Case: 16-2745 Document: 16 Page: 1 Filed: 01/09/2017
`
`2016-2745, 2017-1057
`
`United States Court of Appeals
`for the Federal Circuit
`
`UNIVERSITY OF MARYLAND BIOTECHNOLOGY INSTITUTE,
`
`Appellant,
`
`v.
`
`PRESENS PRECISION SENSING GMBH,
`
`Cross-Appellant.
`
`Appeals from the United States Patent and Trademark Office,
`Patent Trial and Appeal Board in Reexamination No. 95/000,615
`
`OPENING BRIEF FOR APPELLANT
`UNIVERSITY OF MARYLAND BIOTECHNOLOGY INSTITUTE
`_____________________________________
`
`René A. Vazquez
`SINERGIA TECHNOLOGY LAW GROUP, PLLC
`18296 St. Georges Ct.
`Leesburg, VA 20176
`rvazquez@sinergialaw.com
`(571) 353-1520
`
`Counsel for Appellant
`UNIVERSITY OF MARYLAND
`BIOTECHNOLOGY INSTITUTE
`
`(888) 277-3259
`
`January 9, 2017
`
`COUNSEL PRESS, LLC
`
`

`

`Case: 16-2745 Document: 16 Page: 2 Filed: 01/09/2017
`
`CERTIFICATE OF INTEREST
`
`Counsel for Appellant certifies the following:
`
`1.
`
`The full name of the party represented by me is: University of
`
`Maryland Biotechnology Institute (“UMBI”).
`
`2.
`
`The names of the real parties in interest are: (a) University of
`
`Maryland Baltimore County (“UMBC”); and (b) Sartorius Stedim Biotech GmbH.
`
`3.
`
`Parent corporations and publicly held companies that own 10% or
`
`more of stock in the party represented by me: UMBI and UMBC are part of the
`
`University of Maryland system.
`
`4.
`
`The names of all law firms and the partners or associates that
`
`appeared for the party or amicus now represented by me in the trial court or agency
`
`or are expected to appear in this court (and who have not or will not enter an
`
`appearance in this case) are: None.
`
`i
`
`

`

`Case: 16-2745 Document: 16 Page: 3 Filed: 01/09/2017
`
`TABLE OF CONTENTS
`
`Page
`
`CERTIFICATE OF INTEREST............................................................................... i
`
`TABLE OF AUTHORITIES .................................................................................. iv
`
`STATEMENT OF RELATED CASES.................................................................. vi
`
`JURISDICTIONAL STATEMENT ........................................................................ 1
`
`STATEMENT OF THE ISSUES............................................................................. 2
`
`STATEMENT OF THE CASE................................................................................ 3
`
`I. STATUS OF CLAIMS.................................................................................. 3
`
`II. APPEAL TO THE PATENT TRIAL AND APPEAL BOARD................... 4
`
`III. THE CLAIMED SUBJECT MATTER......................................................... 5
`
`SUMMARY OF THE ARGUMENT ...................................................................... 8
`
`ARGUMENT ......................................................................................................... 10
`
`I. STANDARD OF REVIEW......................................................................... 10
`
`II. APPLICABLE LAW................................................................................... 10
`
`III. THE BOARD ERRED IN ITS OBVIOUSNESS ANALYSIS .................. 12
`
`A. A Prima Facie Case of Obviousness was not Established .................... 12
`
`1. The Weigl Reference......................................................................... 12
`
`2. The Bambot Reference...................................................................... 17
`
`3. The Proposed Modification of Weigl in View of Bambot Would
`Change the Principle of Operation of Weigl..................................... 20
`
`4. No Articulated Reasoning with Some Rational Underpinning to
`Support the Legal Conclusion of Obviousness................................. 21
`
`ii
`
`

