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 .
Response to Arguments
Applicant's arguments below filed 11/20/2025 have been fully considered but they are not persuasive | moot in view of the new grounds of rejection.
The Applicant asserts on pages 9-10 of the Response:
“In contrast, Kularatne is directed to a method of use of traditional imaging agents to assess pulmonary tissue and peripheral pulmonary tissue with conventional techniques. Kularatne does not teach or suggest visualizing a nodule external to a bronchus. The portion of Kularatne cited by the Examiner - paragraphs [0005], [0053] and [0063]- discuss, at best, imaging tumors which are within, or are incorporated within, an airway. It does not suggest that nodules external to an airway might be visualized accurately.
In fact, Kularatne teaches away from imaging nodules external to a bronchus. Paragraph [0064], directly following the one cited by the examiner, notes that:
"The disclosure of these methods of imaging is particularly suited to in vivo detection of diseased tissue located at an interior site in the subject ... where the diseased tissue is "in plain view" (i.e., exposed to the human eye) to facilitate a procedure of biopsy or surgical excision of the area that has been highlighted by uptake of the compounds of the present disclosure."'
(emphasis added.) The implication of this statement is that these methods are not particularly suited to in vivo detection of diseased tissue which is not in plain view-for example, nodules which are external to a bronchus.
None of the secondary references cited by the examiner remedy this deficiency of Kularatne. None of Singhal, Trag-Guyon, Sella-Tavor, Hauger, Zupkofska, Kim, Suurs, and Gray describe the use of a fluorescent imaging agent to visualize nodules external to a bronchus. As such, the instant claims are not obvious in light of Kularatne, Singhal, Trag-Guyon Sella-Tavor, Hauger, Zupkofska, Kim, Suurs, and Gray.”
In response the examiner respectfully asserts that Kularatne discloses fluorescent imaging of lung nodules. Kularatne also discloses the use of NIR light to excite the fluorescent compound. One with ordinary skill in the art would recognize that NIR light is capable of penetrating through soft tissue and therefore is capable of illuminating a fluorescent compound that has been taken up by a nodule external to a bronchus. Additionally Kularatne discloses in [0069] “In some aspects, fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”. Therefore if a fluorescent compound that has been taken up by a nodule external to a bronchus and has a emission spectra in the near-infrared range it would fluoresce and be visualized “in plain view” by the endoscope. Therefore the “peripheral pulmonary tissue for tumors, lesions, and nodules” in [0005] of Kularatne is interpreted to include a nodule external to a bronchus. Additionally Kularatne discloses in paragraph [0064] “The disclosure of these methods of imaging is particularly suited to in vivo detection”, therefore Kularatne is suited for in vivo detection of a nodule external to a bronchus.
The Applicant asserts on pages 10-11 of the Response:
“Furthermore, claims 19-21, 28, 33, and 39 are also non-obvious and patentable because none of the prior art suggests the recited dosage ranges of the intraveneously administered molecular imaging agent, particularly for human patients and particularly for VGT-309. It is noted that Suurs discloses the administration of VGT-309 to mice, as part of a mouse model. VGT-309 is expected to be metabolized differently in a mouse than in a human. As such, a skilled artisan would not consider the disclosures of Suurs to meaningfully inform the development of a human dosing protocol. Suurs does not teach or suggest anything related to the subject matter of the instant claims.”
In response the examiner respectfully asserts that claims 19-21 and 33-39 do not claim administration of VGT-309. Claims 19-21 and 33-39 relay on Kim (US20200101175) to teach the dosage and as cited below Kim discloses that the subject may be a human. Regarding claim 28, Suurs discloses on page 8 left column “these far-red fluorophores have not yet been approved for human use by FDA or EMA. In this study, we overcome these hurdles by using a FDA and EMA approved near-infra red fluorophore ICG for target visualization, which has a tissue penetration depth up to 10 mm and can be viewed on widely available surgical imaging systems. This makes the likelihood of clinical adoption of VGT-309 much higher compared to non-ICG and far red fluorophores.” Therefore one with ordinary skill in the art would find it obvious to develop a human dosing protocol. As cited below Kim is used to teach the dosage and that it can be administered to a human in claim 28 and Kim discloses that the pharmaceutical composition may contain a salt in [0057]. The current specification discloses in pages 10-11 “the molecular imaging agent is referred to herein as "VGT-309", which comprises: and includes pharmaceutically acceptable salts or formulation variants thereof”. Therefore one with ordinary skill in the art would find it obvious to use the dosing of Kim for humans.
