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 .
Priority
The present application, filed on 04/13/2023, claims domestic priority over a provisional application PRO 63/330,748 which was filed on 04/13/2022.
Status of Claims
Claims 1-8, 10, 12, 15-19, 21-24, 26-27, and 30, amended on 07/21/2023, are pending and examined under the merits herein.
Information Disclosure Statement
IDS filed on 07/25/2023 have the following informalities. Correction is required:
Reference Document Cite No. P and BZ are duplicates. As such, Document Cite No. P has been lined through and has been indicated on the IDS as a duplicate, “dup”.
Supplementary European Search Report EP 06 73 0751 under Non-Patent Literature is not listed in the IDS.
Supplementary European Search Report EP 11 84 5786 under Non-Patent Literature is not listed in the IDS.
There is no copy of the Foreign Reference Cite No. R, EP-1870459-A4, 09-01-2010, Chugai Pharmaceutical Co Ltd provided and the reference has not been considered. The reference has been lined through. If the applicant wants the reference to be considered, applicant must provide a copy.
Foreign Reference Cite No. U, EP-2647707-A4, 03-30-2014, Chugai Pharmaceutical Co Ltd is listed in IDS but no copy is provided.
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.
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.
Claims 1-8, 10, 12, 15-19, 21-22, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Fast and Paulus, 2020 (US PGPUB Application US2020/0231698 A1, published on 07/23/2020, listed in IDS) in view of Ast et al., 2018 (U.S. Patent 9,914,776, issued on 03/13/2018, listed in IDS) and in further view of Hutchings et al., 2021 (Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner FC, Sureda A, Salles G, Martínez-Lopez J, Crump M, Thomas DN, Morcos PN, Ferlini C, Bröske AE, Belousov A, Bacac M, Dimier N, Carlile DJ, Lundberg L, Perez-Callejo D, Umaña P, Moore T, Weisser M, Dickinson MJ. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol. 2021 Jun 20;39(18):1959-1970. doi: 10.1200/JCO.20.03175. Epub 2021 Mar 19. PMID: 33739857; PMCID: PMC8210975; listed in IDS), FDA Drug Safety Guidance, 2016 (FDA guidance for industry: Safety Considerations for Product Design to Minimize Medication Errors, published April 2016, https://www.fda.gov/files/drugs/published/Safety-Considerations-for-Product-Design-to-Minimize-Medication-Errors-Guidance-for-Industry.pdf), Strickley and Lambert, 2021 (Strickley RG, Lambert WJ. A review of Formulations of Commercially Available Antibodies. J Pharm Sci. 2021 Jul;110(7):2590-2608.e56. doi: 10.1016/j.xphs.2021.03.017. Epub 2021 Mar 28. PMID: 33789155), Falconer, 2019 (Falconer RJ. Advances in liquid formulations of parenteral therapeutic proteins. Biotechnol Adv. 2019 Nov 15;37(7):107412. doi: 10.1016/j.biotechadv.2019.06.011. Epub 2019 Jun 27. PMID: 31254660); Martos et al., 2017 (Martos A, Koch W, Jiskoot W, Wuchner K, Winter G, Friess W, Hawe A. Trends on Analytical Characterization of Polysorbates and Their Degradation Products in Biopharmaceutical Formulations. J Pharm Sci. 2017 Jul;106(7):1722-1735. doi: 10.1016/j.xphs.2017.03.001. Epub 2017 Mar 14. PMID: 28302541); Cremasco et al., 2021 (Cremasco F, Menietti E, Speziale D, Sam J, Sammicheli S, Richard M, Varol A, Klein C, Umana P, Bacac M, Colombetti S, Perro M. Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model. PLoS One. 2021 Jan 6;16(1):e0241091. doi: 10.1371/journal.pone.0241091. PMID: 33406104; PMCID: PMC7787458.) as educational reference Gutka, 2018 (Hiten Gutka. 2018. “Rational Selection of Sugars for Biotherapeutic Stabilization: A Practitioner’s Perspective.” Bioprocessintl.com. October 15, 2018. https://www.bioprocessintl.com/formulation/rational-selection-of-sugars-for-biotherapeutic-stabilization-a-practitioner-s-perspective), Glentham Life Sciences for polysorbate 20, 2020 (Tween 20) (Tween 20, Website: https://web.archive.org/web/20201026004316/https://www.glentham.com/en/products/product/GD9856/, accessed 10/26/2020) and Molarity Calculator Website (https://web.archive.org/web/20220209144352/https://www.tocris.com/resources/molarity-calculator, accessed 02/09 2022).
Anti-CD20/anti-CD3 bispecific antibody
Regarding instant claims 1, 2, 3, and 4, Fast and Paulus, 2020 teach a liquid pharmaceutical composition comprising a bispecific antibody (page 10, paragraph 022, “formulation is in a liquid form”), but do not teach the anti-CD20/anti-CD3 bispecific antibody or the concentration the bispecific antibody.
Ast et al., 2018 teaches the anti-CD20/anti-CD3 bispecific antibody (FIG 2B, right panel, showing the structure of the bispecific antibody, Figure 1 of this office action) wherein the bispecific antigen binding molecule comprising a first Fab molecule which binds to the first antigen, a second Fab molecule that binds to the second antigen and that the first antigen and second antigen could be either the activating T cell antigen or the target cell antigen (page 78, column 3, line 53). Ast et al., further teaches that the first antigen is the target cell antigen CD20 and a second antigen is the activating T cell antigen CD3 (page 78, column 4 , line 22).
Hutchings et al., 2021 teaches the two-step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg (page 1961, column 2, paragraph 1, “Based on safety data and PK or pharmacodynamic modeling, two step-up dosing (SUD) cohorts were subsequently tested with dosing of 2.5 mg (C1D1), 10 mg (C1D8), and 16 mg or 30 mg (C2D1), with the latter being selected as the recommended phase II dose (RP2D)”).
Most common commercially available monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml (Strickley and Lambert, 2021, page 2597, “formulations intended for intravenous infusions are concentrates that are diluted into infusion fluids” and page 2598, column 2, paragraph 1, “The overall range in antibody concentration is 0.012-200 mg/mL). The FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors (page 15, Product Strength, “Developing a product strength that is incongruent with the dosage and administration of the product complicates the calculation, preparation, and administration of a dose and has led to medication dosing errors.” And “titration of dosing should be considered when developing product strengths to ensure that intermediate doses are achievable”). It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance.
Even though Hutchings and Ast do not teach the exact dosage range of the bispecific antibody, the dosage in a composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding instant claim 1 and 5, Fast and Paulus, 2020 do not teach the bispecific antibody containing the SEQ ID NOs of the anti-CD20/anti-CD3 bispecific antibody. Ast et al., 2018 teaches the exact sequences of the Fab molecules encoding SEQ ID NO: 7-8 and 15-16 (Ast et al., 2018 see SEQ ID NO: 39, 71, 35 and 38)). The hypervariable regions of the light chain and heavy chains encoded in SEQ ID NO: 1-6 that binds specifically to CD20 and SEQ ID NO: 9-14 that binds specifically to CD3 are encoded in the SEQ ID NO: 7-8 and 15-16 and therefore these sequences are included in the SEQ ID NOs disclosed in Ast et al., 2018. Ast et al., 2018 further discloses that the bispecific antigen binding molecules designed for T cell activation and re-direction that combine good efficacy and produce ability with low toxicity and favorable pharmacokinetic properties (page 78, column 3, paragraph 13). Fast and Paulus, 2020 teaches that the L-histidine/HCl buffer is the most favorable buffer, sucrose in combination with methionine are the most favorable stabilizers, and polysorbate 20 is the most favorable surfactant to obtain the maximum antibody stability and antibody formulations free from particles (page 12, paragraph 0255). It would have been obvious to the person of ordinary skill in the art to substitute the bispecific antibody and SEQ ID NOs of the pharmaceutical composition with other bispecific antibodies and use the excipients as taught by Fast and Paulus, 2020 to ensure maximum antibody stability and particle-free of the pharmaceutical formulation.
