Bio-Rad Laboratories, Inc.

Patent Trials and Appeals Board

Apr 26, 2021

2020004306 (P.T.A.B. Apr. 26, 2021)

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.
14/171,766 02/03/2014 George Carman QLI347 7557
23581 7590 04/26/2021
KOLISCH HARTWELL, P.C.
520 SW YAMHILL STREET, SUITE 300
PORTLAND, OR 97204
EXAMINER
KAUP, SAHANA S
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
04/26/2021 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):
docketing@khpatent.com
veronica@khpatent.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GEORGE CARMAN, THOMAS H. CAULEY, and
DAVID P. STUMBO
Appeal 2020-004306
Application 14/171,766
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims directed to a system for detection of
spaced droplets as being obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 We use the term “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the real party in interest as Bio-Rad
Laboratories, Inc. (Appeal Br. 4.)
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STATEMENT OF THE CASE
Appellant’s Specification states that “[m]any biomedical applications
rely on high-throughput assays of samples combined with reagents” and
“[t]he trend is toward reduced volumes and detection of more targets.”
(Spec. 1.) Appellant’s Specification explains that “aqueous droplets that
function as independent reaction chambers for biochemical reactions” would
be advantageous for at least a couple of reasons. The Specification explains
that one advantage would be the small reaction volumes used which could
speed reaction rates and allow a much greater number of independent
measurements to be made on a sample as compared to conventional bulk
volume reactions. (Id. at 2.) A second advantage would be the use of lower
amounts of reagents reducing cost per test of consumables. (Id.)
Appellant’s Specification indicates that droplet emulsions have been
used to perform single-copy amplification of nucleic acid target molecules in
droplets. (Id. at 2–3.) “However, detection of signals from closely packed
droplets may be problematic because the signals cannot always be correctly
assigned to individual droplets.” (Id. at 3.) Thus, according to the
Specification “there is a need for systems that space droplets from one
another after reaction and before detection for improved detection
accuracy.” (Id.) Appellant’s invention is directed to such a system. (See id.
at 4.)
Claim 9, reproduced below, is illustrative of the claimed subject
matter:
9. A detection system for droplet-based assays, comprising a
droplet channel including a droplet inlet configured to receive
droplets suspended in a carrier fluid;
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a shell surrounding a portion of the droplet channel and
having an input channel therein;
a porous cylinder disposed within the shell and having a
central bore that forms a portion of the droplet channel, the
porous cylinder having porous walls that provide fluid
communication between a periphery of the porous cylinder and
the central bore;
a source of dilution fluid connected to the input channel
and disposed outside the shell;
a detection channel in fluid communication with, and
disposed downstream from, the droplet channel;
a light source to generate light that irradiates the
detection channel;
one or more pumps operable to (a) drive travel of
droplets and carrier fluid through the central bore and the
detection channel and (b) force flow of dilution fluid into the
central bore via the porous walls; and
a detection region including a fluorescence detector and
one or more optical elements, the one or more optical elements
being configured to direct, to the fluorescence detector,
fluorescence radiation emitted by droplets passing through the
detection channel.
REFERENCES
The prior art relied upon by the Examiner is:
Name Reference Date
David US 6,797,056 B2 Sept. 28, 2004
Makarewicz US 2011/0311978 A1 Dec. 22, 2011

REJECTION
The following rejection by the Examiner is before us on review:
Claims 9, 12–14, 16, and 22–25 are rejected under pre-AIA 35 U.S.C.
§ 103(a) as being unpatentable over Makarewicz and David.

