Ex Parte 6833252 et al

Board of Patent Appeals and Interferences

Mar 14, 2012

95000443 (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 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1
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 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

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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. 6,833,252 B1. 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. 6,833,252 B1
(hereinafter, “the ‘252 patent”), which issued December 21, 2004. The
named inventors are Bernard Dujon, Andre Choulika, Arnaud Perrin, and
Jean-Francois Nicolas.
The claims under reexamination in the ‘252 patent are directed to a
“recombinant mammalian chromosome comprising an exogenous Group I
intron encoded endonuclease site.” The endonuclease site is “within an
integrated nucleic acid sequence from a vector.” The site is selected from a
group of specifically named Group I intron encoded endonuclease sites.
A Group I intron encoded endonuclease (“GIIEE” or “GIIE
endonuclease”) is an endonuclease encoded in the intron of a gene. An
endonuclease is an enzyme which cleaves DNA. In nature, the GIIE
endonuclease makes a double-stranded break in the DNA of a target gene,
initiating a series of events which results in the insertion of the intron that
encodes the GIIEE into the target gene (‘252 patent, col. 2, 33-41).
Cleavage of the target DNA occurs at the “endonuclease site,” a DNA
sequence which is recognized by the GIIE endonuclease (id. at 33-48).
Upon recognition, the GIIE endonuclease cleaves the DNA within the
“endonuclease site” (id.). The intron, or other donor DNA, is subsequently
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inserted into the DNA at the cleaved site and repair is completed (id. at col.
22, ll. 49-54; col. 27, l. 9 to col. 28, l. 11).
The GIIEE can be used to repair genes in a cell and correct genetic
disorders by swapping out the defective copy of a gene of interest and
replacing it with a normal copy (‘252 patent, col. 1, ll. 23-25 & 53-60; col. 2,
ll. 53-60). The GIIEE methods can also be used to create animal models of
genetic disorder by replacing a normal gene with a defective one (id.).
According to the Patent Owner, the inventors of the ‘252 patent
showed that a targeted, double-strand break could be formed at
the endonuclease recognition site in the mammalian
chromosome, and that the resulting double-strand break could
be repaired via homologous recombination with a donor nucleic
acid, allowing the chromosomal DNA to be modified. This
method improved the frequency of homologous recombination
events in the cells tenfold over a random integration of a new
sequence, and at least 500-fold over spontaneous homologous
recombination. ‘252 patent (Ex. 1), col. 25, ll. 46-50. Moreover,
the method allowed for the targeted modification of mammalian
chromosomal DNA.
(Appellant App. Br. 3.)
A request for inter partes reexamination under 35 U.S.C. §§ 311-318
and 37 C.F.R. §§ 1.902-1.997 for the ‘252 patent was filed on March 18,
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 January
18, 2011). The Patent Owners and Appellants in this appeal are the Institut
Pasteur and Université Pierre et Marie Curie (Appellant App. Br. 1, dated
December 15, 2010). The patent has been licensed to Cellectis SA, of Paris,
France (id.).
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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. 95/000,490 for U.S. Patent No.
7,309,605 B1; and
3. Reexamination Control No. 95/000,491 for U.S. Patent No.
6,610,545 B2. 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. iii;
Appellant App. Br., 1.)
Claims 1-18 are pending and stand finally rejected by the Examiner.
Claim 19 is also pending, but its patentability has been confirmed (Right of
Appeal Notice (“RAN”) 36). There are 22 rejections, each of which is
appealed by the Patent Owner (Appellant App. Br. 2-3). All the rejections
are under 35 U.S.C. § 103 as obvious under cited prior art. Claim 1 is the
only independent claim on appeal and reads as follows:
1. A recombinant mammalian chromosome comprising an exogenous
Group I intron encoded endonuclease site,

wherein the endonuclease site is within an integrated nucleic acid
sequence from a vector,

wherein the site is selected from the group consisting of an I-SceIV
site, an I-CsmI site, I-PanI site, I-SceII site, an I-CeuI site, an I-PpoI
site, an I-SceIII site, an I-CreI site, an I-TevI site, an I-TevII site, an I-
TevIII site, and an I-SceI site.

