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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 23, 2026 has been entered.
Claims 1-9, 11 and 15 have been canceled. Claims 10, 12-14 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.
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, 12-14 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 0.16 to 0.20; 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 for evaluating anticoagulation reversal for factor Xa (FXa) inhibitors, comprising mixing FXa with edoxaban (a direct 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, is 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, is 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 assessing residual FXa activity using a modified anti-FXa assay comprises using bovine FXa (p.3 para 6). Finally, Lu does teach it is crucial to better characterize and understand andexanet’s ability to reverse the anticoagulation effects of edoxaban compared with other FXa inhibitors including betrixaban, which will inform correct clinical dosing regimens for Andexanet to reverse the anticoagulation effects of edoxaban in bleeding patients (p.2 para 4). CHMP teaches that the ability of andexanet to bind and neutralise FXa inhibitors was tested in a series of experiments for betrixaban and edoxaban in a buffered system using human FXa and Spectrozyme-FXa, and that andexanet dose-dependently and completely reverses inhibition of FXa by betrixaban as well as edoxaban (p.35 para 1). CHMP teaches functional assays wherein 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 direct inhibitor assay using a bovine FXa and betrixanban 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, since Lu and CHMP both disclose edoxaban and betrixaban are known FXa inhibitors, and Lu discloses that andexanet rapidly reverse the anticoagulation effects of edoxaban and betrixaban, and that it is crucial to better characterize and understrand andexanet’s ability to reverse the anticoagulation effects of edoxaban compared with other FXa inhibitors including betrixaban. Furthermore, 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. Finally, before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to incorporate a bovine FXa, since Lu and CHMP both disclose an assay using a FXa, a direct FXa inhibitor and Spectrozyme-FXa, Lu discloses that bovine FXa is used in a modified anti-FXa assay to assess residual FXa activity, and CHMP discloses that bovine FXa is used in the assay. 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 incorporate a bovine FXa with a reasonable expectation for successfully evaluating anticoagulation reversal for FXa inhibitors.
References cited above do not teach the claimed molar ratio of the BFXa to the FXa inhibitor (claims 10 and 12) as well as the claimed BFXa concentration (claims 13-14).
However, Lu and CHMP do teach an assay using a FXa, a direct FXa inhibitor and Spectrozyme-FXa, Lu does teach that bovine FXa is used in a modified anti-FXa assay to assess residual FXa activity, and CHMP does teach that bovine FXa is used in the assay. Furthermore, 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 the 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 tested, 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 for successfully evaluating anticoagulation reversal for FXa inhibitors.
Response to Arguments
Applicant argues that the instant claims are directed to methods for determining the activity of andexanet in clinical samples, by contrast, the primary reference Lu concerns measuring "edoxaban-andexanet interaction" (heading prior to paragraph 2 on page 3) in amechanistic study, and that the instant specification demonstrates unexpected results.
These arguments are not found persuasive because in a method, active method steps carry patentable weight. In the instant case, the combination of cited references does teach claimed active method steps. In addition, Lu and CHMP do teach an assay using a FXa, a direct FXa inhibitor and Spectrozyme-FXa, Lu does teach that bovine FXa is used in a modified anti-FXa assay to assess residual FXa activity, and CHMP does teach that bovine FXa is used in the assay. One skill in the art understood that bovine and human FXa exhibit functional and structural differences, which directly alter their FXa to FXa inhibitor molar binding ratios. In other words, one skill in the art would expect that the bovine FXa to FXa inhibitor molar ratio is different from the human FXa to FXa inhibitor molar ratio when performing chromogenic anti-Factor Xa assays, especially in the absence of applicant’s data supporting the criticality of the claimed molar ratio.
Conclusion
No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Curtis Mayes can be reached on (571)272-1234. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Lynn Y Fan/
Primary Examiner, Art Unit 1759
