DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The rejection of claims 53-60 and 64-66 and dependent claims under 35 USC 112(b) is withdrawn in view of the amendment to claims 55-58 and 60 stating the product is administered and the cancellation of claims 53-54, 59 and 64-66.
The rejection of claims 61-66 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, for reciting new matter is moot in view of the cancellation of the claims.
The rejection of claims 53, 54, and 64-66 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, related respectively to route of administration and lenalidomide administration is moot in view of the cancellation of the claims. Claims 55-57 remain rejected.
The rejection of claim(s) 49, 53-55 and 59 under 35 U.S.C. 102(a)(1) as being anticipated by US Patent 8,524,672 B2 is withdrawn in view of the limitation of the claims to ianalumab and cancellation of claims.
The rejection of claim(s) 49-52, 67 and 68 under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrial.gov Study NCT03400176 (cited in the IDS filed 5/17/2023) and in light of Applicant’s admission in the specification on p. 17, last paragraph, and Table 1, is withdrawn in view of the amendment to the claims adding the administered dose of ianalumab is about 3 mg/kg or about 9 mg/kg and cancelation of claims. The reference is generic to the species of method now claimed.
The rejection of claim(s) 49-52 and 67-69 under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrial.gov Study NCT021137889 (02/28/2018, https://clinicaltrials.gov/study/NCT02137889?intr=mor6654%20OR%20VAY736%20OR%20ianalumab&rank=14&tab=table) and in light of Applicant’s admission in the specification on p. 17, last paragraph, Table 1, and p. 28, middle, is withdrawn in view of the amendment to the claims adding the administered dose of ianalumab is about 3 mg/kg or about 9 mg/kg and cancelation of claims. The reference is generic to the species of method now claimed.
The rejection of claim(s) 49-55 and 58-60 under 35 U.S.C. 102(a)(1) as being anticipated by WO2010007082 (Heusser, cited in the IDS filed 2/20/2025) is withdrawn in view of the amendment to the claims requiring the subject has a mutation conferring resistance to a Bruton tyrosine kinase (BTK) inhibitor and cancelation of claims.
The provisional rejection of claim(s) 49-69 under 35 U.S.C. 101 as claiming the same invention as that of claims 52-72 of copending Application No. 18/019,469 (reference application) is withdrawn in view of the amendment limiting the instant claims to treating a subject having chronic lymphocytic leukemia (CLL) and the requirement for the subject to have a mutation conferring resistance to a BTIK inhibitor and the claims of the copending application to having diffuse large B-cell lymphoma (DLBCL). However, a new provisional rejection appears below.
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Claims Status
Claims 49-51, 55-58 and 60-62 are currently amended and under examination. Claims 52-54, 59 and 63-69 are cancelled.
Claim Objection
Claim 50 is objected to because of the following informalities: in the second to last line “frequence” should be --frequency--. Appropriate correction is required.
Improper Claim Amendment
Claims 53, 54 and 63-69 were improperly amended as set forth immediately below. Appropriate correction is required.
The amendment to the claims filed on 11/20/2025 does not comply with the requirements of 37 CFR 1.121(c) because canceled claims cannot be completely lined through (see below and MPEP 714(II)(C). Amendments to the claims filed on or after July 30, 2003, must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.”
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number.
Appropriate correction is required.
Specification
Title
The title of the invention remains not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: Method of Treating Chronic Lymphocytic Leukemia with a BAFFR Antibody.
The disclosure remains objected to because of the following informalities: The first occurrence of an abbreviation should be accompanied by its meaning: in the “Field of Invention” paragraph on p. 1, the terms “BAFFR”, BTK and “CLL” should be accompanied by their full name.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claims 53-57 remain 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, for the reasons set forth in the previous Office action and as recast here to address the limiting of the anti-BAFFR antibody to ianlumab at one of two particular doses and removal of additional administration of lenalidomide.
The claims are drawn to administration of anti-BAFFR antibody ianalumab. No route of administration is recited in these claims. However, the claims require one of two particular dosages of drug and frequency of administration. Claim 58 specifies the antibody administration is intravenous (IV). The specification states (p. 10, first paragraph), “[T]he route and/or mode of administration will vary depending upon the desired results, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.” (See also end of p. 9) The specification further recites that the anti-BAFFR antibody was or will be administered intravenously (p. 27, middle, and p. 33, middle). This intravenous route of administration for ianalumab (VAY736, p. 8, ⁋2) agrees with the prior art [e.g., ClinicalTrials.gov Study NCT021137889 (02/28/2018, https://clinicaltrials.gov/study/NCT02137889?intr=mor6654%20OR%20VAY736%20OR%20ianalumab&rank=14&tab=table), which teaches treatment of patients having relapsed or refractory CLL (chronic lymphocytic leukemia) by intravenous administration of antibody VAY736 (Brief and Official Title)].
