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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/02/2025 has been entered.
Response to Arguments
Applicant’s arguments in Applicant’s responses filed with respect to the rejections of claim 15 under 35 U.S.C. 102(a)(1) and claims 1 and 24 under 35 U.S.C. 103 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Regarding claim 15, Rorsman (Rorsman, et al., “Manganese Accumulation in Pancreatic β-cells and its Stimulation by Glucose”, Biochem. J., (1981) Vol. 202, pp. 435-444) has been introduced to teach that the radiomanganese is administered at a first time and at a second time that is different from the first time; and wherein the quantified beta cell mass is indicative of a change in beta cell mass as a function of time, features demonstrated by Applicant as absent in Wooten (Wooten, et al., “Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52" PLoS ONE 12(3): e0174351 pp. 1-14 (Year: 2017)). Specifically, Rorsman teaches measuring of manganese in bet-cell rich pancreatic islets using spectroscopy.
With respect to claim 1, Rorsman assesses the impact of manganese and glucose on insulin secretion by pancreatic beta cells in a subject, noting in the abstract that “At a concentration of 0.25 mM, Mn2+ abolished the insulin-releasing action of o-glucose, exerting only moderate suppression of its metabolism.
With respect to claim 24, Weissleder, et al., US 20140056812 A1, which teaches monitoring of beta cells post transplantation to elucidate success of such transplantation.
Therefore, the rejections are sustained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-9, 12-19, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Wooten, et al., “Biodistribution and PET Imaging of pharmacokinetics of manganese in mice using Manganese-52" PLoS ONE 12(3): e0174351 pp. 1-14 (Year: 2017) in view of Rorsman, et al., “Manganese Accumulation in Pancreatic β-cells and its Stimulation by Glucose”, Biochem. J., (1981) Vol. 202, pp. 435-444.
Regarding claim 1, Wooten discloses a method for quantitatively imaging pancreatic beta cells using positron emission tomography (PET) (the title and abstract describe PET imaging based analysis of biodistribution of radioactive manganese), the steps of the method comprising:
(a) administering radiomanganese to a subject (page 4 discloses how 52Mn is administered to the animals);
(b) acquiring data from a region-of-interest containing a pancreas of the subject using a PET system (last paragraph of page 6 discloses that the study acquired PET/CT images demonstrating the uptake and distribution of 52Mn. The first paragraph under the discussion section on page 7 indicates that the region of interest includes the pancreas and the brain, meaning PET/CT data were acquired of the pancreas);
(c) reconstructing an image of the region-of-interest from the acquired data (the last paragraph of page 6 states “co-registered PET/CT images of two mice (species: C57-Black-6) from a separate but similar study in which larger doses of [52Mn]MnCl2 were administered for in vivo PET imaging”, meaning the acquired PET/CT image data were reconstructed into PET/CT images),
wherein the reconstructed image depicts a preferential uptake of free isotopes of the radiomanganese in pancreatic beta cells in the subject via voltage dependent Ca2+ channels (VDCCs) (the third paragraph of page 7 indicates that the paper studies the biodistribution of free Mn(II) in sixteen different tissue of mice following intravenous injection or inhalation in saline solution, producing the PET/CT images as indicated above, and the second paragraph of page 8 indicates that the study examines the impact of iso-flurane on the uptake of free isotopes of 52Mn by pancreatic cells across voltage-dependent calcium channels. Of note, this paragraph studies the uptake in the pancreas, that is, via the voltage-dependent calcium channels, WITHOUT anesthesia which had 3x greater uptake than with anesthesia, thus corresponding to a preferential uptake of the Mn(II) in the pancreatic cells via the known channel (i.e. VDCCs) through which Mn(II) enters pancreatic beta cells.); and
(d) processing the image with a computer system to estimate a quantitative parameter pancreatic beta cell function based on a measured activity of the free isotopes of the radiomanganese taken up in the pancreatic beta cells in the subject via VDCCs (second paragraph of page 8 indicates that the uptake of free 52Mn by pancreatic beta cells without anesthesia was approximately three times greater than with anesthesia, hence at least teaching a measure of pancreatic beta cell function (i.e. under anesthesia vs. not under anesthesia) based on the activity of the free isotopes. The teaching of a measure of 52Mn(II) uptake teaches quantitative measure of pancreatic beta cell mass which is consistent with Applicant’s disclosure (see paragraph 92 of the instant application indicates that uptake corresponds to accumulation and hence the beta cell mass)),
Wooten does not teach wherein the pancreatic beta cell function indicates insulin secretion of the pancreatic beta cells in the subject.
