Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/28/2025 has been entered.
Claims 22-34, 36, 42-44, 46, 47, and 49-59 are pending.
Claims 24 and 50 are withdrawn.
Claims 22, 31, and 57 are currently amended.
Claims 22, 23, 25-34, 36, 42-44, 46, 47, 49, and 51-59 are under examination on the merits.
Rejections Maintained
35 U.S.C. 103(a)
The rejection of claims 31-34, 36, 42-44, 46,47, 49, and 51-53 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kufer (W02004/106381, published 12/09/2004, on IDS), in view of Kufer (W0099/54440, on IDS), Vlasveld (Cancer Immunology Immunotherapy, Vol. 40, Pg. 37-47, 1995, on IDS), Winkler (Blood, Vol. 94, No. 7, Pg. 2217-2224, 1999, on IDS), Rother (W0O2005/007809, published 01/27/2005), and Chen (US2004/0022869, published 02/05/2004) is maintained.
Nonstatutory Double Patenting
The nonstatutory double patenting rejections of record have been maintained.
Response to Arguments
With respect to the rejection of the claims under 35 U.S.C. 103, Applicant has provided an article by “Jabbour et al. (Blood Cancer Journal (2024) 14:203; ‘Jabbour’; attached as Exhibit A) which provides evidence that treatment with blinatumomab and chemotherapy in patients with acute lymphoblastic leukemia resulted in significantly improved overall survival and relapse-free survival outcomes. Jabbour, at page 12, left column, reported that in the E1910 study, a multinational, randomized, controlled, phase 3 trial that compared chemotherapy alone to chemotherapy plus four cycles of blinatumomab in adults with MRD-negative disease, the 3-year relapse-free survival was 80% for blinatumomab and chemotherapy versus 64% for chemotherapy alone. Further, Jabbour reported that the combination of blinatumomab with standard chemotherapeutic regimens and for different age groups also provided promising results, including the fact that the addition of blinatumomab to chemotherapy regimens resulted in dose-reduced chemotherapy regimens, allowing vulnerable (e.g., older) patients to be treated more effectively. Moreover, for patients who were aged 30 to 39 and were MRD negative, the 3- year overall survival rates were 100% VS 73% (P = .009), and the relapse-free survival rates were 90% VS 69% (P = .03) (Pelosci, Consolidation Blinatumomab Improves Efficacy Vs Chemo in Newly Diagnosed BCR::ABL1- B ALL; June 15, 2025, Conference, European Hematology Association Congress; ‘Pelosci’, attached as Exhibit B).”
These arguments have been fully considered but are not deemed persuasive. First the teachings of Jabbour et al. relate to the administration of blinatumomab, a specific anti-CD3/CD19 bispecific antibody; however claim 1 is broadly drawn to the administration of a genus of anti-CD3/CD19 bispecific antibodies, and one skilled in the art would not have a reasonable expectation that the results of Jabbour et al. are representative of the full genus of anti-CD3/CD19 bispecific antibodies claimed. Furthermore Applicant has not demonstrated that the results of Jabbour et al. are due to a synergistic effect, rather than an additive effect. As stated by Applicant, the 3-year relapse-free survival for acute lymphoblastic leukemia (ALL) was 80% for blinatumomab and chemotherapy; however chemotherapy alone was responsible for a 64% increase in 3-year relapse-free survival. An improved or additive effect would not be surprising given that in the studies of Jabbour et al., an anti-CD3/CD19 bispecific antibody was administered, which would be expected to bring cytotoxic T cells in close association with CD19-expressing cancer cells, thereby improving survival.
