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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`THERMO FISHER SCIENTIFIC INC.
`Petitioner
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`v.
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`Bio-Rad Laboratories, Inc.
`Patent Owner
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`
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`Patent No. 8,236,504
`Issued: August 7, 2012
`Filed: June 30, 2010
`Inventors: Kordunsky et al.
`Title: SYSTEMS AND METHODS FOR FLUORESCENCE DETECTION
`WITH A MOVABLE DETECTION MODULE
`
`
`
`
`
`Inter Partes Review No. – IPR2017-00055
`_______________
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,236,504
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.123
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`Agilent Exhibit 1250
`Page 1 of 62
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`I.
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`II.
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`III.
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`TABLE OF CONTENTS
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`Statement of the precise relief requested and the reasons therefor (37
`C.F.R. § 42.22(A)) .......................................................................................... 1
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`The '504 Patent disclosure and claims ............................................................ 1
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`Person of ordinary skill in the art ................................................................... 2
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`IV. Claim construction .......................................................................................... 3
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`V.
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`Identification of the challenge (37 C.F.R. § 42.104(b)) ................................. 3
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`VI. Ground 1: Claims 1-3, 6-11, 13-17, 19, 20 and 22 would have been
`obvious in view of Pantoliano, Miller, and Gambini under pre-AIA
`§103(a) ............................................................................................................ 5
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`VII. Ground 2: Claim 21 would have been obvious in view of Pantoliano,
`Miller, Gambini and Li under pre-AIA §103(a) ........................................... 38
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`VIII. Ground 3: Claims 1-3, 6-7, 10, 13, 15-16, 19, 20 and 22 would have
`been obvious in view of Iwasaki, Pantoliano and Gambini under pre-
`AIA §103(a) .................................................................................................. 39
`
`IX. Ground 4: Claims 9, 11, 14 and 17 would have been obvious over
`Iwasaki, Pantoliano and Gambini in view of Miller under pre-AIA
`§103(a) .......................................................................................................... 56
`
`X. Ground 5: Claim 21 would have been obvious over Iwasaki,
`Pantoliano and Gambini in view of Li under pre-AIA §103(a) ................... 56
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`XI. Objective indicia do not support patentability .............................................. 56
`XII. Certification that the patent may be contested via inter partes review
`by the Petitioner and standing (37 C.F.R. § 42.104(a)) ................................ 57
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`XIII. Mandatory notices (37 C.F.R. § 42.8(a)(1)) ................................................. 57
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`XIV. Conclusion .................................................................................................... 58
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`Agilent Exhibit 1250
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`I.
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`IPR2017-00055 of USPN 8,236,504
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`Statement of the precise relief requested and the reasons therefor
`(37 C.F.R. § 42.22(A))
`Thermo Fisher Scientific Inc. petitions for Inter Partes Review, seeking
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`
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`cancellation of claims 1-3, 6-11, 13-17 and 19-22 of U.S. Patent No 8,236,504 to
`Kordunsky et al. ("the '504 Patent," Ex. 1001), which on its face indicates that the
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`assignee is Bio-Rad Laboratories, Inc. (no assignment recorded for this patent). As
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`detailed below, claims 1-3, 6-11, 13-17 and 19-22 are unpatentable for
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`obviousness.
`II. The '504 Patent disclosure and claims
`The '504 Patent, titled "Systems And Methods For Fluorescence Detection
`
`With A Movable Detection Module," issued on Aug. 7, 2012, from U.S. App. No.
`
`12/827,521, filed on Jun. 30, 2010. Ex. 1001. The '504 Patent claims priority to
`
`App. No. 11/555,642 filed Nov. 1, 2006, which is a continuation of App. No.
`10/431,708, filed May 8, 2003. Id.
