DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-13 and 16-24 as filed on March 14, 2023 are pending and under consideration.
Priority
2. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
3. Claim 21 is objected to because of the following informalities: the word “About” on line 3 should be “about”. Appropriate correction is required.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
4. Claim(s) 1-7, 9-12, and 16-24 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”.
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 e 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.
5. Claim(s) 1-13 and 16-24 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 1-7, 9-12, and 16-24 above, and further in view of US 2013/0136733 A1 (Parshad et al. May 30, 2013, IDS), “Parshad”.
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.
Conclusion
6. No claims allowed.
7. 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 M-F 8:30-5:30 Eastern Time.
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/PETER J REDDIG/ Primary Examiner, Art Unit 1646