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 .
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US2021/073107, filing date 12/23/2021, which claims the benefit of the prior-filed United States Provisional Patent Application No. 63/130,339, filing date 12/23/2020.
Status of Application/Claims
The preliminary amendment, filed 06/22/2023, is acknowledged. Claims 7, 9-15, 18, 21-47, 50-51, 55-56, 68-99, 102-103, 107-118, 120-123, 126-128, and 131-134 are canceled. Claims 1, 3-6, 8, 16-17, 19, 48, 52-54, 67, 104, 106, 119, 124-125, and 129 are currently amended. Claims 1-6, 8, 16-17, 19-20, 48-49, 52-55, 67, 100-101, 104-106, 119, 124-125, and 129-130 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statement (IDS) submitted on 08/08/2023 has been fully considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Hyperlinks are found on the following pages:
p.184, [0198]:
“http://www.medicines.org.uk/emc/medicine/19322/SPC.” contains a prefix (underlined) and is not limited to the top-level domain (see bold)
p.184, [0200]:
“https://www.drugbank.ca/drugs/DB00041” contains a prefix (underlined) and is not limited to the top-level domain (see bold)
p.206, [0242]“http://tools.thermofisher.com/content/sfs/manuals/cytokine-bioassays. pdf” contains a prefix (underlined) and is not limited to the top-level domain (see bold)
The use of the terms Sephadex, Pierce, Sigma, Bakerbond, Biacore, BioLegend, J.T. Baker, and InvivoGen, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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.
Claim Objections
Claim 67 is objected to because of the following informalities: Claim 67 recites “PD1” in line 2 which should be corrected to “PD-1”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 20 is 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 20 recites, “…wherein the IL-2 variant comprises one or more mutations at a position selected from the group consisting of L18, Q22, F24, K35, R38, F42, K43, E61, P65, Q126, and S130…”. However, the amino acid at position 24 is “I24” not “F24.” Thus, the claim is rejected for indefiniteness. For further examination, the claim is interpreted to mean position “I24.”
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.
Claims 1, 5, 8, 16-17, 19, 48, 67, 119, 124-125, and 129-130 are rejected under 35 U.S.C. 103 as being unpatentable over Jahn, et al. An IL-12-IL2-antibody fusion protein targeting Hodgkin’s lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack. PLOS ONE (2012), 7:9, p.1-13 (herein referred to as Jahn); further in view of Xencor, Inc.—WO2020077276A2 (publication date: 05/16/2020; effective filing date: 12/21/2018; herein referred to as Xencor); and, further in view of Brown, et al. Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors. PLOS ONE (05/05/2020), 15: 3, p.1-21 (herein referred to as Brown).
Jahn teaches cytokine antibody fusion proteins and dual-cytokine antibody fusion proteins/immunocytokines for treatment of mice harboring tumors derived from L540cy lymphoma cancer cells that are expressed using nucleic acids encoding the fusion proteins (i.e., Hodgkin’s lymphoma cells; p.8, col.2, para.3—p.9, col.1, para.1; p.12, col.1, para.3); wherein the immunocytokine comprises an antigen-binding protein that comprises 1) an antigen-binding fragment (i.e., anti-CD30 single chain fragment HRS3-scFv) specifically recognizing a tumor target antigen (i.e., CD30), 2) a cytokine (i.e., IL-12), and 3) an IgG1 Fc domain; wherein the antigen-binding polypeptide comprises the components in from N’ to C’ with the configuration HRS3-scFv-hinge-IL12-hinge-Fc; and, wherein, the p40 and p35 subunits of IL-12 are comprised in a single chain cytokine fragment. That is, the cytokine is positioned at the hinge region and the dimeric cytokine is arranged with the p40 and p35 subunits in tandem at the hinge region (title; abstract; Fig.1, 6th construct). Jahn also teaches immunocytokines additionally comprising a second cytokine IL-2 (title; abstract; Fig.1, 7th construct). Jahn also teaches that antibody-targeted cytokines that accumulate in the lymphoma lesion are thought to be more efficacious than unmodified cytokines (p.1, col.1, para.1). Jahn also teaches that many tumor cells shed the targeted cell-surface-antigen in substantial amounts which competes in binding with the tumor-cell-bound antigen; and, that favored binding to solid-phase bound antigen in the presence of high amounts of soluble antigen is required (p.1, col.1, para.2). Jahn also teaches dimerization via constant IgG domains which rendered fusion proteins more robust against high concentrations of soluble CD30 tumor antigen when targeting lymphoma cells. That is, Jahn teaches immunocytokines wherein there are two polypeptides each comprising cytokines positioned at the hinge region (p.2, col.1, para.2). Jahn also teaches generation of dual cytokine-antibody fusion proteins comprising both IL-2 and IL-12, which takes advantage of the cooperative action of IL-2 and IL-12 (i.e., wherein the cytokines are different; p.2, col.1, para.2; Fig.2).
Jahn does not teach that the antigen-binding fragment’s target antigen is PD-1 (instant claim 1).
Xencor teaches PD-1 targeted cytokine fusion proteins for the purpose of treating cancer (title; abstract). Specifically, Xencor teaches targeting of IL-15/IL-15Ralpha Fc fusion proteins wherein the cytokine is attached at the hinge region of an immunocytokine that also comprises an Fc domain and anti-PD-1 Fab; and, wherein the immunocytokine format comprises two antigen-binding polypeptides each comprising a hinge region wherein only one of the antigen-binding polypeptides comprises the cytokine (title; Fig.28H). Xencor teaches that immune checkpoint proteins such as PD-1 are up-regulated following T cell activation to preclude autoimmunity by exhausting activated T cells upon binding to immune checkpoint ligands such as PD-L1; but, that immune checkpoint proteins are also upregulated in tumor-infiltrating lymphocytes (TILs), and immune checkpoint ligands are overexpressed on tumor cells, contributing to immune escape by tumor cells. Thus, Xencor teaches targeting of tumor cells via PD-1. Further, Xencor specifies that an anti-PD-1 antibody component that can bind to PD-1 but does not compete with nivolumab and pembrolizumab which allows for efficient combination therapies with anti-PD-1 antibodies. That is, by using an anti-PD-1 antigen binding domain that does not compete with approved treatments, the non-competing PD-1 antigen binding domain of the immunocytokine can be used to target the fusion proteins to the tumor but still allow for therapeutic treatment with an additional anti-PD-1 antibody (p.48—49, [00221]). Xencor also teaches immunoadhesin molecules that comprise an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region that can be an Fc region of an immunoglobulin sequence, for purposes of PD-1 inhibition (p.97, [00446]). Xencor further teaches an immunocytokine/immunoadhesin format wherein the cytokine of the is positioned at the hinge region of the heavy chain (i.e., VH; Figure 28H; p.15, [0059]). Xencor teaches pharmaceutical formulations of immunocytokine compositions that are prepared with pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions for the purpose of treating cancer (p.105 , [00482]; p.138, claim 21).
