DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40, 42, 44-49 and 53-55 are pending.
Claim 42 has been withdrawn.
Claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40, 44-49 and 53-55 are currently under examination.
Priority
Applicant’s claim of a priority date of December 1, 2018 has been acknowledged.
35 USC § 112(a) rejections withdrawn
The rejection of claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40 and 44-49 for failing to comply with the written description requirement are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 103 rejections withdrawn
The rejections of claims 1, 3, 9, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40 and 46-49 are rejected under 35 U.S.C. 103 as obvious over Clinical Trial NCT03751293 (first posted November 23, 2018) (of record) in view of U.S. Patent Application Publication No. 20160297884-A1 (of record) and Hendrikx et al. (Oncologist. 2017 Oct; 22 (10): 1212-21), as evidenced by Qu et al. (J. Immunother. Cancer. 2022 Sep; 10 (9): e005145; pp. 1-36) (of record) are withdrawn in view of Applicant’s amendments to claim 1.
NEW REJECTIONS:
Claim Objections
Claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40, 44-49 and 53-55 are objected to because of the following informalities: The claims recite “for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose. However, the specification discloses “the weight of the subject is >50 kg, and the method comprises administering at least one dose of BCMA CAR-T cells, wherein the dose ranges from about 20 x 106 cells/dose to about 480 x 106 cells/dose. In some embodiments, the at least one dose is about 120 x 106 cells/dose, about 360 x 106 cells/dose, or about 480 x 106 cells/dose. In some embodiments, the at least one dose is from about 120 x 106 cells/dose, from about 120 x 106 cells/dose to about 360 x 106 cells/dose”. Appropriate correction is required.
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.
Claim 3 is rejected under 35 U.S.C. 112(b) 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. Claims 3 recites “wherein the at least one dose is about 320 x 106 cells/dose. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
Claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37, 39, 40, 46-49 and 53-55 are rejected under 35 U.S.C. 103 as obvious over Clinical Trial NCT03751293 (first posted November 23, 2018) (of record) in view of Kuo et al (U.S. Patent Application Publication No. 20160297884-A1, of record) and Brudno et al (J Clin Oncol 10:1112-1123, 2016) as evidenced by Qu et al. (J. Immunother. Cancer. 2022 Sep; 10 (9): e005145; pp. 1-36, of record).
The claims are drawn to a method for treating multiple myeloma comprising administering to the subject at least one dose of a population of allogeneic human T cells comprising CD8+ cytotoxic T lymphocytes (CTLs) expressing a chimeric antigen receptor comprising an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide on the surface of the myeloma cells in the subject, a human CD8a hinge region, a human transmembrane domain, and an intracellular signaling domain comprising a costimulatory signaling domain comprising the intracellular portion of human 4-1BB and an activating domain comprising the intracellular portion of human CD3z, wherein for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose, and for subjects whose weight is less than 50 kg the dose is from about 80 x 106 cells cells/dose to about 240 x 106 cells cells/dose, or from about 240 x 106 cells cells/dose to about 360 x 106 cells cells/dose, wherein the BCMA-specific CAR expressed by the CAR-T cells has the structural features recited by the instant claims (e.g., an extracellular ligand binding domain comprising an scFv comprising an VH region comprising SEQ ID NO: 33 and a VL region comprising SEQ ID NO: 34).
Clinical Trial NCT03751293 describes a clinical trial in which human patients having relapsed or refractory multiple myeloma expressing BCMA who previously received at least one or at least two treatment regimens are treated with a target dose of dose of 1.0-9.0 x 106 anti-human BCMA CAR-T cells designated “C-CAR088” per kilogram (see entire document).
If a human subject were a male weighing about 52 kg, the target dose to be administered would be about 52 x 106 cells to about 468 x 106 cells. If the patient were a female weighing about 45 kg, the target dose to be administered would be about 45 x 106 cells to about 405 x 106 cells. Thus, the claimed cell doses fall within the cell doses recited in Clinical Trial NCT03751293.
Furthermore, Brudno disclose the administration of 1-10 X 106 cells/kg of allogeneic CD19 CAR T cells to patients with B cell malignancies (Table 2; Page 113, 2nd paragraph to page 1118, 2nd paragraph). If a human subject were a male weighing about 52 kg, the target dose to be administered would be about 52 x 106 cells/dose to about 520 x 106 cells. If the patient were a female weighing about 45 kg, the target dose to be administered would be about 45 x 106 cells to about 405 x 106 cells/dose. Thus, the allogeneic cells administered falls within the claimed ranges.