However, within the same field of endeavor, Rorsman teaches Electrothermal atomic-absorption spectroscopy for measuring manganese in β-cell-rich pancreatic islets micro dissected from mice. On page 436, under the “Manganese fluxes”, the document describes curves indicative of uptake and efflux of manganese for islets incubated for different periods of time using non-linear least-squares analysis. As can be seen in in table 5, the effect of Mn2+ on the amounts of insulin released was assessed. The second paragraph of the left column on page 443 indicates several conclusions from the study with respect to the effects of Mn2+ on pancreatic beta cell release of insulin, including Mn2+ inhibition of glucose-stimulated insulin release in the presence of Ca2+, and hence teaching the limitation “wherein the pancreatic beta cell function indicates insulin secretion of the pancreatic beta cells in the subject”.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein the pancreatic beta cell function indicates insulin secretion of the pancreatic beta cells in the subject, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 2, Wooten in view of Rorsman teaches all the limitations of claim 1.
Wooten further teaches wherein the radiomanganese comprises at least one of free radioisotopes of manganese or compounds that dissociate to produce free manganese when administered to the subject (third paragraph of page 3 indicates the study examines the uptake and distribution of free Mn(II)).
Regarding claim 3, Wooten in view of Rorsman teaches all the limitations of claim 2.
Wooten in view of Rorsman fails to teach wherein the radioisotopes of manganese include one of Mn-51 or Mn-52g (the abstract states that “In this study, we produced the positron-emitting radionuclide 52Mn (t1/2 = 5.6 d) by proton bombardment (Ep<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography”. Because the half-life of Mn-52g is 5.6d, it means that the radioisotope the used in their study is Mn-52g).
Regarding claim 4, Wooten in view of Rorsman teaches all the limitations of claim 2.
Wooten fails to teach wherein the radiomanganese is administered to the subject in a dose having less than one micromolar of radiomanganese.
However, Rorsman further teaches wherein the radiomanganese is administered to the subject in a dose having less than one micromolar of radiomanganese by stating in the second paragraph of page 436 that “In the first series of experiments, groups of five or six islets were loaded for 60min with 0.25mM-Mn2+ in the presence of 3mM-glucose and then transferred to 5 ml of Mn2+-free medium for further efflux incubation at 37°C in the presence or absence of 20mM-glucose”.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein the radiomanganese is administered to the subject in a dose having less than one micromolar of radiomanganese, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 5, Wooten in view of Rorsman teaches all the limitations of claim 1.
Wooten further teaches wherein the radiomanganese is administered to the subject using a continuous infusion in which the radiomanganese is continuously infused into the subject over a duration of time (last paragraph of page 8 indicates that tail vein infusion at 2mL/h of non-carrier-added 52Mn(II) in radiotracer concentrations in a study that is mimicked for Wooten’s study).
Regarding claim 6, Wooten in view of Rorsman teaches all the limitations of claim 1.
Wooten further teaches wherein the radiomanganese is administered to the subject in a single bolus (third paragraph of page 4 discloses injection of ~100 μL volume, ~0.2±0.4 MBq (~5-10 μCi) of 52Mn, indicating that the 100mL is a single bolus administration).
Regarding claim 7, Wooten in view of Rorsman teaches all the limitations of claim 1.
Wooten further teaches administering a pharmacological agent to the subject before administering the radiomanganese to the subject, wherein the pharmacological agent modulates pancreatic beta cell uptake of divalent metals (third paragraph of page 4 discloses injection of isoflurane before the injection of 52Mn, and second paragraph on page 8 indicates that isoflurane modulates the uptake of divalent metals such as Ca(II) and Mn(II)).
Regarding claim 8, Wooten in view of Rorsman teaches all the limitations of claim 7.
Wooten further teaches wherein the pharmacological agent modulates pancreatic beta cell uptake of Ca2+ (See second paragraph on page 8 which states “Importantly, Graves, et al. [85] have shown that anesthesia by isoflurane can significantly decrease uptake of Mn(II) in the pancreas in fasted mice. This study concluded that isoflurane initiates a sequence in pancreatic β-cells that reduces opening of voltage-dependent calcium channels (VDCCs)-the channels through which Ca(II), Mn(II), and potentially other divalent cations can enter the pancreatic beta cells. In one part of this work, 52Mn(II) in aqueous sodium acetate was administered IV with and without anesthesia by isoflurane, and the uptake in the pancreas at 1 h p.i. under anesthesia was similar to our result (in %ID/g)”).
Regarding claim 9, Wooten in view of Rorsman teaches all the limitations of claim 7.
