DETAILED ACTION
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 .
Status of Claims
Claims 1-13, 15, 19-24, 26, 27 and 29-35 are pending and are examined herein on the merits for patentability.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-13, 15, 19-24, 26, 27 and 29-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 12,161,729. Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a method of visualizing a ureter in a subject, the method comprising (a) administering to the subject an effective amount of a fluorescein-conjugated peptide, wherein the fluorescein-conjugated peptide comprises a peptide having the amino acid sequence of SEQ ID NO:21 conjugated to a fluorescein moiety at its N-terminus; and (b) detecting fluorescence of the fluorescein moiety in a peristaltic urine flow in the ureter (i) after 30 minutes, (ii) within a period of 1 hour or (iii) after 30 minutes and within a period of 1 hour, following administration of the fluorescein-conjugated peptide. The claims of the ‘729 patent are directed to a method of visualizing a ureter in a subject, the method comprising (a) administering to the subject an effective amount of a fluorescein-conjugated peptide, wherein the fluorescein-conjugated peptide comprises a peptide having the amino acid sequence of SEQ ID NO:21 conjugated to a fluorescein moiety at its N-terminus; and (b) detecting fluorescence of the ureter following administration of the fluorescein-conjugated peptide, wherein: detecting fluorescence of the ureter occurs after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, or more than 8 hours following administration of the fluorescein-conjugated peptide; and detecting fluorescence of the ureter comprises detecting the fluorescein moiety in a peristaltic urine flow in the ureter. Accordingly, the claims are overlapping in scope and are obvious variants of one another.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-13, 15, 19-24, 26, 27 and 29-35 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyen et al. (WO 19/028281) in view of Gurevich et al. (US 2021/0007687).
Nguyen teaches peptide sequences that selective bind to human nerves and/or neurons, as well as methods of using those sequences in surgical procedures, for example to preserve nerves and/or to avoid nerve damage during such procedures (paragraph 0007). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HN P401-N-2 with GG linker; SEQ ID NO:21) (paragraph 0028).
In some embodiments, the human neuron or nerve targeting molecule further comprises a cargo, including a fluorescent moiety.
In some embodiments, provided is a method of identifying a human neuron or nerve com prising contacting the human neuron or nerve with a targeting molecule comprising (a) a peptide that specifically binds to the human neuron or nerve, or component of either, and (b) a fluorescent moiety, wherein said targeting molecule comprises a peptide selected from the group consisting of… SEQ ID NO:21, …5FAM-QVPWEEPYYVVKKSSGG-NH2 (HN P401-N-2 with GG linker; SEQ ID NO:104), and/or combinations thereof (paragraph 0055).
In some embodiments, the human neuron or nerve targeting molecule is administered by systemic intravenous injection to a human subject (paragraph 00102). In some embodiments, the human neuron or nerve targeting molecule is administered prior to a surgical procedure. In some embodiments, the surgical procedure is a cancer surgical procedure. In some embodiments, the surgical procedure is a prostate cancer surgical procedure (paragraph 00103).
Figure 7 shows in-vivo labeling of prostatic neurovascular bundle with HNP401. HNP401 labeling of autonomic nerve bundles in live rats.
Figure 16 shows in-vivo fluorescent labelling of the autonomic nerve in a rodent. Low magnification fluorescent image showing bladder, vas deferens and urethra running through the prostate with adjacent autonomic nerve labeled with FAM-NP41 in mice.
Figure 27 shows mass spectroscopy analysis of urine samples from mice injected with nerve binding peptides. Fragmented ion peaks from Cysteine-FAM collected from the urine of mice that were injected with FAM-HNP401 indicating peptide is metabolized.
Figure 28 shows stability of peptides in ex-vivo human plasma and cerebrospinal fluid from rats. FAM-HNP401 peptide detected at 5min (A) and 2hours (B) after incubation at 37 C in human plasma.
