Parte 6,610,545 et al

Board of Patent Appeals and Interferences

Mar 14, 2012

95000491 (B.P.A.I. Mar. 14, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

PRECISION BIOSCIENCES, INC.
Requester & Respondent

v.

INSTITUT PASTEUR &
UNIVERSITÉ PIERRE ET MARIE CURIE
Patent Owner & Appellant
____________

Appeal 2011-010715
Reexamination 95/000,427
Patent 6,610,545 B2
Technology Center 3900
____________

Before SALLY G. LANE, RICHARD M. LEBOVITZ, and JEFFREY B.
ROBERTSON, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
Appeal 2011-010715
Reexamination 95/000,491
Patent 6,610,545 B2

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This is a decision on appeal by the Patent Owner from the Patent
Examiner’s rejections of claims in an inter partes reexamination of U.S.
Patent No. 6,610,545 B2. The Board’s jurisdiction for this appeal is under
35 U.S.C. §§ 6(b), 134, and 315. We affirm all rejections.

STATEMENT OF THE CASE
The patent in dispute in this appeal is U.S. Patent No. 6,610,545 B2
(hereinafter, “the ‘545 patent”), which issued August 26, 2003. The named
inventors are Bernard Dujon, Andre Choulika, Laurence Colleaux, Cecile
Fairhead, Arnaud Perrin, Anne Plessis, and Agnes Thierry.
The claims under reexamination in the ‘545 patent are directed to a
method for in vivo site directed genetic recombination in which a Group I
intron encoded endonuclease (“GIIEE” or “GIIE endonuclease”) is
expressed in a eukaryotic cell. An endonuclease is an enzyme which cleaves
DNA. The GIIE endonuclease is recited in the claim to promote insertion of
a gene of interest into a chromosome of the eukaryotic cells at a specific site
by homologous recombination. Homologous recombination is when a donor
DNA fragment replaces an identical or nearly identical DNA fragment in the
chromosome of the cell. The identical DNA sequences of each fragment
align with each other, and then donor fragment exchanges places with the
fragment residing in the chromosome. The method can be used to repair
genes in a cell and correct genetic disorders by swapping out the defective
copy of a gene of interest, or a portion of it, and replacing it with a normal
copy or portion (‘545 patent, col. 1, ll. 53-60). The methods can also be
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used to create animal models of genetic disorder by replacing a normal gene
with a defective one (id.).
A request for inter partes reexamination under 35 U.S.C. §§ 311-318
and 37 C.F.R. §§ 1.902-1.997 for the ‘545 patent was filed on July 31, 2009
by a Third-Party Requester (Request for Inter Partes Reexamination
Transmittal Form). The Third-Party Requester is Precision BioSciences,
Inc., who is the Respondent in this appeal (Respondent Br. iii, dated March
17, 2011). The Patent Owners and Appellants in this appeal are the Institut
Pasteur and Université Pierre et Marie Curie (Appellant App. Br. 1, dated
February 17, 2011). The patent has been licensed to Cellectis SA, of Paris,
France (id.).
There are three additional pending reexamination proceedings
involving the same parties and related patents:
1. Reexamination Control No. 95/000,427 for U.S. Patent No.
7,214,536 B2;
2. Reexamination Control No. 95/000,443 for U.S. Patent No.
6,833,252 B1; and
3. Reexamination Control No. 95/000,490 for U.S. Patent No.
7,309,605 B1.
All three reexaminations are on appeal before the Board.
In addition, there is a pending litigation in a district court asserting
U.S. Pat. Nos. 7,309,605 B1 and 6,610,545 B2 (Cellectis SA v. Precision
Biosciences, Inc., No. 5:08-cv-119 (E.D.N.C.)) (Respondent Br. R-
1;Appellant App. Br., Appendix C.)
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Claims 7-10 and 12-27 pending and stand finally rejected by the
Examiner. Claims 1-6 are not subject to reexamination. Claims 11 and 28
were canceled. There are 44 rejections, each of which is appealed by the
Patent Owner (Appellant App. Br., Appendix D). Claim 7 is the only
independent claim on appeal and reads as follows (underling indicates
amendments relative to the issued patent claim):
7. A method for in vivo site directed genetic recombination in an
organism comprising:
(a) providing a transgenic eukaryotic cell having at least one
Group I intron encoded endonuclease recognition site inserted at a
unique location in a chromosome;
(b) providing an expression vector that expresses said
endonuclease in said transgenic cell;
(c) providing a plasmid comprising a gene of interest and a DNA
sequence homologous to the sequence of the chromosome,
allowing homologous recombination;
(d) transfecting said transgenic cell with said plasmid of step (c);
(e) expressing said endonuclease from said expression vector in
said cell; and
(f) cleaving said at least one Group I intron encoded endonuclease
recognition site with said endonuclease, whereby said cleavage
promotes the insertion of said gene of interest into said
chromosome of said organism at a specific site by homologous
recombination.

