Agilent Technologies, Inc.

Patent Trials and Appeals Board

Jun 29, 2020

2020002151 (P.T.A.B. Jun. 29, 2020)

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.
14/550,713 11/21/2014 Jeffrey R. Sampson 20140090-03 6669
22878 7590 06/29/2020
Agilent Technologies, Inc.
Global IP Operations
5301 Stevens Creek Blvd
Santa Clara, CA 95051
EXAMINER
KAUP, SAHANA S
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
06/29/2020 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):
Agilentdocketing@cpaglobal.com
ipopsadmin@agilent.foundationip.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JEFFREY R. SAMPSON, NICHOLAS M. SAMPAS, JOEL
MYERSON, PAIGE ANDERSON, and BO CURRY
____________

Appeal 2020-002151
Application 14/550,713
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 appeal1,2 under 35 U.S.C. § 134(a) involving claims to a
method for high throughput gene assembly in droplets. The Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Agilent
Technologies, Inc. (see Appeal Br. 2).
2 We have considered and herein refer to the Specification of Nov. 21, 2014
(“Spec.”); Final Office Action of Jan. 25, 2019 (“Final Act.”); Appeal Brief
of July 23, 2019 (“Appeal Br.”); Examiner’s Answer of Nov. 18, 2019
(“Ans.”); and Reply Brief of Jan. 21, 2020 (“Reply Br.”).
Appeal 2020-002151
Application 14/550,713

2
Statement of the Case
Background
“High-throughput synthesis and assembly of DNA constructs is an
integral part of synthetic biology” (Spec. 1:11–12). Existing methods for
assembling synthetic DNA oligonucleotides into longer constructs “utilize a
combination of polymerase or ligase enzymes to join shorter
oligonucleotides (e.g., molecules that are 50 to 200 nucleotides in length) to
form constructs that are as long as 1,000 to 5,000 base-pairs” (id. at 1:13–
18).
The Specification discloses methods for assembling sets of
oligonucleotides to produce a synthon by enzymatically assembling the
oligonucleotides in a defined order (id. at 14:1–3). “Sequence assembly can
be done using a variety of different methods, including, but not limited to
polymerase chain assembly . . . and ordered ligation” (id. at 10:13–16). Sets
of oligonucleotides include the same terminal indexer sequence, which
locates the set to a discrete feature on an addressable array (id. at 14:13–20).
Figure 1, partially reproduced below, illustrates the step of locating the sets.

Figure 1 illustrates oligonucleotide set A, B, C, and D located
to feature 8 and oligonucleotide set W, X, Y, and Z located to
feature 10 (id. at 14:19–22).
Appeal 2020-002151
Application 14/550,713

3
After locating the sets, the method includes the step of contacting the array
with a solution to produce discrete droplets encapsulating the features (id. at
15:1–4). The droplet solution contains all the necessary reagents to
assemble the hybridized oligonucleotides into a synthon (id. at 15:3–11).
The Claims
Claims 1–8 and 12–16 are on appeal.3 Independent claim 1 is
representative and reads as follows:
1. A method comprising:
(a) obtaining a mixture of multiple sets of
oligonucleotides,
wherein each set of oligonucleotides comprises at
least two different assembly sequences,
wherein the oligonucleotides within each set each
comprise a terminal indexer sequence and each set can be
assembled to produce a synthon,
wherein the oligonucleotides within each set of
oligonucleotides have the same terminal indexer
sequence, and each set of oligonucleotides has a different
terminal indexer sequence;
(b) hybridizing the terminal indexer sequences of the
oligonucleotides in the oligonucleotide mixture to a planar
array, thereby spatially-separating the different sets of
oligonucleotides from one another;
(c) contacting the planar array with a solution, thereby
producing an array of discrete droplets, wherein each droplet
comprises one or more features of the planar array;
(d) placing an immiscible liquid over the droplets,
thereby producing an array of discrete reaction chambers that
are each defined by a droplet; and
(e) after step (d) incubating the planar array under
conditions by which synthons are assembled in the discrete
reaction chambers, while the droplets are on the planar array.

3 Claims 9–11 and 17–20 are cancelled. Appeal Br. 15–16.
Appeal 2020-002151
Application 14/550,713

4
The Issues
A. The Examiner rejected claims 1–3, 6, and 12–16 under 35 U.S.C.
§ 103 as obvious over Jacobson4 and Myerson5 (Ans. 4–12).
B. The Examiner rejected claims 4 and 5 under 35 U.S.C. § 103 as
obvious over Jacobson, Myerson, and Baynes6 (Ans. 12–14).
C. The Examiner rejected claims 7 and 8 under 35 U.S.C. § 103 as
obvious over Jacobson, Myerson, and Myllykangas7 (Ans. 14–16).

