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 .
Acknowledgement of Receipt
Applicant’s Response, filed 7/17/2025, in reply to the Office Action mailed 3/17/2025, is acknowledged and has been entered. Claims 1-4, 9, 19, 20 and 30 have been amended. Claims 34-47 are newly added. Claims 1-6, 8-14, 18-20, 30 and 34-47 are pending and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds for rejection are set forth herein, necessitated by claim amendment.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 2, 8-15, 18-20 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Matthies et al. (Eur. J. of Nuc. Med. and Mol. Imag., 2004, 31(5), p. 797) in view of Cante et al. (Tumori Journal., 2018, 99(1), e6-e10).
Matthies teaches that fluorine-18 fluoroacetate appears to be an interesting alternative to 11C-acetate for imaging prostate cancer with PET. We acquired the first 18F-fluoroacetate PET images in a patient with prostate cancer, rising PSA (101 ng/ml) and progressive bone metastases. Scanning started 70 min after i.v. injection of 280 MBq 18F-fluoroacetate using a combined PET/CT system (Siemens Biograph). The images demonstrate moderate to intense uptake in several (thick arrows) but not all (thin arrows) metastatic bone lesions, with SUVmean of 2.82–4.10 and SUVmax of 3.36–5.11. This compared favourably to accumulation in the liver, with SUVmean of 2.35–2.71 and SUVmax of 3.0–3.58. The mode of excretion was predominantly via the bowel (arrowheads), with low activity in the urine. Compared with 11C-acetate PET, 18F-fluoroacetate offers the possibility of delayed imaging with the potential to further increase the tumour-to-background ratios. Upper row: CT image slices; middle row: combined 18F-fluoroacetate PET/CT; lower row: 18F-fluoroacetate PET.
Matthies does not teach imaging of a subject for leptomeningeal disease.
Cante teaches that metastatic prostate carcinoma commonly involves bones and extrapelvic lymph nodes, with occasional visceral deposits. Central nervous system involvement is unusual and particularly the occurrence of leptomeningeal metastasis (LM) is extremely rare, with few cases described in the medical literature. The clinical presentation is characterized by multifocal neurological deficit and the prognosis is generally dismal, with survival ranging between 3 and 6 months. We report on a patient affected by LM due to prostate cancer who was treated with a combined-modality approach consisting of sequential chemotherapy and radiotherapy. Since LM derived from prostate cancer is likely to become a more common clinical event, such patients would need to be included in clinical trials evaluating new therapeutic approaches, considering that the current treatment strategies have been shown to be rather ineffective.
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform imaging for leptomeningeal disease, which encompasses meninges and pia mater, upon administration of 18F-fluoroacetate when the teaching of Matthies is taken in view of Cante. While Matthies teaches PET imaging of prostate cancer and progressive bone metastases upon administration of 18F-fluoroacetate, imaging of leptomeningeal disease is not taught. One would have been motivated to do so because Cante teaches that leptomeningeal metastases from prostate cancer are known in the prior art and likely to become a more common clinical event. One would have had a reasonable expectation of success in doing so because PET imaging of metastasis from prostate cancer is taught by Matthies.
Claim(s) 1-6, 8-14, 18-20 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Ho et al. (J. Nucl. Med., 2014, 55, p. 749-752) in view of Maharaj et al. (“Nuclear Medicine Imaging in Cancer”, Medicine, 2014, 1-32), in further view of Schluterman et al. (Arch Neurol, 2004, 61(9), p. 1423-1429).
Ho teaches comparison of 11C-acetate with 18F-FDG in a PET/CT evaluation of multiple myeloma (MM), specifically on diagnostic accuracy, identification of high-risk patients, and monitoring of treatment response. Methods: Dual-tracer PET/CT was performed on 35 pathologically and clinically confirmed and untreated patients (26 with symptomatic MM, 5 with smoldering MM, and 4 with monoclonal gammopathy of unknown significance) and 20 individuals with normal marrow. Results: 11C-acetate showed significant incremental value over 18F-FDG (84.6% vs. 57.7%) for positively identifying patients with diffuse and focal symptomatic MM, and was negative in patients with indolent smoldering MM and monoclonal gammopathy of unknown significance. Three functional parameters—number of 11Cacetate–avid and 18F-FDG–avid focal bone lesions and 11C-acetate general marrow activity—strongly correlated with β-2-microglobulin as surrogate imaging markers of tumor burden. After induction chemotherapy, the metabolic change in 11C-acetate general marrow activity correlated with clinical response. Metabolic characterization of MM in diagnosis, risk stratification, and treatment monitoring can be done more accurately by assessing lipid metabolism with 11C-acetate than by assessing glucose metabolism with 18F-FDG (abstract).
