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 . 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.
Priority
The instant application is a 371 of PCT/US2021/047555 filed on 08/25/2021, which claims domestic benefit to US provisional application no. 63/069,876 filed on 08/25/2020.
Status of the Claims
The claim amendments and remarks filed on 02/19/2026 is acknowledged. Claims 1 and 7 are amended. Claim 6 is cancelled.
Accordingly, claims 1-5 and 7-20 are pending and being examined on the merits herein.
Withdrawn Objections
The objection to the drawings is withdrawn in view of the newly filed drawings on 02/19/2026, in which FIG. 1 now has sufficient resolution of the chemical structures and legibility of the associated texts, labels, and symbols.
The objection to claims 1 and 7 are withdrawn in view of “straightchain” being amended to “straight chain”.
Drawings
The drawings filed on 02/19/2026 are objected to because FIG. 1-5 contain color, and a petition for colored drawings has not been filed and granted. See 37 CFR 1.84.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The following grounds of rejection are maintained.
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.
Claim(s) 1-5, 7-10, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Naccari et al. (WO2007010515A1 in IDS filed 05/05/2023) in view of Mehellou et al. (Journal of Medicinal Chemistry, 2017 in PTO-892 dated 08/19/2025) and as evidenced by Karran et al. (Nature Reviews Cancer, 2008 in PTO-892 dated 08/19/2025).
Naccari et al. discloses analogous compounds of 6-thioguanosine triphosphate (see Abstract).
Naccari et al. disclose that azathioprine is the “gold standard” of the immunosuppressive therapy of Crohn’s disease, and further discloses a new mechanism of action of azathioprine, in which Naccari recites “… the metabolite 6-thioguanisine triphosphate represents the real functional metabolite of the drug …” (see Figure 1 and page 3 lines 4-20). Furthermore, as evidenced in Figure 2 on page 27 of Karran, azathioprine converts to 6-mercaptopurine and undergoes successive phosphorylation reactions to produce the active 6-thioguansinse triphosphate metabolite. Naccari et al. discloses that this new mechanism of action is able to explain the well-known “delay” in the therapeutic effect of azathioprine, which needs a long treatment time to elicit a clinical response that is beneficial and can have side effects such as osteoporosis, diabetes, and cataract (see page 3 lines 25-31). Therefore, Naccari et al. discloses new analogous compounds of 6-thioguanisine triphosphate to elicit a faster and more efficacious therapeutic response in comparison with already known compounds such as azathioprine (see page 3 lines 33-35). Naccari et al. discloses their 6-thioguansine triphosphate analogous compounds having a general formula (I) shown below (see claim 1).
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Here, R1, R2, R3, R4, and R5 represent various groups that modify the base 6-thioguanosine structure. Naccari et al. discloses their compounds can be provided in a pharmaceutical composition (see page 62 lines 1-5) and used to treat organ transplant rejection, Crohn’s disease, cancer, and among others (see page 62, lines 7-22). Naccari et al. demonstrates the preparation of 6-Thio-Guanosine-Triphosphate in Example 2 page 68 and as shown below:
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The 6-Thio-Guanosine-Triphosphate compound as shown above in Naccari et al. meets the limitation of the recited compound in instant claim 1 except for the phosphoramidate moiety at the 5’ position.
Mehellou et al. discloses a ProTide technology, which is a prodrug approach for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates and illustrated below (see Abstract).
