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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 6th, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Response to Amendment
Applicant’s amendment to the claims filed on April 6th, 2026, have been acknowledged.
Claims 2-29 are cancelled. Claim 1 has been amended. Currently, claims 1, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 57 are pending and examined under the merits herein.
In response to applicant’s explanation of the IDS filings that were missing, IDS filed July 25, 2023 is complete and has been fully considered.
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.
Claims 1, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 56, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Hutchings (Hutchings et al. 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) and further in view of Fast (WO 2019/020745 A1 Bispecific antibody formulation, IDS included, 01/31/2019), FDA guidance for industry on drug safety (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 (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), Martos (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)and as evidenced by Falconer (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) and Moritz (Moritz, M.L. Why 0.9% saline is isotonic: understanding the aqueous phase of plasma and the difference between osmolarity and osmolality. Pediatr Nephrol 34, 1299–1300 (2019). https://doi.org/10.1007/s00467-018-4084-2) and as a teaching reference IWK Health (IWK Health prepared by NICU CLDs/Pharmacists, Continuous infusion rate calculation guide, April 2021, Website: www.dir.iwk.nshealth.ca/Content/resources/cont_infusion_rate_cal_guide.pdf?t=be491e61-1778-4b40-96bd-b11ee156f9b6, accessed May 22, 2026).
Regarding instant claim 1, Hutchings teaches glofitamab and a two-step-up dosing (SUD) and recommended phase II dose (RP2D) of glofitamab (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)"). However, Hutchings does not teach the excipients of the liquid pharmaceutical composition of glofitamab comprising about 20 mM histidine buffer, about 240 nm sucrose, about 10 mM methionine, and about 0.5 mg/ml of polysorbate 20 (PS20) at a pH of about 5.5. Fast teaches excipients of the liquid pharmaceutical composition comprising a bispecific antibody (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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”). It is noted that the instant claims recite “about” a certain amount of each excipient. As such, the ranges taught by Fast applies to the instant claims. Further, Fast teaches that for obtaining maximum antibody stability and antibody formulations free from particles, 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 (page 32, line 6-8). The excipients comprising a buffering agent, pH ranges, tonicity agent, methionine, and surfactants taught by Fast are commonly used in the art to formulate with antibodies as evidenced by Falconer (page 8, conclusion, "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 llumya™, Aimovig™, Tremfya™, Renflexis, lmfinzi® 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 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 with the glofitamab as taught by Hutchings and formulate with excipients in the pharmaceutical composition taught by Fast to ensure stable liquid formulations of the bispecific antibody and reduce unwelcome side effects and adverse events.
Further, a skilled artisan would have been able to substitute the bispecific antibody taught in Fast with glofitamab in Hutchings and expect reasonable expectation of success at establishing maximum antibody stability and antibody formulation free from particles based on the excipients in the liquid pharmaceutical composition that Fast discloses.
While, Fast teaches the concentration range of the bispecific antibody , Fast does not teach the glofitamab concentration to be 1 mg/ml. 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, 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). Further, 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 glofitamab in the pharmaceutical composition to ensure administering the pharmaceutical composition with the excipients as taught by Fast at the therapeutically effective amount as taught by Hutchings and minimize medical dosing errors as suggested by the FDA drug safety guidance. Further, a skilled artisan would be motivated to make low dose glofitamab to accommodate lower dosing that is required in the step-up dosing regimen of glofitamab as taught by Hutchings. The compound 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 obvious 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 the unit of measurement of polysorbate 20, even though Fast does not teach the polysorbate 20 in mg/ml unit, Martos 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’ teaching, the calculation of polysorbate 20 mg/ml to %(w/v) is as follows 0.5 mg/ml divided by 100 equals 0.05 % (w/v). Martos 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.
Regarding instant claim 30, Hutchings teaches 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 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)").
Regarding instant claims 33, 34, and 35, Fast teaches that the histidine buffer is L-histidine hydrochloride (page 2, line 6-8).
Regarding instant claims 36, 37, 38, 39, and 40, Hutching teaches the cell proliferative disorder is a B cell proliferative disorder and that it is a non-Hodgkin’s lymphoma wherein the NHL is DLBCL and that is relapsed and refractory (page 1962, Table 1, See OA Fig 1.).
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Figure 1. Hutchings, page 1962, Table 1, disclosing patient population that received glofitamab.
Regarding instant claims 41, 42, 43, 44, Fast teaches the liquid pharmaceutical composition is diluted in pharmaceutically acceptable diluents such as saline (page 29, line 1-4, “To administer a formulation of the invention by certain routes of administration, it may be necessary to dilute the formulation in a diluent. Pharmaceutically acceptable diluents include saline, glucose, Ringer and aqueous buffer solutions”) and further teaches that the sodium chloride solution or saline is an isotonic buffer for infusion (page 29 line 13-14). As evidenced by Moritz, 0.9% saline or sodium chloride is isotonic to human plasma and will not cause hypernatremia (page 1, column 1, “0.9% saline is a perfectly isotonic solution that is isoosmolar to human plasma and is not associated with hypernatremia “ and column 2 “The normal plasma sodium concentration of 140 mEq/L reflects the concentration in whole plasma, aqueous and anhydrous. The sodium concentration in the aqueous phase of plasma is approximately 153 mEq/L., very similar to the sodium concentration of 0.9% saline (154 mEq/L)”). Therefore, Fast teaches the saline or sodium chloride is 0.9% as Fast defines the saline as isotonic buffer which is 0.9% as evidenced by Moritz.