Regarding instant claim 6, Fast and Paulus, 2020 does not teach the molecular structure of the anti-CD20/anti-CD3 bispecific antibody.
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Figure 1. CD20 TCB bispecific antibody by Ast et al., 2018 (page 5, FIG 2B, Drawings, U.S. Patent 9,914,776 B2, 03/13/2018)
Ast et al., 2018 teaches the anti-CD20/anti-CD3 bispecific antibody structure (FIG 2B, right panel, showing the structure of the bispecific antibody in Figure 1 of this office action) wherein the first Fab molecule which specifically binds to CD3, wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other; a second Fab molecule and a third Fab molecule which each specifically binds to CD20, wherein in the constant domain CL of each of the second Fab molecule and third Fab molecule the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by lysine (K) or arginine (R)(numbering according to Kabat), and wherein in the constant domain CH1 of each of the second Fab and third Fab molecule the amino acid at position 147 is substituted by glutamic acid (E) (EU numbering) and the amino acid at position 213 is substituted by glutamic acid (E) (EU numbering); (page 83, column 14, line 3, “2+1 IgG CrossFab, inverted” with charge modifications (VH/VL exchange in CD3 binder, charge modification in CD20 binders, EE=147E, 213E; RK=123R, 124K”). Further, Ast et al., 2018 teaches a Fc domain composed of a first and a second subunit capable of stable association (page 92, column 32, paragraph 109, line 15 “T cell activating bispecific antigen binding molecule comprises an Fc domain composed of a first and a second subunit capable of stable association”). Ast et al., 2010 teaches that the bispecific antibody format has advantages over others as it has fewer side products due to introducing charged amino acids with opposite charges at specific amino acid positions in the CH1 and CL domains and therefore improves the ratio of desired bispecific antibody to undesired side products (page 78, column 3, line 35) and that the anti-CD20/anti-CD3 TCB the “inverted” version with charge modifications on the anti CD20 Fab (molecule B or Fig.2A) is the format that could be produced with the highest recovery and final quality (page 114, column 75, paragraph 299, line 32). It would have been obvious to the person of ordinary skill in the art to substitute the bispecific antibody in Fast and Paulus, 2020 with the anti-CD20/anti-CD3 bispecific antibody as disclosed by Ast et al., 2018 that results in a high recovery and better-quality pharmaceutical grade product with the excipients suggested by Fast and Paulus, 2020.
Regarding instant claim 7, Fast and Paulus, 2020 do not teach that the bispecific antibody is glofitamab. Fast and Paulus, 2020 teaches that excipients of the pharmaceutical composition wherein the L-histidine/HCl buffer is the most favorable buffer, sucrose in combination with methionine are the most favorable stabilizers, and polysorbate 20 is the most favorable surfactant to obtain the maximum antibody stability and antibody formulations free from particles (page 12, paragraph 0255). Hutchings et al., 2021 teaches the anti-CD20/anti-CD3 bispecific antibody is glofitamab wherein the bispecific antibody is bivalent to CD20 and monovalent to CD3, is a full-length antibody with longer half-life compared to others and has superior in vitro potency than other 1:1 configurated formats (page 1959-1960, 1, first paragraph). It would have been obvious to the person of ordinary skill in the art to use the excipients taught by Fast and Paulus, 2020 and the bispecific antibody glofitamab taught by Hutchings et al., 2021 to create stable and pharmaceutical grade liquid composition of the bispecific antibody to improve potency and increase half-life of the antibody.
Fast and Paulus, 2020 teach the excipients to formulate the liquid pharmaceutical composition as recited in the instant claims 8, 10, 12, 15, 16, 17, 18, 19, 21, and 22 which are dependent on claim 1. Fast and Paulus, 2020 teach excipients comprising a buffering agent, pH ranges, tonicity agent, methionine, and surfactants that are commonly used in the art (Falconer, 2019; “ some manufacturers of Mabs seem to have settled on formulations comprise histidine or acetate buffers, sucrose or trehalose tonicity modifiers and polysorbate 80 surfactant, such as Ilumya™, Aimovig™, Tremfya™, Renflexis, Imfinzi® and Cyltezo™ (all from 2017 to 18). Close scrutiny of the actual formulations used with Mabs show most differ from this combination in one or more ways, such as addition of an amino acid (arginine, asparagine, or methionine) or the substitution of polysorbate 80 with polysorbate 20.). Falconer, 2019 also discloses that these formulations have been used in commercially available Mabs and ensure efficacious treatment and do not result in unwelcome side effects or adverse reactions in the patients like Humira® (page 1, column 2, paragraph 1). It would have been obvious to the person of ordinary skill in the art to substitute the bispecific antibody in Fast and Paulus, 2020 with the anti-CD20/anti-CD3 bispecific antibody as taught by Hutchings et al., 2021 in the pharmaceutical composition as taught in Fast and Paulus, 2020, to ensure stable liquid formulations and reduce unwelcome side effects and adverse events. The following excipients are examined in detail below:
Buffering agent and pH
Regarding instant claim 1, 8 and 10, Fast and Paulus, 2020 teach the buffering agent concentration is about 10 to 50 mM as recited in instant claim 1 (page 9, paragraph 107 “Preferably, the buffering agent is at a concentration of 10 to 50 mM”) and that it is histidine with a concentration of 15 to 25 mM L-histidine and pH of about 5.2 to about 5.8 as recited in instant claim 8 (page 9, paragraph 0153 and 0157, “15 to 25 mM L-histidine; 0.03 to 0.05% (w/v) polysorbate 20; 220 to 250 mM sucrose; 5 to 15 mM methionine; at a pH of 5.5 + 0.3.”). Further, in instant claim 8 and 10, Fast and Paulus, 2020 teach that the buffering agent is at a concentration of about 20 mM and the pH range is about 5.2 to about 5.8 (page 10, paragraph 0216 and 0220, “5 mg/ml of a CEA CD3 bispecific antibody, preferably CEA TCB; 20 mM L-histidine; 0.05% (w/v) polysorbate 20; 240 mM sucrose; 10 mM methionine; at a pH of 5.5 +/- 0.3.”).
Tonicity agent
Regarding instant claim 1, 12, 15, and 16, Fast and Paulus, 2020 teach the tonicity agent concentration about 200 mM (page 9, paragraph 0120, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 15 to 30 mM L-histidine; 0.02 to 0.05% (w/v) polysorbate 20; 120 to 300 mM sucrose; optionally, 5 to 25 mM methionine”) as recited in instant claim 1. Fast and Paulus, 2020 do not explicitly teach that the sucrose is a tonicity agent but rather a stabilizer, however, Gutka, 2018 teaches that sucrose can be both a tonicity agent and a stabilizer (page 2, line 4, “Tonicity agents/stabilizers (sugars such as sucrose, polyols such as sorbitol)”) and further teaches that sucrose is preferred for the liquid product probably because it is highly soluble, so the liquid solution can be frozen easily as formulated DS, and sucrose remains amorphous during freeze–thaw processing and storage (page 11, paragraph 6). It would have been obvious to the person of ordinary skill in the art to use sucrose as the tonicity and stabilizer agent as taught by Gutka, 2018.
