DETAILED ACTION
Claims 1-16 and 18-21 are pending.
Status of Claims
Claims 1-16 and 18-21 are pending. Claims 1-11 and 18-20 have been withdrawn. Claim 21 has been newly added. Claim 12 has been amended to recite the new limitation “wherein the cancer therapy comprises an effective amount of antithrombin conjugated to a cancer therapy agent”.
Claims 12-16 and 21 are under examination.
Withdrawn Claim Objections and/or Rejections
The rejection of claims 12-15 under 35 USC 103 as being unpatentable over Klein and Knelson et al., as set forth on pp. 3-5 of the previous office action (mailed on 03/31/2026) has been withdrawn in view of the newly amended claims (filed on 06/25/2026).
The rejection of claim 16 under 35 USC 103 as being unpatentable over Klein, Knelson, and Hernandez-Espinosa et al., as set forth on pp. 5-6 of the previous office action (mailed on 03/31/2026) has been withdrawn in view of the newly amended claims (filed on 06/25/2026).
The rejection of claim 17 under 35 USC 103 as being unpatentable over Klein, Knelson, and Zhao et al., as set forth on pp. 6-7 of the previous office action (mailed on 03/31/2026) has been withdrawn in view of the cancelled claim (filed on 06/25/2026).
The rejection of claims 12-16 have been withdrawn due to the amendment of claim 12, specifically, the new limitation of conjugating the cancer therapy to an effective amount of antithrombin. The amendments to claim 12 are considered new in nature because the claim previously recited conjugating the cancer therapy to an effective amount of thrombin, not antithrombin.
Claim Rejections - 35 USC § 112-New: Necessitated by Amendments.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1.Claims 12-16 and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating pancreatic cancer ([0047]), bladder cancer ([0054]), prostate cancer ([0008]), and pancreatic ductal adenocarcinoma (PDAC) ([0008]), and conjugating the antithrombin to a cytotoxic chemotherapy agent ([0045]) does not reasonably provide enablement for treating any cancer, and conjugating the antithrombin to any chemotherapy agent. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use and/or make the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure enables one skilled in the
art to make and use the claimed invention in its full scope without resorting to undue
experimentation include: (1) the quantity of experimentation necessary; (2) the amount of
direction or guidance presented; (3) the presence or absence of working examples; (4) the
nature or complexity of the invention; (5) the state of the prior art; (6) the relative skill of those in
the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. See
In re Wands, 8 USPQ2d. 1400 (Fed. Cir. 1988).
All Wands factors listed above have been considered with regard to the instant claim, with the relevant factors discussed below.
Nature of the invention: The invention is a method of treating a cancer expressing antithrombin-binding heparin 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, wherein the cancer therapy comprises an effective amount of antithrombin conjugated to a cancer therapy agent.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: The specification does not teach nor mention any other cancers that the instant application can be used to treat, other than pancreatic cancer ([0047]), bladder cancer ([0054]), prostate cancer ([0008]), and pancreatic ductal adenocarcinoma (PDAC) ([0008]). The specification does not enable any person skilled in the art to which it pertains, or with which it is most connected, to use the invention commensurate in scope with these claims. Specifically, treating any cancer with antithrombin conjugated to a cancer therapy agent is not well supported by the specification.
Further, the specification does not teach nor mention what cancer therapy agents can be conjugated with antithrombin to treat cancer, other than the broad recitation of cytotoxic chemo agents ([0045]). The specification does not enable any person skilled in the art to which it pertains, or with which it is most connected, to use the invention commensurate in scope with these claims. Specifically, treating a cancer with any cancer therapy agent conjugated to antithrombin is not well supported by the specification.
The working examples and guidance provided: While the specification provides two working examples teaching the treatment of pancreatic cancer ([0047]) and bladder cancer ([0054]), and guidance for treating PDAC and prostate cancer ([0008]), the specification does provide any other examples or support for treating any and all cancers with antithrombin conjugated with a cancer therapy agent.
The specification fails to provide any working examples on the type of cancer therapy agent that is used to conjugate to antithrombin. The specification does not provide any support for treating cancer with any cancer therapy agent conjugated to antithrombin. At [0045] the instant application simply mentions that the cancer therapy agent can be a cytotoxic chemo agent. However, the instant specification fails to provide any examples of the cancer therapy agent or the use of cytotoxic chemo agents.
The specification does not enable any person skilled in the art to which it pertains, or
with which it is most connected, to use the invention commensurate in scope with these claims.
Cancer and treatments are complex and thus the inventor needs to show how the method of the instant application will enable a skilled artisan to treat any and all cancers with antithrombin conjugated to any cancer therapy agent.
Absent specific guidance, one skilled in the art before the effective filing date of the
claimed invention would not know how to practice the claimed invention and would require
undue experimentation to practice over the full scope of the invention claimed.
The state and unpredictable nature of the prior art: The state of the prior art for using an antithrombin conjugated to any cancer therapy agent to treat any cancer was unpredictable before the effective filing fate of the claimed invention. The nature of the invention is complex and unpredictable, involving the effects of an antithrombotic agent conjugated to a cancer therapy agent to treat cancer.
