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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/3/2026 has been entered.
DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Response to Final office action filed on 7/3/2026 is acknowledged.
3. Please do NOT enter the claim filed on 12/15/2025, 1/21/2026 and 4/21/2026.
4. Claim filed on 7/3/2026 is acknowledged.
5. Claims 1-20 have been cancelled.
6. New claims 21-37 have been added.
7. Claims 21-37 are pending in this application.
8. Claims 36 and 37 are withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claims 29, 30 and 32-35 are withdrawn from consideration as being drawn to non-elected species.
9. Applicant elected without traverse Group 1 (claims 1-10) and elected without traverse MePEG2-IEGR as species of compound or a physiologically acceptable salt thereof in the reply filed on 1/12/2024.
Restriction requirement was deemed proper and made FINAL in the previous office actions. Group 1 is drawn to a compound of general formula (I-3) or (I-4)
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, or a physiologically acceptable salt thereof. A search was conducted on the elected species; and prior art was found. Claims 29, 30 and 32-35 are withdrawn from consideration as being drawn to non-elected species. Claims 21-28 and 31 are examined on the merits in this office action.
Withdrawn Objections
10. Objection to claim 5 is hereby withdrawn in view of Applicant’s amendment to the claim.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 103
11. 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.
12. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
13. (Revised due to Applicant’s amendment to the claim) Claims 21-28 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Van Heerde et al (WO 2012/096566 A1, filed with IDS) in view of Aurell et al (Thrombosis Research, 1977, 11, pages 595-609, cited and enclosed in the previous office actions).
The instant claims 21-28 and 31 are drawn to a compound of general formula (I-3) or (I-4)
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, or a physiologically acceptable salt thereof.
Van Heerde et al, throughout the patent, teach a method for in vitro determining generation of a haemostatis factor in a test sample using a chemiluminescent substrate specific for said blood clotting factor, upon cleavage of the substrate, a luminescent signal is generated via aminoluceferin with the aid of a luciferase; wherein the chemiluminescent substrate is -B-X-Arg-NH-Y, X-Arg-NH-Y, B-X-Lys-NH-Y or X-Lys-NH-Y, wherein B is an amino-terminal protecting group, Y is a chemiluminescent reporter molecule linked to the peptide by a hydrolyzable amide bond, X may be any amino acid sequence, dipeptide, tripeptide, or the like and may or may not include a spacer molecule, for example, Abstract; page 1, lines 4-7; page 3, line 31 to page 4, line 3; and page 4, line 26 to page 6, line 15. Van Heerde et al further teach the chemiluminescent substrate for thrombin includes CH3O(CH2CH2O)2-acetyl-Gly-Gly-Arg-aminoluciferin with the structure
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or CH3O(CH2CH2O)2-acetyl-beta-Ala-Gly-Arg-aminoluciferin with the structure
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, wherein Gly-Gly-Arg or beta-Ala-Gly-Arg is the specific substrate for thrombin, for example, page 4, line 26 to page 5, line 14; and claims 13 and 14. It meets the limitations of aminoluciferin and X group in the compound recited in instant claims 21-28 and 31. Van Heerde et al also teach that in addition to thrombin, factor Xa is a haemostatis factor to be monitored in a test sample, for example, page 7, line 18-23; and claim 5.
The difference between the reference and instant claims 21-28 and 31 is that it does not explicitly teach MePEG2-IEGR as the elected species of compound or a physiologically acceptable salt thereof; and the specific chemiluminescent substrate for factor Xa.
However, Aurell et al teach peptide with the amino acid sequence IEGR is a specific substrate for factor Xa, for example, the paragraph bridging pages 595 and 596.
Therefore, it would have been obvious to one of ordinary skilled in the art to modify the chemiluminescent substrate CH3O(CH2CH2O)2-acetyl-Gly-Gly-Arg-aminoluciferin with the structure
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or CH3O(CH2CH2O)2-acetyl-beta-Ala-Gly-Arg-aminoluciferin with the structure
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in Van Heerde et al by substituting/trying IEGR (the specific cleavage sequence for factor Xa) taught in Aurell et al, and in view of the combined teachings of Van Heerde et al and Aurell et al to develop a chemiluminescent substrate with the structure
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, wherein such chemiluminescent substrate is specific for in vitro determining generation of factor Xa in a test sample. It reads on MePEG2-IEGR as the elected species of compound or a physiologically acceptable salt thereof.