Because prostate nerves in mice were very small and challenging to image (i.e. requiring high dose of FAM-NP41) we extended our study to the visualization of autonomic nerve within the prostate of rats. To visualize autonomic nerves in male Sprague Dawley rats, FAM-NP41 was injected intravenously at a dose of 12nmol/gram, followed by imaging. This is a 2.5X lower dose relative to weight compared to the 600nmols used in 20 gram mice. Useful labeling occurred 2 to 6 hours after intravenous administration which was visualized using a customized fluorescence dissecting microscope. FAM-NP41 nerve highlighting enables visualization of nerve fibers running through the middle of the rat prostate (page 117).
Fluorescently labeled nerve-binding peptides can be used to assist surgeons in the visualization of nerves during surgical procedures prior to physically encountering and thus potentially damaging them. This is particularly important during surgery on the prostate gland, because the cavernosal nerves controlling male erections run very near the prostate but are practically invisible ordinarily (paragraph 0361).
It is noted that FAM-NP41 injected intravenously followed by imaging of prostate and surrounding tissue after surgical resection. Strong fluorescence from dye that rapidly accumulates in the bladder hindered visualization of the nerves within the prostate (paragraph 0400).
Nguyen does not specifically teach visualizing a ureter in a subject.
Gurevich teaches that laparoscopic procedures are minimally invasive surgical procedures in the abdominal and pelvic areas. Abdominal and pelvic surgeries pose a risk of accidental injury to the tissues of the renal system, particularly the ureters. Ureters are small-diameter vessels that carry urine from the kidneys to the bladder. Ureters may be difficult to identify in a surgical field due to their small diameter and because they are often covered by other tissue. This is especially true in laparoscopic procedures because the surgeon has a limited view of the surgical field and cannot use tactile perception to aid in identification of the ureters. Thus, in laparoscopic procedures there is often a risk that the ureters may be unintentionally injured. Further, such injuries are often not detected during the surgical procedure and detection may be delayed for days or months (paragraph 0003).
To help avoid injury, intravenous pyelography, retrograde pyelography, or urological computed tomography can be performed preoperatively to locate the ureters.
Fluorescence imaging has been used to visualize ureters intraoperatively. A fluorescence imaging agent that is excreted in the urine, such as methylene blue, is administered to the patient resulting in agent-containing urine moving through the ureters. A fluorescence imaging system captures the fluorescence emission of the agent as it moves through the ureter and generates fluorescence images of the ureters. However, due to the peristaltic nature of urine passage through the ureters, the imaging agent is only intermittently present in the ureters, and therefore, the ureters cannot be imaged continuously by the fluorescence imaging system (paragraph 0005).
Ureters can be imaged by a fluorescence imaging system by utilizing fluorescence imaging agents that concentrate in urine. Imaging agents such as methylene blue enter urine via the kidneys and pass in the urine through the ureters and into the bladder. The passage of the agent through the ureters enables the imaging of the ureters by a fluorescence imaging system. Fluorescence images of the ureter can be displayed to a surgeon during the surgical procedure so that the surgeon can avoid the ureters (paragraph 0101).
A florescence imaging agent that concentrates in the urine is administered to the subject and the passage of the imaging agent in the urine through the ureter is used to image the ureter. Method 200 can be used to persistently visualize the ureter despite the peristaltic nature of the movement of the urine (and, thus, the imaging agent) through the ureter. This can enable the surgeon to continuously visualize the ureter throughout the procedure, helping the surgeon to avoid the ureter. This can help reduce the risk of damaging the ureter, reducing the complications associated with laparoscopic procedures (paragraph 0149).
Methods for imaging the ureters can include injecting an imaging agent into the bloodstream, or direct cannulation, either anterograde or retrograde, into the ureters or bladder, such that it appears in the urine stream (paragraph 0193).
In certain embodiments, the fluorescence imaging agent may be administered less than an hour in advance of performing the measurement of signal intensity arising from the fluorescence imaging agent. For example, the fluorescence imaging agent may be administered to the subject less than 30 minutes in advance of the measurement (paragraph 0200).
