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
Applicant’s reply filed on 12/12/2025 is acknowledged. Claims 1, 28, and 29 have been amended.
Claims 1-30 are pending and under examination.
Rejections Maintained
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.
WRITTEN DESCRIPTION
Claims 1-30 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 claims contain 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The claims are directed to a multispecific antigen-binding molecule comprising a first antigen-binding moiety which specifically binds to a Notch receptor and a second binding moiety which specifically binds an anchor antigen.
The specification teaches antigen-binding molecule refers to any molecule that comprises an antigen-binding site, this definition including molecules such as peptides and proteins having a length of about five amino acids or more (Specification, [0029], emphasis added). The definition provided in the specification also reads on any molecule capable of binding a site on a Notch receptor including nucleic acids and small molecules.
The specification teaches that anchor antigen “can be any relevant antigen as long as the multispecific antigen-binding molecule can trans-activate the Notch signaling pathway in the first target cell” (Specification, [0080]) and that the anchor antigen’s expression is specific, exclusive, or limited to the cell or population of interest (Specification, [0009]). The specification does not provide additional guidance as how to identify anchor antigens suitable for the instant invention.
The specification provides evidence that the inventors were in possession of antigen-binding molecules with the following moieties that bind Notch receptors: α-KLH, Jag1, Jag2, DLL1, DLL3, DLL4; and the following moieties that bind anti-anchor antigen: α-KLH, α-GPC3, α-FAP, and the IgG Fc region (Fig. 8A/B and Pg. 97 Table 4).
The state of the relevant art
Pertaining to the nature of Notch-binding molecules:
Katoh (Int J Mol Med. 2020 Feb;45(2):279-297) teaches the canonical Delta-like Notch ligands (DLL1, DLL3, DLL4) and Jagged Notch ligands (Jag1 and Jag2) (Pg. 279, Right column, Introduction, Lines 1-5). In addition to the canonical ligands, Katoh also teaches a number of engineered biologics that bind the extracellular region of Notch1, including mAbs, ADCs, bsAbs (Pg. 284, Left column, Full paragraph 1, Lines 1-6).
Wang (Int J Biochem Cell Biol. 2011 Nov;43(11):1550-62) teaches in addition to the canonical Notch ligands, there are a multitude of non-canonical ligands that bind Notch receptors (disclosed on Pgs. 5-13) including molecules with repeat EGF-like domains such as thrombospondin 2 and molecules not possessing EGF-like domains such as Microfibril-associated glycoproteins 1 and 2.
Thus, the art teaches great diversity of naturally occurring and engineered molecules that bind Notch1 that far exceeds the scope of the teachings of the instant disclosure.
Pertaining to the antibody-associated binding domains claimed in instant claims 9 and 13:
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
The art thus underscores the importance of fully defined CDRs and evidence from the inventors that they were in possession of each claimed antibody embodiment.
Claim analysis
Based on the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claim 1 is directed to a first antigen-binding moiety which specifically binds to a Notch receptor, but the inventors only show possession of Delta and Jagged ligands and a single VH/VL that binds Notch. These are not representative of the full scope of what is claimed.
Claim 1 is directed to a second antigen-binding moiety which specifically binds to an anchor antigen, but only show possession VH/VL binding moieties that bind KLH, GPC3 and FAP as well IgG Fc that binds Fc receptors. The examples provided are not representative of full scope of “anchor antigens” as claimed.
Claims 9 claims first antigen-binding moiety comprises a Fab, scFv, VHH, VL, VH, or single domain antibody that specifically binds to the Notch receptor, but does not claim the sequences or structures and does not provide evidence of being in possession of each class of antibody-related binding molecules.
Claim 13 claims the second antigen-binding moiety comprises a Fab, scFv, VWHH, VL, VH, single domain antibody that specifically binds to the anchor antigen but does not claim the sequences or structures and does not provide evidence of being in possession of each class of antibody-related binding molecules.
Importantly, claim 21 requires that the multispecific antigen-binding molecule of claim 1 has the function of activating the Notch signaling pathway in a target cell. Claims 28-30 require that the multispecific antigen-binding molecule of claim 1 has the function of treating any Notch-receptor mediated disease or disorder. The disclosure does not provide enough evidence to identify which specific moieties can be used in the invention to produce the claimed results.
