Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-18 are pending and currently under consideration.
Claim 1 and 10 are the independent claims.
Information Disclosure Statement
The references disclosed in IDS filed on 11/7/2023 have been considered by the examiner.
Claim Objections
Claims objected to because of the following informalities:
Claim 9 recites, “wherein the of lymphodepleting agent”, which should read, “wherein the lymphodepleting agent”
Claim 1
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Indefinite Language
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 2, 4, and 11 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.
Claims 2 and 11 recite, “wherein the subject is over 55 or 65 years of age”. The scope of the claim is unclear as it is ambiguous as to whether the limitation includes subjects over 55, over 65, or both. Reciting the exact patient population (i.e. specific age) would obviate the rejection.
Claim 4 recites “wherein the vector encoding IL-37 is administered more than
one day before administration of the T cells”. The claim does not recite a range of days or an upper limit to the number of days between IL-37 and T cell administration making it unclear as to how many days are in between the IL-37 administration and the T cell administration (>1 to infinite). This step is essential to the method claims as a patient will receive maximal therapeutic benefit when the treatments are administered close in time (see page 32 of the specification). Disclosing a specific number of days or a range of days between IL-37 and T cell administration would obviate this rejection.
Correction is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-18 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-14 encompass a broad genus of methods of treating cancers and hematological malignancies wherein the methods encompass broad limitations reciting administering T cells expressing a cancer targeting chimeric antigen receptor and recombinant IL-37; wherein the subject is broadly medically immune suppressed; wherein the vector encoding IL-37 is administered in combination with a broad genus of anticancer agents. The claims encompass a method of treating all cancers with any T-cell expressing any cancer targeting chimeric antigen receptor and any recombinant IL-37 with any anticancer agent wherein the subject can be medically immune suppressed by any biological or therapeutic methods.
Claims 15-18 encompass a broad genus of vectors encoding a chimeric antigen receptor and IL-37.
However, there does not appear to be adequate written description in the specification as-filed of the cancer and hematological subtypes, T-cells, chimeric antigen receptor, rIL-37, anticancer agents, and patient population. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or U.S.C 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification (page 4, lines 12-18) describes a method of treating a cancer and a hematological malignancy (i.e. a broad cancer subtype) selected from leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia, acute monocytic leukemia (AMOL), chronic myeloid leukemia (CML), B-cell acute lymphoblastic leukemia (B-ALL), myeloproliferative neoplasms (MPNs), and lymphomas, Hodgkin's lymphomas, and non-Hodgkin's lymphomas such as Burkitt lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma (DLBCL ). The specification (page 32 lines 3-21; Figure 4B) also provides an in vivo example where immunocompromised mice were transplanted with human B-ALL cells and treated with human CD-19 directed CAR T-cells with coadministration of recombinant IL-37 wherein the combination therapy significantly increased 3-month survival of mice by 60%. However, there are no other examples for other cancer subtypes besides B-ALL. This is not deemed to be predicative of response for all cancers to the claimed cancer regimen. The specification does not reasonably convey possession of the full scope of cancer and hematological malignancies encompassed by the claims. Absent a limiting species for the term “cancer” and “hematological malignancy”, the terms open up the claimed invention to all cancers and all hematological malignancies.
Additionally, the specification (page 11 lines 20-29) describes a functional and structural definition of a chimeric antigen receptor, or “CAR” which introduces an antigen specificity, via an antigen binding domain, onto cells to which it is expressed (for example T cells such as naive T cells, central memory T cells, effector memory T cells or combination thereof) thus combining the antigen binding properties of the antigen binding domain with the T cell activity ( e.g. lytic capacity and self-renewal) of T cells. A CAR typically includes an extracellular antigen-binding domain (ectodomain), a transmembrane domain and a intracellular signaling domain. The intracellular signaling domain generally contains at least one immunoreceptor tyrosine-based activation motif (ITAM) signaling domain, e.g. derived from CD3zeta, and optionally at least one costimulatory signaling domain, e.g. derived from CD28 or 4-IBB. Additionally, the specification (pages 32-38, Figure 5) provides an example of a CD19-directed CAR T cell in the same and separate vectors with recombinant IL-37 wherein the combination therapy significantly increased 3-month survival of mice by 60%. However, there are no other examples for other CAR constructs besides the CD19-directed CAR T cell. The specification does not reasonably convey possession of the full scope of a T cell expressing a cancer targeting chimeric antigen. Absent a limiting species for the term “T cells expressing a cancer targeting chimeric antigen receptor” and “vector encoding a chimeric antigen receptor and IL-37”, the terms open up the claimed invention to encompass all variants of T cells expressing cancer targeting chimeric antigen receptor and all variants of vectors encoding a chimeric antigen receptor and IL-37.
The art of Schettini et al (PTO-892; Reference U) teaches CAR-T cell therapy has shown unprecedent efficacy in several hematologic malignancies as the T cells are engineered to express CARs specifically directed against the tumor surface antigen of interest which is cancer subtype specific due to tumor heterogeneity and plasticity leading to tumor escape base don loss of TSA expression (Schettini; page 2, paragraph 2).
