Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 22-34, 36, 42-44, 46, 47, 49-53, and 55-59 are pending.
Claim 54 is canceled.
Claims 22, 24-27, 29-31, 44, 46, 50-53, and 57 are currently amended.
Claims 24 and 50 are withdrawn.
Claims 22, 23, 25-34, 36, 42-44, 46, 47, 49, 51-53, and 55-59 are under examination on the merits.
Rejections Maintained
35 U.S.C. 103
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 (WO 2004/106381, published 12/09/2004), in view of Kufer (WO 99/054440), Vlasveld (Cancer Immunology Immunotherapy, Vol. 40, Pg. 37-47, 1995), Winkler (Blood, Vol. 94, No. 7, Pg. 2217-2224, 1999), Rother (WO 2005/007809, 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
In Applicant Arguments, dated 05/06/2026, Applicant points out that claim 31 has been amended to include the limitation of now-canceled claim 54, which was not included in the claim rejections under 35 U.S.C. 103; however claim 54 was rejected under 35 U.S.C. 103 at p. 35 of the Non-Final Rejection, dated 08/04/2023 - “With respect to claim 54, Winkler teaches cytokine release syndrome side effects after first doses of rituximab and that this caused temporary interruption of infusion (Pg. 2219, Column 1, Paragraph, final). Rituximab infusions were terminated to prevent further deterioration in patients and in some cases discontinued (Pg. 2220, Column 1, Paragraph, first). Furthermore, Rother teaches that the anti-CD3 antibody OKT3 can cause cytokine release leading to cytokine release syndrome (Pg. 3, Paragraph, first). Therefore, one of ordinary skill in this art is clearly aware that anti-CD3 antibodies can cause cytokine release and cytokine release syndrome based on the art here. Kufer '440 teaches use of additional drugs to handle these reactions but it is clear from Winkler too that antibody administration, such as administration of the bispecific antibody of instant claims, can and sometimes should be terminated to prevent escalation of these reactions and cytokine release syndrome. This would give the patient time to recover from the cytokine release and place them in a healthier position to receive additional therapy. Since this pause in bispecific antibody administration affects patient well-being and health and the concentration of antibody over time in the body, the pause is a result effective variable which will be optimized by routine experimentation as discussed supra. Therefore, when infusion-free periods occur and for how long are optimizable result effective variables. Making claims 54-56 obvious here.”
Applicant also asserts that “the effect of treatment with the recited CD19xCD3 antibody construct under the claimed dosing method is being demonstrated for the first time. Accordingly, there could be no ‘expected result’ for treatment with the combination of the claimed CD19xCD3 antibody construct treatment regimen and a chemotherapy regimen at the filing date. The remarkable advantages of the claimed CD19xCD3 treatment regimens are, themselves, evidence of an unexpectedly beneficial result. Exhibit A merely shows that these advantageous effects, which would be expected to extend over the recited genus of antibody constructs, can only be further enhanced with chemotherapy. As shown in Exhibit A, the combination increased the three-year relapse-free survival of patients versus treatment with chemotherapy alone. Notably, combining CD19xCD3 antibody treatment with chemotherapy allowed for reduced-intensity chemotherapy regimens, which can improve outcomes in vulnerable populations (e.g., older patients), and may allow the overall duration of therapy to be reduced.”
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 (emphasis added).” Therefore at the effective filing date of the invention, it was known in the art that 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.
Applicant also asserts that “[i]t is unclear how the mere mention of ‘low doses’ in Weiner and Kufer ‘440 would render obvious the step-up, cIV [continuous intravenous] dosing regimens presently claimed. The claimed regimens require administration of the recited CD19xCD3 antibody construct in a daily dose delivered over at least six hours by continuous intravenous infusion for at least four weeks, wherein an initial dose of 5 to 80 µg/m² of subject body surface area is followed by a maintenance dose… Neither Weiner nor Kufer refers to step-up clV administration of low doses of a CD19xCD3 antibody construct as recited in the present claims.
These arguments have been fully considered but are not deemed persuasive. At p. 19 and 20, Kufer et al (WO 99/54440) teach that ‘[t]he pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions, etc. Compositions comprising such carriers can be formulated by well known conventional methods. These pharmaceutical compositions can be administered to the subject at a suitable dose. Administration of the suitable compositions may be effected by different ways, e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, topical or intradermal administration. The dosage regiment will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Generally, the regimen as a regular administration of the pharmaceutical composition should be in the range of 1 μg to 10 mg units per day. If the regimen is a continuous infusion, it should also be in the range of 1 μg to 10 mg units per kilogram of body weight per minute, respectively. However, a more preferred dosage for continuous infusion might be in the range of 0.01 μg to 10 mg units per kilogram of body weight per hour. Particularly preferred dosages are recited herein below. Progress can be monitored by periodic assessment.” Therefore Kufer et al (WO 99/54440) teach that the optimal dosage of an anti-CD19xCD3 bispecific antibody will vary depending upon a variety of factors, and importantly, Kufer et al (WO 99/54440) teach that an anti-CD19xCD3 bispecific antibody may be administered intravenously via continuous infusion.