`

`Case: 16-2745 Document: 16 Page: 4 Filed: 01/09/2017
`
`B. Weigl Teaches Away from the Claimed Invention................................ 22
`
`1. Weigl Teaches Away from In Situ, Non-Invasive Measurement
`of Cell Culture Parameters ................................................................ 22
`
`2. Weigl Teaches Away from the Use of More than One Sensing
`Membrane in a Single Flow-Through Cell or Single Cultivation
`Vessel ................................................................................................ 23
`
`3. The Board’s Finding that Weigl Does Not Teach Away from
`the Claimed Invention is Not Supported by Substantial
`Evidence ............................................................................................ 29
`
`CONCLUSION AND STATEMENT OF RELIEF SOUGHT ............................. 30
`
`ADDENDUM ................................................................................................. Appx1
`
`CERTIFICATE OF SERVICE
`
`CERTIFICATE OF COMPLIANCE
`
`iii
`
`

`

`Case: 16-2745 Document: 16 Page: 5 Filed: 01/09/2017
`
`TABLE OF AUTHORITIES
`
`Cases
`Flo Healthcare Sols., LLC v. Kappos,
`697 F.3d 1367 (Fed. Cir. 2012)............................................................................10
`
`Page
`
`Graham v. John Deere Co. of Kan. City,
`383 U.S. 1 (1966).................................................................................................10
`
`In re Adler,
`723 F.3d 1322 (Fed. Cir. 2013)..................................................................... 10, 29
`
`In re Elsner,
`381 F.3d 1125 (Fed. Cir. 2004)............................................................................10
`
`In re Gartside,
`203 F.3d 1305 (Fed. Cir. 2000)..................................................................... 10, 29
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997)............................................................................11
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994)......................................................................... 11, 23
`
`In re Haruna,
`249 F.3d 1327 (Fed. Cir. 2001)..................................................................... 11, 22
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006)..............................................................................11
`
`In re Malagari,
`499 F.2d 1297 (CCPA 1974) ...............................................................................11
`
`In re Ratti,
`270 F.2d 810 (CCPA 1959) .................................................................... 11, 21, 22
`
`In re Samour,
`571 F.2d 559 (CCPA 1978) .................................................................................16
`
`iv
`
`

`

`Case: 16-2745 Document: 16 Page: 6 Filed: 01/09/2017
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007).............................................................................................11
`
`Nat’l Steel Car, Ltd. v. Canadian Pac. Ry., Ltd.,
`357 F.3d 1319 (Fed. Cir. 2004)............................................................................10
`
`Schering Corp. v Geneva Pharm.,
`339 F.3d 1373 (Fed. Cir. 2003)............................................................................17
`
`Spectralytics, Inc. v. Cordis Corp.,
`649 F.3d 1336 (Fed. Cir. 2011)..................................................................... 10, 11
`
`Statutes
`
`28 U.S.C. § 1295(a)(4)(A) .........................................................................................1
`
`35 U.S.C. § 102(b) .....................................................................................................5
`
`35 U.S.C. § 103............................................................................................... 2, 5, 10
`
`35 U.S.C. § 103(a) .......................................................................................... 2, 5, 30
`
`35 U.S.C. § 112..........................................................................................................4
`
`35 U.S.C. § 112(a) .....................................................................................................4
`
`35 U.S.C. § 112(b) .....................................................................................................4
`
`35 U.S.C. § 141..........................................................................................................1
`
`35 U.S.C. § 142..........................................................................................................1
`
`35 U.S.C. § 314(a) .....................................................................................................4
`
`Regulations
`
`37 C.F.R. § 1.530 .......................................................................................................3
`
`37 C.F.R. § 1.530(f)(2) ..............................................................................................3
`
`37 C.F.R. § 1.983 .......................................................................................................1
`
`
`
`v
`
`

`

`Case: 16-2745 Document: 16 Page: 7 Filed: 01/09/2017
`
`STATEMENT OF RELATED CASES
`
`There are no related cases as defined in Federal Circuit Rule 47.5.
`
`vi
`
`

