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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/08/2025 has been entered.
Response to Amendment
Applicant’s remarks and amendments to the claims filed 12/08/2025 have been acknowledged. Claim 14 has been amended. Claims 24 and 25 have been canceled. Claims 26-27 are newly added.
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.
Claims 14-17, 21, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Calatzis et al (WO2016166014A1, of record), hereinafter Calatzis, in view of Wang et al (Wang, M., et al. "PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding." Haemophilia 23.6 (2017): 832-843), hereinafter Wang, and Muto et al (Muto, A., et al. "Anti‐factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation." Journal of Thrombosis and Haemostasis 12.2 (2014): 206-213.), hereinafter Muto, as evidenced by Kobayahsi (Kobayashi, Ken. Journal of mammary gland biology and neoplasia vol. 28,1 8. 1 May. 2023, doi:10.1007/s10911-023-09536-y, of record) and Igawa et al (US20200270363A1, of record), hereinafter Igawa.
Calatzis teaches methods of preventing and/or treating bleeding and bleeding disorders such as hemophilia A with or without inhibitors in a subject comprising administering a pharmaceutical composition (referred to as a medicament) containing a combination of a multi-specific anti-FIX/FX antibody and the coagulation factors FIX, FII, FVII and FX (see entire document, in particular, Abstract, Summary of Invention, Pages 8-11; Page 10, Ln. 19-33 to Page 11, Ln. 1-4; Page 11, Ln. 12-23; Page 51, Ln. 13-19; Page 66, Ln. 26-31 to Page 67; Claims 1, 13, 15, 16, and 18). The term "coagulation factor VII" is defined as any form of factor VII molecule with the typical characteristics of blood coagulation factor VII such as eptacog alfa (Page 46, Ln. 1-8), a recombinant factor VIIa produced in baby hamster kidney (BHK) cells. The multi-specific anti-FIX/FX antibody can be Q499-zl21/J327-zl 19/L404-k (Page 12, Ln. 3-7), also known as ACE910 (or Emicizumab) (see Para. 0040 of Igawa). The combination of an anti-FIX/FX bispecific antibody with coagulation factors FIX, FX and/or FII can also be beneficial in other situations which require a procoagulant treatment, including bleeding complications unrelated to a FVIII deficiency (Page 14, Ln. 16-20). Given that single factor deficiencies are typically treated with the application of the respective factor (e.g. FVIII concentrates in hemophilia A, FIX concentrates in hemophilia B, and FVII concentrate in FVII deficiency) (Page 3, Ln. 29-31), the methods of Calatzis can also be used to treat FIX and FVII deficiency.
Calatzis does not specifically teach that the factor VII is a transgenic factor VII derived from production by epithelial cells of the mammary glands of a transgenic non-human animal such as rabbit.
However, Wang teaches that eptacog beta, an activated human recombinant factor VII such produced in the milk of transgenic rabbits, can be used as a bypass agent to treat bleeding episodes in patients suffering from hemophilia A or B with inhibitors (see entire document, in particular, Abstract, Introduction, and Section: 2.5: Safety assessment). [Note: Mammary epithelial cells are the only cell type that produce milk during lactation (see Kobayashi, in particular, Abstract); thus, eptacog beta is necessarily produced by the mammary epithelial cells of transgenic rabbits]. Eptacog beta consistently achieves a clinically important effect on blood clotting at lower doses than typically reported for its predecessor eptacog alfa across in vitro, ex vivo, preclinical and human pharmacokinetic studies (3rd paragraph of Discussion). In the Persept I, phase 3 trial, the initial dose regimens of eptacog beta (75 ug/kg and 225 ug/kg) demonstrated a sustained, dose-dependent hemostatic efficacy in mild and moderate bleeding episodes in hemophilia patients with inhibitors (see Abstract and Part 5: Conclusions).
Muto further teaches that a single intravenous administration of 1 or 3 mg/kg ACE910 ameliorated bleeding symptoms to an extent equivalent to that achieved with twice‐daily doses of 10 U kg−1 recombinant FVIII (rpoFVIII) (Abstract and 2nd paragraph of Discussion).