Additionally, the art of Sun et al (PTO-892; Reference V) describes that CAR T cell therapy is limited by the selection and heterogeneity of target tumor antigens. Antigen expression varies between tumor types and patients and tumors can lack specific antigens (Sun, page 4, right column, paragraph 2). Therefore, the broad genus of T cells expressing a broad genus of cancer targeting chimeric antigen receptor cannot be used in a method to treat any cancer. The CAR T-cell needs to be cancer subtype specific. Sun also teaches the various specific structural components of a CAR construct to include the antigen recognition domain, transduction domain (i.e. CD3epsilon), and co-stimulatory domain(s) (i.e. CD28, 4-1BB, and/or OX40) (Sun, page 2, left column, paragraph 3). CAR designs can impact CAR T cell persistence, enhance cell-killing capacity, and anti-tumor response, and improve selective and specific recognition (Sun, page 2, right column, paragraph 1).
Regarding recombinant IL-37 (rIL-37), the specification (page 23, lines 1-14) describes IL-37 improving T-cell-mediated immunity and when combined with CAR T-cell therapy, improved their therapeutic capacity in a murine model of B-ALL. Additionally, the specification (page 23, lines 15-20) describes that transgenic IL-37 expression in aged mice rejuvenated the function of aged B-progenitor cells and abrogated the selection of B-cells harboring oncogenic mutations; thereby preventing leukemogenesis. rIL-37 treatment of aged mice also resulted in decreased surface expression of immunosuppressive molecules PD-1, TIM-3, and TIGIT on activated T-cells coincident with increased proliferation after in vitro stimulation (page 24, lines 3-5). When combined with CAR T-cell therapy, rIL-37 prevent high PD-1 surface expression on aged CAR T-cells and increased the function of endogenous and CAR T-cells leading to increased cytokine production ex vivo and the augmented protection of mice with B-ALL (page 24, lines 5-10). However the specification does not reasonably convey possession of the full scope rIL-37. Absent a limiting species for “rIL-37”, the term opens the claimed invention to encompass all variants of rIL-37.
The art of Gu et al (PTO-892; Reference W) teaches that IL-37 has five different splice isoforms (IL-37a – IL37e) each with slight differences in their amino acid sequences making them variable to tissue specific expression patterns (Gu, page 3, paragraph 2). IL-37b is currently the most well-studied in the art due to its complicated and comprehensive biological effects whereas the other IL-37 variants require further exploration into their function (Gu, page 8, paragraph 2). Additionally, Gu teaches that IL-37 can serve as a negative prognostic biomarker in several cancers including HCC, PDAC, CRC, OSCC, GBC, OSCC, NSCLC, breast cancer, CC, endometrial carcinoma, RCC, AML, MM, and soft tissue tumors but other cancer subtypes require further review (Gu, Section 6 Recent advances of IL-37 in cancer). Therefore, IL-37 is not synonymous with a specific amino acid primary sequence and structure and its expression is different in different tissue subtypes; thus, the full scope of the broad genus of rIL-37 cannot be generally used in methods for treating a broad genus of cancer.
Additionally, the specification (pages 17-18) does describe subjects that medically immune suppressed by subject having a compromised immune system and taking immunosuppressive or immunomodulatory medications/therapies with an additional example of treating immunocompromised mice with CD19-directed T cells and rIL-37. However, the specification does not clearly limit the definition of medically immune suppressed to mean due to natural/biologic causes, due to viral or bacterial diseases, or due to prior or concurrent immunosuppressive or immunomodulatory therapies. The specification does not reasonably convey possession of the full scope of medically immune suppressed encompasses by the claims.
The art of Cleveland Clinic (PTO-892; Reference X) establishes a definition of medically immune suppressed where the immune system is not working as well as it should due to a genetic or inherited condition, infections, medications, cancer or other health conditions a subject can acquire throughout life (Overview, paragraph 1). Due to this broad definition, the method can include any subject who is medically immune suppressed. There could be unpredictable consequences with the claimed method of treatment in this broad patient population due to differing disease biology and potential negative side effects with the CAR-T cell and IL-37 combination therapy.
Furthermore, the specification (page 18-19) describes specific examples of anticancer agents comprising checkpoint inhibitors, anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. The specification (page 26, lines 1-10)also describes how rIL-37 prevents the overexpression of PD-1 on aged CAR T cells. However, the specification does not provide example(s) or suggestions of combining rIL-37 with anti-PD-1 antibodies or other anticancer agents and that it produces a beneficial response in vivo or ex vivo.
The art of Ostios-Garcia (PTO-892; Page 2, Reference U) describes various anticancer drugs and/or agents including classical chemotherapy, hormones, tyrosine kinase inhibitors, monoclonal antibodies, and immunomodulatory drugs (Ostios-Garcia, Abstract, Introduction). However, each anticancer drug has a different mechanism of action and is a suitable treatment option for specific cancer(s) or genetic subtypes of cancer(s). Therefore, the broad genus of anticancer agents cannot be used to treat a broad genus of cancer.
Claim 1-18 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Enablement
Claims 1-18 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for : treating B-ALL by administering CD19 directed CAR T cells and IL-37 (SEQ ID NO:18), does not reasonably provide enablement for treating "a cancer" or "a hematological malignancy" "comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor and expressing a recombinant IL-37 protein to a subject in need thereof"; “wherein the subject is medically immune suppressed”; “wherein the vector encoding IL-37 is administered in combination with another anticancer agent”; “wherein the anticancer agent is a checkpoint inhibitor”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification disclosure does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification is not enabled for the method of “treating a cancer” or “Hematological malignancy” “comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor and administering a vector encoding a recombinant IL-37 protein to a subject in need thereof”; “wherein the subject is medically immune suppressed”; “wherein the vector encoding IL-37 is administered in combination with another anticancer agent”. The claims encompass any cancer and hematological malignancy, any T cell expressing any cancer targeting antigen receptor, any IL-37, any subject who is immunocompromised, and any anticancer agent.
