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 .
Claims 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 48-51 are pending and under consideration.
Claims 4-6, 8, 10-11, 13-14, 16-17, 20-21, 26, 29-31, and 35-47 are cancelled.
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.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 9/14/2023 and 7/15/2024 have been considered. It has been noted that the following references listed on the 7/15/2024 IDS are crossed off and not considered because a copy of these references was not attached.
Cite No: 10 – COIFFIER et al., “Diffuse large 8-cell lymphoma: R-CHOP failure-what to do?,” American Society of Hematology, vol 1: 366-378 (2016)
Cite No: 33 – ROSSI, D. et al., “Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome,” Br J Haematol., vol. 142(2):202-15 (2008)
Cite No: 37 – Shen, Q. et al., “Gemcitabine-oxaliplatin plus rituximab (R-GemOx) as first-line treatment in elderly patients with diffuse large B-cell lyphoma: a single-arm, open-label, phase 2 trial,” Elsevier, vol. 5(6):261-269 (2018)
Claim Rejections - 35 USC § 112
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 49-51 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 49-51 encompasses a broad genus of bispecific antibodies that are biosimilar to Epcoritamab. This claim encompasses all biosimilars of Epcoritamab.
However, there does not appear to be adequate written description in the specification as-filed of the essential structural features that provide the recited function of “biosimilar thereof” to Epcoritamab. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or U.S.C 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification (page 17, lines 8-27) describes a definition for the term "biosimilar" ( e.g., of an approved reference product/biological drug) as used herein refers to a biologic product that is similar to the reference product based on data from (a) analytical studies demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product). In some embodiments, the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. In some embodiments, the route of administration, the dosage form, and/or the strength of the biological product are the same as those of the reference product. A biosimilar can be, e.g., a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification, or formulation methods.
Additionally, the specification (page 46, lines 26-30) describes the VH and VL sequences for a limited number of biosimilar species, specifically DuoBody-CD3xCD20 as the instant application’s preferred embodiment which is used interchangeably with Epcoritamab in example 2. Other further embodiments are additionally described with various sequences comprising the VH CDR1-3 and VL CDR1-3 (see Table 9 for summary of SEQ ID NOs, page 93-96). Only one example (example 2) is provided in the specification outlining the clinical impact of lenalidomide on DuoBody-CD3xCD20 (i.e. epcoritamab) -induced T-cell activation and T-cell mediated cytotoxicity (page 72, lines 14-30) with no other examples for the other various VH and VL sequences. The specification does not reasonably convey possession of the full scope of biosimilar antibodies encompasses by the claims.
Absent a limiting definition for the term “biosimilar” the term opens up the claimed invention to encompass variants of epcoritamab. The art of Wang et al (PTO-892; Reference W) teaches that a biosiomilar of rituximab comprises an amino acid change at position 219 (A219V) of the heavy chain which is an allotype of IgG1 (Figure 3A-B). Wang et al discloses that IgG1 allotypes located in the constant region influence the pharmacokinetics through FcRn binding (Discussion). Therefore, a biosimilar does not need to exhibit the same primary amino acid sequence. Additionally, according to Mascarenhas-Melo et al (PTO-892; Reference V) biosimilars, although similar to reference products (RP), are not identical copies and should not be considered generic substitutes to the original (Mascarenhas-Melo et al, Abstract). Mascarenhas-Melo et al further state that generating a biological medicine equal to an RP is impossible due to variations in glycosylation and/or protein folding which can impact the structure and therefore function of the biosimilar (Mascarenhas-Melo et al, section 2.1 Biosimilars, paragraph 4).
As outlined in Amgen Inc. v. Sanofi, 598 U.S. 594 (2023), broad antibody genus claims must be supported either by a sufficient number of representative species or common structural features that define the genus. Disclosure of only one or a few antibody species is insufficient where the claim encompasses a large and structurally diverse genus.
Claim 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 49-51 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written. The examiner recommends narrowing the scope of “epcoritamab or biosimilar thereof” in independent claim 1 to a particular species (i.e. specific CDR or VH/VL sequences).