However, Fast and Hutchings do not teach that the liquid pharmaceutical composition is administered to the subject after dilution in the 0.9% or 0.45% sodium chloride solution to a concentration of 0.1 mg/ml and 0.6 mg/ml of the glofitamab. Hutchings teaches the effective therapeutic doses of glofitamab which is a step-up dosing (2.5mg, 10mg, 30mg) and a recommended phase II dose of 30 mg (page 1961, column 2, paragraph 1) and glofitamab is administered by intravenous infusion for 4 hours (page 1960, column 2, paragraph 2). Given the effective therapeutic doses taught by Hutchings, Strickley teaches “the formulations intended for intravenous infusion are concentrates that are diluted into infusion fluids. Most of the infusion fluids are saline or D5W, with a few using Ringer’s lactate or half normal saline. The volume of infusion is usually 100 mL or 250 mL, with five using 50 mL, two using 500 mL, and one each using 25 mL, 200 mL, 1000 mL or 2000 mL” (page 2597 column 2, paragraph 5). With the step up dosing regimen and the recommended phase II dose of glofitamab and the 4 hour intravenous infusion method as taught by Hutchings, and the bispecific antibody is diluted in saline infusion fluids as taught by Fast and Strickley, a person of ordinary skill in the art would be able to calculate the correct dosing regimen to administer the therapeutically effective dose of the glofitamab to appropriately dilute the glofitamab in the IV fluid bag in the volume required to administer the dose that a patient needs. As a teaching reference, IWK Health website teaches continuous fusion rate calculations for clinicians to use to administer the ordered dose (page 1, “calculate the hourly rate” and see Figure 2 of this OA). Therefore, a skilled artisan would be able to calculate the final concentration of glofitamab given the therapeutic effective doses and the step up doses taught by Hutchings with the commonly used volumes of the IV infusion bags taught by Strickler to arrive at the given concentration of the claimed invention.
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Figure 2. IWK Health 2021, page 1, disclosing routine dose and drip rate calculations to administer IV infusion to patients.
It would further be obvious with that the compound dosages in a composition are clearly a result effective parameter that a person of 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 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." (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." (In re Aller, 220 F.2d 454, 456, 105 USPQ 2).
Regarding instant claim 45 and 46, Hutchings further teaches that “glofitamab was given as an initial 4-hour intravenous (IV) infusion (page 1960, column 2, paragraph 2).
Regarding instant claims 56 and 57, Fast teaches the liquid pharmaceutical composition are filled in sterile glass vials (page 31, lines 20-22, “All formulations were sterile-filtered through 0.22 μm low protein binding filters and aseptically filled into sterile 6 ml glass vials closed with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated rubber stoppers and aluminum crimp caps”). Further, Strickley teaches that most antibodies are packaged in single dose unit vials (page 2606, column 2, paragraph 2 and Fig. 14). In combination with Hutchings’s teachings of glofitamab’s step up dosing regimen and recommended phase II dose, it would have been obvious to the person of ordinary skill in the art to formulate the liquid pharmaceutical composition in single dose vials as taught by Fast and Strickler with the appropriate glofitamab doses needed to achieve the doses in the SUD as taught by Hutchings.
Claims 48, 49, 50, 51, 52, 53, 54, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Hutchings (cited previously), Fast (cited previously), FDA Guidance for industry on drug safety (cited previously), Strickley (cited previously), Martos (cited previously), Falconer and Moritz as evidentiary reference and IWK Health (cited previously) as a teaching reference as applied to claim 1 above and as evidenced by Umokoro (Umukoro, Cynthia, and Sumayya Khan. “Epidemiology, Pathology, and Clinical Features of DLBCL.” LymphomaHub, 11 Feb. 2021, website: lymphomahub.com/medical-information/epidemiology-pathology-and-clinical-features-of-dlbcl. Accessed 22 May 2026).
As described above in claim 1, Hutchings, Fast, Strickler, FDA guidance, and Martos, teach the glofitamab and the excipients to formulate the liquid pharmaceutical composition. Further, Fast, Moritz, Strickler, Hutchings, and IWK Health website teach the liquid pharmaceutical composition is administered to the subject after dilution in 0.9% sodium chloride to a concentration of 0.1 mg/ml and 0.6 mg/ml. Hutching teaches the method of treating R/R DLBCL NOS or trFL as described above for instant claims 36, 37, 38, 39, and 40. Regarding instant claim 52, Hutchings teaches the therapeutically effective doses of glofitamab, as described above.
As a teaching reference, Umokoro teaches that since DLBCL is heterogeneric, DLBCL not otherwise specified (NOS) is a generic collective term of DLBCL cases that have not been defined by morphology, molecular and immunophenotypic subgroups (page 3, paragraph 2). Therefore, Hutchings teaches the different DLBCL NOS (page 1962, Table 1, as described above in Figure 1 of this office action).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 15, 39, 45, 56, 58, 60, 105 of copending Application No. 19/372,448 (herein App’448), with claims filed on February 13th, 2026 in view of Fast (cited previously), Hutchings (cited previously), Strickler (cited previously), FDA guidance for industry on drug safety (cited previously), Moritz (cited previously), and IWK Health (cited previously).
Regarding instant claims 30, 36, 37, 38, 39, 48, 52, App’448 claim 1, 56, 58, and 60, 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.
Regarding instant claim 47 and 52, App’448 claim 15 and 39 recite administering the glofitamab at a dose of 2.5 mg, 10 mg, and 30 mg in a dosing regimen.
Regarding instant claim 40, App’448 claim 45, 105 recite the individual has DLBCL is not otherwise specified (NOS) or high grade B cell lymphoma.
