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 .
Claim Status
Claims 3-5, 9-18, 21-26, 28-34, 37-43, 45-46, 49-54, and 56-58 have been cancelled; claims 1, 6, 8, 27, 36, 44, and 47-48 have been amended; and, claim 59 has been newly added, as requested in the amendment filed on 10/16/2025. Following the amendment, claims 1-2, 6-8, 19-20, 27, 35-36, 44, 47-48, 55, and 59 are pending in the instant application.
Claims 1-2, 6-8, 19-20, 27, 35-36, 44, 47-48, 55, and 59 are under examination in the instant office action.
Priority - Updated
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 1-2, 6-8, 19-20, 27, 35-36, 44, 47-48, 55, and 59 have an effective filing date of June 23, 2020 corresponding to PRO 63/043,042.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/16/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification - Objection Withdrawn
With regard to the objection to the specification regarding the use of trade names or marks used in commerce, it is noted that Applicant has provided a substitute specification such that all trade names and marks used in commerce are properly represented and include generic terminology for the terms. As such, the objection to the specification is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
With regard to the rejection of claim 36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, as pertains to the recitation of dosage ranges, it is noted that Applicant has amended the claim to recite “no more than 500 mg, or no more than about 10 mg/kg”. As such, the claim is considered to be clear and definite and the rejection of claim 36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
With regard to the rejection of claims 3, 13, 16, 26, 31-32, 45-46, and 49-54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, it is noted that claims 3, 13, 16, 26, 31-32, 45-46, and 49-54 have been cancelled, rendering the rejection moot. As such, the rejection of claims 3, 13, 16, 26, 31-32, 45-46, and 49-54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
With regard to the rejection of claims 1-3, 7-8, 13, 16, 19-20, 26-27, 31-32, 35-36, and 44-55 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, it is noted that: (i) claims 3, 13, 16, 26, 31-32, 45-46, and 49-54 have been cancelled, rendering the rejection moot; and (ii) instant claim 1 has been amended such that the anti-CD137 antibody is now defined by six HVRs. As such, the rejection of claims 1-3, 7-8, 13, 16, 19-20, 26-27, 31-32, 35-36, and 44-55 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 is withdrawn.
With regard to the rejection of claims 1-3, 6-8, 13, 16, 19-20, 26-27, 31-32, 35-36, and 44-55 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement, it is noted that Applicant has amended instant claim 1 to recite “wherein: (i) the agent is IL-2 and the cancer is lung cancer or melanoma or (ii) the agent is bendamustine and the cancer is lymphoma”, wherein Applicant further notes on Page 9 of Remarks that the instant specification provides working examples for treating lung cancer and melanoma using a combination of antibody ADG106 and IL-2 (Examples 3 and 10) and treating lymphoma using a combination of antibody ADG106 and bendamustine (Example 4) wherein ADG106 comprises the instantly claimed HVRs recited in amended claim 1. In view of the amendments to instant claim 1, the rejection of claims 1-3, 6-8, 13, 16, 19-20, 26-27, 31-32, 35-36, and 44-55 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement is withdrawn.
Claim Rejections - 35 USC § 112 - Maintained/Updated
Claims 1-2, 6-8, 19-20, 27, 35-36, 44, 47-48, and 55, stand as rejected and new claim 59 is newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite with regard to the term “antibody” as defined in the instant specification. Applicant argues on Page 7 of Remarks (10/16/2025) that the amendment of claim 1 to recite that the antibody comprises “a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3, and a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4; and wherein the VL comprises a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 5, a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 6, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7” structurally defines the antibody by the six HVR sequences. However, it is noted that the claim rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, were with regard to the definition of “antibody”, wherein the term includes both monoclonal and polyclonal antibodies; thus, the antibody of claim as currently amended may still refer to a single antibody molecule comprising all six HVRs or multiple antibody molecules wherein the HVRs are not all present on the same molecule. As such, claim 1, and subsequently all claims which depend from and/or incorporate claim 1, are still considered to have multiple structural interpretations. Thus, the rejection of claims 1-3, 6-8, 13, 16, 19-20, 26-27, 31-32, 35-36, and 44-55 stand as rejected and new claim 59 is newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is maintained.
Claim 6 stands as 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. Applicant argues on Page 8 of Remarks that the specification defines a “cytokine analog” as an engineered polypeptide having insertion(s), deletion(s), and/or substitution(s) of one or more amino acid resides while retaining substantially the same (e.g., 60% or more) activity (e.g., receptor binding) as a wild-type cytokine” wherein the sequence of IL-2 is provided by SEQ ID NO: 43 and exemplary analogs (e.g., aldesleukin and bempegaldesleukin) are provided. However, it is further noted that by definition, as provided at Paragraph 0163, “a cytokine analog has an amino acid sequence having at least about any one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity to the amino acid sequence of a wildtype cytokine”; the sequence of wild-type IL-2 (provided by SEQ ID NO: 43) consists of 153 amino acid residues, and at 80% identity a cytokine analog may comprise as many as 31 amino acid insertion(s), deletion(s), and/or substitution(s). As such, there are thousands of possible analogs by definition, and providing two analogs is not sufficiently representative of the entire claimed genus. One of ordinary skill in this art cannot conclude that Applicant was in possession of just any IL-2 variant/analog that is capable of inducing expression of CD137/CD137L when Applicant has disclosed only a related few. Additionally, one of skill in this art cannot determine the peptide structures encompassed by the claimed/recited genus only defined by function; any future peptide may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genus of peptides. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). As such, the rejection of claim 6 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 is maintained.
Claim Rejections - 35 USC § 103 - Updated
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
The rejections presented below have been updated as necessary corresponding to the instant claim amendments: a rejection for new claim 59 has been added, and new grounds of rejection regarding claims 1 and 27 for the specific embodiment of claim 1(ii) have been added as necessitated by amendment.
Claims 1-2, 6, 8, 19-20, 35-36, 44-48, and 55 stand as rejected, and new claim 59 is newly rejected, under 35 U.S.C. 103 as being unpatentable over non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") in view of US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo").
With regard to claims 1-2 and 47-48, Wilcox teaches NK cells possess both effector and regulatory activities that may be important during the antitumor immune response and the generation of antitumor immunity by the administration of an agonistic mAb against CD137 is NK cell-dependent; NK cells could be induced by IL-2 and IL-15 to express CD137 and ligation of CD137-stimulated NK cell proliferation and IFN-γ secretion and CD137-stimulated NK cells promoted the expansion of activated T cells in vitro, demonstrating immunoregulatory or “helper” activity for CD8+CTL (Abstract). Additionally, CD137-stimulated helper NK cells expressed the high-affinity IL-2R and were hyperresponsive to IL-2, and when taken together with previous findings that CD137 is a critical receptor for co-stimulation of T cells, the findings of the study suggest that CD137 is a stimulatory receptor for NK cells involved in the crosstalk between innate and adaptive immunity (Id.). By triggering NK-associated CD137 using either an agonistic mAb or CD137L-transfected cells, the authors show in this study that CD137 signaling stimulates proliferation and IFN-γ secretion in mouse NK cells, indicating that CD137 ligation delivers a signal for activation of NK cells and CD137-stimulated NK cells support the growth of activated CD8+OT-1 CTL through soluble factors and high-affinity IL-2 receptor is up-regulated on CD137-stimulated NK cells that become hyperresponsive to IL-2 wherein results suggest an important role for CD137 signaling in the activation of NK cells and crosstalk between NK cells and CTL; the ability of CD137-stimulated NK cells to proliferate in response to IL-2 may be attributed to the up-regulation of CD25 following CD137 stimulation (Pages 4234-4235, Discussion). Thus, Wilcox implicates CD137 expression and stimulation in NK cell proliferation, activation, and activity wherein the study also demonstrates that stimulation with IL-2 induces expression of CD137 on NK cells and when combined with CD137 agonistic antibodies promotes NK cell proliferation and expansion of activated T cells; i.e., agonistic CD137 antibodies in combination with IL-2 promote immune activity through NK cells and subsequently T cells. However, it is noted that agonistic antibodies of Wilcox are specific for mouse CD137 and Wilcox does not disclose that said antibodies are capable of binding human CD137. This deficiency is remedied by Luo.