A. 35 U.S.C. § 103(a) over Jacobson and Myerson
The Examiner finds Jacobson teaches a method of assembling
polynucleotide constructs having predefined sequences on an addressable
array (Ans. 4). The Examiner finds Jacobson teaches binding a plurality of
oligonucleotides, i.e., a set, to a discrete feature of the array, hydrating the
array to form a droplet on the feature, and ligating the oligonucleotides to
form a larger nucleotide, i.e., a subassembly (id. at 5). The Examiner finds
“Jacobson teaches the oligonucleotides comprise a unique primer binding
site (i.e.[,] terminal indexer sequence) that is used to selectively amplify a
specific subset of oligonucleotides” (id. at 6).
The Examiner finds Myerson teaches “different sets of
oligonucleotides compris[ing] a unique 5ʹ barcode sequence (i.e.[,] detection
primers) wherein the barcode is the same for each oligonucleotide within an
individual set and wherein each set of oligonucleotides comprises a different
barcode sequence” (id. at 10–11). The Examiner determines it would have

4 Jacobson et al., US 2012/0220497 A1, published Aug. 30, 2012.
5 Myerson, US 2010/0113296 A1, published May 6, 2010.
6 Baynes et al., US 2008/0287320 A1, published Nov. 20, 2008.
7 Myllykangas et al., US 2012/0157322 A1, published June 21, 2012.
Appeal 2020-002151
Application 14/550,713

5
been obvious for one of ordinary skill in the art “to modify the teachings of
Jacobson to feature terminal adaptors that facilitate hybridization to a solid
support as taught by Myerson . . . result[ing] in the predictable outcome of a
method of obtaining oligonucleotides comprising terminal indexer sequences
and hybridizing these oligonucleotides to an array” (id. at 12).
The issue with respect to the rejection is: Does the evidence of record
support the Examiner’s findings that Jacobson and Myerson render the
claims obvious?
Findings of Fact (“FF”)
1. Jacobson teaches “methods and devices for conducting sub-
microvolume specified reactions within a droplet” by providing a substrate
“comprising a plurality of surface-bound single-stranded oligonucleotides at
discrete features” (Jacobson ¶ 11).
2. Jacobson teaches “a set of predefined features may be
selectively hydrated, thereby providing hydrated oligonucleotides,” which
may be “exposed to further processing within a droplet volume” whereby
“the droplet acts as a virtual reaction chamber” (Jacobson ¶ 11).
3. Jacobson teaches “[e]ach plurality of oligonucleotides is bound
to a discrete feature of the support, and the predefined sequence of each
plurality of oligonucleotides attached to the feature is different from the
predefined sequence of the plurality of oligonucleotides attached to a
different feature” (Jacobson ¶ 13; see also Jacobson ¶ 15).
4. Jacobson teaches “the support or array is addressable: the
support includes two or more discrete addressable features at a particular
predetermined location (i.e., an ‘address’) on the support. Therefore, each
Appeal 2020-002151
Application 14/550,713

6
oligonucleotide molecule of the array is localized to a known and defined
location on the support” (Jacobson ¶ 62).
5. Jacobson teaches “features are typically, but need not be,
separated by interfeature spaces to ensure that droplets between two adjacent
features do not merge” (Jacobson ¶ 62).
6. Jacobson teaches “the reagents in the reaction volumes promote
oligonucleotide or polynucleotide assembly . . . the reaction volumes may
contain two or more populations of single-stranded oligonucleotides having
predefined sequences in solution” (Jacobson ¶ 98).
7. Jacobson teaches that “two different or more oligonucleotides
or polynucleotides may be immobilized or synthesized at the same location
(or feature) on the solid support thereby facilitating their interaction after
amplification within the same droplet” (Jacobson ¶ 118).
8. Jacobson teaches “oligonucleotides in a given droplet may
hybridize to each other and may assemble by PCR or ligation” to form a
subassembly (Jacobson ¶ 125).
9. Myerson teaches oligonucleotide microarrays having
addressable features, where each feature is made up of oligonucleotides
bound to a surface of a solid support (Myerson ¶¶ 30, 35).
10. Myerson teaches:
FIG. 4 illustrates the use of a mixture 51 of three different
detection primers, 54, 58 and 59, obtained by the methods such
as shown in FIG. 1 and simultaneously labeled such as shown
in FIG. 2. Primer 54 comprises barcode1, and target-specific
segment1, and 50% of primer 54 has been labeled. Primer 58
comprises barcode2, and target-specific segment2. 25% of
primer 58 was labeled. For primer 59, comprising barcode3 and
target-specific segment3, 0% was labeled. The mixture 51 of
primers is hybridized at step 56 with barcode array 50. The
Appeal 2020-002151
Application 14/550,713

