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 March 17, 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 Amendments
Applicant’s amendment filed on March 17th, 2026 have been acknowledged. Claims 182-189, 191, and 206-208 are cancelled. Claims that recite the bispecific antibody that binds to CD20 and CD3 has been changed to glofitamab, the anti-CD20 antibody is rituximab and Obinutuzumab, and that the chemotherapy is ifosfamide, carboplatin, and etoposide. The amended claims of March 17th, 2026, have been considered by the examiner and new grounds of rejections have been made to reflect the newly amended claims. Claim 32 has been amended to recite acetaminophen and objections to the claim 32 has been withdrawn.
Claim 202 has been amended to “at least one” which renders claim 203 from which claim 202 depends narrow in scope. the Rejections under 35 U.S.C. § 112(d) for claims 202 and 203 have been withdrawn. Claim 207 and 208 have been cancelled and therefore, the rejection under 35 U.S.C. § 112(d) are moot and are withdrawn. Currently, claims 1-4, 6, 8-10, 14, 19, 21, 22, 25, 31, 32, 36, 58-61, 63-65, 67, 68, 73-75, 78, 81, 82, 84, 86, 87, 89, 90, 94, 104, 106, 119-121, 123-125, 127, 133-137, 140, 143, 146, 148-151, 153, 154, 158, 182-189, 191, 192, 195-197, 199, 201-204, and 206-208 are pending.
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, 2, 3, 4, 6, 8, 10, 19, 14, 21, 22, 25, 31, 32, 36, 192, 195, 196, 199, 201, 202, 203, 204, are rejected under 35 U.S.C. 103 as being unpatentable over Ghosh (Ghosh et al. Glofitamab Plus R-CHOP Induces High Response Rates with Minimal Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results from a Dose-Escalation and Safety Run-in Phase 1b Study, Blood, Volume 138, Supplement 1, 2021, Page 2479, ISSN 0006-4971, https://doi.org/10.1182/blood-2021-147780; See IDS), and further in view of 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, See IDS); Griffin (Griffin et al. Children's Oncology Group. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2009 Feb;52(2):177-81. doi: 10.1002/pbc.21753. PMID: 18816698; PMCID: PMC2728935, See PTO-892); Kewalramani (Kewalramani et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004 May 15;103(10):3684-8. doi: 10.1182/blood-2003-11-3911. Epub 2004 Jan 22. PMID: 14739217, See PTO-892); Salvaris (Salvaris et al. Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas. J Pers Med. 2021 Apr 29;11(5):355. doi: 10.3390/jpm11050355. PMID: 33946635; PMCID: PMC8147062.) FDA methylprednisolone (FDA drug label for methylprednisolone, version 10/2011, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011856s103s104lbl.pdf, PTO-892); and FDA obinutuzumab (FDA drug label for GAZYVA®, version 02/2016, https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125486s013lbl.pdf) and in further view of evidentiary references Cairo (Cairo et al. Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. J Pediatr Hematol Oncol. 2001 Jan;23(1):30-8. doi: 10.1097/00043426-200101000-00008. PMID: 11196267. See PTO-892).
Regarding instant claim 1, 4, 6, 21, and 22, Ghosh teaches the method of treating Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL) wherein glofitamab is administered with Obinutuzumab and with the chemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) (abstract). Further, Gosh discloses that Glofit +R-CHOP has tolerable safety (results). Ghosh further teaches the method of administering glofitamab and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) with dosing and cycles of glofitamab and chemotherapy (page 1, methods, “Glofit doses in separate cohorts (70μg, 1800μg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70μg and 1800μg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards”).
In regards to the specific dosage and interval amounts recited in the instant claims 4, 6, 8, 19, reciting glofitamab dosing regimen and cycles and as taught by Ghosh "[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 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious."
However, Ghosh does not teach the chemotherapy ICE in the method of treating a CD20 positive cell disorder with glofitamab recited in claim 1, 9, 14, 21, 22 and 192. Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Kewalramani teaches a chemotherapy R-ICE and dosing regimen to treat relapsed or primary refractory diffuse large B-cell lymphoma wherein patients receive 3 cycles of each cycle comprising 3 doses of etoposide for 3 days (page 3685, column 1, treatment, "Etoposide (100 mg/m2) was administered as an intravenous bolus daily for 3 days, from days 3 to 5"), a single dose of carboplatin (page 3685, column 1, treatment, "Carboplatin (area under the curve [AUC], 5; dose= 5 x [25 + Clcr]), capped at 800 mg, was administered as a bolus infusion on day 4.), and a single dose of ifosfamide (page 3685, column 1, treatment, "lfosfamide (5000 mg/m2) [ ... ] was administered as a continuous intravenous infusion over 24 hours beginning on day 4"). Kewalramani further discloses that “RICE was well tolerated, and, despite its hematologic toxicity, febrile neutropenia occurred in only 7.5% of delivered cycles, much lower than the incidence with several of the other commonly used second-line regimens associated with febrile neutropenia rates of 30% to 65%” (page 3687, column 2, paragraph 4). Kewalramani further teaches that R-ICE appears to be particularly beneficial in patients with relapsed disease (page 3687, column 2, paragraph 2). Hutching teaches that glofitamab has a favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options (page 3688, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to substitute R-CHOP chemotherapy in the method of treating using glofitamab taught by Ghosh with R-ICE chemotherapy taught by Kewalramani to treat relapsed B cell cancers like DLBCL in difficult to treat patients as taught by Hutchings and Kewalramani. A person of ordinary skill in the art would have been motivated to make the chemotherapy substitution of R-CHOP to R-ICE, because Kewalramani teaches that RICE is well tolerated and is beneficial in relapsed disease and Hutchings teaches that glofitamab has a favorable safety profile and combination with chemotherapy is possible.
Even though the day of administering the chemotherapeutic agents in the instant claim are not explicitly taught by Kewalramani, it would have been obvious to the person of ordinary skill in the art to optimize dosing regimen to accommodate the patient's time spent in the hospital for infusion and tolerance to the combination of the therapeutic agents. 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 instant claim 10, Hutchings teaches “seven days before the first dose of glofitamab, all patients received 1000 mg Gpt (obinutuzumab) to deplete peripheral and tissue-based B cells and mitigate serious CRS (page 1960, column 2, paragraph 1). Kewalramani teaches Rituximab (375 mg/m2) was administered on an outpatient basis on day 1 of each cycle and 48 hours before the initiation of the first cycle of ICE (page 3685, treatment, paragraph 1).
Regarding instant claims 19, 21, 22, and 25, Ghosh, Kewalramani, and Hutchings teach the additional dosing cycles of glofitamab and R-ICE. Ghosh teaches 6-8 cycles of glofit + R-CHOP (each 21 days) (page 1, methods) while Kewalramani teaches 3 cycles of RICE (page 3685, column 1, treatment). The number of additional dosing cycles and dosing of glofitamab, rituximab, obinutuzumab, and R-ICE chemotherapy are considered a routine optimization of the treatment that a person of ordinary skill in the art would employ to achieve efficacy of the cancer treatment. In regards to the specific dosage and interval amounts recited in the instant claims "[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 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious.
Regarding instant claims 2 and 3, Ghosh teaches the median age that received the method of treating with glofitamab was 62 years (page 1, results).
Regarding instant claims 1, 195, 196, 197, 199, and 201, Ghosh teaches the CD20 positive cell disorder is a cancer which is relapsed/refractory (R/R) Non-Hodgkin Lymphoma (NHL) and previously untreated diffuse large B-cell lymphoma (DLBCL) (page 1, title).
Regarding instant claims 202, 203, and 204, Ghosh teaches the subject had received at least one prior systemic therapy (page 1, results, “median prior lines of therapy was 2 (range: 1-5)” but is silent on the prior systemic therapy comprises an anti-CD20 antibody and an anthracycline. Hutchings teaches patient characteristics receiving the bispecific CD20/CD3 antibody glofitamab that had one or no more than one prior systemic therapy and received a prior systemic therapy comprises an anti-CD20 antibody and an anthracycline (table 1, Patient demographics and baseline disease characteristics, see patient populations that had "Prior lines of therapy Range from 1-13", "Refractory to any prior therapy", "Refractory to any line of prior CD20 therapy").
While Ghosh teaches adverse events from the glofit treatment (results, page 2) but Ghosh does not teach the additional therapeutic agents as recited in claims 31, 32, and 36. Ghosh does not teach tocilizumab, antihistamine and antipyretics, G-CSF, corticosteroids (dexamethasone, prednisone, and prednisolone), and mesna. Salvaris discloses CRS mitigation strategies with bispecific antibody (bsAbs) treatments that potent T-cell activation induced by bsAbs pose the risk of unique complications such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and suggests prophylaxis should be employed for patients at risk with high tumor burden, circulating disease, elevated LDH and impaired renal functions (page 6, 4. Toxicity and Management of Key Adverse Events, paragraph 1). Salvaris further teaches that the “mitigation strategies to reduce severe CRS are commonly used in bsAbs (bispecific antibodies). Pre-mediations are regularly employed with steroids, antihistamines and acetaminophen or paracetamol” (page 7, paragraph 6). Regarding tocilizumab and dosing, Salvaris teaches the tocilizumab that is used for CRS grade 2 or higher wherein the tocilizumab is “effective at a dose of 8 mg/kg in adults and 12 mg/kg in patients weighing 30 kg, with a maximum recommended dose of 800 mg per infusion” (page 9, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the common CRS mitigation strategies taught by Salvaris to reduce adverse events disclosed by Ghosh in the glofit treatment and ensure efficacious and safe cancer treatment.
Kewalramani teaches the mitigating strategies to toxicities related to R-ICE chemotherapy. Kewalramani teaches the dose and administration of mesna with ifosfamide within the R-ICE chemotherapy in adults (page 3685, column 1, paragraph 3, treatment, "lfosfamide (5000 mg/m2), mixed with an equal amount of mesna, was administered as a continuous intravenous infusion over 24 hours beginning on day 4").
Kewalramani teaches the method of administering acetaminophen and diphenhydramine prior to administering R-ICE (page 3685, column 1, paragraph 3, Treatment, "administration of oral acetaminophen (650 mg) and intravenous diphenhydramine (50 mg)").
However, Kewalramani does not teach acetaminophen and diphenhydramine is administered 30 min before obinutuzumab infusion. The FDA for obinutuzumab discloses doses and treatment regimens of the acetaminophen and diphenhydramine (FDA drug label for obinutuzumab, 2016, page 5, Table 3, "650-1000 mg acetaminophen" and "50 mg diphenhydramine" at least 30 min prior before GAZYVA infusion") to reduce infusion related reactions from obinutuzumab (page 5, table 3). It would have been obvious to use FDA standard treatment recommendations to mitigate infusion related reaction side effect caused by the obinutuzumab infusion.
Regarding G-CSF administration, Griffin teaches a method of administering G-CSF to children receiving R-ICE chemotherapy about one day after the administration of R-ICE therapy (page 3, treatment plan, paragraph 4, "Growth factor support with granulocyte-colony stimulating factory (G-CSF) was begun on day 6 of each course." [Last day of R-ICE regimen in Griffin is day 5 "Etoposide, 100 mg/m2 was given daily as a 1 hour IV infusion on days 3, 4, and 5"]). The reason to administer G-CSF during R-ICE chemotherapy is to mitigate neutropenia due to the high myelosuppression caused by the ICE regimen as evidenced by Cairo (page 31, column 1, paragraph 1, "(ICE) could potentiate both the duration and nadir of neutropenia."). It would have been obvious to the skilled artisan in the art to administer G-CSF in the treatment regimen to mitigate side effect caused by chemotherapeutic agents in R-ICE chemotherapy and expect reasonable success at reducing neutropenia based on the teachings of Cairo and Griffin.
Salvaris teaches corticosteroids have been used as “second line treatment for severe or refractory CRS” and that “corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies” (page 9, paragraph 2).
However, Salvaris does not teach dosing regimen of the corticosteroid dexamethasone, prednisone or prednisolone. The FDA drug label for corticosteroid methylprednisolone (FDA label, published on October 2011) teaches equivalent dosages of prednisone and prednisolone as either oral or intravenous injection and that methylprednisolone is a potent anti-inflammatory steroid (page 3, paragraph 5). It would have been obvious to the skilled artisan to use drug dosing recommendations from FDA methylprednisolone equivalent suggestions to optimize dosage regimens depending on specific patient populations to mitigate high inflammatory responses due to the glofitamab treatment regimen. 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)).
