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 .
Summary
Claims 1-15 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application was filed on August 26, 2024 is a 371 of PCT/US2023/064154 filed March 10, 2023, which in turn claims domestic priority to provisional patent application 63/318,923 filed March 11, 2022.
Information Disclosure Statement
Receipt of the Information Disclosure Statements filed on August 26, 2024, September 2, 2025, and March 16, 2026 are acknowledged. A signed copy of the three documents are attached to this office action.
Claim Objections
Claims 2, 4, and 8 are objected to because of the following informalities:
Claims 2 and 4: In both claims there are three parameters/limitations. After the first parameter/limitation Applicant should insert “and/or” to make it clear to the skilled artisan that any or all parameters/limitations maybe selected.
Claim 8: Since the claim depends from claim 5, please make reference to claim 1 step (b) instead of referring to step (b) within the body of the claim for increased clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 non-obviousness.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Levi et al. (Cancer Research, 2019) in view of Yang et al. (Scientific Reports, 2017), and Tsujikawa et al. (Scientific Reports, 2020).
[The Examiner is going to introduce each reference and then combine them in the rejection of the instant claims.]
1. Levi et al.
Levi et al. is considered the closest prior art to the present invention as it teaches imaging of activated T cells as an early predictor of immune response to anti-PD-1 therapy (see title). Also, Levi et al. disclose compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cellspecific PET agent, (18F)F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy. We determined the specificity of the tracer for activated T cells in vitro and in a virally induced model of rhabdomyosarcoma. Of all immune cells tested, activated human CD8+ effector cells showed the highest accumulation of (18F)F-AraG. Isolation of lymphocytes from the rhabdomyosarcoma tumors showed that more than 80% of the intratumoral signal came from accumulation of (18F)F-AraG in immune cells, primarily CD8+ and CD4+.Longitudinal monitoring of MC38 tumor-bearing mice undergoing anti-PD-1 treatment revealed differences in signal between PD-1 and isotype antibody-treated mice early into treatment. The differences in [18F]F-AraG signal were also apparent between responders and nonresponders to anti-PD-1 therapy. lmportantly, we found that the signal in the tumor-draining lymph nodes provides key information about response to anti-PD-1 therapy. Overall, [18F]F-AraG has potential to serve as a much needed immunomonitoring clinical tool for timely evaluation of immunotherapy.
Significance: These findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches (see abstract).
2. Yang et al.
Yang et al. teach synthesis-free PET imaging of brown adipose tissue and TSPO via combination of disulfiram and 64CuCl2 (see title). Additionally, Yang et al. disclose that PET imaging is a widely applicable but a very expensive technology. On-site synthesis is one important contributor to the high cost. In this report, we demonstrated the feasibility of a synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18 kDa (TSPO) via a combination of disulfiram, an FDA approved drug for alcoholism, and 64CuCl2 (termed 64Cu-Dis). In this method, a step-wise injection protocol of 64CuCl2 and disulfiram was used to accomplish the purpose of synthesis-free. Specifically, disulfiram, an inactive 64Cu ligand, was first injected to allow it to metabolize into diethyldithiocarbamate (DDC), a strong 64Cu ligand, which can chelate 64CuCl2 from the following injection to form the actual PET tracer in situ. Our blocking studies, western blot, and tissue histological imaging suggested that the observed BAT contrast was due to 64Cu-Dis binding to TSPO, which was further confirmed as a specific biomarker for BAT imaging using [18F]-F-DPA, a TSPO-specific PET tracer. Our studies, for the first time, demonstrated that TSPO could serve as a potential imaging biomarker for BAT. We believe that our strategy could be extended to other targets while significantly reducing the cost of PET imaging (see abstract).
3. Tsujikawa et al.
Tsujikawa et al. teach integrated [18F]FDG PET/MRI demonstrates the iron-related bone-marrow physiology (see title). In addition, Tsujikawa et al. disclose that we identified predictors for bone-marrow [18F]FDG uptake and MR signals among complete blood count, C-reactive protein (CRP), and anthropometric factors, and demonstrated the bone-marrow physiology using integrated [18F]FDG-PET/MRI. 174 oncology patients without bone-marrow lesions underwent whole-body [18F]FDG-PET/MRI. The standardized uptake value (SUV), apparent diffusion coefficient (ADC), proton density fat-fraction (PDFF), and a reciprocal of T2* relaxation time (R2*) were measured in lumbar vertebrae (L3–5) and bilateral ilia. Vertebrae, pelvis, and ribs were evaluated by 3-point visual scoring on DWI. The association of the PET/MR features with the predictors was examined. Multi-regression analyses identified CRP as the strongest predictor for lumbar and iliac SUVs (standardized coefficient: β = 0.31 and β = 0.38, respectively), and for lumbar and iliac R2* (β = 0.31 and β = 0.46, respectively). In contrast, age was the strongest factor influencing lumbar and iliac ADCs (β = 0.23 and β = 0.21, respectively), and lumbar and iliac PDFFs (β = 0.53 and β = 0.54, respectively). Regarding DWI-visual scores, age was the strongest predictor for vertebrae (β = − 0.47), and the red cell distribution width (RDW) was the strongest predictor for pelvis and ribs (β = 0.33 and β = 0.47, respectively). The bone-marrow [18F]FDG uptake and R2* reflect anemia of inflammation (increased granulopoiesis and reduced iron metabolism), whereas bone-marrow DWI and PDFF reflect age and anemia-responsive erythropoiesis (see abstract).
