Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June , is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Amendment
Applicant’s Amendments filed on October 17, 2025, has been entered and made of record.
Currently pending Claim(s) 1-22
Independent Claim(s) 1 and 20
Amended Claim(s) 19
Response to Arguments
This office action is responsive to Applicant’s Arguments/Remarks Made in an Amendment received on October 17, 2025.
In view of amendments filed on October 17, 2025, with respect to the claims, the Applicant has amended claim 19 to include a “computer program product stored on a memory” rather than a “computer program” as previously claimed. However, this amendment does not overcome the 35 USC 101 rejection applied to claim 19, because the claim is still directed to a computer program, which could be interpreted as a signal. In the body of rejection below, the Examiner discusses the rejection in more detail and provides an example amendment for overcoming the rejection.
In view of Applicant Arguments/Remarks filed October 17, 2025, with respect to the claims, the Applicant first discussed (on Remarks page 8, paragraphs 3) the rejection to claim 1 made in the Non-Final Rejection (dated June 03, 2025). The Applicant discusses that the Non-Final Rejection used Docherty (US 2008/0071176 A1) to teach some limitations of claim 1, but the Non-Final Rejection concedes that Docherty fails to teach identifying blood vessels based on the flow of ICG over time in the series of fluorescent images. Upon further examination of this statement and the prior art, the Examiner further clarifies that the angiograms are used for identifying vessels [0036-0040], examining the blood flow through a vein/artery [0060], and determining the patency of the vessel lumen [0060]. Docherty uses the images of the fluorescing dye over time for analysis of vessel patency [0060] and rate of blood flow [0060], but doesn’t specifically discuss how time differences in the images are observed and used in calculations.
Next, the Applicant argued (on Remarks page 9, paragraph 1-3) that it would not be obvious to one of ordinary skill in the art to modify Docherty’s invention by identifying blood vessels based on the direction of flow of ICG over time to aid in identifying vessels which provide blood to an abnormality, since the Examiner mischaracterized the references cited in the office action. The Applicant showed that the excerpt quoted by the Examiner [page 3, line 28 – page 4, line 7] teaches destroying florescence and tracking non-fluorescing markers to track blood flow. The Examiner respectfully disagrees with this argument and believes that Alam is analogous to both Docherty and the claimed invention; thus, one of ordinary skill in the art would be motivated to combine the references. The quoted excerpt [page 3, line 28 – page 4, line 7] is one embodiment of Alam that teaches comparing angiograms of fluorescing dye to angiograms of non-fluorescing dye to track the flow of dye through the vessels. Although this specific embodiment differs somewhat from the teachings of Docherty, the preferred embodiment [page 3, lines 12-23] teaches administering boluses at regular time intervals and capturing angiograms of the fluorescing boluses for the purpose of capturing angiograms with higher quality. Both Docherty and Alam teach administering ICG and capturing images to produce angiograms for analyzing blood vessels.
Continuing with this argument, the Applicant argued (on Remarks page 9, paragraph 5) that the excerpt quoted by the Examiner [Page 3, line 28 – Page 4, line 7] from Alam does not disclose generating an oscillating frequency signal from the injection of a fluorescent contrast agent. The Examiner respectfully disagrees. In both the embodiment previously quoted and the preferred embodiment, Alam teaches capturing angiographic sequences of dye administered in boluses over an angiographic procedure ([page 3, lines 12-23] “In particular, the present invention is able to provide angiograms of enhanced clarity by administering a plurality of relatively small boluses at relatively high dye concentrations to an animal undergoing an angiographic procedure. In particular, the method includes introducing boluses of about 0.1 ml to about 1.0 ml of a liquid composition at spaced time intervals into the animal to at least partially fill the blood vessels with the composition, wherein the liquid composition comprises a relatively high fluorescent dye and a carrier… Light energy of a type and in an amount sufficient to cause the dye in each bolus to fluoresce as the dye flows through the blood vessels is then applied, and angiographic images obtained.”). This process would create an oscillating frequency of fluorescent intensity that is detected in the angiographic sequence as each bolus of fluorescent dye is excited and flows in view of the camera. As taught in the background section by Alam, the process of analyzing each region of increased fluorescent signal over time is well-known in the art ([page 2, lines 3-12] “after the dye is injected into the body, the dye enters the vasculature of the eye and begins to fluoresce due to the presence of the appropriate excitation radiation (light). The fluorescing dye, being mixed with the ocular blood, provides each angiogram with an accurate illustration of the extent of ocular blood flow through the ocular vasculature at that moment. By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature.”).
Lastly, the Applicant argued (on Remarks page 9, paragraph 4 – page 10, paragraph 2) that the embodiment quoted by the Examiner [page 3, line 28 – page 4, line 7] from Alam discloses a bleaching method for comparing angiograms of fluorescing and non-fluorescing regions and that Alam fails to disclose analyzing an oscillating waveform of florescent signal. As described above, the injection of boluses at regular intervals taught by Alam creates an oscillation of fluorescent intensity in the images that is observed, and Alam teaches that observing angiograms by analyzing the movement of high florescence (excited ICG boluses) throughout the images over time is used for identifying vessels and mapping vasculature [page 2, lines 3-12].