`

`Case: 16-2745 Document: 16 Page: 8 Filed: 01/09/2017
`
`JURISDICTIONAL STATEMENT
`
`On July 29, 2016, the Patent Trial and Appeal Board (“Board”) issued a
`
`Decision on Appeal in response to a Request for Rehearing filed by UMBI on
`
`January 28, 2016, in which the board denied UMBI’s request for rehearing.
`
`Appellant UMBI timely filed a Notice of Appeal on September 28, 2016 under 35
`
`U.S.C. §§ 141 and 142, and under 37 C.F.R. § 1.983. This Court has jurisdiction
`
`over this final decision under 28 U.S.C. § 1295(a)(4)(A).
`
`1
`
`

`

`Case: 16-2745 Document: 16 Page: 9 Filed: 01/09/2017
`
`STATEMENT OF THE ISSUES
`
`Whether the Board erred in concluding that claims 1, 3-6, 9-11, 13-16, 19
`
`and 20 of U.S. Patent No. 6,673,532 (“the ‘532 Patent”) are obvious under 35
`
`U.S.C. § 103(a) (pre-AIA) in view of Weigl1 and Bambot2.
`
`1 Bernhard H. Weigl et al., Optical triple sensor for measuring pH, oxygen and
`carbon dioxide, 32 journal of Biotechnology 127-138, 1994 (hereinafter “Weigl”).
`
`2 Shabbir B. Bambot et al., Potential applications of lifetime-based, phase-
`modulation fluorimetry in bioprocess and clinical monitoring, 13 TIBTECH 106-
`115, 1995 (hereinafter “Bambot”).
`
`2
`
`

`

`Case: 16-2745 Document: 16 Page: 10 Filed: 01/09/2017
`
`STATEMENT OF THE CASE
`
`On January 13, 2011, Presens filed a Request for Inter Partes
`
`Reexamination requesting reexamination of all claims (claims 1-20) of U.S. Patent
`
`No. 6,673,532 (“the ‘532 Patent”). Appx66. The ‘532 Patent is entitled “Bioreactor
`
`and Bioprocessing Technique” and issued on January 6, 2004. Appx41.
`
`I.
`
`STATUS OF CLAIMS
`
`On May 12, 2011, UMBI submitted an Amendment and Reply under 37
`
`C.F.R. § 1.530, in which claims 1, 3, 6, 11, 13 and 16 were amended, claims 2, 7,
`
`8, 12, 17 and 18 were canceled and new claims 21-31 were added. Appx248-264.
`
`On May 13, 2011, UMBI resubmitted the Amendment and Reply under 37 C.F.R.
`
`§ 1.530 to correct the formatting of the proposed claim amendments, in accordance
`
`with 37 C.F.R. § 1.530(f)(2). Appx273-293.
`
`On September 21, 2011, UMBI submitted an Amendment and Reply under
`
`37 C.F.R. § 1.951, which proposed further amendments to claims 1, 6, 11 and 16,
`
`and the cancelation of claims 21-31. Appx411-428.
`
`On November 25, 2012 UMBI submitted an Amendment and Reply under
`
`37 C.F.R. § 1.530, in which claims 1, 6, 11 and 16 were amended. Appx645-675.
`
`Claims 1, 3-6, 9-11, 13-16, 19 and 20 are pending and stand rejected. Claims
`
`1, 6, 11 and 16 are independent claims.
`
`3
`
`

`

`Case: 16-2745 Document: 16 Page: 11 Filed: 01/09/2017
`
`II.
`
`APPEAL TO THE PATENT TRIAL AND APPEAL BOARD
`
`On May 16, 2014, the Examiner issued a Right of Appeal Notice in which
`
`pending claims 1, 3-6, 9-11, 13-16, 19 and 20 stood finally rejected. The rejections
`
`were as follows:
`
`1. Claims 1, 3-6, 9-11, 13-16, 19 and 20 were rejected under 35 U.S.C. §
`
`314(a) as enlarging the scope of the claims of the patent being reexamined;
`
`2. Claims 1, 3-6, 9-11, 13-16, 19 and 20 were under 35 U.S.C. § 112(a) or 35
`
`U.S.C. § 112 (pre-AIA), first paragraph, as failing to comply with the
`
`written description requirement;
`
`3. Claims 1, 3-6, 9-11, 13-16, 19 and 20 were rejected under 35 U.S.C. 112(a)
`
`or 35 U.S.C. § 112 (pre-AIA), first paragraph, because the specification,
`
`while being enabling for processes using bioreactors, allegedly does not
`
`reasonably provide enablement for using a cultivation vessel comprising a
`
`single continuous volume;
`
`4. Claims 1, 3-6, 9-11, 13-16, 19 and 20 were rejected under 35 U.S.C. §
`
`112(b) or 35 U.S.C. § 112 (pre-AIA), second paragraph, as being indefinite
`
`for failing to particularly point out and distinctly claim the subject matter
`
`which the inventor or a joint inventor or, for pre-AIA, the applicant, regards
`
`as the invention;
`
`4
`
`