Luo teaches antibodies that bind to human CD137 or antigen binding fragments thereof, nucleic acid encoding the same, therapeutic compositions thereof, and their use to enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, such as tumor immunity, and for the treatment of cancer (Abstract). More specifically, Luo teaches antibodies (e.g., isolated antibodies), or one or more antigen-binding fragments thereof, that binds to an extracellular domain of human CD137, and which comprise one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or all 10) of the following functional characteristics: (a) binds one or more amino acid residues within amino acid residues 34-108 of SEQ ID NO:1 (i.e., the extracellular domain of human CD137); (b) does not bind to one or more amino acid residues within amino acid residues 109-112, 125, 126, 135-138, 150 and 151 of SEQ ID NO:1; (c) binds to human CD137 with a KD of 100 nM or less; (d) has agonist activity on human CD137; (e) does not bind to human OX40, CD40, GITR and/or CD27 receptor at concentration up to 1000 nM; (f) is cross-reactive with monkey, mouse, rat, and/or dog CD 137; (g) does not induce ADCC effect; (h) is capable of inhibiting tumor cell growth; (i) has therapeutic effect on a cancer; and/or (j) blocks binding between CD137 and CD137L (Paragraph 0009; emphasis added). Luo discloses an antibody or antigen-binding fragment that comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an HVR-Hl comprising the amino acid sequence of SEQ ID NO:731, an HVR-H2 comprising the amino acid sequence of SEQ ID NO:755, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO:779; and/or wherein the light chain variable region comprises an HVR-Ll comprising the amino acid sequence of SEQ ID NO:803, an HVR-L2 comprising the amino acid sequence of SEQ ID NO:827, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 851 further wherein: (i) in some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:71, and/or the light chain variable region comprises the amino acid sequence of SEQ ID NO:72; and (ii) in some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:657, and/or the light chain comprises the amino acid sequence of SEQ ID NO:658 (Paragraph 0019; antibody identifier of AG10131 as detailed in Table 1b). It is specifically noted that the HVR-H1-3, HVR-L1-3, heavy chain variable, light chain variable, heavy chain, and light chain sequences of Luo are 100% matches to instant SEQ ID NOs: 2-4, 5-7, 8, 9, 10, and 11, respectively. Luo further teaches that CD137 expression is generally activation dependent and is present in a broad subset of immune cells including activated NK and NKT cells, regulatory T cells, dendritic cells (DC), stimulated mast cells, differentiating myeloid cells, monocytes, neutrophils, and eosinophils and the ligand that stimulates CD137 (i.e., CD137L) is expressed on activated antigen-presenting cells (APCs), myeloid progenitor cells, and hematopoietic stem cells (Paragraph 0004). Studies of murine and human T cells indicate that CD137 promotes enhanced cellular proliferation, survival, and cytokine production and other studies have indicated that some CD137 agonist mAbs increase costimulatory molecule expression and markedly enhance cytolytic T lymphocyte responses, resulting in anti-tumor efficacy in various models and have also been demonstrated to inhibit autoimmune reactions; dual activity of CD137 offers the potential to provide anti-tumor activity while dampening autoimmune side effects that can be associated with immunotherapy approaches that break immune tolerance (Paragraph 0006). Luo also teaches methods of treating abnormal cell growth (e.g., a cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the antibodies, antigen-binding fragments, and/or pharmaceutical compositions of the invention (Paragraph 0039). The methods can further comprise administering to the subject a therapeutically effective amount of at least one (e.g., at least one, at least two, at least three, at least four, at least five, at least 10, etc.) additional therapeutic agent; in some embodiments, the at least one additional therapeutic agent is selected from the group consisting of viral gene therapy, immune checkpoint inhibitors, target therapies, radiation therapies, and chemotherapies (Id.). Thus, Luo teaches anti-CD137 antibodies that specifically bind to the extracellular domain of human CD137 which are agonistic antibodies comprising the instantly claimed HVRs, VH, VL, heavy chain, and light chain sequences. Luo also discloses methods of treating abnormal cell growth (e.g., a cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the antibodies, antigen-binding fragments, and/or pharmaceutical compositions of the invention which may further comprise administering to the subject a therapeutically
effective amount of at least one (e.g., at least one, at least two, at least three, at least four, at least five, at least 10, etc.) additional therapeutic agent(s) (Paragraph 0039); it is noted that said methods of the invention can be used to treat cancers in which CD137 is implicated, including solid cancer such as lung, brain, colorectal, liver, kidney, bladder, breast, cervical, and thyroid cancers, and melanoma as well as liquid cancers including leukemias, multiple myeloma, non-Hodgkin lymphomas, and Hodgkin lymphomas (Paragraph 0187; emphasis added). Thus, Luo further discloses methods of treating cancer (e.g., lung cancer, melanoma, and/or lymphoma) comprising administering an anti-CD137 antibody of the invention and one or more additional therapeutic agents.
Wilcox and Luo are considered to be analogous to the present invention as they are in the same field of immunity, and more specifically anti-tumor immunity, as pertains to CD137. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo, which comprise the instantly claimed HVRs, VH, VL, heavy chain, and light chain sequences, could have been administered as suggested by Wilcox wherein said agonistic anti-CD137 antibodies could be used in combination with IL-2 wherein administration of IL-2 induces expression of CD137 on immune cells (e.g., NK cells) and IL-2 in combination with agonistic CD137 antibodies promotes immune response and anti-tumor immunity in cases such as, for example, lung cancer or melanoma as suggested by Luo. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox, wherein said effects would be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and T cells through the up-regulation of CD137 on said NK cells, as suggested by Wilcox and Luo.