App’448 does not teach the liquid pharmaceutical composition of the glofitamab and excipients as recited in instant claim 1, 48, 52, 33, 34, 35, 41, 42, 43, 44, 49, 50, 51, 53, 54, and 55.
As described previously, instant claim 1, 33, 34, 35, 48, 52 recite the excipients with the glofitamab and Fast teaches excipients of the liquid pharmaceutical composition comprising a bispecific antibody (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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, Fast teaches that for obtaining maximum antibody stability and antibody formulations free from particles, 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 (page 32, line 6-8). Further, a skilled artisan would have been able to formulate the glofitamab with the excipients taught in Fast and expect reasonable expectation of success at establishing maximum antibody stability and antibody formulation free from particles based on the excipients in the liquid pharmaceutical composition that Fast discloses.
Further, App’448 claims do not teach the concentration of the glofitamab in the liquid pharmaceutical composition as 1 mg/ml. Fast teaches the bispecific antibody concentration range in the pharmaceutical composition and excipients as described above (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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”). Hutchings teaches glofitamab and a two-step-up dosing (SUD) and recommended phase II dose (RP2D) of glofitamab (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, 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). Further, 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 glofitamab in the pharmaceutical composition to ensure administering the pharmaceutical composition with the excipients as taught by Fast at the therapeutically effective amount as taught by Hutchings and minimize medical dosing errors as suggested by the FDA drug safety guidance. Further, a skilled artisan would be motivated to make low dose glofitamab to accommodate lower dosing that is required in the step-up dosing regimen of glofitamab as taught by Hutchings. The compound 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 obvious 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)).
Instant claim 41, 42, 43, 44, 49, 50, 51, 53, 54, 55 recite the liquid pharmaceutical composition of glofitamab is administered to the subject after dilution in 0.9% or 0.45% sodium chloride to a concentration of 0.1 mg/ml and 0.6mg/ml, Fast teaches the liquid pharmaceutical composition is diluted in pharmaceutically acceptable diluents such as saline (page 29, line 1-4, “To administer a formulation of the invention by certain routes of administration, it may be necessary to dilute the formulation in a diluent. Pharmaceutically acceptable diluents include saline, glucose, Ringer and aqueous buffer solutions”) and further teaches that the sodium chloride solution or saline is an isotonic buffer for infusion (page 29 line 13-14). As evidenced by Moritz, 0.9% saline or sodium chloride is isotonic to human plasma and will not cause hypernatremia (page 1, column 1, “0.9% saline is a perfectly isotonic solution that is isoosmolar to human plasma and is not associated with hypernatremia “ and column 2 “The normal plasma sodium concentration of 140 mEq/L reflects the concentration in whole plasma, aqueous and anhydrous. The sodium concentration in the aqueous phase of plasma is approximately 153 mEq/L., very similar to the sodium concentration of 0.9% saline (154 mEq/L)”). Therefore, Fast teaches the saline or sodium chloride is 0.9% as Fast defines the saline as isotonic buffer which is 0.9% as evidenced by Moritz.
However, Fast and Hutchings do not teach that the liquid pharmaceutical composition is administered to the subject after dilution in the 0.9% or 0.45% sodium chloride solution to a concentration of 0.1 mg/ml and 0.6 mg/ml of the glofitamab. Hutchings teaches the effective therapeutic doses of glofitamab which is a step-up dosing (2.5mg, 10mg, 30mg) and a recommended phase II dose of 30 mg (page 1961, column 2, paragraph 1) and glofitamab is administered by intravenous infusion for 4 hours (page 1960, column 2, paragraph 2). Given the effective therapeutic doses taught by Hutchings, Strickley teaches “the formulations intended for intravenous infusion are concentrates that are diluted into infusion fluids. Most of the infusion fluids are saline or D5W, with a few using Ringer’s lactate or half normal saline. The volume of infusion is usually 100 mL or 250 mL, with five using 50 mL, two using 500 mL, and one each using 25 mL, 200 mL, 1000 mL or 2000 mL” (page 2597 column 2, paragraph 5). With the step up dosing regimen and the recommended phase II dose of glofitamab and the 4 hour intravenous infusion method as taught by Hutchings, and the bispecific antibody is diluted in saline infusion fluids as taught by Fast and Strickley, a person of ordinary skill in the art would be able to calculate the correct dosing regimen to administer the therapeutically effective dose of the glofitamab to appropriately dilute the glofitamab in the IV fluid bag in the volume required to administer the dose that a patient needs. As a teaching reference, IWK Health website teaches continuous fusion rate calculations for clinicians to use to administer the ordered dose (page 1, “calculate the hourly rate” and see Figure 2 of this OA). Therefore, a skilled artisan would be able to calculate the final concentration of glofitamab given the therapeutic effective doses and the step up doses taught by Hutchings with the commonly used volumes of the IV infusion bags taught by Strickler to arrive at the given concentration of the claimed invention.
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Figure 3. IWK Health 2021, page 1, disclosing routine dose and drip rate calculations to administer IV infusion to patients.
It would further be obvious with that the compound dosages in a composition are clearly a result effective parameter that a person of 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 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." (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." (In re Aller, 220 F.2d 454, 456, 105 USPQ 2).
App’448 does not teach the liquid pharmaceutical composition is administered intravenously and via intravenous infusion as recited in instant claims 45 and 46. Hutchings teaches that glofitamab is administered via intravenous infusion (page 1960, column 2, paragraph 2).
