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 .
Claim Status
Applicant’s preliminary amendments received 20MAR2026 are acknowledged.
Claims 13, 34-48, 56-58, and 62-64 have been canceled.
Claims 3-12, 14-21, 24-31, 49-52, and 59-60 have been amended.
Claims 1-12, 14-33, 49-55, and 59-61 are pending in the instant application (i.e., Claim 1 is independent).
Priority
The present application is a Continuation of Application No: 17/552383 (abandoned), filed 16DEC2021, which claims benefit of US Provisional Patent Application No. 63/199277, filed 17DEC2020. Applicant’s claim for the benefit of prior-filed applications is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 20MAR2026 is/are acknowledged and the references cited therein have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9 and 52-55 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The phrase “…at least about 10% below…” in claim 9, wherein “at least” is combined with “about” the boundary of the lower limit is not clearly defined and therefore is considered indefinite. For example, “…at least 10% below…” sets a clear boundary and parallels the upper boundary.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “dosage form” in claims 52-55 is used by the claim to mean “the packaging of the pharmaceutical formulation in a container,” while the accepted meaning is “the physical form in which a drug is manufactured and administered.” In pharmacy, this means the drug’s active ingredient (i.e., the anti-IL5R antibody) is combined with other materials (i.e., surfactants, excipients, etc.) and shaped in a tablet, capsule, liquid, cream, etc. or how a medication is formulated and delivered so the correct dose is administered safely (JINLU, 25JUN2026). In this instance, “dosage form” would be appropriate for claims 50 or 51; however, because the specification does not clearly redefine the term, the term is indefinite as applied to claims 52-55.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-10, 14-17, 21-22, 49, and 60-61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/077391 A2 (AstraZeneca AB, et al., 11MAY2017, and incorporated references, included in IDS), herein referred to as “’391.”
Regarding claims 1, 3 and 4, drawn to antibody sequences, ‘391 teaches the use of anti-IL5R antibody, benralizumab, a specific species of a more broadly claimed subgenus of anti-IL5R antibodies. Benralizumab is also known as MEDI-563, which is for the treatment of eosinophil diseases or disorders. Benralizumab is an IgG1 antibody comprising humanized mouse monoclonal MEDI-523 HC with humanized mouse monoclonal MEDI-523 LC dimer of US Patent No. 8501176 (i.e., SEQ ID NOs: 2 and 4 of US Patent No. 8501176, col 10, lines 2-4 are 100% query match SEQ ID NOs: 10 and 9 of the instant application, respectively, see OA.APPENDIX), or comprises the VH/VL of SEQ ID NOs: 12/13, respectively or comprises six CDRs of SEQ ID NOs: 14-19 (i.e., SEQ ID NOs: 12/13 or 14-19 of ‘391, ¶0245, are 100% query match to SEQ ID NOs: 7/8 or 1-6 of the instant application, respectively, see OA.APPENDIX) administered intravenously or subcutaneously (¶0303).
Regarding claims 2, 5-12, 14-17, and 21-22 drawn to antibody formulation, ‘391 teaches that benralizumab can be provided at a concentration of about 5-200 mg/mL or 5-150 mg/mL, or 5-100 mg/mL, or 30 mg/mL in a pharmaceutical formulation (¶0312). Additionally, exemplary formulations can include polysorbate 80 or poloxamer 188 at an appropriate concentration of 0.001%-0.1% w/v (i.e., below CMC of PS80 is < 0.0015 %w/v and poloxamer 188 is < 0.10 %w/v at room temp). “391 cites US Patent No. 6171586 for a further detail. Col 22, lines 49-59, wherein the amount of surfactant is added such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption (¶0309-0310 and ¶0313). ‘391 further teaches a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient (¶0309-0310).
Regarding claims 49, and 60-61, administration and treatment, ‘391 teaches that benralizumab can be administered intravenously or subcutaneously (¶0309) and used in pulmonary disease treatment. (¶087) and-0091 and fig. 1.
