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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/23/2024 has been entered.
Status of Claims
Cancelled: 19 and 20
Examined Herein: 1-18 and 21
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/1/2021 and 4/14/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
All rejections of claim 19 and 20 are hereby withdrawn; its cancellation moots the rejection.
The rejections of claims 1-21 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention is hereby withdrawn in view of Applicant’s amendments to claims 1, 8, 9, 10, 15 and 16, which moots the rejections.
The rejection of claims 1, 3-6, 8-11, and 15 under 35 USC § 103 over Panichelli, Ferrari, and Valentini is hereby withdrawn in view of Applicant’s remarks regarding the disclosure of Valentini. Upon further search and consideration, the Examiner has identified additional prior art that addresses the claimed subject matter. Thus, the disclosure of Valentini is no longer needed to establish the prima facie case of obviousness presented.
The rejection of claims 1-6, 8-11 and 15 under 35 USC § 103 over Panichelli, Ferrari, Valentini, and Mali is hereby withdrawn in view of Applicant’s remarks regarding the disclosure of Valentini. Upon further search and consideration, the Examiner has identified additional prior art that addresses the claimed subject matter. Thus, the disclosure of Valentini is no longer needed to establish the prima facie case of obviousness presented.
The rejection of claims 1, 3-5, 7-11, and 13-14 under 35 USC § 103 over Righi, Ferrari, and Valentini is hereby withdrawn in view of Applicant’s remarks regarding the disclosure of Valentini. Upon further search and consideration, the Examiner has identified additional prior art that addresses the claimed subject matter. Thus, the disclosure of Valentini is no longer needed to establish the prima facie case of obviousness presented.
The rejection of claims 1, 3-5, 7-14, and 12-14 under 35 USC § 103 over Righi, Ferrari, Valentini, and Vallabhajosula is hereby withdrawn in view of Applicant’s remarks regarding the disclosure of Valentini. Upon further search and consideration, the Examiner has identified additional prior art that addresses the claimed subject matter. Thus, the disclosure of Valentini is no longer needed to establish the prima facie case of obviousness presented.
The rejection of claims 16-19 and 21 under 35 USC § 103 over Kjærgaard and Valentini is hereby withdrawn in view of Applicant’s remarks regarding the disclosure of Valentini. Upon further search and consideration, the Examiner has identified additional prior art that addresses the claimed subject matter. Thus, the disclosure of Valentini is no longer needed to establish the prima facie case of obviousness presented.
The rejection of claims 16-19 and 21 under 35 USC § 103 over Kjærgaard, Valentini, Baeck, and Wikstrom is hereby withdrawn in view of Applicant’s remarks regarding the disclosure of Valentini. Upon further search and consideration, the Examiner has identified additional prior art that addresses the claimed subject matter. Thus, the disclosure of Valentini is no longer needed to establish the prima facie case of obviousness presented.
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 1-18 and 21 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 and 16 recites the limitation “…at a radioconcentration of 2,775 MBq/ml at calibration time.” It is unclear what "at calibration time" means, as there is no calibration step in the claimed method. A skilled artisan would not know if this is the dose that is administered (to the subject, although there is administration step to a subject in the claim), or if the claim only requires that the dose be in the claimed range during a time of calibration any time before or after the administration. Further clarification is required. Dependent claims fall therewith.
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.
Claims 1, 3-6, and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Panichelli (Imaging of Brain Tumors with Copper-64 Chloride: Early Experience and Results, 2016, Cancer Biotherapy and Radiopharmaceuticals, 31:5), in view of Ferrari (Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study, 2015, BioMed Research International, Volume 2015, Article ID 129764) and Welch (US 6,011,825 A, Patent 1/4/2000).
With respect to claim 1, Panichelli discloses a method for diagnosing a neoplasm in a human patient in need thereof, said method comprising;
administering to a human patient afflicted with glioblastoma multiforme (GBM) a diagnostically effective amount of a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient, 64Cu++.
