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 .
Response to Amendment
Applicant’s remarks and amendments to the claims filed 06/08/2026 have been acknowledged. Claim 1 has been amended.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 33, 52, and 81 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Church et al (Church, W R, and T L Messier. “Inhibition of plasminogen activation by monoclonal antibodies to the kringle 5-B chain segment of human plasminogen.” Hybridoma vol. 10,6 (1991): 659-72. doi:10.1089/hyb.1991.10.659, on IDS of 11/21/2022, of record), hereinafter Church as evidenced by Sanderson-Smith et al (Sanderson-Smith, Martina L et al. “Bacterial plasminogen receptors: mediators of a multifaceted relationship.” Journal of biomedicine & biotechnology vol. 2012 (2012): 272148. doi:10.1155/2012/272148).
Church discloses monoclonal antibodies that bind to the Kringle 5-B chain fragment (residues 442-790) of human plasminogen and inhibit plasminogen activation. The anti-plasminogen clone αPg-96 specifically inhibited streptokinase-, tissue plasminogen activator (tPA)-, and urokinase plasminogen activator (uPA)-mediated plasminogen activation (Abstract and Epitope Localization section: pp 663-664). In particular, αPg-96 completely blocked tPA-induced plasma fibrinolytic activity determined using a plasmin-dependent fibrin clot lysis assay (1st para. under Functional Effects section on Page 664). Further, αPg-96 incubated in the presence of plasminogen was incubated prior to the addition of uPA, tPA, or streptokinase reduced plasmin generation. Plasmin generation is inferred from the increase in absorbance due to S-2251 hydrolysis measured using a Vmax spectrophotometer (Figures 2 and 4; Functional Effects section, pp. 665-667). Of note, the term “inhibit” or “reduce” recited in the independent claim can reasonably encompass direct and indirect inhibition/reduction of plasmin activity. As such, an antibody that prevents formation of plasmin can be understood to indirectly inhibit hydrolysis (or proteolysis) of a substrate by plasmin because it reduces or eliminates the hydrolytic activity that would otherwise occur. This is illustrated in Figures 2 and 4. In the absence of antibody (control), “appreciable S-2251 hydrolytic activity” appears after a lag period, consistent with the generation of active plasmin followed by hydrolysis of the S-2251 substrate. By contrast, in the presence of αPg-96, no S-2251 hydrolysis is completely abolished, demonstrating that αPg-96 indirectly inhibits plasmin-mediated hydrolysis by preventing the formation of the active enzyme required for substrate hydrolysis. Further, plasmin is involved in fibrinolysis as evidenced by the instant specification (see Background of the Invention and 2nd paragraph of Page 63 of specification); and fibrin is a plasmin substrate (Page 61, 4th para of specification). As such, “inhibition/reduction of proteolysis of any substrate by plasmin” as recited in claim 1 can also encompass fibrinolysis. Thus, although αPg-96 may not directly inhibit proteolytic activity of plasmin, it nevertheless inhibits plasmin-mediated activity indirectly by preventing formation of plasmin from its precursor plasminogen. Because plasmin is required for the hydrolysis of fibrin or S-2251, preventing generation of plasmin necessarily reduces or inhibits the hydrolytic (or proteolytic) activity that would otherwise occur. Moreover, both plasminogen and plasmin comprising Kringle 1-5 domains as well as the light B chain (corresponding to the serine protease domain) (see Figure 1 of Sanderson-Smith). Accordingly, clone αPg-96, which binds to an epitope in Kringle 5-B chain fragment (residues 442-790) of human plasminogen, is reasonably expected to also bind to plasmin. Taken together, clone αPg-96 have a means for binding to plasminogen and plasmin and reducing/inhibiting (i) urokinase tissue activator (uPA) mediated plasminogen activation and (ii) proteolysis of any substrate by plasmin at least indirectly. Lastly, it is described that following the preparation or purification of the anti-plasminogen antibodies, the antibodies were stored in 50% (v/v) glycerol/H20 (Page 661). Thus, Church discloses a pharmaceutical composition comprising the anti-plasminogen antibody having the functional properties of the instant claims and a pharmaceutically acceptable carrier, diluent, or excipient. The term “pharmaceutical” is the intended use of the composition but does not result in any structural differences between the claimed invention and the prior art.
Thus, Church meets the limitations of instant claims 1, 33, 52, and 81.
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.
Claims 48 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Church, as applied to claims 1, 33, 52, and 81 above, in view of Tolmachev et al (Tolmachev, Vladimir et al. “Methods for radiolabelling of monoclonal antibodies.” Methods in molecular biology (Clifton, N.J.) vol. 1060 (2014): 309-30. doi:10.1007/978-1-62703-586-6_16, of record), hereinafter Tolmachev and Kennedy et al (Kennedy, Patrick J et al. “Antibodies and associates: Partners in targeted drug delivery.” Pharmacology & therapeutics vol. 177 (2017): 129-145. doi:10.1016/j.pharmthera.2017.03.004, of record), hereinafter Kennedy.
The teachings of Church have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the antibody is a fusion protein or conjugated to a label or cytotoxic agent.
However, Tolmachev teaches that the use of radionuclide labels allows to study the pharmacokinetics of monoclonal antibodies, to control the specificity of their targeting and to monitor the response to an antibody treatment with high accuracy (see Abstract).
Goldmacher teaches that the conjugation of cytotoxic agents to monoclonal antibodies enables targeted delivery of the drug payload while reducing systemic toxicity for the treatment of cancer and other diseases (Section 3 and last paragraph of section 3.5.4).
