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 17-18 and 20 are cancelled. Claims 1-16, 19, and 21 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/EP2022/071490 (filed 08/01/2022) which claims benefit of Foreign Application No. EP21188905.0 (filed 07/30/2021). 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 1-16, 19, and 21 have an effective filing date of 07/30/2021 corresponding to Foreign Application No. EP21188905.0.
Information Disclosure Statement
The information disclosure statement filed on 01/29/2024 has been considered. Signed copies are enclosed.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16, 19, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to “an antibody construct comprising
at least four first binding domains (A), wherein said first binding domain (A) is capable of specifically binding to a first target (A') that is an immune-regulatory antigen on the surface of an innate immune effector cell, wherein the immune effector cell is a natural killer cell or a macrophage;
a second binding domain (B), which is capable of specifically binding to a second target (B') that is an antigen on the surface of a target cell; and
a fourth domain (D) comprising a half-life extension domain that comprises two CH3 domains, wherein a first first binding domain and a second first binding domain that are fused to each other (A1A2) are fused to the C terminus of a first CH3 domain of the fourth domain (D), whereas a third first binding domain and a fourth first binding domain that are fused to each other (A3A4) are fused to the C terminus of a second CH3 domain of the fourth domain (D)” (lines 1-13).
As such, claim 1 is drawn to a genus of multivalent bispecific antibodies comprising
at least four first binding domains wherein the first binding domains binds any immune-regulatory antigen on the surface of a macrophage or natural killer cell,
a second binding domain that binds a second target that is any antigen on the surface of a target cell, and
a fourth domain comprising a half-life extension domain that comprises two CH3 domains, wherein a first first binding domain and a second first binding domain that are fused to each other are fused to the C terminus of a first CH3 domain of the fourth domain, whereas a third first binding domain and a fourth first binding domain that are fused to each other are fused to the C terminus of a second CH3 domain of the fourth domain.
The instant specification states “[t]he term ‘antibody construct’ refers to a molecule in which the structure and/or function is/are based on the structure and/or function of an antibody, e.g., of a full-length or whole immunoglobulin molecule and/or is/are drawn from the variable heavy chain (VH) and/or variable light chain (VL) domains of an antibody or fragment thereof” (¶ 0030). This definition includes multiple types of antibodies, including but not limited to Fabs and full-length antibodies, which have distinct structures and functions. For example, Fabs, as opposed to full-length antibodies, lack Fc constant regions; consequently, Fabs are better at penetrating tissues and have reduced immunogenicity risk (Sino Biological, Fab Antibody: Definition, Structure, and Production, 2026, Pg. 1, ¶ 2, “Antibody fragment Fab, lacking the glycosylated Fc constant regions, has the advantage over the full-length antibodies in applications requiring rapid tissue and… reducing its immunogenicity risk when used therapeutically”). The species encompassed by the term “antibody construct” is further broadened when taking into account more than one binding domain, as said term “generally includes multivalent constructs, including bispecific constructs, specifically binding to only two antigenic structures, as well as polyspecific/multispecific constructs, which specifically bind more than two antigenic structures, e.g. three, four or more, through distinct binding domains” (¶ 0035). The minimum structure for the binding domains “preferably based on the structure and/or function of an antibody, e.g. of a full-length or whole immunoglobulin molecule and/or is/are drawn from the variable heavy chain (VH) and/or variable light chain (VL) domains of an antibody or fragment thereof” (¶ 0028, emphasis added). The use of “preferably” indicates this stipulation is optional.
In addition, the first and second binding domains of the antibody construct bind unknown antigens. Regarding the first binding domain, immune-regulatory antigens are varied and include CD16A, CD56, CD137, NKG2A, NKG2D, NKp30, NKp44, NKp46, NKp80, etc. Regarding the seconding binding domain, antigens on the surface of target cells are varied and include CD19, CD20, CD22, CD30, CD33, CD52, CD70, CD74, CD79b, CD123, CLL1, BCMA, FCRH5, EGFR, EGFRvll, HER2, etc. Instead of defining the antibody construct by its structure, the instant application uses functional characteristics, such as the ability to bind certain antigens. Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1 Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately.
Thus, as instantly claimed, the antibody of claim 1 can comprised fewer than 6 parental CDRs, and may, more specifically, comprise no CDRs per binding domain. The instant specification discloses “multivalent anti-CD16A innate cell engagers targeting EGFR” (¶ 0381, Bi-scDb-Fc_02 [SEQ ID NOs: 149], aBi-scDb-Fc_05 [SEQ ID NOs: 158 and 159], Bi-scDb-IgAb_06 [SEQ ID NOs: 162 and 163]) containing 4 anti-CD16A Fv domains and 1-2 Fv anti-EGFR domains. Fv domains contain “the VL and VH domains of a single arm of an antibody” (¶ 0031), i.e. each Fv has 6 CDRs. Therefore, the multivalent anti-CD16A innate cell engagers targeting EGFR contain 12 unique CDRs.