The art of Sun et al (see above) teaches that CAR T cell therapy is limited by the selection and heterogeneity of target tumor antigens and that antigen expression varies between tumor types and patients and tumors can lack specific antigens (Sun, page 4, right column, paragraph 2).
The art of Gu et al (see above) teaches that IL-37 has five different splice isoforms (IL-37a – IL37e) each with slight differences in their amino acid sequences making them variable to tissue specific expression patterns (Gu, page 3, paragraph 2). Additionally, Gu teaches that IL-37 (no variant specified) can serve as a negative prognostic biomarker in several cancers including HCC, PDAC, CRC, OSCC, GBC, OSCC, NSCLC, breast cancer, CC, endometrial carcinoma, RCC, AML, MM, and soft tissue tumors but other cancer subtypes require further review (Gu, Section 6 Recent advances of IL-37 in cancer). Additionally, Gu teaches that recombinant IL-37 treatment can rejuvenate aged endogenous T cell function and boost the efficacy of aged chimeric antigen receptor T cells through downregulating PD-1 surface expression in B-ALL (Gu, page 11, left column, paragraph 2).
The prior art does not appear to provide any evidence as to treatment of the full scope of instant claim 1 of any as such, not any cancer can be treated with any T cell expressing any cancer targeting chimeric antigen receptor with any IL-37 with any anticancer agent without undue experimentation.
The specification (see page 32 and Figures 4A-B, 5) provides sufficient teachings only for the enablement of methods of treating aging and B-ALL comprising administering an effective amount of CD19 targeting CAR T cells and a vector encoding IL-37b. Additionally, the specification (see page 26, lines 1-10) provides sufficient teachings only for combining IL-37 with a PD-1 inhibitor as a means to prevent high PD-1 surface expression on aged CAR T cells. The prior art provides no compensatory guidance for treating other cancer subtypes claimed with other cancer targeting antigens to comprise the antigen binding domain of the CAR, IL-37 splice isoforms, and anticancer agents. Therefore, the amount of experimentation required to practice the invention as broadly claimed would not be reasonable.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Priority
This application is a 371 of PCT/US2022/011618 effectively filed on 1/7/2022 and claims domestic priority to U.S. Provisional Application No. 63/135,218 effectively filed on 1/8/2021.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claim(s) 1, 4-7, 10, 12-13, 15-16, is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0135894 A1 (PT0-892; Reference A; 5/9/2019; "Ma") in view of Caraffa et al (IDS Reference NPL 1; “Caraffa”).
Claim 1 recites:
A method of treating cancer comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor and administering a vector encoding a recombinant IL-37 protein to a subject in need thereof.
Ma teaches CAR T cell therapy seeing major success in hematologic malignancies that are resistant to standard chemotherapies with the most notable being CD19-specific CAR T cell therapies (Ma; [0007]). However, there are major roadblocks in the broader adoption of CAR T cells including selection of antigen target and chimeric antigen receptor(s), CAR design, and tumor heterogeneity, so there is a need to improve CAR-based therapies that are more effective, safe, and provide more efficient targeting of T-cell associated malignancies (Ma; [0009]; [0013]). To address these shortcomings, Ma teaches methods of treating cancer including hematological malignancies comprising administering engineered T cells having a first chimeric antigen receptor polypeptide and an enhancer (Ma; Abstract; [0016] - [0017]; [0019]). The enhancer is a biological molecule such as a cytokine, interleukin (IL-15, IL-18, or IL-21), or immune checkpoint molecule, that promotes or enhances the activity of the engineered cell having a CAR (Ma; [0508]-[0509]). The enhancer is secreted from the engineered CAR T cell and is designed to co-express with the CAR which helps to promote sustained survival and long-lived persistence of CAR cells (Ma; [0511]-[0513]). The vector encoding the enhancer and the engineered T cells can also be administered in combination with an anticancer agent such as PD-L1 or CTLA-4 to reduce tumor suppression that is present in the tumor (Ma; [0551]-[0555]; [0585]; [0590]). Additionally, Ma teaches a CD19, BCMA, Immunoglobulin kappa, or CD138 specific CAR that is separated from the enhancer by a high efficiency P2A self-cleavable spacer in a single vector (The reference P2A self-cleavable spacer matches 100% in sequence and length to the instant invention’s self-cleavable spacer encompassed by SEQ ID NO:21) (Ma; [0016]; [0493]; [0580]; see Figures 24-27, 33A, 34-36). The CAR and enhancer can additionally be in separate vectors (Ma; [0581]).
However, Ma does not teach the treatment comprising administration of a vector encoding a recombinant IL-37, treatment administration to a specific patient population, the treatment timing of IL-37 and T cell therapy, the orientation of the vector encoding the CAR and IL-37, and the IL-37 having the amino acid sequence of SEQ ID NO:18.
Caraffe does teach a methods of treating cancer using CAR T cell therapy and the limitations surrounding CAR T cell therapy including that CAR T cells can provoke a systemic inflammatory response in a patient mediated by inflammatory cytokines such as interleukin (IL)-1 and IL-33 (Caraffe, page 1672, paragraph 1). CAR T cell therapy can also induce expression of IL-18, a cytokine of the IL-1 superfamily, which polarizes CAR T cells, provoking an acute inflammatory response, an effect that can be mediated by IL-37, since it has been demonstrated to play a biological inhibitory role through IL-18 receptor alpha binding (Caraffe, page 1672, paragraph 1). Therefore, IL-37 is a strategy for improving CAR-T therapy by mitigating and offsetting the resulting acute inflammatory response.