One of ordinary skill in the art would have been motivated to apply Brudno’s use of allogeneic CAR T cell to treat B-cell malignancies with Clinical Trial NCT03751293 use of CAR T cells to treat multiple myeloma because both Brudno and Clinical Trial NCT03751293 treat non-solid tumors in patients with CAR T cells. It would have been prima facie obvious to substitute Brudno’s allogeneic CAR T cell for the CAR T cells of Clinical Trial NCT03751293 because Brudno discloses that the allogeneic CAR T cell treatment resulted in complete remission for 6 out of 20 patients and partial remission for 2 out of 20 patients with none of the patients developing new-onset acute graft-versus-host reactions.
In addition, as evidenced by Qu et al., the CAR that is expressed by the disclosed “C-CAR088” allogeneic (donor) human BCMA-specific CAR-T cells, which are administered to the patients, comprises an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide, a transmembrane domain derived from human CD8a, and an intracellular signaling domain comprising a costimulatory signaling domain comprising the intracellular portion of human 4-1BB and an activating domain comprising the intracellular portion of human CD3z (see entire document, e.g., page 2; Figure 1 at page 2; and the supplementary material).
The cited prior art does not expressly teach a human BCMA-specific CAR comprising an extracellular antigen binding domain comprising an scFv comprising a VH region comprising the amino acid sequence of SEQ ID NO: 33 and a VL region comprising the amino acid sequence of SEQ ID NO: 34. In addition, the prior art does not expressly teach the amino acid sequences of the human CD8a transmembrane domain of the disclosed human BCMA-specific CAR or the amino acid sequences of the intracellular human 4-1BB co-stimulatory domain and human CD3z activating domain thereof. Furthermore, the prior art does not expressly teach the CAR comprises a human CD8a hinge region or more particularly a polypeptide comprising SEQ ID NO: 320.
All of these deficiencies are remedied by the teachings of Kuo et al (U.S. Patent Application Publication No. 20160297884-A1).
Kuo teaches an anti-human BCMA antibody or more particularly scFv comprising a VH region comprising an amino acid sequence that is identical to that set forth as SEQ ID NO: 33 by the instant application and a VL region comprising an amino acid sequence that is identical to that set forth as SEQ ID NO: 34 by the instant application; see entire document (e.g., SEQ ID NO: 33; SEQ ID NO: 34; the abstract; and Table 1 at page 18).1 Kuo et al. teaches the scFv comprises a peptide linker comprising (Gly3Ser)3, an amino acid sequence identical to SEQ ID NO: 333 (as set forth by the instant application), which adjoins the VH region and the VL region of the scFv (see, e.g., paragraph [0095]; and SEQ ID NO: 333). Kuo et al. teaches a human BCMA-specific CAR comprising an extracellular antigen binding domain comprising the disclosed anti-human BCMA scFv, as well as an N-terminal human CD8a signal peptide comprising an amino acid sequence identical to SEQ ID NO: 318 (as set forth by this application), a human CD8a hinge region comprising an amino acid sequence identical to SEQ ID NO: 320 (as set forth by this application), a human CD8a transmembrane domain comprising an amino acid sequence identical to SEQ ID NO: 322 (as set forth by this application), a human 4-1BB intracellular signaling or co-stimulatory domain comprising an amino acid sequence identical to SEQ ID NO: 323 (as set forth by this application), and, at the C-terminus, a human CD3z intracellular signaling or activating domain comprising an amino acid sequence identical to SEQ ID NO: 324 (as set forth by this application) (see, e.g., paragraph [0110] and Table 3 at pages 38 and 39). Kuo et al. teaches the disclosed CAR comprises an amino acid sequence identical to SEQ ID NO: 344 (as set forth by this application) (see, e.g., Table 5 at pages 54 and 55).2 Kuo et al. teaches the CAR is expressed by a cytotoxic T lymphocyte expressing CD8 (see, e.g., paragraphs [0030] and [0168]). Kuo et al. teaches the CAR-T cell expressing the BCMA-specific CAR is administered to a human subject having multiple myeloma in order to treat the disease (see, e.g., paragraphs [0008] and [0033]). Kuo et al. teaches the cells or population of cells is administered in one or more doses of about 106 cells per kilogram body weight (see, e.g., paragraph [0188]). Kuo et al. teaches that multiple myeloma is difficult to treat because almost all patients eventually relapse, necessitating an alternative treatment (as disclosed) using BCMA-specific CAR-T cells (see, e.g., paragraph [0007]). Kuo et al. teaches the disclosed treatment is used in conjunction with or either before, concurrently, or after any number (e.g., one, two, or three) of other relevant treatment modalities (e.g., before the subject has received any other therapy for the disease) (see, e.g., paragraph [0189]). Kuo et al. teaches the extracellular ligand binding domain comprising the scFv further comprises a peptide comprising a CD20 epitope recognized by rituximab comprising an amino acid sequence that is identical to SEQ ID NO: 397 (as set forth by the instant application) (see, e.g., paragraph [0179]), which permits the CAR-T cells can be eliminated from the subject