Indefinite Language
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 49-51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The administration step in claim 1 and claims dependent upon are unclear. It is unclear how the administration steps (i.e. weekly, biweekly, or monthly administration) are ordered and the specific number of cycles associated with the administration steps. One of ordinary skill in the art would not know when the patient will receive weekly, biweekly, and monthly administration of epcoritamab or a biosimilar thereof and for how many cycles. It is suggested that Applcant amend the claims to specifying the order and number of cycles for each administration step.
Claims 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 49-51 recite a full dose of epcoritamab or a biosimilar thereof that is 24 or 48 mg and the full dose of 24 mg or 48 mg is administered to patient weekly, biweekly, and monthly. As claim 1 is written, it is unclear as to whether epcoritamab or a biosimilar thereof is administered at only one of the full doses or if the patient could receive 24 mg epcoritamab or a biosimilar thereof at one timepoint and then 48 mg epcoritamab or a biosimilar thereof at another point in the dosage cycle. It is suggested that Applicant amend the claims to recite the exact dosages administered in the 28-day cycles.
Claim 32 recites the limitation "the bispecific antibody" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Appropriate corrections are required.
Double Patenting
Non-Statutory 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 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 34, and 48-51 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, Reference F) 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 1-3, 34, 48-51 of the instant application).
; wherein the bispecific 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 1; (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 1-3, 7, 9, 12, 15, 18-19, 22-24, 27-28, 48-49 of the instant application).
‘383 teaches epcoritamab and other biosimilars that are administered subcutaneously, rituximab is administered intravenously, and lenalidomide is administered orally (claim 1 and 49 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.
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, lines 1-2).
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 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.
Claims 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 34, 48-51 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-13, 15, 16-17, 24, and 26-27 of U.S. Patent No. 11,535,679 B2 (PTO-892; Reference A) in view of Augment (PTO-892; Reference U).
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 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 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 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, ‘391 does not teach lenalidomide treatment or dosing cycle, the motivation to combine lenalidomide with rituximab and epcoritamab,
Augment does teach the combination rituximab and lenalidomide therapy for patients with follicular lymphoma (grades 1-3a and/or Stage I-III) in 28-day cycles wherein, 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 (Augment, “Trial Design and Treatment”, paragraph 2, lines 4-5) wherein, the 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).
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 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. Combining lenalidomide with rituximab has been shown to offer clinically meaningful efficacy advantages and improve safety profiles of follicular lymphoma patients.
Regarding the recited dosing regimens, not it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed Cir. 1989) (determination of suitable dosage amounts in diuretic compositions is considered a matter of routine experimentation and therefore obvious). Given the teachings of prior art to provide a range of antibody doses in the dosage regimens, one of ordinary skill in the art at the time the invention was made would have been motivated to provide the bispecific antibody and optimize it to achieve the desired tumor killing such as CD20 expressing lymphoma cells and CD3+ T cell activation.
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.
Claims 1-3, 7, 9, 12, 15, 27-28, 34, and 49-51 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 in view of Augment (PTO-892; Reference U) and further in view of van Meerten (PTO-892; page 2, Reference U).
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 or refractory lymphoma (indolent follicular lymphoma or grade 3B) in a human subject, the method 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 1;(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,
Application ‘939 does not teach treating a patient with epcoritimab in combination with rituximab and lenalidomide in the dosage regimen of the instant application. ‘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.
However, Augment teaches a combination therapy and dosage regimen of lenalidomide and rituximab for patients with follicular lymphoma (grades 1-3a and/or Stage I-III) in 28-day cycles wherein, 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 (Augment, “Trial Design and Treatment”, paragraph 2, lines 4-5). Lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles. Augment additionally 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, lines 1-2). Finally, Augment teaches 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).