Overall, the Examiner believes that Claim 1 is too broad to overcome the prior art of record. The Applicant pointed out that Alam does not teach specifics, such as analysis of an oscillating signal waveform, but the claims are very broad and do not specifically claim analyzing a waveform. Claim 1 recites continuously identifying blood vessels in the fluorescence images of the tissue based on said time difference(s) and the fluorescent signal oscillating with the predetermined pattern. Alam teaches that mapping vasculature by examining fluorescing ICG over time in an angiogram is well-known in the art [page 2, lines 3-12], and Alam teaches where boluses are administered at regular intervals for the purpose of creating higher quality angiograms [page 3, lines 12-23]. The Examiner interprets examining the fluorescing ICG boluses (which provide detectable and oscillating florescent signal in the images) in an angiogram over time to map vasculature and identify vessels as “identifying blood vessels in the fluorescence images of the tissue based on said time difference(s) and the fluorescent signal oscillating with the predetermined pattern.”
To overcome broad interpretation and to distinguish the claimed invention from the prior art of analyzing angiograms, claim 1 should explain how the claimed method is performed. More specifically, claim 1 should explain how a time difference is determined, what aspects of the waveforms are analyzed, and how the fluorescent images and fluorescent waveforms are both used to identify blood vessels.
Additionally, the Examiner recommends viewing the art of Ferguson et al. (US 10,278,585 B2), hereafter Ferguson, mentioned in the conclusion of this office action. Although, Ferguson is not used in the prior art rejections within this office action, Ferguson was found during a new prior art search for this office action and discloses content similar to claim 1. Ferguson teaches administering ICG and recording image sequences of the fluorescing ICG. The changes in fluorescent intensity over time is analyzed along with the image sequences and used to determine the venous and arterial phases.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 19 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim is NOT directed to a process, machine, manufacture or composition of matter. The claimed “computer program product stored on a memory” is non-structural per se, and the specification does not exclude the “computer program product stored on a memory” from being software (see paragraph 0025). Therefore, a reasonable interpretation in light of the specification leads to the conclusion that the claim encompasses pure software, which does not fall within the definition of a process, machine, manufacture or composition of matter.
The Examiner recommends amending claim 19 to focus on a machine rather than a computer program. For example, claim 19 could be amended as follows: “A non-transitory computer-readable medium comprising instructions which, when executed by a computing device or computing system, cause the computing device or computing system to carry out the method of identifying blood vessels in tissue of a subject according to of claim 1.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-5, 7-8, and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over Docherty et al. (US 2008/0071176 A1), hereafter Docherty, further in view of Alam and Flower (WO 0117561 A1), hereafter Alam.
Regarding claim 1, Docherty teaches a computer implemented method for identifying blood vessels in tissue of a subject, e.g. during a medical procedure (Fig. 1 shows the computer system used to carry out the proposed method.),
the method comprising the steps of –
continuously acquiring fluorescence images of the tissue wherein a fluorescent signal is oscillating with a predetermined pattern, the pattern generated from a series of boluses of at least one fluorescent imaging agent, and wherein the series of boluses is administered with a predefined and/or controlled duration between subsequent boluses determining the pattern (Docherty teaches capturing a series of angiograms for examining blood vessels. Each angiogram consists of injecting a bolus of ICG dye and collecting an angiogram of interlaced images. [0065] “The fluorescence (radiation) emitted by the dye (830 nm) was captured as a series of angiograms using a CCD camera.” [0067] “The laser device included an SDL-820 Laser Diode Driver (SDL Inc., San Jose, Calif.) that maintained a continuous wave output with an average current of 3.95 A, and an SDL-2382-P1 laser diode (SDL Inc.). The laser diode was used to illuminate the area of interest and excite the ICG dye, thereby inducing fluorescence in the region being imaged.” [0070] “After each IV injection of an ICG dye bolus, a series of 264 interlaced images was collected at a rate of 30 per second.”),
- analyzing at least part of the fluorescence images ([0073] “Image analysis was performed using XCAP for Windows 95/98/NT version 1.0 (EPIX Inc., Buffalo Grove, Ill.).” Docherty teaches identifying the areas in the image with high-fluorescence signal over time using an edge detector in 0075-0078).
Although Docherty teaches acquiring angiograms for a series of boluses for analyzing blood vessels and identifying areas of high fluorescent signal [0075-0078], Docherty does not specifically mention analyzing a time difference between detecting fluorescence signals. More specifically, Docherty fails to teach determining at least one time difference selected from the group of: "time difference between bolus injection and artery fluorescent signal or vein fluorescent signal, "time difference between artery fluorescent signal and vein fluorescent signal, "time difference between artery fluorescent signal or vein fluorescent signal and tissue fluorescent signal”, and – continuously identifying blood vessels in the fluorescence images of the tissue based on said time difference(s) and the fluorescent signal oscillating with the predetermined pattern.
