DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1, 5-16, 19-23, and 25-26 are pending in this application.
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 .
Status of Claims
Claims 1, and 22-23 are amended. Claims 2-4, 17-18, 24, and 27-33 are cancelled.
Response to Amendment
The amendments filed on 4 Aug. 2026 have been entered.
Response to Arguments
In view of Applicants amendment, the rejection of claims 1, 5-16, 19-21, and 25-26 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claim 16 under 35 USC 112(d) as being of improper dependent form for failing to further limit the subject matter is withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 22 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention for the reasons cited in the Office action filed on 7 May 2026.
Claim 23 depends on claims 1 and 22 and requires that the human cancer is a human pancreatic cancer. It is not clear if claim 23 further limits claim 1 or requires measuring the redox status between different human pancreatic cancers.
Applicant’s Arguments
Applicants assert that claim 23 is amended to recite human pancreatic cancers.
Applicants’ arguments filed 4 Aug. 2026 have been fully considered but they are not persuasive. Claims 22 and 23 depend to claim 1. Claim 22 recites human cancers and claim 23 recites human pancreatic cancers. Both human cancers and human pancreatic cancers are broader than the pancreatic ductal adenocarcinoma (PDAC) recited in claim 1. It is not clear if claims 22 and 23 further require in addition to diagnosing and monitoring a patient suffering from PDAC measuring the redox status different between cancers other than PDAC such as colon, breast cancer, or a pancreatic neuroendocrine cancer. It is not clear if claims 22 and 23 further limit claim 1.
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 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.
Claim(s) 1, 5-15, 19-23, and 25-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Saito et al. (ISMRM; published 2017), in view of Wilson et al. (US 2013/0149250 A1; published 13 Jun. 2013) and Kimmelman et al. (US 2019/0136238 A1; published 9 May 2019) for the reasons cited in the Office action filed on 7 May 2026.
Saito et al. teach hyperpolarized 13C-MRI and DMPO and NAC for evaluating oxidative stress in living animals (see title). Saito et al. teach having synthesized 13C-labeled NAC and investigating the feasibility of hyperpolarized 13C-NAC for evaluating oxidative stress in mice. 13C-NAC was detected in mouse body after intravenous injection. The results show that 13C-NAC can be applied to some disease models to evaluate oxidative stress in vivo. Saito et al. teach that deuterated [5-13C]DMPO-d9 or 100 µL [1-13C]NAC containing OX064 was mixed with gadolinium chelate prohance and polarized for 1-2 h (3600 sec- 7200 sec) using a hyperpolarizer and rapidly dissolved in PBS (pharmaceutically acceptable carrier; pH 7.4) containing EDTA. [1-13C]NAC was intravenously injected into a mouse through a catheter in the tail vein of the mouse. 13C-spectra in the mouse were acquired ever 1 sec after injection. 13C-MRI studies were performed on a 3 T scanner. The T1 relaxation time of [1-13C]NAC was 18 sec. (Reads on a method of monitoring a patient comprising an effective amount of [1-13C]N-acetyl cysteine together with a pharmaceutically acceptable carrier and monitoring a patient and wherein the monitoring step comprises permeabilizing the [1-13C]NAC through a cell membrane without active transport).
Saito et al. do not teach diagnosing or monitoring a patient suffering from cancer wherein the cancer is a human PDAC and wherein the cell dynamic 13C-NMR spectra of the hyperpolarized [1-13C]NAC on human PDAC comprises three peaks, a major peak at about 176.5 ppm and two peaks at about 176.8 and at about 177.5 ppm. Saito et al. do not further teach a human patient or procuring a pure phantom sample 13C-NMR spectrum and comparing the procured spectrum of the hyperpolarized active agent with the pure phantom sample 13C-NMR spectrum. Saito et al. do not further teach that the diagnosing step comprising preparing a polarizing solution of about 2-5 molar or 3.2 molar of the active agent by titrating the polarizing solution to a pH of about 6.5 to about 7.8 and optionally wherein the solution remains stable overtime at neutral and acidic pH or wherein the polarizing solution build-up time reaching half of the equilibrium polarization in about 10000 secs to about 15000 sec or in about 11000 secs or that the diagnosing step comprises T1 relaxation time at 3T of a 3.2 molar [1-13C]NAC solution of about 10-25 sec, 15-20 sec or 19.6 sec by decay dynamics of 13C MR signal or that the diagnosing step comprises a sensitivity enhancement increase of about 103 to about 107 fold or 105 fold. Saito et al. do not further teach monitoring the redox status of a redox pair such as a glutathione/glutathione disulfide redox pair or that the composition further comprises one or more chemotherapeutic agents such as biological agents.
