N OTE : This disposition is nonprecedential. 

# United States **Court of Appeals**  **for the Federal Circuit**

______________________
UNIVERSITY OF MARYLA ND BIOTECHNOLOGY INSTITUTE, Appellant

v.

PRESENS PRECISION SE NSING GMBH, Cross

- Appellant

______________________

2016

- 2745, 2017

- 1057

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

______________________
Deci ded: November 3 , 2017

______________________

R ENE A. V AZQUEZ , Sinergia Technology Law Group, PLLC, Leesburg, VA, argued for appellant.

M ICHAEL S TEVEN C ULVER , Millen, White, Zelano & Branigan PC, Arlington, VA, argued for cross

- appellant.

______________________
Before L OURIE , O’M ALLEY , and T ARANTO , Circuit Judges

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L OURIE , 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 G mb H 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

. B ACKGROUND Maryland owns t he ’532 patent , which covers methods of measuring parameters in cell culture. Cell culture is a widely used technique to cultivate cells in vitro

. P aram eters 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.

T he ’532 patent discloses an optical method of mon itoring 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 cultiva tion 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).U NIV

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excitation source such as a light

- emitting diode (“ LED ”) shines on the sensors , the sensors emit light correspon ding to the concentration of the relevant analytes. Dete ctors such a s photomultiplier tube s then measure the light emitted by the sensors. Id. col. 4 l. 57

– col. 5 l. 10. Appellee Presens Precision Sensing (“Presens”) pet itioned for inter partes reexamin ation 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 cul ti vation parameters in a cell culture, compri s ing: (a) provid ing a cultivation vessel, wherein the cu ltivation vessel comprises, walls that define a si ngle continuous volume or a non

- planar surface that defines a single contin u ous volume, and at lea st two types of optical chemical senso rs pos itioned 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 d efine the single co n tinuous volume of the cultiv ation vessel or the non

- planar surface that defines the si n gl e continuous volume of the cul tivation

ve s se l , 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 contin u ous culture medium; (d) exciting the optical chemical sensors to gene rate emission and/or light absorption, wherein the optical chemical sensors are ex cited using at least one excitation source per optical chemical sensor ;U NIV

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(e) detecting the emission and/or absorption ge nerated by the at least two optical chem i cal sensors in (d) by at least one detector for each type of opt ical chemical sensor used; and (f) analyzing the detected emission and/or absor ption detected in (c) to asse ss the at least two cult ivation parameters measured.

J.A. 646

– 47, 1005

. The e xaminer rejected the claims as, inter alia , obv ious over Shabbir B. Bambot et al., Potential Applications of Lifetime

- Based, Phase

- Modulation Fluorimetry in Bioprocess and Clinica l Monitoring , 13 Trends in Bi otechnology 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 an aly tes 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 c ultivation vessels housed sensors excitable by several types of exc itation sources , and the sensors’ emissions could be mea sured 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 e xaminer concluded that the claims of the ’532 patent would have been obvious over the refe rences at the time the invention was made

. The Board affirmed the e xaminer’s obviousness reje ction. The Board agreed that Bambot taught placing sensors inside a cultivation vessel, and also disclosedU NIV

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multiple types of sensors, detectors, and exci tation sources. Furthermore, the Board found that Weigl taught monitoring multiple parameters using a separate detector and excitation source for each type of sensor. Cons equently, the Board concluded that “it would have been obvious to arrange more than one sensor inside a cultiv ation 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).

D ISCUSSION
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 u nderlying those determinations for substantial evidence, In re Gartside , 203 F.3d 1305, 1316 (Fed. Cir. 2000). A finding is supported by substa ntial evidence if a reasonable mind might accept the ev idence as adequate to support the finding. Consol. Ediso n Co. v. NLRB , 305 U.S. 197, 229 (193 8).
The legal conclusion of obviousness turns on the familiar 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, w e must “look with care at a patent application that claims as innovation the combination of two known devices accor ding to their established functions.” KSR Int ’ l Co. v. Tel eflex Inc. , 550 U.S. 398, 4 18 (2007). However, we also exercise caution before holding a claimed invention obv ious when combining references would violate the princ iple of operation of the modified reference

. S ee In re Mouttet

, 686 F.3d 1322, 1332 (Fed. Cir. 2012) (discussing In re Ratti , 270 F.2d 810, 813 (CCPA 1959)). This isU NIV

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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 Gord on , 733 F.2d 900, 902 (Fed. Cir. 1984).
Maryland argues that because Weigl’s sensors are p ositioned 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, t he Board did not conclude that claim 1 was obvious by mod ifying the configuration of Weigl’s sensors ; r ather, the Board, citing the e xaminer’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 Ra tti

. A person of ordinary skill is “not an automaton,” KSR

, 550 U.S. at 421, limited to physically combining refe rences, see Mouttet , 686 F.3d at 1332 (citing In re Etter

, 756 F.2d 852, 859 (Fed. Cir. 198 5) (en banc)). Even assuming that extra

- vessel sensors are a “basic principle” of Weigl, Ratti , 270 F.2d at 813, that principle is ind ependent of Weigl’s pertinence to the Board’s obviousness determination. The Board found that Weigl taught measuring mul tiple parameters and using a separate detector and excitation source for each sensor. Substa ntial evidence supports that finding. Figure 1 of Weigl depicts a separate detector and excitation source for eachU NIV

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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 substantia l evidence also supports the Board ’s finding s 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 cult ivation vessels

. For example, B ambot disclosed oxygen sensors embedded within cultivation vessels, J.A. 130

, and stated that the oxygen sensor s “performed satisfact orily in a bioreactor environment,” J.A. 128

– 29

. Bambot also described other optical sensors for pH, carbon dio xide, and glucose , multiple types of excitation sources such as blue LEDs and red laser diodes

, and multiple detectors such as photomultiplier tubes and semiconductor dete ctors

. J.A. 127

– 30

. In its conclusion, Bambot indicated that measurement of “oxygen (and othe r 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 “sugges ted combination of references would require a substantial reconstruction and re design 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 tea c hings . “The combin atio n 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 co ncluding that combining Bambot with Wei gl rendered the claims obvious, regardless of Weigl’s extra

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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 inve ntion’s “continuous volume” limitation ; and (4) Weigl’s device is “invasive” because it requires extra

- vessel se nsors. Presens responds that Maryl and’s teaching away a rguments are not supported by the reference s’ teachings or im properly 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 argument s 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. Su bstantial 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 des ign[]” to Bambot, Fulton , 391 F.3d at 1201 , it did not provide “clear discou ragement” from monitoring carbon dioxide with a stableU NIV

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sensor or from using intra

- vessel sensors

, Ethicon , 844 F.3d at 1344

. We have considered Maryland’s remaining arguments and find them unpersuasive.

C ONCLUSION
Because the Board did not err in concluding that the combination of Bambot and Weigl render s the claims of the ’532 patent obvious, we affirm

. As such, we do not reach Presens’ s conditional cross

- appeal.

AFFIRMED