DETAILED ACTION
Claims 1-2, 4, 15, 96-97, 106, 113-114, 120-123, and 169-183 are pending in the instant application.
Claims 3, 37-38, 40-42, 65-67, 75-82, 85, 87-91, 93, 109, 132, 153-156, and 161-164 are cancelled.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I: claims 1-2, 4, 15, 96-97, 106, 113-114, 120-123, and 169-183 (new claims) drawn to compositions of a bispecific antibody comprising cevostamab in the reply filed on 2/24/2026 is acknowledged.
Claims 3, 37-38, 40-42, 65-67, 75-82, 85, 87-91, 93, 109, 132, 153-156, and 161-164 are cancelled as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/24/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Information Disclosure Statement
The information disclosure statement filed 9/26/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following foreign documents and non-patent literature documents listed below:
Cite No. A: JP-2015-522524-A.
Specification
The disclosure is objected to because of the following informalities:
“In some another particular embodiment” should read “In a particular embodiment”, or “In some embodiment” or “In another particular embodiment”, etc. (page 6, line 14)
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claims 1, 2, 4, 15, 96-97, 106, 113-114, 120, 169-173, and 183 are rejected under 35 U.S.C. 103 as being unpatentable over Dubey et al (WO2020053301 A1, Priority to 9/11/2018; hereinafter Dubey), and further in view of Cohen A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Presented at: ASH Annual Meeting and Exposition; 2020 Dec 5-8. Abstract #292; hereinafter Cohen), Dion et al (Pharm Res, 2018, 35(222):1-11), and Jansson et al (US20190330363 A1, Priority to 11/3/2015; hereinafter Jansson).
Regarding instant claims 1, 2, 4, 15, 96-97, 106, 113-114, 120, 169-173, and 183, Dubey teaches stable pharmaceutical formulations comprising: (i) a bispecific antibody at a concentration between 0.05mg/mL and 15mg/mL; (ii) a stabilizing or tonicity agent selected from the group comprising sucrose, polysorbate-20 (PS20), and amino acids, such as histidine, L-histidine, histidine-HCl, and methionine; (iii) a pH between 5.5 and 7.0 (page 4); and (iv) suitable diluents including sterile water or a pH buffered solution, e.g. sterile saline solution (page 7, lines 1-5), wherein the pharmaceutical formulation can be administered through intravenous administration, for example by injection or infusion (page 17, lines 1-13). Dubey also teaches that the pharmaceutical formulation is liquid (page 6, lines 14-15) which can be administered at single or multiple doses (page 17, lines 14-17), and is stable at about 25°C for at least 1 month (page 5, lines 14-16). Dubey also used SE-HPLC to assess the stability of the pharmaceutical formulation under various conditions (e.g. after multiple freeze-thaw cycles), wherein the purity was above 95%, and changed less than 5% as measured by SE-HPLC (page 33-56, Example 3; Tables 10-24).
However, Dubey does not teach a pharmaceutical composition comprising cevostamab at about 20mg/mL or 1mg/mL, PS20 at about 0.06% or 0.12% w/v, methionine at about 10mM, histidine at about 20mM, sucrose at about 240mM, and N-acetyl-DL-tryptophan (NAT) at about 0.3mM. Furthermore, Dubey does not teach a pharmaceutical formulation comprising glacial acetic acid and/or L-methionine.
The deficiency is resolved by Cohen, Dion, and Jansson.
Cohen teaches an ongoing, multicenter Phase I trial GO39775 (NCT03275103) where a humanized immunoglobulin G-based T-cell-engaging bispecific antibody, BFCR4350A (now known as cevostamab), that targets the Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells was administered to evaluate the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in patients with relapsed/refractory (R/) multiple myeloma (MM) (page 1). Cohen also teaches that in this study, the overall response of the patients were observed at the active dose level of 3.6/20mg and above, wherein patients received 0.15-132mg of BFCR4350A by IV infusion (page 1-2; Table).
