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
1. The Amendment filed April 28, 2026 in response to the Office Action of November 28, 2025 is acknowledged and has been entered. Claims 2- 3, and 14-16 have been cancelled. Claims 1, 5, 12, 17-18 and 21 have been amended.
2. Claims 1, 4-13 and 17-24 are currently being examined.
Rejections Maintained
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.
3. Claim(s) 1, 4-7, 9-12, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0035617 A1 (Crowley et al. Feb. 2, 2023, effectively filed Nov. 13, 2019), “Crowley” in view of Vázquez-Rey et al. (Biotechnol. Bioeng. 2011, 108: 1494-1508, IDS), “Vázquez-Rey” for the reasons of record.
Crowley teaches stable aqueous pharmaceutical formulations with an extended shelf life comprising a Tissue Factor Pathway Inhibitor (TFPI) antibody. See abstract, ¶¶ 0008-0009 and 0162.
Crowley teaches TFPI includes, concizumab (also known as mAb-2021, hz4F36) comprising SEQ ID NOs; 24 and 25. See ¶¶ 0075, 0084, 0164, and 0183 and Table 20.
Crowley teaches a pharmaceutical formulation comprising: about 50 mg/mL to about 250 mg/mL of an antibody that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Factor Pathway Inhibitor (TFPI), 20 mM histidine buffer, 85 mg/mL sucrose, 0.2 mg/mL polysorbate 80, 0.05 mg/mL disodium edetate dihydrate, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 25, and comprises a light chain comprising the amino acid sequence of SEQ ID NO: 24 (concizumab); and wherein the formulation has a pH of 5.8. See ¶¶ 0084 and claim 23.
Crowley teaches the preferably the buffer is histidine, wherein the histidine buffer comprises L-histidine, L-histidine monohydrochloride (also termed as L-histidine monohydrochloride monohydrate and/or L-histidine hydrochloride monohydrate) or a mixture thereof . See ¶¶ 0189. L-histidine monohydrochloride is viscosity lowering agent. See ¶ [0177] of instant the published application)
Crowley teaches that the formulations can comprise a preservative agent that is selected from phenol, m-cresol, benzyl alcohol, benzalkonium chloride, benzalthonium chloride, phenoxyethanol and methyl paraben. See ¶¶ 0205.
Crowley teaches that the concentration of the preservative generally ranges from about 0.001 mg/mL to about 50 mg/mL, from about 0.005 mg/mL to about 15.0 mg/mL, from about 0.008 mg/mL to about 12.0 mg/mL or from about 0.01 mg/mL to about 10.0 mg/mL. Preferably the concentration of preservative can be about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL about 1.0 mg/mL, 2.0 mg/mL, 3.0 mg/mL, about 4.0 mg/mL, about 5.0 mg/mL, about 6.0 mg/mL, about 7.0 mg/mL, 8.0 mg/mL, 9.0 mg/mL about 9.1 mg/mL, about 9.2 mg/mL, 9.3 mg/mL, 9.4 mg/mL, 9.5 mg/mL, 9.6 mg/mL, 9.7 mg/mL, 9.8 mg/mL, 9.9 mg/mL, 10.0 mg/mL. Most preferably, the concentration of preservative is about 0.1 mg/mL or 9.0 mg/mL. See ¶¶ 0206.
Crowley teaches that the that the concentration of the antibody is about 100 mg/ml. See ¶¶ 0079 and 0187.
Crowley teaches that the surfactants include polysorbate 20 and polysorbate 80 and The concentration of the surfactant generally ranges from about 0.01 mg/mL to about 10 mg/mL. See ¶¶ 0196-0197.
Crowley teaches that the polysorbate can be polysorbate 80 at a concentration ranging from about 0.1 mg/mL to about 0.3 mg/mL, for example, at 0.2 mg/mL. See ¶¶ 0198.
Crowley teaches the pH can be in the range of about pH 5.0 to about 6.6, preferably between about pH 5.0 to 6.5 or about 5.0 to 6.0, and most preferably between pH 5.2 to 5.8. See ¶¶ 0204.