Combination of Levi et al. and Yang et al.
Regarding instant claim 1, Levi et al. and Yang et al. teach a method of imaging adipose tissue in a subject. The necessary citations within Levi et al. and Yang et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 1
Levi et al. and Yang et al. Citations
A method of imaging adipose tissue in a subject comprising: (a) administering to the subject a compound having a formula:
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Levi et al. disclose evaluate a T-cell-specific PET agent, 18F-labeled analog of arabinofuranosyl guanine [(18F)F-AraG], as an imaging biomarker predictive of response to checkpoint inhibitor therapy (see abstract within Levi et al.). Additionally, Levi et al. disclose the in vitro and in vivo administration of (18F)F-AraG (see pages 3456-3458, Materials and Methods within Levi et al.). The proposed mechanism of imaging activated T cells with [18F]F-AraG is shown on the following page in Figure I. [18F]F-AraG is transported into cells via nucleoside transporters, followed by the
[18F]phosphorylation by mitochondrial dGK (deoxyguanosine kinase) and to a lesser extent by cytosolic dCK (deoxycytidine kinase). [A web-based search for deoxycytosine kinase reverted to deoxycytidine kinase as the only “hit”. Applicant is encouraged to explain this result.] Phosphorylation leads to entrapment of [18F]F-AraG in activated T cells and allows visualization of these cells via PET imaging (see Figure 1 within Levi et al.). [Please see Figure I, below.]
Figure I
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(see Figure 1 within Levi et al.).
Levi et al. fails to explicitly disclose wherein the cells/tissue is adipose tissue.
Yang et al. is in the field of PET imaging brown adipose tissue (see title within Yang et al.) and teaches wherein the tissue is adipose tissue (see abstract within Yang et al., “A synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18 kDa (TSPO) via a combination of disulfiram, an FDA approved drug for alcoholism and 64CuCl2 (termed 64Cu-Dis)”].
wherein a route of administration is selected so as to allow the compound to be phosphorylated by deoxycytosine kinase and deoxyguanosine kinase present in adipose tissue in the subject; and (b) imaging the subject, wherein detecting the presence of the compound corresponds to the presence of adipose tissue.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Levi et al. and Yang et al. prior to the effective filing date of the claimed invention. Both references are pertaining to imaging technology making them analogous art to the skilled artisan. The motivation to combine the two references would be to create an imaging agent that confirms the presence of adipose tissue.
Regarding instant claim 2, Levi et al. and Yang et al. teach wherein the adipose tissue is brown adipose tissue.
Yang et al. is in the field of PET imaging brown adipose tissue (see title within Yang et al.).
Regarding instant claim 3, Levi et al. and Yang et al. teach wherein the method further comprises observing levels of cellular activation in the adipose tissue, wherein levels of cellular activation in the adipose tissue are observed by observing amounts of the compound in the adipose tissue.
Levi et al. disclose that these findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches (see abstract within Levi et al.). Levi et al. further disclose the visualization of the imaging agent (see Figures 4 and 6 within Levi et al.). A skilled artisan (POSITA; person having ordinary skill in the art) would apply the Levi et al. findings of cellular activation to the adipose tissue research and development of Yang et al. [Please see the discussion and citation within instant claim 1.]
Regarding instant claim 4, Levi et al. and Yang et al. teach wherein the method further comprises simultaneously imaging T cells in the subject; and/or intracerebral infiltration of T cells in the subject; and/or activation of brown adipose tissue and activation of regulated marrow adipose tissue in the subject.
Levi et al. disclose imaging of activated T cells as an early predictor of immune response to anti-PD-1 therapy (see title within Levi et al.).
Regarding instant claims 5-7 and 14-15, Levi et al. and Yang et al. teach wherein the subject is one diagnosed with a pathological condition.
Levi et al. disclose anti-PD-1 therapy (see title and abstract within Levi et al.) directly related to the pathological condition of cancer. A skilled artisan (POSITA) would be able to select pancreatic cancer from within the pathological cancers available to study. Additionally, please see the discussion and citations within instant claim 1 combining both the Levi et al. and Yang et al. disclosures.