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REJECTIONS
There are forty-four grounds of rejections, numbered 65 to 108, each
rejecting the claims as obvious under 35 U.S.C. § 103. (Right of Appeal
Notice (“RAN”) 8-9.) Half of the obviousness rejections cite the Bell-
Pedersen publication1 and the other half cite the Quirk publication.2
Additional secondary references are cited in the rejections for the
independent claims, as well the dependents. The Bell-Pedersen and Quirk
publications were authored by the same research group headed by Dr.
Marlene Belfort. Quirk was published in 1989. Bell-Pedersen was
published in 1990. Both publications involve the same experimental system
of using a GIIE endonuclease to mobilize a modified intron from a plasmid
into a phage DNA by homologous recombination. As Patent Owner did not
appear to distinguish between the disclosures, we address both Quirk and
Bell-Pedersen together.
The rejections cite different combinations of publications, but often
relying on several different publications for the same teachings, but in
independent rejections. For example, claims 7-10, 12, 13, 25, and 26 are
rejected in Ground 65 as obvious in view of Quirk, Old,3 and Eddy92,4 and

1 Deborah Bell-Pedersen et al., Intron mobility in phage T4 is dependent
upon a distinctive class of endonucleases and independent of DNA
sequences encoding the intron core: mechanistic and evolutionary
implications, 18 Nucleic Acid Research 3763 (1990).
2 Susan M. Quirk et al., Intron Mobility in the T-Even Phages: High
Frequency Inheritance of Group I Introns Promoted by Intron Open
Reading Frames, 56 Cell 455 (1989).
3 R.W. Old & S.B. Primrose, Principles of Gene Manipulation 222-295
(Blackwell Scientific Publication 1989) (1980).
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in Ground 87 as obvious in view of Quirk, Old, and Frey5. Eddy92 and Frey
were thus apparently cited for the same teaching. In another set of
rejections, claim 17, which depends on claim 7, is rejected as obvious in
view of Quirk, Seraphin6, and Eddy92 (Ground 69) or as obvious in view of
Quirk, Seraphin, and Frey (Ground 91).
It is also not clear why Eddy92 was cited in some rejections, but not
others, when Eddy92 had a direct suggestion to use a GIIE endonuclease to
target host cell chromosomes.
As the rejections are duplicative by citing different publications in
separate rejections, when the publications are cited for substantially the same
teachings, we shall consider the publications all together as defining the
scope and content of the prior art, a prong of the Graham v. Deere
obviousness test. Graham v. John Deere Co., 383 U.S. 1 (1966).
A number of different declarations by experts were cited as evidence
by both parties in this proceeding and in the related three reexamination
proceedings. For consistency and ease of reference, we have renumbered
the declarations as Exhibits 1001 to 1015, and attached them to
Reexamination 95/000,427 of U.S. Patent No. 7,214,536 B2, which is
Appeal 2011-010572.

4 Sean R. Eddy & Larry Gold, Artificial Mobile DNA Element Constructed
From the EcoRI Endonuclease Gene, 89 Proc. Nat’l Acad. Sci.1544 (1992).
5 B. Frey et al., Specific Cleavage of the Yeast and Bacterial Genomes at a
Single Site Using the Rare Cutter Endonuclease I-SceI (Meganuclease I-
SceI), 343 Fresenius’ J. Analytical Chemistry 122-123 (1992).
6 Bertrand Seraphin et al., The Yeast Mitochondrial Intron a15α Associated
Endonuclease Activity and In Vivo Mobility, 113 Genetics 1-8 (1992).
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Claim 7
Claim 7 is directed to a method comprising the following steps:
(a) providing a GIIE endonuclease recognition site to a eukaryotic
cell;
(b) & (e) providing and expressing a GIIE endonuclease in the cell;
(c) & (d) providing a gene of interest on a plasmid to the cell and
introducing the plasmid into the cell; and
(f) cleaving the GIIEE recognition site with the GIIE endonuclease,
“whereby said cleavage promotes the insertion of said gene of interest into
said chromosome of said organism at a specific site by homologous
recombination.”
We interpret the “whereby” to be a necessary result of carrying out
step (f) in combination with the other recited steps in the claim.
Consequently, we interpret the claim to require that the gene of interest in
steps (c) and (d) become inserted into the organism’s chromosome by
homologous recombination.

