Ex Parte May et al

Patent Trials and Appeals Board

Apr 22, 2019

14751058 - (D) (P.T.A.B. Apr. 22, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/751,058 06/25/2015
132976 7590 04/24/2019
Caribou Biosciences, Inc.
2929 7th Street
Suite 105
Berkeley, CA 94710
FIRST NAMED INVENTOR
Andrew Paul May
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
CBIOll.117 7778
EXAMINER
NGUYEN, QUANG
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
04/24/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
bmcclung@cariboubio.com
gfabian@cariboubio.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANDREW PAUL MAY, RACHELE. HA UR WITZ,
JENNIFER A. DOUDNA, JAMES M. BERGER,
MATTHEW MERRILL CARTER, and PAUL DONOHOUE
Appeal2018-008153
Application 14/751,058
Technology Center 1600
Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1, 2 under 35 U.S.C. § 134(a) involving claims to a
method of tracking cell lineage development using nucleic acid-targeting
nucleic acids. The Examiner rejected the claims as failing to meet the
written description requirement and as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We AFFIRM.
1 Appellants identify the Real Party in Interest as Caribou Biosciences, Inc.
(App. Br. 4).
2 We have considered and herein refer to the Specification of July 3, 2017
("Spec."); Final Office Action of Sept. 13, 2017 ("Final Act."); Appeal Brief
of Feb. 27, 2018 ("App. Br."); and Examiner's Answer of Apr. 27, 2018
("Ans.").
Appeal2018-008153
Application 14/751,058
Statement of the Case
Background
"Genome engineering can use nucleases to cut a nucleic acid thereby
generating a site for ... [altering]" a genome (Spec. ,r 3). "A protein
containing a nuclease domain can bind and cleave a target nucleic acid by
forming a complex with a nucleic acid-targeting nucleic acid" (id.). "A
nucleic acid can be repaired, e.g., by endogenous non-homologous end
joining (NHEJ) machinery" (id.). "NHEJ can introduce [a] unique sequence
signature at each cut site [as] [t]he repair mechanism can result in the
introduction of insertions ... deletions or mutations" (Spec. ,r 829). "The
repaired site can provide a unique barcode sequence to the cell that can be
preserved during cell division and passed on to all progeny of the modified
cell" (id.).
The Claims
Claims 52-55, 59---61, 63, 65---67, and 69 are on appeal. Independent
claim 52 is representative and reads as follows:
52. A method of tracking cell lineage development,
compnsmg:
contacting genomic DNA of one or more cells with one
or more complexes comprising a Type II CRISPR-Cas9 protein
and a nucleic acid-targeting nucleic acid, wherein the one or
more complexes cut one or more target DNA sequences in the
genomic DNA and the contacting introduces one or more
unique sequence signatures in the one or more target DNA
sequences of the genomic DNA of the one or more cells;
propagating the one or more cells into a population of
cells;
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sequencing the genomic DNA of cells in the population
of cells;
identifying and grouping common genomic DNA
sequences comprising the one or more unique sequence
signatures introduced by the contacting of the genomic DNA of
the one or more cells; and
tracking cell lineage development by determining a
clonal structure based on the groupings of the common genomic
DNA sequences.
The Issues
A. The Examiner has rejected claims 52-55, 59---61, 63, 65---67, and 69
under 35 U.S.C. § 112(a) for failing to comply with the written
description requirement (Final Act. 2-6).
B. The Examiner has rejected claims 52-55, 59---61, 63, 65---67, and 69
under 35 U.S.C. § 103 as obvious over Gregory, 3 Mali4 or Cong, 5
and Lu6 (Final Act. 7-13).