`The '504 Patent claims. The '504 Patent has 22 claims, including
`
`independent claims 1 and 13. Exemplary claim 1 is provided below:
`
`1. A fluorescence detection apparatus for analyzing samples located in a
`plurality of wells in a thermal cycler, the apparatus comprising:
`a support structure attachable to the thermal cycler;
`a shuttle movably mounted on the support structure; and
`a detection module attached to the shuttle, the detection module
`including:
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`a housing having an opening oriented toward the plurality of wells;
`an excitation light generator disposed within the housing; and
`an emission light detector disposed within the housing,
`wherein, when the support structure is attached to the thermal cycler, a
`heating element is disposed between the detection module and the sample wells
`and the shuttle is movable to position the detection module in optical
`communication with different wells of the plurality of wells through a plurality
`of openings extending through the heating element.
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`Independent claim 13 is similar, but indicates among other things that the
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`support is disposed within an exterior housing. Ex. 1001, claim 13.
`III. Person of ordinary skill in the art
`A person of ordinary skill in the art ("artisan") is a hypothetical person who
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`is presumed to be aware of all pertinent art, thinks along conventional wisdom, and
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`has ordinary creativity. An artisan in the field of the '504 Patent (optical detection
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`devices) would have known the literature concerning the design and manufacture
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`of analytical instruments for biological applications, which included optical
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`detection devices and scanning assemblies, such as thermal cyclers, sequencers,
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`microarray readers, fluorimeters, plate readers and scanners before May 8, 2003.
`
`Ex. 1002, ¶13.
`
`Regarding the claimed subject matter, an artisan would typically have had (i)
`an undergraduate degree (e.g., B.Sc. or B.A.) in optics, physics, engineering (e.g.,
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`mechanical, electrical or structural), physical chemistry, chemistry, biology or the
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`engineering, biological or chemical sciences, and have had at least about one year's
`experience in the design or manufacture of biological analytical instruments, e.g.,
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`IPR2017-00055 of USPN 8,236,504
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`thermocyclers and scanners. Also, an artisan may have worked as part of a
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`multidisciplinary team and drawn upon not only his or her own skills, but of others
`on the team, e.g., to solve a given problem. For example, a physicist, biologist,
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`chemist and/or an optical engineer may have been part of a team. Ex. 1002, ¶14.
`IV. Claim construction
`No construction is needed, in accordance with 37 C.F.R. § 42.100(b), the
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`terms are given their broadest reasonable interpretations (BRI) in view of the
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`specification and file history. These interpretations are consistent with the claim
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`constructions in Petitioner's concurrent petition IPR2017-00054 against the same
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`claims on other grounds.
`V.
`Identification of the challenge (37 C.F.R. § 42.104(b))
`Petitioner requests inter partes review of claims 1-3, 6-11, 13-17, 19-22 of
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`the '504 Patent based on the unpatentability grounds summarized in the index
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`below. Per 37 C.F.R. § 42.6(c), copies of the cited references accompany the
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`Petition.
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`Ground
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`1
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`2
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`35 U.S.C. §
`(pre-3/16/2013)
`§103(a)
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`§103(a)
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`Index of References
`Pantoliano, Miller and
`Gambini
`Pantoliano, Miller,
`Gambini and Li
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`Claims
`1-3, 6-11, 13-17,
`19, 20, 22
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`21
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`IPR2017-00055 of USPN 8,236,504
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`3
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`4
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`§103(a)
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`§103(a)
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`1-3, 6-8, 10, 13,
`15-16, 19, 20, 22
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`9, 11, 14 and 17
`
`Iwasaki, Pantoliano and
`Gambini
`Iwasaki, Pantoliano,
`Gambini and Miller
`Iwasaki, Pantoliano,
`5
`§103(a)
`21
`Gambini and Li
`U.S. Pat. 6,303,322 ("Pantoliano") published Oct. 16, 2001, and is prior art
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`under pre-AIA §102(b). Pantoliano discloses a thermal cycler for PCR, and is
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`better art than another patent also to Pantoliano applied during prosecution, which
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`does not disclose a thermal cycler for PCR (U.S. Pat. 6,569,631). Ex. 1005, 42:57-
`62, Ex. 1027; Ex. 1002, ¶30. U.S. Pat. 5,528,050 ("Miller") published on Jun. 18,
`1996, and is prior art under pre-AIA §102(b). WO 99/60381 ("Gambini ")
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`published on Nov. 25, 1999, and is prior art under pre-AIA §102(b). Japanese
`Patent Pub. No. P2001-242081A ("Iwasaki," certified translation provided)
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`published on Sep. 7, 2001, and is prior art under pre-AIA §102(b). Chinese Patent
`Publ. No. CN1379236A ("Li," certified translation provided) published in Chinese
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`on Nov. 13, 2002, and is prior art under pre-AIA §102(a).