Van Meerten teaches that the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody (mAb IgG-7D8) binds to a membrane proximal epitope of CD20 which is a different epitope compared to the binding site of rituximab (Discussion, page 2069, paragraph 2, lines 13-18). When comparing mAb IgG-7D8 and rituximab in vitro, mAb IgG-7D8 activates the complement system more efficiently and induces superior cell lysis (Discussion, page 2069, paragraph 1, lines 4-6). Additionally, when both antibodies were examined in combination in vivo, rituximab was able to eliminate CD20high cells but CD20low cells escaped CDC mediated lysis by rituximab in vivo (Results, Figure 4A-D). mAb IgG-7D8 was able to eliminate CD20low expressing cells (Results, Figure 4A-D). van Meerten teaches that CD20low expressing cells may be responsible for why patients with non-Hodgkin’s lymphoma do not respond to treatment or suffer from relapse and additional therapy is required (Abstract, Background). By targeting both CD20high and CD20low expressing population of cells, this can reduce the chance of escape via antigen modulation (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 dosage cycle for patients with refractory or relapsed indolent or grade 3B follicular lymphoma of ‘939 with the combination dosing regimen of lenalidomide and rituximab of Augment and the motivation to treat patients with both rituximab and the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody of van Meerten with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine these elements according to known methods in Augment and van Meerten to yield predictable results to improve follicular lymphoma patient outcomes and prolong their response to treatment.
Regarding the duration of treatment in claim 1, Augment teaches administration of the combination therapy 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. One 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. This is also a commonly used practice in clinical trials to monitor treatment efficacy and patient safety.
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 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32, 48-51 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 (PTO-892; Reference E) in view of Augment (PTO-892; Reference U) and further in view of van Meerten (PTO-892; page 2, Reference U).
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 or a biosimilar thereof, 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; and optionally (c) ibrutinib is administered orally at a dose of 280 to 560 mg from day 1 to day 28 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, epcoritamab or biosimilar thereof is administered at a full dose of 24 mg or 48 mg, 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, epcoritamab 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 is administered on days 15 and 22; (ii) in cycles 2-3, a dose of 24 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-12, a dose of 24 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, wherein epcoritamab 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 is administered on days 15 and 22; (ii) in cycles 2-3, a dose of 24 mg is administered on days 1, 8, 15, and 22; (iii) in cycles 4-24, a dose of 24 mg is administered on day 1; (b) lenalidomide is administered orally at a dose of 20 mg/day on days 1-21 in cycles 1-24 and (c) ibrutinib is administered orally at a dose of 560 mg/day on days 1-28 in cycles 1-24, 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 (instant application's SEQ ID NOs:24-27 are 100% identical over length and sequence to reference SEQ ID NOs:24-27), wherein the method comprises administration of epcoritamab.
‘386 does not teach combination therapy or dosing regimen of lenalidomide-rituximab and epcoritamab or the motivation to combine the three therapies.
However, Augment teaches a combination therapy and dosage regimen of lenalidomide and rituximab for patients with follicular lymphoma (grades 1-3a and/or Stage I-III) in 28-day cycles wherein, 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 (Augment, “Trial Design and Treatment”, paragraph 2, lines 4-5). Lenalidomide is administered orally on days 1 to 21 at a dose of 20mg daily of the 28-day cycles. Finally, Augment teaches 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).
Van Meerten teaches that the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody (mAb IgG-7D8) binds to a membrane proximal epitope of CD20 which is a different epitope compared to the binding site of rituximab (Discussion, page 2069, paragraph 2, lines 13-18). When comparing mAb IgG-7D8 and rituximab in vitro, mAb IgG-7D8 activates the complement system more efficiently and induces superior cell lysis (Discussion, page 2069, paragraph 1, lines 4-6). Additionally, when both antibodies were examined in combination in vivo, rituximab was able to eliminate CD20high cells but CD20low cells escaped CDC mediated lysis by rituximab in vivo (Results, Figure 4A-D). mAb IgG-7D8 was able to eliminate CD20low expressing cells (Results, Figure 4A-D). van Meerten teaches that CD20low expressing cells may be responsible for why patients with non-Hodgkin’s lymphoma do not respond to treatment or suffer from relapse and additional therapy is required (Abstract, Background). By targeting both CD20high and CD20low expressing population of cells, this can reduce the chance of escape via antigen modulation (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 dosage cycle for patients with refractory or relapsed indolent or grade 3B follicular lymphoma of ‘939 with the combination dosing regimen of lenalidomide and rituximab of Augment and the motivation to treat patients with both rituximab and the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody of van Meerten with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine these elements according to known methods in Augment and van Meerten to yield predictable results to improve follicular lymphoma patient outcomes and prolong their response to treatment.