Jahn and Xencor do not teach that the antigen-binding protein specifically binds the PD-1 target antigen with a KD within a range of 10-8M < KD ≥ 10-6M (instant claim 1).
Brown teaches assessment of binding properties for various anti-PD-1 antibodies, including 8 different antibodies with KDs within the range 10-8M < KD ≤ 10-6M (i.e., mAb08, mAb15, mAb07, mAb02, mAb35, mAb14, mAb11, and mAb25 from Table 1, p.5); thus, Brown teaches antigen-binding proteins that specifically bind the PD-1 target antigen with inherent KD binding affinities as recited in instant claim 1.
It would have been prima facie obvious for one of ordinary skill before the effective filing date to combine the teachings of Jahn with the teachings of Xencor by modifying the CD30 antigen binding protein/IL-12 immunocytokine or CD30 antigen binding protein/IL-12/IL-2 immunocytokine (as taught by Jahn) by substituting a PD-1 targeting antigen binding protein (taught by Xencor) in place of the CD30 antigen binding protein (taught by Jahn), to arrive at the instantly claimed invention, because the combination of prior art elements leads to a predictable result and benefit of targeting tumor cells expressing PD-1 for treatment. One of ordinary skill would have a reasonable expectation of success because Jahn and Xencor teach cytokine targeting for cancer treatment using immunocytokines. It would have also been obvious for one of ordinary skill to further modify the PD-1 targeting antigen/immunocytokine (taught by the combination of Jahn/Xencor) to be an extracellular of PD-1 binding portion of PD-L1 or PD-L2 (as taught by Xencor), to arrive at the instantly claimed invention, in order to receive the benefit that the PD-L1/PD-L2 fragment provides for PD-1 inhibition. One would have a reasonable expectation of success because the combination of prior art elements results in a predictable result of producing an IL-12-comprising immunocytokine or IL-2-comprising immunocytokine that comprises a PD-1 targeting antigen-binding protein. It would have also been obvious to further combine the teachings of Jahn and Xencor by modifying the immunocytokine by positioning the cytokine at the hinge region of the heavy chain, in order to arrive at the instantly claimed invention, because the combination of prior art elements results in a predictable result of producing an immunocytokine with the format of instant claim 67.
Regarding the instant claim 1 limitation that the antigen-binding protein that specifically binds the target antigen with a KD within a range of 10-8M < KD ≤ 10-6M: It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Jahn and Xencor with the teachings of Brown by using an anti-PD-1 antibody (i.e., PD-1 antigen-binding protein; as taught by both Xencor and Brown) that has a different antigen binding affinity than pembrolizumab and nivolumab antibodies (as taught by Xencor) as the immunocytokine PD-1 targeting protein (taught by the combination of Jahn/Xencor), to arrive at the instantly claimed invention, because the combination of prior art elements results in the predictable result and benefit of producing an immunocytokine using an anti-PD-1 antibody to target PD-1 antigen with a different/lower binding affinity with a KD within 10-8M < KD ≥ 10-6M (taught by Brown) to target tumor cells that express high levels of PD-1 (taught by Xencor) and that would allow for efficient combination with additional anti-PD-1 therapy. One would have a reasonable expectation of success because Jahn and Xencor teach immunocytokines that target cancer cells, and Xencor and Brown teach several antibodies that target PD-1. Regarding the KD of the anti-PD-1 antibody, instant claim 1 recites a KD binding affinity range of 10-8M < KD ≤ 10-6M, which describes an inherent property of known anti-PD-1 antibodies taught by Brown, which does not render the claim patentably new (see MPEP §2112). Thus, the instant antigen-binding protein that specifically binds PD-1, as claimed, necessarily possesses the same structure/function properties as Brown’s 8 anti-PD-1 antibodies.
Regarding instant claims 17 and 19, it would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to combine the joint teachings of Jahn/Xencor with the additional teachings of Jahn by substituting the IL-12 cytokine positioned at the hinge region of the immunocytokine with the IL-2 cytokine positioned at the C-terminus of the Fc region, to arrive at the instantly claimed invention, because Jahn teaches treatment of cancer with IL-12 and IL-2, as well as the benefit of including both cytokines for the benefit of their cooperative action. The positioning of the cytokines would have been obvious to try based on the formats provided by Jahn as positioning the IL-2 at the hinge region and the IL-12 at the C-terminus of the Fc region involves a simple swapping of the cytokine positions. One would have a reasonable expectation of success because Jahn teaches the benefit of cooperativity when both IL-12 and IL-2 are both incorporated in the immunocytokine.
Claims 6, 8, 17, 19, 48, 67, 125, and 129 are rejected under 35 U.S.C. 103 as being unpatentable over Jahn, Xencor, and Brown, as applied to claims 1 and 17 above; and, further in view of Hombach and Abken. Targeting tow co-operating cytokines efficiently shapes immune responses. OncoImmunology (2013), 2:3, p.1-3, herein referred to as Hombach.
The combination of Jahn/Xencor/Brown teaches an immunocytokine comprising an antigen-binding protein that specifically binds PD-1 with a KD of 10-8M < KD ≤ 10-6M and comprising a cytokine positioned at the hinge region, as applied to instant claim 1 above; and, that the immunocytokine comprises a cytokine that is IL-12 or IL-2 as applied to instant claim 17 above.
