TREATMENT OF CLL

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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/06/2026 has been entered. Response to Amendment The rejection of claims 55-57 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn in view of the amendment specifying that the administration is intravenous. The rejection of claim 55 is moot in view of the cancellation of the claim. Note that inclusion in the rejection of claims 53 and 54, which were cancelled already, was a typographical error. The provision rejection of claims 49-51, 55-58 and 60-62 on the ground of nonstatutory double patenting as being unpatentable over claims 52 and 59-68 of copending Application No. 18/019,469 (‘469) in view of ClinicalTrial.gov Study NCT03400176 (cited in the IDS filed 5/17/2023), Kanagal-Shamanna et al. (Cancer, 125:559-574, 2019) is withdrawn in view Applicant’s argument that cancers CLL and DLBCL are distinct and very different, as has been their treatment (see, e.g.¸ American Cancer Society,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 58 and 60-62 is moot in view of the cancellation of the claims. Claim Objections Claim 49 is objected to because of the following informalities: there is a comma in lines 3 and 4 before “or”. Because the “or” in both cases simply joins two alternatives, clarity would be added by the removal of the comma after the first alternative before the “or”. Appropriate correction is required. 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. 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) 49-51 and 56-57 remain rejected under 35 U.S.C. 103 as being unpatentable over WO2010007082 (Heusser, cited in the IDS filed 2/20/2025) in view of US Patent 9,216,219 (Cosenza), ClinicalTrial.gov Study NCT03400176 (cited in the IDS filed 5/17/2023), Kanagal-Shamanna et al. (Cancer, 125:559-574, 2019) Dömer et al. (Ann. Rheum. Dis. 78:641–647, Mar. 2019) and as admitted by Applicant on p. 17, last paragraph for the reasons set forth in the previous Office action. WO2010007082 (Heusser) teaches the anti-BAFFR antibody MOR06654 having the variable heavy (VH) and variable light (VL) chain sequence of SEQ ID NO: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 that can be in the range of 1-10 mg/kg, including 3 or 10 mg/kg, given once every two weeks or four weeks (p. 46, last paragraph). Administration may be of the antibody in a pharmaceutical combination with another agent (p. 43, second paragraph). It is used to treat B-cell-related diseases, including B-cell chronic lymphocytic leukemia (CLL p. 51, first paragraph), a B-cell malignancy, and Sjögren’s syndrome (SS, p. 50, middle), which are characterized by increased levels of the BAFFR ligand BLyS (a.k.a. BAFF, p. 1, second and third paragraph). The antibody maybe administered as a monotherapy or with a second agent (paragraph bridging pp. 51-52). 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 that the subject being treated has a mutation conferring resistance to a BTK inhibitor or that the subject has relapsed/refractory CLL. Cosenza teaches the anti-BAFFR antibody, MOR6654 (stated as disclosed in WO 2010/007082, col. 15, lines 9-11). It may be used to treat B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (CLL), and autoimmune disorders, such as Sjögren’s syndrome (SS, col. 10, lines 55-64). An effective dose for treatment with an effective amount of the antibody includes from about 0.05 to about 10 mg/kg (col. 12, lines 25-28). The pharmaceutical composition comprising the antibody may also include an additional agent, such as a chemotherapeutic compound (col. 10, lines 50-53). Clinical Trial Study NCT03400176 teaches treatment of patients having CLL and who have failed treatment with ibrulinib, i.e., have not had a complete response or developed a resistance mutation to ibrutinib (Inclusion Criteria and Brief Summary). They are treated with VAY736 in combination with ibrutinib (Arms and Interventions). Kanagal-Shamanna et al. teaches a subset of CLL patient develops resistance to BTK inhibitor (BTKi) therapy, for example with ibrutinib (p. 559, last paragraph). “Patients with CLL who are resistant to BTKi have a poor outcome. 8,16,17 Multiple studies have shown that a substantial percentage of these patients acquire mutations that lead to reactivation of BCR signaling and resistance. These include mutations in BTK (C481) that disrupt irreversible covalent binding of BTKi to the enzyme and mutations in phospholipase C gamma 2 (PLCG2) downstream of BTK, leading to reactivation of BCR signaling. 2,9,10,14,18” (p. 560, start of first paragraph) “In the current study, using targeted deep sequencing of 29 genes associated with CLL, including targets of the B-cell receptor signaling pathway, we demonstrate the spectrum of gene mutations associated with CLL in 29 patients who experienced disease progression or RT while receiving BTKi therapy (ibrutinib or acalabrutinib) in a single institution.” (p. 560 col. 1, second paragraph) It was shown that some patients during disease progression gained a mutation in the TP53 gene (p. 562, col. 2, last paragraph). Of 11 patients tested, none had BTK or PLCG2 mutations before BTK inhibitor therapy (p. 563, col. 1, last paragraph). Median variant allelic frequence (VAF) for BTK mutations varied but was greater than or equal to 1% in those patients with a mutation (e.g., p. 565, col. 1, first paragraph). Fig. 2 shows the distribution of mutations in 29 CLL patients who developed resistance to BTK inhibitors. It is concluded (p. 570, col. 1), “Understanding the diverse mechanisms of resistance to BTK inhibitor therapy, in addition to BTK and PLCG2 mutations already reported in the literature, is essential for the rational design of therapies to treat these patients.” Dömer et al. teaches evaluating the safety and efficacy of anti-BAFFR antibody ianalumab (VAY736, Title) for treatment of primary Sjögren’s syndrome (pSS) with a single infusion of 3 or 10 mg/kg (Objectives and Methods, p. 461). Treatment was well tolerated and a positive therapeutic effect was observed (Results, p. 461). VAY736 competitively inhibits BAFF binding to BAFFR, blocking BAFFR-mediated signaling in B cells (p. 642, col. 1, second paragraph). The preliminary study is described as “the first reported use of ianalumab (VAY736), a novel biologic against the BAFF receptor (BAFF-R) on B cells with a dual mechanism of action: direct lysis of B cells and blockade of Baff-BAFF-R signalling with its receptor.” (p. 541, Key messages, third paragraph) BAFFR is only expressed in mature B cells up to lymphoblastic stage but not earlier stage pro-B and pre-B cells. The antibody was able to sustainably deplete B cells. Applicant admits on p. 17, last paragraph, that antibody ianalumab is also known as MOR6654 or VAY736. 