It would have been obvious to one of ordinary skill in the art to modify the method of treating a bleeding disorder in a subject taught by Calatzis such that 1) recombinant FVII eptacog alfa is substituted with eptacog beta, 2) eptacog beta is administered at a dose of 2.7 to 270 ug/kg; and 3) Emicizumab (ACE910) is administered at a dose of 0.3 to 5 mg/kg. One of ordinary skill in the art would have been motivated to do so since eptacog beta achieves a clinically important effect on blood clotting at lower doses than eptacog alfa and demonstrates sustained, dose-dependent hemostatic efficacy in mild and moderate bleeding episodes in hemophilia patients with inhibitors at initial doses of 75 ug/kg and 225 ug/kg as taught by Wang. Of note, eptacog beta and eptacog alfa have the same function and can be used for the same purpose; therefore, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982). Further, Emicizumab (ACE910) administered at a dose of 1-3 mg/kg can effectively ameliorate bleeding episodes to an extent equivalent to that achieved with twice‐daily doses of recombinant FVIII as taught by Muto. Lastly, given that single factor deficiencies are typically treated with the application of the respective factor (e.g. FVIII concentrates in hemophilia A, FIX concentrates in hemophilia B, and FVII concentrate in FVII deficiency) as taught by Calatzis, the methods disclosed therein can also be used to treat FIX and FVII deficiency in a subject. Therefore, artisans would reasonably expect that a combination of the multi-specific anti-FIX/FX antibody Emicizumab at a dose of 1-3 mg/kg and the coagulation factors FIX, FX, FII, and FVII (e.g. eptacog beta, 75 or 225 ug/kg) can effectively treat a bleeding disorder such as hemophilia A (with or without inhibitors), FVII deficiency, or FIX deficiency in a subject.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Calatzis in view of Wang and Muto as evidenced by Kobayashi and Igawa, as applied to claims 14-17, 21, and 26-27 above, in view of Peters et al (WO2018098363A2, of record), hereinafter Peters.
The teachings of Calatzis in view of Wang and Muto as evidenced by Kobayashi and Igawa have been discussed above but differ from the instantly claimed invention in that it is not specifically taught that the combination of bispecific anti-FIX/FX antibody and coagulation factors including FVII is administered sequentially or simultaneously.
However, Peters teaches that bispecific anti-FIX/FX antibodies can be administered with an additional medicament or therapeutic agent before, during, or after administration of the antibodies for the treatment of coagulation or bleeding disorder such as hemophilia A, wherein the additional medicament or therapeutic agent is used routinely in the treatment of coagulation/bleeding disorders such as clotting factors/factor concentrate replacement therapy. For example, the additional medicament or therapeutic agent and the bispecific anti-FIX/X antibodies can be administered concurrently or within an interval of each other (or separately). In some embodiments, the administrations of the agents are spaced sufficiently close together such as combinatorial (e.g. synergistic) effect is achieved. The combination can also include more than one additional agent (see entire document, in particular, Para. 0300, Para. 0405, Para. 0767-0769, and Para. 0797-0799).
It would have been obvious to one of ordinary skill in the art to administer a pharmaceutical composition comprising a combination of bispecific anti-FIX/FX antibodies and coagulation factors including FVII to a subject either sequentially or simultaneously. One of ordinary skill in the art would have been motivated to do so in order to treat a bleeding disorder such as hemophilia A in a subject. Further, when the agents are administered sufficiently close together a combinatorial (e.g. synergistic) therapeutic effect can be achieved. Therefore, one of ordinary skill in the art would reasonably expect that the administration a pharmaceutical composition comprising a combination of bispecific anti-FIX/FX antibodies and coagulation factors including FVII to a subject either sequentially or simultaneously can effectively treat a bleeding disorder such as hemophilia A in a subject.
Response to Arguments
Applicant's arguments filed 12/08/2025 have been fully considered but they are not persuasive.