The combination of Jahn/Xencor/Brown does not teach an immunocytokine wherein the antigen-binding protein comprises two antigen-binding polypeptides that each comprise a cytokine at the hinge region wherein the cytokine is the same or different.
Hombach teaches engineered antibody-cytokine fusion proteins that harbor two cytokine, namely IL-2 and IL-12, wherein the antibody comprises two heavy chains each with dimeric IL-12 positioned at the hinge region and wherein the p40 and p35 subunits of IL-12 are connected in-tandem for the purpose of treating cancer (i.e., wherein the two cytokines at the hinge region are the same; p.1, col.2, para.1; Fig.1). Hombach teaches that the IgG Fc domains mediate dimerization of the molecule via cysteine disulfide bonds to increase valency of the dual cytokine (p.1, col.2, para.2—col.3, para.1). Hombach also teaches that a benefit of the dimeric antibody is that it is preferentially retained in tumor tissue, whereas the monomeric antibody more easily penetrates tissues in a target-independent manner (p.1, col.3, para.1). Hombach further teaches that a benefit of incorporating both IL-2 and IL-12 is that IL-2 functions as a potent inducer of immune cell proliferation and IL-12 promotes secretion of multiple cytokines including interferon-γ (p.1, col.2, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Jahn/Xencor/Brown with the teachings of Hombach by modifying the immunocytokine comprising a PD-1 antigen-binding protein and IL-12 cytokine (as taught by the combination of Jahn/Xencor/Brown) to be a dual cytokine moiety wherein the same dimeric IL-12 cytokine subunits p40 and p35 are positioned in-tandem at the hinge region (as taught by Hombach), to arrive at the instantly claimed invention, in order to receive the benefit that dimerization of the antibody provides for enhanced retention in target tissue and less target-independent accumulation (as taught by Hombach). One of ordinary skill would have a reasonable expectation of success because Jahn, Xencor, and Hombach teach immunocytokine design for targeting IL-12 and IL-2 to tumors for cancer treatment, and Brown teaches inherent binding affinities for anti-PD-1 antibodies of the claimed KD range for the antigen-binding protein .
Regarding instant claims 6 and 19, it would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to further combine the joint teachings of Jahn/Xencor/Brown/Hombach with the additional teachings of Hombach by substituting one or both of the IL-12 cytokine positioned at the hinge region of the immunocytokine with the IL-2 cytokines positioned at the C-terminus of the Fc region, to arrive at the instantly claimed invention of producing a dual cytokine wherein the cytokines are the same or different, because the combination of prior art teachings results in a predictable result of producing a dual IL-12/IL-2 cytokine wherein two IL-12s are positioned at the hinge regions, two IL-2s are positioned at the hinge regions, or one of each of IL-12 and IL-2 are positioned at a hinge region. The positioning of the cytokines would have been obvious to try based on the formats provided by Jahn and Hombach as positioning the IL-2 at the hinge region on one polypeptide involves a simple swapping of the IL-12 and IL-2 cytokine positions. One would have a reasonable expectation of success because Jahn teaches the benefit of cooperativity when both IL-12 and IL-2 are both incorporated in the immunocytokine, and Hombach teaches specific benefits of IL-2-mediated immune cell proliferation and IL-12-mediated enhanced cytokine secretion. One would also have a reasonable expectation of success because Xencor also shows successful placement of cytokine IL-15 at the hinge region of immunocytokines, supporting that other non-IL-12 cytokines are effective when positioned at the hinge region.
Claims 2-4, 49, 52, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Jahn, Xencor, and Brown, as applied to claims 1, 17, and 48 above; and, further in view of Garcia and Glassman – US20230220031A1 (effective filing date: 04/17/2020; herein referred to as Garcia).
The combination of Jahn/Xencor/Brown teaches an immunocytokine comprising an antigen-binding protein that specifically binds PD-1 with a KD of 10-8M < KD ≤ 10-6M and comprising a cytokine positioned at the hinge region, as applied to instant claim 1 above; and, wherein the cytokine is IL-2 or IL-12, as applied to instant claims 17 and 48 above.
The combination of Jahn/Xencor/Brown does not teach that the IL-12 variant comprises one or more p40 subunit mutations selected from the group consisting of E45, Q56, V57, K58, E59, F60, G61, D62, A63, G64, Q65, and C177 (instant claim 49); that the IL-12 variant comprises E59A and F60A mutations (instant claim 52); or, that the IL-12 variant comprises the sequence of SEQ ID NO: 31 (instant claim 53).
Garcia teaches engineered IL-12 and IL-23 polypeptides, including variants that modulate signal transduction (title; abstract). Garcia teaches that the clinical success of existing therapeutic approaches for treatment of cancer, including IL-12-mediated treatment, and has been limited due to off-target toxicity and pleiotropy, which is largely due to the fact that cytokines have receptors on both desired and undesired responder cells that counterbalance one another and lead to unwanted side effects (p.1, [0005] – [0008]). Garcia teaches various recombinant IL-12 subunit p40 polypeptides with altered binding affinity for its natural receptor, IL-12Rβ1; and, that these partial agonists can exhibit cell-type biased IL-12p40 signaling (p.1, [0009]). Garcia specifically teaches IL-12 mutant of SEQ ID NO: 13, which comprises amino acid substitutions E81A and F82A, which correspond to the E59A and F60A substitutions of instant SEQ ID NO: 31 (see alignment below). Thus, Garcia teaches an IL-12 variant comprising instantly claimed SEQ ID NO: 31 at 100% identity. Garcia also teaches that these amino acid positions are critical at the binding interface of IL-12 and IL-12Rβ1 (Fig.2D), and that the mutant IL-12 E81A/F82A (i.e., instant IL-12 E59A/F60A) results in reduced pSTAT signaling and a bias toward conferring reduced IFNγ production in NK cells while [AltContent: rect][AltContent: textbox (Instant SEQ ID NO: 31 IL-12p40 E59A/F60A vs Garcia SEQ ID NO: 13 IL-12p40 E81A/F82A
[img-media_image1.png])]retaining significant IFNγ production in CD8+ T cells (p.1, [0009]; Fig.2E-2F; Fig. 7G-7I).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Jahn/Xencor/Brown with the teachings of Garcia by modifying the IL-12 cytokine of the immunocytokine (taught by the combination of Jahn/Xencor/Brown) to comprise amino acid substitutions E59A and F60A (as taught by Garcia’s corresponding E81A and F82A substitutions), to arrive at the instantly claimed invention, in order to receive the benefit of modulating IL-12-mediated immune cell responses by altering interaction with immune cell receptors in order to bias signaling toward CD8+ T cell activation while reducing NK cell activation. One of ordinary skill would have a reasonable expectation of success because Garcia teaches the IL-12p40 mutant sequence; and, Jahn, Xencor, and Garcia teach immunocytokine development for the treatment of cancer.