acquiring an image by PET/CT of said patient to evidence any 64Cu uptake by the cancerous GBM cells, wherein evidence of 64Cu uptake was observed; [Panichelli, Page 161, Col. 2, Paragraph 4 and Page 162, Col. 1, Paragraph 1 and Page 163, Table 2]
With respect to claim 3, Panichelli discloses the patient is female or male. [Panichelli, Page 161, Table 1]
With respect to claim 4, Panichelli discloses the human patient is an adult. [Panichelli, Page 161, Table 1]
With respect to claim 5, Panichelli discloses step (b) is performed 1 hour and 3 hours after step (a). [Panichelli, Page 162, Col. 1, Paragraph 1 and Page 163, Table 2]
With respect to claim 6, Panichelli discloses the dose administered in step (a) is 13 MBq/kg. [Panichelli, Page 161, Col. 2, Paragraph 4]
With respect to claim 9, Panichelli discloses step (b) is repeated at least once. [Panichelli, Page 162, Col. 1, Paragraph 1 and Page 163, Table 2]
Panichelli does not disclose the method is drawn to treating a neoplasm in a patient in need thereof or the active ingredient of the radiopharmaceutical composition is in combination with suitable excipients and/or diluents at a radioconcentration of 2,775 MBq/mL at calibration time or the method further comprises instant step (c).
However, with respect to claim 1, Ferrari discloses a method for treating a neoplasm in a subject in need thereof, said method comprising;
Subjecting said subject, mice bearing U-87GM cells, to a treatment cycle comprising administering an effective amount of a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient, 64Cu++. [Ferrari, Page 2, Col. 2, Paragraph 5]
Ferrari discloses two treatment cycles. One treatment cycle comprises administering a single therapeutically effective amount of 333 MBq of 64CuCl2. Under broadest reasonable interpretation of instant claim 1-step (c), the second treatment cycle can be interpreted in two ways: (1) One treatment cycle comprising administering a therapeutically effective amount of 55.5 MBq of 64CuCl2 per dose for six doses or (2) Six treatment cycles each comprising administering a single therapeutically effective amount of 55.5 MBq of 64CuCl2. [Ferrari, Page 2, Col. 2, Paragraph 5]
Ferrari also discloses a method for diagnosing a neoplasm in a subject in need thereof, said method comprising;
administering to said subject, mice bearing U-87GM cells, an effective amount of a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient 64Cu++.
acquiring an image by PET of said subject to evidence any 64Cu uptake by the U-87GM cells, wherein evidence of 64Cu uptake was observed; [Ferrari, Page 2, Col. 2, Paragraph 2, 3]
Ferrari concludes 64CuCl2 can be conveniently exploited as a theragnostic agent due to its dual function as a diagnostic probe and PET agent. [Ferrari, Abstract and Page 5, Col. 2, Paragraph 2]
With respect to claim 5, Ferrari discloses step (b) is performed 1, 2, and 4 hour(s) after step (a) [Ferrari, Page 3, Figure 1]
With respect to claim 8, Ferrari discloses each treatment cycle of step (c) comprises 1 administration and each treatment cycle is repeated 5 times (when the subject is subjected to six treatment cycles each comprising administering a single therapeutically effective amount of 55.5 MBq of 64CuCl2). [Ferrari, Page 2, Col. 2, Paragraph 5]
With respect to claim 9, Ferrari discloses step (b) is repeated 1 time at week one of the treatment cycle. [Ferrari, Page 2, Col. 2, Paragraph 5]
With respect to claim 10, Ferrari discloses the radiopharmaceutical composition in step (c) is administered once a week. Specifically, Ferrari discloses a single dose of 64CuCl2 is administered. [Ferrari, Page 2, Col. 2, Paragraph 2 & 5] A week is a seven-day span. Since a single dose of 64CuCl2 is administered over a seven-day span, it can reasonably be concluded that 64CuCl2 is administered once a week for one week.
With respect to claim 11, Ferrari discloses for each treatment cycle the dosage regimen comprises administering to the subject a fixed dose of 55.5 MBq or 333 MBq of 64CuCl2. [Ferrari, Page 2, Col. 2, Paragraph 5]
Panichelli nor Ferrari disclose the radiopharmaceutical composition is in combination with suitable excipients and/or diluents at a radioconcentration of 2,775 MBq/mL at calibration time.
