DETAILED ACTION
Claims 1-20 are pending.
Election/Restrictions
Applicant’s election without traverse of group III, claims 12-17 in the reply filed on 03/02/2026 is acknowledged.
In a phone interview with Attorney of Record William Warren on 03/25/2026, Applicant elected group III claims 12-17 without traverse and withdrew claims 1-11 and 18-20 without traverse.
Claims 12-17 are under examination.
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.
Claims 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Klein et al., (US 20070037236A1) (IDS filed on 06/15/2023), in view of Knelson et al., “Heparan sulfate signaling in cancer.” Trends in biochemical sciences vol. 39,6 (2014): 277-88. doi:10.1016/j.tibs.2014.03.001 (IDS filed on 06/15/2023).
Instant claim 12 recites “A method of treating a cancer expressing antithrombin-binding heparan sulfate (HSAT) in a subject comprising combining a biological sample of the subject containing HSAT with antithrombin, detecting binding of HSAT and the antithrombin, and treating the subject for the cancer by administering an effective amount of cancer therapy.”.
Klein teaches combining a biological sample of the subject containing HSAT with antithrombin (see claim 1 of Klein, see claims 7-8 of Klein),
detecting binding of HSAT and the antithrombin (see [0024] “In a preferred embodiment of the method of the invention, a citrated plasma sample is initially mixed with a reagent which comprises antithrombin.”, see [0004] “The anticoagulant effect of all heparins derives from their formation of complexes with antithrombin…The binding of heparin to antithrombin results in a change in the antithrombin conformation, which enhances many-fold the inhibitory effect of antithrombin. The binding site in heparin molecules which is responsible for the binding to antithrombin consists of a characteristic pentasaccharide sequence.”, see [0014]), and
treating the subject (see [0012] “In order to be able to carry out the precise determination of heparin in a sample at all, it is thus necessary to know which heparin product is used to treat the patient, so that the measured values can be quantified with the correct calibration curve.”) (instant claim 12).
Klein teaches wherein the HSAT is detected at a higher level than in a control subject (see [0037] “FIG. 1 shows the change in the measured signals (ΔOD/min) over the incubation time with two different heparinase activities in the mixture for plasmas with UFH (Liquemin®) and LMWH (Fragmin®). A heparin-free standard human plasma (SHP) was measured in each case as control. This plasma without heparin showed no change in extinction as a function of the time of incubation of the sample with AT-heparinase reagent. With the heparin-containing plasmas there is an increase in the change in extinction with increasing incubation time” (instant claim 13). Klein teaches determining that the antithrombin inhibits factor Xa (see [0015] “The anti-coagulation activity is reflected in the inhibition of factor Xa protease activity by antithrombin.”, see [0024] “Antithrombin is preferably added in excess, so that more antithrombin is present in the mixture than necessary to inhibit FXa.”, see claim 6 of Klein) (instant claim 14), and the biological sample being blood or urine (see [0014] “in particular in body fluid samples such as blood, plasma, serum or urine, where the heparin activity is determined from the heparin-dependent factor Xa inactivation.”, see claim 24 of Klein) (instant claim 15).
Klein does not explicitly teach treating a cancer that expresses antithrombin-binding heparan sulfate (HSAT), detecting antithrombin as a stain in immunohistochemistry, or as a tracer for in vivo imaging, and the cancer therapy comprising an effective amount of thrombin conjugated to a cancer therapy agent.