Rejection
We begin by addressing Grounds 65 and 66 in which claims 7-10, 12,
13, 25, and 26 were rejected under 35 U.S.C. § 103(a) as obvious in view of
Quirk, Old, and Eddy92, or Bell-Pedersen, Old, and Eddy92.
The Bell-Pedersen and Quirk publications were cited by the Examiner
for describing methods in which a GIIE endonuclease is provided to a cell,
where the GIIE endonuclease promotes insertion of a gene of interest into
the chromosome of a host cell, the same steps recited in claim 7 (Right of
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Appeal Notice (“RAN) 9-10 & 12). The Examiner acknowledged that Bell-
Pedersen or Quirk described promoting insertion of gene of interest into the
chromosome of a prokaryotic cell (bacteria), not a eukaryotic cell (e.g.,
mammal, plant, yeast, etc.) as claimed. However, to meet this deficiency,
the Examiner cited Old for its teaching of methods of introducing genes into
eukaryotic yeast and mammalian cells (id. at 10-11 &13). Eddy92 was
relied upon by the Examiner for its teaching of site-specific insertion of a
gene into a chromosome and suggesting that a GIIE endonuclease be used
for such a process (id. at 11 & 13). Based on these teachings, the Examiner
concluded it would have been obvious to one of ordinary skill in the art “to
have substituted a transgenic eucaryotic [sic] cell containing a group I
encoded endonuclease recognition site, as described by Eddy ‘92, in the
method taught by Quirk [or Bell-Pedersen] in order to transfer of [sic] a gene
of interest into a eukaryotic cell, as is contemplated by both Old and Eddy
‘92.” (Id. at 11 & 13.) The Examiner also concluded that there would have
been a reasonable expectation of success that a GIIE endonuclease would
promote insertion of a gene of interest into a host chromosome in view of
the success of Old and Eddy92 (id. at 11 & 13-14).

Claims 7-10, 12, 13, 25, and 26
Quirk and Bell-Pedersen
Patent Owner contends that the Examiner incorrectly found that the
Quirk and Bell-Petersen publications taught cleavage of a bacterial
chromosome and insertion of a gene of interest into a bacterial chromosome
(Appellant Appeal Brief (“App. Br.”) 9, dated February 17, 2011). Based on
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the totality of evidence before us, we agree with the Patent Owner that the
Examiner erred in this finding. This issue was discussed extensively in
related Appeal No. 2011-010572. Rather than repeating the findings of fact
and analysis upon which our conclusion was based, we refer both parties to
the decision in Appeal 2011-010572, which is being mailed at the same time
as this present decision.

Obviousness issue
Even though we concluded that the evidence was insufficient to
establish that the Bell-Pedersen and Quirk publications taught cleavage of
the bacterial chromosomal DNA and insertion of a gene into the bacterial
chromosome, additional publications are of record that are said by the
Examiner and Requester to have made this step obvious to one of ordinary
skill in the art.
To decide whether a composition, device, or process would have been
obvious in light of the prior art, it must be determined whether, at the time of
invention, “a person of ordinary skill in the art would have had reason to
attempt to make the composition or device, or carry out the claimed process,
and would have had a reasonable expectation of success in doing so.”
PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed.
Cir. 2007). “Obviousness does not require absolute predictability of success
. . . .” In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).