In certain embodiments the dye is or comprises fluorescein isothiocyanate, rhodamine, etc., which is excitable using excitation light wavelengths appropriate to each imaging agent. In some variations, an analogue or a derivative of the fluorescence imaging agent may be used. For example, a fluorescence dye analogue or a derivative may include a fluorescence dye that has been chemically modified, but still retains its ability to fluoresce when exposed to light energy of an appropriate wavelength. In variations in which some or all of the fluorescence is derived from autofluorescence, one or more of the fluorophores giving rise to the autofluorescence may be an endogenous tissue fluorophore (e.g., collagen, elastin, NADH, etc.), 5-aminolevulinic acid (5-ALA), or a combination thereof (paragraph 0201).
In some embodiments, the fluorescence imaging agent may be conjugated to another molecule, such as a protein, a peptide, an amino acid, a synthetic polymer, or a sugar, for example to enhance solubility, stability, imaging properties, or a combination thereof (paragraph 0202).
One or more imaging agents can be used to demarcate at least one tissue of the renal system of a patient during a surgical procedure. For example, various embodiments can be used to enable the surgeon or other healthcare individual to avoid the ureter(s), the bladder, and/or the urethra. In a healthy individual, urine flows from the kidneys through the ureter and collects in the bladder, where it is stored until it is eliminated from the body through the urethra. Thus, according to various embodiments, detection of the optical agent(s) in the ureter and bladder is possible due to the accumulation of the agent(s) in urine present in those structures. Detection of the optical agent(s) in the urethra is possible, for example, where residue of urine containing the optical agents is present on or within the walls of the urethra (paragraph 0206).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide the nerve-targeting fluorescein labeled peptides taught by Nguyen for visualizing a ureter in a subject, and detecting fluorescence of the fluorescein moiety in a peristaltic urine flow in the ureter (i) after 30 minutes, (ii) within a period of 1 hour or (iii) after 30 minutes and within a period of 1 hour, following administration of the fluorescein-conjugated peptide, when the teaching of Nguyen is taken in view of Gurevich. One would have been motivated to do so because Nguyen teaches that the labeled peptide is metabolized in urine and accumulates and can be imaged in the bladder, and Gurevich teaches that fluorescent labels that a florescence imaging agent that concentrates in the urine is administered to the subject and the passage of the imaging agent in the urine through the ureter is used to image the ureter, despite the peristaltic nature of the movement of urine, enabling visualization and reducing damage thereto during a surgical procedure. One would have had a reasonable expectation of success in doing so because Gurevich teaches that fluorescein, including targeting agents conjugated thereto are one of a few suitable imaging agents, and further Nguyen teaches that FAM-HNP401 is metabolized and found in urine. Regarding the claimed timeframe for imaging, Gurevich teaches imaging within 30 minutes or 1 hour, and Nguyen teaches useful labeling occurred 2 to 6 hours after intravenous administration.
Claims 1-13, 15, 19-24, 26, 27 and 29-35 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyen et al. (WO 19/028281) in view of Dalma-Weiszhausz et al. (US 2018/0043037), in further view of Gurevich et al. (US 2021/0007687).
Nguyen teaches peptide sequences that selective bind to human nerves and/or neurons, as well as methods of using those sequences in surgical procedures, for example to preserve nerves and/or to avoid nerve damage during such procedures (paragraph 0007). In some embodiments, the targeting molecule comprises the peptide QVPWEEPYYVVKKSSGG (HN P401-N-2 with GG linker; SEQ ID NO:21) (paragraph 0028).
In some embodiments, the human neuron or nerve targeting molecule further comprises a cargo, including a fluorescent moiety.