Claims 58, 59, 60, 61, 63, 64, 68, 73, 74, 75, 78, 81, 82, 84, 86, 87, 89, 90, 94, 104, 106, are rejected under 35 U.S.C. 103 as being unpatentable over Ghosh, Hutchings, Griffin, Kewalramani, Salvaris, Cairo, FDA obinutuzumab, FDA methylprednisolone, as applied to claims 1, 2, 3, 4, 6, 8, 10, 19, 14, 21, 22, 25, 31, 32, 36, 192, 195, 196, 199, 201, 202, 203, 204, above, and further in view of Djebli (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, Volume 136, Supplement 1, 2020, Pages 1-2, ISSN 0006-4971, https://doi.org/10.1182/blood-2020-136311. (https://www.sciencedirect.com/science/article/pii/S0006497118704254. See IDS), van Rongen (van Rongen et al. An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables. Expert Opin Drug Metab Toxicol. 2022 Feb;18(2):99-113. doi: 10.1080/17425255.2021.2027907. Epub 2022 Feb 25. PMID: 35018879. See PTO-892); Yang (Yang et al. Evaluation of Weight Thresholds for Pediatric Patients to Use Adult Dosage of Therapeutic Monoclonal Antibodies. J Clin Pharmacol. 2019 Oct;59(10):1309-1318. doi: 10.1002/jcph.1434. Epub 2019 May 3. PMID: 31050000. See PTO-892); Temrikar (Temrikar et al. Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007 /s40272-020-00382-7. PMID: 32052309; PMCID: PMC7083806. See PTO-892); Xu (Xu et al. Model-Aided Adults-to-Children Pharmacokinetic Extrapolation and Empirical Body Size-Based Dosing Exploration for Therapeutic Monoclonal Antibodies-ls Allometry a Reasonable Choice? J Clin Pharmacol. 2020 Dec;60(12):1573-1584. doi: 10.1002/jcph.1677. Epub 2020 Jun 23. PMID: 32578225. See PTO-892); WikiEM Diphenhydramine (Website: wikem.org/wiki/Diphenhydramine, last updated on 03/07/2021); Jannin (Jannin et al. Rectal route in the 21st Century to treat children. Adv Drug Del iv Rev. 2014 Jun;73:34-49. doi: 10.1016/j.addr.2014.05.012. Epub 2014 May 25. PMID: 24871671. See PTO-892); IWK Health dexamethasone (Website: www.dir.iwk.nshealth.ca/Home/DDGDetails/aed57259-168de911-80f2-005056b200d2?PatientPopulation=Ped, published on 06/12/2019. See PTO-892).
Regarding instant claim 58, 59, 60, 61, 78, 81, and 82, as described above, Ghosh teaches the dose ranges and dosing cycles of glofitamab.
However, Ghosh does not teach specific dosage of the bispecific antibody based on the body weight of the subject, Djebli teaches the pharmacokinetics of glofitamab wherein glofitamab has linear clearance with retained body weight effect on volumes and clearance and step up dosing regimen (2.5/10/30mg Q3W) to optimize benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whiles allowing escalation to a higher dose associated with a better clinical response (page 1, results). In further view of Djebli, van Rongen teaches methods of allometric scaling methods to extrapolate pediatric dosing from adult clearance and body weight and that it is commonly used for pediatric drug dosing (page 102, 2.1. Linear bodyweight-based scaling). With the recommended dose in adults and pharmacokinetics of the glofitamab as taught by Djebli and glofitamab cycles taught by Ghosh, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by van Rongen. A person of ordinary skill in the art would expect reasonable success in pediatric patients because the linear clearance of glofitamab based on body weight taught by Djebli would allow safe allometric scaling of the adult dosages. However, 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 instant claim 60, Ghosh, Djebli and van Rongen do not teach dosages of the bispecific antibody for subjects with body weights greater than or equal to 45 kg. Yang teaches weight thresholds for weight-tiered dosing based on PK of the therapeutic antibody (abstract). As such any patient that is over 40 kg according to can be dosed at similar ranges as in adults. Djebli teaches adult dosage regimen of the bispecific antibody as described above and combined with the teachings of Yang, it would have been obvious to the person of ordinary skill in the art to assume similar dose effect in adults as in pediatric/adolescent populations with body weights higher than 45 kg.
Regarding instant claim 63, 64, and 68, as described above, Ghosh, Hutchings, and Kewalramani teach the dosing regimen of obinutuzumab and rituximab. However, they do not teach dosages of the Obinutuzumab based on the subject’s body weight. At the time of the effective filing date, there have been no established dosages for pediatric patients (FDA drug label for (obinutuzumab) GAZYVA®, version 02/2016, page 16, 8.4 pediatric use) but rather the FDA obinutuzumab teaches a tested dose range of 50-2000 mg per infusion (page 17, 10 Overdosage) and that the obinutuzumab has linear clearance and that the volume of distribution and steady-state clearance increased with body weight (page 18, 12.3 Pharmacokinetics, "Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification”). Temrikar teaches different dosing strategies in pediatric population wherein the tiered body weight-based dosing strategy is the most widely applied dosing strategy for monoclonal antibodies in children (page 210, 2.7.6-Tiered body weight-based dosing). The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers (page 211, paragraph 2, "The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers."). Xu teaches a strategy to extrapolate pediatric doses based on PK and body weight (abstract, "Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry)"). With the recommended dose in adults and pharmacokinetics of the obinutuzumab as taught by the FDA drug label for obinutuzumab and dosing cycles as taught by Ghosh, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by Temrikar and Xu. It would be obvious to a skilled artisan to expect reasonable success in treating pediatric patients in optimizing the dose of the anti- CD20 antibody from these teachings prior to the effective filing date of the instant application.
Regarding instant claim 64, Ghosh also does not teach split doses of obinutuzumab to be administered on C1D1 and C1D2. The FDA obinutuzumab (FDA (obinutuzumab) GAZYVA®, version 02/2016) teaches split dosing of obinutuzumab in C1D1 at 100 mg and C2D2 at 900 mg (page 3, Table 1). It would have been obvious to try to implement split doses to mitigate infusion related reactions as taught by the FDA drug label.
Regarding instant claims 82 and 84, Kewalramani teaches dosages for rituximab as
described above.
Regarding instant claims 63, 73, 74, 75, 86, and 87, as described above, Ghosh and in further view of Kewalramani and Hutchings teach the glofitamab + RICE combination treatment in adults. However, they do not teach dosing cycle and dosages for R-ICE chemotherapy for pediatric patients 6 months to 17 years. Griffin teaches the dosage regimen for R-ICE for children under the age of 21 wherein patients received 3 cycles, each cycle comprising of Rituximab (375 mg/m2) two days prior to the chemotherapeutic agents (page 3, treatment plan, paragraph 1), 3 doses of ifosfamide, 3 doses of etoposide and 1 single dose of carboplatin (page 3, Treatment plan, paragraph 2, “ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on day 3,4, and 5”; “Etoposide, 100 mg/m2, was given daily as a 1 hour IV infusion on days 3, 4, and 5”; “Carboplatin, 635 mg/m2 (no maximum dose) was given as a 1 hour IV infusion on day 3 only”). However, 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 instant claims 63, 81, 78, 82, 84, 86, and 87, Ghosh and in further view of Kewalramani, teaches dosing cycles of glofitamab and R-ICE as described above.
Regarding instant claim 89 and 90, and as described above, Salvaris teach the dosage and regimen for tocilizumab.
Regarding instant claim 89, 90, 94, 104 and 106, and as described above, Kewalramani and in further view of FDA obinutuzumab label teach the dosage and administration of antihistamines to counteract CRS due to the treatment. However, they do not teach dosages of antihistamine diphenhydramine by age. WikiEm Diphenhydramine teaches pediatric doses at 1.25-1.67mg/kg/dose that can be administered oral or IV (page 2, website: wikem.org/wiki/Diphenhydramine, last updated on 03/07/2021). Further, as recited in instant claim 104, rectal administration of diphenhydramine at about 20 mg is not taught by Kewalramani, FDA obinutuzumab label and WikiEm. Jannin teaches that rectal administration of drugs is a good alternative route as compared to oral in pediatric populations that cannot swallow due to high dosage form and it is absorbed faster in the system (page 35, paragraph 3, “need high doses and cannot be easily formulated in oral solid dosage forms”). It would have been obvious to the person of ordinary skill in the art to substitute different routes of administration of diphenhydramine with standard dosage recommendations as taught by the FDA obinutuzumab drug label and Kewalramani to improve absorption and uptake of the drug in pediatric populations.
In another aspect, as described above, Ghosh, Kewalramani and Hutchings do not teach the dexamethasone dosages by weight, IWK Health website teaches dosage recommendation for children (Website: www.dir.iwk.nshealth.ca/Home/DDGDetails/aed57259-168d-e911-80f2-005056b200d2?PatientPopulation=Ped, published on 06/12/2019). It would have been obvious to the person of ordinary skill in the art to use standard recommended dosages for dexamethasone to treat pediatric populations.
Regarding instant claim 94, as described above, Salvaris and FDA methylprednisone teach corticosteroids that have been used as “second line treatment for severe or refractory CRS” and that “corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies” (Salvaris, page 9, paragraph 2). However, Salvaris does not teach dosing regimen of the corticosteroid dexamethasone, prednisone or prednisolone. The FDA drug label for corticosteroid for methylprednisolone teaches equivalent dosages of prednisone and prednisolone as either oral or intravenous injection and that methylprednisolone is a potent anti-inflammatory steroid (page 3, paragraph 5).
Regarding instant claim 89, 90, and 94, as described above Griffin teaches the dose of G-CSF in children receiving R-ICE chemotherapy (page 3, treatment plan, paragraph 4, "The dosage was 5 μg/kg/day unless peripheral blood stem cell (PBSC) collection was contemplated, in which case the dose was raised to 10 μg/kg/day") and method of administering G-CSF to children receiving R-ICE chemotherapy about one day after the administration of R-ICE therapy (page 3, treatment plan, paragraph 4, "Growth factor support with granulocyte-colony stimulating factory (G-CSF) was begun on day 6 of each course." [Last day of R-ICE regimen in Griffin is day 5 "Etoposide, 100 mg/m2 was given daily as a 1-hour IV infusion on days 3, 4, and 5"]). The reason to administer G-CSF during R-ICE chemotherapy is to mitigate neutropenia due to the high myelosuppression caused by the ICE regimen as evidenced by Cairo (page 31, column 1, paragraph 1, "(ICE) could potentiate both the duration and nadir of neutropenia."). It would have been obvious to the skilled artisan in the art to administer G-CSF in the treatment regimen to mitigate side effect caused by chemotherapeutic agents in R-ICE chemotherapy and expect reasonable success at reducing neutropenia based on the teachings of Cairo and Griffin.
Further, Griffin teaches the administration of mesna in children which is equal amounts with ifosfamide ("ifosfamide, 3000 mg/m2 as a 2-hour IV infusion daily on days 3, 4 and 5. Mesna, 600 mg/m2 was mixed with the dose of ifosfamide and also given as 15-minute IV boluses 3, 6, 9, and 12 hours after the start of the ifosfamide").
Claims 119, 120, 121, 123, 124, 125, 127, 134, 135, 136, 140, 143, 146, 149, 150, 151, 153, 154, and 158 are rejected under 35 U.S.C. 103 as being unpatentable over Ghosh, Hutchings, Griffin, Kewalramani, FDA obinutuzumab, Cairo, and Salvaris as applied to claim 1, 2, 3, 4, 6, 8, 10, 19, 14, 21, 22, 25, 31, 32, 36, 192, 195, 196, 199, 201, 202, 203, 204 above, and further in view of Hendrayana (Hendrayana et al. Anticancer Dose Adjustment for Patients with Renal and Hepatic Dysfunction: From Scientific Evidence to Clinical Application. Sci Pharm. 2017 Feb 27;85(1):8. doi: 10.3390/scipharm85010008. PMID: 28264440; PMCID: PMC5388145. See PTO-892).
Regarding instant claims 119, 120, 121, 140, and 143, as described above, the dosing regimen of glofitamab is taught by Ghosh.
Regarding instant claims 119, 123, 124, 125, 127, 140, 143, and 146, as described above, the dosing regimen of obinutuzumab is taught by Hutchings and Ghosh, rituximab doses and cycles are taught by Ghosh and Kewalramani.
Regarding instant claim 124 and 127, as described above, the FDA drug label for obinutuzumab teaches split dosing of obinutuzumab in C1D1 at 100 mg and C2D2 at 900 mg (page 3, Table 1) to mitigate infusion related reactions as proposed by the FDA obinutuzumab label.
Regarding instant claims 134, 135, 136, and 149, while Kewalramani teaches the dosage for ifosfamide and carboplatin (page 3685, treatment, “Carboplatin (area under the curve [AUC], 5; dose = 5 X [25 + Clcr]), capped at 800 mg, was administered as a bolus infusion on day 4. Ifosfamide (5000 mg/m2), mixed with an equal amount of mesna, was administered as a continuous intravenous infusion over 24 hours beginning on day 4”), however, Kewalramani does not teach the formula for creatinine clearance (CrCl) for male and female subjects and that the dosage of the ifosfamide and etoposide are reduced based on CrCl levels. Hendrayana teaches the formula for CrCI that accounts for male and female (page 3, 2.4 Guideline Application, See equation and "where k = 1 (male) or 0.85 (female)"). Further, Hendrayana teaches dosing guidelines of anticancer agents ifosfamide (page 5, table 1. Cont. "CrCI 46-60 ml/min, 80% of full dose [full dose is 5000mg/ml in instant claim 134]") and etoposide (page 5, table 1. Cont. "CrCI > 15-50 ml/min, 75% of full dose [full dose is 100 mg/m2 in the instant claim 134]"). Hendrayana further suggests that this method helps to adapt the dosing of anticancer agents to the individual requirements of patients with renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic effects due to overdosing (page 2, paragraph 5). It would have been obvious to the person of ordinary skill in the art to include a method to reduce hepatic and renal dysfunction in subjects receiving chemotherapeutic agents and maximize therapeutic outcomes.
Regarding instant claims 123, 140, 143, 146, 148, 149, 150, and 151, Ghosh teaches the dosing cycles as described above.
Regarding instant claims 153, 154, and 158, as described above, Salvaris, Kewalramani and Griffin teach the additional therapeutic agents to administer wherein the therapeutic agents are tocilizumab, antihistamines, antipyretics, corticosteroids dexamethasone, prednisone, prednisolone, G-CSF, and mesna.
