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 .
Response to Amendment
Applicant’s amendment filed on 5/6/2026 is acknowledged.
Claims 1-17 and 19 are pending and under consideration. Claim 18 is cancelled.
Rejections/objections not repeated in this Action is withdrawn or moot.
Response to Arguments
Applicant's arguments filed 5/6/2026 have been fully considered but they are not persuasive.
Written Description and Enablement:
Applicant argues the amended base claim recites the amino acid sequence of SEQ ID NO: 18.
However, the amended claims still require antigen binding domain structures, for example, those binding to the antigens recited in claim 7.
Applicant argues the claimed invention is different from Amgen, since Amgen is about products and the claimed invention is a method. Applicant also cites Teva v. Eli Lilly (Fed. Cir. April 2026) and GBR v. Eli Lilly & Co., 2017-2603, at *2 (Fed. Cir. Oct. 10, 2018).
However, Teva v. Eli Lilly (Fed. Cir. April 2026) involved a small molecule case, not antibodies, not a genus of antibodies in a CAR-T therapy. The more relevant case law to the instantly claimed method is Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1333 (Fed. Cir. 2021), where the Federal Circuit addressed written description in its evaluation of claims in a patent for antigen receptors used in T cell therapy.
Applicant also argues that the claimed embodiments are directed to methods of treating leukemia and hematological malignancies with a vector encoding CD37 having SEQ IN NO: 18 and T cells. Thus, the crux patent boundary lies in the use of CD37 with T cells for treating hematological malignancies such as leukemia.
This argument is not persuasive because the narrowest claims in regard to the scope of antibodies being used in the CAR-T therapy are the subgenus that specifically binds CD138, CD19, immunoglobulin kappa (Ig-Kappa) or B-cell maturation antigen (BCMA) as recited in claim 7.
Applicant also argues that no working example is needed. It is true no working example needs to be present but in order for an invention to be enabled, a nexus should be provided between the claimed invention and why it would work without an undue experimentation by a skilled artisan.
Obviousness Rejections:
Applicant argues that claim 1 has been amended to recite treating leukemia and claims 1 and 10 have been amended to recite IL-37 comprising the amino acid sequence of SEQ ID NO: 18 previously included in now cancelled dependent claim 18. It is noted that dependent claim 18 was not rejected based on Ma and Caraffa. Ma and Caraffa do not teach or suggest a IL-37 having SEQ ID NO: 18.
These arguments have been fully considered but found unpersuasive because on pages 24-25 of the Office action mailed on 02/11/2026, claims 15-18 was rejected because Li teaches a IL-37 having SEQ ID NO: 18. The previous rejection on page 24-25 would be applied to the new rejection of the amended claims. See below.
Claim Rejections - 35 USC § 112
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 are 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.
Applicant is in possession of: a method of treating leukemia comprising administering an effective amount of CD19 CAR T cells and administering a vector encoding a recombinant IL-37 protein to a subject in need thereof wherein IL-37 comprises the amino acid sequence of SEQ ID NO:18; wherein the vector encoding IL-37 is administered in combination another anticancer agent of a checkpoint inhibitor, an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody; wherein the CD19 and recombinant IL-37 are expressed in a single vector or separate vector; wherein the T cells are administered in combination with another anticancer agent of a checkpoint inhibitor, an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody; a vector encoding a CD19 CAR and IL-37 wherein IL-37 comprises the amino acid sequence of SEQ ID NO:18; a vector encoding a CD19 CAR and the nucleic acid of SEQ ID NO:19.
Applicant is not in possession of: a method of treating leukemia comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor of instant claim 1; wherein the subject is medically immune suppressed of instant claim 3; wherein the vector encoding IL-37 is administered in combination with another anticancer agent of instant claim 5; a method of treating hematological malignancy comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor of instant claim 10; the cancer targeting chimeric antigen receptor of instant claims 12-13; wherein the T cells are administered in combination with another anticancer agent of instant claim 14; and the chimeric antigen receptor of instant claims 15-17 and 19.
