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 Amendment
This action is in response to the remarks filed on 2/17/2026.
The amendments filed on 2/17/2026 have been entered. Accordingly claims 1-18 remain pending. Claims 13-18 are withdrawn in light of the restriction requirement as the inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation of “intraoperatively identifying tumor cells in a subject, the method comprising: administering to a subject a detectably labeled p28 probe; performing surgery to remove the tumor cells from the subject;”. Where the claim merely states, inter alia, identifying tumor cells, administering p28, and performing the surgery. Yet, it is not clear how the tumor is identified, what has been performed to identify or what is being used to identify the tumor.
The term “about” in claim 10 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 10 recites the limitation of “wherein the probe is localized to a tumor that is about 1 mm in size” which is not clear in tumor size being 1 mm in size in relation to what how the 1mm is measured in relation to what? In other words, it is not clear if the tumor is 1mm in size across, from top to bottom or something totally different.
Therefore, the claims rendered indefinite.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-8 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goto et al (Real-time intraoperative tumor imaging in a breast cancer PDX model, Cancer Res (2020) 80 (16_Supplement): LB-022.)
Regarding claim 1, Goto teaches method of intraoperatively identifying tumor cells in a subject (“intraoperative tumor imaging in a breast cancer” title; “Image-guided surgery with fluorescent agents” abst), the method comprising:
administering to a subject a detectably labeled p28 probe (“fluorescent agents...real-time detection with a high-resolution image...cell-penetrating peptide (CPP) p28,...p28 was chemically conjugated with Indocyanine green (ICG), a near-infrared red(NIR) fluorescent agent...human breast cancer...mouse model...|CG-p28 injection i.v. opportunistic 0.5mg/kgb.w. ',wherein' p28 was chemically conjugated with Indocyanine green(ICG) is a detectably labeled p28 probe” abst);
performing surgery to remove the tumor cells from the subject (“fluorescence positive mammary tumors with a 2-mm safe margin were resected under real-time guidance of the PDE imaging unit” abst);
wherein the probe is localized to tumor cells (a near-infrared red(NIR) fluorescent agent...human breast cancer...mouse model...|CG-p28 injection i.v. opportunistic 0.5mg/kgb.w. ',wherein' p28 was chemically conjugated with Indocyanine green(ICG) is a detectably labeled p28 probe” abst); and
wherein, during the surgical procedure (“intraoperative tumor imaging in a breast cancer” title), an imaging technique that provides real time images is performed to detect cells labeled by the probe (“Image-guided surgery with fluorescent agents” abst; p28 was chemically conjugated with Indocyanine green(ICG) is a detectably labeled p28 probe” abst), these cells labeled by the probe representing tumor cells (“p28 was chemically conjugated with Indocyanine green(ICG) is a detectably labeled p28 probe” abst).
Regarding claim 2, Goto teaches wherein the detectable label of the p28 probe comprises a near- infrared fluorescent molecule (“fluorescent agents...real-time detection with a high-resolution image...cell-penetrating peptide (CPP) p28... p28 was chemically conjugated with Indocyanine green (ICG), a near-infrared red(NIR) fluorescent agent).
Regarding claim 3, Goto teaches wherein the near-infrared fluorescent molecule is indocyanine green (“p28 was chemically conjugated with Indocyanine green (ICG), a near-infrared red(NIR) fluorescent agent” abst).
Regarding claim 4, Goto teaches wherein the probe is administered to the subject a concentration between about 50 nM and about 250 nM (“After 24h of ICG-p28 injection i.v. opportunistic 0.5 mg/kg b.w., [which is between ~50 to 250nM] NIR-fluorescence positive mammary tumors” abst).
Regarding claim 5, Goto teaches wherein the probe is administered intravenously or subcutaneously (“After 24h of ICG-p28 injection i.v. ” abst).
Regarding claim 6, Goto teaches wherein the time period between administration of the probe and performing the imaging technique is about 24 hours (“After 24h of ICG-p28 injection i.v. opportunistic 0.5 mg/kg b.w., NIR-fluorescence positive mammary tumors with a 2-mm safe margin were resected under real-time guidance of the PDE imaging unit” abst).
Regarding claim 7, Goto teaches wherein the imaging technique delineates the margins of a tumor (“NIR-fluorescence positive mammary tumors with a 2-mm safe margin were resected under real-time guidance of the PDE imaging unit” abst).
Regarding claim 8, Goto teaches wherein the subject has been diagnosed as having breast cancer (“intraoperative tumor imaging in a breast cancer” title).
Regarding claim 10, Goto teaches wherein the probe is localized to a tumor that is about 1 mm in size (tumors with a 2-mm safe margin were resected under real-time guidance of the PDE imaging unit” abst).
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.
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 9 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Goto in view of Pleijhuis et al (Near-infrared fluorescence (NIRF) imaging in breast-conserving surgery: Assessing intraoperative techniques in tissue-simulating breast phantoms; EJSO 37 (2011) 32e39).
Regarding claim 9, Goto teaches all the claimed limitations except for imaging technique comprises a CCD camera unit that detect 800 nm near infra-red (NIR) signals.