However, Alam teaches determining at least one time difference selected from the group of: "time difference between bolus injection and artery fluorescent signal or vein fluorescent signal, "time difference between artery fluorescent signal and vein fluorescent signal, "time difference between artery fluorescent signal or vein fluorescent signal and tissue fluorescent signal” (Alam teaches creating angiograms by injecting boluses of IGC at regular intervals, fluorescing the ICG, and capturing a series of images of the ICG’s movement. [page 3, lines 12-23] “In particular, the present invention is able to provide angiograms of enhanced clarity by administering a plurality of relatively small boluses at relatively high dye concentrations to an animal undergoing an angiographic procedure. In particular, the method includes introducing boluses of about 0.1 ml to about 1.0 ml of a liquid composition at spaced time intervals into the animal… Light energy of a type and in an amount sufficient to cause the dye in each bolus to fluoresce as the dye flows through the blood vessels is then applied, and angiographic images obtained.” Alam also teaches observing the fluorescing boluses in the angiograms over time to determine blood flow direction. [Page 3, line 28 – Page 4, line 7] “Energy of a type and in an amount sufficient to cause the dye in the blood vessel to fluoresce is then applied. Subsequently, energy of a type and in an amount in excess of that required to cause the dye to fluoresce is applied to a portion of the fluorescing dye passing through the blood vessel to cause that portion of the fluorescing dye to stop fluorescing. A series of angiographs of both the fluorescing dye, and of the subsequent non-fluorescing portion thereof (also referred to as the "bleached" dye portion), are obtained, and those angiograms are compared to determine the direction of relative movement of the bleached dye. The direction of relative movement of the bleached dye portion indicates the direction of relative movement of the blood flow in the blood vessel.” Additionally, Alam also teaches that examining excited fluorescence over time is a well-known method for mapping vasculature. [page 2, lines 3-12] “The angiograms provide a record of the extent of dye movement within the ocular vasculature at each specific time interval. More specifically, after the dye is injected into the body, the dye enters the vasculature of the eye and begins to fluoresce due to the presence of the appropriate excitation radiation (light). The fluorescing dye, being mixed with the ocular blood, provides each angiogram with an accurate illustration of the extent of ocular blood flow through the ocular vasculature at that moment. By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature.”).
and – continuously identifying blood vessels in the fluorescence images of the tissue based on said time difference(s) and the fluorescent signal oscillating with the predetermined pattern (As quoted above, on page 3 Alam teaches administering boluses of ICG at regular time intervals, capturing angiograms, and analyzing the movement of boluses over time to determine blood flow direction. At page 2, lines 3-12, Alam explains that identifying vasculature by examining the ICG over time is well-known in the art. Examining the movement of ICG over time is examining the area of the image with higher fluorescent signal as it moves over time.).
Docherty and Alam and analogous in the art because both teach methods of administering ICG into vessels of a patient and capturing a series of fluorescent images observing the flow of the ICG to view and identify vessels. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s invention by considering the timing between injecting boluses and detecting fluorescent signal. This modification would allow for a series of angiograms to be used for mapping the vasculature and locating lesions (Alam [page 2, lines 10-13] By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature and determine the location of a CNV, and may then move to treat this abnormality, e.g., by laser photocoagulation of the CNV itself.” Additionally, examining the movement of boluses over time in the images would enhance the invention by additionally considering the direction of blood flow, which would aid in identifying vessels which provide blood to an abnormality [page 15, lines 14-16] “This method is of significance in identifying those arteries that are providing blood to a lesion, e.g., CNV, tumor or other blood vessel abnormality.”).
Regarding claim 3, Docherty fails to teach identifying the interconnectivity of blood vessels. However, Alam teaches wherein the identified blood vessels are combined to identify one or more networks of interconnected blood vessels (Page 15, lines 13-16 “the present invention also provides a method for determining the direction of blood flow in a blood vessel of a patient. This method is of significance in identifying those arteries that are providing blood to a lesion, e.g., CNV, tumor or other blood vessel abnormality.” Combinations of interconnected blood vessels which provide blood to an abnormality are identified.).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s invention by considering the timing between injecting boluses and detecting fluorescent signal. This modification would allow for a series of angiograms to be used for mapping the vasculature and locating lesions (Alam [page 2, lines 10-13] By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature and determine the location of a CNV, and may then move to treat this abnormality, e.g., by laser photocoagulation of the CNV itself.”).
Regarding claim 4, Docherty teaches wherein the identified blood vessels are continuously displayed and visualized on a screen (Fig. 1; Docherty teaches displaying the angiograms on a screen. [0056] “The camera may also direct images directly to a television 12/VCR 13 system, wherein the images may be displayed in real time and/or recorded for playback at a later time. Preferably, the monitor and/or television are located in the surgical suite, permitting real-time viewing of various aspects of the treated and surrounding vessels.” Blood vessels are identified by viewing the movement of ICG through vessels in the images, and Docherty teaches performing measurements, such as evaluating the diameter, from the images. [0065-0066] “The camera relayed the angiograms to analog-to-digital conversion software running on a PC that digitized the angiograms. The digitized images were then analyzed both qualitatively (by viewing the monitor) and quantitatively. One example of quantitative evaluation that was undertaken was the determination of the mouse femoral artery diameter using software comprising a sub-pixel edge detection system running on the PC. The foregoing fluorescence imaging technique was used on the mouse femoral artery in vivo.”).