Fast and Paulus, 2020 teach that the tonicity agent is a sucrose with a concentration of 200 mM – 280 mM (page 9, paragraph 0111 and 0112, “Preferably the at least one stabilizer is sucrose. Preferably, the at least one stabilizer is at a concentration of 120 to 300 mM”) and about 240 mM (page 9, paragraph 0115, “particularly in embodiments wherein the concentration of the CEA CD3 bispecific antibody is below 50 mg/ml (e.g. 5 mg/ml, or 20 mg/ml), the saccharide is at a concentration of about 240 mM”) as is as recited in instant claim 12, 15, and 16.
Methionine
Regarding instant claims 1, 17, 18, Fast and Paulus, 2020 teach the methionine concentration about 0 to 15 mM methionine as recited in instant claim 1 (page 9, paragraph 0156, “15 to 25 mM L-histidine; 0.03 to 0.05% (w/v) polysorbate 20; 220 to 250 mM sucrose; 5 to 15 mM methionine; at a pH of 5.5 + 0.3.” ), methionine is at a concentration of about 5-15 mM as recited in instant claim 17 (page 9, paragraph 0156, “15 to 25 mM L-histidine; 0.03 to 0.05% (w/v) polysorbate 20; 220 to 250 mM sucrose; 5 to 15 mM methionine; at a pH of 5.5 + 0.3.”) and methionine is at a concentration of about 10 mM as recited in instant claim 18 (page 9, paragraph 0115, “particularly in embodiments wherein the concentration of the CEA CD3 bispecific antibody is below 50 mg/ml (e.g. 5 mg/ml, or 20 mg/ml), the saccharide is at a concentration of about 240 mM and methionine is at a concentration of about 10 mM”).
Surfactants
Regarding instant claim 1, 19, 21, and 22, Fast and Paulus teaches the surfactant concentration as recited in instant claim 1 at 0.2 mg/mI of a surfactant (page 9, paragraph 109 and 0110, “ the surfactant comprised in the formulation is […] most preferably polysorbate 20” and “the surfactant is at a concentration of 0.01 to 0.1% (w/v), more preferably 0.02 to 0.05%, most preferably 0.05%.”). Even though Fast and Paulus do not teach the surfactant in mg/ml unit, Martos et al., 2017 teaches that the percent weight to volume ratio (% (w/v)) can be calculated from mg/ml wherein 0.2 mg/ml is 0.02 % (w/v) (page 1, column 2, “Typical PS concentrations in biopharmaceuticals are between 0.001% and 0.1% (w/v), corresponding to 0.01 and 1 mg/mL.”). Based on Martos et al., 2017, the calculation of polysorbate 20 mg/ml to %(w/v) is as follows 0.2 mg/ml divided by 100 equals 0.02 % (w/v). All other polysorbate 20 concentrations that are in mg/ml recited in the claims, will be converted to % (w/v). Martos et al., 2017 further teaches that the polysorbate 20 is the most common surfactant in biopharmaceutical products in particular to protect proteins against interfacial stress (page 1, abstract). It would have been obvious to the person of ordinary skill in the art to use concentrations of the polysorbate 20 commonly used in biopharmaceutical products to stabilize proteins against interfacial stress in the liquid pharmaceutical composition.
Fast and Paulus teach the concentration of the polysorbate 20 concentration of about 0.2-0.8 mg/ml in instant claim 19, 21 (page 9, paragraph 0110, “the surfactant is at a concentration of 0.01 to 0.1% (w/v), more preferably 0.02 to 0.05%, most preferably 0.05%.”)) and a concentration of about 0.5 mg/ml in instant claim 22 (page 10, paragraph 0217, “5 mg/ml of a CEA CD3 bispecific antibody, preferably CEA TCB; 20 mM L-histidine; 0.05% (w/v) polysorbate 20; 240 mM sucrose; 10 mM methionine; at a pH of 5.5 +/- 0.3” 0.5 mg/ml divided by 100 is 0.05 % (w/v)).
Regarding instant claims 26 and 27, Fast and Paulus, 2020 teaches the polysorbate 20 concentration in mg/ml and weight to volume % (w/v%) but does not teach the polysorbate 20 to bispecific antibody by molar ratio. Cremasco et al., 2021 teaches the molecular weight of the anti-CD20/anti-CD3 bispecific antibody (CD20 TCB in this case) 194.342 kDa (page 23, paragraph 2) and the molecular weight of polysorbate 20 is 1228 g/mol (Glentham Life Sciences Tween 20 Website, page 2).
Based on these known molecular weights, Fast and Paulus, 2020 teaches the polysorbate 20 at 0.05 % (w/v) which is 0.5 mg/ml as described above. The bispecific antibody concentration in the instant claim 1 is between about 1 to 25 mg/ml and further narrowed down to 1 to 5 mg/ml (instant claim 2) and about 0.9 to 1.1 mg/ml (instant claim 3) and finally in instant claim 4 and 24 the concentration is in the range of about 1 mg/ml which has been taught by Hutchings et al., 2021 and others described above). A person of ordinary skill in the art would know how to calculate the molar ratios of the polysorbate 20 to the anti-CD20/anti-CD3 bispecific antibody. The molar ratio is calculated by dividing the molar concentrations of the polysorbate 20 (1228 g/mol at 0.05 mg/ml) to the bispecific antibody (194.342 kDa at 1 mg/ml) using the molecular weight and mass concentration (Tocris Website: https://web.archive.org/web/20220209144352/https://www.tocris.com/resources/molarity-calculator, available on 02/09/2022). The calculation is as followed in Figures 2-4 of the office and action and resulted in a molar ratio of about 79 as recited in instant claim 27:
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Figure 2. Formula to calculate molecular concentration of polysorbate 20 (PS20)
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Figure 3. Formular to calculate molecular concentration of the anti-CD20/anti-CD3 bispecific antibody (mAb)
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Figure 4. Molecular Ratio of the polysorbate 20 and the anti-CD20/anti-CD3 bispecific antibody.
Based on the conversion calculation using the concentration of the polysorbate 20 as taught by Fast and Paulus, 2020, the concentration of bispecific antibody in the instant claims, and molecular weight of the bispecific antibody taught by Cremasco et al., 2021 and polysorbate 20 taught by Glentham Life Sciences Website, a person of ordinary skill in the art would be able to calculate the molar ratio and would come up with the same molar ratio of about 79 as claimed in instant claim 27. Since the molar ratio of 79 falls within the 50-100 molar ratio range recited in instant claim 26, it is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Claims 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Fast and Paulus, 2020 (cited previously) and further in view of Ast et al., 2018 (cited previously); Hutchings et al., 2021(cited previously); Strickley and Lambert, 2021 (cited previously); and FDA Drug Safety Guidance 2016 (cited previously).
Regarding claim instant 23, as described above, Fast and Paulus teaches the excipients of the liquid pharmaceutical composition of a bispecific antibody but does not teach the bispecific antibody is the anti-CD20/anti-CD3 bispecific antibody. Ast et al., 2018 teaches the anti-CD20/anti-CD3 bispecific antibody (FIG 2B, right panel, showing the structure of the bispecific antibody, Figure 1 of this office action) wherein the bispecific antigen binding molecule comprising a first Fab molecule which binds to the first antigen, a second Fab molecule that binds to the second antigen and that the first antigen and second antigen could be either the activating T cell antigen or the target cell antigen (page 78, column 3, line 53). Ast et al., further teaches that the first antigen is the target cell antigen CD20 and a second antigen is the activating T cell antigen CD3 (page 78, column 4 , line 22).
Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg (page 1961, column 2, paragraph 1, “Based on safety data and PK or pharmacodynamic modeling, two step-up dosing (SUD) cohorts were subsequently tested with dosing of 2.5 mg (C1D1), 10 mg (C1D8), and 16 mg or 30 mg (C2D1), with the latter being selected as the recommended phase II dose (RP2D)”).
Most common commercially available monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml (Strickley and Lambert, 2021, page 2597, “formulations intended for intravenous infusions are concentrates that are diluted into infusion fluids” and page 2598, column 2, paragraph 1, “The overall range in antibody concentration is 0.012-200 mg/mL). The FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors (page 15, Product Strength, “Developing a product strength that is incongruent with the dosage and administration of the product complicates the calculation, preparation, and administration of a dose and has led to medication dosing errors.” And “titration of dosing should be considered when developing product strengths to ensure that intermediate doses are achievable”). It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance.
Even though Hutchings and Ast do not teach the exact dosage range of the bispecific antibody, the dosage in a composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Fast and Paulus, 2020 teaches the pharmaceutical composition comprising about 15-25 mM of a histidine buffer; about 200-280 mM sucrose; about 0-15 mM methionine; and about 0.2-0.8 mg/ml of polysorbate 20 at a pH of about 5 to about 6 (page 9, paragraphs 0159- 0164, “15 to 30 mM L-histidine; 0.02 to 0.05% (w/v) polysorbate 20; 120 to 300 mM sucrose; optionally, 5 to 25 mM methionine; at a pH of 5.5±0.5.” [as described above, 0.02 %(w/v) is 0.2 mg/ml polysorbate 20]). The excipient composition and concentrations are clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
The excipients comprising a buffering agent, pH ranges, tonicity agent, methionine, and surfactants taught by Fast and Paulus 2020 are commonly used in the art to formulate with antibodies (Falconer, 2019; “ some manufacturers of Mabs seem to have settled on formulations comprise histidine or acetate buffers, sucrose or trehalose tonicity modifiers and polysorbate 80 surfactant, such as Ilumya™, Aimovig™, Tremfya™, Renflexis, Imfinzi® and Cyltezo™ (all from 2017 to 18). Close scrutiny of the actual formulations used with Mabs show most differ from this combination in one or more ways, such as addition of an amino acid (arginine, asparagine, or methionine) or the substitution of polysorbate 80 with polysorbate 20.). Falconer, 2019 also discloses that these formulations have been used in commercially available Mabs and ensure efficacious treatment and do not result in unwelcome side effects or adverse reactions in the patients like Humira® (page 1, column 2, paragraph 1). It would have been obvious to the person of ordinary skill in the art to substitute the bispecific antibody in Fast and Paulus, 2020 with the anti-CD20/anti-CD3 bispecific antibody in the pharmaceutical composition as taught in Fast and Paulus, 2020, to ensure stable liquid formulations of the bispecific antibody and reduce unwelcome side effects and adverse events.
Regarding instant claim 24, as described above, Fast and Paulus teaches the excipients of the liquid pharmaceutical composition of a bispecific antibody but does not teach the bispecific antibody is glofitamab and its concentration. Hutchings et al., 2021 teaches the anti-CD20/anti-CD3 bispecific antibody is glofitamab wherein the bispecific antibody is bivalent to CD20 and monovalent to CD3, is a full-length antibody with longer half-life compared to others and has superior in vitro potency than other 1:1 configurated formats (page 1959-1960, 1, first paragraph). It would have been obvious to the person of ordinary skill in the art to use the excipients taught by Fast and Paulus, 2020 and the bispecific antibody glofitamab taught by Hutchings et al., 2021 to create stable and pharmaceutical grade liquid composition of the bispecific antibody to improve potency and increase half-life of the antibody.
Regarding concentration of the bispecific antibody, Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg (page 1961, column 2, paragraph 1, “Based on safety data and PK or pharmacodynamic modeling, two step-up dosing (SUD) cohorts were subsequently tested with dosing of 2.5 mg (C1D1), 10 mg (C1D8), and 16 mg or 30 mg (C2D1), with the latter being selected as the recommended phase II dose (RP2D)”).
Most common commercially available monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml (Strickley and Lambert, 2021, page 2597, “formulations intended for intravenous infusions are concentrates that are diluted into infusion fluids” and page 2598, column 2, paragraph 1, “The overall range in antibody concentration is 0.012-200 mg/mL). The FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors (page 15, Product Strength, “Developing a product strength that is incongruent with the dosage and administration of the product complicates the calculation, preparation, and administration of a dose and has led to medication dosing errors.” And “titration of dosing should be considered when developing product strengths to ensure that intermediate doses are achievable”). It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance.
Even though Hutchings does not teach the exact dosage range of the bispecific antibody in the pharmaceutical composition but rather the clinical dose, the dosage in a composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Fast and Paulus, 2020 teaches the pharmaceutical composition comprising about 20 mM of a histidine buffer; about 240 mM sucrose; about 10 mM methionine; about 0.5 mg/ml of polysorbate 20 at a pH of about 5.5 (page 9, paragraphs 0216-0220, “20 mM L-histidine; 0.05% (w/v) polysorbate 20; 240 mM sucrose; 10 mM methionine; at a pH of 5.5±0.3” [as described above, 0.05% (w/v) is 0.5 mg/ml]). The excipients comprising a buffering agent, pH ranges, tonicity agent, methionine, and surfactants taught by Fast and Paulus 2020 are commonly used in the art to formulate with antibodies (Falconer, 2019; “ some manufacturers of Mabs seem to have settled on formulations comprise histidine or acetate buffers, sucrose or trehalose tonicity modifiers and polysorbate 80 surfactant, such as Ilumya™, Aimovig™, Tremfya™, Renflexis, Imfinzi® and Cyltezo™ (all from 2017 to 18). Close scrutiny of the actual formulations used with Mabs show most differ from this combination in one or more ways, such as addition of an amino acid (arginine, asparagine, or methionine) or the substitution of polysorbate 80 with polysorbate 20.). Falconer, 2019 also discloses that these formulations have been used in commercially available Mabs and ensure efficacious treatment and do not result in unwelcome side effects or adverse reactions in the patients like Humira® (page 1, column 2, paragraph 1). It would have been obvious to the person of ordinary skill in the art to substitute the bispecific antibody in Fast and Paulus, 2020 with the anti-CD20/anti-CD3 bispecific antibody in the pharmaceutical composition as taught in Fast and Paulus, 2020, to ensure stable liquid formulations of the bispecific antibody and reduce unwelcome side effects and adverse events.
Claims 30 is rejected under 35 U.S.C. 103 as being unpatentable over Fast and Paulus, 202 in view of Hutchings et al., 2021 (cited previously) and Falconer, 2019 (cited previously).
