Bio-Rad Laboratories, Inc.v.Fluidigm Corporation

Patent Trial and Appeal Board

Apr 21, 2016

11868942 (P.T.A.B. Apr. 21, 2016)

Trials@uspto.gov Paper 29
571-272-7822 Entered: April 21, 2016
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

BIO-RAD LABORATORIES, INC.,
Petitioner,

v.

CALIFORNIA INSTITUTE OF TECHNOLOGY and
FLUIDIGM CORPORATION,
Patent Owner.
____________

Case IPR2015-00010
Patent 8,252,539 B2

Before GRACE KARAFFA OBERMANN, DONNA M. PRAISS, and
KRISTINA M. KALAN, Administrative Patent Judges.

PRAISS, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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Bio-Rad Laboratories, Inc. (“Petitioner”) filed a Petition to institute an
inter partes review of claims 1–17 of U.S. Patent No. 8,252,539 B2 (Ex.
1001, “the ’539 patent”) pursuant to 35 U.S.C. §§ 311–319, relying on the
Declaration of Dr. Shelley Anna (Ex. 1002, the “Anna Declaration”). Paper
1 (“Pet.”). The Board granted the Petition and instituted trial on the
patentability of claims 1–5 and 10–17 under 35 U.S.C. § 103(a) as obvious
over the combination of Stewart II1 and Burns.2 Paper 13 (“Dec. on Inst.”).
During trial, Patent Owner, California Institute of Technology and its
exclusive licensee Fluidigm Corporation (collectively, “Patent Owner”),
filed a Patent Owner Response relying on the Declaration of Dr. Todd
Squires (Ex. 2019, the “Squires Declaration”). Paper 18 (“PO Resp.”).
Petitioner filed a Reply to Patent Owner’s Response. Paper 20 (“Pet.
Reply”). Fluidigm Corporation filed a Motion to Seal Exhibits 2003–2008.
Paper 10.
A consolidated oral hearing was held on January 5, 2016, with
concurrently-filed inter partes review proceeding IPR2015-00009 involving
U.S. Patent No. 7,294,503, which issued from a parent application to the
’539 patent. A transcript of the hearing is included in the record. Paper 27
(“Tr.”).
We have jurisdiction under 35 U.S.C. § 6(c). This final written
decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
For the reasons that follow, we determine that Petitioner has met its
burden to prove by a preponderance of the evidence that claims 1–5 and 10–
17 of the ’539 patent are unpatentable.

1 WO 84/02000, published May 24, 1984 (Ex. 1004).
2 WO 98/22625, published May 28, 1998 (Ex. 1005).
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I. BACKGROUND
A. The ’539 Patent (Ex. 1001)
The ’539 patent, titled “Microfabricated Crossflow Devices and
Methods,” is directed to “[a] microfluidic device for analyzing and/or sorting
biological materials.” Ex. 1001, Abstr. The device comprises a main
channel, through which a fluid incompatible with the biological material
flows, an inlet region in communication with the main channel, and a droplet
extrusion region, through which droplets of solution containing the
biological material are deposited into the main channel. Id. The droplet
extrusion region is “a junction between an inlet region and the main
channel” that “permits the introduction of a pressurized fluid to the main
channel at an angle perpendicular to the flow of fluid in the main channel.”
Id. at 13:15–19. Figures 16A and 16B are reproduced below.

Figures 16A and 16B are exemplary architectures for droplet extrusion
regions in the microfabricated device. Id. at 7:54–55. The channels are
microfabricated, such as by etching a silicon chip. Id. at 17:9–11. Channels
that are rounded and have a diameter between about 2 and 100 microns are
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preferred for particles or molecules that are in droplets within the main
channel flow. Id. at 18:5–9. At these dimensions, the droplets “tend to
conform to the size and shape of the channels, while maintaining their
respective volumes.” Id. at 18:21–23. “[T]he size and frequency of droplets
formed in a main channel of such devices may be precisely controlled by
modifying the relative pressure of the incompatible fluids (e.g., water and
oil) in the device.” Id. at 54:38–41. Modifying the relative pressures
produces water droplets in the oil stream “such that the water enter[s] the
droplet extrusion region, shearing off into discrete droplets.” Id. at 55:27–
29.

B. Illustrative Claim
Claim 1, the sole independent claim at issue, is illustrative:
1. A method of making droplets in a microfluidic device,
comprising
[a] flowing an extrusion fluid through a first input channel at a
first pressure while
[b] flowing a sample fluid through a second input channel at a
second pressure,
[c] wherein the sample fluid is immiscible with the extrusion
fluid,
[d] wherein the first input channel and the second input channel
are in fluidic communication at a junction,
[e] wherein the junction is constructed and arranged so that
sample fluid droplets are sheared into an output channel,
[f] wherein the first and second input channels and the output
channel have diameters between about 2 and 100 microns or
cross-sectional dimensions in the range of 1 to 100 microns.
Ex. 1001, 60:55–67 (paragraphing and bracketed matter added).
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C. Claim Interpretation
In an inter partes review, claim terms in an unexpired patent are
interpreted according to their “broadest reasonable construction in light of
the specification of the patent in which [they] appear[].” 37 C.F.R.
§ 42.100(b). Under that standard, claim terms are given their ordinary and
customary meaning, as would be understood by one of ordinary skill in the
art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
F.3d 1249, 1257 (Fed. Cir. 2007). Also, care is exercised to avoid reading a
particular embodiment appearing in the written description into the claim if
the claim language is broader than the embodiment. See In re Van Geuns,
988 F.2d 1181, 1184 (Fed. Cir. 1993) (“limitations are not to be read into the
claims from the specification”).
In our Decision on Institution, we interpreted two claim terms of the
’539 patent as shown below:
Table 1
Term Construction
sheared severed or broken off
monodisperse sample fluid droplets dispersed droplets of sample fluid of substantially uniform size