Therefore, the inventors were not in possession of the claimed invention as broadly claimed and the disclosure does not provide sufficient guidance and detail for a person skilled in the field to carry out the invention based on the disclosure provided.
Claims 2-30 are rejected under 35 U.S.C. 112(a) for being dependent on claim 1 or comprising the molecule of claim 1 not providing limitations that fully define the claimed molecule and satisfy the written description requirement.
Response to Applicant’s Arguments
Applicant's arguments filed 12/12/2025 have been fully considered but they are not persuasive.
The applicant argues a person skilled in the art, considering the disclosure and guidance of the specification in light of the high level of knowledge and skill in the art relating to the Notch signaling pathway, the sequence and structure of a very large number of representative Notch binding molecules and molecules that bind an anchor antigen, would have been able to readily envision the sequence of a large number of ligand binding molecules that are representative of the claimed compositions and would have reasonably concluded that the inventors were in possession of the invention. (Remarks, Pg. 9).
The applicant further submits that the disclosure of the application combined with the
knowledge in the art provides a sufficient description of the relevant identifying characteristics to
describe the claimed molecule which confers anchorage-dependent Notch trans-activation. The
specification discloses this structure-function correlation by demonstrating anchorage-dependent Notch activation of the claimed molecules using a range of Notch binders (e.g., polypeptide sequences from Delta-like-I (DLL-1), DLL-4, Jagged 1 and Jagged 2, and Notch Agonist antibodies) and various anchor antigens (e.g., a-KLH, a-GPC3, a-FAP, and the IgG Fc region immobilized on a plate to simulate the binding of the anchorage-dependent antigen expressed on the surface of a cell) (see, e.g., Figs. 4-8). (Remarks, Pg. 10)
PNG
media_image1.png
634
786
media_image1.png
Greyscale
In response, the specification discloses the two major canonical Notch receptor ligand species, the Delta and Jagged proteins. The examiner does not concede that those two receptor ligand types are representative of the whole genus of canonical Notch receptor ligands. D’Souza (Curr Top Dev Biol. 2010;92:73-129) teaches canonical ligands shown below:
D’Souza additionally teaches the following non-canonical ligands:
PNG
media_image2.png
644
794
media_image2.png
Greyscale
In light of the large genus of molecules that bind and activate Notch receptor, the applicants were not in possession of the invention as claimed.
SCOPE OF ENABLEMENT
Claims 28 and 29 are 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 certain embodiments of the multispecific antigen-binding molecule, does not reasonably provide enablement for the multispecific antigen-binding molecule as broadly claimed in 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.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that any multispecific antigen-binding molecule comprising a first antigen-binding moiety that binds a Notch receptor and a second antigen-binding moiety that binds an “anchor” antigen can treat any Notch receptor-mediated disease or disorder including a cancer or malignancy; Muscular Dystrophy, Tissue fibrosis; SLE (systemic lupus erythematosus), RA (Rheumatoid arthritis), MS (Multiple sclerosis) or another autoimmune disease.
A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The state of the relevant art and level of predictability in the art
The state of the relevant art is such that the different Notch ligands have diverse effects on T cell effector functions. Kelliher (Front Immunol. 2018 Aug 20;9:1718) teaches that in CD4 T-cells, activation of the TCR in the presence of DLL1/4 skews toward a TH1 phenotype and inhibits TH2 differentiation (38, 39). Conversely, Jagged1/2 ligands may be important for TH2 differentiation, but appear to have no role in TH1 differentiation (Pg. 2, Right column, Full paragraph 2, Lines 1-7).
Kelliher also teaches that Notch activity is deregulated in several malignancies and teaches several diseases characterized by aberrant Notch activation, such as chronic lymphocytic leukemia and non-small cell lung carcinoma (Pg. 1, Lines 8-13). Kelliher’s laboratory has demonstrated the efficacy of Notch1 inhibitors in pre-clinical models (Pg. 1, Lines 12-13). Conversely, Kelliher also teaches that Notch activation is suppressed in tumor-infiltrating T cells and that Notch reactivation induces potent anti-tumor T cell responses in mouse cancer models (Pg. 2, Left column, Full paragraph 1, Lines 13-20).