Regarding the recited dosing regimens, not it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed Cir. 1989) (determination of suitable dosage amounts in diuretic compositions is considered a matter of routine experimentation and therefore obvious). Given the teachings of prior art to provide a range of antibody doses in the dosage regimens, one of ordinary skill in the art at the time the invention was made would have been motivated to provide the bispecific antibody and optimize it to achieve the desired tumor killing such as CD20 expressing lymphoma cells and CD3+ T cell activation.
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 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 34, 49-51 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-7, 9-14, 24, 28, 40, 66 of copending Application No. US 18/833,261 (PTO-892; Reference C) in view of Augment (PTO-892; Reference U) in further view of van Meerten (PTO-892; page 2, Reference U).
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 mgis administered on days 15 and 22;(ii) in cycles 2 and 3, a dose of 24 mg or 48 mgis administered on days 1, 8, 15, and22;(iii) in cycle 4 and onwards, a dose of 24 mg or 48 is administered on day 1;(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.
Augment does teach the combination rituximab and lenalidomide therapy for patients with follicular lymphoma (grades 1-3a and/or Stage I-III) in 28-day cycles wherein, 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 (Augment, “Trial Design and Treatment”, paragraph 2, lines 4-5) wherein, the 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).
Van Meerten teaches that the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody (mAb IgG-7D8) binds to a membrane proximal epitope of CD20 which is a different epitope compared to the binding site of rituximab (Discussion, page 2069, paragraph 2, lines 13-18). When comparing mAb IgG-7D8 and rituximab in vitro, mAb IgG-7D8 activates the complement system more efficiently and induces superior cell lysis (Discussion, page 2069, paragraph 1, lines 4-6). Additionally, when both antibodies were examined in combination in vivo, rituximab was able to eliminate CD20high cells but CD20low cells escaped CDC mediated lysis by rituximab in vivo (Results, Figure 4A-D). mAb IgG-7D8 was able to eliminate CD20low expressing cells (Results, Figure 4A-D). van Meerten teaches that CD20low expressing cells may be responsible for why patients with non-Hodgkin’s lymphoma do not respond to treatment or suffer from relapse and additional therapy is required (Abstract, Background). By targeting both CD20high and CD20low expressing population of cells, this can reduce the chance of escape via antigen modulation (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-lenalidomide dosage cycle for patients with follicular lymphoma of ‘261 with the combination dosing regimen of lenalidomide and rituximab of Augment with the with the motivation to combine the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody and rituximab of van Meerten with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine these elements according to known methods in Augment and van Meerten to yield predictable results to improve follicular lymphoma patient outcomes and prolong their response to treatment.
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 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 34, 48-49, 50-51 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 (PTO-892; Reference B) in view of Augment (PTO-892; Reference U).
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 lyphoma (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 21day cycle, and(iii) a full dose of 24 or 48 mg on day 1 of each subsequent 21day cycle;(b) polatuzumab vedotin is administered intravenously at a dose of1.8 mg/kg on day 1 of each 21day cycle;(c) rituximab is administered intravenously at a dose of 375 mg/m2 on day 1 of each 21 day cycle;(d) cyclophosphamide is administered intravenously at a dose of 750 mg/m2 day 1 of each 21day cycle;(e) doxorubicin is administered intravenously at a dose of 50 mg/m2 on day 1 of each 21-day cycle; and(f) prednisone or prednisolone is administered intravenously or orally at a dose of 100 mg/day on days 1-5 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 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.
Augment does teach the combination rituximab and lenalidomide therapy for patients with follicular lymphoma (grades 1-3a and/or Stage I-III) in 28-day cycles wherein, 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 (Augment, “Trial Design and Treatment”, paragraph 2, lines 4-5) wherein, the 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).