A whole-body radiologic survey is the conventional tool to evaluate osteolytic MM lesions but is insensitive early during disease development. MR imaging and 18F-FDG PET/CT are the current state-of-the-art tools for MM evaluation. However, MR imaging is less reliable in distinguishing active disease from scar or necrosis and thus is suboptimal for early assessment of treatment response. 18F-FDG PET/CT can assess treatment response but is insensitive for diffuse disease. This study aimed to investigate whether metabolic characterization by 11C-acetate, a marker of lipid metabolism upregulated in myeloma cells, may be superior to 18F-FDG for diagnosis, risk stratification, and treatment monitoring of plasma cell neoplasms.
This preliminary study suggests that metabolic characterization of MM in diagnosis, assessment of tumor burden, and monitoring of treatment response can be assessed more accurately bylipid metabolism with 11C-acetate than by glucose metabolism with 18F-FDG.
11C-acetate PET/CT (4-ring high-definition Biograph 40; Siemens) was performed at 20 min after injection, followed by 18F-FDG injection approximately 15 min after 11C-acetate imaging (page 749).
Accordingly, Ho teaches administration of 11C-acetate for imaging blood cells, but does not teach 18F labeled acetate or imaging leptomeningeal disease.
Maharaj teaches that acetate is taken up by cells and activated to acetyl-CoA in both the cytosol and mitochondria by acetyl- CoA synthetase. Acetyl-CoA is a common metabolic intermediate for synthesis of cholesterol and fatty acids, which are then incorporated into the membrane. In normal cells and in myocardium, Acetyl-CoA is oxidized in mitochondria to carbon dioxide and water. In tumour cells, acetate is converted into fatty ac- ids by fatty acid synthetase (overexpressed enzyme in cancer cells). Prostate cancer is the most prevalent tumour for which imaging by PET with 18F-FDG has been found to be generally unsatisfactory. The 60%-70% sensitivity of 18F-FDG PET for prostate cancer is not high enough to justify its routine clinical use for staging or restaging of this disease. The poor performance of 18F-FDG PET is likely related to the low glucose metabolic rate that results from the relatively slow growth of most prostate cancers as well as to other factors, including significant excretion of 18F-FDG into the adjacent urinary bladder, making detection of tumour uptake difficult. PET with 11C-Acetate (11C-ACE) has a high sensitivity for detection of prostate cancer and several other cancers that are poorly detected with 18F-FDG. The short half-life of 11C limits its general availability. 18F-Fluoroacetate (18F-FAC) is an analogue of acetate with a longer radioactive half-life. Results indicate that 18F-FAC is retained longer in tumour tissue than in other organs, suggesting that it is a useful tracer for PET tumour imaging. The liver and kidney appear to be the major metabolic organs. It has not yet been determined as to the precise mechanism for the incorporation of 18F-FAC into tumours. Several authors have indicated 18F-FAC is a useful alternative to 11C-ACE for the detection of prostate tumours. Future indications may include other neoplasms with relatively low glucose use.
Schluterman decribes the neurologic symptoms and signs, imaging, cerebrospinal fluid findings, and the clinical course of patients with central nervous system myeloma invasion, all of whom had leptomeningeal myelomatosis. Review of 23 patients with MM and leptomeningeal myelomatosis proven by malignant plasma cells in their cerebrospinal fluid.
Figure 3 shows spinal leptomeningeal contrast enhancement in leptomeningeal myelomatosis.
Leptomeningeal myelomatosis, although rare, should be considered in patients with MM and symptoms suggestive of widespread nervous system involvement. Patients with multiple myeloma (MM) often have neurologic complications. These include peripheral neuropathies, spinal radiculopathies, cranial nerve palsies, spinal cord compression, and a host of metabolic encephalopathies. The causes include vertebral compression fractures, base of skull and other bony involvement, metabolic derangements (eg, hypercalcemia and uremia), hyperviscosity syndrome, and amyloidosis, in addition to the toxicity and complications of treatment. While infiltration of the leptomeninges by various malignancies is well known, invasion of the central nervous system (CNS) in MM is rare, either as presumed intracerebral metastases or as leptomeningeal myelomatosis (LMM), with approximately 70 cases reported in the English-language literature in the past century, mostly case reports.