App’448 does not teach the article of manufacture comprising the liquid pharmaceutical composition in a single dose vial that has a volume of 2.5 ml or 10 ml as recited in instant claims 56 and 57. Fast teaches the liquid pharmaceutical composition are filled in sterile glass vials (page 31, lines 20-22, “All formulations were sterile-filtered through 0.22 μm low protein binding filters and aseptically filled into sterile 6 ml glass vials closed with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated rubber stoppers and aluminum crimp caps”). Further, Strickley teaches that most antibodies are packaged in single dose unit vials (page 2606, column 2, paragraph 2 and Fig. 14). In combination with Hutchings’s teachings of glofitamab’s step up dosing regimen and recommended phase II dose, it would have been obvious to the person of ordinary skill in the art to formulate the liquid pharmaceutical composition in single dose vials as taught by Fast and Strickler with the appropriate glofitamab doses needed to achieve the doses in the SUD as taught by Hutchings.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 24, 40, 44, 58, 60, 95, 113, 116, and 117 of copending Application No. 19/175,703 (herein App’703), with claims filed on July 22nd, 2025 in view of Fast (cited previously), Hutchings (cited previously), Strickler (cited previously), FDA guidance for industry on drug safety (cited previously), Moritz (cited previously), and IWK Health (cited previously).
Regarding instant claims 30, 36, 37, 38, 39, 48, and 52, App’703 claims 1, 24, 40, recite a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human patient in need thereof, comprising to the human patient an effective amount of glofitamab.
Regarding instant claim 47 and 52, App’703 claim 44, 58, 95, 113, 116, recites glofitamab doses 2.5 mg, 10 mg, and 30 mg in a dosing regimen.
Regarding instant claim 38, 39, 40, 48, and 52, App’703 claim 60 recite the DLBCL is a DLBCL no otherwise specified (DLBCL NOS) or the patient has relapsed or refractory DLBCL NOS and is not a candidate for HSCT. App’703 claim 117 recites the DLBCL is a DLBCL NOS.
App’703 does not teach the liquid pharmaceutical composition of the glofitamab and excipients as recited in instant claim 1, 48, 52, 33, 34, 35, 41, 42, 43, 44, 49, 50, 51, 53, 54, and 55.
As described previously, instant claim 1, 33, 34, 35, 48, 52 recite the excipients with the glofitamab and Fast teaches excipients of the liquid pharmaceutical composition comprising a bispecific antibody (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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, Fast teaches that for obtaining maximum antibody stability and antibody formulations free from particles, 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 (page 32, line 6-8). Further, a skilled artisan would have been able to formulate the glofitamab with the excipients taught in Fast and expect reasonable expectation of success at establishing maximum antibody stability and antibody formulation free from particles based on the excipients in the liquid pharmaceutical composition that Fast discloses.
Further, App’703 claims do not teach the concentration of the glofitamab in the liquid pharmaceutical composition as 1 mg/ml. Fast teaches the bispecific antibody concentration range in the pharmaceutical composition and excipients as described above (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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”). Hutchings teaches glofitamab and a two-step-up dosing (SUD) and recommended phase II dose (RP2D) of glofitamab (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, 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). Further, 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 glofitamab in the pharmaceutical composition to ensure administering the pharmaceutical composition with the excipients as taught by Fast at the therapeutically effective amount as taught by Hutchings and minimize medical dosing errors as suggested by the FDA drug safety guidance. Further, a skilled artisan would be motivated to make low dose glofitamab to accommodate lower dosing that is required in the step-up dosing regimen of glofitamab as taught by Hutchings. The compound 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 obvious 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)).
Instant claim 41, 42, 43, 44, 49, 50, 51, 53, 54, 55 recite the liquid pharmaceutical composition of glofitamab is administered to the subject after dilution in 0.9% or 0.45% sodium chloride to a concentration of 0.1 mg/ml and 0.6mg/ml, Fast teaches the liquid pharmaceutical composition is diluted in pharmaceutically acceptable diluents such as saline (page 29, line 1-4, “To administer a formulation of the invention by certain routes of administration, it may be necessary to dilute the formulation in a diluent. Pharmaceutically acceptable diluents include saline, glucose, Ringer and aqueous buffer solutions”) and further teaches that the sodium chloride solution or saline is an isotonic buffer for infusion (page 29 line 13-14). As evidenced by Moritz, 0.9% saline or sodium chloride is isotonic to human plasma and will not cause hypernatremia (page 1, column 1, “0.9% saline is a perfectly isotonic solution that is isoosmolar to human plasma and is not associated with hypernatremia “ and column 2 “The normal plasma sodium concentration of 140 mEq/L reflects the concentration in whole plasma, aqueous and anhydrous. The sodium concentration in the aqueous phase of plasma is approximately 153 mEq/L., very similar to the sodium concentration of 0.9% saline (154 mEq/L)”). Therefore, Fast teaches the saline or sodium chloride is 0.9% as Fast defines the saline as isotonic buffer which is 0.9% as evidenced by Moritz.