In some embodiments, provided is a method of identifying a human neuron or nerve comrprising contacting the human neuron or nerve with a targeting molecule comprising (a) a peptide that specifically binds to the human neuron or nerve, or component of either, and (b) a fluorescent moiety, wherein said targeting molecule comprises a peptide selected from the group consisting of… SEQ ID NO:21, …5FAM-QVPWEEPYYVVKKSSGG-NH2 (HN P401-N-2 with GG linker; SEQ ID NO:104), and/or combinations thereof (paragraph 0055).
In some embodiments, the human neuron or nerve targeting molecule is administered by systemic intravenous injection to a human subject (paragraph 00102). In some embodiments, the human neuron or nerve targeting molecule is administered prior to a surgical procedure. In some embodiments, the surgical procedure is a cancer surgical procedure. In some embodiments, the surgical procedure is a prostate cancer surgical procedure (paragraph 00103).
Figure 7 shows in-vivo labeling of prostatic neurovascular bundle with HNP401. HNP401 labeling of autonomic nerve bundles in live rats.
Figure 16 shows in-vivo fluorescent labelling of autonomic nerve in rodent. Low magnification fluorescent image showing bladder, vas deferens and urethra running through the prostate with adjacent autonomic nerve labeled with FAM-NP41 in mice.
Figure 27 shows mass spectroscopy analysis of urine samples from mice injected with nerve binding peptides. Fragmented ion peaks from Cysteine-FAM collected from the urine of mice that were injected with FAM-HNP401 indicating peptide is metabolized.
Figure 28 shows stability of peptides in ex-vivo human plasma and cerebrospinal fluid from rats. FAM-HNP401 peptide detected at 5min (A) and 2hours (B) after incubation at 37 C in human plasma.
Because prostate nerves in mice were very small and challenging to image (i.e. requiring high dose of FAM-NP41) we extended our study to the visualization of autonomic nerve within the prostate of rats. To visualize autonomic nerves in male Sprague Dawley rats, FAM-NP41 was injected intravenously at a dose of 12nmol/gram, followed by imaging. This is a 2.5X lower dose relative to weight compared to the 600nmols used in 20 gram mice. Useful labeling occurred 2 to 6 hours after intravenous administration which was visualized using a customized fluorescence dissecting microscope. FAM-NP41 nerve highlighting enables visualization of nerve fibers running through the middle of the rat prostate (page 117).
Fluorescently labeled nerve-binding peptides can be used to assist surgeons in the visualization of nerves during surgical procedures prior to physically encountering and thus potentially damaging them. This is particularly important during surgery on the prostate gland, because the cavernosal nerves controlling male erections run very near the prostate but are practically invisible ordinarily (paragraph 0361).
It is noted that FAM-NP41 injected intravenously followed by imaging of prostate and surrounding tissue after surgical resection. Strong fluorescence from dye that rapidly accumulates in the bladder hindered visualization of the nerves within the prostate (paragraph 0400).
Nguyen does not specifically teach visualizing a ureter in a subject.
Dalma-Weiszhausz teaches surgical tools and methods, and in some more particular aspects relates to tissue specific markers that facilitate the identification of target tissue from adjacent tissue, or a system which includes the marker and methods of use of the marker or markers (paragraph 0008). The benefit for surgeons to be able to easily mark a specific tissue, either for removal or for the purpose of clear identification so that small glands, ducts or difficult to distinguish tissues are not unintentionally removed or damaged is also taught (paragraph 0002).
In another aspect, a tissue specific marker comprises an aptamer or an affimer configured to selectively bind to a non-malignant target tissue and/or a normal tissue; and at least a first indicator element coupled to the aptamer or the affimer, wherein the at least a first indicator element produces a signal, thereby allowing identification of the non-malignant target tissue. In some embodiments, the tissue specific marker comprises the aptamer configured to selectively bind to the non-malignant target tissue (and/or the normal tissue), wherein the aptamer comprises DNA, RNA, a peptide, or any combination thereof (paragraph 0010).
