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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 15, 2026 has been entered.
Application Status
The amended claims filed on January 15, 2026 with the Request for Continued Examination are entered. Claims 1-2, 80, and 82 are amended.
Claims 1-2, 19, 23, 31, 33, 38, 50, 52-53, 55, 69, 72-78, 80, and 82 are pending and under examination herein.
Applicant’s arguments filed January 15, 2026, including Exhibits 1 (Crump), 2 (Kim), and 3 (Bartlett), have been considered by the Examiner.
WITHDRAWN REJECTIONS
The prior grounds of rejection of claims 1-2, 33, 38, 55, and 72-78 under 35 U.S.C. § 103 as being unpatentable over Montanari (ClinicalTrials.gov ID NCT04138875, Record History Version 1 submitted 23 October 2019) in view of Witzig (Ann Oncol 2015 26(8): 1667-77), and of claims 19, 23, 31, 50, 52-53, 69, 80, and 82 further in view of Oflazoglu (U.S. Patent No. 8,263,083), Leuscher (U.S. Patent No. 9,492,563), Niitsu (Clinical Cancer Res (2004) 10(12 Patient 1): 4077-4082), or Chao (WO 2019/157432 A1), are withdrawn based on reconsideration of the claims as presently amended.
NEW REJECTIONS BASED ON CLAIM AMENDMENTS
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.
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 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.
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.
(1)
Claims 1, 19, 23, 31, 33, 38, 50, 52-53, 55, and 72-78 are rejected under 35 U.S.C. 103 as being unpatentable over Witzig (Annals of Oncology (2015) 26(8): 1667-1677; cited in PTO-892 mailed May 19, 2025) in view of Ward (Blood (2015) 126(23): 3988, Abstract) and NCT02086604 (ClinicalTrials.gov ID NCT02086604, “Brentuximab Vedotin and Lenalidomide for Relapsed or Refractory Diffuse Large B-cell Lymphoma”, Study Version V14 dated May 31, 2018), as evidenced by Leuschner (U.S. Patent No. 9,492,563; cited in PTO-892 mailed May 19, 2025) and Oflazoglu (U.S. Patent No. 8,263,083; cited in PTO-892 mailed May 19, 2025).
Witzig reviews the use of lenalidomide (Revlimid®), an oral non-chemotherapy immunomodulator, in relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) (e.g., Abstract). Witzig teaches that treatment with lenalidomide monotherapy (administered orally at 25 mg/day on days 1-21 of 28-day cycles) for aggressive r/r NHL resulted in an overall response rate (ORR) of about 35% and a progression-free survival (PFS) of about 3.7-4.0 months (e.g., pages 1668-1669; Table 1, see NHL-002 and NHL-003). Pertinent to claims 1, 33, 50, 52-531, and 72-78, Witzig further teaches that the combination of lenalidomide (20 mg/day, d1-d21/28) with rituximab (375 mg/m2 I.V.; i.e., an anti-CD20 antibody), termed “R2”, led to a 57% ORR, 36% complete response (CR), and 11.1-month median PFS in r/r mantle cell lymphoma (MCL) (e.g., pages 1669-1670; Table 2). For r/r DLBCL or follicular lymphoma (FL), R2 treatment showed a 33% ORR and median PFS of 3.7 months (e.g., pages 1670-1671; Table 2). Witzig notes that R2 combination treatment is generally well tolerated, “with hematologic [adverse event] rates consistent with those for single-agent therapy” (page 1672).
However, Witzig does not expressly recite a method for treating r/r NHL in a subject that consists essentially of administering to the subject lenalidomide, an anti-CD20 antibody (e.g., rituximab), and an anti-CD30 antibody-drug conjugate that comprises an anti-CD30 antibody conjugated to a monomethyl auristatin.