It would have been obvious to one of ordinary skill in the art to modify the anti-plasminogen antibody αPg-96 disclosed by Church such that the antibody is conjugated to a label—e.g. a radionuclide label— or cytotoxic agent. One of ordinary skill in the art would have been motivated to do so since radionuclide labels facilitate the study of antibody pharmacokinetics, control/target antibodies to specific sites, and enable highly accurate, monitoring of treatment responses as taught by Tolmachev. Further, conjugation of cytotoxic drugs to monoclonal antibodies enables targeted delivery of the drug payload while reducing systemic toxicity for the treatment of cancer and other diseases as taught by Goldmacher. Therefore, one of ordinary skill in the art would reasonably expect the anti-plasminogen antibody αPg-96 conjugated to a to a label—e.g. a radionuclide label— or cytotoxic agent can be used to monitor treatment responses or treat a particular disease in a subject, respectively.
Response to Arguments
Applicant's arguments filed 06/08/2026 have been fully considered but they are not persuasive.
With respect to the rejection made under 35 USC 102(a)(1), Applicant argues that, the Office’s construction of "plasmin activity" is incorrect. In particular, Applicant states that the current specification distinguishes between (a) inhibition of the generation of active plasmin (by the G05 antibody) and (b) inhibition of the activity of plasmin itself (by G11 antibody) on page 108 paragraph 2 of the specification. In other words, by mechanism (a), the level of active plasmin is reduced. By mechanism (b), the levels of plasmin remain the same, but the activity of the plasmin molecule is reduced. Applicant contends that skilled person would not construe "plasmin activity" as including (a), especially in the context of the specification. The Office highlighted that aPg-96 that was incubated in the presence of plasminogen prior to the addition of uPA, tPA, or streptokinase, reduced plasmin generation (page 3 of Office Action). Applicant argues that Church also distinguishes between (a) plasmin generation and (b) plasmin activity, which validates the construction that the skilled person would give to "plasmin activity" in the current application. In fact, page 664 of Church states that: The fibrin plate assay plate assay data for inhibition by antibody aPg-96 could be explained by either antibody-mediated inhibition of plasminogen activation or inhibition of plasmin following activation. To rule out direct antibody inhibition of plasmin, the effect of each antibody on plasmin catalyzed hydrolysis of S-2251 was determined. The abstract (describing the results in Table 2) specifically states, "the other antibodies (referring to aPg-28 and aPg-96) had no significant effect on plasmin activity". As such, Church makes the same distinction between (a) plasmin generation through activation of plasminogen and (b) plasmin activity. Nevertheless, purely to progress prosecution, claim 1 as amended recites that the antigen binding protein comprises a means for binding to plasminogen and plasmin, and that reduces or inhibits (i) uPA activation of plasminogen and (ii) proteolysis of any substrate by plasmin, which Applicant asserts is not taught by the cited prior art.
In response to Applicant’s arguments, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As previously noted, “various assays are known in the art for assessing the ability of a protein to inhibit or reduce plasmin activity” (Page 61 of the Specification). Further, the term “inhibit” or “reduce” recited in the independent claim is not particularly limited and can thus reasonably encompass both direct and indirect inhibition/reduction of plasmin activity. As such, an antibody that prevents formation of plasmin can be understood to indirectly inhibit proteolysis of a substrate by plasmin because it reduces or eliminates the proteolytic activity that would otherwise occur. This is illustrated in Figures 2 and 4 of the cited prior art, Church et al. In the absence of antibody (control), “appreciable S-2251 hydrolytic activity” appears after a lag period of 40 min, consistent with the generation of active plasmin followed by hydrolysis of the S-2251 substrate. By contrast, in the presence of αPg-96, S-2251 hydrolysis is completely abolished, demonstrating that αPg-96 indirectly inhibits plasmin-mediated hydrolysis by preventing the formation of the active enzyme required for substrate hydrolysis. Similarly, the Declaration of Ruby Law filed 12/05/25 states that “plasmin activity” is assessed by measuring cleavage of a synthetic, fluorogenic substrate (AFK-AMC) in response to uPA-induced plasminogen activation in the presence of the anti-plasminogen antibody G11, wherein the formation of fluorescent product (AMC) over time is directly proportional to plasmin activity. In this case, there was no cleaved product generated in the presence of the G11 antibody, indicating that the G11 antibody effectively inhibited/reduced plasmin activity (see Figure A and para. 7-9 of the Declaration). Thus, although the prior art antibody αPg-96 does not directly inhibit proteolytic activity of plasmin, it nevertheless inhibits plasmin-mediated activity indirectly by preventing formation of plasmin from its precursor plasminogen. Because plasmin is required for the hydrolysis of substrates such as fibrin or S-2251, preventing generation of plasmin necessarily reduces or inhibits the hydrolytic (or proteolytic) activity that would otherwise occur.
Moreover, both plasminogen and plasmin comprise Kringle 1-5 domains as well as the light B chain (corresponding to the serine protease domain). Accordingly, clone αPg-96, which binds to an epitope in Kringle 5-B chain fragment (residues 442-790) of human plasminogen, is reasonably expected to also bind to plasmin. Taken together, clone αPg-96 have a means for binding to plasminogen and plasmin and reducing/inhibiting (i) urokinase tissue activator (uPA) mediated plasminogen activation and (ii) proteolysis of any substrate by plasmin at least indirectly.
Thus, the rejection under 35 USC 102(a)(1) is maintained.
Conclusion
Claims 1, 33, 48, 52, 81, and 82 are not allowable. Claims 31, 32, 78, 79, and 80 are allowable. Claim 28 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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