Therefore, the prior art anticipates the invention as presently claimed.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 19-20, 23-33, 50-55, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/077391 A2 (AstraZeneca AB, et al., 11MAY2017, and incorporated references, included in IDS), herein referred to as “’391” as applied to claims 1-10, 14-17, 21-22, 49, and 60-61 and in further view of WO 2020/205716 A1 (Genentech, et al., 08OCT2020, included in IDS), herein referred to as “’716.”
The teachings of ‘391 are summarized above.
However, they do not teach: wherein the pharmaceutical composition further comprises the uncharged excipient of trehalose, mannitol; or further comprises arginine; or further comprises a buffer of histidine; or wherein the histidine buffer is 15-30 mM; or further comprises essentially any buffer; wherein the essentially any buffer is acetate; or succinate; or wherein the pH of the formulation is about 5.5-6.0 (i.e., 4.95-6.6); or wherein the pH is about 5.5 (i.e., 4.95-6.05); or wherein the pH is about 5.6 (i.e., 5.04-6.16)l or wherein the pharmaceutical formulation is a liquid; or wherein the pharmaceutical formulation is a lyophilized formulation or wherein the pharmaceutical formulation is stored in a container; wherein the container is a glass vial; or wherein the container is a pre-filled syringe; or wherein the pre-filled syringe comprises a needle; or a kit comprising the pharmaceutical formulation and instructions for use.
Nevertheless, ‘716 teaches cholate surfactant and therapeutic protein (i.e., therapeutic antibody) compositions, wherein the cholate surfactant is at concentrations below the CMC, for enhancing the stability of antibodies for storage in therapeutically useful formulations (see entire document). ‘716 teaches that cholate surfactants (e.g., CHAPs) below their CMC values (i.e., 2.0 mM or 0.2% w/v) are useful for stabilizing and/or reducing aggregation of antibodies in therapeutically useful formulations and also for reducing the degradation of polysorbate surfactants in such formulations (p 2, lines 10-19). Additionally, ‘716 teaches that the CHAPs concentration may be 0.2% w/v or less (i.e., 0.002% w/v to 0.18% w/v corresponds to 99% below to 10% below CMC of CHAPs) (p. 3, line 14). ‘716 teaches that pharmaceutically acceptable sugars or lyoprotectants comprise trehalose, mannitol, (p 30, lines 10-28); additional excipients include amino acids such as arginine (p 36, line 17-19) and buffers are used to control pH, wherein the buffers may comprise histidine, acetate, or succinate (p 35, lines 13-18). ‘716 further teaches in working example 1 (p 43), the combination of an anti-PD1 monoclonal antibody (1 mg/mL), 0.05% w/v poloxamer 188 (i.e., within the amount of about 0.03% to about 0.08% of poloxamer; and below the CMC), 20 mM histidine acetate (i.e., between 15-30 mM buffer comprising histidine) and 240 mM sucrose (i.e., uncharged excipient; from about 200 mM to about 400 mM; or about 1.5% w/v to about 8.5% w/v) at pH 5.5 (i.e., about 5.5 or about 5.6). Furthermore, ‘716 teaches that the formulations may be packaged into a suitable container such as, bottles, vials, or syringes; the containers may be made of materials such as glass or plastic; containers may also comprise pre-filled syringes, wherein the exemplary syringe is from Vetter, which offers a siliconized coating of their glass syringes (see Vetter pre-filled syringe info); and a kit including a pre-filled syringe, needles, and instructions for use (p 42, lines 6-24).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition of benralizumab for administration to treat an eosinophil disease or disorder disclosed by ‘391 by further comprising specific buffers, excipients, or amino acids, which is stored in a specific dosage form (i.e., liquid or lyophilized) in a specific container (i.e., vial, pre-filled syringe, or a pre-filled syringe with a needle) or providing a kit and instructions for use of the pharmaceutical formulation as disclosed by ‘716. This is because the pharmaceutical compositions further comprising a specific buffer, excipient, or amino acid can further improve the stability of said pharmaceutical composition. One would have been motivated to do so, given the teachings of ‘391 that benralizumab can be administered in the form of a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient. There would have been a reasonable expectation of success, given the knowledge that a pharmaceutical composition further comprising specific buffers, excipients, etc. at specific pH values would result in more stable and therefore safe and effective dosage forms as taught by ‘716.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/077391 A2 (AstraZeneca AB, et al., 11MAY2017, and incorporated references, included in IDS), herein referred to as “’391” as applied to claims 1-10, 14-17, 21-22, 49, and 60-61 and in further view of Guo, et al., (Eur J Pharm Sci, 2013, 49, 175-186), herein referred to as “Guo.”