Regarding claim 5, Docherty fails to teach comprising the step of determining a time difference between artery fluorescent signal and vein fluorescent signal, and distinguishing arteries and veins in the identified blood vessels based on said time difference and the predetermined pattern of the oscillating fluorescent signal.
However, Alam teaches comprising the step of determining a time difference between artery fluorescent signal and vein fluorescent signal, and distinguishing arteries and veins in the identified blood vessels based on said time difference and the predetermined pattern of the oscillating fluorescent signal (Alam teaches creating angiograms by injecting boluses of IGC at regular intervals, fluorescing the ICG, and capturing a series of images of the ICG’s movement. [page 3, lines 12-23] “In particular, the present invention is able to provide angiograms of enhanced clarity by administering a plurality of relatively small boluses at relatively high dye concentrations to an animal undergoing an angiographic procedure. In particular, the method includes introducing boluses of about 0.1 ml to about 1.0 ml of a liquid composition at spaced time intervals into the animal… Light energy of a type and in an amount sufficient to cause the dye in each bolus to fluoresce as the dye flows through the blood vessels is then applied, and angiographic images obtained.” Alam also teaches observing the fluorescing boluses in the angiograms over time to determine blood flow direction. [Page 3, line 28 – Page 4, line 7] “Energy of a type and in an amount sufficient to cause the dye in the blood vessel to fluoresce is then applied. Subsequently, energy of a type and in an amount in excess of that required to cause the dye to fluoresce is applied to a portion of the fluorescing dye passing through the blood vessel to cause that portion of the fluorescing dye to stop fluorescing. A series of angiographs of both the fluorescing dye, and of the subsequent non-fluorescing portion thereof (also referred to as the "bleached" dye portion), are obtained, and those angiograms are compared to determine the direction of relative movement of the bleached dye. The direction of relative movement of the bleached dye portion indicates the direction of relative movement of the blood flow in the blood vessel.” Additionally, Alam teaches that examining excited fluorescence over time is a well-known method for mapping vasculature. [page 2, lines 3-12] “The angiograms provide a record of the extent of dye movement within the ocular vasculature at each specific time interval. More specifically, after the dye is injected into the body, the dye enters the vasculature of the eye and begins to fluoresce due to the presence of the appropriate excitation radiation (light). The fluorescing dye, being mixed with the ocular blood, provides each angiogram with an accurate illustration of the extent of ocular blood flow through the ocular vasculature at that moment. By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature.”).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s invention by considering the timing between injecting boluses and detecting fluorescent signal. This modification would allow for a series of angiograms to be used for mapping the vasculature and locating lesions (Alam [page 2, lines 10-13] By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature and determine the location of a CNV, and may then move to treat this abnormality, e.g., by laser photocoagulation of the CNV itself.”). Additionally, examining the movement of boluses over time in the images would enhance the invention by additionally considering the direction of blood flow, which would aid in identifying vessels which provide blood to an abnormality ([page 15, lines 14-16] “This method is of significance in identifying those arteries that are providing blood to a lesion, e.g., CNV, tumor or other blood vessel abnormality.”).
Regarding claim 7, Docherty teaches wherein a sequence of the acquired fluorescence images are analysed and pixels in the fluorescence images are classified as either 1) artery, 2) vein, 3) surrounding tissue, or 4) otherwise, based on the phase of the fluorescent signal in the respective pixels relative to the predetermined oscillating pattern ([0017] “a camera capable of capturing the radiation emitted by the fluorescing dye within the blood vessel as an angiographic image comprised of a plurality of pixels; and a computer comprising a software program that calculates the diameter of a blood vessel by comparing the number of pixels that correspond to the blood vessel diameter with the number of pixels associated with a preselected unit of measurement.” [0060] “This selected series of images may then be analyzed to determine the diameter of the treated (or any other vessel) at a particular location, as well as the rate and volume of blood flow through the treated vessel and adjacent original vessel.” A series of florescent images capturing ICG flow in blood vessels is analyzed, and pixels which correspond to vessels can be identified using sub-pixel edge detection to calculate the diameter of the vessel. Thus, the computer system differentiates between pixels which correspond to vessels.).
Regarding claim 8, Docherty teaches wherein blood vessels are identified and visualized by image filtering or edge filtering ([0078] “Edge strength, which is automatically calculated by the edge detector in our software, is a measure of the relative strength of the edge, i.e., the ratio of the value of the pixels on one side of the edge to the value of those on the other side. The ratio is highest when the contrast is greatest, which corresponds to the greatest intensity of ICG fluorescence. The vessels that were measured have two edges, thus ten frames in which the product of the edge strengths was the greatest were selected for analysis.”).