Claims 1-6, 8-17, and 19 encompass methods of treating leukemia and a broad genus of hematological malignancies wherein the methods encompass broad limitations reciting administering T cells expressing a broad genus of cancer targeting chimeric antigen receptor; wherein the subject is broadly medically immune suppressed; wherein the claimed IL-37 protein is administered in combination with a broad genus of anticancer agent; and a vector encoding a broad genus of chimeric antigen receptor. The claims encompass a method of treating leukemia and any hematological malignancy with any T-cell expressing any cancer targeting chimeric antigen receptor wherein the claimed IL-37 protein is administered with any anticancer agent wherein the subject can be medically immune suppressed by any natural, biological, therapeutic, or combination method(s). The claims encompass a vector encoding any chimeric antigen receptor and the claimed IL-37.
However, there does not appear to be adequate written description in the specification as-filed of the hematological subtypes, T-cells, chimeric antigen receptor, 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, ,i 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 48) also provides an in vivo example where immunocompromised mice were transplanted with human B-ALL cells and treated with human CD-19 directed CART-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 hematological malignancies encompassed by the claims. Absent a limiting species for the term ""hematological malignancy", the terms open up the claimed invention to 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 CART
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 CART 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 ", 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.
The art of Schettini et al (PTO-892 filed on 2/11/2026; 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 based on loss of TSA expression (Schettini; page 2, paragraph 2).
Additionally, the art of Sun et al (PTO-892 filed on 2/11/2026; 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, 4-1 BB, and/or OX40) (Sun, page 2, left column, paragraph 3). CAR designs can impact CART cell persistence, enhance cell-killing capacity, and anti-tumor response, and improve selective and specific recognition (Sun, page 2, right column, paragraph 1).
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 rll-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 (PT0-892 filed on 2/11/2026; 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-L 1, and anti-CTLA- 4 antibodies. The specification (page 26, lines 1-10)also describes how rll-37 prevents the overexpression of PD-1 on aged CART cells. However, the specification does not provide example(s) or suggestions of combining rll-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 filed on 2/11/2026; 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 leukemia and a broad genus of hematological malignancies.
As such, claims 1-6 and 8-17 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Enablement
Claims, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While being enabled for: a method of treating leukemia comprising administering an effective amount of CD19 CAR T cells and administering a vector encoding a recombinant IL-37 protein to a subject in need thereof wherein IL-37 comprises the amino acid sequence of SEQ ID NO:18; wherein the vector encoding IL-37 is administered in combination another anticancer agent of a checkpoint inhibitor, an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody; wherein the CD19 and recombinant IL-37 are expressed in a single vector or separate vector; wherein the CD-19 CAR T cells are administered in combination with another anticancer agent of a checkpoint inhibitor, an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody; a vector encoding a CD19 CAR and IL-37 wherein IL-37 comprises the amino acid sequence of SEQ ID NO:18; a vector encoding a CD19 CAR and the nucleic acid of SEQ ID NO:19.
The specification does not provide enablement for: a method of treating leukemia comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor of instant claim 1; wherein the subject is medically immune suppressed of instant claim 3; wherein the vector encoding IL-37 is administered in combination with another anticancer agent of instant claim 5; a method of treating hematological malignancy comprising administering an effective amount of T cells expressing a cancer targeting chimeric antigen receptor of instant claim 10; the cancer targeting chimeric antigen receptor of instant claims 12-13; wherein the T cells are administered in combination with another anticancer agent of instant claim 14; and the chimeric antigen receptor of instant claims 15-17 and 19.
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 claims encompass hematological malignancy, any T cell expressing any cancer targeting antigen receptor, any subject who is medically immune suppressed, any anticancer agent, and any vector encoding a chimeric antigen receptor.