With regard to claim 6, it is noted that Wilcox teaches IL-2 administration in combination with agonistic anti-CD137 antibodies induces expression of CD137 on immune cells, specifically NK cells (see, for example, Discussion on pages 4234-4235), wherein the IL-2 was human IL-2 (i.e., wildtype IL-2) (Page 4231, NK Cell Proliferation, IFN-γ Secretion, and Cytolytic Activity). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 19-20, Luo further teaches that CD137 expression is generally activation dependent and is present in a broad subset of immune cells including activated NK and NKT cells, regulatory T cells, dendritic cells (DC), stimulated mast cells, differentiating myeloid cells, monocytes, neutrophils, and eosinophils and the ligand that stimulates CD137 (i.e., CD137L) is expressed on activated antigen-presenting cells (APCs), myeloid progenitor cells, and hematopoietic stem cells (Paragraph 0004). Studies of murine and human T cells indicate that CD137 promotes enhanced cellular proliferation, survival, and cytokine production and other studies have indicated that some CD137 agonist mAbs increase costimulatory molecule expression and markedly enhance cytolytic T lymphocyte responses, resulting in anti-tumor efficacy in various models and have also been demonstrated to inhibit autoimmune reactions; dual activity of CD137 offers the potential to provide anti-tumor activity while dampening autoimmune side effects that can be associated with immunotherapy approaches that break immune tolerance (Paragraph 0006). Luo also teaches methods of treating abnormal cell growth (e.g., a cancer) in a subject in need thereof, comprising administering to the subject a
therapeutically effective amount of any of the antibodies, antigen-binding fragments, and/or pharmaceutical compositions of the invention (Paragraph 0039). The methods can further
comprise administering to the subject a therapeutically effective amount of at least one (e.g., at least one, at least two, at least three, at least four, at least five, at least 10, etc.) additional therapeutic agent; in some embodiments, the at least one additional therapeutic agent is selected from the group consisting of viral gene therapy, immune checkpoint inhibitors, target therapies, radiation therapies, and chemotherapies (Id.). The at least one additional therapeutic agent is selected from a group that includes, an anti-CTLA4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CD20 antibody (e.g., rituximab) (Id.). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 35, Luo further teaches that combination therapy for treating cancer also encompasses the combination of a binding molecule (i.e., anti-CD137 antibodies) with
surgery to remove a tumor, wherein the binding molecule may be administered to the mammal before (i.e., neoadjuvant setting), during, or after (i.e., adjuvant setting) the surgery (Paragraph 0195). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 36, Luo further teaches that the therapeutically effective amount of a CD137 antibody usually ranges from about 0.001 to about 500 mg/kg, and more usually about 0.01 to about 100 mg/kg, of the body weight of the mammal; for example, the amount can be about 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, 50 mg/kg, or 100 mg/kg of body weight of the mammal (Paragraph 0198). The precise dosage level to be administered can be readily determined by a person skilled in the art and will depend on a number of factors, such as the type, and severity of the disorder to be treated, the particular binding molecule employed, the route of administration, the time of administration, the duration of the treatment, the particular additional therapy employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts (Id.). Thus, as evidenced by the reference, it is noted that working doses for anti-CD137 antibodies are recognized as an antibody/therapeutic variable which achieves a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of anti-CD137 antibody dosages for therapeutic methods would be seen as routine optimization. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 44, Luo teaches antibodies (e.g., isolated antibodies), or one or more antigen-binding fragments thereof, that binds to an extracellular domain of human CD137, and which comprise one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or all 10) of the following functional characteristics: (a) binds one or more amino acid residues within amino acid residues 34-108 of SEQ ID NO:1 (i.e., the extracellular domain of human CD137); (b) does not bind to one or more amino acid residues within amino acid residues 109-112, 125, 126, 135-138, 150 and 151 of SEQ ID NO:1; (c) binds to human CD137 with a KD of 100 nM or less; (d) has agonist activity on human CD137; (e) does not bind to human OX40, CD40, GITR and/or CD27 receptor at concentration up to 1000 nM; (f) is cross-reactive with monkey, mouse, rat, and/or dog CD137; (g) does not induce ADCC effect; (h) is capable of inhibiting tumor cell growth; (i) has therapeutic effect on a cancer; and/or (j) blocks binding between CD137 and CD137L (Paragraph 0009; emphasis added). Thus, Luo teaches anti-CD137 antibodies that specifically bind to the extracellular domain of human CD137 (e.g., at one or more of residues 34-108) which can also be cross-reactive. It is specifically noted that exemplary antibodies of the invention, denoted as AG10058, AG10059, and AG10131, are shown to be cross-reactive to human, mouse, cynomolgus money, and/or rat CD137 (Page 33, Example 15, Table 9). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 55, Luo teaches that antibodies of the invention may comprise
a human IgG2 Fc region or a human IgG4 Fc region (Paragraph 0029). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 59, Luo teaches that methods of treating abnormal cell growth (e.g., a cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the antibodies, antigen-binding fragments, and/or pharmaceutical compositions of the invention which may further comprise administering to the subject a therapeutically effective amount of at least one (e.g., at least one, at least two, at least three, at least four, at least five, at least 10, etc.) additional therapeutic agent(s); the at least one additional therapeutic agent may be selected from the group consisting of viral gene therapy, immune checkpoint inhibitors, target therapies, radiation therapies, and chemotherapies wherein the at least one additional therapeutic agent may be selected from a group that includes, an anti-CTLA4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CD20 antibody (e.g., rituximab) (Paragraph 0039; emphasis added). It is noted that said methods of the invention can be used to treat cancers in which CD137 is implicated, including solid cancer such as lung, brain, colorectal, liver, kidney, bladder, breast, cervical, and thyroid cancers, and melanoma as well as liquid cancers including leukemias, multiple myeloma, non-Hodgkin lymphomas, and Hodgkin lymphomas (Paragraph 0187; emphasis added). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 7-8 stand as rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") in view of US 2019/0055314 A1 (previously cited on PTo-892; herein after referred to as "Luo") as applied to claim1-2, 6, 19-20, 35-36, 44-48, 55, and 59 above, and further in view of NCT03318900 Protocol (Jazaeri et. al., 01/15/2020, Accessed From ClinicalTrials.gov; previously cited on PTO-892; herein after referred to as “NCT03318900”).
With regard to claims 7-8, the method of claim 1 is rendered obvious by Wilcox and Luo. However, neither reference explicitly teaches the administration of aldesleukin or bempegaldesleukin, nor a dose of IL-2 of no more than 2.8x106 IU/m2. These deficiencies are remedied by NCT03318900.
NCT03318900 teaches a combined biologic strategy involving the use of adoptively transferred ovarian cancer antigen-specific CD8 T cells and the concomitant administration of anti-CD137 as a means of enhancing the transferred T cell response and promoting the generation of endogenous T cell responses against a broader panel of tumor-associated antigens that are released in a pro-inflammatory environment following lysis of ovarian antigen+ tumors by transferred T cells comprising administration of adoptively transferred antigen-specific CTL alone and in combination with utomilumab (PF-05082566; anti-CD137 antibody) in patients
with advanced ovarian cancer (Page 5). NCT03318900 further teaches that expression of CD137 on tumor-reactive T cells and its ability to increase T-cell recruitment into tumor sites, protect T cells from activation-induced cell death, and enhance their cytotoxic activity make the use of agonistic antibodies against CD-137 an attractive strategy for cancer immunotherapy (Page 9) and current strategies that have been evaluated to extend the in vivo persistence of transferred T cells include the administration of IL-2 and the use of pre-infusion conditioning regimens to inhibit the influence of regulatory cells limiting expansion and to induce lymphopenia and up regulation of homeostatic cytokines such as IL-7 and IL-15; these extrinsic approaches have proven effective, but the development of methods to isolate early stage effector CTL with superior self-renewal capacity would be highly desirable in light of animal studies demonstrating enhanced anti-tumor efficacy (Page 12). Thus, a strategy to generate helper-independent early effector human CD8 T cells which exhibit enhanced self-renewal capacity and high affinity for tumor-associated antigen targets was developed; in vitro priming in the presence of the gamma-chain receptor cytokine, IL-21 and rapamycin, yielded CTL with an optimal balance of high replicative capacity and enhanced effector function and in murine studies evaluating the use of early effector/central memory T cells, a T cell dose that was 100 fold less than the standard dose was sufficient to mediate tumor eradication and in some cases, long term survival (Id.). All patients will receive low-dose cyclophosphamide conditioning (300 mg/m2) 2 days prior to infusion, and low dose IL-2 (250,000 U/m2 s.c. q12h for 14 days; i.e., aldesleukin) after infusion; for Dose Level 1 cohorts, an infusion of ovarian cancer antigen-specific CTL will be administered on Day 0 at a total dose of 1x1010/m2 total, if both antigens are present (0.5x1010 for each antigen) and if only one antigen is present then CTL will be administered on Day 0 at a total dose of 1x1010 (Page 13). In the absence of any dose-limiting toxicity, the subsequent cohorts will be treated with the same number of ovarian cancer antigen-specific CTL in combination with two dose levels of utomilumab wherein utomilumab will be administered within 24 hours of T cell infusion and continued for a total of 6 doses 4 weeks apart (Id.). Thus, NCT03318900 suggests a method of treating cancer comprising administering low-dose IL-2 (e.g., 250,000 U/m2 s.c. q12h for 14 days), an anti-CD137 antibody, and CTLs wherein the motivation for such a combination is to enhance immune response, e.g., enhance T cell survival/proliferation and response (see pages 9 and 12).