`
`Each claim is challenged under two non-redundant Grounds, one based on
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`Pantoliano as primary reference and the other on Iwasaki as primary. Pantoliano
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`discloses a scanning cycler with a generator and detector placed outside the optics
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`head; it would have obvious to place these in-head as a well-known alternative. In
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`contrast, Iwasaki discloses a self-contained optics head with the generator/detector
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`placed in-head; it would have been obvious to use such an optics head in thermal
`cyclers for scanning purposes. Thus, the Grounds are not redundant. The
`Grounds are also not redundant over other Grounds submitted in Petitioner's
`concurrent petition IPR2017-00054 against the same claims, since the Grounds
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`herein are generally based on prior art under pre-AIA §102(b) under the asserted
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`priority date, unlike the Grounds in the other petition. This Petition is supported by
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`a declaration of Petitioner's expert, Professor Richard Mathies (Ex. 1002).
`VI. Ground 1: Claims 1-3, 6-11, 13-17, 19, 20 and 22 would have been
`obvious in view of Pantoliano, Miller, and Gambini under pre-AIA
`§103(a)
`As shown below, claims 1-3, 6-11, 13-17, 19, 20 and 22 would have been
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`obvious over the combination of Pantoliano, Miller, and Gambini. The references
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`together disclosed all elements of the claims, and there were many reasons to
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`combine their teachings, making the claims obvious by their asserted priority date
`of 2003. A detailed Graham analysis is provided below for representative claim 1
`and is also applicable to the other claims as well. Graham v. John Deere Co., 383
`
`U.S. 1 (1966).
`A) The first two Graham inquiries: Determining the scope and content
`of the prior art and ascertaining the differences from the claims: The scope
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`and content of the art is such that there are no real differences between the
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`challenged claims and the art; Pantoliano, Miller, and Gambini together disclose all
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`elements of the claims, except for their combination together. Representative claim
`1 is directed to a fluorescence detection apparatus in a thermal cycler ("cycler")
`which can monitor samples in situ in their wells, where a detection module
`("optics head") is attached to a shuttle movably mounted on a support. The shuttle
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`can move to place the optics head in view of different wells, for example by
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`sequential scanning. Claim 1 has two more features: (1) the light generator and
`detector are placed within the optics head ("in-head") instead of outside it – a
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`placement disclosed by Miller, and (2) a heating element with openings to allow
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`scanning – already a standard component of cyclers, as acknowledged by the '504
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`Patent, and also taught by Gambini. It was obvious to include both these known
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`features in Pantoliano's cycler by May 2003. Ex. 1002, ¶33.
`Independent claim 1: As Professor Mathies explains, the combination of
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`Pantoliano, Miller, and Gambini discloses all elements of claim 1.
`Claim 1 (preamble). A person of ordinary skill in the art ("artisan") would
`have understood that all three references disclose a "fluorescence detection
`apparatus for analyzing samples ... in ... wells." Pantoliano combines two
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`formerly-separate systems together into one single device: (1) thermal cycling
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`block "for ... heating a plurality of samples" and (2) a real-time "fluorescent"
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`sensor "for receiving spectral emission from the samples while ... heated," which
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`"obviates the need to ... transfer the [heated] samples to another apparatus prior to
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`taking" readings, resulting in "more accurate information" in real-time. Ex. 1005,
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`9:9-21, 9:47-58; Ex. 1002, ¶35. Pantoliano's device also has "a plurality of wells …
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`for a plurality of samples." Ex. 1005, 33:37-40, Figs. 29-35; Ex. 1002, ¶35. Miller's
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`apparatus is a "movable compact scan head" for "detection of ... fluorescence," for
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`example in "microtiter" sample wells. Ex. 1006, 1:53-60, 3:2-5, 6:64-8, Figs. 1-4,
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`7; Ex. 1002, ¶35. Gambini's "monitoring instrument is mounted over ... [a] block
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`containing ... vials" of samples. Ex. 1007, 6:30-31, Fig. 2; Ex. 1002, ¶35.