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 1-4, 6, 8-10, 14, 19, 21, 22, 25, 31, 32, 36, 58-61, 63-65, 67, 68, 73-75, 78, 81, 82,
84, 86, 87, 89, 90, 94, 104, 106, 119-121, 123-125, 127, 133-137, 140, 143, 146, 148-151, 153,
154, 158, 195-197, 199, and 201-204 are provisionally rejected on the
ground of nonstatutory double patenting as being unpatentable over claim 1, 15, 16, 19, 28, 29, 33, 39, 45, 55, 58, 60, 63, 64, 65, 69, 89, 90, 93, 94, 97, and 105 of copending Application No. 19/372,448, filed on 02/13/2026 (reference application) in further view of Hutchings (cited previously), Djebli (cited previously), FDA obinutuzumab (cited previously), van Rongen (cited previously), Temrikar (cited previously), Xu (cited previously), Griffin (cited previously), Salvaris (cited previously), IWK Health (cited previously), FDA methylprednisolone (cited previously), WikiEm diphenhydramine (cited previously), Hendrayana (cited previously), and FDA ifosfamide (cited previously).
Regarding instant claim 1, 58, and 119, Reference claim 1, 55, 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 the human individuals an effective amount of glofitamab, rituximab, ifosfamide, carboplatin, and etoposide.
Regarding instant claims 4, 6, 8, 9, 10, 14, 61, 63, 64, 68, 82, 84, 120, 121, 123, 124, 125, 133, 134, 137, and 151, Reference claims 15, 16, and 19 recite doses and dosing regimen of obinutuzumab, glofitamab, rituximab, ifosfamide, carboplatin, and etoposide with at least a first and second dosing cycle where each cycle is a 21-day+ dosing cycle.
Regarding instant claims 19, 21, 22, 25, 78, 140, 143, 146, and 148, Reference claims 28, 29, 33, 39, 93, 94, and 97 recite additional dosing cycles and doses of glofitamab, rituximab, ifosfamide, carboplatin, and etoposide.
Regarding instant claims 2, 3, 195, 196, 197, 199, 201, 202, and 203, Reference claim 45 and 105 recite the individual has received one prior systemic therapy, NHL is DLBCL, or is 18 years or older.
Reference claim does not recite systemic therapy comprises an anti-CD20 antibody and an anthracycline as recited in instant claim 204. Hutchings teaches patient characteristics receiving the bispecific CD20/CD3 antibody glofitamab that had one or no more than one prior systemic therapy and received a prior systemic therapy comprises an anti-CD20 antibody and an anthracycline (table 1, Patient demographics and baseline disease characteristics, see patient populations that had "Prior lines of therapy Range from 1-13", "Refractory to any prior therapy", "Refractory to any line of prior CD20 therapy"). Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Therefore, it would have been obvious to the person of ordinary skill in the art to include patients in the treatment method with prior systemic therapy that comprise anti-CD20 antibody and anthracycline and expect reasonable success at treating difficult-to-treat patients that have already gone through prior systemic therapy but relapsed as taught by Hutchings.
Regarding instant claims 31, 32, 36, 89, 90, 94, 104, 106, 153, 154, and 158, Reference claims 63, 64, 65, 69, 89, and 90 recite the method further comprises administering the individual one or more additional therapeutic agents: tocilizumab, a corticosteroid, an antihistamine, a granulocyte-colony stimulating factor (G-CSF), an antipyretic; and/or mesna in combination with RICE and dosing regimen of each therapeutic agent.
Reference claims do not recite glofitamab doses for patients 6 months to 17 years in instant claim 59, 60, 81, and 82. Djebli teaches the pharmacokinetics of the bispecific CD3/CD20 antibody glofitamab wherein the glofitamab pharmacokinetics (PK) has linear clearance with retained body weight effect on volumes and clearances and step up dosing regimen (2.5/10/30mg Q3W) to optimize benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whilst allowing escalation to a higher dose associated with better clinical response (Results). In further view of Djebli, van Rongen teaches methods of allometric scaling methods to extrapolate pediatric dosing from adult clearance and body weight and that it is commonly used for pediatric drug dosing (page 102, 2.1. Linear bodyweight-based scaling). With the recommended dose in adults and pharmacokinetics of the glofitamab as taught by Djebli, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using al lo metric scaling and extrapolation methods as taught by van Rongen. It would be obvious to expect reasonable success in optimizing the dose of the bispecific antibody in pediatric patients from these teachings prior to the effective filing date of the instant application. 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)).
The reference application does not teach the obinutuzumab dosing regimen based on weight as recited in instant claims 65 and 67. At the time of the effective filing date, there have been no established dosages for obinutuzumab in pediatric patients (FDA (obinutuzumab) GAZYVA®, version 02/2016, page 16, 8.4 pediatric use) but rather the FDA obinutuzumab teaches a tested dose range of 50-2000 mg per infusion (page 17, 10 Overdosage) and that the obinutuzumab has linear clearance and that the volume of distribution and steady-state clearance increased with body weight (page 18, 12.3 Pharmacokinetics, "Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification”). Further, Temrikar teaches different dosing strategies in pediatric population wherein the tiered body weight-based dosing strategy is the most widely applied dosing strategy for monoclonal antibodies in children (page 210, 2.7.6-Tiered body weight-based dosing). The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers (page 211, paragraph 2, "The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers"). Xu teaches a strategy to extrapolate pediatric doses based on PK and body weight (abstract, "Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry)"). With the recommended dose in adults and pharmacokinetics of the obinutuzumab as taught by the FDA obinutuzumab, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by Temrikar and Xu. It would be obvious to expect reasonable success in pediatric patients in optimizing the dose of obinutuzumab from these teachings prior to the effective filing date of the instant application.
The reference application also does not teach split doses of obinutuzumab to be administered on C1D1 and C1D2 as recited in instant claims 64, 124, 125, and 127, The FDA obinutuzumab (FDA obinutuzumab, GAZYVA®, version 02/2016) teaches split dosing of obinutuzumab in C1D1 at 100 mg and C2D2 at 900 mg to mitigate infusion related reactions (page 3, Table 1). It would have been obvious to try to implement split doses to mitigate infusion related reactions as taught by the FDA drug label to mitigate infusion related reactions.
The reference claims do not teach dosing regimen of ifosfamide, carboplatin and etoposide for patients 6 months to 17 years as recited claim 73 and that ifosfamide is administered at a dose of about 3000 mg/m2 for each dose of ifosfamide, carboplatin is administered at a dose of about 635 mg/m2, and etoposide is administered at a dose of about 100 mg/m2 for each dose of etoposide as recited in instant claims 74, 75, 86, and 87. Griffin teaches the dosing regimen of ifosfamide, carboplatin, and etoposide for pediatric populations wherein ifosfamide is given in three doses, carboplatin in a single dose and etoposide is given in three doses (page 1, Abstract, methods). It would have been obvious to the person of ordinary skill in the art to modify dosing regimens as taught by Griffin to administer R-ICE in pediatric patient populations as they would respond differently than adults.
Reference claims do not recite dosing therapeutic agents based on weight as recited in instant claims 32, 90, 94, 104, 106, and 154. Salvaris discloses CRS mitigation strategies with bispecific antibody (bsAbs) treatments that potent T-cell activation induced by bsAbs pose the risk of unique complications such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and suggests prophylaxis should be employed for patients at risk with high tumor burden, circulating disease, elevated LDH and impaired renal functions (page 6, 4. Toxicity and Management of Key Adverse Events, paragraph 1). Salvaris further teaches that the “mitigation strategies to reduce severe CRS are commonly used in bsAbs (bispecific antibodies). Pre-mediations are regularly employed with steroids, antihistamines and acetaminophen or paracetamol” (page 7, paragraph 6). Regarding tocilizumab and dosing, Salvaris teaches the tocilizumab that is used for CRS grade 2 or higher wherein the tocilizumab is “effective at a dose of 8 mg/kg in adults and 12 mg/kg in patients weighing 30 kg, with a maximum recommended dose of 800 mg per infusion” (page 9, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the common CRS mitigation strategies taught by Salvaris to reduce adverse events caused by the glofitamab treatment and ensure efficacious and safe cancer treatment.
Kewalramani teaches the mitigating strategies to toxicities related to R-ICE chemotherapy. Kewalramani teaches the dose and administration of mesna with ifosfamide within the R-ICE chemotherapy in adults (page 3685, column 1, paragraph 3, treatment, "lfosfamide (5000 mg/m2), mixed with an equal amount of mesna, was administered as a continuous intravenous infusion over 24 hours beginning on day 4").
Kewalramani teaches the method of administering acetaminophen and diphenhydramine prior to administering R-ICE (page 3685, column 1, paragraph 3, Treatment, "administration of oral acetaminophen (650 mg) and intravenous diphenhydramine (50 mg)").
However, Kewalramani does not teach acetaminophen and diphenhydramine is administered 30 min before obinutuzumab infusion. The FDA for obinutuzumab discloses doses and treatment regimens of the acetaminophen and diphenhydramine (FDA drug label for obinutuzumab, 2016, page 5, Table 3, "650-1000 mg acetaminophen" and "50 mg diphenhydramine" at least 30 min prior before GAZYVA infusion") to reduce infusion related reactions from obinutuzumab (page 5, table 3). It would have been obvious to use FDA standard treatment recommendations to mitigate infusion related reaction side effect caused by the obinutuzumab infusion.
Regarding G-CSF administration, Griffin teaches a method of administering G-CSF to children receiving R-ICE chemotherapy about one day after the administration of R-ICE therapy (page 3, treatment plan, paragraph 4, "Growth factor support with granulocyte-colony stimulating factory (G-CSF) was begun on day 6 of each course." [Last day of R-ICE regimen in Griffin is day 5 "Etoposide, 100 mg/m2 was given daily as a 1 hour IV infusion on days 3, 4, and 5"]). The reason to administer G-CSF during R-ICE chemotherapy is to mitigate neutropenia due to the high myelosuppression caused by the ICE regimen as evidenced by Cairo (page 31, column 1, paragraph 1, "(ICE) could potentiate both the duration and nadir of neutropenia."). It would have been obvious to the skilled artisan in the art to administer G-CSF in the treatment regimen to mitigate side effect caused by chemotherapeutic agents in R-ICE chemotherapy and expect reasonable success at reducing neutropenia based on the teachings of Cairo and Griffin.
However, reference claims do not teach that dexamethasone is administered intravenously at a dose of between about 0.15 mg/kg to about 0.5 mg/kg at least about one hour prior to the administration of any dose of the bispecific antibody and/or obinutuzumab, and wherein the maximum daily dose is 10 mg as recited in instant claim 94 and 158. Website IWK Health published in 2019 teaches dosage recommendations for children is between 0.125-0.5 mg/kg/dose with a maximum dose is 10 mg/dose (IWK Health website, published on 06/12/2019, "0.125-0.5 mg/kg/dose PO/IV /IM" and "maximum: 10mg/dose"). It would have been obvious to the person of ordinary skill in the art to use standard recommended dosages for dexamethasone to treat pediatric populations.
Reference claims do not teach methylprednisolone is administered intravenously at a dose of between about 1 mg/kg to about 2 mg/kg at least about one hour prior to the administration of any dose of the bispecific antibody and/or obinutuzumab as recited in claim 94 and 158. Salvaris teach corticosteroids that have been used as “second line treatment for severe or refractory CRS” and that “corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies” (Salvaris, page 9, paragraph 2). However, Salvaris does not teach dosing regimen of the corticosteroid dexamethasone, prednisone or prednisolone. The FDA methylprednisolone teaches equivalent dosages of prednisone and prednisolone as either oral or intravenous injection and that methylprednisolone is a potent anti-inflammatory steroid (page 3, paragraph 5). Therefore, it would have been obvious to the person of ordinary skill in the art to optimize corticosteroids as taught by Salvaris to mitigate CRS from bispecific antibody treatments and optimize with equivalent doses of the corticosteroids taught by FDA methylprednisolone.
The reference claim does not teach subject is aged between 6 months and 17 years, and wherein diphenhydramine is administered intravenously at a dose of between about 10 mg to 20 mg with a maximum single dose of about 1.25 mg/kg or the subject is aged less than two years, and wherein diphenhydramine is administered rectally at a dose of about 20 mg as recited in instant claim 104. The website WikiEM teaches pediatric doses of diphenhydramine at 1.25-1.67mg/kg/dose that can be administered oral or IV (page 2, wikem.org/wiki/Diphenhydramine, last updated on 03/07/2021). Further, as recited in instant claim 104, rectal administration of diphenhydramine at about 20 mg is not taught by WikiEm diphenhydramine, rather Jannin teaches that rectal administration of drugs is a good alternative route to oral in pediatric populations that cannot swallow due to high dosage form and it is absorbed faster into the system (page 35, paragraph 3, "need high doses and cannot easily be formulated in oral solid dosage forms"). It would have been obvious to the person of ordinary skill in the art to substitute different routes of administration of diphenhydramine with standard dosage recommendations known in the art to improve absorption and uptake of the drug in pediatric populations to mitigate CRS from the bispecific antibody treatment as taught by Salvaris.
Reference claims do not recite dosing carboplatin based on CreatineClearance (CrCl) rate formula as recited in instant claims 134, 135, 136, 148, 149, and 150. Hendrayana teaches the formula for CrCI that accounts for male and female (page 3, 2.4 Guideline Application, See equation and "where k = 1 (male) or 0.85 (female)"). Further, Hendrayana teaches dosing guidelines of anticancer agents ifosfamide (page 5, table 1. Cont. "CrCI 46-60 ml/min, 80% of full dose [full dose is 5000mg/ml in instant claim 134]") and etoposide (page 5, table 1. Cont. "CrCI > 15-50 ml/min, 75% of full dose [full dose is 100 mg/m2 in the instant claim 134]"). Hendrayana further suggests that this method helps to adapt the dosing of anticancer agents to the individual requirements of patients with renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic effects due to overdosing (page 2, paragraph 5). It would have been obvious to the person of ordinary skill in the art to include a method to reduce hepatic and renal dysfunction in subjects receiving chemotherapeutic agents in RICE and maximize therapeutic outcomes.