It is further noted that Wilcox discloses that NK cells possess both effector and regulatory activities that may be important during the antitumor immune response and the generation of antitumor immunity by the administration of an agonistic mAb against CD137 is NK cell-dependent; NK cells could be induced by IL-2 and IL-15 to express CD137 and ligation of CD137-stimulated NK cell proliferation and IFN-γ secretion and CD137-stimulated NK cells promoted the expansion of activated T cells in vitro, demonstrating immunoregulatory or “helper” activity for CD8+CTL (Abstract; emphasis added). Additionally, CD137-stimulated helper NK cells expressed the high-affinity IL-2R and were hyperresponsive to IL-2, and when taken together with previous findings that CD137 is a critical receptor for co-stimulation of T cells, the findings of the study suggest that CD137 is a stimulatory receptor for NK cells involved in the crosstalk between innate and adaptive immunity (Id.). By triggering NK-associated CD137 using either an agonistic mAb or CD137L-transfected cells, the authors show in this study that CD137 signaling stimulates proliferation and IFN-γ secretion in mouse NK cells, indicating that CD137 ligation delivers a signal for activation of NK cells and CD137-stimulated NK cells support the growth of activated CD8+OT-1 CTL through soluble factors and high-affinity IL-2 receptor is up-regulated on CD137-stimulated NK cells that become hyperresponsive to IL-2 wherein results suggest an important role for CD137 signaling in the activation of NK cells and crosstalk between NK cells and CTL; the ability of CD137-stimulated NK cells to proliferate in response to IL-2 may be attributed to the up-regulation of CD25 following CD137 stimulation (Pages 4234-4235, Discussion; emphasis added).
Luo further teaches that CD137 expression is generally activation dependent and is present in a broad subset of immune cells including activated NK and NKT cells, regulatory T cells, dendritic cells (DC), stimulated mast cells, differentiating myeloid cells, monocytes, neutrophils, and eosinophils and the ligand that stimulates CD137 (i.e., CD137L) is expressed on activated antigen-presenting cells (APCs), myeloid progenitor cells, and hematopoietic stem cells (Paragraph 0004). Studies of murine and human T cells indicate that CD137 promotes enhanced cellular proliferation, survival, and cytokine production and other studies have indicated that some CD137 agonist mAbs increase costimulatory molecule expression and markedly enhance cytolytic T lymphocyte responses, resulting in anti-tumor efficacy in various models and have also been demonstrated to inhibit autoimmune reactions; dual activity of CD137 offers the potential to provide anti-tumor activity while dampening autoimmune side effects that can be associated with immunotherapy approaches that break immune tolerance (Paragraph 0006).
Wilcox, Luo, and NCT03318900 are considered to be analogous to the present invention as they are in the same field of immune response, specifically anti-tumor immunity, as relates to CD137 expression and/or signaling. All three references implicate CD137 expression and its subsequent signaling in immune activation via NK cells, T cells, and/or CTLs. Furthermore, both Wilcox and NCT03318900 suggest the administration of an anti-CD137 antibody in combination with IL-2 (wildtype and aldesleukin, respectively). Wilcox specifically teaches that IL-2 is implicated in upregulating CD137 expression, which with stimulation via anti-CD137 antibodies promotes immune response via NK cells as well as T cells and CTLs; Luo also implicates CD137 in enhanced T cell proliferation and CTL response. Thus, taken together, it would have been obvious to one of ordinary skill in the art that the method rendered obvious by Wilcox and Luo could be further modified such that the IL-2 administered is aldesleukin and the dose is 250,000 U/m2 (s.c. q12h for 14 days), as suggested by NCT03318900, because the simple substitution of one known element for another (i.e., wildtype IL-2 and aldesleukin) would be expected to obtain predictable results with a reasonable expectation of success; IL-2 is implicated in immune response as pertains specifically anti-tumor immunity via T cells and CTLs (as taught by Wilcox and NCT03318900) wherein when combined with agonistic anti-CD137 antibodies would be expected to further stimulate an anti-tumor immune response via T cells and CTLs (as suggested by all three references).
Claims 1 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo"), as applied to claims 1-2, 6, 19-20, 35-36, 44-48, 55, and 59 above, and in further view of non-patent literature by non-patent literature by Kim et. al. (Immunology, 2002, 107, 472-479; previously cited on PTO-892; herein after referred to as "Kim") and non-patent literature by Derenzini et. al. (Leukemia & Lymphoma, 2014, 55(7), 1471-1478; herein after referred to as “Derenzini”).
With regard to claims 1 and 27, the pertinent teachings of Luo and Wilcox are provided above. In summary: (i) Wilcox implicates CD137 expression and stimulation in NK cell proliferation, activation, and activity and stimulation with IL-2 induces expression of CD137 on NK cells and when combined with CD137 agonistic antibodies promotes NK cell proliferation and expansion of activated T cells; i.e., agonistic CD137 antibodies in combination with IL-2 promote immune activity through NK cells and subsequently T cells; (ii) Luo teaches anti-CD137 antibodies that specifically bind to the extracellular domain of human CD137 which are agonistic antibodies comprising the instantly claimed HVR sequences and methods of treating cancer (e.g., non-Hodgkin lymphoma) comprising administering an anti-CD137 antibody of the invention and one or more additional therapeutic agents, wherein an additional therapeutic agent may include chemotherapeutic agents. However, it is noted that Wilcox nor Luo explicitly disclose a method of treating, for example, lymphoma comprising administering an agent that induces expression of expression of CD137 on an immune cell and/or induces expression of CD137L on a cancer cell wherein the agent is bendamustine. However, this deficiency is remedied by the combination of Kim and Derenzini.
Kim teaches that expression of 4-1BB (i.e., CD137) increased in peripheral blood mononuclear cells (PBMCs) after exposure to mitomycin C, and further tested treatment with other DNA-damaging agents including doxorubicin, bleomycin and γ-irradiation; 4-1BB expression increased dose-dependently by said agents and reached a maximum 2-3 days after exposure and ligation of the damage-induced 4-1BB by monoclonal antibody enhanced viability and proliferating capacity of the cells (Abstract). Purified T cells were cultured with the DNA-damaging agents and analyzed by flow cytometry for 4-1BB expression; both CD4+ and CD8+ T cells expressed 4-1BB, wherein the percentage of 4-1BB expressing cells increased in a dose-dependent manner (Fig. 3) indicating that DNA-damaging stimuli act directly on T cells in the absence of APCs or other cells (Pages 474-475). DNA-damaging agent-treated cells (peripheral blood T cells) in wells coated with anti-4-1BB antibody showed higher viability compared to wells coated with control antibody across all three treatment groups; cells in the wells coated with anti-4-1BB antibodies also demonstrated higher proliferation (Page 476, Column 2, Paragraph 1; Fig. 7). Thus, Kim indicates that DNA-damaging agents induce CD137 expression in CD8+ T cells, and said cells upon exposure to anti-4-1BB antibodies demonstrated improved proliferation (i.e., activation).