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Mehellou et al. discloses that nucleoside analogous compounds are widely used as an effective method to treat various cancer and viral infections (see page 2211 left column). Mehellou et al. discloses that these analogous nucleosides enter the cell with the aid of transporters such as concentrative nucleoside transporters as well as peptide transporters or via passive diffusion, and once inside the cell, the nucleoside analogues are activated by a number of kinases which phosphorylates the nucleoside analogue in a stepwise manner resulting in the formation of the mono-, di-, and triphosphorylated nucleoside analogue metabolite (see page 2211 left column). Mehellou et al. discloses that the activated (phosphorylated) nucleoside analogue exerts their therapeutic effects by targeting and inhibiting intracellular enzymes and/or by being incorporated into the viral nucleic acid chains leading to the termination of the elongation process (see page 2211 left column). Mehellou et al. discloses that the formation of the triphosphate metabolite is often the nucleoside analogue active metabolite (see page 2211 left column). However, Mehellou et al. discloses several limitations of nucleoside analogues such as inefficient phosphorylation by cellular or viral kinases due to structural differences, poor bioavailability due to low intestinal permeability, and a number of resistance mechanisms for antiviral and anticancer nucleoside analogue compounds (see page 2211 left and right columns). Mehellou et al. discloses that initial methods to overcome these limitations was to deliver the phosphorylated metabolite of the nucleoside analogue, however the idea of using nucleoside analogue monophosphates as therapeutics faced challenges such as poor in vivo stability due to dephosphorylation in the bloodstream and inefficient transport into cells due to the charged nature of the phosphorylated nucleoside (see page 2211 right column through page 2212 left column first paragraph). Mehellou et al. disclose various approaches to mask the monophosphate or monophosphonate moiety to overcome these challenges, and discloses the ProTide approach, which involves the masking of monophosphate or monophosphonate groups by an aromatic group and an amino acid ester moiety and is enzymatically cleaved off inside cells to release the free nucleoside monophosphate and monophosphonate species (see Abstract). Mehellou et al. discloses the development stages of the ProTide Prodrug Technology in Table 1 on page 2213 and shown below:
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Here, the aryloxy phosphoramidates (stage six) is the latest design in this approach and meets the structure of the phosphoramidate group at the 5’ position the recited compound in instant claim 1 when Ar is Ph (Phenyl), R is methyl, and R1 is iPr (iso-propyl) on the aryloxy phosphoramidate moiety (stage six) of Mehellou shown in Table 1 above. Mehellou et al. demonstrates the effectiveness of their aryloxy phosphoramidates with the drug discovery of new ProTide-based compounds for the nucleoside analogue gemcitabine in section 5.1.1 on page 2218. Mehellou discloses that gemcitabine resistance mechanisms include inadequate conversion of gemcitabine into its pharmacologically active di- and triphosphate forms due to downregulation of deoxycytidine kinase, deamination of gemcitabine to its much less active uridine derivative, and mutations in the membrane transporter that mediates its active uptake into cells (see page 2218, left column). Mehellou et al. exemplifies the Protide-gemcitabine structures in Figure 10 on page 2218 and discloses that this Protide compound led to intracellular concentrations of the active gemcitabine triphosphate metabolite that was 13 times higher than achieved by gemcitabine (see page 2219, left column first paragraph).
It would have been prima facie obvious to combine Naccari and Mehellou et al. before the effective filing date of the claimed invention by substituting the triphosphate moiety on the 6-Thio-Guanosine-Triphosphate disclosed in Naccari with the aryloxy phosphoramidate moiety disclosed in Mehellou et al. to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make this substitution with a reasonable expectation of success because both Naccari and Mehellou disclose similar approaches of modifying a base nucleoside analogue structure to improve its cellular uptake and lead to its active triphosphate nucleoside metabolite. Furthermore, Mehellou discloses that there are several limitations to administering phosphorylated nucleoside metabolites such as poor in vivo stability due to dephosphorylation in the bloodstream and inefficient transport into cells due to the charged nature of the phosphorylated nucleoside. Additionally, Mehellou et al. discloses that their aryloxy phosphoramidate ProTide technology has been used extensively in drug discovery and led to the discovery of various antiviral and anticancer agents, and demonstrates the efficient cellular uptake of ProTide gemcitabine and subsequent conversion to its active triphosphate metabolite form. Therefore, an ordinary skilled artisan would have been motivated to try other approaches such as the ProTide prodrug approach disclosed in Mehellou to find additional structural analogous compounds of the active 6-thioguanosine triphosphate metabolite to improve its therapeutic response as disclosed in Naccari et al.
In regards to claims 7-10, and 15-17, it would have also been prima facie obvious before the effective filing date of the claimed invention to have administrated the modified compound as suggested by Naccari and Mehellou as described above for treating an organ transplant rejection, Crohn’s diseases, or cancer. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Naccari et al. establishes that their analogous 6-thioguanosine triphosphate compounds can be used to treat an organ transplant rejection, Crohn’s diseases, or cancer, and therefore an ordinary skilled artisan would expect that other alternative analogous 6-thioguanosine triphosphate compounds such as described above can also be used to treat these diseases/conditions.
Claim(s) 7, 11-12, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Relling et al. (Blood, 1999 in PTO-892 dated 08/19/2025) in view of Nacaari et al. (WO2007010515A1 in IDS filed 05/05/2023), Mehellou et al. (Journal of Medicinal Chemistry, 2017 in PTO-892 dated 08/19/2025) and as evidenced by Karran et al. (Nature Reviews Cancer, 2008 in PTO-892 dated 08/19/2025).