Dec. on Inst. 5–6. The parties do not challenge our claim constructions.
Consequently, for purposes of this Final Written Decision, we adopt the
constructions as stated in Table 1 in accordance with the analysis set forth in
our Decision on Institution. Id.
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II. ANALYSIS
We turn now to the patentability of the claims. To prevail in its
challenges to the patentability of the claims, Petitioner must establish facts
supporting its challenges by a preponderance of the evidence. 35 U.S.C.
§ 316(e); 37 C.F.R. § 42.1(d). As noted above, the ground of unpatentability
involved in this inter partes review proceeding is claims 1–5 and 10–17 as
obvious under 35 U.S.C. § 103(a) over Stewart II and Burns.
We consider the respective positions of the parties in light of the
complete trial record.
A. Principles of Law
A claim is unpatentable under § 103(a) if the differences between the
claimed subject matter and the prior art are such that the subject matter, as a
whole, would have been obvious at the time the invention was made to a
person having ordinary skill in the art to which said subject matter pertains.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). The question of
obviousness is resolved on the basis of underlying factual determinations,
including: (1) the scope and content of the prior art; (2) any differences
between the claimed subject matter and the prior art; (3) the level of skill in
the art; and (4) where in evidence, so-called secondary conditions. See
Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). We also recognize
that prior art references must be “considered together with the knowledge of
one of ordinary skill in the pertinent art.” In re Paulsen, 30 F.3d 1475, 1480
(Fed. Cir. 1994) (citing In re Samour, 571 F.2d 559, 562 (CCPA 1978)).

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B. Level of Skill in the Art
In determining the level of skill in the art, various factors may be
considered, including “type of problems encountered in the art; prior art
solutions to those problems; rapidity with which innovations are made;
sophistication of the technology; and educational level of active workers in
the field.” In re GPAC, Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995) (citing
Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962
(Fed. Cir. 1986)). There is evidence in the record before us that reflects the
knowledge level of a person with ordinary skill in the art. Petitioner’s
Declarant, Dr. Anna, attests that a person with ordinary skill in the art would
“hav[e] at least the equivalent of a Bachelor’s degree in engineering,
physics, or chemistry and two years of academic, research, or industry
experience related to fluid mechanics, fluid dynamics, or microfluidics.”
Ex. 1002 ¶ 28. Patent Owner does not dispute Dr. Anna’s assessment of the
level of ordinary skill. PO Resp. 3. Thus, we adopt Petitioner’s Declarant’s
attestation as to the level of skill in the art.
C. Overview of Stewart II
Stewart II describes a method and apparatus “particularly suited to the
manipulation of microscopic quantities of reactant with volumes of less than
10 nanolitres . . . .” Ex. 1004, 3. The reactants used in the system “can be
liquids” which “will be supported, defined and moved by another,
immiscible liquid, referred to hereafter as the carrier phase.” Id. at 4. Figure
1, below, depicts two conduits for carrying out the method of producing
droplets of reactants as taught by Stewart II.
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Figure 1 illustrates one method of separating droplets of a predetermined
volume from a larger reservoir of reactant. Id. The stippled areas indicate
carrier phase (1) in one of the conduits. Id. at 2. The droplet volume shown
as (5) is pushed or sucked out of the small opening (3) before separation of
the reactant from the side arm (2) into the carrier phase. A flow of carrier
phase separates the droplet and carries it down the conduit. Id. at 4. The
dimensions of the conduits are described by Stewart II as “[a]ll conduits
should have diameters approximately the same as the droplets to be used in
them.” Id. at 5. The apparatus may be constructed by etching, molding, or
machining “indentations or channels of the appropriate configuration in the
surface of a plate, and [clamping or holding] this plate against another,
producing closed ducts or conduits.” Id. at 7. Suggested materials for the
plate include glass, Teflon, metal, polyvinylchloride, and polypropylene
with one of the plates being preferably transparent to allow “visual
inspection of the procedures.” Id.
Stewart II discloses three methods for determining the volume of the
droplet produced. Id. at 4–5. The second method, quoted below, uses two
currents to generate droplets of reactant in the apparatus described above:
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If large numbers of droplets are required, a continuous flow of
carrier phase flows down the conduit. When reactant is
simultaneously passed through the opening 3 a series of
droplets will be formed, each broken off just before it spans the
conduit. The exact size of the droplets thus produced will
depend on the magnitudes of the two currents.
Id. at 4–5. The droplets may contain micro-organisms. Id. at 7.
D. Overview of Burns
Burns relates to microfabricated substrates and methods for
amplifying and detecting nucleic acids. Ex. 1005, Abstract. Micromachined
structures for use with nanoliter volumes, called “microdevices,”are
preferred. Id. at 5:4–5. Materials such as silicon, quartz, and glass are
preferred because they can be manipulated to define channels, such as by
etching. Id. at 6:23–28. One or more channels in the substrate connect the
components, are preferably in liquid communication, and the channels
configured in microns accommodate “microdroplets.” Id. at 7:9–14.
Illustrative size ranges for the channels are 0.5 to 50 µm in depth and 20 to
1000 µm in width and, for the microdroplets, are “approximately 0.01 and
100 nanoliters (more typically between ten and fifty).” Id. at 7:15–19.
Figure 3B, below, is an embodiment of the device.