Wilson et al. teach hyperpolarized agents for MRI characterization of redox systems in vivo (see title). Wilson et al. teach the GSSG/GSH couple serving as an important indicator of cell redox environment (see [0041], Fig. 1). Intracellular redox has particular relevance to cancer ([0041], [0045]). Wilson et al. teach signal enhancements ([0011], [0082], [0084]). Wilson et al. teach human disease (see [0008]) and human subjects ([0026]). Wilson et al. teach lyophilized conditions (see [0059]). Wilson et al. teach dynamic hyperpolarized spectra ([0014], [0018], [0082]) and a 8M 13C-urea phantom was uses as a chemical shift reference ([0014], [0086]). Wilson et al. teach adding NaOH to [1-13C]vitamin C containing OX063 and a pH of 7.0 ([0092]). Wilson et al. teach concentrations ranging from 0.1 mM to 10 M ([0055]). Wilson et al. teach that the compound of the invention is formulated with an agent that alters the behavior of the redox system being queried by the compound of the invention. These compounds include therapeutic agents ([0064]) including reducing and oxidizing agents ([0078]) such as GSH and vit C ([0091]).
Kimmelman et al. teach targeting the glutamate to pyruvate pathway for treatment of oncogenic kras-associated cancer (see title). Kimmelman et al. teach that PDAC is among the most lethal cancers with a 5-year survival rate of 3%-5% (see [0004]).Kimmelman et al. teach that the PDAC cells are strongly dependent on this series of reactions, as Gln deprivation or genetic inhibition of any enzyme in this pathway led to an increase in ROS and a reduction of reduced glutathione ([0006]). Kimmelman et al. teach determining the efficacy of GPP targeting in a subject and determining the levels of GSSG and GSH and reactive oxygen species (ROS) ([0007]). Kimmelman et al. teach 13C labeled carbons ([0049]). Kimmelman et al. teach N-acetylcysteine (NAC) ([0059]). Kimmelman et al. teach human trials ([0091]). NMR can be used to measure metabolite levels ([0112]).
It would have been obvious to a person of ordinary skill in the art before the to modify the method of Saito et al. (method of diagnosing or monitoring a patient suffering from an ROS associated disease, the method comprising administering a pharmaceutical composition comprising an effective amount of an active agent wherein the active agent is hyperpolarized [1-13C]NAC together with a pharmaceutically acceptable carrier to the patient and diagnosing or monitoring the patient by hyperpolarized 13C-MRI) so that patient, such as a human patient, is suffering from a cancer where the cancer is a human PDAC and the method comprises obtaining a cell dynamic 13C-NMR spectra of the hyperpolarized [1-13C]NAC on human PDAC as taught by Wilson et al. and Kimmelman et al. because the diagnosing or monitoring of human PDAC optionally in a human subject using a method that comprises obtaining a cell dynamic 13C-NMR would have been expect to advantageously enable in vivo determining the ROS status of one of the most lethal human cancers associated with altered levels of ROS and/or enable determining the therapeutic efficacy of GPP targeting known to suppress PDAC. Regarding the recitation that cell dynamic 13C-NMR spectra of the hyperpolarized [1-13C]NAC on human PDAC comprises 3 peaks, a major peak at about 176.5 ppm and two peaks at about 176.8 ppm, and at about 177.5 ppm, the claimed 3 peaks are a non-limiting result derived from obtaining a 13C-NMR spectra of hyperpolarized [1-13C]NAC on PDAC.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Saito et al. so that the method further comprises procuring a cell dynamic 13C-NMR spectra of the hyperpolarized [1-13C]NAC at NMR spectrometer, procuring a phantom sample 13C-spectrum, and comparing the procured spectrum of the hyperpolarized [1-13C]NAC with the pure sample 13C-NMR spectrum as taught by Saito et al. and Wilson et al. because procuring and comparing would have been expected to enable confirming chemical shifts of the [1-13C]NAC and metabolites using a phantom chemical shift reference. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Saito et al. so that the diagnosing step comprises preparing a polarizing solution of about 2-5 molar or about 3.2 molar [1-13C]NAC by titrating the polarizing solution to a pH of about 5.6 to about 7.8 using a base and so that the polarizing solution remains stable over time at both neutral and acidic pH as taught by Saito et al. and Wilson et al. because the titrating and pH would have been expected to advantageously enable that the [1-13C]NAC remains stable and as the active species.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Saito et al. so that the monitoring step further comprises monitoring redox status of a redox pair such as glutathione/glutathione disulfide redox pair as taught by Wilson et al. and Kimmelman et al. because the further monitoring would have been expected to provide an important indicator of cell redox environment.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Saito et al. so that the composition further comprises one or more additional chemotherapeutic agents that are biological agents such reducing agents or GPP targeting agents as taught by Wilson et al. and Kimmelman et al. because the one or more additional therapeutic agents would have been expected to enable evaluating the efficacy of the therapeutic agent on the human PDAC or ROS.