`Pantoliano and Gambini both disclose that their apparatus are "in a thermal
`cycler" as further recited in claim 1 (preamble), and it was obvious that Miller's
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`apparatus is suited for such use, as explained further below. Although applied to
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`thermal-shift assays, Pantoliano's device is a thermal cycler that can "perform
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`polymerase chain reaction, [or] thermal cycling steps for any purpose" as the
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`"temperature of heat conducting block ... can be increased, decreased, or held
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`constant." Ex. 1005, 42:57-62, 35:43-51; Ex. 1002, ¶36. Pantoliano uses a thermal
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`cycler in some actual assays. Ex. 1005, 50:41-46; Ex. 1002, ¶36. Gambini's optical
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`instrument is "mounted over" a block which is a "thermal cycler block." Ex. 1007,
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`6:30-31, 5:25-29; Ex. 1002, ¶36. Miller's optics head can act as a plate reader to
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`scan "microtiter" wells – the most common sample wells in cyclers, such that some
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`cyclers contained plate readers to scan wells, making Miller's optics head an
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`obvious choice for cyclers. Ex. 1006, 1:13-15, 1:23-27, 3:2-5; Ex. 1010, 32; Ex.
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`1011, 178A, right col.; Ex. 1002, ¶36.
`Claim 1(a). Artisans would have understood that all three references taught
`or suggested "a support structure attachable to the thermal cycler." For example,
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`Pantoliano discloses a variety of internal structures such as a "relative movement
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`means 3130", a "servo controller 3118" a "filter housing 3160" that are all
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`interconnected, and are attached to the "base 3100" of the cycler, directly or
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`indirectly. Ex. 1005, 35:7-36:2, Figs. 31-35; Ex. 1002, ¶37. As discussed for claim
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`1(b) below, these structures act as supports for a movable shuttle which is directly
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`or indirectly mounted onto them. Ex. 1002, ¶37. Miller's optics head can be
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`"moved ... along a rail" support which is attachable to any device of interest. Ex.
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`1006, 4:52-64; Ex. 1002, ¶37.
`Claim 1(b). Artisans would have understood that Pantoliano and Miller
`disclosed, and Gambini suggested, a "shuttle movably mounted on the support."
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`Pantoliano's system includes a shuttle in the form of a "sensor armature 3120"
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`which is movably mounted on the various support structures discussed above,
`directly or indirectly (e.g., elements 3118, 3160, 3130 or base 3100 of the cycler).
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`Ex. 1005, 35:7-36:2, Figs. 31-35; Ex. 1002, ¶38. The '504 Patent affirms that the
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`shuttle can be mounted indirectly on the support, for example through a "movable
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`mounting" means. Ex. 1001, 5:44-6:4; Ex. 1002, ¶38. Pantoliano's shuttle is
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`movably mounted on a support since it is connected to a "relative movement means
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`3130" that is in turn attached to Pantoliano's interconnected support structures
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`discussed above. Ex. 1005, 35:7-36:2, Figs. 31-35; Ex. 1002, ¶38. Miller also
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`discloses a movably-mounted shuttle in the form of a "support wall" attached to a
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`"means for moving 76," where the components of the optics head are mounted on
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`this shuttle. Ex. 1006, 5:52-58, 4:52-64, Fig. 4; Ex. 1002, ¶38.
