Ex Parte 6833252 et al

Patent Trial and Appeal Board

Jun 18, 2015

95000443 (P.T.A.B. Jun. 18, 2015)

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.
95/000,443 03/18/2009 6833252 2000706.00135US1 9804
22852 7590 06/18/2015
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
PONNALURI, PADMASHRI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
06/18/2015 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 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
Patent Owner appealed the Board decisions unfavorable to
patentability in this case (“’252 PTAB Decision”), and the related case
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

2
2011-010715 (Reexamination 95/000,427 of US Patent 6,610,545 (“the ’545
patent”)) (“’545 PTAB Decision”) to the Federal Circuit. ’545 PTAB
Decision (March 15, 2012); ’252 PTAB Decision (March 15, 2012). On
appeal, the Federal Circuit reversed the obviousness rejection of the
appealed claims in the ’545 patent and vacated and remanded for further
consideration the case involving the ’252 patent. Institut Pasteur &
Universite Pierre Et Marie Curie v. Focarino, 738 F.3d 1337, 1348,
1349-50 (2013).
Because the obviousness rejections in the Decision were based on
findings and reasoning found to be erroneous (Institut Pasteur, 738 F.3d at
1339), we reverse the appealed obviousness rejections of claims 1–18 as set
forth in the Examiner’s Right of Appeal Notice (“RAN”). See RAN 6–24.
However, in view of the decision in Institut Pasteur, we have reconsidered
the obviousness of claims 1–18 under 35 U.S.C. § 103(a). As explained in
more detail below, we set forth new grounds of rejection of claims 1-15.

Claims
The independent claims in each case are as follows:
’545 patent
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;
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

3
(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.

’252 patent
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.

Background
The method of claim 1 of the ’545 patent had been rejected over a
combination of publications said to suggest the claimed method of using a
Group I intron encoded endonuclease (“GIIEE”) to insert a gene into a
chromosome. ’545 PTAB Dec. 25-45. The Federal Circuit reversed the
obviousness rejection of method claim 1, concluding that it would not have
been obvious to one of ordinary skill in the art to insert a gene by
homologous recombination into a chromosome, particularly because of
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

4
evidence of toxicity and secondary considerations. Institut Pasteur, 738
F.3d at 1345-47. In the ’252 patent, however, the Federal Circuit recognized
that the claim to a recombinant mammalian chromosome did not require
homologous recombination and therefore did not invoke the same
considerations of unpredictability and secondary considerations as for the
’545 patent. Id. at 1348-49. Although the Federal Circuit found the Board’s
reasoning unsupported by substantial evidence in the ’545 patent, the court
found differently for the ’252 patent.
[T]he Board has never considered whether other motivations
would have made the subject matter claimed in the ’252 patent
obvious. Specifically, the Board has not made a finding about
whether a skilled artisan would have introduced a GIIE
endonuclease recognition site into a mammalian chromosome
even without reasonably expecting its successful use for the
site-directed insertion of DNA.
Id. at 1349.
At oral argument, the parties briefly discussed what uses such
recombinant chromosomes would have other than as a first step
for successful targeted gene transfer. Pasteur admitted that,
currently, there are other uses for the chromosomes, including
as laboratory tools or as aids in gene mapping. Oral Argument
at 16:33–17:14 (Pasteur's counsel acknowledging that the
recombinant chromosomes “could have some utility in the
laboratory” without “necessarily hav[ing] to proceed” to
targeted DNA insertion). But obviousness is determined at the
time the invention was made, see 35 U.S.C. § 103, so current
uses for the recombinant chromosomes, without more, would
not establish a sufficient motivation at the time of invention.
The issue of motivation at the relevant time has not been fully
explored. The Board should address it on remand in the first
instance.
Id.
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

5
We remand for consideration of whether one of ordinary skill
would have been motivated simply to create a recombinant
chromosome with a GIIE endonuclease recognition site—
without having the reasonable expectation (as the claims of the
’545 patent but not those of the ’252 patent require) that the
GIIE endonuclease could successfully cleave the recognition
site and that homologous recombination could successfully
repair the break.
Id. at 1348.