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 dosage cycle for patients with follicular lymphoma of ‘391 with the dosing regimen and motivation to combine rituximab with lenalidomide and cycle length of Augment with reasonable expectation of success. One of ordinary skill in the art would have been motivated swap the polatuzumab vedotin, cyclophosphamide, doxorubicin and prednisone, or prednisolone of ‘261 with lenalidomide and combine rituximab-epcoritamab dosing regimen of ‘261 with the lenalidomide dosing regimen and cycle length of Augment. Combining lenalidomide with rituximab has been shown to offer clinically meaningful efficacy advantages and improve safety profiles of follicular lymphoma patients.
Regarding the recited dosing regimens, not it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed Cir. 1989) (determination of suitable dosage amounts in diuretic compositions is considered a matter of routine experimentation and therefore obvious). Given the teachings of prior art to provide a range of antibody doses in the dosage regimens, one of ordinary skill in the art at the time the invention was made would have been motivated to provide the bispecific antibody and optimize it to achieve the desired tumor killing such as CD20 expressing lymphoma cells and CD3+ T cell activation.
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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 48-51 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/223004 A1 (Saville et al, 6/12/2018, “Saville 2018”) in view of Hiemstra et al (PS1301 POTENT ANTI-TUMOR ACTIVITY OF DUOBODY®-CD3XCD20 IN PRECLINICAL MODELS IN VITRO AND IN VIVO. HemaSphere, 3:S1 (2019), “Hiemstra”) in further view of Leonard et al (AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 37, 1188-1199(2019); “Augment”) in further view of van Meerten et al (“HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20 low expressing tumor cells that resist rituximab-mediated lysis”. Haematologica. 2010 Dec; 95(12) : 2063-71; “van Meerten”).
Claim 1 recites:
A method of treating follicular lymphoma in a human subject, the method comprising administering to the subject a bispecific antibody an effective amount of a combination of epcoritamab or a biosimilar thereof, rituximab and lenalidomide in 28-day cycles, wherein
(a) epcoritamab or a 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 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;
(b) rituximab is administered intravenously at a dose of 375 mg/m2 weekly for at least one 28-day cycle;
(c) lenalidomide is administered orally at a dose of 15 mg or 20 mg once a day from day 1 to day 21 of the 28-day cycles;
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.
Saville 2018 teaches an anti-CD3xCD20 bispecific antibody, biosimilar to the bispecific antibody of the instant application, used to treat relapsed or refractory follicular lymphoma in a 28-day dosing cycle wherein on cycle 1 day 1 a priming dose is administered; an intermediate dose is administered after (i.e. different day) the priming dose; and then a full dose of about 0.1 ug/kg to about 170 ug/ kg (Saville 2018, page 31, [0099]) after the intermediate dose (i.e. different day). Weekly administration occurs between 1-9 weeks (Saville 2018, page 32, [0107]). Additionally, Saville 2018 teaches the bispecific antibody being administered biweekly at a dose of about 0.7 ug/kg to about 170 ug/kg (Saville 2018, page 30, [0101]) and a monthly administration at a dose of about 0.7 ug/kg to about 170 ug/kg (Saville 2018, page 29, [0100]). The bispecific antibody is administered until disease progression, unacceptable toxicity, or individual choice (Saville 2018, page 37, [0125]). Saville 2018 further teaches the anti-CD3xCD20 antibody is administered in combination with at least one other therapeutic agent such as an anti-cancer agent or a side-effect ameliorating agent (Saville 2018, page 39, [0138]). Saville 2018 teaches the anti-cancer agent being rituximab (Saville 2018, page 46, [0170]) and lenalidomide (Saville 2018, page 46, [0175]). Administration of the combination therapies occurs sequentially where the bispecific antibody is administered after the administration of lenalidomide and rituximab (Saville 2018, page 40, [0140]). Additionally, Saville 2018 teaches that rituximab and the anti-CD3xCD20 bispecific antibody can be used in combination as the bispecific antibody retained RTCC activity even in the presence of large excess concentration of rituximab and stimulated a similar extent of total T cell-mediated target killing efficacy (Saville 2018, page 94, [0320]). Finally, Saville 2018 teaches that there is a need to improve antibody-based therapeutics particularly with respect to enhancing their clinical efficacy (Saville, [page 1, [002]).