Ward describes an ongoing phase I clinical trial (NCT02086604) investigating the combination of brentuximab vedotin (an antibody-drug conjugate that combines an anti-CD30 antibody and MMAE)2 and lenalidomide for treatment of r/r DLBCL, relevant to claims 1-2, 19, 23, and 31. Ward teaches that as when used as a monotherapy for r/r DLBCL, brentuximab vedotin has a response rate (RR) of 44% (17% CR) in CD30+ r/r DLBCL while lenalidomide has a 27% RR (Background). Ward teaches that for the 17 patients have been analyzed, the overall RR for the combination of brentuximab vedotin and lenalidomide was 53%, including 41% (7 patients) with a complete response (CR) (Results), relevant to claims 72-73. Pertinent to claims 33 and 38, Ward teaches that maximum tolerated doses were 1.2 mg/kg brentuximab vedotin Q21d and continuous 20 mg/d lenalidomide. The study record (NCT02086604, V14) for the clinical trial further teaches that brentuximab vedotin was administered intravenously on Day 1 of every 21-day cycle, while 20 mg lenalidomide was administered orally on days 1-21 of each 21-day cycle (Arms and Interventions).
In view of these teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination method of treatment for r/r NHL described by Witzig, consisting essentially of administering to a subject in need thereof lenalidomide and an anti-CD20 antibody (rituximab), by further administering an anti-CD30 antibody-drug conjugate (brentuximab vedotin). The skilled artisan would have been motivated to do so because Witzig teaches that the combination of rituximab and lenalidomide increases ORR for selected populations with r/r NHL, and Ward further provides that the combination of brentuximab vedotin and lenalidomide in a patient subpopulation with r/r NHL further increases response rates relative to monotherapy alone. There would have been a reasonable expectation of success because it is prima facie obvious to combine two (or more) compositions each of which are taught in the art to be useful for the same purpose, to form a third composition to be used for the very same purpose. As set forth in MPEP § 2144.06(I), “[T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
(2)
Claims 1 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Witzig (Annals of Oncology (2015) 26(8): 1667-1677; supra) in view of Ward (Blood (2015) 126(23): 3988, Abstract; supra) and NCT02086604 (ClinicalTrials.gov ID NCT02086604, Study Version V14 dated May 31, 2018; supra), as evidenced by Leuschner (U.S. Patent No. 9,492,563; supra) and Oflazoglu (U.S. Patent No. 8,263,083; supra), as applied to claims 1, 19, 23, 31, 33, 38, 50, 52-53, 55, and 72-78 above, and further in view of Grillo-Lopez (US 2003/0026804 A1).
The teachings of Witzig are recited in the 35 U.S.C. § 103 rejection above.
However, Witzig does not expressly teach a treatment method for r/r NHL that further comprises the step of administering to the subject granulocyte colony stimulating factor (G-CSF).
Grillo-Lopez describes combination therapeutic regimens for treatment of B-cell lymphomas that comprise anti-CD20 antibodies (e.g., rituximab), based on the finding that a beneficial synergistic effect is achieved when an anti-CD20 antibody is administered in combination with cytokines (e.g., Abstract; ¶ 0002-0008). In one embodiment, Grillo-Lopez teaches administering an anti-CD20 antibody (rituximab) in combination with G-CSF (e.g., ¶ 0015-0016, 0089-0091). Grillo-Lopez teaches that early results in nine patients indicate that this combination yielded an ORR of 67% (44% CR, 22% PR), and that minor toxicity was observed in eight of the nine patients, in line with rituximab treatment alone (¶ 0089-0091).
In view of the further teachings of Grillo-Lopez, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the triple combination treatment method collectively taught by Witzig, Ward, and NCT02086604, by further administering to the subject G-CSF. The skilled artisan would have been motivated to do so because Grillo-Lopez teaches that the addition of G-CSF to a regimen including rituximab has a synergic effect on ORR for patients with low-grade NHL. There would have been a reasonable expectation of success because the combination is shown to be safe in this patient population, having similar toxicity to rituximab treatment alone (as taught by Grillo-Lopez).
(3)
Claims 1, 80, and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Witzig (Annals of Oncology (2015) 26(8): 1667-1677; supra) in view of Ward (Blood (2015) 126(23): 3988, Abstract; supra) and NCT02086604 (ClinicalTrials.gov ID NCT02086604, Study Version V14 dated May 31, 2018; supra), as evidenced by Leuschner (U.S. Patent No. 9,492,563; supra) and Oflazoglu (U.S. Patent No. 8,263,083; supra), as applied to claims 1, 19, 23, 31, 33, 38, 50, 52-53, 55, and 72-78 above, and further in view of Fan (US 2017/0283446 A1).