The route of administration influences what is an effective dose for any particular therapeutic and treatment. The frequency of administration is also related to dose. Pitiot et al. (Antibodies, 11(3):56, 2022, cited in the PTO-892 mailed 8/26/2025) reviewed antibody literature published before April 1, 2022, to describe the state of the art of antibody (Ab) administration. Each route has its limitations. For example, while the advantages of and advancements related to subcutaneous (SC) administration of antibodies are discussed, it is also stated that bioavailability of SC delivered antibodies is difficult to predict. “Advances in preclinical models would be necessary to investigate the fate of Abs at the SC injection site and their diffusion into the blood/lymphatic compartment…. Nevertheless, as no in vitro model is yet accurate enough, the pharmacokinetics of Abs still relies on in vivo studies…. ⁋Formulating Abs for the SC route remains challenging…” (p. 7/25, section 2.1.4) Pitiot et al. discusses (p. 7/25, section 2.2.1) that intramuscular (IM) injection is often used for vaccines but rarely considered for Abs. IM injection requires a more concentrated product than IV administration. While a small number of IM administered antibodies are in phase 3 clinical trials, none have yet been approved by the FDA and/or EMA (Table 3). As to pulmonary administration, it was determined (end of p. 12/25), “Abs administration through systemic routes led to a low bioavailability in the airway compartment [84,85]. This may limit the efficacy of Abs to treat respiratory diseases, if their target antigen primarily acts within the respiratory organ, while exposing the rest of the body to potential side effects [86].” Issues for administration by inhalation include (p. 13/25, first paragraph), “Abs aerosolization is generally difficult since they are highly sensitive to mechanical, thermal, and physical stresses occurring during aerosol generation.” Also, only a single antibody is being developed for nasal inhalation and is not yet approved (p. 13/25, last sentence). Pitiot et al. concludes for inhalation routes (p. 14/25, end of first paragraph), “However, groundwork is still necessary to optimize Abs design and formulation, inhalation devices, as well as improving our knowledge of the physical and biological barriers that may impair the therapeutic response to inhaled Abs.” For localized intratumoral injection, a small number of antibodies, including checkpoint inhibitor antibodies such as pembrolizumab are in phase 2 and 3 clinical trials (Table 7); however, preclinical studies showed that a significantly lower amount of Ab injected intratumorally compared to IV was effective (bottom of p. 14/25), which suggests an IV dosage would not be appropriate for intra-tumoral injection. “For now, clinical validation of intratumoral delivery of Abs is still in the preliminary stages. Further work is needed to optimize the dosage and the formulation according to the type and the stage of the tumor lesion.” (p. 15/25, second paragraph of 2.5.3) Oral administration of antibodies has challenges, including harsh pH conditions and presence of proteases, such that less than 20% of orally administered antibodies have been found to be immunologically active after passage through the gastrointestinal tract, requiring large amounts (p. 18/25, last paragraph, and p. 19/25, first paragraph). Topical administration of Abs has shown low skin penetration, thereby requiring a high dose (p. 19/25, last paragraph). Therefore, no route for these recited doses and also frequencies (claims 55-57) of ianalumab antibody other than IV, as supported by both the instant specification and prior art, meets the requirements for written description under 35 USC 112(a).