Reference claims do not recite mesna is administered intravenously daily as five doses totaling 3000 mg/m2 in amount as recited in instant claim 90 and intravenously at a first dose of about 600 mg/m2 prior to the administration of any dose of ifosfamide and at four repeated doses of about 600 mg/m2 each at about three hours, about six hours, about nine hours, and about 12 hours, respectively, after the first dose of ifosfamide; and/or daily to the subject on Days 3, 4, and 5 of the first dosing cycle, on Days 6, 7, and 8 of the second dosing cycle, and/or on Days 6, 7, and 8 of each additional dosing cycle as recited in instant claim 94. Griffin teaches the administration of mesna in equal amounts with ifosfamide in the RICE therapy in pediatric populations ("ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on days 3, 4 and 5. Mesna, 600 mg/m2 was mixed with the dose of ifosfamide and also given as 15 minute IV boluses 3, 6, 9, and 12 hours after the start of the ifosfamide"). The FDA ifosfamide suggests the dose and usage of mesna in conjunction with ifosfamide to reduce hemorrhagic cystitis caused by ifosfamide (FDA ifosfamide, published 07 /2018, page 1, column 1, "mesna should be used to reduce the incidence of hemorrhagic cystitis"). It would have been obvious to the person of ordinary skill in the art to use the recommended dosage and administration from the FDA ifosfamide and Griffin to formulate dosages and treatment regimen in pediatric populations to mitigate adverse effects caused by ifosfamide in RICE therapy.
This is a provisional non-statutory double patenting rejection.
Claims 1-4, 6, 8-10, 14, 19, 21, 22, 25, 31, 32, 36, 58-61, 63-65, 67, 68, 73-75, 78, 81, 82,
84, 86, 87, 89, 90, 94, 104, 106, 119-121, 123-125, 127, 133-137, 140, 143, 146, 148-151, 153, 154, 158, 195-197, 199, and 201-204 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 6, 8, 9, 12, 13, 62, 63, and 133 of copending Application No. 17/733,909 (Reference) amended on February 6th, 206 in view of Hutchings (cited previously), Djebli (cited previously), FDA obinutuzumab (cited previously), van Rongen (cited previously), Temrikar (cited previously), Xu (cited previously), Griffin (cited previously), Salvaris (cited previously), IWK Health (cited previously), FDA methylprednisolone (cited previously), WikiEm diphenhydramine (cited previously), Hendrayana (cited previously), and FDA ifosfamide (cited previously).
Regarding instant claims 1, 4, 6, 8, 9, 10, 19, 21, 22, 58, 59, 60, 61, 63, 64, 68, 81, 82, 119, 120, 121, 123, 124, 125, 140, 143, 192, reference claim 1 recites a method of treating a subject having a CD20-positive B cell 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 and second dosing cycle wherein the first dosing cycle is 2.5mg, 10 mg, and second dosing comprises 16 or 30 mg. The first dose is administered on day 1 of the first dosing cycle and the second dose is administered on day 8 and a single dose is administered on the second dosing cycle. Reference claim 1 further recites that one dosing cycle is 21 days and the method further comprises administering to the subject 1000 mg of obinutuzumab 7 days before the first dose of the bispecific antibody. Reference claim 104 recites the anti-CD20/anti-CD3 bispecific antibody is glofitamab.
However, reference claims do not recite RICE chemotherapy for subjects over 18 years old and the dosing regimen as recited in instant claims 1, 9, 10, 14, 21, 22, 25, 68, 73, 74, 75, 119, 125, 133, 134, 146, 148, 151. Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Kewalramani teaches a chemotherapy R-ICE and dosing regimen to treat relapsed or primary refractory diffuse large B-cell lymphoma wherein patients receive 3 cycles of each cycle comprising rituximab (page 3685, column 1m “Rituximab (375 mg/m2) was administered on an outpatient basis on day 1 of each cycle and 48 hours before the initiation of the first cycle.”), 3 doses of etoposide for 3 days (page 3685, column 1, treatment, "Etoposide (100 mg/m2) was administered as an intravenous bolus daily for 3 days, from days 3 to 5"), a single dose of carboplatin (page 3685, column 1, treatment, "Carboplatin (area under the curve [AUC], 5; dose= 5 x [25 + Clcr]), capped at 800 mg, was administered as a bolus infusion on day 4.), and a single dose of ifosfamide (page 3685, column 1, treatment, "lfosfamide (5000 mg/m2) [ ... ] was administered as a continuous intravenous infusion over 24 hours beginning on day 4"). Kewalramani further discloses that “RICE was well tolerated, and, despite its hematologic toxicity, febrile neutropenia occurred in only 7.5% of delivered cycles, much lower than the incidence with several of the other commonly used second-line regimens associated with febrile neutropenia rates of 30% to 65%” (page 3687, column 2, paragraph 4). Kewalramani further teaches that R-ICE appears to be particularly beneficial in patients with relapsed disease (page 3687, column 2, paragraph 2). Hutching teaches that glofitamab has a favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options (page 3688, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to add RICE in the method of treating with glofitamab to treat relapsed B cell cancers like DLBCL in difficult to treat patients as taught by Hutchings and Kewalramani. A person of ordinary skill in the art would have been motivated to add the chemotherapy R-ICE because Kewalramani teaches that RICE is well tolerated and is beneficial in relapsed disease and Hutchings teaches that glofitamab has a favorable safety profile and combination with chemotherapy is possible.
Even though the day of administering the chemotherapeutic agents in the instant claim are not explicitly taught by Kewalramani, it would have been obvious to the person of ordinary skill in the art to optimize dosing regimen to accommodate the patient's time spent in the hospital for infusion and tolerance to the combination of the therapeutic agents. 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 instant claim 192, Reference claim 3 recites the anti-20/anti-CD3 bispecific antibody is administered intravenously.
However, reference claims do not teach the age of the subject 18 years or older, 31 years or older as recited in instant claims 2 and 3. Hutchings teaches that the subject is 18 years and older (page 1960, column 1, methods, “Patients of age older than 18 years with histologically confirmed B-NHL expected to express CD20”).
However, reference claims do not recite dosing of Obinutuzumab based on body weight as recited in instant claim 65 and 67 and do recite split dosing of obinutuzumab as recited in instant claim 127. At the time of the effective filing date, there have been no established dosages for pediatric patients (FDA drug label for (obinutuzumab) GAZYVA®, version 02/2016, page 16, 8.4 pediatric use) but rather the FDA obinutuzumab teaches a tested dose range of 50-2000 mg per infusion (page 17, 10 Overdosage) and that the obinutuzumab has linear clearance and that the volume of distribution and steady-state clearance increased with body weight (page 18, 12.3 Pharmacokinetics, "Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification”). Temrikar teaches different dosing strategies in pediatric population wherein the tiered body weight-based dosing strategy is the most widely applied dosing strategy for monoclonal antibodies in children (page 210, 2.7.6-Tiered body weight-based dosing). The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers (page 211, paragraph 2, "The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers."). Xu teaches a strategy to extrapolate pediatric doses based on PK and body weight (abstract, "Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry)"). With the recommended dose in adults and pharmacokinetics of the obinutuzumab as taught by the FDA obinutuzumab, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by Temrikar and Xu. It would be obvious to expect reasonable success in pediatric patients in optimizing the dose of obinutuzumab from these teachings prior to the effective filing date of the instant application.
The reference application also does not teach split doses of obinutuzumab to be administered on C1D1 and C1D2 as recited in instant claims 64, 124, 125, and 127, The FDA obinutuzumab (FDA obinutuzumab, GAZYVA®, version 02/2016) teaches split dosing of obinutuzumab in C1D1 at 100 mg and C2D2 at 900 mg to mitigate infusion related reactions (page 3, Table 1). It would have been obvious to try to implement split doses to mitigate infusion related reactions as taught by the FDA drug label to mitigate infusion related reactions.
Regarding instant claims 19, 21, 22, 63, 78, 87, 123, and 140, Reference claim 6, 8, and 9 recites additional dosing cycles of glofitamab.
Regarding instant claim 195, 196, 197, 199 and 201, Reference claim 12 recites the CD20-positive B cell proliferative disorder is a non-Hodgkin’s lymphoma (NHL), reference claim 13 recites that the NHL is relapsed or refractory, indolent or aggressive and/or a diffuse large B cell lymphoma. Reference claim 133 recites a method of treating a subject having diffuse large B cell lymphoma with the method recited in reference claim 1.
Regarding instant claims 31, 32, 36, 89, 90, 94, 104, 106, 153, 154, and 158, Reference claim 62 recite the subject receives a corticosteroid and 63 recite the subject receives corticosteroid premedication prior to the anti-CD20/anti-CD3 bispecific antibody is prednisolone and methylprednisolone, and/or dexamethasone, and/or the premedication is given prior to first dose of the bispecific antibody.
However, the reference claims do not teach dosing of the therapeutic agents. Salvaris discloses CRS mitigation strategies with bispecific antibody (bsAbs) treatments that potent T-cell activation induced by bsAbs pose the risk of unique complications such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and suggests prophylaxis should be employed for patients at risk with high tumor burden, circulating disease, elevated LDH and impaired renal functions (page 6, 4. Toxicity and Management of Key Adverse Events, paragraph 1). Salvaris further teaches that the “mitigation strategies to reduce severe CRS are commonly used in bsAbs (bispecific antibodies). Pre-mediations are regularly employed with steroids, antihistamines and acetaminophen or paracetamol” (page 7, paragraph 6). Regarding tocilizumab and dosing, Salvaris teaches the tocilizumab that is used for CRS grade 2 or higher wherein the tocilizumab is “effective at a dose of 8 mg/kg in adults and 12 mg/kg in patients weighing 30 kg, with a maximum recommended dose of 800 mg per infusion” (page 9, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the common CRS mitigation strategies taught by Salvaris to reduce adverse events caused by the glofitamab treatment and ensure efficacious and safe cancer treatment.
Kewalramani teaches the mitigating strategies to toxicities related to R-ICE chemotherapy. Kewalramani teaches the dose and administration of mesna with ifosfamide within the R-ICE chemotherapy in adults (page 3685, column 1, paragraph 3, treatment, "lfosfamide (5000 mg/m2), mixed with an equal amount of mesna, was administered as a continuous intravenous infusion over 24 hours beginning on day 4").
Kewalramani teaches the method of administering acetaminophen and diphenhydramine prior to administering R-ICE (page 3685, column 1, paragraph 3, Treatment, "administration of oral acetaminophen (650 mg) and intravenous diphenhydramine (50 mg)").
However, Kewalramani does not teach acetaminophen and diphenhydramine is administered 30 min before obinutuzumab infusion. The FDA for obinutuzumab discloses doses and treatment regimens of the acetaminophen and diphenhydramine (FDA drug label for obinutuzumab, 2016, page 5, Table 3, "650-1000 mg acetaminophen" and "50 mg diphenhydramine" at least 30 min prior before GAZYVA infusion") to reduce infusion related reactions from obinutuzumab (page 5, table 3). It would have been obvious to use FDA standard treatment recommendations to mitigate infusion related reaction side effect caused by the obinutuzumab infusion.
Regarding G-CSF administration, Griffin teaches a method of administering G-CSF to children receiving R-ICE chemotherapy about one day after the administration of R-ICE therapy (page 3, treatment plan, paragraph 4, "Growth factor support with granulocyte-colony stimulating factory (G-CSF) was begun on day 6 of each course." [Last day of R-ICE regimen in Griffin is day 5 "Etoposide, 100 mg/m2 was given daily as a 1 hour IV infusion on days 3, 4, and 5"]). The reason to administer G-CSF during R-ICE chemotherapy is to mitigate neutropenia due to the high myelosuppression caused by the ICE regimen as evidenced by Cairo (page 31, column 1, paragraph 1, "(ICE) could potentiate both the duration and nadir of neutropenia."). It would have been obvious to the skilled artisan in the art to administer G-CSF in the treatment regimen to mitigate side effect caused by chemotherapeutic agents in R-ICE chemotherapy and expect reasonable success at reducing neutropenia based on the teachings of Cairo and Griffin.
However, reference claims do not teach that dexamethasone is administered intravenously at a dose of between about 0.15 mg/kg to about 0.5 mg/kg at least about one hour prior to the administration of any dose of the bispecific antibody and/or obinutuzumab, and wherein the maximum daily dose is 10 mg as recited in instant claim 94 and 158. Website IWK Health published in 2019 teaches dosage recommendations for children is between 0.125-0.5 mg/kg/dose with a maximum dose is 10 mg/dose (IWK Health website, published on 06/12/2019, "0.125-0.5 mg/kg/dose PO/IV /IM" and "maximum: 10mg/dose"). It would have been obvious to the person of ordinary skill in the art to use standard recommended dosages for dexamethasone to treat pediatric populations.
Reference claims do not teach methylprednisolone is administered intravenously at a dose of between about 1 mg/kg to about 2 mg/kg at least about one hour prior to the administration of any dose of the bispecific antibody and/or obinutuzumab as recited in claim 94 and 158. Salvaris teach corticosteroids that have been used as “second line treatment for severe or refractory CRS” and that “corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies” (Salvaris, page 9, paragraph 2). However, Salvaris does not teach dosing regimen of the corticosteroid dexamethasone, prednisone or prednisolone. The FDA methylprednisolone teaches equivalent dosages of prednisone and prednisolone as either oral or intravenous injection and that methylprednisolone is a potent anti-inflammatory steroid (page 3, paragraph 5). Therefore, it would have been obvious to the person of ordinary skill in the art to optimize corticosteroids as taught by Salvaris to mitigate CRS from bispecific antibody treatments and optimize with equivalent doses of the corticosteroids taught by FDA methylprednisolone.
The reference claim does not teach subject is aged between 6 months and 17 years, and wherein diphenhydramine is administered intravenously at a dose of between about 10 mg to 20 mg with a maximum single dose of about 1.25 mg/kg or the subject is aged less than two years, and wherein diphenhydramine is administered rectally at a dose of about 20 mg as recited in instant claim 104. The website WikiEM teaches pediatric doses of diphenhydramine at 1.25-1.67mg/kg/dose that can be administered oral or IV (page 2, wikem.org/wiki/Diphenhydramine, last updated on 03/07/2021). Further, as recited in instant claim 104, rectal administration of diphenhydramine at about 20 mg is not taught by WikiEm diphenhydramine, rather Jannin teaches that rectal administration of drugs is a good alternative route to oral in pediatric populations that cannot swallow due to high dosage form and it is absorbed faster into the system (page 35, paragraph 3, "need high doses and cannot easily be formulated in oral solid dosage forms"). It would have been obvious to the person of ordinary skill in the art to substitute different routes of administration of diphenhydramine with standard dosage recommendations known in the art to improve absorption and uptake of the drug in pediatric populations to mitigate CRS from the bispecific antibody treatment as taught by Salvaris.
However, reference claims do not recite the subject has received at least one prior systemic therapy (instant claim 202), no more than one prior systemic therapy (instant claim 203), and the prior systemic therapy is an anti-CD2 antibody and an anthracycline (instant claim 204). Reference claim does not mention that systemic therapy comprises an anti-CD20 antibody and an anthracycline. Hutchings teaches patient characteristics receiving the bispecific CD20/CD3 antibody glofitamab that had one or no more than one prior systemic therapy and received a prior systemic therapy comprises an anti-CD20 antibody and an anthracycline (table 1, Patient demographics and baseline disease characteristics, see patient populations that had "Prior lines of therapy Range from 1-13", "Refractory to any prior therapy", "Refractory to any line of prior CD20 therapy"). Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Therefore, it would have been obvious to the person of ordinary skill in the art to include patients in the treatment method with prior systemic therapy that comprise anti-CD20 antibody and anthracycline and expect reasonable success at treating difficult-to-treat patients that have already gone through prior systemic therapy but relapsed.
However, reference claims do not teach RICE chemotherapy and dosages for subjects between 6 months and 17 years of age as recited in instant claims 68, 73, 74, 75, 84, 86, and 87. Griffin teaches the dosage regimen for R-ICE for children under the age of 21 wherein patients received 3 cycles, each cycle comprising of Rituximab (375 mg/m2) two days prior to the chemotherapeutic agents (page 3, treatment plan, paragraph 1), 3 doses of ifosfamide, 3 doses of etoposide and 1 single dose of carboplatin (page 3, Treatment plan, paragraph 2, “ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on day 3,4, and 5”; “Etoposide, 100 mg/m2, was given daily as a 1 hour IV infusion on days 3, 4, and 5”; “Carboplatin, 635 mg/m2 (no maximum dose) was given as a 1 hour IV infusion on day 3 only”). However, 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)).
However, reference claims do not teach glofitamab dosing for subjects 6 months to 17 years as recited in instant claims 59, 60, 81, and 82. Djebli teaches the pharmacokinetics of glofitamab wherein glofitamab has linear clearance with retained body weight effect on volumes and clearance and step up dosing regimen (2.5/10/30mg Q3W) to optimize benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whiles allowing escalation to a higher dose associated with a better clinical response (page 1, results). In further view of Djebli, van Rongen teaches methods of allometric scaling methods to extrapolate pediatric dosing from adult clearance and body weight and that it is commonly used for pediatric drug dosing (page 102, 2.1. Linear bodyweight-based scaling). With the recommended dose in adults and pharmacokinetics of the glofitamab as taught by Djebli and glofitamab cycles taught by Ghosh, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by van Rongen. A person of ordinary skill in the art would expect reasonable success in pediatric patients because the linear clearance of glofitamab based on body weight taught by Djebli would allow safe allometric scaling of the adult dosages. However, 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)).
However, reference claims do not teach creatine clearance (CrCl) as recited in instant claims 134, 135, 136, 148, 149, and 150. Hendrayana teaches the equation for CrCI in female and male subjects (page 3, 2.4 Guideline Application, Cockcroft and Gault equation(l) and recommended dosage modifications based on CrCI levels for etoposide and carboplatin (page 4-5, Table 1, No. 4 carboplatin and No. 17 etoposide). Hendrayana further teaches that chemotherapeutic agents can reduce hepatic and renal functions and that using this measurement may improve patient response to treatment (page 2, paragraph 5, "to adapt the dosing of anticancer agents to the individual requirements of patients with renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic effects due to overdosing"). It would have been obvious to the person of ordinary skill in the art to include a method to reduce hepatic and renal dysfunction in subjects receiving chemotherapeutic agents in RICE and maximize therapeutic outcomes.
Reference claims do not recite mesna is administered intravenously daily as five doses totaling 3000 mg/m2 in amount as recited in instant claim 90 and intravenously at a first dose of about 600 mg/m2 prior to the administration of any dose of ifosfamide and at four repeated doses of about 600 mg/m2 each at about three hours, about six hours, about nine hours, and about 12 hours, respectively, after the first dose of ifosfamide; and/or daily to the subject on Days 3, 4, and 5 of the first dosing cycle, on Days 6, 7, and 8 of the second dosing cycle, and/or on Days 6, 7, and 8 of each additional dosing cycle as recited in instant claim 94. Griffin teaches the administration of mesna in equal amounts with ifosfamide ("ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on days 3, 4 and 5. Mesna, 600 mg/m2 was mixed with the dose of ifosfamide and also given as 15 minute IV boluses 3, 6, 9, and 12 hours after the start of the ifosfamide."). The FDA ifosfamide suggests the dose and usage of mesna in conjunction with ifosfamide to reduce hemorrhagic cystitis caused by ifosfamide (ifosfamide FDA drug label, published 07 /2018, page 1, column 1, "mesna should be used to reduce the incidence of hemorrhagic cystitis"). It would have been obvious to the person of ordinary skill in the art to use the recommended dosage and administration from the FDA ifosfamide and Griffin to formulate dosages and treatment regimen in pediatric populations to mitigate adverse effects caused by ifosfamide in RICE therapy.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 8-10, 14, 19, 21, 22, 25, 31, 32, 36, 58-61, 63-65, 67, 68, 73-75, 78, 81, 82,
84, 86, 87, 89, 90, 94, 104, 106, 119-121, 123-125, 127, 133-137, 140, 143, 146, 148-151, 153, 154, 158, 195-197, 199, and 201-204 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 167, 168, 169, 170, 171, 176, 177, 178, 179, 182, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, of copending Application No. 18/964,055 amended on April 11th, 2025 (reference) in view of Hutchings (cited previously), Kewalramani (cited previously), FDA obinutuzumab (cited previously), Temrikar (cited previously), Xu (cited previously), Salvaris (cited previously), Griffin (cited previously), Cairo (cited previously), FDA methylprednisolone (cited previously), WikiEM (cited previously), Jannin (cited previously), IWK Health (cited previously), Hendrayana (cited previously), and FDA ifosfamide.
Regarding instant claims 1, 4, 6, 8, 9, 10, 19, 21, 22, 58, 59, 60, 61, 63, 64, 68, 81, 82, 119, 120, 121, 123, 124, 125, 140, 143, Reference claim 167, 182 recite a method of treating a subject having a CD20-positive cell proliferative disorder comprising administering to the subject glofitamab in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. Reference claim 167 and 182 further recite doses of 2.5mg, 10 mg and 30 mg in first and second dosing cycle of glofitamab as well as administering rituximab, cyclophosphamide, doxorubicin, and a corticosteroid. Reference claim 167 and 182 recite an additional agent polatuzumab vedotin.
However, reference claims do not recite RICE chemotherapy for subjects over 18 years old and the dosing regimen as recited in instant claims 1, 9, 10, 14, 21, 22, 25, 68, 73, 74, 75, 119, 125, 133, 134, 146, 148, 151. Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Kewalramani teaches a chemotherapy R-ICE and dosing regimen to treat relapsed or primary refractory diffuse large B-cell lymphoma wherein patients receive 3 cycles of each cycle comprising rituximab (page 3685, column 1 “Rituximab (375 mg/m2) was administered on an outpatient basis on day 1 of each cycle and 48 hours before the initiation of the first cycle.”), 3 doses of etoposide for 3 days (page 3685, column 1, treatment, "Etoposide (100 mg/m2) was administered as an intravenous bolus daily for 3 days, from days 3 to 5"), a single dose of carboplatin (page 3685, column 1, treatment, "Carboplatin (area under the curve [AUC], 5; dose= 5 x [25 + Clcr]), capped at 800 mg, was administered as a bolus infusion on day 4.), and a single dose of ifosfamide (page 3685, column 1, treatment, "lfosfamide (5000 mg/m2) [ ... ] was administered as a continuous intravenous infusion over 24 hours beginning on day 4"). Kewalramani further discloses that “RICE was well tolerated, and, despite its hematologic toxicity, febrile neutropenia occurred in only 7.5% of delivered cycles, much lower than the incidence with several of the other commonly used second-line regimens associated with febrile neutropenia rates of 30% to 65%” (page 3687, column 2, paragraph 4). Kewalramani further teaches that R-ICE appears to be particularly beneficial in patients with relapsed disease (page 3687, column 2, paragraph 2). Hutching teaches that glofitamab has a favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options (page 3688, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to add RICE in the method of treating with glofitamab to treat relapsed B cell cancers like DLBCL in difficult to treat patients as taught by Hutchings and Kewalramani. A person of ordinary skill in the art would have been motivated to add the chemotherapy R-ICE because Kewalramani teaches that RICE is well tolerated and is beneficial in relapsed disease and Hutchings teaches that glofitamab has a favorable safety profile and combination with chemotherapy is possible.
Even though the day of administering the chemotherapeutic agents in the instant claim are not explicitly taught by Kewalramani, it would have been obvious to the person of ordinary skill in the art to optimize dosing regimen to accommodate the patient's time spent in the hospital for infusion and tolerance to the combination of the therapeutic agents. 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 instant claim 8, 19, 21, 22, 63, 78, 87, 123, 140, and 192, Reference claim 168 recites the dosing cycle is 21 days and the glofitamab is administered intravenously. Reference claim 176 and 193 recite additional dosing cycles of glofitamab.
Regarding instant claim 195, 196, 197, 199, and 201, Reference claim 169, 177, 187, 194 recite the CD20 positive cell proliferative disorder is a B cell disorder. Reference claim 170, 178, 188, 195 recite the disorder is B cell lymphoma and non-Hodgkin’s lymphoma. Reference claim 171, 179, 189, 196 recite the B cell lymphoma is a diffuse large cell lymphoma (DLBCL). Reference claim 190, 197 recite the follicular lymphoma (FL) is a transformed FL. Reference claim 191, 198 recite NHL is an aggressive NHL.
However, reference claims do not teach the age of the subject 18 years or older, 31 years or older as recited in instant claims 2 and 3. Hutchings teaches that the subject is 18 years and older (page 1960, column 1, methods, “Patients of age older than 18 years with histologically confirmed B-NHL expected to express CD20”).
However, reference claims do not recite the subject has received at least one prior systemic therapy (instant claim 202), no more than one prior systemic therapy (instant claim 203), and the prior systemic therapy is an anti-CD2 antibody and an anthracycline (instant claim 204). Reference claim does not mention that systemic therapy comprises an anti-CD20 antibody and an anthracycline. Hutchings teaches patient characteristics receiving the bispecific CD20/CD3 antibody glofitamab that had one or no more than one prior systemic therapy and received a prior systemic therapy comprises an anti-CD20 antibody and an anthracycline (table 1, Patient demographics and baseline disease characteristics, see patient populations that had "Prior lines of therapy Range from 1-13", "Refractory to any prior therapy", "Refractory to any line of prior CD20 therapy"). Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Therefore, it would have been obvious to the person of ordinary skill in the art to include patients in the treatment method with prior systemic therapy that comprise anti-CD20 antibody and anthracycline and expect reasonable success at treating difficult-to-treat patients that have already gone through prior systemic therapy but relapsed.
Regarding instant claims 1, 9, 10, 64, 65, 67, 68, 124, 125, and 127, Reference claim 184, 185, 186, 200, 201, 202, and 203 recite administering to the subject Obinutuzumab seven days prior to the administration of glofitamab and the single dose is about 1000 mg.
However, reference claims do not recite dosing of Obinutuzumab based on body weight as recited in instant claim 65 and 67 and do recite split dosing of obinutuzumab as recited in instant claim 127. At the time of the effective filing date, there have been no established dosages for pediatric patients (FDA drug label for (obinutuzumab) GAZYVA®, version 02/2016, page 16, 8.4 pediatric use) but rather the FDA obinutuzumab teaches a tested dose range of 50-2000 mg per infusion (page 17, 10 Overdosage) and that the obinutuzumab has linear clearance and that the volume of distribution and steady-state clearance increased with body weight (page 18, 12.3 Pharmacokinetics, "Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification”). Temrikar teaches different dosing strategies in pediatric population wherein the tiered body weight-based dosing strategy is the most widely applied dosing strategy for monoclonal antibodies in children (page 210, 2.7.6-Tiered body weight-based dosing). The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers (page 211, paragraph 2, "The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers."). Xu teaches a strategy to extrapolate pediatric doses based on PK and body weight (abstract, "Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry)"). With the recommended dose in adults and pharmacokinetics of the obinutuzumab as taught by the FDA obinutuzumab, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by Temrikar and Xu. It would be obvious to a skilled artisan to expect reasonable success in treating pediatric patients in optimizing the dose of the anti- CD20 antibody from these teachings prior to the effective filing date of the instant application. The FDA obinutuzumab (FDA (obinutuzumab) GAZYVA®, version 02/2016) teaches split dosing of obinutuzumab in C1D1 at 100 mg and C2D2 at 900 mg (page 3, Table 1). It would have been obvious to try to implement split doses to mitigate infusion related reactions as taught by the FDA obinutuzumab.
Regarding instant claim 1, 9, 10, 21, 25, 58, 64, 68, 78, 84, 119, 124, 140, 146, Reference claim 192 and 199 recite rituximab is administered about 1 day before administering glofitamab.
However, reference claims do not teach RICE chemotherapy and dosages for subjects under 18 as recited in instant claims 68, 73, 74, 75, 84, 86, and 87. Griffin teaches the dosage regimen for R-ICE for children under the age of 21 wherein patients received 3 cycles, each cycle comprising of Rituximab (375 mg/m2) two days prior to the chemotherapeutic agents (page 3, treatment plan, paragraph 1), 3 doses of ifosfamide, 3 doses of etoposide and 1 single dose of carboplatin (page 3, Treatment plan, paragraph 2, “ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on day 3,4, and 5”; “Etoposide, 100 mg/m2, was given daily as a 1 hour IV infusion on days 3, 4, and 5”; “Carboplatin, 635 mg/m2 (no maximum dose) was given as a 1 hour IV infusion on day 3 only”). However, 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)).
However, reference claims do not teach glofitamab dosing for subjects between 6 months and 17 years as recited in instant claims 59, 60, 81, and 82. Djebli teaches the pharmacokinetics of glofitamab wherein glofitamab has linear clearance with retained body weight effect on volumes and clearance and step up dosing regimen (2.5/10/30mg Q3W) to optimize benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whiles allowing escalation to a higher dose associated with a better clinical response (page 1, results). In further view of Djebli, van Rongen teaches methods of allometric scaling methods to extrapolate pediatric dosing from adult clearance and body weight and that it is commonly used for pediatric drug dosing (page 102, 2.1. Linear bodyweight-based scaling). With the recommended dose in adults and pharmacokinetics of the glofitamab as taught by Djebli and glofitamab cycles taught by Ghosh, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by van Rongen. A person of ordinary skill in the art would expect reasonable success in pediatric patients because the linear clearance of glofitamab based on body weight taught by Djebli would allow safe allometric scaling of the adult dosages. However, 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 instant claims 31, 32, 36, 89, 90, 94, 104, 106, 153, 154, and 158, Reference claims 204 and 205 recite the corticosteroid is prednisone, prednisolone, or methylprednisolone.
However, reference claims do not teach dosing of tocilizumab, antihistamine and antipyretics, G-CSF, corticosteroids (dexamethasone, prednisone, and prednisolone), and mesna. Salvaris discloses CRS mitigation strategies with bispecific antibody (bsAbs) treatments that potent T-cell activation induced by bsAbs pose the risk of unique complications such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and suggests prophylaxis should be employed for patients at risk with high tumor burden, circulating disease, elevated LDH and impaired renal functions (page 6, 4. Toxicity and Management of Key Adverse Events, paragraph 1). Salvaris further teaches that the “mitigation strategies to reduce severe CRS are commonly used in bsAbs (bispecific antibodies). Pre-mediations are regularly employed with steroids, antihistamines and acetaminophen or paracetamol” (page 7, paragraph 6). Regarding tocilizumab and dosing, Salvaris teaches the tocilizumab that is used for CRS grade 2 or higher wherein the tocilizumab is “effective at a dose of 8 mg/kg in adults and 12 mg/kg in patients weighing 30 kg, with a maximum recommended dose of 800 mg per infusion” (page 9, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the common CRS mitigation strategies taught by Salvaris to reduce adverse events by the glofitamab treatment and ensure efficacious and safe cancer treatment.
Further, Kewalramani teaches the mitigating strategies to toxicities related to R-ICE chemotherapy. Kewalramani teaches the dose and administration of mesna with ifosfamide within the R-ICE chemotherapy in adults (page 3685, column 1, paragraph 3, treatment, "lfosfamide (5000 mg/m2), mixed with an equal amount of mesna, was administered as a continuous intravenous infusion over 24 hours beginning on day 4").
Kewalramani teaches the method of administering acetaminophen and diphenhydramine prior to administering R-ICE (page 3685, column 1, paragraph 3, Treatment, "administration of oral acetaminophen (650 mg) and intravenous diphenhydramine (50 mg)").
However, Kewalramani does not teach acetaminophen and diphenhydramine is administered 30 min before obinutuzumab infusion. The FDA obinutuzumab discloses doses and treatment regimens of the acetaminophen and diphenhydramine (FDA drug label for obinutuzumab, 2016, page 5, Table 3, "650-1000 mg acetaminophen" and "50 mg diphenhydramine" at least 30 min prior before GAZYVA infusion") to reduce infusion related reactions from obinutuzumab (page 5, table 3). It would have been obvious to use FDA standard treatment recommendations to mitigate infusion related reaction side effect caused by the obinutuzumab infusion.
Regarding G-CSF administration, Griffin teaches a method of administering G-CSF to children receiving R-ICE chemotherapy about one day after the administration of R-ICE therapy (page 3, treatment plan, paragraph 4, "Growth factor support with granulocyte-colony stimulating factory (G-CSF) was begun on day 6 of each course." [Last day of R-ICE regimen in Griffin is day 5 "Etoposide, 100 mg/m2 was given daily as a 1 hour IV infusion on days 3, 4, and 5"]). The reason to administer G-CSF during R-ICE chemotherapy is to mitigate neutropenia due to the high myelosuppression caused by the ICE regimen as evidenced by Cairo (page 31, column 1, paragraph 1, "(ICE) could potentiate both the duration and nadir of neutropenia."). It would have been obvious to the skilled artisan in the art to administer G-CSF in the treatment regimen to mitigate side effect caused by chemotherapeutic agents in R-ICE chemotherapy and expect reasonable success at reducing neutropenia based on the teachings of Cairo and Griffin.
Salvaris teaches corticosteroids have been used as “second line treatment for severe or refractory CRS” and that “corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies” (page 9, paragraph 2).
However, Salvaris does not teach dosing regimen of the corticosteroid dexamethasone, prednisone or prednisolone. The FDA drug label for corticosteroid methylprednisolone (FDA label, published on October 2011) teaches equivalent dosages of prednisone and prednisolone as either oral or intravenous injection and that methylprednisolone is a potent anti-inflammatory steroid (page 3, paragraph 5). It would have been obvious to the skilled artisan to use drug dosing recommendations from FDA methylprednisolone equivalent suggestions to optimize dosage regimens depending on specific patient populations to mitigate high inflammatory responses due to the glofitamab treatment regimen. 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)).
However, reference claims do not recite dosing dexamethasone, methylprednisolone, prednisolone, and prednisone for patients over 18 (instant claim 36, 158) and under 17 (instant claims 94). Kewalramani and in further view of FDA obinutuzumab label teach the dosage and administration of antihistamines to counteract CRS due to the treatment. However, they do not teach dosages of antihistamine diphenhydramine by age. WikiEm Diphenhydramine teaches pediatric doses at 1.25-1.67mg/kg/dose that can be administered oral or IV (page 2, website: wikem.org/wiki/Diphenhydramine, last updated on 03/07/2021). Further, as recited in instant claim 104, rectal administration of diphenhydramine at about 20 mg is not taught by Kewalramani, FDA obinutuzumab label and WikiEm. Jannin teaches that rectal administration of drugs is a good alternative route as compared to oral in pediatric populations that cannot swallow due to high dosage form and it is absorbed faster in the system (page 35, paragraph 3, “need high doses and cannot be easily formulated in oral solid dosage forms”). It would have been obvious to the person of ordinary skill in the art to substitute different routes of administration of diphenhydramine with standard dosage recommendations as taught by the FDA obinutuzumab, WikiEm, Jannin, and Kewalramani to improve absorption and uptake of the drug in pediatric populations.
In another aspect, as described above, Ghosh, Kewalramani and Hutchings do not teach the dexamethasone dosages by weight, IWK Health website teaches dosage recommendation for children (Website: www.dir.iwk.nshealth.ca/Home/DDGDetails/aed57259-168d-e911-80f2-005056b200d2?PatientPopulation=Ped, published on 06/12/2019). It would have been obvious to the person of ordinary skill in the art to optimize standard recommended dosages for dexamethasone to mitigate CRS caused by glofitamab and RICE as taught by Salvaris and apply appropriate dosages for pediatric populations as taught by IWK Health.
However, reference claims do not teach creatine clearance (CrCl) as recited in instant claims 134, 135, 136, 148, 149, and 150. Hendrayana teaches the equation for CrCI in female and male subjects (page 3, 2.4 Guideline Application, Cockcroft and Gault equation(l) and recommended dosage modifications based on CrCI levels for etoposide and carboplatin (page 4-5, Table 1, No. 4 carboplatin and No. 17 etoposide). Hendrayana further teaches that chemotherapeutic agents can reduce hepatic and renal functions and that using this measurement may improve patient response to treatment (page 2, paragraph 5, "to adapt the dosing of anticancer agents to the individual requirements of patients with renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic effects due to overdosing"). It would have been obvious to the person of ordinary skill in the art to modify dosages for etoposide and carboplatin based on creatine clearance rates to reduce hepatic and renal toxicity and improve patient responses to treatment.
Reference claims do not recite mesna is administered intravenously daily as five doses totaling 3000 mg/m2 in amount as recited in instant claim 90 and intravenously at a first dose of about 600 mg/m2 prior to the administration of any dose of ifosfamide and at four repeated doses of about 600 mg/m2 each at about three hours, about six hours, about nine hours, and about 12 hours, respectively, after the first dose of ifosfamide; and/or daily to the subject on Days 3, 4, and 5 of the first dosing cycle, on Days 6, 7, and 8 of the second dosing cycle, and/or on Days 6, 7, and 8 of each additional dosing cycle as recited in instant claim 94. Griffin teaches the administration of mesna in equal amounts with ifosfamide ("ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on days 3, 4 and 5. Mesna, 600 mg/m2 was mixed with the dose of ifosfamide and also given as 15 minute IV boluses 3, 6, 9, and 12 hours after the start of the ifosfamide."). The FDA ifosfamide suggests the dose and usage of mesna in conjunction with ifosfamide to reduce hemorrhagic cystitis caused by ifosfamide (ifosfamide FDA drug label, published 07 /2018, page 1, column 1, "mesna should be used to reduce the incidence of hemorrhagic cystitis"). It would have been obvious to the person of ordinary skill in the art to use the recommended dosage and administration taught by FDA ifosfamide and Griffin to formulate dosages and treatment regimen in pediatric populations to mitigate adverse effects caused by ifosfamide in RICE.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 8-10, 14, 19, 21, 22, 25, 31, 32, 36, 58-61, 63-65, 67, 68, 73-75, 78, 81, 82,
84, 86, 87, 89, 90, 94, 104, 106, 119-121, 123-125, 127, 133-137, 140, 143, 146, 148-151, 153, 154, 158, 195-197, 199, and 201-204 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 45, 46, 47, 30, 48, 36, 37, 38, and 39 of copending Application No. 18/299,877 amended on April 6th, 2026 (reference) in view of Ghosh (cited previously), Hutchings (cited previously), Kewalramani (cited previously), FDA obinutuzumab (cited previously), Temrikar (cited previously), Xu (cited previously), Salvaris (cited previously), Griffin (cited previously), Cairo (cited previously), FDA methylprednisolone (cited previously), WikiEM (cited previously), Jannin (cited previously), IWK Health (cited previously), Hendrayana (cited previously), and FDA ifosfamide.
Regarding instant claims 1, 4, 6, 8, 9, 10, 19, 21, 22, 58, 59, 60, 61, 63, 64, 68, 81, 82, 119, 120, 121, 123, 124, 125, 140, 143, 192, Reference claim 1 recites the pharmaceutical composition of glofitamab. Reference claim 45 and 46 recite the pharmaceutical composition is administered intravenously and via intravenous infusion. Reference claim 47 recites the effective amount of the liquid pharmaceutical composition is about 2.5 mg, about 10 mg, or about 30 mg of glofitamab. Reference claim 30 recites 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 according to claim 1. Reference claim 48 recites the method of treating R/R DLBCL NOS or TrFL in a subject in need thereof, the method comprising intravenously administering to the subject an effective amount of a pharmaceutical composition comprising about 1 mg/ml glofitamab.
Regarding instant claim 195, 196, 197, 199 and 201, Reference claim 36 recites the cell proliferative disorder is a cancer, reference claim 37 recites the cancer is a B-cell proliferative disorder, reference claim 38 recites the B cell proliferative disorder is a non-Hodgkin’s lymphoma (NHL) and/or relapsed or refractory. Reference claim 39 recites the NHL is a follicular lymphoma or a diffuse large cell lymphoma (DLBCL).
However, the reference claim do not teach the method of treating comprising administering glofitamab and RICE.
Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options. As a consequence, glofitamab is undergoing expanded evaluation in R/R and untreated B-NHL, alone and in combination with conventional chemotherapy and novel agents”). Kewalramani teaches a chemotherapy R-ICE and dosing regimen to treat relapsed or primary refractory diffuse large B-cell lymphoma wherein patients receive 3 cycles of each cycle comprising 3 doses of etoposide for 3 days (page 3685, column 1, treatment, "Etoposide (100 mg/m2) was administered as an intravenous bolus daily for 3 days, from days 3 to 5"), a single dose of carboplatin (page 3685, column 1, treatment, "Carboplatin (area under the curve [AUC], 5; dose= 5 x [25 + Clcr]), capped at 800 mg, was administered as a bolus infusion on day 4.), and a single dose of ifosfamide (page 3685, column 1, treatment, "lfosfamide (5000 mg/m2) [ ... ] was administered as a continuous intravenous infusion over 24 hours beginning on day 4"). Kewalramani further discloses that “RICE was well tolerated, and, despite its hematologic toxicity, febrile neutropenia occurred in only 7.5% of delivered cycles, much lower than the incidence with several of the other commonly used second-line regimens associated with febrile neutropenia rates of 30% to 65%” (page 3687, column 2, paragraph 4). Kewalramani further teaches that R-ICE appears to be particularly beneficial in patients with relapsed disease (page 3687, column 2, paragraph 2). Hutching teaches that glofitamab has a favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options (page 3688, paragraph 1). Further, Ghosh teaches the method of treating Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL) wherein glofitamab is administered with Obinutuzumab and with the chemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) (abstract). Further, Gosh discloses that Glofit +R-CHOP has tolerable safety (results). Ghosh further teaches the method of administering glofitamab and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) with dosing and cycles of glofitamab and chemotherapy (page 1, methods, “Glofit doses in separate cohorts (70μg, 1800μg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70μg and 1800μg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards”). Therefore, it would have been obvious to the person of ordinary skill in the art to substitute R-CHOP chemotherapy in the method of treating using glofitamab taught by Ghosh with R-ICE chemotherapy taught by Kewalramani to treat relapsed B cell cancers like DLBCL in difficult to treat patients as taught by Hutchings and Kewalramani. A person of ordinary skill in the art would have been motivated to make the chemotherapy substitution of R-CHOP to R-ICE, because Kewalramani teaches that RICE is well tolerated and is beneficial in relapsed disease and Hutchings teaches that glofitamab has a favorable safety profile and combination with chemotherapy is possible.
Even though the day of administering the chemotherapeutic agents in the instant claim are not explicitly taught by Kewalramani, it would have been obvious to the person of ordinary skill in the art to optimize dosing regimen to accommodate the patient's time spent in the hospital for infusion and tolerance to the combination of the therapeutic agents. 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)).
In regards to the specific dosage and interval amounts recited in the instant claims 4, 6, 8, 19, reciting glofitamab dosing regimen and cycles and as taught by Ghosh "[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 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious."
However, reference claims do not teach the age of the subject 18 years or older, 31 years or older as recited in instant claims 2 and 3. Hutchings teaches that the subject is 18 years and older (page 1960, column 1, methods, “Patients of age older than 18 years with histologically confirmed B-NHL expected to express CD20”).
The reference application does not teach the obinutuzumab dosing regimen based on weight as recited in instant claims 65 and 67. At the time of the effective filing date, there have been no established dosages for obinutuzumab in pediatric patients (FDA (obinutuzumab) GAZYVA®, version 02/2016, page 16, 8.4 pediatric use) but rather the FDA obinutuzumab teaches a tested dose range of 50-2000 mg per infusion (page 17, 10 Overdosage) and that the obinutuzumab has linear clearance and that the volume of distribution and steady-state clearance increased with body weight (page 18, 12.3 Pharmacokinetics, "Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification”). Further, Temrikar teaches different dosing strategies in pediatric population wherein the tiered body weight-based dosing strategy is the most widely applied dosing strategy for monoclonal antibodies in children (page 210, 2.7.6-Tiered body weight-based dosing). The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers (page 211, paragraph 2, "The body weight-tiered dosing strategy minimizes the risk of low exposure by adjusting the dose with different body weight tiers"). Xu teaches a strategy to extrapolate pediatric doses based on PK and body weight (abstract, "Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry)"). With the recommended dose in adults and pharmacokinetics of the obinutuzumab as taught by the FDA obinutuzumab, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by Temrikar and Xu. It would be obvious to expect reasonable success in pediatric patients in optimizing the dose of the anti-CD20 antibody from these teachings prior to the effective filing date of the instant application.
The reference application also does not teach split doses of obinutuzumab to be administered on C1D1 and C1D2 as recited in instant claims 64, 124, 125, and 127, The FDA obinutuzumab (FDA obinutuzumab, GAZYVA®, version 02/2016) teaches split dosing of obinutuzumab in C1D1 at 100 mg and C2D2 at 900 mg to mitigate infusion related reactions (page 3, Table 1). It would have been obvious to try to implement split doses to mitigate infusion related reactions as taught by the FDA drug label to mitigate infusion related reactions.
The reference claims do not teach dosing regimen of ifosfamide, carboplatin and etoposide for patients 6 months to 17 years as recited claim 73 and that ifosfamide is administered at a dose of about 3000 mg/m2 for each dose of ifosfamide, carboplatin is administered at a dose of about 635 mg/m2, and etoposide is administered at a dose of about 100 mg/m2 for each dose of etoposide as recited in instant claims 74, 75, 86, and 87. Griffin teaches the dosing regimen of ifosfamide, carboplatin, and etoposide for pediatric populations wherein ifosfamide is given in three doses, carboplatin in a single dose and etoposide is given in three doses (page 1, Abstract, methods). It would have been obvious to the person of ordinary skill in the art to modify dosing regimens as taught by Griffin to administer R-ICE in pediatric patient populations as they would respond differently than adults.
Reference claims do not recite dosing therapeutic agents based on weight as recited in instant claims 32, 90, 94, 104, 106, and 154. Salvaris discloses CRS mitigation strategies with bispecific antibody (bsAbs) treatments that potent T-cell activation induced by bsAbs pose the risk of unique complications such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and suggests prophylaxis should be employed for patients at risk with high tumor burden, circulating disease, elevated LDH and impaired renal functions (page 6, 4. Toxicity and Management of Key Adverse Events, paragraph 1). Salvaris further teaches that the “mitigation strategies to reduce severe CRS are commonly used in bsAbs (bispecific antibodies). Pre-mediations are regularly employed with steroids, antihistamines and acetaminophen or paracetamol” (page 7, paragraph 6). Regarding tocilizumab and dosing, Salvaris teaches the tocilizumab that is used for CRS grade 2 or higher wherein the tocilizumab is “effective at a dose of 8 mg/kg in adults and 12 mg/kg in patients weighing 30 kg, with a maximum recommended dose of 800 mg per infusion” (page 9, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to use the common CRS mitigation strategies taught by Salvaris to reduce adverse events disclosed by Ghosh in the glofit treatment and ensure efficacious and safe cancer treatment.
However, reference claims do not teach that dexamethasone is administered intravenously at a dose of between about 0.15 mg/kg to about 0.5 mg/kg at least about one hour prior to the administration of any dose of the bispecific antibody and/or obinutuzumab, and wherein the maximum daily dose is 10 mg as recited in instant claim 94 and 158. Website IWK Health published in 2019 teaches dosage recommendations for children is between 0.125-0.5 mg/kg/dose with a maximum dose is 10 mg/dose (IWK Health website, published on 06/12/2019, "0.125-0.5 mg/kg/dose PO/IV /IM" and "maximum: 10mg/dose"). It would have been obvious to the person of ordinary skill in the art to use standard recommended dosages for dexamethasone to treat pediatric populations.
Reference claims do not teach methylprednisolone is administered intravenously at a dose of between about 1 mg/kg to about 2 mg/kg at least about one hour prior to the administration of any dose of the bispecific antibody and/or obinutuzumab as recited in claim 94 and 158. Salvaris teach corticosteroids that have been used as “second line treatment for severe or refractory CRS” and that “corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies” (Salvaris, page 9, paragraph 2). However, Salvaris does not teach dosing regimen of the corticosteroid dexamethasone, prednisone or prednisolone. The FDA drug label for corticosteroid for methylprednisolone (FDA label, published on October 2011) teaches equivalent dosages of prednisone and prednisolone as either oral or intravenous injection and that methylprednisolone is a potent anti-inflammatory steroid (page 3, paragraph 5).
The reference claim does not teach subject is aged between 6 months and 17 years, and wherein diphenhydramine is administered intravenously at a dose of between about 10 mg to 20 mg with a maximum single dose of about 1.25 mg/kg or the subject is aged less than two years, and wherein diphenhydramine is administered rectally at a dose of about 20 mg as recited in instant claim 104. The website WikiEM teaches pediatric doses of diphenhydramine at 1.25-1.67mg/kg/dose that can be administered oral or IV (page 2, wikem.org/wiki/Diphenhydramine, last updated on 03/07/2021). Further, as recited in instant claim 104, rectal administration of diphenhydramine at about 20 mg is not taught by WikiEm diphenhydramine, rather Jannin teaches that rectal administration of drugs is a good alternative route to oral in pediatric populations that cannot swallow due to high dosage form and it is absorbed faster into the system (page 35, paragraph 3, "need high doses and cannot easily be formulated in oral solid dosage forms"). It would have been obvious to the person of ordinary skill in the art to substitute different routes of administration of diphenhydramine with standard dosage recommendations known in the art to improve absorption and uptake of the drug in pediatric populations.
Reference claims do not recite dosing carboplatin based on CreatineClearance (CrCl) rate formula as recited in instant claims 134, 135, 136, 148, 149, and 150. Hendrayana teaches the equation for CrCI in female and male subjects (page 3, 2.4 Guideline Application, Cockcroft and Gault equation(l) and recommended dosage modifications based on CrCI levels for etoposide and carboplatin (page 4-5, Table 1, No. 4 carboplatin and No. 17 etoposide). Hendrayana further teaches that chemotherapeutic agents can reduce hepatic and renal functions and that using this measurement may improve patient response to treatment (page 2, paragraph 5, "to adapt the dosing of anticancer agents to the individual requirements of patients with renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic effects due to overdosing"). It would have been obvious to the person of ordinary skill in the art to modify dosages for etoposide and carboplatin based on creatine clearance rates to reduce hepatic and renal toxicity and improve patient responses to treatment.
Reference claims do not recite mesna is administered intravenously daily as five doses totaling 3000 mg/m2 in amount as recited in instant claim 90 and intravenously at a first dose of about 600 mg/m2 prior to the administration of any dose of ifosfamide and at four repeated doses of about 600 mg/m2 each at about three hours, about six hours, about nine hours, and about 12 hours, respectively, after the first dose of ifosfamide; and/or daily to the subject on Days 3, 4, and 5 of the first dosing cycle, on Days 6, 7, and 8 of the second dosing cycle, and/or on Days 6, 7, and 8 of each additional dosing cycle as recited in instant claim 94. Griffin teaches the administration of mesna in equal amounts with ifosfamide ("ifosfamide, 3000 mg/m2 as a 2 hour IV infusion daily on days 3, 4 and 5. Mesna, 600 mg/m2 was mixed with the dose of ifosfamide and also given as 15 minute IV boluses 3, 6, 9, and 12 hours after the start of the ifosfamide."). The FDA ifosfamide suggests the dose and usage of mesna in conjunction with ifosfamide to reduce hemorrhagic cystitis caused by ifosfamide (FDA ifosfamide, published 07 /2018, page 1, column 1, "mesna should be used to reduce the incidence of hemorrhagic cystitis"). It would have been obvious to the person of ordinary skill in the art to use the recommended dosage and administration from the FDA ifosfamide and Griffin to formulate dosages and treatment regimen in pediatric populations to mitigate adverse effects caused by ifosfamide.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed March 17th, 2026 have been fully considered but they are not persuasive.
Claim rejections under 35 U.S.C. § 103
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 this case, the applicant argues that the cited references do not teach or suggest presently claimed dosing regimen for a combination treatment comprising glofitamab and RICE (Applicant’s response to argument, page 25, paragraph 1) and the applicant cites that Chu describes an anti-CD20/anti-CD3 antibody (mosunetuzumab) which has a 1:1 format was different than the 2:1 format as described by Bacac. The applicant further cites that glofitamab is inherently more toxic and needed vastly different clinical management protocols (page 26, paragraph 2). The examiner notes that due to the amendment of the claims by the applicant filed March 17th, 2026, the reference Chu was withdrawn and new grounds of rejection was made in view of Ghosh, Hutchings, and Kewalramani.
Hutchings teaches that the glofitamab which has a format is 2:1, is more potent than other 1:1 formats and recites that the format leads to profound antitumor efficacy in preclinical models of DLBCL (page 1960, column 1, paragraph 1). Hutchings teaches adverse events and mitigation strategies to alleviate the side effects (page 1960, column 2, paragraph 3, “Investigators graded CRS by consensus criteria of Lee et al and managed according to protocol guidance. On-site availability of tocilizumab was a requirement”) but discloses that the potency works well in relapsed and refractory cancer (page 1968, column 2, paragraph 2, “So far, the clinical activity of glofitamab appears to exceed that of blinatumomab and to be in the range of registered CAR-T therapies with possibly a more favorable and temporally predictable safety profile. The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options”).
Further, Hutchings teaches glofitamab is well suited to be combined with conventional chemotherapy and novel agents due to its favorable safety profile compared to CAR-T therapies and is suited for patients that are difficult to treat and have limited treatment options(page 1968, column 2, paragraph 2). Ghosh teaches a combination treatment with glofitamab and RCHOP chemotherapy (title) and discloses that Glofit +R-CHOP has tolerable safety (results). Further, Kewalramani teaches a chemotherapy R-ICE and dosing regimen to treat relapsed or primary refractory diffuse large B-cell lymphoma and discloses that “RICE was well tolerated, and, despite its hematologic toxicity, febrile neutropenia occurred in only 7.5% of delivered cycles, much lower than the incidence with several of the other commonly used second-line regimens associated with febrile neutropenia rates of 30% to 65%” (page 3687, column 2, paragraph 4). Further, Kewalramani notes that RICE may be suitable for autologous stem cell transplantation (ASCT) as patients receiving RICE had no RICE-related toxicity that precluded ASCT (page 3684, abstract). A skilled artisan would understand that a combination therapy that is potent and toxic to cancer cells would also be toxic to non-cancerous cells. As noted by both Hutchings with glofitamab, Ghosh with the combination therapy, and Kewalramani with RICE chemotherapy, adverse events are expected in these treatments and mitigation strategies have both been disclosed by Hutchings and Kewalramani to reduce adverse events. Therefore, it would have been obvious to the person of ordinary skill in the art to combine glofitamab with RICE as taught by Hutchings and Kewalramani to improve treatment options for difficult-to-treat patients and expect reasonable success as taught by Ghosh. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02).