Furthermore at [0273], Chen et al. teach that when administering immunomodulatory agents, the dosage of said immunomodulatory agent may be increased or decreased as treatment progresses - “In another embodiment, a subject is administered one or more doses of a prophylactically or therapeutically effective amount of an immunomodulatory agent, wherein the prophylactically or therapeutically effective amount is not the same for each dose. In another embodiment, a subject is administered one or more doses of a prophylactically or therapeutically effective amount of an immunomodulatory agent, wherein the dose of a prophylactically or therapeutically effective amount of the immunomodulatory agent administered to said subject is increased … as treatment progresses. In another embodiment, a subject is administered one or more doses of a prophylactically or therapeutically effective amount of an immunomodulatory agent, wherein the dose of a prophylactically or therapeutically effective amount of the immunomodulatory agent administered to said subject is decreased … as treatment progresses.” As such Chen et al. suggest that depending upon a patient’s response to treatment with an immunomodulatory agent, the dosage of said immunomodulatory agent may be increased or decreased as needed.
It is also noted, as indicated at p. 34 of the Non-Final Rejection, dated 08/04/2023, that “it would have been obvious to one of ordinary skill in this art that the treatment parameters such as doses (including escalating doses), dose administration time, and duration of treatment are all well known in the prior art for such a bispecific antibody construct or antibodies with related functions. Obviously, as stated by Kufer '381 and Kufer '440, it is well within the skill of one skilled in this art to determine the appropriate treatment parameters for a given patient. Since these parameters will affect the amount of drug in the body over time, then they affect the efficacy of said drug against the cancer and so are all result effective variables. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable.” As such the instantly claimed step-up, continuous intravenous dosing regimens claimed were prima facie obvious at the effective filing date of the invention
Applicant also states that “[a]s discussed above, as well as extensively in the record, one of ordinary skill in the art would not have been able to predict the remarkable advantages of the claimed regimens. These advantages include long-term cytotoxic 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. Indeed, Example 5 (Section 3.2) of the present application demonstrates that the claimed methods can achieve a complete bone marrow response, i.e., total elimination of B lymphoma cells from the bone marrow, a result not demonstrated by or predictable over any of Kufer '381, Kufer '440, Vlasveld, Winkler, Rother, and Chen. The data in the application further demonstrate that patients with B cell non-Hodgkin's lymphoma or B cell leukemia can be successfully treated by the claimed methods while completely avoiding, or at the very least minimizing, adverse side effects associated with previous dosage regimens. These unexpected and highly advantageous results could not have been predicted by the skilled worker with Kufer '381, Kufer '440, Vlasveld, Winkler, Rother, and Chen in hand.”
These arguments have been fully considered but are not deemed persuasive. It is initially noted that a complete bone marrow response was achieved in one of two patients, thus demonstrating the therapeutic potential of the claimed invention; however this finding is not sufficient to overcome a finding of obviousness in the instant case. The references cited teach the administration of a CD19xCD3 bispecific antibody to patients having a CD19-expressing B cell cancer, and one of ordinary skill in the art would reasonably expect said CD19xCD3 bispecific antibody to bring cytotoxic T cells in close association with CD19-expressing cancer cells, thereby providing an anti-cancer effect that would be enhanced when said CD19xCD3 bispecific antibody is administered in combination with an appropriate chemotherapeutic agent.
Furthermore one of ordinary skill in the art would not be surprised to find that the claimed invention has a favorable safety profile. At Example 7, Kufer et al (WO 99/54440) detail the administration of an CD19xCD3 bispecific antibody to a B cell lymphoma patient, and Kufer et al. conclude that the “bscCD19xCD3 proved to be clinically effective at surprisingly low doses which are well-tolerated after systemic administration.”
As such Applicant’s evidence of surprising or unexpected results is not sufficient to overcome a finding of obviousness in the instant case, and the claim rejections under 35 U.S.C. 103 have been maintained.
Given that the claim rejections under 35 U.S.C. 103 have been maintained, the obviousness-type double patenting rejections of record have also 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
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on 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
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