       NOTE: This disposition is nonprecedential.


  United States Court of Appeals
      for the Federal Circuit
                ______________________

 UNIVERSITY OF MARYLAND BIOTECHNOLOGY
                INSTITUTE,
                  Appellant

                           v.

     PRESENS PRECISION SENSING GMBH,
                Cross-Appellant
            ______________________

                 2016-2745, 2017-1057
                ______________________

    Appeals from the United States Patent and Trade-
mark Office, Patent Trial and Appeal Board in No.
95/000,615.
                ______________________

              Decided: November 3, 2017
               ______________________

   RENE A. VAZQUEZ, Sinergia Technology Law Group,
PLLC, Leesburg, VA, argued for appellant.

   MICHAEL STEVEN CULVER, Millen, White, Zelano &
Branigan PC, Arlington, VA, argued for cross-appellant.
                ______________________

Before LOURIE, O’MALLEY, and TARANTO, Circuit Judges.
2   UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH



LOURIE, Circuit Judge.
    The University of Maryland Biotechnology Institute
(“Maryland”) appeals from the inter partes reexamination
decision of the United States Patent and Trademark
Office (“PTO”) Patent Trial and Appeal Board (“the
Board”) affirming the examiner’s rejection of claims 1, 3–
6, 9–11, 13–16, 19, and 20 (“the claims”) of U.S. Patent
6,673,532 (“’532 patent”) as obvious under 35 U.S.C. § 103
(2006). 1 Presens Precision Sensing GmbH v. Univ. of Md.
Biotechnology Inst., No. 2015-006297, 2015 WL 9581532
(P.T.A.B. Dec. 29, 2015) (“Decision”), reh’g denied,
(P.T.A.B. July 29, 2016). Because the Board did not err in
holding the claims invalid as obvious, we affirm.
                           BACKGROUND
     Maryland owns the ’532 patent, which covers methods
of measuring parameters in cell culture. Cell culture is a
widely used technique to cultivate cells in vitro. Parame-
ters such as glucose, pH, and carbon dioxide and oxygen
levels affect the viability of cell cultures. Consequently,
monitoring such parameters is important in optimizing
cell culture conditions. See, e.g., ’532 patent col. 1 ll. 47–
64.
    The ’532 patent discloses an optical method of moni-
toring various cell culture parameters. The method
implements four key components: (1) a cultivation vessel;
(2) a sensor; (3) an excitation source; and (4) a detector.
Id. col. 5 ll. 1–5. Cells are grown in a cultivation vessel
that includes sensors which selectively bind to certain
analytes. The sensors are light-sensitive, so when an


    1 Because the application of the ’532 patent was filed
before March 16, 2013, the pre-Leahy-Smith America
Invents Act version of § 103 applies. See Pub L. No. 112-
29, 125 Stat. 284 (2011); 35 U.S.C. § 103 (2006).
UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH   3



excitation source such as a light-emitting diode (“LED”)
shines on the sensors, the sensors emit light correspond-
ing to the concentration of the relevant analytes. Detec-
tors such as photomultiplier tubes then measure the light
emitted by the sensors. Id. col. 4 l. 57–col. 5 l. 10.
    Appellee Presens Precision Sensing (“Presens”) peti-
tioned for inter partes reexamination of the ’532 patent,
which the PTO granted. Claim 1 of the ’532 patent, as
amended during reexamination, is representative and
reads as follows:
   1. A method of measuring at least two cultivation
   parameters in a cell culture, comprising:
   (a) providing a cultivation vessel, wherein the cul-
   tivation vessel comprises, walls that define a sin-
   gle continuous volume or a non-planar surface
   that defines a single continuous volume, and at
   least two types of optical chemical sensors posi-
   tioned within the single continuous volume;
   (b) placing a continuous culture medium within
   the single continuous volume of the cultivation
   vessel such that the continuous culture medium is
   in contact with at least one of the walls that de-
   fine the single continuous volume of the cultiva-
   tion vessel or the non-planar surface that defines
   the single continuous volume of the cultivation
   vessel, wherein the optical chemical sensors are
   positioned such that they are in contact with the
   continuous culture medium;
   (c) establishing a cell culture in the continuous
   culture medium;
   (d) exciting the optical chemical sensors to gener-
   ate emission and/or light absorption, wherein the
   optical chemical sensors are excited using at least
   one excitation source per optical chemical sensor;
4   UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH



    (e) detecting the emission and/or absorption gen-
    erated by the at least two optical chemical sensors
    in (d) by at least one detector for each type of opti-
    cal chemical sensor used; and
    (f) analyzing the detected emission and/or absorp-
    tion detected in (c) to assess the at least two culti-
    vation parameters measured.
J.A. 646–47, 1005.
    The examiner rejected the claims as, inter alia, obvi-
ous over Shabbir B. Bambot et al., Potential Applications
of Lifetime-Based, Phase-Modulation Fluorimetry in
Bioprocess and Clinical Monitoring, 13 Trends in Bio-
technology 106 (1995) (“Bambot”), and Bernhard H. Weigl
et al., Optical Triple Sensor for Measuring pH, Oxygen
and Carbon Dioxide, 32 J. Biotechnology 127 (1994)
(“Weigl”).
    Bambot described optical methods of measuring ana-
lytes such as glucose, pH, and oxygen and carbon dioxide
levels in bioreactors. The methods implemented the same
set of components as the ’532 patent. Various cultivation
vessels housed sensors excitable by several types of exci-
tation sources, and the sensors’ emissions could be meas-
ured by several different detectors.
    Similarly, Weigl described a triple sensor device for
measuring pH, oxygen, and carbon dioxide in a cultivation
vessel. However, in Weigl the sensors were located in
individual flow-through units outside the cultivation
vessel. Each unit had a dedicated excitation source and
detector. Given the teachings of Bambot and Weigl in
combination, the examiner concluded that the claims of
the ’532 patent would have been obvious over the refer-
ences at the time the invention was made.
    The Board affirmed the examiner’s obviousness rejec-
tion. The Board agreed that Bambot taught placing
sensors inside a cultivation vessel, and also disclosed
UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH   5



multiple types of sensors, detectors, and excitation
sources. Furthermore, the Board found that Weigl taught
monitoring multiple parameters using a separate detector
and excitation source for each type of sensor. Conse-
quently, the Board concluded that “it would have been
obvious to arrange more than one sensor inside a cultiva-
tion vessel and [use] the light excitation and detection
means described in Bambot for each one.” Decision, 2015
WL 9581532, at *13.
   Maryland appealed, and we have jurisdiction under
28 U.S.C. § 1295(a)(4)(A).
                         DISCUSSION
     Our review of a Board decision is limited. In re Baxter
Int’l, Inc. 678 F.3d 1357, 1361 (Fed. Cir. 2012). We review
the Board’s legal determinations de novo, In re Elsner,
381 F.3d 1125, 1127 (Fed. Cir. 2004), but we review the
Board’s factual findings underlying those determinations
for substantial evidence, In re Gartside, 203 F.3d 1305,
1316 (Fed. Cir. 2000). A finding is supported by substan-
tial evidence if a reasonable mind might accept the evi-
dence as adequate to support the finding. Consol. Edison
Co. v. NLRB, 305 U.S. 197, 229 (1938).
    The legal conclusion of obviousness turns on the fa-
miliar Graham factors, including the teachings of the
prior art and the differences between those teachings and
the claimed invention. Graham v. John Deere Co., 383
U.S. 1, 17–18 (1966). In assessing obviousness, we must
“look with care at a patent application that claims as
innovation the combination of two known devices accord-
ing to their established functions.” KSR Int’l Co. v. Tele-
flex Inc., 550 U.S. 398, 418 (2007). However, we also
exercise caution before holding a claimed invention obvi-
ous when combining references would violate the princi-
ple of operation of the modified reference. See In re
Mouttet, 686 F.3d 1322, 1332 (Fed. Cir. 2012) (discussing
In re Ratti, 270 F.2d 810, 813 (CCPA 1959)). This is
6   UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH



because a person of ordinary skill generally would not be
motivated to modify a reference by contradicting its basic
teachings, see id., or by making it “inoperable for its
intended purpose,” In re Gordon, 733 F.2d 900, 902 (Fed.
Cir. 1984).
     Maryland argues that because Weigl’s sensors are po-
sitioned outside the cultivation vessel, Weigl cannot be
modified in view of Bambot without “completely
chang[ing] the fundamental principle of operation of
Weigl.” Appellant’s Br. 20. When such a modification of a
reference is necessary, Maryland contends, it does not
support a determination of obviousness under Ratti, 270
F.2d at 813.
    Presens responds that Maryland misinterprets the
Board’s reliance on Weigl. According to Presens, the
Board did not conclude that claim 1 was obvious by modi-
fying the configuration of Weigl’s sensors; rather, the
Board, citing the examiner’s finding, relied on Weigl for
measuring multiple parameters and using a separate
detector and excitation source for each sensor. Presens
argues that the Board’s obviousness holding was based on
Bambot’s sensor configuration, not Weigl’s, so Maryland’s
application of Ratti is misplaced.
    We agree with Presens that Maryland misapplies Rat-
ti. A person of ordinary skill is “not an automaton,” KSR,
550 U.S. at 421, limited to physically combining refer-
ences, see Mouttet, 686 F.3d at 1332 (citing In re Etter,
756 F.2d 852, 859 (Fed. Cir. 1985) (en banc)). Even
assuming that extra-vessel sensors are a “basic principle”
of Weigl, Ratti, 270 F.2d at 813, that principle is inde-
pendent of Weigl’s pertinence to the Board’s obviousness
determination.    The Board found that Weigl taught
measuring multiple parameters and using a separate
detector and excitation source for each sensor. Substan-
tial evidence supports that finding. Figure 1 of Weigl
depicts a separate detector and excitation source for each
UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH   7