Wooten further teaches wherein the pharmacological agent inhibits uptake of divalent metals by the pancreatic beta cells (See second paragraph on page 8 which states “Importantly, Graves, et al. [85] have shown that anesthesia by isoflurane can significantly decrease uptake of Mn(II) in the pancreas in fasted mice. This study concluded that isoflurane initiates a sequence in pancreatic β-cells that reduces opening of voltage-dependent calcium channels (VDCCs)-the channels through which Ca(II), Mn(II), and potentially other divalent cations can enter the pancreatic beta cells. In one part of this work, 52Mn(II) in aqueous sodium acetate was administered IV with and without anesthesia by isoflurane, and the uptake in the pancreas at 1 h p.i. under anesthesia was similar to our result (in %ID/g)”).
Regarding claim 12, Wooten in view of Rorsman teaches all the limitations of claim 7.
Wooten fails to teach wherein the pharmacological agent stimulates uptake of divalent metals by the pancreatic beta cells.
However, Rorsman further teaches wherein the pharmacological agent stimulates uptake of divalent metals by the pancreatic beta cells (the last sentence in the right column on page 437 states that “The effect of o-glucose on the Mn 2+ uptake at physiological Ca2+ concentrations is shown in Table 1”, and the first paragraph of the left column on page 438 states that “The lack of a stimulatory effect of o-glucose on the initial uptake differed from that observed after incubation of islets for 60min. In the latter case, exposure to 20mM-D-glucose increased the amounts of manganese incorporated compared with controls incubated with an equimolar concentration of 3-O-methyl-o-glucose. Table 2 indicates the effects of including 0.5 mM-EGT A in the cold medium used for the final washing of the islets in the uptake experiments. Whereas the presence of the chelator resulted in a significant decrease of the islet content of manganese, it did not affect the additional amounts of manganese taken up in response too-glucose during 60min of incubation”).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein the pharmacological agent stimulates uptake of divalent metals by the pancreatic beta cells, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 13, Wooten in view of Rorsman teaches all the limitations of claim 12 above.
Wooten fails to teach wherein the pharmacological agent includes one of D-glucose, glibenclamide, or tolbutamide.
However, Rorsman further teaches wherein the pharmacological agent includes one of D-glucose, glibenclamide, or tolbutamide (the last sentence in the right column on page 437 states that “The effect of o-glucose on the Mn 2+ uptake at physiological Ca2+ concentrations is shown in Table 1”, and the first paragraph of the left column on page 438 states that “The lack of a stimulatory effect of o-glucose on the initial uptake differed from that observed after incubation of islets for 60min. In the latter case, exposure to 20mM-D-glucose increased the amounts of manganese incorporated compared with controls incubated with an equimolar concentration of 3-O-methyl-o-glucose. Table 2 indicates the effects of including 0.5 mM-EGT A in the cold medium used for the final washing of the islets in the uptake experiments. Whereas the presence of the chelator resulted in a significant decrease of the islet content of manganese, it did not affect the additional amounts of manganese taken up in response too-glucose during 60min of incubation”).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein the pharmacological agent includes one of D-glucose, glibenclamide, or tolbutamide, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 14, Wooten in view of Rorsman teaches all the limitations of claim 7.
Wooten further teaches wherein step (d) includes correlating a modulated uptake of divalent metals by the pancreatic beta cells with an activity of radiomanganese in the reconstructed image to estimate a quantitative parameter of pancreatic beta cell function (See second paragraph on page 8 which states “Importantly, Graves, et al. [85] have shown that anesthesia by isoflurane can significantly decrease uptake of Mn(II) in the pancreas in fasted mice. This study concluded that isoflurane initiates a sequence in pancreatic β-cells that reduces opening of voltage-dependent calcium channels (VDCCs)-the channels through which Ca(II), Mn(II), and potentially other divalent cations can enter the pancreatic beta cells. In one part of this work, 52Mn(II) in aqueous sodium acetate was administered IV with and without anesthesia by isoflurane, and the uptake in the pancreas at 1 h p.i. under anesthesia was similar to our result (in %ID/g)”. In this case, the uptake of Mn(II) in the presence of isoflurane was correlated with Mn(II) in the absence of isoflurane, hence indicating a modulation of Mn(II) uptake by isoflurane. The indication of reduced uptake in the presence of isoflurane provides a quantitative parameter for measuring pancreatic beta cell function).