The art does enable methods of treating subject comprising specific embodiments of the invention. For example, Magliery (US2020/0277354A1) teaches administration of a multivalent DLL1-Fc polypeptide to tumor-bearing mice in vivo (see “Tumor Model Experiments” [0250], [0254]-[0255]). Administration of the DLL1-Fc polypeptide attenuated tumor growth and improved survival in murine (Fig. 31 A-E).
Thus, treatment of Notch-associated diseases is dependent on the target cell and whether Notch is upregulated or downregulated in the disease.
The amount of direction provided by the inventor and the existence of working examples
The instant disclosure provides a schematic of how the claimed antigen-binding molecule can activate Notch signaling (Fig. 2) and proposes various iterations of the claimed molecule (Fig. 1 and Fig. 3). The specification also provides in vitro co-culture experiments demonstrating that certain embodiments of the invention can activate Notch signaling (see Figs. 4-8).
The specification does not disclose any in vivo working examples that would provide enabling support for use of the claimed method for treating diseases in a subject.
The quantity of experimentation needed to make or use the invention
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is treatment of a patient with a multispecific antigen-binding molecule, a person having ordinary skill in the art would have to perform multiple further in vivo experiments in human clinical trials that are predictive of treatment of human patients with the cells over the broad scope disease and antigen targets claimed. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully Notch-receptor-mediated diseases. Therefore, claims 28-30 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Response to Applicant’s Arguments
The applicant argues the level of knowledge concerning Notch signaling pathways and their roles in associated diseases and disorders was exceptionally high on the filing date. A person skilled in the art considering the specification's disclosure of the anchorage-dependent Notch trans-activation molecule, would have readily understood which Notch-associated diseases or conditions would benefit from activated Notch signaling. Furthermore, the knowledge in the art provided a sufficient foundation to apply the disclosed molecule to these conditions. Thus, the practicing of the claimed methods would require no more than routine experimentation or optimization of parameters well within the skill set of the person skilled in the art, thereby satisfying the legal requirement that the invention can be practiced without undue experimentation. (Remarks, Pg. 9-10)
In response, as described above, the disclosure of D’Souza teaches a large variety of moieties which specifically binds to a Notch receptor. The disclosure in combination with the art does not enable the use of each and every one of the known canonical or noncanonical Notch receptor ligands for the claimed method of treatment without undue experimentation.
In addition, the term “anchor antigen” refers to any number of antigen present on any number of cells. As the disclosure only teaches the use of four antigens (KLH, GPC3, FAP, and the CD32B) the four antigens couldn’t possibly be representative of the innumerable antigens upon which claim 1 reads.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-8, 10-14, and 16-30 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Magliery (US2020/0277354A1, published 09/03/2020, effectively filed 03/26/2018) as evidenced by Sato (Curr Alzheimer Res. 2012 Feb;9(2):227-40) and Smith (Nat Rev Immunol. 2010 May;10(5):328-43).
The disclosure of Magliery is directed monomeric and multimeric Notch-modulating peptides capable of increasing or decreasing an immune response in a subject (see Abstract). The peptides of Magliery’s disclosure are derived from Delta-like (DLL) proteins and Jagged (Jag) proteins ([00020], Lines 1-6).
Regarding claim 1, pertaining to a multispecific antigen binding molecule comprising (i) a first antigen-binding moiety which specifically binds to a Notch receptor on a first target cell, and (ii) a second antigen-binding moiety which specifically binds to an anchor antigen on a second target cell, Magliery discloses a multivalent “clustered” DLL1 polypeptide. Magliery teaches the clustered DLL1 is complex of DLL1-IgG Fc fusion proteins ([0288], Lines 1-7). The clustered DLL1 polypeptides comprise multiple units DDL1-Fc domains linked together ([0009]-[0012] and Fig. 18). The DLL1 portions of the clustered DLL1 polypeptide correspond to the first antigen-binding moiety which specifically binds a Notch receptor and the IgG Fc portions of the clustered DLL1 polypeptide corresponds to the second antigen-binding moiety.