However, with respect to claim 1, Welch discloses a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient 64Cu++ in combination with a suitable excipient, NH4OAc, at a radioconcentration of 37 MBq/mL to 25,900 MBq/mL (1-175 mCi/0.25-1.0 mL). [Welch, Col. 27, Line 14-15]
Modifying the method disclosed by Panichelli by further subjecting the patient to a treatment cycle, which comprises administering a 64CuCl2 composition, and modifying the 64CuCl2 composition so that it has a radioconcentration of 37 MBq/mL to 25,900 MBq/mL, including 2,775 MBq/mL, results in the method of instant claim 1.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Panichelli by further subjecting the human patient to a treatment cycle, which comprises administering a 64CuCl2 composition and have a reasonable expectation of success. Panichelli discloses a method for diagnosing a neoplasm in a human patient in need thereof comprising (a) administering 64CuCl2 to a human patient afflicted with a neoplasm and (b) acquiring an image by PET/CT of said patient, to evidence any 64Cu++ uptake by the neoplasm. Similarly, Ferrari discloses a method for diagnosing a neoplasm in a subject in need thereof comprising (a) administering 64CuCl2 to a mice afflicted with a neoplasm and (b) acquiring an image by PET of said mice, to evidence any 64Cu++ uptake by the neoplasm. Ferrari additionally discloses a method for treating a neoplasm in a subject in need thereof comprising subjecting the mice to a treatment cycle, which comprises administering 64CuCl2. So, Ferrari establishes that a subject with a neoplasm can be subjected to both a diagnostic method and a therapeutic method and demonstrates that 64CuCl2 is effective as a theragnostic agent. Thus, the combined teachings of Panichelli and Ferrari suggest the diagnostic method disclosed by Panichelli may be combined with the therapeutic method disclosed by Ferrarri. Therefore, it is reasonable to expect the method disclosed by Panichelli may be modified by further subjecting the human patient to a treatment cycle, which comprises administering a 64CuCl2 composition. One would have been motivated to do so because it is prima facie obvious to combine teachings when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Ferrari discloses 64CuCl2 can be conveniently exploited as a theragnostic agent due to its dual function as a diagnostic probe and PET agent. [Ferrari, Abstract and Page 5, Col. 2, Paragraph 2] Therefore, one would have been motivated by the expectation that the aforementioned modification would allow 64CuCl2 to be exploited as a theragnostic agent.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Panichelli and Ferrari so that the 64CuCl2 composition has a radioconcentration of 2,775 MBq/mL and have a reasonable expectation of success. Panichelli and Ferrari disclose a theragnostic method comprising administering to a human patient a 64CuCl2 composition that has an unspecified radioconcentration. Welch discloses a 64CuCl2 composition that, in one embodiment, has a radioconcentration of 2,775 MBq/mL. So, Panichelli and Ferrari disclose a 64CuCl2 composition and Welch discloses such a composition may have a radioconcentration of 2,775 MBq/mL. Thus, the combined teachings of Panichelli, Ferrari, and Welch suggest the 64CuCl2 composition disclosed by Panichelli and Ferrari may have a radioconcentration of 2,775 MBq/mL. Therefore, it is reasonable to expect the method disclosed by Panichelli and Ferrari may be modified so that the 64CuCl2 composition has a radioconcentration of 2,775 MBq/mL. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Welch discloses 64CuCl2 with a radioconcentration of 37 MBq/mL to 25,900 MBq/mL is suitable for radiopharmaceutical diagnostic and therapeutic applications. [Welch, Abstract and Col. 27, Line 7-30] Ferrari discloses 64CuCl2 is a theragnostic agent due to its dual function as a diagnostic probe and PET agent. [Ferrari, Abstract and Page 5, Col. 2, Paragraph 2] Therefore, one would have been motivated by the expectation that the aforementioned modification would yield a 64CuCl2 composition with a radioconcentration suitable for use as a theragnostic agent.
Claims 1-6 and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Panichelli, Ferrari, and Welch, as applied to claim 1, 3-6, and 8-11 above, and further in view of Mali (Changes In Serum Copper Levels In Patients With Malignant Diseases Undergoing Radiotherapy, January 1998, Indian Journal of Clinical Biochemistry, 13(1):36-40).
With respect to claim 1, Panichelli, Ferrari, Welch disclose the teachings above.
With respect to claim 2, Panichelli discloses the method is preceded by i) collecting a blood sample from the human patient. [Panichelli, Page 160, Col. 2, Paragraph 3]
Panichelli further discloses copper metabolism is altered in cancer patients and elevated copper levels have been found in both serum and tumor tissue in a variety of cancers. [Panichelli, Page 160, Col. 1, Paragraph 3]
Panichelli, Ferrari, and Welch do not disclose the method is preceded by step ii) detecting the content of chemical copper in such sample; wherein step (c) is practiced only if serum copper level detected in the sample are over 150 ug/dL.
