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 .
DETAILED ACTION
The Amendment filed 9/8/2025 in response to Office Action of 4/7/2025, is acknowledged and has been entered. Claims 21, 47, 49, 51, 53, 55, 57 and 59-65 are now pending. Claims 49, 51, 53, and 55 are amended. Claims 59-65 are new. Claims 21,47,49,51,53,55,57 and 59-65 are currently being examined.
Maintained Rejection
(Arguments Addressed)
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.
Claim(s) 21, 22, 47, 49, 53, 55, 57, 59-61, and 63-65 are rejected under 35 U.S.C. 103 as being unpatentable over Apgar et al (WO2017029583 A2, Published 2/23/2017; of record), in view of Breinholt et al (AU2014200227 A1, Published 1/30/2014; of record) and Cardinal et al 09/2018 (A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers. J Thromb Haemost. 2018;16(9):1722-1731; of record).
Apgar teaches a method for treating hemophilia, comprising administering to a subject an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [7, 31] Apgar teaches that the antibody comprises: (i) a heavy chain comprising the amino acid of SEQ ID NO: 64 and 63, which matches 100% to the instantly claimed SEQ ID NOs: 19 and 18, respectively, and (ii) a light chain comprising the amino acid of SEQ ID NO: 36 and 37, which matches 100% to the instantly claimed SEQ ID NOs: 12 and 11, respectively. Apgar further teaches that the treatment of hemophilia with the anti-TFPI antibody, had hemostatic effects that lasted hours after administration. [289] Apgar teaches that the antibody or antigen binding fragment is administered subcutaneously. [222, 226]
Apgar teaches the method further comprises administering a clotting agent to the subject, such as factor VIIa, factor VIII, factor IX, or tranexamic acid. [233-235] Apgar teaches that this method shortens bleeding time, [31, 63, 66] Apgar teaches that the anti-TFPI antibody may be administered at dose of 1 to 100 mg once weekly. [228-230] Apgar successfully demonstrates the procoagulant activity of the anti-TFPI antibody in Example 18 using assays known in the art to measure hemostatic activity, including rotational thromboelastography (ROTEM), thrombin generation assay (TGA), and dilute prothrombin time (dPT) assays. Apgar teaches that the anti-TFPI antibody reduced clotting time and increased maximum clot firmness compared to negative controls. [Example 18, 322] Apgar teaches and demonstrates that the antibody was able to achieve at least 5% of normal activity. [0323-0327]
However, Apgar does not explicitly teach the instantly claimed dosing regimen of the antibody or antigen binding fragment that binds to TFPI, that is an initial dose of 300 mg, followed by subsequent weekly doses of 150 mg, or administered once a weekly at a doe of 300 mg.
Breinholt teaches a method for treating hemophilia, comprising administering to a subject an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [pgs 2, 11, 18 (last paragraph), and 49] Breinholt teaches that the antibody or antigen binding fragment is administered subcutaneously. [pg 46] Breinholt teaches that the antibody or antigen binding fragment may be administered as a single dose or multiple doses, where the doses may be reduced based on the therapeutic situation. [pg 47, third and fourth paragraphs] Breinholt teaches that the dose may be administered weekly, and may also be administered with an additional therapeutic agent, such as a clotting agent. Breinholt teaches that that this may be administered with Factor VIIa or Factor VIII. [pg 48] Breinholt further teaches that this method significantly reduces bleeding loss and time. [pg 49]
Cardinal teaches a method for treating hemophilia, comprising administering to a subject PF-06741086, an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [pg 1723] Cardinal teaches that this antibody may be administered subcutaneously, at a dose of 300 mg. Cardinal teaches that the 300 mg administered subcutaneously demonstrated a procoagulant pharmacological effect, and that this dose had a near-maximum effect, and duration of at least 168 hours. Cardinal teaches that the results provide a rationale for testing a once-weekly subcutaneous treatment regimen of PF06741086 in individuals with severe hemophilia A or B. [pg 1729]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat subjects with the dosing regimen of the antibody or antigen binding fragment that binds to TFPI, that is an initial dose of 300 mg, followed by subsequent weekly doses of 150 mg, or a flat dose of 300 mg once weekly, in the method of Apgar. One would have been motivated to because: (1) Apgar, Cardinal, and Breinholt all specifically teach treating hemophilia comprising administering an antibody that binds to TFPI, (2) Cardinal teaches administering an anti-TFPI antibody at a dose of 300 mg, and (3) Breinholt teaches that an initial dose given may be higher than the subsequent doses, wherein the subsequent doses are given on a weekly basis. One would have had are reasonable expectation of success, because: (1) the cited art successfully demonstrates treating hemophilia comprising administering an antibody that binds to an epitope in K2 of TFPI, and (2) Cardinal teaches that the 300 mg dose demonstrated a near-maximum effect and that this dose provided rationale for weekly subcutaneous treatment. The cited art recognizes the need in the art to treat hemophilia with an antibody that binds to TFPI. Given the recognized need to treat hemophilia, given the known function of an antibody or antigen binding fragment that binds to TFPI, the known successes demonstrated by the prior art, and the known methods of repeated administration, one of skill in the art could have pursued administering the antibody at the instantly claimed dosing regimens in the method of Apgar, with a reasonable expectation of success.