Du et al., Cancer systems biology: embracing complexity to develop better anticancer
therapeutic strategies. Oncogene. 2015 Jun;34(25):3215-25. doi: 10.1038/onc.2014.291. Epub 2014 Sep 15. PMID: 25220419 teaches that at a protein level, the frequent involvement of complex signaling networks makes it difficult to anticipate the influences of oncogenic perturbations to predict how to effectively reverse those influences with pharmacological agents (see page 3215). Du teaches that cancer treatments are complex and unpredictable (see page
3215). Furthermore, in re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991),
the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was
appropriate given the relatively incomplete understanding in the biotechnological field involved,
and the lack of a reasonable correlation between the narrow disclosure in the specification and
the broad scope of protection sought in the claims.
The level of one of ordinary skill: Based on the complexity and unpredictability of cancer and cancer treatments, the level of a person having ordinary skill in the art is not high enough to determine which cancer types the treatment will work on and what cancer therapy agents are to be conjugated with antithrombin.
The breadth of the claims: The claims are drawn to a method of treating a cancer expressing HSAT in a subject by detecting the binding of HSAT and treating the subject for cancer by administering an effective amount of antithrombin conjugated to a cancer therapy agent.
Due to the large quantity of experimentation necessary to determine the cancers that can be treated with antithrombin and cancer therapy agents, and which cancer therapy agents are conjugated to antithrombin, the lack of direction/guidance presented in the specification, the complex nature of the invention, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claim Rejections - 35 USC § 103: New- Necessitated by Amendments
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.
2.Claims 12-15 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Klein et al., (US 20070037236A1) (IDS filed on 06/15/2023), Daly et al. “Hemostatic regulators of tumor angiogenesis: a source of antiangiogenic agents for cancer treatment?.” Journal of the National Cancer Institute vol. 95,22 (2003): 1660-73. doi:10.1093/jnci/djg101, and in view of Bezuhly et al., (WO 2014087240 A2).
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, wherein the cancer therapy comprises an effective amount of antithrombin conjugated to a cancer therapy agent”.
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), and the cancer therapy comprising an effective amount of antithrombin conjugated to a cancer therapy agent.
Daly teaches the effects of HSAT on cancer and cancer treatments by teaching that the inhibitory activity of antithrombin depends on the integrity of its reactive loop and antithrombin binding of heparin in vitro, or heparin sulfate in vivo, leads to the exposure of the look and an increase in the rate of thrombin inhibition (see page 1663). Daly teaches that cleavage within the loop causes a conformational change, trapping thrombin and resulting in an inactive complex that dissociates slowly, releasing cleaved antithrombin (see page 1663). Daly teaches using antithrombin as for antiangiogenic effects (see page 1664) (instant claim 12).
Bezuhly teaches treating cancer with an effective amount of antithrombin and a cancer therapy agent (see claim 1 of Bezuhly, see [0075] teaching the use of Ticagrelor, a known antithrombic, see [0006], see claim 24, see [0047]) (instant claim 12). Bezuhly teaches the cancer being bladder cancer and/or prostate (see [0046]) or pancreatic (see [0005], [0046], [0053]) (instant claim 21). While Bezuhly does not explicitly state that the antithrombin is conjugated to the cancer therapy agent, it would have been obvious to one of ordinary skill in the art to conjugate the two as it will allow for simultaneous and synchronized delivery, increasing efficacy, and making it easier on the patient.
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 teachings the correlation of antithrombin and cancer taught by Daly, and with the method of treating a subject who has cancer with antithrombin and a cancer therapy agent taught by Bezuhly. Daly teaches that the use of cleaved, latent, and pre-latent forms of antithrombin suppressed growth factor stimulated proliferation of endothelial cells and inhibited angiogenesis (see page 1663). Daly teaches that cleaved and latent antithrombin inhibited the growth of a neuroblastoma cell line in mice and pre-latent antithrombin reduced tumor volume by 75% in a murine fibrosarcoma model, indicative of increased apoptosis and induced apoptosis of endothelial cells in vitro (see page 1663). Thus, it would have been obvious to one of ordinary skill in the art at the time of the instant application to use antithrombin in conjunction with a cancer treatment, because antithrombin has been shown to be effective in inhibiting the growth of cancer. Bezuhly teaches that antithrombic agents, clopidogrel and ticagrelor, can prevent platelets from sticking to cancer cells, thereby preventing or reducing metastases and improving patient survival (see [0005], see [0073], see [0078]). 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.
3.Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Klein, Daly, and Bezuhly et al., as it pertains to claims 12-15 and 21 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, Daly, and Bezuhly as it pertains to claims 12-15 and 21 are discussed in the 35 USC 103 rejection above.
Klein does not teach detecting 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 teachings the correlation of antithrombin and cancer taught by Daly, with the method of treating a subject who has cancer with antithrombin and a cancer therapy agent taught by Bezuhly, and with the method of detecting antithrombin as a stain in immunohistochemistry taught by Espinosa. Espinosa teaches 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 further teaches 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.
Response to Arguments
Applicant's arguments filed 06/25/2026 have been fully considered but they are not persuasive.
On p. 6 applicant argues that Klein does not teach a conjugated cancer therapy agent. However, Bezuhly teaches antithrombin and a cancer therapy agent. Klein teaches combining a biological sample of the subject containing HSAT with antithrombin, detecting the binding of HSAT and the antithrombin, and treating the subject.
Applicant does not provide any arguments pertaining to the Hernansez-Espinosa et al reference.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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