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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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`VISIONSENSE CORP.
`Petitioner,
`
`v.
`
`NOVADAQ TECHNOLOGIES INC.
`Patent Owner.
`
`Patent No. 8,892,190
`
`
`_______________
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`
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`Inter Partes Review No. IPR2017-01426
`____________________________________________________________
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`PATENT OWNER’S PRELIMINARY RESPONSE
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`I.
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`INTRODUCTION ........................................................................................... 1
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`TABLE OF CONTENTS
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`II.
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`THE ’190 PATENT ......................................................................................... 4
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`III. CLAIM CONSTRUCTION ............................................................................ 6
`
`A.
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`“vessel graft” ................................................................................................. 7
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`“the vessel graft and at least a portion of the blood vessels being
`B.
`exposed” ................................................................................................................. 8
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`“capturing the radiation emitted by the fluorescent dye with a camera
`C.
`capable of imaging a series of angiographic images within the vessel graft
`and said exposed portion of the interconnected group of blood vessels” .............. 9
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`“evaluating the angiographic images to assess blood flow through the
`D.
`vessel graft relative to blood flow through the interconnected group of blood
`vessels” ................................................................................................................. 10
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`IV. THE ASSERTED PRIOR ART REFERENCES ..........................................13
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`A.
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`Little ............................................................................................................. 13
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`B. Flower I ....................................................................................................... 18
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`C. Flower II ...................................................................................................... 20
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`D. Goldstein...................................................................................................... 20
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`E.
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`Jibu .............................................................................................................. 22
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`V.
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`RESPONSE TO GROUNDS OF CHALLENGE .........................................23
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`A. Ground 1: Little Fails to Anticipate Claims 1 and 2 .................................. 23
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`Little fails to disclose or suggest “capturing the radiation emitted by
`1.
`the fluorescent dye with a camera capable of imaging a series of
`angiographic images within the vessel graft” ................................................... 24
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`Little fails to disclose or suggest “evaluating the angiographic images
`2.
`to assess blood flow through the vessel graft relative to blood flow through
`the interconnected group of blood vessels” ...................................................... 30
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`Little fails to disclose or suggest “the vessel graft . . . being exposed,”
`3.
`as recited in claim 1 ........................................................................................... 32
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`B. Ground 2: Claims 1–3 are not obvious over Little in view of Flower I
`and Flower II ........................................................................................................ 34
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`1. Claims 1 and 2 .......................................................................................... 35
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`2. Claim 3 ..................................................................................................... 38
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`C. Ground 3: Claims 1–3 are not obvious over Flower I, Flower II, and
`Little, or Goldstein. ............................................................................................... 40
`
`1.
`
`The deficiencies of Flower I, Flower II, and Little .................................. 42
`
`2. Goldstein fails to disclose or suggest “evaluating the angiographic
`images to assess blood flow through the vessel graft relative to blood flow
`through the interconnected group of blood vessels” ......................................... 42
`
`Flower I, Flower II, and Goldstein fail to disclose or suggest “the
`3.
`vessel graft . . . being exposed” ......................................................................... 48
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`The Petitioner fails to provide reasoning in support of the
`4.
`combination of Flower I, Flower II, and Goldstein .......................................... 49
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`D. Ground 4: Claims 1–3 are not obvious over Jibu, Flower I, and Little,
`or Goldstein .......................................................................................................... 50
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`The Petitioner failed to meet its evidentiary burden of providing a
`1.
`copy of Jibu in its original Japanese and providing an affidavit attesting to
`the accuracy of the English translation of Jibu ................................................. 51
`
`2.
`
`Jibu fails to cure the deficiencies of Little, Goldstein, and Flower I. ...... 52
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`VI. PATENT OWNER’S FINAL COMMENTS ................................................54
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`VII. CONCLUSION ..............................................................................................55
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`Exhibit List for Inter Partes Review of U.S. Patent No. 8,892,190
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`Exhibit Description
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`Exhibit #
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`Little, John R., et al. “Superficial temporal artery to middle cerebral
`artery anastomosis: Intraoperative evaluation by fluorescein
`angiography and xenon-133 clearance.” Journal of Neurosurgery 50.5
`(1979): 560-569
`
`Declaration of Brian Wilson (“Wilson Decl.”)
