IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`VISIONSENSE CORPORATION
`
`Petitioner,
`
`V.
`
`Patent Owner of
`
`US. Patent No. 8,892,190
`
`IPR Trial No. TBD
`
`DECLARATION OF DAVID J. LANGER, M.D.,
`IN SUPPORT PETITION FOR INTER PARTES REVIEW OF
`
`US. Patent No. 8,892,190
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`VISIONSENSE CORPORATION
`
`Petitioner,
`
`V.
`
`Patent Owner of
`
`US. Patent No. 8,892,190
`
`IPR Trial No. TBD
`
`DECLARATION OF DAVID J. LANGER, M.D.,
`IN SUPPORT PETITION FOR INTER PARTES REVIEW OF
`
`US. Patent No. 8,892,190
`
`
`
`DECLARATION OF DAVID J. LANGER, M.D.,
`IN SUPPORT OF VISIONSENSE CORPORATION’S
`
`PETITION FOR INTER PARTES REVIEW
`
`1)
`
`My name is David J. Langer. I am the Chairman of
`
`Neurosurgery at Lenox Hill Hospital in New York City. I am also a
`
`Professor of Neurological Surgery at Hofstra University School of Medicine.
`
`I make this declaration in support of Visionsense Corporation’s (“Petitioner”
`
`or “Visionsense”) petition for Inter Partes Review (“IPR”) of U.S. Patent
`
`No. 8,892,190 (the “’ 190 Patent”). My current curriculum vitae is attached.
`
`Some highlights follow.
`
`2)
`
`After I earned my MD. from the University of Pennsylvania
`
`School of Medicine (1991), I did an internship in General Surgery at the
`
`Hospital of the University of Pennsylvania (1991—1992) and then served as
`
`Resident in Neurological Surgery, also at the Hospital of the University of
`
`Pennsylvania (1992—1998). I then became a Neurovascular Fellow and the
`
`Institute of Neurology and Neurosurgery at the Beth Israel North Medical
`
`Center (1998- 1999).
`
`3)
`
`I was an Attending Neurosurgeon at the Institute of Neurology
`
`and Neurosurgery Beth Israel Singer Medical Center (1999—2004), after
`
`which I was appointed Attending Neurosurgeon/ Director of
`
`Cerebrovascular Neurosurgery at St. Lukes/Roosevelt Hospital Medical
`
`
`
`Center (2004).
`
`I was appointed Associate Adjunct Surgeon in the
`
`Department of Otolaryngology, New York Eye and Ear Infirmary (2005)
`
`and Attending Neurosurgeon at Long Island College Hospital (2005).
`
`4)
`
`I completed a fellowship in Interventional Neuroradiology at
`
`SUNY Buffalo in 2010.
`
`5)
`
`I was appointed to my current role as Chairman of
`
`Neurosurgery at Lenox Hill Hospital in New York City in 2016. I became
`
`Professor of Neurological Surgery in at Hofstra University School of
`
`Medicine in 2015.
`
`6)
`
`I have authored more than twenty papers, published in leading
`
`neurosurgery journals. A full list of my publications is attached.
`
`7)
`
`I currently serve as a clinical advisor to Sony/Olympus in their
`
`video microscope device development program.
`
`8)
`
`I currently use ICG—based fluorescence imaging in my clinical
`
`practice for verification of vessel grafts using a Leica microscope.
`
`9)
`
`I am familiar with the content of the ‘190 Patent. In addition, I
`
`have considered the various documents referenced in this declaration as well
`
`as additional background materials.
`
`10)
`
`Counsel has informed me that I should consider these materials
`
`through the lens of one of ordinary skill in the art related to the ‘ 190 Patent
`
`
`
`as of its effective filing date, and I have done so during my review of these
`
`materials. I believe one of ordinary in the art as of the effective filing date
`
`(which I am informed is September 24, 1999) would be a medical doctor
`
`with 2—3 years’ experience using or designing imaging equipment for use
`
`during medical procedures. I base this on my own personal experience,
`
`including my knowledge of colleagues and others.
`
`11)
`
`I have no financial interest in either party or in the outcome of
`
`this proceeding. I am being compensated for my work as an expert on an
`
`hourly basis. My compensation is not dependent on the outcome of these
`
`proceedings or the content of my opinions.
`
`12) My opinions are based on my education, experience and
`
`background in the fields discussed above.
`
`13)
`
`For convenience, in this declaration, I refer to a number of
`
`publications, either by an exhibit number, or by an abbreviation, as set forth
`
`in the below table.