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Eddy92
Eddy92 constructed an artificial mobile element from the gene for the
restriction enzyme Eco RI that was capable of facilitating site-specific
insertion of the modified DNA into a phage genome (Eddy92 1544) [FF1].7
The Eco RI was used as a generic endonuclease to mobilize an artificial
DNA element into recipient DNA (Eddy92 1544) [FF2]. Eddy92
“configured the experimental system to closely mirror that used to measure
the mobility of the mobile T4 td and sunY introns” described in Bell-
Pedersen (Eddy92 1546, col. 2) [FF3]. Based on these experiments, Eddy
concluded:
It should be possible to use DSBR-based targeting of
homologous recombination to effect site-directed gene
conversions in a variety of organisms. The extreme specificity
of intron-encoded endonucleases . . . could allow targeting of a
single specific site in a genome, either by the good fortune of
having a usable site already in the genome or by the one-time
transgenic introduction of a “landing site” containing the
endonuclease recognition site and flanking exon homology to
some shuttle vector construct.
(Eddy92 1547, col. 2) [FF4].
Eddy92 also wrote:
We thus presume that any differences between the mobility of
our artificial EcoRI element and an authentic mobile group I
intron reflect differences between a restriction enzyme and an
intron-encoded homing endonuclease.
(Eddy92 1546, col. 2) [FF5].

7 When a finding of fact (“FF”) first appears in the decision, it is defined by
a number within brackets. Thereafter, reference to the finding is made by
the specific fact number without brackets.
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Patent Owner contends that Eddy92 did not use eukaryotic cells,
eukaryotic chromosomes, or GIIE endonucleases in its experiments as
required by claim 7 (Appellant App. Br. 15). Patent Owner acknowledged
Eddy92 suggested using intron-encoded endonucleases in its method (FF4,
Eddy92 1547, col. 2; Appellant App. Br. 16-17), but contends that such
suggestion was speculative and “not the same as actual teachings about the
likelihood of success of using a GIIEE in the method of” the ‘545 patent
(Appellant App. Br. 17). Patent Owner also contends that the Examiner did
not show the interchangeability of phage and E. coli DNAs as described in
the Quirk and Bell-Pedersen publications, nor a suggestion to use a
eukaryotic cell in the Quirk and Bell-Pedersen methods with reasonable
expectation of success (id. at 17 & 20).
We disagree with Patent Owner that there would have been no reason
to substitute the phage and E. coli DNA described in Quirk and Bell-
Pedersen with chromosomal DNA of a eukaryotic cell. Eddy92 expressly
suggested using the Bell-Pedersen system in a “variety of organisms.” (FF4,
Eddy92 1547, col. 2) Based on Old’s teaching of known methods to transfer
genes into eukaryotic cells and their known advantages, persons of ordinary
skill in the art would have had reason to have followed Eddy92’s suggestion
of using intron-encoded endonucleases in its method and adapting it to
eukaryotic cells. See also Decision in Appeal 2011-010572, pp. 26-28, and
any additional findings of fact therein).
Patent Owner argued that Quirk, Bell-Pedersen, Old, and Eddy:
were not tasked with trying to demonstrate site-directed
insertion of a gene of interest into a eukaryotic chromosome of
an organism. This disconnect prompts the question: why then,
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would the skilled artisan have looked to Quirk, Bell-Pedersen,
Old, and Eddy ‘92 for a solution to the problem that
confounded workers in the field until Dujon's invention was
made?
(Appellant App. Br. 40.)
Appellant’s argument overlooks Eddy92’s express suggestion of using
a GIIE endonuclease for “targeting of homologous recombination to effect
site-directed gene conversions in a variety of organisms.” (FF4, Eddy92
1547, col. 2). We agree that Eddy92 did not carry out such experiment, but
Eddy92’s suggestion to do so is evidence that the authors believed
homologous recombination could be achieved successfully in a variety of
organisms with a GIIE endonuclease. Eddy92 recognized differences
between the Eco RI endonuclease used in its publication and those of an
intron-encoded homing endonuclease (FF5, Eddy92 1546, col. 2), but Eddy
did not state that these differences would translate into failure. Thus, we do
not agree that the Examiner exercised impermissible hindsight in concluding
that claim 7 would have been obvious in view of prior art (Appellant App.
Br. 41).
With respect to the interchangeability argument, we understand Patent
Owner to be arguing that there would have been no reasonable expectation
of success. We agreed with the Patent Owner with respect to the claims of
U.S. Pat. No. 7,214,536 B2 (“the ‘536 patent”) in Appeal 2011-010572 that
there was a certain degree of unpredictability in whether a GIIEE would
cleave animal or plant chromosomal DNA of a viable cell. However, the
claims at issue in this appeal differ in at least two aspects. The claims of the
‘536 patent were limited to animal or plant cells, while those of the ‘545
patent are drawn to the broader class of eukaryotes, which would include
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yeast cells, a class of cells excluded by the ‘536 patent claims. The claims
of the ‘536 patent also require “viable” plant and animal cells, but viability
is not required by the ‘545 patent claims in this appeal.
Because the claims of the ‘545 patent cover eukaryotic cells,
including yeast cells, we look to the Frey and Dujon (1990)8 (hereinafter,
“Dujon90”) publications, both which describe results using GIIE
endonucleases in yeast.
Frey tested the ability of a GIIE endonuclease (I-SceI) to cleave
chromosomal DNA. Frey inserted a I-SceI recognition site into a yeast
chromosome (Frey 122, col. 2) [FF6]. “Purified, intact chromosomes from
the resulting strain were digested with I-SceI.” (Frey 122, col. 2) [FF7]
“Results showed that I-SceI specifically cleaves chromosome III to
completion at its” recognition site (Frey 122-123) [FF8]. Frey suggested
that this result suggested that I-SceI could be used for mapping genes (Frey
123) [FF9].
Dujon90 coauthored by Bernard Dujon who is also one of the co-
inventors of the patent in this proceeding, described I-SceI and its ability to
cleave yeast chromosomal DNA. According to Dujon90:
I-Sec I can be expressed in the yeast nucleus from artificial
constructs and the protein is able to cleave efficiently both its
natural site within mitochondria and an artificially placed site
within the nucleus. In the latter case, double strand break repair
and homologous recombination follow the formation of the cut
in a manner which parallels that obtained with the HO
endonuclease.
Dujon90, Abstract [FF10].