`
`Definition of “graft,” excerpt of Stedman’s Medical Dictionary for
`the Health Professions and Nursing; 6th Ed. (2008)
`
`2001
`
`2002
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`2003
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`Definition of “Expose,” excerpt of Merriam Webster’s Medical Desk
`Dictionary (1993)
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`2004
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`I.
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`INTRODUCTION
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`Patent Owner Novadaq Technologies Inc. (“Patent Owner”) respectfully
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`requests that the Board decline to initiate an inter partes review of U.S. Patent
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`No. 8,892,190 (“the ’190 patent”) because petitioner Visionsense Corp. has failed
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`to show a reasonable likelihood of prevailing with respect to any of the challenged
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`claims. (35 U.S.C. § 314(a).)
`
`The Petition fails for a fundamental reason: the lead reference, Little, simply
`
`does not disclose or suggest several claimed elements. Neither the Petition nor
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`Petitioner’s expert grapple with this basic problem, which is plain from the very
`
`figures of Little relied upon in the Petition. As shown below, the Petition is built
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`upon a mischaracterization of Little, deficient claim construction, and weak and
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`unsubstantiated arguments.
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`The claims in the ’190 patent are all directed to methods for assessing the
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`blood flow through a vessel graft and through the downstream vessels that it feeds
`
`to evaluate the success of a grafting procedure. A camera images the movement of
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`a fluorescent dye wavefront both in the exposed vessel graft and in an
`
`interconnected group of blood vessels downstream from the attachment point
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`(anastomosis) of the vessel graft. The images are evaluated to assess the relative
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`blood flow through the vessel graft as compared to blood flow through the
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`interconnected group of blood vessels. This relative assessment requires
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`comparing the degree of flow in the vessel graft to the degree of flow in the
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`interconnected group of blood vessels, not simply assessing whether there is blood
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`flow in the vessel graft or not. Unlike methods that simply identify whether there
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`is blood flow in the interconnected group of blood vessels, the claimed methods
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`enable determination of how well the vessel graft is feeding the interconnected
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`group of blood vessels.
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`Little, which describes fluorescence imaging after a vessel grafting
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`procedure, does not image the actual vessel graft at all. Little only images and
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`evaluates blood flow through the native vessel to which the vessel graft is attached
`
`and downstream vessels, using this blood flow alone to assess the efficacy of the
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`grafting procedure. In fact, not only is blood flow within the vessel graft not
`
`imaged, Little states and shows that the vessel graft is not exposed during
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`imaging, which is fatal to the Petition because each claim explicitly requires the
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`vessel graft to be exposed for imaging.
`
`Exposure of the vessel graft and imaging of blood flow within the vessel
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`graft itself is central to each of the claims of the ’190 patent. By not exposing the
`
`vessel graft and not imaging blood flow within the vessel graft, Little fails to
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`disclose or suggest: (1) the explicit requirement in the claims that the vessel graft
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`be exposed; (2) “capturing the radiation emitted by the fluorescent dye . . . within
`
`the vessel graft”; and (3) “evaluating the angiographic images to assess blood flow
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`through the vessel graft relative to blood flow through the interconnected group of
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`blood vessels.” Thus, Little (which is used in all of the Petition’s grounds) neither
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`discloses nor suggests key claim limitations.
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`The Petition and Petitioner’s expert either failed to understand or
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`disregarded the fact that Little does not expose and image the vessel graft at all. In
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`fact, Petitioner and Petitioner’s expert falsely assert that Little’s images show “the
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`site of the vessel graft upstream of the anastomosis,” when, in fact, the images only
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`show the native vessel to which the vessel graft is anastomosed and downstream
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`vessels. (Petition at 29; Langer Decl. at 19.) As shown in each of the figures of
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`Little—even those specifically relied upon by the Petitioner—the vessel graft is
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`covered by connective tissue and fat, preventing blood flow within from being
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`imaged. In support of its’ response, Patent Owner provides the Declaration of Dr.