One of ordinary skilled in the art would have been motivated to modify the chemiluminescent substrate CH3O(CH2CH2O)2-acetyl-Gly-Gly-Arg-aminoluciferin with the structure
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or CH3O(CH2CH2O)2-acetyl-beta-Ala-Gly-Arg-aminoluciferin with the structure
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in Van Heerde et al by substituting/trying IEGR (the specific cleavage sequence for factor Xa) taught in Aurell et al, and in view of the combined teachings of Van Heerde et al and Aurell et al to develop a chemiluminescent substrate with the structure
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, wherein such chemiluminescent substrate is specific for in vitro determining generation of factor Xa in a test sample, because Aurell et al teach that peptide with the amino acid sequence IEGR is a specific substrate for factor Xa. And Van Heerde et al explicilty teach that in addition to thrombin, factor Xa is a haemostatis factor to be monitored in a test sample.
A person of ordinary skilled in the art would have reasonable expectation of success in modifying the chemiluminescent substrate CH3O(CH2CH2O)2-acetyl-Gly-Gly-Arg-aminoluciferin with the structure
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or CH3O(CH2CH2O)2-acetyl-beta-Ala-Gly-Arg-aminoluciferin with the structure
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in Van Heerde et al by substituting/trying IEGR (the specific cleavage sequence for factor Xa) taught in Aurell et al, and in view of the combined teachings of Van Heerde et al and Aurell et al to develop a chemiluminescent substrate with the structure
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, wherein such chemiluminescent substrate is specific for in vitro determining generation of factor Xa in a test sample.
Response to Applicant's Arguments
14. Applicant argues that the claimed compounds outperform what the prior art would have suggested; these results are particularly surprising because there was no reasonable expectation that switching from chromogenic to luminescent probe systems would maintain functionality, let alone improve performance so substantially; and the prior art provides no basis for expecting the substantial improvements in selectivity and sensitivity that the claimed compounds actually deliver.
15. Applicant's arguments have been fully considered but have not been found persuasive.
First, the Examiner would like to point out that instant claims 21-28 and 31 are rejected under 35 U.S.C. 103 (obviousness type); and the rejection is based on the combined teachings of Van Heerde et al and Aurell et al. Therefore, it is not necessary for each of the cited prior art references to teach all the limitations of instant claims 21-28 and 31. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV).
Second, it appears to the Examiner that Applicant is trying to argue about unexpected results. The Examiner would like to bring Applicant’s attention to MPEP § 716.02, which provides the guidelines for allegations of unexpected results. As stated in MPEP: “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness.” (see MPEP § 716.02(e)); and “Unexpected Results Commensurate in Scope With Claimed Invention [R-08.2012] 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."…” (see MPEP § 716.02(d)). In the instant case, the closest prior art is the chemiluminescent substrate disclosed in Van Heerde et al. Furthermore, the instant claimed general formula (I-3) or (I-4) is very broad. Taken all these together, Applicant is suggested to provide data for unexpected results according to the guidelines for allegations of unexpected results as set forth in MPEP.
Third, with regards to Applicant’s arguments related to Chan reference, it is unclear what the cited Chan reference is. Therefore, Applicant’s arguments based on Chan reference is moot.
Fourth, with regards to Applicant’s arguments about the difference observed between the chromogenic probe in Aurell et al and instant claimed luminescent probe, in the instant case, the Examiner would like to point out that both the probe and the testing condition/method in Aurell et al are different from instant claimed luminescent probe and the testing condition/method used by Applicant. Therefore, there is no reason for one of ordinary skilled in the art to expect which of the two probes would be better or worse, let alone the percentage difference. And, it is unclear to the Examiner how and/or why one of ordinary skilled in the art would reach the conclusion that the instant claimed luminescent probe should not be better than the chromogenic probe in Aurell et al. Further clarification is required.
Furthermore, as stated in the previous office actions, in the instant case, in view of the teachings of Aurell et al as a whole, one of ordinary skilled in the art would understand and reasonably expect that the chemiluminescent substrate developed from the combined teachings of Van Heerde et al and Aurell et al is specific for in vitro determining generation of factor Xa in a test sample. And in view of the combined teachings of Van Heerde et al and Aurell et al, a person of ordinary skilled in the art would have reasonable expectation of success in developing a chemiluminescent substrate with the structure
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, wherein such chemiluminescent substrate is specific for in vitro determining generation of factor Xa in a test sample. In addition, with regards to the expectation of success, the MPEP states: “Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.” (see MPEP § 2145).