if necessary to limit undesirable effects or unacceptable levels of toxicity associated with the presence of the cells in the body of the subject (see, e.g., paragraph [0178]). More particularly, Kuo et al. teaches the inclusion of a peptide comprising an amino acid sequence that is identical to SEQ ID NO: 398 (as set forth by the instant application) between the VL region and the hinge region within the extracellular domain of the CAR for use in depleting the CAR-T cells in a subject using an antibody that binds to an epitope of which the peptide is comprised (see, e.g., paragraph [0180]). Kuo et al. teaches the T cells used to produce the CAR-T cells can be TCRa-deficient to reduce the risk of development of GvHD (see, e.g., paragraph [0177] and Example 5 and in particular, the disclosure in paragraph [0235]). Furthermore, Kuo et al. teaches the gene encoding TCRb can also be inactivated (see, e.g., paragraphs [0175] and [0175]). Kuo et al. teaches the conjunctive use of T cell ablative therapy using, e.g., fludarabine, cyclophosphamide, and the anti-CD52 antibody CAMPATH3 to facilitate engraftment and expansion of the CAR-T cells administered to the subject by depleting CD52-expressing effector immune cells (NK cells) in the subject prior to the administration of the CAR-T cells and thereby reduce the risk of graft rejection and the development of GvHD (see, e.g., paragraph [0189]; and Example 6). Kuo et al. teaches the gene encoding CD52 in the CAR-T cell can be disrupted to permit immunosuppressive treatment using a humanized anti-human CD52 antibody to facilitate engraftment and expansion of the CAR-T cells administered to the subject (see, e.g., paragraphs [0031] and [0149]; and Example 6). Kuo disclose that the CAR T cells may be autologous or allogeneic (paragraphs [0076, 0153, 0185].
Accordingly, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art as of the effective filing date of the claimed invention to have practiced the claimed invention, as suggested by collective teachings of the prior art, by administering to a human subject having multiple myeloma expressing BCMA at least one dose, if not two, of a population of allogeneic human T cells comprising CD8+ cytotoxic T lymphocytes (CTLs) expressing a chimeric antigen receptor comprising an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide on the surface of the myeloma cells in the subject, a human CD8a hinge region, a human transmembrane domain, and an intracellular signaling domain comprising a costimulatory signaling domain comprising the intracellular portion of human 4-1BB and an activating domain comprising the intracellular portion of human CD3z, wherein for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose, and for subjects whose weight is less than 50 kg the dose is from about 80 x 106 cells cells/dose to about 240 x 106 cells cells/dose, or from about 240 x 106 cells cells/dose to about 360 x 106 cells cells/dose, wherein the CAR has the structural features recited by the instant claims.4 In addition, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art as of the effective filing date of the claimed invention to have practiced the claimed invention, as suggested by collective teachings of the prior art, by administering T cell ablative therapy using, e.g., a combination of fludarabine, cyclophosphamide, and the anti-CD52 antibody CAMPATH5 in order to facilitate engraftment and expansion of the CAR-T cells administered to the subject by depleting CD52-expressing effector immune cells (NK cells) in the subject prior to the administration of the CAR-T cells and thereby reduce the risk of graft rejection and the development of GvHD. It would have been prima facie obvious to one ordinarily skilled in the art as of the effective filing date of the claimed invention to have done so by administering to the patient at least a first dose of the one or a combination of more than one of the therapeutic agents comprising the T cell ablative therapy (i.e., fludarabine, cyclophosphamide, and the anti-CD52 antibody CAMPATH) at least 1, 2, 3, 4, or 5 days prior to the administration of the CAR-T cells to the patient. This is because it would be desirable to allow ample time for the T cell ablative therapy to act, so that the objective of administering the T cell ablative therapy is met, namely the facilitation of engraftment and expansion of the CAR-T cells in the patient after their administration to the patient. Moreover, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art as of the effective filing date of the claimed invention to have done so by administering to the patient at least a daily dose of the one or a combination of more than one of the therapeutic agents comprising the T cell ablative therapy (i.e., fludarabine, cyclophosphamide, and the anti-CD52 antibody CAMPATH) beginning at least 5 days prior to the administration of the CAR-T cells to the patient over the course at least 3 days. Again, this is because it would be desirable to administer sufficient amounts of one or a combination of the therapeutic agents comprising the immunodepletion regimen over a period of time sufficient to achieve the goal of treating the patient using this regimen, which is again the facilitation of engraftment and expansion of the CAR-T cells in the patient after their administration to the patient.