However, with respect to claim 2, Mali discloses a method comprising;
collecting a blood sample from human patients afflicted with neoplastic diseases;
detecting the content of chemical copper in the sample. [Mali, Page 37, Col. 1, Paragraph 2 and Page 38, Table 2-3]
Mali further discloses serum copper levels are elevated, or greater than 150ug/dL, in patients afflicted with neoplastic diseases compared to healthy patients. [Mali, Page 38, Table 2-3] Additionally, Mali discloses declining serum copper levels are strongly related to patients’ response to radiotherapy and is helpful in monitoring cancer treatment. [Mali, Page 39, Col. 2, Paragraph 3]
Modifying the method disclosed by Panichelli, Ferrari, and Welch by preceding the method with the step of detecting the content of chemical copper in the sample, wherein serum copper levels greater than 150ug/dL indicates a patient is afflicted with a neoplastic disease, thus rendering the patient in need of treatment, results in the method of instant claim 2.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Panichelli, Ferrari, and Welch by preceding the method with the step of detecting the content of chemical copper in the sample and have a reasonable expectation of success because Panichelli, Ferrari, and Welch disclose a method drawn to diagnosing and treating a neoplasm in a human patient comprising administering 64CuCl2. Panichelli discloses the method is preceded by collecting a blood sample from the patient. Panichelli also discloses copper metabolism is altered in cancer patients and elevated copper levels have been found in both serum and tumor tissue in a variety of cancers. Mali discloses a method for detecting the content of chemical copper in the sample comprising;
collecting a blood sample from human patients afflicted with neoplastic diseases and detecting the content of chemical copper in the sample. Mali further discloses serum copper levels are elevated, or greater than 150ug/dL, in patients afflicted with neoplastic diseases compared to healthy patients. Thus, Panichelli discloses collecting a blood sample from human patients afflicted with a neoplasm and Mali establishes serum copper level can be detected from such a sample. Therefore, it is reasonable to expect the method disclosed by Panichelli, Ferrari, and Welch may be modified by preceding the method with the step of detecting the content of chemical copper in the sample. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, the method disclosed by Panichelli, Ferrari, and Welch is carried out on human patients with a neoplasm. Mali discloses serum copper levels are elevated, or greater than 150ug/dL, in patients afflicted with neoplastic diseases compared to healthy patients. [Mali, Page 38, Table 2-3 and Page 39, Col. 2, Paragraph 3] Therefore, one would have been motivated by the expectation that serum copper level may be used as an indicator to determine patients that are in need of the method and may be helpful in treatment monitoring.
Claims 1, 3-5, 8-11, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Righi (Biokinetic and dosimetric aspects of 64CuCl2 in human prostate cancer: possible theranostic implications, 3/1/2018, EJNMMI Research, 8:18), in view of Ferrari and Welch.
With respect to claim 1, Righi discloses a discloses a method for diagnosing a neoplasm in a human patient in need thereof, said method comprising;
administering to a human patient afflicted with human prostate cancer (PCa) lesions a diagnostically effective amount of a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient 64Cu++;
acquiring an image by PET/CT of said patient to evidence any 64Cu uptake by the cancerous PCa cells, wherein evidence of 64Cu uptake was observed; [Righi, Page 2, Col. 2, Paragraph 4]
With respect to claim 3, Righi discloses the patient is male. [Righi, Figure 2]
With respect to claim 4, Righi discloses the human patient is an adult. [Righi, Figure 2]
With respect to claim 5, Righi discloses step (b) is performed 1 and 4 hour(s) after step (a). [Righi, Page 2, Col. 2, Paragraph 4]
With respect to claim 14, Righi discloses the PET imaging in step (b) is evaluated to evidence any uptake of 64CuCl2 by neoplastic cells of the cancer lesions of the patient through the determination of a target to background ratio (TBR). Righi discloses the TBRmax value was 5.0, 7.0, and 6.2, or higher than 5, and evidenced an uptake of 64CuCl2. [Righi, Abstract and Page 3, Col. 2, Paragraph 2 and Page 4, Col. 1, Paragraph 2 – Col. 2, Paragraph 1]
Righi does not disclose the method is drawn to treating a neoplasm in a patient in need thereof or the active ingredient of the radiopharmaceutical composition is in combination with suitable excipients and/or diluents at a radioconcentration of 2,775 MBq/mL at calibration time or the method further comprises instant step (c).
However, with respect to claim 1, Ferrari discloses a method for treating a neoplasm in a subject in need thereof, said method comprising;
Subjecting the subject, mice bearing U-87GM cells, to a treatment cycle comprising administering an effective amount of a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient copper-64 in ionic form.