`
`
`
`
`Descri tion
`
`U.S. Patent No. 8,892,190. “Method and
`
`apparatus for performing intra—operative
`u
`aniorah ” filed March 13, 2012.
`
`
`
`Abbreviation
`
`‘ 190 Patent
`
`
`Little, John R., et al. “Superficial temporal
`
`artery to middle cerebral artery anastomosis:
`
`
`intraoperative evaluation by fiuorescein
`angiography and xenon— 13 3 clearance.”
`
`
`Journal of neurosurgery 50.5 (Q79L560—569.
`
`
`
`
`
`1003
`
`FlowerI
`
`U.S. Patent 6,351,663. “Methods for
`diagnosing and treating conditions associated
`with abnormal vasculature using fluorescent
`dye angiography and dye-enhanced
`hotocoagulation,” filed September 10, 1999.
`1004
`Japanese Laid Open Patent Publication No.
`Jibu
`H9—309845 (Translation). “NEAR—INFRED
`FLUORESCENT TRACER AND
`
`
`
`1005
`
`FLUORESCENE IMAGING IVIETHOD,”
`filed May 21, 1996.
`U.S. Patent No. 5,394,199. “Methods and
`apparatus for improved visualization of
`choroidal blood flow and aberrant vascular
`
`structures in the eye using fluorescent dye
`aniorah ,” filed Ma 17, 1993.
`
`Flower II
`
`1007
`
`1008
`
`Argus 20
`Specification of Argus 20 with C2400-75i,
`1006
`
`S ecification
`dated May 1997
`Goldstein et al., "Intraoperative Angiography Goldstein
`to Assess Graft Patency After Minimally
`Invasive Coronary Bypass," Ann Thorax
`Surg, 66: 1978-1982, (1998).
`Eren, Serdar, et a1. "Assessment of
`microcirculation of an axial skin flap using
`indocyanine green fluorescence angiography."
`Plastic and reconstructive surgery 96.7
`
`1995 :1636—1649
`
`
`
`Eren
`
`
`
`
`1009
`
`1010
`
`1011
`
`1012
`
`Decision of European Patent Office Technical EPO Decision
`Board of Appeal revoking Counterpart Patent
`No. 1 143 852
`
`Translation of Decision of Japanese Patent
`Office Trial Board revoking Counterpart
`
`Patent No. 3,881,550
`
`JPO Decision
`
`Summary of Invention Submitted to European Invention
`Patent Office
`
`Novadaq 5 10K showing X—Ray Fluoroscopy
`
`as Predicate Device
`
`1013
`
`Takayama et al., Intraoperative Coronary
`Angiography Using Fluorescein, Ann Thorac
`Sur.51:140-143 1991
`
`Takayama
`
`
`
`Hyvarinen, Lea and Robert W. Flower.
`“Indocyanine green fluorescence
`angiography.” Acta ophthalmological 58.4
`1980 2528—538
`
`
`
`Hyvarinen
`
`274.
`
`The Sony U-Mastic Videocassette Recorder
`
`
`Joseph, et al. “Evaluation of the circulation of oseph
`reconstructive flaps using laser—induced
`fluorescence of indocyanine green.” Annals
`ofplastic surgery 42.3 (March 1999): 266-
`
`
`
`
`14)
`
`The balance of this declaration is organized under the following
`
`headings: 1) Technology Background; 11) Claim Construction; 111) The
`
`Primary References; IV) The Claims of the ‘ 190 Patent are in the Prior Art;
`
`and V) Execution.
`
`I.
`
`TECHNOLOGY BACKGROUND
`
`15)
`
`The technology in the ‘190 Patent relates to imaging blood flow
`
`by adding a fluorescent dye to the blood, exciting it with excitation light to
`
`emit fluorescence, and taking a Video image using a CCD camera to
`
`visualize how the dye transitions through vessels. Claims 1—3 of the ‘ 190
`
`Patent claim use of this well—known fluorescence imaging technique to
`
`analyze the patency of a vascular graft.
`
`16) All claims require a camera capable of capturing images of the
`
`“wavefront” (i.e., the boundary between fluorescent and non—fluorescent
`
`regions of the blood) where the fluorescent dye is first introduced. Claim 3
`
`
`
`requires that the fluorescent dye have its peak absorption and emission
`
`spectrum in the range of 800—850 nm, which corresponds to that of the well-
`
`known dye, indocyanine green (ICG) (Ex. 1001, 14:29), and that the image
`
`capture rate of the CCD camera be at least 15 images per second, Which is
`
`What a CCD camera could obtain. (See Ex. 1011.)