The teachings of ‘391 are summarized above.
However, they do not teach: wherein the surfactant in the pharmaceutical formulation is TPGS at an amount of about 0.001% w/v to about 0.02% w/v.
Nevertheless, Guo teaches that FDA-approved TPGS is a nonionic surfactant which has been widely used as an absorption enhancer, emulsifier, solubilizer, additive and permeation enhancer, stabilizer, etc. in drug delivery systems (see entire document). Specifically, in drug delivery systems, when TPGS is used at concentrations below the CMC (i.e., less than 0.02% w/v) TPGS could act as an inhibitor of P-gp (i.e., drug efflux pump), responsible for facilitating multidrug resistance (see section 2.1). This discovery resulted in the utilization of TPGS at concentrations below the CMC for inhibition of P-gp mediated drug transport and multidrug resistance in drug delivery systems (see section 2.1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition of benralizumab for administration to treat an eosinophil disease or disorder disclosed by ‘391 by utilizing FDA-approved TPGS at a concentration below the CMC disclosed by Guo because in addition to providing stabilization to drug delivery systems, use of TPGS below the CMC results in the added benefit of inhibition of multidrug resistance by inhibiting P-gp (i.e., drug efflux pump). One would have been motivated to do so, given the teachings of ‘391 that benralizumab can be administered in the form of a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient. There would have been a reasonable expectation of success, given the knowledge that using TPGS at a concentration between 0.001% w/v and 0.02% w/v would result in a stable drug delivery system which has the added benefit of inhibiting P-gp and potentially reducing multidrug resistance, as taught by Guo.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/077391 A2 (AstraZeneca AB, et al., 11MAY2017, and incorporated references, included in IDS), herein referred to as “’391” as applied to claims 1-10, 14-17, 21-22, 49, and 60-61 and in further view of Wang, et al., (Eur J Pharmaceutics and Biopharmaceutics, 2017, 114, 263-277, included in IDS), herein referred to as “Wang.”
The teachings of ‘391 are summarized above.
However, they do not teach: wherein the surfactant in the pharmaceutical formulation is a Brij series surfactant at an amount of about 0.001% w/v to about 0.01% w/v.