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 ianalumab (VAY736 or MOR06654 or MOR6654) at a dose of about 3 mg/kg every two weeks or about 9 mg/kg every four weeks because these doses and administration frequencies are within the range taught by Heusser and Cosenza and close to those used by Dömer et al. for depletion of B cells, which would have been desirable if not necessary for treatment of B cell malignancies, such as CLL. 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 to be treated had failed at least one prior line of standard care therapy, such as ibrutinib, which was a common treatment for CLL, including patients having relapsed or refractory CLL, as supported by clinical trial NCT003400176 and Kanagal-Shamanna et al. It would have been obvious to have intravenous administration of antibody ianalumab as taught by Heussar, Cosenza, Dömer et al. and NCT003400176. It further would have been obvious wherein the subject being treated had a mutation conferring resistance to a BTK inhibitor, e.g., ibrutinib, because as taught by Kanagal-Shamanna et al., it would have been reasonably expected that a subject having relapsed/resistant CLL had a mutation conferring resistance to a BTK inhibitor such as ibrutinib, wherein the variant allele frequency was greater than 1% and was a BTK, PLCG2 and/or TP53 allele. Applicant’s admission is not necessary for the rejection but cited only to show that MOR06654 and VAY736 have the same sequence as the anti-BAFFR antibody of the instant claims. Applicant argues (end of p. 5 through p. 6 or REMARKS/ARGUMENTS) that independent claim 49 has been amended to require intravenous administration of ianalumab every Q2W or Q4W in a dose of 3 or 9 mg/kg. The patient receiving the treatment has relapsed/refractory CLL and a mutation conferring resistance to a BTK inhibitor. However, the application discloses significant and surprising benefits of the claimed treatment. Applicant discusses Example 2 as a clinical trial of patients having CLL who are currently taking ibrutinib. There was a high treatment response overall and eradication of ibrutinib resistance mutations at C9D1, which was unexpected and non-obvious in view of the references relied upon. The argument has been fully considered but is not persuasive. As discussed in MPEP 716.02(d) (see In re Clements, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”” The data in the specification is based on treatment that includes not only ianalumabn (VAY736), but also ibrutinib (p. 21, middle). Even though the patients in Arm B of the clinical trial had a known ibrutinib resistance mutation (p. 23, “b. Arm B:..”), it is unclear if the ianalumab altered the CLL sensitivity to ibrutinib, which would have made the inclusion of ibrutinib in the treatment impactful. As stated in the specification (p. 35, second paragraph), “Of the patients who had baseline ibrutinib resistance mutations at C9D1 assessments, 1 patient (1/6) tested negative for ibrutinib resistance mutations at C9D1.” Results for overall response rate and time to progress are not provided in the specification (p. 34, middle). Rogers et al. (Clin. Canc. Res., 31:5145-58, 2025, cited in the PTO-892 mailed 3/3/2026) reviews ClinicalTrial.gov Study NCT030400176 (cited in the IDS filed 5/17/2023) which mirrors parts of the Example 2 of the instant application, with Arm B described as having patients with ibrutinib resistance mutations in their CLL (n=5, Rogers et al., p. 5149, col. 2, third paragraph). Figure 3 of Rogers et al. shows that having an Ibrutinib resistance mutation meant the patient was more likely to have a smaller percent change in MRD ( ) Because most patients in the trial reviewed by Rogers did not have an ibrutinib mutation, Rogers says conclusions cannot be drawn to how baseline mutations influenced treatment outcomes or how the mutation status altered the treatment (p. 5156, col. 2, first full paragraph). Rogers et al. noted (p. 5156, col. 2, third full paragraph) that, “Addition of ianalumab to covalent BTKi (BTK inhibitor, e.g., ibrutinib) in the treatment of CLL holds potential. The combination could offer a safer therapeutic option with improved selectivity and reduced side effects and possibly allow some patient to discontinue BTKi after achieving uMRD, resulting in a shorter treatment duration and a lower toxicity….. [A] strategy of adding ianalumab to ibrutinib could be beneficial in deepening disease responses and improving PFS or allowing patients to stop BTKi therapy with minimal toxicity.” Rogers supports the possibility that it is the combination of ibrutinib and ianalumab that leads to the results in instant Example 2 that Applicant calls “significant and remarkable” (last paragraph of p. 6 of REMARKS). Therefore, it reasonably appears that the evidence Applicant points to for support of unexpected/significant results is not commensurate in scope with the claims, which do not require concomitant treatment with ibrutinib. The rejection is maintained for the reasons of record. Conclusion All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600. Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice . Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Claire Kaufman /Claire Kaufman/ Primary Examiner, Art Unit 1674 September 24, 2026