8 Bernard Dujon et al., Mobile Introns, Abstract in Molecular Mechanisms of
Transposition and its Control (1990).
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In sum, each of Frey and Dujon90 showed that a GIIE endonuclease
cleaved yeast chromosomal DNA when expressed in yeast cells (FF8, Frey
122-123 & FF10, Dujon90 Abstract). As the present claims cover
expression of a GIIE endonuclease in yeast cells, we conclude that the Frey
and Dujon90 publications provided one of ordinary skill in the art of a
reasonable expectation that the teachings of Quirk and Bell-Pedersen could
be successfully applied to yeast cells.
Patent Owner contends that the “prior art established the existence of
the problem” of achieving site-directed insertion of a gene into a eukaryotic
chromosome by homologous recombination (Appellant App. Br. 40).
However, Eddy92 expressly suggested that the method of Bell-Pedersen be
adapted to achieve this goal, and Frey and Dujon90 achieved cleavage of
eukaryotic chromosomes using a GIIEE, giving rise to a reasonable
expectation of success that the claimed invention could be practiced
successfully. Dujon90 also expressly referred to homologous recombination
following endonuclease cleavage (FF10, Dujon90 Abstract), providing
evidence that the skilled worker prior to the filing date of the claimed
invention had a reasonable expectation that such event could be achieved in
a eukaryotic chromosome. Patent Owner’s argument to the contrary
(Appellant App. Br. 4-6) is thus outweighed by the evidence of Eddy92,
Dujon90, and Frey.

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Toxicity
Patent Owner contends that “invention’s intended use required a
viable cell,” and toxicity was concern, pointing away from the claimed
invention (Appellant App. Br. 39). As evidence, Patent Owner cites Quirk’s
teaching about the toxicity of a GIIE endonuclease when expressed in E. coli
bacterial cells (id.).
This argument is not persuasive. As indicated above, claim 7 is not
limited to “viable” eukaryotic cells. While the ‘545 patent may disclose the
use of viable cells, we do not import limitations from the patent specification
into the claims. Sjolund v. Musland, 847 F.2d 1573, 1581 (Fed. Cir. 1988);
In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993). Moreover, as
discussed above, each of Frey and Dujon90 showed that a GIIEE was
successful in introducing a double-stranded break in eukaryotic
chromosomal DNA without reporting toxicity.
In the 95/000,427 reexamination of US 7,214,536 (Appeal 2011-
010572), we found unpredictability based on teachings in Morgan, which
taught that endonuclease expression in mammalian cells caused DNA
damage and toxicity (2011-010572 Decision, pp. 31 & 40). However, the
claims in this appeal are drawn to eukaryotic cells, a broader class of cells
than in the related proceeding involving the 7,214,536 patent. The claims in
this appeal also do not expressly require that the cells remain viable. Thus,
our analysis in the decision Reexamination 95/000,427 of the 7,214,536
patent does not apply here.