Dion teaches that the bioactivity of therapeutic proteins, including monoclonal antibodies, depends on conformational and biochemical stability. Dion teaches that given their sensitivity to degradation, biotherapeutics are formulated with excipients intended to buffer and stabilize them. Dion also discloses that oxidation is one of many degradation concerns, and to address this problem, the addition of antioxidants to liquid formulation has become a popular alternative for controlling therapeutic protein oxidation during manufacture and storage (page 2, left column, first and second paragraph). Dion teaches that in particular, N-acetyl-DL-tryptophan (NAT) has been identified as a desirable antioxidant as it has a lower oxidation potential than L-tryptophan, and therefore should more readily absorb oxidative stress than tryptophan residues in the protein. Furthermore, NAT has superior photo-stability relative to L-tryptophan (and other indole derivatives), as it produces lower levels of peroxide when exposed to light (4 µM H2O2 vs. 13 µM H2O2 over 4 h) (page 2, left column, fourth paragraph). Dion discloses that throughout the studies, 1mg/mL of antibodies were prepared with (i) 0.05mM to 0.3mM of NAT and 5mM of L-methionine for stress studies; or (ii) 0.3mM NAT and 5mM L-methionine at a pH of 5.8 for animal studies (page 3, right column, second paragraph – page 4, left column, second paragraph; page 4, right column, fifth and sixth paragraph – page 5, left column, third paragraph). Dion also teaches that NAT and L-methionine may be safe and effective as antioxidant excipients in biotherapeutic formulations, which provides an important new option in formulation development for the management of tryptophan and/or methionine oxidation (Figs. 1-4; page 10, left column, second paragraph).
Finally, Jansson teaches a pharmaceutical composition comprising 20mg/mL of a CD38 antibody, about 0.01% w/v to 0.1% w/v PS20 (page 13, paragraphs [192]-[197]), 0.1mg/mL to 5mg/mL (about 0.7mM to 33mM) methionine (page 15, paragraphs [0255]-[0259]), about 240mM sucrose (page 14, paragraph [0246]), and 10mM or 20mM histidine (page 14, paragraphs [0220], [0222], and [0224]), wherein the pH of the pharmaceutical composition is at pH 5.3-5.8 (page 15, paragraphs [0261]-[0263]). Jansson further teaches using glacial acetic acid to pH the formulation buffer (page 23, paragraph [0578]).
Regarding instant claims 1, 2, 96-97, 172, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the stable pharmaceutical formulation comprising (i) a bispecific antibody at a concentration between 0.05mg/mL and 15mg/mL; (ii) stabilizing agents comprising sucrose, polysorbate-20 (PS20), and amino acids histidine and methionine; (iii) suitable diluents including water and sterile saline solution as taught by Dubey to include the BFCR4350A (cevostamab) bispecific antibody of Cohen, and to include 0.3mM NAT of Dion, and 0.1% w/v PS20, 0.7mM to 33mM methionine, about 240mM sucrose, and 10mM histidine, as taught by Jansson. This is obvious because, Dubey teaches stable pharmaceutical formulations comprising (i) a bispecific antibody at a concentration between 0.05mg/mL and 15mg/mL; (ii) stabilizing or tonicity agents (e.g. sucrose, polysorbate-20 (PS20), and amino acids, such as histidine and methionine); and (iii) suitable diluents including sterile water and/or sterile saline solution wherein the pharmaceutical formulation is at a pH between 5.5 and 7.0, and wherein the pharmaceutical formulation can be administered through intravenous administration at single or multiple doses, Cohen teaches using the bispecific antibody BFCR4350A (now known as cevostamab), that targets the Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells, in an ongoing, multicenter Phase I trial to evaluate the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in patients with relapsed/refractory MM, Dion teaches adding 0.3mM NAT with L-methionine at pH of 5.8 was safe and effective as antioxidant excipients in biotherapeutic formulations based on animal studies, and Jansson teaches a pharmaceutical composition comprising about 0.01% w/v to 0.1% w/v PS20, 0.1mg/mL to 5mg/mL (about 0.7mM to 33mM) methionine, about 240mM sucrose, and 10mM histidine at a pH of 5.3-5.8. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the stable pharmaceutical formulation comprising (i) a bispecific antibody at a concentration between 0.05mg/mL and 15mg/mL; (ii) stabilizing agents comprising sucrose, polysorbate-20 (PS20), and amino acids histidine and methionine; (iii) suitable diluents including water and sterile saline solution, wherein the pharmaceutical formulation is liquid that can be administered through intravenous administration at single or multiple doses as taught by Dubey and modify the pharmaceutical formulation to comprise the bispecific antibody cevostamab taught by Cohen, 0.3mM NAT as taught by Dion, about 0.01% w/v to 0.1% w/v PS20, about 0.7mM to 33mM methionine, about 240mM sucrose, and 10mM histidine as taught by Jansson, wherein the pharmaceutical formulation is at pH 5.8 as taught by Dion to form the instant pharmaceutical composition comprising cevostamab, PS20, methionine, histidine, sucrose, NAT, and water, wherein cevostamab is at a concentration of about 1 mg/ml, the PS20 is at a concentration of about 0.06% w/v, the methionine is at a concentration of about 10 mM, the histidine is at a concentration of about 20 mM, the sucrose is at a concentration of about 240 mM, the NAT is at a concentration of about 0.3 mM, and the pH of the instant pharmaceutical composition is from 5.5 to 6.1, wherein the instant pharmaceutical composition is a liquid formulation diluted with normal saline solution comprising 0.9% (w/v) NaCl in a unit dosage form for intravenous administration.
Regarding instant claims 4 and 15, it would have been obvious for a person having ordinary skill in the art at the time of filing to identify that the pharmaceutical composition comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson would naturally cause no more than 6% or 10% oxidation of the methionine at position 257, according to EU numbering, of the Fc region of the cevostamab over two weeks at 40°C.
Regarding instant claims 106, 113-114, and 120, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical formulation wherein the pharmaceutical formulation is stable at 25°C for at least 1 month, wherein SE-HPLC was used to assess the stability of the pharmaceutical formulation wherein the purity was above 95% and changed less than 5% as measured by SE-HPLC as taught by Dubey and substitute the pharmaceutical formulation with the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson. This is obvious because, Dubey teaches stable pharmaceutical formulations stable at about 25°C for at least 1 month wherein SE-HPLC was used to assess the stability of the pharmaceutical formulation under various conditions, wherein the purity was above 95%, and changed less than 5% as measured by SE-HPLC, and the combined teachings of Dubey, Cohen, Dion, and Jansson teach a stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT to prevent degradation from oxidation, buffer solutions 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine, and water, wherein the pharmaceutical formulation is at pH 5.8. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical formulation wherein the pharmaceutical formulation is stable at 25°C for at least 1 month, wherein SE-HPLC was used to assess the stability of the pharmaceutical formulation wherein the purity was above 95% and changed less than 5% as measured by SE-HPLC as taught by Dubey and substitute the pharmaceutical formulation with the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson to form the instant pharmaceutical composition wherein the pharmaceutical composition is stable for about two weeks or longer at about 25°C, wherein the stability of the instant pharmaceutical composition is assessed by SE-HPLC wherein: (i) the instant pharmaceutical composition maintains a purity that is changed by less than 5 as measured by SE-HPLC; and (ii) the instant pharmaceutical composition has a purity of about 95% or higher as assessed by SE-HPLC.
Regarding instant claims 169 and 173, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and substitute histidine with L-histidine as taught by Dubey and methionine with L-methionine as taught by Dion. This is obvious because, the combined teachings of Dubey, Cohen, Dion, and Jansson teach a stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT to prevent degradation from oxidation, buffer solutions 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine, and water, wherein the pharmaceutical formulation is at pH 5.8, Dubey teaches that L-histidine is a stabilizing or tonicity agent used in pharmaceutical formulations, and Dion teaches that NAT and L-methionine used together is safe and effective as antioxidant excipients in biotherapeutic formulations, which provides an important new option in formulation development for the management of tryptophan and/or methionine oxidation. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and substitute histidine with L-histidine as taught by Dubey and methionine with L-methionine as taught by Dion to form the instant pharmaceutical composition comprising cevostamab, PS20, L-methionine, L-histidine, sucrose, NAT, and water, wherein the pH of the instant pharmaceutical composition is from 5.5 to 6.1.
