DETAILED ACTION
This Office action details a non-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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 24 Dec. 2025 has been entered.
Status of Claims
Claim 12 is cancelled. Claims 14-17 are new.
Response to Amendment
The amendments filed on 24 Dec. 2025 have been entered.
Response to Arguments
The rejection of claims 1-6, 8, 10-11, and 13 under 35 USC 103 as being unpatentable over Chifotides et al. (Inorg. Chem.; published 1992), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013) and Amin et al. (J. Radioanal. Nucl. Chem.; published 2010) is withdrawn.
The rejection of claims 1-8, 10-11, and 13 under 35 USC 103 as being unpatentable over Chifotides et al. (Inorg. Chem.; published 1992), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013) and Amin et al. (J. Radioanal. Nucl. Chem.; published 2010), in further view of Chapman et al. (WO 00/43004 A1; published 27 Jul. 2000) is withdrawn.
The rejection of claims 1-11, and 13 under 35 USC 103 as being unpatentable over Chifotides et al. (Inorg. Chem.; published 1992), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013) and Amin et al. (J. Radioanal. Nucl. Chem.; published 2010), in further view of Riche et al. (Bioorg. Med. Chem.; published 2011) is withdrawn.
New Grounds of Rejection
Claim Objections
Claims 5 and 13 are objected to because of the following informalities: in claim 5, the “and” at “and 89Zr” should be removed; and in claim 13, “erythematosus/Lupus” should be replaced with “erythematosus, Lupus”. Appropriate correction is required.
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 8, 9, and 15 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. Claim 8 recites the limitation "the pharmaceutical composition" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 8 is directed to a kit comprising the compound according to claim 1 and claim 1 is directed to a compound of the formula therein. In claim 9, the reaction scheme represented by
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the arrows used in the scheme are not defined in the claim and otherwise not understood. The arrows seem to represent an SN2 reaction mechanism but the claim other require that the reacting of chemical formula 1 and chemical formula 2 is only by SN2 reaction mechanism. The Examiner suggests removing the arrows from the reaction scheme. In claim 15, the recitation of “(Cs2CO3)” is indefinite because it is not clear if this is an example of a cesium carbonate or a required limitation.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-6 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Instant claim 3 depends to claim 1 and requires that the chelator is chelating a metal ion; however, claim 1 does not allow for metal complexes wherein the chelator chelates a metal ion. Instead claim 1 merely asserts that R2 is a chelator with nitrogen containing tetraazacyclic ring. The Examiner suggests amending claim 3 to recite “the chelator is further chelating a metal ion”. Claims 4-6 depend to claim 3 and fall therewith. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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; see attached 892), in view of Tsao et al. (Appl. Radiat. Isot.; published 2013).
Sanad et al. teach radiolabeling, preparation, and bio-evaluation of 99mTc-azathioprine as a potential targeting agent for solid tumors (see title). Sanad et al. teach azathioprine as an immunosuppressive medication used to treat rheumatoid arthritis, Corn’s disease, ulcerative colitis and kidney transplants to prevent rejection (pg. 478). 99mTc-azathioprine was used to determine the accumulation of radiotracer in solid tumors using γ-camera detection (pg. 478). Sanad et al. teach gamma camera imaging (pg. 479) and the biodistribution of 99mTc-azathioprine in normal mice (pg. 481). Sanad et al. teach flesh blood and bone Sanad et al. teach that 99mTc-azathioprine can be considered as a better tumor hypoxia imaging agent. 99mTc-azathioprine shows promise as a new radiopharmaceutical for tumor imaging (pg. 482).
Sanad et al. do not teach a compound of the instant formula having R1-R2 wherein R1 is a C2-7 alkyl and R2 is a chelator with a nitrogen containing tetraazacyclic ring optionally a cyclam chelator optionally chelating 99mTc or Tc or a cold kit containing the compound and an instrument for administering. Sanad et al. do not teach a method of scanning tumors comprising administering to an animal containing tumors an imaging amount of the compound and imaging bones with an imaging technology for detecting cancer, optionally SPECT imaging or a treatment method for cancer comprising administering a compound of claim 1.