Nevertheless, Wang teaches the comparison of two different monoclonal IgG1 antibodies at low and high concentrations of antibody with varied concentrations of PS20, PS80, Brij35 (i.e., Brij series surfactant), CHAPS, Triton X100, F68 (Poloxamer 188), F127 (Poloxamer 407), or SDS with and without 100 mM arginine-HCl and evaluates the turbidity of the formulations after agitation as well as the antibody structure over the various conditions (see entire document). For both antibodies, the Brij35 surfactant was able to reduce turbidity after agitation and for JM2, the Brij35 surfactant was able to reduce aggregation (i.e., maintain monomer structure), wherein the observed effects were a result of a formulation comprising 0.02 mg/mL or 0.002% w/v Brij35 (i.e., below the CMC of Brij35 and within the range of 0.001% w/v and 0.01% w/v of instant claim 12) (see section 3.1.2, Fig 3, and Fig 4). Wang teaches that the efficiency of aggregation prevention appears to be dependent on the absolute mass concentration regardless of the molecular weight of the surfactants (i.e., mg/mL or % wt/vol) and that stabilization effects do not have to be above the CMCs (Section 4). Furthermore, the stabilizing effect of surfactants is generally attributed to two reasons: one is decreased surface-induced structure perturbation by reducing protein adsorption on to the air-liquid and solid-liquid interfaces and the other is inhibited protein-protein interactions (PPI) through competitive binding at the hydrophobic surfaces.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition of benralizumab for administration to treat an eosinophil disease or disorder disclosed by ‘391 by utilizing alternate surfactants in antibody formulations below their CMC disclosed by Wang because the use of the lowest concentration of surfactant within the antibody formulation not only provides reduced aggregation it also reduces the potential of perturbing the antibody structure following agitation. One would have been motivated to do so, given the teachings of ‘391 that benralizumab can be administered in the form of a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient. There would have been a reasonable expectation of success, given the knowledge that using Brij35 at a concentration between 0.001% w/v and 0.01% w/v would lead to a stable antibody formulation which provides reduced turbidity and maintains antibody structure following agitation, as taught by Wang.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/077391 A2 (AstraZeneca AB, et al., 11MAY2017, and incorporated references, included in IDS), herein referred to as “’391” as applied to claims 1-10, 14-17, 21-22, 49, and 60-61 and in further view of Massant, et al., (Eur J Pharmaceutics and Biopharmaceutics, 2020, 156, 131-142), herein referred to as “Massant.”
The teachings of ‘391 are summarized above.
However, they do not teach: wherein the pharmaceutical formulation further comprises an uncharged excipient at an amount of about 20 mM to about 80 mM.
Nevertheless, Massant teaches various formulations of two therapeutic IgG4 antibodies at concentrations of 50 mg/mL, wherein the excipients such as trehalose or sucrose (i.e., uncharged excipients) and/or amino acids are used at various concentrations to preserve the stability of the antibody during the process of freeze-drying (i.e., lyophilization) (see entire document, specifically see Table1 and Table 3). Specifically, Massant teaches at concentrations of 25 mg/mL of sucrose or trehalose (i.e., 73 mM or 66-73 mM, respectively or between 20-80 mM uncharged excipient) the rate of change in high molecular weight species from initial to pre-spray drying or after four weeks of storage in the lyophilized form at 40 ºC decreased significantly compared to 5 mg/mL (i.e., < 20 mM sucrose or trehalose) (Fig 9 and 10) suggesting that 73 mM of an uncharged excipient is able to improve the stability of an antibody during the process of lyophilization and storage in lyophilized conditions.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the pharmaceutical composition of benralizumab for administration to treat an eosinophil disease or disorder disclosed by ‘391 by utilizing lower concentrations of uncharged excipient disclosed by Massant because 73 mM of sucrose or trehalose was enough to improve the stability of an antibody during the process of lyophilization and storage in lyophilized conditions. One would have been motivated to do so, given the teachings of ‘391 that benralizumab can be administered in the form of a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient. There would have been a reasonable expectation of success, given the knowledge that using sucrose or trehalose at a concentration between 20-80 mM would lead to a stable antibody formulation pre-lyophilization and following lyophilization over four weeks, as taught by Massant.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
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 1-10, 12, 14-17, 19-23, 25-29, 31-33, 49-50, 52, 54-55, and 59-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 12,582,716 B2 (Leach, et al., Application No. 16/298474), herein referred to as “the ‘716 patent” in view of WO 2017/077391 A2 (AstraZeneca AB, et al., 11MAY2017, and incorporated references, included in IDS), herein referred to as “’391” and Wang, et al., (Eur J Pharmaceutics and Biopharmaceutics, 2017, 114, 263-277, included in IDS), herein referred to as “Wang.”