Hutchings et al., 2021 teaches the a method of treating or delaying the progression of a cell proliferative disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab (page 1960, “Glofitamab was given as an initial 4-hour intravenous (IV) infusion, reduced to 2 hours once a prior infusion had occurred without complications.”; page 1960, “Patients of age older than18 years with histologically confirmed B-NHL expected to express CD20”; page 1961, “Based on safety data and PK or pharmacodynamic modeling, two step-up dosing (SUD) cohorts were subsequently tested with dosing of 2.5 mg (C1D1), 10 mg (C1D8), and 16 mg or 30 mg (C2D1), with the latter being selected as the recommended phase II dose (RP2D)”). The pharmaceutical composition of instant claim one is drawn to the anti-CD20/anti-CD3 bispecific antibody and excipients comprising a buffering agent, pH ranges, tonicity agent, methionine, and surfactants taught by Fast and Paulus 2020 are commonly used in the art to formulate with antibodies (Falconer, 2019; “ some manufacturers of Mabs seem to have settled on formulations comprise histidine or acetate buffers, sucrose or trehalose tonicity modifiers and polysorbate 80 surfactant, such as Ilumya™, Aimovig™, Tremfya™, Renflexis, Imfinzi® and Cyltezo™ (all from 2017 to 18). Close scrutiny of the actual formulations used with Mabs show most differ from this combination in one or more ways, such as addition of an amino acid (arginine, asparagine, or methionine) or the substitution of polysorbate 80 with polysorbate 20.). Falconer, 2019 also discloses that these formulations have been used in commercially available Mabs and ensure efficacious treatment and do not result in unwelcome side effects or adverse reactions in the patients like Humira® (page 1, column 2, paragraph 1). It would have been obvious to the person of ordinary skill in the art to substitute the bispecific antibody in Fast and Paulus, 2020 with the anti-CD20/anti-CD3 bispecific antibody taught by Hutchings et al., 2021 in the pharmaceutical composition as taught in Fast and Paulus, 2020, to ensure stable liquid formulations of the bispecific antibody and reduce unwelcome side effects and adverse events.
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.
U.S. Patents
Claims 1, 2, 3, 4, 5, 6, 7 , 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 7, 8, 11, 15, 17, 22, and 23 of U.S. Patent No. 12195547 B2 issued on 01/14/2025 (herein referred to as Lechner Pat’547) in view of Fast and Paulus, 2020 (cited previously); Kang and Penera, 2016 (Kang et al., "Rapid formulation development for Monoclonal Antibodies," BioProcess International. 14(4):40-45 (2016), listed in IDS); Hutchings et al., 2021 (cited previously); Strickley and Lambert 2021 (cited previously); and FDA Drug Safety Guidance 2016 (cited previously) . Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims are drawn to the pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and the copending application claims are drawn to the method of treating a cell proliferative disorder in a subject, wherein comprising administering to the subject and effective amount of the anti-CD20/anti-CD3 bispecific antibody glofitamab.
Regarding claim 30, Lechner Pat’547 claim 1, 2, and 11 recite a method of treating a subject having a CD20-positive cell proliferative disorder or having a relapsed and/or refractory NHL (Lechner Pat’547 claim 11) comprising administering to the subject polatuzumab vedotin and glofitamab in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle (Lechner Pat’547 claim 1), or comprising 12 dosing cycles (Lechner Pat’547 claim 2 and 11), wherein the glofitamab clinical dose is 2.5 mg/10 mg/30 mg.
Regarding claim 30, Lechner Pat’547 claim 7 and 22 recite the CD20-positive cell proliferative disorder is a B cell proliferative disorder.
Regarding claim 30, Lechner Pat’547 claim 8 and 23 recite the B cell proliferative disorder is a non-Hodgkin's lymphoma (NHL) or a central nervous system lymphoma (CNSL).
Lechner Pat’547 claims do not teach the exact dosage range of the bispecific antibody in the pharmaceutical composition but rather the clinical dose. Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg (page 1961, column 2, paragraph 1, “Based on safety data and PK or pharmacodynamic modeling, two step-up dosing (SUD) cohorts were subsequently tested with dosing of 2.5 mg (C1D1), 10 mg (C1D8), and 16 mg or 30 mg (C2D1), with the latter being selected as the recommended phase II dose (RP2D)”).
Most common commercially available monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml (Strickley and Lambert, 2021, page 2597, “formulations intended for intravenous infusions are concentrates that are diluted into infusion fluids” and page 2598, column 2, paragraph 1, “The overall range in antibody concentration is 0.012-200 mg/mL). The FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors (page 15, Product Strength, “Developing a product strength that is incongruent with the dosage and administration of the product complicates the calculation, preparation, and administration of a dose and has led to medication dosing errors” and “titration of dosing should be considered when developing product strengths to ensure that intermediate doses are achievable”). It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance.
Even though Lechner Pat’547 does not teach the exact dosage range of the bispecific antibody in the pharmaceutical composition but rather the clinical dose, the dosage in the pharmaceutical composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize based on the FDA drug safety guidance, Hutchings et al., 2021, and Strickley and Lambert 2021. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Lechner Pat’547 claims does not recite the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab as recited in instant claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27. Fast and Paulus, 2020 teaches the concentrations and excipients of the liquid pharmaceutical composition as described above (i.e. page 10, paragraph 0217, “5 mg/ml of a CEA CD3 bispecific antibody, preferably CEA TCB; 20 mM L-histidine; 0.05% (w/v) polysorbate 20; 240 mM sucrose; 10 mM methionine; at a pH of 5.5 +/- 0.3” 0.5 mg/ml divided by 100 is 0.05 % (w/v)). Kang and Penera, 2016 discloses that although every antibody is unique, the molecules are highly similar structurally. Lessons learned from successful examples are invaluable in developing stable and effective formulations for new MAbs (page 1, column 2) and that the formulation of the antibody is crucial for investigational new drug filings (page 1, column 1, “Formulation development, an important aspect of product development, is often on the critical path to successful clinical manufacturing and stability studies, which are essential to investigational new drug (IND) filings.”) and lists excipients (polysorbate 20, sucrose, methionine and histidine) that are most common in approved and commercially available Mabs for clinical use (Page 2, Table 1). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody with the pharmaceutical composition as recited in instant claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27 with the excipients taught by Kang and Penera, 2016 to accelerate approved IND applications and use them in human clinical trials.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 4, 5, 6, 23, 35, and 36 of U.S. Patent No. 9914776 issued on 03/13/2018 (herein referred to as Ast Pat’776) in view of Fast and Paulus, 2020 (cited previously) and Falconer 2019 (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application recites a liquid pharmaceutical composition comprising the anti-CD20/anti-CD3 bispecific antibody while Ast et al., 2018 recites the T cel activating antigen-binding molecule which binds to CD20 and CD3 and further claims a pharmaceutical composition comprising the T cell activating bispecific antigen-binding and a pharmaceutically acceptable carrier.
Regarding claim 1, 5 and 6, Ast Pat’776 claim 1 recites a T cell activating bispecific antigen binding molecule comprising: (a) a first Fab molecule which specifically binds to CD20, wherein the first Fab molecule comprises a heavy chain complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 47, a heavy chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 49, a light chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 50, and a light chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 51; (b) a second Fab molecule which specifically binds to CD3, wherein the second Fab molecule comprises a heavy chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 5, a heavy chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 6, a light chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 8, a light chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 9, and a light chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 10, wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain of the second Fab molecule, respectively, are replaced by each other, and (c) a third Fab molecule which specifically binds to CD20, wherein the third Fab molecule comprises a heavy chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 47, a heavy chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR 1 comprising the amino acid sequence of SEQ ID NO: 49, a light chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 50, and a light chain CDR 3 comprising the amino acid sequence of SEQ ID NO: 51, and wherein: (i) in the constant domain CL of the first Fab molecule and the third Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the first Fab molecule and the third Fab molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D); or (ii) in the constant domain CL of the second Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), arginine (R), or histidine (H), and, in the constant domain CH1 of the second Fab molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D).