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer and hematological malignancies comprising an engineered T cell comprising a cancer targeting CAR and an enhancer of Ma with the motivation to target IL-37 in combination with a CAR T-cell of Caraffe with reasonable expectation of success.
One of ordinary skill would have been motivated to make this modification and combine CAR T-cell therapy with recombinant IL-37 before the effective filing date of the instant application since Ma teaches CAR T-cell therapy improving patient outcomes and when administered in combination with an enhancer which can include cytokines, interleukins, and other immunomodulatory molecules results in sustained survival and long-lived persistence of CAR T cells. Caraffe further supports the combination of CAR T-cell and recombinant IL-37 therapy as IL-37 can also further support CAR T cell persistence and help overcome an acute inflammatory response resulting from CAR T cell therapy.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine these elements to yield predictable results to enhance the IL-37 and CAR-T cell’s ability to infiltrate the tumor immune microenvironment to target and kill cancer cells.
Regarding the recited dosing regimen of the vector encoding recombinant IL-37 and CAR T-cells, dosing regimens are considered as result-effective variable which is considered a matter of routine optimization and therefore obvious. One of ordinary skill in the art would have been motivated to provide recombinant IL-37 and the CAR T cel and optimize the timing of administration to a patient to achieve sustained survival of CAR T-cells and enhance a patient’s response to treatment.
From the combined teachings of Ma and Caraffe, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim(s) 1-2 and 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma and Caraffe in further view of Krok-Schoen et al (PTO-892; Page 2, Reference W; “Krok-Schoen”).
Ma and Caraffe have been discussed above. The claimed invention differs from the prior art in the recitation of the method of treating cancer wherein the subject is over 55 or 65 years of age in claim 2 and the method of treating a hematological malignancy wherein the subject is over 55 or 65 years of age of claim 11.
However, Krok-Schoen teaches that there is a need for better treatment options for cancer patients with hematological malignancies (HMs) as half of HMs are diagnosed in patients who are 65 years and older and 70% of cancer deaths occurs in this population (Krok-Schoen; Introduction, page 1, right column). Krok-Schoen also teaches the U.S. population continuing to age with a 67% increase in cancer incidence expected in the older adult population (Krok-Schoen; Introduction, page 1, right column).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the combined method of administering CAR T-cell therapy and recombinant IL-37 of Ma and Caraffe with a patient population of 55 or 65 years of age of Krok-Schoen with reasonable expectation of success.
One of ordinary skill would have been motivated to administer CAR T-cell therapy and recombinant IL-37 to a patient population over 55 or 65 years of age before the effective filing date of the instant application as the combination of Ma and Caraffe teach the combination of CAR T-cell and IL-37 therapy is efficacious in cancer patients and Krok-Schoen teaches an older patient population needing improved therapies as this patient population encompasses half of all HMs diagnosed in the U.S. and 70% of cancer deaths.
Therefore, it would have been obvious to a person of ordinary skill in the art to treat an older patient population (over 55 or 65 years of age) with combined CAR T-cell and IL-37 therapy to improve this patient population’s response and survival outcomes.
From the combined teachings of Ma, Caraffe, and Krok-Schoen, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim(s) 1 and 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma and Caraffe, in further view of Norris et al (PTO-892; page 3, Reference X; “Norris”).
Ma and Caraffe have been discussed above. The claimed invention differs from the prior art in the recitation of the method of treating cancer wherein the subject is medically immune suppressed in claim 3.
However, Norris teaches that cancer can cause a patient to become immune suppressed as the tumor can cause a widespread and variable disruption of the immune system (Norris; page 2). Norris teaches that even before a patient receives treatment, the cancer can weaken the immune system’s response to viral and/or bacterial infections (Norris; page 4). Additionally, Norris teaches that cancer immunotherapy is even more effective in patients whose immune systems are mounting a response as the treatment needs to be able to stimulate preexisting immune system cells especially killer T cells in order to boost their ability to effectively attack tumor cells (Norris; page 5).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer and hematological malignancies comprising administering CAR T-cells and recombinant IL-37 of Ma and Caraffe with a patient who is medically immune suppressed of Norris with reasonable expectation of success.
One of ordinary skill would have been motivated to make this modification to treat a medically immune suppressed patient with combination CAR T-cell therapy with recombinant IL-37 before the effective filing date of the instant application since Norris teaches that patients, before receiving any treatment, are already medically immune suppressed and will benefit from CAR T-cell therapy since their immune system is already stimulated and Ma and Caraffe teach combination CAR T-cell and recombinant IL-37 treatment is efficacious in cancer patients.
Therefore, it would have been obvious to a person of ordinary skill in the art to treat a patient who is medically immune suppressed with combined CAR T-cell and IL-37 therapy since cancer patients are already medically immune suppressed inherently from their cancer and CAR-T cell therapy is even more effective in patients who have already mounted an immune response against their cancer.
From the combined teachings of Ma, Caraffe, and Norris, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim(s) 1, 8, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma and Caraffe, in further view Neelapu et al (PTO-892; page 3, Reference U; “Neepalu”).