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REJECTIONS
There are twenty-two grounds of rejections, each rejecting the claims
as obvious under 35 U.S.C. § 103 (Appellant App. Br. 2-3). All of the
obviousness rejections cite the Old publication,1 which is a chapter from a
book that describes methods of transferring genes into mammal and other
cells. In addition, all of the rejections cite either Quirk2 or Bell-Pedersen,3 or
both, each which describes a system in which a GIIE endonuclease was used
to mobilize a modified donor intron sequence into a recipient DNA.
Additional secondary references are cited in the rejections for the
independent claims, as well the dependent claims.
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.
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

1 R.W. Old & S.B. Primrose, Principles of Gene Manipulation 222-295
(Blackwell Scientific Publication 1989) (1980).
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 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).
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same experimental system of using a GIIE endonuclease a mobilize a
modified DNA sequence from a plasmid to a phage in a bacterial cell. Both
publications were relied upon for the same teachings. For example, claim 2
was rejected in Ground 5 over Bell-Pedersen, Old, and Seraphin,4 and in
Ground 7, over Quirk, Bell-Pedersen, Old, and Seraphin. Consequently, we
shall address both publications together.
In addition, there were several scientific publications that were cited
in the three related reexaminations, not all of which are relied upon in the
pending rejections of this present reexamination proceeding. However, in
making an obviousness determination, we must consider the scope and
content of the prior art. Graham v. John Deere Co., 383 U.S. 1 (1966). As
such publications form the scope and content of the prior art, and both
parties to this proceeding had full knowledge of them, we shall consider
them as defining the scope and content of the prior art.

Claim 1
Claim 1, the only pending independent claim, is directed to a
recombinant mammalian chromosome comprising an exogenous GIIE
endonuclease site.

4 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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Rejection
We begin by addressing Grounds 1 and 3 which reject claims 1, 10,
11, and 14-18 under 35 U.S.C. § 103 as obvious in view of Bell-Pedersen
and Old, or Quirk, Bell-Pedersen, and Old.
The Bell-Pedersen and Quirk publications were cited by the Examiner
for describing methods of inducing a site-directed double stranded break in
the DNA of an organism using a GIIE endonuclease and introducing a GIIE
cleavage site integrated into the DNA (RAN 6-9). The Examiner
acknowledged that neither Bell-Pedersen nor Quirk described a recombinant
a mammalian chromosome comprising a GIIE endonuclease site. However,
the Examiner cited Old as describing the state of art of genetic engineering
(RAN 7). The Examiner found that Old taught a variety of methods for
introducing genes of interest into mammal cells (RAN 6-9). The Examiner
also found that Old taught homologous recombination and genetic
modification of animal cells (RAN 7-9; Old at 267; [FF1]5). The Examiner
concluded it would have been obvious to have applied the Quirk and Bell-
Pedersen GIIEE methods to mammalian cells since Old taught that genetic
engineering methods were applied to mammalian cells (RAN 7-8).
Patent Owner challenges the Examiner’s determination on the
following grounds (Appellant App. Br. 14-15):
(1) the Examiner failed to show the interchangeability of the bacterial
cells of Bell-Pedersen and the mammalian cells of the invention;

5 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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(2) the Examiner failed to provide a suggestion for using mammalian
cells instead of bacterial cells in the method of Bell-Pedersen;
(3) the Examiner has disregarded the undisputed fact that Bell-
Pedersen and Quirk did not seek to achieve chromosomal cleavage and
insertion of a gene of interest into a bacterial chromosome, and indeed,
provide no evidence of such;
(4) the Examiner relied on the conflicting conjectures of experts to
make up for the lack of specific teachings and evidence, but the conjectures
by the Requester's experts are unsupported and inadequate; and
(5) the Examiner inappropriately relied on Dr. Bell-Pedersen's use of
Dujon's invention as the motivation to probe into what might have occurred
in Bell-Pedersen and Quirk.