However, Fast and Hutchings do not teach that the liquid pharmaceutical composition is administered to the subject after dilution in the 0.9% or 0.45% sodium chloride solution to a concentration of 0.1 mg/ml and 0.6 mg/ml of the glofitamab. Hutchings teaches the effective therapeutic doses of glofitamab which is a step-up dosing (2.5mg, 10mg, 30mg) and a recommended phase II dose of 30 mg (page 1961, column 2, paragraph 1) and glofitamab is administered by intravenous infusion for 4 hours (page 1960, column 2, paragraph 2). Given the effective therapeutic doses taught by Hutchings, Strickley teaches “the formulations intended for intravenous infusion are concentrates that are diluted into infusion fluids. Most of the infusion fluids are saline or D5W, with a few using Ringer’s lactate or half normal saline. The volume of infusion is usually 100 mL or 250 mL, with five using 50 mL, two using 500 mL, and one each using 25 mL, 200 mL, 1000 mL or 2000 mL” (page 2597 column 2, paragraph 5). With the step up dosing regimen and the recommended phase II dose of glofitamab and the 4 hour intravenous infusion method as taught by Hutchings, and the bispecific antibody is diluted in saline infusion fluids as taught by Fast and Strickley, a person of ordinary skill in the art would be able to calculate the correct dosing regimen to administer the therapeutically effective dose of the glofitamab to appropriately dilute the glofitamab in the IV fluid bag in the volume required to administer the dose that a patient needs. As a teaching reference, IWK Health website teaches continuous fusion rate calculations for clinicians to use to administer the ordered dose (page 1, “calculate the hourly rate” and see Figure 2 of this OA). Therefore, a skilled artisan would be able to calculate the final concentration of glofitamab given the therapeutic effective doses and the step up doses taught by Hutchings with the commonly used volumes of the IV infusion bags taught by Strickler to arrive at the given concentration of the claimed invention.
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Figure 4. IWK Health 2021, page 1, disclosing routine dose and drip rate calculations to administer IV infusion to patients.
It would further be obvious with that the compound dosages in a composition are clearly a result effective parameter that a person of 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 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." (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." (In re Aller, 220 F.2d 454, 456, 105 USPQ 2).
App’703 does not teach the liquid pharmaceutical composition is administered intravenously and via intravenous infusion as recited in instant claims 45 and 46. Hutchings teaches that glofitamab is administered via intravenous infusion (page 1960, column 2, paragraph 2).
App’703 does not teach the article of manufacture comprising the liquid pharmaceutical composition in a single dose vial that has a volume of 2.5 ml or 10 ml as recited in instant claims 56 and 57. Fast teaches the liquid pharmaceutical composition are filled in sterile glass vials (page 31, lines 20-22, “All formulations were sterile-filtered through 0.22 μm low protein binding filters and aseptically filled into sterile 6 ml glass vials closed with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated rubber stoppers and aluminum crimp caps”). Further, Strickley teaches that most antibodies are packaged in single dose unit vials (page 2606, column 2, paragraph 2 and Fig. 14). In combination with Hutchings’s teachings of glofitamab’s step up dosing regimen and recommended phase II dose, it would have been obvious to the person of ordinary skill in the art to formulate the liquid pharmaceutical composition in single dose vials as taught by Fast and Strickler with the appropriate glofitamab doses needed to achieve the doses in the SUD as taught by Hutchings.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4, 6, 22, 58, 59, 60, 61, 81, 82, 119, 120, 121, 192, 195, 196, 197, 199, and 201 of copending Application No. 18/188,168 (herein App’168), with claims filed on March 17th, 2026 in view of Fast (cited previously), Hutchings (cited previously), Strickler (cited previously), FDA guidance for industry on drug safety (cited previously), Moritz (cited previously), and IWK Health (cited previously).
Regarding instant claims 30, 36, 37, 38, 39, 48, and 52, App’168 claims 1, 58, and 119 recite the method of treating a subject having a CD20-positive cell proliferative disorder comprising administering to the subject an effective amount of glofitamab.
Regarding instant claim 47 and 52, App’168 claims 4, 6, 22, 59, 60, 61, 81, 82, 120, 121 recite glofitamab doses 2.5 mg, 10 mg, and 30 mg.
Regarding instant claim 45 and 46, App’168 claim 192 recite the glofitamab is administered intravenously.
Regarding instant claim 38, 39, 40, 48, and 52, App’168 claims 195, 196, 197, 199, 201, recite the B cell proliferative disorder is a relapsed and/or refractory mature B cell Non-Hodgkin’s lymphoma.
App’168 does not teach the liquid pharmaceutical composition of the glofitamab and excipients as recited in instant claim 1, 48, 52, 33, 34, 35, 41, 42, 43, 44, 49, 50, 51, 53, 54, and 55.
As described previously, instant claim 1, 33, 34, 35, 48, 52 recite the excipients with the glofitamab and Fast teaches excipients of the liquid pharmaceutical composition comprising a bispecific antibody (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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, Fast teaches that for obtaining maximum antibody stability and antibody formulations free from particles, 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 (page 32, line 6-8). Further, a skilled artisan would have been able to formulate the glofitamab with the excipients taught in Fast and expect reasonable expectation of success at establishing maximum antibody stability and antibody formulation free from particles based on the excipients in the liquid pharmaceutical composition that Fast discloses.
Further, App’168 claims do not teach the concentration of the glofitamab in the liquid pharmaceutical composition as 1 mg/ml. Fast teaches the bispecific antibody concentration range in the pharmaceutical composition and excipients as described above (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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”). Hutchings teaches glofitamab and a two-step-up dosing (SUD) and recommended phase II dose (RP2D) of glofitamab (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, 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). Further, 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 glofitamab in the pharmaceutical composition to ensure administering the pharmaceutical composition with the excipients as taught by Fast at the therapeutically effective amount as taught by Hutchings and minimize medical dosing errors as suggested by the FDA drug safety guidance. Further, a skilled artisan would be motivated to make low dose glofitamab to accommodate lower dosing that is required in the step-up dosing regimen of glofitamab as taught by Hutchings. The compound 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 obvious 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)).