Ma and Caraffe have been discussed above. The claimed invention differs from the prior art in the recitation of the method of treating cancer wherein wherein the vector encoding IL-37 is administered to a subject with a lymphodepleted environment due to prior or concurrent administration of a lymphodepleting agent in claim 8 and wherein the lymphodepleted agent is cyclophosphamide, fludarabine, or combination thereof in claim 9.
However, Neepalu teaches that treating patients with cancer with a lymphodepleting agent such as cyclophosphamide and/or flurdarabine before anti-CD19 CAR T-cell therapy improved CAR T-cell expansion and persistence and better clinical outcomes compared to patients who did not receive lymphodepleting agents (Neepalu; Abstract; right column, paragraph 2; Figure 1). Neepalu also teaches lymphodepleting conditioning regimen likely works by multiple mechanisms, including eliminating sinks for homeostatic cytokines, such as interleukin-2 (IL-2), IL-7, and IL-15, eradicating immunosuppressive elements, such as regulatory T cells and myeloid-derived suppressor cells, inducing costimulatory molecules and downregulating indoleamine 2,3-dioxygenase in tumor cells, and promoting expansion, function, and persistence of adoptively transferred T cells (Neepalu; Abstract; right column, paragraph 2; Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer and hematological malignancies comprising administering CAR T-cells and recombinant IL-37 of Ma and Caraffe with a patient who has a lymphodepleted environment of Neepalu with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification to treat a patient with a vector encoding IL-37 who has a lymphodepleted environment due to prior or concurrent administration of a lymphodepleting agent such as cyclophosamide, flurarabine, or combination thereof as Ma and Caraffe teach that IL-37 can help prolong survival of CAR T-cells and Norris teaches lymphodepleting agents such as cyclophosamide and flurarabine have a similar effect on CAR T-cells of promoting expansion, function, and persistence of CAR T-cells.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine these elements of treating a patient with a vector encoding recombinant IL-37 who has a lymphodepleted environment to yield predictable results to enhance CAR T-cell’s function and efficacy in a cancer patient and improve a cancer patient’s survival.
From the combined teachings of Ma, Caraffe, and Neepalu, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim(s) 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable Ma and Caraffe in further view of Shaimardanova et al (PTO-892; Page 2, Reference V; “Shaimardanova”).
Ma and Caraffe have been discussed above. The claimed invention differs from the prior art in the recitation of the vector encoding a CAR and IL-37 in claim 15; wherein the chimeric antigen receptor and IL-37 are separated by a self-cleaving spacer, SEQ ID NO:21, in claim 16; wherein the IL-37 is connected to the N-terminal of the self-cleaving spacer and the chimeric antigen receptor is connected to the C-terminal of the self-cleaving spacer in claim 17.
However, Shaimardanova teaches multicistronic vectors where the encoded genes are separated either by an internal ribosome entry site (IRES) or a self-cleaving 2A peptide for gene and cell therapy to treat and prevent various human diseases such as cancer (Shaimardanova; Abstract; Graphical Abstract). Shaimardanova teaches one of the major disadvantages of using IRES vectors is that the second protein encoded in the vector exhibits relatively low expression and 2A peptides show more correlated gene expression (Shaimardanova; Section 3, paragraph 7; Section 10, paragraph 1). Specifically, P2A showed the best cleavage efficiency when compared to other 2A peptide sequences (Shaimardanova; Section 3) (Reference P2A is a 100% match in sequence and in length to the instant P2A self-cleavable spacer (SEQ ID NO:21) of the instant application). Specifically in cancer therapy, Shaimardanova that P2A-based multicistronic vectors in the production of chimeric proteins consisting of several subunits will continue to grow (Shaimardanova; Section 10, paragraph 2).
While Ma does teach the expression vector encoding the CAR and enhancer in the same vector separated by a P2A spacer wherein the CAR is located at the C terminal domain of the P2A spacer and the enhancer is located at the N terminal domain of the P2A spacer and Caraffe teaches combining IL-37 and CAR T-cell therapy, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to select the order of the CAR and IL-37 in the vector as Shaimardanova teaches that the P2A spacer does not significantly affect gene expression of the second protein that is seen when using IRES vector and showed more correlated gene expression. Additionally, gene order represents a result-effective variable and routine experimentation would have been employed to determine an order of genes providing suitable expression of each gene. See In re Aller, 220 F.2d 454 (CCPA 1955).
From the combined teachings of Ma, Caraffe, and Shaimardanova, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim(s) 15-18 is/are rejected under 35 U.S.C. 103 as being unpatentable Ma, Caraffe, and Shaimardanova, in further view of Li et al (IDS NPL Reference 8; “Li”).
Ma, Caraffe and Shaimardanova have been discussed above. The claimed invention differs from the prior art in the recitation of the vector encoding a CAR and IL-37 in claim 15; wherein IL-37 has the amino acid sequence of SEQ ID NO:18.