Regarding instant claims 170 and 171, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and modify the pharmaceutical composition wherein histidine is histidine HCl as taught by Dubey, and to further comprise glacial acetic acid as taught by Jansson. This is obvious because, the combined teachings of Dubey, Cohen, Dion, and Jansson teach a stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT to prevent degradation from oxidation, buffer solutions 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine, and water, wherein the pharmaceutical formulation is at pH 5.8, Dubey teaches adding amino acids such as histidine-HCl to the stabilizing or tonicity agents to form stable pharmaceutical formulations, and Jansson teaches using glacial acetic acid to pH the pharmaceutical composition to about pH 5.5. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and modify the pharmaceutical composition wherein histidine is histidine HCl as taught by Dubey, and to further comprise glacial acetic acid as taught by Jansson to form the instant pharmaceutical composition comprising cevostamab, PS20, methionine, histidine-HCl, sucrose, NAT, water, and glacial acetic acid wherein the pH of the instant pharmaceutical composition is from 5.5 to 6.1.
Regarding instant claim 183, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM L-methionine, 240mM sucrose, 10mM L-histidine, water, and glacial acetic acid wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and modify the concentration of the antibody cevostamab to 20mg/mL and the concentration of L-histidine to 20mM as taught by Jansson. This is obvious because, the combined teachings of Dubey, Cohen, Dion, and Jansson teach a stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT to prevent degradation from oxidation, buffer solutions 0.06% w/v PS20, 10mM L-methionine, 240mM sucrose, 10mM L-histidine, water, and glacial acetic acid to pH, wherein the pharmaceutical formulation is at pH 5.8, and Jansson teaches a pharmaceutical composition comprising 20mg/mL of the antibody and L-histidine, wherein the concentration of histidine is 20mM. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM L-methionine, 240mM sucrose, 10mM L-histidine, water, and glacial acetic acid wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and modify the concentration of the antibody cevostamab to 20mg/mL and the concentration of L-histidine to 20mM as taught by Jansson to form the instant pharmaceutical composition comprising 20 mg/ml cevostamab, 0.06% w/v PS20,10 mM L-methionine, 20 mM L-histidine, 240 mM sucrose, 0.3 mM N-acetyl-DL-tryptophan, glacial acetic acid, and water, wherein the pH of the pharmaceutical composition is 5.8.
Claims 121-123 are rejected under 35 U.S.C. 103 as being unpatentable over Dubey et al (WO2020053301 A1, Priority to 9/11/2018; hereinafter Dubey Cohen A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Presented at: ASH Annual Meeting and Exposition; 2020 Dec 5-8. Abstract #292; hereinafter Cohen), Dion et al (Pharm Res, 2018, 35(222):1-11), and Jansson et al (US20190330363 A1, Priority to 11/3/2015; hereinafter Jansson), as applied to claim 1 above, and further in view of, Milenic et al (Pharmaceuticals, 2015, 8:435-454; hereinafter Milenic) and Pang (Bachelor Thesis, 2011, “Monoclonal antibody formations used in subcutaneous administration: excipients purpose”, pages 1-25; hereinafter Pang).
Regarding instant claims 121-123, the combined teachings of Dubey, Cohen, Dion, and Jansson are discussed above.
However, the combined teachings of Dubey, Cohen, Dion, and Jansson do not teach a pharmaceutical composition wherein the purity of the pharmaceutical composition as assessed by SE-HPLC is maintained at: (i) about the same for about 36 months or longer at about 5°C; (ii) about the same for about 42 months or longer at about 5°C; or (iii) about the same for about 64 months or longer at about 5°C.