The scope of the claims encompass hundreds if not millions of CAR structural possibilities and anticancer agents that perform the recited function of a “chimeric antigen receptor” and “anticancer agent” in a method for treating leukemia and hematological malignancy in combination with the claimed recombinant IL-37 protein in a patient that is medically immune suppressed.
The prior art does not appear to provide any evidence as to treatment of the full scope of instant claims 1-6, 8-17, and 19 of any as such, not any leukemia and hematological malignancy can be treated with any T cell expressing any cancer targeting chimeric antigen receptor and any anticancer agent in combination with the claimed recombinant IL-37 without undue experimentation.
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 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 CART 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 hematological malignancy subtypes claimed with other cancer targeting antigens to comprise the antigen binding domain of the CAR 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.
Claims 1, 4-7, 10, and 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0135894 A1 (PT0-892 filed on 2/11/2026; Reference A; "Ma") in view of Caraffa et al (IDS filed on 11/7/2023; Reference NPL 1; "Caraffa") and Li et al (IDS filed on 11/7/2023; NPL Reference 8; “Li”).
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 CART cell therapies (Ma; [0007]). However, there are major roadblocks in the broader adoption of CART 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]; [00131). To address these shortcomings, Ma teaches methods of treating cancer such hematological malignancies including leukemia comprising administering engineered T cells having a first chimeric antigen receptor polypeptide and an enhancer (Ma; Abstract; [0016] - [0019]; [00191). 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]-[05131). 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 inhibitors to reduce tumor suppression that is present in the tumor (Ma; [0551]-[0555]; [0585]; [05901). Additionally, Ma teaches a CD19, BCMA, lmmunoglobulin 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 wherein IL-37 comprises the amino acid sequence of SEQ ID NO:18 of instant claim 1; wherein the vector encoding IL-37 is administered more than one day before administration of the T cells of instant claim 4; a vector encoding a chimeric antigen receptor and IL-37 wherein IL-37 comprises the amino acid sequence of SEQ ID NO:18 of instant claim 15; and the vector of claim 15 comprising the nucleic acid of SEQ ID NO:19 of instant claim 19.
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.
Li does teach 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 filed on 2/11/2026). 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 method of treating leukemia 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 the IL-37b protein of Li reasonable expectation of success. One of ordinary skill would have been motivated to modify the enhancer component of the engineered CAR T cell of Ma with the motivation to target IL-37 in combination with a CAR T cell of Caraffe with IL-37b protein of Li since Ma teaches CART-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 and Caraffe further teaches IL-37 can further supports CAR T cell persistence and help overcome an acute inflammatory response resulting from CAR T cell therapy. 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 modify the enhancer of the engineered CAR T cell in a method of treating leukemia and hematological malignancies of Ma with the IL-37b protein of Li with the motivation to target IL-37 in combination with a CAR T cell of Caraffe to yield predictable results of increasing CAR T cell survival and persistence in a patient.
It would also have been prima facie obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components and the optimal timing of administration of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
From the combined teachings of Ma, Caraffe, and Li, 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 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ma, Caraffe, and Li in further view of Krok-Schoen et al (PTO-892 filed on 2/11/2026; Page 2, Reference W; "Krok-Schoen").
Ma, Caraffe, and Li have been discussed above. The claimed invention differs from the prior art in the recitation of the method of treating leukemia wherein the subject is over 55 years of age in claim 2 and the method of treating a hematological malignancy wherein the subject is over 55 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 method of treating leukemia and hematological malignancies comprising administering CAR T-cell therapy and recombinant IL-37b of Ma, Caraffe, and Li with a patient population of 65 years of age or over 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-37b of Ma, Caraffe, and Li to a patient population of 65 years of age or over before the effective filing date of the instant application as the combination of Ma, Caraffe, and Li teach the combination of CAR T-cell and IL-37b therapy sustains CAR T cell activity and persistence in a patient with leukemia and hematological malignancies 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 65 years of age) with combined CAR T-cell and IL-37 therapy to improve this patient population's treatment options and increase response and survival outcomes.