Instant claim 41, 42, 43, 44, 49, 50, 51, 53, 54, 55 recite the liquid pharmaceutical composition of glofitamab is administered to the subject after dilution in 0.9% or 0.45% sodium chloride to a concentration of 0.1 mg/ml and 0.6mg/ml, Fast teaches the liquid pharmaceutical composition is diluted in pharmaceutically acceptable diluents such as saline (page 29, line 1-4, “To administer a formulation of the invention by certain routes of administration, it may be necessary to dilute the formulation in a diluent. Pharmaceutically acceptable diluents include saline, glucose, Ringer and aqueous buffer solutions”) and further teaches that the sodium chloride solution or saline is an isotonic buffer for infusion (page 29 line 13-14). As evidenced by Moritz, 0.9% saline or sodium chloride is isotonic to human plasma and will not cause hypernatremia (page 1, column 1, “0.9% saline is a perfectly isotonic solution that is isoosmolar to human plasma and is not associated with hypernatremia “ and column 2 “The normal plasma sodium concentration of 140 mEq/L reflects the concentration in whole plasma, aqueous and anhydrous. The sodium concentration in the aqueous phase of plasma is approximately 153 mEq/L., very similar to the sodium concentration of 0.9% saline (154 mEq/L)”). Therefore, Fast teaches the saline or sodium chloride is 0.9% as Fast defines the saline as isotonic buffer which is 0.9% as evidenced by Moritz.
However, Fast and Hutchings do not teach that the liquid pharmaceutical composition is administered to the subject after dilution in the 0.9% or 0.45% sodium chloride solution to a concentration of 0.1 mg/ml and 0.6 mg/ml of the glofitamab. Hutchings teaches the effective therapeutic doses of glofitamab which is a step-up dosing (2.5mg, 10mg, 30mg) and a recommended phase II dose of 30 mg (page 1961, column 2, paragraph 1) and glofitamab is administered by intravenous infusion for 4 hours (page 1960, column 2, paragraph 2). Given the effective therapeutic doses taught by Hutchings, Strickley teaches “the formulations intended for intravenous infusion are concentrates that are diluted into infusion fluids. Most of the infusion fluids are saline or D5W, with a few using Ringer’s lactate or half normal saline. The volume of infusion is usually 100 mL or 250 mL, with five using 50 mL, two using 500 mL, and one each using 25 mL, 200 mL, 1000 mL or 2000 mL” (page 2597 column 2, paragraph 5). With the step up dosing regimen and the recommended phase II dose of glofitamab and the 4 hour intravenous infusion method as taught by Hutchings, and the bispecific antibody is diluted in saline infusion fluids as taught by Fast and Strickley, a person of ordinary skill in the art would be able to calculate the correct dosing regimen to administer the therapeutically effective dose of the glofitamab to appropriately dilute the glofitamab in the IV fluid bag in the volume required to administer the dose that a patient needs. As a teaching reference, IWK Health website teaches continuous fusion rate calculations for clinicians to use to administer the ordered dose (page 1, “calculate the hourly rate” and see Figure 2 of this OA). Therefore, a skilled artisan would be able to calculate the final concentration of glofitamab given the therapeutic effective doses and the step up doses taught by Hutchings with the commonly used volumes of the IV infusion bags taught by Strickler to arrive at the given concentration of the claimed invention.
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Figure 5. IWK Health 2021, page 1, disclosing routine dose and drip rate calculations to administer IV infusion to patients.
It would further be obvious with that the compound dosages in a composition are clearly a result effective parameter that a person of 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 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." (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." (In re Aller, 220 F.2d 454, 456, 105 USPQ 2).
App’168 does not teach the article of manufacture comprising the liquid pharmaceutical composition in a single dose vial that has a volume of 2.5 ml or 10 ml as recited in instant claims 56 and 57. Fast teaches the liquid pharmaceutical composition are filled in sterile glass vials (page 31, lines 20-22, “All formulations were sterile-filtered through 0.22 μm low protein binding filters and aseptically filled into sterile 6 ml glass vials closed with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated rubber stoppers and aluminum crimp caps”). Further, Strickley teaches that most antibodies are packaged in single dose unit vials (page 2606, column 2, paragraph 2 and Fig. 14). In combination with Hutchings’s teachings of glofitamab’s step up dosing regimen and recommended phase II dose, it would have been obvious to the person of ordinary skill in the art to formulate the liquid pharmaceutical composition in single dose vials as taught by Fast and Strickler with the appropriate glofitamab doses needed to achieve the doses in the SUD as taught by Hutchings.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 167, 168, 169, 170, 171, 172, 176, 177, 178, 182, 187, 188, 189, and 193 of copending Application No. 18/964,055 (herein App’055), with claims filed on April 11, 2025 in view of Fast (cited previously), Hutchings (cited previously), Strickler (cited previously), FDA guidance for industry on drug safety (cited previously), Moritz (cited previously), and IWK Health (cited previously).
Regarding instant claims 30, 36, 37, 38, 39, 47, 48, and 52, App’055 claim 167, 176, 182 recite a method of treating a subject having a CD20-positive cell proliferative disorder comprising administering glofitamab in a dosing regimen with glofitamab doses 2.5 mg, 10 mg, and 30 mg.
Regarding instant claim 46 and 46, App’055 claim 168, 182, 193, recite glofitamab is administered intravenously.
Regarding instant claim 38, 39, 40, 48, and 52, App’055 claim 169, 170, 171, 177, 178, 179, 187, 188, and 189, recite the CD20 positive cell proliferative disorder is a B cell lymphoma is a diffuse-large B cell lymphoma (DLBCL). App’055 claim 172 recite the DLBCL is DLBCL not otherwise specified (NOS).
App’055 claims does not teach the liquid pharmaceutical composition of the glofitamab and excipients as recited in instant claim 1, 48, 52, 33, 34, 35, 41, 42, 43, 44, 49, 50, 51, 53, 54, and 55.