Ferrari discloses two treatment cycles. One treatment cycle comprises administering a single therapeutically effective amount of 333 MBq of 64CuCl2. Under broadest reasonable interpretation of instant claim 1-step (c), the second treatment cycle can be interpreted in two ways: (1) One treatment cycle comprising administering a therapeutically effective amount of 55.5 MBq of 64CuCl2 per dose for six doses or (2) Six treatment cycles each comprising administering a single therapeutically effective amount of 55.5 MBq of 64CuCl2. [Ferrari, Page 2, Col. 2, Paragraph 5]
Ferrari also discloses a method for diagnosing a neoplasm in a subject in need thereof, said method comprising;
administering to said subject, mice bearing U-87GM cells, an effective amount of a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient copper-64 in ionic form.
acquiring an image by PET of said patient to evidence any copper-64 uptake by the U-87GM cells, wherein evidence of copper-64 uptake was observed; [Ferrari, Page 2, Col. 2, Paragraph 2, 3]
Ferrari concludes 64CuCl2 can be conveniently exploited as a theragnostic agent due to its dual function as a diagnostic probe and PET agent. [Ferrari, Abstract and Page 5, Col. 2, Paragraph 2]
With respect to claim 5, Ferrari discloses step (b) is performed 1, 2, and 4 hour(s) after step (a) [Ferrari, Page 3, Figure 1]
With respect to claim 8, Ferrari discloses each treatment cycle of step (c) comprises 1 administration and each treatment cycle is repeated 5 times (when the subject is subjected to six treatment cycles each comprising administering a single therapeutically effective amount of 55.5 MBq of 64CuCl2). [Ferrari, Page 2, Col. 2, Paragraph 5]
With respect to claim 9, Ferrari discloses step (b) is repeated 1 time at week one of the treatment cycle. [Ferrari, Page 2, Col. 2, Paragraph 5]
With respect to claim 10, Ferrari discloses the radiopharmaceutical composition in step (c) is administered once a week. Specifically, Ferrari discloses a single dose of 64CuCl2 is administered. [Page 2, Col. 2, Paragraph 2 & 5] A week is a seven-day span. Since a single dose of 64CuCl2 is administered over a seven-day span, it can reasonably be concluded that 64CuCl2 is administered once a week for one week.
With respect to claim 11, Ferrari discloses for each treatment cycle the dosage regimen comprises administering to the subject a fixed dose of 55.5 MBq or 333 MBq of 64CuCl2. [Ferrari, Page 2, Col. 2, Paragraph 5]
Righi nor Ferrari disclose the radiopharmaceutical composition is in combination with suitable excipients and/or diluents at a radioconcentration of 2,775 MBq/mL at calibration time.
However, with respect to claim 1, Welch discloses a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient 64Cu++ in combination with a suitable excipient, NH4OAc, at a radioconcentration of 37 MBq/mL to 25,900 MBq/mL (1-175 mCi/0.25-1.0 mL). [Welch, Col. 27, Line 14-15]
Modifying the method disclosed by Righi by further subjecting the patient to a treatment cycle comprising administering a 64CuCl2 composition and modifying the 64CuCl2 composition so that it has a radioconcentration of 37 MBq/mL to 25,900 MBq/mL, including 2,775 MBq/mL, results in the method of instant claim 1.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Righi by further subjecting the human patient to a treatment cycle, which comprises administering a 64CuCl2 composition and have a reasonable expectation of success. Righi discloses a method for diagnosing a neoplasm in a human patient in need thereof comprising (a) administering 64CuCl2 to a human patient afflicted with a neoplasm and (b) acquiring an image by PET/CT of said patient, to evidence any 64Cu++ uptake by the neoplasm. Similarly, Ferrari discloses a method for diagnosing a neoplasm in a subject in need thereof comprising (a) administering 64CuCl2 to a mice afflicted with a neoplasm and (b) acquiring an image by PET of said mice, to evidence any 64Cu++ uptake by the neoplasm. Ferrari additionally discloses a method for treating a neoplasm in a subject in need thereof comprising subjecting the mice to a treatment cycle, which comprises administering 64CuCl2. So, Ferrari establishes that a subject with a neoplasm can be subjected to both a diagnostic method and a therapeutic method and demonstrates that 64CuCl2 is effective as a theragnostic agent. Thus, the combined teachings of Panichelli and Ferrari suggest the diagnostic method disclosed by Righi may be combined with the therapeutic method disclosed by Ferrarri. Therefore, it is reasonable to expect the method disclosed by Righi may be modified by further subjecting the human patient to a treatment cycle, which comprises administering a 64CuCl2 composition. One would have been motivated to do so because it is prima facie obvious to combine teachings when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Ferrari discloses 64CuCl2 can be conveniently exploited as a theragnostic agent due to its dual function as a diagnostic probe and PET agent. [Ferrari, Abstract and Page 5, Col. 2, Paragraph 2] Therefore, one would have been motivated by the expectation that the aforementioned modification would allow 64CuCl2 to be exploited as a theragnostic agent.