Response to Arguments
Applicants argue that none of the references teach administering a 300 mg loading dose of the claimed antibody followed by administration of a subsequent weekly dose of 150 mg of the antibody to treat hemophilia to establish a prima facie case of obviousness. Applicant argues that the initial dosing dose is surprising and unexpected and not taught by the prior art. Applicant submits a declaration by Satyaprakash Nayak stating that the clinical development of marsatacimab was the identification of a dosing regimen that was both safe and effective as well as convenient for patients, provided a reduced risk of dosing errors and was cost effective. The Applicants also argue that through analysis of PD and PK, that the loading dose of 300 mg followed by 150 mg maintains peak thrombin within normal physiologic range based on observed data in healthy participants and maintains steady-state trough concentrations in the target range over the entire dosing interval.
Applicant’s arguments have been considered but are not persuasive. With regards to surprising and the unexpected results, the MPEP states:
716.02(c) Weighing Evidence of Expected and Unexpected Results [R-08.2012]
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I. EVIDENCE OF UNEXPECTED AND EXPECTED PROPERTIES MUST BE WEIGHED
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Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (Claims directed to a method of effecting analgesia without producing physical dependence by administering the levo isomer of a compound having a certain chemical structure were rejected as obvious over the prior art. Evidence that the compound was unexpectedly nonaddictive was sufficient to overcome the obviousness rejection. Although the compound also had the expected result of potent analgesia, there was evidence of record showing that the goal of research in this area was to produce an analgesic compound which was nonaddictive, enhancing the evidentiary value of the showing of nonaddictiveness as an indicia of nonobviousness.). See MPEP § 716.01(d) for guidance on weighing evidence submitted to traverse a rejection.
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Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) (Claims were directed to a display/memory device which was prima facie obvious over the prior art. The court found that a higher memory margin and lower operating voltage would have been expected properties of the claimed device, and that a higher memory margin appears to be the most significant improvement for a memory device. Although applicant presented evidence of unexpected properties with regard to lower peak discharge current and higher luminous efficiency, these properties were not shown to have a significance equal to or greater than that of the expected higher memory margin and lower operating voltage. The court held the evidence of nonobviousness was not sufficient to rebut the evidence of obviousness.); In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (Evidence of improved feed efficiency in steers was not sufficient to rebut prima facie case of obviousness based on prior art which specifically taught the use of compound X537A to enhance weight gain in animals because the evidence did not show that a significant aspect of the claimed invention would have been unexpected.).
Thus, the Applicants arguments about the antibody’s surprising effect of loading dose and maintenance dose of the claimed antibody is known and taught in in the art.
First, the cited combination of references establishes motivation and reasonable expectation of success to administer the antibody that binds to K2 of TFPI to at dose of 300 mg followed by 150 mg weekly to treat hemophilia. (1) Apgar teaches a method for treating hemophilia comprising administering the instantly claimed antibody, and that this antibody is administered once weekly, (2) Breinholt teaches a method of treating hemophilia comprising administering an antibody that binds to an epitope Kunitz Domain 2 (K2) of (TFPI), wherein it is administered in a single dose or multiple doses, and doses can be reduced based on the specific therapeutic situation, and that the method reduces bleeding loss and time, and (3) Cardinal teaches a method of treating hemophilia comprising administering an antibody that binds to an epitope Kunitz Domain 2 (K2) of (TFPI) and can be administered at a dose of 300 mg, and specifically teaches that at this dose, this had a near-maximum effect, that lasted 168 hours, and specifically states that this provided a rationale for once weekly treatment in patients with severe hemophilia.