With respect to the rejection made under 35 USC 103, Applicant first argues that the Office’s interpretation on the scope of the unexpected results in the specification—the alleged synergy in the drug combination of Helimbra® (Emicizumab) and Sevenfact® (eptacog beta)— is unduly narrow and overly restrictive in view of In re Chupp (MPEP 2145). Further, Applicant disagrees that the specific doses and administration routes in the test data would be essential for synergy, stating that it is improper to make inferences regarding the synergy of the claimed drug combination based on evidenced that tramadol/acetaminophen combination exhibits synergy under specific conditions since these are unrelated drugs of different structure and medical use. Nevertheless, Applicant contends that claim 14 as amended to recite “wherein the multispecific antibody is Emicizumab” is sufficiently commensurate in scope with the unexpected results in the present application, noting that the transgenic factor VII is already narrowly defined via the clause “wherein the transgenic factor VII is a human factor VII derived from production by epithelial cells of the mammary glands of a transgenic rabbit”.
Second, Applicant argues that a person of ordinary skill in the art would not know how ex vivo “molar potency” or “differences in glycosylation and binding to cellular sites” of eptacog beta described by Ducore would translate to the in vivo context of treating hemophilia in a patient in combination with multispecific anti-FIX/FX antibody. Applicant further notes that Ducore states there exists “an absences of validated pharmacodynamic markers to predict clinical efficacy” and “without clinically validated PD markers to predict bypassing agent efficacy in bleeding hemophilia subjects with inhibitors, a subsequent Phase 3 study was initiation”.
In view of the above, Applicant contends that Kobayashi, Igawa, and Peters fail to cure the deficiencies of Calatzis and Ducore.
With respect to Applicant’s first argument, the Examiner notes that In re Chupp demonstrated unexpected superiority of the claimed herbicide relative to the closest prior art compound. In Chupp, the Applicant provided comparative data showing that the claimed herbicide was more effective than the closest prior art compound in controlling specific weeds in certain crops. In the present case, the drug combination Hemlibra® (Emicizumab: 300 nM) and SevenFact® (eptacog beta: 20, 40, or 100 nM) yielded a synergistic effect on thrombin generation relative to the predicted additive effect (Examples 4 and 5 of the instant specification). Previously, Hartmann et al demonstrated that a sequence-identical analog of Emicizumab combined with recombinant FVIIa [rFVIIa is defined as eptacog alfa (activated), 3rd para. of Introduction; thus, the rVIIa used in the study is likely eptacog alfa] in vitro produced only an additive effect in thrombin generation (Hartmann, R., et al. "In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents." Journal of Thrombosis and Haemostasis 16.8 (2018): 1580-1591). However, Applicant has not provided comparative data demonstrating that the claimed combination is unexpectedly superior to the prior art combination of Emicizumab and eptacog alfa under substantially the same test conditions. A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements regarding unusually low immune response or unexpected biological activity that were unsupported by comparative data held insufficient to overcome prima facie case of obviousness) (emphasis added) (MPEP 2145).
Further, while evidence of unexpected results for a single species or narrow portion of a claimed range may, in some circumstances, support broader claims, such evidence must demonstrate a discernible trend that would allow a skilled artisan to reasonably extend the probative value of the results across the full scope of the claims ( In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (MPEP 2145). No such trend has been established here to support the broad scope of independent claims 14 and 27 (and dependent claim 26), including the specific ranges recited in claims 26 and 27, as the alleged synergistic effect is shown only at a single Hemlibra® (Emicizumab) concentration (600 nM) across limited SevenFact® (eptacog beta) doses (20 nM, 40 nM, and 100 nM) not presently recited in the claims.
The independent claims, as presently written, broadly recite a method of treating hemophilia or preventing bleeding in a patient with FVII, FVIII, or FIX deficiency comprising administering Emicizumab with a transgenic human FVII agent, without further limitation as to the particular dose of each agent, mode or sequence of administration (simultaneous vs sequential), or the specific transgenic human FVII product employed corresponding to the alleged unexpected results observed in the working examples.
As stated in the last response, drug dose or dose ratio are critical determinants of whether a drug combination exhibits synergistic, additive, or antagonistic effects as demonstrated in the tramadol + acetaminophen study (see Tallarida, of record). The order of administration (simultaneous versus sequential) can also influence the combined effect as shown in the MTX + cytarbine study (see Akutsu, of record). These examples were not cited to imply structural or therapeutic similarity to the claimed agents, but rather to illustrate that, in the field of combination drug therapy, synergy is not readily predictable and depends on multiple variables.