From the combined teachings of Ma, Caraffe, Li, 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.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Ma, Caraffe, and Li, in further view of Norris et al (PTO-892 filed on 2/11/2026; page 3, Reference X; "Norris").
Ma, Caraffe, and Li 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 of instant 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 leukemia and hematological malignancies comprising administering CAR T-cells and recombinant IL-37b of Ma, Caraffe, and Li 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-37b since Norris teaches that patients, before receiving any treatment, are already medically immune suppressed and will benefit from CART-cell therapy since their immune system is already stimulated and Ma, Caraffe, and Li teach combination CAR T-cell and recombinant IL-37b treatment can help increase CAR T cell persistence in a patient. 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, Li, 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.
Claims 1, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Ma, Caraffe, and Li, in further view Neelapu et al (PTO-892 filed on 2/11/2026; page 3, Reference U; "Neepalu").
Ma, Caraffe, and Li have been discussed above. The claimed invention differs from the prior art in the recitation of 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 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 CART-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 leukemia and hematological malignancies comprising administering CAR T-cells and recombinant IL-37b of Ma, Caraffe, and Li 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 leukemia 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, Caraffe, and Li 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, Li, 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.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Ma, Caraffe, and Li in further view of Shaimardanova et al (PTO-892 filed on 2/11/2026; Page 2, Reference V; "Shaimardanova").
Ma, Caraffe, and Li 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, Caraffe teaches combining IL-37 and CART-cell therapy, and Li teaches the IL-37b isoform is the most extensively studied isoform of IL-37 and exhibits antiinflammation effects and inhibits pro-inflammatory cytokines, 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-37b 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, Li, 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.
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, 4-5, 7-12 and 14-17 of copending Application No. 18/876,140 (“‘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 and 10); wherein the recombinant IL-37 protein comprises the amino acid sequences VLKSG (reference SEQ ID NO:24, D73K mutation) (instant claim 1, 10 and 15); wherein the recombinant IL-37 protein comprises the amino acid sequences of MSFVGENSGVKMGSEDWEKDEPQCCLEDPAGSPLEPGPSLPTMNFVHTSPKVKN LNPKKFSIHDQDHKVLVLKSGNLIAVPDKNYIRPEIFFALASSLSSASAEKGSPILLGVSK GEFCLYCDKDKGQSHPSLQLKKEKLMKLAAQKESARRPHIFYRAQVGSWNMLESAAHPGWFICTSCNCNEPVGVTDKFENRKHIEFSFQPVCKAEMSPSEVSD (reference SEQ ID NO:27) (instant claims 1, 10 and 15) (Reference SEQ ID NO:27 and 24 when combined are 100% sequence identical in sequence and length to instant SEQ ID NO:18); 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 recombinant IL-37 protein comprises the amino acid sequences of VLKSG (SEQ ID NO: 24, D73K mutation) (instant claim 15); wherein the recombinant IL-37 protein comprises the amino acid sequences of MSFVGENSGVKMGSEDWEKDEPQCCLEDPAGSPLEPGPSLPTMNFVHTSPKVKN LNPKKFSIHDQDHKVLVLKSGNLIAVPDKNYIRPEIFFALASSLSSASAEKGSPILLGVSK GEFCLYCDKDKGQSHPSLQLKKEKLMKLAAQKESARRPHIFYRAQVGSWNMLESAAHPGWFICTSCNCNEPVGVTDKFENRKHIEFSFQPVCKAEMSPSEVSD (reference SEQ ID NO:27) (instant claim 15) (Reference SEQ ID NO:27 and 24 when combined are 100% sequence identical in sequence and length to instant SEQ ID NO:18); 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 100% sequence identical in length and sequence to 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).