Regarding claim 15, Wooten teaches a method for imaging pancreatic beta cells using positron emission tomography (PET) (the title and abstract describe PET imaging based analysis of biodistribution of radioactive manganese), the steps of the method comprising:
(a) providing to a computer system (first paragraph of page 9 discloses a PET scanner which inherently includes a computer system), a first image of a subject acquired with a PET system following a first administration of radiomanganese to the subject (second paragraph of page 8 indicates a portion of the study comparing the effect of isoflurane on 52Mn(II) uptake using PET/CT images for administrations without isoflurane, see PET/CT images and post-imaging data under “Supporting information” on pages 9-10),
wherein the first image depicts a first radiomanganese activity in the subject based on a first uptake of free isotopes of the radiomanganese in the subject's pancreas via voltage dependent Ca2+ channels (VDCCs) (second paragraph of page 8 indicates assessment of 52Mn(II) uptake in the pancreas with isoflurane);
(b) providing to the computer system(first paragraph of page 9 discloses a PET scanner which inherently includes a computer system), a second image of the subject acquired with the PET system following a second administration of radiomanganese to the subject (second paragraph of page 8 indicates a portion of the study comparing the effect of isoflurane on 52Mn(II) uptake using PET/CT images for administrations with anesthesia by isoflurane, see PET/CT images and post-imaging data under “Supporting information” on pages 9-10),
wherein the second image depicts a second radiomanganese activity in the subject based on a second uptake of free isotopes of the radiomanganese in the subject's pancreas via VDCCs (second paragraph of page 8 indicates a portion of the study comparing the effect of isoflurane on 52Mn(II) uptake using PET/CT images for administrations with anesthesia by isoflurane, see PET/CT images and post-imaging data under “Supporting information” on pages 9-10);
(c) computing a difference between the first activity and the second activity (second paragraph on page 8 indicates that a difference in the uptake of 52Mn(II) is quantified for injections with isoflurane and injections without anesthesia by isoflurane. The difference being that the uptake in the pancreas without anesthesia being 3X greater than with anesthesia); and
(d) quantifying a pancreatic beta cell mass based on the computed difference (second paragraph on page 8 indicates that a difference in the uptake of 52Mn(II) is quantified for injections with isoflurane and injections without isoflurane. The teaching of a measure of 52Mn(II) uptake teaches quantitative measure of pancreatic beta cell mass which is consistent with Applicant’s disclosure (see paragraph 92 of the instant application which indicates that uptake corresponds to accumulation and hence the beta cell mass)).
Wooten fails to teach that the radiomanganese is administered at a first time and at a second time that is different from the first time; and wherein the quantified beta cell mass is indicative of a change in beta cell mass as a function of time.
However, within the same field of endeavor, Rorsman teaches Electrothermal atomic-absorption spectroscopy for measuring manganese in β-cell-rich pancreatic islets micro dissected from mice. On page 436, under the “Manganese fluxes” section, the document states that “groups of five or six islets were incubated for different periods of time in 1 ml of Mn 2+ -containing medium followed by the cold washing”. Fig. 2 shows at least six time points when such different time periods of incubation. This teaches the administration of at least first and a second dose as claimed. The “Manganese fluxes” section on page 436 further describes that curves indicative of uptake and efflux of manganese for islets incubated for different periods of time using non-linear least-squares analysis. As can be seen in in table 5, the effect of Mn2+ on the amounts of insulin released was assessed. Under the “Islet uptake of manganese” section in the right column on page 437. Rorsman teaches in the first paragraph under “Manganese fluxes” section page 436 that curves describing uptake and efflux of manganese for islets incubated for different periods of time were determined from experimental values by a computerized non-linear least-squares analysis and indicates, with respect to fig. 2, that “The manganese contents of islets incubated for various periods of time with 0.25mM-Mn2+ are shown in Fig. 2. No steady state was reached during the observation period of 90min. By plotting dV/dt semilogarithmically, two distinct components of manganese uptake were displayed. The rate constants were 0.279min-1 and 4.75 x 10-4min-1 for the fast and slow phases respectively”. Fig. 3 also demonstrates the concentration-dependence of the initial uptake and fig. 4 shows the amounts of manganese remaining in pre-loaded islets after different periods of efflux and hence teaching the limitation “wherein the quantified beta cell mass is indicative of a change in beta cell mass as a function of time”.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein radiomanganese is administered at a first time and at a second time that is different from the first time; and wherein the quantified beta cell mass is indicative of a change in beta cell mass as a function of time, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 16, Wooten in view of Rorsman teaches all the limitations of claim 15 above.