Regarding instant claims 2-4, the combination of prior art teaches the immunocytokines wherein the cytokine is an IL-12 E59A/F60A variant of an immunocytokine comprising an antigen binding polypeptide comprising an antigen binding domain that is an anti-PD-1 antibody or that is either the PD-L1 or PD-L2 peptide. Instant claims 2-4 recite additional limitations of the cytokine’s biological activity, which describe and encompass the inherent properties of the known IL-12 E59A/F60A variant/PD-1 binding immunocytokine (as evidenced by the disclosure; see Tables 3-4, 14, 18) that does not render the claim patentably new (see MPEP §2112). The instantly claimed immunocytokine necessarily possesses the same properties as the combination of teachings provided by the prior art. Thus, the combination of Jahn, Xencor, Brown, and Garcia teaches instant claims 2-4 based on inherent structure/function properties.
Claims 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Jahn, Xencor, and Brown, as applied to claims 1, 17, and 48 above; further in view of Chen, et al. Fusion protein linkers: Property, design and functionality. Adv Drug Deliv Rev. (2013), 65:10, p.1357-1369 (herein referred to as Chen); further in view of Garcia; further in view of UniProt. P29459: IL12A_HUMAN, 01/23/2002, p.1-9 (herein referred to as UP-IL12p35; and, further in view of Morisseau, et al –WO2012175222A1 (publication date: 12/27/2012; herein referred to as Morisseau).
The combination of Jahn/Xencor/Brown teaches an immunocytokine comprising an antigen-binding protein that specifically binds PD-1 with a KD of 10-8M < KD ≤ 10-6M and comprising a cytokine positioned at the hinge region, as applied to instant claim 1 above; and, wherein the cytokine is IL-2 or IL-12, as applied to instant claims 17 and 48 above.
The combination of Jahn/Xencor/Brown/Garcia teaches an immunocytokine comprising an IL-12 variant comprising an IL-12p40 subunit harboring E59A and F60A substitution as described for instant claims 1, 17, 48, 49, 52, and 53 above.
The combination of Jahn/Xencor/Brown/Garcia does not teach that the p40 and p35 subunits of the IL-12 cytokine or variant thereof are connected by a linker (instant claim 54); or, that the IL-12 variant comprises the sequence of SEQ ID NO: 36 (instant claim 55).
Chen teaches property, design, and functionality rationales for the use of different types of linkers for fusion proteins (title; abstract). Chen teaches that flexible and rigid linkers are generally used for linking functional domains of proteins together while cleavable linkers are generally used to release a free functional domain in vivo (abstract). Chen teaches that linkers may offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles (abstract). Additionally, Chen teaches that direct fusion of functional domains without a linker may lead to many undesirable outcomes, including misfolding of the fusion protein, low yield in protein production, or impaired bioactivity; and, that contributing linker properties include length, hydrophobicity, and secondary structure (p2, para.2). Chen teaches that flexible linkers are usually applies when the joined domains require a certain degree of movement or interaction; and, are generally composed of small, non-polar (e.g., Gly) or polar (e.g., Ser or Thr) amino acids (p.4, para.3). Further, Chen teaches that the most commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker); for example, linkers comprising the sequence of (GGGGS)n; and, that by adjusting the “n” copy number, the length of the GS linker can be optimized to achieve appropriate separation of the functional domains (p.4, para.4).
Morisseau teaches immunocytokines comprising cytokine fusion proteins comprising various flexible GS linkers, including SEQ ID NO: 16, which comprises instant SEQ ID NO: 228 of sequence GGGGSGGGGSGGGGSGGGGSG (see p.20 and p.30 for GS linkers; also, see alignment below):
[AltContent: textbox (Instant SEQ ID NO: 228 GS linker vs Morisseau SEQ ID NO: 16 GS linker
[img-media_image2.png])]It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Jahn/Xencor/Brown with the teachings of Chen and Morisseau by modifying the dimeric IL-12 cytokine of the immunocytokine by using a flexible linker comprising stretches of Gly and Ser (as taught by Chen) in order to arrive at the claimed invention because the combination of prior art results in the predictable formation of a multi-subunit cytokine fusion protein and because Chen teaches that flexible GS linkers are primarily used to link subunits to facilitate their movement and interaction. It would have further been obvious to use the linker comprising the GS linker of instant SEQ ID NO: 228 (as taught by Morisseau) because the prior art teaches several GS linkers of comparable length to instant SEQ ID NO: 228 (taught by Chen and Morisseau) and that adjusting the length of the linker can optimize separation and interaction between fusion protein domains (taught by Chen). One of ordinary skill would have a reasonable expectation of success because Morisseau teaches several GS linkers for immunocytokines, and Chen teaches the rationale for flexible GS linker optimization.
Regarding instant claim 55: Instant SEQ ID NO: 36 encodes an IL-12 variant comprising the IL-12p40 E59A/F60A subunit (instant SEQ ID NO: 31), flexible GS linker (instant SEQ ID NO: 228), and the wild type IL-12p35 subunit (instant SEQ ID NO: 29).
The combination of Jahn/Xencor/Brown/Garcia teaches an immunocytokine comprising the IL-12p40 E29A/F60A fragment (i.e., via Garcia SEQ ID NO: 13).
The combination of Jahn/Xencor/Brown/Chen/Morisseau teaches the rationale for the flexible GS linker fragment of amino acid instant SEQ ID NO: 228 as described above (i.e., via Morisseau SEQ ID NO: 16).
The combination of Jahn/Xencor/Brown/Garcia and the combination of Jahn/Xencor/Brown/Chen/Morisseau do not teach the amino acid sequence for the p35 IL-12 subunit (instant claim 55).