`
`Brian Wilson, an expert in intraoperative fluorescence imaging systems, who
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`confirms that Little fails to image blood flow within the vessel graft. (Declaration
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`of Brian Wilson, Ex. 2002 (“Wilson Decl.”).) Petitioner and Petitioner’s expert
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`missed or disregarded this fundamental deficiency.
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`By failing to establish a teaching of several of the limitations of the claims,
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`the Petitioner has failed to show a reasonable likelihood of prevailing with respect
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`to any of the challenged claims. (35 U.S.C. § 314(a).) Accordingly, the Patent
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`Owner respectfully requests that the Board deny inter partes review.
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`II. THE ’190 PATENT
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`The ’190 patent is directed to fluorescence imaging of blood flow through
`
`vessels in support of vascular disease diagnosis and treatment. As explained in the
`
`background section of the patent, a common treatment for certain cardiovascular
`
`diseases, such as atherosclerosis, is bypass grafting. (Ex. 1001 at 1:26–46.)
`
`Atherosclerosis is characterized by the narrowing (stenosis) of a blood vessel,
`
`which in its most severe form may result in complete blockage (occlusion) of the
`
`vessel. (Id.) Bypass graft surgery may be performed to bypass the stenosis or
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`occlusion to restore blood flow to downstream blood vessels. During this
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`procedure, a vascular graft, such as a healthy vein or artery, is surgically attached
`
`to a native vessel in a manner that permits blood to bypass the stenotic or occluded
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`portion of the native vessel. (Id.) The success of bypass graft surgery depends
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`upon the degree of blood flow through the graft and the downstream vessels that
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`the graft is intended to feed. (See id. at 1:56–64.)
`
`The ’190 patent describes techniques for imaging the flow of blood through
`
`the graft and the downstream vessels to assess the success of a grafting procedure.
`
`The imaging techniques include administering a fluorescent dye, such that the dye
`
`enters the vessel graft and downstream vessels while the graft and downstream
`
`vessels are exposed, and exciting the dye with a suitable source of illumination to
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`cause the dye to emit radiation. (See, e.g., id. at 3:16–20, 7:19–27, 11:51–56.) The
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`radiation emitted from both the vessel graft and downstream vessels is captured by
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`a camera, which generates a series of angiographic images that show the
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`movement of the dye through the vessels. (See, e.g., id. at 10:12–17, 13:14–15.)
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`The ’190 patent describes administering the dye, and imaging the vessel graft and
`
`downstream vessels, in such a manner that the movement of a fluorescent
`
`wavefront through the vessel graft and downstream vessels is captured in the series
`
`of images. (See id. at 11:65–67.)
`
`The ’190 patent describes evaluating the images to assess graft and
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`anastomosis patency (openness), but also to assess the degree of blood flow in the
`
`graft and in the downstream vessels. (Id. at 10:12–17.) Patency can be determined
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`from a single image. For example, as explained in the ’190 patent, “[a] line of
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`substantially uniform thickness indicates a vessel that is free of atherosclerotic
`
`plaques. In contrast, a line that is ragged, or that becomes thinner in certain
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`sections, indicates the presence of stenosis, while a discontinuation of a line
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`indicates the presence of an occlusion.” (Id. at 6:48–54.) The degree of blood
`
`flow, on the other hand, requires evaluation of the series of images to observe the
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`movement of the fluorescent wavefront through the vessel graft and then through
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`the downstream vessels.
`
`The claims of the ’190 patent are directed to this latter evaluation. As
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`explained below, the claims require evaluation of the series of images to assess the
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`blood flow through the vessel graft relative to blood flow through the downstream
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`interconnected group of blood vessels. Because the series of images captures the
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`movement of the fluorescent wavefront through the graft and downstream vessels,
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`the degree of blood flow in both the vessel graft and the downstream vessels can be
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`determined from the images, and an assessment can be made as to the degree of the
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`blood flow in the graft relative to the degree of blood flow in the downstream
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`vessels.