With particular regard to claims 17 and 18, it is further submitted that it would have been prima facie obvious to one ordinarily skilled in the art as of the effective filing date of the claimed invention to have practiced the claimed invention, as suggested by collective teachings of the prior art, by using the invention to treat multiple myeloma in a subject who has either not received any prior therapy for the disease or a subject who has received prior therapies for the disease.
With particular regard to claim 3 and claim 9, if, arguendo, the prior art does not expressly teach the patient or subject receives a dose of about 320 x 106 CAR-T cells or about 480 x 106 CAR-T cells, respectively, Applicant is reminded that it is a common objective in the art to establish a dose that is both safe and effective, so as achieve optimal therapeutic effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). See In re Peterson, 65 USPQ2d 1379 1382 (CA FC 2003): “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In this instance, then, it would have been prima facie obvious to practice the claimed invention as suggested by the collective teachings of the prior art by varying the dosages administered to patients or subjects to determine which dosages are best used to achieve optimal therapeutic efficacy including, for example, doses falling in the range recited by the claims, in general, or a combination of more than one of the therapeutic agents comprising the T cell ablative therapy (i.e., fludarabine, cyclophosphamide, and the anti-CD52 antibody CAMPATH) beginning at least 5 days prior to the administration of the CAR-T cells to the patient over the course at least 3 days. Again, this is because it would be desirable to administer sufficient amounts of one or a combination of the therapeutic agents comprising the immunodepletion regimen over a period of time sufficient to achieve the goal of treating the patient using this regimen, which is again the facilitation of engraftment and expansion of the CAR-T cells in the patient after their administration to the patient.
With particular regard to claims 17 and 18, it is further submitted that it would have been prima facie obvious to one ordinarily skilled in the art as of the effective filing date of the claimed invention to have practiced the claimed invention, as suggested by collective teachings of the prior art, by using the invention to treat multiple myeloma in a subject who has either not received any prior therapy for the disease or a subject who has received prior therapies for the disease.
With particular regard to claim 3 and claim 9, if, arguendo, the prior art does not expressly teach the patient or subject receives a dose for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose, and for subjects whose weight is less than 50 kg the dose is from about 80 x 106 cells cells/dose to about 240 x 106 cells cells/dose, or from about 240 x 106 cells cells/dose to about 360 x 106 cells cells/dose, respectively, Applicant is reminded that it is a common objective in the art to establish a dose that is both safe and effective, so as achieve optimal therapeutic effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). See In re Peterson, 65 USPQ2d 1379 1382 (CA FC 2003): “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In this instance, then, it would have been prima facie obvious to practice the claimed invention as suggested by the collective teachings of the prior art by varying the dosages administered to patients or subjects to determine which dosages are best used to achieve optimal therapeutic efficacy including, for example, doses falling in the range recited by the claims, in general, or as recited by claim 3 or claim 9, a dose for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose, and for subjects whose weight is less than 50 kg the dose is from about 80 x 106 cells cells/dose to about 240 x 106 cells cells/dose, or from about 240 x 106 cells cells/dose to about 360 x 106 cells cells/dose. Moreover, it is submitted that it would have been prima facie obvious to practice the claimed invention as suggested by the collective teachings of the prior art by comparing the efficacy of any of a range of doses of the CAR T cells, each of which falls in the range recited by the claims, to that of weight-based doses of equivalent numbers of the CAR T cells, so as to determine if it is possible to achieve equivalent efficacy using a single fixed dose of the CAR T cells, regardless of the weight of the subject, as opposed to a dose that varies depending upon body weight. This is simply because it would be appreciated that flat-fixed dosing regimens can be used with greater safety because of the avoidance of potential dose calculation mistakes when using weight-based or body surface area dosing regimens.