Claim 1, which is directed to the multispecific antigen-binding molecule, also provides limitations directed to the function of the antigen-binding molecule which are inherent to the molecule based on the claimed structure. Specifically, the molecule of Magliery is capable of binding the two different antigens on two different cells, particularly because Magliery teaches in vivo administration of the clustered DLL1 polypeptide which would bring the polypeptide into contact with multiple target cells with which it could bind simultaneously (see “Tumor Model Experiments” [0250])
The multimeric clustered DLL1-Fc polypeptide also anticipates the following claims of the instant disclosure directed to the antigen-binding molecule:
Regarding claim 2, wherein the first target cell is an activated CD4 T-lymphocyte, Magliery teaches the multivalent clustered DLL1-Fc polypeptide activates Notch and induces factors promoting Th1 type differentiation of T cell [0038].
Regarding claim 3, wherein the tissue stem cell is a satellite cell, adult intestinal stem cell or crypt base columnar (CBC) cell, Notch is expressed on muscle satellite cells as evidenced by Sato (Pg. 3, Full paragraph 1, Line 10) and can thus be bound by Magliery’s clustered DLL1-Fc polypeptide.
Regarding claims 4-7, wherein the first-binding moiety comprises a Notch-binding domain of a Notch receptor ligand (claim 4), wherein the Notch receptor ligand is a ligand to a Notch1, Notch2, Notch3, or Notch4 receptor (claim 5), wherein the Notch receptor ligand is a Delta protein or Jagged protein (claim 6), and wherein the Delta protein is a Delta Like Ligand 1 (DLL1), DLL3, or DLL4, Magliery teaches DLL1 is a ligand for the Notch family, Notch1-4 ([0003], Lines 1-9).
Regarding claims 10-12, wherein the second target cell is an immune cell that expresses FgRIIB (claim 10), the immune cell that expresses multiple immune cells express FcgRIIB is selected from the group consisting of a circulating B lymphocyte, monocyte, neutrophil, lymphoid-dendritic cell and myeloid-dendritic cell (claim 11), and wherein the anchor antigen on the second target cell is FcgRIIB (claim 12), FcgRIIB is expressed on several immune cells such as B cells, plasma cells, monocytes, macrophages, dendritic cells, and neutrophils as evidenced by Smith (Fig. 1). The IgG Fc regions of the clustered DLL1-Fc polypeptide bind FcgRIIB.
Regarding claim 13, wherein the second antigen-binding moiety comprises engineered Fc region that specifically binds to the anchor antigen, the clustered DLL1-Fc polypeptide comprises an engineered Fc region.
Regarding claim 14, wherein the multispecific antigen-binding molecule further comprises an Fc region, the clustered DLL1 polypeptide comprises IgG Fc regions fused to DLL1.
Regarding claim 16, wherein the second antigen-binding moiety comprises an engineered Fc region which specifically binds to FcgRIIB, the engineered Fc region of the clustered DLL1 is human IgG1 ([0038], Lines 20-21), which binds FcgRIIB.
Regarding claim 17, wherein the multispecific antigen-binding molecule further comprises one more of the first antigen-binding moiety, the clustered DLL1 polypeptide is multivalent, comprising multiple DLL1-Fc fusions proteins joined with a peptide linker (see Fig. 18).
Regarding claims 18 and 19, wherein the multispecific antigen-binding molecule further comprises a third antigen-binding moiety which specifically binds to an anchor antigen on a third target cell (claim 18), and wherein the second target cell and the third target cell are different cells or the same cells (claim 19), one of the embodiments of the multivalent clustered DLL1-Fc polypeptide comprises four DLL1-Fc fusions and is thus capable of binding multiple targets on multiple cells (see Fig 18).
Regarding claim 30, wherein each of the first target cell and the second target cell is in a tumor microenvironment or in a non-tumor microenvironment, the claim reads on cells in any microenvironment and the ability of the clustered DLL1 polypeptide to bind a variety of cells has been established above.