Claim(s) 51 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Apgar et al (WO2017029583 A2, published 2/23/2017), Breinholt et al (AU2014200227 A1, published 1/30/2014) and Cardinal et al 09/2018 (A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers. J Thromb Haemost. 2018;16(9):1722-1731) (combined references), as applied to claims 21, 22, 47, 49, 51, 53, 55, and 57 above, and further in view of Chowdary et al. (Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13(5):743-754) and Korte et al. (The Potential Close Future of Hemophilia Treatment - Gene Therapy, TFPI Inhibition, Antithrombin Silencing, and Mimicking Factor VIII with an Engineered Antibody. Transfus Med Hemother. 2018;45(2):92-96)
The combined references teachings are recited above.
However, they do not explicitly teach that the administration of the antibody or antigen binding fragment provides a reduction of at least 20% in annualized bleeding rate (ABR).
Chowdary teaches a method of treating hemophilia, comprising administering an antibody, concizumab, which binds to K2 domain of TFPI. Chowdary teaches that TFPI is a potent inhibitor of the initiation pathway, which inhibits tissue factor-activated FVII. Chowdary teaches that the binding site of the antibody prevents binding of Factor Xa to TFPI, and prevents inhibition of the TF-FViia complex. This results in enhanced Factor Xa and thrombin generation. [pg 744] Chowdary teaches that the fibrinogen level percentage change in patients with hemophilia was a 50% decrease in the first 10 days. [pg 747, 2nd column] Chowdary further demonstrates that that no significant bleeding events occurred. [pg. 750]
Korte teaches the role of TFPI in controlling tissue factor associated with procoagulant response. Korte teaches that TFPI inhibits tissue factor activated factor VIIa and Factor Xa, and inhibiting TFPIs shortens bleeding time in hemophilia. Korte further teaches that inhibition of TFPI can be achieved through specific antibodies. [pg 93, 1st paragraph] Korte teaches that antibodies to TFPI are known to shorten clotting times and enhance the generation of FXa and thrombin. Korte teaches that two known anti-TFPI antibodies, concizumab and PF-06741086, augment the effects of thrombin and restore hemostasis [pg 92, antibodies to TFPI]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention to administer the antibody of Apgar to provide a reduction of at least 20% in ABR. One would have been motivated to, and have a reasonable expectation of success, because: (1) the cited art recited above teach the known method of treating hemophilia comprising administering an antibody that binds to TFPI, (2) the combined references teach that the antibody significantly reduce bleeding loss and time, (3) Chowdary teaches that TFPI prevents binding to factors and increased in fibrinogen level was decreased in patients who received the antibody, and that no significant bleeding events occurred, and (4) Korte teaches the procoagulant effects of TFPI in the role of inhibiting factor VIIa and Factor Xa, which shortens bleeding events and time. Given the recognized need to treat hemophilia, given the known function of antibody or antigen binding fragment that binds to TFPI on the effect of reducing bleeding events and rates, and the known successes demonstrated by the prior art, one of skill in the art could have pursued administering the antibody with the expectation of reducing annualized bleeding rates by 20%, with a reasonable expectation of success.
Response to Arguments
Applicant argues that that dependent claim 51 further recites “administration of the antibody or antigen-binding fragment thereof provides a reduction of at least 20% in annualized bleeding rate (ABR) as compared to ABR observed in subjects that have coagulation disorders. Applicant argues that the cited art does not render claim 51 obvious. Applicant argues that Chowdary did not evaluate bleeding rate in their study, and that nothing in the teachings of Chowdary, or in combination with the cited prior art, teach or suggest that the dosing regimen results in a reduction of ABR as stated in claim 51. Applicant states that Kort is silent to ABR and does not provide or mention bleeding rate.
Applicant’s arguments have been considered but are not persuasive. As shown above and stated in previous office action, the combined references, render the method of claim 21 as obvious, however, they do not explicitly teach the outcome of claim 51, that is, the reduction in annualized bleeding rate by at least 20%.