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Righi and Ferrari so that the 64CuCl2 composition has a radioconcentration of 2,775 MBq/mL and have a reasonable expectation of success. Righi and Ferrari disclose a theragnostic method comprising administering to a human patient a 64CuCl2 composition that has an unspecified radioconcentration. Welch discloses a 64CuCl2 composition that, in one embodiment, has a radioconcentration of 2,775 MBq/mL. So, Righi, and Ferrari disclose a 64CuCl2 composition and Welch discloses such a composition may have a radioconcentration of 2,775 MBq/mL. Thus, the combined teachings of Righi, Ferrari, and Welch suggest the 64CuCl2 composition disclosed by Righi may have a radioconcentration of 2,775 MBq/mL. Therefore, it is reasonable to expect the method disclosed by Righi and Ferrari may be modified so that the 64CuCl2 composition has a radioconcentration of 2,775 MBq/mL. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Welch discloses 64CuCl2 with a radioconcentration of 37 MBq/mL to 25,900 MBq/mL is suitable for radiopharmaceutical diagnostic and therapeutic applications. [Welch, Abstract and Col. 27, Line 7-30] Ferrari discloses 64CuCl2 is a theragnostic agent due to its dual function as a diagnostic probe and PET agent. [Ferrari, Abstract and Page 5, Col. 2, Paragraph 2] Therefore, one would have been motivated by the expectation that the aforementioned modification would yield a 64CuCl2 composition with a radioconcentration suitable for use as a theragnostic agent.
Claims 1, 3-5, 7-15 are rejected under 35 U.S.C. 103 as being unpatentable over Righi, Ferrari, and Welch, as applied to claim 1, 3-5, 8-11, and 14 above, and further in view of Valentini (US 2016/0296644 A1, Published 10/13/2016).
With respect to claim 1, Righi, Ferrari, and Welch disclose the teachings above.
Ferrari further discloses 20 weeks after the conclusion of the treatment cycles, a PET image of the mice was acquired. All of the surviving mice experienced significant tumor volume reduction, indicating the treatment cycle(s) was/were effective. [Ferrari, Page 2, Col. 2, Paragraph 6 – Page 3, Col. 1, Paragraph 1]
Righi, Ferrari, and Welch do not disclose the method is repeated on said human patient at least 30 days after ending each treatment cycle.
However, with respect to claim 15, Valentini discloses treatment with 64CuCl2 should be repeated every three months, according to the outcomes of the treatment. [Valentini, 0053]
Modifying the method disclosed by Righi, Ferrari, and Welch by repeating the method on the human patient at least 30 days after ending each treatment cycle, results in the method of claim 15
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Righi, Ferrari, and Welch by repeating the method on the human patient at least 30 days after ending each treatment cycle and have a reasonable expectation of success because Righi, Ferrari, and Welch disclose a method drawn to diagnosing and treating a neoplasm comprising administering 64CuCl2. Ferrari discloses after the conclusion of the treatment cycles, a PET image revealed all of the surviving mice exhibited significant tumor volume reduction but only a few exhibited tumor eradications. Valentini discloses treatment with 64CuCl2 should be repeated every three months according to the outcomes of the treatment. Thus, the combined teachings of Ferrari and Valentini suggest that at the conclusion of the treatment cycles, most mice still have a neoplasm and are in need of further treatment and treatment with 64CuCl2 can be repeated after at least 30 days. Therefore, it is reasonable to expect the method disclosed by Righi, Ferrari, and Welch may be modified by repeating the method on the human patient at least 30 days after ending each treatment cycle. One would have been motivated to do so because complete tumor eradication is a known outcome of the method and can reasonably be attained if the method is repeated on a patient still bearing a neoplasm after treatment. [Ferrari, Page 5, Table 1]
With respect to claim 7, Righi, Ferrari, and Welch do not disclose the dose administered in step (c) is from 13 MBq/kg and 105 MBq/kg.