Regarding instant claim 8, Levi et al. and Yang et al. teach wherein the subject is selected to be a patient that has been administered a therapeutic agent and/or undergone a therapeutic intervention, and the one or more images of the adipose tissue obtained in step (b) are used to obtain information on the on the effects of the therapeutic agent or therapeutic intervention.
Levi et al. disclose (18F)F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy (therapeutic agent; see abstract within Levi et al.).
Regarding instant claims 9 and 10, Levi et al. and Yang et al. teach wherein the method further comprises observing one or more images of the adipose tissue on a first date; observing one or more images of the adipose tissue on a second date; and comparing the images obtained on the first date with the images obtained on the second date so as to observe changes in the adipose tissue over time.
Levi et al. disclose monitoring murine models at three distinct timepoints (1, 2, and 3 weeks) (see Figure 4 within Levi et al.). This methodology could be expanded under routine experimental conditions to include adipose tissue from the Yang et al. disclosure. Please see the discussion and citations within instant claim 1. Furthermore, it would be within the scope of a skilled artisan to monitoring daily, weekly, or monthly depending upon the condition being studied.
Regarding instant claim 11, Levi et al. and Yang et al. teach a method of observing the effects of a test agent on the activation of adipose tissue cells, the method comprising: combining the adipose tissue cells with the test agent; observing the presence or absence of changes in the activation of the adipose tissue cells combined with the test agent; and comparing the activation of the adipose tissue cells combined with the test agent with control adipose tissue cells that have not been combined with the test agent such that the effects of the test agent on the activation of adipose tissue cells is observed.
The protocol listed within instant claim 11 is standard and would be followed by a skilled artisan (POSITA). This method is not radically different than current imaging procedures. Also, please see the discussion and citations within instant claims 1, 9, and 10 for additional relevant rejection text.
Regarding instant claim 12, Levi et al. and Yang et al. teach wherein the adipose tissue cells are combined with the test agent in vitro.
Levi et al. disclose the in vitro testing of (18F)F-AraG (see pages 3456-3458, Materials and Methods within Levi et al.). In vitro testing is often the first step in the preclinical evaluation of a therapeutic or imaging agent. The protocol listed within instant claim 12 is standard and would be followed by a skilled artisan (POSITA). This method is not radically different than current imaging procedures. Also, please see the discussion and citations within instant claims 1, 9, and 10 for additional relevant rejection text.
Combination of Levi et al., Yang et al., and Tsujikawa et al.
Regarding instant claim 13, Levi et al., Yang et al., and Tsujikawa et al. teach wherein the adipose tissue cells are activated marrow adipose tissue cells.
Tsujikawa is in the field of PET imaging bone marrow tissue (see title within Tsujikawa et al.) and teaches wherein the adipose tissue cells are activated marrow adipose tissue cells (see pg. 9, para. 6 within Tsujikawa et al.). A skilled artisan (POSITA) using the teachings of Levi et al. and Yang et al., would employ the disclosure of Tsujikawa et al. to include imaging of marrow adipose tissue cells.
Analogous Art
The Levi et al., Yang et al., and Tsujikawa et al. references are directed to the same field of endeavor as the instant claims, that is, a method of imaging adipose tissue in a subject, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the imaging agent [18F]F-AraG disclosed by Levi et al., using the teachings of both Yang et al. and Tsujikawa et al. in order to arrive at the subject matter of the instant claims.
The Levi et al., Yang et al., and Tsujikawa et al. references all have considerable overlap in the imaging arts. In this instance, Levi et al. supplies the template for the imaging agent [18F]F-AraG composition, Yang et al. supplies support for monitoring adipose tissue, while Tsujikawa et al. supplies support for the imaging of bone-marrow tissue. All references are directed to imaging research and development. These citations therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to develop a adipose imaging agent comprising [18F]F-AraG.
Given these teachings, a POSITA would have been motivated to combine the imaging agent [18F]F-AraG composition as disclosed by Levi et al., monitoring adipose tissue disclosed by Yang et al., and the support for the imaging of bone-marrow tissue as disclosed by Tsujikawa et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the imaging agent [18F]F-AraG taught by Levi et al. along with the use of the necessary claim limitations taught by both Yang et al. and Tsujikawa et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by both Yang et al. and Tsujikawa et al. would have been viewed by a POSITA as routine design optimizations or known modifications for the imaging agent [18F]F-AraG compositions. The motivation to combine the three references would be to create an imaging agent that confirms the presence of adipose tissue including the bone-marrow tissue. Implementing these features in Levi et al.’s imaging agent [18F]F-AraG would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Levi et al., Yang et al., and Tsujikawa et al. provides all the elements of the claimed invention. The resulting imaging agent [18F]F-AraG designed for adipose tissue, constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
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