Wooten further teaches teach wherein the radiomanganese includes one of Mn-51 or Mn-52g (the abstract states that “In this study, we produced the positron-emitting radionuclide 52Mn (t1/2 = 5.6 d) by proton bombardment (Ep<15 MeV) of chromium metal, followed by solid-phase isolation by cation-exchange chromatography”. Because the half-life of Mn-52g is 5.6d, it means that the radioisotope the used in their study is Mn-52g).
Regarding claim 17, Wooten in view of Rorsman teaches all the limitations of claim 15 above.
Wooten further teaches wherein the first image is acquired with a PET system following administration of pharmacological agent that modulates pancreatic beta cell uptake of divalent metals before the administration of the radiomanganese (third paragraph of page 4 discloses injection of isoflurane before the injection of 52Mn, and second paragraph on page 8 indicates that isoflurane modulates the uptake of divalent metals such as Ca(II) and Mn(II)).
Regarding claim 18, Wooten in view of Rorsman teaches all the limitations of claim 17 above.
Wooten further teaches wherein the pharmacological agent modulates pancreatic beta cell uptake of Ca2+ (See second paragraph on page 8 which states “Importantly, Graves, et al. [85] have shown that anesthesia by isoflurane can significantly decrease uptake of Mn(II) in the pancreas in fasted mice. This study concluded that isoflurane initiates a sequence in pancreatic β-cells that reduces opening of voltage-dependent calcium channels (VDCCs)-the channels through which Ca(II), Mn(II), and potentially other divalent cations can enter the pancreatic beta cells. In one part of this work, 52Mn(II) in aqueous sodium acetate was administered IV with and without anesthesia by isoflurane, and the uptake in the pancreas at 1 h p.i. under anesthesia was similar to our result (in %ID/g)”).
Regarding claim 19, Wooten in view of Rorsman teaches all the limitations of claim 17 above.
Wooten further teaches wherein the pharmacological agent inhibits uptake of divalent metals by the pancreatic beta cells (See second paragraph on page 8 which states “Importantly, Graves, et al. [85] have shown that anesthesia by isoflurane can significantly decrease uptake of Mn(II) in the pancreas in fasted mice. This study concluded that isoflurane initiates a sequence in pancreatic β-cells that reduces opening of voltage-dependent calcium channels (VDCCs)-the channels through which Ca(II), Mn(II), and potentially other divalent cations can enter the pancreatic beta cells. In one part of this work, 52Mn(II) in aqueous sodium acetate was administered IV with and without anesthesia by isoflurane, and the uptake in the pancreas at 1 h p.i. under anesthesia was similar to our result (in %ID/g)”).
Regarding claim 21, Wooten in view of Rorsman teaches all the limitations of claim 18.
Wooten fails to teach wherein the pharmacological agent stimulates uptake of divalent metals by the pancreatic beta cells.
However, Rorsman further teaches wherein the pharmacological agent stimulates uptake of divalent metals by the pancreatic beta cells (the last sentence in the right column on page 437 states that “The effect of o-glucose on the Mn 2+ uptake at physiological Ca2+ concentrations is shown in Table 1”, and the first paragraph of the left column on page 438 states that “The lack of a stimulatory effect of o-glucose on the initial uptake differed from that observed after incubation of islets for 60min. In the latter case, exposure to 20mM-D-glucose increased the amounts of manganese incorporated compared with controls incubated with an equimolar concentration of 3-O-methyl-o-glucose. Table 2 indicates the effects of including 0.5 mM-EGT A in the cold medium used for the final washing of the islets in the uptake experiments. Whereas the presence of the chelator resulted in a significant decrease of the islet content of manganese, it did not affect the additional amounts of manganese taken up in response too-glucose during 60min of incubation”).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein the pharmacological agent stimulates uptake of divalent metals by the pancreatic beta cells, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 22, Wooten in view of Rorsman teaches all the limitations of claim 21 above.
Wooten fails to teach wherein the pharmacological agent includes one of D-glucose, glibenclamide, or tolbutamide.
However, Rorsman further teaches wherein the pharmacological agent includes one of D-glucose, glibenclamide, or tolbutamide (The first paragraph of the left column on page 438 states that “The lack of a stimulatory effect of o-glucose on the initial uptake differed from that observed after incubation of islets for 60min. In the latter case, exposure to 20mM-D-glucose increased the amounts of manganese incorporated compared with controls incubated with an equimolar concentration of 3-O-methyl-o-glucose. Table 2 indicates the effects of including 0.5 mM-EGT A in the cold medium used for the final washing of the islets in the uptake experiments. Whereas the presence of the chelator resulted in a significant decrease of the islet content of manganese, it did not affect the additional amounts of manganese taken up in response too-glucose during 60min of incubation”).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten wherein the pharmacological agent includes one of D-glucose, glibenclamide, or tolbutamide, as taught by Rorsman, as such modification would provide a useful clinical tool for elucidating how functionally important Ca2+ is regulated in pancreatic beta cells. (see second paragraph of right column on page 435), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 23, Wooten in view of Rorsman teaches all the limitations of claim 15 above.