`Claim 1(c). Artisans would have understood that all three references
`disclosed a "detection module" ("optics head"), which is further "attached to the
`shuttle" in Pantoliano and Miller. Pantoliano discloses an optics head that is a
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`"sensor" – such as a fiber-optic probe or a CCD camera – attached to a movable
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`shuttle in the form of a "sensor armature." Ex. 1005, 35:19-35, 33:1-8, 40:39-41,
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`Figs. 31-38; Ex. 1002, ¶39. In particular, a "sensor such as fiber optic probe 3122
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`or CCD camera 3000 is moved over … samples" where the "sensor is removably
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`attached to a sensor armature" (shuttle), "so that the sensor is sequentially
`positioned over each sample." Id. Miller discloses an optics head that is a "movable
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`compact scan head," which is mounted on a shuttle in the form of a "support wall"
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`attached to a "means for moving." Ex. 1006, 1:53-54, 5:52-58, 4:52-64, Fig. 4; Ex.
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`1002, ¶39. Gambini similarly discloses an optics head such as a "scanning device
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`... with a single photodetector" that is "mounted over" the thermal cycling block,
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`making a movable shuttle obvious. Ex. 1007, 11:15-16, 6:30-31; Ex. 1002, ¶39.
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`Claim 1(d). Artisans would have understood the detection modules ("optics
`head") of all three references each had a "housing." Miller's optics head is shown
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`in Figs. 1-4 and 7 to have a box-like housing enclosing all optical components
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`"within a small space." Ex. 1006, 1:55-56, Figs. 1-4, 7; Ex. 1002, ¶40. Pantoliano's
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`optics head includes a "sensor such as fiber optic probe 3122 or CCD camera 3000
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`... moved over ... samples," where the "fiber optic" embodiment has a housing
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`shown in Fig. 35, element 3122, and the CCD-camera embodiment is shown in
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`Fig. 30 to have a housing with a lens. Ex. 1005, 40:39-41, 35:20, Fig. 35, 30; Ex.
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`1002, ¶40. Gambini's optical module also has a "housing containing the light
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`source [and] the detector." Ex. 1007, claims 12, 29; Ex. 1002, ¶40.
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`Artisans would have further found that the housing in all three references
`has an "opening ... toward the ... wells." Ex. 1002, ¶41. Miller's optics head has two
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`openings in the form of objective lenses 22 (Fig. 1) and 40 (Figs. 2 and 7) through
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`which light passes between the head and the sample wells. Ex. 1006, Figs. 1, 2 &
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`7; Ex. 1002, ¶41. Pantoliano's CCD camera sensor in Fig. 30 and fiberoptic sensor
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`in Fig. 35 are shown to have a housing with an opening towards the wells for
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`"transmitting ... excitatory light ... to samples" and "receiving spectral emission ...
`
`from samples." Ex. 1005, 35:20-24, Figs. 31, 35; Ex. 1002, ¶41. In Gambini's
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`module, "[a]bove … the vials is a lens 2b" or "field lens 3" (lens openings) with its
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`"focal point centered … in the vials" through which "light is passed upwardly … to
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`a detector." Ex. 1007, 7:1-18, 8:7-12, Figs. 1-2; Ex. 1002, ¶41. Artisans would
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`have understood that such lenses were "openings" (a term defined to include
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`transparent materials or alternatively holes, as discussed in Petitioner's other
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`concurrently-filed petition) and were oriented towards the samples in order to
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`direct light onto and collect light from the samples. Ex. 1001, 6:59-64; Ex. 1002,
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`¶41.
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`Claim 1(e) and (f). Artisans would have understood that the apparatus of all
`three references included an "excitation light generator" and an "emission light
`detector." Pantoliano's device includes a generator that is a "[l]ight source 2906
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`[which] excites samples 2910 with excitatory light" such as a laser, and also
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`includes a detector in the form of a "spectral receiving means or sensor" for
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`"receiving spectral emission from the samples," such as a CCD or photomultiplier
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`tube. Ex. 1005, 33:49-65, 34:16-23; Ex. 1002, ¶42. Miller's dual-headed detection
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`module has two optics heads side by side (each head called a "side"), the head on
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`one side having a "LED light source" generator and the other head having a "laser
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`diode" generator. Ex. 1006, 1:53-67; Ex. 1002, ¶42. Each optics head within
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`Miller's detection module also includes a "detector" within its housing. Ex. 1006,
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`2:30-33, 4:16-18, 5:35-38, Figs. 1-4, 7; Ex. 1002, ¶42. Gambini's optical module
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`"compris[es] a housing containing the light source [and] the detector." Ex. 1007,
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`claims 12, 29; Ex. 1002, ¶42.