7
features on array 50 comprise “antibarcode” probes that are
complementary to the barcode sequences of the respective
primers. For example, for antibarcode1, probe sequence 52 is
exactly complementary to barcode1. Both of the labeled
primers 54 and 54ʹ, as well as the unlabelled primers 54″ and
54‴ are hybridized at feature 66 comprising probe sequence 52.
Labeled primer 58, and unlabeled primers 58ʹ, 58″, and 58‴ are
hybridized at feature 67. Unlabeled primers 59, 59ʹ, 59″, and
59‴ are hybridized at feature 68.

(Myerson ¶ 95).

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’l 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 (Ans. 4–12; FF 1–10) and agree that the
claims are rendered obvious by Jacobson and Myerson. We address
Appellant’s arguments below.
Appellant contends “Jacobson does not disclose or suggest discrete
droplets comprising sets of oligonucleotides comprising at least two
different assembly sequences because the droplets of Jacobson are not
discrete” (Appeal Br. 7; see also Reply Br. 5–6). Appellant contends that
“the droplets of Jacobson must be manipulated, moved and merged in order
for desired chemical reactions to occur. In other words, the droplets
Appeal 2020-002151
Application 14/550,713

8
described by Jacobson are not discrete droplets and do not form discrete
reaction chambers” (id. at 7). Appellant further asserts that modifying
Jacobson “to exclude manipulating, moving and merging droplets would
change the principle operation of its teachings” (Reply Br. 6).
We find this argument unpersuasive for two reasons. First, the
Specification expressly states that “[e]ach discrete droplet may occupy a
single feature of an array . . . or each discrete droplet may occupy multiple
features of an array (where the droplets are actively induced to bleed into
each other in a pre-defined way so that one droplet can contain multiple
oligonucleotides)” (Spec. 8:3–8, emphasis added; see also Ans. 19).
Accordingly, Appellant’s Specification expressly defines the discrete droplet
to read on Jacobson’s embodiments of droplets, which merge into each other
in pre-defined way. “When the specification explains and defines a term
used in the claims, without ambiguity or incompleteness, there is no need to
search further for the meaning of the term.” Multiform Desiccants Inc. v.
Medzam Ltd., 133 F.3d 1473, 1478 (Fed. Cir. 1998).
Second, Jacobson teaches embodiments of merging droplets, as well
as “discrete features” that are separated by “interfeature spaces to ensure that
droplets between two adjacent features do not merge” (FF 1, 2, 5). Jacobson
teaches that each separate droplet may function as a reaction chamber
because two or more different oligonucleotides may be immobilized at the
same feature on the solid support thereby facilitating their interaction within
the same droplet (FF 7). Specifically, Jacobson teaches “oligonucleotides in
a given droplet may hybridize to each other and may assemble by PCR or
ligation” (FF 8, emphasis added). Contrary to Appellant’s argument,
Appeal 2020-002151
Application 14/550,713

9
choosing one of Jacobson’s several embodiments would not change its
principle of operation.
Appellant contends that the prior art does not teach multiple sets of
oligonucleotides wherein the oligonucleotides within each set have the same
terminal indexer sequence but different assembly sequences (see Appeal Br.
9–10; see also Reply Br. 3). Appellant asserts “Jacobson does not disclose
or suggest the claimed sets of oligonucleotides wherein each set has a
different terminal indexer sequence” (Reply Br. 3). Appellant asserts
“Myerson does not disclose a set of oligonucleotides comprising at least two
different assembly sequences wherein the oligonucleotides within each set
each comprise a terminal indexer sequence and each set can be assembled to
produce a synthon” (id. at 4, emphasis omitted).
We do not find this argument persuasive. Appellant argues against
the references individually. However, “[n]on-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references.” In re Merck & Co., Inc.,
800 F.2d 1091, 1097 (Fed. Cir. 1986). Jacobson teaches immobilizing
different oligonucleotides having predefined sequences on the same feature
and assembling the oligonucleotides into a larger subassembly (FF 6–8).
Therefore, Jacobson teaches a set of oligonucleotides comprising at least two
different assembly sequences that can be assembled to produce a synthon.
Jacobson further teaches “[e]ach plurality of oligonucleotides is bound to a
discrete feature of the support, and the predefined sequence of each plurality
of oligonucleotides attached to the feature is different from the predefined
sequence of the plurality of oligonucleotides attached to a different feature”
(FF 3). Therefore, Jacobson teaches that each set of oligonucleotides has a
Appeal 2020-002151
Application 14/550,713