`
`17)
`
`For convenience, in this declaration, I refer to various claim
`
`limitations in the ‘ 190 Patent by abbreviations, as set forth in the below
`
`table.
`
`[(Tlaim Limitations
`Abbreviation
`l. A method for assessing blood
`Vessel Graft Preamble
`flow moving through a vessel graft
`anastomosed in fluid
`
`communication with an
`
`
`
`
`
`Administering Step
`
`
`
`Illuminating Step
`
`interconnected group of blood
`vessels in an animal, the vessel graft
`and at least a portion of the blood
`vessels being exposed during a
`surgical procedure on the animal,
`the method cgrpprising the steps of:
`(a) administering a fluorescent dye
`to the animal such that the dye
`enters the vessel graft and the
`interconnected group of blood
`
`vessels;
`
`(b) exciting the fluorescent dye
`Within the vessel graft and said
`exposed portion of the
`interconnected group of blood
`vessels with a source of
`
`illumination, thus causing the dye to
`emit radiation;
`
`
`
`
`
`(c) capturing the radiation emitted Wavefront Capturing Step
`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, the images
`including at least an image of a
`fluorescent wavefront
`
`corresponding to an interface
`between the flowing blood that first
`contains the fluorescent dye
`introduced, such image being
`captured by the camera as the
`fluorescent wavefront transitions
`
`through the exposed vessel graft and
`interconnected croup of blood
`
`vessels; and
`
`
`
`
`
`2. The method of claim 1, further
`
` Evaluation Step
`(d) evaluating the angiographic
`images to assess blood flow through
`
`the vessel graft relative to blood
`
`flow through the interconnected
`group of blood vessels.
`
`
`
` Modifying Step
`
`
`comprising:
`modifying said anastomosed vessel
`
`graft based on results of said
`evaluating step, thereby improving
`
`resultant blood flow through said
`
`vessel raft.
`
`
` Vessel Graft Preamble
`3. A method for assessing blood
`flow moving through an [sic] vessel
`
`
`graft in an animal, the vessel graft
`
`being exposed during a surgical
`
`procedure on the animal,
`comprising the steps of:
`
`
`
`
`
`
`Administering Step
`
`(a) administering a fluorescent dye
`to the animal such that the dye
`
`
`enters the vessel raft;
`(b) exciting the fluorescent dye
`Illuminating Step
`within the vessel graft with a source
`of illumination, thus causing the dye
`to emit radiation, the fluorescent
`dye having a peak absorption and
`emission in the range of 800 to 850
`
`mm;
`
`
`
`
`
`800—850 Wavelength Requirement
`
` 15 Images/Second Requirement
`
`(c) capturing the radiation emitted
`by the fluorescent die with a camera
`capable of imaging a series of
`angiographic images of the vessel
`graft at a rate of at least 15 images
`per second while the subject’s heart
`is beating, the images including at
`least an image of a fluorescent
`wavefront corresponding to an
`interface between the flowing blood
`that first contains the fluorescent
`
`dye introduced, such image being
`captured by the camera as the
`fluorescent wavefront transitions
`
`through the exposed vessel graft;
`and
`
`Wavefront Capture Step
`
`
`
`Evaluation Step
`
`(d) evaluating the angiographic
`images to assess blood flow through
`the vessel graft relative to blood
`flow through a group of blood
`vessels interconnected to the vessel
`
`graft.
`
`18)
`
`The sole figure in the ‘ 190 Patent shows the exemplary device
`
`proposed for looking at vessel grafts during an operation using fluorescence:
`
`
`
`
`
`NH000
`
`
`
`19)
`
`In the figure, a laser 1 emits radiation through bandpass filter 5
`
`and optics 7 using a wavelength that Will illuminate a fluorescent dye
`
`injected into the tissues of interest 3 in a patient. The preferred dye injected
`
`into the tissue of interest 3 is ICG. CCD camera 2 captures the emissions
`
`from the dye and can be fitted With a bandpass filter 6, polarizing filter 14a
`
`and lens system 8. A distance detection system 9, 9a may be used. The
`
`camera 2 may relay the captured images to an analog-to—digital converter 10,
`
`PC 15 and monitor 11. A printer 13, VCR 13 and monitor 12 may also be
`
`used for recording, printing or playback.