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`This angiographic imaging and relative assessment developed by the
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`inventors provides an effective method for evaluating the success of a grafting
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`procedure that is simply not disclosed or suggested by any of the references or any
`
`of the combinations of references set forth by the Petitioner. None of the art cited
`
`by the Petitioner shows assessing blood flow through a vessel graft relative to
`
`blood flow through the interconnected group of blood vessels.
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`III. CLAIM CONSTRUCTION
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`As explained below, the Petitioner failed to construe, or incorrectly
`
`construed, limitations that are central to the claims. In fact, the Petitioner’s claim
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`construction is set forth with little more than one-line, conclusory statements
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`supported by little or no reasoning or analysis.
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`During inter partes review, the Board gives claims their “broadest
`
`reasonable construction in light of the specification of the patent” of which they are
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`a part. (37 C.F.R. § 42.100(b); Cuozzo Speed Tech., LLC. v. Lee, 136 S.Ct. 2131,
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`2144 (2016) (affirming the propriety of the broadest reasonable construction
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`standard during inter partes review proceedings). Claim construction must be
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`“reasonable in light of the totality of the written description.” In re Baker Hughes,
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`Inc., 215 F.3d 1297, 1303 (Fed. Cir. 2000). Absent any special definitions, claim
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`terms receive their “ordinary and customary meaning” as would be understood by
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`one of ordinary skill in the art at the time of the invention. In re Translogic Tech.,
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`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
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`A.
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`“vessel graft”
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`“Vessel graft” is used throughout the claims. The broadest reasonable
`
`construction of “vessel graft” is a vessel that is implanted into a subject. This is
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`consistent with its ordinary meaning1 and with the disclosure of the ’190 patent.
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`For example, the ’190 patent states:
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`During this procedure, a vascular graft, e.g., a vein or artery
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`or, alternatively, a flexible artificial tube, is surgically inserted
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`in a manner that permits blood to bypass the stenotic or
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`occluded portion of a native vessel. . . . In CABG, a graft,
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`commonly a saphenous vein or internal mammary artery, is
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`1 See, e.g., “Graft”; Stedman’s Medical Dictionary for the Health Professions and
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`Nursing; 6th Ed. (2008) (“Any free (unattached) tissue or organ for
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`transplantation.”). Patent Owner provides excerpt as Exhibit 2003.
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`harvested or dissected from the patient, respectively, and then
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`located within the patient to permit blood flow to bypass the
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`stenotic or occluded vessel portion. Alternatively, or in addition
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`thereto, a graft may be used to permit blood to flow directly
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`from the aorta to a location downstream of a stenotic or
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`occluded portion of an artery.
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`(Ex. 1001 at 1:43–55 (emphasis added).) The ’190 patent explains that the
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`vascular (i.e., vessel) graft is inserted (i.e., implanted) in a manner that permits
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`blood to bypass the stenotic or occluded portion of a native vessel. The ’190
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`patent also explains that, “[w]hen bypass is undertaken, an anastomosis, i.e., the
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`junction of the native and graft vessels, is created.” Thus, “vessel graft” should be
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`construed as a vessel that is implanted into a subject.
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`In construing this term, the Petitioner states only that a “[v]essel graft can be
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`the graft of any vessels. It can be vessels in the leg, heart or brain.” (Petition at
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`19.) The Petitioner appears to be concerned with “vessel graft” not being
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`construed as limited to any particular vasculature. Patent Owner agrees that the
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`broadest reasonable construction of vessel graft is not limited as to particular
`
`vasculature.
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`B.
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`“the vessel graft and at least a portion of the blood vessels being
`exposed”
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`Claim 1 recites “the vessel graft and at least a portion of the blood vessels
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`being exposed,” and claim 3 recites “the vessel graft being exposed.” The ordinary
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`meaning of “exposed” is laid open to view.2 Thus, this phrase should be construed
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`as meaning that the vessel graft and at least a portion of the blood vessels are laid
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`open to view. In other words, any tissue covering the vessels is removed so that
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`the vessels are viewable.