`

`Case: 16-2745 Document: 16 Page: 12 Filed: 01/09/2017
`
`5. Claims 1, 3 and 4 were rejected under pre-AIA 35 U.S.C. § 102(b) as
`
`anticipated by Weigl;
`
`6. Claims 1, 3-6, 9-11, 13-16, 19 and 20 were rejected under pre-AIA 35
`
`U.S.C. § 103(a) as obvious over Weigl in combination with Bambot;
`
`7. Claims 1, 3 and 4 were rejected under pre-AIA 35 U.S.C. § 103(a) as
`
`obvious over Weigl in combination with European Patent Application 0 333
`
`253 (hereinafter “EP ‘253”); and
`
`8. Claims 5, 6, 9-11, 13-16, 19 and 20 were rejected under pre-AIA 35 U.S.C.
`
`§ 103(a) as obvious over Weigl in combination with EP ‘253 as applied to
`
`claims 1, 3 and 4, and further in view of Bambot.
`
`Appx861.
`
`UMBI appealed all 8 of the above-listed rejections to the Patent Trial and
`
`Appeal Board. Appx913-915. The Board reversed rejections 1-5, affirmed
`
`rejection 6, and did not reach a decision on rejections 7 and 8 because rejection 6,
`
`which was affirmed, covers all the pending claims. Appx1-29.
`
`UMBI filed a Request for Rehearing, which the Board rejected. Appx30-36.
`
`III. THE CLAIMED SUBJECT MATTER
`
`The ‘532 Patent claims a novel and nonobvious system for the in situ and
`
`non-invasive measurement of multiple parameters of a cell culture while the cell
`
`culture is in a cultivation vessel, without having to remove samples of the cell
`
`5
`
`

`

`Case: 16-2745 Document: 16 Page: 13 Filed: 01/09/2017
`
`culture from the cultivation vessel in order to perform a measurement. Appx41
`
`(Abstract), Appx49, Appx61 (12:28-36, 48-51).
`
`Claims 1, 6, 11 and 16 are independent claims. However, claim 1 recites key
`
`features present in all the independent claims, and is reproduced below:
`
`A method of measuring at least two cultivation
`1.
`parameters in a cell culture, comprising:
`
`(a) providing a cultivation vessel, wherein the cultivation
`vessel comprises,
`
`walls that define a single continuous volume or a non-
`planar surface that defines a single continuous volume, and
`
`at least two types of optical chemical sensors positioned
`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 define the single continuous volume of the
`cultivation 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 generate
`emission and/or light absorption, wherein the optical chemical
`sensors are excited using at least one excitation source per
`optical chemical sensor;
`
`(e) detecting the emission and/or absorption generated by
`the optical chemical sensors in (d) by at least one detector for
`each type of optical chemical sensor used; and
`
`6
`
`