Discussion
The inter partes reexamination of the ’252 patent was initiated March
10, 2009 with the filing of a Corrected Request for Reexamination
(“Corrected Request”). In the Corrected Request, the Requester proposed 76
substantial new questions of patentability (“SNQ”). Corrected Request 4–
11. Each SNQ of patentability was said to involve “previously unconsidered
prior art references relating to the known role of Group I intron encoded
endonucleases in promoting homologous recombination by creating double-
stranded DNA breaks, and their actual or potential use in genetic
engineering.” Id. at 28. The Request for Reexamination was granted for
each of the SNQs of patentability. Order Granting Request for Inter Partes
Reexamination (May 27, 2009). The subsequent rejections adopted by the
Examiner involved the obviousness of inserting a gene of interest into a
GIIEE recognition site integrated into the chromosome of a cell and then
providing the GIIEE to the cell. Non-Final Action (May 27, 2009) 10. The
reason why no other “motivation” to make the claimed recombinant
mammalian chromosome was considered was because the SNQ of
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

6
patentability to be resolved under 35 U.S.C. 313
1
involved the obviousness
of introducing a GIIEE restriction site into a mammalian chromosome for
the purpose of introducing a gene of interest into the chromosome.
Upon remand, we have been directed to consider whether there was
“motivation” to make the claimed recombinant mammalian chromosome
“without having the reasonable expectation . . . that the GIIE endonuclease
could successfully cleave the recognition site and that homologous
recombination could successfully repair the break.” In other words, we have
been asked to determine whether an obviousness rejection can be made
involving a different reason to have produced the claimed recombinant
mammalian chromosome that does not involve homologous recombination.
In this case, the evidence of record suggesting a different
“motivation” for making a recombinant mammalian chromosome with a
GIIEE recognition site emanates from the genome mapping literature. The
cited prior art in this inter partes reexamination that relates to genome
mapping is the Frey (1992) publication.
2
Frey was not part of the Corrected
Request for Inter Partes Reexamination, but was provided later in an
Information Disclosure Statement filed by Patent Owner on August 25,

1
§ 313. If, in a determination made under section 312(a), the Director finds
that a substantial new question of patentability affecting a claim of a patent
is raised, the determination shall include an order for inter partes
reexamination of the patent for resolution of the question. The order may be
accompanied by the initial action of the Patent and Trademark Office on the
merits of the inter partes reexamination conducted in accordance with
section 314.
2
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).

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

7
2010. Frey was not cited by the Examiner in the subsequent Right of Notice
of Appeal (Sept. 16, 2010). Patent Owner did not cite Frey in their Appeal
Brief (Dec. 15. 2010) or Rebuttal Brief (May 27, 2011).
Frey, however, was discussed by Requester in their Respondent Brief:
“Frey (Ex. 1) recognized the utility of GIIEEs for mapping genomes. As a
proof of concept, Frey inserted an I-SceI recognition site into a yeast
chromosome and successfully cleaved it in vitro.” Requester Resp’t Br. 1.
Requester, however, did not provide any reasoning as to why Frey would
have made it obvious to have produced a mammalian chromosome
comprising an inserted SceI recognition site.
The issue of how Frey’s teaching of genome mapping in yeast would
make obvious a mammalian chromosome with a GIIEE site inserted into it
for the purpose of genome mapping has not been considered in this
reexamination. The following teachings in Frey regarding genome mapping
are pertinent to this question:
[1] As a control, Frey made a recombinant yeast chromosome by
introducing the I-SceI site into it:
For usage in a control reaction, we have constructed a
transgenic yeast strain (FY23/C6) by inserting the I-SceI
recognition site into the non-essential gene YCRS21 in
chromosome III.
Frey 122.
[2] Frey also suggested using the yeast I-SceI for genome mapping:
I-SceI is the first endonuclease that can be used in vitro to
cleave an entire eucaryotic genome at a unique site. These
findings suggest that I-SceI may be an extremely useful enzyme
for mapping genomes. Therefore we have constructed a Tn5
derivative containing the I-SceI recognition sequence. Insertion
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

8
of Tn5 into the genomes of gram negative bacteria will
facilitate the construction of physical restriction maps of their
chromosomes.
Id. at 123.
To decide whether a composition 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).
In this case, the only requirement of the claim is that a mammalian
chromosome comprise an exogenous GIIE endonuclease site. Frey inserted
the I-SceI recognition site, a GIIE endonuclease recognition sequence, into a
yeast chromosome [1]. Frey stated that its findings about I-SceI in
eukaryotic genomes “suggest that [it] . . . may be an extremely useful
enzyme for mapping genomes.” [2] This disclosure would have
“motivated” one of ordinary skill in the art to apply this teaching to other
eukaryotic genomes, specifically a mammalian genome.
3
Consequently, the
skilled worker would have had reason to have inserted the I-SceI site into
mammalian chromosomes for genome mapping purposes. The technology
to integrate DNA, including DNA comprising endonuclease recognition
sequences, into chromosomal DNA of mammals is well-known in the art.

