DETAILED ACTION
Applicant’s amendment and response to the Restriction/Election Requirement received on 5/4/26 has been entered. Claims 1-2, 6-7, 9, 12-15, 18-19, 22-25, 27-39, and 42 are pending in this application.
Applicant’s elections without traverse of Group I, and the species d) VH without traverse is acknowledged. In view of applicant’s election of species d) VH and upon further consideration, the restriction requirement between Groups I and II is withdrawn. The election of species requirement, however, stands. Therefore, claims 1-2, 6-7, 9, 12-15, 18-19, 22-25, 27-39, and 42 are currently under examination based on the election of VH as the species of antigen recognition domain.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/23/23 and 10/3/24 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner and initialed and signed copies of the 1449s are attached to this action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 32-33 are rejected 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.
Claim 32 depends on claim 12 and recites the limitation where “the first infusion, the second infusion, and/or the third infusion of the first composition”. However, claim 12 upon which claim 32 depends on recites the use of first infusion and a second infusion. As such, claim 32 lacks antecedent basis for “the third infusion”. Thus, the metes and bounds of claim 32 cannot be determined. Claim 33 depends on claim 32 and is therefore included in this rejection.
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.
Claims 1-2, 6-7, 9, 12-15, 18-19, 22-25, 27-39, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Lam et al. (January 15, 2020) Nat. Commun., Vol. 11:283. doi.org/10.1038/s41467-019-14119-9, pages 1-14, in view of Mikkilineni et al. (2019) Blood, Vol. 134(Suppl. 1):3230. doi.org/10.1182/blood-2019-129088, pages 1-5, U.S. Patent Application Publication 2022/0169694 (6/2/22), hereafter referred to as Bot et al., with an effective filing date of 2/20/2020, Jensen et al. (2010)Biol. Blood Marrow Transplant., Vol. 16, 1245-1256, Dai et al. (2016) Mol. Clin. Onc., Vol. 4, 667-671, Solimando et al.(2016) Hosp. Pharm., Vol. 51(11), 888-893, Andersen et al. (2015) Clin. Cancer. Res., Vol. 22(15), 3734-3745, Brudno et al.(2018) Nat. Rev., Vol. 15, 31-46, Patel et al. (2013) Leuk. Res. Treat., Vol. 2013, dx.doi.org/10.1155.2013/62983, pages 1-4, Turtle et al. (2015) Blood, Vol. 23:184, doi.org/10.1182/blood.V126.23. 184.184,abstact, and Zhang et al. (2011) Blood, Vol. 117(7), 2223-2226.
Lam et al. teaches an anti-BCMA CAR comprising a human heavy chain only antibody antigen recognition domain with the structure FHVH33, a CD8alpha hinge and transmembrane region (TM), and both 4-1BB and CD3 zeta signaling domains (Lam et al. Figure 1). Lam et al. teaches T cells expressing the CAR and methods of treating multiple myeloma comprising the infusion of 1X10-6 or 2X10-6 CAR T cells to a mouse with multiple myeloma resulting in a significantly decreased tumor burden and increased survival compared to mice which received T cells with signaling defective CAR (Lam et al., Figure 6). Note that the mice comprising the multiple myeloma tumor have not been previously been treated with an anti-cancer agent. Lam et al. also teaches that the presence of the 4-1BB signaling domain increased T cell persistence compared to the use of a CD28 signaling domain. Mikkilineni et al. also teaches an anti-BCMA CAR FHVH33, the same as Lam et al., with CD8 hinge and TM domains, and 4-1BB and CD3zeta signaling domains (FHVH33-CD8BBZ). Mikkilineni et al. teaches T cells expressing the CAR (FHVH-BCMA-T) which were used in clinical trials in human patients with multiple myeloma (Mikkilineni et al., pages 1-2). Patients receive conditioning chemotherapy on days -5 to -3 with 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine followed by infusion of FHVH-BCMA-T on day 0 (Mikkilineni et al. page 2). Twelve patients received FHVH-BCMA-T at dosages of 0.75x10-6, 1.5x10-6 or 3x10-6 CAR+ T cells/kg of bodyweight with several partial response and several complete responses (Mikkilineni et al., page 2).