`
`lO
`
`
`
`II. CLAIM CONSTRUCTION
`
`20)
`
`I am informed by counsel that in this proceeding, the claims of
`
`the ‘ 190 Patent are to be given the broadest reasonable construction. I am
`
`informed that under a broadest reasonable interpretation, words of the claim
`
`must be given their plain meaning, unless such meaning is inconsistent with
`
`the specification. The plain meaning of a term means the ordinary and
`
`customary meaning given to the term by those of ordinary skill in the art at
`
`the time of the invention
`
`21) Under the broadest reasonable construction of the claims, the
`
`“190 Patth permits at least the following constructions:
`
`o
`
`“Vessel graft” can be the graft of any vessels. It can be vessels
`
`in the leg, heart or brain.
`
`(‘ 190 Patent, 1:36—41.)
`
`0
`
`“Animal” can be a human or non-human animal.
`
`(‘ 190 Patent,
`
`4: 1 5- 17.)
`
`o The amount of “fluorescent dye” is not limited as to minimum
`
`or maximum quantities in the Administering Step, nor is there
`
`any requirement that the dye be injected in a single
`
`administration (bolus) or in multiple successive administrations.
`
`ll
`
`
`
`o The method of exciting the fluorescent dye is not limited in the
`
`Illuminating Step and may be done in any manner (e. g., laser,
`
`filtered broad-band light source, etc.).
`
`o The Modifi/ing Step is not limited to a particular modification
`
`of the vessel graft.
`
`0 Evaluation of blood flow through the vessel graft relative to
`
`interconnected vessels is not limited to numerical comparisons
`
`of fluorescence intensities in the vessel graft and connected
`
`vessels. Any type of comparison (e.g., fluorescence signal in
`
`the graft and no signal in the downstream vessels) would
`
`qualify as relative evaluation.
`
`III. THE PRIMARY REFERENCES
`
`A. LITTLE (EX. 1002)
`
`22)
`
`Little describes a method for using fluorescent—dye angiography
`
`to assess blood flow intraoperatively, during an anastomosis (graft) of two
`
`cerebral arteries. (Little, EX. 1002, 561—62.) In particular, Little describes
`
`administering the dye (sodium fluorescein) to the patient; exciting the dye
`
`(with a strobe light to induce fluorescence); capturing multiple images of the
`
`resultant fluorescence in a manner that permits observation of the changing
`
`interface between the fluorescing and non—fluorescing portions of the
`
`12
`
`
`
`vasculature (i.e., the dye wavefront, id. at Figs. 1—3) as the dye flows through
`
`the vasculature; and evaluating the efficacy (in particular the patency) of the
`
`graft on the basis of the angiograms. (Id. at 562.) Figure 2, in particular,
`
`shows the sequential transition of dye fluorescence wavefront from early
`
`arterial to venous phase.
`
`23)
`
`Little further discloses that where the angiogram shows an
`
`occlusion in the graft, further surgical intervention may be carried out to
`
`improve blood flow, and offers clinical examples of such modifications to
`
`the graft. (Id.at 562.)
`
`B. FLOWER I (EX. 1003)
`
`24)
`
`Flower I describes a variety of methods for using fluorescent
`
`dyes in the treatment and observation of animal (including human)
`
`vasculature, and in particular vascular abnormalities. (Flower, 1, Ex. 1003,
`
`2:27-30; 1028-19.) The methods include techniques for enhancing the clarity
`
`of the fluorescent angiograms and observing the direction of the blood flow
`
`through the vasculature. (Id. at 2:31-67.) Flower I discloses that the
`
`angiograms may be captured during surgery. (Id. at 9:23-26.)
`
`25)
`
`Flower I recommends the use of the “readily available” dye
`
`ICG, which Flower I discloses as having its peak absorption and emission
`
`spectra in the range of 800—850 nm. (Id. at 5:41-55.) Flower I also describes
`
`l3
`
`
`
`the use of a CCD video camera to aid the visualization. (Id. at 1:42-47, 10:3-
`
`7.) F lower I observes that the disclosed methods permit observation of the
`
`wavefront of the dye as it transits through the blood vessels.
`
`(Id. at 4:36—46.)
`
`C. FLOWER II (EX. 1005)
`
`26)
`
`Flower II describes a method for generating ICG angiograms to
`
`show blood flow through aberrant blood vessels such as choroidal
`
`neovascularization in the eye. (Flower 11, Ex. 1005, 3:56—62.)
`
`27)
`
`Like Flower 1, Flower II discloses the use of ICG dye,
`
`illumination with a laser with 805 nm range (see light source 44)), use of a
`
`CCD camera 36 that captures at up to 29 frames a second (claim 5) and
`
`visualization of aberrant vascular structures (Abstract).