`

`Case: 16-2745 Document: 16 Page: 14 Filed: 01/09/2017
`
`(f) analyzing the detected emission and/or absorption
`detected in (e) to assess the at least two cultivation parameters
`measured.
`
`All the independent claims recite providing a cultivation vessel that
`
`comprises walls that define a single continuous volume or a non-planar surface that
`
`defines a single continuous volume and at least two types of optical chemical
`
`sensors positioned within the single continuous volume.
`
`A continuous culture medium is placed 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 define the single continuous volume of the cultivation
`
`vessel or the non-planar surface that defines the single continuous volume of the
`
`cultivation vessel. The optical chemical sensors are positioned such that they are in
`
`contact with the continuous culture medium.
`
`A cell culture is established in the continuous culture medium, and the
`
`optical chemical sensors are excited, using at least one excitation source per optical
`
`chemical sensor, to generate emission and/or light absorption. The emission and/or
`
`absorption generated by the optical chemical sensors is detected by at least one
`
`detector for each type of optical chemical sensor used. The detected emission
`
`and/or absorption is analyzed to assess the at least two cultivation parameters
`
`measured. Appx646-650, Appx1005, Appx1006-1008, Appx1009-1010.
`
`7
`
`

`

`Case: 16-2745 Document: 16 Page: 15 Filed: 01/09/2017
`
`SUMMARY OF THE ARGUMENT
`
`The Board’s affirmance of the Examiner’s obviousness rejection based on
`
`Weigl and Bambot is inconsistent with the Board’s conclusions regarding the
`
`teachings of Weigl, inconsistent with the Examiner’s conclusions regarding the
`
`teachings of Bambot, and fails to give proper weight to teachings in Weigl that
`
`explicitly teach away from the claimed invention and teach away from the system
`
`taught by Bambot.
`
`The Board conceded that Weigl provides no teaching and no enablement
`
`with regards to how its three separate sensor units would be positioned inside a
`
`single cultivation vessel, nor any teaching as to how the inlet and waste outlet of
`
`each sensor unit would be configured with respect to a cultivation vessel to form a
`
`continuous volume, as required by the claims. Further, the Examiner conceded that
`
`Bambot fails to teach how multiple light sources, sensors and detectors would be
`
`arranged to meet the claimed invention.
`
`In spite of this lack of teaching in both Weigl and Bambot as to how
`
`multiple chemical sensors with respective light sources and detectors would be
`
`arranged in a common cultivation vessel, the Board erroneously, as a matter of
`
`law, concluded that the Weigl and Bambot references render the claims obvious.
`
`The Board also erred by concluding that Weigl does not teach away from the
`
`claimed invention, even though the core principle of operation of Weigl’s system is
`
`8
`
`

`

`Case: 16-2745 Document: 16 Page: 16 Filed: 01/09/2017
`
`based on drawing a sample from a cell culture environment and passing it through
`
`flow-through cells (which house the chemical sensors). This core principle of
`
`operation is completely counter to the core principle of operation of the claimed
`
`invention, which is monitoring multiple cell culture parameters in the sterile
`
`environment of a cultivation vessel without having to draw and transport samples
`
`from the cell culture to a remote sensor. Weigl further teaches away from the
`
`claimed invention by explicitly discouraging the placement of multiple sensor
`
`membranes in the cultivation vessel that contains the cell culture.
`
`In short, a person of ordinary skill in the art, upon reading the Weigl
`
`reference, would have been led in a direction that diverges from the path taken by
`
`the inventor of the ‘532 Patent.
`
`9
`
`

`

`Case: 16-2745 Document: 16 Page: 17 Filed: 01/09/2017
`
`I.
`
`STANDARD OF REVIEW
`
`ARGUMENT
`
`Obviousness under 35 U.S.C. § 103 is a question of law based on underlying
`
`findings of fact. Flo Healthcare Sols., LLC v. Kappos, 697 F.3d 1367, 1375 (Fed.
`
`Cir. 2012) (citing cases). This Court reviews the Board’s legal conclusions de
`
`novo. In re Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004).
`
`Factual findings of the Board are reviewed under the substantial evidence
`
`standard of review. In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000). Evidence
`
`is substantial “if a reasonable mind might accept it as adequate to support the
`
`finding.” In re Adler, 723 F.3d 1322, 1325 (Fed. Cir. 2013).
`
`“Whether the prior art teaches away from the claimed invention is a question
`
`of fact.” Spectralytics, Inc. v. Cordis Corp., 649 F.3d 1336, 1343 (Fed. Cir. 2011).
`
`II.
`
`APPLICABLE LAW
`
`Obviousness under Section 103 hinges on four fact driven findings: “(1) the
`
`scope and content of the prior art; (2) the differences between the prior art and the
`
`claims; (3) the level of ordinary skill in the art; and (4) objective evidence of
`
`nonobviousness.” Nat’l Steel Car, Ltd. v. Canadian Pac. Ry., Ltd., 357 F.3d 1319,
`
`1334 (Fed. Cir. 2004) (citing Graham v. John Deere Co. of Kan. City, 383 U.S. 1,
`
`17-18 (1966)). “There must be some articulated reasoning with some rational
`
`underpinning to support the legal conclusion of obviousness.” KSR Int’l Co. v.
`
`10
`
`

