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 12/05/2025 have been acknowledged. Claims 1, 28, 31-33, 48, 50, 54, 68, 70-72, 76, and 78-85 have been amended. Claims 7, 14, 16, 17, 20, 22, 29, and 30 have been canceled. Claims 78-85 are newly added. Newly added claims 83-85 will be classified under the invention of Group III, directed to method of treatment (see Restriction Requirement of 04/17/2025) and are thus withdrawn from consideration as being directed to a non-elected invention.
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.
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 as 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). Thus, αPg-96 completely blocked uPA, tPA, and streptokinase- induced plasminogen activation and plasmin activity. Of additional note, fibrinolysis is involved in fibrinolysis as evidenced by the instant specification (see Background of the Invention and 2nd paragraph of Page 63). Thus, a plasmin activity as recited in claim 1 can encompass fibrinolysis. Taken together, clone αPg-96 have a means for binding to plasminogen and reducing/inhibiting (i) urokinase tissue activator (uPA) mediated plasminogen activation and (ii) plasmin activity. Moreover, 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), 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), 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 12/05/2025 have been fully considered but they are not persuasive.
With respect to the rejection made under 35 USC 102(a)(1), Applicant argues that, as discussed in the Declaration of Ruby Law, (1) the anti-plasminogen clones αPg-28 and αPg-96 disclosed by Messier do not have a significant effect on plasmin activity, in contrast to the G11 antibody of the instantly claimed invention as shown in Figure 5; and (2) anti-plasminogen clones αPg-28 and αPg-247 do not reduce or inhibit uPA activation of plasminogen, in contrast to the G11 antibody. Thus, Applicant asserts that claim 1 is novel over the cited prior art.
In response to Applicant’s arguments, the Examiner reiterates that the anti-plasminogen clone αPg-96 as disclosed by the cited prior art inhibited streptokinase-, tissue plasminogen activator (tPA)-, and urokinase plasminogen activator (uPA)-mediated plasminogen activation and fibrinolytic activity. Plasmin activity is not particularly defined in the specification, but “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). For example, as demonstrated in the Declaration of Ruby Law filed 12/05/25, 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). Similarly, the cited prior art demonstrates that clone αPg-96 completely blocked urokinase-induced plasminogen activation and plasmin activity. The generation of plasmin was inferred from the increase in absorbance due to S-2251 hydrolysis measured using a Vmax spectrophotometer in the presence of the anti-plasminogen antibody. There was no evidence of plasmin after a 2 hr incubation with uPA in the presence of antibody αPg-96 (see Figure 4A of Church). Hence, contrary to Applicant’s assertion, clone αPg-96 disclosed by the cited prior art does indeed meet the functional limitations of instant claim 1, including binding to plasminogen and reducing/inhibiting (i) uPA-induced plasminogen activation and (ii) plasmin activity, wherein plasmin activity was determined using a similar assay employed by Applicant – i.e. monitoring the formation of a cleaved plasmin substrate in response to uPA-induced plasminogen activation in the presence of an anti-plasminogen antibody. In contrast, in the example cited by Applicant, in which αPg-96 reportedly had no significant effect on plasmin hydrolysis of the substrate S-2251, plasmin was incubated with anti-plasminogen antibody in the presence of substrate. Thus, the experimental setup was different than that used by Applicant to determine plasmin activity in the Declaration and thus does not serve as a useful basis for comparison when drawing the conclusion that the antibodies disclosed by the cited prior art—particularly αPg-96 –do not possess the recited functional properties. Lastly, the emphasis on clones αPg-28 and αPg-247 by Applicant as lacking in the claimed functional properties does not overshadow the fact that these properties are present in clone αPg-96 as discussed above. Thus, the rejection under 35 USC 102(a)(1) is maintained.
Applicant’s arguments with respect to the rejection made under 35 USC 112(a) written description has been fully considered and are persuasive. Specifically, Applicant stated that in the recent Ex Parte Chamberlain decision, the Board held that a similar means-plus-function limitation (“a means for binding human C5 protein”) complied with the written description requirement based on the disclosure in the specification of clone 5G.1.1 and further that disclosure of equivalents is not necessary to satisfy the written description requirement. Thus, Applicant asserts that written description of the means-plus-function element is similarly satisfied at least by structure of the G11 antibody provided in the instant specification.
The Examiner further notes that in the Declaration of Ruby Law filed 12/05/2025, clone G11 reduce/inhibit uPA activation of plasminogen and plasmin activity, wherein plasmin activity was indirectly determined by measuring the level of a cleaved fluorescent plasmin substrate in response to uPA-induced plasminogen activation in the presence of G11 antibody. In particular, the reaction mixture comprised 25 nM plasminogen , 5 U/mL uPA, 20 mM EACA, and 100 uM of AFK-AMC fluorogenic substrate. No plasmin activity was detected, indicating that G11 effectively reduced/inhibited uPA activation of plasminogen. Thus, in view of the foregoing, disclosure of the G11 clone (as well as G05 clone) appears to satisfy written description of the means-plus-function limitation recited in claim 1. As such, the rejection under 35 USC 112(a) written description is withdrawn.
Applicant’s cancellation of claims 7, 17, 20 renders moot the rejection of the claims under 35 USC 112(b). The amendments of claims 33 and 48 to remove indefinite language overcome the 35 USC 112(b) rejection of these claims.
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.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641