sensor membrane. J.A. 366. Weigl described each flow-
through unit as “independent,” id., and implemented
different types of excitation sources and detectors for
different sensors, J.A. 367, 369.
    The Board’s findings regarding Weigl are consistent
with Bambot’s principle of operation, as substantial
evidence also supports the Board’s findings that Bambot
taught intra-vessel sensors in addition to multiple types
of sensors, detectors, and excitation sources, and that
Bambot suggested measuring multiple analytes in culti-
vation vessels. For example, Bambot disclosed oxygen
sensors embedded within cultivation vessels, J.A. 130,
and stated that the oxygen sensors “performed satisfacto-
rily in a bioreactor environment,” J.A. 128–29. Bambot
also described other optical sensors for pH, carbon diox-
ide, and glucose, multiple types of excitation sources such
as blue LEDs and red laser diodes, and multiple detectors
such as photomultiplier tubes and semiconductor detec-
tors. J.A. 127–30. In its conclusion, Bambot indicated
that measurement of “oxygen (and other analytes)” in
cultivation vessels was feasible, J.A. 132, and proposed a
separate “multianalyte sensing system,” J.A. 131.
    Unlike in Ratti, we cannot say here that the “suggest-
ed combination of references would require a substantial
reconstruction and redesign of the elements shown” in
Bambot, or a “change in [its] basic principles.” 270 F.2d
at 813. Rather, Bambot and Weigl taught every element
of the claimed invention and the combination of the
references accords with their teachings. “The combina-
tion of familiar elements according to known methods is
likely to be obvious when it does no more than yield
predictable results.” KSR, 550 U.S. at 416. That is the
case here. Consequently, the Board did not err in con-
cluding that combining Bambot with Weigl rendered the
claims obvious, regardless of Weigl’s extra-vessel sensors.
8   UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH



    Maryland also argues that Weigl teaches away from
the claimed invention because: (1) Weigl’s carbon dioxide
sensor is unstable; (2) each of Weigl’s flow-through units
has only one sensor, not multiple sensors; (3) Weigl’s
various outlets are inconsistent with the claimed inven-
tion’s “continuous volume” limitation; and (4) Weigl’s
device is “invasive” because it requires extra-vessel sen-
sors.
    Presens responds that Maryland’s teaching away ar-
guments are not supported by the references’ teachings or
improperly attempt to distinguish Weigl from technical
features not in the claims.
    We agree with Presens that Maryland’s teaching
away arguments do not demonstrate Board error. Like its
argument based on the positioning of Weigl’s sensors,
Maryland’s teaching away arguments narrowly focus on
Weigl’s physical arrangement. But “mere disclosure of
alternative designs does not teach away.” In re Fulton,
391 F.3d 1195, 1201 (Fed. Cir. 2004). Rather, teaching
away requires “clear discouragement” from implementing
a technical feature. In re Ethicon, Inc., 844 F.3d 1344,
1351 (Fed. Cir. 2017).
    Maryland directs us to no such discouragement. Sub-
stantial evidence supports the Board’s finding that a
person of ordinary skill would not be limited to Weigl’s
unstable carbon dioxide sensor, but would instead look to
Bambot’s alternative carbon dioxide sensor. The same is
true regarding Weigl’s flow-through units, outlets, and
alleged invasiveness, as the Board’s finding that Bambot
taught cultivation vessels with sensors embedded inside,
which did not require flow-through units or outlets, is
supported by substantial evidence. See supra at 7. While
Weigl did adopt an “alternative design[]” to Bambot,
Fulton, 391 F.3d at 1201, it did not provide “clear discour-
agement” from monitoring carbon dioxide with a stable
UNIV. OF MD. BIOTECH   v. PRESENS PRECISION SENSING GMBH   9



sensor or from using intra-vessel sensors, Ethicon, 844
F.3d at 1344.
   We have considered Maryland’s remaining arguments
and find them unpersuasive.
                         CONCLUSION
    Because the Board did not err in concluding that the
combination of Bambot and Weigl renders the claims of
the ’532 patent obvious, we affirm. As such, we do not
reach Presens’s conditional cross-appeal.
                         AFFIRMED