Tsao et al. teach 99mTc-N4amG (see title; fig. 1). Tsao et al. teach that the results demonstrate the feasibility of using 99mTc-N4amG in tumor specific imaging (abstract). Tsao et al. teach that radiolabeled nucleoside analogues are ideal tumor cell proliferative markers (pg. 106). A single homing chelator conjugate can be labeled with two or more different radioisotopes for various purposes. 99mTc and 68Ga-labeled compounds can be used for SPECT and PET imaging respectively. N4 (cyclam) was chosen because it is a closed ring structure, which is more rigid to stabilize isotopes. Higher lipophilicity of N4 is preferred because it will help molecules to penetrate cell membrane, leading to greater uptake, decrease kidney accumulation and reduced renal toxicity. The ribose ring acts as a spacer between the hydroxymethyl groups and the base and keeps them in correct orientation. Many of them have been successfully developed as therapeutic agents in anticancer medicine (pg. 107). Tsao et al. teach a synthesis were Cycam-(Boc)2 was dissolved DMF and ethyl bromo acetate and potassium carbonate were added at the reaction stirred at 80-85 oC for 16 h(pg. 107). The carbon chain makes penciclovir resistant to metabolism. After being transported into cell, a hydroxyl group can be phosphorylated by cellular deoxyguanosine (pg. 112). Tsao et al. teach Gd and MRI (pg. 112).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify compound of Sanad et al. (azathioprine and 99mTc complex thereof) 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 et al. and Tsao et al. because the hydroxy substituted alkyl linker would have been expected to advantageously make the compound resistant to metabolism and advantageously enable phosphorylation and because the cyclam chelator would have been expected to advantageously enable greater uptake, 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 MRI imaging or a cold reference compound. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Sanad et al. by further forming a kit comprising the obvious compound and an instrument for administering the composition as taught by Tsao et al. because that kit would have been expected to advantageously enable easy onsite product storage, manufacturing and administering of the obvious compounds suitable for imaging and treatment of cancer. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Sanad et al. to arrive at a method that scans tumors comprising administering to an animal containing tumors and imaging the bones and the rest of the body optionally with SPECT as taught by Sanad et al. and Tsao et al. because the scanning would have been expected to advantageously enable whole body in vivo detection of cancer. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Sanad et al. by further treating cancer by administering the compound made obvious by Sanad et al. and Tsao et al. because the administering would have been expected to enable effective anticancer treatment.
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; see attached 892), 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).
Sanad et al. teach as discussed above.
Sanad et al. do not further teach instant SC06-L-1 or a compound of claim 1 wherein R1 is a 2-hydroxypropyl group and optionally wherein the chelator is cyclam.
Tsao et al. teach as discussed above.
Chapman et al. teach 1,4,8,11-tetraazacyclotetradecane derivatives as radio-diagnostic agents and their use in determining hypoxia and radio-resistance to tumors (see title). Chapman et al. teach cyclam derivative of formula (I) wherein one of R1, R2, R3, or R4 contain a nitroimidazole moiety, the linking group comprising carbon atoms optionally being substituted with a hydroxyl group (see pg. 4). Chapman et al. teach a kit comprising a cyclam derivative and instruction the cyclam derivative with a radiometal to produce a complex (see pgs. 5 and 15). Chapman et al. teach the linking structure -CH2-CH(OH)-CH2- that makes that mono-substituted compound resolvable into a pair of optical isomers (see pg. 8). Chapman et al. teach a N-[2-hydroxy)-3-(2-nitroimidazole-1-yl)propyl]-1,4,8,11-tetraazacyclotetradecanato-technetium V technetium and copper(II) complex (pgs. 15-16).
It would have been obvious a person of ordinary skill in the art before the effective filing date to further modify Sanad et al. by further substituting the obvious linker-cyclam chelator with a 2-hydroxypropyl linker attached to a cyclam chelator to arrive at instant formula SC-06-L-1 as further taught by Chapman et al. because that 2-hydropropyl linker attached to the cyclam would have been expected to advantageously enable a linker chelator combination that easily resolves into a pair of optical isomers.