However, Saville 2018 does not teach the CD3xCD20 bispecific antibody (i.e. epcoritamab with VH and VL amino acid sequences of SEQ ID NO:24-25 and SEQ ID NO:26-27, respectively) of the instant invention, the dosing regimen or cycles of combination epcoritamab-rituximab-lenalidomide, the motivation to combine epcoritamab-rituximab-lenalidomide or the stage and grade of patients with follicular lymphoma of claims 1-3, 7, 9, 12, 15, 18-19, 22-25, 27-28, 32-34, and 48-51.
Hiemstra does teach DuoBody-CD3xCD20 (GEN3013, i.e. epcoritamab and biosimilars thereof of the instant invention) (see ABSS sequence alignment attached), a bispecific anti-CD3xCD20 full length IgG1 generated by controlled Fab-arm exchange with an effector function silenced Fc region.
Hiemstra further teaches that the DuoBody-CD3xCD20 bispecific antibody after subcutaneous administration 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 ~ 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 and could produce a synergistic effect when combined (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).
Augment teaches a combination therapy of lenalidomide and rituximab for patients with relapsed or refractory follicular lymphoma (grades 1-3a 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, lines 4-5). 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).
Finally, van Meerten teaches that the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody (mAb IgG-7D8) binds to a membrane proximal epitope of CD20 which is a different epitope compared to the binding site of rituximab (Discussion, page 2069, paragraph 2, lines 13-18). When comparing mAb IgG-7D8 and rituximab in vitro, mAb IgG-7D8 activates the complement system more efficiently and induces superior cell lysis (Discussion, page 2069, paragraph 1, lines 4-6). Additionally, when both antibodies were examined in combination in vivo, rituximab was able to eliminate CD20high cells but CD20low cells escaped CDC mediated lysis by rituximab in vivo (Results, Figure 4A-D). mAb IgG-7D8 was able to eliminate CD20low expressing cells (Results, Figure 4A-D). van Meerten teaches that CD20low expressing cells may be responsible for why patients with non-Hodgkin’s lymphoma do not respond to treatment or suffer from relapse and additional therapy is required (Abstract, Background). By targeting both CD20high and CD20low expressing population of cells, this can reduce the chance of escape via antigen modulation (Discussion).
It would have been prima facie obvious to one of ordinary skill, in the art as of the effective filing date, to have modified the CD3xCD20 bispecific antibody treatment and dosage regimen in combination with rituximab and lenalidomide of Saville 2018 with the DuoBody-CD3xCD20 bispecific antibody of Hiemstra with the dosing regimen of lenalidomide and rituximab of Augment with the motivation to combine the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody and rituximab of van Meerten with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Augment teaches rituximab and lenalidomide were known to be effective in treating follicular lymphoma (grades 1-3a and/or Stage I-III) by working synergistically and Hiemstra teaches the DuoBody-CD3xCD20 bispecific antibody also being effective in treating follicular lymphoma. Hiemstra and Saville 2018 teach the DuoBody-CD3xCD20 and the alternative bispecific anti-CD3xCD20 antibody induced T cell-mediated cytotoxicity which led to killing of tumor cells. Additionally, van Meerten teaches that combining the CD20 arm of the DuoBody-CD3xCD20 bispecific antibody with rituximab can target the heterogenous population of both CD20high and CD20low expressing cells in a tumor and reduce the chance of CD20low cell escape to prolong a patient’s therapeutic benefit. Therefore, it would have been obvious to combine these elements according to known methods to yield predictable results to improve follicular lymphoma patient outcomes and prolong their response to treatment.
Regarding the recited dosing regimens, not it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed Cir. 1989) (determination of suitable dosage amounts in diuretic compositions is considered a matter of routine experimentation and therefore obvious). Given the teachings of prior art to provide a range of antibody doses in the dosage regimens and the sequential administration of therapy doses, one of ordinary skill in the art at the time the invention was made would have been motivated to provide the bispecific antibody and optimize it to achieve the desired tumor killing such as CD20 expressing lymphoma cells and CD3+ T cell activation.
Regarding the duration of treatment in claim 1, Saville 2018 and Augment both teach administration of the combination therapy 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. One 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.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH ELIZABETH STEIN whose telephone number is (571)272-0093. The examiner can normally be reached M-F 8-5:30 EST.
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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641