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 .
DETAILED ACTION
Claims 1-3, 8, 11, 14, 16, 17, 20, 25, 26, 29-31, 33-35, 39-43, and 48 are pending.
Claims 65 and 66 are canceled.
Claims 1-3 are amended.
Claims 1-3, 8, 11, 14, 16, 17, 20, 25, 26, 29-31, 33-35, 39-43, and 48 are under examination on the merits.
Rejections Withdrawn
35 U.S.C. 112(b)
The rejection of claims 1-3, 11, 14, 16, 17, 20, 25, 26, 39-43, and 48 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of the claim amendments, dated 02/05/2026. Claim 65 is canceled.
Rejections Maintained
35 U.S.C. 103
The rejection of claims 1-3, 8, 11, 14, 16, 17, 20, 25, 26, 29-31, 33-35, 39, 40, 43, and 48 under 35 U.S.C. 103 as being unpatentable over Hutchings et al. (Lancet, 398: 1157- 1169, 2021) and Pordehnad et al. (WO 2016/007854, international publication date: 01/14/2014) is maintained. Claims 65 and 66 are canceled.
The rejection of claims 41 and 42 under 35 U.S.C. 103 as being unpatentable over Hutchings et al. (Lancet, 398: 1157-1169, 2021) and Pordehnad et al. (WO 2016/007854, international publication date: 01/14/2014), as applied to claims 1-3, 8, 11, 14, 16, 17, 20, 25, 26, 29-31, 33-35, 39, 40, 43, and 48, and further in view of Trede (WO 2020/102770, international publication date: 05/22/2020) is maintained.
Nonstatutory Double Patenting
The nonstatutory double patenting rejections of record are maintained. Applicant has requested that these rejections remain in abeyance at this point in prosecution.
Response to Arguments
In Applicant Arguments, dated 02/05/2026, Applicant asserts that “[n]othing in the teachings of Hutchings would have motivated the skilled artisan to treat patients with lenalidomide (and optionally ibrutinib), let alone suggest that these agents can be administered in combination with epcoritamab with a reasonable expectation of success… Pordehnad fails to cure the deficiencies of Hutchings… Nowhere does Pordehnad teach or suggest that lenalidomide can be used in combination with a bispecific CD3xCD20 antibody, much less epcoritamab.”
These arguments have been fully considered but are not deemed persuasive. As stated at p. 5 of the Non-Final Rejection, dated 11/05/2025, Hutchings et al. teach the treatment of B cell non-Hodgkin lymphoma, specifically diffuse large B cell lymphoma (DLBCL), using epcoritamab, which is a CD3/CD20 bispecific antibody that induces T cell cytotoxicity against CD20+ B cells, see Abstract. Furthermore Pordehnad et al. teach that lenalidomide and ibrutinib synergistically kill DLBCL cell. See [00201]. As such one of ordinary skill in the art would have been motivated to modify the invention of Hutchings et al. to comprise the administration of lenalidomide and ibrutinib, because there would have been a reasonable expectation that the resultant invention is effective in treating DLBCL by combining the administration of multiple medicaments that are known to treat DLBCL.
Applicant further points to the unpredictability associated with combination therapies that utilize cancer drugs. “As discussed in a review article by Henricks et al. (Cancer Treatment Reviews 41:859-867, 2015; Appendix A), many combination therapies containing antibodies led to detrimental effects, which were thought to be due to (1) excessive toxicity; (2) negative interaction between different signaling pathways; and (3) off-target pharmacodynamic interaction (see, page 864, 2ⁿᵈ column). The authors conclude that even when antibodies are theoretically suitable for use in combination therapy, the efficacy of particular combinations is not predictable… Given this backdrop, nothing within the combined teachings of Hutchings and Pordehnad would have motivated the skilled artisan to modify the teachings of these references in the manner asserted by the Office.”
These arguments have been fully considered but are not deemed persuasive. One of ordinary skill in the art would appreciate that there is some measure of unpredictability when treating patients with cancer drug combination therapies. Furthermore it is difficult, in the absence of empirical determination, to be certain that a particular cancer drug combination will provide a safe, yet effective, therapeutic regimen; however a finding of obviousness does not require a certainty of success - a finding of obviousness only requires that one of ordinary skill in the art have a reasonable expectation of success. In the instant case, given the teachings of the prior art, one of ordinary skill in the art would have been motivated to motivated to modify the invention of Hutchings et al. to comprise the administration of lenalidomide and ibrutinib, because there would have been a reasonable expectation that the resultant invention is effective in treating DLBCL by combining the administration of multiple medicaments that are known to treat DLBCL.