Still, with particular regard to claim 39, if, arguendo, the prior art does not expressly teach the patient or subject receives an immunodepletion regimen comprising a combination of fludarabine, cyclophosphamide, and an anti-CD52 antibody comprising a heavy chain variable domain comprising CDRs comprising SEQ ID NOs: 402, 403, and 404 and a light chain variable domain comprising CDRs comprising SEQ ID NOs: 405, 406, and 407 (or more particularly the anti-human CD52 antibody CAMPATH (alemtuzumab) prior art after receiving the first dose of CAR-T cells, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art before the effective filing date of the claimed invention to do use a combination of fludarabine and cyclophosphamide in addition to the anti-CD52 antibody, particularly when the CAR-T cells are engineered such that the gene encoding CD52 is disrupted. One ordinarily skilled in the art before the effective filing date of the claimed invention would have been motivated to do so in order to better prepare the patient or subject to receive the CAR-T cells, while reducing the risk of graft rejection and development of GvHD in the patient or subject.
Therefore, in conclusion, absent a showing of any unexpected results, it is submitted that the disclosures by the prior art would have rendered the claimed invention an obvious variation of the method of treating multiple myeloma in human patients as specified by the clinical trial in view of the teachings of Kuo et al.
Claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40, 44-49 and 53-55 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT03751293 (first posted November 23, 2018) (of record) in view of U.S. Patent Application Publication No. 20160297884-A1 (of record) and Brudno et al (J Clin Oncol 10:1112-1123, 2016, of record) as evidenced by Qu et al. (J. Immunother. Cancer. 2022 Sep; 10 (9): e005145; pp. 1-36) (of record) and further in view of Clinical Trial NCT03093168 (first posted March 28, 2017) (of record), Brentjens et al. (Blood. 2011 Nov 3; 118 (18): 4817-28) (of record), Kanda et al. (Int. J. Hematol. 2011 May; 93 (5): 586-593) (of record), and Turtle et al. (Sci. Transl. Med. 2016 Sep 7; 8 (355): 355ra116; pp. 1-13) (of record).
The claims are herein drawn to the method according to claim 1, wherein the subject receives a first lymphodepletion regimen prior to administration of the at least one dose of CAR-T cells (claim 38), wherein the regimen comprises administering fludarabine, cyclophosphamide, and an anti-CD52 antibody or more particularly CAMPATH (alemtuzumab) (claim 40), wherein the dosage of fludarabine is about 30 mg/m2/day, the dosage of cyclophosphamide is about 300 mg/m2/day, and the dosage of the antibody is about 13 to about 30 mg/day (claim 44) or more particularly about 13, about 20, or about 30 mg/day (claim 45).
As evidenced by Qu et al., Clinical Trial NCT03751293 and U.S. Patent Application Publication No. 20160297884-A1 teaches that which is set forth in the above rejection, but the prior art does not expressly teach the dosage of fludarabine, the dosage of cyclophosphamide, or the dosage of CAMPATH (alemtuzumab).
These deficiencies are remedied by the teachings of Clinical Trial NCT03093168, Brentjens et al., Kanda et al., and Turtle et al.
Clinical Trial NCT03093168 (first posted March 28, 2017) describes a clinical trial in which human multiple myeloma patients are treated with anti-BCMA CAR-T cells, fludarabine, and cyclophosphamide (see entire document). The CAR that is expressed by the T cells administered to the patients comprises an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide, a transmembrane domain, and an intracellular signaling domain comprising a costimulatory signaling domain comprising the intracellular portion of human 4-1BB and an activating domain comprising the intracellular portion of human CD3z (see, e.g., “Arms and Interventions”). The dose of fludarabine that is administered to the patients is 25mg/m2/d; and the dose of cyclophosphamide administered is 40 mg/kg (see, e.g., “Arms and Interventions”).
Brentjens et al. teaches effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, which can be achieved through the use of chemotherapy agents and radiotherapy and moreover the study described by Brentjens et al. teaches highlights the importance of preconditioning. The study, as described by Brentjens et al., included two cohorts of ALL and CLL patients, the first receiving no prior conditioning and the second receiving 1.5-3.0 g/m2 cyclophosphamide one day prior to receiving cancer associated antigen-specific CAR (designated “19-28z”) T cells; see entire document (e.g. the entire document). Brentjens et al. teaches patients receiving cyclophosphamide showed greater CAR T cell persistence, as well as enhanced clinical activity (see, e.g., the abstract).