Regarding instant claim 6, Ast Pat’776 claim 2 recites the T cell activating bispecific antigen-binding molecule, wherein, in the constant domain CL of the first Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), arginine (R), or histidine (H); and, in the constant domain CH1 of the first Fab molecule, one or both of the amino acids at positions 147 and 213, according to the Kabat EU index, are substituted by glutamic acid (E) or aspartic acid (D).
Regarding instant claim 6, Ast Pat’776 claim 3 recite the T cell activating bispecific antigen-binding molecule, wherein, in the constant domain CH1 of the first Fab molecule, the amino acid at position 147, according to the Kabat EU index, is substituted by glutamic acid (E) or aspartic acid (D).
Regarding instant claim 6, Ast Pat’776 claim 4 recite the T cell activating bispecific antigen-binding molecule, wherein, the amino acid at position 123, according to Kabat, is substituted by lysine (K), arginine (R), or histidine (H) in the constant domain CH1 of the first Fab molecule, and the amino acid at position 213, according to the Kabat EU index, is substituted by glutamic acid (E) or aspartic acid (D).
Regarding instant claim 6, Ast Pat’776 claim 5 and 6 recite the T cell activating bispecific antigen-binding molecule wherein, in the constant domain CL of the first Fab molecule, the amino acid at position 124, according to Kabat, is substituted by lysine (K), and the amino acid at position 123, according to Kabat, is substituted by arginine (R) or substituted by lysine (K), and in the constant domain CH1 of the first Fab molecule, the amino acid at position 147, according to the Kabat EU index, is substituted by glutamic acid (E), and the amino acid at position 213, according to the Kabat EU index, is substituted by glutamic acid (E).
Regarding instant claim 6, Ast Pat’776 claim 23 recites the T cell activating bispecific antigen-binding molecule, wherein the Fc domain comprises a modification promoting the association of the first and the second subunit of the Fc domain.
Regarding instant claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27, Ast Pat’776 claim 35 recites a pharmaceutical composition comprising the T cell activating bispecific antigen-binding molecule and a pharmaceutically acceptable carrier. Fast and Paulus, 2020 teaches the concentrations and excipients of the liquid pharmaceutical composition in the instant application as described above (i.e. page 10, paragraph 0217, “5 mg/ml of a CEA CD3 bispecific antibody, preferably CEA TCB; 20 mM L-histidine; 0.05% (w/v) polysorbate 20; 240 mM sucrose; 10 mM methionine; at a pH of 5.5 +/- 0.3” 0.5 mg/ml divided by 100 is 0.05 % (w/v)). The excipients comprising a buffering agent, pH ranges, tonicity agent, methionine, and surfactants are pharmaceutically accepted and commonly used in the art to formulate with antibodies (Falconer, 2019; “ some manufacturers of Mabs seem to have settled on formulations comprise histidine or acetate buffers, sucrose or trehalose tonicity modifiers and polysorbate 80 surfactant, such as Ilumya™, Aimovig™, Tremfya™, Renflexis, Imfinzi® and Cyltezo™ (all from 2017 to 18). Close scrutiny of the actual formulations used with Mabs show most differ from this combination in one or more ways, such as addition of an amino acid (arginine, asparagine, or methionine) or the substitution of polysorbate 80 with polysorbate 20.). Falconer, 2019 also discloses that these formulations have been used in commercially available Mabs and ensure efficacious treatment and do not result in unwelcome side effects or adverse reactions in the patients like Humira® (page 1, column 2, paragraph 1). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody in the pharmaceutical composition with the excipients as taught in Falconer, 2019 and Fast and Paulus, 2020 to ensure stable liquid formulations of the bispecific antibody and reduce unwelcome side effects and adverse events.
Copending U.S. Patent Applications
Claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 8, 12, 15, 16, 17, 32, 33, 34, 39, 40, 41, 47, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 96, 97, 98, 106, and 107, of copending Application No. 19/372,448 (herein referred to as Dixon App’448) in view of Fast and Paulus, 2020 (cited previously); Hutchings et al., 2021 (cited previously); Kang and Penera, 2016 (cited previously); Strickley and Lambert, 2021 (cited previously), and FDA Drug Safety Guidance 2016 (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims are drawn to the pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and the copending application claims are drawn to the method of treating a cell proliferative disorder in a subject, wherein comprising administering to the subject and effective amount of the anti-CD20/anti-CD3 bispecific antibody glofitamab.
Regarding instant claim 30, Dixon App’448 claim 1, 5, 8, 9, 52, 53, 56, 57, 58, 59, 60, 61, and 62 recite a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human individual in need thereof, comprising administering to the human individual an effective amount of glofitamab, rituximab, ifosfamide, carboplatin, and etoposide, wherein administering such treatment to a plurality of human individuals results in:
an improvement in complete response (CR) rate as recited in Dixon App’448 claims 1, 5, 52, 56); or
an improvement in OR rate as recited in Dixon App’448 claim 8, 9, 53, 57; or
in a cytokine release syndrome (CRS) event rate or Grade 2 or higher (Dixon App’448 claim 58, 59, 60); or
in a serious adverse event (SAE) rate of about 39.5%, 41.5, or 45.2% (Dixon App’448 claim 61); or
in a Grade 3 or 4 adverse event (AE) event rate of about 60.5% (Dixon App’448 claim 62).
Dixon App’448 does not teach the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and excipients as recited in instant claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27. As described above, Fast and Paulus, 2020 teaches the excipients to formulate the bispecific antibody in a pharmaceutical composition and Kang and Penera, 2016 discloses that the formulation of the antibody is crucial for investigational new drug filings (page 1, column 1, “Formulation development, an important aspect of product development, is often on the critical path to successful clinical manufacturing and stability studies, which are essential to investigational new drug (IND) filings.”). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody with the pharmaceutical composition with the excipients taught by Fast and Paulus, 2020 and Kang and Penera, 2016 to accelerate approved IND applications and use them in human clinical trials.
Regarding instant 7, 24, and 30, Dixon App’448 claim 15 as well as claims 33, 39, and 97 recite a clinical dose of glofitamab (2.5 mg/10 mg/30 mg) and a single dose of 30 mg. However, Dixon App’448 claims do not teach the dosage range of the bispecific antibody in the pharmaceutical composition.
As described previously, Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg. Strickley and Lambert, 2021 teaches that the monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml and that the FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors. It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance. The dosage in the pharmaceutical composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize based on the FDA guidance and Strickley and Lambert 2021. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding claim 30, Dixon App’448 claim 54 and 55 recite the “use of glofitamab in the manufacture of a medicament for treating…” which results in an improvement in CR rate or OR rate in treated individuals compared to individuals who did not receive glofitamab.
Regarding claim 30, as described above, Dixon App’448 claim 107 recites the glofitamab for use in treating relapsed diffuse large B-cell lymphoma (DLBCL) in a patient eligible for autologous stem cell transplant or CAR-T cell therapy, wherein the patient has relapsed less than 12 months after receiving prior therapy, comprising 3 treatment cycles, wherein Roche Docket No.: P39658-US-2 a) Treatment cycle 1 comprises administering Obinutuzumab on day 1, administering ifosfamide, carboplatin, and etoposide or etoposide phosphate on days 1, 2 and 3,administering 2.5 mg glofitamab on day 8 and 10 mg glofitamab on day 15 b) Treatment cycles 2 and 3 comprise administering rituximab on day 1 of the respective cycle, administering ifosfamide, carboplatin, and etoposide or etoposide phosphate on days 1, 2 and 3 of the respective cycle and, administering 30 mg glofitamab on day 8 of the respective cycle.