As described previously, instant claim 1, 33, 34, 35, 48, 52 recite the excipients with the glofitamab and Fast teaches excipients of the liquid pharmaceutical composition comprising a bispecific antibody (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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, Fast teaches that for obtaining maximum antibody stability and antibody formulations free from particles, 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 (page 32, line 6-8). Further, a skilled artisan would have been able to formulate the glofitamab with the excipients taught in Fast and expect reasonable expectation of success at establishing maximum antibody stability and antibody formulation free from particles based on the excipients in the liquid pharmaceutical composition that Fast discloses.
Further, App’055 claims do not teach the concentration of the glofitamab in the liquid pharmaceutical composition as 1 mg/ml. Fast teaches the bispecific antibody concentration range in the pharmaceutical composition and excipients as described above (page 27, line 1 and page 25, line 4-9, “1 to 10 mg/ml of a CEA CD3 bispecific antibody; 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”). Hutchings teaches glofitamab and a two-step-up dosing (SUD) and recommended phase II dose (RP2D) of glofitamab (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, 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). Further, 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 glofitamab in the pharmaceutical composition to ensure administering the pharmaceutical composition with the excipients as taught by Fast at the therapeutically effective amount as taught by Hutchings and minimize medical dosing errors as suggested by the FDA drug safety guidance. Further, a skilled artisan would be motivated to make low dose glofitamab to accommodate lower dosing that is required in the step-up dosing regimen of glofitamab as taught by Hutchings. The compound 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 obvious 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)).
Instant claim 41, 42, 43, 44, 49, 50, 51, 53, 54, 55 recite the liquid pharmaceutical composition of glofitamab is administered to the subject after dilution in 0.9% or 0.45% sodium chloride to a concentration of 0.1 mg/ml and 0.6mg/ml, Fast teaches the liquid pharmaceutical composition is diluted in pharmaceutically acceptable diluents such as saline (page 29, line 1-4, “To administer a formulation of the invention by certain routes of administration, it may be necessary to dilute the formulation in a diluent. Pharmaceutically acceptable diluents include saline, glucose, Ringer and aqueous buffer solutions”) and further teaches that the sodium chloride solution or saline is an isotonic buffer for infusion (page 29 line 13-14). As evidenced by Moritz, 0.9% saline or sodium chloride is isotonic to human plasma and will not cause hypernatremia (page 1, column 1, “0.9% saline is a perfectly isotonic solution that is isoosmolar to human plasma and is not associated with hypernatremia “ and column 2 “The normal plasma sodium concentration of 140 mEq/L reflects the concentration in whole plasma, aqueous and anhydrous. The sodium concentration in the aqueous phase of plasma is approximately 153 mEq/L., very similar to the sodium concentration of 0.9% saline (154 mEq/L)”). Therefore, Fast teaches the saline or sodium chloride is 0.9% as Fast defines the saline as isotonic buffer which is 0.9% as evidenced by Moritz.
However, Fast and Hutchings do not teach that the liquid pharmaceutical composition is administered to the subject after dilution in the 0.9% or 0.45% sodium chloride solution to a concentration of 0.1 mg/ml and 0.6 mg/ml of the glofitamab. Hutchings teaches the effective therapeutic doses of glofitamab which is a step-up dosing (2.5mg, 10mg, 30mg) and a recommended phase II dose of 30 mg (page 1961, column 2, paragraph 1) and glofitamab is administered by intravenous infusion for 4 hours (page 1960, column 2, paragraph 2). Given the effective therapeutic doses taught by Hutchings, Strickley teaches “the formulations intended for intravenous infusion are concentrates that are diluted into infusion fluids. Most of the infusion fluids are saline or D5W, with a few using Ringer’s lactate or half normal saline. The volume of infusion is usually 100 mL or 250 mL, with five using 50 mL, two using 500 mL, and one each using 25 mL, 200 mL, 1000 mL or 2000 mL” (page 2597 column 2, paragraph 5). With the step up dosing regimen and the recommended phase II dose of glofitamab and the 4 hour intravenous infusion method as taught by Hutchings, and the bispecific antibody is diluted in saline infusion fluids as taught by Fast and Strickley, a person of ordinary skill in the art would be able to calculate the correct dosing regimen to administer the therapeutically effective dose of the glofitamab to appropriately dilute the glofitamab in the IV fluid bag in the volume required to administer the dose that a patient needs. As a teaching reference, IWK Health website teaches continuous fusion rate calculations for clinicians to use to administer the ordered dose (page 1, “calculate the hourly rate” and see Figure 2 of this OA). Therefore, a skilled artisan would be able to calculate the final concentration of glofitamab given the therapeutic effective doses and the step up doses taught by Hutchings with the commonly used volumes of the IV infusion bags taught by Strickler to arrive at the given concentration of the claimed invention.
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Figure 6. IWK Health 2021, page 1, disclosing routine dose and drip rate calculations to administer IV infusion to patients.
It would further be obvious with that the compound dosages in a composition are clearly a result effective parameter that a person of 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 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." (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." (In re Aller, 220 F.2d 454, 456, 105 USPQ 2).