A. 35 U.S.C. l l 2(a), written description
The Examiner finds "the instant claims encompass a method of
tracking cell lineage development utilizing one or more complexes
comprising a Type II CRISPR-Cas9 protein and any nucleic acid-targeting
3 Gregory et al., US 2011/0027235 Al, published Feb. 3, 2011.
4 Mali et al., US 9,023,649 B2, issued May 5, 2015.
5 Cong et al., US 8,871,445 B2, issued Oct. 28, 2014.
6 Lu et al., Tracking single hematopoietic stem cells in vivo using high-
throughput sequencing in conjunction with viral genetic barcoding, 29
Nature Biotechnology 928-934 (2011).
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Application 14/751,058
nucleic acid" (Final Act. 3) ( emphasis omitted). The Examiner finds
"'nucleic acid-targeting nucleic acid' is defined by the present application to
refer to any nucleic acid (DNA and/or RNA) that can hybridize to another
nucleic acid" (Final Act. 3--4) (citing Spec. ,r,r 177-178) (emphasis omitted).
The Examiner concludes that:
[a]part from disclosing the nucleic acid-targeting nucleic acid in
the form of a double-guide crRNA:tracrRNA duplex and/or a
single guide RNA (sgRNA) ... the instant disclosure fails to
provide sufficient written description for any other nucleic acid-
targeting nucleic acids to be utilized in the method as claimed
broadly.
(Final Act. 4) ( emphasis omitted).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner's conclusion that the Specification fails to
provide descriptive support for the claims?
Principles of Law
[T]he determination of what is needed to support generic claims
to biological subject matter depends on a variety of factors,
such as the existing knowledge in the particular field, the extent
and content of the prior art, the maturity of the science or
technology, the predictability of the aspect at issue.
Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005).
Analysis
Appellants contend "[t]he present Specification discloses that a
nucleic acid-targeting nucleic acid can interact with a Cas9 protein to form a
complex, and the nucleic acid-targeting nucleic acid can guide the complex
to a target nucleic acid to which the spacer sequence of the nucleic acid-
targeting nucleic acid can hybridize" (App. Br. 9) ( citing Spec. ,r,r 283-290,
350-353). Appellants argue the Specification discloses "[m]odifications of
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Application 14/751,058
nucleic acid-targeting nucleic acids ... including, for example, base
modifications, backbone modifications, conjugated groups, and addition of
affinity tags" (App. Br. 9) (citing Spec. ,r,r 135-142, 179-191).
Furthermore, Appellants argue the Specification describes specific
engineered nucleic acid-targeting nucleic acids, "including DNA templates"
and "RNA sequences" for nucleic acid-targeting nucleic acids (id. ( citing
Spec. ,r,r 787-823)).
We are persuaded that Appellants' Specification provides descriptive
support for the claimed nucleic acid-targeting nucleic acid. Appellants'
claim recites a genus using functional language to define a desired result,
i.e., a nucleic acid-targeting nucleic acid.
[A] sufficient description of a genus ... requires the disclosure
of either a representative number of species falling within the
scope of the genus or structural features common to the
members of the genus so that one of skill in the art can
"visualize or recognize" the members of the genus.
AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d
1285, 1299 (Fed. Cir. 2014) (citation omitted). We find Appellants'
Specification provides both. For example, the Specification lists numerous
species of nucleic acid-targeting nucleic acids and their activity (see Spec.
,r 823). The Specification further describes structural features common to
the members of the genus, e.g., a spacer, CRISPR repeat, and a tracrRNA
(see Spec. ,r,r 283-290).
Conclusion of Law
The evidence of record does not support the Examiner's conclusion
that the Specification fails to provide descriptive support for the claims.
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B. 35 U.S.C. § 103 over Gregory, Mali,7 Cong, and Lu
The Examiner finds Gregory teaches tracking cell lineage
development by integrating a lineage-specific reporter into a cell's target
genomic DNA sequence using zinc finger nucleases (ZFNs) or TALENs
(see Final Act. 8-9). The Examiner acknowledges that Gregory does not
teach using a CRISPR-Cas9 complex to introduce a unique sequence
signature in the target DNA sequence; nor tracking cell lineage development
by identifying and grouping common genomic DNA sequences to determine
a clonal structure (see Final Act. 9).