UP-IL12p35 teaches the wild type amino acid sequence comprising the p35 subunit of IL-12 (p.7).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the IL-12 immunocytokine that comprises dimeric IL-12p40/p35 (taught by the combination of Jahn/Xencor/Brown) by using the flexible GS linker of instant SEQ ID NO: 228 (taught by the combination of Chen/Morisseau) to connect the IL-12 p40 E59A/F60A variant encoded by instant SEQ ID NO: 31 (taught by the combination of Jahn/Xencor/Brown/Garcia) and the wild type IL-12 p35 subunit encoded by instant SEQ ID NO: 29 (taught by UP-IL12p35), to arrive at the instantly claimed invention, in order to receive the benefits that the GS linker would facilitate movement and interaction of the subunits and that the p40 variant would allow for modulated cell-type specific activation of CD8+ T cells while reducing NK cell activation. One of ordinary skill in the art would have a reasonable expectation of success because the prior art teaches all amino acid sequence fragments for the [AltContent: textbox (Instant SEQ ID NO: 36 IL-12 fusion protein vs Garcia SEQ ID NO: 13 IL-12p40/Morisseau SEQ ID NO: 16 GS linker/UP-IL12p35 WT subunit
[img-media_image3.png])]instantly claimed IL-12 cytokine (see alignment below), as well as the rationales and motivations for the above-described design of immunocytokines for the treatment of cancer.
Claim 104 is rejected under 35 U.S.C. 103 as being unpatentable over Jahn, Xencor, and Brown, as applied to claims 1 and 16 above; and, further in view of UniProt. Q9BQ51: PD1L2_HUMAN, 05/10/2005, p.1-9 (herein referred to as UP-PDL2).
The combination of Jahn/Xencor/Brown teaches an immunocytokine comprising an antigen-binding protein that specifically binds PD-1 with a KD of 10-8M < KD ≤ 10-6M and comprising a cytokine positioned at the hinge region, as applied to instant claim 1 above; and, wherein, the antigen-binding fragment is PD-L2, as applied to instant claim 16 above.
The combination of Jahn/Xencor/Brown does not teach that the PD-L2 comprises the sequence of SEQ ID NO: 176 (instant claim 104).
[AltContent: textbox (Instant SEQ ID NO: 176 PD-L2 ECD vs UP-PDL2 wild type PD1L2[img-media_image4.png])]Instant SEQ ID NO: 176 encodes for the wild type human PD-L2 extracellular domain (ECD), which is taught by UP-PDL2 (see p.3 and p.8; also, see alignment below).
It would have been prima facie obvious for one of ordinary skill before the effective filing date of the claimed invention to further modify the teachings of Jahn/Xencor/Brown with the teachings of UP-PDL2 by using the human wild type PD-L2 extracellular domain amino acid sequence (taught by UP-PDL2) as the sequence encoding the PD-L2 ECD of the antigen-binding domain of the immunocytokine (taught by the combination of Jahn/Xencor/Brown), to arrive at the instantly claimed invention, because the combination of prior art elements results in a predictable result of producing an immunocytokine that encodes an antigen-binding domain comprising the PD-L2 ECD, and Xencor teaches the benefit of PD-L1 inhibition via the PD-L2 ECD. One of ordinary skill in the art would have a reasonable expectation of success because the prior art teaches the amino acid sequence for PD-L2 and identifies the ECD domain.
Claims 105 and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Jahn, Xencor, Brown, and UP-PDL2 as applied to claims 1, 16, and 104 above; further in view of Garcia; further in view of Chen; further in view of Morisseau; further in view of UP-IL12p35; further in view of UniProt. P0DOX5: IGG1_HUMAN, 07/18/2018, p.1-9 (herein referred to as UP-IGG1); further in view of Escobar-Cabrera – US11098105B2 (publication date: 04/14/2016; effective filing date: 05/31/2013; herein referred to as Escobar-Cabrera); further in view of Dixit, et al. Asymmetric Fc engineering for bispecific antibodies with reduced effector function. Antibodies (2017), 6:7, p.1-16 (herein referred to as Dixit); and, further in view of Bland-Ward, et al. – US11779604B2 (publication date: 09/12/2019; herein referred to as Bland-Ward).
The combination of Jahn/Xencor/Brown/UP-PDL2 teaches an immunocytokines, including dual cytokines comprising two polypeptides that dimerize, wherein the antigen-binding polypeptides comprise an antigen-binding protein that specifically binds PD-1 with a KD of 10-8M < KD ≤ 10-6M and comprising a cytokine positioned at the hinge region, as applied to instant claim 1 above; wherein, the antigen-binding fragment is PD-L2, as applied to instant claim 16 above; and, wherein the PD-L2 comprises the sequence of SEQ ID NO: 176, as applied to instant claim 104 above.
The combination of Jahn/Xencor/Brown/UP-PDL2 does not teach a first antigen-binding polypeptide of instant SEQ ID NO: 186 with comprises an IL-12 variant comprising instant SEQ ID NO: 36 (instant claim 105); or, a second antigen-binding polypeptide of instant SEQ ID NO: 178 (instant claim 106).
Instant SEQ ID NO: 186 encodes a first antigen-binding polypeptide that comprises the following amino acid fragments, in order from N-terminus to C-terminus: a PD-L2 ECD encoded by instant SEQ ID NO: 176; a short GS linker “GSG”; IL-12 variant encoded by SEQ ID NO: 36; and, the Fc fragment of the first antigen-binding polypeptide. Instant SEQ ID NO: 178 encodes a second antigen-binding peptide that comprises the following amino acid fragments, in order from N-terminus to C-terminus: a PD-L2 ECD encoded by instant SEQ ID NO: 176, and, the Fc fragment of the second antigen-binding polypeptide. The combination of Jahn/Xencor/Brown/Garcia teaches the PD-L2 ECD fragment (i.e., via Garcia SEQ ID NO: 13) as described above. The combination of Jahn/Xencor/Brown/Chen/Morisseau/UP-IL12p35 teaches the IL-12 variant, formed by the IL-12p40 E59A/F60A and IL-12p35 dimer, that is encoded by instant SEQ ID NO: 36 as described above.