Regarding claim 13, Docherty teaches wherein the series of boluses is injected automatically by a controllable injection pump ([0043] “Administration is typically accomplished via parenteral, IV injection, or other suitable means, with IV injection of the composition as a bolus being preferred, with the carrier being selected in view of the desired mode of administration.”).
Regarding claim 14, Docherty teaches wherein the imaged tissue is part of an anatomical structure in the gastrointestinal tract, selected from the buccal cavity; pharynx; the small intestine including duodenum, jejunum, and ileum; the stomach, including esophagus, cardia, and pylorus; the large intestine including cecum, colon, rectum and the anal canal ([0032] “This aspect of the present invention further contemplates assessing the blood flow in other body tissues including, but not limited to, muscle, stomach, liver, intestine, bladder, esophagus, lung, kidney and brain tissue. Angiographic images may be obtained beneath the surface of these tissues to a depth not exceeding that which permits the vasculature of interest to be evaluated.”).
Regarding claim 15, Docherty teaches wherein the imaged tissue is subject to peristaltic movement during the medical procedure ([0032] “This aspect of the present invention further contemplates assessing the blood flow in other body tissues including, but not limited to, muscle, stomach, liver, intestine, bladder, esophagus, lung, kidney and brain tissue. Angiographic images may be obtained beneath the surface of these tissues to a depth not exceeding that which permits the vasculature of interest to be evaluated.” The stomach and the esophagus are subject to peristaltic movement.).
Regarding claim 16, Docherty teaches wherein the imaged tissue is part of an internal organ of the subject, or part of the skin of the subject, or part of a wound of the subject ([0014] “A further aspect of the present invention permits a physician to accurately determine the extent to which a selected portion of body tissue, e.g., heart tissue, tumor, is well perfused, to assist in the identification and diagnosis of improperly (or properly) perfused tissue.”).
Regarding claim 17, Docherty teaches that the images of the blood vessels are identified and visualized to medical personnel involved in the surgery (Docherty Fig. 1; [0056] “The camera may also direct images directly to a television 12/VCR 13 system, wherein the images may be displayed in real time and/or recorded for playback at a later time. Preferably, the monitor and/or television are located in the surgical suite, permitting real-time viewing of various aspects of the treated and surrounding vessels.”).
Docherty and Alam teach methods which can be used intraoperatively but fail to teach that the methods apply to thyroid surgery. However, the methods taught of Docherty and Alam can be applied wherein the images are acquired during thyroid surgery and wherein blood vessels in one or more of the parathyroid glands ([0031] “This aspect of the present invention further contemplates assessing the blood flow in other body tissues including, but not limited to, muscle, stomach, liver, intestine, bladder, esophagus, lung, kidney and brain tissue. Angiographic images may be obtained beneath the surface of these tissues to a depth not exceeding that which permits the vasculature of interest to be evaluated… Angiographic images may be obtained beneath the surface of these tissues to a depth not exceeding that which permits the vasculature of interest to be evaluated. Again, and preferably, this depth is at least about 0.5 cm from the surface of any of the foregoing tissue, and more preferably at least about 1 cm, with access to the tissue by endoscope being a preferred route.”). These methods are applicable for capturing angiographic images of tissue within a patient.
Regarding claim 18, Docherty teaches wherein the at least one fluorescence imaging agent is selected from the group of: indocyanine green (ICG), fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, ophthaldehyde, fluorescamine, rose Bengal, trypan blue, fluoro-gold, green fluorescence protein, a flavin, methylene blue, porphysomes, cyanine dye, IRDDye8000W, CLR 1502 combined with a targeting ligand, OTL38 combined with a targeting ligand, or a combination thereof ([0040] “While any fluorescent dye may be used that provides an image as described herein, indocyanine green (ICG) (IC-GREEN™, CARDIO-GREEN™, marketed by Akorn, Inc.), analogue members of the tricarbocyanine dyes, and mixtures thereof, are preferred.”).
Regarding claim 19, Docherty teaches a computer program product stored on a memory having instructions which, when executed by a computing device or computing system, cause the computing device or computing system to carry out the method of identifying blood vessels in tissue of a subject according to claim 1 (Fig. 1; [0056] “…image-capture and processing software running on a PC 15.”).
Regarding claim 20, Docherty teaches a system for identifying blood vessels in tissue of a subject (Fig. 1 shows the computer system used to carry out the proposed method; [0012] “…during an invasive procedure in which the vessel is treated.”),
the system configured for –
continuously generating a fluorescent signal from blood vessels in the tissue wherein the fluorescent signal is oscillating with a predetermined pattern, the pattern generated from a series of boluses of at least one fluorescent imaging agent, and wherein the series of boluses is administered with a predefined and/or controlled duration between subsequent boluses determining the pattern - continuously receiving fluorescence images of the tissue – (Docherty teaches capturing a series of angiograms for examining blood vessels. Each angiogram consists of injecting a bolus of ICG dye and collecting an angiogram of interlaced images. [0065] “The fluorescence (radiation) emitted by the dye (830 nm) was captured as a series of angiograms using a CCD camera.” [0067] “The laser device included an SDL-820 Laser Diode Driver (SDL Inc., San Jose, Calif.) that maintained a continuous wave output with an average current of 3.95 A, and an SDL-2382-P1 laser diode (SDL Inc.). The laser diode was used to illuminate the area of interest and excite the ICG dye, thereby inducing fluorescence in the region being imaged.” [0070] “After each IV injection of an ICG dye bolus, a series of 264 interlaced images was collected at a rate of 30 per second.”),
analysing at least part of the fluorescence images ([0073] “Image analysis was performed using XCAP for Windows 95/98/NT version 1.0 (EPIX Inc., Buffalo Grove, Ill.).” Docherty teaches identifying the areas in the image with high-fluorescence signal over time using an edge detector in 0075-0078.).
