DETAILED ACTION
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 .
Preliminary Amendment
The preliminary amendments of claims, filed 08/16/2024, has been fully considered.
Status of Claims
Claim 1-4, 6-11, 13, 16-20, 23, 29-30, and 32 are pending and under examination.
Claims 5, 12, 14-15, 21-22, 24-28, 31, and 33-41 have been canceled.
Information Disclosure Statement
The information disclosure statement (IDS) document(s) submitted on 02/16/2024 and 02/02/2026 are compliant with the provisions of 37 CFR 1.97. Accordingly, the IDS document(s) has/have been fully considered by the examiner.
Claim Objections
Claims 1 and 32 are objected to because of the following informalities:
Claim 1 line 1 refers to “the activity of human coagulation factor VIII”. The examiner requests applicant change article “the” to “an” when a new feature is first introduced into the claims. A similar objection is also made over claim 32.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10, 16-18 and 19-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 10 refers to “the capture antibody”. There is insufficient antecedent basis for this term in the claims and it is unclear what applicant is referring to by this phrase. Perhaps Applicant is intending to recite “the capture agent”, as previously defined in claim 1? For purposes of examination, the examiner is interpreting “the capture antibody” as “the capture agent”.
Claim 16 recites “a small molecule”. The term “small” is a a relative term and it is unclear what would or would not be considered “small” (See MPEP 2173.05b) which renders the claim indefinite. The term “small” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree (of “small”), and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claims 17-18 are also rejected by their dependency from claim 16.
Claim 19 refers to “c1”, “c2”. However, claim 19 is dependent from claim 1 which does not refer to these steps. Claim 3 defines “c1”, “c2”. However, claim 19 does not depend from claim 3 and it is unclear what applicant is referring to by these steps. Claim 20 is also rejected by its dependency from claim 19.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 32 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Weber et al. (US 2012/0329072 – hereinafter “Weber”) where Technoclone (Technochrom FVIII:C package insert, Ref. 5344101, June 2016 – hereinafter “Technoclone”) is used as supporting document.
Regarding claim 32, Weber disclose a kit for measuring the activity of human coagulation factor VIII (FVIII) in a sample (Weber; [0006, 0009, 0095-0096, 0164-0167, 0171, 0201]) comprising
i. a capture agent that selectively binds the human FVIII, wherein the capture agent is attached to a solid support (Weber; [0166]);
ii. a first vial comprising one or more of activated factor IX (FIXa), factor X (FX), calcium ion, phospholipids and thrombin (Weber teach a chromogenic assay is performed following the standard chromogenic procedure using the Immunochrom FVIII kit (Technoclone, GmbH, Vienna, Austria); [0171, 0201]. The Technoclone package insert defines Reagent A and Reagent B as comprising FIXa, FX, Calcium ions, Phospholipid, and Thrombin; p.2, “Composition”);
iii. a second vial comprising an FXa specific chromogenic substrate (Weber teach the chromogenic assay is performed following the standard chromogenic procedure using the Immunochrom FVIII kit (Technoclone, GmbH, Vienna, Austria); [0171, 0201]. The Technoclone pack insert defines “Substrate FXa-1 + αNAPAP; p.2, “Composition”); and/or
iv. optionally, a third vial comprising a stopping agent (Weber disclose stopping a reaction using 20% acetic acid (40 µL/well); [0171, 0201]).
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, 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 8-11, 13, 16-20, 23, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Weber where Technoclone is used as supporting document, and further in view of Tripodi et al., (Emicizumab, the factor VIII mimetic bi-specific monoclonal antibody and its measurement in plasma, September 4, 2020, Clin Chem Lab Med, Volume 59, No. 2, pp. 365-371 – hereinafter “Tripodi”).