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`Miller also discloses an in-head configuration in which both the light
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`generator and the light detector are "mounted on the scan head directly" and are
`shown in Figs. 1-4 and 7 to be "within the housing" as claimed. Ex. 1006, 2:30-33,
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`4:16-18, 5:35-38, claims 28, 36; Ex. 1002, ¶43. For example, Figs. 1-4 and 7 depict
`an optics head with a housing containing a generator (e.g., an LED shown as
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`"LED" or "32", or a laser diode shown as "L/D" or "14") and detector (shown as
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`"DET" or "in-head detectors 30 and 50"). Ex. 1006, Figs. 1-4 & 7, 6:41-45; Ex.
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`1002, ¶43. Gambini's optical module "compris[es] a housing containing the light
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`source [and] the detector." Ex. 1007, claims 12, 29; Ex. 1002, ¶43. Finally, in-head
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`placement would have been obvious in Pantoliano's device since Miller discloses
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`that in-head placement is not only as effective as placement outside the optics head
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`but also makes the overall device smaller, quicker and cheaper, as discussed below.
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`Ex. 1006, Figs. 1-4, 4:16-18, 5:35-38, 2:30-33, 2:65-3:2, 1:46-49; Ex. 1002, ¶43.
`Claim 1(g). Artisans would have understood that Pantoliano's and Gambini's
`support structures are "attached to the thermal cycler" – in particular, support
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`structures such as the servo controller 3118 or filter housing 3160 are both attached
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`to the base 3100 of Pantoliano's thermocycler. Ex. 1005, 35:6-36:2, Figs. 31-35;
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`Ex. 1002, ¶44. Gambini's "monitoring instrument is mounted over" the "thermal
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`cycler" block. Ex. 1007, 6:30-31, 5:25-28, Figs. 1-2; Ex. 1002, ¶44. Miller's optics
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`head can be incoporated into any scanning device of interest, for example by
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`attachment to a "rail" support Ex. 1006, 4:58-59; Ex. 1002, ¶44. Artisans would
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`have understood that Miller's optics head could work effectively when attached to
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`a cycler, since it was adapted to scan microtiter wells, the most common well
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`format in cyclers. Ex. 1006, 3:2-5; Ex. 1011, 178A, right col.; Ex. 1002, ¶44.
`Claim 1(h). Artisans would have understood that Gambini taught a cycler in
`which "a heating element [wa]s disposed between the detection module and the
`sample wells." Gambini discloses two heating elements – a thermal cycling block
`
`and a heated lid. Ex. 1007, 6:24-7:7, Fig. 1, 5:25-28; Ex. 1002, ¶45. Gambini
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`further explains that sample wells should be covered "to prevent contamination and
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`evaporation loss" during real-time monitoring by an optical system "mounted over"
`the sample wells. Id. Since this requires light transmission through the caps of
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`sample tubes, Gambini's sample-tube caps are heated by a heating element "to
`prevent condensation under the caps" which can occlude the optical path. Id.
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`Gambini's heating element is very similar to the "lid heater" of the '504 Patent: it is
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`a "platen 2 ... over the vial caps" which is heated "sufficiently to prevent
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`condensation under the caps," with "an array of holes 2a therethrough" that allows
`light to pass between the vials below and Gambini's detector above. Id. Like the lid
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`heater of the '504 Patent, Gambini's platen is a heated, lid-like structure placed on
`top of the sample vials. Id. Incorporating Gambini's lid heater and Miller's optics
`head into Pantoliano's cycler results in the lid heater being "disposed between" the
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`sample wells and optics head, as would have been apparent to artisans. Ex. 1002,
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`IPR2017-00055 of USPN 8,236,504
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`¶45.