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DISCUSSION
The Examiner finds that Makarewicz teaches a microfluidic device
having a channel network with a droplet inlet channel having a central
bore/channel and at least one dilution channel which come together in a
confluence region that has a droplet outlet region. (Final Action 3, 7, 9;
Ans. 12.) The Examiner notes that, “multiple dilution channels may be
associated with the droplet inlet channel.” (Final Action 3 (citing
Makarewicz ¶ 49).) The Examiner explains that the dilution channels
provide fluid to the stream of droplets emerging from the droplet inlet
channel, where the flow rate through the channels can be controlled with
pumps, and where the controlled flow impacts the spacing between the
droplets flowing to the droplet outlet region. (Id. at 3–4, 6.)
The Examiner finds that Makarewicz teaches an embodiment in which
the confluence region can be covered by a connector or housing, which the
Examiner finds meets the shell limitation of the claim. (Id. at 3 (referring to
Makarewicz Figs. 19 and 21), 9.)
The Examiner also finds that Makarewicz teaches “structural
components of the[] device that encourage fluid focusing.” (Id. at 7, 10.) In
particular, the Examiner notes that Makarewicz teaches an embodiment
where the shell component has a space between the inner wall of the shell
and the outer wall of the droplet input channel “such that the space provides
fluid that surrounds and dilutes droplets emitted from the droplet input
channel. (Id. at 7 (referring to Makarewicz Fig. 13).) In addition, the
Examiner finds that the embodiment showing the confluence region covered
by a connector or housing, includes “a plurality of dilution channels” that
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provide dilution fluid into the confluence region. (Id. (referring to
Makarewicz Fig. 19).)
The Examiner also finds that Makarewicz teaches that the confluence
region is followed by an examination region that is connected to a detector.
(Id. at 4.) In addition, the Examiner finds that Makarewicz teaches inclusion
of optical components to facilitate detection of target molecules. (Id. at 5.)
The Examiner concludes that Makarewicz:
renders obvious a system comprising a discrete connector
housing that covers the junction of multiple dilution channels
and the droplet inlet channel ( i.e. a shell surrounding a portion
of the droplet channel and having including an input channel
therein) wherein the multiple dilution channels, i.e. “any
suitable number”, feeding into a droplet inlet channel provide
enough dilution fluid to space droplets according to user’s
choice (i.e. a source of dilution fluid connected to the input
channel and disposed outside the shell).
(Ans. 13; see also Final Action 7.)
The Examiner recognizes that Makarewicz does not teach the system
includes a porous cylinder as required by the claims. (Final Action 7.)
However, the Examiner concludes that inclusion of a porous cylinder would
have been an obvious “substitution of the walls surrounding the central bore
as taught by Marakrewicz” in light of the teachings of David. (Id. at 8, 10.)
In particular, the Examiner finds that David teaches a microfluidic
device that has multiple adjacent channels where the common wall of the
adjacent channels “is semi-permeable and includes a frit.” (Id. at 9.) The
Examiner notes that use of such a wall “inherently allows the selective
diffusion of fluid and impede[s] the transport of other molecular
components.” (Id.) The Examiner finds that it would have been obvious to
one of ordinary skill in the art to modify the “fluid focusing components
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comprising a housing and multiple channels” that add “dilution fluid to a
central channel as taught by Makarewicz to include a central channel
comprising semipermeable common walls with adjacent channels” because
one of ordinary skill in the art “would have recognized that the substitution
of the walls surrounding the central bore” in this way “would result in the
predictable outcome of microfluidic structural components that allow fluid
communication between multiple fluid channels and a central channel.” (Id.
at 10 (emphasis added).)
We do not agree with the Examiner’s conclusion of obviousness
because we find the Examiner has failed to provide a rational evidentiary
basis supporting the proposed modification. (Appeal Br. 20).
When describing the use of multiple dilution channels, Makarewicz
nowhere teaches channels, if they are parallel to each other, are also adjacent
to each other such that walls would be shared. (See, e.g., Makarewicz Figs.
18, 19, 22, and 23.) Makarewicz describes the use of a cross-shaped spacer
where a pair of dilution channels are positioned opposite to one another and
which channels empty into the confluence region through which the droplet