Lam et al. and Mikkilineni et al. differ from the instant methods by not teaching to further administer an anti-CD20 antibody before, at the same time, and/or after the administration of the anti-BCMA CAR T cells. Bot et al. teaches CAR T cell therapy comprising the infusion of CAR T cells in combination with anti-CD20 antibody, where the CAR is specific for BCMA, or where the anti-CD20 antibody is given prior to the T cells as part of depletion regimen, at the same time as the T cells, or after administration of the T cells (Bot et al., paragraphs 365-370, 957, and 976). In particular, Bot et al. teaches the use of the anti-CD20 antibody rituximab for preconditioning, or to be administered concurrently with T cells (Bot et al., paragraph 984). Other anti-CD20 antibodies taught by Bot et al., include ofatumumab, and ibritumumab (Bot et al., paragraph 984). Bot et al. teaches to administer rituximab at a dosage of 375 mg/m2 for 1 day or weekly (Bot et al., paragraph 734). In addition, Bot et al. teaches administering one or more additional doses of the CAR T cells after the initial dose, where in some embodiments, the treatments are administered at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, less than a year apart (Bot et al., paragraphs 887 and 977). Bot et al. further teaches an infusion dosage of 10-4 to 10-10 T cells/kg body weight, preferably 1X10-6 - 9X10-7 or up to 1X10-8 cells/kg body weight (Bot et al., paragraphs 968-969, and 976-977). Bot et al. also teaches that the dosage of T cells is present in an infusion bag for infusion to a patient (Bot et al., paragraph 1142 and Tables 4 and 6). Bot et al. teaches the infusion of the CAR T cells and anti-CD20 antibody for the treatment of myeloma, particularly multiple myeloma (Bot et al., paragraph 30). Finally, Bot et al., like Mikkilineni et al., teaches the use of a pre-conditioning regimen prior to CAR T cell infusion where the pre-conditioning regimen comprises fludarabine 30 mg/m2 IV and cyclophosphamide at a dose of 500 mg/m2 IV on days -5, -4, -3, or alternatively a dose of 200-300 mg/m2 (Bot et al., paragraphs 975-977).
Therefore, in view of the motivation provided by Bot et al. to combine CAR T cell therapy with anti-CD20 administration, where the anti-CD20 antibody is administered as part of a pre-conditioning regimen prior to the administration of the CAR T cells, concurrently with the CAR T cells, or after administration of the CAR T cells, and to further administer a lymphodepleting conditioning regimen comprising fludarabine and cyclophosphamide in conjunction with the CAR T cells and the anti-CD20 antibody for the treatment of multiple myeloma, it would have been prima facie obvious to the skilled artisan at the time of filing to treat multiple myeloma according to both Lam et al. and Mikkilineni et al. using a pre-conditioning regimen comprising fludarabine, cyclophosphamide, and an anti-CD20 antibody, followed by infusion of FHVH-BCMA-T on day 0, either alone or in combination with the anti-CD20 antibody, and to further administer additional infusions of the FHVH-BCMA-T cells and/or anti-CD20 antibody as taught by Bot et al. with a reasonable expectation of success.