However, Applicant is claiming a large and structurally diverse genus of antibodies comprising (i) at least four first binding domains wherein the first binding domains binds any immune-regulatory antigen on the surface of a macrophage or natural killer cell and (ii) a second binding domain that binds a second target that is any antigen on the surface of a target cell, wherein the antibody can comprise fewer than 6 parental CDRs or potentially no CDRs per binding domain. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) which CDRs would specifically bind said antigens, (ii) how many CDRs/what combinations of CDRs yield antibodies capable of specifically binding said antigens, and (iii) the identity of said antigens (i.e. what immune-regulatory antigen on the surface of a macrophage or natural killer cell and antigen on the surface of a target cell the antibody binds).
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed antibody and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed a species within the genus claimed (i.e. multivalent anti-CD16A innate cell engagers targeting EGFR). However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of one adequately described species is not sufficiently representative of the entire genus. Dickopf et al. state “[t]here is no ‘standard procedure’ to achieve [the generation of bispecific antibodies with desired functionalities], it rather has to be tackled on a case-by-case basis depending on the under lying biology and structural conditions” (Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies, Comput Struct Biotechnol J, 2020, Pg. 1226, ¶ 6, lines 3-5). As “the design and choice of format can have a profound impact on the antibody functionality” (Dickopf et al., Pg. 1221, Abstract, lines 2-3), particularly in regard to multispecific formats, it is not possible to predict the structures encompassed in a genus of multispecific antibodies from one disclosed structure.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR amino acid sequences (or combinations thereof) that confer upon an antibody the ability to bind any immune-regulatory antigen on the surface of a macrophage or natural killer cell and any antigen on the surface of a target cell. It is well-known in the art that antibodies generally comprise six parental CDRs, or multiples of six if the antibody is multispecific. Here, the antibody construct is bispecific and would require 12 CDRs/ The amino acid sequences of the CDRs are hypervariable, and the amino acid residues contained within the 12 CDRs determine the antigen specificity of a particular antibody. Absent a description of the at least minimal structural features correlating with a functional ability to bind immune-regulatory antigens on the surface of a macrophage or natural killer cell and antigens on the surface of a target cell which are shared by members of a genus of antibodies, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which CDR amino acid sequences (or combinations thereof) may be combined such that the resultant antibody comprises 12 CDRs that confer the ability to bind said antigens.
Although screening techniques can be used to antibodies that possess the ability to bind immune-regulatory antigens on the surface of a macrophage or natural killer cell and antigens on the surface of a target cell, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the difficulty associated with predicting CDR combinations that yield antibodies capable of binding immune-regulatory antigens on the surface of a macrophage or natural killer cell and antigens on the surface of a target cell, and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The specification does not reasonably convey possession of the subject matter of claim 1. Claim 1 fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Claims 2-16, 19, and 21 are included in this rejection as they incorporate and/or depend on claim 1.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treatment or amelioration of breast cancer and Burkitt's lymphoma comprising administering to a subject in need thereof multivalent anti-CD16A innate cell engagers targeting EGFR, does not reasonably provide enablement for a method of treatment or amelioration of all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders comprising administering to a subject in need thereof any antibody construct as delineated by claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (2) the state of the prior art
Claim 19 is drawn to “a method of treatment or amelioration of a proliferative disease, a tumorous disease, a viral disease or an immunological disorder, comprising the step of administering to a subject in need thereof the antibody construct of claim 1” (lines 1-3, emphasis added). Claim 1 is drawn to treatment of a variety of diseases characterized by contrasting etiologies and further drawn to “an antibody construct comprising:
at least four first binding domains (A), wherein said first binding domain (A) is capable of specifically binding to a first target (A') that is an immune-regulatory antigen on the surface of an innate immune effector cell, wherein the immune effector cell is a natural killer cell or a macrophage;
a second binding domain (B), which is capable of specifically binding to a second target (B') that is an antigen on the surface of a target cell; and
a fourth domain (D) comprising a half-life extension domain that comprises two CH3 domains, wherein a first first binding domain and a second first binding domain that are fused to each other (A1A2) are fused to the C terminus of a first CH3 domain of the fourth domain (D), whereas a third first binding domain and a fourth first binding domain that are fused to each other (A3A4) are fused to the C terminus of a second CH3 domain of the fourth domain (D)” (lines 1-13).
Tumorous diseases
While the state of the art is relatively high with regard to the treatment of specific tumorous disease (i.e. cancer) types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. Even within a given cancer type, “[i]ntertumor and intratumor heterogeneity are important obstacles to overcome when designing the most effective therapeutic strategies for patients with cancer. The genotypic and phenotypic variability of tumors can have important consequences for diagnosis, prognosis, and treatment” (Lovly et al., 2016, Pg. e586, Integrating the Heterogeneity of Cancer in Clinical Decision Making, first paragraph).
Proliferative diseases
Proliferative diseases are defined by “excessive proliferation of cells and turnover of cellular matrix contribute significantly to the pathogenesis of several diseases, including cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver” (Sporn and Harris, Proliferative Diseases, The American Journal of Medicine, 1981, Pg. 1, Abstract). As mentioned above, no known anticancer agent that is effective against all cancer cell types. This issue of a broadly effective agent is only further exacerbated when including all proliferative diseases of varying pathology. For example, atherosclerosis is a hardening of the arteries due to plaque formation and treated most commonly with statins. Statins would not be effective against cancer.
