DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election without traverse of the below-listed species in the reply filed on 08/27/2026 is acknowledged.
Elected Species:
An adaptive cell therapy (ACT) immune cell that is a T cell.
An ACT immune cell that comprises a chimeric antigen receptor (CAR).
A tumor associated antigen (TAA) targeted by the CAR that is CD20.
A checkpoint inhibitor that is an anti-PD1 antibody comprising HCVR, HCDR1, HCDR2, HCDR3, LCVR, LCDR1, LCDR2, LCDR3, HC, and LC amino acid sequences of SEQ ID NOs: 20, 21, 22, 23, 5, 6, 7, 8, 24, and 25, respectively (corresponding to REGN10597).
A cancer that is lymphoma.
An additional therapeutic agent that is a chemotherapeutic agent.
Claim Status
Claims 6 and 42 have been cancelled and claims 1-5, 7-20, 22, 24-25, and 28-40 have been amended, as requested in the preliminary amendment filed on 01/12/2024. Following the amendment, claims 1-5 and 7-41 are pending in the instant application.
Claims 1-5 and 7-41 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-5 and 7-41 have an effective filing date of October 31, 2022 corresponding to PRO 63/381,590.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/30/2023 and 03/06/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The specification is objected to for the use of the terms, for example, FICOLL, nanobodies, small modular immunopharmaceuticals, and Dynabeads, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The specification is further objected to because of the following informalities: SEQ ID NOs: 7 and 35 are indicated as "000" in the sequence listing. Applicants must delete reference to the SEQ ID NOs and spell out the sequence in the specification. Appropriate correction is required.
Claim Interpretation
With regard to the sequence language in the instant claims, the following are noted:
The recitation of, for example, “comprising an amino acid sequence selected from SEQ ID NOs: 1, 11, and 20” is being interpreted such that a reference sequence meets the limitation when the reference sequence comprises or consists of a full-length sequences corresponding to one of SEQ ID NOs: 1, 11, or 20. This interpretation pertains to claims 10 and 16.
The recitation of, for example, “comprise the amino acid sequence” or “comprise the amino acid sequences” are being interpreted such that a reference sequence, or reference sequences, meet the limitation(s) when the reference sequence(s) comprise or consist of the full-length sequences recited with the above-listed limitations. This interpretation pertains to claims 11, 15, 17-19, 21, 23, and 27.
The recitation of, for example, “comprises a HCVR/LCVR amino acid sequence pair selected from SEQ ID NOs: 1/5, 11/15, and 20/5” is being interpreted such that in order for a reference sequence or a pair of reference sequences to meet the above limitation, the reference sequence or pair of reference sequences must comprise exact matches to each of SEQ ID NOs: 1 and 5, 11 and 15, or 20 and 5. This interpretation pertains to claim 12.
Claim Objections
Claim 11 is objected to because of the following informalities: SEQ ID NO: 7 is indicated as "000" in the sequence listing. Applicants must delete reference to the SEQ ID NO and spell out the sequence in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 21-24 and 32 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 recites the limitation "the IL2" in line 1. There is insufficient antecedent basis for this limitation in the claim. It is unclear if “the IL2” is intended to refer to the “IL2 moiety” as a whole, or if it is intended to refer to “wild type IL2”, and as such the claim is considered to be indefinite.
Claim 22 recites the limitations "the IL2 or fragment thereof" and "the IL2Ra or fragment thereof" in lines 2-3. There is insufficient antecedent basis for these limitations in the claim. Claim 22 depends from claim 1, and neither of claims 1 or 22 recite an IL2 or fragment thereof, nor an IL2Ra or a fragment thereof, and as such the claim is considered to be indefinite because it is unclear what "the IL2 or fragment thereof" and "the IL2Ra or fragment thereof" are referring to.
Claim 23 recites the limitations "the IL2Ra or fragment thereof" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 23 depends from claim 22, and the recitation of “the IL2Ra or fragment thereof” also lacks antecedent basis in claim 22; thus the recitation of “the IL2Ra or fragment thereof” in claim 23 also lacks antecedent basis and the claim is considered to be indefinite because it is unclear what "the IL2Ra or fragment thereof" is referring to.
Claim 24 recites the limitation “the heavy chain constant region of each monomer” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 24 depends from claim 1, and neither of claims 1 or 24 recite a heavy chain constant region, and as such the claim is considered to be indefinite because it is unclear what “the heavy chain constant region of each monomer” is referring to.
With regard to claim 32, the claim is considered to be indefinite because it is unclear if in the list of the recited therapeutic effects, of which one or more are required, if the recitation of “increase in survival, partial response, and complete response” is intended to be interpreted as a single limitation wherein an increase in each of survival, partial response, and complete response are required to meet that limitation, or if “increase in survival, partial response, and complete response” is intended to be interpreted as separate limitations wherein an increase in survival, and increase in partial response, or an increase in complete response. Thus, the claim is considered to be indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 26 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the clam upon which it depends. Claim 26 fails to further limit the subject matter of claim 25 from which it depends. Claim 25 is drawn to the method of claim 1, wherein the targeted immunocytokine comprises a PD-1 targeting moiety and an IL2 moiety; it is specifically noted that the PD-1 targeting moiety corresponds to the immunoglobulin antigen-binding domain of a checkpoint inhibitor, as recited in claim 1. Thus, the recitation of “wherein the PD-1 targeting moiety comprises an immunoglobulin antigen-binding domain that binds specifically to PD-1” does not further limit the PD-1 targeting moiety recited in claim 25. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5 and 7-41 are rejected under 35 U.S.C. 103 as being unpatentable over US 2021/0188934 A1 (herein after referred to as "Wu") in view of US 12,528,851 (herein after referred to as "Bloch") and non-patent literature by Zheng et. al. (Cell & Molecular Immunology, January 2022, 19, 192-209; herein after referred to as “Zheng”).