`
`28)
`
`Flower II recognizes the “obvious[ ]” utility of tracking a
`
`sharply—defined wavefront through the vascular network. (Flower II, EX.
`
`1005, 2:40-42.) Flower II also discloses taking a sequence of angiograms
`
`“at high speeds (15-30 images/second).” (Id. at 4:64—65.)
`
`14
`
`
`
`D.
`
`JIBU (EX. 1004)
`
`29)
`
`Jibu describes a method of administering fluorescent dye into a
`
`living body that is illuminated to cause it to fluoresce. (Jibu, EX. 1004, 3).
`
`Jibu discloses the use of the dye during surgery. (Id. at 15.)
`
`30)
`
`Jibu describes detection of the fluorescence With a CCD camera
`
`(C24000-75i, manufactured by Hamamatsu Photonics K.K.) outfitted With
`
`an image processing device (Argus 20, manufactured by Hamamatsu
`
`Photonics K.K.) (Jibu, EX. 1004, 13—14), a combination Whose frame rate
`
`exceeds 15 images per second.
`
`1006; see also EX. 1010, 5-6.)
`
`31)
`
`Jibu discloses ICG, a dye that fluoresces at a wavelength of at
`
`least 700nm, but that is preferably 800 nm or higher, and describes one such
`
`dye (ICG) that fluoresces at 835 nm. (Jibu, EX. 1004, 7—8, 13.)
`
`15
`
`
`
`E. GOLDSTEIN (EX. 1007)
`
`32) Goldstein describes a method for the use of intraoperative
`
`fluoroscopic angiography to assess a coronary artery bypass graft.
`
`(Goldstein, EX. 1007, 1979.) Goldstein describes the benefits of the
`
`intraoperative angiogram, which provides real-time imaging and thus
`
`permits “surgical revision” and optimal surgical result. (Id; see also, e. g.,
`
`id. at 1980 (“intraoperative coronary angiography using a portable
`
`fluoroscopic system documents the immediate results of MINCAB
`
`[minimally invasive coronary artery bypass grafting] .
`
`.
`
`. and provides timely
`
`data that could influence intraoperative treatment and patient outcome”).)
`
`Goldstein discloses the use of 30/frame per second fluoroscope.
`
`33) Goldstein shows using a more complex (X-ray based)
`
`fluoroscope during open heart surgery. One of skill in the art would
`
`consider simpler equipment shown in Flower I, Flower II or Jibu. For
`
`example, Novadaq Technologies, Inc. cites fluoroscopy equipment as a
`
`predicate device. (EX. 1012).
`
`IV. THE CLAIMS OF THE ‘190 PATENT ARE IN THE PRIOR ART
`
`A. Claims 1 and 2 are fully disclosed by Little
`
`34)
`
`The Vessel Graft Preamble of Claim 1 recites “[a] method for
`
`assessing blood flow moving through a vessel graft anastomosed in fluid
`
`16
`
`
`
`communication with an interconnected group of blood vessels in an animal,
`
`the vessel graft and at least a portion of the blood vessels being exposed
`
`during a surgical procedure on the animal.”
`
`35) Assuming the preamble provides a claim limitation, it is
`
`disclosed by Little. Little describes “[fjluorescein angiography [that]
`
`provided an immediate assessment of anastomotic patency and clearly
`
`displayed the distribution of blood entering the epicerebral circulation
`
`through” an artery. (Little, EX. 1002, 560). In other words, Little discloses
`
`using a dye—fluorescence angiography procedure to intraoperatively evaluate
`
`blood flow through a graft.
`
`36)
`
`Limitation 13), the Administering Step, describes
`
`“administering a fluorescent dye to the animal such that the dye enters the
`
`vessel graft and the interconnected group of blood vessels.”
`
`37)
`
`Little discloses this element. Recognizing that “[t]he technique
`
`of fluorescein angiography has been described in detail elsewhere,” Little
`
`discloses the use of fluorescein angiography “performed before and after
`
`anastomosis” by way of sodium fluorescein dye being “injected rapidly into
`
`the ipsilateral [common carotid artery] through the indwelling catheter.”
`
`(Little, EX. 1002, 562.) Little thus discloses the administration of a
`
`fluorescent dye in a vessel graft.
`
`l7
`
`
`
`38) Element 1b}, the Illuminating Step, describes “exciting the
`
`fluorescent dye within the vessel graft and said exposed portion of the
`
`interconnected group of blood vessels with a source of illumination, thus
`
`causing the dye to emit radiation.”