Regarding claim 1, Weber disclose a method for measuring the activity of human coagulation factor VIII (FVIII) in a sample (Weber disclose methods, systems and kids for modification-dependent activity assay (MDAAs); [0006]. The method includes binding an antibody to a solid support, washing the solid support, and running a chromogenic assay on the solid support [0032] where the MDAAs are suitable for measuring the activity of human coagulation factor VIII in a sample as described in examples 1-2, 7 and 8; [0008, 0030-0032, 0038, 0044-0045, 0080, 0108-0109, 0115, 0139, 0147-0150, 0163, 0169-0176, 0199-0208]), said method comprising the steps of:
a) incubating the sample with a capture agent that selectively binds the human FVIII under conditions and for a time sufficient to allow the capture agent to selectively bind to the human FVIII, whereby forming a reaction mixture, wherein the capture agent is attached to a solid support (Weber disclose the MDAAs comprise a capture agent bound to a solid support and incubating the sample to selectively bind the sample to the solid support with the capture agent; [0031-0032, 0056-0066, 0068, 0071, 0074-0075, 0095, 0098, 0111, 0135, 0141, 0147-0150, 0165-0166, 0169-0176, 0199-0208]);
b) removing unbound fraction of human FVIII from the reaction mixture (Weber disclose endogenous non-modified compounds can be removed by washing; [0031-0032, 0071, 0096, 0169-0176, 0199-0208]); and
c) measuring the activity of human FVIII in the reaction mixture using a chromogenic assay (Weber disclose the MDAAs running a chromogenic assay on the solid support; [0032, 0076, 0079-0081, 0159, 0169-0176, 0199-0208]).
Weber does not teach wherein the sample comprises one or more FVIII-activity mimicking agents or incubating the sample in the presence of the one or more FVIII-activity mimicking agents.
However, Tripodi teach the analogous art of a method for measuring the activity of human coagulation factor VIII (FVIII) in a sample (Tripodi teach the one-stage assay (OSA) used to measure FVIII; p. 365, Abstract), wherein the sample comprises one or more FVIII-activity mimicking agents (Tripodi teach the OSA for testing FVIII was modified to test plasma samples for emicizumab concentrations, and the chromogenic assay for FVIII with bovine reagents was used to assess for the FVIII inhibitor in patients on emicizumab; p. 365, Abstract and pp. 366-367, “Materials and methods”).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the sample and method of Weber with the sample comprising emicizumab, as taught by Tripodi, because Tripodi teach the sample comprising Emicizumab is often found in patients who are treated for prophylaxis of hemophilia A (Tripodi; pp. 365-366, “Introduction”). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since Weber and Tripodi both teach chromogenic assay methods for measuring FVIII activity.
Regarding claim 2, modified Weber teach the method of claim 1 above, further comprising d) determining the activity of human FVIII in the reaction mixture by comparing with an FVIII reference preparation (The modification of the sample and method of Weber with the sample comprising emicizumab, as taught by Tripodi, has previously been discussed in claim 1 above. Tripodi teach a commercially available plasma at certified emicizumab concentrations, different from that used to prepare test plasma samples was used as standard to construct emicizumab calibration curves aimed to derive emicizumab concentration for the test plasmas, and that FVIII inhibitors were determined using the chromogenic assay with bovine reagents; pp. 366-369, “Materials and methods”, “Measurement of the inhibitor to FVIII, Table 1).
Regarding claim 3, modified Weber teach the method of claim 1 above, wherein the chromogenic assay is performed by (Weber teach the chromogenic assay is performed following the standard chromogenic procedure using the Immunochrom FVIII kit (Technoclone, GmbH, Vienna, Austria); [0171, 0201]. The Technoclone package insert disclose the steps and reagents to perform chromogenic assay)
c1) adding to the reaction mixture activated factor IX (FIXa), factor X (FX), calcium ion, phospholipids, and thrombin, and incubating the reaction mixture under conditions and for a time sufficient to generate activated FX (FXa) (Weber disclose the wells were filled with 20 µL reagent A and reagent B. The plate was then incubated at 37±5˚C for 5 minutes; [0171, 0201]. The Technoclone package insert defines Reagent A and Reagent B as comprising FIXa, FX, Calcium ions, Phospholipid, and Thrombin; p.2, “Composition”);
c2) adding to the reaction mixture an FXa specific chromogenic substrate and incubating the reaction mixture under conditions and for a time sufficient to generate a measurable signal (Weber disclose after c1, pre-warmed substrate solution was added (100 µL/well) and incubated at 37 ±5˚ for 15 min; [0171, 0201]. The Technoclone pack insert defines “Substrate FXa-1 + αNAPAP; p.2, “Composition”);
c3) optionally, adding to the reaction mixture a stopping agent to stop signal generation from the FXa specific chromogenic substrate (Weber disclose after c2, the reaction was stopped by adding 20% acetic acid (40 µL/well); [0171, 0201]); and
c4) measuring the signal generated from the reaction mixture (Weber disclose after c3, the plate was measured at 405 nm (reference wavelength 620 nm) with an ELISA reader; [0171, 0201]).