Wooten further teaches wherein step (d) includes quantifying a functional pancreatic beta cell mass (second paragraph on page 8 indicates that a difference in the uptake of 52Mn(II) is quantified for injections with isoflurane and injections without isoflurane. The teaching of a measure of 52Mn(II) uptake teaches quantitative measure of pancreatic beta cell mass which is consistent with Applicant’s disclosure (see paragraph 92 of the instant application which indicates that uptake corresponds to accumulation and hence the beta cell mass)).
Claims 10 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wooten in view of Rorsman, as applied to claims 9 and 19, respectively above, and further in view of Roper et al., “Effect of the insulin mimetic L-783,281 on intracellular Ca2+ and insulin secretion from pancreatic beta-cells” Diabetes vol. 51 Suppl 1 (2002): S43-S49.
Regarding claim 10, Wooten in view of Rorsman teaches all the limitations of claim 9.
Wooten in view of Rorsman fails to teach wherein the pharmacological agent includes one of nifedipine or diazoxide.
However, in a similar study in the same field of endeavor, Roper examines the effects of insulin mimetic L-783,281, which is an antidiabetic fungal metabolite, on intracellular calcium and insulin secretion from pancreatic beta cells (see abstract). In the second paragraph of the left column on page S45, Roper states that “To determine if the increase in [Ca2+]i was associated with Ca2+ entry through voltage-dependent Ca2+ channels, the effect of nifedipine was investigated on the L-783,281–evoked [Ca2+]i response. As shown in Fig. 2, pretreatment with 20 µmol/l nifedipine reduced the L-783,281–induced Ca2+ increase 33 ± 6% (n = 6 cells, P
<
0.05). At this concentration, nifedipine completely abolishes the [Ca2+]i increases because of stimulation by K+ or tolbutamide (data not shown), compounds that evoke an influx of extracellular Ca2+ through voltage-dependent Ca2+ channels”, hence teaches the limitation “wherein the pharmacological agent includes one of nifedipine or diazoxide”. Of note, Ca2+ is a divalent cation.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten, as modified by Rorsman, wherein the pharmacological agent includes one of nifedipine or diazoxide, as taught by Roper, as such modification would improve upon the field’s understanding of impact of insulin mimetics in beta cells as a tool in studying insulin signaling in beta cells and for a potential role in diabetes treatments, which would improve clinical outcomes (see conclusion section on page S48), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Regarding claim 20, Wooten in view of Rorsman teaches all the limitations of claim 19.
Wooten in view of Rorsman fails to teach wherein the pharmacological agent includes one of nifedipine or diazoxide.
However, in a similar study in the same field of endeavor, Roper examines the effects of insulin mimetic L-783,281, which is an antidiabetic fungal metabolite, on intracellular calcium and insulin secretion from pancreatic beta cells (see abstract). In the second paragraph of the left column on page S45, Roper states that “To determine if the increase in [Ca2+]i was associated with Ca2+ entry through voltage-dependent Ca2+ channels, the effect of nifedipine was investigated on the L-783,281–evoked [Ca2+]i response. As shown in Fig. 2, pretreatment with 20 µmol/l nifedipine reduced the L-783,281–induced Ca2+ increase 33 ± 6% (n = 6 cells, P
<
0.05). At this concentration, nifedipine completely abolishes the [Ca2+]i increases because of stimulation by K+ or tolbutamide (data not shown), compounds that evoke an influx of extracellular Ca2+ through voltage-dependent Ca2+ channels”, hence teaches the limitation “wherein the pharmacological agent includes one of nifedipine or diazoxide”. Of note, Ca2+ is a divalent cation.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten, as modified by Rorsman, wherein the pharmacological agent includes one of nifedipine or diazoxide, as taught by Roper, as such modification would improve upon the field’s understanding of impact of insulin mimetics in beta cells as a tool in studying insulin signaling in beta cells and for a potential role in diabetes treatments, which would improve clinical outcomes (see conclusion section on page S48), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Wooten in view of Rorsman, as applied to claim 9 above, and further in view of Tichauer, et al., US 20170119330 A1.
Regarding claim 11, Wooten in view of Rorsman teaches all the limitations of claim 9 above.