3
While Frey specifically mentions the I-SceI recognition site was
introduced into a yeast chromosome “[f]or usage in a control reaction,” even
a “control” would meet the claimed requirement of a “recombinant
mammalian chromosome comprising an exogenous Group I intron encoded
endonuclease site,” where the control is for the purpose of genome mapping.
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

9
Old
4
255, 265, 271, 274. See also RAN 7 and 9. Thus, there would have
been a reasonable expectation of success that I-SceI would be successfully
inserted into the mammalian chromosome.

Dependent claims 2-15
Dependent claims 2-13 recite specific GIIE endonucleases. The
endonucleases are described in the following publications:
Claim 2: Seraphin
5
(RAN 10);
Claim 3: Colleaux (1990)
6
(RAN 11-12);
Claim 4: Admission at 252 patent, col. 12, 64-66 (RAN 13);
Claim 5: Sargueil (1990)
7
(RAN 15);
Claim 6: Marshall (1991)
8
(RAN 16-17);
Claim 7: Muscarella (1990)
9
(RAN 17-18);

4
R.W. Old & S.B. Primrose, Principles of Gene Manipulation 222-295
(Blackwell Scientific Publication 1989) (1980).
5
Bertrand Seraphin et al., The Yeast Mitochondrial Intron a15α Associated
Endonuclease Activity and In Vivo Mobility, 113 Genetics 1-8 (1992).
6
Lauerence Colleaux at al., The Apocytochrome b gene of Chlamydomonas
Smithii Contains a Mobile Intron Related to both Saccharomyces and
Neurospora Introns, 223(2) Molecular & General Genetics 288 (1990).
7
B. Sargueil et al., In Vivo and In Vitro Analyses of an Intron-Encoded DNA
Endonuclease from yeast Mitochondria. Recognition Site by Site-Directed
Mutagenesis, 18(19) Nucleic Acid Research 5659 (1990).
8
Philip Marshall et al., Cleavage Pattern of the Homing Endonuclease
Encoded by the Fifth Intron in the Chloroplast Large Subunit rDNA-
Encoding Gene of Chlamydomonas Eugametos, 104 Gene 241 (1991).
9
Donna E. Muscarella et al., Characterization of I-Ppo, an Intron-Encoded
Endonuclease that Mediates Homing of a Group I Intron in the Ribosomal
DNA of Physarum Polycephalum 10(7) Molecular and Cellular Biology
3386 (July 1990).
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

10
Claim 8: Sargueil (1991)
10
(RAN 19);
Claim 9: Durrenberger (1991)
11
(RAN 20-21);
Claim 10: Bell-Pederson
12
(RAN 6);
Claim 11: Bell-Pederson (RAN 6);
Claim 12: Eddy (1991)
13
(RAN 22); and
Claim 13: Colleaux (1988)
14
(RAN 23-24).
It would have been obvious to a person of ordinary skill in the art at
the time the invention was made to incorporate different Group I intron
encoded endonuclease sites into chromosomal DNA for the purpose of
genome mapping since the Group I intron encoded endonucleases have
similar properties as established by the aforementioned publications.
Dependent claims 14 and 15 are directed to a mammalian
chromosome which is murine and mouse respectively. As indicated by Old,
mouse is a model genetic system, making it obvious to map its genome.

10
B, Sargueil et al., A New Specific DNA Endonuclease Activity in Yeast
Mitochondria, 225 Molecular & General Genetics 340 (1991).
11
F. Durrenberger et al., Chloroplast Ribosomal Intron of Chlamydomonas
Reinhardtii: in Vitro Self-Splicing, DNA Endonuclease Activity and In Vico
Mobility, 10(11) EMBO 3495 (1991).
12
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).
13
S.R. Eddy et al., The Phage T4 nrdB Intron: a Deletion Mutant of a
Version found in the Wild, 5 Genes & Development 1032 (1991).
14
L. Colleaux et al., Recognition and Cleavage Site of the Intron-Encoded
Omega Transposase, 86 Proc. Natl. Acad. Sci 6022 (1988).
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

11
Dependent claims 16-18
Claim 16 is directed to a recombinant cell comprising the recombinant
chromosome of any of claims 1-13. Claims 17 and 18 are directed to
recombinant cells comprising the recombinant chromosomes of claims 14
and 15, respectively. Since Frey does not teach that its genome mapping is
performed on recombinant chromosomes in a cell, there is insufficient
evidence that the skilled worker, at the time of the invention, would have
had reason to make the subject matter of claims 16-18.