Crowley teaches a method of treating or preventing a deficiency in blood coagulation or a bleeding disorder or a method treating or preventing hemophilia A, B or C (a coagulopathy) comprising administering to a subject in need thereof a therapeutically effective amount of the concizumab pharmaceutical composition. See ¶¶ 0084, 0094, 0095 and 0098-0100.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Crowley to add a preservative agent like phenol to the concizumab pharmaceutical composition to prevent contamination of the composition. One of skill in the art would have been motivated to optimize the concentrations of the components of the pharmaceutical composition to optimize the stability and shelf-life of the concizumab pharmaceutical formulations.
Although Crowley does not teach the methods of producing the claimed pharmaceutical compositions, product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I).
Crowley additionally teaches at paragraph [0005]
A major aim in the development of antibody formulations is to maintain antibody, solubility, stability and potency of its antigen binding. For an antibody to remain biologically active, a formulation must preserve the conformational integrity of at least a core of the antibody's antigen-binding amino acids. It is also particularly desirable to avoid aggregates and particulates in solution which would require sterile filtration before use for intravenous or subcutaneous injection and limit route of administration. Salts, surfactants, pH and tonicity agents such as sugars can be used to overcome aggregation or denaturation problems. Formulation of antibody preparations requires careful selection of these factors among others to avoid denaturation of the protein and loss of antigen-binding activity.
Crowley teaches as set forth above, but does not specifically teach the ordered method of preparation of claim 1.
Vázquez-Rey teaches that protein aggregation of monoclonal antibodies is a common issue that compromises the quality, safety and efficacy of antibodies. Vázquez-Rey teaches that aggregation can occur at different steps of the manufacturing process including purification and formulation. See abstract.
Vázquez-Rey teaches that low pH conditions can contribute to protein aggregation. See p. 1498-right column.
Vázquez-Rey teaches that ions in buffers to make antibody compositions can contribute to protein aggregation. Additionally antimicrobial preservatives, like benzyl alcohol and phenol, used to ensure sterility can also induce protein aggregation. See p. 1499-righ column.
Vázquez-Rey teaches that surfactants such as polysorbate can be used to mitigate protein aggregation. See p. 1499-righ column.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Crowley and Vázquez-Rey and add surfactants, like polysorbate-80, to aqueous compositions comprising concizumab and preservatives used for sterility because Crowley teaches that it is desirable to avoid aggregate formation during preparation of the antibody compositions and Crowley and Vázquez-Rey teach that surfactants can be used to minimize aggregation caused by the formulation process, such as adding preservatives. One would have been motivated to modify and optimize the order of addition, concentration of the components and pH in making the pharmaceutical concizumab composition to minimize aggregation of the antibodies so that the compositions can be used for administration to a patient with a blood coagulation or a bleeding disorder, e.g., hemophilia.
Response to Arguments
4. Applicant argues that a combination of Crowley and Vazquez-Rey doesn't teach or suggest the preparation method as presented recited in claims 1, 4-7 and 17.
Applicant argues that as acknowledged by the Office, Crowley does not teach the ordered method of preparation of claim 1 (page 6 of the Office Action). Such deficiencies are not remedied by Vazquez-Rey.
Applicant argues that the present application discloses a method of preparing a pharmaceutical formulation suitable for multiple use comprising concizumab as API, an antimicrobial preservative which needs to be blended for multiple use, and a surfactant, and such formulation is chemically and physically stable.
Applicant argues that as shown by Example 6 of the present application, among seven different methods of preparing concizumab formulation, only method one, the order of which is set forth in the present claims, produced clear solutions and homogenization of all ingredients.
Vazquez-Rey does not provide any teaching or guidance as to the order of the preparation method to arrive at a clear solution with minimal aggregate, thus does not cure the deficiencies of Crowley.
Applicant argues that for at least the reasons above, the combination of Crowley and Vazquez-Rey does not render claims 1, 4-7 and 17 obvious.
Applicant argues that claims 9-12 and 18-22 are not obvious over Crowley, either.
Applicant argues that as shown in Example 2 of the specification, the clarity of the solution differs greatly depending on the combination of the type of antimicrobial preservative and the type of surfactant. Crowley does not provide any teaching or suggestions with respect to the specific combination as presently claimed, thus does not render claims 9-12, and 18-22 obvious.
