DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment and response filed on 12/17/2025 have been received and entered into the case. Claims 1-9 and 15 have been canceled. Claims 10-14 and 16-17 are pending and have been considered on the merits, insofar as they read on the elected species of a molar ratio of BFXa to FXa inhibitor from 0.17 to 0.19, more specifically 0.18, and BFXa concentration of 14 to 18 nM, more specifically 16.2 nM. All arguments have been fully considered.
Withdrawn Rejections
Rejections of Claim 15 under 35 U.S.C. 103 as being unpatentable over Lu et al (PLoS One. 2018;13(3):e0195122.) in view of CHMP (European Medicines Agency. 2019;1-142.) are withdrawn in view of applicant’s amendments – Claim 15 has been canceled.
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 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 of this title, 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 10-14 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (PLoS One. 2018;13(3):e0195122.) in view of CHMP (European Medicines Agency. 2019;1-142.).
The instant claims recite a method for determining the activity of an andexanet sample, comprising: admixing a test sample comprising andexanet with a mixture comprising a bovine factor Xa (BFXa) and a direct factor Xa (FXa) inhibitor, wherein the molar ratio of the BFXa to the FXa inhibitor is from 0.15:1 to 0.25:1; adding a chromogenic FXa substrate to the mixture, wherein the chromogenic FXa substrate is able to release a chromophore upon reaction with the BFXa; detecting the amount of released chromophore; and calculating, from the amount of the released chromophore, the activity of the andexanet sample in releasing the BFXa from the direct FXa inhibitor, wherein the direct fXa inhibitor is selected from the group consisting of betrixaban, apixaban, rivaroxaban, edoxaban, otamixaban, letaxaban and eribaxaban.
Lu teaches a method comprising mixing factor Xa (FXa) with edoxaban (a direct factor Xa (FXa) inhibitor) in the presence of varying andexanet concentrations, wherein the concentration of FXa is 3.0 nM and edoxaban is at 2.5, 5.0 and 7.5 nM, and residual FXa activity is measured by cleavage of Spectrozyme-FXa (same as the claimed chromogenic FXa substrate, therefore, able to release a chromophore upon reaction with the BFXa) (p.3 para 2 & 6).
Lu does not teach detecting the amount of released chromophore, and calculating, from the amount of the released chromophore, the activity of the andexanet sample in releasing the BFXa from the direct FXa inhibitor (claim 10), wherein FXa is a bovine FXa (claim 10), and the direct FXa inhibitor is betrixaban (claim 16).
However, Lu does teach the method comprises adding Spectrozyme-FXa (same as the claimed chromogenic FXa substrate, therefore, able to release a chromophore upon reaction with the BFXa) to the mixture, wherein residual FXa activity is measured by cleavage of Spectrozyme-FXa. In addition, Lu does teach andexanet has demonstrated in pre-clinical studies to rapidly reverse the anticoagulation effects of direct and indirect FXa inhibitors including betrixaban (p.2 para 3). CHMP teaches direct potency of andexanet is determined by its ability to bind to direct FXa inhibitor betrixaban and reverse the inhibition of human FXa by betrixaban in an assay mixture composed of andexanet, human FXa, and betrixaban. The restored human FXa activity is measured with an FXa-specific chromogenic substrate, which releases a chromophore upon cleavage by FXa (p.22 last para). And a bovine FXa is incorporated in the direct inhibitor assay where betrixanban is used as FXa inhibitor (p.23 para 3).
Thus, before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to substitute betrixaban for edoxaban to achieve the predictable result of determining the activity of an andexanet sample, since Lu discloses that betrixaban and edoxaban are known direct FXa inhibitors, Lu and CHMP both disclose that FXa activity is measured by cleavage of a chromogenic FXa substrate, and CHMP discloses that FXa activity is measured with an FXa-specific chromogenic substrate, which releases a chromophore upon cleavage by FXa. In other words, the amount of released chromophore is detected and calculated, and the activity of the andexanet sample in releasing the FXa from the direct FXa inhibitor is determined.
References cited above do not teach the claimed molar ratio of the BFXa to the FXa inhibitor (claims 10-12) as well as the claimed BFXa concentration (claims 13-14).
However, Lu does teach the method comprises 3.0 nM FXa and 2.5, 5.0 and 7.5 nM edoxaban (the FXa inhibitor). Therefore, the molar ratio taught in the prior is 1.2 (3.0/2.5), 0.6 (3.0/5.0) and 0.4 (3.0/7.5). In addition, Lu does teach a molar ratio of 1.6:1 (andaxanet to edoxaban) significantly decreased anti-FXa activity and blood loss associated with edoxaban (FXa inhibitor) treatment, and ≥1.3:1 molar ratio was sufficient to reverse the anticoagulant effects of rivaroxaban (FXa inhibitor) in the same animal model (p.13 last para). Therefore, activity of an andexanet sample depends on specific FXa inhibitor used.
Thus, before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to optimize the concentration of BFXa as well as the molar ratio of the BFXa to a FXa inhibitor depending on specific FXa inhibitor used in the method, since Lu discloses that activity of an andexanet sample and concentration of FXa depend on specific FXa inhibitor used. Moreover, before the effective filing date of the claimed invention, one of ordinary skill in the art would have been motivated by the cited reference to optimize the concentration of BFXa as well as the molar ratio of the BFXa to a FXa inhibitor with a reasonable expectation of success.
Response to Arguments
Applicant argues surprising discovery and points to para 0031 and 0033 in the instant specification.
These arguments are not found persuasive because evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. In the instant case, there was no comparison of the claimed invention (determining the activity of an andexanet sample comprising bovine factor Xa (BFXa) and a direct factor Xa (fXa) inhibitor at a molar ratio of BFXa to fXa inhibitor from 0.15:1 to 0.25:1) with the closest prior art (a molar ratio of FXa to fXa inhibitor at 1.2 (3.0/2.5), 0.6 (3.0/5.0) and 0.4 (3.0/7.5)), and thereby lack of basis for judging the practical significance of data with regard to the disclosed unexpected results. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In the instant case, para 0031 in the instant specification discloses that “Yet another surprising finding is that betrixaban was less potent in inhibiting the bovine than the human fXa”, this data evidence is not commensurate in scope with the claims, since betrixaban is not required in claims 10-14 and 17. (MPEP 716.02)
Conclusion
No claims are 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 extension fee 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.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN Y FAN whose telephone number is (571)270-3541. The examiner can normally be reached on M-F 7am-4pm.
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/Lynn Y Fan/
Primary Examiner, Art Unit 1759