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform a method of imaging cancerous cells in a subject, wherein the cancerous cells are localized to the central nervous of the subject, the method comprising: administering to the subject an effective amount of 18F-fluoroacetate; detecting a first signal emitted by 18F-fluoroacetate; and generating an image, including wherein the cancerous cells are blood cells when the teaching of Ho is taken in view of Maharaj. While Ho teaches imaging multiple myeloma upon administration of 11C-acetate and PET imaging thereof, 18F-fluoroacetate is not taught. It would have been obvious to one of ordinary skill in the art to substitute 18F-fluoroacetate as a functionally equivalent radionuclide to 11C-acetate, with a reasonable expectation of success, because Maharaj teaches that 18F-Fluoroacetate (18F-FAC) is an analogue of acetate with a longer radioactive half-life and that results indicate that 18F-FAC is retained longer in tumour tissue than in other organs, suggesting that it is a useful tracer for PET tumour imaging. Further, several authors have indicated 18F-FAC is a useful alternative to 11C-ACE for the detection of prostate tumours and future indications may include other neoplasms with relatively low glucose use. It would have been further obvious to perform imaging for leptomeningeal disease, which encompasses meninges and pia mater, when the teachings of Ho and Maharaj are taken in view of Schulterman. One would have been motivated to do so, with a reasonable expectation of success, because Ho is directed to PET imaging in patients with multiple myeloma upon administration of radiolabeled acetate and Schulterman teaches the association between leptomeningeal disease and multiple myeloma, including leptomeningeal myelomatosis. Regarding claims 5-6, association with leukemia is also taught in Schluterman.
Claim(s) 34-47 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Matthies et al. (Eur. J. of Nuc. Med. and Mol. Imag., 2004, 31(5), p. 797) in view of Schaffer et al. (WO 2018035610).
Matthies teaches that fluorine-18 fluoroacetate appears to be an interesting alternative to 11C-acetate for imaging prostate cancer with PET. We acquired the first 18F-fluoroacetate PET images in a patient with prostate cancer, rising PSA (101 ng/ml) and progressive bone metastases. Scanning started 70 min after i.v. injection of 280 MBq 18F-fluoroacetate using a combined PET/CT system (Siemens Biograph). The images demonstrate moderate to intense uptake in several (thick arrows) but not all (thin arrows) metastatic bone lesions, with SUVmean of 2.82–4.10 and SUVmax of 3.36–5.11. This compared favourably to accumulation in the liver, with SUVmean of 2.35–2.71 and SUVmax of 3.0–3.58. The mode of excretion was predominantly via the bowel (arrowheads), with low activity in the urine. Compared with 11C-acetate PET, 18F-fluoroacetate offers the possibility of delayed imaging with the potential to further increase the tumour-to-background ratios. Upper row: CT image slices; middle row: combined 18F-fluoroacetate PET/CT; lower row: 18F-fluoroacetate PET.
Matthies does not teach imaging of leukemia cells in a subject.
Schaffer teaches 18F-labeled amino acids or derivatives thereof having formula (I) and methods of making same, which can be suitable for PET imaging.
In accordance with another aspect of the invention, there is provided methods and use of the compounds of formula (I) for PET imaging. In accordance with another aspect of the invention, there is provided methods and use of the compounds of formula (I) in diagnosis of proliferative diseases (pages 3-4).
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Proliferative diseases in oncology are characterized by the presence of tumor and/or metastases. Preferably tumors include but are not limited to malignomas of the gastrointestinal or colorectal tract, liver carcinoma, pancreas carcinoma, kidney carcinoma, bladder carcinoma, thyroid carcinoma, prostate carcinoma, endometrial carcinoma, ovary carcinoma, testes carcinoma, melanoma, small-cell and non-small-cell lung carcinoma, dysplastic oral mucosa carcinoma, invasive oral cancer; breast cancer, including hormone- dependent and hormone-independent breast cancer, squamous cell carcinoma, neurological cancer disorders including neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma, soft tissue sarcoma, haemangioma and endocrine tumors, including pituitary adenoma, chromocytoma, paraganglioma, haematological tumor disorders including lymphoma and leukaemias. In some embodiments, the radiolabeled amino acids of the present invention are useful in PET imaging of glioma, prostate cancer and/or tumours (page 18). ALL leukemia cells are disclosed (page 21).