Wu teaches that the therapeutic indices of a variety of IL2 molecules with various degrees of receptor attenuation can be improved by appropriately balancing the ability of an IL2 agonist to be localized to a site or cell type of interest (e.g., the tumor environment generally or tumor reactive T cells specifically) and modulating the level activity of the IL2 component at the site of interest and/or until it reaches the site or cell type of interest (Paragraph 0014); the inventors have developed IL2 molecules (referred to herein as IL2 agonists) that are believed to be more effective than the CD122 directed IL2 molecules currently under development for the treatment of cancer, wherein the IL2 agonists of the disclosure have an IL2 moiety and (1) an optional tumor targeting moiety and/or (2) an optional multimerization, e.g., dimerization, moiety and/or (3) an optional stabilization moiety wherein the tumor targeting moiety, e.g., an antigen binding domain ("ABD") of an antibody, can, for example, bind to a target molecule present on the tumor surface (e.g., a tumor associated antigen), the tumor microenvironment, and/or tumor reactive lymphocytes, which reads on a targeted immunocytokine (Paragraph 0015). The IL2 moiety of the IL2 antagonists of the disclosure comprises a wild type or variant IL2 domain, which is optionally fused to an IL2 binding domain of IL-2Ra, optionally via a linker; when present, the IL2 binding domain of IL-2Ra can be N-terminal or C-terminal to the wild type or variant IL2 domain (Paragraph 0188). The incorporation of targeting moieties in the IL2 agonists of the disclosure permits the delivery of high concentrations of IL2 into the tumor microenvironment or to tumor reactive lymphocytes (including CART lymphocytes) with a concomitant reduction of systemic exposure, resulting in fewer side effects than obtained with wild type IL2 (Paragraph 0212). For example, Wu teaches molecule ILM3 (corresponding to Wu SEQ ID NO: 101), which comprises an Fc domain linked via -(GGGS)3- to human IL-2Ra linked via -(GGGS)5- to human IL2, wherein the Fc domain is Wu SEQ ID NO: 31, corresponding to an IgG4 Fc having reduced effector function (see Table 5A at Pages 35-38). Wu further teaches T1, which is a targeting moiety that is an anti-murine PD-1 antibody (Table 5A, Page 37); Wu further teaches molecule T1-ILM3 in Table 5B (Pages 38-40), wherein molecule ILM3 is modified by adding an N-terminal anti-PD-1 antibody. It is specifically noted that Wu SEQ ID NO: 101 comprises (i) an IL2 moiety comprising IL2 connected via linker to the C-terminal end of IL-2Ra wherein the sequence of IL-2Ra corresponds to instant SEQ ID NO: 28 and the sequence of IL2 corresponds to wild-type IL2 comprising instant SEQ ID NO: 29; (ii) uses linkers comprising instant SEQ ID NOs: 30 and 31; and (iii) an exact match to instant SEQ ID NO: 27 at residues 244-566 and Wu further suggests that such a fusion protein can further comprise an anti-PD-1 antibody. It is further noted that Wu teaches additional embodiments wherein the Fc domain is an IgG4 Fc domain, wherein exemplary IgG4 Fc domains having reduced binding to Fc receptors include those provided in Table 4, wherein one such IgG4 Fc sequence is Wu SEQ ID NO: 52 (Paragraph 0298; Table 4 at Pages 18-20); it is specifically noted that Wu SEQ ID NO: 52 is an exact match to instant SEQ ID NO: 26. Wu further teaches that certain IL2 agonists entail dimerization between two Fc domains that, unlike a native immunoglobulin, are operably linked to non-identical N-terminal regions, e.g., one Fc domain connected to a Fab and the other Fc domain connected to an IL2 moiety (Paragraph 0302). Typically, each Fc domain in the Fc heterodimer comprises a CH3 domain of an antibody, and the CH3 domains are derived from the constant region of an antibody of any isotype, class or subclass, and preferably of IgG (IgGl, IgG2, IgG3 and IgG4) class, wherein heterodimerization of the two different heavy chains at CH3 domains give rise to the desired IL2 agonist (Paragraphs 0303-0304). In a preferred embodiment, the polypeptides that associate to form an IL2 agonist of the disclosure will contain CH3 domains with modifications that favor heterodimeric association relative to unmodified Fc domains (e.g., “knob-into-hole” mutations, electrostatic steering) (Paragraphs 0304-0308). In particular embodiments, the target molecule recognized by the targeting moiety is PD1 (Paragraph 0223). The targeting moiety can be any type of antibody or fragment thereof that retains specific binding to an antigenic determinant, wherein in one embodiment the antigen binding moiety is a full-length antibody; in one embodiment the antigen binding moiety is an immunoglobulin molecule, particularly an IgG class immunoglobulin molecule, more particularly an IgG1 or IgG4 immunoglobulin molecule (Paragraph 0225). Thus, Wu suggests an immunocytokine comprising a targeting moiety that is an IgG1 or IgG4 anti-PD-1 antibody or antigen binding fragment. IL2 agonists may be used in eliminating cells involved in immune cell-mediated disorders, including lymphoma; autoimmunity, transplantation rejection, graft-versus-host disease, ischemia and stroke (Paragraph 0393). The IL2 agonists of the disclosure can be advantageously used in combination with chimeric antigen receptor ("CAR")-expressing cells, e.g., CAR-expressing T ("CAR-T") cells, for example CAR-T in the treatment of cancer or autoimmune diseases (Paragraph 0409). Wu further provides methods of treating cancer in a human subject in need thereof, comprising administering to the subject an effective amount of an IL2 agonist of the disclosure and administering to the CAR-expressing cells, e.g., the CAR-expressing T cells (or "CART cells"), wherein particularly useful T cell subtypes for the treatment of cancer are T cells with robust CAR mediated cytotoxicity, e.g., CD3+CD8+ T cells (Paragraph 0463). The CAR-expressing cells can be administered in an amount ranging from 104 to 109 cells/kg body weight, preferably 105 to 106 cells/kg body weight, including all integer values within those ranges; T-cell compositions may also be administered multiple times at these dosages wherein, in some embodiments, the CAR-expressing cells are administered in doses of 1x106 to 1x1011 cells or 1x107 to 1x108 cells (Paragraph 0411). The CAR-expressing cells, e.g., T cells, are preferably autologous to the subject (Paragraph 0413); the population of cells comprises T-cells obtained from the subject that have been engineered to recombinantly express the CAR (Paragraph 0418). For treatment of cancer, the extracellular