Dixon App’448 claim 107 does recite the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab as recited in instant claim 1, 2, 3, 4, 7, 23, 24 and 30. Fast and Paulus, 2020 teaches the excipients in the liquid pharmaceutical composition as described previously while Kang and Penera, 2016 teaches that the excipients are commonly formulated in antibody formulations as described above. It would have been obvious to formulate the bispecific antibody glofitamab as recited in Dixon App’448 with the excipients taught by Fast and Paulus, 2020 and Kang and Penera to use the bispecific antibody in a clinical setting.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 24, 40, 44, 45, 58, 95, 113, 114, 116, of copending Application No. 19/175,703 (hereinafter referred to Dixon App’703) in view of Fast and Paulus, 2020 (cited previously); Kang and Penera, 2016 (cited previously), Hutchings et al., 2021 (cited previously); Strickley and Lambert 2021 (cited previously); and FDA Drug Safety Guidance 2016 (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims are drawn to the pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and the copending application claims are drawn to the method of treating a cell proliferative disorder in a subject, wherein comprising administering to the subject and effective amount of the anti-CD20/anti-CD3 bispecific antibody glofitamab.
Regarding instant claim 30, Dixon App’703 claims 1 and 24 recite a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, comprising administering to the human patient an effective amount of: (a) glofitamab, (b) gemcitabine, and (c) oxaliplatin, wherein administering such treatment to a plurality of human patients results in an improvement in:
progression-free survival (PFS) of the plurality of human patients as compared to a reference PFS, wherein the reference PFS is the PFS of a plurality of human patients who have received a control treatment comprising: (a) rituximab, (b) gemcitabine, and (c) oxaliplatin, in the absence of glofitamab (Dixon App’703 claim 1); or
overall survival (OS) of the plurality of human patients as compared to a reference OS, wherein the reference OS is the OS of a plurality of human patients who have received a control treatment comprising: (a) rituximab, (b) gemcitabine, and (c) oxaliplatin, in the absence of glofitamab (Dixon App’703 claim 24).
Dixon App’703 claims 1 and 24 do not recite the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab as recited in instant claim 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27. Fast and Paulus, 2020 teaches the excipients to formulate the bispecific antibody in a pharmaceutical composition as described above and Kang and Penera, 2016 discloses that the formulation of the antibody is crucial for investigational new drug filings (page 1, column 1, “Formulation development, an important aspect of product development, is often on the critical path to successful clinical manufacturing and stability studies, which are essential to investigational new drug (IND) filings.”). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody with the pharmaceutical composition with the excipients taught by Fast and Paulus, 2020 and Kang and Penera, 2016 to accelerate approved IND applications and use them in human clinical trials.
Regarding 7, 24, and 30, Dixon App’703 claims 44 and 95, and 113 recite a clinical dosing regimen of the glofitamab (2.5 mg/10 mg/30 mg) but does not recite administering the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody.
As described previously, Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg. Strickley and Lambert, 2021 teaches that the monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml and that the FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors. It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance. The dosage in the pharmaceutical composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize based on the FDA guidance and Strickley and Lambert 2021. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, 22, 58, 59, 60, 61, 81, 82, 119, 120, 121, 182, 183, 184, 185, 186, 187, 192, 188, 189, of copending Application No. 18/188,168 (herein after referred to as Filippou-Frye App’168) in view of Fast and Paulus, 2020 (cited previously); Kang and Penera 2015 (cited previously); Hutchings et al., 2021 (cited previously); Strickley and Lambert, 2021 (cited previously); and FDA Drug Safety Guidance 2016 (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims are drawn to the pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and the copending application claims are drawn to the method of treating a cell proliferative disorder in a subject, wherein comprising administering to the subject and effective amount of the anti-CD20/anti-CD3 bispecific antibody glofitamab.
Regarding instant claim 1 and 5, Filippou-Frye App’168 claims 182, 183, 184, 185, 186, and 187 recite the exact SEQ ID NO: 1-6 and 9-14 which encode the 6 heavy and light chain variable regions of the antigen binding domains that binds to CD20 and CD3 and SEQ ID NO: 7-8 and 15-16 encode for the heavy and light chain variable regions of the antibody that contain antigen binding domains that specifically binds to CD20 and CD3.
Regarding instant claim 7, Filippou-Frye App’168 claim 192 recite that the anti-CD20/anti-CD3 bispecific antibody is glofitamab.
Regarding instant claim 6, Filippou-Frye App’168 claim 188 and 189 recite the bispecific antibody;(a) is bivalent for CD20 and monovalent for CD3;and/or (b) a humanized antibody and that the bispecific antibody comprises two Fab molecules which specifically bind to CD20 and one Fab molecule which specifically binds to CD3. Hutchings et al., 2021 teaches that the glofitamab is a 2:1 configuration antibody format enabling the bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells and that its CD3-binding region is fused to one of the CD20-binding regions in a head-to-tail manner via a flexible linker for improved target effector cell binding (page 1960, column 1, paragraph 1). It would have been obvious to the person of ordinary skill in the art to envisage the bispecific antibody glofitamab to have the 2:1 configuration and expect improved target effector cell binding as taught by Hutchings et al., 2021.
Regarding instant claim 30, Filippou-Frye App’168 claims 1, 58, 119 recite a method of treating a subject having a CD20-positive cell proliferative disorder comprising administering to the subject an effective amount of a bispecific antibody that binds to CD20 and CD3.
Filippou-Frye App’168 claims 1, 58, and 119 do not recite the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab as recited in instant claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27. Fast and Paulus, 2020 teaches the excipients to formulate the bispecific antibody in a pharmaceutical composition as described above and Kang and Penera, 2016 discloses that the formulation of the antibody is crucial for investigational new drug filings (page 1, column 1, “Formulation development, an important aspect of product development, is often on the critical path to successful clinical manufacturing and stability studies, which are essential to investigational new drug (IND) filings.”). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody with the pharmaceutical composition with the excipients taught by Fast and Paulus, 2020 and Kang and Penera, 2016 to accelerate approved IND applications and use them in human clinical trials.
Regarding 7, 24, and 30, Filippou-Frye App’168 claims 4, 6, 22, 59, 60, 61, 81, 82, 120, and 121, recite a clinical dosing regimen of the glofitamab (2.5 mg/10 mg/30 mg) but does not recite administering the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody.
As described previously, Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg. Strickley and Lambert, 2021 teaches that the monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml and that the FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors. It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance. The dosage in the pharmaceutical composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize based on the FDA guidance and Strickley and Lambert 2021. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 167, 168, 176, 177, 182, 183, 187, 193, and 194 of copending Application No. 18/964,055 (Lechner App’055) in view of Fast and Paulus, 2020 (cited previously) and Kang and Penera 2016 (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims are drawn to the pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and the copending application claims are drawn to the method of treating a cell proliferative disorder in a subject, wherein comprising administering to the subject and effective amount of the anti-CD20/anti-CD3 bispecific antibody glofitamab.
Regarding claim 7, 24, and 30, Lechner App’055 claim 167, 176, 182, and 193 recite a method of treating a subject having a CD20- positive cell proliferative disorder comprising administering to the subject polatuzumab vedotin and glofitamab and dosing cycles (also recited in Lechner App’055 claim 168 and 183), and that the CD20-positive cell proliferative disorder is a B cell proliferative disorder (Lechner App’055 claims 169, 177, 187, and 194) wherein the B cell proliferative disorder is a B cell lymphoma (Lechner App’055 claims 170 and 178) and a non- Hodgkin's lymphoma (NHL) or a central nervous system lymphoma (CNSL) (Lechner App’055 claims 188 and 195).