`

`Case: 16-2745 Document: 16 Page: 18 Filed: 01/09/2017
`
`Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441 F.3d 977, 988
`
`(Fed. Cir. 2006)).
`
`If a proposed modification of a prior art invention or a combination of a
`
`prior art reference with another prior art reference would change the principle of
`
`operation of the prior art invention being modified, then the teachings of the
`
`references are not sufficient to render the claims prima facie obvious. In re Ratti,
`
`270 F.2d 810, 813 (CCPA 1959).
`
`“A prima facie case of obviousness can be rebutted if the applicant . . . can
`
`show ‘that the art in any material respect taught away’ from the claimed
`
`invention.” In re Haruna, 249 F.3d 1327, 1335 (Fed. Cir. 2001) (quoting In re
`
`Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Malagari, 499 F.2d
`
`1297, 1303 (CCPA 1974))). “A reference may be said to teach away when a person
`
`of ordinary skill, upon reading the reference, . . . 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). “[I]n general, a reference will teach away if it suggests
`
`that the line of development flowing from the reference’s disclosure is unlikely to
`
`be productive of the result sought by the applicant.” Id.
`
`“‘Teaching away’ does not require that the prior art foresaw the specific
`
`invention that was later made, and warned against taking that path.” Spectralytics,
`
`649 F.3d at 1343. “It is indeed of interest if the prior art warned against the very
`
`11
`
`

`

`Case: 16-2745 Document: 16 Page: 19 Filed: 01/09/2017
`
`modification made by the patentee, but it is not the sole basis on which a trier of
`
`fact could find that the prior art led away from the direction taken by the patentee.”
`
`Id.
`
`III. THE BOARD ERRED IN ITS OBVIOUSNESS ANALYSIS
`
`A.
`
`A Prima Facie Case of Obviousness was not Established
`
`1.
`
`The Weigl Reference
`
`Weigl discloses an “optical triple sensor” that utilizes a “flow-through cell
`
`unit.” Appx366 at Figure 1. The “flow-through cell unit,” in turn, is made up of
`
`three discreet, individual flow-through cells, with each flow-through cell
`
`containing a single chemical sensor. Appx366-367. Weigl does not get into any
`
`detail regarding the possible applications for the optical triple sensor. Weigl does
`
`mention that the optical triple sensor is intended for use in bioreactors, however,
`
`there is absolutely no teaching regarding how the optical triple sensor would be
`
`connected to a bioreactor or cultivation vessel and how the measurements would
`
`take place. Indeed, the illustrations in Weigl do not even show a bioreactor or a
`
`cultivation vessel, nor does Weigl even present data related to actual bioreactor
`
`use.
`
`This is because the optical triple sensor in Weigl is not designed to be
`
`incorporated in a bioreactor or cultivation vessel. Rather, a sensor membrane is
`
`positioned in a flow-through cell, and is designed to work by receiving a cell
`
`12
`
`

`

`Case: 16-2745 Document: 16 Page: 20 Filed: 01/09/2017
`
`culture sample that is taken from a remote location and pumped through the flow-
`
`through cell.
`
`The flow-through cell embodiments shown in Figures 2 and 3 of Weigl
`
`(reproduced below) confirm this. Figure 2 illustrates the flow-through cell
`
`configuration that is used for measurement of pH or carbon dioxide, and Figure 3
`
`illustrates the flow-through cell configuration for measurement of oxygen.
`
`Appx367.
`
`13
`
`