To reiterate the teachings of the prior art, Chowdary teaches a method of treating hemophilia, comprising administering an antibody, concizumab, which binds to K2 domain of TFPI. Chowdary teaches the mechanism of action of TFPI and the mechanism of action of the antibody. The binding site of the antibody prevents binding of Factor Xa to TFPI and prevents inhibition of the TF-FViia complex, which allows for enhanced Factor Xa and thrombin generation. is a potent inhibitor of the initiation pathway, which inhibits tissue factor-activated FVII. This results in decreased bleeding as demonstrated by fibrinogen level decrease when a patient is administered the antibody. The purpose of Korte is to demonstrate the role of TFPI, and Korte explicitly states that inhibiting TFPI via antibodies will shorten bleeding time in hemophilia. As demonstrated above in section (7) Examiner has established: (1) there is a recognized need to treat hemophilia comprising administering the instantly claimed antibody or antigen binding fragment that binds to Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI), (2) the cited art recognizes that administering this antibody or antigen binding fragment on a weekly basis, that includes 300 mg followed by lowered dose in subsequent weeks, and (3) one of ordinary skill in the art could have pursued administering 300 mg of the instantly claimed antibody followed by 150 mg once weekly to treat hemophilia with a reasonable expectation of success. Although, the prior art does not explicitly show 20% ABR reduction, the result of the claimed method (reduction in ABR) is inherent to the method as suggested by the prior art, and that the cited art does not need to be recognized by the art. [see MPEP 2112]
Therefore, the cited prior art provides motivation and a reasonable expectation of success rendering claims 51 and 62 obvious.
Double Patenting
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21, 22, 47, 49, 53, 55, 57, 59-61, and 63-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. US 10,550,200 B2 in view of Apgar et al (WO2017029583 A2, published 2/23/2017) and Breinholt et al (AU2014200227 A1, Published 1/30/2014), Cardinal et al 09/2018 (A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers. J Thromb Haemost. 2018;16(9):1722-1731), Chowdary et al. (Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13(5):743-754) and Korte et al. (The Potential Close Future of Hemophilia Treatment - Gene Therapy, TFPI Inhibition, Antithrombin Silencing, and Mimicking Factor VIII with an Engineered Antibody. Transfus Med Hemother. 2018;45(2):92-96).
The U.S Patent claims an antibody or antigen-binding fragment that binds to an epitope in Kunitz Domain 2 (KT) of Tissue Pathway Factor Inhibitor (TFPI), wherein the antibody comprises: (i) a heavy chain comprising the amino acid of SEQ ID NO: 64 and 63, which matches 100% to the instantly claimed SEQ ID NOs: 19 and 18, respectively, and (ii) a light chain comprising the amino acid of SEQ ID NO: 36 and 37, which matches 100% to the instantly claimed SEQ ID NOs: 12 and 11, respectively. The U.S. Patent claims that the antibody decreases clotting time in a plasma that is deficient in Factor VIII or Factor IX.
However, the U.S. Patent does not recite: (1) the method of treating hemophilia comprising the instantly claimed TFPI antibody at the instantly claimed dosing regimen, (2) administering the antibody with a clotting agent, and (3) administration of the antibody or antigen binding fragment provides a reduction of at least 20% in annualized bleeding rate (ABR).
Apgar teaches a method for treating hemophilia, comprising administering to a subject an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [7, 31] Apgar teaches that the antibody comprises: (i) a heavy chain comprising the amino acid of SEQ ID NO: 64 and 63, which matches 100% to the instantly claimed SEQ ID NOs: 19 and 18, respectively, and (ii) a light chain comprising the amino acid of SEQ ID NO: 36 and 37, which matches 100% to the instantly claimed SEQ ID NOs: 12 and 11, respectively. Apgar teaches the method further comprises administering a clotting agent to the subject, such as factor VIIa, factor VIII, factor IX, or tranexamic acid. [233-235] Apgar teaches that this method shortens bleeding time, [31, 63, 66] Apgar further teaches that the treatment of hemophilia with the anti-TFPI antibody, had hemostatic effects that lasted hours after administration. [289] Apgar teaches that the antibody or antigen binding fragment is administered subcutaneously. [222, 226] Apgar teaches that the anti-TFPI antibody may be administered at dose of 1 to 100 mg once weekly. [228-230] Apgar successfully demonstrates the procoagulant activity of the anti-TFPI antibody in Example 18 using assays known in the art to measure hemostatic activity, including rotational thromboelastography (ROTEM), thrombin generation assay (TGA), and dilute prothrombin time (dPT) assays. Apgar teaches that the anti-TFPI antibody reduced clotting time and increased maximum clot firmness compared to negative controls. [Example 18, 322] Apgar teaches and demonstrates that the antibody was able to achieve at least 5% of normal activity. [0323-0327]