New Grounds of Rejection
In view of the above discussion, the following new grounds of
rejection of claim 1-15 are set forth:
1. Claims 1, 14, and 15 are rejected under 35 U.S.C. § 103(a) as
obvious in view of Frey and Old.
2. Claim 2 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Seraphin.
3. Claim 3 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Colleaux (1990).
4. Claim 4 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Admission at ’252 patent, col. 12, 64-66.
5. Claim 5 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Sargueil (1990).
6. Claim 6 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Marshall (1991).
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

12
7. Claim 7 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Muscarella (1990).
8. Claim 8 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Sargueil (1991).
9. Claim 9 is rejected under 35 U.S.C. § 103(a) as obvious in view of
Frey, Old, and Durrenberger (1991).
10. Claims 10 and 11 are rejected under 35 U.S.C. § 103(a) as
obvious in view of Frey, Old, and Bell-Pederson.
11. Claim 12 is rejected under 35 U.S.C. § 103(a) as obvious in view
of Frey, Old, and Eddy (1991).
12. Claim 13 is rejected under 35 U.S.C. § 103(a) as obvious in view
of Frey, Old, and Colleaux (1988).

NEW GROUND OF REJECTION
This decision contains a new ground of rejection pursuant to
37 C.F.R. § 41.77(b) which provides that "[a]ny decision which includes a
new ground of rejection pursuant to this paragraph shall not be considered
final for judicial review." Correspondingly, no portion of the decision is
final for purposes of judicial review. A requester may also request rehearing
under 37 C.F.R. § 41.79, if appropriate, however, the Board may elect to
defer issuing any decision on such request for rehearing until such time that
a final decision on appeal has been issued by the Board.
For further guidance on new grounds of rejection, see 37 C.F.R.
§ 41.77(b)–(g). The decision may become final after it has returned to the
Board. 37 C.F.R. § 41.77(f).
37 C.F.R. § 41.77(b) also provides that the Patent Owner, WITHIN
ONE MONTH FROM THE DATE OF THE DECISION, must exercise one
of the following two options with respect to the new grounds of rejection to
avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. The owner may file a response requesting
reopening of prosecution before the examiner. Such a response must be
Appeal 2011-011261
Reexamination 95/000,443
Patent 6,833,252 B1

13
either an amendment of the claims so rejected or new evidence relating to
the claims so rejected, or both.
(2) Request rehearing. The owner may request that the proceeding be
reheard under § 41.79 by the Board upon the same record. …
Any request to reopen prosecution before the examiner under 37
C.F.R. § 41.77(b)(1) shall be limited in scope to the "claims so rejected."
Accordingly, a request to reopen prosecution is limited to issues raised by
the new ground(s) of rejection entered by the Board. A request to reopen
prosecution that includes issues other than those raised by the new ground(s)
is unlikely to be granted. Furthermore, should the patent owner seek to
substitute claims, there is a presumption that only one substitute claim would
be needed to replace a cancelled claim.
A requester may file comments in reply to a patent owner response.
37 C.F.R. § 41.77(c). Requester comments under 37 C.F.R. § 41.77(c) shall
be limited in scope to the issues raised by the Board's opinion reflecting its
decision to reject the claims and the patent owner's response under
paragraph 37 C.F.R. § 41.77(b)(1). A newly proposed rejection is not
permitted as a matter of right. A newly proposed rejection may be
appropriate if it is presented to address an amendment and/or new evidence
properly submitted by the patent owner, and is presented with a brief
explanation as to why the newly proposed rejection is now necessary and
why it could not have been presented earlier.
Compliance with the page limits pursuant to 37 C.F.R. § 1.943(b), for
all patent owner responses and requester comments, is required.
The examiner, after the Board's entry of a patent owner response and
requester comments, will issue a determination under 37 C.F.R. § 41.77(d)
as to whether the Board's rejection is maintained or has been overcome. The
proceeding will then be returned to the Board together with any comments
and reply submitted by the owner and/or requester under 37 C.F.R. §
41.77(e) for reconsideration and issuance of a new decision by the Board as
provided by 37 C.F.R. § 41.77(f).

REVERSED; 41.77(b)

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

14

ack

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