In light of the examiners remarks above the pending claims remain rejected under 35 USC § 103.
Information Disclosure Statement
The information disclosure statements filed 11/26/2025 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because both information disclosure statements include EP4371472 however the foreign document was not provided. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 11, 16-17, 22, 24, 29-30, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) hereinafter Kularatne and further in view of Singhal (US 20170232119) hereinafter Singhal.
Regarding claim 1, Kularatne discloses a method (abstract – “The present disclosure relates to method”) comprising:
navigating an instrument ([0020] – “the method is used in fluorescence-guided surgery”, [0055] – “(c) guiding a flexible probe to the intervention site”), via a minimally invasive route ([0002] – “Endoscopy is a minimally invasive or non-invasive procedure to examine the hollow interior of an organ or body cavity”, [0019] – “the bronchoscopy is non-invasive”), into a patient to whom a molecular imaging agent has been […] administered ([0055] – “(a) administering a compound or a composition comprising the compound to a human or animal subject, wherein the compound comprises a targeting moiety and a fluorescence imaging agent”), to position the instrument in an area of a tissue abnormality ([0055] – “allowing time for the compound to distribute at an intervention site of the subject; (c) guiding a flexible probe to the intervention site”, [0063] – “an intervention site, such as a tumor nodule or bed”); and
visualizing, via the instrument, tissue in the area under near-infrared (NIR) light ([0053] – “illuminating the compound that has been taken up by the tissue facilitates visualization of the tumor by the near-infrared fluorescence of the compound”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”), wherein the molecular imaging agent, as administered, causes abnormal tissue in the area to fluoresce under the NIR light and enable the fluorescing abnormal tissue to be localized within the area ([0054] – “(d) illuminating the biological tissue; and (e) detecting the optical signal emitted by the compound”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”),
wherein the fluorescing abnormal tissue is in the patient’s lungs ([0054], [0065] – “the biological tissue is a tumor…the tumor…is in or near the lung”), and
wherein the fluorescing abnormal tissue comprises a nodule external to a bronchus ([0005] – “Non-invasive diagnostic procedures typically involve flexible bronchoscopy to assess pulmonary tissue and peripheral pulmonary tissue for tumors, lesions, and nodules”, [0053] – “allows an improved and accurate removal of even small tumors”, [0063] – “image-guided biopsy, ablation, resection, incision, cutting, and/or cauterization can be performed on primary lung tumor nodules, metastatic lung lesions, and regional metastatic lung lymph nodes”, for clarification if nodules in the patients lungs are taking up the compound any nodule that is peripheral to the bronchoscope would be fluorescing when illuminated with NIR light including nodules that are external to the bronchus).
Conversely Kularatne does not explicitly teach a molecular imaging agent has been intravenously administered.
However Singhal discloses a molecular imaging agent has been intravenously administered ([0087] – “The targeting constructs and supplemental targeting constructs used in practice of the disclosure method can be administered by any route known to those of skill in the art, such as…intravenously”).
The disclosure of Singhal is an analogous art considering it is in the field of fluorescence imaging.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the molecular imaging agent being intravenously administered of Singhal to achieve the same results. One would have motivation to combine because it allows one to administer the imaging agent to the local desired region rapidly.
Regarding claim 2, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses further comprising diagnosing and/or treating the fluorescing abnormal tissue ([0064] – ““see” in real-time the exact outlines, size, etc., of the mass of the inflamed areas for diagnosis and imaging”, [0020] – “the method is used in fluorescence-guided surgery or fluorescence-guided tumor resection”).
Regarding claim 3, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses wherein the navigating of the instrument, via the minimally invasive route, is an endoluminal procedure ([0005] – “During bronchoscopy, a flexible endoscope…is guided through the patient's airways (bronchus)”, [0066] – “the biological tissue (i.e., tumor, metastatic lesion, synchronous lesion, tumor margins, or lymph node)…can be accessed during a bronchoscopy. In a further aspect, the bronchoscopy is non-invasive”).
Regarding claim 4, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Conversely Kularatne does not teach wherein the area of the tissue abnormality is identified from one or more preoperative scans.