Derenzini teaches that bendamustine is a unique bifunctional molecule with both alkylating and antimetabolite properties, resulting in high efficacy, low toxicity and good combinatory properties, which is now approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for rituximab/refractory follicular and low-grade lymphoma, chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) (Page 1471, Column 1, First Paragraph). Bendamustine induces DNA damage with inter- and intra-strand breaks in a more extensive and durable way compared with other alkylators such as melphalan,
carmustine and cyclophosphamide; bendamustine induces cell death by apoptosis by activating cell cycle DNA damage checkpoints in an ataxia telangiectasia mutated (ATM)-p53-dependent manner and bendamustine can trigger cell death by non-apoptotic mechanisms by inducing mitotic catastrophe in a p53- independent manner (Page 1472, Chemistry, Structure, and Mechanism of Action). The efficacy of bendamustine as a single agent or in combination with rituximab for different histologic subtypes of B-cell indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL) are presented in Table II; the results of the studies presented in Table II include promising results for bendamustine as a single agent and in combination approaches (Pages1472-1474, Indolent B Cell Lymphoma (Including Follicular Lymphoma); Table II). Thus, Derenzini teaches that bendamustine is a DNA-damaging agent that demonstrates anti-cancer effects as a single agent and in combinatorial approaches.
As such, the combination of Kim and Derenzini suggests that bendamustine, an anti-cancer agent that causes DNA damage, would be expected to upregulate CD137 on immune cells.
Wilcox, Luo, Kim, and Derenzini are considered to be analogous to the present invention as they are in the same field of immunity/anti-tumor immunity as pertains to CD137 and/or cancer therapeutics. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo, which comprise the instantly claimed HVR sequences, could have been administered as suggested by Wilcox further wherein said agonistic anti-CD137 antibodies could be used in combination with bendamustine instead of IL-2, wherein the bendamustine would be expected to induce expression of CD137 on immune cells (e.g., CD8+ T cells, as suggested by Kim) and such that the bendamustine in combination with agonistic CD137 antibodies would promote an immune response and anti-tumor immunity in cases such as, for example, lymphoma (e.g., NHL) as suggested by Luo and Derenzini. Combining prior art elements according to known methods would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox, and similar to IL-2 it would be expected that bendamustine also upregulates CD137 on immune cells (as suggested by Kim and Derenzini) wherein when the CD137 antibody and bendamustine are combined in a therapeutic method (as suggested by Wilcox and Luo) it would be expected that said combination would more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and/or T cells through the up-regulation of CD137 on said NK cells/T cells, as suggested by the combination of teachings by Wilcox, Luo, Kim, and Derenzini.
Double Patenting - Updated
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 6, 8, 19-20, 35-36, 44-48, and 55 stand as rejected, and new claim 59 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 10-11, 13, 15-18, 51-22, 25, and 28-29 of U.S. Patent No. 11,242,395 (U.S. Patent corresponding to US 2019/0055314 A1; herein after referred to as "reference patent") in view of non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo").
Claims 1-2, 6, 19-20, 35-36, 44-48, 55 and 59 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims of the second reference patent over related subject matter only further supports this obviousness.
Reference patent claim 1 is drawn to an isolated antibody or antigen binding fragment thereof that binds to an extracellular domain of human CD173, comprising the recited HVR-H1-3 and HVR-L1-3 sequences, and claims 17-18 further define residues of CD173 that are bound by said antibody while claims 21-22 further recite the heavy/light chain variable sequence and heavy/light chain sequences, respectively. It is specifically noted that the sequences recited in reference patent claims 1, 21, and 22 are 100% identical to those recited in instant claims 46, 47, and 48, respectively. Reference patent claims 4-5 recite cross-reactivity of the CD137 antibody or antigen binding fragment of claim 1, claims 10-11 recite activities associated with exposing human cells expressing CD137 to the CD137 antibodies of the invention, claims 13 and 25 recite that the CD137 antibodies or antigen binding fragments thereof comprise a human IgG4 Fc region, and claims 15 and 28-29 recite pharmaceutical composition comprising the CD137 antibodies or antigen binding fragments thereof. However, it is noted that the reference patent does not disclose methods generally comprising (i) treating cancer in a subject comprising administering a therapeutically effective amount of an anti-CD137 antibody nor (ii) administering a therapeutically effective amount of an agent that induces expression of CD137/CD137L. These deficiencies are addressed by the cited references, as provided
by the teachings specified in the 103 section.
The reference patent, Wilcox, and Luo are considered to be analogous to the present invention as they are in the same field of CD137 antibodies and/or immunity, more specifically anti-tumor immunity, as pertains to CD137. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo and/or the reference patent, which comprise the instantly claimed HVRs, VH, VL, heavy chain, and light chain sequences, could have been administered as suggested by Wilcox wherein said agonistic anti-CD137 antibodies could be used in combination with IL-2 wherein administration of IL-2 induces expression of CD137 on immune cells (e.g., NK cells) and IL-2 in combination with agonistic CD137 antibodies promotes immune response and anti-tumor immunity in cases such as, for example, lung cancer or melanoma as suggested by Luo. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo and the reference patent are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox wherein said effects would be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and T cells through the up-regulation of CD137 on said NK cells, as suggested by Wilcox and Luo.
Claims 7-8 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 10-11, 13, 15-18, 51-22, 25, and 28-29 of U.S. Patent No. 11,242,395 (U.S. Patent corresponding to US 2019/0055314 A1; herein after referred to as "reference patent"), non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox"), and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo") as applied to claims 1-2, 6, 8, 19-20, 35-36, 44-48, 55 and 59 above, and further in view of NCT03318900 Protocol (Jazaeri et. al., 01/15/2020, Accessed From ClinicalTrials.gov; previously cited on PTO-892; herein after referred to as “NCT03318900”).
Instant claim 1 is rendered obvious by the combined teachings of the reference patent, Wilcox, and Luo. Claim 7 is further rendered obvious over the additional prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims of the reference patent over related subject matter only further supports this obviousness. The reference patent Wilcox, Luo, and NCT03318900 are considered to be analogous to the present invention as they are in the same field of CD137 antibodies and/or immune response, specifically anti-tumor immunity, as relates to CD137 expression and/or signaling. All three prior art references implicate CD137 expression and its subsequent signaling in immune activation via NK cells, T cells, and/or CTLs. Furthermore, both Wilcox and NCT03318900 suggest the administration of an anti-CD137 antibody in combination with IL-2 (wildtype and aldesleukin, respectively). Wilcox specifically teaches that IL-2 is implicated in upregulating CD137 expression, which with stimulation via anti-CD137 antibodies promotes immune response via NK cells as well as T cells and CTLs; Luo also implicates CD137 in enhanced T cell proliferation and CTL response. Thus, taken together, it would have been obvious to one of ordinary skill in the art that the method rendered obvious by the reference patent, Wilcox, and Luo could be further modified such that the IL-2 administered is aldesleukin and the dose is 250,000 U/m2 (s.c. q12h for 14 days), as suggested by NCT03318900, because the simple substitution of one known element for another (i.e., wildtype IL-2 and aldesleukin) would be expected to obtain predictable results with a reasonable expectation of success; IL-2 is implicated in immune response as pertains specifically anti-tumor immunity via T cells and CTLs (as taught by Wilcox and NCT03318900) wherein when combined with agonistic anti-CD137 antibodies would be expected to further stimulate an anti-tumor immune response via T cells and CTLs (as suggested by all three prior art references).