Relling et al. discloses that 6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL) (see Abstract). Relling discloses that in studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS) (see Abstract).
The difference between Relling and the claimed invention is that Relling does not disclose administering the recited compound in claim 7.
The independent teachings of Naccari, Mehellou, and Karran are as described above.
It would have been prima facie obvious to combine Relling with Naccari and Mehellou et al. before the effective filing date of the claimed invention by substituting the 6MP of Relling with the modified compound as suggested by the combined teachings of Naccari and Mehellou described above for the treatment of childhood acute lymphoblastic leukemia. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Relling et al. provides guidance that 6-mercaptopurine is useful for treating childhood acute lymphoblastic leukemia, and Naccari provides guidance that their analogous 6-thioguanosine triphosphate compounds can be administered to treat cancer and is used as an alternative to azathioprine, which is known to convert to 6-mercaptopurine and lead to the active 6-thioguanosine triphosphate metabolite as described above.. Therefore, an ordinary skilled artisan would expect that alternative thioguanine nucleotides such as the modified compound as suggested by the combined teachings of Naccari and Mehellou described above can also be used to treat childhood acute lymphoblastic leukemia as disclosed in Relling.
In regards to claims and 18 and 20, it would have also been prima facie obvious before the effective filing date of the claimed invention to have combined the modified compound as suggested by Relling, Naccari, and Mehellou described above with the methotrexate as disclosed in Relling for treating childhood acute lymphoblastic leukemia. One of ordinary skill in the art would have combined these two agents with a reasonable expectation of success because both the modified compound as suggested by Relling, Naccari, and Mehellou and the methotrexate of Relling and are useful for the same purpose of treating childhood acute lymphoblastic. See In re Kerkhoven, MPEP 2144.06 section I.
Claim(s) 7 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Shay et al. (US20140303239A1 in PTO-892 dated 08/19/2025) in view of Naccari et al. (WO2007010515A1 in IDS filed 05/05/2023), Mehellou et al. (Journal of Medicinal Chemistry, 2017 in PTO-892 dated 08/19/2025), and as evidenced by Karran et al. (Nature Reviews Cancer, 2008 in PTO-892 dated 08/19/2025).
Shay et al. discloses the use of 6-mercaptopurine ribosides and analogs thereof for the treatment of cancer and other hyperproliferative diseases (see Abstract). Shay et al. discloses that their compounds can be converted in vivo to 5′-triphosphate telomerase substrates and exemplifies 2′-deoxyguanosine 5′-triphosphate (see paragraph 0032). Shay et al. discloses that the cancer for treatment can include numerous species including sarcomas such as rhabdomyosarcoma (see paragraph 0047).
The difference between Shay and the claimed invention is that Shay does not disclose a method of treating the recited cancers in claims 13-14.
The independent teachings of Naccari, Mehellou, and Karran are as described above.
It would have been prima facie obvious to combine Shay with Naccari and Mehellou before the effective filing date of the claimed invention by substituting the 6-mercaptopurine riboside of Shay with the modified compound as suggested by the combined teachings of Naccari and Mehellou described above for the treatment of sarcoma cancers such as rhabdomyosarcoma. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Shay et al. establishes a similar thiopurine analog compound, which converts to the active triphosphate metabolite, can be used to treat sarcoma cancers. Therefore, an ordinary skilled artisan would expect other alternative thiopurine analog compounds such as the modified compound as suggested by the combined teachings of Naccari and Mehellou described above would also be able treat sarcoma cancers as disclosed in Shay.
Claim(s) 1-5, 7-10, 15-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Ewe et al. (Gastroenterology, 1993 in PTO-892 dated 08/19/2025) in view of Naccari et al. (WO2007010515A1 in IDS filed 05/05/2023, Mehellou et al. (Journal of Medicinal Chemistry, 2017 in PTO-892 dated 08/19/2025) and as evidenced by Karran et al. (Nature Reviews Cancer, 2008 in PTO-892 dated 08/19/2025).
Ewe et al. discloses the combination of azathioprine with standard prednisolone therapy for treatment of active Crohn’s disease (see Abstract). Ewe et al. demonstrates that 16 of 21 patients (76%) in group 1 (combined treatment of azathioprine and prednisolone) were in remission (CDAI < 150), compared with 8 of 21 (38%) in group 2 (prednisolone alone) (see Abstract). Ewe et al. concludes that the combination of prednisolone and azathioprine was superior to the treatment with prednisolone alone in active Crohn’s disease (see Abstract).