Issued claims of the ‘716 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘716 patent and italics corresponds to the additional claim limitations.
PNG
media_image1.png
326
295
media_image1.png
Greyscale
PNG
media_image2.png
346
291
media_image2.png
Greyscale
A pharmaceutical formulation, comprising:
an antibody or antigen binding fragment thereof comprising a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 1; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:2; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:3; a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:4; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:5; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:6; and
a surfactant at an amount below the critical micelle concentration (CMC) of said surfactant, wherein the surfactant is not polysorbate 20 (PS20).
The pharmaceutical formulation of claim 1, wherein the surfactant is polysorbate 80 (PS80), poloxamer, a Brij series surfactant, or tocopheryl polyethylene glycol succinate (TPGS).
The pharmaceutical formulation of claim 1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising SEQ ID NO:7 and a light chain variable region comprising SEQ ID NO:8.
The pharmaceutical formulation of claim 1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO: 10.
The pharmaceutical formulation of claim 1, comprising about 2 mg/mL to about 200 mg/mL of the antibody or antigen binding fragment thereof.
The pharmaceutical formulation of claim 1, comprising about 2 mg/mL to about 150 mg/mL of the antibody or antigen binding fragment thereof.
The pharmaceutical formulation of claim 1, comprising about 2 mg/mL to about 100 mg/mL of the antibody or antigen binding fragment thereof.
The pharmaceutical formulation of claim 1, comprising about 30 mg/mL of the antibody or antigen binding fragment thereof.
The pharmaceutical formulation of claim 1, wherein the amount of surfactant is at least about 10% below to at least 80% below the CMC of said surfactant.
The pharmaceutical formulation of claim 1, wherein the surfactant is PS80 at an amount of about 0.0004% w/v to about 0.0012% w/v.
The pharmaceutical formulation of claim 1, wherein the surfactant is a Brij series surfactant at an amount of about 0.001% w/v to about 0.01% w/v.
The pharmaceutical formulation of claim 1, wherein the surfactant is a poloxamer at an amount of about 0.027% w/v to about 0.08% w/v.
The pharmaceutical formulation of claim 1, wherein the surfactant is a poloxamer at an amount of about 0.03% w/v to about 0.08% w/v.
The pharmaceutical formulation of claim 15, wherein the Poloxamer is poloxamer 188.
The pharmaceutical formulation of claim 1, further comprising an uncharged excipient.
The pharmaceutical formulation of claim 17, comprising about 200 mM to about 400 mM uncharged excipient.
The pharmaceutical formulation of claim 17, comprising about 1.5% w/v to about 8.5% w/v of the uncharged excipient. (i.e., 8.5% w/v of trehalose is 225 mM)
The pharmaceutical formulation of claim 17, wherein the uncharged excipient is fructose, glucose, mannose, sorbose, xylose, lactose, maltose, sucrose, dextran, pullulan, dextrin, cyclodextrin, soluble starch, trehalose, sorbitol, erythritol, isomalt, lactitol, maltitol, xylitol, glycerol, lactitol, hydroxyethyl starch, water-soluble glucan, or a combination thereof.
The pharmaceutical formulation of claim 21, wherein the uncharged excipient is sucrose.
The pharmaceutical formulation of claim 21, wherein the uncharged excipient is trehalose.
The pharmaceutical formulation of claim 1, further comprising arginine.
The pharmaceutical formulation of claim 1, further comprising a buffer comprising histidine.
The pharmaceutical formulation of claim 1, further comprising about 15 mM to about 30 mM buffer comprising histidine.
The pharmaceutical formulation of claim 1, further comprising a buffer.
The pharmaceutical formulation of claim 28, wherein the buffer comprises acetate.
The pharmaceutical formulation of claim 1, wherein the pH of the formulation is about 5.5 to about 6.0.
The pharmaceutical formulation of claim 31, wherein the pH of the formulation is about 5.5.
