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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/06/2027 has been entered.
Response to Amendment
The rejection of claims 67-69 and dependent claims 64-66 under 35 USC 112(b) is withdrawn in view of the amendment to the claims deleting “is to be”.
The rejection of claims 59-60 under 35 USC 112(a), written description, is withdrawn in view of the amendment specifying that the administration is intravenous and due to the cancellation of claim 59.
The rejection of claim(s) 52, 59 and 61-64 under 35 U.S.C. 102(a)(1) as being anticipated by WO2010007082 (Heusser, cited in the IDS filed 1/18/2025) is withdrawn in view of the amendment deleting the dose of 3 mg/kg and the cancellation of the claims 59 and 61.
The provision rejection of claims 52 and 59-69 on the ground of nonstatutory double patenting as being unpatentable over claim 49, 55-58, 60-62 of copending Application No. 18/019,467 (‘467) in view of Mondello et al. (The Oncologist, 21:1107-1112, 2016) and Rodig et al. (Human Pathol. 36:111-119, 2005, cited in the IDS filed 5/29/2025) is withdrawn in view of Applicant’s argument (p. 7 of REMARKS) that cancers CLL and DLBCL are distinct and very different, as has been their treatment (see, e.g., American Cancer Society, https://www.cancer.org/content/dam/CRC/PDF/Public/8720.00.pdf,pp. 39-40 and 43, 15 Feb. 2024). The rejection of claims 59 and 61 is moot in view of the cancellation of the claims.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 52, 60 and 62-70 remain rejected under 35 U.S.C. 103 as being unpatentable over WO2010007082 (Heusser, cited in the IDS filed 2/20/2025) as applied to claims 52, 59 and 61-64 above, and further in view of Mondello et al. (The Oncologist, 21:1107-1112, 2016) and Rodig et al. (Human Pathol. 36:111-119, 2005, cited in the IDS filed 5/29/2025) and as admitted by Applicant in [0055] and Table 1 for the reasons set forth in the previous Office action and as recast here to reflect the deletion of 3 mg/lg dose of ianalumab in the claims.
WO2010007082 (Heusser) teaches the anti-BAFFR antibody MOR06654 having the variable heavy (VH) and variable light (VL) chain sequence of SEQ ID NOs: 51 and 45, respectively, comprising HCDR1-3 of SEQ ID NO:3, 10, 17, and LCDR1-3 of SEQ ID NO:24, 31, 38 (p. 62, Table). The subject treated may be a human, such that antibody administration kills human B cells (p. 49, second and fourth paragraphs). Administration is intravenous in a dose of 1 to 10 mg/kg, including 5 mg/kg or 10 mg/kg, given once every two weeks or four weeks (p. 46, last paragraph). It is used to treat a B-cell neoplasm, including diffuse large cell lymphoma (p. 51, first paragraph). The antibody can be administered in combination with another active agent, such as an immunomodulating agent, e.g., leflunomide (p. 51, second paragraph). The pharmaceutical composition comprising the antibody can be administered with other therapeutic agents, such as a chemotherapeutic agent (p. 43, second paragraph). Intravenous administration to cynomolgus monkeys every 4 weeks at a dose of 20 mg/kg resulted in rapid B cell depletion, which was maintained or increased with subsequent doses (Example 3, pp. 67-68). The effect was reversible when treatment was stopped (Id.). Heusser does not teach a dosage exactly of 9 mg/kg or treatment with an immunomodulatory imide drug that is lenalidomide.
Mondello et al. teaches many patients with diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, relapse or die. Early clinical trials have shown that lenalidomide is safe and effective for treating DLBCL (Abstract:Background, and p. 1107, col. 1, first sentence). “Lenalidomide can stimulate the innate immune system, potentiate the antitumor activity of rituximab, and inhibit angiogenesis [18, 19]. These effects can be explained by the ability to inhibit tumor necrosis factor-α, vascular endothelial growth factor, and NF-kB in cancer cells [19, 20].” (p. 1108, col. 1, second full paragraph). Mondello et al. did a retrospective study of 123 patients with relapsed/refractory DLBCL treated with lenalidomide (p. 1108, col. 1, fourth full paragraph). Patients received either 15 mg/day or 25 mg/day, with both doses leading to progression-free survival (PFS) and remission in a percentage of patients (p. 1109, col. 2, third paragraph).
Rodig et al. teach that BAFF-R is a cell-surface receptor expressed in a majority of B-cell lymphoproliferative diseases, including a subset of diffuse large B-cell lymphomas (p. 1114, col. 1, second paragraph, p. 1115, col. 1, first paragraph). The expression profile of BAFF-R in normal and malignant cells “support the notion that signaling through BAFF-R can provide critical survival signals at several stages of B-cell differentiation and present BAFF-R as a candidate receptor mediating the survival of select subsets of lymphoproliferative disorders.” (p. 1115, col. 1, end of first paragraph). This includes BAFF-R expression in the majority of diffuse large B-cell lymphoma cases (78%; Table 1). It is suggested that BAFF-R could be a target for immunological therapy (p. 1118, col. 2, end of first full paragraph).