Applicant argues that furthermore, claims 22-24 ultimately depend from claim 13, which was not rejected under 35 U.S.C. §103 over Crowley and Vazquez-Rey. For this reason alone, claims 22-24 are not obvious over a combination of Crowley and Vazquez-Rey, either.
For at least the reasons above, Applicants respectfully request withdrawal of all 35 U.S.C. §103 rejection over Crowley and Vazquez-Rey.
5. Applicant’s arguments have been considered, but have not been found to be fully persuasive.
With regard to Example 6, the specification teaches that method 1, which embodies the currently claimed manufacturing method, all solutions in each manufacturing step were clear after dissolution and homogenization, for both concizumab 10 mg/ml drug product and 100 mg/ml drug product. The increase in % HMWP was minor and at an acceptable level. See paragraph bridging pp. 64-65.
Method 1 recites:
1. L-Arginine HCl, L Histidine, Sucrose, Sodium Chloride and Phenol was dissolved in Water For Injection (10% of final volume for 100 concizumab mg/ml DP and 75% of the final volume for 10 concizumab mg/ml DP). This solution contained 4.7 mg/ml Phenol for a 10 mg/ml concizumab DP and 35 mg/ml Phenol for a 100 mg/ml concizumab DP). [0541] 2. pH was adjusted to 6.0 using 2N Hydrochloric acid and/or 2N Sodium Hydroxide and the solution is homogenised. pH was adjusted to 6.0 using 2N Hydrochloric acid and/or 2N Sodium Hydroxide and the solution was homogenized. [0542] 3. Concizumab drug substance (115 mg/ml) was added to the solution and homogenised. The volume of this solution was 84% of the final DP volume for a 10 mg/ml concizumab DP and 97% of the final DP volume for a 100 mg/ml concizumab DP). The volume of this solution was 84% of the final DP volume for a 10 mg/ml concizumab DP and 97% of the final DP volume for a 100 mg/ml concizumab DP. [0543] 4. Polysorbate 80 (30 mg/ml stock solution) was added and homogenised. This solution contained 0.32 mg/ml Polysorbate 80 and 4.5 mg/ml Phenol for 10 mg/ml DP and 0.26 mg/ml polysorbate 80 and 3.6 mg/ml Phenol for 100 mg/ml DP. [0544] 5. Water For Injection was added to 100% of the final volume. The formulation was homogenized before being sterile filtered and filled into cartridges
See p. 59.
However, the instant claims are not limited to the specific concentrations of concizumab and concentrations and types of additive components used in Method 1. Additionally, the claims do not require homogenization of the compositions of the claims at any step.
MPEP 716.02 (d) teaches:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”
Given that the presented evidence relates to only a single method of preparing a pharmaceutical formulation of concizumab that produces a clear solution the presented evidence is not commensurate in scope with the claimed invention and is not sufficient to support Applicant’s assertion of non-obviousness of the claimed invention.
Additionally, as previously set forth, Crowley teaches that it is desirable to avoid aggregate formation during preparation of the antibody compositions and Crowley and Vázquez-Rey teach that surfactants can be used to minimize aggregation caused by the formulation process, such as adding preservatives. Thus, one would have been motivated to modify and optimize the order of addition, concentration of the components and pH in making the pharmaceutical concizumab composition to minimize aggregation of the antibodies so that the compositions can be used for administration to a patient with a blood coagulation or a bleeding disorder, e.g., hemophilia
In response to Applicant's arguments against Crowley individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally the claims are not limited to any particular level of clarity in the pharmaceutical formulations. Further, the evidence in Example 2 is not commensurate in scope with the claimed invention as it does not include all of the steps and components of independent claim 1, e.g. no concizumab is included in the formulations of Example 2.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. Thus, the rejection of claims 1, 4-7, 9-12, and 17-21 is maintained for the reasons of record.
The rejection of claims 22-24 is withdrawn because they depend from claim 13, which was not rejected.
6. Claim(s) 1, 4-13 and 17-24 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0035617 A1 (Crowley et al. Feb. 2, 2023, effectively filed Nov. 13, 2019), “Crowley” in view of Vázquez-Rey et al. (Biotechnol. Bioeng. 2011, 108: 1494-1508, IDS), . “Vázquez-Rey” as applied to claims 1, 4-7, 9-12, and 17-21 above, and further in view of US 2013/0136733 A1 (Parshad et al. May 30, 2013, IDS), “Parshad” for the reasons of record.