domain of the CAR can target a tumor associated antigen, wherein one such tumor associated antigen is CD20 (Paragraph 0464). Thus, Wu reads on adoptive cell therapy (CD20-targeting CAR-T cell therapy) in combination with targeted immunocytokine therapy. Notably, Paragraph 0388 explicitly suggests IL2 agonists as an adjunct therapy for adoptive cell transfer therapies, such as CAR-expressing cell therapies. Combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate compositions), and separate administration, in which case, administration of the IL2 agonist of the disclosure can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent and/or adjuvant (Paragraph 0407). The IL2 agonist is suitably administered to a patient at one time or over a series of treatments, wherein depending on the type and severity of the disease, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) of IL2 agonist can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion (Paragraph 0396). One typical daily dosage might range from about 1 μg/kg to 100 mg/kg or more; repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs, wherein one exemplary dosage of the IL2 agonist would be in the range from about 0.005 mg/kg to about 10 mg/kg (Id.). Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 5.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the patient, wherein such doses may be administered intermittently, e.g., every week or every three weeks (e.g., such that the patient receives from about two to about twenty, or e.g., about six doses of the IL2 agonist); other dosage regimens may be useful and the progress of this therapy is easily monitored by conventional techniques and assays (Id.). The IL2 agonists of the disclosure will generally be used in an amount effective to achieve the intended purpose; for use to treat a disease condition, the IL2 agonists of the disclosure, or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount wherein determination of a therapeutically effective amount is well within the capabilities of those skilled in the art (Paragraph 0397). Pharmaceutical compositions can be administered to a patient by a variety of routes such as orally, transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intratumorally, intrathecally, topically or locally, and typically the pharmaceutical composition will be administered intravenously or subcutaneously (Paragraph 0376). Conditioning or lymphodepletion therapy, e.g., a regimen of cyclophosphamide and fludarabine (i.e., chemotherapeutic agents), can also be administered to a subject receiving CAR and IL2 agonist therapy; such therapy is usually performed in the days prior to administration of the CAR-expressing cells to the subject (Paragraph 0410). In example 7.16 (Page 44), Wu teaches that Tl-IL2M3 shows superior anti-tumor efficacy to the combination of anti-PD-1 and IL2M3, wherein it is specifically noted that Tl-IL2M3 induces specific expansion of activated effector memory CD8+ T cells that are CD44hiCD62Llo and PD-1+ and causes less undesired proliferation of Tregs; this result demonstrates that Tl-IL2M3 fusion is able to redirect IL2M3 to antigen-activated CD8+ T cells that express PD-1, wherein activated T cells upregulate PD-1, resulting in T cell inhibition, and Tl-IL2M3 can specifically re-activate and expand these cells by stimulating IL2 signaling, in addition to blocking PD-1 signaling in these cells (Paragraph 0551).
However, Wu does not explicitly teach or suggest the use of anti-PD1 antibodies comprising the instantly claimed HCDRs, LCDRs, HCVR, LCVR, HC, or LC sequences. This deficiency is remedied by Bloch.
Bloch teaches fusion proteins of the present disclosure comprise an antigen-binding moiety that specifically binds to human PD-1, which targets tumor-reactive T cells, wherein the antigen-binding moiety is helpful in selectively reconstituting activity on tumor-reactive T cells; the fusion proteins further comprise an IL2 moiety wherein the IL2 moiety comprises IL2 bound to IL2Ra wherein the fusion protein comprises the IL2 moiety in a trans-sequestered conformation, which maintains engagement with activated CD8+ T cells, and the bound configuration of the IL2 moiety helps in masking of the IL2 and attenuating its activity, thus leading to reduced systemic toxicity (Column 2, Lines 7-29). The fusion proteins of the invention provide enhanced anti-tumor efficacy and improved therapeutic index as compared to IL2 alone or in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody or antigen- binding fragment thereof) (Id.). In one aspect, the disclosed technology relates to a fusion protein including: (i) an antigen-binding moiety that binds specifically to human programmed cell death protein 1 (PD-1) and (ii) an interleukin 2 (IL2) moiety; in some embodiments, the antigen-binding moiety includes an antibody or antigen-binding fragment thereof that binds specifically to human PD-1, wherein in some embodiments the antibody or antigen-binding fragment thereof that binds to human PD-1 is a human monoclonal antibody (Column 2, Lines 30-38). In some embodiments, the HCVR includes the amino acid sequence of SEQ ID NO: 41 and the LCVR includes the amino acid sequence of SEQ ID NO: 10 (Column 3, Lines 1-14). In some embodiments, the antigen-binding moiety includes a heavy chain constant region of SEQ ID NO: 55 and a light chain constant region of SEQ ID NO: 56; in some embodiments, the antigen-binding moiety includes a heavy chain/light chain sequence pair of SEQ ID NOs: 61/62, 57/58, or 59/60 (Id.). It is specifically noted that: (i) Bloch SEQ ID NOs: 41 and 10 are exact matches to instant SEQ ID NOs: 20 and 5, respectively, and comprise exact matches to instant SEQ ID NOs: 21/22/23 and 6/7/8, respectively; (ii) Bloch SEQ ID NO: 55 is an exact match to instant SEQ ID NO: 26; and (iii) Bloch SEQ ID NOs: 61 and 62 are exact matches to instant SEQ ID NOs: 24 and 25, respectively. Bloch further teaches REGN10597, which includes the heavy chain (HC) SEQ ID NO: 61 (which includes the amino acid sequences of the HCVR (SEQ ID NO: 41) and the heavy chain constant region (SEQ ID NO: 55), the linker (SEQ ID NO: 50), and the IL2 moiety (SEQ ID NO: 54)) (Column 34, Lines 22-27).
However, neither Wu nor Bloch explicitly teach or suggest that administering therapeutically effective amounts of (i) an ACT and (ii) an immunocytokine would result in improved efficacy and duration of response, nor delayed tumor growth, reduced tumor cell number, tumor regression, increased survival, increased partial response, and/or increased complete response. This deficiency is remedied by Zheng.