The Examiner finds Mali teaches Type II CRISPR-Cas9 as an
alternative tool to ZFNs and TALENs for target sequence-specific genome
editing (see Final Act. 9). The Examiner further finds Mali teaches NHEJ,
caused by CRISPR-Cas9 genome editing, creates indels which can be
identified by DNA sequencing (see Final Act. 9-10). The Examiner finds
Lu teaches a method of tracking cell lineage development by incorporating a
DNA barcode with a unique sequence signature into a cell's genomic DNA
(see Final Act. 11 ). The Examiner further finds Lu teaches using DNA
sequencing to examine clonality of cell populations containing the DNA
barcode (see Final Act. 11-12).
The Examiner finds a person of ordinary skill in the art would have
been motivated to combine the references in order to apply the advantages
offered by the CRISPR-Cas9 system in the place of zinc finger nucleases to
track cell lineage in a heterologous cell population (Final Act. 12-13).
7 Cong's and Mali's teachings are similar. Therefore, we discuss only Mali
in this Decision.
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Therefore, the Examiner concludes:
it would have been obvious for an ordinary skilled artisan
before the effective filing date of the present application to
modify the teachings of Gregory et al by also using the
CRISPR-Cas9 system to introduce one or more sequences of
interest (e.g., lineage-specific reporter constructs) into a
genomic DNA of a cell along with high throughput sequencing
of genomic DNAs of a propagated heterologous cell population
to track single cell lineage development based on a common
repaired genomic DNA sequence at a target site, in light of the
teachings of ... [Mali] ... along with Lu
(Final Act. 12).
The issue with respect to this rejection is: Does a preponderance of
the evidence support the Examiner's conclusion that claim 52 is obvious?
Findings of Fact
1. Gregory teaches "methods for targeted integration of one or
more sequences of interest into the genome of a stem cell .... Stem cells
comprising lineage-specific reporters can ... be used as a tracking system to
follow ... differentiation fate" (Gregory ,r 9).
2. Gregory teaches "[t]argeted integration of the construct is
facilitated by targeted double-strand cleavage of the genome in the region of
interest. Cleavage is targeted ... through the use of fusion proteins
comprising a zinc finger DNA binding domain, which can be engineered to
bind any sequence of choice" (Gregory ,r 18).
3. Gregory teaches a method of:
providing a population of stem cells ... comprising a
sequence that is transcribed or translated into [a] gene product,
wherein the sequence is integrated into a non-essential site in
the stem cells, and culturing the population of stem cells,
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wherein the population of cultured stem cells uniformly
expresses the gene product.
(Gregory ,r 24).
4. Gregory teaches "[a]ny nuclease can be used in the methods
disclosed herein" including meganucleases and T AL effector nucleases
(TALENs) (Gregory ,r,r 138-142).
5. Mali teaches CRISPR-Cas9 "RNA-guided [genome] editing is
target sequence specific and demonstrates similar targeting efficiencies as
ZFNs or TALENs" (Mali 15:31-58).
6. Mali teaches CRISPR mediated genome editing was examined
using deep sequencing of the targeted loci (Mali 14:41--44).
7. Mali teaches "[d]eep sequencing ... confirms that while Cas9
shows robust NHEJ at the targeted loci, the D 1 OA mutant has significantly
diminished NHEJ rates ... Also, consistent with the known biochemistry of
the Cas9 protein, NHEJ data confirms that most base-pair deletions or
insertions occurred near the 3' end of the target sequence" (Mali 14:49-55).
8. Lu teaches a method of tracking single cells in a heterogeneous
population using genetic barcoding and high-throughput sequencing for a
direction examination of the clonality of cell populations (Lu 928).
9. Lu teaches "[t]he experimental system uses synthesized
barcodes drawn from a large, semi-random, 33-mer DNA barcode library to
uniquely label and track individual cells" (Lu 929).