Applicant further asserts that “antibody therapies often need to be interrupted because of undesired side effects from the treatment, including cytokine release syndrome (CRS). Although such undesired side effects occur after treating patients with B cell malignancies with various antibody formats, including bispecific antibodies, the instant application teaches that these undesired side effects occur in patients after repeated bolus infusions of equal doses of the bispecific single chain antibody. The present invention solved the problem of the adverse side effects of CRS by the dosing schedule recited in the claimed method. The claimed dosing schedule further resulted in an improved T cell expansion and activation resulting in the unexpected and improved clinical response. The specification teaches that the daily continuous infusion of low doses of bispecific antibody resulted in the specific T cell activation/increase between infusion days 7-21 (see Figure 6 and page 35). Compared to their starting values, CD8+ and CD4+ T cells showed a 3.5- to 4-fold expansion in the blood (see the application-as-filed, at pages 53-54). The instant application teaches that continuous infusion of the bispecific antibody for two weeks is important for the increase and activation of T cells (see the application-as-filed, at pages 17- 18, and at pages 51-60 (Example 5)) and the associated clinical response (see Figures 14- 16), which in some cases resulted in complete remission. The specification teaches that long term T cell activation and an expansion of T cells, such as CD8+ T cells, leads to a higher cytotoxic activity and the expansion of the T cells improves the effector:target (E:T) ratio and the therapeutic outcome. The proliferation of cytotoxic T cells seems to be a prerequisite for a clinical benefit as underlined by the observations that both the absolute cell number reached during expansion and the relative increase compared to pre-treatment levels contribute to an optimal clinical response resulting from the continuous administration of the bispecific antibody construct of the claimed method… Additionally, the continuous uninterrupted administration of the CD19xCD3 bispecific single chain antibody construct for the longer period of time recited in the claims allows sufficient T cell activation to advantageously clear all diseased cells from the body. Since the rate of uninterrupted administration of the CD19xCD3 bispecific single chain antibody construct is kept low, the therapeutic agent may be delivered for a longer period of time without the risk of adverse side effects in the patient.”
These arguments have been fully considered but are not deemed persuasive. At the effective filing date of the invention, it was known in the art that low dose infusion of a bispecific antibody may provide advantages over high dose infusion. For example at p. 14, Weiner et al. (WO 99/67359, international publication date: 12/29/1999) teach that “[b]ispecific antibodies have been utilized in a variety of therapeutic applications. U.S. Patent No. 5,601,819 (along) discloses the use of a combinational CD3, and CD28 or interleukin 2 receptor bispecific antibody to selectively cause proliferation and destruction of specific T cell subsets. Belani, et al showed that bispecific IgG functions in a B cell lymphoma model to retarget the specificity of T cells in low dose, and to cause nonspecific T cell activation with systemic cytokine production at higher doses.” Furthermore at p. 43, Kufer et al. (WO 99/54440, international publication date:0 10/28/1999) teach that “[t]he novel bscCD19xCD3 caused a shrinkage of the previously enlarged spleen and lymph nodes of the patient, as shown in the ultrasound examination. Since enlargement of spleen and lymph nodes is caused by infiltrations with malignant B-cells, the shrinkage reflects the destruction of malignant B-cells as result of administration of bscCD19xCD3. In sharp contrast to any other bispecific CDI9xCD3 antibody known in the art, the bispecific CD19xCD3 antibody of the invention (bscCDl9xCD3) exhibits clinical efficacy in B-cell derived non-Hodgkin lymphoma as measured by the shrinkage of lymphoid organs infiltrated by malignant B-cells. Advantageously, bscCD19xCD3 proved to be clinically effective at surprisingly low doses which are well-tolerated after systemic administration.” Therefore at the effective filing date of the invention, it was known in the art that bispecific antibodies may be used in the treatment of B-cell lymphoma and that said bispecific antibodies may be administered at low doses, leading to T cell-mediated elimination of cancerous B cells with acceptable toxicity.
Applicant also asserts that “[m]oreover, the Declaration provides affidavit evidence establishing that the claimed method of administering by a continuous intravenous infusion in a daily dose over at least 6 hours of a CD19xCD3 bispecific single chain antibody construct provided wholly unexpected results in the treatment of indolent or aggressive B cell non-Hodgkin lymphoma (B NHL) or B cell leukemia, i.e., T-cell activation and expansion, and complete and sustained B cell depletion, resulting in clinical efficacy not found in the prior art or expected in view of the prior art. The Declaration also establishes that the application-as-filed provides unexpected results, i.e., that patients with B cell non-Hodgkin’s lymphoma or B cell leukemia can be successfully treated by the claimed method while completely avoiding, or at the very least minimizing, adverse side effects associated with previous dosage regimens.”
These arguments have been fully considered but are not deemed persuasive. As indicated above at the effective filing date of the invention, it was known in the art that bispecific antibodies, including CD19xCD3 bispecific antibodies, may be used in the treatment of B-cell lymphoma and that said bispecific antibodies may be administered at low doses, leading to T cell-mediated elimination of cancerous B cells with acceptable toxicity.
Conclusion
No claims are allowed.
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, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642