The deficiency is resolved by Milenic et al and Pang.
Milenic teaches a study wherein the stability of TCMC-trastuzumab stored at 2-8°C (page 437, section 2.1; Figure 1) was studied over a 60 month period (analyzed at T0, 3, 6, 12, 18, 24, 36, 48, and 60 months) using SE-HPLC (page 435, Abstract; page 451, section 4.7.1; Figure 2). Milenic discloses that there is minimal variance in the % species that elutes at ~15 min, consistent with the elution time of an antibody under the conditions that the samples are applied and eluted (pages 438-439, Section 2.2.2; Figure 2). Furthermore, Milenic teaches that out of eleven tests were selected and performed on the cGMP TCMC-trastuzumab at pre-vialing, vialing, 3, 6, 12, 18, 24, 36, 48 and 60 months; only two tests have indicated the possibility of product failure, indicating that the immunoconjugate was stable under these conditions (page 452, Conclusion).
Pang teaches various types of excipients commonly found in biopharmaceutical formulations that can be used to attain a multi-year shelf life (Abstract). Pang taught the specific type and class of excipients in Table 1, and the number of appearance of the type of excipients in Table 2 (pages 22-25).
Regarding instant claims 121-123, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 and is stable at 25°C for at least 1 month as assessed by SE-HPLC as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and maintain it at about the same purity as assessed by SE-HPLC up to about 64 months or longer at about 5°C as taught by Milenic and Pang. This is obvious because, the combined teachings of Dubey, Cohen, Dion, and Jansson teach a stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT to prevent degradation from oxidation, buffer solutions 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine, and water, wherein the pharmaceutical formulation is at pH 5.8, Milenic teaches that the antibody formulation TCMC-trastuzumab stored at 2-8°C remained stable over a 60 month period (analyzed at timepoints T0, 3, 6, 12, 18, 24, 36, 48, and 60 months) as assessed by SE-HPLC, and Pang teaches that biopharmaceutical formulations that comprises excipients such as sugar, salt and surfactant can attain a multi-year shelf life. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 and is stable at 25°C for at least 1 month as assessed by SE-HPLC as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and maintain it at about the same purity as assessed by SE-HPLC up to about 64 months or longer at about 5°C as taught by Milenic and Pang to form the instant pharmaceutical composition comprising cevostamab, PS20, methionine, histidine, sucrose, NAT, and water wherein the pH of the instant pharmaceutical composition is from 5.5 to 6.1 and maintain the purity of the instant pharmaceutical composition at: : (i) about the same for about 36 months or longer at about 5°C; (ii) about the same for about 42 months or longer at about 5°C; or (iii) about the same for about 64 months or longer at about 5°C.
Claims 174-182 are rejected under 35 U.S.C. 103 as being unpatentable over Dubey et al (WO2020053301 A1, Priority to 9/11/2018; hereinafter Dubey), Cohen A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Presented at: ASH Annual Meeting and Exposition; 2020 Dec 5-8. Abstract #292; hereinafter Cohen), Dion et al (Pharm Res, 2018, 35(222):1-11), Jansson et al (US20190330363 A1, Priority to 11/3/2015; hereinafter Jansson), as applied to claim 1 above, and further in view of, Kang et al. (BioProcess International, 2016, 14(4):40-45, IDS entered on 12/19/2023; hereinafter Kang).
Regarding instant claims 174-182, the combined teachings of Dubey, Cohen, Dion, and Jansson are discussed above.
However, the combined teachings of Dubey, Cohen, Dion, and Jansson do not teach formulation optimization or development to achieve the different combinations recited in instant claims 174-182.
The deficiency is resolved by Kang.