10. Lu teaches:
A DNA barcode consists of a common 6-bp library ID at
the 5' end followed by a random 27-bp cellular barcode ... The
6-bp library ID helps to identify barcodes in the sequencing
result. Identical 33-bp barcodes are combined allowing for
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mismatches and indels up to 2 bp in total. The barcodes are
then compared across different cell populations that originate
from the same starting cell population.
(Lu 929).
11. Lu teaches "[i]n this barcode tracking system, the mapping
between DNA barcodes and target cells is randomly established and the
exact linkages cannot be a priori determined. Conclusions can be drawn
only after the experimental condition has been applied" (Lu 932) ( emphasis
added).
Principles of Law
"[W]hen the question is whether a patent claiming the combination of
elements of prior art is obvious," the answer depends on "whether the
improvement is more than the predictable use of prior art elements according
to their established functions." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,
417 (2007).
Analysis
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. ,r,r 7-13; FFs 1-11), and agree
that the claims are obvious over Gregory, Mali, and Lu. We address
Appellants' arguments below.
Appellants argue "[ c ]hanging the technique of introducing reporter
constructs would not change the method of examining cell lineage discussed
in [Gregory] ... , which would remain dependent on the use of regulatory
elements of known lineage specific or cell genes" (App. Br. 16). Thus,
Appellants argue "[c]ombining [Gregory] ... with [Mali] ... or [Cong] ... ,
fails to teach ... identifying and grouping common genomic DNA
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sequences comprising ... unique sequence signatures ... and tracking cell
lineage development by determining a clonal structure based on the
groupings of the common genomic DNA sequences" (id.).
We are not persuaded by Appellants' argument against Gregory alone
as "[ n ]on-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references. . . . [The reference] must be read, not in
isolation, but for what it fairly teaches in combination with the prior art as a
whole." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Here,
Appellants do not address the combined teaching of the references as cited
by the Examiner. For example, Appellants do not address Mali's teaching
that NHEJ following CRISPR-Cas9 cleavage introduces indels identified by
DNA sequencing (see FFs 6, 7). Moreover, Appellants do not address the
combination with Lu, which teaches tracking cell lineage by using DNA
sequence to determine a clonal structure (see FF 8).
Appellants contend "unlike the method of [Gregory] ... , the
presently claimed method can determine clonal structure without prior
knowledge of lineage specific genes or cell fate genes and their regulatory
elements" (App. Br. 15-16). Appellants apply the same reasoning to
distinguish Lu, arguing:
Unlike the method of Lu, et al., the presently claimed method
can be used to determine clonal structure without the
complications of generating and characterizing the lentiviral
barcode library prior to the introduction of such barcode
libraries into cells, and without use of a tracking sequence, such
as a Library ID, whose sequence is known from the outset
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(App. Br. 16-17). Therefore, Appellants argue that the combined prior art
does not teach a method of tracking cell lineage development "that does not
require knowing the regulatory pattern of a reporter or using a known
tracking sequence as a starting point ... or that does not require
characterization of sequences before such sequences are introduced into
cells" (App. Br. 17).
We are not persuaded by Appellants' argument for two reasons. First,
we determine Appellants' claims do not exclude using known tracking
sequences requiring prior knowledge of the sequence. "[D]uring
examination proceedings, claims are given their broadest reasonable
interpretation consistent with the specification." In re Hyatt, 211 F.3d 1367,
1372 (Fed. Cir. 2000).