In addition to teaching longer flexible GS linkers, including the GS linker of instant SEQ ID NO: 36 and SEQ ID NO: 228 above, Chen also teaches short and medium length flexible GS linkers. Additionally, as mentioned above, Chen also teaches a rational approach for design, stating that the longer linkers are generally required when the flanking domains require interaction. The “GSG” linker of the instantly claimed antigen-binding polypeptide for the immunocytokine joins the anti-PD-1 binding PD-L2 domain and the dimeric IL-12, which do not reasonably require interaction as the two domains have different biological functions. Thus one of ordinary skill would be drawn to start with a small or medium length flexible GS linker. The addition of additional G or S residues is a matter of routine optimization (also taught by Chen). Thus, it would have been prima facie obvious for one of ordinary skill in the art to connect the anti-PD-1 PD-L2 protein (taught by the combination of Jahn/Xencor/Brown as described for instant claim 16) with the IL-12 variant comprising the IL-12p40 E59A/F60A (taught by the combination of Jahn/Xencor/Brown/Chen/Morisseau/UP-IL12p35 as described for instant claim 55).
The combination of Jahn/Xencor/Brown teaches immunocytokines, including dual cytokines comprised withing two polypeptides, wherein the antigen-binding polypeptides comprise Fc domains, as described for instant claims 1, 2, 6, and 16 above.
The combination of teachings by Jahn/Xencor/Brown and the teachings of Jahn/Xencor/Brown/Garcia/Chen/Morisseau/UP-IL12p35 does not teach the amino acid sequence for the Fc domain fragments (instant claim 105 and 106).
The remaining C-terminal fragment/Fc domain fragment for each of the first and second antigen-binding polypeptides encoded by instant SEQ ID NO: 186 and instant SEQ ID NO: 178, respectively, is taught by UP-IGG1 which teaches the human IgG1 sequence which 1) aligns with instant SEQ ID NO: 186 except that instant SEQ ID NO: 186 comprises amino acid substitutions at the following positions relative to SEQ ID NO: 186: L14D, L15E, T130V, L131Y, D136E, L138M, S180E, F185A, and Y187V; and, 2) aligns with instant SEQ ID NO: 178 except that instant SEQ ID NO: 178 comprises amino acid substitutions at the following positions relative to SEQ ID NO: 178: L14D, L15E, T130V, D136E, L138M, T146L, N170R, K172M, and T174W (see alignments for Fc domains below; differences marked by solid boxes, arrows, and arrowheads, which are described in subsequent paragraphs below).
The combination of Jahn/Xencor/Brown, the combination of Jahn/Xencor/Brown/ Garcia/Chan/Morisseau/UP-IL12p35, and UP-IGG1 does not teach the IgG1 mutations described for the first and second polypeptides listed in the preceding paragraph (numbering relative to instant SEQ ID NO: 186; instant claim 105 and 106).
Escobar-Cabrera teaches heteromultimeric peptides comprising a first and second Fc polypeptide comprising hinge and Fc regions, including IgG1 with mutations in the Fc region for the purpose of reducing effector function (title; abstract; p.4, last para). Escobar specifically teaches hinge region mutations of both polypeptides comprising modifications that include L234D and L235E, which correspond to positions L14D and L15E of instant SEQ ID NO: 186 and instant SEQ ID NO: 178 (see solid boxes in sequence alignments below).
[AltContent: textbox (Instant SEQ ID NO: 186 human IgG1 Fc mutant1 vs UP-IGG1
[img-media_image5.png]Instant SEQ ID NO: 178 human IgG1 Fc mutant2 vs UP-IGG1 [img-media_image6.png])] It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Jahn/Xencor/Brown/UP-PDL2/Garcia/Chen/Morisseau/UP-IL12p35 with the teachings of UP-IGG1 and Escobar-Cabrera by modifying an immunocytokine comprised of two polypeptide chains wherein the first polypeptide chain encodes the PD-L2 ECD/GSG linker/IL-12 variant connected to a C-terminal Fc domain (taught by the combination of Jahn/Xencor/Brown/UP-PDL2/Garcia/Chen/Morisseau/UP-IL12p35) and wherein the second polypeptide comprises the PD-L2 ECD connected to a C-terminal Fc domain (i.e., only one polypeptide comprises the cytokine) by using the hinge/Fc fragment encoded by the human IgG1 amino acid sequence (taught by UP-IGG1), because the combination of prior art elements results in an immunocytokine that comprises two polypeptides, wherein the first polypeptide comprises the cytokine and each polypeptide comprises a PD-L2 antigen-binding protein and Fc domain. One of ordinary skill in the art would have a reasonable expectation of success because the combination of prior art teachings provides all amino acid sequence fragments for each of the first and second polypeptides; and, the combination of prior art teachings teaches IL-12 immunocytokines of two polypeptides for the purpose of treating cancer by targeting tumor cells via the anti-PD-1 antigen-binding protein PD-L2. It would also be obvious to one of ordinary skill to modify the Fc regions of the polypeptides by incorporating the “L234D” and “L235E” mutations (taught by Escobar-Cabrera), in order to arrive at an immunocytokine with Fc mutants in order to receive the benefit of reduced effector function (also taught by Escobar-Cabrera).
Dixit teaches Fc engineering for bispecific antibodies with reduced effector function and teaches antibody constructs comprising the IgG1 framework but with mutations T350V/L351Y/S400E/F405A/Y407V and T350V/T366L/N390R/ K392M/T394W for chains A and B (i.e., a first and second polypeptide), respectively (title; abstract; p2, para.3). These mutations correspond to the IgG1 mutations of instant SEQ ID NO: 186 and instant SEQ ID NO: 178, respectively (see arrows in sequence alignments above).