Claims 1 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 10-11, 13, 15-18, 51-22, 25, and 28-29 of U.S. Patent No. 11,242,395 (U.S. Patent corresponding to US 2019/0055314 A1; herein after referred to as "reference patent"), non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox"), and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo") as applied to claims 1-2, 6, 8, 19-20, 35-36, 44-48, 55 and 59 above,, and in further view of non-patent literature by non-patent literature by Kim et. al. (Immunology, 2002, 107, 472-479; previously cited on PTO-892; herein after referred to as "Kim") and non-patent literature by Derenzini et. al. (Leukemia & Lymphoma, 2014, 55(7), 1471-1478; herein after referred to as “Derenzini”).
With regard to claims 1 and 27, the pertinent teachings of Luo and Wilcox are provided above in the 103 section, the 103 being incorporated here. In summary: (i) Wilcox implicates CD137 expression and stimulation in NK cell proliferation, activation, and activity and stimulation with IL-2 induces expression of CD137 on NK cells and when combined with CD137 agonistic antibodies promotes NK cell proliferation and expansion of activated T cells; i.e., agonistic CD137 antibodies in combination with IL-2 promote immune activity through NK cells and subsequently T cells; (ii) Luo teaches anti-CD137 antibodies that specifically bind to the extracellular domain of human CD137 which are agonistic antibodies comprising the instantly claimed HVR sequences and methods of treating cancer (e.g., non-Hodgkin lymphoma) comprising administering an anti-CD137 antibody of the invention and one or more additional therapeutic agents, wherein an additional therapeutic agent may include chemotherapeutic agents. However, it is noted that Wilcox nor Luo explicitly disclose a method of treating, for example, lymphoma comprising administering an agent that induces expression of expression of CD137 on an immune cell and/or induces expression of CD137L on a cancer cell wherein the agent is bendamustine. However, this deficiency is remedied by the combination of Kim and Derenzini as applied in the 103 section above, the 103 being incorporated here.
The reference patent, Wilcox, Luo, Kim, and Derenzini are considered to be analogous to the present invention as they are in the same field of immunity/anti-tumor immunity as pertains to CD137 and/or cancer therapeutics. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo and/or the reference patent, which comprise the instantly claimed HVR sequences, could have been administered as suggested by Wilcox further wherein said agonistic anti-CD137 antibodies could be used in combination with bendamustine instead of IL-2, wherein the bendamustine would be expected to induce expression of CD137 on immune cells (e.g., CD8+ T cells, as suggested by Kim) and such that the bendamustine in combination with agonistic CD137 antibodies would promote an immune response and anti-tumor immunity in cases such as, for example, lymphoma (e.g., NHL) as suggested by Luo and Derenzini. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another and one CD137 inducing agent for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo and/or the reference patent are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox, wherein said effects would be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and/or T cells through the up-regulation of CD137 on said NK cells/T cells, as suggested by the combination of teachings by Wilcox, Luo, Kim, and Derenzini.
Similarly, claims 1-2, 6, 8, 19-20, 35-36, 44-48, and 55 stand as rejected, and new claim 59 is newly rejected, on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patent Nos. in view of non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo").
Patent Number
Brief Description of the Invention
Pertinent Claims
11859003
Method for Treating Cancer Comprising Administering an Anti-CD137 Antibody
1-7, 9-11, 14, 18
11952681
Activatable Antibody that Binds Human CD137
1, 14-16, 19-22, 25-28, 31-34, 36-37, 39-40, 42-43
Claims 1-2, 6, 8, 19-20, 35-36, 44-48, 55 and 59 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims over related subject matter only further supports this obviousness.
It is noted that all of the above-mentioned patents are generally drawn to CD137 antibodies and/or methods of treating cancer thereof. However, it noted that the above-mentioned patents do not necessarily teach a method of treating cancer in a subject generally comprising: (i) administering a therapeutically effective amount of anti-CD137 antibody that specifically binds an extracellular domain of human CD137 at one or more residues recited in instant claim 1; and (ii) administering a therapeutically effective amount of an agent that increases expression of CD137/CD137L. These deficiencies are addressed by the cited references, as provided in the teachings specified in the 103 section.
The above-identified patents, Wilcox, and Luo are considered to be analogous to the present invention as they are in the same field of CD137 antibodies and/or immunity, more specifically anti-tumor immunity, as pertains to CD137. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo and/or the above-identified patents, which may comprise the instantly claimed HVRs, VH, VL, heavy chain, and light chain sequences, could have been administered as suggested by Wilcox wherein said agonistic anti-CD137 antibodies could be used in combination with IL-2 wherein administration of IL-2 induces expression of CD137 on immune cells (e.g., NK cells) and IL-2 in combination with agonistic CD137 antibodies promotes immune response and anti-tumor immunity in cases such as, for example, lung cancer or melanoma as suggested by Luo. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo and/or the reference patents are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox wherein said effects would be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and T cells through the up-regulation of CD137 on said NK cells, as suggested by Wilcox and Luo.
Claims 7-8 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims the above-listed patents, non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox"), and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo") as applied to claims 1-2, 6, 8, 19-20, 35-36, 44-48, 55 and 59 above, and further in view of NCT03318900 Protocol (Jazaeri et. al., 01/15/2020, Accessed From ClinicalTrials.gov; previously cited on PTO-892; herein after referred to as “NCT03318900”).
Instant claim 1 is rendered obvious by the combined teachings of the above-listed patents, Wilcox, and Luo. Claims 7-8 are further rendered obvious over the additional prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims of the above-listed patents over related subject matter only further supports this obviousness.
The above-listed patents, Wilcox, Luo, and NCT03318900 are considered to be analogous to the present invention as they are in the same field of CD137 antibodies and/or immune response, specifically anti-tumor immunity, as relates to CD137 expression and/or signaling. All three prior art references implicate CD137 expression and its subsequent signaling in immune activation via NK cells, T cells, and/or CTLs. Furthermore, both Wilcox and NCT03318900 suggest the administration of an anti-CD137 antibody in combination with IL-2 (wildtype and aldesleukin, respectively). Wilcox specifically teaches that IL-2 is implicated in upregulating CD137 expression, which with stimulation via anti-CD137 antibodies promotes immune response via NK cells as well as T cells and CTLs; Luo also implicates CD137 in enhanced T cell proliferation and CTL response. Thus, taken together, it would have been obvious to one of ordinary skill in the art that the method rendered obvious by the above-listed patents, Wilcox, and Luo could be further modified such that the IL-2 administered is aldesleukin and the dose is 250,000 U/m2 (s.c. q12h for 14 days), as suggested by NCT03318900, because the simple substitution of one known element for another (i.e., wildtype IL-2 and aldesleukin) would be expected to obtain predictable results with a reasonable expectation of success; IL-2 is implicated in immune response as pertains specifically anti-tumor immunity via T cells and CTLs (as taught by Wilcox and NCT03318900) wherein when combined with agonistic anti-CD137 antibodies would be expected to further stimulate an anti-tumor immune response via T cells and CTLs (as suggested by all three prior art references).
Claims 1 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the above-listed U.S. Patent Nos. in view of non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo"), and in further view of non-patent literature by non-patent literature by Kim et. al. (Immunology, 2002, 107, 472-479; previously cited on PTO-892; herein after referred to as "Kim") and non-patent literature by Derenzini et. al. (Leukemia & Lymphoma, 2014, 55(7), 1471-1478; herein after referred to as “Derenzini”).