The pharmaceutical formulation of claim 31, wherein the pH of the formulation is about 5.6.
The pharmaceutical formulation of claim 1, suitable for intravenous, subcutaneous, or intramuscular administration.
The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is a liquid pharmaceutical formulation.
52. A dosage form comprising the pharmaceutical formulation of claim 1 in a container.
54. The dosage form of claim 52, wherein the container is a pre-filled syringe.
55. The dosage form of claim 54, wherein the pre-filled syringe comprises a needle.
59. A kit comprising the pharmaceutical formulation of claim 1 and instructions for use.
60. A method of treating a pulmonary disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of claim 1.
61. The method of claim 60, wherein the pulmonary disease or disorder is an eosinophilic disease or disorder.
The claimed antibody structures in the reference claims and the instant claims are same.
The main difference between two above surfactants being used. The instant claim excludes PS20 that is used in the reference claims as surfactant. Instead the instant claims use other known surfactants, PS80, P188, Brij35, or TPGS at specific concentrations which are below each surfactants CMC; or wherein the antibody comprises SEQ ID NOs: 7 and 8 corresponding to the VH and VL; or wherein the antibody comprises SEQ ID NOs: 9 and 10, corresponding to the HC and LC; or wherein the surfactant that is not PS20 is at least about 10%-80% below the CMC; or wherein the pharmaceutical formulation is suitable for subQ, IV, or IM injections; or a method of treating an eosinophilic disease or disorder comprising administering a therapeutically effective amount of the pharmaceutical formulation comprising the anti-IL5R antibody and essentially any surfactant except PS20 at a concentration below the CMC.
‘391 teaches the use of anti-IL5R antibody, benralizumab (i.e., also known as MEDI-563, for the treatment of eosinophil diseases or disorders, wherein benralizumab is an IgG1 antibody comprising humanized mouse monoclonal MEDI-523 HC with humanized mouse monoclonal MEDI-523 LC dimer of US Patent No. 8501176 (i.e., SEQ ID NOs: 2 and 4 of US Patent No. 8501176, col 10, lines 2-4 are 100% query match SEQ ID NOs: 10 and 9 of the instant application, respectively, see OA.APPENDIX), or comprises the VH/VL of SEQ ID NOs: 12/13, respectively or comprises six CDRs of SEQ ID NOs: 14-19 (i.e., SEQ ID NOs: 12/13 or 14-19 of ‘391, ¶0245, are 100% query match to SEQ ID NOs: 7/8 or 1-6 of the instant application, respectively, see OA.APPENDIX) administered intravenously or subcutaneously (¶0303). Furthermore, ‘391 teaches that benralizumab can be administered in the form of a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient (¶0309-0310). ‘391 further teaches that benralizumab can be provided at a concentration of about 5-200 mg/mL or 5-150 mg/mL, or 5-100 mg/mL, or 30 mg/mL in a pharmaceutical formulation (¶0312). Additionally, exemplary formulations can include polysorbate 80 or poloxamer 188 at an appropriate concentration of 0.001%-0.1% w/v (i.e., below CMC of PS80 is < 0.0015 %w/v and poloxamer 188 is < 0.10 %w/v at room temp) as disclosed in US Patent No. 6171586 (included in IDS), col 22, lines 49-59, wherein the amount of surfactant is added such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption (¶0309-0310 and ¶0313).