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Figure 3B shows “a schematic of . . . a device (10) to split a nanoliter-
volume liquid sample and move it using external air”. Id. at 50:17–18. Gas
is injected (lower arrow) “to split a microdroplet of length ‘L’.” Id. at
50:24–27. “[L]iquid . . . placed at the inlet (20) is drawn in by surface
forces”. Id. at 50:17–29. “[O]verflow ports (30) may be blocked or may be
loaded with excess water to increase the resistance to flow.” Id. at 50:28–
29. “[A] hydrophobic gas vent (70) further down the channel . . . can stop
the liquid microdroplet (60) after moving beyond the vent (70).” Id. at 51:1–
3.
E. Obviousness over Stewart II and Burns
Independent Claim 1
Petitioner argues that Stewart II discloses all limitations of claim 1
(Pet. 7–15) except the particular dimensions of the conduits as required by
claim 1 (and dependent claim 2) (id. at 29). According to Petitioner, “Burns
specifically recites that ‘illustrative ranges for channels may be between 0.5
and 50/µm in depth (preferably between 5 and 20/µm) and between 20 and
1000/µm in width (preferably 500/µm).’” Pet. 29 (quoting Ex. 1005, 7:16–
19). Petitioner provides a rationale for combining Stewart II with the
microdroplet transport channels of Burns based on the teaching in Stewart II
to use channel sizes less than 10 nanoliters in volume, which is calculated to
be a diameter of less than 267 microns.3 Id. at 30 (citing Ex. 1002 ¶¶ 82–
88). Channels smaller than 267 microns in diameter are specifically
described by Burns for use in microfluidic devices. Therefore, Petitioner