However, Li teaches IL-37 having 5 isoforms (IL-37a – e) with IL-37b encoding the longest transcript variants and most extensively studied IL-37 isoform (Li; Introduction, paragraph 1). Li teaches recombinant IL-37 inhibits tumor growth, angiogenesis, and migration capacity of tumor cells (Li; Introduction, paragraph 2). Additionally, IL-37b has a 218 amino acid precursor state which is cleaved by caspase-1 are residue 20 and an alternative cleavage site to produce longer, mature intracellular IL-37b and a shorter, mature extracellular IL-37b (The reference IL-37b is 100% match in sequence and in length to the instant application’s SEQ ID NO:18 of recombinant IL-37b) (See NCBI Blast sequence alignment attached). Both forms exhibit anti-inflammation effects and inhibits pro-inflammatory cytokines (Li; Introduction, paragraph 3). Li teaches decreased IL-37 expression is associated with poor prognosis in patients and correlated with tumor metastasis (Li; Results, paragraph 1). Li further teaches intracellular mature IL-37 is an endogenous inhibitor of Rac1, which is overexpression and hyperactivity being associated with aggressive tumor growth and malignant characteristics (Li; Introduction, paragraph 1; Discussion, paragraph 7). Therefore, IL-37 is a target for inhibiting tumor progression and metastasis.
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the vector encoding a CAR and IL-37 of Ma, Caraffe, and Shaimardanova with the IL-37b variant of Li with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification to combine the vector encoding a CAR and IL-37 of Ma, Caraffe, and Shaimardanova with the specific IL-37b with SEQ ID NO:18 of Li with reasonable expectation of success. Ma, Caraffe, and Shaimardanova teach a vector encoding a CAR and IL-37 wherein the CAR and IL-37 are separated by a P2A self-cleavable spacer and combining CAR and IL-37 treatment is prolongs CAR T cell survival to enhance patient survival and outcomes. Li teaches the specific IL-37b with amino acid sequence SEQ ID NO:18 which is the most extensively studied IL-37 splice isoform and exhibits anti-inflammation effects and inhibits pro-inflammatory cytokines.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine these elements of a vector encoding a CAR and IL-37 of Ma, Caraffe, and Shaimardanova with the IL-37b of Li to yield predictable results and enhance CAR T-cell’s function and efficacy in a patient while also inhibiting pro-inflammatory cytokines and increase anti-inflammation effects.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 5-7, 10 and 12-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9-12 and 16-17 of copending Application No. 18/876,140 in view of Ma (see above). '140 teaches a method of treating cancer comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor and administering a vector encoding a recombinant IL-37 protein to a subject in need thereof (instant claim 1); wherein the cancer targeting chimeric antigen receptor and recombinant IL-37 protein are expressed either in a single vector or separate vector (instant claims 12-13); wherein the T cells are administered in combination with another anticancer agent (instant claim 14). '140 teaches a vector encoding a chimeric antigen receptor and IL-37 (instant claim 15); wherein the chimeric antigen receptor and IL-37 are separated by a self-cleaving spacer having the amino acid sequence of GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 21) (reference SEQ ID NO: 21 is a 100% exact match in length and sequence as instant SEQ ID NO:21) (instant claim 16); wherein the IL-37 is connected to the N-terminal of the self-cleaving spacer and the chimeric antigen receptor is connected to the C-terminal of the self-cleaving spacer (instant claim 17).
'140 does not teach instant claims 2-4, 6-10, and 18 wherein the method of treating cancer wherein the subject is over 55 or 65 years of age; wherein the subject is medically immune suppressed; wherein the vector encoding IL-37 is administered more than one day before the administration of the T cells; wherein the anticancer agent is a checkpoint inhibitor, an anti-PD-I, anti-PD-LI anti-CTLA4 antibody or combinations thereof; wherein the chimeric antigen receptor specifically binds CD138, CD19, immunoglobulin kappa (lg-Kappa) or B-cell maturation antigen (BCMA); wherein the vector encoding IL-37 is administered to a subject with a lymphodepleted environment due to prior or concurrent administration of a lymphodepleting agent; wherein the lymphodepleting agent is cyclophosphamide, fludarabine, or combination thereof; a method of treating a hematological malignancy comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor and expressing a recombinant IL-37 protein to a subject in need thereof; and the vector encoding the CAR and IL-37 wherein IL-37 has the amino acid sequence of reference SEQ ID NO:18.
Ma teaches CAR T cell therapy seeing major success in hematologic malignancies that are resistant to standard chemotherapies with the most notable being CD19-specific CAR T cell therapies (Ma; [0007]). However, there are major roadblocks in the broader adoption of CAR T cells including selection of antigen target and chimeric antigen receptor(s), CAR design, and tumor heterogeneity, so there is a need to improve CAR-based therapies that are more effective, safe, and provide more efficient targeting of T-cell associated malignancies (Ma; [0009]; [0013]). To address these shortcomings, Ma teaches methods of treating cancer including hematological malignancies comprising administering engineered T cells having a first cancer targeting chimeric antigen receptor polypeptide and an enhancer (Ma; Abstract; [0016] - [0017]; [0019]). The enhancer is a biological molecule such as a cytokine, interleukin, or immune checkpoint molecule, that promotes or enhances the activity of the engineered cell having a CAR (Ma; [0508]-[0509]). The enhancer is secreted from the engineered CAR T cell and is designed to co-express with the CAR which helps to promote sustained survival and long-lived persistence of CAR cells (Ma; [0511]-[0513]). The vector encoding the enhancer and the engineered T cells can also be administered in combination with an anticancer agent such as PD-L1 or CTLA-4 to reduce tumor suppression that is present in the tumor (Ma; [0551]-[0555]; [0585]; [0590]). Additionally, Ma teaches a CD19, BCMA, Immunoglobulin kappa, or CD138 specific CAR that is separated from the enhancer by a high efficiency P2A self-cleavable spacer in a single vector (The reference P2A self-cleavable spacer matches 100% in sequence and length to the instant invention’s self-cleavable spacer encompassed by SEQ ID NO:21) (Ma; [0016]; [0493]; [0580]; see Figures 24-27, 33A, 34-36). The CAR and enhancer can additionally be in separate vectors (Ma; [0581]).