Kang teaches that by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang additionally teaches that although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang also teaches lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang discloses 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentrations ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Kang also discloses Table 1, which lists excipients used in these antibody formulations. Kang further teaches that some commonalities can be observed: histidine is present in 35% of formulations (page 40, middle column, second bullet), sucrose was present in 30% of liquid formulations (page 40, right column, first bullet), an 80% of formulations used one of three surfactants that includes PS20 (page 40, middle column, third bullet). Kang also teaches that histidine has a pKa value of 6 (page 42, middle column, second to last paragraph). Finally, Kang teaches formulation development wherein stage 1 identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Additionally, Kang discloses that in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph).
Regarding claims 174-182, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical composition comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and identify the optimal weight per volume percentage of PS20, histidine, methionine, and pH of the formulation as taught by Kang. This is obvious because, the combined teachings of Dubey, Cohen, Dion, and Jansson teach a stable pharmaceutical formulation comprising 1mg/mL cevostamab, 0.3mM NAT to prevent degradation from oxidation, buffer solutions 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine, and water, wherein the pharmaceutical formulation is at pH 5.8, and Kang teaches formulation development wherein stage 1 identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. Additionally, Kang recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Further, Kang teaches that it is common for commercial antibodies to have a formulation with histidine, sucrose, and a surfactant as PS20, and that histidine has a pKa of 6. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical composition comprising 1mg/mL cevostamab, 0.3mM NAT, 0.06% w/v PS20, 10mM methionine, 240mM sucrose, 10mM histidine and water, wherein the pharmaceutical formulation is at pH 5.8 as taught by the combined teachings of Dubey, Cohen, Dion, and Jansson and identify the optimal weight per volume percentage of PS20, histidine, methionine, and pH of the formulation as taught by Kang to form the instant pharmaceutical compositions comprising 0.06% or 0.12% w/v PS20, 10mM methionine or L-methionine, 20mM histidine or L-histidine, 240mM sucrose, 0.3mM NAT, glacial acetic acid, and water, wherein the pH of the instant pharmaceutical composition is from 5.5 to 6.1, or 5.8.
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.
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Claims 1-2, 4, 15, 96, and 172-183 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 19, 21-22, 27-45, 53, 55-56, and 61-66 of copending Application No. 17/168,621 (US20210155715 A1; hereinafter ‘715). This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1-2, 4, 15, 96, and 172-183, claims 1-11, 21-22, 27-28, and 31-32 of ‘715 teaches a liquid formulation comprising: (i) a polypeptide, wherein the polypeptide is an antibody wherein the antibody is an IgG1 multispecific antibody wherein the concentration in the formulation is about 1mg/mL to about 250mg/mL; (ii) NAT at a concentration about 0.05mM to about 1.0mM; (iii) L-methionine at a concentration about 1mM to about 125mM, wherein the liquid formulation is formulated for intravenous administration, and (iv) a pH of about 4.5 to about 7.0. Claims 29 and 30 of ‘715 further teach that the liquid formulation further comprises one or more excipients, wherein the one or more excipients are selected from the group consisting of a stabilizer, a buffer, a surfactant, and a tonicity agent. Instant claims 1-2, 96, 172-183 teach a pharmaceutical composition that is a liquid formulation for intravenous administration, wherein the instant pharmaceutical composition comprises the bispecific antibody cevostamab at a concentration of 1mg/mL, PS20, 10mM methionine or L-methionine, 20mM histidine or L-histidine, 240mM sucrose, 0.3mM NAT, glacial acetic acid, and water, wherein the pH of the instant pharmaceutical composition is from 5.5 to 6.1. Claim 19 of ‘715 teach that the antibody has one or more methionine residues located in the constant region of the antibody. Instant claims 4 and 15 recite that oxidation of the methionine at position 257 of the Fc region of the bispecific antibody is less than about 6% or 10% over two weeks at 40°C. Claims 35-45, 53, 55-56, and 61-66 of ‘715 comprise of a method of reducing oxidation of a polypeptide comprising the same liquid formulation as in the claims discussed above. A claimed product is obvious over a method comprising the product. Therefore, although the claims at issue are not identical, the instant claims are not patentably distinct from the claims in the copending application.