3 Dr. Anna computed less than 267 microns in diameter (Ex. 1002 ¶ 83),
which Petitioner refers to as less than 270 microns in its Petition (Pet. 30).
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asserts, one of ordinary skill in the art looking for an appropriate channel
size with which to construct the Stewart II device would have included the
channel dimensions described by Burns and would have understood the use
of channel sizes in the range of 1–100 microns would have predictably
yielded smaller channel and droplet sizes. Id. at 29–30. Petitioner provides
the Anna Declaration as support for the contention that the forces governing
the behavior of fluid in a channel with a diameter of 267 microns are the
same as those governing the behavior of a fluid in a channel with a diameter
of 100 microns. Id. at 30; Ex. 1002 ¶ 47. The basis for Dr. Anna’s opinion
is that the relative magnitudes of the capillary forces, viscous forces, and
inertia governing droplet formation or breakup are similar in sub-millimeter
devices. Ex. 1002 ¶ 47.
Patent Owner contends that the Anna Declaration should be given
little weight because Dr. Anna has taken inconsistent positions and her
explanations are not credible. PO Resp. 4–9. Dr. Anna testified at
deposition that “Thorsen [a named inventor on the ’539 patent and author of
a 2001 article (Ex. 2017)] was the first to publish generating droplets at a
microfluidic T-junction”. PO Resp. 6–8 (citing Ex. 2018, 62:8–63:21).
According to Patent Owner, Dr. Anna’s deposition testimony is consistent
with statements attributed to her in a 2007 article (Ex. 2016), that Patent
Owner quotes as follows:
3.2 Droplet breakup in cross-flowing streams
One of the most common microfluidic methods of generating
droplets uses cross-flowing continuous and dispersed phase
streams. In microfluidics, this is typically implemented using T-
shaped microchannel junctions, depicted schematically in figure
1(b). Droplet formation in a T-shaped device was first reported
by Thorsen et al [53], who used pressure controlled flow in
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microchannels 35μm wide and 6.5μm deep to generate droplets
of water in a variety of different oils.
Id. at 5 (quoting Ex. 2016, R322). Patent Owner contends the statements in
the article “were made well after the work of Stewart and Burns had
published” and independent of this proceeding, but inconsistent with her
positions regarding Stewart II, Burns, and the ’539 patent in this proceeding.
Id. at 5–6. Patent Owner contends that Dr. Anna’s explanation that Stewart
II “would not have been considered part of the popular microfluidics field
that we think of that I was referring to in this review article” is inconsistent
with her declaration statement that “Stewart II falls squarely within the
definition of microfluidics.” Id. at 8 (quoting Ex. 2018, 66:18–21, Ex. 1002
¶ 42). Patent Owner also contends that the 2007 article contains no
qualifiers to support Dr. Anna’s testimony that the article pertained to a
particular time period. Id. at 8.
Patent Owner further contends that Dr. Anna’s Declaration should be
given little weight because she “was unable to answer basic questions about
the understanding a person of ordinary skill in the art would have regarding
the disclosure of the prior art.” Id. at 10. Patent Owner specifically asserts a
“lack of ability to answer question[s] on how . . . a reduction in channel
[size] would affect the operation of the Stewart II device undercuts her
credibility on this point.” Id. at 11.
Patent Owner also asserts that the combination of Burns with Stewart
II is improper because (1) Burns teaches away from Stewart II and (2) the
combination is unpredictable and lacks a reasonable chance of success. Id.
at 26–37. Patent Owner argues that “having the ‘microdroplet’ remain in
contact with the channel walls is expressly discouraged by Stewart II”
because Stewart II maintains a film of the continuous phase around the
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reactant to reduce or eliminate contamination of the reactant while Burns’s
channels contact the dispersed phase and, therefore, are incompatible with
forming a spherical droplet and the smaller dimensions of Burns’s channels
“would increase the possibility of an obstruction, protrusion, or imperfection
on the wall from contacting the dispersed phase.” Id. at 26, 34 (citing Ex.
2019 ¶¶ 39–42). Patent Owner further argues that there is no reasonable
expectation of success of using the channel dimensions of Burns in a
continuous flow of carrier phase embodiment of Stewart II because (1)
Stewart II is internally contradictory in stating “the present invention does
not operate a continuous stream,” and (2) Stewart II lacks any example of
“using the alleged continuous flow embodiment.” PO Resp. 45–46. Patent
Owner further notes that Burns does not disclose “any method of generating
droplets while both fluids are flowing.” Id. at 47.
Regarding predictability, Patent Owner contends that has not been
demonstrated because Dr. Anna’s declaration states that the teachings of the
references are compatible with each other, not that their combination yields
a predictable result. Id. at 29–30. Additionally, Dr. Anna’s deposition
testimony regarding needing more factors in order to predict how changing
one variable would affect Stewart II’s system evidences unpredictability,
according to Patent Owner. Id. at 30–31 (citing Ex. 2018, 110:12–13,
111:17–19, 112:10–12, 114:3–8). Patent Owner asserts that “the factors
involved in droplet formation are numerous and complex,” would not have
been known well enough to be manipulated predictably at the time of the
invention of the ’539 patent, and the prior art does not “provide[] guidance
on what combinations would succeed.” Id. at 31–34 (citing Ex. 2019 ¶¶ 23–
27, 29, 30, 37, 38).
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Patent Owner also asserts that “implausible and inconsistent
statements within Stewart II” would “cause skepticism” about successful
droplet formation and evidence unreliability of the Stewart II disclosure. Id.
at 35–36. Specifically, Patent Owner asserts that Stewart II’s claim that the
T-junction can generate droplets at volumes from more than 1 liter to less
than 10 nL is “impossible under any reasonable operating parameters.” Id.
at 35 (citing Ex. 2019 ¶ 35). Patent Owner further contends that Stewart II’s
disclosure of generating a large amount of droplets using a continuous flow
of carrier phase is inconsistent with both the statement that “the present
invention does not operate a continuous stream” and its method of
combining droplets for chemical reactions “using a sequence of distinct and
discrete steps.” Id. at 36 (citing Ex. 2019 ¶¶ 47–48). Patent Owner also
argues that the second channel or side arm of Stewart II would not
necessarily have the same dimension as the main channel because the side
arm does not also contain droplets. Id. at 40–43.
Dependent Claims 2–5 and 10–17
Regarding the channel dimensions required by claim 2, Petitioner
relies on the same arguments made for claim 1 as discussed above. Pet. 29–