Although Docherty teaches acquiring angiograms for a series of boluses for analyzing blood vessels and identifying areas of high fluorescent signal [0075-0078], Docherty does not specifically mention analyzing a time difference between detecting fluorescence signals. More specifically, Docherty fails to teach determining at least one time difference selected from the group of: " time difference between bolus injection and artery fluorescent signal or vein fluorescent signal, " time difference between artery fluorescent signal and vein fluorescent signal, " time difference between artery fluorescent signal or vein fluorescent signal and tissue fluorescent signal, and - continuously identifying blood vessels in the fluorescence images of the tissue based on said time difference(s) and the fluorescent signal oscillating with the predetermined pattern.
Alam teaches determining at least one time difference selected from the group of: " time difference between bolus injection and artery fluorescent signal or vein fluorescent signal, " time difference between artery fluorescent signal and vein fluorescent signal, " time difference between artery fluorescent signal or vein fluorescent signal and tissue fluorescent signal (Alam teaches creating angiograms by injecting boluses of IGC at regular intervals, fluorescing the ICG, and capturing a series of images of the ICG’s movement. [page 3, lines 12-23] “In particular, the present invention is able to provide angiograms of enhanced clarity by administering a plurality of relatively small boluses at relatively high dye concentrations to an animal undergoing an angiographic procedure. In particular, the method includes introducing boluses of about 0.1 ml to about 1.0 ml of a liquid composition at spaced time intervals into the animal… Light energy of a type and in an amount sufficient to cause the dye in each bolus to fluoresce as the dye flows through the blood vessels is then applied, and angiographic images obtained.” Alam also teaches observing the fluorescing boluses in the angiograms over time to determine blood flow direction. [Page 3, line 28 – Page 4, line 7] “Energy of a type and in an amount sufficient to cause the dye in the blood vessel to fluoresce is then applied. Subsequently, energy of a type and in an amount in excess of that required to cause the dye to fluoresce is applied to a portion of the fluorescing dye passing through the blood vessel to cause that portion of the fluorescing dye to stop fluorescing. A series of angiographs of both the fluorescing dye, and of the subsequent non-fluorescing portion thereof (also referred to as the "bleached" dye portion), are obtained, and those angiograms are compared to determine the direction of relative movement of the bleached dye. The direction of relative movement of the bleached dye portion indicates the direction of relative movement of the blood flow in the blood vessel.” Additionally, Alam also teaches that examining excited fluorescence over time is a well-known method for mapping vasculature. [page 2, lines 3-12] “The angiograms provide a record of the extent of dye movement within the ocular vasculature at each specific time interval. More specifically, after the dye is injected into the body, the dye enters the vasculature of the eye and begins to fluoresce due to the presence of the appropriate excitation radiation (light). The fluorescing dye, being mixed with the ocular blood, provides each angiogram with an accurate illustration of the extent of ocular blood flow through the ocular vasculature at that moment. By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature.”),
and - continuously identifying blood vessels in the fluorescence images of the tissue based on said time difference(s) and the fluorescent signal oscillating with the predetermined pattern (As quoted above, on page 3 Alam teaches administering boluses of ICG at regular time intervals, capturing angiograms, and analyzing the movement of boluses over time to determine blood flow direction. At page 2, lines 3-12, Alam explains that identifying vasculature by examining the ICG over time is well-known in the art. Examining the movement of ICG over time is examining the area of the image with higher fluorescent signal as it moves over time.).
Docherty and Alam and analogous in the art because both teach methods of administering ICG into vessels of a patient and capturing a series of fluorescent images observing the flow of the ICG to view and identify vessels. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s invention by considering the timing between injecting boluses and detecting fluorescent signal. This modification would allow for a series of angiograms to be used for mapping the vasculature and locating lesions (Alam [page 2, lines 10-13] By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature and determine the location of a CNV, and may then move to treat this abnormality, e.g., by laser photocoagulation of the CNV itself.”) Additionally, examining the movement of boluses over time in the images would enhance the invention by additionally considering the direction of blood flow, which would aid in identifying vessels which provide blood to an abnormality ([page 15, lines 14-16] “This method is of significance in identifying those arteries that are providing blood to a lesion, e.g., CNV, tumor or other blood vessel abnormality.”).