`

`Case: 16-2745 Document: 16 Page: 21 Filed: 01/09/2017
`
`The sample enters the flow-through cells via a “steel ferrule” along a path
`
`that is marked with the word “sample”. The sample then flows through the cell and
`
`exits via another “steel ferrule” along a path labeled “waste”. The caption of Figure
`
`2 also confirms that it is a sample that is passed through the flow-through cell. The
`
`caption states, inter alia, “[m]ost of the light from the LED is reflected on the
`
`boundary between the sensor membrane and the sample solution . . .” Appx367
`
`(emphasis added).
`
`This “sample” has to originate from somewhere, and that somewhere is
`
`physically separated from the optical triple sensor since the figures show that it is
`
`routed to the flow-through cell via steel ferrules. Accordingly, Weigl necessarily
`
`separates the optical triple sensor from the source of the sample being measured.
`
`The fact that the optical triple sensor is designed to be a remote sensor (i.e.,
`
`14
`
`

`

`Case: 16-2745 Document: 16 Page: 22 Filed: 01/09/2017
`
`positioned outside of a cultivation vessel) is further confirmed by Figure 4 of
`
`Weigl, which is reproduced below. Appx368.
`
`The configuration of Figure 4 was used by Weigl to characterize the
`
`performance of the sensing membranes, however, it provides the only teaching by
`
`Weigl as to how Weigl's sensor could be used in conjunction with a cultivation
`
`vessel. In view of this teaching, one would necessarily conclude that the cultivation
`
`15
`
`

`

`Case: 16-2745 Document: 16 Page: 23 Filed: 01/09/2017
`
`vessel would take the place of either the calibration gas container (a) or the buffer
`
`solution container (b). Thus, like the samples from the calibration gas container (a)
`
`or the buffer solution container (b), samples from a cell culture in the cultivation
`
`vessel would be directed to the flow-through cell for measurement using the motor
`
`valve and the peristaltic pump.
`
`What is abundantly clear about the Weigl sensor is that it operates in an
`
`entirely different manner than the claimed invention. The primary difference is that
`
`the optical triple sensor resides outside the container that holds the solution being
`
`measured, and is designed to work by drawing samples of the solution being
`
`measured and sending the samples to the individual flow-through cells that make
`
`up the optical triple sensor.
`
`Indeed, the Board concluded that Weigl provides no teaching as to how the
`
`individual flow-through cells would be positioned inside a single cultivation
`
`vessel:
`
`“While Weigl mentions ‘testing and using the sensors in bioreactors’
`(FF6), the only configuration of the triple sensor unit described in
`Weigl is of a housing containing three separate units, with an inlet for
`a sample and outlet for waste for each unit. FF1, FF3, FF5. The
`disclosure provides no explaination [sic] as to how this configuration
`would be positioned with respect to a cultivation vessel as required by
`the claim . . . Weigl does not enables [sic] placing the housing
`comprising all three triple sensor units inside a single cultivation
`vessel as required by the claims.”
`
`Appx20 (citing In re Samour, 571 F.2d 559 (CCPA 1978); Schering Corp. v
`
`16
`
`