Interchangeability and suggestion (1, 2, and 5)
Patent Owner contends that the PTO has not cited a pertinent
reference which would have shown or suggested that the bacterial cell of
Bell-Pedersen and Quirk would be interchangeable with a mammalian cell
(Appellant App. Br. 15). Patent Owner contends that generating a double-
strand break in the chromosomal DNA of a mammalian cell, in order to
facilitate site-directed insertion of a gene of interest, would not have been
predictable (id. at 16). Patent Owner contends that, prior to the claimed
invention, introducing a double-stranded breaks into DNA to facilitate
insertion of a donor DNA “was a rare event” and the “mechanism [was]
largely unknown” (id. at 5-6). Patent Owner also cites the Belfort
declaration in which Dr. Belfort testified that “‘[g]roup I intron encoded
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endonucleases did not evolve in nature to cleave double-stranded DNA in
plant and animal cells.’ First Belfort Declaration A (Ex. 59) at 16, ¶ 70.”
(Appellant App. Br. 16.)
These arguments are not persuasive. The Examiner cited Old as
teaching methods of homologous recombination in animal cells (RAN 7).
Old provided express reason to use Bell-Pedersen’s homologous
recombination method in mammal cells:
The armoury of techniques available to the gene
manipulator allows any cloned gene sequence to be altered as
desired in vitro. It would be a great advance if such alterations
could be engineered into copies of a chosen gene in situ within
the chromosomes of a living animal cell. The strategy for
achieving this desirable aim is to bring about the change in the
endogenous gene through homologous recombination between
it and incoming mutated copies of the gene introduced by a
DNA transfection procedure. If this capability were available
for mouse cells it would, for example, be possible to introduce a
mutation into a chosen gene within embryo-derived stem (ES)
cells in culture. These cells can then be incorporated into
mouse embryos at the blastocyst stage.
(FF1, Old 267.)
Thus, the prior art Old contains an express suggestion to have used
mammalian cells in a homologous recombination method. As both Quirk’s
and Bell-Pedersen’s methods involve homologous recombination (Bell-
Pedersen 3768, col. 2 [FF2]), a person of ordinary skill in the art would have
considered them reasonably suggested by Old’s disclosure of the value of
homologous recombination to modify mammalian genomes. As held in KSR
Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 417 (2007):
[I]f a technique has been used to improve one device, and a
person of ordinary skill in the art would recognize that it would
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improve similar devices in the same way, using the technique is
obvious unless its actual application is beyond his or her skill.
Sakraida and Anderson’s-Black Rock are illustrative – a court
must ask whether the improvement is more than the predictable
use of prior art elements according to their established
functions.
In this case, Patent Owner has not provided evidence that it would
have been unpredictable, using a prior art technique as disclosed in Old, to
insert a GIIE endonuclease site into a mammalian chromosome, the only
recited requirement of claim 1. Patent Owner’s arguments focus on
homologous recombination and endonuclease cleavage. However, neither
steps are recited in the claims at issue in this appeal.
In addition to Old, Eddy926 described utilizing double-stranded
breaks in DNA to promote homologous recombination in a variety of
organisms. Eddy92 specifically mentioned the GIIE endonuclease system
described in Bell-Pedersen. (Eddy92 p. 1032, 1040.) Thus, Eddy92 also
would have reasonably suggested to a person of ordinary skill in the art that
Bell-Pedersen’s GIIE system could be used as a homologous recombination
system to target mammalian genes.
Patent Owner contends that the Examiner in hindsight “found Dujon’s
solution to the problem in Bell-Pedersen, Quirk, and Old. But Bell-
Pedersen, Quirk, and Old were not tasked with trying to demonstrate site-
directed insertion of a gene of interest into a mammalian chromosome.”
(Appellant App. Br. 29).