30. Petitioner argues that claims 3, 4, and 5 are obvious over Stewart II and
Burns because it was known to control liquid flow by controlling pressure,
and also the selection of a particular fluid pressure would have been nothing
more than routine optimization. Id. at 31. Petitioner further asserts that
optimizing fluid flow, which is supported by Burns, is routine and within the
level of ordinary skill in the art. Id. (quoting Ex. 1005, 23; citing Ex. 1002
¶¶ 90–94).
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Regarding claim 11, which specifies that the biological material of
claim 10 is a polynucleotide or enzyme, Petitioner asserts that Stewart II
discloses that its droplets contain microorganisms, but not specifically a
polynucleotide or enzyme. Id. Petitioner asserts that Burns teaches using
nucleic acids as well as biological samples obtained from blood, plasma, and
urine, which contain enzymes, in a microfluidic device. Id. at 32.
According to Petitioner, using Burns’s samples in the device of Stewart II
would have been desired to perform reactions and analyses, as well as
technically simple, and would have yielded predictable results. Id. at 32–33
(citing Ex. 1002 ¶ 99).
Regarding claim 12, which recites “the sample fluid droplets contain a
reporter molecule,” and claim 13, which recites “the reporter molecule is a
fluorescent agent,” Petitioner asserts Burns teaches a reporter molecule that
can be a “fluorescent label.” Id. at 33–34. Petitioner also relies on the Anna
Declaration to show that the use of a fluorescent reporter molecule was
routinely used at the time of the invention of the ’539 patent to observe
and/or measure results of chemical reactions. Id. at 34 (citing Ex. 1002
¶¶ 100–01). Dr. Anna testifies that fluorescent reporter molecules “were
well known and routinely used in microfluidics at the time of the alleged
invention of the ’539 Patent” (Ex. 1002 ¶ 100 (citing Ex. 1016, 14–16)) and
that Stewart II discloses optical analysis of its droplets with a photometer,
which would “detect the presence or amount of a fluorescent agent” (id. at
¶ 101). According to Dr. Anna, the use of a fluorescent reporter molecule in
the process of Stewart II “would be technically simple and would yield
predictable results, as such techniques were well known and used in many
areas of chemical and biological studies.” Id. at ¶ 101 (citing Ex. 1016, 14).
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Regarding claims 14 and 15, Petitioner asserts Burns further teaches
detecting a signal produced by a polymerase chain reaction (PCR), as
required by claim 15, and isothermal amplification reactions, which are both
chemical reactions of a substrate catalyzed by an enzyme as required by
claim 14. Pet. 34–36 (citing Ex. 1002 ¶¶ 102, 103, 105, 106).
Regarding claim 16, Petitioner asserts that modifying Stewart II so
that at least one droplet would contain no more than one particle of the
biological material would have been obvious at the time of the invention,
because Burns teaches that “‘particular components, amounts of components
and/or reactants and the particular conditions of the reaction may be
modified in order to optimize [a reaction.]’” Id. at 36–37.
Regarding claim 17, which recites “the sample fluid droplets contain a
sample of molecules for small scale chemical reactions,” Petitioner asserts
that Stewart II discloses carrying out such chemical reactions using volumes
of reactants that may range from more than a liter to less than 10 nanoliters,
and that Burns also discloses biological samples contained in droplets
suitable for carrying out reactions in the device of Stewart II. Id. at 37–38.
Patent Owner does not separately argue the patentability of dependent
claims 2–5 and 10–17.
Discussion
At the outset, we note that Patent Owner contends that the testimony
of Dr. Anna should be given little weight, but does not seek to exclude the
Anna Declaration. Patent Owner does not challenge Dr. Anna’s
qualifications as an expert in the field of microfluidics. Tr. 28:16–18.
Instead, Patent Owner argues that the credibility of her statements regarding
Stewart II is diminished by her cross-examination at deposition on the
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subject of (a) her paper, independent of this proceeding, that acknowledges
the Thorsen 2001 Article and (b) hypotheticals concerning the Stewart II
device presented at deposition. PO Resp. 4–11.
Patent Owner essentially contends that Dr. Anna’s deposition and
declaration statements in this proceeding concerning Stewart II are
inconsistent with statements in her earlier publication indicating that the
named inventors on the ’539 patent were the first to report droplet formation
in a T-shaped device. Dr. Anna explained she was unaware of Stewart II at
the time of her publication and that, even in view of Stewart II, her
published statements about the Thorsen 2001 Article being the first to report
on microdroplet formation in a T-shaped device would still be accurate
because Stewart II was not part of the body of work reported in the academic
literature. Ex. 2018, 31:9–11, 59:21–60:3, 61:2–12, 63:11–21. The veracity
of Dr. Anna’s explanation is supported by Patent Owner’s expert, Dr.
Squires, who testified at deposition that he does not typically include patents
in his own academic review papers and did not cite the patent literature in
his own papers on the subject of microfluidics. Ex. 1017, 31:5–9, 37:19–
38:21, 40:20–41:17. Dr. Anna’s deposition testimony, in fact, clarifies any
apparent inconsistency between her declaration and the Thorsen 2001
Article. Accordingly, we are not persuaded that Dr. Anna’s testimony
should be given diminished weight in light of her prior statements about the
Thorson 2001 Article.
Regarding hypothetical modifications to the Stewart II device that Dr.
Anna allegedly could not answer during deposition, Patent Owner asserts
Dr. Anna was “asked to discuss the effect that reducing the channel size
would have on Stewart II’s device.” PO Resp. 10–11 (citing Ex. 2018,
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113:4–115:5, 109:24–110:13). Patent Owner’s questions, however, were
hypotheticals concerning contamination or pressure, which, Dr. Anna
testified, required additional information about the nature of the
contamination. Ex. 2018, 113:4–6, 113:11–14, 114:9–12. Patent Owner
further asserts that Dr. Anna was not able to explain “how one of ordinary
skill in the art would understand the dimensions and operation of SII’s
device in light of the disclosure it works at both 10nl and 1L volumes.” PO
Resp. 10 (citing Ex. 2018, 107:21–109:16). That assertion is unpersuasive,
because the questions presented to Dr. Anna were directed to the forces that
govern droplet formation at 10nl and 1L; Dr. Anna testified that the relevant
forces were the same, specifically, viscous forces, capillary forces, and
inertia. Ex. 2018, 107:21–108:2, 108:10–19.
We do not find Dr. Anna’s deposition testimony to undermine the
credibility of Dr. Anna’s Declaration in this proceeding because the