Breinholt teaches a method for treating hemophilia, comprising administering to a subject an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [pgs 2, 11, 18 (last paragraph), and 49] Breinholt teaches that the antibody or antigen binding fragment is administered subcutaneously. [pg 46] Breinholt teaches that the antibody or antigen binding fragment may be administered as a single dose or multiple doses, where the doses may be reduced based on the therapeutic situation. [pg 47, third and fourth paragraphs] Breinholt teaches that the dose may be administered weekly, and may also be administered with an additional therapeutic agent, such as a clotting agent. Breinholt teaches that that this may be administered with Factor VIIa or Factor VIII. [pg 48] Breinholt further teaches that this method significantly reduces bleeding loss and time. [pg 49]
Cardinal teaches a method for treating hemophilia, comprising administering to a subject PF-06741086, an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [pg 1723] Cardinal teaches that this antibody may be administered subcutaneously, at a dose of 300 mg. Cardinal teaches that the 300 mg administered subcutaneously demonstrated a procoagulant pharmacological effect, and that this dose had a near-maximum effect, and duration of at least 168 hours. Cardinal teaches that the results provide a rationale for testing a once-weekly subcutaneous treatment regimen of PF06741086 in individuals with severe hemophilia A or B. [pg 1729]
Chowdary teaches a method of treating hemophilia, comprising administering an antibody, concizumab, which binds to K2 domain of TFPI. Chowdary teaches that TFPI is a potent inhibitor of the initiation pathway, which inhibits tissue factor-activated FVII. Chowdary teaches that the binding site of the antibody prevents binding of Factor Xa to TFPI, and prevents inhibition of the TF-FViia complex. This results in enhanced Factor Xa and thrombin generation. [pg 744] Chowdary teaches that the fibrinogen level percentage change in patients with hemophilia was a 50% decrease in the first 10 days. [pg 747, 2nd column] Chowdary further demonstrates that that no significant bleeding events occurred. [pg. 750]
Korte teaches the role of TFPI in controlling tissue factor associated with procoagulant response. Korte teaches that TFPI inhibits tissue factor activated factor VIIa and Factor Xa, and inhibiting TFPIs shortens bleeding time in hemophilia. Korte further teaches that inhibition of TFPI can be achieved through specific antibodies. [pg 93, 1st paragraph] Korte teaches that antibodies to TFPI are known to shorten clotting times and enhance the generation of FXa and thrombin. Korte teaches that two known anti-TFPI antibodies, concizumab and PF-06741086, augment the effects of thrombin and restore hemostasis [pg 92, antibodies to TFPI]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat hemophilia comprising the antibody of the U.S. Patent and at the instantly claimed dosing regimen of antibody or antigen binding fragment that binds to TFPI, that is an initial dose of 300 mg, followed by subsequent weekly doses of 150 mg. One would have been motivated to because: (1) the U.S. Patent recites the instantly claimed antibody as binding to an epitope in K2 of TFPI, and recites it is comprised in a pharmaceutical composition indicating pharmaceutical use, (2) Apgar specifically teaches treating hemophilia comprising administering the instantly claimed antibody that binds to TFPI, (3) Cardinal and Breinholt specifically teach treating hemophilia comprising administering an antibody subcutaneously that binds to K2 of TFPI, (4) Cardinal teaches administering an antibody or antigen binding fragment that binds to TFPI, antibody at a dose of 300 mg, and (5) Breinholt teaches that the an initial dose given may be higher than the subsequent doses, wherein the subsequent doses are given on a weekly basis. One would have had are reasonable expectation