Regarding claim 21, Docherty teaches comprising a controllable injection pump for holding at least one first fluorescence imaging agent, the injection pump being configured for injecting a series of predefined boluses of said first fluorescence imaging agent into a vein of the subject ([0043] “Administration is typically accomplished via parenteral, IV injection, or other suitable means, with IV injection of the composition as a bolus being preferred, with the carrier being selected in view of the desired mode of administration.”),
thereby generating the fluorescent signal which is oscillating with the predetermined pattern ([0070] “After each IV injection of an ICG dye bolus, a series of 264 interlaced images was collected at a rate of 30 per second.” Florescent images are captured after the administration of each bolus of ICG. Additionally, as shown in claim 1, Alam teaches).
Claims 2 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Docherty and Alam, further in view of Abels et al. (WO 9731582 A1), hereafter Abels.
Regarding claim 2, Docherty and Alam fail to teach the specific time period between bolus injections. However, Abels teaches wherein the pattern comprises a period of between 1 and 5 minutes over a time period of at least 15 minutes and wherein the fluorescent signal is oscillating in intensity in accordance with this predetermined pattern (Page 12 “ICG, for example, may be administered as an aqueous solution (30-50 ml), either as a bolus or by rapid i.v. infusion. ICG is rapidly removed by the liver from circulating blood (serum half- life = 12 minutes). The dye can be administered rapidly as a single dose, or alternatively, in two or more doses at least 5 minutes (preferably 5-25 minutes) apart.”).
Docherty and Abels are analogous in the art because both teach method of ICG administration. Therefore, it would have been obvious to one of ordinary skill in the art to modify Docherty’s and Alam’s methods by administering boluses of ICG in 5-minute intervals. This modification of applying short intervals between injections would allow for Docherty’s and Alam’s methods to be used for imaging the liver; ICG injections saturate quickly in the liver due to high metabolization capacity (Page 11 “At the same time, this first injection will saturate to a certain degree the metabolization capacity of the liver, resulting in a longer serum half-life for a second injection. Thus, the therapeutic window may be extended by additional administrations of dye.” Page 12 “ICG is rapidly removed by the liver from circulating blood (serum half- life = 12 minutes)”).
Regarding claim 9, Docherty and Alam teach wherein a series of boluses of at least one fluorescent imaging agent is provided into a vein of the subject during the image acquisition thereby generating the predetermined pattern of oscillating fluorescent intensity ([0067] “The laser device included an SDL-820 Laser Diode Driver (SDL Inc., San Jose, Calif.) that maintained a continuous wave output with an average current of 3.95 A, and an SDL-2382-P1 laser diode (SDL Inc.). The laser diode was used to illuminate the area of interest and excite the ICG dye, thereby inducing fluorescence in the region being imaged.” [0070] “After each IV injection of an ICG dye bolus, a series of 264 interlaced images was collected at a rate of 30 per second.”),
Docherty and Alam fail to teach a predefined duration between the series of boluses. However, Abels teaches wherein the series of boluses is administered with a predefined duration between subsequent boluses (Page 12 “ICG, for example, may be administered as an aqueous solution (30-50 ml), either as a bolus or by rapid i.v. infusion. ICG is rapidly removed by the liver from circulating blood (serum half- life = 12 minutes). The dye can be administered rapidly as a single dose, or alternatively, in two or more doses at least 5 minutes (preferably 5-25 minutes) apart.”). Therefore, it would have been obvious to one of ordinary skill in the art to modify Docherty’s and Alam’s methods by administering boluses of ICG in 5-minute intervals. This modification of applying short intervals between injections would allow for Docherty’s and Alam’s methods to be used for imaging the liver; ICG injections saturate quickly in the liver due to high metabolization capacity (Page 11 “At the same time, this first injection will saturate to a certain degree the metabolization capacity of the liver, resulting in a longer serum half-life for a second injection. Thus, the therapeutic window may be extended by additional administrations of dye.” Page 12 “ICG is rapidly removed by the liver from circulating blood (serum half- life = 12 minutes)”).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Docherty and Alam, further in view of Ho et al. (US 20160228579 A1), hereafter, Ho.
Regarding claim 6, Docherty and Alam fail to teach the use of white light images for visualizing blood vessels. However, Ho teaches wherein the identified arteries and veins are superimposed into white light images, visually enhanced such that arteries and veins are visually distinguishable and displayed on a screen (Fig. 2B; [0034] “(B) White light image of the two identical capillary tubes filled with different formulations of ICG in panel A.” [0196] “White light and NIR images were captured within 15 min of the preparation of capillary tubes and tissue cuboids using a custom NIR charge-coupled device (CCD) camera built by Hamamatsu Photonics K.K. (Hamamatsu, Japan).” Although Ho teaches methods for injecting ICG into lymph node vessels, Paragraph 0023 tells that other embodiments consider this method for blood vessels.).
Docherty and Ho are analogous in the art because both teach methods of administering ICG to map vessels with fluorescent imaging. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s and Alam’s invention by utilizing white light images on the display screen. This modification allows for the use of a CCD camera, which captures white light images ([0196]).