Regarding the recited dosing regimen of the vector encoding recombinant IL-37 and CAR T-cells, dosing regimens are considered as result-effective variable which is considered a matter of routine optimization and therefore obvious. One of ordinary skill in the art would have been motivated to provide recombinant IL-37 and the CAR T cel and optimize the timing of administration to a patient to achieve sustained survival of CAR T-cells and enhance a patient’s response to treatment.
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of treating cancer comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor of ‘140 with a CD19, BCMA, Immunoglobulin kappa, or CD138 specific cancer targeting CAR T cell of Ma with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification to treat cancer with a CD19, BCMA, Immunoglobulin kappa, or CD138 specific cancer targeting CAR as Ma teaches identification of appropriate target(s) is an important step for CAR design and the CAR design is important to address tumor heterogeneity, CAR persistency, and tumor microenvironment suppression and CD19-specific CAR T-cell therapies having remarkable results including long-term remission in B-cell malignancies (Ma; [0014]).
Therefore, it would have been obvious to a person of ordinary skill in the art to combine these elements to yield predictable results to enhance the cancer targeting CAR T-cell’s antigen specificity and improve the CAR T-cell’s response to tumor heterogeneity.
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer comprising administering an effective amount of T cells expressing a cancer targeting CAR and a vector encoding a recombinant IL-37 protein wherein the IL-37 vector is administered in combination with another anticancer agent of ‘140 with an anti-PD-L1, or CTLA-4 antibody of Ma with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification and combine the CAR T-cell, IL-37, and anticancer agent treatment of ‘140 with an anticancer agent being anti-PD-L1 or anti-CTLA-4 antibodies of Ma in order to reduce tumor suppression that is present in the tumor, enhance the efficacy of the CAR T-cell treatment, and help eliminate a tumor.
Therefore, it would have been obvious to one of ordinary skill in the art to combine these elements of CAR T-cell, IL-37, and anti-PD-L1 or anti-CTLA-4 antibody treatment to yield predictable results of treating and eliminating a patient’s tumor.
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer of ‘140 with the method of treating a hematological malignancy of Ma with reasonable expectation of success.
One of ordinary skill would have been motivated to make this modification to treat hematological malignancies with combination CAR T-cell and IL-37 therapy as Ma teaches that there is a need to improve and create more efficient CAR T-cell therapy for hematological malignancies and combining a CAR T-cell with an enhancer such as an anti-inflammatory interleukin can increase CAR T-cell persistence and increase the efficacy of CAR T-cell therapy.
Therefore, it would have been obvious to a person of ordinary skill in the art to treat a hematological malignancy with combination CAR T-cell and IL-37 therapy to improve CAR T-cell based therapies and patient outcomes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claims 1-2, 4-7 and 10-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9-12 and 16-17 of copending Application No. 18/876,140 in view of Ma (see above) as applied above in further view of Krok-Schoen (see above).
‘140 and Ma have been discussed above. The claimed invention differs from ‘140 and Ma (see above) with respect to instant claims 2 and 11, the method of treating cancer and the method of treating an hematological malignancy wherein the subject is over 55 or 65 years of age, as Krok-Schoen teaches that there is a need for better treatment options for cancer patients with hematological malignancies (HMs) as half of HMs are diagnosed in patients who are 65 years and older and 70% of cancer deaths occurs in this population (Krok-Schoen; Introduction, page 1, right column). Krok-Schoen also teaches the U.S. population continuing to age with a 67% increase in cancer incidence expected in the older adult population (Krok-Schoen; Introduction, page 1, right column).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method treating cancer and hematological malignancies comprising administering CAR T-cell therapy and recombinant IL-37 of ‘140 and Ma with a patient population of 55 or 65 years of age of Krok-Schoen with reasonable expectation of success.
One of ordinary skill would have been motivated to administer CAR T-cell therapy and recombinant IL-37 to a patient population of 55 or 65 years of age before the effective filing date of the instant application as ‘140 and Ma teach the combination of CAR T-cell and IL-37 therapy is efficacious in cancer and hematological malignancy patients and Krok-Schoen teaches an older patient population needing improved therapies as this patient population encompasses half of all HMs diagnosed in the U.S. and 70% of cancer deaths.
Therefore, it would have been obvious to a person of ordinary skill in the art to treat an older patient population (55 or 65 years of age) with combined CAR T-cell and IL-37 therapy to improve this patient population’s response and survival outcomes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of copending Application No. 18/876,140 in view of Norris (see above).
'140 has been discussed above. The claimed invention differs from '140 from above with respect to instant claim 3, the method of treating cancer wherein the subject is medically immune suppressed, as Norris teaches that cancer can cause a patient to become immune suppressed as the tumor can cause a widespread and variable disruption of the immune system (Norris; page 2). Norris teaches that even before a patient receives treatment, the cancer can weaken the immune system’s response to viral and/or bacterial infections (Norris; page 4). Additionally, Norris teaches that cancer immunotherapy is even more effective in patients whose immune systems are mounting a response as the treatment needs to be able to stimulate preexisting immune system cells especially killer T cells in order to boost their ability to effectively attack tumor cells (Norris; page 5).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer comprising administering CAR T-cells and recombinant IL-37 of ‘140 with a patient who is medically immune suppressed of Norris with reasonable expectation of success.