Regarding claim 8, wherein the Notch receptor ligand is a Jagged 1 or Jagged 2, Magliery teaches an alternative embodiment wherein the Notch-binding region is a member of the Jagged family of proteins, specifically Jagged 1 or Jagged ([0012], Lines 1-6).
Regarding claim 20, pertaining to a pharmaceutical composition comprising the multispecific antigen-binding molecule of claim 1 and a pharmaceutically acceptable carrier, Magliery teaches pharmaceutical compositions comprising the Notch-modulating peptides of the disclosure and a pharmaceutically acceptable carrier ([0162], Lines 1111-3).
Regarding claims 21 and 22, pertaining to a method for activating Notch signaling pathway in a first target cell, comprising contacting the first target cell with an effective amount of the multispecific antigen-binding molecule of claim 1 (claim 21) and wherein the first target cell is in a mammalian subject in vivo (claim 22), Magliery teaches administration of the multivalent clustered DLL1 to mice in vivo ([0255], Lines 1-5). The in vivo administration of the molecule would enable the molecule to contact target cells and activate Notch.
Regarding claim 23, wherein the subject is a human, Magliery teaches the “subject” of the disclosure that received treatment is a human ([0093], Lines 1-4).
Regarding claims 24-27, pertaining to an isolated nucleic acid encoding the multispecific antigen-binding molecule of claim 1 (claim 24), a vector comprising the nucleic acid (claim 25), a host cell comprising the nucleic acid (claim 26), and a method of producing the antigen-binding molecule comprising culturing the host cell (claim 27), Magliery teaches production of the antigen-binding molecule in E. coli host cells (Fig. 11) using vectors comprising nucleic acid constructs encoding the antigen-binding molecules ([0394]-[0395]).
Regarding claims 28 and 29, pertaining to a method of treating a Notch receptor-mediated disease or disorder comprising administering an effective amount of the multispecific antigen-binding molecule of claim 1 to a subject (claim 28), and wherein the Notch receptor-mediated disease or disorder is selected from a cancer or malignancy, Magliery teaches administration of the multivalent clustered DLL1 to tumor-bearing mice in vivo ([0254]-[0255]).
Claims 1, 2, 4-11, 13, 20, and 24-30 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Bernstein (US2019/0248894A1, published 08/15/2019, effectively filed 03/26/2018) as evidenced by Smith (Nat Rev Immunol. 2010 May;10(5):328-43).
The disclosure of Bernstein is directed to compositions and methods for targeted cell-specific inhibition of Notch receptor signaling (see Abstract).
Regarding claim 1, pertaining to a multispecific antigen binding molecule comprising (i) a first antigen-binding moiety which specifically binds to a Notch receptor on a first target cell, and (ii) a second antigen-binding moiety which specifically binds to an anchor antigen on a second target cell, Bernstein teaches a bispecific molecule for targeted inhibition of Notch signaling in a cell-type of interest, comprising: a cell-targeting domain that specifically binds to an antigen characteristic of the cell type of interest; and a Notch-binding domain (Pg. 33, claim 1). The main exemplary embodiment of the disclosure comprises DLL4 region fused to an anti-CD33 VH/VL (Fig. 1A).
Claim 1, which is directed to the multispecific antigen-binding molecule, also provides limitations directed to the function of the antigen-binding molecule which are inherent to the molecule based on the claimed structure. Specifically, the bispecific molecule of Berstein is capable of binding the two different antigens on two different cells, particularly because Bernstein teaches administration to a subject which would bring the polypeptide into contact with multiple target cells with which it could bind simultaneously (Pg. 34, claim 37).
The DLL4-αCD33 bispecific molecule of Bernstein also anticipates the following claims of the instant disclosure directed to the antigen-binding molecule:
Regarding claim 2, wherein the first target cell is a pro-tumorigenic cell, Berstein teaches Notch expression on leukemic cells ([0028], Lines 17-20).