inlet also passes perpendicularly to the dilution channels. (See id. ¶¶ 145–
146, 151, 156, 157, Figs 18, 19.) There is an alternative embodiment that
Makarewicz describes with multiple dilution channels that are positioned
serially. (Id. ¶¶ 166–167; Figs. 22, 23.) Makarewicz explains that the
additional serially placed dilution channel “increase[s] the separation
between droplets in two or more steps.” (Id. ¶ 166.) Makarewicz explains
that, in the system that includes the serial spacers, “the shear force exerted
on droplets at each confluence region” is reduced. (Id. ¶ 167.) Makarewicz
describes that shear forces that reduce droplet integrity by causing droplets
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to break up or coalesce is not desirable in a droplet-based assay system
where the droplet or its contents are to be examined. (See, e.g., id. ¶¶ 50,
155.)
The Examiner does not explain why one of ordinary skill in the art
would have combined multiple dilution channels positioned serially spaced
apart with the channels sharing a porous wall, as in David, in this
embodiment except to say that doing so would “allow fluid communication
between multiple fluid channels and a central channel.” (Final Action 10.)
But that does not provide a reason why one of skill in the art would have
wanted to provide such fluid communication where Makarewicz teaches
serial separation of more than one dilution channel so as to provide for
further distancing between droplets in the droplet outlet channel with
reduced shear force being exerted on the droplets at each confluence region.
David teaches that the porous membrane connectivity would allow
diffusion between adjoining lumens over at least a portion of the length of
the lumens which share a common wall (David 4:63–66), but the Examiner
does not provide a reason that one of ordinary skill in the art would want to
encourage lateral diffusion of the dilution fluid with Makarewicz’s serial
spaced apart dilution channel microfluidic device. “[R]ejections on
obviousness grounds cannot be sustained by mere conclusory statements;
instead, there must be some articulated reasoning with some rational
underpinning to support the legal conclusion of obviousness.” KSR Int’l Co.
v. Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441 F.3d
977, 988 (Fed. Cir. 2006).
As the Examiner recognized, Makarewicz teaches an alternative
embodiment for fluid focusing to increase the distance between closely
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spaced sample-containing droplets where the dilution channel is concentric
with the droplet channel. (Makarewicz ¶¶ 105–106, Fig. 13.) Although,
Makarewicz does not specifically described multiple concentric dilution
channels in such a configuration, as the Examiner explained, Makarewicz
teaches that the microfluidic device may include more than one dilution
channel and also notes that “the dilution channel may communicate with the
confluence region circumferentially.” (Makarewicz ¶ 49.) In light of the
foregoing, we can envision the addition of another concentric dilution inlet
tubing to this concentric design of Makarewicz depicted in Figure 13, and
such a design would result in dilution channels having shared walls, i.e., the
outer wall of the more central tube would form an inner wall of the outer
dilution channel.
It is not altogether clear to us, however, that one of ordinary skill in
the art would find such a design facilitates increased distance between
closely spaced sample-containing droplets, which is the reason that
Makarewicz teaches including multiple dilution channels. But more
importantly, the Examiner does not provide any rational underpinning for
why one of ordinary skill in the art would want to substitute a porous wall,
taught by David, over a portion of the concentrically arranged dilution tubes
where there is a shared wall. Instead, the Examiner simply posits that such a
substitution, suggested by David, “would result in the predictable outcome
of microfluidic structural components that allow fluid communication
between multiple fluid channels and a central channel.” (Ans. 15; Final
Action 10.) Such is not a rational explanation as to why the substitution
would have been carried out in the first instance. Why would one of
ordinary skill in the art want to have fluid communication between multiple
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concentrically arranged dilution tubes where Makarewicz teaches including
multiple dilution channels in order to increase distance between closely
spaced sample-containing droplets? The Examiner does not say, and the
reason is not apparent.
For the foregoing reasons, we do not affirm the Examiner’s rejection
of claims 9, 12–14, 16, and 22–25 as being obvious from Makarewicz and
David.

DECISION SUMMARY
Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
9, 12–14,
16, 22–25
103(a) Makarewicz,
David
9, 12–14,
16, 22–25

REVERSED