Bland-Ward teaches antibodies and methods thereof for treatment of disease including cancer (title; abstract). Bland-Ward also teaches antibody constructs that are conjugated to IL-2 or IL-12 and cites several references for methods of conjugating these cytokines to antibodies for cancer treatment (col.175, para.6)). Bland-Ward also teaches IgG1 mutations that provide the benefit of reduced binding to protein A, including amino acid substitutions D356E and L358M, which correspond to instant SEQ ID NO: 186 and instant SEQ ID NO: 178 substitutions D136E and L138M (col.152, para.2; also, see sequence alignments above).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Jahn/Xencor/Brown/UP-PDL2/Garcia/Chen/Morisseau/UP-IL12p35/UP-IGG1/Escobar-Cabrera with the teachings of Dixit and Bland-Ward by modifying the dual polypeptide IL-12 immunocytokine (taught by the combination of Jahn/Xencor/Brown/UP-PDL2/Garcia/Chen/Morisseau/UP-IL12p35/UP-IGG1/Escobar-Cabrera) by additionally mutating the Fc domain of the first and second polypeptides to comprise mutation combination “T350V/L351Y/S400E/F405A/Y407V” and mutation combination “T350V/T366L/N390R/ K392M/T394W,” respectively (taught by Dixit); and to additionally mutate the Fc domain to comprise substitutions “D356E” and “L138M” (taught by Bland-Ward); in order to arrive at the instantly claimed invention of a polypeptide encoded by instant SEQ ID NO: 186 (instant claim 105) and a polypeptide encoded by instant SEQ ID NO: 178, because the combination of prior art teachings leads to a predictable result of generating a two-peptide immunocytokine encoded by instant polypeptide SEQ ID NO: 186 and SEQ ID NO: 178 wherein the Fc domains harbor the three sets of mutations (taught by Escobar-Cabrera, Dixit, and Bland-Ward) wherein the Escobar-Cabrera and Dixit mutations provide the benefit of reduced effector binding and the Bland-Ward mutations provide the benefit of reduced binding to protein A. One of ordinary skill in the art would have a reasonable expectation of success because the combination of prior art teachings teaches “immunocytokines”/”antibody-cytokine bioconjugates” for the purpose of treating cancer and because all fragments and Fc domain amino acid substitutions and rationales are also provided by the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 5-6, 8, 16-17, 19-20, 48-49, 52-55, 100-101, 104-106, 119, 124-125, and 129-130 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 135, 141-143, 147-151, 154, and 156-162 of copending Application No. 18/099,009 (herein referred to as App’009); and, further in view of Jahn, Xencor, and Brown.
App’009 teaches an immunocytokine comprising an Fc fusion protein that consists of a PD-L2 ECD, linker, dimeric IL-12 variant, hinge region, and Fc (App’009 claim 1; instant claims 1, 8, 16-17, 48, 67); wherein, the PD-L2 ECD is encoded by SEQ ID NO: 176 which is the same as instant SEQ ID NO: 176 (App’009 claim 147instant claim 104); and, wherein the immunocytokine first polypeptide is encoded by SEQ ID NO: 186 which is the same as instant SEQ ID NO: 186 (App’009 claim 149; instant claim 105) and the second polypeptide is encoded by SEQ ID NO: 185 (App’009 claim 149; instant claim 106). App’009 teaches the second polypeptide comprising a PD-L2, hinge, and Fc domain (App’009 claim 148; instant claim 5); and, wherein the second polypeptide also comprises a cytokine that is IL-2 (i.e., different from IL-12; App’009 claim 150; instant claims 6, 17, 19). App’009 teaches that the IL-2 is a variant that comprises mutations at a positions selected from L18, Q22, R38, E61, Q126, and S130 (App’009 claim 150; instant claim 20). App’009 teaches that the IL-12 variant comprises p40 subunit E59A and F60A substitutions encoded by SEQ ID NO: 31, which is the same as instant SEQ ID NO: 31 (App’009 claim 1; instant claims 49, 52-53). App’009 teaches that the p40 and p35 subunits are connected by a liner (App’009 claim 142; instant claim 54), thus producing an immunocytokine wherein the IL-12 variant is encoded by SEQ ID NO: 36, which is the same as instant SEQ ID NO: 36 (App’009 claim 143; instant claim 55). App’009 also teaches an isolated nucleic acid encoding the cytokine (App’009 claim 156; instant claim 119) and a method of treating cancer comprising administering the immunocytokine (App’009 claim 158-160; instant claim 125 and 129).
App’009 does not teach an immunocytokine wherein the PD-L2 ECD has a PD-1 binding affinity in the range of 10-8M < KD ≤ 10-6M (instant claim 1); a pharmaceutical composition comprising the immunocytokine (instant claim 124); or, that the method is for a specific type of cancer (instant claim 130).
Jahn teaches cytokine antibody fusion proteins and dual-cytokine antibody fusion proteins/immunocytokines for treatment of mice harboring tumors derived from L540cy lymphoma cancer cells that are expressed using nucleic acids encoding the fusion proteins (i.e., Hodgkin’s lymphoma cells; p.8, col.2, para.3—p.9, col.1, para.1; p.12, col.1, para.3); wherein the immunocytokine comprises an antigen-binding protein that comprises 1) an antigen-binding fragment (i.e., anti-CD30 single chain fragment HRS3-scFv) specifically recognizing a tumor target antigen (i.e., CD30), 2) a cytokine (i.e., IL-12), and 3) an IgG1 Fc domain; wherein the antigen-binding polypeptide comprises the components in from N’ to C’ with the configuration HRS3-scFv-hinge-IL12-hinge-Fc; and, wherein, the p40 and p35 subunits of IL-12 are comprised in a single chain cytokine fragment. That is, the cytokine is positioned at the hinge region and the dimeric cytokine is arranged with the p40 and p35 subunits in tandem at the hinge region (title; abstract; Fig.1, 6th construct). Jahn also teaches immunocytokines additionally comprising a second cytokine IL-2 (title; abstract; Fig.1, 7th construct). Jahn also teaches that antibody-targeted cytokines that accumulate in the lymphoma lesion are thought to be more efficacious than unmodified cytokines (p.1, col.1, para.1). Jahn also teaches that many tumor cells shed the targeted cell-surface-antigen in substantial amounts which competes in binding with the tumor-cell-bound antigen; and, that favored binding to solid-phase bound antigen in the presence of high amounts of soluble antigen is required (p.1, col.1, para.2). Jahn also teaches dimerization via constant IgG domains which rendered fusion proteins more robust against high concentrations of soluble CD30 tumor antigen when targeting lymphoma cells. That is, Jahn teaches immunocytokines wherein there are two polypeptides each comprising cytokines positioned at the hinge region (p.2, col.1, para.2). Jahn also teaches generation of dual cytokine-antibody fusion proteins comprising both IL-2 and IL-12, which takes advantage of the cooperative action of IL-2 and IL-12 (i.e., wherein the cytokines are different; p.2, col.1, para.2; Fig.2).