Taken all these together, the rejection is still deemed proper and is hereby maintained.
Obviousness Double Patenting
16. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
17. (Revised due to Applicant’s amendment to the claim) Claims 21-28 and 31 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-20 of US patent 9856510 B2 in view of Aurell et al (Thrombosis Research, 1977, 11, pages 595-609, cited and enclosed in the previous office actions).
18. Instant claims 21-28 and 31 are drawn to a compound of general formula (I-3) or (I-4)
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, or a physiologically acceptable salt thereof.
19. Claims 1-20 of US patent 9856510 B2 are drawn to a chemiluminescent substrate selected from the group consisting of: PEGn-acetyl-X-Lys-NH-Y and PEGn-acetyl-X-Arg-NHY, or a salt of thereof, wherein n is an integer in the range of 1-5, wherein Y is a chemiluminescent reporter moiety linked to the Lys or Arg by a hydrolyzable amide bond, and wherein X is an amino acid sequence; PEGn-acetyl-Phe-Arg-aminoluciferin, wherein n is an integer in the range of 1-5; CH3O(CH2CH2O)n-acetyl-beta-Ala-Gly-Arg-aminoluciferin, wherein n is 1, 2, 3 or 4; CH3O(CH2CH2O)n-acetyl-Gly-Gly-Arg-aminoluciferin, wherein n is 1, 2, 3 or 4; or a salt thereof; a kit for in vitro determining generation of a blood hemostasis in a test sample, comprising a first container holding a chemiluminescent substrate selected from claim 1 and one or more additional containers each holding a distinct reagent selected from the group consisting of luciferase, ATP, an Mg2+ source and a trigger molecule for inducing generation of said blood hemostasis factor; and a method for in vitro determining the generation of a
blood hemostasis factor in a test sample comprising: contacting a test sample with a trigger molecule for inducing the generation of said blood hemostasis factor in the test sample, a chemiluminescent substrate selected from claim 1 which contains a cleavage site specific for said blood haemostasis factor to obtain a reaction mixture; measuring a luminescent signal which indicates that said blood hemostasis factor has cleaved the chemiluminescent substrate to release the aminoluciferin reporter moiety from the substrate; and determining the amount of said blood hemostasis factor based on the measurement of the luminescent signal.
In the instant case, in view of the combined teachings of claims 1-20 of US patent 9856510 B2, it would have been obvious to one of ordinary skilled in the art to develop a chemiluminescent substrate specific for factor Xa with the structure CH3O(CH2CH2O)n-acetyl-amino acid sequence as substrate specific for factor Xa-aminoluciferin, wherein n is 1, 2, 3 or 4.
20. The difference between the chemiluminescent substrate specific for factor Xa developed from the combined teachings of claims 1-20 of US patent 9856510 B2 above and the compound recited in instant claims 21-28 and 31 is it does not teach the peptide sequence in the compound recited in instant claims 21-28 and 31.
However, Aurell et al teach peptide with the amino acid sequence IEGR is a specific substrate for factor Xa, for example, the paragraph bridging pages 595 and 596.
Therefore, in view of the teachings of Aurell et al, it would have been obvious to one of ordinary skilled in the art to modify the chemiluminescent substrate specific for factor Xa developed from the combined teachings of claims 1-20 of US patent 9856510 B2 and develop the compound recited in instant claims 21-28 and 31.
21. (Revised due to Applicant’s amendment to the claim) For the same and/or similar reasoning/rational as the rejection set forth in Sections 17-20 above, instant claims 21-28 and 31 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-15 of US patent 10465230 B2 in view of the teachings of Aurell et al (Thrombosis Research, 1977, 11, pages 595-609, cited and enclosed in the previous office actions) as set forth in Sections 13 and 20 above.
Response to Applicant's Arguments
22. Applicant argues that “Applicant requests that the rejection be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications.”
23. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant’s arguments about the ODP rejections, the Examiner would like to point out that none of the ODP rejections is provisional. And, until a proper terminal disclaimer is filed and approved by the Office, these double patenting rejections are maintained.
Conclusion
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
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