`
`39)
`
`Little discloses this element as well, describing that
`
`“[i]illumination for photography was provided by a strobe light .
`
`.
`
`. [and]
`
`[b]arrier filters .
`
`.
`
`. were used to keep unwanted exciting radiation from
`
`reaching the film.” (Little, Ex. 1002, 562.) In other words, the strobe light
`
`excites the fluorescein dye, which fluoresces in response.
`
`40) Element gel, the Wavefront Capture Step, describes
`
`“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, the
`
`images including at least an image of a fluorescent wavefront corresponding
`
`to an interface between the flowing blood that first contains the fluorescent
`
`dye introduced, such image being captured by the camera as the fluorescent
`
`wavefront transitions through the exposed vessel graft and interconnected
`
`group of blood vessels.”
`
`41)
`
`Little discloses this element, describing the taking of “[r]apid,
`
`serial photographs of the cortex .
`
`.
`
`. with a motorized camera” that is fitted
`
`18
`
`
`
`with a “data-back digital timer [that] automatically printed the time in one—
`
`hundredths of a second in the corner of each frame.” (Little, EX. 1002, 562).
`
`Little discloses an exemplary sequence of these images that shows the
`
`camera capturing the wavefront as the dye as it is introduced and transitions
`
`through the graft and the connected vasculature.
`
`(1d. at 562 & Fig. 1.) The
`
`first image in the sequence was taken before the fluorescence wavefront; the
`
`second image is taken as blood with fluorescent dye entered the vascular
`
`system under observation, thus demonstrating that the camera and system
`
`described can and did capture the fluorescent wavefront. Figure 2 shows the
`
`sequential transition of dye fluorescence wavefront from early arterial to
`
`venous phase.
`
`42) Element 1d}, the Evaluation Step, describes “evaluating the
`
`angiographic images to assess blood flow through the vessel graft relative to
`
`blood flow through the interconnected group of blood vessels.”
`
`43)
`
`Little discloses this element as well. For example, in Figure 1,
`
`the image bearing the time stamp 01:13 shows the filling of the cortical
`
`receptor artery, the site of the vessel graft upstream of the anastomosis
`
`(Little, EX. 1002, 563), while the image bearing the time stamp 03:01 shows
`
`the evaluation of the cortical branches.
`
`(1d,) The accompanying caption
`
`notes transition of blood with fluorescent dye to the artery downstream of
`
`19
`
`
`
`the graft, thus demonstrating the evaluation of the graft. (Id. (“The cortical
`
`branches of the middle cerebral artery filled in an anterograde direction. The
`
`microcirculation supplied by the receptor artery also has filled”). Similarly,
`
`Little’s use of time recording accurate to 1/100 of second demonstrates that
`
`the camera images were used to analyze blood flow; this level of accuracy
`
`permitted a comparison of vessel transit times before and after anastomosis.
`
`(See id. at 5 62 (“Studies performed before anastomosis showed delayed
`
`filling of the cortical branches of the MCA. The mean duration between
`
`injection of fluorescein into the ipsilateral CCA and its initial appearance in
`
`the epicerebral circulation was 2.4 + 0.4 seconds, compared with 0.7 + 0.3
`
`seconds following anastomosis”).)
`
`44)
`
`Little discloses the evaluation of the interconnected vessels in
`
`particular. The upper left image and the image time stamped 03:01 in Little
`
`Figure 1 (Little, EX. 1002, 5 63), illustrate a comparison between the blood
`
`flow through the vessel graft area and the flow in the interconnected vessels.
`
`Little describes this comparison in the body text of the article as well.
`
`(Little, EX. 1002, 5 64 (“Fluorescein angiography showed the distribution of
`
`blood supplied by the STA through the anastomosis. Of the 14 patients who
`
`underwent surgery for occlusive disease of the ICA, nine had filling of
`
`multiple MCA cortical branches (Fig. 1) and five had filling predominantly
`
`20
`
`
`
`in the receptor artery territory (Fig. 2)”).)
`
`45)
`
`In summary, Little discloses all the elements of Claim 1.
`
`46)
`
`Little also discloses all the elements of Dependent Claim 2,
`
`which adds the Modifying Step: “modifying said anastomosed vessel graft
`
`based on results of said evaluating step, thereby improving resultant blood
`
`flow through said vessel graft.”