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`Claim 1(i). Artisans would have understood that all three references disclose
`"position[ing] the detection module in optical communication with different wells
`of the plurality of wells," and that Pantoliano and Miller further disclose that the
`"shuttle is movable to position the detection module" during scanning. Pantoliano's
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`thermocycler contains a shuttle such as a sensor armature "used to move the sensor
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`so that the sensor is sequentially positioned over each sample in the array of
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`samples." Ex. 1005, 33:1-8, 35:19-35, 21:2-26, 40:39-41, Fig. 29-35; Ex. 1002,
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`¶46. For example, a "precision X-Y mechanism" with a "fiber-optic probe to
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`quantify the fluorescence in each well" scans a 96-well microplate in "under one
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`minute." Ex. 1005, 21:2-26, Fig. 29; Ex. 1002, ¶46. Similarly, Miller's optics head
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`and associated shuttle ("support wall 60") can be "moved across a sample in two
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`dimensions." Ex. 1006, 4:52-64; Ex. 1002, ¶46. Miller further discloses scanning
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`"in a point-by-point imaging manner" where samples in "microtiter" plate wells are
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`"sequentially subjected to stimulation and detection." Ex. 1006, 3:2-5, 4:52-64; Ex.
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`1002, ¶46. Finally, Gambini discloses that "a scanning device may be used with a
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`single photodetector." Ex. 1007, 11:14-15; Ex. 1002, ¶46.
`Claim 1(j). Artisans would have also understood from Gambini that the
`optics head could view the sample wells "through a plurality of openings extending
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`through the heating element." As discussed for claim 1(h), Gambini's heating
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`IPR2017-00055 of USPN 8,236,504
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`element is a heated platen with "an array of holes 2a therethrough aligned with the
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`vials" to allow light to pass through the opaque aluminum of the platen. Ex. 1007,
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`6:24-7:7, Fig. 1; Ex. 1002, ¶47.
`B) The third Graham inquiry: the level of ordinary skill in the art in the
`pertinent art and the state of the art. The knowledge of a person of ordinary
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`skill ("artisan") was exceptionally deep and rich with respect to the claimed subject
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`matter. The claims are directed to thermal cyclers – devices which were not merely
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`a matter of academic interest, but part of everyday life to artisans since the advent
`of "end point" PCR in the mid-1980s, and of real-time PCR (i.e., quantitative PCR
`
`that involves optical detection during PCR) in the 1990s. Ex. 1010, 31; Ex. 1013,
`17; Ex. 1012, 247; Ex. 1002, ¶16. Real-time thermal cyclers (hereafter "cyclers")
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`were found in every lab and clinic, and typically were one of the most-used
`instruments there. Id. The claims recite features that were not only taught in the art,
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`but were already implemented in cyclers on the market well before 2003, the
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`effective date of the claims. In fact, artisans did not need the teachings of the
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`applied references to recognize the various features of the claims, and to find the
`claims obvious.
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`For example, artisans already knew and used a "heating element" (claim 1)
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`or "heater" (claim 13) with a "plurality of openings" as claimed, since such heating
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`elements were already marketed in most cyclers. So-called "heated lids" were
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`IPR2017-00055 of USPN 8,236,504
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`already in use, which were placed on sample tubes to prevent sample condensation;
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`these heated lids started out as high-end "optional" accessories for end-point PCR
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`instruments in the early 1990s (before real-time cyclers were on the market) to
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`avoid condensation of the heated liquid contents onto the caps of sample tubes
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`throughout PCR. Ex. 1014, 1; Ex. 1013, 17, 19; Ex. 1002, ¶17. Since such
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`condensation further obstructed optical detection through the caps, heated lids
`became a "standard" component of real-time cyclers by the late 1990s. Id. The '504
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`Patent itself acknowledges that its "lid heater" could be of "conventional design."
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`Ex. 1001, 5:40-41; Ex. 1002, ¶17. And because sample tubes in cyclers with metal
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`sample blocks were typically monitored from above, through the heated lids, the
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`lids had optical openings to let light through, just as the claims require. Ex. 1002,
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`¶17. Petitioner's expert is aware of at least eight prior-art references disclosing
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`cyclers having the claimed heating element with openings. Ex. 1015, ¶46; Ex.