It would have been obvious to one of ordinary skill in the art at the time of the invention to extend the teaching of Matthies directed to PET imaging of prostate cancer metastases upon administration of 18F-fluoroacetate to include additional proliferative diseases when the teaching of Matthies is taken in view of Schaffer. Schaffer teaches imaging of proliferative diseases to include leukemia and metastases thereof upon administration of 18F-labeled compounds of Formula I and derivatives thereof. It is noted that Formula I variables n1-n3 may be 0 and R1-5 may be hydrogen. Accordingly, it would have been obvious to one of ordinary skill in the art to modify the compound taught in the reference to arrive at the claimed homologous compound, with the expectation of providing a compound having similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). As a methyl group (C1) is homologous to an ethyl group (C2) as recited in the claim, it is considered that one of ordinary skill in the art would have found it obvious to provide the ethyl group homolog with the expectation of providing similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Claim(s) 1-6, 8-14, 18-20, 30, 34-47 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Matthies et al. (Eur. J. of Nuc. Med. and Mol. Imag., 2004, 31(5), p. 797) in view of Schaffer et al. (WO 2018035610), in further view of Nuvoli et al. (Case Rep Neurol, 2018, 10(1), p. 45–53).
The rejection over Matthies in view of Scaffer is applied as above with regard to claims 34-47.
With regard to claims 1-6, 8-14, 18-20, 30, Matthies and Schaffer do not specifically recite imaging a subject for leptomeningeal disease.
Nuvoli teaches that leptomeningeal carcinomatosis (LC) is a secondary infiltration by neoplastic cells in the meningeal space. It represents a relatively rare complication that has been observed in 1– 5% of patients with solid tumors and in 5–15% of patients with leukemia and lymphomas. Breast and lung carcinomas and melanoma are the most common primary tumors that metastasize in meningeal space, while the most frequent histological type among solid tumors is represented by the adenocarcinoma; in particular, breast tumor is the most common solid tumor to show leptomeningeal metastatic diffusion and it is frequent for most patients to have intraparenchymal brain metastases concurrent with LC and widely disseminated cancer. Generally, LC represents the final phase of metastatic dissemination (>70%), but in 20% of cases it was diagnosed after a period of free diseases or, occasionally (5–10% of cases), it could be the first clinical evidence of tumor presence also without other general symptoms. LC is characterized by a poor prognosis, especially if derived from solid tumors, the survival being between 6 and 8 weeks in absence of treatment, mainly depending on patient general conditions. However, there are numerous studies that have pointed out that adequate therapeutic approaches, stabilizing neurological symptoms, can improve patient clinical conditions; moreover, the combined use of systemic and local treatments seems to give benefits in terms of survival, especially in patients with breast cancer with a median survival of 7–12 months. Before any therapy, when LC from a solid tumor is suspected, magnetic resonance imaging (MRI) is necessary for its identification, and some studies have reported that cranial and spinal MRI with contrast medium can evidence enhancing lesions in about 70–80% of cases.
Moreover, among the diagnostic imaging procedures, brain 18F-fluorodeoxyglucose (18FFDG) and 11C-methionine positron emission tomography (PET) and PET/computed tomography (CT) [14, 15], have also been employed in LC diagnosis; however, up to date, only few cases of spinal and intracranial LC have been reported, more frequently derived from breast and lung cancers, all with positive results suspected for LC, and confirmed by repeated CSF cytology exams positive for tumor cells (page 46).
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform imaging of a subject for leptomeningeal disease upon administration of 18F-fluoroacetate when the teachings of Matties and Schaffer are taken in view of Nuvoli. One would have been motivated to do so, with a reasonable expectation of success because Schaffer teaches that 18F-labeled analogs of Formula 1 are suitable for imaging various proliferative disaease and their metastases, including prostate, breast, leukemia, etc., and it is known from Nuvoli that leptomeningeal carcinomatosis (LC) is a secondary infiltration by neoplastic cells in the meningeal spaceand has been observed in patients with solid tumors and patients with leukemia and lymphomas, where breast and lung carcinomas and melanoma are the most common primary tumors that metastasize in meningeal space, while the most frequent histological type among solid tumors is represented by the adenocarcinoma, and can be imaged with 18F-labeled reporters.
Conclusion
No claims are allowed at this time.
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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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618