However Singhal discloses wherein the area of the tissue abnormality is identified from one or more preoperative scans ([0123] – “Subjects had previously undergone CT scanning with 1 mm slice thickness that was reviewed by a specialized thoracic radiologist to confirm the presence of a pulmonary nodule and identify other suspicious nodules”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the preoperative scans of Singhal to achieve the same results. One would have motivation to combine because it provides a general location of a nodule to then be further localized by fluorescence imaging.
Regarding claim 5, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 2.
Kularatne further discloses wherein: the instrument comprises a biopsy needle or other biopsy tool ([0063] – “a practitioner can ensure the endoscope attachment (e.g., biopsy needle”); and
the diagnosing and/or treating comprises collecting one or more biopsy samples from the fluorescing abnormal tissue ([0055], [0062] – “the interventional procedure may involve biopsy”).
Regarding claim 6, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 2.
Kularatne further discloses wherein the diagnosing and/or treating comprises resection or destruction of the fluorescing abnormal tissue ([0055], [0062] – “the interventional procedure may involve biopsy, ablation, resection, incision, cutting, and/or cauterization of target tissue”).
Regarding claim 7, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 6.
Kularatne further discloses wherein the destruction of the fluorescing abnormal tissue comprises (i) ablation ([0055], [0062] – “the interventional procedure may involve biopsy, ablation, resection, incision, cutting, and/or cauterization of target tissue”), and/or (ii) local administration of a drug to the fluorescing abnormal tissue.
Regarding claim 11, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses wherein: the instrument comprises a flexible bronchoscope ([0017] – “the flexible probe is a flexible endoscope, fluorescence endoscopic imaging probe, fiber scope, video scope, gastroscope, colonoscope, bronchoscope”), and
the navigating comprises guiding the flexible bronchoscope through the patient’s airway ([0005] – “During bronchoscopy, a flexible endoscope…is guided through the patient's airways (bronchus)”).
Regarding claim 16, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses which is done without a preoperative marking procedure (Paragraphs [0054] - [0056] disclose the method steps for performing an interventional procedure which do not include a preoperative marking procedure).
Regarding claim 17, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Conversely Kularatne does not teach wherein the molecular imaging agent is administered between 2 hours and 4 days prior to the navigating.
However Singhal discloses wherein the molecular imaging agent is administered between 2 hours and 4 days prior to the navigating ([0110] – “the compound is administered about 3 to about 6 hours prior to resection”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the timing of administration of the imaging agent of Singhal to achieve the same results. One would have motivation to combine because it would allow enough time for the imaging agent to bind to the target tissue to clearly show the location of the tumor.
Regarding claim 22, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses wherein the molecular imaging agent is configured to covalently bind to a target molecule that is present at larger amounts in solid tumors than in normal tissues ([0052] – “the compounds are used to identify a target cell type in a biological sample…allow for binding of the compound to at least one cell of the target cell type. The bound compound is then optically detected…indicated that the target cell type is present in the biological sample”).
Regarding claim 24, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses wherein the molecular imaging agent comprises VGT-309 or a pharmaceutically acceptable salt thereof ([0057] – “In some aspects, the compound is in the form of a pharmaceutically acceptable salt”).