Zheng teaches that ACT in the treatment of cancer has several limitations, including the insufficient invasion of transferred cells into the lesion and the inability of transferred T cells to persist and maintain functionality in the body; in clinical practice, the concurrent administration of IL-2 improves the survival, function, and antitumor activity of transplanted T cells, but its pleiotropy (which simultaneously stimulates and suppresses immune responses and systemic toxicity) severely limits its clinical use (Page 204, Column 1, First Paragraph). Zheng further discloses previous work comprising the design of an orthogonal (ortho) IL-2 cytokine-receptor complex that transmits natural IL-2 signals but does not interact with their natural cytokines and receptors; specifically, introducing orthoIL-2Rβ into T cells allowed orthoIL-2 to selectively target engineered CD4+ cells and CD8+ T cells in vivo and in vitro with limited off-target effects and negligible toxicity (Id.). The orthoIL-2 signal was effective in a preclinical mouse cancer model treated with adoptive cells and may, therefore, represent a synthetic approach to achieve selective enhancement of engineered cells (Id.). Zheng further teaches that IL-2 has been widely used for in vitro amplification and in vivo persistence of adoptive transfer of CAR-T cells or tumor-infiltrating lymphocytes wherein a combination of cytokines and tumor-infiltrating lymphocytes is being evaluated in multiple cancer types in multiple clinical trials, including different doses of IL-2; Zheng specifically indicates that supercytokines could act as superassistants in ACT therapy in the future (Page 205, Column 2, Second Paragraph). Zheng also teaches that the concept of immunocytokines was attributed mainly to the formation of fusion proteins by combining cytokines with antibodies against tumors or lesions, which was conducive to enhancing the local effect of cytokines; scientists have evaluated the fusion of cytokines with antibodies against immune checkpoints in preclinical and clinical studies (Page 205, Column 2, Third Paragraph). Antibody therapy against immune checkpoints has shown great clinical success, wherein immunotherapies such as PD-1 blockade can significantly enhance endogenous antitumor immunity and improve the survival of cancer patients, but only a small proportion of patients respond to such therapies; the efficacy of immune checkpoint inhibitors may be extended by cytokines wherein mechanistic studies have shown that immune checkpoint proteins are highly expressed in local immune cells of the TME, and thus the fusion proteins described (see Table 1) can also act as targeted cytokines facilitating aggregation to the lesion; these bifunctional fusion proteins block immune checkpoints and simultaneously deliver cytokines to T cells with high levels of immune checkpoint expression, enabling them to survive or function efficiently and such fusion proteins can also promote the expansion of tumor neoantigen-specific T cells (Page 205, Column 2, Third Paragraph through Page 206, Column 1, First Paragraph). In one example provided by Zheng, for blood malignancies, the anti-CD20 immunocytokine DI-Leu16-IL-2 (Provenance Biopharmaceuticals) is currently in a phase-I/II clinical trial in patients with B-cell lymphoma (Page 200, Column 1, First Paragraph). Thus, Zheng suggests the use of IL-2 (including as fusion proteins/immunocytokines) in cancer therapy wherein the IL-2 functions in in vivo persistence of CAR-T cell therapies, and when combined with immune checkpoint inhibitors can serve to specifically deliver IL-2 to target populations (e.g., T cells) to promote survival, function, and expansion.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method(s) of Wu, comprising administering a therapeutically effective amount of an ACT, wherein the ACT is CAR-T cell therapy specific to CD20, in combination with an immunocytokine, wherein the immunocytokine comprises an anti-PD1 targeting moiety and an IL2 moiety comprising IL2Ra and IL2, such that the immunocytokine of Wu is substituted with the immunocytokine of Bloch, which reads directly on the immunocytokine REGN10597 because one of skill in the art could have substituted one known PD1 targeted IL2-based immunocytokine for another, and the results of combining such an immunocytokine with an ACT would have been predictable, wherein it would have reasonably been predictable that, based on the teachings of Zheng and Wu, that such a combination would be useful in the treatment of cancer, including lymphoma, and wherein such a combination would reasonably be expected to have increased efficacy and duration of anti-tumor response and at least one of a reduction in tumor cell number, tumor regression, increased survival, increased partial response, or increased complete response because Zheng suggests the use of IL-2 (including as fusion proteins/immunocytokines) in cancer therapy wherein the IL-2 functions in in vivo persistence of CAR-T cell therapies, and when combined with immune checkpoint inhibitors can serve to specifically deliver IL-2 to target populations (e.g., T cells) to promote survival, function, and expansion.
Claims 1-5, 8-15, 18-29, and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over US 2021/0188934 A1 (herein after referred to as "Wu") in view of US 9,987,500 (herein after referred to as "Murphy"), and non-patent literature by Zheng et. al. (Cell & Molecular Immunology, January 2022, 19, 192-209; herein after referred to as “Zheng”).