Regarding claims 4-7, wherein the first-binding moiety comprises a Notch-binding domain of a Notch receptor ligand (claim 4), wherein the Notch receptor ligand is a ligand to a Notch1, Notch2, Notch3, or Notch4 receptor (claim 5), wherein the Notch receptor ligand is a Delta protein or Jagged protein (claim 6), and wherein the Delta protein is a Delta Like Ligand 1 (DLL1), DLL3, or DLL4, Bernstein teaches the Notch binding domain is the Notch receptor ligand DLL1, DLL3, or DLL4 (Pg. 33, claims 4-6) with the exemplary embodiment comprising DLL4.
Regarding claims 10 and 11, wherein the second target cell is an immune cell that expresses FgRIIB (claim 10) and the immune cell that expresses multiple immune cells express FcgRIIB is selected from the group consisting of a circulating B lymphocyte, monocyte, neutrophil, lymphoid-dendritic cell and myeloid-dendritic cell (claim 11), FcgRIIB is expressed on several immune cells such as B cells, plasma cells, monocytes, macrophages, dendritic cells, and neutrophils as evidenced by Smith (Fig. 1). The IgG Fc regions of the clustered DLL1 polypeptide binds FcgRIIB. The limitations of claims 10 and 11 require that the second target cell expresses FcgRIIB, but does not claim that FcgRIIB is the target antigen of the binding domain.
Regarding claim 13, wherein the second antigen-binding moiety comprises a Fab, scFv, VHH, VL, VH, or single domain antibody that specifically binds to the anchor antigen, Bernstein teaches the cell-targeting domain comprises an antibody or antibody-like molecule (Pg. 33, claim 16), wherein the antibody-like molecule is a Fab, VHH, and scFv (Pg. 33, claims 17-18) with the exemplary molecule expressing α-CD3 VH/VL.
Regarding claim 30, wherein each of the first target cell and the second target cell is in a tumor microenvironment or in a non-tumor microenvironment, the claims read on cells in any microenvironment and the ability of the bispecific molecule to bind a variety of cells has been established above.
Regarding claim 8, wherein the Notch receptor ligand is a Jagged 1 or Jagged 2, Bernstein teaches an embodiment wherein the Notch-binding region is a member of the Jagged family of proteins, specifically Jagged 1 or Jagged 2 ([0034], Lines 1-7).
Regarding claim 9, wherein the first antigen-binding moiety comprises a Fab, scFv, VHH, VL, VH, or single domain antibody that specifically binds to the Notch receptor, Bernstein teaches the Notch-binding domain comprises an antibody or antibody-like molecule (Pg. 33, claim 14), wherein the antibody-like molecule is a Fab, VHH, and scFv (Pg. 33, claims 17-18).
Regarding claim 20, pertaining to a pharmaceutical composition comprising the multispecific antigen-binding molecule of claim 1 and a pharmaceutically acceptable carrier, Bernstein provides a pharmaceutical composition comprising the bispecific molecules of the disclosure and additionally pharmaceutically acceptable carriers ([0057], Lines 1-4).
Regarding claims 24-27, pertaining to an isolated nucleic acid encoding the multispecific antigen-binding molecule of claim 1 (claim 24), a vector comprising the nucleic acid (claim 25), a host cell comprising the nucleic acid (claim 26), and a method of producing the antigen-binding molecule comprising culturing the host cell (claim 27), Bernstein teaches construction of the bispecific DLL4-αCD33 fusion molecule comprising the generation of a vector comprising nucleic acids encoding the extracellular domain of DLL4, a linker, and an αCD33 scFv ([0104], Lines 1-10) and expression of the fusion protein by infection of host cells ([0107], Lines 1-3).
Regarding claims 28 and 29, pertaining to a method of treating a Notch receptor-mediated disease or disorder comprising administering an effective amount of the multispecific antigen-binding molecule of claim 1 to a subject (claim 28), and wherein the Notch receptor-mediated disease or disorder is selected from a cancer or malignancy, Bernstein teaches a method of inhibiting cancer in a subject in need comprising a therapeutically effective amount of the disclosed pharmaceutical composition (Pg. 34, claim 37).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-8, and 10-30 are rejected under 35 U.S.C. 103 as being unpatentable over Magliery (US2020/0277354A1, published 09/03/2020, effectively filed 03/26/2018) as applied to claims 1-8, 10-14, and 16-30 above, and further in view of Schlothauer (Protein Eng Des Sel. 2016 Oct;29(10):457-466).