`
`47)
`
`Little discloses the Modifying Step. In several of the surgical
`
`cases Little describes, the fluorescence angiogram revealed an occlusion of
`
`the graft, on the basis of which the clinicians made corrective surgical
`
`modifications. (Little, EX. 1002, 562 (“Patency of the anastomosis was
`
`demonstrated in 13 patients. In one of these patients .
`
`.
`
`.
`
`, partial obstruction
`
`of the STA was seen .
`
`.
`
`.
`
`. This was corrected by gentle manipulation .
`
`.
`
`. The
`
`anastomosis was found to be occluded in two patients. A thrombus was
`
`successfully removed and patency restored in one of these patients .
`
`.
`
`.
`
`. In
`
`the other [patient] .
`
`.
`
`., patency was re—established .
`
`. .”).)
`
`48)
`
`Little thus discloses the elements of Dependent Claim 2.
`
`B. Claims 1, 2 and 3 are shown in Little, Flower I and Flower II
`
`49) As observed, Little anticipates the Vessel Graft Preamble.
`
`Little describes “[f]luorescein angiography [that] provided an immediate
`
`assessment of anastomotic patency and clearly displayed the distribution of
`
`21
`
`
`
`blood entering the epicerebral circulation through” an artery. (Little, EX.
`
`1002, 560.)
`
`50)
`
`Little also anticipates the Administering Step, noting that
`
`“[t]he technique of fluorescein angiography has been described in detail
`
`elsewhere,” and going on to disclose the use of fluorescein angiography
`
`“performed before and after anastomosis” by way of sodium fluorescein
`
`being “injected rapidly into the ipsilateral [common carotid artery] through
`
`the indwelling catheter.” (Little, EX. 1002, 562.)
`
`51) Also, as noted, Little anticipates the Illuminating Step,
`
`describing that “[i]llumination for photography was provided by a strobe
`
`light .
`
`.
`
`. [and] [b]arrier filters .
`
`.
`
`. were used to keep unwanted exciting
`
`radiation from reaching the film.” (161.)
`
`52)
`
`Little likewise anticipates the Wavefront Capture Step
`
`describing the taking of “[r]apid, serial photographs of the corteX .
`
`.
`
`. with a
`
`motorized camera” that is fitted with a “data-back digital timer [that]
`
`automatically printed the time in one—hundredths of a second in the corner of
`
`each frame.” (Id. at 562). Little discloses an exemplary sequence of these
`
`images demonstrating that the camera and system described can and did
`
`capture the fluorescent wavefront. (Id. at 562 & Fig. l.)
`
`22
`
`
`
`53)
`
`The Wavefront Capture Step, is also disclosed in the Flower
`
`references. Specifically, FlowerI discloses the angiographic observation of
`
`the wavefront of the fluorescent dye as it transits through the blood vessels.
`
`(Flower 1, Ex. 1003, 4:36—46.) Flower II similarly recognizes the “obvious”
`
`utility of angiographically tracking a sharply-defined fluorescent-dye
`
`wavefront through a vascular network. (Flower II, EX. 1005, 2:40-42.)
`
`Flower II states that observation of the relevant vasculature “with
`
`fluorescent dye angiography is best accomplished when a very small volume
`
`dye bolus having a sharply defined wavefront passes through.” (Id. at 2:28-
`
`29.) Thus, in view Flower I and Flower II a person having ordinary skill in
`
`the art would be motivated to angiographically capture and assess the
`
`wavefront in tracking the flow of dye through a vascular graft. This
`
`technique is known from Flower I and II and could be easily done in the
`
`context of Little with predictable results.
`
`54)
`
`That a person having ordinary skill would be motivated to
`
`combine in this manner is further confirmed by Eren, EX. 1008, which
`
`describes the influx of fluorescent die through tissue and provides images
`
`(Eren, Ex. 1008, 1631 Fig. 3) showing a portion of the vasculature as die
`
`transitions through it, thus differentiating the blood containing the dye from
`
`that not containing the dye.
`
`23
`
`
`
`55) As to the Evaluation Step, this, too, is disclosed by Little. As
`
`noted, in Figure 1, the image bearing the time stamp 01 :13 shows the filling
`
`of the cortical receptor artery, the site of the vessel graft upstream of the
`
`anastomosis (Little, EX. 1002, 563), while the image bearing the time stamp
`
`03:01 shows the evaluation of the cortical branches. (Id.) The
`
`accompanying caption notes transition of blood with fluorescent dye to the
`
`artery downstream of the graft, thus demonstrating the evaluation of the
`
`graft. (Id. (“The cortical branches of the middle cerebral artery filled in an
`
`anterograde direction. The microcirculation supplied by the receptor artery
`
`also has filled.”).)