Wu teaches that the therapeutic indices of a variety of IL2 molecules with various degrees of receptor attenuation can be improved by appropriately balancing the ability of an IL2 agonist to be localized to a site or cell type of interest (e.g., the tumor environment generally or tumor reactive T cells specifically) and modulating the level activity of the IL2 component at the site of interest and/or until it reaches the site or cell type of interest (Paragraph 0014); the inventors have developed IL2 molecules (referred to herein as IL2 agonists) that are believed to be more effective than the CD122 directed IL2 molecules currently under development for the treatment of cancer, wherein the IL2 agonists of the disclosure have an IL2 moiety and (1) an optional tumor targeting moiety and/or (2) an optional multimerization, e.g., dimerization, moiety and/or (3) an optional stabilization moiety wherein the tumor targeting moiety, e.g., an antigen binding domain ("ABD") of an antibody, can, for example, bind to a target molecule present on the tumor surface (e.g., a tumor associated antigen), the tumor microenvironment, and/or tumor reactive lymphocytes, which reads on a targeted immunocytokine (Paragraph 0015). The IL2 moiety of the IL2 antagonists of the disclosure comprises a wild type or variant IL2 domain, which is optionally fused to an IL2 binding domain of IL-2Ra, optionally via a linker; when present, the IL2 binding domain of IL-2Ra can be N-terminal or C-terminal to the wild type or variant IL2 domain (Paragraph 0188). The incorporation of targeting moieties in the IL2 agonists of the disclosure permits the delivery of high concentrations of IL2 into the tumor microenvironment or to tumor reactive lymphocytes (including CART lymphocytes) with a concomitant reduction of systemic exposure, resulting in fewer side effects than obtained with wild type IL2 (Paragraph 0212). For example, Wu teaches molecule ILM3 (corresponding to Wu SEQ ID NO: 101), which comprises an Fc domain linked via -(GGGS)3- to human IL-2Ra linked via -(GGGS)5- to human IL2, wherein the Fc domain is Wu SEQ ID NO: 31, corresponding to an IgG4 Fc having reduced effector function (see Table 5A at Pages 35-38). Wu further teaches T1, which is a targeting moiety that is an anti-murine PD-1 antibody (Table 5A, Page 37); Wu further teaches molecule T1-ILM3 in Table 5B (Pages 38-40), wherein molecule ILM3 is modified by adding an N-terminal anti-PD-1 antibody. It is specifically noted that Wu SEQ ID NO: 101 comprises (i) an IL2 moiety comprising IL2 connected via linker to the C-terminal end of IL-2Ra wherein the sequence of IL-2Ra corresponds to instant SEQ ID NO: 28 and the sequence of IL2 corresponds to wild-type IL2 comprising instant SEQ ID NO: 29; (ii) uses linkers comprising instant SEQ ID NOs: 30 and 31; and (iii) an exact match to instant SEQ ID NO: 27 at residues 244-566 and Wu further suggests that such a fusion protein can further comprise an anti-PD-1 antibody. It is further noted that Wu teaches additional embodiments wherein the Fc domain is an IgG4 Fc domain, wherein exemplary IgG4 Fc domains having reduced binding to Fc receptors include those provided in Table 4, wherein one such IgG4 Fc sequence is Wu SEQ ID NO: 52 (Paragraph 0298; Table 4 at Pages 18-20); it is specifically noted that Wu SEQ ID NO: 52 is an exact match to instant SEQ ID NO: 26. Wu further teaches that certain IL2 agonists entail dimerization between two Fc domains that, unlike a native immunoglobulin, are operably linked to non-identical N-terminal regions, e.g., one Fc domain connected to a Fab and the other Fc domain connected to an IL2 moiety (Paragraph 0302). Typically, each Fc domain in the Fc heterodimer comprises a CH3 domain of an antibody, and the CH3 domains are derived from the constant region of an antibody of any isotype, class or subclass, and preferably of IgG (IgGl, IgG2, IgG3 and IgG4) class, wherein heterodimerization of the two different heavy chains at CH3 domains give rise to the desired IL2 agonist (Paragraphs 0303-0304). In a preferred embodiment, the polypeptides that associate to form an IL2 agonist of the disclosure will contain CH3 domains with modifications that favor heterodimeric association relative to unmodified Fc domains (e.g., “knob-into-hole” mutations, electrostatic steering) (Paragraphs 0304-0308). In particular embodiments, the target molecule recognized by the targeting moiety is PD1 (Paragraph 0223). The targeting moiety can be any type of antibody or fragment thereof that retains specific binding to an antigenic determinant, wherein in one embodiment the antigen binding moiety is a full-length antibody; in one embodiment the antigen binding moiety is an immunoglobulin molecule, particularly an IgG class immunoglobulin molecule, more particularly an IgG1 or IgG4 immunoglobulin molecule (Paragraph 0225). Thus, Wu suggests an immunocytokine comprising a targeting moiety that is an IgG1 or IgG4 anti-PD-1 antibody or antigen binding fragment. IL2 agonists may be used in eliminating cells involved in immune cell-mediated disorders, including lymphoma; autoimmunity, transplantation rejection, graft-versus-host disease, ischemia and stroke (Paragraph 0393). The IL2 agonists of the disclosure can be advantageously used in combination with chimeric antigen receptor ("CAR")-expressing cells, e.g., CAR-expressing T ("CAR-T") cells, for example CAR-T in the treatment of cancer or autoimmune diseases (Paragraph 0409). Wu further provides methods of treating cancer in a human subject in need thereof, comprising administering to the subject an effective amount of an IL2 agonist of the disclosure and administering to the CAR-expressing cells, e.g., the CAR-expressing T cells (or "CART cells"), wherein particularly useful T cell subtypes for the treatment of cancer are T cells with robust CAR mediated cytotoxicity, e.g., CD3+CD8+ T cells (Paragraph 0463). The CAR-expressing cells can be administered in an amount ranging from 104 to 109 cells/kg body weight, preferably 105 to 106 cells/kg body weight, including all integer values within those ranges; T-cell compositions may also be administered multiple times at these dosages wherein, in some embodiments, the CAR-expressing cells are administered in doses of 1x106 to 1x1011 cells or 1x107 to 1x108 cells (Paragraph 0411). The CAR-expressing cells, e.g., T cells, are preferably autologous to the subject (Paragraph 0413); the population of cells comprises T-cells obtained from the subject that have been engineered to recombinantly express the CAR (Paragraph 0418). For treatment of cancer, the extracellular domain of the CAR can target a tumor associated antigen, wherein one such tumor associated antigen is CD20 (Paragraph 0464). Thus, Wu reads on adoptive cell therapy (CD20-targeting CAR-T