6 Sean R. Eddy & Larry Gold, Artificial Mobile DNA Element Constructed
From the EcoRI Endonuclease Gene, 89 Proc. Nat’l Acad. Sci.1544 (1992).
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The evidence does not support Patent Owner’s position. As quoted
above, Old expressly gave a reason to have utilized homologous
recombination to modify mammalian chromosomes. Old also taught ways
of achieving it (Old 267) [FF7]. For example, Old described utilizing
restriction enzyme cleaved fragments to achieve homologous recombination
in mouse DNA (Old 268-269) [FF3]. Old also taught that a brute force
method could be used to achieve homologous recombination in mammals
(Old 270 & 272-273) [FF4]. Eddy92 suggested using double-stranded break
systems to target DNA in a variety of organisms (Eddy92 1547, col. 2
[FF5]). Bell-Pedersen’s system was specifically referred to by Eddy92
(Eddy92 1546, col. 2 [FF6]), providing further reason to have applied it to
mammalian DNA.
Patent Owner’s “interchangeability” argument appears to be directed
the question of whether GIIE endonucleases would have been expected to
function in “plant and animal cells.”7 Dr. Belfort testified in her written
declaration that GIIE endonucleases did not evolve in plant and animal cells.
However, the claims do not require endonuclease activity. Claim 1 is
directed to a mammalian chromosome with a GIIEE cleavage site. There is
no requirement that the chromosome be cleaved by an endonuclease. Thus,
Patent Owner is arguing a limitation that does not appear in the claims.
With regard to the arguments concerning mechanism and frequency of
homologous recombination, we note that the claims do not require

7 The claims are not directed to animal and plant cells, but a “recombinant
mammalian chromosome.”
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homologous recombination to have occurred and thus the arguments are
unpersuasive.

Cleavage of bacterial chromosome in Quirk and Bell-Pedersen (3 & 4)
Patent Owner contends that the claimed invention is pioneering
“because it allowed for the efficient and predictable targeting of specific
nucleic acid sequences to specific locations in mammalian chromosomal
DNA. The invention allowed artisans to dramatically increase the frequency
of targeted homologous recombination events by targeting the location of
double-strand breaks in the genome of a plant or animal cell.” (Appellant
App. Br. 7.) Based on the totality of evidence before us, we agree with the
Patent Owner that the Examiner erred in these findings. This issue was
discussed extensively in related Appeal No. 2011-010572. Rather than
repeat the findings of fact and analysis upon which our conclusion was
based, we refer both parties to this decision, which is being mailed at the
same time as this present decision.
Nonetheless, we do not agree with Patent Owner that this is a
dispositive issue. The claims do not require cleavage nor insertion of a gene
of interest sequence into the mammalian chromosome at the GIIEE cleaved
site. Thus, Patent Owner is arguing a limitation that does not appear in the
claims.

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Secondary considerations
Patent Owner, in this case, asserted that the claimed invention is
pioneering “because it allowed for the efficient and predictable targeting of
specific nucleic acid sequences to specific locations in mammalian
chromosomal DNA. The invention allowed artisans to dramatically increase
the frequency of targeted homologous recombination events by targeting the
location of double-strand breaks in the genome of a plant or animal cell.”
(Appellant App. Br. 7.) Based on this discovery, Patent Owner contends
that the claimed invention was praised, copied, and licensed by the industry,
each a secondary consideration that must be considered when determining
the obviousness of the claimed invention.
We have considered this evidence, but do not find it persuasive. The
claims are drawn to a recombinant mammalian chromosome comprising an
exogenous GIIE endonuclease site. However, the table of publications in
Exhibit 124 largely refer to homologous recombination (publications 1, 2, 3,
6, 7, 8, 11, 12, 13, & 14) and double-stranded breaks (publications 4, 5, 9,
10, & 15), neither of which are recited or required by the claims. 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. In this case,
Patent Owner did not establish a nexus between the features of the claimed
invention and the merits of the invention as commented on in Exhibit 124.
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In regard to the evidence of copying set forth in Exhibit 125, Patent
Owner did not show that the cited publications referenced Choulika’s
method or that of the ‘252 patent, rather than following another publication.

Summary
For the foregoing reasons, we affirm the obviousness rejections of
claims 1, 10, 11, 14-18 in Grounds 1 and 3. Claims argued not separately
fall with claim 1.

Grounds 5, 7, 9, 11, 13 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,
and 43
In challenging the obviousness rejections of remaining claims 2-9, 12,
and 13 under grounds 5, 7, 9, 11, 13 15, 17, 19, 21, 23, 25, 27, 29, 31, 33,
35, 37, 39, 41, and 43, Patent Owner contends that the additionally cited
publications do not remedy the inadequacies of the combination of Bell-
Pedersen, Quirk, Old, etc. (Appellant App. Br. 33-40). As we did not find
these arguments persuasive, we affirm the rejections of claims 2-9, 12, and
13 for the reasons discussed above.

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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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