Kanda et al. teaches alemtuzumab, an anti-human CD52 antibody has been widely used for preventing acute graft-versus-host disease (GVHD) when administered prior to allogeneic stem cell transplantation (SCT); see entire document (e.g., the abstract). However, because, as Kanda et al. teaches, T cells express CD52, it is not practical to engraft the patient while alemtuzumab still remains in the blood, but as Kanda et al. also teaches, because alemtuzumab could remain in the blood at the lympholytic level 1–2 months after transplantation, immune reconstitution is substantially delayed, leading to a high incidence of viral infection and relapse (see, e.g., the abstract). These teachings would have provided the artisan of ordinary skill in the art with an impetus to modify the T cells to be engrafted by inactivating or disrupting the gene encoding CD52, such that the cells do not express CD52, and will not be targeted by alemtuzumab. Kanda et al. teaches that the administration of 100 mg of alemtuzumab before transplantation has been found to result in a low incidence of acute GVHD in HLA-matched and mismatched transplantation from either related or unrelated donors (abstract). Kanda et al. teaches different studies reporting different daily dosages of alemtuzumab including, e.g., at least three in which the daily doses were about 10, about 20, or about 30 mg (page 587). Kanda et al. teaches alemtuzumab is used in combination with fludarabine and/or cyclophosphamide (see, e.g., page 588). For example, Kanda et al. discloses one study in which the combination of all three agents was used to prevent GVHD prior to transfer of donor cells in which fludarabine was administered to patients at a dosage of 30 mg/m2 daily beginning 5 days before the transfer for 4 days, cyclophosphamide was administered at a dosage of 500 mg/m2 daily beginning 5 days before the transfer for 4 days, and alemtuzumab was administered at a dosage of 20 mg daily beginning 4 days before the transfer for 4 days (including the day the cells were administered) (page 588).
Turtle et al. teaches preconditioning regimens including fludarabine were superior to those with cyclophosphamide alone, inducing 50% and 8% CRRs, respectively; see entire document (e.g., the abstract).
In view of the collective teachings of the prior art, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art before the effective filing date of the claimed invention to practice the method suggested by Clinical Trial NCT03751293 but using genetically engineered BCMA-specific CAR T cells that do not express CD52 as a consequence of the inactivation or disruption of an allele of the gene encoding CD52, as taught or suggested by the teachings of Kuo et al., Brentjens et al., and Kanda et al., as well as a preconditioning lymphodepleting regimen comprising administering to the patient a combination of fludarabine, cyclophosphamide, and the anti-human CD52 antibody designated CAMPATH (alemtuzumab), as suggested by Kuo et al., Clinical Trial NCT03093168, Brentjens et al., and Kanda et al. This is, in part, because, as Brentjens et al. teaches, effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, because Clinical Trial NCT03093168 (first posted March 28, 2017) describes a clinical trial in which human multiple myeloma patients are treated with anti-BCMA CAR-T cells, fludarabine, and cyclophosphamide, and because according to Kanda et al. teaches alemtuzumab has been widely used for lymphodepleting preconditioning prior to allogeneic transplantation to prevent or reduce the risk of GVHD, which is associated with morbidity and mortality. One ordinarily skilled in the art before the effective filing date of the claimed invention would have been motivated to do so in order to more efficaciously treat multiple myeloma expressing BCMA in human subjects (patients). Moreover, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art before the effective filing date of the claimed invention to practice the method suggested by Clinical Trial NCT03751293, but as modified per the suggestions of the teachings of Clinical Trial NCT03093168, Brentjens et al., Kanda et al., and Turtle et al. by using a lymphodepleting preconditioning regimen comprising the administration to the subject of alemtuzumab and both of fludarabine and cyclophosphamide. This is because it would be sensible to determine which regimen when used in conjunction with the genetically engineered T cell expressing a BCMA-specific CAR is used with the greatest efficacy. The T cells expressing the CAR will not be depleted following the administration of alemtuzumab because the cells do not express CD52, but inasmuch as it is always a common objective to optimize treatment methods, the addition of one or both of fludarabine and cyclophosphamide to the lymphodepleting preconditioning regimen should be investigated. It might be expected that a preconditioning regimen that includes fludarabine will be found to be superior to a regimen using only cyclophosphamide since Turtle et al. teaches preconditioning regimens including fludarabine were superior to those with cyclophosphamide alone; but regardless of the outcome of the investigation, because it is a common objective in the art to establish a treatment regimen that is both safe and effective, so as achieve optimal therapeutic effect and maximal benefit, it would have been immediately obvious to practice the claimed invention in light of the prior art’s teachings. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). See In re Peterson, 65 USPQ2d 1379 1382 (CA FC 2003): “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” Therefore, with particular regard to claims 44 and 45, if the prior art does not expressly teach the use of the recited lymphodepleting regimen prior to the administration of the CAR-T cells, it is submitted that it would have been prima facie obvious to one ordinarily skilled in the art before the effective filing date of the claimed invention to practice the method using such regimens in which the anti-CD52 antibody is administered at a dose of about 13, 20, or 30 mg/day and/or the regimen is initiated between 1 and 15 days prior to the administration of a first dose of the BCMA- specific CAR T cells and/or over a course of 1-5 days, wherein the dosage of fludarabine is about 30 mg/m2/day and the dosage of cyclophosphamide is about 300 mg/m2/day.