Appellants' claims recite contacting genomic DNA with CRISPR-
Cas9 to introduce one or more unique sequence signatures, identifying and
grouping the unique sequence signatures, and determining a clonal structure
based on the groupings. Appellants do not identify any express exclusion in
the plain language of the claim. Rather, as noted by the Examiner, the
dependent claims specifically list using CRISPR-Cas9 to contact genomic
DNA with known donor sequences (see Ans. 9) ( citing claim 55
incorporating coding sequences for a fluorescent protein). Moreover,
Appellants do not direct us to any express definition or disclaimer in the
Specification that would limit the claims as argued. See In re Bigio, 381
F.3d 1320, 1325 (Fed. Cir. 2004). In the absence of any express definition
or disclaimer, we do not limit the claims to a method of tracking cell lineage
development with a sequence that is unknown before the sequence is
introduced into a cell. See In re Self, 671 F.2d 1344, 1348 (CCPA 1982)
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("[A]ppellant's arguments fail from the outset because ... they are not based
on limitations appearing in the claims.")
Second, assuming arguendo the unique sequence signature is
unknown prior to being introduced into a cell's genomic DNA and the clonal
structure is determined without prior knowledge of the tracked sequence, Lu
expressly teaches these features. More specifically, Lu teaches generating a
unique sequence including a random 27-bp barcode, were "mapping
between DNA barcode and target cells is randomly established and the exact
linkages cannot be a priori determined" (FFs 9-11) (emphasis added).
Combined with the teaching of Mali that CRISPR-Cas9 initiated NHEJ
causes indels identified by sequencing (FF 7), we find it would have been
obvious to a person of ordinary skill in the art to track cell lineage
development by determining a clonal structure based on the groupings of
common indels using the previously unknown sequences as disclosed by Lu.
Appellants argue "there is no articulated reasoning with rational
underpinning of how the method of [Gregory] ... , for examination of cell
lineage in the context of reporter constructs based on lineage-specific gene
or cell-fate gene regulatory elements could be modified by a lentiviral-based
barcode labeling process such as described by Lu" (App. Br. 17).
We are not persuaded by Appellants' argument as both Gregory and
Lu are directed to tracking cell lineage development by incorporating
tracked sequences into a target cells' genomic DNA (see FFs 1, 8). We find
that combining the specific methods for incorporating the sequences into a
cell's genomic DNA, and the unique signature of the sequences themselves
is merely "the predictable use of prior art elements according to their
established functions." See KSR, 550 U.S. at 417. Therefore, we are not
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persuaded that the Examiner erred in determining claim 52 is prima facie
obvious over the prior art.
Appellants cite Mc Kenna 8 for describing "a method similar to that of
the presently claimed invention showing that 'genome editing of synthetic
target arrays for lineage tracing (GESTALT) can be used to generate large-
scale maps of cell lineage in multicellular systems for normal development
and disease'" (App. Br. 17). McKenna was published after the priority date
of the application at issue (id.).
We are not persuaded by this evidence as Appellants do not establish
a nexus between McKenna and the merits of the claimed invention. See
Wyers v. Master Lock Co., 616 F.3d 1231, 1246 (Fed. Cir. 2010). Without a
nexus, we do not accord substantial weight to the evidence. It is unclear
what specific reason McKenna' s post priority publication shows regarding
obviousness, but McKenna does not evidence that the claim is unobvious.
See id. Therefore, we conclude claim 52 would have been obvious to a
person of ordinary skill in the art.
Conclusion of Law
A preponderance of the evidence of record supports the Examiner's
conclusion that claim 52 is unpatentable as obvious over Gregory, Mali or
Cong, and Lu.
SUMMARY
In summary, we reverse the rejection of claims 52-55, 59---61, 63, 65-
67, and 69 under 35 U.S.C. § 112(a) as lacking written description support.
8 McKenna et al., Whole organism lineage tracing by combinatorial and
cumulative genome editing, 353 Science.aaf7907, 1-11 (2016).
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We affirm the rejection of claim 52 under 35 U.S.C. § 103(a) as
obvious over Gregory, Mali or Cong, and Lu. Claims 53-55, 59-61, 63,
65-67, and 69 fall with claim 52.
No time period for taking any subsequent action in connection with
this appeal may be extended under 3 7 C.F .R. § 1.13 6( a).
AFFIRMED
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