Regarding claim 29, Kularatne discloses a method of performing a biopsy (Abstract – “method of performing an interventional procedure”, [0062] – “the interventional procedure may involve biopsy”) comprising:
[…] administering a molecular imaging agent to the patient ([0055] – “(a) administering a compound or a composition comprising the compound to a human or animal subject, wherein the compound comprises a targeting moiety and a fluorescence imaging agent”);
navigating a biopsy needle to the location of the tissue abnormality ([0055] – “(c) guiding a flexible probe to the intervention site; (d) illuminating biological tissue at the intervention site; and (e) performing intervention of the biological tissue at the intervention site”, [0062] – “the interventional procedure may involve biopsy”, [0063] – “endoscope attachment (e.g., biopsy needle”);
visualizing the tissue under near-infrared (NIR) light ([0053] – “illuminating the compound that has been taken up by the tissue facilitates visualization of the tumor by the near-infrared fluorescence of the compound”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”), wherein the molecular imaging agent is effective to cause tissue at the location to fluoresce under the NIR light ([0054] – “(d) illuminating the biological tissue; and (e) detecting the optical signal emitted by the compound”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”); and
collecting one or more biopsy samples from the fluorescing tissue ([0078] – “facilitate a procedure of biopsy”),
wherein the biopsy needle is navigated to the location via a minimally invasive route and the fluorescent tissue guides (i) the navigation of the biopsy needle and/or (ii) the collection of the one or more biopsy samples ([0055] – “(c) guiding a flexible probe to the intervention site; (d) illuminating biological tissue at the intervention site; and (e) performing intervention of the biological tissue at the intervention site”, [0062] – “the interventional procedure may involve biopsy”, [0063] – “endoscope attachment (e.g., biopsy needle”, [0002] – “Endoscopy is a minimally invasive or non-invasive procedure to examine the hollow interior of an organ or body cavity”),
wherein the fluorescing abnormal tissue is in the patient’s lungs ([0054], [0065] – “the biological tissue is a tumor…the tumor…is in or near the lung”), and
wherein the fluorescing abnormal tissue comprises a nodule external to a bronchus ([0005] – “Non-invasive diagnostic procedures typically involve flexible bronchoscopy to assess pulmonary tissue and peripheral pulmonary tissue for tumors, lesions, and nodules”, [0053] – “allows an improved and accurate removal of even small tumors”, [0063] – “image-guided biopsy, ablation, resection, incision, cutting, and/or cauterization can be performed on primary lung tumor nodules, metastatic lung lesions, and regional metastatic lung lymph nodes”, for clarification if nodules in the patients lungs are taking up the compound any nodule that is peripheral to the bronchoscope would be fluorescing when illuminated with NIR light including nodules that are external to the bronchus).
Conversely Kularatne does not teach identifying a tissue abnormality on a patient’s preoperative scans;
intravenously administering a molecular imaging agent.
However Singhal discloses identifying a tissue abnormality on a patient’s preoperative scans ([0123] – “Subjects had previously undergone CT scanning with 1 mm slice thickness that was reviewed by a specialized thoracic radiologist to confirm the presence of a pulmonary nodule and identify other suspicious nodules”);
intravenously administering a molecular imaging agent ([0087] – “The targeting constructs and supplemental targeting constructs used in practice of the disclosure method can be administered by any route known to those of skill in the art, such as…intravenously”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the preoperative scans and the molecular imaging agent being intravenously administered of Singhal to achieve the same results. One would have motivation to combine because it provides a general location of a nodule to then be further localized by fluorescence imaging and allows one to administer the imaging agent to the local desired region rapidly.
Regarding claim 30, Kularatne discloses a method of removing or destroying a tumor in a patient (Abstract – “method of performing an interventional procedure”, [0062] – “the interventional procedure may involve biopsy, ablation, resection, incision, cutting, and/or cauterization of target tissue”), the method comprising:
wherein the molecular imaging agent is configured to covalently bind to a target molecule that is present at larger amounts in solid tumors than in normal tissues ([0052] – “the compounds are used to identify a target cell type in a biological sample…allow for binding of the compound to at least one cell of the target cell type. The bound compound is then optically detected…indicated that the target cell type is present in the biological sample”),
visualizing tissue at the location under near-infrared (NIR) light ([0053] – “illuminating the compound that has been taken up by the tissue facilitates visualization of the tumor by the near-infrared fluorescence of the compound”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”), wherein the molecular imaging agent is effective to cause tissue in the tumor at the location to fluoresce under the NIR light ([0054] – “(d) illuminating the biological tissue; and (e) detecting the optical signal emitted by the compound”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”); and
then resecting or destroying the fluorescing tissue of the tumor, using the surgical instrument ([0055] – “(c) guiding a flexible probe to the intervention site; (d) illuminating biological tissue at the intervention site; and (e) performing intervention of the biological tissue at the intervention site”, [0062] – “the interventional procedure may involve…resection”, [0066] – “The bronchoscopy also may comprise biopsy, ablation, resection, incision, or cauterization”);
wherein the surgical instrument is navigated to the location via a minimally invasive route and the fluorescent tissue guides (i) the navigation of the surgical instrument and/or (ii) the resecting or destroying ([0026] – “Flexible probe will be guided by the NIR signal to direct the probe to the lung tumors”, [0053] – “surgical resection of the areas that fluoresce upon excitation”, [0002] – “Endoscopy is a minimally invasive or non-invasive procedure to examine the hollow interior of an organ or body cavity”, [0019] – “the bronchoscopy is non-invasive”),
wherein the fluorescing abnormal tissue is in the patient’s lungs ([0054], [0065] – “the biological tissue is a tumor…the tumor…is in or near the lung”), and
wherein the fluorescing abnormal tissue comprises a nodule external to a bronchus ([0005] – “Non-invasive diagnostic procedures typically involve flexible bronchoscopy to assess pulmonary tissue and peripheral pulmonary tissue for tumors, lesions, and nodules”, [0053] – “allows an improved and accurate removal of even small tumors”, [0063] – “image-guided biopsy, ablation, resection, incision, cutting, and/or cauterization can be performed on primary lung tumor nodules, metastatic lung lesions, and regional metastatic lung lymph nodes”, for clarification if nodules in the patients lungs are taking up the compound any nodule that is peripheral to the bronchoscope would be fluorescing when illuminated with NIR light including nodules that are external to the bronchus).