Lechner App’055 claims 167, 176, 182, 193, however, do not recite the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab as recited in instant claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, and 27 Fast and Paulus, 2020 teaches the excipients to formulate the bispecific antibody in a pharmaceutical composition as described above and Kang and Penera, 2016 discloses that the formulation of the antibody is crucial for investigational new drug filings (page 1, column 1, “Formulation development, an important aspect of product development, is often on the critical path to successful clinical manufacturing and stability studies, which are essential to investigational new drug (IND) filings.”). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody with the pharmaceutical composition with the excipients taught by Fast and Paulus, 2020 and Kang and Penera, 2016 to accelerate approved IND applications and use them in human clinical trials.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 6, 12, 26, 27, 34, 36, 40, 50, 52, 67, 68, 71, 72, 76, 79, 80, 84, 95, 96, 99, 104, 123, 124, 125, 126, 127, 128, 129, 130 of copending Application No. 17/733,909 (hereinafter referred to as Lechner App’909) in view of Fast and Paulus, 2020 (cited previously); Kang and Penera 2016 (cited previously); Hutchings et al., 2021 (cited previously); Strickley and Lambert 2021 (cited previously); and FDA Drug Safety Guidance 2016 (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application claims are drawn to the pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab and the copending application claims are drawn to the method of treating a cell proliferative disorder in a subject, wherein comprising administering to the subject and effective amount of the anti-CD20/anti-CD3 bispecific antibody glofitamab.
Regarding instant claim 30, Lechner App’909 claim 1, 3, 6 recite a method of treating a subject having a CD20-positive B cell proliferative disorder comprising administering to the subject an anti-CD20/anti-CD3 bispecific antibody in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, or 1-10 additional dosing cycles wherein: (a) the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the anti-CD20/anti-CD3 bispecific antibody, wherein the C1D1 is 2.5 mg, and the C1D2 is 10 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of either 16 or 30 mg of the anti-CD20/anti-CD3 bispecific antibody. Similarly, Lechner App’909 claim 30, 34, 36, 40, 71, 76, 79, 80 80 72, 84 recite a method comprises administering a dosing regimen with dosing cycles and dosages of the anti-CD20/anti-CD3 bispecific antibody to a subject having CD20-positive B cell proliferative disorder, follicular lymphoma. Furthermore, Lechner App’909 claim 12 recite the CD20-positive B cell proliferative disorder is a non-Hodgkin's lymphoma (NHL).
As described previously, Hutchings et al., 2021 teaches the two step-up dosing (SUD) and recommended phase II dose (RP2D) of the anti-CD20/anti-CD3 bispecific antibody at 2.5mg/10mg/30mg. Strickley and Lambert, 2021 teaches that the monoclonal antibody dosages are designed to be diluted in normal saline or NaCl for intravenous infusions and the overall range of commercially available clinical antibody concentrations is 0.012-200mg/ml and that the FDA guidance for industry on drug safety, issued in April 2016, teaches that the product strength or the product concentration should be designed to facilitate correct administration of the therapeutic clinical dose to minimize medical dosing errors. It would have been obvious to the person of ordinary skill in the art to design concentrations of the bispecific antibody in the pharmaceutical composition to ensure administering the pharmaceutical composition at the correct dosages as taught by Hutchings et al., 2021 and minimize medical dosing errors as suggested by the FDA drug safety guidance. The dosage in the pharmaceutical composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize based on the FDA guidance and Strickley and Lambert 2021. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding instant claim 30, Lechner App’909 claim 26, 27, 50, 52, 68 recite the method of treating a population of subjects having the CD20-positive B cell proliferative disorder or FL (Follicular lymphoma) exhibits cytokine release syndrome after being administered the anti-CD20/anti-CD3 bispecific antibody, results in a range of rate of the cytokine release syndrome grades, overall and complete response rates.
Regarding instant claim 1, Lechner App’909 claim 95, 123, and 127 recite the anti-CD20/anti-CD3 bispecific antibody comprises: (a) at least one antigen binding domain that specifically binds to CD20, comprising a heavy chain variable region comprising: (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; and a light chain variable region comprising: (i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and/or (b) at least one antigen binding domain that specifically binds to CD3 comprising a heavy chain variable region comprising: (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:11;and a light chain variable region comprising: (i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14.
Regarding instant claim 5, Lechner App’909 claim 96, 124, and 128 recite the anti-CD20/anti-CD3 bispecific antibody comprises: (a) at least one antigen binding domain that specifically binds to CD20 comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8; and/or (b) at least one antigen binding domain that specifically binds to CD3 comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.
Regarding instant claim 6, Lechner App’909 claim 99, 125, and 129 recite that the anti-CD20/anti-CD3 bispecific antibody comprises: (a) an antigen binding domain that specifically binds to CD3 and is a cross-Fab molecule wherein the variable domains or the constant domains of the Fab heavy and light chain are exchanged; (b) an IgGi Fc domain comprising one or more amino acid substitutions that reduce binding to an Fc receptor and/or effector function; (c) an IgGi Fc domain comprising the amino acid substitutions L234A, L235A, and P329G (numbering according to Kabat EU index); (d) at least one Fab molecule comprising an antigen binding domain that specifically binds to CD20, wherein in the constant domain CL of the Fab molecule the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) or lysine (K) (numbering according to Kabat), and wherein in the constant domain CH1 of the Fab molecule the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index); and/or (e) two antigen binding domains that specifically bind to CD20 and one antigen binding domain that specifically binds to CD3.
Regarding instant claim 7 and 24, Lechner App’909 claim 104, 126, and 130 recite the anti-CD20/anti-CD3 bispecific antibody is glofitamab. However, the instant claim 7 does not recite that the bispecific antibody is bivalent for CD20 and monovalent for CD3; (b) the anti-CD20/anti-CD3 bispecific antibody comprises (i) an antigen binding domain that specifically binds to CD3 which is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain; (ii) a first antigen binding domain that specifically binds to CD20 which is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the antigen binding domain that specifically binds to CD3; and (iii) a second antigen binding domain that specifically binds to CD20 which is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain. Hutchings et al., 2021 teaches that the glofitamab is a 2:1 configuration antibody format enabling the bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells and that its CD3-binding region is fused to one of the CD20-binding regions in a head-to-tail manner via a flexible linker for improved target effector cell binding (page 1960, column 1, paragraph 1). It would have been obvious to the person of ordinary skill in the art to envisage the bispecific antibody glofitamab to have the 2:1 configuration and expect improved target effector cell binding as taught by Hutchings et al., 2021.
Lechner App’909 claims 104, 126, and 130, however, do not recite the liquid pharmaceutical composition of the anti-CD20/anti-CD3 bispecific antibody glofitamab as recited in instant claim 24. Fast and Paulus, 2020 teaches the excipients to formulate the bispecific antibody in a pharmaceutical composition as described above and Kang and Penera, 2016 discloses that the formulation of the antibody is crucial for investigational new drug filings (page 1, column 1, “Formulation development, an important aspect of product development, is often on the critical path to successful clinical manufacturing and stability studies, which are essential to investigational new drug (IND) filings.”). It would have been obvious to the person of ordinary skill in the art to formulate the anti-CD20/anti-CD3 bispecific antibody with the pharmaceutical composition with the excipients taught by Fast and Paulus, 2020 and Kang and Penera, 2016 to accelerate approved IND applications and use them in human clinical trials.
Conclusion
No claims are allowed.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647