Ma teaches CAR T cell therapy seeing major success in hematologic malignancies including leukemia 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]; [00131). To address these shortcomings, Ma teaches methods of treating cancer such hematological malignancies including leukemia comprising administering engineered T cells having a first chimeric antigen receptor polypeptide and an enhancer (Ma; Abstract; [0016] - [0019]; [00191). 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]-[05131). 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 inhibitors to reduce tumor suppression that is present in the tumor (Ma; [0551]-[0555]; [0585]; [05901). Additionally, Ma teaches a CD19, BCMA, lmmunoglobulin 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).
It would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of treating cancer comprising administering T cells expressing a cancer targeting chimeric antigen receptor and IL-37 of SEQ ID NO:24 and 27 of ‘140 with the method of treating hematological malignancies including leukemia of Ma with reasonable expectation of success. One of ordinary skill in the art would have been motivated to treat hematological malignancies including leukemia of Ma with the T cells expressing a cancer targeting chimeric antigen receptor and IL-37 of SEQ ID NO:24 and 27 of ‘140 since Ma teaches there is a need to improve CAR-based therapies that are more effective, safe, and provide more efficient targeting of T-cell associated malignancies and a T cell expressing a CD19, BCMA, lmmunoglobulin kappa, or CD138 specific chimeric antigen receptor polypeptide and an enhancer (cytokine, interleukin, etc.) can help overcome these shortcomings. Therefore, one of ordinary skill in the art would have been motivated to combine the T cells expressing a cancer targeting chimeric antigen receptor and IL-37 of SEQ ID NO:24 and 27 of ‘140 with the method of treating hematological malignancies including leukemia of Ma to provide more effective, safe, and efficient targeting for patients with hematological malignancies including leukemia.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of treating cancer comprising administering T cells expressing a cancer targeting chimeric antigen receptor and IL-37 of SEQ ID NO:24 and 27 of ‘140 with administration of an anticancer agent including PD-L1 or CTLA-4 inhibitors of Ma with reasonable expectation of success. One of ordinary skill in the art would have been motivated to combine the method of treating cancer of ‘140 with administering an anticancer agent including PD-L1 or CTLA-4 inhibitors since Ma teaches 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 inhibitors to reduce tumor suppression that is present in the tumor. Therefore, it would have been obvious to a person of ordinary skill in the art to combine the method of treating cancer comprising administering T cells expressing a cancer targeting chimeric antigen receptor and IL-37 of SEQ ID NO:24 and 27 of ‘140 with administration of an anticancer agent including PD-L1 or CTLA-4 inhibitors of Ma to yield predictable results of reducing tumor suppression that is present in the tumor.
It would also have been prima facie obvious to one of ordinary skill in the art at the time Applicant's invention was made to determine all operable features of optimal dosage of the components and the optimal timing of administration of the components because dosage is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. The determination of the optimal dosage of antibody, including timing, frequency and route of treatment are well within the purview of one of ordinary skill in the art at the time the invention was made and lend no patentable import to the claimed invention. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454,456,105 USPQ 233; 235 (CCPA 1955). see MPEP § 2144.05 part II.
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 2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-4 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 leukemia and the method of treating an hematological malignancy wherein the subject is over 55 years of age.
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 leukemia and hematological malignancies comprising administering CART-cell therapy and recombinant IL-37 of '140 and Ma with a patient population of 55 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 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 for patients with hematological malignancies including leukemia 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 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 Ma (see above) as applied above in further view of Norris (see above).
'140 and Ma have 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.
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 leukemia comprising administering CAR T-cells and recombinant IL-37 of '140 and Ma 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 Ma (see above) as applied above in further view of Neepalu (see above).
'140 and Ma have 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.
Neepalu teaches that treating patients with cancer with a lymphodepleting agent such as cyclophosphamide and/or flurdarabine before anti-CD19 CART-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 leukemia comprising administering CAR T-cells and recombinant IL-37 of '140 and Ma 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.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH ELIZABETH STEIN whose telephone number is (571)272-0093. The examiner can normally be reached M-F 8-5:30 EST.
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/LEAH ELIZABETH STEIN/ Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641
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