Conversely Kularatne does not teach intravenously administering a molecular imaging agent to the patient;
navigating a surgical instrument to a location of the tumor, as indicated by a preoperative scan and/or biopsy, wherein the molecular imaging agent is administered between 2 hours and 4 days prior to the navigating;
However Singhal discloses intravenously administering a molecular imaging agent to the patient ([0087] – “The targeting constructs and supplemental targeting constructs used in practice of the disclosure method can be administered by any route known to those of skill in the art, such as…intravenously”);
navigating a surgical instrument to a location of the tumor, as indicated by a preoperative scan and/or biopsy ([0123] – “Subjects had previously undergone CT scanning with 1 mm slice thickness that was reviewed by a specialized thoracic radiologist to confirm the presence of a pulmonary nodule and identify other suspicious nodules”, [0129] – “During minimally invasive pulmonary resection, the operating surgeon manipulated the lobe to localize the preoperatively described nodule”), wherein the molecular imaging agent is administered between 2 hours and 4 days prior to the navigating ([0110] – “the compound is administered about 3 to about 6 hours prior to resection”);
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the preoperative scans and the molecular imaging agent being intravenously administered of Singhal to achieve the same results. One would have motivation to combine because it provides a general location of a nodule to then be further localized by fluorescence imaging and allows one to administer the imaging agent to the local desired region rapidly.
Regarding claim 37, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses wherein the navigating the instrument comprises use of a robotic or robotically-assisted system ([0066] – “the bronchoscopy can be performed manually or using robotic-assisted technology”).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Singhal (US 20170232119) as applied to claim 1 above, and further in view of Tran-Guyon (US 20230203014).
Regarding claim 8, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Conversely Kularatne does not teach wherein the tissue abnormality comprises a tumor with poorly defined margins.
However Tran-Guyon discloses wherein the tissue abnormality comprises a tumor with poorly defined margins ([0052] – “in pancreatic cancer, the tumors are particularly difficult to remove completely by surgery, as they are not easily delimited”).
The disclosure of Tran-Guyon is an analogous art considering it is in the field of fluorescence imaging.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the tumor with poorly defined margins of Tran-Guyon to achieve the same results. One would have motivation to combine because “it possible to obtain better visualization of the contours of the tumors owing to the differentiation of labeling between tumor tissue and healthy tissue, and thus more effective tumor resection by surgery” (Tran-Guyon [0052]).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Singhal (US 20170232119) as applied to claim 1 above, and further in view of Hauger (US 20110280810).
Regarding claim 15, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claim 1.
Kularatne further discloses an endoscope that is inserted into the fluorescing tissue to directly visualize live cells and their organization within the tissue abnormality ([0064] – “If the putative diseased site is a natural body cavity or surgically produced interior site, an endoscopic attachment can be used to deliver the excitation light to the site, to receive fluorescence emanating from the site within a body cavity, and to aid in the formation of a direct image of the fluorescence from the diseased tissue”).
Conversely Kularatne does not explicitly teach an NIR-enabled confocal microscope.
However Hauger discloses an NIR-enabled confocal microscope ([0004] – “tumor cells detected by intraoperative confocal endomicroscopy in the near infrared wavelength”).
The disclosure of Hauger is an analogous art considering it is in the field of fluorescence detection.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the NIR-enabled confocal microscope of Hauger to achieve the same results. One would have motivation to combine because “the surgeon can use confocal endomicroscope 110 to accurately identify tumor margins” (Hauger [0041]).