Claims 1-2, 4, 15, 96-97, 106, 113-114, 120-123, 169, 172, and 174-183 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/600,194 (US20230331861 A1; hereinafter ‘186) in view of Cohen A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Presented at: ASH Annual Meeting and Exposition; 2020 Dec 5-8. Abstract #292; hereinafter Cohen). This is a provisional nonstatutory double patenting rejection.
Claims 1-3 of ‘186 teach a pharmaceutical composition comprising mosunetuzumab, PS20, methionine, a buffering agent, and a carrier, wherein the concentration of PS20 is from 0.01% to 0.1% weight-by-volume (w/v), the concentration of methionine is from 1 mM to 50 mM, and the concentration of the buffering agent is from 5 mM to 20 mM, wherein the pharmaceutical composition further comprises a tonicity agent comprising a sugar and is in a unit dosage form formulated for intravenous administration. Claim 4 of ‘186 recites that mosunetuzumab has a methionine at position 257 of the Fc region wherein the oxidation of the methionine at position257 of the Fc region is less than about 10% over two weeks at 40°C. Claims 5-11 of ‘186 teach a pharmaceutical composition comprising mosunetuzumab, a surfactant, methionine, and a carrier, wherein the pharmaceutical composition has a pH of about 5.8, and wherein:
the concentration of mosunetuzumab is about 10 mg/ml or less;
the concentration of the surfactant is from about 0.05% to about 0.1% (w/v); wherein the surfactant is PS20 at a concentration of 0.06% (w/v) and
the concentration of methionine is of about 10 mM,
wherein the pharmaceutical composition is in unit dosage form and wherein the unit dosage form is a liquid formulation for dilution with a normal saline solution comprising 0.9% (w/v) NaCl. Claims 12 and 13 of ‘186 recite that the pharmaceutical compositions described in claims 1 and 5 are stable for about two weeks or longer at about 25° C, wherein the stability of the pharmaceutical composition is assessed by SE-HPLC, wherein the pharmaceutical composition is determined to be stable if the pharmaceutical composition maintains a purity that is changed by less than 5% as measured by SE-HPLC (claims 14-17 of ‘186). Furthermore, claim 18 of ‘186 recite the pharmaceutical composition recited in claim 1 of ‘186, wherein the pharmaceutical composition comprises 1 mg/ml mosunetuzumab, 10 mM L-histidine acetate, 240 mM sucrose, 0.06% (w/v) PS20, and 10 mM methionine, pH 5.8, and wherein the pharmaceutical composition is formulated for administration by infusion after dilution with a normal saline solution comprising 0.45% or 0.9% NaCl.
However, ‘186 does not teach a pharmaceutical composition comprising cevostamab.
The deficiency is resolved by Cohen.
The teachings of Cohen are discussed above in the 103 rejection.
Regarding instant claims 1-2, 4, 15, 96-97, 106, 113-114, 120-123, 169, 172, and 174-183, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical composition comprising mosunetuzumab, PS20, methionine, a buffering agent, and a carrier, wherein the pharmaceutical composition has a pH of 5.8 as taught by ‘186 and substitute mosunetuzumab with cevostamab as taught by Cohen. This is obvious because, ‘186 teaches a pharmaceutical composition comprising mosunetuzumab, PS20, methionine, a buffering agent, and a carrier, wherein the pharmaceutical composition has a pH of 5.8, and Cohen teaches using the bispecific antibody BFCR4350A (now known as cevostamab), that targets the Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells, in patients with relapsed/refractory MM to evaluate the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical composition comprising mosunetuzumab, PS20, methionine, a buffering agent, and a carrier, wherein the pharmaceutical composition has a pH of 5.8 as taught by ‘186 and substitute mosunetuzumab with cevostamab as taught by Cohen to form the instant pharmaceutical composition comprising cevostamab, PS20, methionine, histidine, sucrose, NAT, and water, wherein cevostamab is at a concentration of about 1 mg/ml, the PS20 is at a concentration of about 0.06% w/v, the methionine is at a concentration of about 10 mM, the histidine is at a concentration of about 20 mM, the sucrose is at a concentration of about 240 mM, the NAT is at a concentration of about 0.3 mM, and the pH of the instant pharmaceutical composition is from 5.5 to 6.1, wherein the instant pharmaceutical composition is a liquid formulation diluted with normal saline solution comprising 0.9% (w/v) NaCl in a unit dosage form for intravenous administration.