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`This meaning is consistent with the disclosure of the ’190 patent. For
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`example, the ’190 patent explains that, in one exemplary embodiment, “the skin
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`over the femoral vasculature was resected [i.e., cut out] to expose the vasculature
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`of interest.” (Ex. 1001 at 11:55–56 (emphasis added).)
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`The Petitioner failed to construe this limitation.
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`C.
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`“capturing the radiation emitted by the fluorescent dye with a
`camera capable of imaging a series of angiographic images within the
`vessel graft and said exposed portion of the interconnected group of
`blood vessels”
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`Claim 1 recites “capturing the radiation emitted by the fluorescent dye with
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`a camera capable of imaging a series of angiographic images within the vessel
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`graft and said exposed portion of the interconnected group of blood vessels.” The
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`broadest reasonable construction of this limitation is that both the vessel graft and
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`the interconnected group of blood vessels are imaged—not just one or the other.
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`The Petitioner failed to construe this limitation.
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`2 “Expose”; Merriam Webster’s Medical Desk Dictionary (1993) (“To lay open to
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`view”). Patent Owner provides excerpt as Exhibit 2004.
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`D.
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`“evaluating the angiographic images to assess blood flow through the
`vessel graft relative to blood flow through the interconnected group
`of blood vessels”
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`Claim 1 recites “evaluating the angiographic images to assess blood flow
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`through the vessel graft relative to blood flow through the interconnected group of
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`blood vessels.” The Petition refers to this limitation as the “evaluation step,” and
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`this shorthand is used within for the Board’s convenience.
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`The broadest reasonable construction of the evaluation step requires
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`assessment of the degree of blood flow in the vessel graft, assessment of the degree
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`of blood flow in the interconnected group of blood vessels, and a comparison of
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`the two.
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`This meaning is consistent with the specification. For example, the
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`specification describes a relative assessment of blood flow according to one
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`embodiment, as follows:
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`Software may also be used to compare images of pre- and post-
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`treatment vessels to determine the relative flow rate of blood
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`at or downstream of the treatment site. This comparison is
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`accomplished by calculating and comparing the area of
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`fluorescence (i.e., number of pixels associated with the
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`fluorescing dye) in pre- and post-treatment images associated
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`with a preselected section of the vessel, and/or comparing the
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`relative average maximum fluorescent intensity of a preselected
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`section of the vessel in each such image. A greater number of
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`pixels, or greater average maximum fluorescent intensity,
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`respectively, in the post-treatment images indicates improved
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`blood flow in the preselected vessel section as a result of the
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`treatment.
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`(Ex. 1001 at 10:18–31 (emphases added).) In this example, the relative assessment
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`of the flow rate of blood can indicate improved blood flow as a result of treatment.
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`Whether the blood flow has improved (i.e., the relative assessment) can only be
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`determined by assessing the flow rate pre-treatment and the flow rate post-
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`treatment, and comparing the two flow rates. It is not enough to simply determine
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`that there is flow, or to simply determine the absolute flow rates. Rather, the flow
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`rates must be compared. Similarly, the evaluation step of the claims requires
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`assessment of the degree of blood flow in the vessel graft, assessment of the degree
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`of blood flow in the interconnected group of blood vessels, and a comparison of
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`the two.
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`The analogous limitation in claim 3 is: “evaluating the angiographic images
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`to assess blood flow through the vessel graft relative to blood flow through a group
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`of blood vessels interconnected to the vessel graft.” This “evaluation step” does
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`not differ in any material way from the evaluation step of claim 1 and, therefore,
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`should be construed identically.
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`The Petitioner’s construction of the evaluation step3 is wrong. The
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`Petitioner asserts the following regarding the meaning of the evaluation step:
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`Any type of comparison (e.g., fluorescence signal in the graft
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`and no signal in the downstream vessels) would qualify as
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`relative evaluation.