Claims 18 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Singhal (US 20170232119) as applied to claims 1 and 30 above, and further in view of Zupkofska (US 20160178519).
Regarding claims 18 and 32, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 30.
Conversely Kularatne does not teach wherein the molecular imaging agent is administered between 12 hours and 36 hours prior to the navigating.
However Zupkofska discloses wherein the molecular imaging agent is administered between 12 hours and 36 hours prior to the navigating ([0091] – “a time period in the range of 20-30 minutes, in the range of several hours, in the range of a day, in the range of several days, or more may be necessary to allow the marker to permeate into the nodule”).
The disclosure of Zupkofska is an analogous art considering it is in the field of fluorescence detection.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the administration of the molecular imaging agent occurring between 12 hours and 36 hours prior to the navigating of Zupkofska to achieve the same results. One would have motivation to combine to allow enough time for the imaging agent to bind to the target tissue to clearly show the location of the tumor.
Claims 19-21, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Singhal (US 20170232119) as applied to claims 1 and 30 above, and further in view of Kim (US 20200101175).
Regarding claims 19 and 33, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 30.
Conversely Kularatne does not teach wherein the patient is a human and the molecular imaging agent is administered to the patient at a dose from 0.01 mg/kg to 0.7 mg/kg.
However Kim discloses wherein the patient is a human and the molecular imaging agent is administered to the patient at a dose from 0.01 mg/kg to 0.7 mg/kg ([0025] – “the fluorescent contrast agent may be administered in an amount of 0.1-0.5 mg per unit body weight (1 kg) of the subject, specifically 0.25 mg per unit body weight of the subject”, [0053] – “In the present disclosure, the “subject” may be a mammal such as rat, livestock, human, etc. Specifically, it may be human”).
The disclosure of Kim is an analogous art considering it is in the field of fluorescence detection.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the dosage of Kim to achieve the same results. One would have motivation to combine because “if the dosage of the administered fluorescent contrast agent is less than 0.1 mg/kg, it is difficult to clearly distinguish the boundary of cancer. And, if it is more than 1 mg/kg, the possibility of allergic reactions is increased” (Kim [0045]).
Regarding claim 20, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 19.
Conversely Kularatne does not teach wherein the dose is from 0.015 mg/kg to 0.65 mg/kg.
However Kim discloses wherein the dose is from 0.015 mg/kg to 0.65 mg/kg ([0025] – “the fluorescent contrast agent may be administered in an amount of 0.1-0.5 mg per unit body weight (1 kg) of the subject, specifically 0.25 mg per unit body weight of the subject”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the dosage of Kim to achieve the same results. One would have motivation to combine because “if the dosage of the administered fluorescent contrast agent is less than 0.1 mg/kg, it is difficult to clearly distinguish the boundary of cancer. And, if it is more than 1 mg/kg, the possibility of allergic reactions is increased” (Kim [0045]).
Regarding claim 21, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 19.
Conversely Kularatne does not teach wherein the dose is from 0.1 mg/kg to 0.4 mg/kg.
However Kim discloses wherein the dose is from 0.1 mg/kg to 0.4 mg/kg ([0025] – “the fluorescent contrast agent may be administered in an amount of 0.1-0.5 mg per unit body weight (1 kg) of the subject, specifically 0.25 mg per unit body weight of the subject”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the dosage of Kim to achieve the same results. One would have motivation to combine because “if the dosage of the administered fluorescent contrast agent is less than 0.1 mg/kg, it is difficult to clearly distinguish the boundary of cancer. And, if it is more than 1 mg/kg, the possibility of allergic reactions is increased” (Kim [0045]).
Claim 23, 35, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Singhal (US 20170232119) as applied to claims 1 and 30 above, and further in view of Suurs et. al. NPL 2020 (“Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model”).
Regarding claims 23 and 35, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 30.
Conversely Kularatne does not teach wherein the molecular imaging agent is configured to bind to a cathepsin.
However Suurs discloses wherein the molecular imaging agent is configured to bind to a cathepsin (Abstract: Purpose – “We developed a cathepsin-targeted, quenched fluorescent activity-based probe”).
The disclosure of Suurs is an analogous art considering it is in the field of fluorescence detection.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the molecular imaging agent being configured to bind to a cathepsin of Suurs to achieve the same results. One would have motivation to combine because “these results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques.” (Suurs – Abstract: Conclusion).