Viral diseases
While the state of the art is relatively high with regard to the treatment of specific types of viral infections, the state of the art in regard to treating viral infections broadly is underdeveloped. Heise and Virgin teach viral infections vary greatly in pathology, affected by “many complex factors unique to a particular virus, a particular species, and an individual host. The interplay of these factors determines the nature of infection, whether disease occurs, and the severity of disease” (Basicmedical Key, Pg. 1, ¶ 3). For example, HIV and hepatitis C virus (HCV) are both chronic infections; however, HCV can be completely cured while HIV cannot (Heise and Virgin, Pg. 2, middle). HIV and HCV need different treatment plans consequently.
Immunological disorders
Fugger et al. state “present therapies [to treat autoimmune diseases] are broadly acting and non-disease specific; consequently, they are associated with numerous side effects” (Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases, Cell, 2020, Pg. 63, first paragraph in green text, lines 2-3). Fugger et al. argue that personalized medicine would be a more effective treatment “based on a molecular and clinical understanding of the specific autoimmune diseases in individual patients” (Pg. 63, column 2, ¶ 1).
The instant specification states “[t]he term ‘antibody construct’ refers to a molecule in which the structure and/or function is/are based on the structure and/or function of an antibody, e.g., of a full-length or whole immunoglobulin molecule and/or is/are drawn from the variable heavy chain (VH) and/or variable light chain (VL) domains of an antibody or fragment thereof” (¶ 0030). This definition includes multiple types of antibodies, including but not limited to Fabs and full-length antibodies, which have distinct structures and functions. For example, Fabs, as opposed to full-length antibodies, lack Fc constant regions; consequently, Fabs are better at penetrating tissues and have reduced immunogenicity risk (Sino Biological, Fab Antibody: Definition, Structure, and Production, 2026, Pg. 1, ¶ 2, “Antibody fragment Fab, lacking the glycosylated Fc constant regions, has the advantage over the full-length antibodies in applications requiring rapid tissue and… reducing its immunogenicity risk when used therapeutically”). The species encompassed by the term “antibody construct” is further broadened when taking into account more than one binding domain, as said term “generally includes multivalent constructs, including bispecific constructs, specifically binding to only two antigenic structures, as well as polyspecific/multispecific constructs, which specifically bind more than two antigenic structures, e.g. three, four or more, through distinct binding domains” (¶ 0035). The minimum structure for the binding domains “preferably based on the structure and/or function of an antibody, e.g. of a full-length or whole immunoglobulin molecule and/or is/are drawn from the variable heavy chain (VH) and/or variable light chain (VL) domains of an antibody or fragment thereof” (¶ 0028, emphasis added). The use of “preferably” indicates this stipulation is optional.
In addition, the first and second binding domains of the antibody construct bind unknown antigens. Regarding the first binding domain, immune-regulatory antigens are varied and include CD16A, CD56, CD137, NKG2A, NKG2D, NKp30, NKp44, NKp46, NKp80, etc. Regarding the seconding binding domain, antigens on the surface of target cells are varied and include CD19, CD20, CD22, CD30, CD33, CD52, CD70, CD74, CD79b, CD123, CLL1, BCMA, FCRH5, EGFR, EGFRvll, HER2, etc.
Instead of defining the antibody construct by its structure, the instant application uses functional characteristics, such as the ability to bind certain antigens. Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1 Abstract, lines 6-9). An antibody’s structure cannot be predicted from function alone accurately. Thus, as instantly claimed, the antibody of claim 1 can comprised fewer than 6 parental CDRs, and may, more specifically, comprise no CDRs per binding domain.
As such, claim 1 is drawn to a genus of multivalent bispecific antibodies comprising
at least four first binding domains wherein the first binding domains binds any immune-regulatory antigen on the surface of a macrophage or natural killer cell,
a second binding domain that binds a second target that is any antigen on the surface of a target cell, and
a fourth domain comprising a half-life extension domain that comprises two CH3 domains, wherein a first first binding domain and a second first binding domain that are fused to each other are fused to the C terminus of a first CH3 domain of the fourth domain, whereas a third first binding domain and a fourth first binding domain that are fused to each other are fused to the C terminus of a second CH3 domain of the fourth domain.
Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) which CDRs would specifically bind said antigens, (ii) how many CDRs/what combinations of CDRs yield antibodies capable of specifically binding said antigens, and (iii) the identity of said antigens (i.e. what immune-regulatory antigen on the surface of a macrophage or natural killer cell and antigen on the surface of a target cell the antibody binds) (see 122[a] rejection for written description for more information).
It is unclear how the genus of antibodies of claim 1 could treat or ameliorate all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders as recited in claim 19.
As such, claim 19 generally reads on a method of treatment or amelioration of all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders comprising administering to a subject in need thereof any antibody construct as delineated by claim 1, the full scope of which is not enabled by the method as instantly claimed.