cell therapy) in combination with targeted immunocytokine therapy. Notably, Paragraph 0388 explicitly suggests IL2 agonists as an adjunct therapy for adoptive cell transfer therapies, such as CAR-expressing cell therapies. Combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate compositions), and separate administration, in which case, administration of the IL2 agonist of the disclosure can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent and/or adjuvant (Paragraph 0407). The IL2 agonist is suitably administered to a patient at one time or over a series of treatments, wherein depending on the type and severity of the disease, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) of IL2 agonist can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion (Paragraph 0396). One typical daily dosage might range from about 1 μg/kg to 100 mg/kg or more; repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs, wherein one exemplary dosage of the IL2 agonist would be in the range from about 0.005 mg/kg to about 10 mg/kg (Id.). Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 5.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the patient, wherein such doses may be administered intermittently, e.g., every week or every three weeks (e.g., such that the patient receives from about two to about twenty, or e.g., about six doses of the IL2 agonist); other dosage regimens may be useful and the progress of this therapy is easily monitored by conventional techniques and assays (Id.). The IL2 agonists of the disclosure will generally be used in an amount effective to achieve the intended purpose; for use to treat a disease condition, the IL2 agonists of the disclosure, or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount wherein determination of a therapeutically effective amount is well within the capabilities of those skilled in the art (Paragraph 0397). Pharmaceutical compositions can be administered to a patient by a variety of routes such as orally, transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intratumorally, intrathecally, topically or locally, and typically the pharmaceutical composition will be administered intravenously or subcutaneously (Paragraph 0376). Conditioning or lymphodepletion therapy, e.g., a regimen of cyclophosphamide and fludarabine (i.e., chemotherapeutic agents), can also be administered to a subject receiving CAR and IL2 agonist therapy; such therapy is usually performed in the days prior to administration of the CAR-expressing cells to the subject (Paragraph 0410). In example 7.16 (Page 44), Wu teaches that Tl-IL2M3 shows superior anti-tumor efficacy to the combination of anti-PD-1 and IL2M3, wherein it is specifically noted that Tl-IL2M3 induces specific expansion of activated effector memory CD8+ T cells that are CD44hiCD62Llo and PD-1+ and causes less undesired proliferation of Tregs; this result demonstrates that Tl-IL2M3 fusion is able to redirect IL2M3 to antigen-activated CD8+ T cells that express PD-1, wherein activated T cells upregulate PD-1, resulting in T cell inhibition, and Tl-IL2M3 can specifically re-activate and expand these cells by stimulating IL2 signaling, in addition to blocking PD-1 signaling in these cells (Paragraph 0551).
However, Wu does not explicitly teach or suggest the use of anti-PD1 antibodies comprising the instantly claimed HCDRs, LCDRs, HCVR, or LCVR sequences. This deficiency is remedied by Murphy.
Murphy teaches isolated recombinant monoclonal antibodies or antigen-binding fragments thereof that bind specifically to PD-1; in certain embodiments, the antibodies are fully human (Column 2, Lines 55-58). According to certain embodiments, the invention provides antibodies, or antigen-binding fragments thereof, comprising an HCVR/LCVR amino acid sequence pair contained within any of the exemplary anti-PD-1 antibodies listed in Table 1 (see Columns 43-44); in certain embodiments, the HCVR/LCVR amino acid sequence pair is selected from a group which comprises, for example, SEQ ID NOs: 234/202 (i.e., H4xH9048P) (Column 3, Lines 17-36). It is specifically noted that Murphy SEQ ID NOs: 234 and 202 are exact matches to instant SEQ ID NOs: 20 and 5, respectively, and comprise exact matches to instant SEQ ID NOs: 21/22/23 and 6/7/8, respectively.
However, neither Wu nor Murphy explicitly teach or suggest that administering therapeutically effective amounts of (i) an ACT and (ii) an immunocytokine would result in improved efficacy and duration of response, nor delayed tumor growth, reduced tumor cell number, tumor regression, increased survival, increased partial response, and/or increased complete response. This deficiency is remedied by Zheng.
Zheng teaches that ACT in the treatment of cancer has several limitations, including the insufficient invasion of transferred cells into the lesion and the inability of transferred T cells to persist and maintain functionality in the body; in clinical practice, the concurrent administration of IL-2 improves the survival, function, and antitumor activity of transplanted T cells, but its pleiotropy (which simultaneously stimulates and suppresses immune responses and systemic toxicity) severely limits its clinical use (Page 204, Column 1, First Paragraph). Zheng further discloses previous work comprising the design of an orthogonal (ortho) IL-2 cytokine-receptor complex that transmits natural IL-2 signals but does not interact with their natural cytokines and receptors; specifically, introducing orthoIL-2Rβ into T cells allowed orthoIL-2 to selectively target engineered CD4+ cells and CD8+ T cells in vivo and in vitro with limited off-target effects and negligible toxicity (Id.). The orthoIL-2 signal was effective in a preclinical mouse cancer model treated with adoptive cells and may, therefore, represent a synthetic approach to achieve selective enhancement of engineered cells (Id.). Zheng further teaches that IL-2 has been widely used for in vitro amplification and in vivo persistence of adoptive transfer of CAR-T cells or tumor-infiltrating lymphocytes wherein a combination of cytokines and tumor-infiltrating lymphocytes is being evaluated in multiple cancer types in multiple clinical trials, including different doses of IL-2; Zheng specifically indicates that supercytokines could act as superassistants in ACT therapy in the future (Page 205, Column 2, Second Paragraph). Zheng also teaches that the concept of immunocytokines was attributed mainly to the formation of fusion proteins by combining cytokines with antibodies against tumors or lesions, which was conducive to enhancing the local effect of cytokines; scientists have evaluated the fusion of cytokines with antibodies against immune checkpoints in preclinical and clinical studies (Page 205, Column 2, Third Paragraph). Antibody therapy against