Regarding claim 36, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 30 and 35.
Conversely Kularatne does not teach wherein the molecular imaging agent comprises VGT-309.
However Suurs discloses wherein the molecular imaging agent comprises VGT-309 (Abstract: results – “VGT-309 delineated tumor tissue during image-guided surgery”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate VGT-309 as the imaging agent of Suurs to achieve the same results. One would have motivation to combine because “these results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques.” (Suurs – Abstract: Conclusion).
Claims 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) hereinafter Kularatne and further in view of Suurs et. al. NPL 2020 (“Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model”).
Regarding claim 25, Kularatne discloses a method (abstract – “The present disclosure relates to method”) comprising:
navigating an instrument ([0020] – “the method is used in fluorescence-guided surgery”, [0055] – “(c) guiding a flexible probe to the intervention site”), via an endoluminal route ([0005] – “During bronchoscopy, a flexible endoscope…is guided through the patient's airways (bronchus)”, into a human patient to whom [… an imaging agent] has been […] administered ([0055] – “administering a compound or a composition comprising the compound to a human or animal subject, wherein the compound comprises a targeting moiety and a fluorescence imaging agent”), to position the instrument in a target area ([0055] – “guiding a flexible probe to the intervention site”);
visualizing, via the instrument, the target area under near-infrared (NIR) light ([0053] – “illuminating the compound that has been taken up by the tissue facilitates visualization of the tumor by the near-infrared fluorescence”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”); and
identifying in real time the location of any abnormal or cancerous tissue within the target area by the florescence of the abnormal or cancerous tissue caused by the […imaging agent] under the NIR light ([0064] – “the methods employing the compounds of the present disclosure provide a valuable guide to pathologists, immunologists, technicians and surgeons alike, who needs to “see” in real-time the exact outlines, size, etc., of the mass”, [0069] – “fluorescence imaging agent has an excitation and emission spectra in the near-infrared range”),
wherein the fluorescing abnormal tissue is in the patient’s lungs ([0054], [0065] – “the biological tissue is a tumor…the tumor…is in or near the lung”), and
wherein the fluorescing abnormal tissue comprises a nodule external to a bronchus ([0005] – “Non-invasive diagnostic procedures typically involve flexible bronchoscopy to assess pulmonary tissue and peripheral pulmonary tissue for tumors, lesions, and nodules”, [0053] – “allows an improved and accurate removal of even small tumors”, [0063] – “image-guided biopsy, ablation, resection, incision, cutting, and/or cauterization can be performed on primary lung tumor nodules, metastatic lung lesions, and regional metastatic lung lymph nodes”, for clarification if nodules in the patients lungs are taking up the compound any nodule that is peripheral to the bronchoscope would be fluorescing when illuminated with NIR light including nodules that are external to the bronchus).
Conversely Kularatne does not teach a patient to whom VGT-309 has been intravenously administered;
florescence of the abnormal or cancerous tissue caused by the VGT-309 under the NIR light.
However Suurs discloses a patient to whom VGT-309 has been intravenously administered (Pg. 3 right col. – “intravenously injected with 100 μL of 0.5 mg/mL VGT309 (20 nmol)”);
florescence of the abnormal or cancerous tissue caused by the VGT-309 under the NIR light (Pg. 4 left col. – “The Explorer Air has two LED lights for 800 nm illumination and one LED light for white light illumination, enabling both fluorescence and white light images to be simultaneously recorded”, pg. 4 right col. – “the tumor margin could be delineated by the fluorescent signal as soon as 1 h after injection of 20 nmol VGT-309”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate VGT-309 as the imaging agent of Suurs to achieve the same results. One would have motivation to combine because “these results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques” (Suurs – Abstract: Conclusion).
Regarding claim 26, Kularatne and Suurs disclose all the elements of the claimed invention as cited in claim 25.
Conversely Kularatne does not teach wherein the VGT-309 is administered between 2 hours and 4 days prior to the navigating.
However Suurs discloses wherein the VGT-309 is administered between 2 hours and 4 days prior to the navigating (Pg. 8 right column – “Quantified fluorescent images of organs of interest from all the experimental mice in different time points (1, 2, 4, 8 and 24 hours post VGT-309 injection)”, Abstract: methods – “Image-guided surgery was performed at multiple time points”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate VGT-309 being administered between 2 hours and 4 days prior to the navigating of Suurs to achieve the same results. One would have motivation to combine because “these results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques” (Suurs – Abstract: Conclusion).