questions asked of the witness were fairly answered. Therefore, after
considering arguments and evidence by both Petitioner and Patent Owner,
we are not persuaded that Dr. Anna’s testimony is entitled to little or no
weight.
Regarding Petitioner’s prior art challenges, there is no dispute that the
10 nanoliter volume disclosed in Stewart II translates to a 267 micron
diameter in the size of a spherical droplet in the channel. Ex. 1002 ¶ 44; Ex.
1017, 149:15–150:10. There also is no dispute that Stewart II discloses a
microfluidic device having two channels arranged so that droplets of a
sample fluid in the second channel are capable of being sheared into the
main channel containing an extrusion fluid. Ex. 1002 ¶¶ 45–48, 50–57; Ex.
1017, 163:17–168:16. The key issue is whether the disclosure in Burns of a
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particular channel size (between 5 and 20 microns in depth) for microfluidic
devices is properly combined with the disclosures of Stewart II regarding
forming droplets in a main channel having a continuous fluid flow from a
side arm through which sample fluid is introduced.
Based on the complete record in this proceeding, the preponderance of
the evidence is that the selection of known channel sizes for microfluidic
devices as disclosed in Burns would have been obvious as a predictable
variation in the same field, because the dimensions of Burns are less than
267 microns as directed by Stewart II. KSR, 550 U.S. at 417. The
combination is supported by the Anna Declaration. Dr. Anna testified that
the fluid behavior in the Stewart II device would be “substantially the same”
at the dimensions disclosed by Burns. Ex. 1002 ¶ 47 (“fluid behavior
(including flow characteristics, fluid forces, etc.) would be substantially the
same in devices designed for droplets of less than 267 microns as they would
be in devices designed for droplets of less than 100 microns.”). See Ex.
2019 ¶¶ 23–27, 29, 30, 37, 38. Dr. Squires’s opinion is based on Stewart II
being unbelievable because it does not disclose operating data. Id. at ¶¶ 29–
30. Referring to Burns, Dr. Squires further states “[n]or does the mere fact
that channels with dimensions smaller than 100 microns could be fabricated
at the time of invention provide a basis for one of ordinary skill in the art to
believe that Stewart II’s device would operate as described by Stewart II
when using channels with dimensions of 100 microns or less.” Id. at ¶ 37.
The formation of microdroplets, however, is disclosed in both Stewart II and
Burns. Stewart II discloses droplet formation in a microfluidic device at
dimensions less than 267 microns in diameter. Ex. 1004, 3–4. Burns
discloses droplet formation in a microfluidic device at the claimed
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dimensions. Ex. 1005, 7. While multiple factors may affect droplet
formation, the formation of droplets in devices having a channel that is less
than 267 microns in diameter (Stewart II) or in the claimed range (Burns) is
supported by the evidence.
Dr. Squires’s testimony regarding the combination of Stewart II and
Burns is based also on his assertion that the 10nL size disclosed in Stewart II
would not be accepted by one of ordinary skill in the art at the time of the
invention because “the upper bound volume in Stewart II is so implausible.”
Ex. 2019 ¶ 36. However, Dr. Squires admitted at deposition that it was
“physically possible” to make one liter droplets using Stewart II’s device
under low gravity and pressure conditions, such as in outer space. Ex. 1017,
176:21–177:6. Stewart II states that some types of chemical analysis or
synthesis can be conducted in its device in space. Ex. 1004, 8 (“It could also
be used for chemical analysis or synthesis in outer space, in conditions of
very low gravity and pressure.”). Stewart II also discloses a continuous flow
embodiment having two currents that form a series of droplets when a
reactant passes through an opening, such that each droplet is “broken off just
before it spans the conduit” and that “[a]ll conduits should have diameters
approximately the same as the droplets.” Id. at 4, 5. In a determination of
obviousness, a reference may be relied upon for all that it would have
reasonably suggested to one having ordinary skill in the art. Merck & Co. v.
Biocraft Labs., 874 F.2d 804, 807 (Fed. Cir. 1989) (“That the [prior art]
patent discloses a multitude of effective combinations does not render any
particular formulation less obvious.”).
Dr. Squires asserts that “one of ordinary skill in the art would have to
perform his or her own independent experimentation and research to
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determine what operating parameters could be combined to form a droplet
using the T-junction geometry disclosed by Stewart II.” Ex. 2019 ¶ 30.
Such experimentation has not been shown on this record to be undue
experimentation. In addition to the formation of microdroplets in the
devices of Stewart II and Burns, the evidence shows, as Dr. Squires
concedes, that for given materials, dimensions, and geometries, it would be a
matter of “simple optimization” to adjust pressure to form droplets and is
relatively easy to do. Ex. 1017, 134:12–135:5. Therefore, in view of the
totality of the evidence in the record, we credit Dr. Anna’s testimony on the
combination of Stewart II and Burns to arrive at the method of making
droplets in a microfluidic product as claimed in claim 1.
We are not persuaded that Burns teaches away from the asserted
combination as argued by Patent Owner. See PO Resp. 26. “A reference
may be said to teach away when a person of ordinary skill, upon reading the
reference, would be discouraged from following the path set out in the
reference, or would be led in a direction divergent from the path that was
taken by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
According to Patent Owner, the operation of Burns’s system showing a
droplet in contact with a channel wall is incompatible with Stewart II in two
ways: (1) Stewart II requires a continuous phase between the channel and
the dispersed phase to reduce contamination by the reactants in the dispersed
phase, and (2) Stewart II requires droplets to be spherical. PO Resp. 26–28.
These distinctions between the two references do not amount to
discouraging one skilled in the art from the path leading to the claimed
invention. Both Burns and Stewart II address contamination of the walls and
disclose ways in which to reduce contamination, including making the walls
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smooth and washing them. Ex. 1005, 108; Ex. 1004, 2, 7. The common
objective of Burns and Stewart II would have provided a further reason to
combine the references, rather than discouraging the combination. In
addition, the evidence does not support a particular droplet geometry being
critical to the microfluidic device of Stewart II, as asserted by Patent Owner.
See PO Resp. 28. Dr. Squires testified that the droplets shown in Figure 1 of
Stewart could have alternate shapes. Ex. 1017, 143:11–13.