Applicant further asserts that “the presently claimed dosage regimen cannot be considered a result of ‘routine optimization.’ For instance, the Office has not provided any support that the prior art suggested the desirability or need for the presently claimed dosage regimen (e.g., priming dose on day 1, intermediate dose on day 8, and full dose on days 15 and 22 of epcoritamab for cycle 1, once a week administration of epcoritamab for cycles 2-3, and once every 4 weeks of epcoritamab for cycles 4+, in combination with lenalidomide from day 1-day 21 of each cycle and optionally ibrutinib from day 1 to day 28 of each cycle), nor has the Office demonstrated, without the benefit of hindsight as discussed above, that the skilled artisan would have combined the teachings of Hutchings and Pordehnad to achieve the claimed method with a reasonable expectation of success. Nor could it have been predicted, reasonably expected, or extrapolated from the combined teachings of Hutchings and Pordehnad that the presently claimed dosage regimen of epcoritamab, lenalidomide, and optionally ibrutinib would be both safe and effective. A general unsupported assertion that the claimed invention was the result of ‘routine optimization’ is insufficient to establish obviousness…”
These arguments have been fully considered but are not deemed persuasive. As indicated in the Non-Final Rejection, at p. 1160, Hutchings et al. teach that “[t]he step-up dosing approach was intended to mitigate the severity of CRS [cytokine release syndrome]. Patients received the priming dose of subcutaneous epcoritamab on day 1 of cycle 1 and an intermediate dose (introduced at the 1·5 mg full dose level to bridge the widening gap between the priming dose and the full dose) on day 8 of cycle 1. Subcutaneous epcoritamab (1 mL) was administered in 28-day cycles until disease progression or unacceptable toxicity, according to the following schedule: weekly dosing in cycles 1 and 2 (days 1, 8, 15, 22), dosing every 2 weeks in cycles 3-6 (days 1, 15), and dosing every 4 weeks from cycle 7 onward…” At the Abstract, Hutchings et al. teach that “[o]verall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45–86), with 45% achieving a complete response at full doses of 12–60 mg. At 48 mg, the overall response rate was 88% (47–100), with 38% achieving a complete response.” As such Hutchings et al. teach a method of treating DLBCL in a human subject, the method comprising administering epcoritamab to a subject in a 28-day cycle, wherein epcoritamab is administered as a priming dose on day 1 of said 28-day cycle, an intermediate dose on day 8 of said 28-day cycle, and a full dose (48 mg) following the intermediate dose, wherein epcoritamab is administered at days 1, 8, 15, and 22 of said 28-day cycle, and wherein multiple 28-day cycles are administered to the subject until disease progression or unacceptable toxicity occurs. Furthermore Hutchings et al. teach dose ranges of between 12-60 mg epicoritamab and specifically teaches a 48 mg dose. Hutchings et al. teach weekly dosing cycles of days 1, 8, 15, 22. Given that 1) Hutchings et al. teach the claimed priming, intermediate, and full dose as a means of managing toxicity (CRS) and 2) Hutchings et al. teach weekly dosing cycles of days 1, 8, 15, 22, hindsight reasoning is not required to arrive at the claimed invention in view of the cited references. Furthermore one of ordinary skill in the art would have been motivated to determine optimal doses of epicoritamab as well as optimal dosing schedules, as such optimization would provide a means for determining safe and effective doses of epicoritamab.
Applicant further asserts that “[t]he data provided in the Examples of the present application demonstrate that T-cell- mediated cytotoxicity resulting from the combination of epcoritamab and lenalidomide was robust. In Example 1, T-cells were activated with immobilized anti-CD3 in the presence or absence of lenalidomide for three days and subsequently tested for their cytotoxic capacity in response to epcoritamab. Higher maximum percent cytotoxicity and higher activity at lower epcoritamab concentrations were observed with T cells pre-treated with lenalidomide and anti-CD3, demonstrating that lenalidomide may enhance the T cell activation by epcoritamab observed in patients, which in turn can lead to more efficient T cell-mediated cytotoxicity against the target cells. With respect to the claimed methods, the data provided in the Example 2 demonstrates that, unexpectedly, epcoritamab can be combined with lenalidomide to achieve successful treatment of DLBCL patients. Among three DLCBL patients treated with the presently claimed methods (24 mg epcoritamab + 25 mg lenalidomide) with available post-baseline efficacy assessments, all three achieved an overall response (100% ORR) and a complete response (100% CRR). These preliminary results could not have been predicted, particularly in view of the state of the art as discussed above, and thus provide evidence that the presently claimed methods are non-obvious.”
These arguments have been fully considered but are not deemed persuasive. At Table 4, Hutchings et al. teach that the administration of epcoritamab alone led to an 88% ORR at a 48 mg dose and a 100% ORR at a 60 mg dose. Furthermore as indicated above, Pordehnad et al. teach that that the combination of lenalidomide and ibrutinib synergistically kills DLBCL cell lines. Therefore one of ordinary skill in the art would reason that the combination of epcoritamab, lenalidomide, and ibrutinib is highly effective in treating DLBCL. Furthermore Applicant’s alleged evidence of unexpected results was obtained using 24 mg epcoritamab and 25 mg lenalidomide; however the claims are drawn to an epcoritamab dosage of 24 or 48 and a lenalidomide dose of 20-30 mg. As such Applicant’s alleged evidence of unexpected results does not appear to be commensurate in scope with the claims. The claim rejections under 35 U.S.C. 103 have been maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 extension fee 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 NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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