Applicant argue that Qu was published in 2022, after the effective
filing date of the instant application and is thus not prior art. Applicant argues that the non-prior art Qu is not relevant in the determination of obviousness.
In response, it is noted that Qu is not being used as prior art Qu is being used to describe the CAR that is expressed by the disclosed “C-CAR088” (donor) human BCMA-specific CAR-T cells from Clinical Trial NCT03751293, which are administered to the patients, comprises an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide, a transmembrane domain derived from human CD8a, and an intracellular signaling domain comprising a costimulatory signaling domain comprising the intracellular portion of human 4-1BB and an activating domain comprising the intracellular portion of human CD3ζ.
Qu does disclose that BCMA-specific CAR-T cells were produced using T cells from healthy donors. Brudno disclose the administration of 1-10 X 106 cells/kg of allogeneic CD19 CAR T cells to patients with B cell malignancies. Kuo disclose that the CAR T cells may be autologous or allogeneic (paragraphs [0076, 0153, 0185]. Thus, the art make obvious administering to the subject allogeneic chimeric antigen receptor (CAR)T cells comprising an anti-human B-cell maturation antigen (BCMA) CAR (BCMA CAR-T cells). Using allogeneic CAR-T cells for administering to cancer patients was well known in the art. Absent unexpected results it would have been obvious to administer allogeneic BCMA CAR-T cells.
In addition, Applicant argues that on the issue of optimizing numerical ranges, MPEP 2144.05 states that there must be an articulated rationale for finding obviousness. Applicant argues that "the examiner must make findings of relevant facts, and present the underpinning reasoning in sufficient detail." In the instant case, the prior art involved autologous (patient's own) cells (Clinical Trial 2018) and the invention involves allogeneic cells. Applicant argues that the Examiner is required to explain why the numbers are directly transferrable from autologous cells to allogeneic cells.
Applicant argues that neither the primary reference Clinical Trial 2018, nor Kuo, nor Hendrikx provide any guidance on translating the data from an autologous setting to an allogeneic setting. Applicant argues that the examiner has not presented any reasoning underpinning the conclusion that these differences would not have mattered to one of ordinary skill in the art. MPEP 2142 states that impermissible hindsight must be avoided.
Applicant also argues that a single reference (Clinical Trial 2018) providing a cell dose close to the applicant's was selected to represent the entire state of the art. However, a contemporaneous review article by Pettitt, reveals that at the time of the invention, clinical trials of CAR-T cells utilized dosages within a 1,000,000-fold range, from 104 to 1010 cells/kg (Pettitt, Table 3). Applicant argues that Kuo suggests selecting a dose of 104-109 cells/kg or a 100,000 - fold range. Applicant argues that the examiner has not provided an explanation why within the range used in the art, one of ordinary skill would have selected the single reference to the exclusion of all others. Applicant argues that selecting Clinical Trial 2018 to the exclusion of all other art is the "selective culling" based on impermissible hindsight that cannot be used to establish a prima facie
case.
Applicant argues that for the experimentation to be considered routine or ordinary, the prior art must "have suggested to one of ordinary skill in the art that this [experimentation] process should be carried out and would have a reasonable
likelihood of success, viewed in light of the prior art." Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed. Cir. 1989). MPEP 2143 likewise requires feasibility and a
reasonable expectation of success for any experimentation to yield an obvious result.
Applicant argues that on the question of whether the experimentation should be carried out, the knowledge in the art leads to the conclusion that the proposed optimization would have been unfeasible. Applicant argues that the true state of the art would have taught one of ordinary skill that the desired dose lies within at least a 100,000-fold range and possibly, within a 1,000,000-fold range. Optimization within such a range would require unrealistically massive human clinical trials involving hundreds of thousands if not millions of patients. Applicant argues that there are not enough patients to conduct the optimization proposed by the Examiner.