`
`56)
`
`Similarly, Little’s use of time recording accurate to 1/100 of
`
`second demonstrates that the camera images were used to analyze blood
`
`flow; this level of accuracy permitted a comparison of vessel transit times
`
`before and after anastomosis.
`
`(See id. at 562 (“Studies performed before
`
`anastomosis showed delayed filling of the cortical branches of the MCA.
`
`The mean duration between injection of fluorescein into the ipsilateral CCA
`
`and its initial appearance in the epicerebral circulation was 2.4 + 0.4
`
`seconds, compared with 0.7 + 0.3 seconds following anastomosis”).)
`
`57)
`
`Little also discloses the evaluation of interconnected vessels.
`
`The upper left image and the image time stamped 03:01 in Little Figure l
`
`24
`
`
`
`(Id. at 563), illustrate a comparison between the blood flow through the
`
`vessel graft area and the flow in the interconnected vessels. Little describes
`
`this comparison in the body text of the article as well. (Id. at 564
`
`(“Fluorescein angiography showed the distribution of blood supplied by the
`
`STA through the anastomosis. Of the 14 patients who underwent surgery for
`
`occlusive disease of the ICA, nine had filling of multiple MCA cortical
`
`branches (Fig. 1) and five had filling predominantly in the receptor artery
`
`territory (Fig. 2)”.)
`
`58)
`
`The Evaluation Step is also disclosed in the Flower references.
`
`Flower I describes methods for using fluorescent dyes to evaluate vascular
`
`abnormalities (Flower 1, Ex. 1003, 1028—19) during surgery (id. at 9:23-26),
`
`including specifically in the heart (id. at 8:46-49). Flower 11, too, describes a
`
`method for generating angiograms to show blood flow through certain blood
`
`vessels, including aberrant vessels (Flower II, EX. 1005, Abstract & 3:56—
`
`62), and through a vascular network.
`
`(Id. at 2:40—42.) It is also expected
`
`that any physician doing procedures such as those shown in Little would do
`
`evaluation
`
`that’s the whole point of using fluorescence imaging.
`
`59)
`
`In view Flower I and Flower II a person having ordinary skill in
`
`the art would understand that widely-known fluorescent dye evaluative
`
`techniques, could be used to track the flow of dye in a clinical situation such
`
`25
`
`
`
`as that described in Little, namely during an arterial anastomosis. (See also
`
`Eren, EX. 1008, 1640 (describing the use of fluorescent dye through
`
`vasculature).)
`
`60) As to Dependent Claim 2, which adds the Modifying Step, this
`
`is anticipated by Little, as noted supra. In several of the cases Little
`
`describes, the fluorescence angiogram revealed an occlusion of the graft,
`
`which prompted the authors to make surgical modification. (Little, EX.
`
`1002, 562 (“[P]artial obstruction of the STA was seen .
`
`.
`
`.
`
`. This was
`
`corrected by gentle manipulation .
`
`.
`
`. The anastomosis was found to be
`
`occluded in two patients. A thrombus was successfully removed and patency
`
`restored in one of these patients .
`
`.
`
`.
`
`. In the other [patient] .
`
`.
`
`. patency was
`
`re-established .
`
`. .”).)
`
`61)
`
`Claim 3 adds two requirements to Claim 1: the 800—850
`
`Wavelength Requirement and the 15 Images/Second Requirement. Each of
`
`these requirements is shown in the prior art in light of the Flower references.
`
`62)
`
`The 800-850 Wavelength Reg uirement is in the prior art.
`
`Flower I discloses the use of ICG for angiographic imaging, describing ICG
`
`as “[t]he preferred fluorescent dye .
`
`.
`
`. because it is readily available, has
`
`long been approved for administration to humans .
`
`.
`
`. and is suitable for both
`
`diagnosis and treatment procedures.” (Flower I, EX. 1003, 5:47-51.) Flower
`
`26
`
`
`
`I discloses that ICG has peak absorption and emission in the range of 800-
`
`850 nm. (Id. at 5:41-55.) Flower II also discloses the use ofICG in
`
`angiography (Flower II, EX. 1005, 3:56—62), as does Eren (EX. 1008, 1640),
`
`which discloses an emission range of ICG in serum of 805 to 835 nm.
`
`63)
`
`Thus, a person having ordinary skill in the art performing an
`
`intraoperative angiogram would be motivated to use ICG, the “p
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