(3) The relative skill of those in the art and (4) the predictability or unpredictability of the art,
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
While the use of antibodies to treat or ameliorate proliferative diseases, tumorous diseases, viral diseases, and immunological disorders is well known by a person having ordinary skill in the art, i.e. someone with a PhD and/or MD (the relative skill of those in the art), the use of any antibody to treat or ameliorate all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders within the scope of claim 19 is not predictable.
Zahavi and Weiner state, even when monoclonal antibodies for therapeutic treatment exist, “clinical resistance to these agents continues to be a major issue. Only a minority of patients will respond, with the vast majority developing refractory disease within one year (Monoclonal Antibodies in Cancer Therapy, Antibodies, 2020, Pg. 9, ¶ 2, lines 2-3). This teaching indicates the existence of a monoclonal antibody alone is not sufficient to establish its efficacy in treatment. The predictability of applying any antibody to treat or ameliorate all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders would be low given that 1) antibodies vary drastically in mechanism of action, in the instant case which antigens the first and second binding domains bind, 2) a link between any and all antibodies in the genus of claim 1 and all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders is not established, and 3) the instant application fails to demonstrate treatment or amelioration of all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders with any and all antibodies (the predictability or unpredictability of the art).
(6) The amount of direction or guidance presented, (7) the presence or absence of working examples, and (8) the quantity of the experimentation
The instant specification discloses “multivalent anti-CD16A innate cell engagers targeting EGFR” (¶ 0381, Bi-scDb-Fc_02 [SEQ ID NOs: 149], aBi-scDb-Fc_05 [SEQ ID NOs: 158 and 159], Bi-scDb-IgAb_06 [SEQ ID NOs: 162 and 163]) containing 4 anti-CD16A Fv domains and 1-2 Fv anti-EGFR domains. Fv domains contain “the VL and VH domains of a single arm of an antibody” (¶ 0031), i.e. each Fv has 6 CDRs. Therefore, the multivalent anti-CD16A innate cell engagers targeting EGFR contain 12 unique CDRs.
In the treatment of a tumorous disease, the multivalent anti-CD16A innate cell engagers targeting EGFR were used to on MCF-7 target cells and were “not only advantageous regarding potency of [antibody-dependent cell-mediated cytotoxicity]-inducing innate cell engagers, but also regarding efficacy in target cell lysis mediated by NK cells” (¶ 0381, Example 9, MCF-7 target cells are derived from human breast cancer). A similar result was seen when using Daudi cells (¶ 0382, Example 10, Daudi cells derived from Burkitt's lymphoma). The specification does not provide any additional examples or guidance on how to use antibodies other than multivalent anti-CD16A innate cell engagers targeting EGFR to treat any other disease besides breast cancer and Burkitt’s lymphoma as recited in claim 19 (the amount of direction or guidance presented and the presence or absence of working examples). The instant application is not enabled for treating or ameliorating all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders with any and all antibodies delineated in claim 1.
The amount of experimentation would not be reasonable because it would require determining which antibodies to use to treat or ameliorate various diseases. The genus of antibodies of claim 1 comprise a diverse class of molecules that require a person having ordinary skill in the art to determine (i) which CDRs would specifically bind antigens on immune effector cells and target cells, (ii) how many CDRs/what combinations of CDRs yield antibodies capable of specifically binding said antigens, and (iii) the identity of said antigens (i.e. what immune-regulatory antigen on the surface of a macrophage or natural killer cell and antigen on the surface of a target cell the antibody binds) (see 122[a] rejection for written description for more information). It is not routine to determine how such a broad class of molecules would treat or ameliorate all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders.
Undue experimentation would be required to determine whether the genus of antibodies of claim 1 would treat or ameliorate all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders (the quantity of the experimentation, see MPEP 2164.06).
(5) The breadth of the claims
The scope of claim 19 is extremely broad; it recites multiple diseases and the use of antibodies that require the specification of the instant application to provide support for the entire scope of the claim. The specification fails to show that a person having ordinary skill in the art could treat all recited diseases without undue experimentation.
The genus of antibodies of claim 1 comprise a diverse class of molecules that require a person having ordinary skill in the art to determine (i) which CDRs would specifically bind antigens on immune effector cells and target cells, (ii) how many CDRs/what combinations of CDRs yield antibodies capable of specifically binding said antigens, and (iii) the identity of said antigens (i.e. what immune-regulatory antigen on the surface of a macrophage or natural killer cell and antigen on the surface of a target cell the antibody binds) (see 122[a] rejection for written description for more information).
It is unclear how the genus of antibodies of claim 1 could treat or ameliorate all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders as recited in claim 19. These diseases are varied and do not share common pathologies. There is no known agent that can broadly treat all the recited diseases (see nature of the invention and the state of the prior art).
Claim 19 is directed to complex and unpredictable arts such as chemistry and biology, where the success treatment or amelioration of proliferative diseases, tumorous diseases, viral diseases, or immunological disorders cannot be readily extrapolated from the limited number of disclosed examples in the instant application. Furthermore, a link between any and all antibodies in the genus of claim 1 and all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders is not established.