10
different pre-defined sequence attached to a different feature. Myerson
teaches sets of oligonucleotides characterized by the same barcode or
“terminal indexer sequence” (FF 10). Accordingly, the combination of
Jacobson and Myerson teaches sets of oligonucleotides having different
assembly sequences and the same terminal indexer sequence.
Appellant contends step (b) of claim 1 requires that “the mixture of
different sets of oligonucleotides . . . is ‘sorted’ to different locations on an
array by hybridizing the oligonucleotides to an array, where the terminal
indexer sequences, which are the same within each set but different from set
to set, lead the sets to distinct features on the array” (Reply Br. 4).
Appellant asserts that “Jacobson does not teach the mixture of
oligonucleotides as claimed, and cannot teach the further sorting of the
mixture” (id. at 5).
We find that Appellant raises this argument for the first time in the
Reply Brief, without explaining why it could not have been raised in the
principal brief. See Ex parte Borden, 93 USPQ2d 1473, 1477 (BPAI 2010)
(informative) (“Properly interpreted, the Rules do not require the Board to
take up a belated argument that has not been addressed by the Examiner,
absent a showing of good cause.”) Nevertheless, the Examiner finds the
combination of Jacobson and Myerson teaches step (b) (Ans. 7.) As
discussed above, Jacobson teaches contacting a plurality of oligonucleotides
having different pre-defined sequences, i.e., a mixture, with an addressable
array, thereby binding the oligonucleotides to specific features on the array,
i.e., sorting (FF 3). Likewise, Myerson teaches sorting mixtures of
oligonucleotides by using barcode sequences to bind the oligonucleotides to
specific features on an addressable array (FF 10).
Appeal 2020-002151
Application 14/550,713

11
Finally, Appellant contends “Jacobson and Myerson disclose distinct
approaches that are directed to solving different problems. These distinct
problems and approaches cannot be combined in a meaningful manner to
arrive at the claimed technology with any reasonable expectation of success”
(Appeal Br. 11). Specifically, Appellant contends “Jacobson describes
droplets that must be moved, merged and/ or modified,” but Myerson
describes detection primers that “remain distinct, immobilized and spatially
separated” (id.).
We do not find this argument persuasive. As discussed above,
Jacobson teaches multiple embodiments, including performing reactions in
discrete droplets without moving or merging the droplets. Furthermore,
Jacobson teaches using pre-defined sequences to direct oligonucleotides to
specific features on addressable arrays (FF 3, 4). Likewise, Myerson teaches
using barcode sequences to direct sets of oligonucleotides to specific
features on an addressable array (FF 9, 10). “Prior art is analogous if it is
from the same field of endeavor or if it is reasonably pertinent to the
particular problem the inventor is trying to solve.” Circuit Check Inc. v.
QXQ Inc., 795 F.3d 1331, 1335 (Fed. Cir. 2015). Contrary to Appellant’s
argument, Jacobson and Myerson are directed to the same field of endeavor
and solve the same problem, i.e., directing oligonucleotides to specific
features on an addressable array. Accordingly, using Myerson’s barcode
sequences to direct Jacobson’s oligonucleotides to specific features on the
array is a predictable use of the prior art elements according to their establish
functions. “Obviousness does not require absolute predictability of success
. . . all that is required is a reasonable expectation of success.” In re Kubin,
561 F.3d 1351, 1360 (Fed. Cir. 2009).
Appeal 2020-002151
Application 14/550,713

12
Conclusion of Law
A preponderance of the evidence of record support the Examiner’s
conclusion that Jacobson and Myerson render the claims obvious.

B. and C. 35 U.S.C. § 103 over Jacobson, Myerson, and Baynes or
Myllykangas
Appellant does not separately argue these obviousness rejections,
instead relying upon their arguments to overcome the combination of
Jacobson and Myerson (see Appeal Br. 12). Having affirmed the
obviousness of claims 1–3, 6, and 12–16 for the reasons given above, we
also find that further combination with Baynes or Myllykangas renders the
rejected claims obvious for the reasons given by the Examiner (see Ans. 12–
16).
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–3, 6, 12–
16
103 Jacobson, Myerson 1–3, 6, 12–
16

4, 5 103 Jacobson, Myerson,
Baynes
4, 5
7, 8 103 Jacobson, Myerson,
Myllykangas
7, 8
Overall
Outcome
1–8, 12–16

Appeal 2020-002151
Application 14/550,713

13
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED