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 .
Response to Amendment
Applicant’s amendment filed on 4/27/2026 is acknowledged.
Claims 1, 12, 15, 23-25, 27-28, 32-34 and 49-63 are pending. Claims 2-3, 7, 9, 18-19, 22, and 48 are cancelled. Applicant’s amendments to the claims has overcome each and every 112(b) and 112(a) Written Description previously set forth in the Non-Final Office Action mailed on 1/27/2026.
The following 35 USC § 112 and 35 USC § 103 rejections as set forth below have been necessitated by Applicant’s amendment filed on 4/27/2026.
Information Disclosure Statement
The references disclosed in the information disclosure statement (IDS) filed on 4/27/2026 have been considered by the Examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 25, 28, and 57 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 25 recites, “wherein rituximab, lenalidomide, and epcoritamab or the biosimilar thereof are administered on the same day”. This limitation does not further limit the scope of independent claim 1 as claim 1 recites the three therapies to be delivered on the same day (i.e. days 1, 8, and 15 for cycles 1-12).
Claim 28 recites, “a full dose of 48 mg is administered” on lines 4 and 6-8. This limitation does not further limit the scope of independent claim 1 since the full dose of epcoritamab or the biosimilar thereof recited in independent claim 1 is 24 mg.
Claim 57 recites, “wherein rituximab, lenalidomide, and epcoritamab or the biosimilar thereof are administered on the same day”. This limitation does not further limit the scope of independent claim 52 as claim 52 recites the three therapies to be delivered on the same day (i.e. days 1, 8, and 15 for cycles 1-12).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Priority
This application claims domestic priority to U.S. Provisional Application No. 63/076,740 effectively filed on 09/10/2020 and is a 371 of PCT/EP2021/075017 effectively filed on 9/10/2021.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 12, 15, 23-24, 27, 32-34, 49-56, and 58-63 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Publication 2018/0134798 A1 (IDS filed on 9/14/2023; U.S. Patent Application Publications Reference 22; "Chu") in view of Leonard et al (IDS filed on 9/14/2023; Non-Patent Literature Documents Reference 7; "Augment"), Leonard et al (PTO-892; Reference W, "Alliance"), Hiemstra et al (IDS filed on 4/27/2026; Non-Patent Literature Documents Reference 15; "Hiemstra"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”) as evidenced by Guo et al (PTO-892; Reference V; “Guo”).
Chu teaches methods of dosing for the treatment of cancers such as B cell proliferative disorders which includes relapsed and/or refractory follicular lymphoma (grade 1-3, Stage I-III) with a CD20/CD3 bispecific antibody since there is an unmet need for the development of efficacious methods of dosing therapeutic bispecific antibodies that achieve a more favorable benefit-risk profile (Abstract; [0001]-[0004]; [0018]; [0085]; Examples 1-2). Chu teaches a weekly double-step fractionated dose escalation dosing regimen with a first cycle dosing comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody wherein the C1D1 and C1D2 are no greater than the C1D3, wherein C1D1 is between 0.0056 mg to about 12.50 mg, C1D2 is between 0.0125 mg to about 20.00 mg, and C1D3 is between 0.0500 mg to about 50 mg wherein C1D1, C1D2, and C1D3 are administered on Days 1, 8, and 15, respectively, of the first dosing cycle (Chu; [0086]-[0087]; [0091]). The second dosing cycle comprises C2D1 which is equal to C1D3 and is administered weekly in a 28-day cycle (Chu; [0086]; [0093]). Chu also teaches the administration of the anti-CD20/anti-CD3 antibody being co-administered or separately administered prior to, simultaneously, and/or following the administration of additional therapeutic agents such as rituximab and a biological modifier including lenalidomide (Chu; [0016]; [0110]; [120]).
However, Chu does not teach the anti-CD20/anti-CD3 bispecific being epcoritamab or a biosimilar comprising a heavy chain and light chain consisting of the amino acid sequence of SEQ ID NOs:24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs:26 and 27, respectively; the motivation to combine epcoritamab or a biosimilar thereof with rituximab and lenalidomide therapy; wherein rituximab is administered intravenously at a dose of 375 mg/m2, on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 2-5; wherein lenalidomide is administered orally at a dose of 15 mg or 20 mg once a day from day 1 to day 21 of cycles 1-12; wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs of instant claims 1 and 52; wherein lenalidomide is administered at a dose of 15 mg in cycle 1 of instant claims 23 and 55; wherein lenalidomide is administered at a dose of 20 mg in cycle 2 to cycle 12 of instant claims 24 and 56; the method of instant claim 1 wherein epcoritamab or the biosimilar thereof is administered (iii) in cycles 4-9, a full dose of 24 mg is administered on days 1 and 15, (iv) in cycle 10 and subsequent cycles, a full dose of 24 mg is administered on day 1, (b) rituximab is administered on days 1, 8, 15, and 22 in cycle 1, and day 1 in cycles 2-5, (c) lenalidomide is administered on days 1-21 in cycles 1-12 of instant claim 27; wherein epcoritamab or the biosimilar thereof, rituximab, and lenalidomide are administered sequentially of instant claim 32.
Hiemstra does teach DuoBody-CD3xCD20 (GEN3013, i.e. epcoritamab and biosimilars thereof of the instant invention) (see ABSS sequence alignment attached filed on 1/27/2026 – epcoritamab comprises 100% sequence identity to instant SEQ ID NOs:24-27), a bispecific anti-CD3xCD20 full length lgG1 generated by controlled Fab-arm exchange with an effector function silenced Fc region. Hiemstra further teaches that the DuoBody-CD3xCD20 bispecific antibody induces potent activation and cytotoxic activity against CD4+ and CD8+ T cells in a diverse panel of diffuse large B-cell and mantle cell lymphoma cell lines (Hiemstra, Background). It is 10- 100-fold more potent than another anti-CD3xCD20 bsAb currently tested in clinical trials (Hiemstra, Results). Additionally, the DuoBody-CD3xCD20 bispecific antibody can be administered alongside rituximab as the anti-tumor activity of the DuoBody-CD3xCD20 bispecific antibody was not inhibited by high doses of rituximab which competes for target binding (Hiemstra, Results). Hiemstra also discloses that the DuoBody-CD3xCD20 bispecific antibody is currently being tested in a Phase I clinical trial (NCT03625037) (Hiemstra, Summary/Conclusion).
Guo does teach that in oncology the dose of a treatment and the timing of administration of the treatment needs to be optimized in order for the treatment to be tolerable and sufficiently active to warrant testing of its anti-tumor efficacy (Guo; Abstract; page 1, paragraph 1). Guo teaches that physicians are mostly interested in the how to administer the treatment agent within each treatment cycle to achieve low toxicity and high efficacy (Guo; page 2, paragraph 3). Guo teaches that even after the initiation of the treatment, both the efficacy and toxicity outcomes should be observed to allow for adaptive dose and schedule assignment (Guo; page 11, paragraph 1).
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for treating relapsed and/or refractory follicular lymphoma (grade 1-3, Stage I-III) with an anti-CD20/CD3 bispecific antibody, rituximab, and lenalidomide of Chu with DuoBody-CD3xCD20 (GEN3013, i.e. epcoritamab and biosimilars thereof of the instant invention) of Hiemstra with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the method for treating relapsed and/or refractory follicular lymphoma (grade 1-3, Stage I-III) with an anti-CD20CD3 bispecific antibody, rituximab, and lenalidomide of Chu with DuoBody-CD3xCD20 antibody of Hiemstra since Chu teaches there is an unmet need to improve the efficacy of treatment methods of bispecific antibodies that achieve a more favorable benefit-risk profile and Hiemstra teaches the DuoBody-CD3xCD20 antibody induces potent activation and cytotoxic activity against CD4+ and CD8+ T cells and is 10-100-fold more potent than another anti-CD3xCD20 bsAb currently tested in clinical trial. Hiemstra also teaches that the DuoBody-CD3xCD20 antibody was not inhibited by excess rituximab that competes for target binding. Therefore, a person of ordinary skill in the art would have been motivated to substitute the anti-CD20/CD3 bispecific antibody of Chu with the DuoBody-CD3xCD20 antibody of Hiemstra to yield predictable results of potent activation and cytotoxic activity against CD4+ and CD8+ T cells.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the dosing regimen including the timing, frequency, and dosing of the anti-CD20/CD3 bispecific antibody of Chu with the DuoBody-CD3xCD20 antibody of Hiemstra with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine since the dosing regimen (i.e., C1D1 priming dose, C1D2 intermediate dose, C1D3 full dose, and C2D1 full dose) of the anti-CD20/CD3 bispecific antibody of Chu with the DuoBody-CD3xCD20 antibody of Hiemstra since Chu teaches there is an unmet need to improve the development of efficacious methods of dosing anti-CD20/CD3 bispecific antibodies that achieve a more favorable benefit-risk profile and Hiemstra teaches that the DuoBody-CD3xCD20 antibody demonstrates promising preclinical activity and is more potent than other anti-CD3xCD20 bispecific antibodies currently being tested in clinical trials. Therefore, a person of ordinary skill in the art would have been motivated to combine the anti-CD20/CD3 bispecific antibody dosing regimen of Chu with the DuoBody-CD3xCD20 antibody of Hiemstra to yield predictable results of more effectively treating patients with follicular lymphoma.
Regarding the specific doses of 0.8 priming dose, 0.16 intermediate dose, and full dose of 24 mg of instant claims 1 and 27 and full dose of 48 mg of instant claim 52 of the anti-CD20/CD3 bispecific antibody and in cycles 4-9 a biweekly (days 1 and 15) administration of the full dose of the anti-CD20/CD3 bispecific antibody and in cycle 10 and subsequent cycles, a one every four weeks on day 1 administration of the anti-CD20/CD3 bispecific antibody of instant claims 1, 27, and 52 and Guo’s recitation that dosing and timing of administration of an oncology therapy needing to be optimized to determine if the therapy is tolerable and sufficiently active, it would also have been obvious to one of ordinary skill in the art, at the time Applicant's invention was made, to determine all operable features of optimal dosage of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of the antibody, including dosing, timing, frequency, and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. 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. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method for treating relapsed and/or refractory follicular lymphoma (grade 1-3, Stage I-III) with the DuoBody-CD3xCD20 antibody, rituximab, and lenalidomide of Chu and Hiemstra with the rituximab and lenalidomide dosage regimen of Augment with the lenalidomide dosage regimen of Alliance with the motivation to combine an anti-CD20 antibody and anti-CD20/CD3 bispecific antibody of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the method for treating relapsed and/or refractory follicular lymphoma (grade 1-3, Stage I-III) with the DuoBody-CD3xCD20 antibody, rituximab, and lenalidomide of Chu and Hiemstra with the rituximab and lenalidomide dosage regimen of Augment with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Chu and Hiemstra teach DuoBody-CD3xCD20 antibody, rituximab, and lenalidomide can be co-administered; Augment teaches rituximab (375 mg/m2 administered weekly intravenously cycle 1 and monthly cycles 2-5) and lenalidomide (20mg administered orally on days 1-21 of cycles 1-12) combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; Alliance teaches the incremental increase in dose of lenalidomide where lenalidomide is administered at 15 mg during cycle 1 days 1-21 and increases to 20mg during subsequent cycles to mitigate onset of side effects rituximab and lenalidomide offer a promising chemotherapy-free treatment option for patients with follicular lymphoma where it can be combined with biologic triplet therapy to improve efficacy of treatment and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine the DuoBody-CD3xCD20 antibody, rituximab, and lenalidomide as combination treatment at the specific cycle frequencies and doses to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
From the combined teachings of the reference, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the reference, especially in the absence of evidence to the contrary.
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, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 13-16 of U.S. Patent No. US 11,608,383 B2 (PTO-892 filed on 1/27/2026, Reference F; “’383”) in view of Leonard et al (PTO-892; Reference U; "Augment").
Although the claims are not identical they are not patentably distinct from each other because the claims of the '383 patent are directed towards methods of treating follicular lymphoma (grade 1, 3, or 3a or Stage I, II, or III relapsed or refractory) in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of rituximab and lenalidomide, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively (SEQ ID NOs:24-27 are 100% identical over length and sequence to reference SEQ ID NOs:24-27) or is epcoritamab or a biosimilar thereof ( claims 1, 34, 49-52, 58, and 60-63 of the instant application) ; wherein the bi specific antibody is administered at a dose of 24mg or 48 mg, wherein rituximab, lenalidomide, and the bispecific antibody are administered in 28-day cycles, and wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on days 15 and 22; (ii) in cycles 2 and 3, a dose of 24 mg or 48 mg is administered on days 1, 8, 15, and 22; 50 (iii) in cycles 4-9, a dose of 24 mg or 48 mg is administered on days 1 and 15; and (iv) in cycle 10 and subsequent cycles, a dose of 24 mg or 48 mg is administered on day l; (b) rituximab is administered on days 1, 8, 15, and 22 in cycle 1, and day 1 in cycles 2-5 at a dose of 375 mg/m2; and (c) lenalidomide is administered on days 1-21 in cycles 1-12 at a dose of 15 mg in cycle 1 and 20 mg in cycles 2-12 (claims 1, 12, 15, 23-24, 27, 32 and 52-56 of the instant application). '383 teaches epcoritamab and other biosimilars that are administered subcutaneously, rituximab is administered intravenously, and lenalidomide is administered orally (claims 1 and 52 of the instant application).
However, '383 does not teach wherein the administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs of instant claims 1 and 52.
Augment teaches the combination therapies continues until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs (Augment, "Trial Design and Treatment", paragraph 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have combined the combination bispecific antibody-rituximab-lenalidomide dosage regimen of ‘383 with the duration of treatment of Augment with reasonable expectation of success. A person of ordinary skill in the art would have been motivated to use this duration of treatment in order to minimize a patient's harmful side effects and ensure patient safety and survival.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Applicant's arguments directed towards the non-statutory double patenting filed 4/27/2026 have been fully considered but they are not persuasive. Applicant argues on page 17 [bullet point (1)] of Applicant’s Remarks: (1) “Notwithstanding, filing a terminal disclaimer before the pending claims are indicated otherwise allowable would be premature. Accordingly, Applicant respectfully requests that the rejection be held in abeyance. If appropriate, Applicant will consider filing a terminal disclaimer once the claims are indicated as being otherwise allowable”. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Therefore, an application must not be allowed unless the required compliant terminal disclaimer is filed and/or the withdrawal of the nonstatutory double patenting rejection is made of record by the examiner (see MPEP § 804.02 (IV) for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995). Therefore, the Examiner has updated the provisional nonstatutory double patenting rejection to reflect the amendments made to the claims.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-13, 15-17, 24, and 26-27 of U.S. Patent No. 11,535,679 B2 (PTO-892 filed on 1/27/2026; Reference A; “’679”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '679 patent is directed to methods of treating follicular lymphoma (grade 1, 2, or 3a and Stage II, III, or IV) in a human subject the method comprising administering to the subject epcoritamab bispecific antibody and an effective amount of rituximab and bendamustine, wherein the bispecific antibody is administered at a dose of 24 mg or 48 mg, and wherein rituximab, bendamustine, and the bispecific antibody are administered in 28-day cycles, wherein the bispecific antibody, rituximab, and bendamustine are administered in the same cycle for the first 6 cycles, and the bispecific antibody is administered alone for subsequent cycles, and wherein a priming dose of the bispecific antibody is administered on day 1 of cycle 1 and an intermediate dose is administered on day 8 of cycle 1 before the dose of 24 mg or 48 mg on days 15 and 22 of cycle 1, wherein the bispecific antibody is administered once every week (weekly administration) for 2.5 28-day cycles, wherein after the weekly administration, the bispecific antibody is administered once every two weeks (biweekly administration) for six 28-day cycles, wherein after the biweekly administration, the bispecific antibody is administered once every four weeks for up to two years total duration of treatment with the bispecific antibody from initiation of rituximab and bendamustine, wherein rituximab, bendamustine, and the bispecific antibody are administered on the same day, wherein administration is performed m 28- day cycles, and wherein: (a) the bispecific antibody is administered as follows: (i) m cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg IS administered on day 8, and a dose of 24 mg is administered on days 15 and 22; (ii) in cycles 2 and 3, a dose of 24 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-9, a dose of 24 mg is administered on days 1 and 15; and (iv) m cycle 10 and subsequent cycles, a dose of 24 mg IS administered on day 1; (b) rituximab is administered on day 1 cycles 1-6; and ( c) bendamustine is administered on days 1 and 2 in cycles 1-6, wherein administration is performed in 28-day cycles, and wherein: (a) the bispecific antibody is administered as follows: (i) cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on days 15 and 22; (ii) in cycles 2 and 3, a dose of 48 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4- 9, a dose of 48 mg is administered on days 1 and 15; and (iv) in cycle 10 and subsequent cycles, a dose of 48 mg is administered on day 1; (b) rituximab is administered on day 1 in cycles 1-6; and (c) bendamustine is administered on days 1 and 2 in cycles 1-6. Methods of treating follicular lymphoma in a human subject, the method comprising administering to the subject epcoritamab bispecific antibody and an effective amount of rituximab and bendamustine,; wherein the bispecific antibody is administered at a dose of 24 mg or 48 mg, and wherein rituximab, bendamustine, and the bispecific antibody are administered in 28-day cycles, wherein the bispecific antibody,rituximab, and bendamustine are administered in the same cycle for the first 6 cycles, and the bispecific antibody is administered alone for subsequent cycles, and wherein a priming dose of the bispecific antibody is administered on day 1 of cycle 1 and an intermediate dose is administered on day 8 of cycle 1 before the dose of 24 mg or 48 mg on days 15 and 22 of cycle 1, wherein administration is performed in 28-day cycles, and wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on days 15 and 22; (ii) in cycles 2 and 3, a dose of 24 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-9, a dose of 24 mg is administered on days 1 and 15; and (iv) in cycle 10 and subsequent cycles, a dose of 24 mg is administered on day 1; (b) rituximab is administered on day 1 in cycles 1-6; and (c) bendamustine is administered on days 1 and 2 in cycles 1-6, wherein the priming dose is 0.16 mg and the intermediate dose is 0.8 mg.
However, ‘679 does not teach lenalidomide treatment or dosing cycle, the motivation to combine lenalidomide with rituximab and epcoritamab.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Therefore, it would have been prima facie obvious to one of ordinary skill, in the art before the effective filing date, to have modified the epcoritamab-rituximab- bendamustine dosage cycle for patients with follicular lymphoma of '679 and swap the bendamustine with the dosing regimen of lenalidomide of Augment and Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated swap bendamustine with lenalidomide and combine rituximab-epcoritamab dosing regimen of '679 with the lenalidomide dosing regimen and cycle length of Augment and Alliance. Combining lenalidomide with rituximab has been shown to offer clinically meaningful efficacy advantages and improve safety profiles of follicular lymphoma patients.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Applicant's arguments directed towards the non-statutory double patenting filed 4/27/2026 have been fully considered but they are not persuasive. Applicant argues on page 17-18 [bullet point (2)] of the Applicant’s Remarks: (2) “The reference claims of US 11,535,679 are directed to methods of treating follicular lymphoma by administering epcoritamab, rituximab, and bendamustine. However, US 11,535,679 does not disclose administering epcoritamab in combination with rituximab and lenalidomide, as claimed, and fails to provide any motivation which would have led the skilled artisan to modify the claims of the reference applications in the manner asserted by the Office to arrive at the presently claimed methods, even when taken in combination with the teachings of Augment. Moreover, as discussed in the previous section, the presently claimed methods are associated with unexpected efficacy in patients with follicular lymphoma which could not have been predicted or reasonably expected from the teachings of the cited reference patent and Augment, further evidencing the nonobviousness of the claimed invention. Thus, the teachings of US 11,535,679, even when combined with those of Augment, fail to render obvious the presently claimed dosage regimen in which epcoritamab, rituximab, and lenalidomide are administered at specific dosages and frequencies. Accordingly, reconsideration and withdrawal of these rejections is respectfully requested”.
It is noted that the features upon which applicant relies (i.e., the lack of disclosure of administering epcoritamab in combination with rituximab and lenalidomide and failure of providing a motivation to combine the treatments) are directly stated in Augment where rituximab and lenalidomide offered clinically meaningful efficacy advantages over single agent- rituximab in the context of safety profile and should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma (see Non-Final Office Action mailed on 1/27/2026, see pages 11 and 33-34). Additionally, the Applicant asserts that the epcoritamab-rituximab-lenalidomide combination therapy is associated with unexpected results where the combination achieved effective and safe treatment for patients with follicular lymphoma (i.e. manageable toxicity profile with no new safety profiles) and durable responses (see Section IV of Applicant’s Remarks). The Examiner notes that the asserted unexpected results are also taught by Augment where rituximab and lenalidomide are safely administered in combination and offered clinically meaningful efficacy advantages in the context of safety profile and US Patent No. 11,535,679 teaches epcoritamab and rituximab can be administered together, so it would be obvious to combine epcoritamab, rituximab, and lenalidomide since US Patent No 11,535,679 and Augment provide rationale that the treatments can be combined safely and efficaciously. Therefore, Applicant’s argument asserting unexpected results is not persuasive.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 8-12, 15-22, and 25 of copending Application No. US 18/633,939 (reference application) (“’939”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims are not identical, they are not patentably distinct from each other because the claims of the '939 application are directed towards methods of treating relapsed o refractory lymphoma (indolent follicular lymphoma or grade 3B) in a human subject, the metho comprising administering to the subject epcoritamab, wherein epcoritamab is administered subcutaneously in a 28 day cycle comprising administering a priming dose on day 1 of about 0.05 mg to about 0.35 mg, a first intermediate dose on about day 8 of about 0.6 mg to 5 mg, a second intermediate dose on about day 15 of about 1 mg to about 10 mg, followed by at least one weekly dose of between about 20-100 mg; or wherein the bispecific antibody epcoritamab is administered subcutaneously in a 35 day cycle comprising administering a priming dose on day 1 of about 0.05 mg to about 0.35 mg, a first intermediate dose on about day 8 of about 0.6 mg to 5 mg, a second intermediate dose on about day 15 of about 1 mg to about 10 mg, followed by at
least two weekly doses of between about 20-100 mg wherein after the 28 day or 35 day cycle, the epcoritamab is administered once a week, once every two weeks, once every four weeks or a combination thereof to the subject, wherein the priming dose is about 0.16 mg, wherein the first intermediate dose is about 0.6-1.2 mg, wherein the first intermediate dose is about 0.8 mg, wherein the second intermediate dose is about 3-6 mg, wherein the second intermediate dose is 3 mg, wherein the second intermediate dose is 6 mg, wherein the weekly dose is between about 20 to 60 mg, wherein the weekly dose is about 24 mg, wherein the weekly dose is about 48 mg, wherein the weekly administration is performed at least 4 times, wherein after the weekly administration of epcoritamab is administered once every two weeks, wherein the biweekly administration once every two weeks of the epcoritamab is performed at least six (6) times, wherein after the biweekly administration, the epcoritamab is administered once every four weeks. The method comprising: a first cycle of 28-days wherein (i) the priming dose of the epcoritamab is administered on Day l;(ii) the first intermediate dose of the epcoritamab is administered on Day 8; (iii) the second intermediate dose of the epcoritamab is administered on Day 15; (iv) a dose of 24 mg of the epcoritamab is administered on Day 22; and (b) cycles 2-3 each comprising 28 days wherein a dose of 24 mg of the epcoritamab is administered on Days 1, 8, 15 and 22; ( c) cycles 4-9 each comprising 28 days wherein a dose of 24 mg of the epcoritamab is administered on Days 1 and 15; and (d) further subsequent 28 day cycles, wherein a dose of 24 mg of the epcoritamab is administered on Day 1.
'939 does not teach treating a patient with epcoritamab in combination with
rituximab and lenalidomide in the dosage regimen of the instant application of instant claims 1 and 52. '939 also does not teach the duration of treatment wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs of instant claims 1 and 52.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage cycle for patients with refractory or relapsed indolent or grade 3B follicular lymphoma of '939 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘939 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment with lenalidomide and rituximab combination treatment to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have combined the combination bispecific antibody-rituximab-lenalidomide dosage regimen of ‘939, Augment, Alliance, and Morschhauser with the duration of treatment of Augment with reasonable expectation of success. A person of ordinary skill in the art would have been motivated to use this duration of treatment in order to minimize a patient's harmful side effects and ensure patient safety and survival.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 8, 11, 14, 16, 29, 33, 39, 65-66 of copending Application No. US 18/160,386 (reference application) (“’386”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '386 application are directed to methods of treating Diffuse large B-cell lymphoma (DLBCL) wherein the DLBCL is follicular lymphoma Grade 3B, wherein the DLBCL is relapsed and/or refractory DLBCL, in a human subject, the method comprising administering to the subject a combination of epcoritamab, lenalidomide and optionally, an effective amount of ibrutinib in 28-day cycles, wherein(a) epcoritamab or biosimilar thereof is administered subcutaneously, wherein (i) a priming dose is administered on day 1 of the first 28-day cycle, an intermediate dose is administered on day 8 of the first 28-day cycle, and a full dose of 24 or 48 mg is administered on day 15 and day 22 of the first 28-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose,(ii) a full dose of 24 or 48 mg is administered on days 1, 8, 15 and 22 of the second and third 28-day cycles;(iii) a full dose of 24 or 48 mg is administered once every four weeks on day 1 of each subsequent 28-day cycle;(b) lenalidomide is administered orally at a dose of 20 to 30 mg from day 1 to day 21 of each 28-day cycle; wherein administration of the combination in 28-day cycles continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs; wherein the administration of epcoritamab once every four weeks is performed for at least twenty 28-day cycles; wherein the priming dose is 0.16 mg; wherein the intermediate dose is 0.8 mg; wherein lenalidomide is administered for at least twelve 28-day cycles;
'386 does not teach combination therapy or dosing regimen of lenalidomide-rituximab and epcoritamab or the motivation to combine the three therapies of instant claims 1 and 52.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-lenalidomide dosage cycle for patients with refractory or relapsed indolent or grade 3B follicular lymphoma of ‘386 with the combination dosing regimen of lenalidomide and rituximab of Augment and Alliance and the motivation to treat patients with both rituximab and DuoBody-CD3xCD20 bi specific antibody of Morchhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine epcoritamab-lenalidomide dosage cycle for patients with refractory or relapsed indolent or grade 3B follicular lymphoma of ‘386 with the combination dosing regimen of lenalidomide and rituximab of Augment and Alliance and the motivation to treat patients with both rituximab and DuoBody-CD3xCD20 bi specific antibody of Morchhauser since Augment and Alliance teaches rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab-lenalidomide dosage cycle for patients with refractory or relapsed indolent or grade 3B follicular lymphoma of ‘386 with the combination dosing regimen of lenalidomide and rituximab of Augment and Alliance and the motivation to treat patients with both rituximab and DuoBody-CD3xCD20 bispecific antibody of Morchhauser to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-7, 9-14, 24, 28, 40, and 66 of copending Application No. US 18/833,261 (reference application) (“’261”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '261 application is directed to methods of treating Diffuse large B-cell lymphoma (DLBCL): follicular lymphoma Grade 3B: and/or (d) relapsed and/or refractory DLBCL, in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof and lenalidomide and optionally, an effective amount of ibrutinib, wherein the epcoritamab or biosimilar thereof is administered subcutaneously at a dose of 24 mg or 48 mg, and wherein- lenalidomide, the epcoritamab or biosimilar thereof and optionally ibrutinib are administered in 28-day cycles, epcoritamab or biosimilar thereof is administered at a dose of 24 mg or 48 mg, wherein epcoritamab or biosimilar thereof is administered once every week (weekly administration), wherein the weekly administration of 24 mg or 48 mg is performed for 2.5 28-day cycles, wherein after the weekly administration, the epcoritamab or biosimilar thereof is administered once every four weeks on day 1 of each 28-day cycle, wherein the administration once every four weeks is performed for at least eight 28-day cycles, for at least twelve 28-day cycles, or for at least twenty 28-day cycles, wherein prior to the weekly administration of 24 mg or 48 mg, a priming dose of the epcoritamab or biosimilar thereof is administered in cycle 1 of the 28-day cycles, wherein the priming dose is administered two weeks prior to administering the first weekly dose of 24 mg or 48 mg, wherein the priming dose is 0.16 mg, wherein after administering the priming dose and prior to administering the first weekly dose of 24 mg or 48 mg, an intermediate dose of the epcoritamab or biosimilar thereof, wherein the priming dose is administered on day 1 and the intermediate dose is administered on day 8 before the first weekly dose of 24 mg or 48 mg on days 15 and 22 of cycle 1, wherein the intermediate dose is 0.8 mg, wherein administration is performed in 28- day cycles, and wherein:(a) the epcoritamab or biosimilar thereof is administered as follows:(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on days 15 and 22;(ii) in cycles 2 and 3, a dose of 24 mg or 48 mg is administered on days 1, 8, 15, and22;(iii) in cycle 4 and onwards, a dose of 24 mg or 48 is administered on day l;(b) lenalidomide is administered orally on days 1-21 of each 28-day cycle, and(c) ibrutinib is optionally administered orally on days 1-28 each 28-day cycle, wherein administration is performed in 28-day cycles, and wherein: (a) the epcoritamab or biosimilar thereof is administered subcutaneously as follows:(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on days 15 and 22;(ii) in cycles 2-3, a dose of 24 mg or 48 mg is administered on days 1, 8, 15, and 22;(iii) in cycles 4-12, a dose of 24 mg or 48 mg is administered on day 1; and(b) lenalidomide is administered orally at a dose of 25 mg/day on days 1-21 in cycles 1-12.
'261 does not teach rituximab combination therapy, rituximab dosage regimen, or the motivation to combine lenalidomide-rituximab-epcoritamab of instant claims 1 and 52.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-lenalidomide dosage cycle for patients with follicular lymphoma of '261with the combination dosing regimen of lenalidomide and rituximab of Augment and Alliance and the motivation to treat patients with both rituximab and DuoBody-CD3xCD20 bi specific antibody of Morchhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine epcoritamab-lenalidomide dosage cycle for patients with follicular lymphoma of '261 with the combination dosing regimen of lenalidomide and rituximab of Augment and Alliance and the motivation to treat patients with both rituximab and DuoBody-CD3xCD20 bispecific antibody of Morchhauser since Augment and Alliance teaches rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab-lenalidomide dosage cycle for patients with follicular lymphoma of '261 with the combination dosing regimen of lenalidomide and rituximab of Augment and Alliance and the motivation to treat patients with both rituximab and DuoBody-CD3xCD20 bispecific antibody of Morchhauser to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 11, 14, 48, 63-64, 66-67 of copending Application No. US 18/160,391 (reference application) (“’391”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '391 application is directed towards methods of treating diffuse large B-cell lymphoma (DLBCL) (follicular lymphoma grade 3b) in a human subject, the method comprising administrating to the subject a combination comprising epcoritamab or a biosimilar thereof, polatuzumab vedotin, ritixumab, cyclophosphamide, doxorubicin and prednisone, or prednisolone in 21-day cycles, wherein (a) epcoritamab or biosimilar thereof is administered subcutaneously, wherein (i) a priming dose is administered on day 1 of the first 21- day cycle, an intermediate dose is administered on day 8 of the first 21-day cycle, and a full dose of 24 or 48 mg on day 15 of the first 21- day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose, (ii) a full dose of 24 or 48 mg on days 1, 8 and 15 of the second to fourth 21 day cycle, and(iii) a full dose of 24 or 48 mg on day 1 of each subsequent 21 day cycle; (c) rituximab is administered intravenously at a dose of 375 mg/m2 on day 1 of each 21 day cycle; wherein administration of the combination in 21 day cycles continues until the subject exhibits a complete response (CR) or until progressive disease develops or unacceptable toxicity occurs, epcoritamab or biosimilar thereof IS administered at a full dose of 24 mg or 48 mg, wherein the administration of the full dose of epcoritamab or biosimilar thereof is performed on day 1 for at least cycles 4-8, wherein the priming dose of epcoritamab is 0.16 mg, wherein the intermediate dose is 0.8 mg; wherein the method comprises administering epcoritamab or a biosimilar of epcoritamab comprising a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs:26 and 27, respectively (instant application's SEQ ID NOs:24-27 are 100% identical over length and sequence to reference SEQ ID NOs:24-27).
However, '391 does not teach lenalidomide treatment or dosing cycle, the motivation to combine lenalidomide with rituximab and epcoritamab, or a cycle length of 28 days of instant claims 1, 23-24, 27, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-rituximab dosage cycle for patients with follicular lymphoma of '391 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘939 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment with lenalidomide and rituximab combination treatment to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Applicant's arguments directed towards the non-statutory double patenting filed 4/27/2026 have been fully considered but they are not persuasive. Applicant argues on page 18 [bullet points (3)] of the Applicant’s Remarks: (3) Applicant respectfully notes that the present application has an earlier filing date than U.S. Application Nos. 18/633,939, 18/160,386, 18/833,261, and 18/160,391, and thus requests that the rejections be held in abeyance until the claims are otherwise in condition for allowance, at which time Applicant requests withdrawal of the rejections in accordance with MPEP §804(1)(B)(l)(b )(i).”
Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Therefore, an application must not be allowed unless the required compliant terminal disclaimer is filed and/or the withdrawal of the nonstatutory double patenting rejection is made of record by the examiner (see MPEP § 804.02 (IV) for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995). Therefore, the Examiner has updated the provisional nonstatutory double patenting rejection to reflect the amendments made to the claims.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 22-33 of U.S. Patent No. US 11,845,805 B2 (PTO-892, Reference B; “’805”) in view Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims are not identical they are not patentably distinct from each other because the claims of the ‘805 patent are directed towards A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of (a) rituximab, (b) cyclophosphamide, ( c) doxorubicin, ( d) vincristine and ( e) prednisone, wherein the bispecific antibody comprises:(i) a first binding arm comprising a first antigen-binding region which binds to human CD3c ( epsilon) and comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the CDRl, CDR2 and CDR3 sequences that are in the VH sequence of SEQ ID NO: 6, and the VL comprises the CDRl, CDR2 and CDR3 sequences that are in the VL sequence of SEQ ID NO: 7; and 60 (ii) a second binding arm comprising a second antigen binding region which binds to human CD20 and comprises a VH and a VL, wherein the VH comprises the CDRl, CDR2 and CDR3 sequences that are in the VH sequence of SEQ ID NO: 13, and the VL comprises the CDRl, CDR2 and CDR3 sequences that are in the VL sequence of SEQ ID NO: 14 wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles; and wherein (a) a priming dose of the bispecific antibody is administered on day 1 of cycle 1 of the 21-day cycles, an intermediate dose of the bispecific antibody is administered on day 8 of cycle 1 of the 21-day cycles, a dose of 24 mg or 48 mg of the bispecific antibody is administered on day 15 of cycle 1 of the 21-day cycles, and a dose of 24 or 48 mg of the bispecific antibody is administered weekly starting on day 1 of cycle 2 of the 21-day cycles; (b) rituximab is administered once every three weeks for six or eight 21-day cycles of reference claim 1; The method of claim 1, wherein the bispecific antibody is administered at a weekly dose of 24 mg starting on day 1 of cycle 2 of the 21-day cycles of reference claim 2; The method of claim 1, wherein the bispecific antibody is administered at a weekly dose of 48 mg starting on day 1 of cycle 2 of the 21-day cycles of reference claim 3; The method of claim 1, wherein the weekly administration of 24 mg or 48 mg of the bispecific antibody is performed for three and one-third 21-day cycles of reference claim 4; The method of claim 4, wherein after the weekly administration of the bi specific antibody for three and one third 21-day cycles, the bispecific antibody is administered once every three weeks for two or four 21-day cycles of reference claim 5; The method of claim 5, wherein after the administration of the bispecific antibody once every three weeks for two or four 21-day cycles, the bispecific antibody is administered once every four weeks in 28-day cycles for up to one year total duration of treatment with the bispecific antibody of reference claim 6; The method of claim 1, wherein (a) the priming dose of the bispecific antibody is 0.16 mg, (b) intermediate dose of the bispecific antibody is 0.8 mg, or (c) the priming dose of the bispecific antibody is 0.16 mg and the intermediate dose of the bispecific antibody is 0.8 mg of reference claim 7; The method of claim 1, wherein rituximab is administered at a dose of 375 mg/m2 of reference claim 8; The method of claim 1, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 24 mg or 48 mg is administered on day 1 (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6 of reference claim 9; The method of claim 9, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7 of reference claim 10; The method of claim 1, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15;(ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg or 48 mg is 55 administered on day 1 ; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8 of reference claim 11; The method of claim 11, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9 of reference claim 12; The method of claim 1, wherein the bispecific antibody is administered subcutaneously of reference claim 13; The method of claim 1, wherein rituximab is administered intravenously of reference claim 14; The method of claim 1, wherein (b) the DLBCL is follicular lymphoma Grade 3B of reference claim 15; The method of claim 1, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively of reference claim 22 (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27); The method of claim 1, wherein the bispecific antibody is epcoritamab, or a biosimilar thereof of reference claim 23; method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of ( a) rituximab, (b) cyclophosphamide, ( c) doxorubicin, ( d) vincristine and ( e) prednisone, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27 (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27), respectively, and wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 24 mg or 48 mg is administered on day 1 ; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6 of reference claim 24; The method of claim 24, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7 of reference claim 25; A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of (a) rituximab, (b) cyclophosphamide, ( c) doxorubicin, ( d) vincristine and ( e) prednisone, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively, (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27) and wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg 1s administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg or 48 mg 1s administered on day 1 ; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8 of reference claim 26; The method of claim 26, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9 of reference claim 27; The method of claim 1, wherein administration of (a) rituximab … in 21-day cycles continues at least until the subject exhibits a complete metabolic response (CMR), or a partial metabolic response of reference claim 28; A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a combination of epcoritamab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, wherein the combination is administered in 21-day cycles; and wherein (a) a priming dose of epcoritamab is administered subcutaneously on day 1 of cycle 1 of the 21-day cycles, an intermediate dose of epcoritamab is administered subcutaneously on day 8 of cycle 1 of the 21-day cycles, a full dose of 24 mg or 48 mg of epcoritamab is subcutaneously administered on day 15 of cycle 1 of the 21-day cycles, and a full dose of24 or 48 mg of the epcoritamab is administered subcutaneously weekly starting on day 1 of cycle 2 of the 21-day cycles, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose; (b) rituximab is administered intravenously at a dose of 375 mg/m2 once every three weeks for six or eight 21-day cycles wherein administration of the combination in 21-day cycles continues at least until the subject exhibits a complete metabolic response (CMR), or a partial metabolic response of reference claim 29; The method of claim 29, wherein the epcoritamab is administered at a full dose of 24 mg of reference claim 30; The method of claim 29, wherein the epcoritamab is administered at a full dose of 48 mg of reference claim 31; The method of claim 29, wherein the priming dose of epcoritamab is 0.16 mg of reference claim 32; The method of claim 29, wherein the intermediate dose of epcoritamab is 0.8 mg of reference claim 33.
‘805 does not teach the 28-day cycle regimen and lenalidomide dosing regimen recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-rituximab- cyclophosphamide, ( c) doxorubicin, ( d) vincristine and ( e) prednisone dosage regimen of ‘805 with the 28-day cycle regimen and dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to swap cyclophosphamide, ( c) doxorubicin, ( d) vincristine and ( e) prednisone dosage regimen of ‘805 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment in a 28-day cycle offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to swap the cyclophosphamide, (c) doxorubicin, (d) vincristine and ( e) prednisone dosage regimen in combination with epcoritamab and rituximab of ‘805 with lenalidomide and rituximab combination treatment in a 28-day cycle of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, 13-18, 24, and 26-27 of U.S. Patent No. US 11,548,952 B2 (PTO-892, Reference A; “’952”) in view Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims are not identical they are not patentably distinct from each other because the claims of the ‘952 patent are directed towards A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of (a) rituximab, (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin, wherein the bispecific antibody comprises: (i) a first binding arm comprising a first antigen-binding region which binds to human CD3c ( epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDRl, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDRl, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and(ii) a second binding arm comprising a second antigen binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDRl, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDRl, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14; wherein the bispecific antibody is administered at a dose of 24 mg or 48 mg, and wherein rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin, and the bispecific antibody are administered in 21-day cycles, wherein the bispecific antibody, rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin are administered in the same cycle for the first 3 cycles, and the bispecific antibody is administered alone for subsequent cycles, and wherein a priming dose of the bispecific antibody is administered on day 1 of cycle 1 and an intermediate dose is administered on day 8 of cycle 1 before the dose of 24 mg or 48 mg on day 15 of cycle 1 of reference claim 1; The method of claim 1, wherein the bispecific antibody is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein the bispecific antibody is administered at a dose of 48 mg of reference claim 3; The method of claim 1, wherein the bispecific antibody is administered once every week (weekly administration) for three and one-third 21-day cycles of reference claim 4; The method of claim 1, wherein the priming dose is 0.16 mg and wherein the intermediate dose is 0.8 mg of reference claim 6; The method of claim 1, wherein rituximab is administered once every three weeks for three 21-day cycles of reference claim 7; The method of claim 1, wherein: (a) the bispecific antibody is administered in 21-day cycles as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; and (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (b) rituximab is administered in 21-day cycles on day 1 in cycles 1-3 of reference claim 13; The method of claim 1, wherein rituximab is administered at a dose of 375 mg/m2 of reference claim 14; The method of claim 1, wherein the bispecific antibody is administered subcutaneously of reference claim 16; The method of claim 1, wherein rituximab is administered intravenously of reference claim 17; The method of claim 1, wherein (b) the DLBCL is follicular lymphoma Grade 3B, and/or ( c) the subject has relapsed after or is refractory to at least one prior therapy of reference claim 18; The method of claim 1, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27) of reference claim 24; method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of (a) rituximab, (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27) wherein the bispecific antibody is administered at a dose of 24 mg, and wherein rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin, and the bispecific antibody are administered in 21-day cycles, wherein: (a) the bispecific antibody is administered in 21-day cycles as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; and (ii) in cycles 2-4, a dose of 24 mg is administered on days 1, 8, and 15; (b) rituximab is administered in 21-day cycles on day 1 in cycles 1-3 of reference claim 26; A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of (a) rituximab, (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27); wherein the bispecific antibody is administered at a dose of 48 mg, and wherein rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin, and the bispecific antibody are administered in 21-day cycles, wherein: (a) the bispecific antibody is administered in 21-day cycles as follows: (i) in cycle 1, a priming dose of0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; and( ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; (b) rituximab is administered in 21-day cycles on day 1 in cycles 1-3 of reference claim 27.
‘952 does not teach the 28-day cycle regimen and lenalidomide dosing regimen recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-(a) rituximab, (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin dosage regimen of ‘952 with the 28-day cycle regimen and dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to swap (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin dosage regimen of ‘805 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment in a 28-day cycle offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to swap the (b) dexamethasone, (c) cytarabine, and (d) oxaliplatin/carboplatin dosage regimen in combination with epcoritamab and rituximab of ‘952 with lenalidomide and rituximab combination treatment in a 28-day cycle of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 23, and 25-26 of U.S. Patent No. US 11,858,995 B2 (PTO-892, Reference C; “’995”) in view Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims are not identical they are not patentably distinct from each other because the claims of the ‘995 patent are directed towards A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising subcutaneously administering to the subject a bispecific antibody comprising: wherein the bispecific antibody is administered at a full dose ranging from 12-60 mg in 28-day cycles, and wherein a priming dose of the bispecific antibody is administered on day 1 of cycle 1, and an intermediate dose of the bispecific antibody is administered on day 8 of cycle 1 before administration of the first full dose of the bi specific antibody on day 15 of cycle 1, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose; and wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein after administration of the priming dose and the intermediate dose the bispecific antibody is administered at a full dose of 24 mg of reference claim 2; The method of claim 1, wherein after administration of the priming dose and the intermediate dose the bispecific antibody is administered at a full dose of 48 mg of reference claim 3; The method of claim 1, wherein the bispecific antibody is administered once every week (weekly administration) for 2.5 28-day cycles of reference claim 4; The method of claim 4, wherein after the weekly administration, the bispecific antibody is administered once every two weeks (biweekly administration) for six 28-day cycles of reference claim 5; The method of claim 5, wherein after the biweekly administration, the bispecific antibody is administered once every four weeks of reference claim 6; The method of claim 1, wherein the priming dose is in the range of 0.05-0.35 mg of reference claim 7; The method of claim 1, wherein said priming dose is 0.16 mg or about 0.16 mg of reference claim 8; The method of claim 1, wherein said intermediate dose is in the range of 0.6-1.2 mg of reference claim 9; The method of claim 1, wherein said intermediate dose is 0.8 mg or about 0.8 mg of reference claim 10; The method of claim 1, wherein the bispecific antibody is administered in 28-day cycles, wherein: a) in cycle 1, a priming dose is administered on day 1, an intermediate dose on day 8, and a full dose of 12-60 mg on days 15 and 22; b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1 of reference claim 11; The method of claim 11, wherein the full dose is 24 mg or about 24 mg of reference claim 12; The method of claim 11, wherein the full dose is 48 35 mg or about 48 mg of reference claim 13; The method of claim 1, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27) of reference claim 23; The method of claim 1, wherein the bispecific antibody is epcoritamab, or a biosimilar thereof of reference claim 24; method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising subcutaneously administering to the subject a bispecific antibody comprising: a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively, (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27) wherein the bispecific antibody is administered at a dose ranging from 12-60 mg in 28-day cycles, wherein: a) in cycle 1, a priming dose of0.16 mg is administered on day 1, an intermediate dose of0.8 mg on day 8, and a full dose of 12-60 mg on days 15 and 22; b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1 of reference claim 25; A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising subcutaneously administering epcoritamab to the subject at a dose ranging from 12-60 mg in 28-day cycles, wherein: a) in cycle 1, a priming dose of0.16 mg is administered on day 1, an intermediate dose of 0.8 mg on day 8, and a full dose of 12-60 mg on days 15 and 22; b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1, wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 26; The method of claim 26, wherein the full dose of epcoritamab is 24 mg of reference claim 27; The method of claim 26, wherein the full dose of epcoritamab is 48 mg of reference claim 28.
‘995 does not teach treating follicular lymphoma patients (refractory and/or relapsed, stage, or grade) and the lenalidomide and rituximab dosing regimen recited in instant claims 1, 23-24, 27-28, 50-52, 55-56, 60, and 62-63.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage of ‘995 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘995 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment with lenalidomide and rituximab combination treatment to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 11-12, and 15 of U.S. Patent No. US 12,435,154 B2 (PTO-892; Reference D; “’154”) in view Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims are not identical they are not patentably distinct from each other because the claims of the ‘154 patent are directed towards A method of treating a B-cell non-Hodgkin lymphoma (B-NHL) in a human subject, the method comprising subcutaneously administering a dose of 0.16 mg of epcoritamab to the subject on day one (1) of treatment and subcutaneously administering a dose of 0.8 mg of epcoritamab to the subject on day eight (8) of treatment, wherein the subject does not experience cytokine release syndrome (CRS) or experiences manageable cytokine release syndrome of grade 1 or grade 2, and wherein after day eight (8) of treatment epcoritamab is subcutaneously administered in intervals to the subject until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein 48 mg of epcoritamab is administered subcutaneously to the human subject on days 15 and 22 of treatment of reference claim 2; The method of claim 2, wherein said B-NHL is selected from the group consisting of … follicular lymphoma (FL)… of reference claim 3; The method of claim 3, wherein said B-NHL is follicular lymphoma (FL) of reference claim 6; The method of claim 1, wherein 24 mg of epcoritamab is administered subcutaneously to the human subject on days 15 and 22 of treatment of reference claim 11; The method of claim 11, wherein said B-NHL is selected from the group consisting of … follicular lymphoma (FL)… of reference claim 12; The method of claim 11, wherein said B-NHL is follicular lymphoma (FL) of reference claim 15.
‘154 does not teach treating follicular lymphoma (refractory and/or relapsed, stage, or grade) patients and the lenalidomide and rituximab dosing regimen recited in instant claims 1, 23-24, 27-28, 50-52, 55-56, 60, and 62-63.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage of ‘154 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘154 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment with lenalidomide and rituximab combination treatment to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69-70, 72, 75, 82, 85, 88, 98-99, and 102 of copending Application No. US 17/923,317 (reference application) (“’317”) in view Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘317 application is directed to methods of treating B-cell non-Hodgkin lymphoma (B-NHL) in a human subject, the method comprising subcutaneously administering a dose of 0.16 mg of epcoritamab to the subject on day one (1) of treatment and subcutaneously administering a dose of 0.8 mg of epcoritamab to the subject on day eight (8) of treatment, wherein the subject does not experience cytokine release syndrome (CRS) or experiences manageable cytokine release syndrome of grade 1 or grade 2, and wherein after day eight (8) of treatment a dose of 48 mg of epcoritamab is subcutaneously administered in intervals to the subject until progressive disease develops or unacceptable toxicity occurs of reference claim 69; wherein 48 mg of epcoritamab is administered subcutaneously to the human subject on days 15 and 22 of treatment of reference claim 70; wherein said B-NHL is selected from the group consisting of … follicular lymphoma … of reference claim 72; wherein said B-NHL is follicular lymphoma (FL) of reference claim 75; wherein said B-NHL is selected from the group consisting of … follicular lymphoma … wherein the patient achieves a complete response (CR) of reference claim 82; wherein said B-NHL is follicular lymphoma (FL) of reference claim 85; wherein said B-NHL is relapsed or refractory B-NHL of reference claim 88; A method of treating a B-cell non-Hodgkin lymphoma (B-NHL) in a human subject, the method comprising administering epcoritamab subcutaneously in 28-day cycles, wherein: a) a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 48 mg is administered on days 15 and 22 of the first cycle; b) a full dose of 48 mg is administered on days 1, 8, 15 and 22 of cycles 2-3; c) a full dose of 48 mg is administered on days 1 and 15 of cycles 4-9; and d) a full dose of 48 mg is administered on day 1 of subsequent cycles until progressive disease develops or unacceptable toxicity occurs of reference claim 98; wherein said B-NHL is selected from the group consisting of … follicular lymphoma … of reference claim 99; wherein said B-NHL is follicular lymphoma (FL) of reference claim 102.
‘317 does not teach treating follicular lymphoma (refractory and/or relapsed, stage, or grade) patients and the lenalidomide and rituximab dosing regimen recited in instant claims 1, 23-24, 27-28, 50-52, 55-56, 60, and 62-63.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage of ‘317 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘317 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment with lenalidomide and rituximab combination treatment to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32-34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 12, 15, 17, 33, 34-35, 36-37, 45-46, 48, 50, and 65-67 of copending Application No. US 18/025,203 (reference application) (“’203”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘203 application is directed to methods of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a combination of (a) epcoritamab or a biosimilar thereof, wherein the biosimilar comprises a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 26 and 27, respectively, (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27) (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, (e) vincristine and (f) prednisone, in 21-day cycles, wherein (a) epcoritamab or a-the biosimilar thereof is administered subcutaneously, wherein (i) a priming dose is administered on day 1 of the first 21-day cycle, an intermediate dose is administered on day 8 of the first 21-day cycle, and a full dose of 24 or 48 mg on day 15 of the first 21-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose, (ii) a full dose of 24 or 48 mg on days 1, 8 and 15 of the second, third and fourth 21- day cycles; and (iii) a full dose of 24 or 48 mg is administered once day 1 of two to four subsequent 21-day (b) rituximab is administered intravenously at a dose of 375 mg/m² once every cycle wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response, or a stable disease, or-until progressive disease develops, or unacceptable toxicity occurs of reference claim 1; wherein epcoritamab or a-the biosimilar thereof is administered at a full dose of 24 mg of reference claim 2; wherein epcoritamab or the biosimilar thereof is administered at a full dose of 48 mg of reference claim 3; wherein the priming dose is 0.16 mg of reference claim 12; wherein the intermediate dose is 0.8 mg of reference claim 15; wherein the administration of rituximab once every cycle is performed for six or eight 21-day cycles of reference claim 17; The method of claim 1 wherein: (a) epcoritamab or the biosimilar thereof is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 24 mg is administered on day 15; (ii) in cycles 2-4, a full dose of 24 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a full dose of 24 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6 of reference claim 33; The method of claim 1, wherein: (a) epcoritamab or the biosimilar thereof is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 48 mg is administered on day 15; (ii) in cycles 2-4, a full dose of 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a full dose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6 of reference claim 34; The method of claim 33, wherein epcoritamab or the biosimilar thereof is administered in 28-day cycles on day 1 from cycle 7 of reference claim 35; The method of claim 1, wherein: (a) epcoritamab or the biosimilar thereof is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 24 mg is administered on day 15; (ii) in cycles 2-4, a full dose of 24 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a full dose of 24 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8 of reference claim 36; The method of claim 1 wherein: (a) epcoritamab or the biosimilar thereof is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 48 mg is administered on day 15;( (ii) in cycles 2-4, a full dose of 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a full dose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8 of reference claim 37; The method of claim 36, wherein epcoritamab or the biosimilar thereof is administered in 28-day cycles on day 1 from cycle 1 and thereafter of reference claim 38; The method of claim 1, wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and epcoritamab or the biosimilar thereof are administered sequentially of reference claim 45; The method of claim 1, wherein prednisone is administered first, rituximab is administered second, cyclophosphamide is administered third, doxorubicin is administered fourth, vincristine is administered fifth, and epcoritamab or the biosimilar thereof is administered last if rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and epcoritamab or the biosimilar thereof are administered on the same day of reference claim 46; wherein the DLBCL is follicular lymphoma Grade 3B of reference claim 48; The method of claim 1, wherein the method comprises administration of epcoritamab of reference claim 65; The method of claim 34, wherein epcoritamab or the biosimilar thereof is administered in 28-day cycles on day 1 from cycle 7 and thereafter of reference claim 66; The method of claim 34, wherein epcoritamab or the biosimilar thereof is administered in 28-day cycles on day 1 from cycle 9 and thereafter of reference claim 67.
‘203 does not teach the 28-day cycle regimen and lenalidomide dosing regimen recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-rituximab- cyclophosphamide, doxorubicin, vincristine and prednisone dosage regimen of ‘203 with the 28-day cycle regimen and dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to substitute cyclophosphamide, doxorubicin, vincristine and prednisone dosage regimen of ‘203 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment in a 28-day cycle offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to swap the cyclophosphamide, doxorubicin, vincristine and prednisone dosage regimen in combination with epcoritamab and rituximab of ‘203 with lenalidomide and rituximab combination treatment in a 28-day cycle of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32-34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-6, 11-18, 37-40, 47-48, 51-53, and 68 of copending Application No. US 18/025,206 (reference application) (“’206”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘206 application is directed to A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof, wherein the biosimilar comprises a heavy chain and a light chain consisting of the amino acid sequences of SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequences of SEQ ID NOs: 26 and 27, respectively, (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27), rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin, wherein (a) epcoritamab or a biosimilar thereof is administered subcutaneously at a full dose of 24 or 48 mg; (b) rituximab is administered intravenously at a dose of 375 mg/m²; wherein epcoritamab or a biosimilar thereof, rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin are administered in 21-day cycles at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered at a full dose of 24 mg reference claim 2; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered at a full dose of 48 mg reference claim 3; The method of claim 1, wherein a full dose of epcoritamab or a biosimilar thereof is administered once every week (weekly administration) reference claim 5; The method of claim 5, wherein the weekly administration of epcoritamab or a biosimilar thereof at a full dose of 24 mg or 48 mg is performed for three and one-third 21-day cycles of reference claim 6; The method of claim 5, wherein prior to the weekly administration of epcoritamab or a biosimilar thereof at a full dose of 24 mg or 48 mg, a priming dose of epcoritamab or a biosimilar thereof is administered in cycle 1 of the 21-day cycles reference claim 11; The method of claim 11, wherein the priming dose of epcoritamab or a biosimilar thereof is administered two weeks prior to administering the first weekly full dose of 24 mg or 48 mg of epcoritamab or a biosimilar thereof reference claim 12; The method of claim 1, wherein the priming dose of epcoritamab or a biosimilar thereof is 0.16 mg reference claim 13; The method of claim 11, wherein after administering the priming dose and prior to administering the first weekly full dose of 24 mg or 48 mg of epcoritamab or a biosimilar thereof, an intermediate dose of epcoritamab or a biosimilar thereof is administered of reference claim 14; The method of claim 14, wherein the priming dose of epcoritamab or a biosimilar thereof is administered on day 1 and the intermediate dose of epcoritamab or a biosimilar thereof is administered on day 8 before the first weekly full dose of 24 mg or 48 mg on day 15 of cycle 1 reference claim 15; The method of claim 1, wherein the intermediate dose of epcoritamab or a biosimilar thereof is 0.8 mg of reference claim 16; The method of claim 1, wherein rituximab is administered once every three weeks reference claim 17; The method of claim 1, wherein the administration of rituximab once every three weeks is performed for three 21-day cycles of reference claim 18; The method of claim 1, wherein rituximab, dexamethasone, and oxaliplatin/carboplatin, and epcoritamab or a biosimilar thereof are administered on the same day reference claim 34; The method of claim 1, wherein: (a) epcoritamab or a biosimilar thereof is administered in 21-day cycles as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 24 mg is administered on day 15; and (ii) in cycles 2-4, a full dose of 24 mg is administered on days 1, 8, and 15; (b) rituximab is administered in 21-day cycles on day 1 in cycles 1-3 of reference claim 37; The method of claim 1, wherein: (a) epcoritamab or a biosimilar thereof is administered in 21-day cycles as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 48 mg is administered on day 15; and (ii) in cycles 2-4, a full dose of 48 mg is administered on days 1, 8, and 15; (b) rituximab is administered in 21-day cycles on day 1 in cycles 1-3 of reference claim 38; The method of claim 37, wherein the bispecific antibody is administered once every two weeks in 28-day cycles from cycle 5 to cycle 9 or to when ASCT is performed, whichever is earlier of reference claim 39; The method of claim 39, wherein if ASCT is not performed by the end of cycle 9, the bispecific antibody is administered once every four weeks in 28-day cycles from cycle 10 to when ASCT is performed of reference claim 40; The method of claim 1, wherein rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin, and epcoritamab or a biosimilar thereof are administered sequentially of reference claim 47; the method of claim 1, wherein dexamethasone is administered first, rituximab is administered second, oxaliplatin/carboplatin is administered third, epcoritamab or a biosimilar thereof is administered fourth, and cytarabine is administered last of reference claim 48; The method of claim 1, wherein the DLBCL is follicular lymphoma Grade 3B of reference claim 51; The method of claim 1, wherein the subject has relapsed after at least one prior therapy of reference claim 52; The method of claim 1, wherein the subject is refractory to at least one prior therapy of reference claim 53; The method of claim 1, wherein the method comprises administering epcoritamab of reference claim 68.
‘206 does not teach the 28-day cycle regimen and lenalidomide dosing regimen recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab, rituximab, dexamethasone, cytarabine, and oxaliplatin/carboplatin dosage regimen of ‘206 with the 28-day cycle regimen and dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to substitute dexamethasone, cytarabine, and oxaliplatin/carboplatin dosage regimen of ‘206 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment in a 28-day cycle offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to substitute the (dexamethasone, cytarabine, and oxaliplatin/carboplatin dosage regimen in combination with epcoritamab and rituximab of ‘206 with lenalidomide and rituximab combination treatment in a 28-day cycle of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32-34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 9, 12, 15, 24-25, 29-30, 32-34, of copending Application No. US 18/025,208 (reference application) (“’208”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘208 application is directed to A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject epcoritamab, gemcitabine and oxaliplatin in 28-day cycles, wherein (a) epcoritamab is administered subcutaneously, wherein (i) a priming dose is administered on day 1 of the first 28-day cycle, an intermediate dose is administered on day 8 of the first 28-day cycle, and a full dose of 24 or 48 mg on days 15 and 22 of the first 28-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose, (ii) a full dose of 24 or 48 mg is administered weekly on days 1, 8, 15 and 22 for at least 2.5 28-day cycles; (iii) a full dose of 24 or 48 mg is administered biweekly on day 1 of two to six subsequent 28-day cycles; and (iv) a full dose of 24 or 48 mg is administered once every four weeks on day 1 of each subsequent 28-day cycle wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein epcoritamab is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered at a dose of 48 mg of reference claim 3; The method of claim 1, wherein the biweekly administration is performed for six 28-day cycles of reference claim 7; The method of claim 1, wherein the administration once every four weeks is performed for at least two 28-day cycles of reference claim 9; The method of claim 1, wherein the priming dose is 0.16 mg of reference claim 12; The method of claim 1, wherein the intermediate dose is 0.8 mg of reference claim 15; the method of claim 1, wherein: (a) epcoritamab is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 24 mg is administered on days 15 and 22; (ii) in cycles 2 and 3, a full dose of 24 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-9, a full dose of 24 mg is administered on days 1 and 15; and (iv) in cycle 10 and subsequent cycles, a full dose of 24 mg is administered on day 1 of reference claim 24; The method of claim 1, wherein: (a) epcoritamab or is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on days 15 and 22; (ii) in cycles 2 and 3, a dose of 48 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-9, a dose of 48 mg is administered on days 1 and 15; and (iv) in cycle 10 and subsequent cycles, a dose of 48 mg is administered on day 1 of reference claim 25; The method of claim 1, wherein the epcoritamab, gemcitabine, and oxaliplatin are administered sequentially of reference claim 29; the method of claim 1, wherein gemcitabine is administered first, oxaliplatin is administered second, and epcoritamab is administered last when gemcitabine, oxaliplatin, and epcoritamab are administered on the same day of reference claim 30; The method of claim 1, wherein the DLBCL is follicular lymphoma Grade 3B of reference claim 32; The method of claim 1, wherein the subject has relapsed after at least one prior therapy of reference claim 33; The method of claim 1, wherein the subject is refractory to at least one prior therapy of reference claim 34.
‘208 does not teach the lenalidomide and rituximab dosing regimen in combination with epcoritamab or a biosimilar thereof recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage of ‘208 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘208 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment of ‘208 with lenalidomide and rituximab combination treatment of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 11-12, 15-19, and 41-49 of copending Application No. US 18/025,202 (reference application) (“’202”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘202 application is directed towards A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof, wherein the epcoritamab or a biosimilar thereof is subcutaneously administered at a full dose ranging from 12-60 mg in 28-day cycles, prior to administering the full dose, a priming dose of epcoritamab or a biosimilar thereof is administered in cycle 1 of the 28-day cycles, and wherein after administering the priming dose and prior to administering the full dose, an intermediate dose of the epcoritamab or biosimilar thereof is administered; and wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered at a dose of 48 mg of reference claim 3; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered once every week (weekly administration) of reference claim 4; The method of claim 4, wherein the weekly administration is performed for 2.5 28-day cycles of reference claim 5; The method of claim 4, wherein after the weekly administration, epcoritamab or a biosimilar thereof is administered once every two weeks (biweekly administration) of reference claim 6; The method of claim 6, wherein the biweekly administration is performed for six 28-day cycles of reference claim 7; The method of claim 6, wherein after the biweekly administration, epcoritamab or a biosimilar thereof is administered once every four weeks of reference claim 8; The method of claim 1, wherein the priming dose is in the range of 0.05 - 0.35 mg of reference claim 11; The method of claim 1, wherein said priming dose is 0.16 mg or about 0.16 mg of reference claim 12; The method of claim 1, wherein said intermediate dose is in the range of 0.6-1.2 mg of reference claim 15; The method of claim 1, wherein said intermediate dose is 0.8 mg or about 0.8 mg of reference claim 15; The method of claim 1, wherein epcoritamab or a biosimilar thereof is administered subcutaneously in 28-day cycles, wherein: a) in cycle 1, a priming dose is administered on day 1, an intermediate dose on day 8, and a full dose of 12-60 mg on days 15 and 22; b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1 of reference claim 17; The method of claim 17, wherein the full dose is 24 mg or about 24 mg of reference claim 18; The method of claim 17, wherein the full dose is 48 mg or about 48 mg of reference claim 19; The method of claim 1, wherein the method comprises administering a biosimilar of epcoritamab comprising a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 26 and 27, respectively, of reference claim 41 (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27); The method of claim 1, wherein the method comprises administration of epcoritamab of reference claim 42; The method of claim 17, wherein the priming dose is in the range of 0.05 - 0.35 mg of reference claim 43; The method of claim 17, wherein said priming dose is 0.16 mg or about 0.16 mg of reference claim 44; The method of claim 17, wherein said intermediate dose is in the range of 0.6-1.2 mg of reference claim 45; The method of claim 17, wherein said intermediate dose is 0.8 mg or about 0.8 mg of reference claim 46; A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof, wherein epcoritamab or a biosimilar thereof is administered subcutaneously in 28-day cycles, wherein: a) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg on day 8, and a full dose of 12-60 mg on days 15 and 22; b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1, wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 47; A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof, wherein epcoritamab or a biosimilar thereof is administered subcutaneously in 28-day cycles, wherein: a) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg on day 8, and a full dose of 24 mg on days 15 and 22; b) in cycles 2-3, a full dose of 24 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 24 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 24 mg is administered on day 1, wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 48; A method of treating chronic lymphocytic leukemia (CLL) in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof wherein epcoritamab or a biosimilar thereof is administered subcutaneously in 28-day cycles, wherein: a) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg on day 8, and a full dose of 48 mg on days 15 and 22; b) in cycles 2-3, a full dose of 48 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 48 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 48 mg is administered on day 1, wherein administration of the full dose of the bispecific antibody continues at least until the subject exhibits a complete response (CR), a partial response (PR) or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 49.
‘202 does not teach treating follicular lymphoma (refractory and/or relapsed, stage, or grade) patients and the lenalidomide and rituximab dosing regimen recited in instant claims 1, 23-24, 27-28, 50-52, 55-56, 60, and 62-63.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage of ‘202 with the dosing regimen of lenalidomide and rituximab to treat follicular lymphoma patients (all stages and grades) of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘202 with the dosing regimen of lenalidomide and rituximab to treat follicular lymphoma patients of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment of ‘202 with lenalidomide and rituximab combination treatment for follicular lymphoma patients of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32-34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 12, 15, 17, 33-38, 46, 48, 64-65, 66-67 of copending Application No. US 18/500,799 (reference application) (“’799”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘799 application is directed towards A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject (a) a bispecific antibody, (b) rituximab, (b) (c) cyclophosphamide, (c)(d) doxorubicin, (d)(e) vincristine and (e)(f) prednisone in 21 day cycles, wherein (a) the a-bispecific antibody comprises: (i) a first binding arm comprising which binds to human CD3ε (epsilon) and comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and (ii) a second binding arm comprising which binds to human CD20 and comprises and a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27 (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27), wherein a priming dose of the bispecific antibody is administered subcutaneously on day 1 of the first 21-day cycle, an intermediate dose of the bispecific antibody is administered subcutaneously on day 8 of the first 21-day cycle, and a full dose of 24 or 48 mg of the bispecific antibody is administered subcutaneously on day 15 of the first 21-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose (b) rituximab is administered intravenously at a dose of 375 mg/m² once every three weeks wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein the bispecific antibody is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein the bispecific antibody is administered at a dose of 48 mg of reference claim 3; The method of claim 1, wherein the bispecific antibody is administered once every week (weekly administration) of reference claim 4; The method of claim 4, wherein the weekly administration of 24 mg or 48 mg is performed for three and one-third 21-day cycles of reference claim 5; The method of claim 4 wherein after the weekly administration, the bispecific antibody is administered once every three weeks of reference claim 6; The method of claim 6, wherein the administration once every three weeks is performed for two or four 21-day cycles of reference claim 7; The method of claim 7, wherein after the administration once every three weeks, the bispecific antibody is administered once every four weeks in 28-day cycles of reference claim 8; the method of claim 1, wherein the priming dose is 0.16 mg of reference claim 12; The method of claim 1, wherein the intermediate dose is 0.8 mg of reference claim 15; The method of claim 1, wherein the administration of rituximab once every three weeks is performed for six or eight 21-day cycles of reference claim 17; the method of claim 1, wherein (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 24 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6 of reference claim 33; the method of claim 1, wherein (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6 of reference claim 34; The method of claim 33 wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7 of reference claim 35; the method of claim 1, wherein administration is performed in 21-day cycles, and wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8 of reference claim 36; the method of claim 1 wherein administration is performed in 21-day cycles, and wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8 of reference claim 37; The method of claim 36, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9 of reference claim 38; The method of claim 1, wherein prednisone is administered first, rituximab is administered second, cyclophosphamide is administered third, doxorubicin is administered fourth, vincristine is administered fifth, and the bispecific antibody is administered last if rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered on the same day of reference claim 46; the method of claim 1 wherein the DLBCL is follicular lymphoma Grade 3B of reference claim 48; the method of claim 1, wherein the bispecific antibody comprises a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 26 and 27, respectively, of reference claim 64 (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27); the method of claim 1, wherein the bispecific antibody is epcoritamab, or a biosimilar thereof of reference claim 65; the method of claim 34, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7 of reference claim 66; The method of claim 37, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9of reference claim 67.
‘799 does not teach the 28-day cycle regimen and lenalidomide dosing regimen recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone dosage regimen of ‘799 with the 28-day cycle regimen and dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to substitute cyclophosphamide, doxorubicin, vincristine, prednisone dosage regimen of ‘799 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment in a 28-day cycle offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to substitute the cyclophosphamide, doxorubicin, vincristine, prednisone dosage regimen in combination with epcoritamab and rituximab of ‘799 with lenalidomide and rituximab combination treatment in a 28-day cycle of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-20, 27-28, 80, and 82 of copending Application No. US 18/500,673 (reference application) (“’673”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U), Leonard et al (PTO-892; Reference W, "Alliance"), and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘673 application is directed towards A method of treating Richter’s syndrome (RS) in a human subject, the method comprising administering to the subject a bispecific antibody comprising: (i) a first binding arm comprising a first antigen-binding region which binds to human CD3¢ (epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and (ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14; wherein the bispecific antibody is administered at a dose ranging from 12-60 mg in 28-day cycles, wherein administration of the bispecific antibody continues at least until the subjectexhibits a complete response (CR), a partial response (PR), or stable disease, or until progressive disease develops or unacceptable toxicity occurs of reference claim 1; The method of claim 1, wherein the bispecific antibody is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein the bispecific antibody is administered at a dose of 48 mg of reference claim 3; the method of claim 1 wherein the bispecific antibody is administered once every week (weekly administration) for 2.5 28-day cycles of reference claim 4; the method of claim 4 wherein after the weekly administration, the bispecific antibody is administered once every two weeks (biweekly administration) for six 28-day cycles of reference claim 6; the method of claim 6 wherein after the biweekly administration, the bispecific antibody is administered once every four weeks of reference claim 8; the method of claim 4, wherein prior to administering the first weekly dose of 12-60 mg, a priming dose of the bispecific antibody is administered in cycle 1 of the 28-day cycles of reference claim 9; The method of claim 9, wherein the priming dose is administered two weeks prior to administering the first weekly dose of 12-60 mg of reference claim 10; the method of claim 9, wherein the priming dose is in the range of 0.05-0.35 mg of reference claim 11; the method of claim 9, wherein said priming dose is 0.16 mg or about 0.16 mg of reference claim 12; the method of claim 9, wherein after administering the priming dose and prior to administering the first weekly dose of 12-60 mg, an intermediate dose of the bispecific antibody is administered of reference claim 13; The method of claim 13, wherein the priming dose is administered on day 1 and the intermediate dose is administered on day 8 before the first weekly dose of 12-60 mg on days 15 and 22 of cycle 1 of reference claim 14; the method of claim 13, wherein said intermediate dose is in the range of 0.6-1.2 mg of reference claim 15; the method of claim 13, wherein said intermediate dose is 0.8 mg or about 0.8 mg of reference claim 16; the method of claim 13, wherein the bispecific antibody is administered in 28-day cycles, wherein: a) in cycle 1, a priming dose is administered on day 1, an intermediate dose on day 8, and a full dose of 12-60 mg on days 15 and 22; b) in cycles 2-3, a full dose of 12-60 mg is administered on days 1, 8, 15, and 22; c) in cycles 4-9, a full dose of 12-60 mg is administered on days 1 and 15; and d) in cycle 10 and subsequent cycles, a full dose of 12-60 mg is administered on day 1 of reference claim 17; The method of claim 17, wherein the full dose is 24 mg or about 24 mg of reference claim 18; The method of claim 17, wherein the full dose is 48 mg or about 48 mg of reference claim 19; the method of claim 1, wherein the bispecific antibody is administered subcutaneously of reference claim 20; the method of claim 1, wherein the subject achieves a complete metabolic response or a partial metabolic response of reference claim 28; the method of claim 1 wherein the bispecific antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively of reference claim 80 (Reference SEQ ID NOs:24-27 are 100% sequence identical to instant SEQ ID NOs:24-27); the method of claim 1; wherein the bispecific antibody is epcoritamab, or a biosimilar thereof of reference claim 82.