Applicant argues (pp. 6-7 of REMARKS) that difficulty in optimization of dosing and administration route is not relevant to possession of the invention, which supports written description. “While optimization of dose, frequency, and route could provide improved efficacy, a skilled person can reasonably conclude that a treatment as claimed would meet the definition of treatment as disclosed and defined in the specification.” The argument has been fully considered but is not persuasive. The scope of claims 55-57 are different from the other claims because these claims not only require treating a subject having relapsed/refractory chronic lymphocytic leukemia (R CLL) by administering ianalumab, but doing so within a range of doses (3 or 9 mg/kg as amended in independent claim 49) and with a particular dosage regimen of once every 2 weeks or 4 weeks. This limits the amount that is administered, unlike in claim 49 which does not specify frequency of dose (e.g., administration could be every hour for 5 days). The specification does not support treatment of R CLL at this dose and frequency when the administration route is anything other than intravenous (IV). Contrary to Applicant’s assertion, it does not appear the inventors were in possession of treatment of R CLL under the claimed regimen wherein administration is by other than by intravenous administration. The claims require treatment. There is no basis in the specification for treatment as claimed in claims 55-57 where the route is not by intravenous injection or infusion. Based on the prior art use of VAY73 (ianalumab) by intravenous administration and general knowledge of antibody efficacy by different administration routes as reviewed by the post-filing reference Pitiot et al. (see rejection), the skilled artisan would not have recognized that the inventors were in possession of the full scope of the invention. The prior art as a whole supports only intravenous administration of ianalumab for treatment as exemplified by WO 2010/007082 (Example 3 of peripheral B cell depletion in cynomolgus monkeys; cited in the IDS filed 2/20/2025), ClinicalTrial.gov Study NCT030400176* [cited in the IDS filed 5/17/2023, which as reviewed by Rogers et al. (Clin. Canc. Res. 31:5145–58, 2025, attached) used ianalumab to treat patients with R CLL by intravenous administration (Abstract:Purpose and Patients and Methods sections)], and ClinicalTrial.gov Study NCT02137889 v.8 (cited in the PTO-892 mailed 8/26/2025, treatment of R CLL by intravenous ianalumab, see Official Title). Even use of ianalumab for treatment of a different disease, Sjögren’s syndrome, was administered by IV infusion (Dömer et al., Ann. Rheum. Dis. 78:641-647, 2019, cited in the IDS filed 8/26/2025, Abstract:Method). *N.b., NCT03400176 (see “Unique Protocol ID”) is study CVAY736Y2102 referred to in Example 2 of the instant specification. The specification states VAY736 was administered intravenously (section 2.1.5). There is no written description for other routes that the skilled artisan could readily envision as meeting the limitations of the claims for treatment of R CLL with the species of prescribed dose and administration frequency.
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) 49-69 is/are 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.
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 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 is taught, resulting 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 develop resistance to BTK inhibitor 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 Heussar 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.
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 49-51, 55-58 and 60-62 are provisionally rejected 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) and as defined in the instant specification on p. 17, last paragraph.
Both applications claim a method of treating a subject having a B-cell malignancy by administering ianalumab at a dose of 3 mg/kg or 9 mg/kg, including wherein 3 mg/kg is administered once every two weeks or 9 mg/kg once every four weeks (instant claims 49, 55-57, and claims 52, 59-60 and 62 of ‘469). The administration is intravenous (instant claim 58 and claim 61 of ‘469). The administration may comprise an additional agent(s), including wherein the ianalumab is in a pharmaceutical combination therewith (instant claims 60-62, and claims 63-68). The copending application does not claim wherein the disease is relapsed/refractory CLL (instant independent claim 49), but instead is drawn to DLBCL. The copending application does not claim wherein the subject has a mutation conferring resistance to a BTK inhibitor (instant independent claim 49 and dependent claims 50-51).
NCT03400176 teaches treatment of patients having CLL and who have failed treatment with ibrutinib, 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 that CLL is a neoplastic B cell-mediated disease (p. 559, first full paragraph of Introduction). A subset of CLL patient develop resistance to BTK inhibitor 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) They showed 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.”
The instant specification defines antibody ianalumab as VAY736.
It would have been obvious to treat a subject having CLL instead of DLBCL with the same antibody and dosage as in ‘469 because both are B-cell neoplastic-based diseases. It further would have been obvious to use ianalumab for treatment of CLL in view of the clinical trial doing so, and optionally include an additional agent to facilitate treatment, e.g., ibrutinib as taught by the clinical trial and Kanagal-Shamanna et al. 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.
This is a provisional nonstatutory double patenting rejection.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Sedlarikova et al. (Front. Oncol. 10:894, June 2020) teaches that for CLL patients who have taken ibrutinib, 80% have ibrutinib failure and acquire mutations in BTK and PLCG2 genes (p. 2, col. 2). Ibrutinib is a BTK inhibitor (p. 2, col. 1, start of first full paragraph). Table 1 shows the frequency of CLL patients with ibrutinib resistance-associated mutations and their kind, as well as variant allele frequency, which is greater than 1% is most cases. TP53 mutations are also found in CLL patients (p. 4, paragraph bridging cols. 1-2). Sedlarikova et al. shows the state of the art as it relates to mutations conferring resistance to BTK inhibitors in CLL patients. This reference is cumulative with Kanagal-Shamanna et al. (Cancer, 2019, relied upon above).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
February 26, 2026