Regarding claim 4, modified Weber teach the method of claim 3 above, wherein the chromogenic substrate is CH30CO-D-cyclohexylalanine-Gly-Arg-pNA, and/or the stopping agent is acetic acid (Weber disclose after c1, pre-warmed substrate solution was added (100 µL/well) and incubated at 37 ±5˚ for 15 min; [0171, 0201]. The Technoclone pack insert defines “Substrate FXa-1 + αNAPAP; p.2, “Composition”. Weber disclose after c2, the reaction was stopped by adding 20% acetic acid (40 µL/well); [0171, 0201]).
Regarding claim 8, modified Weber teach the method of claim 1 above, wherein the capture agent does not bind the B domain of human FVIII (Weber disclose various capture agents including rabbit anti-PEG antibodies and mouse anti-polysialic acid NCAM antibodies as disclosed in examples 1, 2, 7 and 8 which do not bind the B domain of human FVIII; [0068, 0169, 0174, 0200, 0207]).
Regarding claim 9, modified Weber teach the method of claim 1 above, wherein the capture agent is an antibody, an antigen-binding fragment, an affibody, an aptamer or an affinity ligand (Weber disclose various capture agents including rabbit anti-PEG antibodies and mouse anti-polysialic acid NCAM antibodies as disclosed in examples 1, 2, 7 and 8; [0068, 0169, 0174, 0200, 0207]).
Regarding claim 10, modified Weber teach the method of claim 9, wherein the capture antibody is GMA-8024, GMA-8023,or an antigen-binding fragment or a variant thereof (Weber disclose various capture agents including an antigen-binding fragment or a variant thereof; [0068, 0169, 0174, 0200, 0207]).
Regarding claim 11, modified Weber teach the method of claim 1 above, wherein the sample comprises plasma and/or serum from a non-human animal or a laboratory animal (Weber disclose testing samples comprising plasma and/or serum from non-human animals or a laboratory animal including rat, mouse and cynomolgus monkey; [0205-0208, 0223, 0224, 0245-0247]).
Regarding claim 13, modified Weber teach the method of claim 11 above, wherein the non-human animal is sheep, goat, cynomolgus monkey, rabbit, rat, rhesus macaque, mouse, swine, hamster, minipig, or guinea pig (Weber disclose testing samples comprising plasma and/or serum from non-human animals or a laboratory animal including rat, mouse and cynomolgus monkey; [0205-0208, 0223, 0224, 0245-0247]).
Regarding claim 16, modified Weber teach the method of claim 1 above, wherein the FVIII-activity mimicking agent is an antibody, an antigen-binding fragment, a peptide, a nucleic acid, or a small molecule (The modification of the sample and method of Weber with the sample comprising emicizumab, as taught by Tripodi, has previously been discussed in claim 1 above. Emicizumab is a bispecific monoclonal antibody).
Regarding claim 17, modified Weber teach the method of claim 16 above, wherein the FVIII-activity mimicking agent is a bispecific antibody (The modification of the sample and method of Weber with the sample comprising emicizumab, as taught by Tripodi, has previously been discussed in claim 1 above. Emicizumab is a bispecific monoclonal antibody).
Regarding claim 18, modified Weber teach the method of claim 17 above, wherein the bispecific antibody is Emicizumab (The modification of the sample and method of Weber with the sample comprising emicizumab, as taught by Tripodi, has previously been discussed in claim 1 above. Emicizumab is a bispecific monoclonal antibody).
Regarding claim 19, modified Weber teach the method of claim 1 above, wherein
(1) the sample is diluted prior to step a) (Weber; [0170, 0201]),
(2) the incubation in step a) is performed for about 1 hour at room temperature (Weber disclose the samples were loaded to the plate and incubated at about 18˚C to about 26˚C for 60±10 minutes; [0171, 0201]);
(3) the incubation in step c1) is performed for about 15 min at room temperature (Weber see examples 3 and 12; [0180, 0227]);
(4) the incubation in step c2) is performed for about 25 min at room temperature; and/or
(5) the removal of unbound fraction of human FVIII in step b) is performed by washing the solid support with a washing buffer (Weber; [0179, 0201]).