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; see attached 892), 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 Riché et al. (Bioorg. Med. Chem.; published 2001) and Rabie et al. (Res. Chem. Intermed.; published 2017; see attached 892).
Sanad et al. teach as discussed above.
Sanad et al. do not further teach the instant for of preparing a compound according to claim 1 comprising reacting a compound of formula 1 with a compound of formula 2 optionally performed in the presence of cesium carbonate in DMG at a temperature of about 100oC. Sanad et al. do not further teach the compound SC-06-L-02.
Tsao et al. teach as discussed above.
Chapman et al. teach as discussed above.
Riché et al. teach nitroimidazoles and hypoxia imaging: synthesis of three technetium-99m complexes bearing a nitroimidazole group (see title). Riché et al. teach the synthesis scheme 1
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(see pg. 72). Riché et al. teach technetium and rhenium surrogates (see ref. 17).
Rabie et al. teach cesium carbonate as a mediated inorganic base in some organic transformations (see title). Cesium carbonate as has high solubility in DMF and appears to act as a good base for abstraction of protons (see pg. 1981). Rabie et al. teach nucleophilic substitution. Cesium carbonate proved to be the most powerful among bases tested in nucleophilic substitution (pgs. 2005-2006). The mild conditions, the short reaction times, the ease of work-up procedures and the excellent percent yields of the products encourage researchers to uses cesium carbonate as an inorganic base (pg. 2013).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Sanad et al. so that cyclam gets attached to the N(9) of azathioprine using an alkyl linker to arrive at a compound of instant formula SC-06-L-2 as taught by Riche et al. because that linker would have been expected provide an equivalent azathioprine conjugate having a lipophilic linker that does not phosphorylated and enables tumor SPECT imaging. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Sanad et al. so that the obvious compounds are formed by reacting a compounds of instant formula 1 with a compound of instant formula 2 optionally in the presence of Cs2CO2 in DMF at a temperature of about 100oC as taught by Riché et al. and Rabie et al. because that reacting would have been expected to advantageously enable the formation of the obvious compounds by nucleophilic substitution optionally wherein the cesium carbonate enables excellent yields and mild conditions. The reaction temperature 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. MPEP2144.05.II. A person of ordinary skill in the art would have 100oC through routine experimentation in order to arrive at optimal chemical yields.
Applicants Arguments
Applicants assert that Chifotides discloses that the Rh metal is attached to the N-3 position, not the N-9 position. Chifotides teaches that a hydrogen bond is formed a N-9 hydrogen to increase stability. A person of ordinary skill would modify the N-3 of AZA, not the N-9. In Tsao, the metal serves as a radiolabel for imaging tumors. Modifying the metal complex of Chifotides would contravene the original purpose of Chifotides invention.
Applicant's arguments filed 24 Dec. 2025 have been fully considered but they are not persuasive. Applicant’s arguments are moot because Chifotides is no longer being used in rejection of claims. Sanad provides for a 99mTc-labeled AZA, a purine nucleoside mimetic, for tumor imaging. According to Sanad, 99mTc-AZA shows high selectivity to high-replicating tumors. In this case, the purpose of the 99mTc metal is to enable in vivo detection. Sanad, however, 99mTc-labels AZA without a chelator. Tsao teaches an analogous purine tumor imaging agent 99mTc-N4-guanine. Tsao teaches and suggests that it is advantageous to attach the 99mTc label at the claimed AZA position using a cyclam chelator moiety attached to a hydroxyl substituted alkyl linker. According to Tsao, the cyclam chelator provides a closed ring structure to stabilize isotopes. The higher lipophilicity of cyclam is preferred because it will help molecules penetrate the cell membrane, leading to greater uptake, decrease kidney accumulation and reduced renal toxicity. The short alkyl linker substituted by a hydroxyl group reduces metabolism and enables phosphorylation by cellular kinases. 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 99mTc-AZA taught by Sanad by substituting the 99mTc label with a 99mTc-C2-7 alkyl(OH)-cyclam label because the substituting would have been expected to advantageously enable a 99mTc-AZA having high stability and improved tumor uptake and phosphorylation by cellular kinases.
Conclusion
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