In some embodiments, the non-malignant target tissue comprises a nerve, a blood vessel, a ureter, a bile duct, endometrial tissue, hepatic duct, lymph nodes, bacteria or fungus (paragraph 0013, 0018).
Oral or intravenous administration are taught (paragraph 0026).
The disclosure provides tissue specific marker compositions that can be used to identify or mark a particular tissue (e.g., healthy parathyroid tissue) during preoperative and intraoperative surgical procedures. The identification of a specific tissue type during a surgical procedure may be particularly helpful for mitigating damage to or loss of healthy tissues and organs. In some preferred embodiments, the tissue specific marker is used to mark a specific healthy tissue (e.g., parathyroid tissue) in order to distinguish it from a different tissue type (e.g., thyroid tissue, adipose tissue) or diseased tissue (e.g., adenoma, hyperplasia or thyroid malignant tumor). In some cases, the tissue specific marker compositions are used to mark healthy tissue to be avoided or preserved during surgery. In other cases, the tissue specific marker compositions are used to mark diseased tissue or other target tissue for surgical removal. In some cases, multiple tissue specific markers may be used.
FIG. 3 is a schematic diagram showing the location of the ureters relative to the spine, exemplary adjacent nerve tissue originating from the spine, the bladder, pelvis, kidneys and the spinal cord. The tissue specific marker may be applied in diagnostic, preoperative or intraoperative surgical procedures related to the ureters as well as nerve tissue including nerve tissue in or around the depicted region of a patient's body. The tissue specific marker can also be selected to bind to a non-solid target, for example one that goes through an anatomic lumen such as urine, and this may be another way for ureter identification and preservation (paragraph 0087).
Gurevich teaches that laparoscopic procedures are minimally invasive surgical procedures in the abdominal and pelvic areas. Abdominal and pelvic surgeries pose a risk of accidental injury to the tissues of the renal system, particularly the ureters. Ureters are small-diameter vessels that carry urine from the kidneys to the bladder. Ureters may be difficult to identify in a surgical field due to their small diameter and because they are often covered by other tissue. This is especially true in laparoscopic procedures because the surgeon has a limited view of the surgical field and cannot use tactile perception to aid in identification of the ureters. Thus, in laparoscopic procedures there is often a risk that the ureters may be unintentionally injured. Further, such injuries are often not detected during the surgical procedure and detection may be delayed for days or months (paragraph 0003).
To help avoid injury, intravenous pyelography, retrograde pyelography, or urological computed tomography can be performed preoperatively to locate the ureters.
Fluorescence imaging has been used to visualize ureters intraoperatively. A fluorescence imaging agent that is excreted in the urine, such as methylene blue, is administered to the patient resulting in agent-containing urine moving through the ureters. A fluorescence imaging system captures the fluorescence emission of the agent as it moves through the ureter and generates fluorescence images of the ureters. However, due to the peristaltic nature of urine passage through the ureters, the imaging agent is only intermittently present in the ureters, and therefore, the ureters cannot be imaged continuously by the fluorescence imaging system (paragraph 0005).
Ureters can be imaged by a fluorescence imaging system by utilizing fluorescence imaging agents that concentrate in urine. Imaging agents such as methylene blue enter urine via the kidneys and pass in the urine through the ureters and into the bladder. The passage of the agent through the ureters enables the imaging of the ureters by a fluorescence imaging system. Fluorescence images of the ureter can be displayed to a surgeon during the surgical procedure so that the surgeon can avoid the ureters (paragraph 0101).
A florescence imaging agent that concentrates in the urine is administered to the subject and the passage of the imaging agent in the urine through the ureter is used to image the ureter. Method 200 can be used to persistently visualize the ureter despite the peristaltic nature of the movement of the urine (and, thus, the imaging agent) through the ureter. This can enable the surgeon to continuously visualize the ureter throughout the procedure, helping the surgeon to avoid the ureter. This can help reduce the risk of damaging the ureter, reducing the complications associated with laparoscopic procedures (paragraph 0149).