`

`Case: 16-2745 Document: 16 Page: 24 Filed: 01/09/2017
`
`Geneva Pharm., 339 F.3d 1373, 1381 (Fed. Cir. 2003)).
`
`2.
`
`The Bambot Reference
`
`Bambot is a review article directed at surveying the use of lifetime-based,
`
`phase-modulation fluorimetry for bioprocess and clinical monitoring, and thus
`
`focuses on the chemistry and physics of lifetime–based, phase-modulation
`
`fluorimetry. To this end, Bambot shows various rudimentary and generalized
`
`examples of parameter monitoring utilizing fluorimetry techniques as a proof of
`
`concept.
`
`Although Bambot describes various optical sensors that can be used for
`
`oxygen, pH, pCO2 and glucose sensing, the generalized and conceptual examples
`
`of systems for optical monitoring of parameters are limited to: (1) a probe
`
`containing one chemical sensor, one excitation source and one emission detector
`
`(Figure 1); (2) a conceptual drawing showing a sensor patch for glucose
`
`monitoring, excitation light entering the sensor patch area and emission light
`
`exiting the sensor patch area (Figure 2); (3) several spinner flasks each with a
`
`single silicone oxygen sensor patch attached to the interior and in contact with the
`
`culture medium, which are excited by a single blue excitation source and whose
`
`emission is detected by a single photo multiplier tube (Figure 3); and (4) a
`
`conceptual drawing of a blood-gas instrument that utilizes a single laser diode light
`
`17
`
`

`

`Case: 16-2745 Document: 16 Page: 25 Filed: 01/09/2017
`
`source for exciting O2, CO2 and pH sensor patches whose emission is detected by
`
`a single detector.
`
`Bambot provides no teaching regarding the use of multiple types of chemical
`
`sensors with respective optical excitation sources and emission detectors, in which
`
`the chemical sensors are in contact with a continuous culture medium that resides
`
`within the single continuous volume of the cultivation vessel. Bambot discloses the
`
`existence of different types of chemical sensors for the monitoring of different
`
`types of cultivation parameters, but all of the examples given with respect to the
`
`monitoring of cultivation parameters involve a single chemical sensor in contact
`
`with the culture medium, a single excitation source and a single detector for
`
`detecting the emission from the chemical sensor.
`
`The only example given that shows the monitoring of multiple parameters is
`
`in the context of a blood-gas instrument, not a culture vessel (Figure 4 of Bambot).
`
`Appx131-132. In the blood-gas instrument shown in Figure 4, which is reproduced
`
`below, a probe containing multiple chemical sensors is inserted into the body in
`
`order to measure various parameters in the blood stream, which is clearly an
`
`invasive application that is not applicable to non-invasive monitoring of cell
`
`culture parameters in a cultivation vessel.
`
`18
`
`

`

`Case: 16-2745 Document: 16 Page: 26 Filed: 01/09/2017
`
`Furthermore, even in the blood-gas instrument shown in this example, a
`
`single excitation source is used for all three chemical sensors shown and a single
`
`detector is shown for detecting the emission from all three chemical sensors.
`
`Indeed, the Examiner conceded that Bambot fails to teach how multiple light
`
`sources, sensors and detectors would be arranged to meet the claimed invention:
`
`“[T]here is no teaching of simultaneous monitoring in a single
`spinner flask of at least two parameters using at least one
`individual detector, light source and sensor for each parameter .
`
`19
`
`

`

`Case: 16-2745 Document: 16 Page: 27 Filed: 01/09/2017
`
`. . [e]ven if it could be implied from Bambot that several
`different parameters could be monitored in a single bioreactor,
`there is no clear teaching of how a light source, sensor and
`detector would be arranged to meet the claimed invention.”
`
`Appx388 (emphasis added).
`
`3.
`
`The Proposed Modification of Weigl in View of Bambot Would
`Change the Principle of Operation of Weigl
`
`The primary reference used by the Examiner to support the obviousness
`
`rejection is the Weigl reference. Appx867-870. Thus, the Examiner’s argument is
`
`that the deficiencies in Weigl can be remedied by the Bambot reference.
`
`As discussed supra, Weigl discloses an optical triple sensor that resides
`
`outside the container that holds the solution being measured, and is designed to
`
`work by drawing samples of the solution being measured and sending the samples
`
`to the individual flow-through cells that make up the optical triple sensor. In
`
`contrast, Bambot discloses the use of a single chemical sensor in contact with a
`
`culture medium for monitoring a single cell culture parameter.
`
`Modifying Weigl in view of Bambot to obtain the claimed invention would
`
`completely change the fundamental principle of operation of Weigl. Namely,
`
`Weigl would have to be changed from a remote sensing system that d