Applicant admits in [0055] that MOR6654 is disclosed in WO 2010/007082 and is also known as VAY726 or ianalumab ([0107]), having the sequences of Table 1, which is the same as that disclosed for MOR06654 of Heusser (WO 2010/007082).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have administered anti-BAFFR antibody VAY736 at a dose of 9 mg/kg every two weeks or every four weeks because this dose and administration frequencies are within the range taught by Heusser for depletion of B cells, including for B cell neoplasias, such as diffuse large B-cell lymphoma, which depletion would have been desirable if not necessary for treatment of B cell neoplasias. Further, determining the optimal dosage at a particular dosing frequency would have been obvious because “It is not inventive to discover the optimum or workable ranges by routine experimentation” In re Aller, 220, F.2d 4554, 456, (CCPA); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). “Discovery of an optimum value of a result effective variable in a known process is ordinary within the skill of the art.” In re Boesch, 617 F. 2d 272, 276 (CCPA1980). It further would have been obvious where the subject was treated with an additional therapeutic besides ianalumab, such as lenalidomide, because the immunomodulatory imide drug (IMiD) lenalidomide had been shown to be safe and effective in the treatment of DLBCL, including in a dose of 15-25 mg/day, as taught by Modello et al. Because Heusser showed that the anti-BAFFR antibody led to B-cell depletion and Modello showed effectiveness of lenalidomide in the treatment of DLBCL, which was identified by Rodig et al. as expressing BAFFR in most cases, there would have been a reasonable expectation of success.
Applicant argues (middle of p. 6) that “In spite of newer therapies being introduced for treatment of B cell malignancies, including relapsed/refractory NHL such as DLBCL and MCL, there is still a high unmet medical need for patients with B cell malignancies.” Applicant notes that 30-35% of non-Hodgin’s lymphomas (NHLs) are DLBCL and of these, about one-third will develop relapsed and/or refractory disease, representing a major cause of morbidity and mortality. This argument has been fully considered but is not persuasive. As stated in MPEP 716.04(I), “Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution.” Also, the “long-felt need must not have been satisfied by another before the instant invention and the invention must satisfy the long-felt need. There were successful treatments of DLBCL prior to the disclosure of the instant invention, including treatment with other B-cell-depleting therapeutics such as CD19-targeting therapies and standard chemotherapy (e.g., Zhao et al., Ann, Hematol. 99:1681-1699, 2020, p. 1684, col. 1, second and third paragraph cited in the IDS filed 5/9/2023). Therefore, there were solutions for treatment of DLBCL. Note that the claims do not require that the DLBCL be relapsed and/or refractory. There is no evidence that the instant invention is superior for treatment of DLBCL or for relapse/refractory DLBCL than treatments used at the time of the invention.
Applicant argues (pp. 6-7) that the examples provide significant and surprising benefits of the claimed treatment. Example 1 shows cells of a DLBCL cell line subcutaneous implanted into SCID (severe combined immunodeficiency) mice and treated with ianalumab significantly slowed tumor growth compared to vehicle control (Figs. 1A-1C). Example 2 showed the combination of ianalumab and lenalidomide enhanced ADCC induced by the antibody in vitro. Applicant discusses Example 3 as preliminary safety and activity data from a clinical trial of patients having CLL who are currently taking ibrutinib and that is combined with ianalumab. Example 4 is a phase Ib clinical trial protocol for treatment of NHLs such as DLBCL. Examples 5-6 show ianalumab can deplete healthy B cells in vivo in both mice and cynomolgus monkeys. “The data included in the application as filed go well beyond the cited references and data support the non-obviousness of the invention defined by the amended claims.” The argument has been fully considered but is not persuasive. It is maintained that in view of the prior art, it is not surprising that ianalumab exhibits excellent B-cell depleting capabilities and that these are supported by addition of lenalidomide, which has been shown to be safe and effective in the treatment of DLBCL (Modello et al., 2016). The depletion of B-cells in cynomolgus monkey shown by Heusser supports the expectation of at least slowed DLBCL tumor growth in SCID mice of Example 1. Nor are the in vitro results of instant Example 2 surprising, which are reported ([0115]) as showing that, “Addition of lenalidomide generally demonstrated enhanced VAY736-dependent specific lysis of SUDLH4 cells,” in view of the Modello et al. The specification discusses ([0119]), “Without being bound by theory, it is believed that this observation may be due to the positive effect lenalidomide has on T cell IL2 secretion; IL2 would in turn provide positive activation signals for NK cells. In conclusion, these in vitro studies support the combination of VAY736 and lenalidomide for treating B-cell malignancies, such as DLBCL.” The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 195 USPQ 430, 433 (CCPA 1977). Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) MPEP § 716.2 It is not agreed that the properties differ from the prior art to such an extent to be considered unexpected. Example 3 is directed to treatment of CLL, which Applicant argues (p. 7, fourth paragraph, of REMARKS) is a distinct B-cell malignancy from DLBCL “due to fundamental differences in cellular morphology, biology, and clinical behavior.” “As can be seen from the cited references, there is very little overlap between treatments for indolent CLL and the aggressive DBLCL diseases.” (ibid., second to last paragraph) Example 4 is a protocol for a dose escalation study (e.g., [0136]) with no data. The showing in Examples 5 and 6 that ianalumab depletes healthy B cells in vivo is not an advance over or surprising in view of the prior art of record. As stated in the rejection (see previous Office action p. 10 first paragraph), Heusser taught that, “Intravenous administration to cynomolgus monkeys every 4 weeks at a dose of 20 mg/kg resulted in rapid B cell depletion, which was maintained or increased with subsequent doses (Example 3, pp. 67-68). The effect was reversible when treatment was stopped (Id.).” It is not agreed that the properties differ from the prior art to such an extent to be considered unexpected or to provide significant and surprising benefits over the prior art. The rejection is maintained.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
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