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`1016, 17:31-35; Ex. 1017, ¶112-113; Ex. 1018, 5:55-62; Ex. 1019, Fig. 1, 5:43-61;
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`Ex. 1020, 7:8-23; Ex. 1021, 7:28-8:9; Ex. 1022, 15:18-36; Ex. 1002, ¶17.
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`In addition, the claimed in-head placement of optical components within the
`
`optics head itself was already found in scanning devices used to scan DNA
`
`samples on chips and microtiter wells – the most common sample-well format in
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`cyclers. Ex. 1006, 3:2-5; Ex. 1010, 32; Ex. 1011, 178A, right col.; Ex. 1002, ¶18.
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`The pertinent and analogous field for fluorescence detection in real-time cyclers
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`IPR2017-00055 of USPN 8,236,504
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`was the field of optical devices in general, not limited to cyclers alone. Ex. 1011,
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`178A, right col.; Ex. 1018, 1:53-59; Ex. 1023, 5:51-6:3; Ex. 1002, ¶18. There were
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`historical reasons for this: cyclers were in advanced development as non-optical
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`devices well before real-time PCR introduced optical detection into the world of
`cyclers in 1993. Id. Rather than reinventing optical systems from scratch, artisans
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`making optical cyclers naturally looked to existing optical systems in other devices
`as relevant. Id. Real-time PCR merely required scanning or imaging of a 2D planar
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`area, something practically any optical detector could do. Ex. 1002, ¶18. Artisans
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`performed real-time PCR by combining non-optical thermal cyclers with a wide
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`variety of optical devices, such as video cameras, fluorometers, plate readers and
`laser scanners. Id., Ex. 1017, ¶61; Ex. 1024, 4518; Ex. 1025, p. 3-10, Fig. 3-6; Ex.
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`1002, ¶18. Only the desired scanning format, rather than the nature of the sample,
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`dictated the choice of scanner: artisans used the same scanner to scan gels,
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`phosphorimage plates, glass slides and microtiter-well plates alike. Ex. 1006, 3:2-
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`5; Ex. 1002, ¶18. In illustrative examples, a prior-art DNA chip reader had an
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`optics head design taken from optical-disk devices; and a prior-art gel scanner had
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`an optical system taken from a microscope. Ex. 1008, ¶26; Ex. 1026, 2:22-25; Ex.
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`1002, ¶18. Moreover, cyclers themselves were also designed to accept an equally
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`wide variety of sample formats such as tubes, microwells, capillaries, and glass
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`slides. Ex. 1014, 7; Ex. 1002, ¶18. Artisans thus treated the general body of
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`optical-detection systems as pertinent and analogous art for real-time cyclers,
`irrespective of sample format. Id. Microtiter plate readers such as Miller's scan
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`head were a natural match for cyclers since the same microtiter format was the
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`most popular well format in cyclers, and devices which integrated thermal cyclers
`
`with plate readers were on the market by 2001. Ex. 1024, 4518; Ex. 1010, 32; Ex.
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`1011, 178A, right col.; Ex. 1002, ¶18. Since optics heads had already been
`
`designed to scan microtiter wells in other devices, it was only a matter of time –
`
`not inventiveness – before these optics heads were used in cyclers as well. Ex.
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`1002, ¶18.
`C) Rationales for obviousness. Pantoliano's thermocycler meets all
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`limitations of the challenged claims except for two predictable features: (1) in-head
`
`placement of the generator and detector – a known configuration for optics heads
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`taught by Miller, and (2) a heater with optical holes – a standard component of
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`real-time thermocyclers, taught for example by Gambini. Ex. 1002, ¶48. The
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`combination of Pantoliano, Miller and Gambini rendered claim 1 obvious by
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`several independent rationales.
`Teachings to combine within the applied references: The references
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`themselves provided strong incentives to combine. Ex. 1002, ¶49. In Pantoliano's
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`1997 thermocycler, the source and detector were too big to fit inside the optics
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`head itself, making in-head placement undesirable since the optics head would be
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`slowed d