With regard to claims 1 and 27, the pertinent teachings of Luo and Wilcox are provided above in the 103 section, the 103 being incorporated here. In summary: (i) Wilcox implicates CD137 expression and stimulation in NK cell proliferation, activation, and activity and stimulation with IL-2 induces expression of CD137 on NK cells and when combined with CD137 agonistic antibodies promotes NK cell proliferation and expansion of activated T cells; i.e., agonistic CD137 antibodies in combination with IL-2 promote immune activity through NK cells and subsequently T cells; (ii) Luo teaches anti-CD137 antibodies that specifically bind to the extracellular domain of human CD137 which are agonistic antibodies comprising the instantly claimed HVR sequences and methods of treating cancer (e.g., non-Hodgkin lymphoma) comprising administering an anti-CD137 antibody of the invention and one or more additional therapeutic agents, wherein an additional therapeutic agent may include chemotherapeutic agents. However, it is noted that Wilcox nor Luo explicitly disclose a method of treating, for example, lymphoma comprising administering an agent that induces expression of expression of CD137 on an immune cell and/or induces expression of CD137L on a cancer cell wherein the agent is bendamustine. However, this deficiency is remedied by the combination of Kim and Derenzini as applied in the 103 section above, the 103 being incorporated here.
The above-listed reference patents, Wilcox, Luo, Kim, and Derenzini are considered to be analogous to the present invention as they are in the same field of immunity/anti-tumor immunity as pertains to CD137 and/or cancer therapeutics. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo and/or the reference patents, which comprise the instantly claimed HVR sequences, could have been administered as suggested by Wilcox further wherein said agonistic anti-CD137 antibodies could be used in combination with bendamustine instead of IL-2, wherein the bendamustine would be expected to induce expression of CD137 on immune cells (e.g., CD8+ T cells, as suggested by Kim) and such that the bendamustine in combination with agonistic CD137 antibodies would promote an immune response and anti-tumor immunity in cases such as, for example, lymphoma (e.g., NHL) as suggested by Luo and Derenzini. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another and one CD137 inducing agent for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo and/or the reference patents are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox, wherein said effects would be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and/or T cells through the up-regulation of CD137 on said NK cells/T cells, as suggested by the combination of teachings by Wilcox, Luo, Kim, and Derenzini.
Similarly, claims 1-2, 6, 8, 19-20, 35-36, 44-48, and 55 stand as provisionally rejected, and new claim 59 is newly provisionally rejected, on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patent Nos. in view of non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") in view of US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo").
Application Number
Brief Description of the Invention
Pertinent Claims
17924540
Method for Treating Cancer Comprising Administering an Anti-CD137 Antibody
1, 7, 10, 20-23, 44-45, 59-60, 71-72, 75
18842313
Masked Antibody that Binds Human CD137, Method of Treating Cancer, and Kit Thereof
1, 39, 42, 51, 56
Claims 1-2, 6, 8, 19-20, 35-36, 44-48, 55 and 59 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the co-pending claims over related subject matter only further supports this obviousness.
It is noted that all of the above-mentioned applications are generally drawn to CD137 antibodies and/or methods of treating cancer thereof. However, it noted that the above-mentioned applications do not necessarily teach a method of treating cancer in a subject generally comprising: (i) administering a therapeutically effective amount of anti-CD137 antibody that specifically binds an extracellular domain of human CD137 at one or more residues recited in instant claim 1; and (ii) administering a therapeutically effective amount of an agent that increases expression of CD137/CD137L. These deficiencies are addressed by the cited references, as provided in the teachings specified in the 103 section.
The above-identified applications, Wilcox, and Luo are considered to be analogous to the present invention as they are in the same field of CD137 antibodies and/or immunity, more specifically anti-tumor immunity, as pertains to CD137. Thus, it would have been obvious to one of ordinary skill in the art that the method of Wilcox could have been modified such that the agonistic anti-CD137 antibodies of Luo and/or the above-identified applications, which specifically bind an extracellular domain of human CD137 and would bind at one or more residues recited in instant claim 1, could have been administered as suggested by Wilcox wherein said agonistic anti-CD137 antibodies could be used in combination with IL-2 wherein administration of IL-2 induces expression of CD137 on immune cells (e.g., NK cells) and IL-2 in combination with agonistic CD137 antibodies promotes immune response and anti-tumor immunity. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo and the reference patent are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox.
This is a provisional nonstatutory double patenting rejection.
Claims 7-8 stand as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims the above-listed applications, non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox"), and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo") as applied to claim1-2, 6, 8, 19-20, 35-36, 44-48, 55 and 59 above, and further in view of NCT03318900 Protocol (Jazaeri et. al., 01/15/2020, Accessed From ClinicalTrials.gov; previously cited on PTO-892; herein after referred to as “NCT03318900”).
Instant claim 1 is rendered obvious by the combined teachings of the above-listed patents, Wilcox, and Luo. Claims 7-8 are further rendered obvious over the additional prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the above-listed applications over related subject matter only further supports this obviousness.
The above-listed applications, Wilcox, Luo, and NCT03318900 are considered to be analogous to the present invention as they are in the same field of CD137 antibodies and/or immune response, specifically anti-tumor immunity, as relates to CD137 expression and/or signaling. All three prior art references implicate CD137 expression and its subsequent signaling in immune activation via NK cells, T cells, and/or CTLs. Furthermore, both Wilcox and Luo suggest the administration of an anti-CD137 antibody in combination with IL-2 (wildtype and aldesleukin, respectively). Wilcox specifically teaches that IL-2 is implicated in upregulating CD137 expression, which with stimulation via anti-CD137 antibodies promotes immune response via NK cells as well as T cells and CTLs; Luo also implicates CD137 in enhanced T cell proliferation and CTL response. Thus, taken together, it would have been obvious to one of ordinary skill in the art that the method rendered obvious by the above-listed applications, Wilcox, and Luo could be further modified such that the IL-2 administered is aldesleukin and the dose is 250,000 U/m2 (s.c. q12h for 14 days), as suggested by NCT03318900, because the simple substitution of one known element for another (i.e., wildtype IL-2 and aldesleukin) would be expected to obtain predictable results with a reasonable expectation of success; IL-2 is implicated in immune response as pertains specifically anti-tumor immunity via T cells and CTLs (as taught by Wilcox and NCT03318900) wherein when combined with agonistic anti-CD137 antibodies would be expected to further stimulate an anti-tumor immune response via T cells and CTLs (as suggested by all three prior art references).
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the above-listed applications in view of non-patent literature by Wilcox et. al. (J. Immunol., 2002, 169(8), 4230-4236; previously cited on PTO-892; herein after referred to as "Wilcox") and US 2019/0055314 A1 (previously cited on PTO-892; herein after referred to as "Luo"), and in further view of non-patent literature by non-patent literature by Kim et. al. (Immunology, 2002, 107, 472-479; previously cited on PTO-892; herein after referred to as "Kim") and non-patent literature by Derenzini et. al. (Leukemia & Lymphoma, 2014, 55(7), 1471-1478; herein after referred to as “Derenzini”).
With regard to claims 1 and 27, the pertinent teachings of Luo and Wilcox are provided above in the 103 section, the 103 being incorporated here. In summary: (i) Wilcox implicates CD137 expression and stimulation in NK cell proliferation, activation, and activity and stimulation with IL-2 induces expression of CD137 on NK cells and when combined with CD137 agonistic antibodies promotes NK cell proliferation and expansion of activated T cells; i.e., agonistic CD137 antibodies in combination with IL-2 promote immune activity through NK cells and subsequently T cells; (ii) Luo teaches anti-CD137 antibodies that specifically bind to the extracellular domain of human CD137 which are agonistic antibodies comprising the instantly claimed HVR sequences and methods of treating cancer (e.g., non-Hodgkin lymphoma) comprising administering an anti-CD137 antibody of the invention and one or more additional therapeutic agents, wherein an additional therapeutic agent may include chemotherapeutic agents. However, it is noted that Wilcox nor Luo explicitly disclose a method of treating, for example, lymphoma comprising administering an agent that induces expression of expression of CD137 on an immune cell and/or induces expression of CD137L on a cancer cell wherein the agent is bendamustine. However, this deficiency is remedied by the combination of Kim and Derenzini as applied in the 103 section above, the 103 being incorporated here.