With respect to claim 13, Righi, Ferrari, and Welch do not disclose each treatment cycle the dosage regimen comprises the administrations of instant claim 13.
However, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II)(A) In the instant case, the general conditions of the claim 1 are disclosed by Righi, Ferrari, and Welch, as described above. Thus, it is not inventive to discover the optimum or workable dosage regimen for the treatment cycle of step (c).
it would have been routine optimization to arrive at the dosage of instant claim 7, 12, and 13 because one of ordinary skill in the art would recognize the need to determine a therapeutically effective dose of 64CuCl2 to administer to a human patient with a neoplasm. Valentini discloses a method for treating a neoplasm comprising administering a therapeutic dose of 64CuCl2. [Valentini, 0052-0054] Valentini further discloses the dose of 64CuCl2 administered is calculated based on the patient, the type of tumor, and the extent of the tumor. [Valentini, 0050] Therefore, one of ordinary skill in the art, in view of the disclosure of Valentini, would recognize the dose of 64CuCl2 administered in the method disclosed by Righi, Ferrari, and Welch needs to be optimized according to the patient and the characteristics of their tumor. A person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range because Welch discloses 64CuCl2 with a radioconcentration of 37 MBq/mL to 25,900 MBq/mL is a suitable dose for radiopharmaceutical diagnostic and therapeutic applications. [Welch, Abstract and Col. 27, Line 7-30]
It would have been routine optimization to arrive at the regimen of instant claim 12 and 13 because one of ordinary skill in the art would recognize administering 7 doses of 64CuCl2 per treatment cycle as a design choice. Ferrari discloses subjecting a subject to a treatment cycle comprising administering a total of 333 MBq of 64CuCl2 in a single dose or over the course of 6 doses. [Ferrari, Page 2, Col. 2, Paragraph 6] Ferrari demonstrates that the number of doses administered in a treatment cycle may vary, so long as the subject receives an effective amount of 64CuCl2 per treatment cycle. Administering to the subjects a single dose or multiple doses did not significantly affect the outcomes of the treatment. [Ferrari, Page 5, Table 1-2 & Col. 1, Paragraph 2] Therefore, one of ordinary skill in the art, in view of the disclosure of Righi, would arrive at the seven-dose regimen of the claimed invention, so long as the subject receives an effective amount of 64CuCl2 per treatment cycle. A person of ordinary skill in the art would have a reasonable expectation of success in arriving at the claimed invention because Ferrari establishes a technique for adjusting the number of doses in a treatment cycle while maintaining that an effective total amount of 64CuCl2 is administered. Therefore, the means for arriving at the claimed invention are known in the art.
The burden now shifts to the Applicant to demonstrate administering a dose of from 13 MBq/kg and 105 MBq/kg in step (c) and the dosage regimen of the treatment cycle of instant claim 13 is critical. This is generally accomplished by showing that the claimed range achieves unexpected results relative to the prior art range. MPEP 2144.05(III)(A)
Claims 16-18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kjærgaard ((Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT, 6/18/2020, EJNMMI Radiopharmacy and Chemistry, 5:15), in view of Welch.
With respect to claim 16-18, Kjærgaard discloses a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient 64Cu++ and a counter ion, chloride, in combination with an excipient, HCl and sodium acetate buffer, in a saline solution. Specifically, Kjærgaard discloses the composition comprises 10% CuCl2, 5% sodium acetate buffer, and 85% sterile saline. [Kjærgaard, Page 2, Paragraph 5]
With respect to claim 21, Kjærgaard discloses the radiopharmaceutical composition has a pH of 5. [Kjærgaard, Page 2, Paragraph 5]
Kjærgaard does not disclose the radiopharmaceutical composition has a radioconcentration of 2,775 MBq/mL.
However, with respect to claim 16 and 17, Welch discloses a radiopharmaceutical composition, 64CuCl2, comprising as the active ingredient 64Cu++ in combination with a suitable excipient, NH4OAc, at a radioconcentration of 37 MBq/mL to 25,900 MBq/mL (1-175 mCi/0.25-1.0 mL). [Welch, Col. 27, Line 14-15]
Modifying the radiopharmaceutical composition disclosed by Kjærgaard so that the composition has a radioconcentration of 2,775 MB/mL, results in the in the radiopharmaceutical composition of instant claim 16 and 17.