immune checkpoints has shown great clinical success, wherein immunotherapies such as PD-1 blockade can significantly enhance endogenous antitumor immunity and improve the survival of cancer patients, but only a small proportion of patients respond to such therapies; the efficacy of immune checkpoint inhibitors may be extended by cytokines wherein mechanistic studies have shown that immune checkpoint proteins are highly expressed in local immune cells of the TME, and thus the fusion proteins described (see Table 1) can also act as targeted cytokines facilitating aggregation to the lesion; these bifunctional fusion proteins block immune checkpoints and simultaneously deliver cytokines to T cells with high levels of immune checkpoint expression, enabling them to survive or function efficiently and such fusion proteins can also promote the expansion of tumor neoantigen-specific T cells (Page 205, Column 2, Third Paragraph through Page 206, Column 1, First Paragraph). In one example provided by Zheng, for blood malignancies, the anti-CD20 immunocytokine DI-Leu16-IL-2 (Provenance Biopharmaceuticals) is currently in a phase-I/II clinical trial in patients with B-cell lymphoma (Page 200, Column 1, First Paragraph). Thus, Zheng suggests the use of IL-2 (including as fusion proteins/immunocytokines) in cancer therapy wherein the IL-2 functions in in vivo persistence of CAR-T cell therapies, and when combined with immune checkpoint inhibitors can serve to specifically deliver IL-2 to target populations (e.g., T cells) to promote survival, function, and expansion.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method(s) of Wu, comprising administering a therapeutically effective amount of an ACT, wherein the ACT is CAR-T cell therapy specific to CD20, in combination with an immunocytokine, wherein the immunocytokine comprises an anti-PD1 targeting moiety and an IL2 moiety comprising IL2Ra and IL2, such that the PD1 targeting moiety of the immunocytokine of Wu is substituted for the anti-PD1 antibody or Murphy, which reads directly on the instantly claimed HCDR, LCDR, HCVR, and LCVR sequences, because one of skill in the art could have substituted one known PD1 targeting antibody for another, and the results of such an modification would have been predictable in that (i) the resultant immunocytokine would have been PD1 specific such that the cytokine is specifically delivered to target immune cells, and (ii) the resultant immunocytokine in combination with an ACT would yielded predictable results wherein, based on the teachings of Zheng and Wu, such a combination would be useful in the treatment of cancer, including lymphoma, and wherein such a combination would reasonably be expected to have increased efficacy and duration of anti-tumor response and at least one of a reduction in tumor cell number, tumor regression, increased survival, increased partial response, or increased complete response because Zheng suggests the use of IL-2 (including as fusion proteins/immunocytokines) in cancer therapy wherein the IL-2 functions in in vivo persistence of CAR-T cell therapies, and when combined with immune checkpoint inhibitors can serve to specifically deliver IL-2 to target populations (e.g., T cells) to promote survival, function, and expansion.
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).
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Claims 1-5 and 7-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-19, 23-33, 39-40, and 43-44 of U.S. Patent No. 12,528,851 (herein after referred to as “reference patent”) in view of US 2021/0188934 A1 (herein after referred to as "Wu") and non-patent literature by Zheng et. al. (Cell & Molecular Immunology, January 2022, 19, 192-209; herein after referred to as “Zheng”).
Reference patent claim 1 is drawn to a fusion protein comprising: (i) an antigen-binding moiety that binds specifically to human programmed cell death protein 1 (PD-1) and (ii) an interleukin 2 (IL2) moiety, wherein the antigen-binding moiety comprises an antibody or antigen-binding fragment thereof that binds specifically to human PD-1 and comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2, and LCDR3), wherein the antigen-binding moiety comprises a heavy chain constant region linked to the HCVR, and wherein: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the respective amino acid sequences of: (i) SEQ ID NOs: 43, 45, 47, 12, 14, and 16; (ii) SEQ ID NOs: 4, 6, 8, 12, 14, and 16; or (iii) and SEQ ID NOs: 24, 26, 28, 32, 14, and 35; and wherein the IL2 moiety comprises: (i) IL2 or a fragment thereof and (ii) IL2 receptor alpha (IL2Ra) or a fragment thereof; wherein the IL2 or fragment thereof is connected to the C-terminal of the IL2Ra or fragment thereof via a first linker, and the IL2 moiety is connected to the C-terminal of the heavy chain constant region via a second linker. IT is specifically noted that reference patent SEQ ID NOs: 43/45/47 and 12/14/16 are exact matches to instant SEQ ID NOs: 21/22/23 and 6/7/8, respectively. Claim 2 of the reference application further limits claim 1 wherein the antigen-binding moiety comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising respective amino acid sequences of SEQ ID NOs: 43, 45, 47, 12, 14, and 16. Claim 3 of the reference patent further limits claim 1 wherein the antigen-binding moiety comprises a heavy chain variable region (HCVR) comprising an amino acid sequence of SEQ ID NO: 41, 2, or 22; and a light chain variable region (LCVR) comprising an amino acid sequence of SEQ ID NO: 10 or 30, and claim 6 of the reference patent further limits claim 3 wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 41 and the LCVR comprises the amino acid sequence of SEQ ID NO: 10. It is specifically noted that reference patent SEQ ID NOs: 41 and 10 are exact matches to instant SEQ ID NOs: 20 and 5, respectively. Claim 7 of the reference patent further limits claim 1 wherein he antigen-binding moiety comprises a heavy chain constant region of SEQ ID NO: 55 and a light chain constant region of SEQ ID NO: 56. It is specifically noted that reference patent SEQ ID NO: 55 is an exact match to instant SEQ ID NO: 26. Reference patent claims 8-9, respectively, further limit claim 1 wherein the antigen-binding moiety (i) comprises a heavy chain/light chain sequence pair of SEQ ID NOs: 61/62, 57/58, or 59/60 or (ii) comprises a heavy chain/light chain sequence pair of SEQ ID NOs: 61/62. It is specifically noted that reference patent SEQ ID NOs: 61 and 62 are exact matches to instant SEQ ID NOs: 24 and 25, respectively. Reference patent claims 10-11 further limit the method of claim 1 wherein the IL2 or fragment thereof is human IL2 (hIL2) or a fragment thereof, and wherein the IL2Ra or fragment thereof is human IL2Ra (hIL2Ra) or a fragment thereof. Reference