The difference between Ewe et al. and the claimed invention is that Ewe et al. does not disclose administering the recited compound of claim 1.
The independent teachings of Naccari, Mehellou, and Karran are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the azathioprine of Ewe et al. with the modified compound as disclosed in the combined teachings of Naccari and Mehellou described above to arrive at the claimed invention. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Ewe et al. establishes the combined treatment of azathioprine and prednisolone for the treatment of Crohn’s disease, and the combined teachings of Naccari and Mehellou disclose a compound that can be used as an alternative to azathioprine for increased efficacy and treating the same Crohn’s disease as described above. Therefore, an ordinary skilled artisan would expect the synergistic effect with prednisolone for treating Crohn’s disease as disclosed in Ewe et al. would also apply for the modified compound suggested by Naccari and Mehellou described above.
Response to Arguments
Applicant’s arguments filed on 02/19/2026 have been fully considered but were not persuasive.
Applicant states that their invention yields unexpected improved properties over the prior art. Here, Applicant states that their invention provides prodrugs of 6-MP that were found to inhibit tumor growth as a single agent at a lower dose than the parent 6-MP compound, without evidence of liver toxicity, thereby improving on the wide pharmacogenomic variation of 6-MP tolerability and efficacy.
Applicant refers to FIG. 2A and FIG. 2B as well as FIG. 3 A-D to support the unexpected result. Here, FIGs 2A and 2B demonstrate that parent compound 6-MP administered at a dosage of 20 mg/kg for ten days partially inhibits growth of tumors in a murine sarcoma model in vivo but with evidence for liver transaminase elevation (ALT, a marker of liver inflammation, increased two-fold in 6-MP treatment mice compared to vehicle treated mice).
In contrast, Applicant states that their claimed prodrug 6-MP (MK-905) administered at a dosage of 13 mg/kg for fourteen days inhibited tumor growth more significantly than the parent 6-MP compound, and additionally serum ALT levels was normal and not significantly different between vehicle treated and MK-905 treated mice.
In response to Applicant’s showing of an unexpected result, Applicant must compare the unexpected result to the closest prior as stated in MPEP 716.02(e). The closet prior art in this case is Naccari, which disclose several 6-thioguanosine triphosphate analogue compounds to elicit a faster and more efficacious therapeutic response in comparison with already known compounds such as azathioprine.
Here, Applicant has not demonstrated that the alleged unexpected result would also apply over the closest prior art (Nacarri) because Applicant has only provided comparisons to the parent 6-MP compound, and has not provided comparisons that are comparable to the 6-thioguanisine triphosphate analogue compounds as disclosed in Naccari.
Therefore, Applicant’s showing of an unexpected result is not sufficient to establish non-obviousness over Naccari in view of Mehellou as described above.
Furthermore, it is noted that Applicant has not compared to the same dosage amount and treatment duration between the parent 6-MP (20 mg/kg for ten days) and prodrug 6-MP (MK-905) (13 mg/kg for fourteen days). Therefore, it is difficult to ascertain if the lowered ALT levels are due to a difference in the dosage amount / regimen, or due to modification of a prodrug moiety to the 6-MP parent compound.
Lastly, Applicant’s showing of an unexpected result does not appear to be unexpected in view of the prior art because Mehellou discloses that the ProTide moiety helped to increase the effectiveness of a drug as well as reduce unwanted side effects. Specifically, Mehellou discloses that a prodrug called TAF, which is a tenefovir that has the ProTide prodrug moiety (Figure 3 on page 2212), demonstrated increased anti-HIV activity, higher in vivo stability, and was endowed with fewer side effects than both tenofovir and TDF, which is another prodrug tenofovir form (see second paragraph left column page 2221). Mehellou discloses that TAF had significantly lower plasma levels and higher intracellular tenofovir concentrations compared to TDF, which explained the lower incidence of tenofovir-associated side effects such as bone mineral density losses and kidney nephrotoxicity (see second paragraph left column page 2221). Mehellous discloses that TAF was superior not only in its antiviral activity but also in the fact that therapeutic effects could be achieved at much lower doses than TDF, thus reducing the incidence of adverse effects (see left paragraph right column page 2221).
Therefore, an ordinary skilled artisan could have expected that the substitution of the triphosphate moiety on the 6-Thio-Guanosine-Triphosphate disclosed in Naccari with the ProTide moiety disclosed in Mehellou would yield similar results in reducing the dosage needed as well as reducing unwanted side effects.
Conclusion
No claim is found allowable.
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.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693