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 .
Response to Amendment
Applicant’s remarks and amendments to the claims filed 06/05/2026 have been acknowledged. Claim 14, 26, and 27 have been amended. Claim 28 is 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 26-28 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, of record), 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, of record.), 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 (i.e. as recombinant factor VIIa bypassing agents to facilitate hemostasis in hemophilia patients); 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 26-28 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 06/05/2026 have been fully considered but they are not persuasive.
With respect to the rejection made under 35 USC 103, Applicant first argues that the claims have been amended to recite dose ranges of Emicizumab and the transgenic factor VII eptacog beta and are thus more clearly commensurate in scope with the test data achieving unexpected results as disclosed in the present specification.
Applicant states that the Office’s interpretation on the scope of the unexpected results in the specification is unduly narrow and overly restrictive in view of In re Chupp (MPEP 2145) and asserts that the Office should not continue to apply an excessively narrow standard of what is "commensurate in scope" with the test data. Nevertheless, to further prosecution Applicant has limited claim scope as explained above, including even narrower scope in claims 26 and 28.
To further clarify, Applicant notes that the dose ranges in the present claims are entirely consistent with the test data in the Examples, as explained in Example 4 at paragraph [0222]:
The highest therapeutic dose of FVlla [i.e., eptacog beta] is 270 ug/kg, which corresponds to 6 ug/mL of FVlla (or 120 nM) in the plasma. The use of this dose can be considered as a maximum potential for thrombin generation. On the basis of the product concentrations in the bloodstream obtained in patients, SevenfactTM concentrations comprised 20 and 100 nM are also studied.
Hemlibra® (Roche/Genentech/Chugai, USA) [i.e., emicizumab], a bispecific antibody imitating the function of FVIII, is used at a maximum concentration of 120 ug/mL. The concentration actually detected in patients on treatment is 50 ug/mL (or 300 nM) (Oldenburg et al. NEJM, 2017). Thus, Hemlibra® is used here at approximately 300 nM (50 ug/mL).
Secondly, Applicant argues that eptacog beta and eptacog alfa are not functionally equivalent such that it would have been obvious to artisans to rely on Wang to replace the eptacgo alfa of Calatzis with eptacog beta disclosed in Wang. Haartman et al, as Applicant notes, further emphasizes that “careful judgement will be required when breakthrough bleeding is treated in patients receiving emicizumb”. Thus, Applicant asserts that artisans would have not have considered replacing eptacog alfa with eptcago beta to be used in combination with Emicizumab.
With respect to Applicant’s arguments, the Examiner reiterates 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, of record). 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 appears to have been established here to support the broad ranges of independent claims 14 and 27 as amended, including the narrower range recited in claim 26. Indeed, Applicant’s statement regarding the test data, rather than providing further clarification, raises additional questions regarding what the reported data represent. Specifically, it is unclear whether the concentrations of Hemlibra® (Emicizumab) (300 nM) and SevenFact® (eptacog beta) (20 nM, 40 nM, and 100 nM) listed in Table 1 on Page 25 correspond to the amounts used in the assay or to the target plasma concentrations. If the latter, Applicant must explain how the recited dose ranges were derived or how it was determined that administration of the recited dose ranges results in the target plasma concentrations described in the examples. It is not readily apparent that administration of the recited dose ranges predictably results in the reported plasma concentrations in Table 1 (if the values reported are indeed plasma concentrations) in patients with hemophilia.
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 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.
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 for each component that were used/administered. Accordingly, these results cannot be extrapolated to the broad genus of dosage ranges recited in the independent claims.
The Examiner further clarifies that the statement regarding eptacog alfa and eptacog beta were identified as functionally equivalent only with respect to their use as bypassing agents. The Examiner’s position is not that the two products are identical in every aspect, but rather that both are used for the same relevant purpose—i.e. as recombinant factor VIIa bypassing agents to facilitate hemostasis in hemophilia patients. Nevertheless, as previously set forth in the obviousness analysis, Wang provides sufficient motivation to select eptacog beta based on its recognized consistency in achieving a clinically important effect on blood clotting at lower doses than typically reported for its predecessor eptacog alfa. Although Hartmann states that careful judgement should be exercised when treating bleeding episodes in patients receiving Emicizumab, such a statement does not teach away from the use of a bypassing agent (e.g. eptacog beta) in combination with Emicizumab. Instead, Hartmann advises caution in the clinical management of such patients. Applicant has not provided any persuasive evidence or technical reasoning demonstrating why a person of ordinary skill in the art would have been unable to apply the recommended clinical judgment when administering the combination.
Therefore, the rejections made under 35 USC 103 are maintained.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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