Wooten further teaches estimating a quantitative parameter of beta cell mass based on a measured activity of the free isotopes of the radiomanganese taken up in the pancreatic beta cells in the subject via VDCCs (second paragraph of page 8 indicates that the uptake of free 52Mn by pancreatic beta cells without anesthesia was approximately three times greater than with anesthesia, hence at least teaching a measure of pancreatic beta cell function (i.e. under anesthesia vs. not under anesthesia) based on the activity of the free isotopes. The teaching of a measure of 52Mn(II) uptake teaches quantitative measure of pancreatic beta cell mass which is consistent with Applicant’s disclosure (see paragraph 92 of the instant application indicates that uptake corresponds to accumulation and hence the beta cell mass)),
wherein the image reconstructed in step (c) comprises a first image subject (second paragraph of page 8 indicates a portion of the study comparing the effect of isoflurane on 52Mn(II) uptake using PET/CT images for administrations without isoflurane, see PET/CT images and post-imaging data under “Supporting information” on pages 9-10), and step (d) includes providing a second image that depicts an uptake of radiomanganese in pancreatic beta cell mass in the region-of-interest without modulation by the pharmacological agent VDCCs (second paragraph of page 8 indicates a portion of the study comparing the effect of isoflurane on 52Mn(II) uptake using PET/CT images for administrations with isoflurane, see PET/CT images and post-imaging data under “Supporting information” on pages 9-10. Specifically, Wooten studies collection of images without isoflurane, which was confirmed to modulate Mn uptake),
wherein a difference value is generated by computing a difference from comparison between the uptake values of first image and the uptake values of the second image (second paragraph on page 8 indicates that a difference in the uptake of 52Mn(II) is quantified for injections with isoflurane indicated in the first image, and without isoflurane, indicated in the second image. The uptake without isoflurane being 3X the uptake with isoflurane),
wherein the difference value indicates an estimate of quantitative pancreatic beta cell mass as a result of computing the difference between the first image and the second image in order to reduce nonspecific exocrine pancreas tracer uptake in the second image (Wooten teaches wherein an uptake difference of 3X the value without anesthesia compared with anesthesia, wherein the comparison indicates an estimate of pancreatic beta cell mass (Consistent with paragraph 92 of the instant application that indicates that uptake corresponds to accumulation and hence the beta cell mass). Furthermore, the use of isoflurane achieves the recited reduction of nonspecific exocrine pancreas tracer uptake in the second image consistent with paragraphs 80 and 92 of the instant application which indicate that the isoflurane accomplishes the said reduction of tracer uptake).
Wooten in view of Rorsman does not teach that the comparison generates a difference image.
However, within the same field of endeavor, Tichauer teaches methods to account for image-confounding nonspecific uptake of targeted imaging agents in medical imaging according to paragraph 22, the method comprising generating a difference image from comparing images to emphasize the difference in target binding (paragraphs 51-52 state “Step 2. Emphasize Target-Based Contrast and/or Quantify Target-To-Targeted Tracer Activity by: [0052] (a) Apply a simple subtraction/ratio-ing/comparison of corrected images: If it is desired to emphasize the difference in target binding (increase target-specific contrast) without need for quantification of the target activity, a simple difference calculation at some timepoint or timepoints after the tracers have been administered may suffice. This can be achieved by subtracting, ratioing, scaling and subtracting, or otherwise comparing the non-targeted image set from the corresponding images of the targeted image sequence”. Paragraph 53 discloses a resultant difference image. Note, the images are PET image data according to paragraphs 67-69).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Wooten, as modified by Rorsman, for generating a difference image from two images, as taught by Tichauer, as such modification would allow emphasizing differences in target binding of the tracer of interest within the region of interest which can be viewed by a user (Paragraph 52), with a reasonable expectation of success, as Wooten also strives to improve upon the field’s examination of manganese in clinical applications as described in the first paragraph of page 9.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Weissleder, et al., US 20140056812 A1 in view of Wooten.