One of ordinary skill would have been motivated to make this modification to treat a medically immune suppressed patient with combination CAR T-cell therapy with recombinant IL-37 before the effective filing date of the instant application since Norris teaches that patients, before receiving any treatment, are already medically immune suppressed and will benefit from CAR T-cell therapy since their immune system is already stimulated.
Therefore, it would have been obvious to a person of ordinary skill in the art to treat a patient who is medically immune suppressed with combined CAR T-cell and IL-37 therapy since cancer patients are already medically immune suppressed inherently from their cancer and CAR-T cell therapy is even more effective in patients who have already mounted an immune response against their cancer.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 8, and 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/876,140 in view of Neepalu (see above).
'140 has been discussed above. The claimed invention differs from '140 from above with respect to instant claims 8-9, the method of treating cancer wherein the vector encoding IL-37 is administered to a subject with a lymphodepleted environment due to prior or concurrent administration of a lymphodepleting agent wherein the lymphodepleting agent is cyclophosphamide, fludarabine, or combination thereof, as Neepalu teaches that treating patients with cancer with a lymphodepleting agent such as cyclophosphamide and/or flurdarabine before anti-CD19 CAR T-cell therapy improved CAR T-cell expansion and persistence and better clinical outcomes compared to patients who did not receive lymphodepleting agents (Neepalu; Abstract; right column, paragraph 2; Figure 1). Neepalu also teaches lymphodepleting conditioning regimen likely works by multiple mechanisms, including eliminating sinks for homeostatic cytokines, such as interleukin-2 (IL-2), IL-7, and IL-15, eradicating immunosuppressive elements, such as regulatory T cells and myeloid-derived suppressor cells, inducing costimulatory molecules and downregulating indoleamine 2,3-dioxygenase in tumor cells, and promoting expansion, function, and persistence of adoptively transferred T cells (Neepalu; Abstract; right column, paragraph 2; Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the method of treating cancer comprising administering CAR T-cells and recombinant IL-37 of ‘140 with a patient who has a lymphodepleted environment of Neepalu with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification to treat a cancer patient with a vector encoding IL-37 who has a lymphodepleted environment due to prior or concurrent administration of a lymphodepleting agent such as cyclophosamide, flurarabine, or combination thereof as Neepalu teaches lymphodepleting agents such as cyclophosamide and flurarabine promote the expansion, function, and persistence of CAR T-cells.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine these elements of treating a patient with a vector encoding recombinant IL-37 who has a lymphodepleted environment to yield predictable results to enhance CAR T-cell’s function and efficacy in a cancer patient and improve a cancer patient’s survival.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 15, 17, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15, 17, and 18 of copending Application No. 18/876,140 in view of Li (see above).
‘140 has been discussed above. The claimed invention differs from '140 from above with respect to instant claims 15, 17, and 18, a vector encoding a CAR and IL-37 wherein the IL-37 is connected to the N-terminal of the self-cleaving spacer and the CAR is connected to the C-terminal of the self-cleaving spacer wherein IL-37 has the amino acid sequence of SEQ ID NO:18, as Li teaches IL-37 having 5 isoforms (IL-37a – e) with IL-37b encoding the longest transcript variants and most extensively studied IL-37 isoform (Li; Introduction, paragraph 1). Li teaches recombinant IL-37 inhibits tumor growth, angiogenesis, and migration capacity of tumor cells (Li; Introduction, paragraph 2). Additionally, IL-37b has a 218 amino acid precursor state which is cleaved by caspase-1 are residue 20 and an alternative cleavage site to produce longer, mature intracellular IL-37b and a shorter, mature extracellular IL-37b (The reference IL-37b is 100% match in sequence and in length to the instant application’s SEQ ID NO:18 of recombinant IL-37b) (See NCBI Blast sequence alignment attached). Both forms exhibit anti-inflammation effects and inhibits pro-inflammatory cytokines (Li; Introduction, paragraph 3). Li teaches decreased IL-37 expression is associated with poor prognosis in patients and correlated with tumor metastasis (Li; Results, paragraph 1). Li further teaches intracellular mature IL-37 is an endogenous inhibitor of Rac1, which is overexpression and hyperactivity being associated with aggressive tumor growth and malignant characteristics (Li; Introduction, paragraph 1; Discussion, paragraph 7). Therefore, IL-37 is a target for inhibiting tumor progression and metastasis.
It would have been prima facie obvious to one of ordinary skill in the art, before of the effective filing date of the instant application, to have modified the vector encoding a CAR and IL-37 of ‘140 with the IL-37b variant of Li with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification to combine the vector encoding a CAR and IL-37 with a P2A self-cleavable spacer of ‘140 with the specific IL-37b with SEQ ID NO:18 of Li as Li teaches the specific IL-37b with amino acid sequence SEQ ID NO:18 which is the most extensively studied IL-37 splice isoform and exhibits anti-inflammation effects and inhibits pro-inflammatory cytokines.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine these elements of a vector encoding a CAR and IL-37 separated by a P2A self-cleavable spacer with the IL-37b of Li to yield predictable results and enhance CAR T-cell’s function and efficacy in a patient while also inhibiting pro-inflammatory cytokines and increase anti-inflammation effects.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/LEAH ELIZABETH STEIN/ Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641