of success, to because: (1) the cited art (Apgar, Cardinal, and Breinholt) successfully demonstrate treating hemophilia comprising administering an antibody that binds to an epitope in K2 of TFPI, and (2) Cardinal teaches that the 300 mg dose demonstrated a near-maximum effect and that this dose provided rationale for weekly subcutaneous treatment. The cited art recognizes the need in the art to treat hemophilia with an antibody or antigen binding fragment that binds to TFPI. Given the recognized need to treat hemophilia, given the known function of an antibody that binds to TFPI, the known successes demonstrated by the prior art, and the known methods of repeated administration, one of skill in the art could have pursued administering the antibody at an initial dose of 300 mg, followed by 150 mg weekly doses, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat hemophilia comprising the antibody of the U.S. Patent and a clotting agent. One would have been motivated to, and have a reasonable expectation of success, because: (1) the U.S. Patent recites the instantly claimed is comprised in a pharmaceutical composition indicating pharmaceutical use, (2) Apgar teaches the method of treating hemophilia comprises administering the instantly claimed antibody that binds to TFPI and a clotting agent to the subject, such as factor VIIa, factor VIII, factor IX, or tranexamic acid, (3) Cardinal and Breinholt successfully demonstrate treating hemophilia comprising administering an antibody that binds to an epitope in K2 of TFPI, and (4) Breinholt teaches that that this may be administered with clotting agents, such as Factor VIIa or Factor VII, and that this method significantly reduces bleeding loss and time.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention to administer the antibody of the U.S. Patent to provide a reduction of at least 20% in ABR. One would have been motivated to, and have a reasonable expectation of success, because: (1) the U.S. Patent recites the instantly claimed is comprised in a pharmaceutical composition indicating pharmaceutical use, (2) the cited art recited above teach the known method of treating hemophilia comprising administering an antibody that binds to TFPI and teach that the antibody significantly reduce bleeding loss and time, (3) Chowdary teaches that TFPI prevents binding to factors and increased in fibrinogen level was decreased in patients who received the antibody, and that no significant bleeding events occurred, and (4) Korte teaches the procoagulant effects of TFPI in the role of inhibiting factor VIIa and Factor Xa, which shortens bleeding events and time. Given the recognized need to treat hemophilia, given the known function of antibody or antigen binding fragment that binds to TFPI on the effect of reducing bleeding events and rates, and the known successes demonstrated by the prior art, one of skill in the art could have pursued administering the antibody with the expectation of reducing annualized bleeding rates by 20%, with a reasonable expectation of success.
Claims 21, 22, 47, 49, 53, 55, 57, 59-61, and 63-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. US 10,875,929 B2 in view of Breinholt et al (AU2014200227 A1, Published 1/30/2014), Cardinal et al 09/2018 (A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers. J Thromb Haemost. 2018;16(9):1722-1731), Chowdary et al. (Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13(5):743-754) and Korte et al. (The Potential Close Future of Hemophilia Treatment - Gene Therapy, TFPI Inhibition, Antithrombin Silencing, and Mimicking Factor VIII with an Engineered Antibody. Transfus Med Hemother. 2018;45(2):92-96).
The U.S Patent claims a method of reducing activity of TFPI comprising administering an antibody or antigen-binding fragment that binds to an epitope in Kunitz Domain 2 (KT) of Tissue Pathway Factor Inhibitor (TFPI), wherein the antibody comprises: (i) a heavy chain comprising the amino acid of SEQ ID NO: 64 and 63, which matches 100% to the instantly claimed SEQ ID NOs: 19 and 18, respectively, and (ii) a light chain comprising the amino acid of SEQ ID NO: 36 and 37, which matches 100% to the instantly claimed SEQ ID NOs: 12 and 11, respectively. The U.S. Patent claims treating a subject that suffers from hemophilia A, and further administering a clotting agent.
However, the U.S. Patent does not recite: (1) the instantly claimed antibody dosing regimen, and (2) administration of the antibody or antigen binding fragment provides a reduction of at least 20% in annualized bleeding rate (ABR).