Crowley and Vázquez-Rey teach as set forth above. Crowley additionally teaches that , preferably, the concentration of the sucrose in the formulation is about 50 mg/mL to about 120 mg/mL. See ¶ 0195. Crowley additionally teaches that sucrose, a polyol, can be used at a concentration of about 51 mg/mL. See ¶¶ 0193 and 0194.
Crowley and Vázquez-Rey teach as set forth above, but do not teach using L-Histidine at about 33 mM, sodium chloride, or L-arginine HCl, which are viscosity lowering agents (see ¶ [0177] of instant the published application), in the pharmaceutical compositions.
Parshad teaches that the invention is drawn to a stable, multi-dose liquid composition comprising an antibody and one or more preservatives for use in therapy. See abstract and ¶¶ 0007-0010.
Parshad teaches that data is presented herein which surprisingly shows that formulations containing an antibody in combination with a variety of differing preservatives, resulted in formulations with a low content of aggregates during 4 weeks of storage at 40 °C and storage at 5 °C and 40 °C for 3 months. See ¶ 0011 and Examples 1-4.
Parshad teaches using amino acids (e.g., L-histidine, L-arginine) as tonicity modifying agents. See ¶¶ 0038 and 0046.
Parshad teaches using a 33 mM histidine buffer and 25 mM arginine. See ¶¶ 0065-0089 and claims 10-12
Parshad teaches using sodium chloride and arginine hydrochloride as salts in combination. See ¶¶ 0036, 0037. 0046, 0058-0092 and 0221-304 and claims 10-12.
Parshad teaches using 25 mM sodium chloride. See ¶¶ 0065-0089 and claims 10-12.
Parshad teaches the antibody can be an anti-TFPI monoclonal antibody like HzTFPI4F36, which is concizumab. See ¶¶ 0056 and 0311 and Table 20 of Crowley..
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Crowley, Vázquez-Rey and Parshad and use L-Histidine, sodium chloride, or L-arginine HCl in the stable aqueous pharmaceutical formulations of Crowley and Vázquez-Rey because Parshad teaches these agents can also be used in the formulation of stable antibody compositions with low content of aggregates. One of skill in the art would have been motivated to optimize the types and concentrations of the components of the pharmaceutical antibody compositions to optimize the stability and shelf-life of the antibody formulations and to reduce the level of aggregate formation in the composition.
Response to Arguments
7. Applicant argues that the Office acknowledged that Crowley and Vazquez-Rey do not teach using L-Histidine at about 33 mM sodium chloride or L-arginine HCl, which are viscosity lowering agents in the pharmaceutical compositions and alleged that Parshad cured such deficiencies.
Applicant argues that as stated above, Crowley and Vazquez-Rey fail to teach or suggest the order of the method and the specific combination of the type of antimicrobial preservative, and the type of surfactant as presently claimed. Parshad does not provide teaching or suggestions on these claimed features, either.
Applicant argues that for at least the reasons above, Applicants respectfully request withdrawal of all 35 U.S.C. §103 rejection over Crowley, Vazquez-Rey and Parshad.
Applicant's arguments have been considered, but have not been found persuasive and the rejection is maintained. Applicant is reiterating the arguments with respect to Crowley and Vazquez-Rey as set forth above. Thus, for the reasons set forth above, the arguments are not found persuasive.
With regard to Parshad, it would have been obvious to use L-Histidine, sodium chloride, or L-arginine HCl in the stable aqueous pharmaceutical formulations of Crowley and Vázquez-Rey because Parshad teaches these agents can also be used in the formulation of stable antibody compositions with low content of aggregates. One of skill in the art would have been motivated to optimize the types and concentrations of the components of the pharmaceutical antibody compositions to optimize the stability and shelf-life of the antibody formulations and to reduce the level of aggregate formation in the composition
Thus, the reject is maintained for the reason previously set forth and above.
Conclusion
8. All other objections and rejections recited in the Office Action of November 28, 2025 are withdrawn in view of Applicant’s amendments and arguments.
9. No claims allowed.
10. 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 extension fee 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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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/Peter J Reddig/
Primary Examiner, Art Unit 1646
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