F. Objective Indicia of Non-Obviousness
In addition to the contentions above, Patent Owner argues that
objective indicia, including industry praise (PO Resp. 14–23) and long-felt
but unmet need (id. at 23–26) is probative evidence showing the inventions
of the claims at issue are non-obvious. Id. at 13. In support, Patent Owner
relies on the Squires Declaration (Ex. 2019), the Anna Declaration (Ex.
1002), the Anna 2007 Article (Ex. 2016), and other evidence (Exs. 1007,
2018, 2021–25, 2027).
Industry Praise
Patent Owner contends that “the Thorsen 2001 Article is substantially
similar to Example 12 in the ’539 patent” and provides a chart setting forth
how the Thorsen 2001 Article (Ex. 2017) discloses the elements of claim 1.
PO Resp. 17–21. Patent Owner also sets forth how researchers in the field,
including Dr. Anna, praised the Thorsen 2001 Article as (1) first reporting
“droplet formation in a T-shaped device” (Ex. 2016), (2) “first introduc[ing
microfluidic T-junction geometry] for the controlled formation of water-in-
oil dispersions” (Ex. 2022), (3) “first incorporat[ing T-junction geometry]
into a microfluidic chip” (Ex. 2023), (4) “first[] consider[ing] droplet
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formation within a T-junction microchannel” (Ex. 2024), and (5) “first
report[ing] “[d]roplet formation in a T-shaped device” (Ex. 2025). PO Resp.
14–17.
It is not sufficient, however, that a product or its use merely falls
within the scope of a claim in order for objective evidence of
nonobviousness tied to that product to be given substantial weight. There
must also be a causal relationship, termed a “nexus,” between the evidence
and the claimed invention. Merck & Co., Inc. v. Teva Pharm. USA, Inc., 395
F.3d 1364, 1376 (Fed. Cir. 2005). Nexus must exist in relation to all types
of objective evidence of nonobviousness. See In re GPAC, Inc., 57 F.3d
1573, 1580 (Fed. Cir. 1995) (generally); Ormco Corp. v. Align Tech., Inc.,
463 F.3d 1299, 1312 (Fed. Cir. 2006) (long-felt but unmet need);
Muniauction, Inc. v. Thomson Corp., 532 F.3d 1318, 1328 (Fed. Cir. 2008)
(praise). A showing of sufficient nexus is required in order to establish that
the evidence relied upon traces its basis to a novel element in the claim, not
to something in the prior art. Institut Pasteur & Universite Pierre Et Marie
Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013). Objective
evidence that results from something that is not “both claimed and novel in
the claim” lacks a nexus to the merits of the invention. In re Kao, 639 F.3d
1057, 1068 (Fed. Cir. 2011). Thus, establishing nexus involves a showing
that novel elements in the claim, not prior-art elements, account for the
objective evidence of nonobviousness. Id. The stronger the showing of
nexus, the more weight will be accorded the objective evidence of
nonobviousness. See GPAC, 57 F.3d at 1580 (“To the extent that the
patentee demonstrates the required nexus, his objective evidence of
nonobviousness will be accorded more or less weight.”); Ashland Oil, Inc. v.
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Delta Resins & Refractories, Inc., 776 F.2d 281, 306 (Fed. Cir. 1985) (“The
objective evidence of secondary considerations may in any given case be
entitled to more or less weight, depending upon its nature and its relationship
to the merits of the invention.”).
As noted, the objective evidence cited by Patent Owner requires a
nexus with the claimed subject matter. Patent Owner’s evidence of praise
relies, however, on Thorsen being first to report on a T-shaped junction
geometry for a microfluidic device to produce droplets and, more generally,
to “landmark work” in droplet based microfluidics, not any specific praise
for the method itself even if encompassed by claim 1. See PO Resp. 14–17;
Ex. 2016, R322; Ex. 2021, 25; Ex. 2022, 142–44; Ex. 2023, 438; Ex. 2024,
712; Ex. 2025, 2036. As discussed above, T-shaped junctions were known
in the art for use in microfluidic devices as early as 1984. Ex. 1004, Fig. 1.
Consequently, it cannot be used to tie the objective evidence to the claimed
subject matter. Thus, even if being recognized as first to report in the
academic literature on a particular microfluidic structure for forming
droplets constitutes praise for the method of making droplets in a
microfluidic device, we are not persuaded that Patent Owner establishes
sufficient nexus in relation to the microfluidic device being praised versus
what is “both claimed and novel in the claim.” Kao, 639 F.3d at 1068.
Accordingly, we are not persuaded by Patent Owner’s contentions in relation
to praise in the industry.
Long-Felt but Unmet Need
Patent Owner also contends that long-felt need is established by the
length of time between Stewart II’s disclosure of a T-junction structure in
1984, Manz’s disclosure of capillary tubing having internal diameters
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between 0.9 µm and 24 µm in 1990, and the earliest priority date of the ’539
patent in November 8, 2000. PO Resp. 23–26 (citing Leo Pharmaceutical
Prods., Ltd. v. Rea, 726 F.3d 1346, 1357–59 (Fed. Cir. 2013)).
Patent Owner’s evidence of a long-felt but unmet need is premised on
the prior art T-junction structure to form droplets of Stewart II not meeting
the need for miniaturization of microfluidic devices. See PO Resp. 23–24.
When asked about direct evidence of long-felt need at oral hearing, Patent
Owner answered, “Dr. Anna’s statement that Stewart II professed a desire to
reduce the size of his device.” Tr. 54:1–3. Patent Owner essentially takes
Petitioner’s reason to combine references and characterizes it as a “desire”
or “need” rather than a direction to use devices that are smaller than 267
microns in size. Patent Owner then measures the length of time between
Stewart II’s publication in 1984 and the November 8, 2000 filing date of the
’539 patent to argue an analogous situation to the finding of long-felt need in
Leo Pharma. PO Resp. 24–26. The problem with this argument is that
Stewart II does not evidence difficulty in constructing a T-junction