Evidence of efficacy of multivalent anti-CD16A innate cell engagers targeting EGFR in antibody-dependent cell-mediated cytotoxicity, specifically in MCF-7 target cells (¶ 0381, Example 9, MCF-7 target cells are derived from human breast cancer) and Daudi cells (¶ 0382, Example 10, Daudi cells derived from Burkitt's lymphoma) is provided in the instant specification.
Therefore, the method of treatment or amelioration of breast cancer and Burkitt's lymphoma comprising administering to a subject in need thereof multivalent anti-CD16A innate cell engagers targeting EGFR is supported. The method of treatment or amelioration of all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders comprising administering to a subject in need thereof any antibody construct as delineated by claim 1 is not supported.
Claim 19 is not enabled because a person having ordinary skill in the art as of the effective filing date of the application would not be able to treat all proliferative diseases, all tumorous diseases, all viral diseases, or all immunological disorders with any antibody construct as delineated by claim 1 with a predictability of success for the reasons outlined above.
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.
Claims 1-16, 19, and 21 are 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.
Regarding claim 1, the phrases "first binding domain (A),” “first target (A'),” “second binding domain (B),” “second target (B'),” “fourth domain (D),” “a first first binding domain and a second first binding domain that are fused to each other (A1A2),” and “a third first binding domain and a fourth first binding domain that are fused to each other (A3A4)” render the claim indefinite because it is unclear whether the limitations in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d). Claims 2-16, 19, and 21 are included in this rejection as they incorporate and/or depend on claim 1.
For the purposes of claim interpretation, phrases in the parentheses will be treated as optional.
Regarding claim 2, the phrases “first target (A'),” “DNAM-1 (CD226),” “SLAMF7 (CD319),” and “CD244 (2B4)” render the claim indefinite because it is unclear whether the limitations in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrases in the parentheses will be treated as optional.
Regarding claim 3, the phrases “third binding domain (C),” “third target (C'),” and “second target (B')” render the claim indefinite because it is unclear whether the limitations in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrases in the parentheses will be treated as optional.
Regarding claim 4, the phrase “second binding domain (B)” renders the claim indefinite because it is unclear whether the limitation in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrase in the parentheses will be treated as optional.
Regarding claim 5, the phrase “second target (B')” renders the claim indefinite because it is unclear whether the limitation in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrase in the parentheses will be treated as optional.
Regarding claims 6, 8 and 11, the phrase “first binding domain (A)” renders the claims indefinite because it is unclear whether the limitation in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrase in the parentheses will be treated as optional.
Regarding claim 7, the phrase “first target (A')” renders the claim indefinite because it is unclear whether the limitation in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrase in the parentheses will be treated as optional.
Regarding claim 8, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the limitation following “preferably” (i.e. the epitope comprises Y158 of SEQ ID NO: 13) will not be regarded as part of the claimed invention.
Regarding claims 9-10, the phrases “second binding domain (B)” and “fourth domain (D)” render the claims indefinite because it is unclear whether the limitations in parentheses provide further definitions or are defining what is actually recited in the claims. See MPEP § 2173.05(d).
For the purposes of claim interpretation, phrases in the parentheses will be treated as optional.
Regarding claim 12, the phrase "an amino acid sequence" render the claim indefinite because it is unclear the exact identity of the antibody as this recitation includes a large number of fragments.
For the purposes of claim interpretation, “an amino acid sequence” will include fragments.
Regarding claim 14, the phrase "a nucleic acid molecule" renders the claim indefinite because it is unclear whether this recitation refers to the nucleic acid molecule of claim 13 or introduces an additional nucleic acid molecule.
For the purposes of claim interpretation, “a nucleic acid molecule” will be treated as “the nucleic acid molecule.”
Claim 15 recites “[a] method of producing an antibody construct of claim 1, said method comprising culturing the host cell comprising a nucleic acid molecule comprising a sequence encoding said antibody construct under conditions allowing for the expression of said antibody construct” (lines 1-4).
The phrase “under conditions allowing for the expression of said antibody construct” is indefinite because it fails to specify what exact conditions are required for expression. The claim does not identify parameters such as how expression is induced nor how the nucleic acid molecule encoding the antibody is introduced into the host cell.
The instant specification nucleic acid sequences encoding the antibody construct include ”replication and control sequences derived from a species compatible with the host cell that is used for expression as well as selection markers conferring a selectable phenotype on transformed or transfected cells” (¶ 0217).
“If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, is appropriate” (MPEP 2173.02[II]).
Claim 15 fails to clearly and distinctly point out the conditions for antibody expression that the applicant regards as the invention, as indicated in the specification of the instant application. As a result, a person having ordinary skill in the art would not be able to determine the metes and bounds of the claim.
Regarding claim 15, the phrase "a sequence encoding said antibody construct" renders the claim indefinite because it is unclear whether the antibody is encoded by one or multiple sequences.
For the purposes of claim interpretation, the phrase "a sequence encoding said antibody construct" will be treated optionally as both one or multiple sequences encoding the antibody construct.