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Secondary considerations
Legal Principles
Evidence of secondary considerations, including evidence of
unexpected results and commercial success, are but a part of the
“totality of the evidence” that is used to reach the ultimate
conclusion of obviousness. [citation omitted]. In some cases
such evidence is the most probative of obviousness. See, e.g.,
Stratoflex, 713 F.2d at 1538[]. The existence of such evidence,
however, does not control the obviousness determination. See
Newell, 864 F.2d at 768 [] (“First, as indicated, obviousness is
not a factual inference; second, although these factors must be
considered, they do not control the obviousness conclusion.”)
(citations omitted); Ryko, 950 F.2d at 719 [] (the weight of
secondary considerations may be of insufficient weight to
override a determination of obviousness based on primary
considerations). Therefore, we must consider all of the evidence
under the Graham factors before reaching our decision.
Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1483 (Fed. Cir. 1997).

Evidence
Once a prima facie case of obviousness has been established, an
appellant can rebut the case with evidence of secondary considerations.
Patent Owner, in this case, asserted that the claimed invention is pioneering
“because it allowed for the efficient and predictable targeting of a gene of
interest to a specific location in eukaryotic chromosomal DNA. The
invention allowed artisans to dramatically increase the frequency of targeted
homologous recombination events by targeting the location of double-strand
breaks and insertion of the gene of interest into the genome of a eukaryotic
cell.” (Appellant App. Br. 7.) Based on this discovery, Patent Owner
contends that the claimed invention was praised, copied, and licensed by the
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industry, each a secondary consideration that must be considered when
determining the obviousness of the claimed invention.
With respect to the praise and copying of the claimed invention,
Patent Owner stated:
As a result, Dujon’s invention received
acknowledgement and accolades from other scientists working
in the art. Shortly after the invention was made, it was
published in Molecular and Cellular Biology by Choulika et al.
(Ex.93). . . .
. . .
Choulika[’s] publication was followed by praise and
acknowledgement, and copying of the Dujon invention. Patent
Owners submitted Exhibits 53, 149, and 150 identifying fifteen
journal articles showing praise and acknowledgement of the
invention, and twenty-two journal articles evidencing copying
of the claimed invention.
(Id.)
As evidence of praise by the industry, Patent Owner submitted a list
of 15 publications (Ex. 150) with references to “Choulika” (Ex. 93), a
scientific paper said by Patent Owner to represent the same work disclosed
in the ‘545 patent. The first author of the “Choulika” publication is Andre
Choulika, who is also a co-inventor of the ‘545 patent. The step commented
on in the publications was that of the homologous recombination event that
occurs after the site specific doubled stranded break in the chromosomal
DNA catalyzed by the GIIE endonuclease corresponding to step (f) of claim
7. For example, citing Choulika, Chen et al. stated:
To date, the most efficient method for inducing [homologous
recombination] involves introduction of a DNA double-
stranded break (DSB) in the target gene locus, which results in
a 10- to 10,000 fold increased rate of HR [homologous
recombination] . . . .
(Exhibit 150, p. 1-2) [FF11].
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Exhibit 149 listed 22 publications that Patent Owner argued were
evidence of copying of the claimed invention of the ‘545 patent. The exhibit
is a table of the publications showing how the homologous recombination
methods described in the publications correspond to and meet the steps
recited in claim 7. Exhibit 149, however, does not provide citations to
Choulika, as did Exhibit 150.
Patent Owner also supplied a declaration by Dr. Andre Choulika, co-
inventor of the ‘545 patent and CEO of Cellectis S.A., a license of the ‘545
patent (Choulika Decl. ¶¶ 1, 2, & 6; Exhibit 148). Dr. Choulika testified in
his written declaration that Cellectis had entered into a dozen sub-license
agreements giving the parties access “access to the invention described and
claimed in the ‘545 patent.” (Choulika Decl. ¶¶ 7-9; Exhibit 148) [FF12].