It should be further noted that in a recent study by Knudsen et al, the combination of NovoSeven® (10 ug/mL) and Hemlibra® (50 or 100 nM) appears to yield a greater-than-additive (synergistic) effect on peak thrombin levels [see Figure 1: Hemlibra® alone is represented by the vehicle control with 50 or 100 nM Hemlibra® added, whereas NovoSeven® alone is represented by 10 ug/mL NovoSeven® with no Hemlibra® added (0 nM)]. This finding is in contrast to the study by Hartmann et al wherein a sequence identical analog of Emicizumab (600 nM) combined with rVIIa (eptacog alfa, 1.75 ug/mL) only yielded an additive effect on thrombin generation. These results highlight how the dose of each agent can influence whether pharmacodynamic interaction between Hemlibra®/emicizumab and rFVIIa yields an additive or synergistic effect.
Variations in the physical and chemical properties of individual drugs, e.g. protein structure and conformational dynamics, further impact synergy (see Lin et al, of record). While Applicant contends that the transgenic factor VII is already narrowly defined via the clause “wherein the transgenic factor VII is a human factor VII derived from production by epithelial cells of the mammary glands of a transgenic rabbit”, it has not been established that the properties of eptacog beta, including any contribution to the alleged synergistic effect, are generalizable to all transgenic human factor VII products encompassed by the claims. Differences in expression systems, purification methods, or other aspects of production could result in variations in activity, stability, or pharmacokinetics for a therapeutic agent made, including transgenic human FVII (Kesik-Brodacka, see 3rd paragraph of Section1.2: Generics versus biosimilars). Eptacog beta (SevenFact®) is made by a proprietary protein production process known as rPro® Technology belonging to the biopharmaceutical company LFB USA (see Wang, 4th para. of Introduction; and LFB USA About the Company page, particularly 3rd paragraph, OA.Appendix) and exhibits specific post-translational modifications, which can influence many of the protein’s properties such as stability, bioactivity, plasma half-life and immunogenicity (Abstract and Introduction, particularly the 3rd paragraph). As such, the alleged unexpected results obtained with eptacog beta do not necessarily predict the effect of all transgenic human factor VII compositions not made by the proprietary rPro® technology encompassed by the claims.
For the above reasons, the purported synergistic effect observed with Hemlibra® and Sevenfact® is limited to the specific experimental conditions disclosed in the specification, including particular doses and administration modes. Accordingly, these results cannot be extrapolated to the broad genus of transgenic factor VII agents, doses, or administration regimens recited in the independent claims.
With respect to Applicant’s second argument, the Examiner notes that the rejections in the present Office Action do not rely upon the teachings of Ducore et al, rendering Applicant’s arguments directed to this reference moot. The Examiner nevertheless maintains the positions previously set forth in the prior Office Action regarding Ducore et al.
Lastly, the Examiner notes that Igawa is used as an evidentiary reference to teach that the multi-specific anti-FIX/FX antibody can be Q499-zl21/J327-zl 19/L404-k disclosed by Calatzis is known as ACE910 (or Emicizumab). Kobayashi is used as an evidentiary reference to teach that mammary epithelial cells are the only cell type that produce milk during lactation. Thus, eptacog beta produced in the milk of transgenic rabbits as disclosed by Wang necessarily meets the claim limitation of transgenic human FVII derived from production by mammary epithelial glands of a transgenic rabbit. Neither Kobayashi nor Igawa is relied upon as a prior art teaching. Peters, as discussed in the rejection above, is relied upon to teach that bispecific anti-FIX/FX antibodies can be administered sequentially or simultaneously with other therapeutic agents such as clotting factors/factor concentrate replacement therapy. Thus, artisans would have been motivated to administer Emicizumab in combination with eptacog beta or another transgenic human FVIIa product either sequentially or simultaneously to effectively treat bleeding disorders or prevent bleeding episodes in a subject having FVIII, FVII deficiency, or FIX deficiency.
Therefore, the rejections made under 35 USC 103 are maintained.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641