Applicant further argues that even if the dose-optimizing trials were feasible, obviousness requires an expectation of success. Applicant argues that none existed at the effective filing date in 2018. Applicant argues that no allogeneic CAR-T cell
therapy of any kind has been approved by the US FDA and no allogeneic BCMA-targeting CART cell therapy was even cleared to start clinical trials. In fact, the first such clinical trial (NCT04093596) was initiated by the applicant on September 23, 2019. Applicant argues that of the effective filing date, one of ordinary skill in the art would have no reasonable expectation of success with any dose of BCMA-targeting allogeneic CAR-T cells.
Applicant’s arguments have been considered but are not persuasive. As discussed above, Brudno disclose the administration of 1-10 X 106 cells/kg of CD19 CAR T cells to patients with B cell malignancies (Table 2; Page 113, 2nd paragraph to page 1118, 2nd paragraph). If a human subject were a male weighing about 52 kg, the target dose to be administered would be about 52 x 106 cells/dose to about 520 x 106 cells. If the patient were a female weighing about 45 kg, the target dose to be administered would be about 45 x 106 cells to about 405 x 106 cells/dose. Thus, the allogeneic cells administered falls within the claimed ranges.
Furthermore, Clinical Trial NCT03751293 describes a clinical trial in which human patients having relapsed or refractory multiple myeloma expressing BCMA who previously received at least one or at least two treatment regimens are treated with a target dose of dose of 1.0-9.0 x 106 anti-human BCMA CAR-T cells designated “C-CAR088” per kilogram. If a human subject were a male weighing about 52 kg, the target dose to be administered would be about 52 x 106 cells to about 468 x 106 cells. If the patient were a female weighing about 45 kg, the target dose to be administered would be about 45 x 106 cells to about 405 x 106 cells. Thus, the claimed cell doses fall within the cell doses recited in Clinical Trial NCT03751293 and overlap with the doses of allogeneic CAR-T cells of Brudno.
In addition, given the success of Brudno in treating B-cell malignancies with the CD19 CAR-T cells one of ordinary skill in the art would have had a reasonable expectation of success in treating multiple myeloma with treating multiple myeloma allogeneic human T cells comprising CD8+ cytotoxic T lymphocytes (CTLs) expressing a chimeric antigen receptor comprising an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide on the surface of the myeloma cells in the subject, a human CD8a hinge region, a human transmembrane domain, and an intracellular signaling domain comprising a costimulatory signaling domain comprising the intracellular portion of human 4-1BB and an activating domain comprising the intracellular portion of human CD3z, wherein for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose, and for subjects whose weight is less than 50 kg the dose is from about 80 x 106 cells cells/dose to about 240 x 106 cells cells/dose, or from about 240 x 106 cells cells/dose to about 360 x 106 cells cells/dose.
As discussed previously, optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal therapeutic regimens needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of parameters in therapeutic regimens would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Therefore, in conclusion, absent a showing of any unexpected results, it is submitted that the disclosures by the prior art would have rendered the claimed invention an obvious variation of the method of treating multiple myeloma in human patients as specified by the clinical trial in view of the teachings of Kuo et al.
In response to Appellants’ argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed below, there is ample motivation to combine the references independent of the inherent feature.
With respect to Applicant’s argument that one of skill in the art would not be motivated to optimize the CAR T cell doses, MPEP 2144.05(II)(B) recites that there is a motivation to optimize result-effective variables.
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In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. As evidenced by Brudno, the CAR T cell doses was a results-effective variable.
Thus, absent unexpected results it would have been obvious treat multiple myeloma comprising administering a population of allogeneic human T cells comprising CD8+ cytotoxic T lymphocytes (CTLs) expressing a chimeric antigen receptor comprising an extracellular antigen binding domain comprising an scFv that specifically binds to a human BCMA polypeptide on the surface of the myeloma cells in the subject, wherein for subjects whose weight is greater than 50 kg, the dose is from about 120 x 106 cells/dose to about 360 x 106 cells/dose, and for subjects whose weight is less than 50 kg the dose is from about 80 x 106 cells cells/dose to about 240 x 106 cells cells/dose, or from about 240 x 106 cells cells/dose to about 360 x 106 cells cells/dose
It is noted that Applicant previously argued unexpected results for a fixed dose of 320 X 106 cells cells/dose or about 480 X 106 cells cells/dose.
Summary
Claims 1, 3, 14, 17, 18, 23, 26-28, 31, 32, 34, 35, 37-40, 44-49 and 53-55 stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark Halvorson whose telephone number is (571) 272-6539. The examiner can normally be reached on Monday through Friday from 9:00 am to 6:00 pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Janet Epps-Smith, can be reached at (571) 272-0757. The fax phone number for this Art Unit is (571) 273-8300.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USP