Regarding claim 15, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the limitation following “optionally” (i.e. recovering the produced antibody construct from the culture) will not be regarded as part of the claimed invention.
Regarding claims 16 and 21, the phrase "an antibody construct" renders the claims indefinite because it is unclear whether this recitation refers to the antibody construct of claim 1 or introduces an additional antibody construct.
For the purposes of claim interpretation, “an antibody construct” will be treated as “the antibody construct.”
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 1-7, 9-10, 12-16, 19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190031785 A1 (referred to as US ‘785; filed 2017-01-13, published 2019-01-31) as evidence by Sino Biological (Fab Antibody: Definition, Structure, and Production, 2026).
Claims 1-3, 5, and 7
With respect to claim 1, US ‘785 teaches a trispecific antibody comprising antigen-binding modules 1-3 (ABM1, ABM2, and ABM3) (¶ 0019, “a multispecific immunomodulatory antigen-binding construct [MIAC] polypeptide, comprising: an antigen-binding module 1 [ABM1] that binds specifically to an antigen expressed by a cancer cell; an antigen-binding module 2 [ABM2] that binds specifically to an activating receptor expressed by an effector immune cell,… and an antigen-binding module 3 [ABM3] that binds specifically to an inhibitory receptor expressed by the effector immune cell”; ¶ 0039, “each ABM is an antibody or an antigen-binding fragment thereof”; claim 1).
With respect to claims 1-2, 5, and 7, US ‘785 further teaches the antibody can comprise:
A first binding domain capable of binding to an immune-regulatory antigen, specifically CD16A, on the surface of an innate immune effector cell, specifically a natural killer (NK) cell (¶ 0005, “effector cells, such as… natural killer [NK] cells”; ¶ 0019, the antibody “binds specifically to an activating receptor expressed by an effector immune cell”; ¶ 0042, “the activating receptor is selected from… CD16); ¶ 0052, later specified that CD16 encompasses both CD16A and CD16B; refer to ABM2; claims 1-2 and 7),
A second binding domain capable of binding to a second target, specifically HER2, on the surface of a target cell, specially a cancer cell (¶ 0041, “the antigen expressed by the cancer cell is selected from HER2”; refer to ABM1; claims 1 and 5), and
A third binding domain capable of binding to a third target, specifically PD-1, that is an antigen of a target cell, specifically a NK cell, that is different than the second target (¶ 0005, “effector cells, such as… natural killer [NK] cells”; ¶ 0045, inhibitory receptor expressed by the effector immune cell or NK cell “is selected from PD-1”; refer to ABM3; claim 3).
With respect to claim 1, US ‘785 further teaches the antibody can comprise four first binding domains linked to the C terminus of two CH3 domains (Fig. 14A, depicts four scFv domains that bind ABM2 represented as 202, corresponding to the first binding domain; ¶ 0024, “ABM2 is linked to the C terminus of Fc”; ¶ 0182, “dimeric IgG Fc comprises an IgG CH2 and an IgG CH3” meaning ABM2 can be connected to both CH3 domains of Fc; claim 1).
With respect to claim 1, US ‘785 does not explicitly state that CH3 domains extend the half-life of the antibody. However, full-length antibodies (i.e. antibodies containing CH2 and CH3 domains) are known have a longer half-life compared to Fabs (i.e. antibodies not containing CH2 and CH3 domains) (Sino Biological, Pg. 4, ¶ 1, “the absence of the Fc region also means that Fab antibodies typically have a shorter half-life in the body due to rapid degradation”). A person having ordinary skill in the art would recognize CH3 domains extend half-life (claim 1).
With respect to claim 1, US ‘785 further teaches the first binding domains can be fused to one another (¶ 0281, “ABMs are covalently associated with each other”; Fig. 16A depicts AMB2 labeled as 202, corresponding to the first binding domain of the instant application, fused to itself; claim 1).
US ‘785 further teaches “[multispecific immunomodulatory antigen-binding constructs] provided herein can comprise any suitable fusion protein structure, and the selection of the appropriate fusion protein can be carried out by one of skill in the art depending, for example, upon the desired valency and molecular weight” (¶ 0283).
US ‘785 does not teach the antibody of the instant application in one embodiment.
Trispecific antibodies and their modifications were known and used prior to the effective filing date of the application. US ‘785 teaches their disclosed antibodies, including trispecific ones, can be modified to target certain antigens and adjust the valency, there is motivation for creating a trispecific antibody with the specific structure and binding domains as delineated in instant claims 1-3, 5, and 7.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
US ‘785 teaches their disclosed trispecific antibodies are modular by selecting the antigens targeted and, by adjusting the number of antigen-binding domains, changing the valency as desired. Therefore, a person having ordinary skill in the art would have been motivated to modify the trispecific antibody of US ‘785 by incorporating the antigen-binding domains to the targets on NK cells and cancer cells (CD16A, HER2, and PD-1) with the desired valency to arrive at the claimed invention.