The teachings of Witzig are recited in the 35 U.S.C. § 103 rejection above.
However, Witzig does not expressly teach a treatment method for r/r NHL that further comprises the step of administering to the subject granulocyte colony stimulating factor (G-CSF).
Fan discloses non-peptide based small organic molecule modulators of the C5a receptor (C5aR) having utility in the treatment of cancers such as DLBCL and non-Hodgkin’s lymphoma (e.g., Abstract; ¶ 0007-0025, 0118-0119). Fan discloses pharmaceutical compositions comprising the C5aR modulators of the invention in combination with one or more additional therapeutic agents, e.g., rituximab and brentuximab vedotin (e.g., ¶ 0079-0102), relevant to claim 80. Fan further discloses kits comprising one or more pharmaceutical compositions and instructions for use thereof (¶ 0139-0141), relevant to claim 82.
In view of the further teachings of Fan, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a pharmaceutical composition or kit consisting essentially of lenalidomide, an anti-CD30 ADC such as brentuximab vedotin, and an anti-CD20 antibody such as rituximab. The skilled artisan would have been motivated to do so because packaging a combination of therapeutic agents into a single composition or kit would enable healthcare practitioners to administer the therapies to the patient with greater ease, increased convenience, and decreased opportunity for human error. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the use of a combination pharmaceutical composition or kit constitutes use of a known technique to improve similar products in the same way, and furthermore, the pharmaceutical compositions and kits disclosed by Fan similarly comprise or consist of a small molecule drug, an anti-CD20 antibody, and an anti-CD30 antibody-drug conjugate as presently claimed.
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Jacobsen (Blood (2015) 125(9): 1394-1402; cited in IDS) investigated the efficacy of brentuximab vedotin in combination with rituximab in several NHL subtypes including DLBCL (e.g., Abstract). Jacobsen recites that “the combination of brentuximab vedotin with rituximab was generally well tolerated and had activity similar to brentuximab vedotin alone” (Abstract).
Allowable Subject Matter
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant has presented arguments and post-filing Exhibits showing that the treatment combination consisting essentially of lenalidomide, brentuximab vedotin (i.e., an anti-CD30 antibody-drug conjugate), and rituximab (i.e., an anti-CD20 antibody) results in a significantly greater objective response rate of 64% in relapsed/refractory DLBCL patients. These arguments regarding unexpected results, considered together with the teachings of the prior art, are considered persuasive. Witzig (supra) teaches that for DLBCL, the combination of lenalidomide and rituximab achieves a similar ORR (33%) as that observed with lenalidomide alone (35%). Jacobsen (supra) further teaches that the combination of brentuximab vedotin with rituximab had similar activity to that of brentuximab vedotin alone. Thus, Witzig and Jacobsen appear to teach that there is not a synergistic effect observed from combining lenalidomide and rituximab or combining brentuximab vedotin and rituximab in the treatment of relapsed/refractory DLBCL.
Conclusion
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
1 As evidenced by Leuschner (Table C, col 19-20), the heavy chain variable region (VH) and light chain variable region (VL) of rituximab (Rituxan®), comprise the amino acid sequences of SEQ ID NOs: 51 and 50, respectively, which share 100% sequence identity with instant SEQ ID NOs: 17 and 18, respectively, and the respective CDR sequences thereof. See also sequence alignments in non-final Office action mailed May 19, 2025.
2 As evidenced by Oflazoglu (e.g., col 29-30, 68), brentuximab vedotin (also known in the art as “cAC10-vcMMAE”) comprises an anti-CD30 antibody portion comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 2 (which shares 100% sequence identity to instant SEQ ID NO: 7, with corresponding CDRs matching the amino acid sequences of instant SEQ ID NOs: 1-3) and a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 10 (which shares 100% sequence identity to instant SEQ ID NO: 8, with corresponding CDRs matching instant SEQ ID NOs: 4-6). See also sequence alignments in non-final Office action mailed May 19, 2025.
Prosecution Insights