The build-up time for reaching half of the equilibrium polarization is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at a build-up time of about 10000-15000 sec or 11000 sec through routine experimentation in order to arrive at optimal build-up time in short time to maximized the amount of hyperpolarized [1-13C]NAC. The T1 relaxation time at 3T of the 3.2 molar active agent is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrive at 10-25 sec, 15-20 sec or 19.6 sec through routine experimentation by decay dynamics of 13C magnetic resonance signal in order to arrive at an optimal T1 relaxation time for imaging experiments. The sensitivity enhancement increase via hyperpolarization is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize at the time of invention. A person of ordinary skill in the art would have arrived at a sensitivity enhancement of about 103-107- or 105-fold through routine experimentation in order to arrive at an optimal signal intensity for imaging experiments.
Applicants’ Arguments
Applicants assert that Saito does not teach the claim limitations including diagnosing a patient suffering from cancer wherein the cancer is a PDAC comprising the step of obtaining a cell dynamic 13C-NMR spectra of the hyperpolarized active agent at NMR spectrometer wherein cell dynamic 13C-NMR of the [1-13C]NAC on human PDAC comprises three peaks, a major peak at about 176.5 ppm and two at about 176.8 and at about 177.5 ppm. Saito discloses the hyperpolarized [1-13C]NAC requires some optimization for use in in vivo imaging of oxidative stress and also for cancer and the skilled person would not find a motivation in any of the cited references for selecting a probe involved at a different stage of the ROS much less for selecting [1-13C]NAC. Neither Wilson nor Kimmelman cure the deficiencies of Saito and the claims are not obvious over this combination.
Applicants’ arguments filed 4 Aug. 2026 have been fully considered but they are not persuasive. Saito teaches hyperpolarized [1-13C]NAC for evaluating oxidative stress in living animals. At synopsis, Saito teaches that the [1-13C]NAC provided a single peak at 174 ppm and that [1-13C]NAC can be applied to some disease models to evaluate oxidative stress in vivo. Together with the statement at conclusion stating optimization of the experimental conditions is necessary for further animal experiment, Saito is understood to be teaching that in vivo [1-13C]NAC in some disease models is feasible and within the purview of one ordinary skill in the art with a reasonable expectation of success and without unreasonable experimentation. Accordingly, Saito provides one of ordinary skill adequate reason and motivation to select [1-13C]NAC and then use the [1-13C]NAC to evaluate ROS associated disease in living animal with a reasonable expectation of success.
Saito, Wilson, and Kimmelman teach and motivate all of the claim limitations. Regarding instant claim 1, Saito provides for a method of diagnosing or monitoring a patient suffering from ROS associated disease comprising administering a pharmaceutical composition comprising an effective amount of [1-13C]NAC together with a pharmaceutically acceptable carrier and diagnosis or monitoring the patient by hyperpolarized 13C-MRI comprising obtaining a 13C-NMR spectra (peak at 174 ppm) of the hyperpolarized active agent at NMR spectrometer. Regarding the recitation of cancers and human PDAC, Kimmelman provides adequate reason and motivation to modify the method of Saito so that the [1-13C]NAC is applied to a human PDAC model to evaluate oxidative stress in vivo. Kimmelman teaches that human PDAC is one or the most lethal cancers. Kimmelman teaches and suggests that in some cancers glutamine (Gln) is used to fuel anabolic processes. In this case, PDAC relies on a distinct pathway (termed “glutamine to pyruvate pathway” or “GPP”. Gln deprivation or genetic inhibition of any enzyme led to an increase in ROS and reduction of glutathione. Knockdown of any component or enzyme in this series results in pronounced suppression of PDAC growth. Kimmelman teaches, suggests, and motivates evaluating the efficacy of PDAC therapy by determining ROS levels. The therapy is considered effective if ROS levels are increased. NAC is an antioxidant structurally related to glutathione. Wilson teaches hyperpolarized agent for MRI characterizations of redox systems in vivo. Wilson teaches and suggests obtaining cell dynamic 13C-NMR spectra of the hyperpolarized agent at an NMR spectrometer. A recognized advantage is the strongest reason to combine.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Saito so that it is a method that diagnoses or monitors a patient suffering from PDAC that is undergoing therapy wherein the method comprises administering an effective amount of [1-13C]NAC to the patient and diagnoses or monitors the patient by hyperpolarized 13C-MRI comprising the step of obtaining a cell dynamic 13C-NMR spectra of the hyperpolarized [1-13C]NAC as taught by Kimmelman et al. because the diagnosing and monitoring of the patient suffering from PDAC would have been expected to advantageously enable evaluating the effectiveness of a therapy leading to a significant reduction in PDAC growth.
Regarding the recitation of wherein the cell dynamic 13C-nuclear magnetic resonance (NMR) spectra of the hyperpolarized [1-13C]N-acetyl cysteine on human pancreatic ductal adenocarcinoma (PDAC) comprises three peaks…, the recitation mere recites a non-limiting result of the previous step of administering the an effective amount of [1-13C]NAC to the patient suffering from human PDAC cancer. The administration of an effective amount of 1-13C]NAC to the patient suffering from human PDAC cancer would result in a cell dynamic 13C NMR comprising three peaks, a major peak at about 176.5 ppm and two peaks at about 176.8 and at about 177.5 ppm.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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