microfluidic device in dimensions below 267 microns. Rather, Stewart II
discloses “the manipulation of microscopic quantities of reactant with
volumes of less than 10 nanolitres,” which the parties do not dispute
translates to droplets of less than 267 microns and channels of less than 267
microns in diameter. Ex. 1004, 3; Ex. 1002 ¶¶ 42, 44 (“Because Stewart II
expressly states that it is suited for volumes of less than 10 nanoliters, or less
than 267 microns, Stewart II expressly relates to smaller droplets as well . . .
.”); Ex. 1017, 149:19–150:10, 158:2–9 (When Stewart II says “ten nanoliters
or less” and spherical droplets are involved, this translates into a channel
width of “267 microns or less.”). Therefore, we are not persuaded that the
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evidence on the complete record establishes a long-felt, unmet need for
microfluidic channels in the claimed range of 2 to 100 microns.
We also are not persuaded that the time gap drawn between Stewart
II’s 1984 publication and the ’539 patent priority date is sufficient to
establish long-felt need in view of the fourteen year gap in Leo Pharma, 726
F.3d at 1359. PO Resp. 24–26. Leo Pharma involved “the need for a single
formulation to treat psoriasis” where benefits of the separate components,
vitamin D and corticosteroids, were known from the cited prior art
references twenty-two years and fourteen years before the filing of the patent
at issue. Leo Pharma, 726 F.3d at 1359. The factual background of Leo
Pharma includes evidence that “several medical research articles . . .
discourag[ed] the combination of a vitamin D analog with a corticosteroid
because of the stability problems of vitamin D analogs at lower pHs.” Id. at
1353. There was also a finding that the cited prior art formulations were not
storage stable and the problem of storage stability was not recognized. Id. at
1354, 1357. Thus, Leo Pharma included circumstances that are not present
here, not just the mere passage of time. See Nike, Inc. v. Adidas AG, 812
F.3d 1326, 1338 (Fed. Cir. 2016) (the decision in Leo Pharma “hinged on
the fact that nothing in the cited prior art appreciated the problem the
invention recognized and then solved” not merely the passage of time); Iron
Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1325 (Fed. Cir.
2004) (“the mere passage of time without the claimed invention is not
evidence of nonobviousness.”). Even if the time span between cited prior art
and the priority date of a patent were sufficient to establish long-felt need,
Patent Owner has not addressed the Burns reference, published two years
prior to the ’539 patent priority date and relied upon by Petitioner in each of
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its obviousness challenges. Ex. 1005. The evidence is insufficient to
establish that any long-felt need was solved by the invention of the ’539
patent, as opposed to the prior art techniques reflected in Burns.
Consequently, we are not persuaded by Patent Owner’s contentions with
respect to long-felt need.
G. Conclusion
After considering Petitioner’s and Patent Owner’s positions, as well as
their supporting evidence, we determine the preponderance of the evidence
demonstrates that claims 1–5 and 10–17 of the ’539 patent would have been
obvious over Stewart II and Burns for the reasons provided by Petitioner.
See Pet. 28–38; Pet. Reply 2–24. Patent Owner’s objective evidence is not
sufficient to overcome the strong showing of obviousness in this case.
H. Motion to Seal
Fluidigm Corporation’s Motion to Seal Exhibits 2003–2008 (Paper
10) is unopposed and is granted. There is an expectation that information
will be made public where the information is identified in a final written
decision, and that confidential information that is subject to a protective
order ordinarily becomes public 45 days after final judgment in a trial,
unless a motion to expunge is granted. 37 C.F.R. § 42.56; Office Patent
Trial Practice Guide, 77 Fed. Reg. 48,756, 48,761 (Aug. 14, 2012). In
rendering this Final Written Decision, it was not necessary to identify, nor
discuss in any detail, any confidential information because it was not relied
upon by the parties in their trial briefing. However, a party who is
dissatisfied with this Final Written Decision may appeal the Decision
pursuant to 35 U.S.C. § 141(c), and has 63 days after the date of this
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Decision to file a notice of appeal. 37 C.F.R. § 90.3(a). Thus, it remains
necessary to maintain the record, as is, until resolution of an appeal, if any.
In view of the foregoing, the confidential documents filed in the instant
proceeding will remain under seal, at least until the time period for filing a
notice of appeal has expired or, if an appeal is taken, the appeal process has
concluded. The record for the instant proceeding will be preserved in its
entirety, and the confidential documents will not be expunged or made
public, pending appeal. Notwithstanding 37 C.F.R. § 42.56 and the Office
Patent Trial Practice Guide, neither a motion to expunge confidential
documents nor a motion to maintain these documents under seal is necessary
or authorized at this time. See 37 C.F.R. § 42.5(b).
This is a final written decision of the Board under 35 U.S.C. § 318(a).
Parties to the proceeding seeking judicial review of this decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.
III. ORDER
Accordingly, it is hereby:
ORDERED that, as set forth in Section II.G above, claims 1–5 and
10–17 of the ’539 patent have been shown to be unpatentable.
FURTHER ORDERED that the Motion to Seal Exhibits 2003–2008
(Paper 10) is granted.
FURTHER ORDERED that the parties to the proceeding seeking
judicial review of this Final Written Decision must comply with the notice
and service requirements of 37 C.F.R. § 90.2.

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PETITIONER:

Dion Bregman
Michael Lyons
MORGAN LEWIS & BOCKIUS LLP
dbregman@morganlewis.com
mlyons@morganlewis.com

PATENT OWNER:

James P. Murphy
Margaux A. Savee
POLSINELLI PC
jpmurphy@polsinelli.com
msavee@polsinelli.com