Lam et al., Mikkilineni et al., and Bot et al. differ from the instant methods by not teaching exact flow rates, and/or concentrations, and/or the timing of any repeat administrations, and/or the number of repeat administration of the CAR T cells, or the anti-CD20 antibody rituximab, or the combination of fludarabine and cyclophosphamide. Jensen et al. further supplements Lam et al., Mikkilineni et al., and Bot et al. by providing additional instructions for CAR T cell infusions to patients. Jensen et al. teaches infusion methods for CAR T cells where the CAR T cells are infused i.v. over 30 minutes using an infusion bag (Jensen et al., page 1247). Jensen et al. also teaches multiples infusions of the CAR T cells comprising 3-5 doses, where the dosages are administered every 14 days, or administered as a first dose at day 0, followed two weeks later by weekly infusions of dosages 2-5 ( Jensen et al., Figure 2). While Jensen et al. does not specifically teach the amount of liquid in the T cell infusion bad, the size and mL capacity of an infusion bag of T cells was well known at the time of filing. Andersen et al., for example, teaches a common method of preparing an infusion bag for intravenous administration. Andersen et al. teaches the suspension of a therapeutic number of T cells in 250 ml of sodium chloride in an infusion bag which is then administered to the patient intravenously over 30 minutes (Andersen et al., page 3736). In regards to the number of infusions of the CAR T cells, Bot et al., as noted above, teaches that administration of multiple doses of the CAR T cells which can be separated by 2 or 3 weeks, or by 1, 2, 3, or 4 months or more. Jensen et al. also teaches multiple infusions, 3-5 doses, of CAR T cells which occur every 14 days, or which can be weekly infusions. Brudno et al. also teaches a CAR T cell therapy method where the rituximab is administered prior to the CAR T cells, and that the CAR T cell therapy is further preceded by a conditioning regimen for lymphodepletion which enhances the activity of the adoptively transferred CAR T cells (Brudno et al., page 31). Brudno et al. teaches the use of a first dose of CAR T of 1X10-8 cells/kg followed the next day by a dose of 3X10-8 cell/kg (Table I). Note that second dose of CAR T cells administered by Brudno et al. is about two thirds of the total dose of the administered T cells. Thus, based on the combined teachings of Bot et al., Jensen et al., and Brudno et al., it is would have been prima facie obvious to the skilled artisan at the time of filing to prepare an infusion bag comprising the FHVH-BCMA-T cells according to Lam et al. and Mikkilineni et al., where the T cells are present in an amount of 1X10-6 - 9X10-7 or up to 1X10-10 cells/kg body weight in a 250 ml infusion bag and to administer the infusion bag to a patient with multiple myeloma according to the methods of Lam et al., Mikkilineni et al., and Bot et al. where the cells are administered every week, every two weeks, or every three weeks with a reasonable expectation of success. Further based the various concentrations of the multiple dosages of CAR T cells, and the various timing between dosages taught by Bot et al., Jensen et al., and Brudno et al., it would have been prima facie obvious at the time of filing that both the timing of the infusions and the dosages of each infusion can be varied with a reasonable expectation of success up to an including splitting the total dosage of CAR T cells into two dosages separated by at least 10 days where the first dose has about 1/3 of the T cells and the second dose has the remaining 2/3 of the T cells, or where the total dosage of CAR T cells is split into three dosages separated by at least 10 days and where each of the three dosages are 1/3 of the total dosage as each of these protocols are encompassed by the breadth of the regimens taught by the cited supporting references, and each of these references demonstrates successful effects on tumors using different T cell doses, different numbers of doses, and timing of the multiple doses.
Further in regards to the dosages and infusion protocols for fludarabine, cyclophosphamide, and rituximab, as noted above, Mikkilineni et al. already teaches a conditioning regimen comprising 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine, and Bot et al. already teaches to administer rituximab at a dosage of 375 mg/m2 for 1 day or weekly. However, neither references teaches the specific infusion rate of each compound. Solimando et al. teaches clinically approved infusion rates for human patients for cyclophosphamide and for rituximab, and teaches that cyclophosphamide should be administered by IV infusion over 10-30 minutes and that rituximab should be administered by IV infusion at a starting rate of 50 mg/h and increased every 30 min to 400 mg/hr for the first dose, or can at 100 mg/hr increasing every 30 min to 400 mg/hr for repeat doses (Solimando et al., pages 888-889). Patel et al. also teaches specific methods for infusion of rituximab in a subject, including in one method, the