Analysis
There are numerous cases in which objective considerations of
nonobviousness, including substantial evidence of commercial success,
praise, copying, and licensing were inadequate to overcome a strong case of
prima facie obviousness. See Wyers v. Master Lock Co., 616 F.3d 1231,
1245-46 (Fed. Cir. 2010); Leapfrog Enters., Inc. v. Fisher-Price, Inc., 485
F.3d 1157, 1162 (Fed. Cir. 2007) (holding that the objective considerations
of nonobviousness presented, including substantial evidence of commercial
success, praise, and long-felt need, were inadequate to overcome a strong
showing of primary considerations that rendered the claims at issue invalid);
Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1483 (Fed. Cir. 1997).
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Here, we conclude that the strong case of obviousness outweighs the
statements in the scientific literature praising Choulika, the evidence said to
establish copying, and the degree of licensing. The evidence of obviousness
includes:
• Strong and explicit reason to have used a GIIE endonuclease to
cleave chromosomal DNA of a variety of organisms (FF3, Eddy92 1546,
col. 2; FF4, Eddy92 1547, col. 2; & FF10, Dujon90 Abstract);
• Strong and explicit statement that homologous recombination would
follow after double stranded break in eukaryotic yeast DNA catalyzed by a
GIIE endonuclease (FF10, Dujon90 Abstract).
• Availability of techniques to accomplish gene transfer in eukaryotic
cells (Old, Eddy92, RAN 10-11 & 13; FF4, Eddy92 1547, col. 2); and
• Successful endonuclease cleavage by a GIIE endonuclease in several
systems in which it had been attempted (Bell-Pedersen; FF7, Frey 122, col.
2; FF8, Frey 122-123; & FF10, Dujon90 Abstract);
While we have accorded Patent Owner’s evidence of secondary
considerations weight, there were certain weaknesses in such evidence that
we note below. For example:
Dr. Choulika’s declaration was an attempt by Patent Owner to
establish licensing to the third parties as a significant secondary
consideration. Dr. Choulika stated that the sub-license agreements gave
third parties “access to the inventions described and claimed in the ‘545
patent.” (FF12, Choulika Decl. ¶¶ 7-9; Exhibit 148; emphasis added).
However, Dr. Choulika did not establish that the third parties specifically
licensed the patent family to gain access to the subject matter claimed in the
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‘545 patent, rather than other technology described in the patent but not
claimed or claimed in related patents.
In regard to the evidence of copying set forth in Exhibit 149, as
indicated above, Patent Owner did not show that the cited publications
referenced Choulika’s method or that of ‘545 patent, rather than following
another publication.
It is well established that for evidence of secondary considerations to
be accorded substantial weight, there must be a nexus between the claimed
invention and what is relied upon as the secondary consideration. In re
GPAC, Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995). A nexus is established
when the secondary consideration is attributed to a feature of the claimed
invention. Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1311-12. Even
when a nexus has been established between the merits of the claimed
invention and the secondary consideration, the secondary consideration may
be insufficient when the claimed feature which underlies it was possessed by
the closest prior art. Thus, in In re Baxter Travenol Labs., 952 F.2d 388,
392 (Fed. Cir. 1991), the prior art possessed the function relied upon by the
patent applicant to establish unexpected results and therefore was not a basis
for rebutting a prima facie finding of obviousness. As held in J.T. Eaton &
Co., Inc. v. Atlantic Paste & Glue Co., 106 F.3d 1563, 1571 (Fed. Cir.
1997), “the asserted commercial success of the product [a secondary
consideration] must be due to the merits of the claimed invention beyond
what was readily available in the prior art.”
Here, we find there is nexus between the praise by the industry and
the homologous recombination step which is claimed. However, the
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21
statement in the Dujon90 abstract that homologous recombination followed
cleavage at an artificial site in yeast DNA (FF10, Dujon90 Abstract),
embodies and strongly suggests the claimed step of:
cleaving said at least one Group I intron encoded
endonuclease recognition site with said endonuclease, whereby
said cleavage promotes the insertion of said gene of interest
into said chromosome of said organism at a specific site by
homologous recombination.
We acknowledge it is unclear whether Dujon90 actually carried out
the homologous recombination step, and if so, what exogenous DNA was
inserted into the yeast DNA. Nonetheless, Dujon90’s statement about
homologous recombination at an artificially placed site in the yeast nucleus
made the very step relied on by Patent Owner as praised and copied by the
industry “readily available” (Eaton, 106 F.3d at 1571) to one of ordinary
skill in the art. Dujon90’s statement is almost indistinguishable from the
case where the experiment was actually accomplished. Thus, because the
step relied upon by Patent Owner as a basis for patentability was possessed
by the prior art, it is not a proper basis to rebut the prima face case of
obviousness established by the Examiner.