Magliery teaches a multivalent “clustered” DLL1-Fc polypeptide, which is a complex of DLL1-IgG Fc fusion proteins ([0288], Lines 1-7).
Magliery does not teach that the Fc regions of the molecule exhibit reduced binding affinity to human Fc gamma receptor, as compared to a native human IgG1 Fc domain.
The deficiency is taught by Schlothauer.
The disclosure of Schlothauer is directed to investigating various Fc mutation strategies for attenuating the cytotoxic Fc effector functions to increase the safety profile of therapeutic antibodies (see Abstract).
Regarding claim 15, wherein the Fc region of the antigen-binding molecules is an engineered Fc region which exhibits reduced binding affinity to human Fc gamma receptor as compared to a native human IgG1 Fc domain, Schlothauer teaches the human IgG1-P329G-LALA mutant (L234A, L235A, P329G) with abolished ability to bind FcγRI (Fig 1A), FcγRIIa (Fig. 2A), FcγRIIb (Fig. 3), and FcγRIIIa (Fig. 4A). Functionally, the IgG1-P329G-LALA mutant demonstrated no cytotoxicity (Pg. 462, Right column, Lines 8-9).
It would have been obvious to one having ordinary skill in the art to modify the clustered DLL1-Fc fusion polypeptides of Magliery with the IgG1-P329G-LALA Fc mutant taught by Schlothauer. One would have been motivated to do so because Schlothauer teaches the attenuated Fc variant does not display cytotoxicity and has an increased safety profile for therapeutic administration. Schlothauer also discloses five antibodies expressing the P329G LALA IgG1 isotype in active clinical trials (Pg. 465, Right column, Full paragraph 2, Lines 1-6). There would be an expectation of success in combining the teachings of Magliery and Schlothauer to arrive at the instant invention because the Fc mutations of Schlothauer could be readily incorporated into the engineered Fc regions of Magliery at the time of filing.
Response to Applicant’s Arguments
The applicant argues that Magiliery does not disclose a molecule as claimed that binds a Notch receptor on one target cell and anchor antigen on a different target cell, that activates the Notch signaling pathway in an anchorage-dependent manner. (Remarks, Pg. 11)
Further pertaining to Magliery, the applicant argues a person skilled in the art considering Magliery would be discouraged from developing monomeric forms when looking to develop an activator of Notch signaling. Having arrived at the conclusion that protein constructs comprising Notch binding domains activate Notch signaling in multimeric form while they inhibit signaling in monomeric form (Magliery, paragraph [0359]) (Remarks, Pg. 14)
Pertaining to Bernstein, the applicant argues that Bernstein does not disclose or suggest a multispecific antigen-binding molecule that activates the Notch signaling pathway. Likewise, Bernstein does not disclose or suggest at least a multispecific antigen-binding molecule that specifically binds to a Notch receptor on a first target cell and an anchor antigen on a second target cell. (Remarks, Pg. 12)
In response, pursuant to the written description rejection above, the multi-specific antigen binding molecule is defined by function only. The only tangible structure taught in claim 1 is a multispecific antigen-binding molecule comprising first and second antigen-binding moiety. The disclosure of Magliery and Bernstein both disclose structures that broadly, but reasonably anticipate the claimed structure without reading in limitations from the specification or imposing limitations based on the exemplary embodiments. The broadest reasonable interpretation of the product does not require that the first and second cell are different cell types or that the molecule binds them at the same time. The specification does not define the newly added term “anchorage-dependent manner” or how this provides a structural limitation to the product.
To this end, the specification does teach an exemplary first binding moiety is DLL1 and an exemplary second binding moiety is a moiety that binds the Fc gamma RIIB. Magliery, for example, provides a molecule that broadly, but reasonably anticipates this structure by disclosing a molecule comprising DLL1 and an Fc region.
Pertaining to the argument that Magliery teaches away from developing the monomer cited in claim 1, none of the claims recite a monomeric molecule. The use of the word “comprising” means that at a minimum the molecule must contain the two claimed binding moieties, but does not exclude any additional moieties.
For these reasons, the prior art rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646