Xencor teaches PD-1 targeted cytokine fusion proteins for the purpose of treating cancer (title; abstract). Specifically, Xencor teaches targeting of IL-15/IL-15Ralpha Fc fusion proteins wherein the cytokine is attached at the hinge region of an immunocytokine that also comprises an Fc domain and anti-PD-1 Fab; and, wherein the immunocytokine format comprises two antigen-binding polypeptides each comprising a hinge region wherein only one of the antigen-binding polypeptides comprises the cytokine (title; Fig.28H). Xencor teaches that immune checkpoint proteins such as PD-1 are up-regulated following T cell activation to preclude autoimmunity by exhausting activated T cells upon binding to immune checkpoint ligands such as PD-L1; but, that immune checkpoint proteins are also upregulated in tumor-infiltrating lymphocytes (TILs), and immune checkpoint ligands are overexpressed on tumor cells, contributing to immune escape by tumor cells. Thus, Xencor teaches targeting of tumor cells via PD-1. Xencor also teaches immunoadhesin molecules that comprise an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region that can be an Fc region of an immunoglobulin sequence, for purposes of PD-1 inhibition (p.97, [00446]). Xencor further teaches an immunocytokine/immunoadhesin format wherein the cytokine of the is positioned at the hinge region of the heavy chain (i.e., VH; Figure 28H; p.15, [0059]). Xencor teaches pharmaceutical formulations of immunocytokine compositions that are prepared with pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions for the purpose of treating cancer (p.105 , [00482]; p.138, claim 21).
App’009, Jahn, and Xencor do not teach that the antigen-binding protein specifically binds the PD-1 target antigen with a KD within a range of 10-8M < KD ≥ 10-6M (instant claim 1).
Brown teaches assessment of binding properties for various anti-PD-1 antibodies, including 8 different antibodies with KDs within the range 10-8M < KD ≤ 10-6M (i.e., mAb08, mAb15, mAb07, mAb02, mAb35, mAb14, mAb11, and mAb25 from Table 1, p.5); thus, Brown teaches antigen-binding proteins that specifically bind the PD-1 target antigen with inherent KD binding affinities as recited in instant claim 1.
It would have been prima facie obvious for one of ordinary skill before the effective filing date to combine the teachings of App’009 with the teachings of Jahn and Xencor by formulating a pharmaceutical composition (taught by Xencor) comprising the immunocytokine (taught by App’009) and a pharmaceutical excipient (taught by Xencor) for the treatment of cancer that is lymphoma (taught by Jahn), in order to arrive at the instantly claimed invention because the combination of teachings by co-pending App’009 and the prior art results in a predictable result and benefit of treating lymphoma. One of ordinary skill in the art would have a reasonable expectation of success because App’009 teaches all components of the immunocytokine and teaches a method of treating cancer by administrating the cytokine, and Xencor teaches how to formulated immunocytokine compositions.
Regarding the instant claim 1 limitation that the antigen-binding protein that specifically binds the target antigen with a KD within a range of 10-8M < KD ≤ 10-6M: It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of App’009/Jahn/Xencor with the teachings of Brown by using an anti-PD-1 antibody as the PD-1 antigen-binding protein, to arrive at the instantly claimed invention, because the combination of prior art elements results in the predictable result of substituting an anti-PD-1 antibody in place of the PD-L2 antigen-binding protein of App’009 for the benefit of targeting the immunocytokine to cancer cells expressing PD-1 antigen. One would have a reasonable expectation of success because App’009, Jahn and Xencor teach immunocytokines that target cancer cells, and Xencor and Brown teach several antibodies that target PD-1. Regarding the KD of the anti-PD-1 antibody, instant claim 1 recites a KD binding affinity range of 10-8M < KD ≤ 10-6M, which describes an inherent property of known anti-PD-1 antibodies taught by Brown, which does not render the claim patentably new (see MPEP §2112). Thus, the instant antigen-binding protein that specifically binds PD-1, as claimed, necessarily possesses the same structure/function properties as Brown’s 8 anti-PD-1 antibodies.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
Claims 100 and 101 are objected to as being dependent upon rejected base claims, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The claimed immunocytokine wherein the anti-PD-1 antibody comprises the nivolumab VH harboring one the following mutations is novel: D100N, D100G, D100R, N99G, N99A, or N99M.
While the prior art teaches the VH and VL chains of nivolumab (see alignments below for VH provided by NCBI PDB: 5WT9_H, p.1-4, herein referred to as NCBI-1; and, for VL provided by NCBI PDB: AYN59474.1, p.1-6, herein referred to as NCBI-2), the prior art does not teach the specific claimed VH substitutions nor provide a rationale [AltContent: textbox (Instant SEQ ID NO: 103 nivolumab VL vs. NCBI-2 anti-PD-1 VL
[img-media_image7.png])][AltContent: textbox (Instant SEQ ID NO: 102 nivolumab VH vs. NCBI-1 anti-PD-1 VH
[img-media_image8.png])]for the substitutions.
The closest prior art is provided by Lee, et al., Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy. Nature Communications (2016), 7:13354, p.1-10, herein referred to as Lee. Lee teaches crystal structures for checkpoint molecules in complex with Fab fragments of anti-PD-1 antibodies, including pebrolizumab and nivolumab (abstract). Lee teaches PD-1 residues that participate in van der Waals contacts with nivolumab positions G26, I27, N31, and G33 of HCDR1; V50, W52, and Y53 of HCDR2; N99, D100, D101, and Y102 of HCDR3; L46, A55, and T56 of LCDR2; and, S91 of LCDR3 (p.2, col.2, para.5 — p.3, col.1, para.1). However, Lee does not provide for specific substitutions at the N99 or D100 positions nor a rationale for making such substitutions.
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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