Claim 9
Claim 9 is directed to the method of claim 7, further reciting that the
“endonuclease recognition site has been introduced into said [eukaryotic]
cell by retroviral insertion.” The Examiner found that Bell-Pedersen did not
teach that the endonuclease recognition site of claim 7 was introduced by
retroviral insertion, as in claim 9 (RAN 12). However, the Examiner found
that Old taught the use of retroviral vectors for introducing foreign genes
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into cells and thus would have been obvious to have used Old’s technique
(id. at 13-14).
Patent Owner contends that modifying Bell-Pedersen and Quirk as
proposed by the Examiner would change the principles of operation of the
claimed invention and require substantial redesign (Appellant App. Br. 44-
45). Patent Owner also argued that “the Examiner provided no explanation
of why one would use a retroviral insertion vector to insert a GIIEE
recognition site into a chromosome, albeit the chromosome of a bacterial
cell, when the authors of Bell-Pedersen and Quirk instead used a genetically-
engineered phage as the means of introducing the site into a bacterial
chromosome.” (Appellant App. Br. 44.)
This argument is not persuasive. The rejection was based on a
combination of cited publications, including Old and Eddy92 which
provided the incentive to modify the teachings of Quirk and Bell-Pedersen.
Patent Owner’s argument has not properly addressed the basis for the
rejection as articulated by the Examiner.

Claim 10
Claim 10 is directed to the method claim 7, further reciting that the
“organism is yeast.” Patent Owner contends that the Examiner did not show
the equivalency between yeast cells and the bacterial cells utilized in the
Quirk and Bell-Pedersen experiments. We have already addressed this
argument. Based on Dujon90 and Frey, there is substantial evidence of a
reason to have utilized yeast cells and a reasonable expectation that such
cells would successfully work in the claimed method.
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Claim 12
Claim 12 is directed to the method claim 7, further reciting that the
“organism is a mammal.” Patent Owner again contends that the Examiner
did not show equivalency between the bacterial cells described in Quirk and
Bell-Pedersen and mammalian cells as claimed. Patent Owner argues:
Indeed, nothing in Quirk, Bell-Pedersen, Old, or Eddy '92
would have suggested to an artisan that a mammal would be an
acceptable substitute for the bacterial cells in the experiments of
Quirk and Bell-Pedersen.
(Appellant App. Br. 46.)
This argument is not persuasive. Based on the teachings of Eddy92
and Old, the Examiner provided adequate reason to have utilized
mammalian cells in the Quirk and Bell-Pedersen system. Patent Owner has
not shown a defect in this reasoning.

Summary
The rejection of claims 7, 9, 10, and 12 are affirmed. Claims 8, 13,
25, and 26, which depend on claim 7, fall with claim 7 because separate
reasons for their patentability were not provided. 37 C.F.R. §
41.37(c)(1)(vii).

Grounds 87 and 88
Ground 87 rejected claims 7-10, 12, 13, 25, 26 under 35 U.S.C. §
103(a) as obvious in view of Quirk, Old, and Frey. Ground 88 rejected
claims 7-10, 12, 13, 25, 26 under 35 U.S.C. § 103(a) as obvious in view of
Bell-Pedersen, Old, and Frey. These rejections differ from Grounds 65 and
66 only in relying on Frey, rather than Eddy92.
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Frey and Eddy92 form the scope and content of the prior art, and thus
are both relevant to the issue of whether it would have been obvious to have
applied the teachings of Bell-Pedersen and Quirk to eukaryotic cells.
Graham, 383 U.S. 1 (1966). For this reason, it was necessary and proper for
us to consider both publications in assessing the propriety of all the
rejections. Rejections 87 and 88 are affirmed for the reasons already
discussed.

Grounds 67-86 and 89-108
Grounds 67-86 and 89-108 reject claims 13-24 and 27 based on a
combination of additional secondary publications. Patent Owner did not
separately contest the patentability of these claims. We therefore affirm the
rejections for the reasons given by the Examiner.

TIME PERIOD FOR RESPONSE
Requests for extensions of time in this inter partes reexamination
proceeding are governed by 37 C.F.R. § 1.956. See also 37 C.F.R. § 41.79.

AFFIRMED

KMF

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25

For Patent Owner:
Kenneth J. Meyers, Esq.
Finnegan, Henderson, Farabow, Garrett & Dunner LLP
901 New York Avenue, NW
Washington, DC 20001-4413

For Third Party Requester
Michael J. Twomey, Esq.
Wilmer Cutler Pickering Hale and Dorr LLP
60 State Street
Boston, MA 02109