There is a reasonable expectation of success as trispecific antibodies and their modifications were known and used prior to the effective filing date of the instant application. US ‘785 teaches their trispecific antibodies can be modified to target a certain antigen and arrive at the desired valency. In addition, these modifications were all expressly suggested by US ‘785 and utilized components disclosed therein. The claimed antibody construct represents the predictable result of following the teachings in a single prior art reference.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to modify the trispecific antibody of US ‘785 by incorporating the antigen-binding domains to the targets on NK cells and cancer cells (CD16A, HER2, and PD-1) with the desired valency to arrive at the claimed invention.
Claims 4 and 6
With respect to claims 4 and 6, US ‘785 further teaches the antigen-binding domain comprises a VH domain and a VL domain (¶ 0039, “each [antigen-binding module] is… an scFv”; ¶ 0133, “’scFv’ fragments comprise a VH domain and a VL domain in a single polypeptide chain”; claims 4 and 6).
Claims 9-10
With respect to claim 9, US ‘785 further teaches the second binding domain is fused to the N terminus of the hinge of the fourth domain (¶ 0024, “ABM1 is linked to the N terminus of Fc” wherein ABM1 is the second binding domain of the instant application and Fc contains 2 CH3 domains as described above; ¶ 0050, “each linkage is direct or via a linker, optionally wherein the linker is… an immunoglobulin hinge region”; claim 9).
With respect to claim 9, US ‘785 further teaches another second binding domain is fused to the N terminus of another hinge of the fourth domain (Fig. 14A, depicts ABM1 [201] as an IgG wherein the antibody has two second binding domains of the instant application attached in the same manner as described for claim 9; claim 10).
Claim 12
With respect to claim 12, US ‘785 further teaches the antibody has the amino acid sequence of SEQ ID NO: 181 of the instant application, corresponding to SEQ ID NO: 8 of US ‘785 (claim 12).
Claims 13-15
With respect to claims 13-14, US ‘785 further teaches a nucleic acid comprising a sequence encoding the antibody construct and a host cell comprising the nucleic acid (¶ 0355, “The invention also provides isolated nucleic acids encoding [multispecific immunomodulatory antigen-binding constructs], vectors and host cells comprising the nucleic acids”; claims 13-14).
With respect to claim 15, US ‘785 further teaches a method of producing the antibody construct comprising culturing the host cell comprising the nucleic acid under conditions allowing for the expression of said antibody construct (¶ 0359, “host cell can be used to produce the MIACs”; ¶ 0365, “culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression”; claim 15).
Claim 16
With respect to claim 16, US ‘785 further teaches a pharmaceutical composition of the antibody construct (¶ 0060, “a pharmaceutical composition comprising a [multispecific immunomodulatory antigen-binding construct]”; claim 16).
Claim 19
With respect to claim 19, US ‘785 further teaches a method of treatment of a tumorous disease comprising administering to a subject in need thereof the antibody construct (¶ 0061, “ a method of treating a subject with cancer comprising administering an effective amount of a [multispecific immunomodulatory antigen-binding construct]”; ¶ 0064, “a cancer is selected from… brain tumor”; claim 19).
Claim 21
With respect to claim 21, US ‘785 further teaches a kit comprising the antibody construct (¶ 0071, “a kit comprising a [multispecific immunomodulatory antigen-binding construct]”; claim 21).
Accordingly, claims 1-7, 9-10, 12-16, 19, and 21 are rendered obvious over US ‘785 as evidenced by Sino Biological.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over US ‘785 as evidenced by Sino Biological as applied to claim 1 above, and further in view of US 20200190213 A1 (referred to as US ‘213; filed 2019-12-16, published 2020-06-18).
Claim 11
Claim 1 is rendered obvious over US ‘785 as evidenced by Sino Biological. However, it is noted that the combination of references does not teach the first binding domain comprises a VH region comprising CDR-H1, CDR-H2 and CDR-H3 and a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from (a)-(c) of claim 11.
With respect to claim 11, US ‘213 teaches the CDRs delineated in claim 11 part (c). SEQ ID NOs: 19, 89, and 79 of the instant application are found in SEQ ID NO: 214 of US ‘213. SEQ ID NOs: 80-82 of the instant application are found in SEQ ID NO: 215 of US ‘213.
US ‘213 further teaches SEQ ID NO: 214 and 215 correspond to the VH and VL of an anti-CD16A antibody respectively (¶ 103, Table 1, anti-CD16A VH for SEQ ID NO: 214 and anti-CD16A VL for SEQ ID NO: 215; ¶ 0135, “anti-CD16A antibody… See SEQ ID NOs: 212-215”).
US ‘213 further teaches the anti-CD16A antibody stimulates NK cells to kill cancer cells, indicating the anti-CD16A antibody activates NK cells (¶ 0201, a method “engineered to engage NK cells via a CD16A antibody. The engagement of NK cells via the anti-CD16 antibody can induce cancer cell killing”).
US ‘213 further teaches a bispecific antibody with anti-HER2 or anti-PD-1 binding moieties (¶ 0070, “first and/or second targeting moiety comprises an antibody”; ¶ 0071, “second targeting moiety binds… HER2 [or]… PD-1”; Abstract, “Each component comprises a targeting moiety that binds a tumor antigen expressed by the cancer or an antigen expressed by a non-cancer cell in the tumor microenvironment” for the purpose of treating cancer). This description allows for anti-CD16A and anti-HER2 or anti-PD-1 in a bispecific antibody for the purpose of treating cancer, although this exact combination is not explicitly stated.