Regarding claim 20, modified Weber teach the method of claim 19 above, wherein the sample is diluted by a factor of between 1:1 to about 1:100,000, between 1:2 to about 1:20,000, or about 1:10 (Weber; [0179, 0201]).
Regarding claim 23, modified Weber teach the method of claim 1 above, wherein the solid support is a flask, ELISA plate, multi-well plate, a film, a tube, a sheet, a column, or a microparticle (Weber disclose the solid support is a F96 Maxisorp plate; [0170, 0200]).
Regarding claim 29, modified Weber teach the method of claim 1 above, wherein the human FVIII is a recombinant FVIII (Weber; [0179, 0201]).
Regarding claim 30, modified Weber teach the method of claim 1 above, wherein the human FVIII is full-length FVIII, or B-domain deleted FVIII (Weber; [0179, 0201]).
Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Weber in view of Tripodi where Technoclone is used as supporting document, and further in view of Schellenberger et al. (US 2015/0158929 – hereinafter “Schellenberg”).
Regarding claim 6, modified Weber teach the method of claim 1 above, comprising the capture agent (Weber; [0068]).
Modified Weber does not explicitly teach wherein the capture agent selectively binds to the A1, A2, A3, B, C1, or C2 domain of human FVIII.
However, Schellenberg teach the analogous art of methods, assays and kits for measuring fVIII activity in a sample (Schellenberg; [0267]), wherein the capture agent selectively binds to the A1, A2, A3, B, C1, or C2 domain of human FVIII (Schellenberg; Table 10, [0267]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the capture agent of modified Weber with the capture agent that selectively binds to a desired domain of human FVIII, as taught by Schellenberg, because Schellenberg teach the Table which summarizes the binding domains allows clinicians and/or researchers to test in vitro assays with anti-factor VIII antibodies selected from an antibody having a target domain (Schellenberg; [0267]). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since modified Weber and Schellenberg both teach measuring activity of human FVIII using chromogenic assays.
Regarding claim 7, modified Weber teach the method of claim 1 above, comprising the capture agent (Weber; [0068]).
Modified Weber does not explicitly teach the capture agent selectively binds to the A2 domain of human FVIII.
However, Schellenberg teach the analogous art of methods, assays and kits for measuring fVIII activity in a sample (Schellenberg; [0267]), wherein the capture agent selectively binds to the A2 domain of human FVIII (Schellenberg; Table 10, [0267]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the capture agent of modified Weber with the capture agent that selectively binds to a desired domain of human FVIII, as taught by Schellenberg, because Schellenberg teach the Table which summarizes the binding domains allows clinicians and/or researchers to test in vitro assays with anti-factor VIII antibodies selected from an antibody having a target domain (Schellenberg; [0267]). One of ordinary skill in the art would have expected this modification could have been performed with a reasonable expectation of success since modified Weber and Schellenberg both teach measuring activity of human FVIII using chromogenic assays.
Other References Cited
The prior art of made of record and not relied upon is considered pertinent to Applicant’s disclosure include:
Christophe Nougier et al., (Emicizumab treatment: Impact on coagulation tests and biological monitoring of haemostasis according to clinical situations (BIMHO group proposals), July 15, 2020, European Journal of Haemotology, Volume 105, Issue 6, pp. 675-681 – hereinafter “Nougier”).
Aniara Diagnostic LLC ("Biophen FVIII:C technical file (#A221402) (A221406 in progress), August 2009) disclose chromogenic kit with reagents and substrates.
Gilbert (US 2019/0064159) teach methods, systems, and kits for measurement of factor VIII activity.
Citations to art
In the above citations to documents in the art, an effort has been made to specifically cite representative passages, however rejections are in reference to the entirety of each document relied upon. Other passages, not specifically cited, may apply as well.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CURTIS A THOMPSON whose telephone number is (571) 272-0648. The examiner can normally be reached on M-F: 7:00 a.m. - 5:00 p.m..
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E-mail communication Authorization
Per updated USPTO Internet usage policies, Applicant and/or applicant’s representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS Web (using PTO/SB/439) or Central Fax (571-273-8300):
Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file.
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/C.A.T./Examiner, Art Unit 1798
/JOHN MCGUIRK/Examiner, Art Unit 1798
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