patent claims 12-16, respectively, limit claim 1 wherein: (i) the IL2 or fragment thereof comprises the amino acid sequence of SEQ ID NO: 53; (ii) the IL2Ra or fragment thereof comprises the amino acid sequence of SEQ ID NO: 51; (iii) the first and/or second linker comprises an amino acid sequence of one or more repeats of GGGGS (SEQ ID NO: 67); (iv) the first linker comprises an amino acid sequence of SEQ ID NO: 52, and the second linker comprises an amino acid sequence of SEQ ID NO: 50; and (v) the IL2 moiety comprises the amino acid sequence of SEQ ID NO: 54. It is specifically noted that reference patent SEQ ID NOs: 53, 51, 54, and 52 are exact matches to instant SEQ ID NOs: 29, 28, 27, and 31 respectively. Reference patent claim 17 is drawn to a fusion protein comprising: (i) a first polypeptide comprising a light chain variable region (LCVR) of an antibody; and (ii) a second polypeptide that comprises (a) a heavy chain variable region (HCVR) of the antibody and a heavy chain constant region linked to the HCVR of the antibody and (b) an IL2 moiety; wherein the antibody binds specifically to human programmed cell death protein 1 (PD-1), the HCVR comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2, and HCDR3), and the LCVR comprises three light chain CDRs (LCDR1, LCDR2, and LCDR3), wherein: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the respective amino acid sequences of: (i) SEQ ID NOs: 43, 45, 47, 12, 14, and 16; (ii) SEQ ID NOs: 4, 6, 8, 12, 14, and 16; or (iii) and SEQ ID NOs: 24, 26, 28, 32, 14, and 35; and wherein the IL2 moiety comprises: (i) IL2 or a fragment thereof and (ii) IL2 receptor alpha (IL2Ra) or a fragment thereof; wherein the IL2 or fragment thereof is connected to the C-terminal of the IL2Ra or fragment thereof via a first linker, and the IL2 moiety is connected to the C-terminal of the heavy chain constant region via a second linker. Reference patent claim 18 further limits claim 17 wherein the antigen-binding moiety comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising respective amino acid sequences of SEQ ID NOs: 43, 45, 47, 12, 14, and 16. Claim 19 of the reference patent further limits claim 17 wherein the HCVR and the comprise respective amino acid sequences of (i) SEQ NOs: 41 and 10; (ii) SEQ ID NOs: 2 and 10; or (iii) SEQ ID NOs: 22 and 30. Reference patent claims 23-33, respectively, further limit claim 17 wherein: (i) the first polypeptide comprises a light chain sequence of SEQ ID NO: 62, 58, or 60; (ii) the second polypeptide comprises a heavy chain sequence of SEQ ID NO: 61, 57, or 59; (iii) the fusion protein comprises a heavy chain/light chain sequence pair of SEQ ID NOs: 61/62, 57/58, or 59/60; (iv) the fusion protein comprises a heavy chain/light chain sequence pair of SEQ ID NOs: 61/62; (v) the IL2 or fragment thereof is human IL2 (hIL2) or a fragment thereof; (vi) the IL2Ra or fragment thereof is human IL2Ra (hIL2Ra) or a fragment thereof; (vii) the IL2 or fragment thereof comprises the amino acid sequence of SEQ ID NO: 53; (viii) the IL2Ra or fragment thereof comprises the amino acid sequence of SEQ ID NO: 51; (ix) the first and/or second linker comprises an amino acid sequence of one or more repeats of GGGGS (SEQ ID NO: 67); (x) the first linker comprises an amino acid sequence of SEQ ID NO: 52, and the second linker comprises an amino acid sequence of SEQ ID NO: 50; and (xi) the IL2 moiety comprises the amino acid sequence of SEQ ID NO: 54. Reference patent claims 39-40, respectively, further limit claim 1 wherein (i) the fusion protein forms a dimeric fusion protein, and (ii) the fusion protein dimerizes through their respective heavy chain constant regions. Reference patent claims 43-44 are drawn to pharmaceutical compositions comprising the fusion proteins of claims 1 and 17, respectively. Thus, the claims of the reference patent are drawn to an immunocytokine comprising (i) an anti-PD-1 antibody and (ii) an IL2 moiety, wherein the PD-1 antibody and IL2 moiety comprise the instantly claimed sequences; furthermore it is noted that the immunocytokine(s) encompassed by the claims of the reference patent read directly on the immunocytokine REGN10597 (comprises a PD-1 antibody corresponding to HC/LC SEQ ID NOs: 61 and 62, respectively, linked to the IL2 moiety of SEQ ID NO: 54 via linker SEQ ID NO: 52; the IL2 moiety corresponding to IL2Ra of SEQ ID NO: 51 linked to IL2 of SEQ ID NO: 53 via linker SEQ ID NO: 50).
However, the claims of the reference patent are not drawn to a method of increasing the efficacy of ACT nor treating cancer, generally comprising administering an immunocytokine in combination with an ACT. These deficiencies are remedied by Wu and Zheng, whose teachings are detailed in the 103 section above.
Thus it would have been prima facie obvious to one of ordinary skill in the art that the immunocytokine claimed by the reference patent could be used in the method(s) of Wu, drawn to methods comprising administering a therapeutically effective amount of an ACT, wherein the ACT is CAR-T cell therapy specific to CD20, in combination with an immunocytokine, wherein the immunocytokine comprises an anti-PD1 targeting moiety and an IL2 moiety comprising IL2Ra and IL2. It would have been obvious to one of ordinary skill in the art to substitute the immunocytokine claimed by the reference patent for the immunocytokine of the method(s) of Wu such that such that the immunocytokine claimed by the reference patent, which reads directly on the immunocytokine REGN10597, is administered in combination with a therapeutically effective amount an ACT that is CAR-T cell therapy specific to CD20, because one of skill in the art could have substituted one known PD1 targeted IL2-based immunocytokine for another, and the results of combining such an immunocytokine with an ACT would have been predictable, wherein it would have reasonably been predictable that, based on the teachings of Zheng and Wu, that such a combination would be useful in the treatment of cancer, including lymphoma, and wherein such a combination would reasonably be expected to have increased efficacy and duration of anti-tumor response and at least one of a reduction in tumor cell number, tumor regression, increased survival, increased partial response, or increased complete response because Zheng suggests the use of IL-2 (including as fusion proteins/immunocytokines) in cancer therapy wherein the IL-2 functions in in vivo persistence of CAR-T cell therapies, and when combined with immune checkpoint inhibitors can serve to specifically deliver IL-2 to target populations (e.g., T cells) to promote survival, function, and expansion.
Conclusion
Claims 1-5 and 7-41 are pending. Claims 1-5 and 7-41 are rejected. No claims are allowed.
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