Furthermore, Wang teaches that surfactants are widely used as stabilizers in the biopharmaceutical formulations to minimize protein aggregation. To determine the effect of different surfactants or different antibodies, Wang evaluates two different monoclonal IgG1 antibodies at low and high concentrations of antibody with varied concentrations of PS20 (i.e., Tween®20), PS80 (i.e., Tween®80), Brij35 (i.e., Brij series surfactant), CHAPS, Triton X100, F68 (Poloxamer 188), F127 (Poloxamer 407), or SDS with and without 100 mM arginine-HCl and evaluates the turbidity of the formulations after agitation as well as the antibody structure over the various conditions (see entire document). Wang shows that formulations at 50 mg/mL of JM1 or JM2 after agitation at concentrations of 0.002 mg/mL or 0.0002% w/v of PS20 or PS80 (i.e., below the CMC) performed equally (i.e., minimal turbidity) (Fig 6). Additionally, for both antibodies, the Brij35 surfactant was able to reduce turbidity after agitation and for JM2, the Brij35 surfactant was able to reduce aggregation (i.e., maintain monomer structure), wherein the observed effects were a result of a formulation comprising 0.02 mg/mL or 0.002% w/v Brij35 (i.e., below the CMC of Brij35 and within the range of 0.001% w/v and 0.01% w/v of instant claim 12) (see section 3.1.2, Fig 3, and Fig 4). Wang teaches that the efficiency of aggregation prevention appears to be dependent on the absolute mass concentration regardless of the molecular weight of the surfactants (i.e., mg/mL or % wt/vol) and that stabilization effects do not have to be above the CMCs (Section 4). With regard to the antibodies, Wang teaches that higher concentrations of antibodies does not necessarily require higher amounts of stabilizing surfactants (Section 4). Furthermore, the stabilizing effect of surfactants is generally attributed to two reasons: one is decreased surface-induced structure perturbation by reducing protein adsorption on to the air-liquid and solid-liquid interfaces and the other is inhibited protein-protein interactions (PPI) through competitive binding at the hydrophobic surfaces.
It would have been obvious to artisans to modify the issued products of an antibody formulation comprising benralizumab, a surfactant of PS20 at a concentration below the CMC, a buffer at 10-30 mM, and an excipient at 200-400 mM with a pH of about 5.5 to 6.5 as claimed by the ‘716 patent to an antibody formulation comprising benralizumab which utilizes a surfactant that is not PS20 at a concentration below the CMC for treatment of an eosinophilic disease or disorder, as taught by ‘391 and Wang. This is because ‘391 teaches that benralizumab can be administered in the form of a composition comprising one or more additional components such as a physiologically acceptable carrier, excipient, or diluent, wherein one or more substances are selected from the group consisting of a buffer (for example, histidine), an antioxidant such as ascorbic acid, a low MW polypeptide (such as those having fewer than 10 aa), a protein, an amino acid (for example, arginine), a carbohydrate such as glucose, sucrose or dextrin, a chelating agent such as EDTA, glutathione, a stabilizer (for example, a surfactant), and an excipient and because Wang teaches that modification of the surfactant from PS20 to for example PS80 at a concentration below the CMC provides similar stability results at 48 h after agitation. One would have been motivated to do so, given the direction by the ‘716 patent that the currently claimed concentration of PS20 within the antibody formulation is below the CMC and results in a stable antibody formulation and given the teaching of Wang that utilizing PS80 for example at a concentration below the CMC results in a similarly stable antibody solution following agitation. Furthermore, in Ex parte WILLIAM LEACH, RACHAEL LEWUS, JAMES MCGIVNEY, KELCY NEWELL, and KEVIN DOUGLAS STEWART, “Appellant recognizes that the state of the art is such that one skilled in the art would know how to formulate antibody compositions such as those claimed. Appeal Br. 35. Appellant further recognizes that before the effective filing date of Appellant’s claimed invention, one of ordinary skill in this art would have routinely screened antibody formulations for such factors as pH, ionic strength, and excipients and that the art would have provided ample guidance as to suitable buffers and excipients. Id. 35-37” There would have been a reasonable expectation of success, given the knowledge that by modifying the stable antibody formulation taught by the ‘716 by utilizing a different surfactant at a concentration below the CMC would lead to another stable antibody formulation, which could be used for treatment of an eosinophilic disease or disorder, as taught by ‘391 and Wang.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