Regarding claim 27, Kularatne and Suurs disclose all the elements of the claimed invention as cited in claim 25.
Conversely Kularatne does not teach wherein the VGT-309 is administered between 12 hours and 36 hours prior to the navigating.
However Suurs discloses wherein the VGT-309 is administered between 12 hours and 36 hours prior to the navigating (Pg. 8 right column – “Quantified fluorescent images of organs of interest from all the experimental mice in different time points (1, 2, 4, 8 and 24 hours post VGT-309 injection)”, Abstract: methods – “Image-guided surgery was performed at multiple time points”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate VGT-309 being administered between 12 hours and 36 hours prior to the navigating of Suurs to achieve the same results. One would have motivation to combine because “these results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques” (Suurs – Abstract: Conclusion).
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Suurs et. al. NPL 2020 (“Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model”) as applied to claim 25 above, and further in view of Kim (US 20200101175).
Regarding claim 28, Kularatne and Suurs disclose all the elements of the claimed invention as cited in claim 25.
As cited above Suurs discloses the VGT-309 conversely Kularatne and Suurs do not teach wherein the […imaging agent] is administered to the patient at a dose between 0.01 mg/kg and 0.7 mg/kg.
However Kim discloses wherein the […imaging agent] is administered to the patient at a dose between 0.01 mg/kg and 0.7 mg/kg ([0025] – “the fluorescent contrast agent may be administered in an amount of 0.1-0.5 mg per unit body weight (1 kg) of the subject, specifically 0.25 mg per unit body weight of the subject”, [0053] – “In the present disclosure, the “subject” may be a mammal such as rat, livestock, human, etc. Specifically, it may be human”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the dosage of Kim to achieve the same results. One would have motivation to combine because “if the dosage of the administered fluorescent contrast agent is less than 0.1 mg/kg, it is difficult to clearly distinguish the boundary of cancer. And, if it is more than 1 mg/kg, the possibility of allergic reactions is increased” (Kim [0045]).
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151) and Singhal (US 20170232119) as applied to claim 24 above, and further in view of Gray (US 20230117826).
Regarding claim 38, Kularatne and Singhal disclose all the elements of the claimed invention as cited in claims 1 and 24.
Conversely Kularatne does not teach wherein the molecular imaging agent is administered to the patient between 48 hours and 96 hours prior to the navigating.
However Gray discloses wherein the molecular imaging agent is administered to the patient between 48 hours and 96 hours prior to the navigating ([0062] – “Imaging may be performed…50 hours after administration”).
The disclosure of Gray is an analogous art considering it is in the field of fluorescence detection.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the molecular imaging agent being administered to the patient between 48 hours and 96 hours prior to the navigating of Gray to achieve the same results. One would have motivation to combine to allow enough time for the imaging agent to bind to the target tissue to clearly show the location of the tumor.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Kularatne (US 20210353151), Singhal (US 20170232119), and Gray (US 20230117826) as applied to claim 38 above, and further in view of Kim (US 20200101175).
Regarding claim 39, Kularatne, Singhal, and Gray disclose all the elements of the claimed invention as cited in claims 1, 24, and 38.
Conversely Kularatne does not teach the patient is human and wherein the molecular imaging agent is administered to the patient at a dose from 0.015 mg/kg to 0.65 mg/kg.
However Kim discloses the patient is human and wherein the molecular imaging agent is administered to the patient at a dose from 0.015 mg/kg to 0.65 mg/kg ([0025] – “the fluorescent contrast agent may be administered in an amount of 0.1-0.5 mg per unit body weight (1 kg) of the subject, specifically 0.25 mg per unit body weight of the subject”, [0053] – “In the present disclosure, the “subject” may be a mammal such as rat, livestock, human, etc. Specifically, it may be human”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kularatne to incorporate the dosage of Kim to achieve the same results. One would have motivation to combine because “if the dosage of the administered fluorescent contrast agent is less than 0.1 mg/kg, it is difficult to clearly distinguish the boundary of cancer. And, if it is more than 1 mg/kg, the possibility of allergic reactions is increased” (Kim [0045]).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/R.C.L./ Examiner, Art Unit 3797
/CHRISTOPHER KOHARSKI/ Supervisory Patent Examiner, Art Unit 3797