It would be obvious to one of ordinary skill in the art to modify the radiopharmaceutical composition disclosed by Kjærgaard so that the composition has a radioconcentration of 2,775 MB/mL and have a reasonable expectation of success. Kjærgaard discloses a radiopharmaceutical composition, 64CuCl2, comprising 1 mL of 64CuCl2 dissolved in HCl, sodium acetate buffer, and saline. Similarly, Welch discloses a radiopharmaceutical composition, 64CuCl2, comprising 1 mL of 64CuCl2 dissolved in NH4OAc, wherein the composition has a radioconcentration of 2,775 MBq/mL. So, Kjærgaard discloses a 64CuCl2 composition and Welch discloses such a composition may have a radioconcentration of 2,775 MBq/mL. Thus, the combined teachings of Kjærgaard and Welch suggest the 64CuCl2 composition disclosed by Kjærgaard may have a radioconcentration of 2,775 MBq/mL. Therefore, it is reasonable to expect the composition disclosed by Kjærgaard may be modified so that the 64CuCl2 composition has a radioconcentration of 2,775 MBq/mL. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Welch discloses 64CuCl2 with a radioconcentration of 37 MBq/mL to 25,900 MBq/mL is suitable for radiopharmaceutical diagnostic and therapeutic applications. [Welch, Abstract and Col. 27, Line 7-30] Therefore, one would have been motivated by the expectation that the aforementioned modification would yield a 64CuCl2 composition with a radioconcentration suitable for use as a theragnostic agent.
Response to Arguments
Applicant’s arguments with respect to the radioconcentration of 64CuCl2 taught by Valentini have been considered but are moot because the new ground of rejection does not rely on Valentini for this teaching. [See Remarks 8/15/2025, Page 7-11]
The declaration under 37 CFR 1.132 filed 8/15/2025 is insufficient to overcome the rejection of all claims based upon 35 U.S.C. 103 as set forth in the last Office action because the disclosure is drawn exclusively to the radioconcentration of 64CuCl2 taught by Valentini. However, the new ground of rejection does not rely on this teaching by Valentini. [See AF/D.1332 8/15/2025, Paragraph 1-11]
The declaration under 37 CFR 1.132 filed 8/15/2025 is insufficient to overcome the rejection of all claims based upon 35 U.S.C. 103 as set forth in the last Office action because the disclosure fails to set forth facts that would sufficiently overcome the rejection of record. Specifically, Applicant asserts “We rebut as follows the Examiner's position relating to the Copper-64 vs. Iodine131 (see page 36 of the Office Action). 12, Valentini Declaration.” [Remarks 8/15/2025, Page 11-13] [See AF/D.1332 8/15/2025, Paragraph 12-21]
Applicant’s arguments seem to essentially state that 131I and 64CuCl2 have different properties and therefore the behavior of one cannot be expected on the basis of the other. However, this is not persuasive because the Examiner is not drawing a comparison to 131I and 64CuCl2. In the OA of 5/16/2025, the Examiner stated “The correlation between drug radioconcentration and cell-killing, the impacts thereof, and effects thereof, in humans is not unexpected… because this correlation was already known in the art.” This assertion is drawn to the correlation between radioconcentration and cell death, not 131I and 64CuCl2. Zhao demonstrates as the radioconcentration of a radionuclide increased, the apoptosis rate of human cancer cells increased. Thus, Zhao establishes that increasing the amount of radiation applied to the cells results in an increase in the number of cells killed. No statement made by the Applicant negates this finding by Zhao.
Furthermore, Applicant has provided no data that describes the effect of a radioconcentration higher than 2,775 MBq/mL. Without this information, it is not possible to determine whether the observed increase in cell killing is unique to the claimed radioconcentration or part of an expected trend that increases as the radioconcentration increases.
Moreover, Applicant’s remarks of 8/15/2025 make it unclear what results are claimed to be unexpected. In the Remarks of 12/23/2024, Applicant asserted “…the Applicant has found for the first time that the impact of the drug radioconcentration has been correlated to the cell-killing effect for the translation to humans.” [Reply 12/23/2024, Page 6-8] This assertion has been disproven by the disclosure of Zhao. Now Applicant makes several assertions that depart from this original statement. For example, Applicant asserts “it would not be obvious for a skilled person that increasing the radioconcentration of 64Cu radiopharmaceuticals can bring to a benefit for the biological effect” and “64CuCl2 at 2,775 MBq/mL would have a significantly superior cytotoxic profile compared to lower concentrations.” To avoid miscommunication and ensure both the Office and Applicant are addressing the same issue, Applicant should clarify what specific result is alleged to be unexpected in a future reply.
Conclusion
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618