Knelson teaches that antithrombin binds to the thrombin, factor IXa, and fact Xa to prevent coagulation in HSPGs (see figure 1, see page 2). Knelson teaches HSPGs can be found at the surface of cancer cells, and can also be shed by cancer and stromal cells to enhance or suppress cell signaling and influence cancer cell biology (see page 2, see figure 3). Knelson teaches treating a subject with cancer by administering an effective amount of cancer therapy (see page 3 “overexpression of the HSPGs GPCl and SDCl in breast cancer cells enhances the proliferative response to treatment with FGF2, HBEGF, and HGF [16]. GPCl has similar effects in pancreatic cancer and gliomas…”, see page 7 “Data from epidemiologic studies and clinical trials demonstrate a protective and therapeutic effect for heparin treatment on tumor growth and metastasis”, see page 8) (instant claim 12).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify the method of determining and treating a subject with antithrombin-expressing heparan sulfate (HSAT) taught by Klein, with the method of treating a subject with cancer taught by Knelson. Knelson provides motivation by teaching that heparin has therapeutic effects which include inhibition of selectin binding, inhibition of heparinase and sulfatases, decreased platelet signaling to suppress tumor angiogenesis, and enhanced terminal differentiation of cancer cells (see page 8). Knelson further provides motivation by teaching that heparin prevents binding of platelets to selectins and integrins, which shields cancer cells from immuno surveillance, but also suppresses platelet release of tumor angiogenic signals, which makes it a promising therapeutic potential (see page 8). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Klein and Knelson as applied to claims 12-15 above, in view of Hernández-Espinosa et al., “Inhibition of proteasome by bortezomib causes intracellular aggregation of hepatic serpins and increases the latent circulating form of antithrombin.” Laboratory investigation; a journal of technical methods and pathology vol. 88,3 (2008): 306-17. doi:10.1038/labinvest.3700717 (IDS filed on 06/15/2023).
The teachings of Klein and Knelson as they pertain to claims 12-15 are discussed in the 25 USC 103 rejection above.
Klein does not teach wherein the HSAT is detected by further detecting the antithrombin as a stain in immunohistochemistry, or as a tracer for in vivo imaging.
Espinosa teaches wherein the HSAT is detected by further detecting the antithrombin as a stain in immunohistochemistry (see figure 2C) (instant claim 16).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify the method of determining and treating a subject with antithrombin-expressing heparan sulfate (HSAT) taught by Klein, with the method of detecting antithrombin as a stain in immunohistochemistry taught by Espinosa. Espinosa provides motivation by teaching that immunohistochemistry shows physical changes like punctuate-like pattens to clustered-like patterns (see page 311). Espinosa teaches that immunohistochemistry has been successfully performed on antithrombin (see page 308). Espinosa provides further motivation by teaching that immunohistochemistry can show the formation of aggregates of antithrombin (see page 310). Immunohistochemistry staining is a commonly used technique in the art. The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Klein and Knelson as applied to claims 12-15 above, in view of Zhao et al., “Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation”. Signal Transduct Target Ther. 2020 Jul 10;5(1):117. doi: 10.1038/s41392-020-0167-1. PMID: 32647187; PMCID: PMC7347850 (2020).
The teachings of Klein and Knelson as they pertain to claims 12-15 are discussed in the 25 USC 103 rejection above.
Klein does not teach wherein the cancer therapy comprises an effective amount of thrombin conjugated to a cancer therapy agent.
Zhao teaches cancer therapy comprising an effective amount of thrombin conjugated to a cancer therapy agent (see page 8 “Combination therapy with DTIP and an EGFR inhibitor resulted in improved antitumor efficacy EGFR-TKIs, including gefitinib, erlotinib, and so on, as angiogenesis inhibitors have significantly improved clinical outcomes. However, most NSCLC patients do not respond (primary resistance) and those who initially respond eventually progress (acquired resistance).”, see figure 6).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to modify the method of determining and treating a subject with antithrombin-expressing heparan sulfate (HSAT) taught by Klein, with the treatment comprising thrombin conjugated to a cancer therapy agent taught by Zhao. Zhao provides motivation by teaching that thrombin contributes to tumor progression (see abstract). Zhao teaches that novel thrombin inhibitors r-hirudin and DTIP inhibited vasculogenic mimicry (VM) formation and spontaneous metastasis in subcutaneous tumors (see abstract). The artisan would have reasonable expectation of success based on the cumulative disclosure of these prior art references at the time the instant application was filed.
Conclusion
No claim is allowed.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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