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`(Petition at 20.) Thus, according to the Petitioner, all that is required by the
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`evaluation step is a determination of whether there is blood in the vessel graft or
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`not, and of whether there is blood in the downstream vessels or not. This
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`construction reads “relative to” completely out of the claim. As explained above,
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`the inclusion of “relative to” in the evaluation step requires assessing the degree of
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`blood flow through the vessel graft, assessing the degree of blood flow through the
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`interconnected group of vessels, and comparing the two. The Petitioner’s
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`construction does not require a relative assessment and, so, is not a correct
`
`construction of the evaluation step. Not surprisingly, the Petitioner did not provide
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`any evidence, such as that in the specification, or reasoning to support the asserted
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`construction.
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`3 The Petitioner’s construction of the evaluation step does not differentiate between
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`the evaluation steps of claims 1 and 3. (Petition at 20.)
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`IV. THE ASSERTED PRIOR ART REFERENCES
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`Before addressing the grounds presented by the Petition, the Patent Owner
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`briefly summarizes the asserted art for the Board’s benefit.
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`A.
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`Little4
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`Little is relied upon for Ground 1 as anticipating claims 1 and 2 for each of
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`the obviousness Grounds 2–4. (Petition at 21.) Little discloses performing
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`fluorescein dye angiography during bypass surgery on the brain to assess the
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`success of a superficial temporal artery (“STA”) to middle cerebral artery
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`(“MCA”) anastomosis. (Ex. 1002 at 560; Wilson Decl. at 6.) During this
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`procedure, vessels downstream from the anastomosis are imaged to show the blood
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`flow in the downstream vessels, but, fatally to the Petitioner, the vessel graft itself
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`is not imaged. As described above, imaging the vessel graft is central to the
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`claims and is included in multiple limitations. Little only images the blood flow
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`through the vessel to which the vessel graft is attached and downstream vessels,
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`using this information alone to gauge the success of the grafting procedure. Little
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`4 The copy of Little provided by the Petitioner as Exhibit 1002 includes poor-
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`quality images. Accordingly, Patent Owner provides as Exhibit 2001 a copy of
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`Little scanned at higher resolution but otherwise identical. The images of Little
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`reproduced within are from the copy provided as Exhibit 2001.
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`does not make a comparison between the degree of blood flow in the vessel graft
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`and the degree of blood flow in the downstream vessels.
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`The anastomosis procedure is described in Little as follows:
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`An inverted U-shaped scalp flap was turned. The larger STA
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`branch, together with a generous cuff of connective tissue, was
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`mobilized carefully. A relatively large temporoparietal
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`craniotomy was performed. The largest exposed cortical artery,
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`usually the angular branch of the MCA, was selected as the
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`receptor vessel. Mean STA diameter was 1.3 mm (range: 0.9 to
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`1.6 mm) and mean receptor artery diameter was 1.2 mm (range:
`
`0.9 to 1.6 mm). Continuous suturing was performed for the
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`anastomosis in all but the initial three patients, in whom the
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`standard interrupted suture technique was used. The operations
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`were carried out by one surgeon (J.R.L.).
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`(Ex. 1002 at 562.) In the operative procedure, the MCA was selected as the
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`receptor vessel, and the STA was selected as the vessel graft. (Wilson Decl. at 6-
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`7.) The STA was anastomosed to the MCA to bypass blockage in the upstream
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`internal carotid artery or upstream portion of the MCA. (Ex. 1002 at 560; Wilson
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`Decl. at 7.)
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`Little includes images that show blood flow in the vessel to which the vessel
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`graft is attached and downstream vessels, but none of the images shows blood
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`flow in the vessel graft. As detailed below, this is because the vessel graft was
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`not exposed during the imaging. Instead, it was covered with a layer of tissue
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`and fat that prevented imaging of the blood flow within the vessel graft.
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`The upper left image of Figure 1 is a white-light image of the surgical sight
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`after anastomosis of the STA to the MCA receptor vessel. (Ex. 1002 at 563;
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`Wilson Decl. at 7.) The caption of Figure 1 explains that, in this image, the STA is
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`covered by “a generous cuff of connective tissue and fat (X).” (Id.) The upper left
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`image of Figure 1 is provided below with annotations.