‘673 does not teach treating follicular lymphoma (refractory and/or relapsed, stage, or grade) patients and the lenalidomide and rituximab dosing regimen in combination with epcoritamab or a biosimilar thereof recited in instant claims 1, 23-24, 27-28, 50-52, 55-56, 60, and 62-63.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab dosage of ‘673 with the dosing regimen of lenalidomide and rituximab to treat follicular lymphoma patients (all stages and grades) of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab dosing cycle of ‘673 with the dosing regimen of lenalidomide and rituximab to treat follicular lymphoma patients of Augment with the lenalidomide dosing regimen of Alliance with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment and Alliance teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment of ‘673 with lenalidomide and rituximab combination treatment for follicular lymphoma patients of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-14, 24, 29, 40, and 66 of copending Application No. US 18/833,261 (reference application) (“261”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Morschhauser et al (PTO-892; Reference U; “Morschhauser”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘267 application is directed towards A method of treating Diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject epcoritamab or a biosimilar thereof and lenalidomide and optionally, an effective amount of ibrutinib, wherein the epcoritamab or biosimilar thereof bispecific antibody is administered subcutaneously at a dose of 24 mg or 48 mg, and wherein; lenalidomide, the epcoritamab or biosimilar thereof and optionally ibrutinib are administered in 28-day cycles of reference claim 1; The method of claim 1, wherein the epcoritamab or biosimilar thereof bispecific antibody is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein the epcoritamab or biosimilar thereof bispecific antibody is administered at a dose of 48 mg of reference claim 3; the method of claim 1, wherein epcoritamab or biosimilar thereof is administered once every week (weekly administration) of reference claim 4; The method of claim 4, wherein the weekly administration of 24 mg or 48 mg is performed for 2.5 28-day cycles of reference claim 5; the method of claim 4, wherein after the weekly administration, epcoritamab or the biosimilar thereof is administered once every four weeks on day 1 of each 28-day cycle of reference claim 6; The method of claim 6, wherein the administration once every four weeks is performed for at least eight 28-day cycles, for at least twelve 28-day cycles, or for at least twenty 28-day of reference claim 7; The method of claim 1, wherein prior to the weekly administration of 24 mg or 48 mg, a priming dose of epcoritamab or biosimilar thereof is administered in cycle 1 of the 28-day cycles of reference claim 9; The method of claim 9, wherein the priming dose is administered two weeks prior to administering the first weekly dose of 24 mg or 48 mg of reference claim 10; the method of claim 9, wherein the priming dose is 0.16 mg of reference claim 11; the method of claim 9, wherein after administering the priming dose and prior to administering the first weekly dose of 24 mg or 48 mg, an intermediate dose of the epcoritamab or biosimilar thereof is administered of reference claim 12; The method of claim 12, wherein the priming dose is administered on day 1 and the intermediate dose is administered on day 8 before the first weekly dose of 24 mg or 48 mg on days 15 and 22 of cycle 1 of reference claim 13; the method of claim 12, wherein the intermediate dose is 0.8 mg of reference claim 14; the method of claim 1, wherein (a) lenalidomide is administered once a day at a dose of 10 to 30 mg from day 1 to day 21 of each 28-day cycle of reference claim 24; the method of claim 1, wherein administration is performed in 28-day cycles, and wherein: (a) the epcoritamab or biosimilar thereof is administered subcutaneously as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on days 15 and 22; (ii) in cycles 2-3, a dose of 24 mg or 48 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-12, a dose of 24 mg or 48 mg is administered on day 1; and (b) lenalidomide is administered orally at a dose of 25 mg/day on days 1-21 in cycles 1-12 of reference claim 29; the method of claim 1, wherein the DLBCL is (c) follicular lymphoma Grade 3B of reference claim 40; the method of claim 1, wherein the method comprises administering epcoritamab or a biosimilar thereof of reference claim 66.
‘261 does not teach the rituximab dosing regimen in combination with lenalidomide and epcoritamab or a biosimilar thereof as recited in instant claims 1, 27, and 52.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Morschhauser does teach methods of treating DLBCL patients with RG6026, a CD20-TCB comprising two fragment antigen binding regions that bind CD20 and one that binds CD3 in combination with a CD20 monoclonal antibody, obintuzumab, which demonstrates strong and sustained tumor regression driven by multiple mechanisms of action including induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by obintuzumab as well as recruitment into the tumor and T-cell cytotoxicity mediated by CD20-TCB (Morschhauser; paragraph 1). Morschhauser teaches RG6026 and obintuzumab in clinical trial to investigate safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity in relapsed and/or refractory NHL patients in a 28-day cycle wherein the patients received a pretreatment of obintuzumab to mitigate cytokine release syndrome and then RG6026 and obintuzumab are administered on the same day in cycle 2 (Morschhauser; paragraph 2). Morschhauser teaches RG6026 and obintuzumab can be safely administered together and that the RG6026 and obintuzumab provide highly promising clinical activity and supports the promise of combining CD20/CD3 bispecific antibodies with anti-CD20 antibodies (Morschhauser; paragraph 5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab-lenalidomide dosage regimen of ‘261 with the dosing regimen of lenalidomide and rituximab Augment with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the epcoritamab-lenalidomide dosage regimen of ‘261 with the dosing regimen of lenalidomide and rituximab with the motivation to combine anti-CD20 and CD20-TCB of Morschhauser since Augment teach rituximab and lenalidomide combination treatment offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma; and Morschhauser teaches anti-CD20/CD3 bispecific antibodies and anti-CD20 antibodies are a highly promising combination therapy for patients with follicular lymphoma since they demonstrate strong and sustained tumor regression driven by multiple mechanisms of action and can be safely administered together. Therefore, a person of ordinary skill in the art would have been motivated to combine epcoritamab treatment of ‘261 with lenalidomide and rituximab combination treatment for follicular lymphoma patients of Augment to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 12, 15, 23-24, 27, 32, 34, 49-56, 58, and 60-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-14, 33-36, 38, 41, 6, and 66 of copending Application No. US 18/833,267 (reference application) (“267”) ”) in view of Augment (PT0-892 filed on 1/27/2026; Reference U) and Leonard et al (PTO-892; Reference W, "Alliance").
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘267 application is directed towards A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a combination of epcoritamab or a biosimilar thereof, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone wherein epcoritamab or biosimilar thereof is administered subcutaneously at a dose of 24 mg or 48 mg, and wherein polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisone, and epcoritamab or a biosimilar thereof antibody are administered in 21-day cycles of reference claim 1; The method of claim 1, wherein the epcoritamab or biosimilar thereof is administered at a dose of 24 mg of reference claim 2; The method of claim 1, wherein the epcoritamab or biosimilar thereof is administered at a dose of 48 mg of reference claim 3; the method of claim 1, wherein epcoritamab or biosimilar thereof is administered once every week (weekly administration) of reference claim 4; The method of claim 4, wherein the weekly administration of 24 mg or 48 mg is performed for three and one-third 21-day cycles of reference claim 5; the method of claim 4, wherein after the weekly administration, the epcoritamab or biosimilar thereof is administered once every three weeks, on day 1 of each 21 day cycle of reference claim 6; The method of claim 6, wherein the administration once every three weeks is performed for at least four 21-day cycles of reference claim 7; the method of claim 4 wherein prior to the weekly administration of 24 mg or 48 mg, a priming dose of the epcoritamab or biosimilar thereof is administered in cycle 1 of the 21-day cycles of reference claim 9; The method of claim 9, wherein the priming dose is administered two weeks prior to administering the first weekly dose of 24 mg or 48 mg of reference claim 10; the method of claim 9, wherein the priming dose is 0.16mg of reference claim 11; the method of claim 9, wherein after administering the priming dose and prior to administering the first weekly dose of 24 mg or 48 mg, an intermediate dose of the epcoritamab or biosimilar thereof is administered of reference claim 12; The method of claim 12, wherein the priming dose is administered on day 1 and the intermediate dose is administered on day 8 before the first weekly dose of 24 mg or 48 mg on day 15 of cycle 1 of reference claim 13; the method of claim 12, wherein the intermediate dose is 0.8mg of reference claim 14; the method of claim 1, wherein (b) rituximab is administered once every three weeks of reference claim 33; the method of claim 33 wherein (c) rituximab is administered for six 21-day cycles of reference claim 34; the method of claim 1 wherein, (c) rituximab is administered at a dose of 375 mg/mm of reference claim 35; the method of claim 1 wherein (c) rituximab is administered on day 1 of each 21 day cycle of reference claim 36; The method of claim 1, wherein administration is performed in 21-day cycles, and wherein: (a) the epcoritamab or biosimilar thereof is administered subcutaneously as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycle 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg or 48 mg is administered on day 1; (b) polatuzumab vedotin, rituximab, cyclophosphamide and doxorubicin are administered on day 1 in cycles 1-6 of reference claim 38; the method of claim 1 wherein, (a) rituximab is administered intravenously of reference claim 41; the method of claim 1, wherein (c) the DLBCL is follicular lymphoma Grade 3B of reference claim 46; The method of claim 1, wherein the method comprises administering epcoritamab of reference claim 66.
‘267 does not teach the 28-day cycle regimen and lenalidomide dosing regimen recited in instant claims 1, 23-24, 27-28, 52, and 55-56.
Augment does teach teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades l-3a and/or Stage I-III) in 28-day cycles wherein the rituximab is administered intravenously 375 mg/m2 per week on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 and lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles (Augment, "Trial Design and Treatment", paragraph 2). After the weekly doses of rituximab, Augment teaches rituximab is administered once every four weeks for four cycles (Augment, page 1189, trial design and treatment, paragraph 2). Augment teaches lenalidomide administration from cycle 1 to cycle 12 of the 28-day cycle at a dose of 20 mg daily (Augment, page 1189, trial design and treatment, paragraph 2). Augment found that combination therapy offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients (Augment, Discussion, paragraph 3). Rituximab and lenalidomide combination therapy was administered to determine the efficacy of the treatment with measurements including the primary end point of PFS and secondary end points of ORR, CR, duration of response, OS, event-free survival, and time to next anti-lymphoma treatment (Augment; “Efficacy and Safety Assessments”, paragraph 1).
Alliance does teach methods of treating patients with follicular lymphoma with lenalidomide and rituximab combination treatment as a chemotherapy-free treatment regimen where rituximab was administered at a dose of 375 mg/m2 per week on days 8, 15, 22, 29 (beginning 1 week after initiation of lenalidomide) and lenalidomide was administered at a starting dose of 15 mg per day orally on days 1 through 21 for the first 28 day cycle and then increased to 20 mg per day orally on days 1 through 21 for the second 28 day cycle with the option to increase to 25 mg per day orally on subsequent 28 day cycles to mitigate side effects (Alliance; Abstract; page 3636, “Eligibility Criteria” and “Study Plan”). Alliance teaches the combination therapy of lenalidomide and rituximab to be safe and efficacious in patients with follicular lymphoma and provides sufficient evidence to move toward combination biologic triplet therapy to further improve efficacy and in a direction of more rationally designed chemotherapy-free therapeutic regimens (Alliance; page 3639, “Discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, to have modified the epcoritamab, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone dosage regimen of ‘267 with the 28-day cycle regimen and dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance with reasonable expectation of success. One of ordinary skill in the art would have been motivated to substitute polatuzumab vedotin, cyclophosphamide, doxorubicin and prednisone dosage regimen of ‘267 with the dosing regimen of lenalidomide and rituximab of Augment with the lenalidomide dosing regimen of Alliance since Augment and Alliance teach rituximab and lenalidomide combination treatment in a 28-day cycle offered clinically meaningful efficacy advantages over single-agent rituximab in the context of safety profile and that this combination should replace rituximab monotherapy as a standard of care for patients with follicular lymphoma. Therefore, a person of ordinary skill in the art would have been motivated to substitute the polatuzumab vedotin, cyclophosphamide, doxorubicin and prednisone dosage regimen in combination with epcoritamab and rituximab of ‘267 with lenalidomide and rituximab combination treatment in a 28-day cycle of Augment and Alliance to improve therapy options and increase the safety and efficacy of treatment for patients with follicular lymphoma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641
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