DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-11, and 13-17 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 3, 5, 8-9,13, and 15 are amended.
Response to Amendment
The amendments filed on 22 May 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the objection to claims 5 and 13 because of minor informalities is withdrawn.
In view of Applicants amendments, the rejection of claims 8, 9, and 15 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claims the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 3-6 under 35 USC 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends is withdrawn.
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) 1-6, 8, 10-11, and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sanad et al. (Radiochem.; published 2019), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013) for the reasons cited in the Office action filed on 27 Feb. 2026.
Claim(s) 1-8, 10-11, 13-14, and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sanad et al. (Radiochem.; published 2019), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013), in further view of Chapman et al. (WO 00/43004 A1; published 27 Jul. 2000) for the reasons cited in the Office action filed on 27 Feb. 2026.
Claim(s) 1-11, and 13-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sanad et al. (Radiochem.; published 2019), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013) and Chapman et al. (WO 00/43004 A1; published 27 Jul. 2000), in further view of Riche et al. (Bioorg. Med. Chem.; published 2001) and Radie et al. (Res. Chem. Intermed.; published 2017) for the reasons cited in the Office action filed on 27 Feb. 2026.
Applicants Arguments
Applicants’ asset that the combination of Sanad and Tsao is based on impermissible hindsight and lacks proper motivation to combine. The biological mechanism and metabolic pathway of AZA and other thiopurines are fundamentally different from those of the penciclovior derivatives in Tsao. The biological activity and tumor targeting capability of AZA rely on this specific enzymatic conversion, not merely a simple phosphorylation of cellular kinases. A person of ordinary skill in the art would have no reasonable expectation of success or rational motivation to graft Tsao’s hydroxyalkyl chain. A person of ordinary skill in the art would readily recognize that appending such a bulky cyclam chelating agent to the AZA molecule is highly likely to introduce severe steric hindrance. Such steric effects would be expected to disrupt or completely destroy the ability of AZA to bind to the binding pockets of its specific metabolic enzymes. The prior art does not provide a teaching, suggestion or motivation to force a structural modification designed for kinase phosphorylation (Tsao) onto a drug molecule dependent on glutathione/XO/NPRT/TPMT enzymatic conversion (Sanad). The unpredictable steric effects of adding a massive chelator AZA teaches away from the proposed combination.
Applicant's arguments filed 22 May 2026 have been fully considered but they are not persuasive. Sanad teaches the 99mTc-AZA that gets 99mTc-labeled by adding azathioprine to a flask after which SnCl-H2O was added. A 1 mL portion of the 99mTcO4- solution is added to the reaction vessel and the pH of the reaction mixture was adjusted to pH 5 and the reaction mixture was left at ambient temperature of 15 min. The 99mTc-AZA is rapidly accumulated in tumor cells. The 99mTc shows promise as a new radiopharmaceutical for tumor imaging. In this case, the 99mTc-AZA comprising a sterically inhibiting 99mTc metal performed as expected enabling the advantageous detection of tumors. As noted, AZA gets metabolized by transfer of a 5-phosphoribosyl group into 6-thioguanosine-5‘-phosphate (6-thio-GMP) and 6-thioinosine monophosphate (6-thio-IMP) both inhibit nucleotide conversions and de novo purine synthesis. Tsao teaches the 99mTc-N4-guanine comprising the following three elements (1) the hydroxymethyl group which is necessary for phosphorylation of the molecule by cellular kinases to achieve biological activity; (2) heterocyclic base moiety; and (3) a ribose ring. Regarding phosphorylation, Tsao teaches that after being transported inside the cell, the hydroxyl groups of penciclovir will be trapped inside the cell and may be further involved in DNA synthesis. The higher lipophilicity of N4 will help to penetrate cell membrane leading to greater uptake, decrease kidney accumulation and thereby reduce renal toxicity. At pg. 112, Tsao teaches that 99mTc-N4-Guan can target highly proliferating cells. 99mTc-N4-Guan is involved in cell nucleus activity. A recognized advantage is the strongest reason to combine. In this case a person of ordinary skill in the art would have been motivated to modify 99mTc-AZA in Sanad by incorporating a hydroxyalkyl linker attached to N4 in a manner similar to the 99mTc-N4amG in Tsao because the hydroxyalkyl-N4 would have been expected to advantageously enable by-passing typical AZA metabolism including by steric effect and allowing for phosphorylation by cellular kinases resulting in 6-thio-GMP and 6-thio-IMP derivates that can be incorporated in replicating DNA and block the de novo pathway of purine synthesis. The lipophilicity of the N4 chelator would have been expected to advantageously enhance cell uptake. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Sanad by incorporating a hydroxy substituted C5 alkyl linker attached to a cyclam chelator optionally complexing 99mTc or Tc or Gd at the N9 position as taught by Sanad and Tsao because the hydroxyl substituted alkyl linker would have been expected advantageously enable by-passing typical AZA metabolism and advantageously enable phosphorylation and because the N4 chelator would have been expected to enable greater cell uptake and decreased kidney accumulation and stable complexation of 99mTc and 68Ga and because complexing 99mTc or Tc or Gd would have been expected to enable SPECT or MR imaging or a cold reference compound.
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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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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