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`(Ex. 2001 at Figure 1 (annotation added).) The above annotation of this image
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`outlines the cuff of connective tissue and fat to help illustrate the location of the
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`STA, which is covered by the cuff of connective tissue and fat. (Wilson Decl. at 7-
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`8.) That portion of the image was marked with an “X” in Little itself.
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`After anastomosis, fluorescence imaging was performed to assess the
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`success of the anastomosis procedure. (Ex. 1002 at 564; Wilson Decl. at 8.) The
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`remaining five images in Figure 1 are fluorescence images showing the movement
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`of fluorescent dye through the vessel to which the vessel graft is attached and
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`downstream vasculature. (Ex. 1002 at Figure 1 caption; Wilson Decl. at 8.) The
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`top right image, bearing the time stamp of 01:13, is reproduced below.
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`(Ex. 2001 at Figure 1 (annotated).) The caption of Figure 1 explains that the white
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`area (indicated by the arrow in the above annotation) illustrates the “filling of the
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`cortical receptor artery.” (Ex. 1002 at Figure 1 caption; Wilson Decl. at 9.) As
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`explained above, Little discloses that the “largest exposed cortical artery, usually
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`the angular branch of the MCA, was selected as the receptor vessel.” (Ex. 1002 at
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`562 (emphasis added).) Thus, the “cortical receptor artery” mentioned in the
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`caption of Figure 1 is the MCA. (Wilson Decl. at 9.) So, the portion of the upper
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`right image of Figure 1 of Little showing fluorescence response is the MCA
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`receptor vessel. (Wilson Decl. at 9.) Because of the covering by the cuff of
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`connective tissue and fat, the STA (i.e., the vessel graft) is not captured in the
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`above image. (Wilson Decl. at 10.) The central portion of the image—the location
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`of the cuff of connective tissue and fat—is completely dark. (Wilson Decl. at 10.)
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`In the four other fluorescence images of Figure 1, fluorescence radiation in
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`the MCA receptor vessel and downstream vessels is captured, but the STA vessel
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`graft continues to be completely obscured by the cuff of connective tissue and fat.
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`(Ex. 1002 at Figure 1; Wilson Decl. at 10.) The lower central portion of each
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`image—the location of the cuff covering the STA—is completely dark. (Id.) Each
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`of the procedures depicted in the figures of Little included a cuff of connective
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`tissue and fat over the STA that prevented any fluorescence signal from dye within
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`the STA.5 (Ex. 1002 at 564–66; Wilson Decl. at 11.)
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`5 The image on the right in Figure 4 includes some fluorescence signal in the
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`vicinity of the cuff but, as explained in the caption, this is due to leakage of the
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`Thus, Little describes assessing blood flow in the cortical receptor vessel and
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`downstream vasculature to evaluate success of the STA-to-MCA anastomosis. The
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`angiography shows the distribution of blood supplied by the STA through the
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`anastomosis, but does not show the blood flow within the STA itself.
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`B.
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`Flower I
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`Flower I is relied upon for Grounds 2 through 4 for its “general teaching for
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`using fluorescence imaging to evaluate blood flow through vessels and diagnosing
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`abnormal vasculature.” (Petition at 22, 35, 42.) Flower I describes various
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`fluorescence-based methods, primarily for the diagnosis and treatment of vascular
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`abnormalities occurring in the eye. These methods include using boluses of
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`relatively high dye concentration to enhance the clarity of fluorescent dye
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`angiograms, determining the direction of blood flow via a technique called dye-
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`bleaching in which excess excitation radiation causes dye to stop fluorescing, and
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`reducing blood flow to a tumor through coagulation of blood flowing to the tumor
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`brought on by heating the fluorescent dye. (Ex. 1003 at 2:31–34, 2:46–67, 3:25–
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`32.)
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`Although primarily directed to ophthalmic applications, Flower I also
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`describes “methods for visualizing blood vessels at locations other than in the eye.”
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`fluorescein dye into the walls of the STA and the surrounding tissue, and is not
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`radiation from dye within the STA. (Ex. 1002 at 566; Wilson Decl. at 12.)
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`(Id. at 8:6–7.) Flower I explains that the methods permit angiograms of blood
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`vessels and other abnormalities