Breinholt teaches a method for treating hemophilia, comprising administering to a subject an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [pgs 2, 11, 18 (last paragraph), and 49] Breinholt teaches that the antibody or antigen binding fragment is administered subcutaneously. [pg 46] Breinholt teaches that the antibody or antigen binding fragment may be administered as a single dose or multiple doses, where the doses may be reduced based on the therapeutic situation. [pg 47, third and fourth paragraphs] Breinholt teaches that the dose may be administered weekly, and may also be administered with an additional therapeutic agent, such as a clotting agent. Breinholt teaches that that this may be administered with Factor VIIa or Factor VIII. [pg 48] Breinholt further teaches that this method significantly reduces bleeding loss and time. [pg 49]
Cardinal teaches a method for treating hemophilia, comprising administering to a subject PF-06741086, an antibody or antigen binding fragment that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI). [pg 1723] Cardinal teaches that this antibody may be administered subcutaneously, at a dose of 300 mg. Cardinal teaches that the 300 mg administered subcutaneously demonstrated a procoagulant pharmacological effect, and that this dose had a near-maximum effect, and duration of at least 168 hours. Cardinal teaches that the results provide a rationale for testing a once-weekly subcutaneous treatment regimen of PF06741086 in individuals with severe hemophilia A or B. [pg 1729]
Chowdary teaches a method of treating hemophilia, comprising administering an antibody, concizumab, which binds to K2 domain of TFPI. Chowdary teaches that TFPI is a potent inhibitor of the initiation pathway, which inhibits tissue factor-activated FVII. Chowdary teaches that the binding site of the antibody prevents binding of Factor Xa to TFPI, and prevents inhibition of the TF-FViia complex. This results in enhanced Factor Xa and thrombin generation. [pg 744] Chowdary teaches that the fibrinogen level percentage change in patients with hemophilia was a 50% decrease in the first 10 days. [pg 747, 2nd column] Chowdary further demonstrates that that no significant bleeding events occurred. [pg. 750]
Korte teaches the role of TFPI in controlling tissue factor associated with procoagulant response. Korte teaches that TFPI inhibits tissue factor activated factor VIIa and Factor Xa, and inhibiting TFPIs shortens bleeding time in hemophilia. Korte further teaches that inhibition of TFPI can be achieved through specific antibodies. [pg 93, 1st paragraph] Korte teaches that antibodies to TFPI are known to shorten clotting times and enhance the generation of FXa and thrombin. Korte teaches that two known anti-TFPI antibodies, concizumab and PF-06741086, augment the effects of thrombin and restore hemostasis [pg 92, antibodies to TFPI]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat hemophilia comprising the antibody of the U.S. Patent at the instantly claimed dosing regimen of antibody or antigen binding fragment that binds to TFPI, that is an initial dose of 300 mg, followed by subsequent weekly doses of 150 mg. One would have been motivated to because(1) the U.S. Patent recites a method of treating hemophilia at the instantly claimed TFPI antibody , (2) Cardinal and Breinholt specifically teach treating hemophilia comprising administering an antibody subcutaneously that binds to K2 of TFPI, (3) Cardinal teaches administering an antibody or antigen binding fragment that binds to TFPI, antibody at a dose of 300 mg, and (4) Breinholt teaches that the an initial dose given may be higher than the subsequent doses, wherein the subsequent doses are given on a weekly basis. One would have had are reasonable expectation of success, to because: (1) Cardinal and Breinholt successfully demonstrate treating hemophilia comprising administering an antibody that binds to an epitope in K2 of TFPI, and (2) Cardinal teaches that the 300 mg dose demonstrated a near-maximum effect and that this dose provided rationale for weekly subcutaneous treatment, and The cited art recognizes the need in the art to treat hemophilia with an antibody or antigen binding fragment that binds to TFPI. Given the recognized need to treat hemophilia, given the known function of an antibody that binds to TFPI, the known successes demonstrated by the prior art, and the known methods of repeated administration, one of skill in the art could have pursued administering the antibody at an initial dose of 300 mg, followed by 150 mg weekly doses, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention to administer the antibody of the U.S. Patent to provide a reduction of at least 20% in ABR. One would have been motivated to, and have a reasonable expectation of success, because: (1) he U.S. Patent recites a method of treating hemophilia at the instantly claimed TFPI antibody, (2) the cited art recited above teach the known method of treating hemophilia comprising administering an antibody that binds to TFPI and teach that the antibody significantly reduce bleeding loss and time, (3) Chowdary teaches that TFPI prevents binding to factors and increased in fibrinogen level was decreased in patients who received the antibody, and that no significant bleeding events occurred, and (4) Korte teaches the procoagulant effects of TFPI in the role of inhibiting factor VIIa and Factor Xa, which shortens bleeding events and time. Given the recognized need to treat hemophilia, given the known function of antibody or antigen binding fragment that binds to TFPI on the effect of reducing bleeding events and rates, and the known successes demonstrated by the prior art, one of skill in the art could have pursued administering the antibody with the expectation of reducing annualized bleeding rates by 20%, with a reasonable expectation of success.
Response to Arguments
Applicants reiterate the arguments in 103 above.
Applicant’s arguments have been addressed in response to arguments noted above.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/SARAH A ALSOMAIRY/ Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600