The above-listed applications, Wilcox, Luo, Kim, and Derenzini are considered to be analogous to the present invention as they are in the same field of immunity/anti-tumor immunity as pertains to CD137 and/or cancer therapeutics. Thus, it would have been obvious to one of ordinary skill in the art that the method rendered obvious by the above-listed applications, Wilcox, and Luo could be further modified such that the agonistic anti-CD137 antibodies of Luo and/or the reference applications, which comprise the instantly claimed HVR sequences, could have been administered as suggested by Wilcox further wherein said agonistic anti-CD137 antibodies could be used in combination with bendamustine instead of IL-2, wherein the bendamustine would be expected to induce expression of CD137 on immune cells (e.g., CD8+ T cells, as suggested by Kim) and such that the bendamustine in combination with agonistic CD137 antibodies would promote an immune response and anti-tumor immunity in cases such as, for example, lymphoma (e.g., NHL) as suggested by Luo and Derenzini. The simple substitution of one known element for another (i.e., one agonistic CD137 antibody for another and one CD137 inducing agent for another) would be expected to obtain predictable results with a reasonable expectation of success; specifically the antibodies of Luo and/or the above-listed applications are demonstrated to be cross-reactive in mice and thus would be expected to exhibit similar effects as observed by Wilcox, wherein said effects would be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and/or T cells through the up-regulation of CD137 on said NK cells/T cells, as suggested by the combination of teachings by Wilcox, Luo, Kim, and Derenzini.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 10/16/2025 have been fully considered but they are not persuasive in view of the updated claim rejections provided above.
More specifically, on Pages 9-11 Applicant argues that neither reference discloses a method of treating a cancer in a subject, comprising administering an anti-CD137 antibody as recited in amended claim 1, and an agent that induces expression of CD137 on an immune cell and/or induces expression of CD137L on a cancer cell, wherein (i) the agent is IL-2 and the cancer is lung cancer or melanoma, or (ii) the agent is bendamustine and the cancer is lymphoma. Applicant also argues that neither reference discloses any data for treating the specific cancer types as recited in amended claim 1. Thus, Applicant argues that a skilled person reading the references would not have a reasonable expectation that a combination of the anti-CD 137 antibody and IL-2 will be effective in treating lung cancer or melanoma, or that a combination of the anti-CD137 antibody and bendamustine will be effective in treating lymphoma. Applicant further argues unexpected results in support of non-obviousness:
In Example 3, the therapeutic efficacy of treating lung cancer with ADG 106 ( comprising the six HVR sequences recited in claim 1) in combination with IL-2 was tested in a lung cancer model. In mice treated with ADG106, 5/7 experienced tumor growth, and 2/7 experienced a complete response (CR; no tumor growth). FIG. 3C-3D shows that mice treated with IL-2 alone under both treatment regimens all experienced tumor growth, with none experiencing CR. However, a combination of ADG 106 and IL-2 resulted in surprisingly superior anti-tumor efficacy as compared to ADG 106 or IL-2 alone, with 3/7 (FIG. 3E) and 5/7 (FIG. 3F) mice experiencing CR at the two different dosing regimens. Taken together, these results demonstrate the remarkable efficacy for treating lung cancer of the presently claimed method as a result of the anti-CD 137 antibody having the six HVRs recited in claim 1 as amended, exemplified by ADG106, and the CD137-inducing agent, IL-2.
In Example 4, the therapeutic efficacy of treating B cell lymphoma with ADG 106 in combination with Bendamustine was tested in a B cell lymphoma model. BALB/c mice with established B cell lymphoma were treated with vehicle alone, ADG106, Bendamustine alone, and a combination of ADG 106 and Bendamustine, by intraperitoneal injection. As shown in FIGs. 4A- 4E, Combination of ADG106 with Bendamustine exhibited enhanced antitumor efficacy compared to ADG 106 and Bendamustine monotherapies. Additionally, no obvious toxicity was observed for the combination therapy.
In Example 10, the therapeutic efficacy of treating melanoma was tested in a melanoma model. C57BL/6 mice with established melanoma were treated with vehicle alone, ADG106, anti-PDl antibody 2E5, IL-2 alone, a combination of ADG 106 and IL-2, a combination of 2E5 and IL-2, or a combination of ADG 106, 2E5 and IL-2. As shown in FIGs. 13A-13I, ADG 106 combined with IL-2 exhibited enhanced anti-tumor efficacy compared to ADG 106, IL-2 and 2E5 monotherapies.
With regard to the arguments above, it is noted that:
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e.
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
It is particularly noted that the claim rejections under both 35 U.S.C. 103 and nonstatutory double patenting have been updated above; the combination of teachings from the prior art references render obvious the method of claim 1, even as instantly amended. The only argument provided against the prior art was that neither reference (i.e., individually) teaches the method of claim 1, however it is noted that the provided claim rejections are under 35 U.S.C. 103, not 35 U.S.C. 102. No specific arguments against the prior art references and their combination have been provided. As such, the argument regarding the prior art references is deemed not persuasive. With regard to unexpected results, it is noted that Wilcox suggested by that agonistic anti-CD137 antibodies could be used in combination with IL-2 wherein administration of IL-2 induces expression of CD137 on immune cells (e.g., NK cells) and IL-2 in combination with agonistic CD137 antibodies promotes immune response and anti-tumor immunity. Luo discloses methods of treating cancer, e.g., lung cancer, melanoma, and/or lymphoma, comprising the administration of agonistic CD137 antibodies, including antibodies identical to those instantly claimed, wherein said method may further comprise the administration of an additional therapeutic agent. The combination of Luo and Wilcox such that the antibody of Luo is administered in combination with IL-2, as suggested by Wilcox, would reasonably be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated NK cells and T cells through the up-regulation of CD137 on said NK cells, as suggested by Wilcox and Luo, thus enhancing the anti-cancer effects compared to IL-2 or CD137 agonist antibodies alone. Similarly, the combination of Kim and Derenzini suggest that DNA-damaging agents (e.g., bendamustine) may have a similar effect to IL-2 wherein administration of DNA-damaging agents upregulates CD137 expression on immune cells (e.g., CD8+ T cells). The administration of the CD137 antibody of Luo in combination with a CD137 regulatory agent that increases CD137 expression on immune cells, as suggested by Wilcox, wherein such an agent may be bendamustine, as suggested by the combination of Kim and Derenzini, would reasonably be expected to more efficaciously treat cancer by more efficiently/effectively promoting the activation of immune responses via activated immune cells (e.g., CD8+ T cells) through the up-regulation of CD137 on said T cells, as suggested by Kim and Derenzini, thus enhancing the anti-cancer effects compared to bendamustine or CD137 agonist antibodies alone. The teachings of the cited prior art reference thus suggest that administration of an agent that enhances CD137 expression on immune cells in combination with a CD137 agonist antibody would be expected to enhance immune responses and subsequently enhance anti-tumor responses through the increased activation of immune cells. As such, Applicant’s arguments with regard to unexpected results are deemed not persuasive absent a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.
Conclusion
Claims 1-2, 6-8, 19-20, 27, 35-36, 44, 47-48, 55, and 59 are pending. Claims 1-2, 6-8, 19-20, 27, 35-36, 44, 47-48, 55, and 59 are rejected. No claims are allowed.
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642