Claims 1, 4, 15, 96-97, 170, and 174-183 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-8, 12-19, 21-22 and 26-28 of copending Application No. 19/647,343 (hereinafter ‘343) in view of Cohen A, et al. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Presented at: ASH Annual Meeting and Exposition; 2020 Dec 5-8. Abstract #292; hereinafter Cohen) and Kang et al. (BioProcess International, 2016, 14(4):40-45, IDS entered on 12/19/2023; hereinafter Kang). This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 7-8, and 21-22 of ‘343 teach a pharmaceutical composition comprising 10 mg/ml mosunetuzumab, about 10 mM L-histidine, about 240 mM sucrose, about 0.06% (w/v) PS20, and about 10 mM methionine, wherein the pharmaceutical composition has a pH of 5.8, wherein the pharmaceutical composition further comprises histidine acetate and is in a unit dosage form formulated for intravenous administration. Claims 12-18 and 26-28 of ‘343 teach pharmaceutical compositions comprising different concentrations of mosunetuzumab, with about 10 mM L-histidine, about 240 mM sucrose, about 0.06% (w/v) PS20, and about 10 mM methionine wherein the pharmaceutical composition has a pH of 5.8. Claims 5 and 19 of ‘343 recite that mosunetuzumab has a methionine at position 257 of the Fc region wherein the oxidation of the methionine at position257 of the Fc region is less than about 10% over two weeks at 40°C.
However, ‘343 does not teach a pharmaceutical composition comprising cevostamab.
The deficiency is resolved by Cohen and Kang.
The teachings of Cohen and Kang are discussed above in the 103 rejection.
Regarding instant claims 1, 4, 15, 96-97, 170, and 174-183, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the pharmaceutical composition comprising different concentrations of mosunetuzumab, with about 10 mM L-histidine, about 240 mM sucrose, about 0.06% (w/v) PS20, and about 10 mM methionine wherein the pharmaceutical composition has a pH of 5.8 as taught by ‘343 and substitute mosunetuzumab with cevostamab as taught by Cohen and Kang. This is obvious because, ‘343 teaches a pharmaceutical composition comprising different concentrations of mosunetuzumab, with about 10 mM L-histidine, about 240 mM sucrose, about 0.06% (w/v) PS20, and about 10 mM methionine wherein the pharmaceutical composition has a pH of 5.8, Cohen teaches using the bispecific antibody BFCR4350A (now known as cevostamab), that targets the Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells, in patients with relapsed/refractory MM to evaluate the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy, and Kang teaches formulation development wherein stage 1 identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients. Additionally, Kang recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Further, Kang teaches that it is common for commercial antibodies to have a formulation with histidine, sucrose, and a surfactant as PS20, and that histidine has a pKa of 6. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to take the pharmaceutical composition comprising different concentrations of mosunetuzumab, with about 10 mM L-histidine, about 240 mM sucrose, about 0.06% (w/v) PS20, and about 10 mM methionine wherein the pharmaceutical composition has a pH of 5.8 as taught by ‘343 and substitute mosunetuzumab with cevostamab as taught by Cohen and Kang to form the instant pharmaceutical composition comprising cevostamab, PS20, methionine, histidine, sucrose, NAT, and water, wherein cevostamab is at a concentration of about 1 mg/mL or 20mg/mL, the PS20 is at a concentration of about 0.06% w/v, the methionine is at a concentration of about 10 mM, the histidine is at a concentration of about 20 mM, the sucrose is at a concentration of about 240 mM, the NAT is at a concentration of about 0.3 mM, and the pH of the instant pharmaceutical composition is from 5.5 to 6.1.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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