Claims 10-12 and 22 are rejected under 35 U.S.C. 103 as being unpatentable Docherty, Alam, and Abels, further in view of Rubenstein et al., (WO 02/094085 A2), hereafter, Rubenstein.
Regarding claim 10, Docherty and Alam fail to teach the size of the injected boluses in relation to body weight. However, Rubenstein teaches wherein the fluorescent imaging agent is ICG and wherein each bolus of ICG corresponds to less than 0.01 mg ICG/kg body weight ([0041] “A dose of about 0.005 mg / kg is preferred because this dose results in a peak blood concentration of 0.001 mg / ml or less.”).
Docherty and Rubenstein are analogous in the art because both teach methods of injecting ICG for observing blood vessels with fluorescent imaging. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s, Alam’s, and Ho’s inventions by using a bolus size of 0.005 mg ICG/kg body weight. This dosage would allow for a peak blood concentration of 0.001 mg/ml or less ([0041]).
Regarding claim 11, Docherty, Alam, and Ho fail to teach a bolus size smaller than 0.005 mg ICG/kg body weight. However, Rubenstein teaches wherein the fluorescent imaging agent is ICG and wherein each bolus of ICG corresponds to less than 0.005 mg ICG/kg body weight ([0041] “A dose of about 0.005 mg / kg is preferred because this dose results in a peak blood concentration of 0.001 mg / ml or less.”). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s, Alam’s, and Ho’s inventions by using a bolus size of 0.005 mg ICG/kg body weight. This dosage would allow for a peak blood concentration of 0.001 mg/ml or less ([0041]).
Regarding claim 12, Docherty, Alam, and Ho fail to teach a bolus size smaller than 0.004 mg ICG/kg body weight. However, it would have been obvious to one of ordinary skill in the art to lower the ICG dosage—further than the 0.005 ICG/kg body weight taught by Rubenstein ([0041])—as determined through routine experimentation to achieve predicable results in order to achieve a lower peak blood concentration. As taught by Rubenstein, the dosage of ICG correlates to the peak blood concentration of ICG. ([0041] “A dose of about 0.005 mg / kg is preferred because this dose results in a peak blood concentration of 0.001 mg / ml or less.”).
Regarding claim 22, Docherty and Alam fail to teach a bolus size smaller than 0.004 mg ICG/kg body weight and a specific time interval between injecting boluses. However, Rubenstein teaches wherein the fluorescence agent is ICG and wherein the amount of ICG in a predefined bolus is less than 0.005 mg /kg body weight ([0041] “A dose of about 0.005 mg / kg is preferred because this dose results in a peak blood concentration of 0.001 mg / ml or less.”). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Docherty’s, Alam’s, and Ho’s inventions by using a bolus size of 0.005 mg ICG/kg body weight. This dosage would allow for a peak blood concentration of 0.001 mg/ml or less ([0041]).
Additionally, Abels teaches wherein the system is configured to inject boluses with an interval of between 1 and 5 minutes (Page 12 “ICG, for example, may be administered as an aqueous solution (30-50 ml), either as a bolus or by rapid i.v. infusion. ICG is rapidly removed by the liver from circulating blood (serum half- life = 12 minutes). The dye can be administered rapidly as a single dose, or alternatively, in two or more doses at least 5 minutes (preferably 5-25 minutes) apart.”). Therefore, it would have been obvious to one of ordinary skill in the art to modify Docherty’s and Alam’s methods by administering boluses of ICG in 5-minute intervals. This modification of applying short intervals between injections would allow for Docherty’s and Alam’s methods to be used for imaging the liver; ICG injections saturate quickly in the liver due to high metabolization capacity (Page 11 “At the same time, this first injection will saturate to a certain degree the metabolization capacity of the liver, resulting in a longer serum half-life for a second injection. Thus, the therapeutic window may be extended by additional administrations of dye.” Page 12 “ICG is rapidly removed by the liver from circulating blood (serum half- life = 12 minutes)”).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ferguson et al. (US 10,278,585 B2) teaches methods of quantifying angiography in real-time by administering IGC, capturing image sequences of the fluorescing ICG, and making intraoperative decisions from the resulting the angiograms. The method involves analyzing the fluorescent intensity over time from each image sequence and synchronizing the curves based on peak intensity to align the angiography cycles.
Son et al. (Quantitative analysis of colon perfusion pattern using indocyanine green (ICG) angiography in laparoscopic colorectal surgery. Surg Endoscopy. 33(5). 1640–1649.) teaches methods for examining colon perfusion patterns of colorectal cancer patients. The method involves slowly injecting ICG into peripheral blood vessels and performing fluorescent imaging on the
Yamamoto et al. (Indocyanine Green Angiography for Intra-operative Assessment in Vascular Surgery. European Journal of Vascular and Endovascular Surgery. 43(4). 426-432.) teaches methods for intra-operative assessment of the graft vessel using ICG angiography. The method involves examining the time delay in the increase in fluorescent intensity between the proximal artery and the distal stenotic region.
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/Eric Shoemaker/
Patent Examiner
/JENNIFER MEHMOOD/Supervisory Patent Examiner, Art Unit 2664