Regarding claim 24, Weissleder teaches a method for assessing a pancreatic tissue transplant using positron emission tomography (PET) (paragraph 5 states that “The present disclosure provides, inter alia, compositions and methods of making and using peptide-detectable agent conjugates that can be used to image beta cell mass in vivo and ex vivo”. Paragraph 122 indicates assessment of beta cell transplantation based on the imaging of the beta cells), the steps of the method comprising:
(a) administering radiomanganese to a subject who has received a pancreatic tissue transplant (paragraph 118 states “administering to a subject one or more peptide-detectable agent conjugates described herein; optionally allowing conjugate to distribute within the subject”. Of note, the peptide detectable agent comprises manganese chelates (e.g. MnDPDP) according to paragraph 111, and paragraph 122 indicates monitoring post transplantation of beta cells);
(b) acquiring an image from a region-of-interest containing a pancreas of the subject with a PET system (paragraph 118 further states “imaging the subject, e.g., by fluoroscopy, radiography, computed tomography (CT), MRI, PET, SPECT, laparoscopy, endomicroscopy, or other whole body imaging modality to detect the presence of beta cell mass”),
(c) computing a pancreatic beta cell mass from the acquired image (paragraph 118 further states that “it is understood that the methods (or portions thereof) can be repeated at intervals to evaluate the subject and detect any changes in beta cell mass over time. Information provided by such in vivo imaging, for example, the presence, absence, or level of emitted signal, can be used to detect and/or monitor the loss of beta cell mass or increase of beta cell mass, e.g., after medical treatment”, such treatment being islet transplantation according to paragraph 122) ;
(d) generating a report based on the computed pancreatic beta cell mass that contains information associated with an assessment of transplant viability of the pancreatic tissue transplant (paragraph 122 states “the peptide-detectable agent conjugates can be used to monitor an increase in beta cell mass after treatment. For example, the peptide-detectable agent conjugates can be used to assess the effectiveness of islet transplantation, e.g., where islets are taken from the pancreas of a deceased organ donor”. Paragraph 118 states that “Information provided by such in vivo imaging, for example, the presence, absence, or level of emitted signal, can be used to detect and/or monitor the loss of beta cell mass or increase of beta cell mass, e.g., after medical treatment”. That is, the information garnered from the images serves as the report for monitoring transplant viability or effectiveness).
Weissleder does not teach wherein the image depicts an uptake of free isotopes of the radiomanganese in the subject's pancreas via voltage dependent Ca2" channels (VDCCs); a measured activity of the free isotopes of the radiomanganese taken up in the pancreatic beta cells in the subject via VDCCs.
However, within the same field of endeavor, Wooten teaches a method of assessing biodistribution of radioactive free manganese radicals in pancreatic beta cells using PET (see abstract) comprising administering radiomanganese to a subject (page 4 discloses how 52Mn is administered to the animals), wherein the image, that is the PET data, depicts an uptake of free isotopes of the radiomanganese in the subject's pancreas via voltage dependent Ca2" channels (VDCCs) and the PET image data further provides a measured activity of the free isotopes of the radiomanganese taken up in the pancreatic beta cells in the subject via VDCCs (see last paragraph of page 6 and third paragraph of page 7).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Muller for administering radiomanganese to a subject; such that the image depicts an uptake of free isotopes of the radiomanganese in the subject's pancreas via voltage dependent Ca2" channels (VDCCs); measured activity of the free isotopes of the radiomanganese taken up in the pancreatic beta cells in the subject via VDCCs, taught by Wooten, as this modification would allow for an effective means for assessing pancreatic beta cell in clinical settings (see paragraphs 2 and 3 of page 3), with a reasonable expectation of success as Weissleder also seeks to assess beta cell mass and the functional state of islets for clinical applications (paragraph 4).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Weissleder, et al., US 20140056812 A1 in view of Wooten, as applied to claim 25, and further in view of Lewis, et al., “52Mn Production for PET/MRI Tracking Of Human Stem Cells Expressing Divalent Metal Transporter 1 (DMT1)”, Theranostics, 2015; Vol. 5 Is. 3 pp: 227-239.
Regarding claim 25, Weissleder in view of Wooten teaches all the limitations of claim 24.
Weissleder in view of Wooten fails to teach wherein the pancreatic tissue transplant comprises a stem cell-based transplant.
However, within the same field of endeavor, Lewis teaches long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions using a divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain (see abstract). The abstract further states that “After cell transplantation in the rat striatum, increased uptake of Mn-based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese-enhanced MRI (MEMRI) and ex vivo PET and autoradiography”, and hence teaching wherein the pancreatic tissue transplant comprises a stem cell-based transplant, as required by the claim.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to configure Weissleder as modified by Wooten, wherein the pancreatic tissue transplant comprises a stem cell-based transplant, as taught by Lewis, as such modification would provide a clinically applicable means of accessing stem cell transplant viability (see abstract), with a reasonable expectation of success as modified Weissleder also strives to improve clinical assessment of beta cell transplantation (see paragraph 4).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Farouk A Bruce whose telephone number is (408)918-7603. The examiner can normally be reached Mon-Fri 8-5pm PST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Koharski can be reached on (571) 272-7230. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application inform