Methods for imaging the ureters can include injecting an imaging agent into the bloodstream, or direct cannulation, either anterograde or retrograde, into the ureters or bladder, such that it appears in the urine stream (paragraph 0193).
In certain embodiments, the fluorescence imaging agent may be administered less than an hour in advance of performing the measurement of signal intensity arising from the fluorescence imaging agent. For example, the fluorescence imaging agent may be administered to the subject less than 30 minutes in advance of the measurement (paragraph 0200).
In certain embodiments the dye is or comprises fluorescein isothiocyanate, rhodamine, etc., which is excitable using excitation light wavelengths appropriate to each imaging agent. In some variations, an analogue or a derivative of the fluorescence imaging agent may be used. For example, a fluorescence dye analogue or a derivative may include a fluorescence dye that has been chemically modified, but still retains its ability to fluoresce when exposed to light energy of an appropriate wavelength. In variations in which some or all of the fluorescence is derived from autofluorescence, one or more of the fluorophores giving rise to the autofluorescence may be an endogenous tissue fluorophore (e.g., collagen, elastin, NADH, etc.), 5-aminolevulinic acid (5-ALA), or a combination thereof (paragraph 0201).
In some embodiments, the fluorescence imaging agent may be conjugated to another molecule, such as a protein, a peptide, an amino acid, a synthetic polymer, or a sugar, for example to enhance solubility, stability, imaging properties, or a combination thereof (paragraph 0202).
One or more imaging agents can be used to demarcate at least one tissue of the renal system of a patient during a surgical procedure. For example, various embodiments can be used to enable the surgeon or other healthcare individual to avoid the ureter(s), the bladder, and/or the urethra. In a healthy individual, urine flows from the kidneys through the ureter and collects in the bladder, where it is stored until it is eliminated from the body through the urethra. Thus, according to various embodiments, detection of the optical agent(s) in the ureter and bladder is possible due to the accumulation of the agent(s) in urine present in those structures. Detection of the optical agent(s) in the urethra is possible, for example, where residue of urine containing the optical agents is present on or within the walls of the urethra (paragraph 0206).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide the nerve-targeting fluorescein labeled peptides taught by Nguyen for visualizing a ureter in a subject, and detecting fluorescence of the fluorescein moiety in a peristaltic urine flow in the ureter (i) after 30 minutes, (ii) within a period of 1 hour or (iii) after 30 minutes and within a period of 1 hour, following administration of the fluorescein-conjugated peptide, when the teaching of Nguyen is taken in view of Dalma-Weiszhausz and Gurevich. Each of Nguyen and Dalma-Weiszhausz are directed to fluorescence imaging upon administration of a targeted marker and mitigation of damage to healthy nerves, tissues or organs. One would have been motivated to do so because Dalma-Weiszhausz teaches that the location of the ureters can be determined upon administration of a tissue specific marker from exemplary adjacent nerve tissue originating from the spine, the bladder, pelvis, kidneys and the spinal cord. The tissue specific marker may be applied in diagnostic, preoperative or intraoperative surgical procedures related to the ureters as well as nerve tissue including nerve tissue in or around the depicted region of a patient's body. One would have had a reasonable expectation of success in doing so because Dalma-Weiszhausz teaches that the tissue specific marker can also be selected to bind to a non-solid target, for example one that goes through an anatomic lumen such as urine, and this may be another way for ureter identification and preservation, and Nguyen teaches that FAM-HNP401 is metabolized and found in urine and detected in bladder. Further, Gurevich teaches the peristaltic nature of urine passage through the ureters, and that imaging agents may enter urine via the kidneys and pass in the urine through the ureters and into the bladder. The passage of the agent through the ureters enables the imaging of the ureters by a fluorescence imaging system. Regarding the claimed timeframe for imaging, Gurevich teaches imaging within 30 minutes or 1 hour, and Nguyen teaches useful labeling occurred 2 to 6 hours after intravenous administration.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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