US ‘213 does not teach a trispecific antibody.
An anti-CD16A antibody comprising (i) a VH region comprising instant SEQ ID NOs: 19, 89, and 79 for CDRH1-3 respectively and (ii) a VL region comprising instant SEQ ID NOs: 80-82 for CDRL1-3 respectively was known and used prior to the effective filing date of the instant application. In addition, both US '785 and US ‘213 are directed to analogous arts (i.e. treatment of cancer with anti-CD16A antibodies). Since US ‘213 teaches (i) the anti-CD16A antibody comprising instant SEQ ID NOs: 19, 79, 80-82, and 89 stimulates NK cells to kill cancer cells and is thereby useful in a treatment of cancer and (ii) said anti-CD16A antibody can be further combined with other antigen-binding moieties such as anti-HER2 or anti-PD-1, there is motivation for creating a trispecific antibody containing anti-CD16A, anti-HER2, and anti-PD-1 binding domains (the full structure of said trispecific antibody delineated in the rejection of claim 1) wherein the first binding domain to CD16A comprises SEQ ID NOs: 19, 79, 80-82, and 89.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. [i] the anti-CD16A antibody comprising instant SEQ ID NOs: 19, 79, 80-82, and 89 stimulates NK cells to kill cancer cells and is thereby useful in a treatment of cancer and [ii] said anti-CD16A antibody can be further combined with other antigen-binding moieties such as anti-HER2 or anti-PD-1 as taught in US ‘213) would have led one of ordinary skill to modify the prior art reference (i.e. a trispecific antibody containing anti-CD16A, anti-HER2, and anti-PD-1 binding domains as taught in US ‘785 wherein the first binding domain to CD16A comprises SEQ ID NOs: 19, 79, 80-82, and 89) to arrive at the claimed invention.
There is a reasonable expectation of success as an anti-CD16A antibody comprising (i) a VH region comprising instant SEQ ID NOs: 19, 89, and 79 for CDRH1-3 respectively and (ii) a VL region comprising instant SEQ ID NOs: 80-82 for CDRL1-3 respectively was known and used prior to the effective filing date of the instant application. In addition, both US '785 and US ‘213 are in analogous arts (i.e. treatment of cancer with anti-CD16A antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use SEQ ID NOs: 19, 79, 80-82, and 89 for the anti-CD16A binding domain as taught in US ‘213 in a trispecific antibody containing anti-CD16A, anti-HER2, and anti-PD-1 binding domains as taught in US ‘785.
Claim 8
With respect to claim 8, US ‘213 does not explicitly state the anti-CD16A antibody comprising instant SEQ ID NOs: 19, 79, 80-82, and 89 binds to an epitope on CD16A which is C-terminal to the physiological Fcγ receptor binding domain and said epitope preferably comprises Y158 of SEQ ID NO: 13 (claim 8).
The instant specification states the antibody construct comprising SEQ ID NOs: 19, 79, 80-82,and 89 binds to an epitope on CD16A which is C-terminal to the physiological Fcγ receptor binding domain and said epitope comprises Y158 of SEQ ID NO: 13 (¶ 0175, “an epitope of CD16A which comprises amino acid residues of the C-terminal sequence SFFPPGYQ [positions 201-209 of SEQ ID NO: 13], and/or residue G147 and/or residue Y158 of CD16A… relative to the physiological Fcγ receptor binding domain of CD16A” and “A binding domain that specifically binds to an epitope comprising Y158 is preferred… Examples for respective binding domains are characterized e.g. by the following groups of CDRs:” SEQ ID NOs: 19, 79, 80-82, and 89).
US ‘213 teaches an anti-CD16A binding domain that is identical to the claimed anti-CD16A binding domain of the instant application. As the claimed anti-CD16A binding domain uses the same SEQ ID NOs for the CDRs, the ability of the anti-CD16A binding domain to bind the epitope on CD16A which is C-terminal to the physiological Fcγ receptor binding domain and said epitope comprises Y158 of SEQ ID NO: 13 is an inherent characteristic that necessarily occurs.
“A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present” (MPEP 2112.01).
The ability to bind the epitope on CD16A which is C-terminal to the physiological Fcγ receptor binding domain and said epitope comprises Y158 of SEQ ID NO: 13 is an inherent characteristic of the anti-CD16A binding domain, inseparable from its chemical structure.
Therefore, despite the fact that this function is not stated in US ‘213, a person having ordinary skill in the art would recognize the function recited in claim 8 as inherent.
Accordingly, claims 8 and 11 are rendered obvious over US ‘785 in view of US ‘213 as evidenced by Sino Biological.
Conclusion
Claims 17-18 and 20 are cancelled. Claims 1-16, 19, and 21 are pending. Claims 1-16, 19, and 21 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jessica M Priest whose telephone number is (571)272-8469. The examiner can normally be reached Mon-Fri 8am-5pm.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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