However, in the same field of endeavor, Pleijhuis teaches near-infrared fluorescence (NIRF) imaging in BCS for pre- and intraoperative tumour localization, margin status assessment and detection of residual disease was assessed in tissue-simulating breast phantoms. Fluorescent tumour-like inclusions containing indocyanine green (ICG) were positioned at predefined locations in the phantoms to allow for simulation of (i) preoperative tumour localization, (ii) real-time NIRF-guided tumour resection, and (iii) intraoperative margin assessment. Optical imaging was performed using a custom-made clinical prototype NIRF intraoperative camera (abst). Irradiate the breast with light in the NIR spectral range (650e900 nm). Upon excitation, the fluorophore will release photons of a higher NIR wavelength. Because NIR light is invisible to the naked eye, a dedicated optical imaging system is necessary to capture the NIR signal from the surgical field and digitally convert it to a visible image. Recently, we and our co-workers developed a multispectral NIRF intraoperative camera system that is suitable for intraoperative use with NIR fluorophores (pg. 33 left col.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the method and/or device of the modified combination of reference(s) as outlined above with imaging technique comprises a CCD camera unit that detect 800 nm near infra-red (NIR) signals as taught by Pleijhuis because it provides the surgeon with imaging information on tumour location, margin status, and presence of residual disease in real-time (abst of Pleijhuis).
Regarding claim 11, Goto teaches all the claimed limitations except for the subject has reduced tumor recurrence after surgical removal of a tumor when compared to subjects that had surgery to remove a tumor without the additional imaging technique during the operative procedure.
However, in the same field of endeavor, Pleijhuis teaches the location of the tumour-like inclusion was assessed non-invasively using a NIRF camera system (B). Intraoperatively, the inclusion was excised under real-time NIRF guidance or guided solely by visual and tactile information (CII). At the end of the surgical procedure, the NIRF camera system was applied to inspect for residual disease and evaluate the extend of surgery (fig. 1). In case of residual fluorescence, the surgeon could detect and excise (theranostic procedure) the remnant inclusion under real-time NIRF guidance (Figure 3C-IV and supplemental video 1). In all cases, NIRF-guided re-excision resulted in a complete excision, without the need for additional excision of large breast phantom fragments (pg. 37 left col.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the method and/or device of the modified combination of reference(s) as outlined above with subject has reduced tumor recurrence after surgical removal of a tumor when compared to subjects that had surgery to remove a tumor without the additional imaging technique during the operative procedure as taught by Pleijhuis because it provides the surgeon with imaging information on tumour location, margin status, and presence of residual disease in real-time (abst of Pleijhuis).
Regarding claim 12, Goto teaches all the claimed limitations except for postoperatively evaluating a subject for remaining tumor cells, the method comprising: wherein the imaging technique positively identifies cells expressing a tumor marker, thus identifying any remaining tumor cells.
However, in the same field of endeavor, Pleijhuis teaches the location of the tumour-like inclusion was assessed non-invasively using a NIRF camera system (B). Intraoperatively, the inclusion was excised under real-time NIRF guidance or guided solely by visual and tactile information (CII). At the end of the surgical procedure, the NIRF camera system was applied to inspect for residual disease and evaluate the extend of surgery (fig. 1). In case of residual fluorescence, the surgeon could detect and excise (theranostic procedure) the remnant inclusion under real-time NIRF guidance (Figure 3C-IV and supplemental video 1). In all cases, NIRF-guided re-excision resulted in a complete excision, without the need for additional excision of large breast phantom fragments (pg. 37 left col.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the method and/or device of the modified combination of reference(s) as outlined above with postoperatively evaluating a subject for remaining tumor cells, the method comprising: wherein the imaging technique positively identifies cells expressing a tumor marker, thus identifying any remaining tumor cells as taught by Pleijhuis because it provides the surgeon with imaging information on tumour location, margin status, and presence of residual disease in real-time (abst of Pleijhuis).
Response to Arguments
Applicant's arguments have been fully considered but they are not persuasive at least for the following reasons;
Regarding the rejection of claims under 35USC 112, the applicant argues the following;
In claim 1, it is allegedly not clear how the tumor is identified, what has been performed to identify or what is being used to identify the tumor. Applicant respectfully disagree that it is unclear how the tumor is identified and what is performed to identify. In particular, Applicant references lines 6-8 of claim 1 which states: "during the surgical procedure, an imaging technique that provides real time images is performed to detect cells labeled by the probe, these cells labeled by the probe representing tumor cells". This phrase indicates how the tumor is identified (cells labeled by the probe representing tumor cells) and what is done to identify the tumor (an imaging technique that provides real time images is performed to detect cells labeled by the probe).
However, although, lines 6-8 of claim 1 which states: "during the surgical procedure, an imaging technique that provides real time images is performed to detect cells labeled by the probe, these cells labeled by the probe representing tumor cells", it is still not clear WHAT identifies the representation of the tumor cells; or how is it being identified; or how is the representation of the tumor cells being related to the identification process.
Therefore, the rejections are maintained.
Regarding the prior art rejection of claims, the applicant argues the following;
Applicant respectfully submits that this reference is improperly applied. Please review the claimed provisional document 63/264,732 filed on December 1, 2021 which is properly identified on the ADS.
The first page of Goto clearly indicated the references to be "published online 30 January 2022." Clearly this publication is after the filing of the instant application, and this reference is not prior art.
Contrary to the applicant’s assertion, the cited prior art of Goto appears to be published on 8/15/2020 as can be seen in the below re-produced image of the 1st page of the abstract;
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As can be clearly and factually seen above, the cited sections of the prior art ONLY relies on the what is being published abstract.
Further, MPEP 2128 “Printed Publications” as Prior Art clearly outlines what is being considered as “published” which states “I. A REFERENCE IS A “PRINTED PUBLICATION” IF IT IS ACCESSIBLE TO THE PUBLIC A reference is proven to be a “printed publication” “upon a satisfactory showing that such document has been disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it.”
Therefore, the rejections are maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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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/SERKAN AKAR/ Primary Examiner, Art Unit 3797