App’055 does not teach the article of manufacture comprising the liquid pharmaceutical composition in a single dose vial that has a volume of 2.5 ml or 10 ml as recited in instant claims 56 and 57. Fast teaches the liquid pharmaceutical composition are filled in sterile glass vials (page 31, lines 20-22, “All formulations were sterile-filtered through 0.22 μm low protein binding filters and aseptically filled into sterile 6 ml glass vials closed with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated rubber stoppers and aluminum crimp caps”). Further, Strickley teaches that most antibodies are packaged in single dose unit vials (page 2606, column 2, paragraph 2 and Fig. 14). In combination with Hutchings’s teachings of glofitamab’s step up dosing regimen and recommended phase II dose, it would have been obvious to the person of ordinary skill in the art to formulate the liquid pharmaceutical composition in single dose vials as taught by Fast and Strickler with the appropriate glofitamab doses needed to achieve the doses in the SUD as taught by Hutchings.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed April 6th, 2026 have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., low-dose concentration of glofitamab on page 9) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Further, Fast teaches within the dosage range of a bispecific antibody formulated in the liquid pharmaceutical composition with the excipients that allow maximum antibody stability and antibody formulation (“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” page 32, line 6-8). In addition, Strickler teaches that the antibody ranges that have been used in clinical settings are within the range of the claimed invention (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). Further Strickler teaches methods to stabilize to allow low dose antibodies to be mixed in the intravenous infusion bags to prevent adhesion, lists several antibody formulations that have been diluted in the IV infusion bags and discloses that surfactants like polysorbate 80 precent surface adsorption of the antibody (page 2598, Intravenous infusion solution stabilizer, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use Strickler and Fast and develop the glofitamab liquid pharmaceutical composition at 1 mg/ml and expect reasonable success at stabilizing the formulation with the excipients listed in Fast. The specific concentration 1 mg/ml is a result of an optimization and routine experimentation to allow ease of administration of the step up dosing and recommended phase II dose in clinical setting as taught by Hutchings. Hutchings teaches intravenous infusion of the glofitamab with the step up dosing regimen (page 1960, methods). Djebli et al., 2020 (Djebli et al. Population Pharmacokinetics and Exposure-Response Analyses for glofitamab in relapsed/refractory B cell Non-Hodgkin Lymphoma (R/R NHL): Confirmation of Efficacy and CRS mitigation in Patients with Step-Up Dosing, Blood (2020) 136 (Supplement 1) : 1. http://doi.org/10.1182/blood-2020-136311.) teaches that the SUD regimen for glofitamab was selected to optimize the benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whilst allowing escalation to higher doses associated with better clinical response (page 1, results). Therefore, a skilled artisan would have been motivated to formulate glofitamab at 1 mg/ml doses in the liquid pharmaceutical composition with the excipients as taught by Fast to allow ease of dosing for SUD regimen of glofitamab.
Applicant’s argument that the examples show criticality of the pH, the concentration of PS20 and the concentration of sucrose to the claimed formulation (page 10), was not persuasive. Fast teaches the excipient components within the range in the range of the bispecific antibody. Further, Strickler discloses methods and motivations to formulate the antibody in the similar pH ranges, PS20 concentration, and sucrose concentrations that would allow a person of ordinary skill in the art to expect that the antibody is stable in the liquid formulation as well as in the intravenous infusion. The excipients are well known in the art as demonstrated by Strickler, as they teach several similar antibody formulations for intravenous infusions. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In response to applicant's argument that Strickler teaches 126 entirely different commercial antibody formulations and that they are distinct (page 11) and that a skilled artisan would have not predicted the suitable formulation for any particular antibody even with teachings from Fast and Hutchings, is not persuasive because the combination of their references prior to the effective filing date of the claimed invention teaches the glofitamab and the pharmaceutical composition with the excipients needed to formulate into the doses required for SUD and as an intravenous infusion. The concentrations of each excipient taught by Fast is within the range of the claimed formulation and teaches the motivation that these excipients are the most favorable and would result in maximum antibody stability (page 32, line 6-8). In addition, Strickler teaches each component of the excipient and teaches advantages of formulating with them for administration. It would have been obvious to the person of ordinary skill in the art to optimize the liquid pharmaceutical composition with the excipients as taught by Fast and Strickler to arrive at the claimed invention.
In response to the Applicant’s argument of claim 30 that the optimized low-concentration liquid pharmaceutical composition for glofitamab is not taught by Hutchings (page 14), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Fast and Strickler teach the excipients needed to formulate a liquid pharmaceutical composition for the bispecific antibody as an intravenous infusion. Hutchings teaches the therapeutically effective doses and dosing regimen to treat a cell proliferative disorder such as DLBCL, as well as that the glofitamab was administered by intravenous infusion for 4 hours. Further, the FDA guidance for industry on drug safety 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"). As described prior, a person of ordinary skill in the art would have been able to formulate liquid pharmaceutical composition of glofitamab suitable for clinical use with the excipients needed to keep the antibody stable in the vial as well as when mixed with 0.9% saline for intravenous infusion as taught by Fast, Strickler, FDA and Hutchings.
US Patent No. 9914776 issued on March 13th, 2018 has been withdrawn base on claim amendments made in the instant application on April 6th, 2026.
In response to Applicant’s argument that the optimized low-dose concentration of the pharmaceutical composition for glofitamab is not recited in the co-pending applications (page 15), nonstatutory double patenting rejections for co-pending applications 19/372,448, 19/175,703, 18/188,168, and 18/964,055 are still maintained. All co-pending application recite methods of using the product glofitamab to treat a disorder with the same dosing regimen as taught by Hutchings. As described prior, Fast and Strickler teach the excipients that allow maximum stability of the antibody in vial and when used as an intravenous infusion for subjects in need thereof. Further, the FDA guidance for industry on drug safety 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 formulate the glofitamab in pharmaceutically acceptable excipients taught by Fast and Strickler in the doses that would allow ease and effective administration of the antibody to the subject in need thereof in the methods of treating in combination with or without other additional therapeutic agents.
Conclusion
No Claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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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
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