Further, as noted by the examiner, the instant claims and specification describe the specific mitigation strategies to reduce CRS due to glofitamab and RICE but are known in the art. Salvaris discloses CRS mitigation strategies with bispecific antibody (bsAbs) treatments that potent T-cell activation induced by bsAbs pose the risk of unique complications such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and suggests prophylaxis should be employed for patients at risk with high tumor burden, circulating disease, elevated LDH and impaired renal functions (page 6, 4. Toxicity and Management of Key Adverse Events, paragraph 1). Salvaris further teaches that the “mitigation strategies to reduce severe CRS are commonly used in bsAbs (bispecific antibodies). Pre-mediations are regularly employed with steroids, antihistamines and acetaminophen or paracetamol” (page 7, paragraph 6). Before the effective filing date of the instant application, IWK Health, FDA methylprednisolone, WikiEM diphenhydramine, FDA ifosfamide all teach dosages for specific populations for the therapeutic agents that are known and routine in the art to mitigate side effects commonly seen in cancer treatments and immunotherapy as described in Salvaris. "In regards to the specific dosage and interval amounts recited in the instant claims "[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 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious." In response to applicant's arguments against the references individually, 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).
Applicant’s amendments filed March 17th, 2026 have been fully considered and new grounds of rejections have been made. As described above, Hutchings, Ghosh, Kewalramani and others teach the dosing regimen of the glofitamab, anti-CD20 antibody rituximab and Obinutuzumab, the chemotherapy R-ICE, and how to manage CRS toxicities before the effective filing date of the invention.
As described above, Ghosh teaches the method of treating Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL) wherein glofitamab is administered with Obinutuzumab and with the chemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) (abstract). Further, Gosh discloses that Glofit +R-CHOP has tolerable safety (results).
As described above, Hutchings teaches glofitamab and discloses the 2:1 format and that the glofitamab is well suited to be combined with other anti-CD20 antibodies including rituximab and that Obinutuzumab is used to deplete peripheral and tissue-based B cells and mitigate serious CRS (page 1960, column 2, paragraph 1). Hutchings further teaches that the glofitamab has a favorable and temporally predictable safety profile and that the glofitamab is highly active in difficult-to-treat patient group with few clinical treatment options. Hutchings then discloses that glofitamab is undergoing expanded evaluation in combination with conventional chemotherapy and novel agents (page 1968, column 2, paragraph 2).
As described above, Kewalramani teaches that the R-CHOP is one of the conventional chemotherapies a to treat untreated DLBCL (page 3684, column 2, paragraph 2). Kewalramani further discloses that R-ICE is beneficial in patients with relapsed disease (page 3687, column 2, paragraph 1) and that ICE is an effective, dose-intensive, short-course cytoreductive regimen capable of mobilizing peripheral blood progenitor cells with minimal extramedullary toxicity (page 3684, column 1, paragraph 3).
All three cited reference above, in combination, teaches the claimed combined treatment method. Further, Hutchings suggests glofitamab is combined with other conventional chemotherapies, while Ghosh teaches a combination of glofitamab with chemotherapy RCHOP while Kewalramani suggests an alternative to RCHOP, RICE that is suitable for relapsed disease. In combination, all three references teach the motivation to combine the glofitamab with RICE to relapsed disease and expect reasonable success at treating the disease. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02). Also, the simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
In response to applicant’s argument of the surprising result of the combined treatment of glofitamab and RICE (page 27, paragraph 1), the examiner notes that the instant claims and the specification do not show evidence of the increased complete remission and reduced severity of CRS in the combination treatment of glofitamab and RICE. The provided reference in IDS provided by the applicant on march 17th, 2026 (Cite No. A, NCT5364424 clinical trial) does not show the alleged unexpected result. Diefenbach reference as recited by the applicant was not provided by the applicant at the time of filing (reference citation: Catherine S. Diefenbach, Paolo F. Caimi, Nakhle S Saba, Fernando Vargas Madueno, Mehdi Hamadani, Luis E. Fayad, Peter A. Riedell, Andrew Gillis-Smith, Stephen Simko, Victor Orellana-Noia, Maria Filippou-Frye, Amy V. Kapp, James Relf, Linda Lundberg, Lauren C. Pinter-Brown; Glofitamab in Combination with Rituximab Plus Ifosfamide, Carboplatin, and Etoposide Shows Favorable Efficacy and Manageable Safety in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Eligible for Stem Cell Transplant or Chimeric Antigen Receptor T-Cell Therapy: Results from a Phase Ib Study. Blood 2024; 144 (Supplement 1): 987. doi: https://doi.org/10.1182/blood-2024-198452). Therefore, arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 2145.I. See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
In response to applicant’s arguments that the body weight based dosing of glofitamab is not taught by the prior art references for claims 58-61, 63-65, 67, 68, 73-75, 78, 81, 82, 84, 86, 87, 89, 90, 94, 104, and 106 (page 28-30), Djebli teaches the pharmacokinetics of glofitamab wherein glofitamab has linear clearance with retained body weight effect on volumes and clearance and step up dosing regimen (2.5/10/30mg Q3W) to optimize benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whiles allowing escalation to a higher dose associated with a better clinical response (page 1, results). In further view of Djebli, van Rongen teaches methods of allometric scaling methods to extrapolate pediatric dosing from adult clearance and body weight and that it is commonly used for pediatric drug dosing (page 102, 2.1. Linear bodyweight-based scaling). With the recommended dose in adults and pharmacokinetics of the glofitamab as taught by Djebli and glofitamab cycles taught by Ghosh, it would have been obvious to the person of ordinary skill in the art to extrapolate and optimize dosages for pediatric patients aged 6 months to 17 years based on weight using allometric scaling and extrapolation methods as taught by van Rongen. A person of ordinary skill in the art would expect reasonable success in pediatric patients because the linear clearance of glofitamab based on body weight taught by Djebli would allow safe allometric scaling of the adult dosages. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Further, applicant’s response that scaling is impractical in clinical practice and not applied for any of the mAbs approved for pediatric indications” (page 30) , the examiner disagrees. Van Rongen discloses “Pediatric drug clearance scaling is applied in the design of first-in-child studies, but also in clinical practice for off-label or unlicensed drug prescription. When there are no pediatric pharmacokinetic (PK) data available for a specific drug, a variety of scaling methods with a wide range in complexity are available to scale drug clearance across the pediatric age-range based on adult value” (page 1, column 1, paragraph 1). At the time of filling and as of 10/2025 of the reference FDA COLUMVI, glofitamab was not approved for pediatric populations by the FDA ( FDA drug label for COLUMVI, listed in IDS 03/17/2026), page 16, 8.4, “the safety and efficacy of COLUMVI in pediatric patients have not been established”). Therefore, it would have been obvious to the person of ordinary skill in the art to use allometric scaling methods for pediatric populations to determine the optimal dosage for this specific population to test at the time of the effective filing date of the instant application. Optimization of dosages and regimen is a routine skill in the art that a skilled artisan would know how to practice. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989).
In response to applicant’s arguments regarding claims 119-121, 123-125, 127, 133-137, 140, 143, 146, 148, 151, 153, 154, 158 (page 12, first paragraph) that Hendrayana teaches the formulas for CrCl and the claimed combination treatment comprising glofitamab and R-ICE is nowhere taught or suggested by the references cited in the rejection, 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 this case, Hendrayana teaches the suggestion that the calculating CrCl helps to adapt the dosing of anticancer agents to the individual requirements of patients with renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic effects due to overdosing (page 2, paragraph 5) and proceeds to recite the aforementioned ifosfamide and etoposide dosing. As taught by Kewalramani and Griffin, RICE and glofitamab is used for patient that have relapsed disease. Furthermore, patients that receive glofitamab and RICE need additional therapeutic agents to mitigate CRS outcomes or adverse events as taught by Kewalramani and Ghosh. One of ordinary skill in the art would have been motivated to utilize methods in optimizing ifosfamide and etoposide as taught by Hendrayana to reduce renal and hepatic dysfunction in an already at risk patient population. In regards to the specific dosage and interval amounts recited in the instant claims "[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 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious.
Provisional non-statutory double patenting rejections
Provisional non-statutory double patenting rejections for co-pending applications 19/372,448 (“ ‘448”), 17/733,909 (“ ‘909”) , 18/964,055 (“ ‘055 ”), and 18/299,877 (“ ‘877”) have been re-considered upon the instant claim amendments of March 17th, 2026.
Applicant traversed and states that the ‘448 Application was filed on October 29, 2025, while the instant application was filed March 22, 2023. MPEP § 804(I)(B)(1)(b)(i) states :
If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent.
The examiner agrees that the copending ‘448 Application is later than the instant application and but the provisional non-statutory double patenting rejection for the copending application ‘448 is maintained as the MPEP recites “if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date.” However, claim rejections under U.S.C. § 103 are still maintained for the pending claims and therefore the provisional non-statutory double patenting rejection cannot be withdrawn. The amended claims of the copending Application ‘448 filed on February 13, 2026, has also been re-considered after Applicant’s amendment on March 17th, 2026 and the non-statutory double patenting rejection is maintained.
In regards to the co-pending application ‘877 filed on April 23, 2023, is later than the instant application filed March 22nd, 2023 according to Applicant’s argument and acknowledged by the examiner. Upon reconsideration of the amended claims with the co-pending claims amended on January 6, 2026, the arguments are not persuasive and the provisional non-statutory double patenting rejection is maintained. In response that the present claims are patentably distinct due to the surprising and synergistic safety and efficacy results, 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). The claims in the copending application ‘877 and the instant claims recite the method of treating a subject having a CD20-positive cell proliferative disorder, diffuse large B cell lymphoma and non-Hodgkin’s lymphoma using glofitamab. It would have been obvious to the person of ordinary skill in the art to combine with RICE to treat patients with relapsed and/or refractory disease. CRS due to glofitamab and RICE chemotherapy have been disclosed by Salvaris, Ghosh, and Kewalramani and therefore it would have been obvious to the person of ordinary skill in the art to administer therapeutic agents to mitigate CRS from both anti-cancer agents. WikiEm, IWK Health, and Jannin teach the dosing regimen for the therapeutic agents specific for pediatric populations. Hendrayana teaches the optimizing RICE doses based on creatine clearance rate to control side effects. Xu, Temrikar, Djebli, van Rongen, and Yang teach scaling adult doses of therapeutic antibodies for pediatric patient populations. It would have been obvious to the person of ordinary skill in the art to combine and optimize the doses of the combined treatment with mitigation strategies for pediatric and adult patient populations.
In response to co-pending application ‘055 claims, the arguments are not persuasive and the provisional non-statutory double patenting rejection is maintained. The co-pending application of ‘055 filed on April 11th, 2025 and the instant claims are not distinct from each other regarding the method of treating a subject having a CD20-positive cell proliferative disorder, diffuse large B cell lymphoma and non-Hodgkin’s lymphoma using glofitamab, Obinutuzumab and a corticosteroid. It would have been obvious to the person of ordinary skill in the art to combine with RICE to treat patients with relapsed and/or refractory disease. CRS due to glofitamab and RICE chemotherapy have been disclosed by Salvaris, Ghosh, and Kewalramani and therefore it would have been obvious to the person of ordinary skill in the art to administer therapeutic agents to mitigate CRS from both anti-cancer agents. WikiEm, IWK Health, and Jannin teach the dosing regimen for the therapeutic agents specific for pediatric populations. Hendrayana teaches the optimizing RICE doses based on creatine clearance rate to control side effects. Xu, Temrikar, Djebli, van Rongen, and Yang teach scaling adult doses of therapeutic antibodies for pediatric patient populations. It would have been obvious to the person of ordinary skill in the art to combine and optimize the doses of the combined treatment with mitigation strategies for pediatric and adult patient populations.
Regarding co-pending application ‘909, the amended co-pending claims filed on February 6th, 2026 have been re-considered with the amended instant claims of March 17th, 2026. Applicant’s arguments are not persuasive and the provisional non-statutory double patenting rejection for copending application ‘909 is still maintained. Co-pending claims of ‘909 recite a method of treating a subject having a CD20-positive cell proliferative disorder, diffuse large B cell lymphoma and non-Hodgkin’s lymphoma using glofitamab, Obinutuzumab and a corticosteroid. It would have been obvious to the person of ordinary skill in the art to combine with RICE to treat patients with relapsed and/or refractory disease. CRS due to glofitamab and RICE chemotherapy have been disclosed by Salvaris, Ghosh, and Kewalramani and therefore it would have been obvious to the person of ordinary skill in the art to administer therapeutic agents to mitigate CRS from both anti-cancer agents. WikiEm, IWK Health, and Jannin teach the dosing regimen for the therapeutic agents specific for pediatric populations. Hendrayana teaches the optimizing RICE doses based on creatine clearance rate to control side effects. Xu, Temrikar, Djebli, van Rongen, and Yang teach scaling adult doses of therapeutic antibodies for pediatric patient populations. It would have been obvious to the person of ordinary skill in the art to combine and optimize the doses of the combined treatment with mitigation strategies for pediatric and adult patient populations.
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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