administration of rituximab at a flow rate starting at 50 mg/hr which is then increased every 30 minutes to a maximum rate of 400 mg/hr (Patel et al., pages 1-2). For subsequent infusions, Patel et al., like Solimando et al., teaches a starting rate of 100 mg/hr increasing every 30 minutes to a maximum of 400 mg/hr (Patel et al., pages 1-2). It is further noted that Patel et al. teaches various regimens involving multiple infusions of rituximab including the weekly infusion of rituximab of 8 weeks (Patel et al., page 3). Dai et al. teaches a conditioning regimen prior to cell transplantation comprising the administration of fludarabine, where the 30 mg/m2 of fludarabine is infused intravenously into the patient over a period of 30 min daily for 4 days (Dai et al., pages 667-668). Therefore, in view of the teachings of Solimando et al., Patel, and Dai et al. concerning current infusion rates for clinical trials and for clinical use in humans, it would have been prima facie obvious to the skilled artisan at the time of filing to administer one or more 30 mg/m2 doses of fludarabine intravenously over a period of 30 min, to administer one or more 300 mg/m2 doses of cyclophosphamide intravenously over 30 min, and to administer one or more 375 mg/m2doses of rituximab intravenously at a starting rate of 50 mg/h and increasing every 30 min to 400 mg/hr for the first dose, or at a starting rate of 100 mg/hr increasing every 30 min to 400 mg/hr for repeat doses with a reasonable expectation of success. Furthermore, based on teachings of Bot et al. and Patel. for dosing regimens for rituximab, the timing between doses and number of dosages, and the timing of dosages in relation to the administration of CAR T cells, it would have been prima facie obvious at the time of filing that both the timing of the infusions and the dosages of each rituximab infusion, particularly in relation to the administration of CAR T cells, can be varied with a reasonable expectation of success up to an including the administration of a first dose of rituximab at 12 days prior to the first infusion of CAR T cells, wherein a second dose of rituximab is administered at 5 days prior to the first infusion of the CAR T cells, and wherein subsequent doses are administered once per week after the first infusion of the CAR T cells for at least 8 weeks.
Finally, in regards to the effects of anti-CD20 antibody administration on anti-drug antibody (ADA) response to CAR T cells, and more particularly where at least a 50% decrease in ADA response is observed when anti-CD20 antibody is administered along with CAR T cells, it is noted that Jensen et al. teaches that CAR T cells induce anti-CAR immune responses that attenuate CAR T cell persistence (Jensen et al., page 1247 and Figure 3). Jensen et al. teaches that a 5 day course of fludarabine was not enough to substantially reduce the anti-CAR response and suggests using a more effective lymphodepleting regimen to increase CAR T cell persistence. Turtle et al. supplements Jensen et al. by teaches that a combination fludarabine and cyclophosphamide preconditioning regimen for lymphodepletion comprising administration of 60 mg/kg cyclophosphamide and 25 mg/m2 fludarabine daily for 3-5 days followed 2-4 days later with the infusion of 2X10-5, 2X10-6, or 2X10-7 CAR-T cells/kg results in substantially increased persistence and expansion of CAR T cells in humans (Turtle et al., abstract). In addition, at the time of filing, it was known that heterologous therapeutics induce inhibitory anti-drug antibodies (ADA). Zhang et al. teaches that anti-CD20 antibodies can be used effectively to prevent/reduce an anti-drug antibody (ADA) responses to a therapeutic in a subject by depleting various B cell subtypes (Zhang et al., 2223-2224). Zhang et al. teaches that both pre-drug exposure or post-drug exposure treatment of mice with an anti-CD20 antibody (IgG1 or IgG2a) substantially reduced the formation of inhibitor antibodies to recombinant human FVIII administration (Zhang et al., Figure 2 and Figure 4). In particular, Zhang et al. demonstrates that anti-CD20 administration decreased inhibitor antibody activity by more than 50%- see Figures 2 and 4. Therefore, in view of the of Jensen et al. and Turtle et al., that lymphodepletion is important for increasing the persistence of adoptively transferred T cells in a subject, the teachings of Zhang et al. that anti-drug antibodies are a problem for therapeutics which can be reduced by more than 50% by the administration of anti-CD20 antibodies that deplete B cells, and the clear teachings of Bot et al. to combine anti-CD20 administration with the administration of CAR T cells, it would have been prima facie obvious at the time of filing that following the methods of Lam et al. in view of Mikkilineni et al., and Bot et al. as discussed in detail above, would result in a reduction of at least 50% of ADA responses against the CAR T cells with a reasonable expectation of success.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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